HU180234B - Process for producing oktahydro-pyrasolo-aracket-3,4-g-bracket closed-quinolines - Google Patents

Abstract

The title compds. of formula (XIII) were prepd. by reacting compds. of formula (XII) with pyridine hydrochloric acid salts and chromium trioxides. In the formulas, R is C1-3 alkyl, alkyl, or benzyl, and Z' is C1-2 alkyl or phenyl-substd. C1-2 alkyl. C1-3 alkyl includes n- propyl and iso-propyl, and C1-2 alkyl includes methyl and ethyl.

Description

Process for the preparation of octahydropyrazolo [3,4-g] quinolines

The present invention relates to a process for the preparation of octahedropyrrolo [4,4] quinolines of the formulas Ia and 1b, respectively, and pharmaceutically acceptable salts thereof, wherein R is a C 1-3 alkyl group or an allyl group and ^E 1 is a hydrogen atom or a -CH 8 SHCH 3 group.

According to the invention there is provided a compound of formula VIIIa wherein

R is hydrogen, cyano, (C 1 -C 3) alkyl or allyl;

R ^{1 is} hydrogen or -C-O (C 1-2) -alkyl

The hydrate is reacted with z, acetic acid and the resulting compound, wherein R is hydrogen, is reacted with an alkyl or allyl halide or subjected to reductive alkylation with an appropriate aldehyde and metal hydride.

followed by reaction of the resulting compound, wherein R ^x is other than hydrogen, with a metal hydride, wherein the intermediate thus obtained, wherein R 1 is -OHHOH, is preferably reacted with a nucleophilic reagent with tosyl chloride, C 1-3 alkylsulfonyl chloride, phosphorus trichloride, phosphorus trichloride and reacting the thus obtained as intermediates where RI site -CHgCl group CII2 Br group -GII ₂ -0S0 ₂ -phenyl, -CH ₂ ~ 0 tozlLesöpört or -Cil 0o0 ^ ₂ / 1-3 carbon atoms / alkyl reacted νεη, methylmercaptan sodium salts to form compounds of formula Ia and Ib in which _'R-CH? SCII. '

The compounds of the formulas Ia and Ib and their pharmaceutically acceptable salts exhibit therapeutic activity, in particular for use as a dopamyl agonist.

In the formulas, "C 1-2 alkyl" includes methyl and ethyl, and C 1-3 alkyl even includes n-propyl and isopropyl.

Pharmaceutically acceptable acid addition salts of compounds of Formulas Ia-Ib include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid and the like, and the like. lots of mono- and dicarboxylic acids, phenyl / substituted / alkanoic acids, hydroxyalkanoic acids and alkanedioic acids * aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogensulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, plophosphate, chloride, bromide, bromide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, phoxmate, isobutixate, capronate, heptanoate, propiolate. oxalate. malonate, succinate, suberate, sebacate, fumarate, maleat. mandelate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, cloxobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, texephalate, benzenesulfonate, toluenesulfonate , chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, Α-hydroxybutyrate, glycolate, maleinate, tartrate, methanesulfonate * propanesulfonate, , naphthalene-2-sulfonate and the like.

The compounds of formula Ia are systematically named 4,4a, 5,6 *, 8,8a, 9-octahydro-1H-pyrazolo [3,4- b] quinolines and the compounds of formula Ib are 4 * 4a, 5,6, 7,8,8a, 9-oktahidxo-2H-pyrazolo 4-gJkiholinok. These two structures represent a tautomeric pair and the tautemers represented by the structures are in dynamic equilibrium. In addition, the compounds of the formulas Ia and Ib wherein R ^{1 is} hydrogen have two chiral centers at the carbon atoms 8a and 4a at the ring attachment. Thus, the compounds may exist in the form of two racemates, commonly referred to as trans-rd1-racemate and cis-d1-racemate. However, based on the IJq MMR spectra, it is assumed that during the reduction of the oligoborohydride, when hydrogen is introduced into the quinolln bridgehead, this step results in transiently linked decahydroquinoline, one step in the synthetic preparation of the compounds la and Ib. While the arguments based on MMR spectra data to support the trans configuration must be accepted, X-ray crystallography

-2180234 was also determined for a crystalline enamon (compound VIIIa) of the decahydroquinoline series R5. This X-ray analysis clearly shows that ring coupling at the quinolln radical is trans. Further operations on the decahydroquinoline molecule to condense the plrozole ring do not change the configuration of the bridgehead hydrogen atoms. Thus, only the trans racemate is prepared by the following synthetic procedures, and the compounds of formulas Ia and Ib are preferably depicted as trans-d1-satereolomexes. The two trans stereoisomers of the 2H tautomer can be represented by the formulas IIa and IIb. Λ If and Ilb represent my pair. Similar pairs of rays can be set up on the 1H tautomer (formulas IIc and IId).

These cancers can be resolved into their optical antipodes by known methods, and some of the trans-d and trans-1 isomers are also within the scope of the invention.

In addition, when iA is other than hydrogen, a third chiral center is introduced at the 7-position carbon. However, it is believed that the configuration at the carbon atom is primarily / ¾ relative to the position 8a hydrogen as in the formula Ha. In the image compound of the formula IIb, the R 10 is at the α-position of the a-position 8a hydrogen, so that the transd 17-substituted octahydropyrazolo-4,4-g 7 quinolines of the formulas Ia and Ib are obtained essentially as a single racemate or diastereoisomeric pair.

In the case of the compounds of the present invention, the names of one compound also include the other teutons, since the two teutons are always in equilibrium with each other. In many tautomeric mixtures, the 2H tautomer appears to be predominant. In addition, neither the orientation of the substituents nor the configuration of the hydrogen atoms 4a and 8a are given, but it will be appreciated that the hydrogen atoms are in trans position relative to one another and that the substituent at position 7 is in trans position with respect to hydrogen 8a; that is, when the hydrogen atom 8a has an o-configurational bond, the 7-substituent and when the 8a hydrogen atom is the 7-substituent oC configuration.

The compounds of the formulas Ia and Ib in which R 1 is hydrogen are prepared by the reaction sequence A /. In the drawing, for the sake of simplicity, only one of the stereoisomeric forms of the racemic pair, 4aA, SaoCisomer, is depicted, however, it should be recalled that each of them is a decahydroquinoline and octahydropyrazolo, 4-g / quinoline racemate.

In the reaction sequence in the drawing, Z-CO represents an acyl protecting group wherein Z is a C 1-3 alkyl group,

Represents a C 2 -C 3 alkenyl group, a C 2 -C 3 alkynyl group, a C 5 -C 6 cycloalkyl group, a phenyl group or a substituted phenyl group where the substituent may be methyl _λ methoxy, chlorine or the like and may occupy any position on the phenyl ring. Thus, the Z-CO group may be, for example, acetyl, proponyl, butyryl, propioloyl, acryloyl, benzoyl, ρ-toluyl, ο-chlorobenzene, m-methoxybenzoyl, etc.

