DE2352585A1 - PYRIDINE DERIVATIVES - Google Patents

Description

PATENT LAWYERS '
DR. W. KINZEBACH - DIPL.-ING. O. HELLEBRAND -2352585

8München80 October 19, 1975 Walpurgisstrasse 6 Telephone 0811/470 5034 telegrams; Hekipat (Munich)

OASIS; H-123/134/144/146

JOHN WYETH & BROTHER LIMITED Huntercombe lane South, Taplow Maidenheadρ Berkshire, England

Pyridine derivatives.

The invention relates to new pyridine derivatives, their preparation and pharmaceutical compositions containing these new derivatives.

The compounds according to the invention can be described by the general formula I:

12 6

wherein R, R and R, which are the same or different, are hydrogen, trifluoromethyl or an alkyl, aralkyl or aryl

4098 19/119 4

Η-123/134/144/146

represent radical, each of these radicals by alkyl, alkoxy, Halogen, nitro or trifluoromethyl can be substituted or

1 ?
R and R together represent an alkylene chain -0Η ₂ (0Η ₂ ) _{η 0Η 2} -, in which η is 1, 2 or 3,

R for single or multiple substitution by hydrogen or alkyl, aralkyl or aryl radicals, each of these radicals being substituted by alkyl, alkoxy, halogen, nitro or trifluoro

1 2 methyl can be substituted, and when R and R together one Alkylene chain, the resulting ring can be replaced by a

7th
or more R radicals, as they have been defined above, be substituted,

X stands for cyano, CONR ⁵ R ⁴ , CSNR ³ R ⁴ "or CO ₀ R ⁵ , in which R ⁵ , R ⁴ and R represent hydrogen or alkyl, aralkyl or aryl radicals and each of these radicals is represented by alkyl, alkoxy, halogen, Nitro or trifluoromethyl can be substituted, and

12 m is 1, 2 or 3, but if R and R together represent an alkylene chain, then "n" is "m". The metal, for example alkyl metal salts of the compounds in which R ^{5 is} hydrogen, and the acid addition salts of the compounds of the formula I also belong to the present invention.

7th
R can be in the same position as X,

When any of R, R, R ⁵ , R, R ⁵ , R

7th
or R is an alkyl radical, then this is preferably a lower alkyl radical, which can be straight-chain or branched and contains 1-6 carbon atoms, e.g. methyl, ethyl,

7 n- and iso-propyl and n-, s- and t-butyl; at R it can

7 are a gem.-dimethyl group and if R 'is a It can represent a single radical on the same carbon atom stand like group X. The term alkyl radical should also cyclic alkyl radicals, e.g. cyclobutyl, cyclopentyl and cyclo-

1 2 hexyl. If one of the residues R, R,

χ λ cg 7
R, R, R, R or R is an aralkyl radical, then is

- 2 -
U 0 9 8-1 9/1 194

H-123/134/144/146

this is preferably an aryl lower alkyl red, in which the lower alkyl part the constitution given above for a lower alkyl radical may have. The aryl part is preferably a phenyl radical «,

If one of the radicals R, R _f, R ³ , R, R ⁵ , R or R 'is an aryl radical, then this is preferably a phenyl or a substituted phenyl radical (substituted by alkyl, alkoxy, halogen, nitro or Trifluoromethyl). However, other usable aryl radicals also include the naphthyl radical.

Particularly preferred compounds are those in which

1 2

one of the radicals R and R is methyl and the other is hydrogen. Compounds in which m is 2 are also preferred. Compounds in which R ^ and R are hydrogen and methyl are also preferred. In a preferred embodiment, therefore, the invention relates to compounds of Pormel II: '

(II)

X-

1 2 and their acid addition salts, where one of the radicals R, R

and R ^{6 represents} hydrogen or methyl and X represents CN, CONR ⁵ R ⁴ , CSNR ³ R ⁴ or CO ₂ R ⁵ , where R ³ , R ⁴ and R ^{5 have} the meanings mentioned in connection with Formula I; and metal salts, for example alkali metal salts of those compounds in which R ^ is hydrogen. X is preferably CSNH ₂ or · CSNHCH »in the case of the compounds of formula II.

Another preferred embodiment of the present invention concerns compounds of formula III:

- 3 4098Ί 9/1 194

H-1-23 / 134/144/146

(in)

and their acid addition salts, where X has the meanings mentioned in connection with formula I. X is preferably CSNH ₂ .

The compounds of formula I can be mixed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid, or with organic acids, e.g. oxalic acid, fumaric acid, maleic acid or tartaric acid, acid addition salts form. These acid addition salts also belong to the present invention.

In the compounds of the formula I, the carbon atom is on that the remainder X is bound, asymmetrically. As a result, you can the compounds exist in optically active d- and 1-forms. These optically active forms and the racemates are natural also to the present invention. The otpically active forms can be separated in the usual way, either by Formation of an acid salt with an optically active acid or in the case of a compound in which X is COOH, by use an optically active base.

Compounds of the formula I in which X stands for CSNR'ir and Compounds in which X is CN and at least one of

1 2 6 '7
The radicals R, R, R and R 'have a meaning other than hydrogen, are anti-ulcer agents. The antiulcer activity was measured by the method of Brodie and Hanson, Gastroenerology, Jjj,. 1, 1960, determined. It was found quite generally that compounds of the formula I in which X stands for CSNR R act against ulcers. In the above test, 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide, 2-phenyl-, 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide, and 2- and 3-methyl -5,6,7,8-tetrahydroquinoline-8-thiocarboxamide demonstrated good effectiveness. Ver

- 4 40981 9/1194

"5 4-bonds of the formula I in which X stands for CONRm * or ₂ or salts of compounds in which X stands for CO ₂ H generally represent intermediates for the preparation

3 4 of compounds of formula I in which X is CSNR R. Compounds of the formula I in which X stands for CSNR ^ R often have antisecretory activity in the test by H. Shay, D. Sun and H. Greenstein, Gastroenterology 1954, 26 »906-13. For example, 5,6,7,8-tetrahydroehinoline-8-thiocarboxamide, the analogous 2- and 3-methyl compounds thereof, and the analogous 3-methyl-8-N-methyl compound showed remarkable effectiveness in this test. Some nitriles of Formula I where X is CN are also effective in this test. Compounds of the formula I in which X stands for CN also represent intermediates for the thioamides of the formula I in which X stands for CSNR ³ R ⁴ ″.

The compounds of the formula I can by various methods are prepared, all of which are the subject of the present invention. As part of a general method of manufacture of the compounds of formula I is a corresponding compound in which X is hydrogen, in a known manner treated to introduce the desired group X.

A process for the preparation of compounds of the formula I in which X stands for CO ₂ R uses the carboxylation of a corresponding compound in which X stands for hydrogen in order to prepare a compound of the formula I in which X stands for COOH and if desired, the product comes with

5 5

a hydroxyl compound R OH, in which R, apart from hydrogen, has the meaning given above, esterified. The carboxylation can be achieved by using a metal salt the compound of the formula I, in which X is COOH, by preparing a corresponding compound in which X is Is hydrogen, treated with a metal alkyl. The metal alkyl can be an alkyl of a monovalent

- 5 9 8 19/1194 ORIGINAL INSPECTED

Metal, for example MR, in which M is sodium, potassium or lithium and R is alkyl, aryl or aralkyl, or it is an alkyl of a ^ divalent metal M (R) ₂ f in which M is calcium or magnesium. This is followed by a treatment of the product in situ with carbon dioxide, whereby CO ₂ gas is simply bubbled into the reaction mixture. The compound of the formula I in which X is CO ₂ H is obtained by treating the product, which is a metal salt of a compound of the formula I in which X is COOH, with acid, for example with hydrochloric acid or hydrobromic acid. A convenient method is to treat a solution of the salt with gaseous hydrogen chloride. A suitable MR reagent is lithium phenyl or n-butyl lithium.

It has been found that when a compound of formula I in which R is for Is methyl and R, R and R 'are hydrogen and X is hydrogen, the carboxylation is carboxylated can occur either at the methyl group R or in the desired X position. Usually a mixture of the desired and the undesired product, but the desired product can be formed in the subsequent work-up be separated.

The esterification of a compound of the formula I in which X is CO ₉ H can be carried out using a hydroxyl compound R OH, in which Br has the abovementioned meaning other than hydrogen, by customary procedures, e.g. in the presence of an acidic catalyst, such as a little concentrated sulfuric acid or after saturation with hydrogen chloride gas or a Lewis acid, e.g. boron trifluoride, if desired with heating, or by treating the silver salt (X = COOAg) with an iodide R ^ J, where R ^ apart from hydrogen, has the meaning given above.

The ester yield can be improved by following the CO »treatment adds further metal alkyl and then

409819/1194

H-123/134 / H4 / H6

introduces CO _{2 again.} The further reaction with metal alkyl and CO ₂ presumably results in the metal salt of the bis-acid of the formula IV:

, 6

(IV)

where R. R.

6 7
R and R- have the meanings defined in connection with formula I and M represents the metal of the metal alkyl, for example sodium, potassium or lithium, and this salt decarboxylates spontaneously during the esterification.

Another process for the preparation of esters of the formula I in which X is CO ₂ R ^, uses the treatment of a compound of the formula I defined above, in which X is a hydrogen atom, with a metal alkyl (as defined above) and the subsequent treatment of the product with a halogen formate of the formula HaICOOR, in which Hai represents a halogen atom, for example chlorine or bromine, and R- has the meaning given above. The product is usually a mixture of the desired compound of the formula I, wherein X

5
stands for COgR, and the corresponding bis-ester of the formula V:

CO ₂ R? CO ₂ R ⁵

(V)

These bis-esters are suitable for the preparation of the corresponding Compounds of the formula I in which X is COJS. It has been found that this mixture of mono- and bis-esters

- 7 4098 19/1194

ORIGINAL INSPECTED

directly into the corresponding compound of formula I, where X is COpH stands that can be converted by saponification with a Alkali or alkaline earth metal hydroxide, whereby a mixture of the metal salt of the monoacid of the formula I, where X stands for COJH,

and the metal salt of the diacid of formula V, where R is H, receives. Treatment of this mixture with a mineral acid, e.g. hydrochloric acid, gives the desired acid of formula I, where X stands for GOpH, since the diacid decarboxylates spontaneously and forms the monoacid.

The product from the reaction with haloformate can with a further amount of metal alkyl and then reacted with a further amount of haloformate in order to produce more bis-esters (V).

Another method for the preparation of compounds of the formula I in which X stands for COpH makes use of decarboxylation a compound of the formula V:

CO ₂ R 'CO ₂ R

12 5
wherein R, R, R ^ and m have the meanings given earlier.

The decarboxylation can be achieved by heating the dicarboxylic acid of formula II in which R is hydrogen. The dicarboxylic acid is usually prepared in situ by hydrolysis of the corresponding diester, in which R, in addition to hydrogen, has the meanings given above. The hydrolysis and decarboxylation can be effected by heating with a dilute mineral acid, for example HCl or sulfuric acid, or the diester can be saponified with an alkali, for example sodium or potassium hydroxide. The resulting salt is then acidified and decarboxylated by heating.

- 8 4098 19/1194

ORIGINAL SMSPECTEiD

■ "■. H-123/134 / U4 / H6

Compounds of the formula I "in which X stands for COM R can be prepared with ammonia by treating a corresponding compound of the formula I in which X stands for COGl or CO ₂ R- 'and R, in addition to hydrogen, has the meanings given above, this gives a compound of the formula I in which X stands for CONH «, which can then be alkylated to obtain the

3/4 ■ 3 4

Introduce groups R and / or R, where R and R have the meanings given above, except hydrogen. A compound of the formula I where X is CO ₉ R, where R is lower alkyl, in particular methyl or ethyl, is expediently treated with ammonia. Alternatively, substituted amines of the formula I, where X is CONR ⁵ R and one of the radicals R ⁵ and R has a meaning other than hydrogen, can be prepared by using the carboxylic acid ester of the formula I in which

C .C

X stands for CO ₀ R ^ and R ^ has a meaning other than hydrogen

_ 3 3

has, treated with an amine of the formula R NH ₂ , in which R has the abovementioned meanings except hydrogen. The substituted amides can easily be prepared from the acid chloride of the formula I, where X is COCl, by treatment with a primary or secondary amine R ⁵ NH ₂ or R ⁵ R ⁴ NH. An example of a primary amine that can be used in the above reactions is methylamine and dimethylamine is a secondary amine that can be used in the reaction with the acid chloride.