Z is C 1 -C 8 alkyl, C 5 -C 6 cycloalkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl

-3180234 port. According to Scheme A, Jones, E.R.H. and Sondheimer, F. prepared / J.Chem.Soc., 615 · / 1549 · //

4-Acylloxylcyclohexanone, such as 4-benzolloxycyclohexanone, is reacted with pyrrolidine in the presence of an acidic catalyst to give pyrrolidine-enamine. This enamyl is reacted with acrylamide to give dl-6-acyloxl-3,4,5 of formula III.

A mixture of 6,7,8-hexahydro-2-1 / 11 / quinolinone and dl-6-acylloxy-3,4,4a, 5,6,7hexahydx-2/11 / quinolinone is obtained, wherein the dashed line is indicates possible bonding positions.

Subsequently, the acidic nitrogen atom (which is acidic because it is in the o-position relative to the carbonyl group) is alkylated with an alkyl halide of the formula RX wherein R is as defined above and X is a halogen such as chlorine, bromine or iodine. In this way, the dl-1- (C 1-3) -alkyl- or benzyl- (6-acyloxy-3,4,5,6,7,8-hexahydro-2 / III) -carboxy-1- (C 1 -C 3) -alkyl- a mixture of quinollnone θ ³ Δ isomers is obtained. This amide is reduced by the addition of lithium aluminum hydride or other suitable organic metal reducing agent to the d1-l- (1-3C) alkyl-or-allyl or benzene of formula V- 11-6-hydroxy-1,2,3,4 the mixture of isomers is obtained 5,6,7,8-octahydro-quinoline and Δ ^0th In this reaction mixture, there are conditions which convert the acyloxy group at the 6-position to the hydroxy group by hydrogenolysis. This is then followed by the dl-1- (1-3-carbon) -alkyl- or -al-

111- or benzyl- (6-hydroxy-octahydro-quinol) is converted to the hydrochloride by treatment with int-hydrochloric acid, and the hydrochloride is then reduced with sodium cyanoborohydride to form a trans-d1-C 1-3 alkyl-alkyl of formula VI or allyl or benzyl N-6-hydroxydecahydroquinoline is obtained. Subsequently, the trans -dl-1- (C1-C3) -alkyl- or allyl- or -6-hydroxydecahydroquinoline of formula VI is converted to the corresponding 6-oxo compound of formula VII. is oxidized, preferably with chromium dioxide in acetic acid. This 6-oxo compound of formula VII is reacted with an acetate, preferably dimethylformamide dimethyl acetate, to give the 7-dimethylaminomethylene-6-oxo-3 derivative of formula VIII. This derivative is reacted with hydrazine hydrate to prepare a tautomeric mixture of the tricyclic derivative, which is predominantly a trans -dl-5- (C1-C3) -alkyl or allyl or benzyl-4,4a, 5 6,7,8,8a, 9-octahydro-2H-pyrazolo [4], 4-g7quinoline and, to a lesser extent, the 1H tautomer of formula IXa.

In the above reaction sequence, it is evident from the dltrans-1- (substituted) -6-keto-decahydroquinoline of Formula VII that the reaction with dimethylformamide dimethylacetate can take place at both the 5- and 7-carbon atoms, since both carbon atoms relative to the ketone (at the X-position and thus accessible to the reaction.) The X-ray crystallographic analysis of the enamine of Formula VIII discussed above clearly showed that the reaction was not

5-position. but takes place on carbon 7-position. so the

The tricyclic end products of formulas IX and IXa are not angular tricyclic compounds (which should be referred to as 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolyl, 3-yquinolines), but linear pyrazolyl, 4 gjkinollnok. .

Compounds in which R ^{x is} other than hydrogen may be prepared in a manner known per se from Scheme B / B, which is slightly different.

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As in Scheme Λ, the process is illustrated with reference to the stereochemistry of the bridgehead only with the single stereoisomer, 4afy, 8atf. '

In the formulas, Z and Z 'represent Hal, chlorine or bromine, as defined above in connection with Scheme A, and Z * is part of an easy-to-bridge Z'O-CO- group, such as C 1-2 alkyl or phenyl. a substituted (C 1 -C 2) alkyl moiety such as benzyl, phenethyl, p-methoxybenzyl, methyl or ethyl.

In Scheme B, an X is reacted with 4-acylloxycyclohexanone with a © (-halo-ethyl) acrylate ester, illustrated with an ethyl ester and an amine of formula KHIg, wherein R 1 is a C 1 -C 4 alkyl, allyl or benzyl group. Dl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,3,

A mixture of 4,5,6,7,8-octahydroquinoline and 11-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,4a, 5,6,7-octahydroquinoline; in the formula, the dashed line indicates possible positions of the double bonds. The hydrochlorides of these isomers are prepared and the resulting mixture is reduced with sodium cyanoborohydride to give the trans dl-1-substituted-3-ethoxycarbonyl-6-acyloxy-decahydroquinoline of formula XI. This dlester is hydrolyzed to a 6-hydroxy-3-carboxylic acid, and the carboxylic acid group is re-esterified with ethanol or another appropriate alcohol in the presence of an acid to give a trans-dl-1-substituted-3-ethoxycarbonyl-6-hydroxy XII intermediate. -d.ekahiuro-clnolln is obtained. The hydroxyl group is oxidized with Sarett's reagent (plridine hydrochloride and chromium trioxide) to give the new 6-oxo intermediate of general formula XIII. This 6-oxo derivative is treated with dimethylformamldaoaletal, preferably dmmotylformamyldimethyloaletal, whereupon the 7-position is adjacent to the keto group / carbon atom, and the trans-dl-1-substituent XIV is added as a new intermediate. etoxy lyses bonyl 6-oxo-7 / dimethylaminomethylene / decahydroxoquinoline. This derivative was reacted similarly to the A / hidrazinhldráttal reaction variants, such as the trans-dl-5-ethoxycarbonyl-7-helyettcsiteót ^7! A mixture of 4a, 5,6,7, α 8a, 9-octahydro-1H-pixazolo [3,4-g] quinoline and 216 tanomeres is obtained, which is represented in the drawing by the single stereoisomer of formula XV. The compound may be isolated and purified as the free base or as the dihydrochloride prepared in known manner.

In Scheme A, the dimethylformamide acetals used in the preparation of compounds of Formula VIII and Scheme B, for the preparation of the compounds of Formula XIV correspond to the formula: -CH2- / ₂ ir-CH- / O-Z / ₂ , wherein Z 'is 1-8. C 1-4 alkyl, C 3-8 cycloalkyl, C 3-4 alkenyl, C 3-4 alkynyl. Preferably, the acetals of dimethyllioxymamide are available in the form of acetal, i.e., dimethyl, diethyl, diisopxopyl, dibutyl, dicyclohexyl, propyl or benzopentyl acetate.

Λ In formula XV, R is an alkyl, allyl or benzyl group having 1 to 3 carbon atoms. The octahydropyrazolo XV of Formula XV represents a single tautomer, 5.4 µg of the quinoline, and only one of the dense stereoisomers.

-5180234

A mirror image of compound XV is also prepared. By analogy to D-ergolines, it is believed that the diastereoisomer of Formula XV is a dopamine agonist. The trans-dl racemate containing the compound of formula XV and its mirror image is, of course, a valuable dopamine agonist, although most of the desired effect is shown by one of the stereoisomers.

The intermediates in Schemes A and B correspond to the formulas XII, XIII and XIV, wherein R is a C13 alkyl group, an allyl group or R is a benzyl group and R1 is a -COOZ2 group wherein Z * 1-2 C 1 -C 4 alkyl or phenyl-substituted C 1 -C 2 -alkyl. They are prepared as described in Schemes A and B.

Compounds of formula XV wherein R is ethyl, allyl or n-propyl can be prepared by two different methods. In the first method, the amine of formula RKHp used to prepare the compound of formula X may be ethyl, n-propyl or allylamine, so that the group is introduced directly. Alternatively, a compound of Formula XV wherein R is methyl or benzyl can be converted to a compound wherein R is hydrogen by removal of the methyl or benzyl group with bxomyclane. The intermediate 5-cyano derivative (R is olanoic) can be subjected to reductive cleavage (zinc and acetic acid) to give a compound wherein R is hydrogen. In addition, the benzylic bristles may be removed by hydrogenation with palladium-on-carbon to give intermediates in which R is hydrogen. The secondary amine can be alkylated by reaction with an alkyl halide of formula RC1, RBr or RJ. Alternatively, the secondary amine group may be reacted with an aldehyde such as acetaldehyde, acrolein or proplonaldehyde under reducing conditions with a metal hydride such as sodium cyanoborohydride such as N-ethyl, N-allyl or N-propyl.

The dopamine agonist compounds of formulas Ia and Ib, wherein R1 is -GHpSCH2-, are prepared from the compounds of formula XV using the procedure outlined in Scheme 0 /.

In formula XVII, Y is a leaving group, i.e., chlorine, bromine, -OSC1-phenyl, -O-tosyl or -SOg (C 1 -C 10) -alkyl, R 2 is hydrogen, -SOpphenyl, toyl or -SO 2 _? C 1 -C 3 -alkyl and in formula XVIII X is -CN, -SCH 3, -OCH 3 or a group.

As depicted above, only one tautomer, the 2H tautomer, is depicted in Scheme C /. The 2H tautomer occurs as a racemate and only one diastereoisomer, 4a _? 7 / ^ »8aoC isomer. The mirror image compound is, of course, prepared at a level as it represents half of the starting material of formula XV. Transduced racemates of Formula XVIII are valuable dopamine agonists because they contain the active agonist. The racemates intermediates of Formulas XV, XVI and XVII are valuable because they each contain a diastereoisomer which is chemically

-6180234 dopamtn to throat.

According to Λ C / alkylating a panel z ^ L-5-substituted 1- 'to 1t-4,4a, 5 * 6,7,8, 9-oct AHI Ca _f dr o-2H-1 r olo » ^{2 |} -gjkin O 11 n-7-carboxylate oster is reduced to a pyrazolo [1,4-g] quinol of Formula XVI with a Fe-hydride reducing agent such as lithium aluminum hydride. The so-called 'hydroxyl group is then substituted', i.e., a nucleophilic reagent such as chlorine, bromine and halo-esters, tosylate (generally p-toluenesulfonate), alkylsulfonate, bis (benzenesulfonate), is replaced by an easily displaceable group. Λ chlorine or bromine leaving groups PClj, COClg, ΡΟΙ ^, ΡΟΟΙ ^ I'Br? and similar reagents, and the sulfonate ester groups with the corresponding sulfonyl cloxyl. By reacting the compounds of formula XVII with sodium methylate / methylmercaptan sodium salt or other basic salts of methylmercaptan to give a compound of formula Ia or Ib in which R ^{1 is} -CH 2, -CCH 3. These basic reaction conditions also serve to provide, when present in the pyrazole ring; zulfonyl group, they are hydrolyzed to give tautomeric mixture of formula XVIII (only the 2H tautomer is shown).

The following examples illustrate the process of the invention.

Starting materials

Example A trans-5-cyano-4,4a _? 5,6,7 _? Preparation of 8 · Ca, 9-octahydro-1 H and-2 H 1 -pyrazolo [3,4-g] quinoline g 4-Bonoyloxycyclohexanone, 58 ml pyrrolidine, some p-toluenesulfonic acid monohydroxate crystals and 1000 ml benzene are mixed. The reaction mixture was refluxed for one hour under nitrogen atmosphere in a Dean-Stark water separator. The reaction mixture is then cooled and the volatiles removed in vacuo. The residue of the pyrrolidine enamine formed by the reaction of 4-benzoyloxycyclohexanone is dissolved in 1000 ml of dioxane without further purification and 64 g of acrylamide are added. The reaction mixture was then refluxed under nitrogen for two days, cooled and the volatiles removed by evaporation in vacuo. The reaction mixture was then diluted with ethyl acetate, and the ethyl acetate layer was separated, washed first with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate phase was sealed and the volatiles were removed by vacuum evaporation. The rest of the

2-oxo-6-benzoyloxy-5,4,5,6,7,8-hexahydroquinoline and 2-oxo-

6-Benzoyloxy-5,4,4a, 5,6,7-hexahydroquinoline ₍ a mixture formed during the reaction, is dissolved in chloroform and the chloroform solution is chromatographed on florilsilene with increasing amounts of chloroform containing 0-2% ethanol). The fractions containing 2-oxo-6-benzoyloxy-5,4,5,6,7,8-hexahydro-clnoline and its 2-8 / 8a / isomer by TLC were combined and the solvent removed in vacuo. The residue with hexane

The crystalline mixture of 6-benzolloxy-3,4,5,6,7,8-oxahydro-1H-quinolin-2-one and the corresponding 3,4,4a, 5,6,7-hexahydxo derivative is obtained by crystallization. is obtained. After recrystallization from ether / hexane, the mixture melts at 130-150 ° C.

Analysis results:

Calculated: C 70.83%, H 6.32%, N 5.16%;

Found: C, 71.05; H, 6.19; N, 5.35.

The product isolated as described above was NMR spectra of the product so that the mixture was about 60% 6-benzoyloxyl-3,4,5,6,7.