The acid chlorides can be prepared by treating the corresponding acid of the formula I, where X stands for CO ₂ H, with thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.

Another method of making compounds of the

1 p

Formula I, in which R and R have the meanings defined above and X is CONHR, where R ^- V is hydrogen or alkyl, relates to the treatment of an ester compound of the formula I in which X is CO ₀ R ^ and R ^ is alkyl, with

9 3
an amide of the formula R CONHR or a salt thereof, wherein

- 9 -Λ 0 9 8 T 9/119 A

^ SPECTED

H-123/134 / H4 / H6

TE Q

R is hydrogen or alkyl and R is hydrogen or lower alkyl "means in the presence of an alkali metal alcoholate.

One mole equivalent of alkali metal alcoholate is preferably used per mole of ester of the formula I. The alkali metal alcoholate can be derived from a lower alkanol with 1-6 carbon atoms, e.g. from methanol or ethanol. The alkali metal is preferred Sodium.

The ester of formula I is preferably a lower alkyl ester.

9 3
The amide R CONHR is preferably an amide,

9 3

"where R is hydrogen or methyl". R also means preferably hydrogen or methyl. Preferred amides are therefore formamide, N-methylformamide, acetamide and N-methylacetamide. Salts, especially alkali metal salts, of these amides can be used as starting materials.

The reaction can be carried out by heating the reactants together.

The amides of the formula I in which X stands for CONH ₂ can also be prepared by partial hydrolysis of the corresponding nitriles of the formula I where X stands for CN. This hydrolysis can be carried out in the usual way, for example with concentrated sulfuric acid (for example $ 96).

The thioamides of the formula I in which X is CSNR R, where R ^ and R have the meanings already mentioned, can be obtained by treating the corresponding compounds in which X is CONR R with £ ₂ ^S 5 », for example by refluxing in Pyridine can be produced. As stated below, dehydration of the nitrile can occur when the starting material is a compound in which X is CONHp. It has been found that this avoids this dehydration

10 19/1194

ORIGINAL INSPECTED

can be that the P ₀ S, - reaction in the presence of H ₉ S by- * ά ρ. <-

•leads. Alternatively, the thioamides can be prepared by treating a nitrile of the formula I, where X is CN, with HpS, so that the unsubstituted thioamide, where X is CSNH _2, is obtained. Substituted thioamides can be obtained by carrying out this reaction in the presence of a primary amine

3 "■" "-" '34 3 4

R NH ₂ or a secondary amine RR NH, where R and R have the meanings given above except hydrogen. The HpS reaction can be carried out in a suitable solvent in the presence of a catalyst such as a tertiary amine, for example in the presence of a trialkylamine such as triethylamine.

Substituted thioamides can also be obtained by treating a substituted thioamide of the formula I, in which X is CSNH ₀

3 4 3 4, with an amine of the formula R R NH, where R and R are as are defined above, but one of them has a meaning other than hydrogen, are prepared in the presence of HpS will. The amine can be a mono- or dialkylamine, e.g., methylamine or dimethylamine.

The nitriles of the formula I where X is CN can be prepared by dehydrating the corresponding amides of the formula I where X is CONH ₂ . Such dehydration can be carried out with PpOv as the dehydrating agent. Other dehydrating agents are phosphorus pentachloride or thionyl chloride. It has also been found that this dehydration can be brought about with P ₂ S ^ - it is assumed that this is a per se new reaction. Dehydration with PpS ₅ was found to be a side reaction in the conversion of the amides of the formula I, where X stands for CONH ₂ , to the corresponding thioamides, where X stands for CSNH ₂ , when using P ₂ S ₁ -. The nitrile can either be separated off, for example by chromatography, or the mixture can be mixed with H ₂ S to convert the nitrile into the corresponding

/ ΠυΟΊΟ / Ί ^ Ο / ί

η U 3 O I ο / I IwH ■

ORiGINAL iNSPECTED

Thioamide treated. Dehydration can also be effected by heating the amide in hexamethylphosphoric triamide solvent. It has been found that using this solvent a compound of formula I, where X is CONMe ₂ , can be prepared as an important by-product. The latter reaction is probably also a new reaction per se.

Another process for preparing the thioamides of the formula I, where X is CSNH ₂ , relates to the reaction of a nitrile of the formula I, where X is CN, with a thioamide of the formula R CSNH ₂ , where R is an alkyl group, for example a lower alkyl group having 1-6 carbon atoms, preferably a methyl group, in a suitable solvent such as dimethylformamide which is saturated with hydrogen chloride.

The starting compounds of the formula I used in the above-mentioned carboxylation reaction, in which X is hydrogen 'can be prepared by cyclizing a compound of formula VI in the presence of hydroxylamine:

H ₂ N.OH

^{R (0Η}

(VI)

1 2

in the above formulas, R- and R have the meanings given earlier, However, R preferably represents a different radical

6 7

as hydrogen and R and R 'have the meanings given above. When X is hydrogen, R is hydrogen

7 7

and R represents hydrogen or, if R 'is not hydrogen means that is not on the carbon atom adjacent to the pyridine ring, starting compounds of the formula I by reducing the corresponding 5-oxo compound (VIl)

- 12 4098 19/1194

Η-123/134 / Η4 / 146

be prepared using a reducing agent which does not have the double bonds of the fused pyridine ring attacks, e.g. hydrazine, i.e. it becomes a Wolff-Kishner reduction applied.

(VII)

(VIIa)

2 6

The starting material of formula VII, wherein R and R are hydrogen can be made in the following ways:

+ HC ^ GCHO

(CH ₂ )

The reaction can be carried out in a suitable solvent, e.g. dimethylformamide, be carried out at room temperature, followed by distillation of the product.

Compounds of the formula VIIa in which X is hydrogen,

1 2

R represents hydrogen and R has a meaning other than hydrogen * can be prepared by known methods will.

The compounds of the formula VI (in which R is hydrogen or is not in both positions of the oxo group) can be prepared in one of the following ways:

t> 6
A)

(CH

e.

+ R ¹ COCH ₃

- 13 4098 19/1194

H-123/134 / H4 / H6

R ' f ~ j + R ¹ COCHR ² CHR ⁶ NMe ₂

(CH ^) _1n ⁼

12 6 in the above reaction equations R, R, R _1, R 'and m have the meanings given above and R has a meaning other than hydrogen. The reactants used are "known compounds or can be prepared by methods known for analogous compounds.

The starting compounds of the formula V can also be prepared by methods which follow the above reaction routes
A and B are analogous.

NMe ₂ + R ¹ COCH ₂ R ² R ⁷ -2 steps

(CH ₂ )

+ R ¹ COCHR ² CHR ⁶ NMe,

2 steps

CO ₂ R- ⁷ CO ₂ R

According to Reaction Schemes C and D is a diketone that the Products of schemes A and B is analogous, first prepared and then reacted with hydroxylamine. In Scheme C, R and are R as defined above, with the exception of hydrogen, and R

• j
and R have the meaning mentioned in connection with formula I

P.
services and in scheme D, R has the meanings given above

7th
and R stands for hydrogen or, if this radical is not

-H-09819 / 1.194

^ r ₀ TQc H-1234/134/144/146

stands for hydrogen, it is not adjacent to the pyridine ring in the product. The reactants of this reaction scheme are also known compounds or they can be according to methods known for analogous compounds.

Other compounds for the preparation of starting compounds of the formula I in which X is hydrogen are in the Literature described, see e.g. Breitmaier & Bayer, (Tetrahedron Letters No. 38, 1970, 3921-3924, where methods for preparation

12th

of compounds are given in which X, R and R water

2 are substance and X is hydrogen and R is alkyl * A another method for the production of certain compounds of the

Formula I in which X is CO ₀ R ⁵ , GONR ⁵ R ⁴ or OSNR ³ R ⁴ ,

3 4-where R and R have the meanings mentioned in connection with formula I, R ^{v is} alkyl, aryl or aralkyl and a

7th
Group R, which represents something other than hydrogen, is on the carbon atom to which X is bonded, relates to the reaction of a compound of the formula:

(VIII). D 0 ^ 1 ■■ · ■ '·,

12 6
wherein R, R and R are those mentioned in connection with formula I.

Have meanings and the X adjacent R remainder the in connection has the meaning mentioned with formula I except hydrogen

7th
and the other R radical has the meanings mentioned in connection with formula I and X has the meanings given immediately above, with hydroxylamine.

Another method for the preparation of thioamides of the formula I, in which X stands for CSR ⁵ R ⁴ , where R ⁵ and R ^{4 have} the meanings mentioned in connection with formula I, relates to the treatment of a thioester of the formula I in which X- stands for CSSR ^

- 15 4 09 819/1194

R denotes alkyl or aralkyl "with a compound of the formula R ⁵ R ⁴ NH, where R * and R have the meanings given in connection with formula I. The thioester starting materials can be prepared by treating a compound of the formula I in which X is Is hydrogen, can be prepared with a metal alkyl MR ° .or M (R °) ₂ , as already discussed above, and then the product can be treated with carbon disulfide so that the metal salt of the thioic acid of the formula I is obtained with an alkyl halide R Hai, where R ^ is an alkyl or aralkyl group and Hal is chlorine, bromine or iodine.

The invention also relates to pharmaceutical agents which contain a compound of the formula I in which X stands for CSNR R and R ^v and R have the meanings given in connection with formula I,

12 or X is cyano and at least one of the radicals R, R, R

7th
and R is other than hydrogen, and contain a pharmaceutical carrier.

As the pharmaceutical carrier, any one known in the art can be used suitable carriers for the manufacture of pharmaceutical Funds are used. In such an agent, the carrier can be a solid, liquid, or mixture of a solid and be a liquid. Solid agents include powders, tablets, and capsules. With a solid support, it can are one or more substances that can also be used as flavorings, lubricants, solubilizers, suspending agents, Binders or act as a means to disintegrate tablets; it can also be encapsulation material Act. In the case of powders, the carrier is a finely divided solid substance, which is present in a mixture with the finely divided active ingredient. For tablets, the active ingredient is combined with a carrier, the having the required binder properties, mixed in suitable proportions and to the desired shape and Size pressed. The powders and tablets preferably contain

- 16 409Ö19 / 1194

$ 5-99, preferably $ 10-80, active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" or "agent" is intended to mean the formulation of an active ingredient with encapsulating material as a carrier so that a capsule is obtained in which the active ingredient (with or without other carriers) is surrounded by the carrier which is therefore in contact with it , lock in. Cachets are also included. Agents in sterile liquid form include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier such as sterile water, sterile organic solvent, or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for example aqueous propylene glycol containing 10-75% by weight of the glycol is generally suitable. In other cases, agents can be prepared by adding the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil _? ^j dispersed in arachis oil, for example. The pharmaceutical agent is preferably in the form of dose units, the agent being subdivided into dose units _s containing the appropriate amounts of active ingredient; the dose unit can be a packaged agent, the pack containing specific amounts of the agent, for example it can be a packaged powder or vial or ampoule. The dose unit itself can be a capsule, a cachet or a tablet, or it can be a suitable number of one of these preparations in packaged form special requirements and the effectiveness of the active ingredient. The invention also includes the compounds without a carrier, where the compounds are in the form of dosage units. '<■

- 17 - 4 0 9 8 19/1194

Lie agents according to the invention against UIcera are administered orally, either administered in the form of a liquid or solid agent. These agents may contain one or more antacid ingredients, e.g. aluminum hydroxide, magnesium hydroxide or bismuth carbonate, Aluminum glycinate, calcium carbonate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Patent 1,284,394.

The following examples serve to further illustrate the invention; all temperatures are given in ^° C.

example 1 A) 2-phenyl-5,6,7,8-tetrahydroquinoline

2- (3'-Phenyl-3'-oxopropyl) cyclohexanone is according to the method of ¥. Hahn and J. Epsztain (Roczniki Chem. 1963, 37, 403-12): A mixture of ^ -dimethylaminopropiophenone (27 g) and cyclohexanone (37.5 g) is refluxed for 5 hours under nitrogen and the solvent is then removed in vacuo. The oily residue is distilled and 2- (3'-phenyl-3'-oxopropyl) cyclohexanone (14 g) is obtained, which is cyclized to the compound named in the title by the method of Hahn and Epsztain by adding the diketone (12 g) dissolved in ethanol (65 ml), treated with hydroxylamine hydrochloride (9 g) and refluxed for 1 hour. The cooled reaction mixture is poured into water (300 ml), extracted with ether (2 × 50 ml), the extracts are discarded. The aqueous solution is _{made basic with K 2} CO ^ and extracted with ether (3 x 50 ml). The combined ether extracts are dried and the solvent is removed in vacuo. The oil residue is distilled and gives the compound mentioned in the title as a colorless oil (7 g), bp = 134-8 ° C / 15 mm.