Contains 8-hexahydroxo-11-quinolin-2-one and 40% 3,4,4a, 5,6,7-hexahydroisornomer.

g of 4-benzoyloxycyclohexanone prepared as above

A mixture of 2-oxo-6-benzoyloxyl-3,4,5,6,7,8-hexahydroquinoline and its δ, 8b / isomer is dissolved in 300 ml of tetrahydrofuran and 300 ml of dimethylformamide without further purification. 14 g of sodium hydroxide are added to give the clnoline sodium salt. After stirring for 20 minutes at room temperature under nitrogen, 55 g of benzyl bromide in 75 ml of tetrahydrofuran are added slowly over 10 minutes. The reaction mixture was stirred for an additional hour at 32-45 ° C and then diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was separated, washed with water and saturated brine and then squeezed. By evaporation of ethyl acetate, 1-benzyl-2-oxo-6-benzolloxy-3,4,5,6,7,8-hexahydroquinoline and 1-benzyl-2-oxo-6-benzoyloxy-3,4,4a A mixture of 5,6,7-hexahydroquinoline is obtained; Yield: 106 g.

106 g of the above mixture are dissolved in 1 liter of tetrahydrofuran and the solution is cooled in an ice-water bath and 40 g of lithium aluminum hydride are added in portions. After the addition was complete, the reaction mixture was refluxed under nitrogen for about 4 hours. The mixture was cooled and the excess lithium aluminum hydroxide decomposed with ethyl acetate. Addition of 10% aqueous sodium hydroxide decomposes the organometallic compounds present in the mixture. The reaction mixture was then diluted with water. The resulting aqueous mixture was extracted several times with chloroform. The chloroform extracts were separated and combined. The combined extracts were washed with a saturated aqueous sodium chloride solution and dried. The residue from the evaporation of chloroform was 1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-benzyl-6-hydroxy-1,2,3,4,4a. , A mixture of 5,6,7-octahydroquinoline. (Both the 2-oxo and 6-benzoyloxy groups react with the 11thium aluminum hydride to form octahydroquinoline, which has a free alcohol group at its 6 carbon atom. The compound complexes thus obtained are dissolved in ether, the ethical solution is cooled and anhydrous hydrochloric acid is added to form the hydrochloride of the clnoline isomers. The quinoline hydrochlorides are insoluble and are separated by decanting the ether. The residual salts were dissolved in a mixture of methanol (100 mL) and tetrahydrofuran (400 mL). The solution is cooled and 30 g of sodium cyanoborohydride are added in portions. After the addition was complete, the histophore was removed and the reaction mixture was removed

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After stirring for 1.25 hours at room temperature, the reaction mixture was poured into a mixture of aqueous hydrochloric acid. The acidic solution is extracted with ether and the ether extract is discarded. The acidic solution is made basic with 10% aqueous sodium hydroxide solution and the basic mixture is extracted several times with a mixture of chloroform-isopropanol. The organic extracts were combined, and the combined extracts were washed with brine and dried. Evaporation of the solvent gave tran-3-dl-1-benzyl-6-hydroxydecahydroquinoline; Yield: 55.0 g. Total yield of six steps based on recovered d-benzolloxycyclohexanone starting anchor 75 7.

g t r an s z-d1-1-b en z11-6 -hydroxide de hydr o k in ο 1 i n t

Methylene chloride (1.5 L) was dissolved in chloride and cooled in an ice-water bath. JOG bromoane was added and the reaction mixture was stirred for 15 hours at room temperature. The mixture was successively washed with n aqueous hydrochloric acid and water and then sprinkled. Evaporation of the solvent gave a residue containing t-trans-dl-1-cyano-6-hydroxydecahydroquinoline. This residue is dissolved in chloroform and the chloroform solution is chromatographed on 500 µl of fluorine isylene, eluting with chloroform containing 0% to 2% methanol. TLC analysis revealed that the fractions containing the desired cyano compound were combined and the solvent removed by vacuum evaporation from the combined fractions. This gives 22.5 g of trans-dl-1-clano-6-hydroxy-decahydroquinoline.

Trans-dl-1-cyano-6-hydroxydecahydroquinoline (22.5 g) was dissolved in 1200 ml of methylene chloride. Pyridine hydrochloride: chromium trioxide (Sarett's) reagent (55 g) was added and the reaction mixture was stirred at room temperature under nitrogen for about 6 hours and then filtered. The filtrate was evaporated in vacuo and the concentrate was chromatographed on 300 g of florisilene. Chloroform containing 1% methanol was used as eluent. The fractions containing TLC containing trans-dl-1-cyano-6-oxo-decahydroquinoline were combined and the combined fractions evaporated to dryness in vacuo. The residue was recrystallized from ether / chloroform to give trans-dl-1-cyano-6-oxo-decahydroquinoline, m.p. 86-88 ° C; yield: 18.9 g.

Analysis: Calculated: · 0 67.59%, H 7.92%, N 15.72%;

Found: C, 67.15; H, 7.75; H, 15.46.

Trans-dl-1-cyano-6-oxo-decahydroquinoline (17.6 g) was dissolved in benzene (200 ml) to which dimethylformamide dimethylacetal (100 g) was added. The reaction mixture was heated under reflux for about 20 hours under nitrogen and then cooled. The solvent was evaporated in vacuo to give a residue containing trans-dll-cyano-6-oxo-7-dimethylaminomethylene-decahydroquinoline. The compound was purified by chromatography on 500 g of florisil using an increasing amount of chloroform containing 0% to 2% methanol as eluent. This way

10.2 g of trans-dl-1-cyano-6-oxo-7-dimethylaminomethylene-decahydroquinoline are obtained, m.p. 159-163 ° C. The product was recrystallized from toluene to give crystals, m.p. 162-164 ° C.

-9180234

Analysis results:

s z óm i t o 11: found:

C, 66.92%

C, 67.14%,

H, 8.21%

II, 8.16%

N, 18.01%;

N, 18.04%.

10.2 g of tranaza-dl-1-cyano-6-oxo-7-dimethyllaminomethylene-decacydroquinoline are dissolved in 400 ml of methanol. 2.8 g of 85% hydrazine are added and the reaction mixture is stirred under nitrogen for about one day. The volatile components are then removed by vacuum evaporation. The residue was dissolved in chloroform and the broth was chromatographed on 150 g of florisil. Chloroform containing increasing amounts (2-5%) of methanol was used as eluent. The fractions containing the desired octahydropyrazolokinoline by TLC were combined and evaporated to dryness by evaporation of the solvent. Yield: 6.3 g. The residue was recrystallized from ethanol to give a mixture of trans-dl-5-cyano-4,4a, 5,6,7,8,8a, 9-octahydro-211-pyrazolo-4,4-gquinoline and 1H-tautomer, m.p. 195 ° 0.

Found: C, 65.32; H, 6.98; N, 27.70. Found: 0, 65.48; H, 6.80; N, 27.64.

Example B Preparation of trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-1 H and 2 H

860 mg of Z-powder of trans-dl-5-Clano-4,4a, 5,6,7,8,8a, 9-octahydro-1H and -2H-pyrazolo [3,4-g] quinoline obtained in Example A. Water (10 ml) and acetic acid (50 ml). The mixture was refluxed under nitrogen for 18.5 hours, then filtered and the filtrate was poured onto ice. The resulting aqueous mixture was basified with 14N ammonium hydroxide solution and the resulting alkaline-aqueous phase was extracted several times with a mixture of chloroform-isopropanol. The organic extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and dried. The residue obtained by evaporation of the solvent contains trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-2II-pyrazolo [3,4-g] clinolinyl and tautomeric III. The residue was dissolved in ethanol and 0.70 ml of 12N aqueous saline solution was added. The dihydrochlorides of trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-211 -plrazolo [1,4-g] quinoline and 1H-tautomer melt at 284-287 ° C; yield 780 mg.

Found: C, 48.04; H, 6.85; N, 16.80;

Found: C, 48.07; H, 7.05; N, 16.83.

Example C tr ans z-dl-5-n-propyl-7-oxy-carboxyl-1-4,4a, 5,6,7,8,8a, 9octahydro-11'-and -2H-pyrazolo [3], Preparation of 4 gquinoline A mixture of n-propylamine (ml) and toluene (400 ml) was cooled in an ice-water bath. A solution of 16.5 S ethyl K- (bromomethyl) acrylate in 50 mL of toluene was added dropwise and the mixture was stirred under cooling for about 25 minutes. 11 g of 4-benzoyloxycyclohexanone in 75 ml of toluene are then added dropwise.

-10180234. The resulting mixture was refluxed under nitrogen for about 23 hours. Λ Reflux condenser equipped with a 5ox sieve Soxhlet. The reaction mixture was cooled and filtered. The filtrate was concentrated to give a residue of 1-n-propyl-3-ethoxycarbonyl-6-benzolloxy-1,2,3,

Mixture of 4,5,6,7,8-octahydroquinoline and 1-n-propyl-3-ethoxyxaxbonyl-6-bronzolloxy-1,2,3,4,4a, 5,6,7-octahydroxyquinoline. The residue was dissolved in a mixture of ether and chloroform and the resulting solution was saturated with hydrogen chloride gas while maintaining the temperature at 0-5 ° C. The solvent was then decanted from the crystalline hydrochloride salts formed and the salts dissolved in 100 mL of methanol. Tetrahydrofuran (300 mL) was added and the resulting solution was cooled in an ice water bath. 15 g of sodium cyanoborohydride are then added portionwise with stirring and cooling. After the addition was complete, the reaction mixture was stirred for an additional 1.25 hours and then diluted with aqueous sodium bicarbonate solution. The aqueous alkaline mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and sealed. Evaporation of the solvent afforded trans-dl-1-n-propyl-3-ethoxycarbonyl-G-benzoyloxide decahydroquinoline. This was dissolved in a mixture of 4-00 ml of methanol and 100 ml of 2N aqueous sodium hydroxide solution. The solution was stirred for 64 hours at room temperature under nitrogen and the volatiles were removed by evaporation in a vacuum. The residue was suspended in a mixture of 800 ml of ethanol and 15 ml of 12N aqueous hydrochloric acid. The esterification mixture was heated to reflux and distilled to remove about 300 mL of solvent. An additional 300 mL of ethanol was added to the reaction mixture and refluxed for 26 hours in an apparatus equipped with a 3ox sieve with Soxhlet. The reaction mixture was cooled, diluted with aqueous sodium hydrogencarbonate solution and extracted with chloroform several times. The chloroform extracts were combined and the combined extracts were washed with saturated aqueous sodium chloride and dried. Evaporation of the chloroform and chromatography of 150 g of the residue on 150 ml of florisil gives 10.3 β of the residue formed by the above hydrolysis with z-dl-ln-pr opyl-3-θtoxiocarboxyl-6-hydroxy-. but it consists of cahydroquinoline. Chromatography is carried out with increasing amounts of chloroform containing 2-10% methanol.

A solution of 8.8 g of trans-dl-1-n-propyl-3-quentoxylcarbonyl-6-hydroxy-decahydroquinoline and 400 ml of methylene chloride is prepared. To this solution was added 4.1 g of sodium acetate followed by 10.8 g of pyridine hydrochloride: chromo-trioxide and the mixture was stirred for about 22 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting concentrate was dissolved in chloroform and the chloroform solution was chromatographed on 150 g of florisil. Chloroform containing increasing amounts (1-2%) of methanol was used as eluent. The fractions containing TLC showed trans-dl-n-propyl-3-ethoxycarbonyl-6-oxo-decahydroquinoline and the solvent was removed from the combined fractions. 3 to 48 g of 6-oxo-aza are obtained as a residue. The 6-oxo derivative is dissolved in 100 ml of toluene

-11180234 up to which 2? ml of dinethylXormamld-dimethylacetal was added. The resulting mixture was refluxed for 44 hours under alkaline reflux under nitrogen and then allowed to stand at room temperature for a further 4 days. Vacuum the matching ingredients! removed, I α residue, which during the reaction. formed from txans3-dl-l-n-propyl-3-atoxycarbonyl-6-oxo-7- (methylmethylaminomethylone) -decahydroquinoline, chromatographic purification was carried out. The kx ohm is dissolved in chloroform for chromatography and chromatographed on florisil using chloroform containing increasing amounts (2-5%) of methanol. The fractions containing the desired 7-dimethylaminomethylene compound as determined by thin layer chromatography were pooled and the solvent was evaporated in vacuo.

Physical constants of the compound:

I.P., / CIIC1, /

1720 om ¹ ester ^ 0 = 0 1540 ohm ¹ N 2 -C = NMR / CDCl 3 / / 60 Hz / = 0-0 = 0 1 1 52 eps, triple, »~ N-GH ₂ CH ₂ CH 74 eps, triplet, -O-OHgCHj 246 eps, quartet, -O-CII ₂ -CIIj 186 ops, singles, Carbamic / CII _5/2 448 eps, broad singlet, p-C «<

C-H

A solution of trans-dl-1-n-pronyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylene-decahydroquinyl (2.24 g) and ethanol (150 ml) was prepared. Hydrazine hydroxide (0.45 mL) was added and the mixture was stirred for about 17 hours at room temperature. The reaction mixture was then concentrated in vacuo. Trans-dl-5- n-pronyl-7-ethoxycarbonyl 11-4,4a, 5,6,7, 5,8a, 9'-octahydro-2II-pixazololp, 4-g] clnoline and trans-dl The residue containing a mixture of -5-n-propyl-7,7-ethoxytorbonyl-4,4a, 5,6,7,7, 8,8,9,9-octahydro-1 H -pyrazolo-3β-g / quinoline is dissolved in chloroform and the resulting solution Chromatograph 8 floriselen. Chloroform containing 2% methanol was used as eluent. The fractions which were found to contain the desired pyrazolocnoline by TLC were combined and the solvent evaporated in vacuo. After recrystallization from ether / hexane, trans-dl-5-n-propyl-x7-ethoxycarbonyl-4,4a, 5,6,7,7,8,8a, 9-octahydro-2H-pixazolo [3,4-g] clnoline was obtained. and the 1H tautomer thereof having a melting point of 125-127 ° C. Yield: 75%.