Analysis calculated for G ₁₅ H ₁₅ N: 0.86.00; H, 7.2; N, $ 6.7

Found: G ₉ 85.4Oj H, 7.5; N, 6.9 *.

- 18 4098 1 9/1 1 94

23b258b ^H - ^{123/134/144/146}

B) methyl 2-phenyl-5,6,7.S-tetrahydroquinoline-S-carboxylate

A solution of ^ -Phenyl- ^ o.TjS-tetrahydroquinoline (20 g) in ether (50 ml) is added dropwise over 30 minutes to a previously prepared ethereal solution of phenyllithium (made from bromobenzene (40 g) and lithium ( 2 "78 g) in dry ether (Ί60 ml)). The reaction mixture is stirred for 1 hour at room temperature and _{treated with dry CO 2} gas until the color has disappeared. The solvent is removed in vacuo and the residue is dissolved in ethanol which is saturated with dry HGl gas (250 ml), the plague substance is filtered off and recrystallized from water to give 2-phenyl-5,6,7J8- tetrahydroquinoline-8-carboxylic acid hydrochloride (12 g). This substance is dissolved in methanol (200 ml) and the solution is treated with dry HGl gas while refluxing for 4 hours. The solvent is removed in vacuo, the residue is dissolved in water (50 ml), made basic with 2N NaOH and extracted in chloroform (3 × 100 ml). The combined extracts are dried r evaporated to dryness and the remaining Festsubstanz- _s is recrystallized from petroleum ether there is obtained the compound named in the title as colorless needles (11 g), m.p. = 75 ° G. ■

Analysis calculated for G ₁₇ H ₁₇ Ns C, 76.4; H, β, 4; N, $ 5.2. ■. "Gef"; C, 76.8; H, 6.5; K, 5,

Example 2

2-phenyl-5,6,7,8-tetrahydroquinoline-S -carboxamide

Methyl 2-phenyl-5,6,7, S-tetrahydroquinoline-e-carboxylate (4 g) is dissolved in methanol saturated with ammonia (90 ml) and heated in a sealed tube at 100 ° C. for 4 days. Removal of the solvent in vacuo gives an oily solid substance which, on recrystallization from ethyl acetate, gives the compound mentioned in the heading as colorless needles (1.5 s) t I ¹ P = 145 ^° C

- 19 4098 19/1194

23b2585 H-123/134/144/146

Analysis "Calculated for C ₁₆ H ₁₆ N ₂ O: C, 76.2; H, 6.4; N, 11.1 $

Found: C, 76.4; H, 6.5; N, 11.1%.

Example 3

2-phenyl-5,6,7, S-tetrahydroquinoline-e-thiocarboxamide

8 g of 2-phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide are dissolved in pyridine (20 ml), _{treated with P 3} S ₅ (5.2 g) and the mixture is allowed to stand for 30 minutes The solvent is removed in vacuo, the oil residue is dissolved in dilute HGl, washed with ether (2 × 50 ml) and the washing liquid is discarded, the aqueous solution is made basic, extracted with chloroform (3 × 50 ml), the combined Extracts are dried and evaporated to dryness, the oil residue is chromatographed on silica gel, eluted with chloroform, and 8-cyano-2-phenyl-5,6,7,7-tetrahydroquinoline (1.2 g) is obtained as colorless needles of ether , Mp = 100 ⁰ C; analysis calculated for C ₁₆ H ₁₄ N ₂ : C, 82.0; H, -6.0; N, 11.9%

Found: C, 82.0; H, 6.2; N, 11.7%.

Further elution with chloroform yields the the title compound (1.1 g) as colorless needles from ether, m.p. = 154 ⁰ Cf.

Analysis calculated for C ₁₆ H ₁₆ N ₂ S: C, 71.6; H, 6.0; N, 10.4%

. Found: C, 71.8? K, 6.1; N, 10.2%.

Example 4

N, N-Mmethyl-2-phenyl-5,6,7, S-tetrahydroquinoline-e-carboxamide

2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (6 g) is dissolved in hexamethylphosphoric triamide (24 ml) and the solution is ^{heated at 220 °} C. for 2 hours. The cooled reaction mixture is poured into water (50 ml), extracted with chloroform (3 × 100 ml), the combined extracts are washed with water (3 × 100 ml), dried and evaporated to dryness. The oil residue is chromatographed on silica gel, eluted with chloroform and yields 2-phenyl8-cyano-5,6,7,8-tetrahydroquinoline

- 20 - 409819/1194

235258b H-123/134/144/146

(2.5 g), recrystallized from ether as colorless needles, Pp = 100 ^° C. Further elution with chloroform gives N, N-dimethyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1.1 g) , which crystallizes from ether as colorless needles, Pp = 140 ⁰ C; Analysis calculated for C ₁₈ H ₂₀ N ₂ O: C, 77.11; H, 7.19; N, $ 9.99

Found: 0.77.17} H, 7.22; N, 10.24%.

Example 5

2-phenyl-5,6,7 «S-tetrahydroquinoline-S-thiocarboxamide

2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g) is dissolved in pyridine (5 ml) and triethylamine (1.3 ml), the solution is treated with HpS gas for 6 hours, the reaction mixture is then allowed to stand at room temperature for 12 hours. The solvent is removed, the oily residue is dissolved in dilute HCl, extracted with ether (2 × 50 ml) and the extracts are discarded. The aqueous solution is made basic, extracted with chloroform (3 x 50 ml) and the combined extracts are dried, evaporated in vacuo to give 2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide, which is dissolved in ethanol ( 5 ml) is dissolved, diluted with ether (25 ml), and the solution is saturated with HCl gas. The solvent is removed in vacuo, the remaining Pestus substance is recrystallized from methanol / ether and the hydrochloride of the compound mentioned in the title is obtained as colorless needles, Pp = 211 ^° C .; Analysis calculated for C ^ gH ^ gNpS · HCl:

C, 63.04; H, 5.62; N, $ 9.19 Found: C, 63.41; H, 5.70; N, $ 8.94.

Example 6 A) 5,6,7,8-tetrahydroquinoline

5-Oxo-5H-6,7,8-trihydroquinoline is prepared according to the method of P. Zymalkawski (Arch. Chem. 1961i 294, 759) prepared by propionaldehyde (16 g) is added to a solution of 3-aminocyclohex-2-enone (31 g) in DMP (150 ml) over 5 minutes.

- 21 409819/1194

As soon as the exothermic reaction has subsided, the flask is set up for the descending distillation and the reaction mixture is heated at 100 G under a vacuum of 15 mm, the The distillate is collected and discarded. The temperature is increased to 160-170 ° C., the distillate being collected and dissolved in dilute HCl (75 ml) and with ether (2 χ 50 ml) is extracted. The combined essential extracts are discarded. The aqueous solution is made basic and with Ether (3 x 150 ml) extracted, the combined essential Extracts are dried and evaporated in vacuo. The oil residue is distilled and 5-oxo-5H-6,7,7-trihydroquinoline is obtained (21 g), b.p. 133-134 ° G / 15 mm, dissolved in diethylene glycol (190 ml) and dissolved with hydrazine hydrate (14 g) and sodium hydroxide (14, g) is treated. The reaction mixture is refluxed for 30 minutes and then for 3 1/2 hours long under a Dean and Stark water trap. The cooled reaction mixture is poured onto water (100 ml), extracted with ether (3 x 100 ml) and the combined extracts are dried and evaporated in vacuo. One distills the oil residue and receives the compound named in the heading as a colorless oil (10 g), bp = 100-1O5 ° C / 15 mm.

B) methyl 5,6,7, S-tetrahydroquinoline e-carboxylate

A solution of 5,6,7,8-tetrahydroquinoline (14 g) in dry Ether (100 ml) is added dropwise over half an hour to an ethereal solution of phenyllithium (made from Bromobenzene (42 g) and lithium (3.7 g) in dry ether (300 ml)) and stir the reaction mixture at room temperature for a further For hours. The cooled reaction mixture is saturated with dry COp gas, evaporated in vacuo and the residue is treated with methanol previously saturated with dry HCl (500 ml), then the solution becomes for 12 hours heated to reflux. The solvent is removed in vacuo, v »

dissolves the residue in water (50 ml), extracts with ether (3 × ISO ml) and discards the extracts. The aqueous solution

- 22 -

"409819/1194

is made basic and extracted with ether (3 x 100 ml). The combined ethereal extracts are dried, evaporated in vacuo, the oil residue is distilled and yields methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate as a colorless oil (13 g) _f . Bp = 92 ° C./0.5 "mm. The hydrochloride is produced by saturating an ethereal solution with dry HGl gas and recrystallizing the resulting pest substance from methanol / ether, the hydrochloride of the compound named in the title being obtained as colorless needles , M.p. 173 ^° C .;
Analysis calculated for C ₁₁ H ₁ JTO ₂ HCl:

. ./ C, 58.0; H, 6.2; N, $ 6.2

Found: C, 58.2; H, 6.3; N, 6.3%.

Example 7

5,6,7, -e-IEetrahydroOh-inoline-S-carboxamide

9 g of methyl 5, ö ^ jS-tetrahydroquinoline-S-carboxylate is dissolved in methanol which has been previously saturated with ammonia (27Ö ml) and heated in a bomb for 5 days at 100 ⁰ C, "The solvent was removed and rub the oil residue with hot petroleum ether (40 - 60 °). The Pestsubstanz obtained is filtered off, then recrystallized from ethyl acetate and yields the compound named in the title as färblose needles, Pp '= 132 ⁰ C (5 g) ?.

Analysis calculated for C ₁₀ H ₁₂ N ₂ O: 0.68.1; H, 6.9; N, $ 15.9

Found: C, 67.7; H, 7.1? N, 16.0%.

Example 8

5,6,7 "S-tetrahydroquinoline-S-thiocarboxamide

A solution of 5,6,7, S-tetrahydroquinoline-S-carboxamide (1.2 g) in pyridine (15 ml) is _{treated with P 2} S ₅ (0.8 g) and the mixture is refluxed for 30 minutes heated. The solvent is removed in vacuo, the oil residue is treated with 2N NaOH (5 ml), saturated with solid K ₂ CO, and extracted with chloro

- 23 4 0 9 8 19/1194

shape (.3 x 50 ml). The combined extracts are dried and the solvent is removed in vacuo, the oil residue is dissolved in pyridine (4 ml) and triethylamine (1 ml), the solution is _{saturated with H 2} S (6 hours) and left to stand overnight. Removal of the solvent gives a solid substance (850 mg) which, when recrystallized from methanol, gives the compound mentioned in the heading as 1/4 hydrate, colorless needles, mp = 16Q ⁰ G;
Analysis calculated for C ₁₀ H ₁₂ N ₂ S · 1/4 H ₂ Q:

0.59.6? H, 6.4; N ₁ . 13.93 $ G, 59.8; H, 6.2; N, 14,

The UV, IR and NMR spectra de.r mentioned in the heading Connection are the following:

1. ÜV spectrum in 95 $ ethanol (1.07 mg in 1QQ ml)

2, IR spectrum

323Q cm \ _m backward oscillation
3Q6Q cnT'J -

1660 cm "-NH _Q deformations ^ or / and Q == QN stretching vibration

- 1

1575 Qm Q ~ Q stretch vibration;

1500 * 900 Gm "■" Fingerprint Grgbie, t "; numerous bands \> e .->

caused by kgmplixe and coupled vibrations. Two gangs occur particularly hevgr: —1 1

128Q cm and 1Q2Q sqm '

- 1

8Q2 em "\ -CH Defarmatign, Qharakteri§tisQh for 2,3 720 cm ~ U -statuated

NMR ^ -Spelctrum- in 4 ^ DMSQ (1QQ

S 1.5-2.1 wide mul ^ iplet 4 pr-tones. CHg -6 and

S 2.7 Multiplet 2 proteins GH _g ~ 5

S 4.15 Triplet (J ^ Sz) 1 iratQü GB-8

S 7.08 Quartet 1 Pro.tan H ^ -3

S 7.44 Quartet 1! Red H ^ 4

S 8.29 Quartet 1 froton 1-2

g9,4§ bre.itis doublet 2 protons

^: ™ 24 «·

409819/1194

Coupling constants: Jp- * = 5Hz, Jp ^ = 1.5 Hz, J ~, = 8 Hz

In the index of "Chemical Abstracts" it is indicated that 5,6,7,8-, Tetrahydroquinoline-S-thioearboxamide in Z. Naturforsch. _6b, 147— 155 (1951), the actual abstract is disclosed however not that connection and an investigation has has shown that the information in the index is incorrect, since the compound actually disclosed is 8-quinoline-thiocarboxamide acts whose benzene ring has been represented without the unsaturation drawn according to a custom, see "Organic Chemistry", Paul Karrer, 4th English edition, Elsevier, 1950, e.g. page 813.