Analysis: Calculated: 0 65-95% ♦ Found: C 65.75%,

N, 14.42%;

N, 14.16%.

H 8.65% »

H, 8.42%

Example D tr ans z-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,7,8,8a »9 octahldxo-1H / e -2H / pyrazole. ^r 3,4-g 'Preparation quinoline

-12180234

The trans-dl-5-n-propyl-7-e obtained by the spray method of G. poda is toxicoxarone-4,4a, 5,6,7,8,8a, 9-octahydro-2II-pyr. A mixture of oloquinoline hydrochloride and tautomer II (3.7 mol / 200 ml) was dissolved in tetrahydrofuran. 1 g of lithium urn urine hydride is added portionwise. The reaction mixture was stirred at room temperature under nitrogen for about 16 hours and then cooled. Ethyl acetate and 10% aqueous sodium hydroxide solution were added to react with excess lithium aluminum hydroxide and destroy the organic organic compound present. The reaction mixture was then diluted with water and the aqueous mixture was extracted several times with a mixture of chloroform and isopropanol. The organic layers were separated and combined. The combined phases were washed with a saturated aqueous sodium chloride solution and dried. Evaporation of the solvent yields the tautomers of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [beta], 4-jjquinoline and IIIa. mixture. The residue was dissolved in ethanol to which was added 0.2 ml of 12N aqueous hydrochloric acid. The residue obtained by evaporation of the volatile constituent is trans-1-5,4-n-propoxyl-7,4-hydroxymethyl-1-4,4a, 5,6,7,8,8a, 9-octyl dr-2H and -1II-. pyrazole consists of £ 3,4- ^ quinoline dihydrocloxides. The residue was dissolved in a mixture of methanol and acetone to give crystals melting at 270-275 ° C with decomposition. Yield: 350 mg.

The above reaction was repeated with 1.55 g of tr ans z-dl-5-n-pi: opil-7-ethoxycarbonyl ~ 4,4a, 5 _? 6,7,8,8a, 9-octahydro-2H-pyrazolo0,4- (1'-quinoline is reduced with excess lithium aluminum oxide in tetrahydrofuran. The reaction product, tr ans z-dl-5-n-propyl-7-ylxoxymethyl-4 4a, 5,6,7,8,8a, 9-octahydro-1 H- and 2 H -pyrazolo [4, 4] 7 quinoline are crystallized from a mixture of chloroform and ethanol, m.p. 167-169 ° C.

Analysis: Calculated: C 67.43%, II 9.30%, N 16.35%;

Found: C, 67.21; H, 9.15; N, 16.62.

Example E

In 1-n-propyl-6, z-oxyloxy-3,4,5,6,7,8-hexahydro-2H-quinoline and in-pro-yl-6-benzolloxy-3,4,4a Preparation of 5,6,7Tyloxahydro-2H / quinoline

4.4 g of 4-benzoyloxycyclohexanone / obtained according to Jones, ERH and Sondheimer, E.; J. Chem. Soc., 615, (1949) _. A mixture of 2.5 ml of n-propylamine and 100 ml of toluene was prepared. The mixture was refluxed for about 2 hours under a nitrogen atmosphere using a Dean-Gtark water separator. The reaction mixture is then refluxed for a further 2 hours in the presence of a molecular sieve to remove water. The reaction mixture was cooled and the solvent was evaporated in vacuo. Methyl acrylate (4 mL) and dioxane (100 mL) were added to the residue and the mixture was refluxed overnight under nitrogen. The reaction mixture is then cooled again and the volatiles are removed in vacuo. The resulting ethereal solution of the residue was chromatographed on 200 g of florisilene using ether as eluent. so the 1-n-

-13180234, -beryloxl-3,4, J, 6,7,8-nexahydxo-2 (11) -quinolone and 1-nyl-6-buuzollox-η 4,4a, 5,6,7-hexahydro-2 / 1H / -quinoline light, ho z am · 2.1g. _

The coin is blue

Example 1 Preparation of Trons-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1 H and 21 1 -plrazolo (3,4-g) quinoline

11ansz 6.5 g of dl-5-cyano-4,4a, 5,6,7,8,8a ^a, 9-octahydro-2HP / i-gjkinolin and tautomer mixture of 1H / prepared from A / Example ázérinti way / A mixture of 50 g of zinc powder and 75 ml of water was prepared.

ρΐυ,

-Ί ...! , pir η zol ο az

Of 575 ml of acetic acid and

The reaction mixture was refluxed for 16 hours under nitrogen, then filtered and the filtrate poured onto ice. The resulting aqueous mixture was made basic by the addition of 14N aqueous ammonium hydroxide solution, and the alkaline phase was extracted several times with a mixture of chloroform and isopropanol. The organic extracts are combined, the combined extracts are washed with saturated aqueous sodium chloride solution, and the extracts are combined. Evaporation of the solvent afforded a residue containing trans-dl-4,4a, 5,6,7,8,8,8a, 9-octahydro-2H-pyrazolo [4], 4-giquinoline and the taut-tautomer. The residue F was dissolved in 500 ml of methanol to which 1.9 g of sodium cyanoborohydride was added. Propionaldehyde (20 ml) was then added and the resulting mixture was stirred at room temperature under nitrogen for 28 hours. The reaction mixture was then poured into n aqueous hydrochloric acid. The aqueous phase is extracted with ether and the ether extracts are discarded; the aqueous phase is made basic by the addition of an excess of 14N aqueous ammonium hydroxide solution and the resulting lugo phase is extracted several times with a mixture of chloroform and isopropanol. The organic extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and concentrated. By evaporation of the solvent ΐχοη3ζ-ά1-5- ^ ~ Ρ ^ ορί- ^{: ι} · “4,4α _| 5,6,7, θ, θβ,

A residue consisting of 9-octahydro-α- and -2H-pyrazolo [3,4-g] -clinoline is obtained. Mass Spectrum: M ⁺ - 219 ·

The residue was dissolved in 100 ml of boiling acetone to which was added dropwise 5 ml of 12N aqueous hydrochloric acid. The mixture was cooled and the dihydrochloride of the trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H- and -2II-pixazolo [3,4-g] quinoline formed by filtration. We separated.

Yield: 4.6 g; mp 250-257 ° C ·

Analysis results: Calculated: Found:

Ο 53.45%, Η 7.93%, Ν 14.58%, G1 24.26%;

C 53.15%, Η 7.91%, Ν 14.47%, Cl 24.53%.