Example 9 A) 2-t-Butyl-5,6,7,8-tetrahydroquinoline

5-dimethylamino-2,2-dimethylpentan-3-one hydrochloride (100 g), made from pinacolon using the Casey & Ison method (Tetrahedron, 1969, .25, 641-6) is dissolved in water (50 ml) and the pH is adjusted to 12.0 with 10N NaOH, then extracted with ether (3 × 50 ml), the combined ether extracts are dried (MgSO.), evaporated in vacuo and the oil residue is dissolved in cyclohexanone (300 ml). The mixture is refluxed for 8 hours and then cooled away. The reaction mixture is then distilled at 15 mm Remove excess cyclohexanone then at 1 mm distilled, with 2- (3'-t-butyl-3'-oxopropyl) cyclohexanone (82 g) is obtained, which is dissolved in 275 ml of ethanol and treated with hydroxyl amine hydrochloride (70 g) we'd treated. You heat them up Mix for 2 hours at reflux temperature as in the general method of W. Hahn and J. Epsztain (Roczniki Chem. 1963, J57, 403-12). The solvent is in vacuo removed -and the oil residue dissolved in ether (100 ml). The ether solution is washed with dilute HCl (3 × 20 ml) and discarded she. The aqueous solution is made basic with 2N NaOH

- 25 -.
8 19/1194 '

makes, extracted with ether (3 x 50 ml) and the combined extracts are dried and evaporated in vacuo. The oil residue is distilled and gives the compound named in the title as a colorless oil, bp = 80-86 ° C. / 1 mm, (Yield 47g, 64%).

B) 2-t-butyl-5,6,7, S-tetrahydroquinoline-S-carboxamide

Methyl 2-t-butyl-5,6,7,8-tetrahydroquinoline-S-carboxylate will from 2-t-butyl-5,6,7,8-tetrahydroehinoline (18.9 g, 0.1 m) and Phenyllithium (0.1 m) prepared according to the general method described in Example 1B and as a pale yellow oil (9g) isolated, bp = 106 ° C / 0.4 mm.

The compound mentioned in the title is prepared from methyl 2-t-butyl-Sjö ^ e-tetrahydroquinoline-S-carboxylate (8 g) according to the general method described in Example 2 and in the form of colorless needles (3 g) after recrystallization isolated from η-hexane, 3? p = 131 ⁰ C; Analysis calculated for G ₁₄ H ₂₀ N ₂ O: C, 72.38; H, 8.68; N, 12.06%

Found: C, 72.06; H, 8.71; N-, 11.62%.

Example 10

2-t-Butyl-5,6,7,8-tetrahydroquinoline-S-thiocarboxamide

The title compound is prepared from 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (4 g) and P ₂ S, - (3 g) as described in Example 8 and isolated as creamy needles after recrystallization from η-hexane, Pp = 126 ° C. (650 mg). . ., .- .. -, - ■ .- ■. ■ "■■

Analysis calculated for G ₁₄ H ₂₀ N ₂ Si C, 67.70; H, 8.12; N, 11.23%

Found: C, 68.18; H, 8.25; N, 11.14%.

Example 11

5,6,7,8-tetrahydroquinoline "

3-methoxyacrolein is made from 1,1,3,3-tetramethoxypropane (HeIv.

Chim. Acta 1959, 4_2, 851) and according to the method of

- £ 26 0981 9/1194

2 3 b 2 b S b S-r125 / 134/1 <H / H6

Breitsiaier and Gassgnmann (Ghem. Ler. 1971,, 1Oi »665-67) in 3T-AjninoaQrplein converted.

, ^ y is derived from 3 ^ aminoacrolein according to Breit-

ma.ier and layer (fet, letters 1J70, 3g, 3891). A mixture of 1-aminoacrolein (7.3 g, 0.1 HpI) and cyclohexanone. (12 g _t 0.11 MQI) is (ml 5) with QJriathylamin and piperidinium 'aeetat (Q _f 1 g) and the mixture is §tund in an oil bath 24? N at 12Q ^Q HEATER' Me 'cooled Reaktionsmis Ghu; ng is dissolved in ither (100 ml), giwasehenj with water and 2N HCJl (2 × 20 ml) the acidic washing liquids are combined ^ with JiatriumQarbQnat: made basic and extracted with ether Trer§inigt§n Ixtrakti, dainpft, distilled the Rügkstaiid and receives qLiff in the connection called tibersehrift as a light yellow. Oil (4 _? § g _?, Ig ^), Ip s 1QQ ^§ / 1§ mm,

yl ^ l «g, T ₁ S = ^ t etrahydreehinQlin.

yirg | g _k n ^ 8 =: 0 _: n, h.erg§st§llt & us Ageton. and DiethyiL amiii (tTeQ.S »1 | I7 _? | 1) _# Will ml.t eyei@lie.xan.§ii after the general methgie in GA,, 1fI47 | h _t b © s§hri§bfmen umggsftzit and

■ -λ Ä

^ Mgtiiyl «l" - §x.Q | rQByl) sy§lQhgxajQQi alg colorless,

oil, gfh's- 1J © ^@ / g9 msu

The connection named in the tJber ^ ghrift becomes from. 1 ^ (3 -Methyl- «, N_ _n _, .., _ ä§r in t§n

BesQhriebgnen allpm§ingn Me ^ hetle h
Oil isQligrt,! © "s 11 # ^ 12Q ^Q / 1i mm

B e i s ^ i e l 'IJj g, 6.7. i-t

g of g ^ methyl ^ i, ^,? ^^^^^^^^? !!! ^^ !!!! with and ishlendioxyd and subsequent esterification

4 038 TSH 114

23b 2 5 8b H-123/134 / 1U / H6

The general method described in Examples 1B and 6B gives a non-separable mixture of methyl 2-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and methyl-5.6 _t 7,8-tetrahydroquinoline-2-acetate , which is converted into a mixture of 2-methyl-S ^^ jS-tetrahydroquinoline-e-carboxamide and 5,6,7,8-tetrahydroquinoline-2-acetamide without purification by using ammonia according to the method described in Example 2 implements. Fractional recrystallization from diisopropyl ether gives the compound mentioned in the heading as colorless needles, Pp = 114 ° (total yield $ 30);

Analysis calculated for C ₁₁ H ₁₄ N ₂ O: C, 69.45; H, 7.42; N, $ 14.72

Found: C, 69.31; H, 7.45; N, $ 14.7.

Example 14 _{2-Methyl-5,6) t} 7 8-tetrahydroquinoline-8-thiocarboxamide

a-Methyl-Sfö ^^ - tetrahydroquinoline-e-carboxamide is used with? _{Treated 2} ^S 5 and gives 2-methyl-8-cyano-5,6,7,8-tetrahydroquinoline, which is _{treated with H 2} S (both reactions are carried out according to the method described in Example 8) and gives the in the Compound named under the heading as colorless needles from ethyl acetate ($ 28), Pp = 98 °;

Analysis calculated for C ₁₁ H ₁₄ N ₃ S: C, 64.04; H, 6.84; N, $ 13.58

Found: C, 64.32; H, 6.93; N, $ 13.52.

Example 15

3-methyl-5,6,7,8-tetrahydroquinoline

The compound named in the title is made from commercially available 3-amino-2-methylacrolein and cyclohexanone according to the method of Breitmaier and Bayer (let.Letters, 1970, J58, 3291-94) and isolated as a pale yellow oil, bp = 120 ° / 15 mm ($ 30 yield).

Example 16 Methyl 3-methyl-5,6,7, S-tetrahydroquinoline-S-carboxylate

The compound mentioned in the heading is made from 3-methyl-

- 28 - Λ0 9 8 19/1194

■■ · ■. ■ 23b258b H-123/134/144/146

aa

5,6,7,8-tetrahydroquinoline prepared by the general method described in Example IB and isolated as a pale yellow oil, bp = 120 ° / 0.25 mm (80 $ yield). The hydrochloride is prepared in the usual way (cf. Example 6B) and isolated as colorless needles from ethanol / ether, mp = 146 °; Analysis calculated for C ₁₂ H ₁₅ NO ₂ HCl: C, 59.60; H, 6.7; N, 5.8%

Found: C, 59.95 H, 6.7; H, 6.096.

Example 17 3-Methyl-5,6.7 _t 8-tetrahydroquinoline-8-carboxamide

The compound mentioned in the heading is prepared from methyl 3-methyl-5, ö ^ jS-tetrahydroquinoline-S-carboxylate by the method described in Example 2 and isolated as colorless needles from hexane, mp = 118 ° (50% yield) ; Analysis calculated for C ₁₁ H ₁₄ N ₂ O: C, 69.5; H, 7.4; N, 14.7% '

Found: C, 69.6; H, 7.5; N, 14.8%.

Example 18 3-methyl-5 _t 6.7 _f 8-tetrahydroquinoline-8-thiocafboxamide

3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide is _{treated with P 2} S ₁ - and gives S-methyl-S-cyano- ^ o ^ S-tetrahydroquinoline, which is _{treated with H 2} S, as described in Example 8, the compound mentioned in the title is obtained as colorless needles from benzene, mp = 151 ° (50% yield); Analysis calculated for. C,., H ₁₄ N ₂ S: C, 64.04; H, 6.84; N, 13.58%

Found: C, 63.71; H, 6.85; N, -13.38%.

The hydrochloride is obtained by dissolving in the heading mentioned compound in the smallest amount isopropanol and Addition of an Xther solution saturated with dry HCl gas. The hydrochloride precipitates out as colorless needles, Mp = 219 °;

Analysis calculated- for C ₁ → ₁₅ N ₂ SCl: -G, 54.42; H, 6.23; N, 11.54%

: C, 54.33; H, 6.23, -N, 11.42%.

- 29 98 1 9/1 19 4

Example 19 Methyl-3-methyl-5,6,7 »8-tetrahydroquinoline-8-carbox.vlat

n-butyl bromide (285 ml), in dry ether. (500 ml) (g 42, 6 moles) to clean lithium wire in dry ether (11) under nitrogen at such a rate that an inner temperature of -15 ⁰ C maintained will. After the addition has ended, the reaction mixture is stirred until the temperature has ^{risen to 10 °} C. (approximately 2 hours). The butyllithium concentration is calculated by adjusting against n / 10 HGl and the amount of 3-methyl-5,6,7,8-tetrahydroquinoline which is required in the next stage is adjusted so that a 1.2 mol Excess butyllithium is present.

A solution of 3-methyl-5,6,7,7-tetrahydroquinoline is treated (147 g, 1 mol) in dry ether (700 ml) with stirring with a freshly prepared butyllithium solution (860 ml a 1.4 molar solution, that is 1.2 mol) under nitrogen, the reaction mixture is stirred for another 15 minutes and a slow stream of dry COp gas is introduced into the reaction mixture until it is colorless. You dilute the Reaction mixture with water (1.2 l), filtered, the aqueous phase is separated off and extracted with ether (3 × 500 ml). the combined ethereal extracts are worked up and give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (40 g), Kp = 116-12O ° / 15 mm.

The aqueous layer is evaporated to dryness and the remaining particulate matter is treated with a methanol solution previously saturated with dry HCl gas (1.5 l) and left to stand at room temperature for 12 hours. The volatile constituents are removed in vacuo. The remaining oil is redissolved in water (11), extracted with ether (3 × 250 ml) and the extracts are discarded. The aqueous solution is adjusted _{to pH 9.0 with Na 2} CO ₅ and extracted with ether (4 × 250 ml). The combined extracts

- 30 4 0 9 8 1 9/1194

are dried and the solvent is removed in vacuo, the compound mentioned in the heading is obtained as a pale yellow oil (85 g, 42%), GLG (10% SE30, T = 200 °), R ₁ = 3.25 minutes, 93% purity.

Example 20 Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-S-carboxylate

A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (5 g, 0.034 mol) in dry ether (5β ml) is treated in portions with a butyllithium solution in hexane (0.04 mol) under nitrogen and the mixture is left to stand at room temperature for 30 minutes. A slow COp gas stream is introduced until the reaction mixture is colorless, then a further 0.02 mol of butyllithium solution in hexane is added. The mixture is allowed to stand for 30 minutes and then treated with dry COp gas as above. The reaction mixture is diluted with water (20 ml), the aqueous layer is extracted twice with ether (3 x 50 ml) and the combined extracts are retained for recovery of unreacted 3-methyl-5,6,7,8-tetrahydroquinoline. The aqueous phase is evaporated to dryness in vacuo, the solid substance obtained is treated with methanol which has previously been treated with dry HCl gas (50 ml) and left to stand for 3 hours at room temperature. The solvent is removed, dissolved the oil residue dissolved in water (20 ml) and with ether (3 x 25 ml), the extracts are discarded * The aqueous phase is adjusted with Na ₂ CO to pH 9.0 and with ether (3 x 50 ml) extracted. The combined extracts are dried, evaporated in vacuo and give the compound named in the title as a colorless oil (4.3 g, 60 $) GLC (10% SE30, 0? = 200 °), R ₁ = 3.25 minutes , 98% pure.

Example 21

3-methyl-5,6 _< 7,8-tetrahydroquinoline-8-carboxamide A mixture of methyl-3-methyl-5,6,7,8-teti: ahydrochiolin-8-

Λ. '- 31 A 0 9 8 A 9/1 1 9 U

carboxylate (25 g, 0.13 mol),! formamide (11.6 g, 0.26 mol) and sodium methylate (from 2.99 g> ¹ 3 mol sodium) are stirred in an oil bath for 1 hour Heated to 120 °. The reaction mixture is further heated at 100 ° under reduced pressure (15 mm Hg) for 3 hours. The cooled reaction mixture is diluted with 2N HCl, so that an acidic solution is obtained which is extracted with ethyl acetate (2 × 50 ml), and the combined extracts are discarded. The aqueous solution is _{adjusted to pH 9.0 with solid Na 2} CO, saturated with NaGl and extracted with chloroform (3 × 100 ml). The combined extracts are dried and evaporated to give a pale yellow oil which solidifies on trituration with η-hexane. Recrystallization from ethyl acetate gives the compound named in the title as colorless cubes (18.6 g, $ 88), pp = 110 °;

Analysis calculated for C ₁₁ H ₁₄ N ₂ O: C, 69.5; H, 7.4; N, 14.7%

Found: C, 69.6; H, 7.4; H, H, 4 #.

Example 22

3-methyl-5,6,7,8-tetrahydroquinoline-8-earboxamide

A mixture of methyl "-3-methyl-5,6,7,7-tetrahydroquinoline-8-carboxylate (25 g, 0.13 mol), formamide (11.6 g, 0.26 mol) and Sodium methylate (from 2.99 g, 0.13 mol sodium) is on a Steam bath heated for 1 hour while bubbling nitrogen through the mixture to remove that produced by the reaction Distribute formic acid methyl ester. The cooled reaction mixture is diluted with 2N HCl as described in Example 21 worked up and gives the compound mentioned in the title in 90% yield.

Example 23

3-methyl-5,6,7, S-tetrahydroquinoline-S-thiocarboxamide

A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9 g, 0.14 mol) in dry pyridine (300 ml) saturated with H ₂ S gas is made with P ₃ S ₅ (26 g, 0.14 mol) treated and

- 32 409819/1194

Heated under reflux for 45 minutes, a slow _{stream of H 2} S gas being maintained. The reaction mixture is evaporated to dryness in vacuo, cooled to ⁰ ° C., made alkaline with 10% sodium hydroxide and the solution is extracted with chloroform (3 × 100 ml). The combined extracts are washed with brine, dried and evaporated in vacuo. The oil residue is triturated with benzene, the solid substance a "b is filtered off and recrystallized from benzene, giving the compound named in the title as pale yellow needles, JFp = 149 ° (21.8 g, $ 87). The hydrochloride is as already described in Example 18, prepared and isolated in the form of colorless needles, .Pp = 219 ° C.

Example 24 Methyl 3-methyl-5,6,7, S-tetrahydroquinoline-S-carboxylate

Charge a 3-necked flask with 3-methyl-tetrahydroquinoline (45 g, 0.29 mol) and ether (400 ml) and stir. Phenyllithium solution (330 ml of a 1 molar solution, 0.3 mol in ether) is added so quickly that the solution is gently refluxed, refluxed for 2 hours, cooled in an ice bath and CO ₂ bubbled through the solution until no more Change takes place. Water (70 / O ml) is added to dissolve the solid substance, the aqueous layer is separated off and washed three times with ether. The aqueous layer is evaporated to dryness in vacuo, the residue is treated with a saturated methanolic HCl solution (11) and left to stand overnight at room temperature. It is evaporated to dryness in vacuo and the residue is dissolved in water. The aqueous solution is washed three times with ether, made basic with solid sodium carbonate and extracted with ether (a heavy white precipitate also separates out, but this does not interfere with the extraction). The ethereal layer is washed with water and then with brine, dried and. evaporated, you get 25 g (44 $), GLC = 88 $ pure.

- 33 Α098Ί9 / .1194

Example 25 Methyl 3-methyl-5,6 _t 7 ₁ 8-tetrahydroquinolin-8-carboxylate

A solution of 15% n-butyllithium in hexane (51 ml, approx. 0.12 mol) is added in portions to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g, 0.12 mol). 1 mol) in ether (100 ml) and the mixture is left to stand at room temperature for 1 hour, then it is added dropwise with stirring to a cooled solution of methyl chloroformate (9.45 g, °, 1 mol) in ether (100 ml) . The mixture is stirred for 1 hour at 50 ^° C., it is diluted with water (20 ml) and then treated with 2N HCl until it is acidic. The ethereal solution is separated off and washed with 2N HCl (2 × 25 ml). The combined washing solutions are extracted with ether, the ethereal extracts are discarded. The aqueous solution is adjusted _{to pH 9.0 with Na 2} CO and extracted with chloroform (3 × 50 ml), the combined extracts are dried and evaporated, and a pale yellow oil (16 g) is obtained which is found in the GLC analysis (3% SE30) discloses a mixture of unreacted tetrahydroquinoline (45%), the compound mentioned in the title (23%) and the 8,8-dicarboxylic acid ester (20%). The mixture is treated with 10% sodium hydroxide (75 ml) and refluxed with stirring for 4 hours, cooled and extracted with ether (3 × 50 ml). The combined ethereal extracts are dried, evaporated, distilled and unreacted 3-methyl-5,6,7,8-tetrahydroquinoline (7 g), bp = 116 ° / 18 mm Hg. The basic solution is made up with concentrated HCl pH 8.5-9.0, evaporated to dryness, the residue is treated with methanol which has previously been saturated with dry HCl (50 ml) and left to stand for 5 hours at room temperature. The solvent is removed, the residue is dissolved in V / ater (20 ml) and extracted with ether (2 × 50 ml). The aqueous solution is _{adjusted to pH 9.0 with Na 2} CO ₅ , extracted with chloroform (3 × 25 ml), the combined extracts are dried, evaporated and give the compound named in the title (3 g).

- 34 -

40981 9/1194

B e i s. Ρ i e 1 26

3-methyl-5,6,7, S-tetrahydroquinoline-S-thiocarboxamide hydrochloride

Crystal Form A

3-methyl-5,6,7,8-tetrahydroquinoline-S-thiocarboxamide (1 g), prepared as described in Example ¹ 18, is dissolved in boiling isopropyl alcohol (25 ml), filtered and · allowed to stand at 40 ⁰ C. An excess of ethereal hydrogen chloride solution is added, followed by enough ether to cause turbidity. On cooling, the compound named in the heading is isolated in the form of fine, colorless needles (0.95 g), mp = 244 ^° C.; Analysis calculated for C ₁₁ H ₁₄ N ₃ S • HCl: C, 54.4; H, 6.2; N, $ 11.5

. G-ef.i C, 54.3; H, 6.2; N, $ 11.4.

IR V _n ^ _x NuQol Mull 3300 (shoulder), 3230 (wide), 3060 (wide), 2540 (wide), 1650 (thick), 1605, 1555 cm ". This IR spectrum is similar to that of the product of Example 18 identical.

Crystal form B ""

3-Methyl-5, ö ^ sS-tetrahydroquinoline-S-thiocarboxamide (1 g), prepared as described in Example 18, is dissolved in boiling isopropyl alcohol (15 ml) and a small excess of ethereal hydrogen chloride solution is added without cooling. The compound mentioned in the title is obtained in the form of fine colorless needles (950 mg), mp = 244 ^° C .; Analysis calculated for C ₁₁ H ₁₄ N ₂ S • HCl: C, 5, 4.42; H, 6.23; N, $ 11.54

Found: C, 54.58; H, 6.29; N, $ 11.34

IR spectrum: ^ T _max Nujöl Mull 3260 (broad), 3220 (broad), 3050, 2630 (broad), 1655 - 1630 (3 sharp bands), 1555 cnT ¹ .

Crystal form B - alternative method

3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.5 g) is dissolved in methanol (1 ml) and treated with a methanol solution saturated with hydrogen chloride (1 ml) and the Solution is heated to boiling. During the evaporation of the

- 35 4098 19/1194

Methanoles are added to ethyl acetate until cloudy. At the After cooling, the compound named in the title is isolated in the form of fine, colorless needles (0.4 g), Pp = 244 °;

Analysis calculated for C ₁₁ H ^ NoS HGl:

^{4 ά} C, 54.42; H, 6.23; N, 11.54% Found: C, 54.11; H, 6.18; N, 11.51%.

Crystal form A could not be converted into crystal form B by crystallization from isopropyl alcohol / ether or methanol / ethyl acetate. Form A returned to Form B after standing for 2 to 3 days. Form A could also be converted by heating for 6 hours at 4-0 ⁰ C under vacuum in the form of B.

Example 27

3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide

Crystal form A

3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1 g), prepared as described in Example 17, is dissolved in boiling diisopropyl ether (80 ml), filtered and allowed to cool. The compound named in the title is isolated as fine, colorless cubes (0.85 g), mp = 118 ^° C.; Analysis calculated for C ₁₁ H ₁₄ N ₂ O: C, 69.5; H, 7.4; N, 14.7%

Found: C, 69.6; H, 7.5; N, 14.8%.

IR spectrum: ^T _max Nujol 3395, 3195, 1650 (strong), 1620, 1605 (shoulder), 1595, 1560, 1235, 875 (strong), 620 (strong) cm " ^1. The IR spectrum is with that of the Product of Example 17 identical.

Crystal form B

3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1g) as described in Example 17, is dissolved in boiling ethyl acetate (2 ml), filtered and allowed to cool. Man isolates the compound named in the title as colorless rhombic crystals (0.80 g), mp = 113 °;

(- 36'-

U 0 9 B 1 9 / Ί 1 9 A

Analysis calculated for C ₁₁ H ₁₄ N ₂ O; C ₅ 69 _s 50; H, 7.40; N, $ 14.70

Found: C, "68.81; - H, 7.40; N, $ 14.45.

IR spectrum: YV ^ Nujol ■ 3395, 3280, 3185, 1680 (strong), 1605,

max -j

1595, 1560, - 900 (strong), 575 (strong) cm ".