Example 2 Preparation of transxrdl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H / 2H / pyrazolo [3,4-f] quinoline

1.2 g of trans-dl-5 'Oiano-4,4a, ₅ 6,7,8,8a, 9-octahydro-2IIpirazolo / p.4-1H tqutomerjénefc gJkinolin and heated as in Example 1. · zinc dust and acetic acid react ORDERS such as trans-dl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-plrazolo [3,4-g] quinoline

A mixture of -14180234 and III tautomoric song is obtained, which is isolated as a residue. Dissolve the residue in 50 ml of dimethylformamide to which 1,7 β-potassium carbonate is added. 0.6 ml of n-propyl iodide are then added and the resulting mixture is stirred for about 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water and the resulting aqueous mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined, and the combined extracts were washed successively with water-saturated aqueous sodium chloride solution and filtered. By evaporation of ethyl acetate, trans-dl-5-n-propyl- ^z . A residue of 4a, 5,6,7,8,8a, 9-octahydro-2II-pyrazole-1,4-δ-clnoline and tautomer III is obtained, which is purified by chromatography on ^0 g of fluorine isylene. Eluting with increasing amounts of chloroform containing 2-10% methanol. The fractions which were found to contain t-trans-p-5-n-propyl-4,4a, 5,6,7,3,8a, 9-octahydxo-2H- and -1H-pyrazoloyl, ² -ijquinoline by TLC, combine and concentrate the combined extracts to dryness. 0.28 g of trans-dl-5n-proylsyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-p1r are obtained in the form of 0,4-glucoquinoline and 1 H tautomer of ol. The residue was dissolved in ethanol to which was added 0.16 ml of 12N aqueous hydrochloric acid. Thus, trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H -pyrazolo gave dihydrochloride of £ 3,4-gjquinoline and 1H tautomer. The reaction mixture was concentrated in vacuo and the concentrate was diluted with ether. A mixture of ίΧ3ηεζ- (2.1-5-η-ρχορί1- ^{ζ ζ} , 4α, 5,6,7,8,88,9-οΙ <1αhydro-1H and -2H-pyrazolo {3,4-g) quinoline dihydrochloride m.p. 276278 ° C.

Example J Preparation of trans-dl-5-n-propyl-7-methyl mexcaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H and -2H-pyrazolo [3,4-g] quinoline mmol of trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1 H- and -2 H A suspension of pyridine is prepared. Methanesulfonyl chloride (1 mL) was added and the resulting mixture was allowed to stand overnight at room temperature. It is then diluted with dilute aqueous ammonium hydroxide solution and the resulting alkaline phase is extracted several times with chloroform. The chloroform extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and concentrated. Evaporation of the solvent gave a solid residue. The residual chloroform solution was chromatographed on 30 g of florisil, eluting with increasing amounts of chloroform containing 1-2% methanol. The fractions which were found to be trans-dl by TLC.

Containing 2-methanesulfonyl-5-η-Μ-opyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [4,4-a] quinoline, combine and evaporate the solvent we will remove them. In this way, tr an s z-dl-2-m y is ulf on 11-5-n-propyl-7-meshoxime t1-4,4a, 5-,

6,7,8,8 a, 9-kt ahi dr o-2H-p and ο 1 o 0,4-gJ ki η ο 1 int, which, after recrystallization from ether, 152-154 ° C. are.

Analysis results:

Calculated: 0 47.39%, II 6.71%, N 10.36%, 3 15.81%; Found: C, 47.60; H, 6.71; N, 10.32; S, 15.69.

-15180234

: .-. Ό .. · · · 011; also obtained during the chromatographic branch, based on the data of .i: trw.i, trans-dl-2-methanesulfonyl) -opoly-y-i .ο :; 10 lo: d of 2: 1 ar dny u of the methyl 11-4,4a, 5,6,7,8,8a, 9-octahthydro-2II-plasrazole, *> -% of the quinoline and l-methanazvl-III-1 H ke v û c é ko.

Methylmercaptan (g) was dissolved in 4-0 ml dimethylformamide. The solution was cooled in a jcge3 water bath. About 1 g of sodium hydroxide (in the form of a 50% suspension in mineral oil) is added portionwise. The hütőfüxdőt removed and added to 0.4 g ·, prepared as described above ^ a small amount of trans-dl-1met ans z Ulf on 11-5-n-pr one of l- ^r / z 1L oxli methyl; BC t trans-dl-2-methanesulfonyl-5-n * -P-opyl-containing 1,1,4,4a, 5,6,7,8,8a, 9-octahydro-11-pyrazole [1,4-g] quinoline. A solution of 7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pixazolo [1,4-g] quinoline in 10 ml of dimethylformamide. The reaction mixture was stirred at room temperature for about 5 hours and then diluted with water. The aqueous mixture was extracted several times with ethyl acetate. The ethyl acetate phases are separated and combined. The combined extracts were washed with water and brine, and dried. Evaporation of the solvent afforded an oily residue which was trans-dl-5-n-propyl-7-methyl-mercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-11 and -2II-pyrazolo , Consisting of 4- ^ Jkinolin; Yield: 0.17 g · Dissolve the residue in ethanol and try to prepare both the hydrochloride and the oxalate. Initially, both salts are not crystalline. The free bases are then recovered from the non-crystalline oxalate by dissolving the oxalate in water, adding lag, and extracting the mixture with ether. The thus purified trans-dl-5-n-propyl-7-methylmimethyl-aptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1 H- and 2 H -plrazolo [1,4-g] quinoline crystallizes upon evaporation of the ether. . 175-177 ° C; Yield: 40 mg.

Analysis results:

Calculated: C 64.47%, H 9.02%, N 15.04%, S 11.47%; Found: 064.47%, H 8.96%, N 15.09%, 811.29%.

The tautomeric mixture of the free base purified as above was dissolved in ethanol and an excess of 12N hydrochloric acid was added. The volatiles were removed by evaporation and the resulting residue consisting of the corresponding dihydrochloride salts was crystallized from a mixture of acetone and methanol.

Analysis results:

Calculated: 0 51.15%, H 7.72%, N 11.95%, 01.20.10%,

S, 9.10%;

Found: 0 50.89%, H 7.57%, N 12.15%, Cl 20.18%,

S 9.51% ·

Example 4 trg.nsz _z dl-5-methyl-4.4a, _5? Preparation of 6,7,8,8a, 9-octahydro-1H and -2H / plrazolo-1,4-g / clnolln

46.5 6, about 60% 6-benzolloxl-3,4,5,6,7,8-bexahydro-1H-clnolln-2-one burns 40% 3,4,4a, 5,6,7-hexahydro- isomers

The mixture of isomers containing -16180234 is dissolved in 400 ml of tetrahydrofuran. Methyl iodide (80 µl) was added and the resulting mixture was cooled in an ice water bath. 9.0 g of sodium hydride (in the form of a 50% suspension in mineral oil) are added portionwise. After the addition of the total amount of sodium hydride suspension, the cooling bath was removed and the reaction mixture was stirred at room temperature under nitrogen for about 4 hours. The reaction mixture was then diluted with water and the aqueous mixture was extracted thoroughly with chloroform. The chloroform extracts are combined, the combined extracts are washed with saturated aqueous sodium chloride solution and occupied. The solution was evaporated to dryness in vacuo to remove chloroform to give a orange oil (47.3 g). This residue was recrystallized from ether / hexane to give crystalline 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2H-clnoline and the corresponding 3,4,4a, 5,6 7-hexahydro isomer is obtained.