The crystal forms A and "B can be converted into one another by crystallization from suitable solvents. Crystallization of form A from ethyl acetate results in crystal form B and crystallization of form B from diisopropyl ether results in crystal form Al

Ex iel .28

3-methyl-5,6 ^ 7, S-tetrahydroquinoline-S- (N-methyl) t hiocarboxamide

is dissolved in 33 $ methylamine in ethanol (50 ml), the solution is heated in a stainless steel bomb at 150 ° for 24 hours. The solvent is removed in vacuo. The oil residue crystallizes on standing. Recrystallization from 2-propanol / n-hexane gives 3-methyl-5,6,7,8-tetrahydroquinoline-8- (N-methyl) carboxamide as colorless needles (4 g, $ 85). A sample is characterized as a hydrochloride, which is obtained by treating a solution of the base in ethanol with ethereal HGl and isolated as colorless needles, Pp = 185 °. Analysis calculated for G ₁₂ H-JgN ₂ O HGl:

C, 59.87; H, 7.12; N, $ 11.64 G, 59.81; H, 7.11; N, $ 11.34.

A solution τοη 3-methyl-5,6,7,8-tetrahydroquinoline-8- (N-methyl) -carboxamide (1.2 g) in pyridine (9 ml) is treated with phosphorus pentasulphide (1.2 g) and the mixture is left for 3 hours heated to reflux. The solvent is removed in vacuo and treats the residue with an aqueous sodium hydroxide solution, until it's alkaline. The solution is extracted with chloroform (3 × 50 ml), and the combined extracts are washed with water (2 × 20 ml), saline solution, dry and evaporate.

"- 37 409819/1194

23S258b H-125/134 / H4 / H6

The remaining oily solid substance is recrystallized from benzene and gives the compound named in the title as colorless needles (0.9 g, 65%), mp = 159 °; Analysis calculated for Ci ₂ ^H i6 ^N 2 ^{S: G} ' ⁶ 5.41; .H, 7.32; N, 12.72%

Found: G, 65.12; · H, 7.26; N, 12.56%.

Beis piel 29

3-Meth.yl-5,6,7, S-tetrahydro-S-iNjlT diinethylJthiocarbox-amide

3-methyl-5,6,7,8-tetrahydroquinoline ~ 8-thiocarboxamide (1 g) is in a mixture of ethanol (100 ml) previously with Hydrogen sulfide has been saturated, and 33% dimethylamine dissolved in ethanol (50 ml), the mixture is heated in a stainless steel bomb for 3 days at 120 °. Man removed the volatile materials in vacuo and the solid residue recrystallized from ethyl acetate, thereby obtaining the in the title compound as pale yellow needles (0.5 g, 44%), Pp = 135 °;

Analysis calculated for C ₁₅ H ₁₈ N ₃ S: C, 66.62; 'H, 7.74; N, 11.95%

G-ef .; C, 66.50; H, 7.82; N, 11.75%.

Example 30 Sym. ~ Octahydroacridine-2-thiocarboxamide

Sym.-Octahydroacridin is made by adding cyclohexanone converted into di- (2-oxo-cyclohex-1-yl) methane and further reacted with hydroxylamine, according to the method of Gill et al (JACS 1952, 74, 4923), and it is isolated as a colorless oil, Kp = 110-115 ° / 0.5 mm in 40% overall yield.

A solution of sym.-octahydroacridine (5 g, 0.026 mol) in dry ether (50 ml) is treated dropwise with a 15% solution of butyllithium in hexane (11 ml; 0.026 mol) and the mixture is stirred at room temperature for 15 minutes under a nitrogen atmosphere. The nitrogen is replaced by COp Displaces gas that is bubbled through the reaction mixture,

- 38 -

U 09819/1194

"until it is colorless. The reaction mixture is diluted with water (50 ml), the organic layer is separated off and the aqueous phase is extracted with ether (2 × 50 ml). The combined extracts are stored for recovery of sym.-octahydroacridine. The The aqueous phase is evaporated to dryness, the residue is treated with methanol which has previously been saturated with dry HGl (50 ml) and the solution is left to stand for 3 hours at room temperature. The solvent is removed in vacuo, the residue is diluted with water (20 ml) and extracted with ether. The aqueous phase is _{adjusted to pH 10 with solid Na 2} CO and extracted with ether (3 × 20 ml). The combined extracts are washed with brine, dried and evaporated and give methyl sym. -octahydroagridin-2-carboxylate (1 g,

A solution of methyl symroctahydroacridine-2-carboxylate (5g) in methanol ₉ which has previously been saturated with ammonia (80 ml) is heated in a stainless steel bomb at 140 ° for 3 days. The solvent is removed and the solid residue is recrystallized from diisopropyl ether, giving sym.-octahydroacridiri-2-carboxamide as colorless needles (2.6 g, 57/0, pp = 159 °;

Analysis calculated for C ₁₄ H ₁₈ N ₂ O: C, 75.01; H, 7.88; N, 12.17%

Found: C, 72.98; H, 8.04; N, 12.01%.

A solution of sym _e- octahydroacridine-2-carboxaraid (1.8 g) in pyridine (17. ml) is treated with hydrogen sulfide for 5 minutes. The reaction mixture is treated with phosphorus pentasulphide (1.4 g) and refluxed for 45 minutes while maintaining a slow flow of hydrogen sulfide. The cooled reaction mixture is evaporated and the residue is treated with 10% sodium hydroxide until it is alkaline. The aqueous solution is extracted with chloroform (3 x 50 ml) ^ and the combined extracts are washed with brine, dried, evaporated and the solid

- 39 - ■
8 19/1194

The residue is recrystallized from diisopropyl ether, whereby the compound named in the title is obtained as a pale yellow powder (0.3 g), Pp = 104-106 ° (solidifies and melts again at 148 °).

Analysis calculated for G ₁₄ H ₁₈ N ₂ S; C _f 68 ₉ 26; H _s 7.36; F, 11,

C, 68.69? H, 7.54; N, 10,

Beis piel 51

3-methyl -5 _T 6 _t 7,8-tetrahydrochi ^^

A solution of oxalic acid dihydrate (650 mg) in hot ethanol (6.5 ml) is added to a solution of S-carboxamide (1 g) in hot ethanol (10 ml). The solution is filtered and allowed to cool, during which the oxalate crystallizes. The oxalate is filtered off, washed with ether and dried. Yield: 1 g, Pp = 186 - 188 ⁰ G; Analysis calculated for C ₁₅ H ₁₆ N ₂ O ₄ S j C, 52.70; H, 5.44; N, 9.46 <fo

Found; C, 52.71; H, 5.63; N, $ 9.19.

Example 32

5-methyl-5.6,7,8-tet rahydroquinoline-S-thiocarboxamide tartrate

To a solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (13 g) in hot isopropyl alcohol (130 ml) is added a solution of 9.5 g of tartaric acid in hot isopropyl alcohol (65 ml). The solution is filtered and allowed to cool. The precipitated crystals of the tartrate are filtered off, washed with a little cold isopropyl alcohol and dried. Yield 10.2 g, Ep = ■ 158-160 ⁰ G;

Analysis calculated for ^c -j5 ^H 20 ^N 2 ° 6 ^{S: C} '^ 0.55 »H, 5.65; N, 7.86 ^

Found: C, 50.56; H, 5.67; N, 7.90 #.

Example 33

3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide

3-methyl-8-cyano-5,6,7,8-tetrahydroquinoline '(1.7 g, 0.01 mol) and thioacetamide (1.5 g, 0.02 mole) are in dimethylformamide

- 40 Λ09819 / 1194

(50 ml), the solution is extracted with dry hydrogen chloride gas saturated and then heated on a steam bath for 4 hours. The cooled reaction mixture is poured into water (200 ml) poured, washed with ethyl acetate (2 × 200 ml), the extracts are discarded. The aqueous solution is mixed with 46% sodium -hydroxyd adjusted to pH 10.0 and with methylene chloride (2 χ 200 ml) extracted, 'The combined extracts are dried (Sodium sulphide), evaporated in vacuo and the oil residue is triturated with isopropanol and filtered. Recrystallization from benzene gives the compound named in the heading as pale yellow needles (1.3g, $ 63), ϊρ = 149 °.

Example 34,

Methyl 3 _ι -meth yj _: c ^ γclo hepteno / b7pyridin-9-carb _ι O _ι xylat

3-methylcyclohepteno / b / pyridine is made from oycloheptanone and 3-amino ~ 2-methyl = acrolein according to Breitmaier's method (Tet. Lett. 1970, J58, 3291) and in.der in the synthesis of 5,6,7,8-setrahydroquinoline (Example 11) described manner and isolated as a colorless oil, bp = 140 ° / 14 mm.

A 15% ep-butyllithium solution in hexane (16 ml, approx. 0.04 mol) is added in portions to a solution of 3-methylcyclohepteno- / b / pyridine (5 g, 0.03 mol) in ether (50 ml) under nitrogen, the mixture is allowed to stand at room temperature for 30 minutes. The mixture is treated with OO ₂ gas until the red color has disappeared and the solvent is removed in vacuo. ■ The residue is dissolved in water (25 ml) and extracted with ether (3 x 50 ml). The aqueous solution is evaporated in vacuo and the residue is treated with methanol which has previously been saturated with HGl gas (100 ml) and left to stand at room temperature for 12 hours. The solvent is removed and the oil residue is dissolved in water (50 ml), extracted with ether (3 × 50 ml), the aqueous solution is adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml). The combined extracts are dried, concentrated in vacuo.

1-97

evaporates and gives the compound named in the title as a pale yellow oil (0.8 g, 11%), GLC: R ^ = 6.1 / 4 minutes (F11, 10% SE30, R = 150 °). IR spectrum: V " _max film 1740; 1460; 1440, 1120-1200 (wide) cm" ¹ .

Example 35

Methyl-3-methylcyclopente no./b/pyridin -7-carboxylate

3-Methylcyclopenteno / b / pyridine is made from cyclopentanone and 3-amino-2-methylacrolein prepared according to the Breitmaier method (Tet. Lett. 1970, J58, 3291) and isolated as a colorless oil, Kp = 100-1O5 ° / 15 mm.

A solution of 3-methylcyclopenteno / b7pyridine (10 g, 0.078 mol) in ether (150 ml) is treated with a 15% n-butyllithium solution in hexane (30 ml, oa. 0.08 mol), and the mixture is treated treated with CO ₂ gas. The lithium salt of 3-methylcyclopenteno / b / pyridine-8-carboxylic acid is isolated and esterified with methanol which has previously been saturated with HCl gas, as for methyl 3-methylcyclohepteno / b / pyridine-9-carboxylate (Example 34 ) described. The compound named in the title is isolated as a pale yellow oil (1.1 g, 10%), GIC R ^ = 1 1/2 minutes (Pye 104, 3% SE30, T = 200 °)., IR spectrum: V * ■ EiIm 1738, 1460, 1422, 1160-1220 (wide) cm " ¹ .

Example 36 Methyl 3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline-8-carboxylate

3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline (17.5 g, 0.1 mole) is dissolved in dry ether (200 ml) and with a solution of n-butyllithium in hexane (15% solution, 56 ml) under nitrogen treated. The reaction mixture is allowed to stand at room temperature for 30 minutes and then treated with COp gas bis the intense red color has disappeared. The solvent is removed and the oily solid that remains is dissolved in water (20 ml), then extracted with ether (3 x 50 ml) and

- 42 - 40981 9/1194

"Retains the essential extracts to recover unreacted starting material" The aqueous solution is evaporated to dryness, the residue is treated with methanol previously saturated with dry HCl (100 ml) and the solution is left at room temperature for 8 hours The solvent is removed, the oil residue is dissolved in water (50 ml), extracted with ether (3 x 50 ml) and the extracts are discarded. The aqueous solution is adjusted to pH 9.0 with sodium carbonate, extracted with ether ( -3 x 50 ml) ', dry the combined extracts, evaporate in vacuo and obtain the compound named in the heading as a pale yellow oil (1.8 g, -10j6); IR spectrum ι V _{m & x} PiIm 1748, 1570 , 1460, 1160, 1030 cm " ¹ . GLG R ^ = 3 1/2 minutes (EIL ₉ 2 <fo 0V17, T = 150 °;.). . ■

The picrate of the compound named in the title is prepared by dissolving the free base (1-00 mg) in ethanol (1 ml) and adding a saturated solution of picric acid in ethanol (5 ml) and allowing the picrate to crystallize. The picrate is filtered off, dissolved in the smallest volume of ethanol and precipitated by adding ether, yellow needles are obtained, Ep = 95-97 °.
Analysis calculated for C ₁₄ H ₁ QNO ₂ • picrate • 3/4 H ₂ O;

C, 5.0.5; H, 5.0; N ,. 11.8% found s C, 50.2; H, 4.7; N, 12.1 #.

Example 37

3-methyl-5 , 6,7, 8-tetrahydroquinoline-S-th iocarboxamide

To a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (10 g, 0.068 mol) in dry hexane (50 ml) are added dropwise to 50 ml of a 15% strength solution of n-butyllithium in hexane (0.09 mol) with stirring under a nitrogen atmosphere. The 'dark red solution is stirred for 15 minutes at room temperature and then treated with carbon disulfide (10 ml). The resulting pale yellow suspension is poured into water (100 ml),

£ 098 19/1194

2 3 b 2 5 8 b H-123/134 / H4 / H6

the aqueous solution is washed with ether (3 × 100 ml).

The aqueous solution of the lithium salt of 3-methyl-5,6,7,8-tetrahydroquinoline-8-dithiocarboxylic acid is stirred vigorously and methyl iodide (40 ml) is added. The solution is stirred For 2 1/2 hours "at room temperature, extracted with ether (3 χ 75 ml), dry the ethereal solution over anhydrous magnesium sulphate and evaporate. Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-dithiocarboxylate remains as red oil.

The oil is dissolved in methanol previously saturated with ammonia (200 ml) and the solution is left to stand for 16 hours. The solvent is evaporated off, the residue is dissolved in ether (100 ml), the ethereal solution is washed with water and the aqueous layer is discarded. The solution is then extracted with 2N HGl (50 ml) and water (50 ml). The combined extracts are washed with ether and the pH of the solution is adjusted to 9 with saturated sodium carbonate solution. The solution is extracted with ether (3 x 50 ml), the ether solution is dried over anhydrous magnesium sulphate, evaporated and the crude 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (2.5 g) is obtained, Thin layer chromatography on silica gel P254 in ethyl acetate: R _f = 0.4 and in ethanol R ^ = 0.8, identical to authentic material *

Example 38

8-Gyano-5,6.7,8-tetrahydroquinoline

Sjo ^ e-Tetraliydroquinoline-S-carboxamide (2 g) is refluxed and stirred with P ₃ S ₅ (1.4 g) in pyridine (25 ml) for 3 hours. The mixture is evaporated to dryness in a vacuum, then dilute sodium hydroxide is added to the residue and then solid potassium carbonate. The product is taken up in chloroform, the chloroform extract is washed with water and dried over MgSO 4. The dried extract

- 44 409819/1194

IS ¹

is evaporated to dryness and the residue is purified by column chromatography on silica gel with benzene / ethyl acetate (4: 1) as the eluent. The nitrile is dissolved in ethanol / ether and ethereal HCl is added. The solution is evaporated to dryness and the hydrochloride of the compound mentioned in the title is obtained as 1/4 hydrate, 800 mg, Pp = 185 ^° G (with decomposition).
Analysis calculated for C ₁₀ H ₁₀ W ₂ HCl · 1/4 H ₂ O:

C, 60.5; H, 5.8; N, 14, wk Found: C, 60.8; H, 5.7; N, $ 14.0.

B e i --S ρ i e 1 39

3-methyl-5,6 ₁ 7, S-tetrahydro-S-carboxylic acid.

Methyl ^ .o ^ S-tetrahydroquinoline-S-carboxylate (5 g) is treated with 10 $ NaOH (40 ml) and refluxed for 1 1/2 hours. The cooled reaction mixture is extracted with ether, the aqueous layer is acidified to pH 7 with acetic acid, filtered and evaporated to dryness under reduced pressure. The residue is triturated with benzene. The benzene solution is filtered, evaporated under reduced pressure and the residue is triturated with ether, the sodium salt of the compound named in the title being obtained as a white powder, 1.8 g;
Analysis calculated for C-,., H ₁₂ NO ₂ Na 1/2 HgO:

C, 59.6; H, 5.8; N, $ 6.4 Found: C, 60.0; H, 5.6; N, $ 6.4. The pKa values are 3.42 and 6.72. .

A further 1.4 g of sodium salt are obtained by further extraction of the benzene-insoluble material.

Example 40 . ■ '".

8-cyano-3-methyl-5,6,7,8-tetrahydroquinoline

One treats S-

(3.6 g) in pyridine (54 ml) with P ₃ S ₅ (7.56 g), and heat the

- 45 409 8 19/1 19A

"Mixture at reflux for 3 hours with stirring. The solvent is removed under reduced pressure, the residue is cooled in ice water and then made basic with 10% NaOH. The basic solution is extracted with chloroform (three times) and the combined extracts are washed with 2N HCl The combined acidic extracts are basified with solid sodium carbonate and extracted with chloroform (three times) The combined chloroform extracts are washed with brine, dried (MgSO.), evaporated to give the title compound, 1.7 g. This compound is converted into the hydrochloride by dissolving in ether and adding ethereal HCl. An oily residue is formed from which the supernatant liquid is decanted. The residue is triturated twice with dry ether and the remaining powder substance is recrystallized from isopropyl alcohol, this gives the hydrochloride of the Ve mentioned in the heading rbindung, mp 189 ⁰ C. Analysis calculated ₁₁ H ₁₂ N ₂ · HCl C:

C, 63.30; H, 6.28; N, 13.43% Found: C, 63.08; H, 6.26; N, 13.34%

The following examples illustrate the invention pharmaceutical compositions.

Example A. Suspension% w / v

Aluminum hydroxide gel BP 5% Al ₃ O ₅
Magnesia Magma 12% w / v MgO

5,6,7,8-tetrahydroquinoline-e-thiocarboxamide 2.0%

Glycerin B.P. 3.0%

Alcohol 60 O.P. * 0.08%

Peppermint Oil B.P. 0.015%

Saccharin Sodium B.P. 0.01%

Methyl p-hydroxybenzoate sodium salt 0.1%

- 46 Λ098 1 9/1 194

% W / v 02% ο, 01 ο, 00% 100,

., - ν -...- - ■ "; ■ 23b2-58b h-i23 / 134/144/146

suspension

Propyl p-hydroxybenzoate sodium salt Butyl p-hydroxybenzoate sodium salt Water ad '■ ■ ■

* O.P. means "over percent". 60 O.P. means 91% w / v. Ethanol / water.

The above suspension is prepared according to the following procedure. Magnesia and then magma are added to the aluminum gel the '5,6,7 jS-tetrahydroquinoline-S-thiocarboxamide, dispersed in glycerine, the peppermint oil is added dissolved in alcohol, the sodium saccharin dissolved in water and the p-hydroxybenzoates are also dissolved in water. With water becomes the volume is replenished and the mixture is stirred well. Dose: 5 ml-t.d.s. . . -

Example B. Antacid Tablet (Chewable) mg

Saccharin 1.0

It hydrates aluminum oxide sucrose powder »- 750.0

5,6,7,8-tetrahydroquinoline-8-thiocarboxamicf 100.0

Mannitol B.P. * 170.0

Corn starch B.P., dried 30.0

Talc, purified, B.P. 28.0 '

Magnesium stearate B.P. 20.0

Peppermint Oil BP 1.0

'1080.0

Antacid tablets of the above formulation are made up of the following Made wisely: rub peppermint oil with talc (light Mesh size of the sieve = 0.42 mm; 40 mesh). Give the rubbed Mixture and other ingredients in a blender and mix thoroughly. The powder turns into large, hard pellets processed, the shot grains are passed through a sieve '

- 47 Α098Ί9 / 1,194

granulated with a mesh size of 1.4 mm (H mesh), the granulate is compressed into tablets of the required size on a suitable compression device.

Example C Anti-ulcer tablets (without antacids) mg / tablet

5,6,7,8-Tetrahydroquinoline-8-thiocarboxamide 100.0 mg

Gelutab H7.5 mg

Magnesium stearate 2.3 mg

250.0 mg

The tablets are made in the following way: Mix the ingredients in a suitable mixer and compress the mixed ingredients on a suitable press to tablets with the above composition.

Celutab is a technical product containing 90 - o 2 ° / dextrose, 3 - $ 5 contains maltose and higher as the remainder Glucosesaccharide; spray crystallized.

Example D

A suspension is prepared as in Example A, but 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide is replaced by 3-methyl-5,6,7,8-tetrahydroquinoline-S-thiocarboxamide.

Example E.

An antacid tablet is produced according to Example B, but 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide is replaced by 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide.

Example F

A tablet against ulcers according to Example C is produced, replaced however S ^ ö ^ fS-tetrahydroquinoline-e-thiocarboxamide through 3-methyl-5,6,7, e-tetrahydroquinoline-e-thiocarboxamide.

- 48 -0 9.8 1 9 / Ί 1 94

Claims (1)

PATENT CLAIMS 1. Pyridine derivatives of the general formula Ii (D R ¹ and their acid addition salts, where in the above formula 12 6 "'"
R, R and R, which are identical or different, denote hydrogen, trifluoromethyl or an alkyl, aralkyl or aryl radical and each of the radicals can be substituted by alkyl, alkoxy, halogen, nitro or trifluoromethyl or 1 2 · ' R and R together represent an alkylene chain -CH ₂ (CH ₂ ) CH ₂ -, wherein η is 1, 2 or 3,. . R represents a single or multiple substitution by hydrogen or alkyl, aralkyl or aryl, each of the Radicals by alkyl, alkoxy, halogen, nitro or trifluoromethyl • '12 may be substituted and when R and R are taken together form an alkylene chain, the resulting ring can be replaced by a 7 ° or more R 'radicals, as defined above, be substituted, - 49 -40 9 8 1 9/119 4 23b? 58 b H-123/134/144/146 SO X stands for cyano, CONR ⁵ R ⁴ ", CSNR ⁵ R ⁴ or CO ₉ R ⁵ , in which R ⁵ , R ⁴ and R stand for hydrogen or alkyl, aralkyl or aryl radicals and each of these radicals by alkyl, alkoxy, halogen , Nitro or trifluoromethyl can be substituted and 1 2 m stands for 1, 2 or 3, where when R and R together represent an alkylene chain, "n" is "m", as well as the Metal salts of the compounds in which R ^ is hydrogen. 6 7 2. Compounds according to claim 1, in which R and R Represent hydrogen. 1 2 3. Compounds according to claim 2, in which R and R represent hydrogen and lower alkyl. 1 2 4. Compounds according to claim 3, in which R and R stand for hydrogen and methyl. 1 2 5. Compounds according to claim 3, in which R and R represent hydrogen and t-butyl. 12th 6. Compounds according to claim 2, in which R and R stand for hydrogen and phenyl. 7. Compounds according to any one of claims 2 to 6, at where η stands for 2. 1 2 8. Compounds according to claim 2, in which R and R together form an alkylene chain -CH ₂ (CH ₂ ) -CHg- and η and m each represent the number 2. 9. Compounds according to any one of claims 2 to 8, at where X stands for cyano. 10. Compounds according to any one of claims 2 to 8, in which X is CONR ⁵ R ⁴ ", in which R and R ^{4 are} hydrogen and methyl. - 50 409819/1194 23 b 2 5 8 b H-125/134 / H4 / 146 11. Compounds according to any one of claims 2 to 8, at
where X is C SNR V, where R ⁵ and R ^{4 are} hydrogen and
Represent methyl. _ 12. Compounds according to any one of claims 2 to 8, at which X represents. where X is CO ₂ R ^, where R is hydrogen and methyl 13. Compounds according to claim 1, in which R is a or several lower alkyl groups. 14. Compounds according to claim 13, wherein R is a or more methyl groups. 15. Compounds according to claim 14, in which R is a gem. Represents dimethyl group. 16. 2-phenyl-5,6,7, e-tetrahydroquinoline-e-thiocarboxamide. 17. 5, o ^ jS-Tetrahydroquinoline-e-thiocarboxamide (with the following NMR spectrum in dgDMSO (100MHz)). cfi, 5 - 2.3 wide multiplet 4 "protons CH ₂ -6 and 7 cf2.7 multiplet cf4.15 triplet (J = 7Hz) cf7.08 quartet ei 7.44 - Quartet 6 8.29 quartet f / 9.25 and 9.45 wide doublet Coupling constants: J ₂ , = 5Hz, J ₂₄ = 1.5Hz, J ,, = 8Hz. 18. 2-t-Butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide. 19. 2-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide. 20. 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide. - 51 -. AOa-ö'i 9 / Ί Ί 94 2 Protons CH ₂ -5 1 proton CH-8 1 proton . H-3 1 proton H-4 1 proton H-2 2 Protons NH ₂ 21. 3-methyl-5,6,7,8-tetrahydroquinoline-8- (N-methyl) - 22. · 5-Methyl-5,6,7,8-tetraixydrocliinolin-8- (E, N-dimethyl) -thi oc arboxamid. 25. Sym.-Octahydroacridine-2-thiocarboxamide. 24. 8-Cyano-2-phenyl-5,6,7,8-tetrahydroquinoline. 25. 2-methyl-8-cyano-5,6,7,8-tetrahydroquinoline. 26. 5-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline. 27. Acid addition salts of the compounds of claims 6 to 26. 28. 2-Phenyl-5,6,7,8-tetraliydroquinoline-e-carboxylic acid. 29. Methyl 2-phenyl-5,6,7,8-tetrahydroquinoline-S-carboxylate. 30th 31. Methyl 2-t-'butyl-5,6,7,8-tetrahydroquinoline-8-carboxylate. 32. Methyl 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate. 35. Methyl syin.-octahydroacridine-2-carboxylate. 34. 2-phenyl-5,6,7,8-tetrahydroquinoline-e-carboxamide. 35. N, N-dimethyl-2-phenyl-5,6,7, e-tetrahydroquinoline-e carboxamide. - 52 409819/1194 36. 5,6,7,8-tetrahydroquinoline-8-carboxamide. 37. 2-t-Butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide. 38. 2-methyl-5,6,7,8-tetrahydroquinoline-S-carboxamide. 39. 3-Methyi-5,6,7,8-tetrahydroquinoline-8-carboxamide. 40. 3-methyl-5,6,7,8-tetrahydrocholine-8- (N-methyl) -carboxamide. . 41. Sym.-Oc-tahydroacridine-2-oar'boxamide. \ ■ 42. Acid addition salts of the compounds of the claims 28 to 41. - 43. A process for the preparation of a compound according to claim 1, wherein X is CSNR ⁵ R ⁴ ", where R ³ and R ^{4- have} the meanings given in claim 1, characterized in that a corresponding nitrile of the formula I, wherein X is CN, is converted into the thioamide in a manner known per se. 44. The method according to claim 43, characterized in that "the compound in which X is cyano is treated with HpS, if desired in the presence of an amine of the formula R RTiH, wherein at least one of the radicals R and R has a" meaning other than Has hydrogen, or with a compound of the formula R CSNH ₂ , in which R ^{9 is} an alkyl group. 45. The method according to claim 43, characterized in that that a compound is used as the starting material the R and R 'mean hydrogen. - 53 Λ09819 / 119Λ 46. The method according to claim 45, characterized in that that a compound is used as the starting material 1 2 R and R have the meanings given in claims 3 to 8. 47. A process for the preparation of a thioamide of the formula I according to claim 1, wherein X stands for CSNR IT and R and R ^ have the meanings given in claim 1, characterized in that a corresponding amide in which X stands for CONR R with P _O S _{C is} treated. 48. The method according to claim 47, characterized in that a compound is used as the starting material 6 7
the R and R represent hydrogen. 49. The method according to claim 48, characterized in that that a compound is used as the starting material 1 2 R and R have the meanings given in claims 3 to 8 to have. 50. The method according to claim 48 or 49, characterized in that an amide is used in which X stands for CONH ₂ and the 2 ₂ ^S 5 reaction is carried out in the presence of HgS. 51. Process for the preparation of compounds of the formula I according to claim 1, in which X is CSNR R, in which 3 4
at least one of the radicals R and R has a meaning other than hydrogen, characterized in that a corresponding compound in which X is CSNHr, with an amin of the formula RR NH, in which R and R have the meanings given above, is present is treated by HpS. 52. The method according to claim 51, characterized in that that a mono- or dialkylamine is used as the amine. , - 54 409819 / 1T94 53. The method according to claim 52, characterized in that that methylamine or dimethylamine is used as the amine. 54. Process for the preparation of compounds of the formula I according to claim 1, in which X stands for cyano, characterized in that a corresponding compound of the formula I, in which X stands for CONH _2, is dehydrated. 55. The method according to claim 54, characterized in that the dehydration with phosphorus pentoxide, phosphorus pentachloride or thionyl chloride is carried out. 56. The method according to claim 54, characterized in that that the dehydration is carried out with phosphorus pentasulphide 57. The method according to any one of claims 54 "to 56, characterized in that a compound is used as the starting material is used in which R and R are hydrogen. ' 58. The method according to claim 57, characterized in that that a compound is used as the starting material 1 2 R and R have the meanings given in claims 3 to 8. 59. A process for the preparation of amides of the formula I according to claim 1, in which X is CONR ⁵ R ^ and R ⁵ and R ^ have the meanings given in claim 1, characterized in that a corresponding compound in which X is CO ₂ R and R has the meanings mentioned in claim 1, except "hydrogen, is ^{treated with ammonia, a primary amine of the formula R 5} NH ₂ or a compound of the formula I in which X is COCl, with ammonia, a primary amine R ⁵ NH or a secondary amine of the formula R ⁵ R ⁴ NH and, if desired, a product in which X is CONH « - 55 4098 1 9/11 94 is then alkylated to form the groups R and / or R to introduce. 60. The method according to claim 59, characterized in that a compound is used as the starting material, "at 6 7 the R and R 'mean hydrogen ". 61. The method according to claim 60, characterized in that a compound is used as the starting material in which R ¹ and R ²
have services. 1 2 the R and R the meaning mentioned in claims 3 to 8 62. A process for the preparation of amides of the formula I according to claim 1, in which X is CONHR ^, where R ^ is hydrogen or alkyl, characterized in that an ester of the formula I according to claim 1, in which X is GO ₂ R ^ stands ^ ⁵ and R ^ is alkyl, with an amide of the formula R ^ CONHR- ⁵ or a salt thereof, where R is hydrogen or alkyl and R represents hydrogen or lower alkyl, in the presence an alkali metal alcoholate is treated. 63. The method according to claim 62, characterized in that 6 7 that a starting material is used in which R and R ' Means hydrogen. 64. The method according to claim 63, characterized in that 1 ? that a starting material is used in which R and R have the meanings given in claims 3 to 8. 65. A process for the preparation of compounds according to claim 1, in which X is CO ₂ R ^, where R ^ has the meanings given in claim 1, or of a metal salt of a compound in which R is hydrogen, characterized in that a compound of the formula I according to claim 1, in which X is hydrogen, with a metal ^{alkyl compound MR °, where R 10 is} alkyl, aryl or aralkyl - 56 Λ 0 "9 8 1 9/1 1 9A and M is sodium, potassium or lithium, or with one
Metal alkyl compound M (R) ₂ , in which M is calcium or magnesium, is treated, the product is treated with carbon dioxide and, if desired, the product is acidified or esterified. 66. The method according to claim 65, characterized in that an output
mean substance. that a starting material is used in which R and R water 67. The method according to claim 66, characterized in that 1 2 that a starting material is used in which R and R have the meanings given in claims 3 to 8. 68. The method according to claim 66 or 67, characterized in that that lithium phenyl is used as the metal alkyl. 69. The method according to claim 66 or 67, characterized in that that η-butyllithium is used as the metal alkyl. 70. The method according to any one of claims 66 to 69, characterized in that the methyl ester is produced. 71. A process for the preparation of compounds of the formula I according to claim 1, in which X stands for CO ₂ H, characterized in that a compound of the formula: 125 7 wherein R, R, R and R and m have the meanings given in claim 1 have, is decarboxylated. - 57 -40 9 8 1 9/119 72. The method according to claim 71, characterized in that 6 7. that R and R. ' Hydrogen "mean. 73. The method according to claim 72, characterized in that R ¹ and R ²
have services. 1-2 that R and R have the meaning mentioned in claims 3 to 8 74. The method according to claim 65, characterized in that after the treatment with carbon dioxide, the product with a another amount of metal alkyl and then another amount of carbon dioxide is treated. 75. The method according to claim 74, characterized in that one of the starting compounds defined in claims 66 to 70 or metal alkyl compounds is used. 76. · Process for the preparation of compounds according to claim 1, in which X stands for GOpR, where R in claim 1 has the meanings mentioned, or of a metal salt of a compound, in which R represents hydrogen, characterized in that a compound of the formula I according to Claim 1, in which 10 X is hydrogen, with a metal alkyl compound MR, in which R is alkyl, aryl or aralkyl and M is sodium, Potassium or lithium, or with a metal alkyl compound M (R) p, in which M is calcium or magnesium 5, the product with a halogen formate of the formula HaICOOR, 5 in which Hal denotes a halogen atom and R has the abovementioned meanings, except hydrogen, is treated and, if desired, the product is saponified with an alkali or alkaline earth metal hydroxide to give a corresponding metal salt of the acid of the formula I, in which X is CO ₂ H, and if this metal salt is desired to be acidified to the corresponding acid. ' 77. The method according to claim 76, characterized in that an output measure
mean hydrogen. 6 7 that a starting material is used in which R and R 'water - 58 - 409819/1194 23b2 58 b H-123/134 / H4 / H6 78. The method according to claim 77, characterized in that 1 2 that a starting material is used "in which R and R have the meanings given in claims 3 "to 8. 79. The method according to any one of claims 76 "to 78, characterized characterized in that after the treatment with the haloformate, the product with a further amount of metal alkyl and then with another amount of hemogenous formate is treated. 80. Process for the preparation of a thioamide according to a XA 7 A of claims 1 to 8, wherein X stands for CSNR ^ R ^ and R- ^ and R have the meanings mentioned earlier, characterized in that a thioester of the formula I in which X stands for CSSR ⁵ and R ^ is alkyl or aralkyl , with a compound of the formula R RTTH, in which R ^ and R have the meanings given earlier, is treated. 81., The method according to claim 80, characterized in that the thioester is obtained by treating a compound of the formula I in which X is hydrogen with a metal alkyl compound MR in which R is alkyl, aryl or aralkyl and M is sodium, potassium or lithium, or with a metal _{alkyl compound M. (R) 2} , in which M is calcium or magnesium, and then the product is prepared with carbon disulfide and then with an alkyl or aralkyl halide R ⁵ Hal, in which R is an alkyl or aralkyl group and Hai is chlorine , Bromine or iodine is treated. 82. Process for the preparation of a compound of formula I. according to claim 1, wherein X is CO ₀ R ⁵ , CONR ⁵ R ^ or CSNRV, "• 5 A κ wherein R ^ and R are as defined in claim 1 ,. R -alkyl, aryl or aralkyl and a group R; which has a different meaning has as hydrogen on the carbon atom to which the radical X is bonded, characterized in that one Compound of the formula: - 59 Α098Ί 9/1194 GO , 6 235258 5 η-125/134/144/146 wherein R ¹ , R ² and R are as defined in claim 1, R 'in the vicinity of X has the meanings given in claim 1, 7 besides hydrogen, the other radical R as in claim 1 is defined and X has the meanings given above, is treated with hydroxylamine. . 83. A process for the preparation of an amide of the formula I according to claim 1, in which X is CONMe ₂ , characterized in that a corresponding compound in which X is CONH ₂ is heated with hexamethylphosphoric triamide. 84. The method according to claim 83, characterized in that a starting material according to one of claims 2 to 8 is used. 85. 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide oxalate or tartrate. 86. 3-methyl-5,6,7, e-tetrahydroquinoline-S-thiocarboxamide according to example 26. 87. 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide according to example 27. 88. 8 ~ Cyano-5,6,7,8-tetrahydroquinoline. 89. 3-methyl-5,6,7, S-tetrahydroquinoline-e-carboxylic acid or a metal salt thereof. - 60 409819/1 1 9 90. A pharmaceutical composition containing a compound of the formula I according to claim 1 or a salt thereof, wherein X stands for GSNR R and R ^ and R as defined in claim 1 1 2 6 are or X is cyano and one of the radicals R, R, R and R 'has a meaning other than H and a pharmaceutically acceptable carrier. 91. A pharmaceutical agent according to claim 90 in torrn of dose units. 92. A pharmaceutical agent according to claim 90 or 91 containing an antacid component. 93. "Pharmaceutical agent according to one of the claims 90 to 92 containing as a compound of the formula I a compound according to any one of claims 2 to 9, 11 or 16 to 94. Pharmaceutical agent according to one of claims 90 to 92, containing a compound according to claims 13 to 15 as compound of formula I. - 61 0 9 819/1194