Analysis results:

Calculated: C 71.56%, H 6.71%, N 4.91%;

Found: C, 71.33%; H, 6.90%; N, 4.67%.

47.3 g of 1-methyl-6-benzollox1-3,4,5,6,7,8-hexahydro-2H / quinoline and the corresponding 5.4 * 4a, 5,6,7-hexahydro-isomer The mixtures prepared above were dissolved in 800 ml of tetrahydrofuran and cooled to about 0 ° C. Lithium aluminum aluminum hydride (20 g) was added portionwise and the mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled and the excess lithium aluminum hydride was quenched by addition of ethyl acetate. Subsequently, 10% sodium hydroxide solution is added and the organic metal compound is present. dilute with water to decompose. The aqueous mixture was extracted several times with a mixture of chloroform and isopropanol. The organic extracts were combined and the combined extracts were washed with saturated aqueous sodium chloride solution and taken up. By evaporation of the solvent, the remainder of the reaction formed, i.e., 1-methyl-6-hydroxy-1,

A mixture of 2,3,4,5,6,7,8-octahydroquinoline and 1-methyl-6-hydroxy-1,2,3,4,4a, 5,6,7-octahydroquinoline is obtained. / A lithium aluminuml-. The hydride reduction served to remove the benzoyl group at the 6-position as the benzyl alcohol residue to leave the free hydroxyl group at the 6-position. The A / P residue was dissolved in ether (about 30 ° C) without further purification and saturated with hydrogen chloride gas. Thus, the hydrochloride of the enamine mixture is prepared. The ether was removed by decantation and the residue was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (50 mL). This solution was cooled in an ice-water bath. Under cooling and stirring, 12 g of sodium cyanoborohydride are added. After the addition of the total amount of cyanoboxybenzide, the reaction mixture was stirred for an additional 60 minutes and then poured into a mixture of ice and n aqueous hydrochloric acid. The acidic aqueous solution is extracted with chloroform and the chloroform extract is discarded. The solution is then conjugated with 14N aqueous ammonium hydroxide solution. The tranazole-dl-1-methyl-6-hydroxydecahydroquinoline * formed in the reaction, which is insoluble in the alkaline medium, is separated and extracted several times with chloroform / isopropanol. The combined extracts were washed with a saturated aqueous sodium chloride solution and filtered. Evaporation of the solvent gave 15 g of transdl-1-methyl-6-hydroxydecahydroquinoline.

-17180234

The resulting residue was dissolved in ethanol and 2 mL of n hydrochloric acid was added. The acidic solution is evaporated to dryness. The residue was crystallized from ethanol to give tranaz-d-5-diethyl-4,4a, 5,6,7, 8,8a, 9-octahydro-1H-and -2H-pyrazolo [1,4-g] quinoline dihydride. yields a tautomeric mixture of chlorides, m.p. 268-270 ° C with decomposition; Yield: 140 mg.

Analysis results:

Calculated: C 50.01%, H 7.25%, N 15.90%, Cl 26.84%; Found: C, 49.82; H, 7.08; N, 15.66; Cl, 26.80.

Example 5 · Preparation of trons z-dl-5-all 11-4,4a, 5,6,7,8,10a, 9-octahydro-III / and -2H / pyrazolo [beta] -4- {[beta] quinoline

In the same manner as in Example A, 65 g of 4-benzoyloxycyclohexanone, 18 ml of pyrrolidine and some crystals of p-toluenesulfonic acid monohydrate were dissolved in 1000 ml of cyclohexane. The resulting mixture was heated at reflux under nitrogen for about 1/2 hour using a Dean-Stark edge. The mixture was cooled and the solvents removed by evaporation in vacuo. The residue, which is composed of the pyrrolidin-enamine of 4-benzolloxyclclohexanone, is mixed with 55 g of acrylamide in 1000 ml of dioxane. The reaction mixture was refluxed under nitrogen for about one day, then cooled and the volatiles removed by evaporation. The residue was diluted with water and the aqueous mixture was extracted with ethyl acetate; the ethyl acetate extract was separated with water and. saturated aqueous sodium hydroxide solution was washed with 1 U of dry solution and squeezed. Evaporation of the solvent afforded a mixture of 6-benzolloxy-5,4,5,6,7,8-hexahydro-11-clinolin-2-one and the corresponding 3,4,4a, 5,6,7-hexahydro compound.

The above mixture was dissolved in a mixture of 250 ml of tetrahydrofuran and 250 ml of dibutylformamide. To the solution was added 12 g of sodium hydride as a 50% suspension in mineral oil and the mixture was stirred to completely convert the quinolin-2-one into the sodium salt. A solution of allyl bromide (30 g) in tetrahydrofuran (75 ml) was added and the resulting mixture was stirred for 24 hours. The reaction temperature rises rapidly and external cooling is applied. After completion of the reaction, the reaction mixture was diluted with water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was separated, washed with water and a saturated aqueous sodium chloride solution, and dried. Evaporation of the solvent gave 1-allyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and the corresponding 3,4,4a, 5,6,7-h-exahydroxo. to give a mixture of compound.

The N-allyl derivative thus obtained was dissolved in 750 ml of tetrahydrofuran and cooled in an ice-water bath. _s Add 20 g of lithium aluminum hydride in portions. After the addition is complete, the resulting mixture is refluxed under nitrogen for about three hours. The reaction mixture was then cooled in an ice-water bath and the excess lithium aluminum hydride decomposed with ethyl acetate. Subsequently, 10% aqueous sodium hydroxide solution is added to decompose the organometallic compounds present and

-18180234 was diluted with water. The aqueous mixture was quenched with chloroform and the chloroform extracts were combined. THE:·. The combined extracts were washed with saturated aqueous sodium hydroxide and filtered. Evaporation of the solvent also resulted in the addition of residues from 1-allyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1,2, J, 4 ^,; ia, 5,6,7-octahydro-isomer is good. The residue was dissolved in 75 µl of ether and the aqueous solution was saturated with water. The hl dro clone of the octahydric oxinoline mixture, which is insoluble in ether, precipitates out and the ether is decanted: '! Ί · ο. · Ι1. The hydrochloride was dissolved in a mixture of 100 ml of methanol and 300 ml of tetraindidol solution. This solution was cooled in an ice-water bath. 20 g of cyanoborohydride are added portionwise while the reaction mixture is cooled. After the addition is complete, the hot bath is removed. The reaction mixture was stirred at room temperature for about one hour and then diluted with saturated aqueous sodium hydroxide solution. The alkaline phase is extracted several times with chloroform. The chloroform extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and dried. Evaporation of the solvent gave about 12.8 g of trans-dl-1-allyl-6-hydroxydecahydroquinoline.

The trans-dl-1-allyl-6-hydroxydecahydroquinoline thus obtained was dissolved in 500 ml of methylene chloride, to which

8.2 g of sodium acetate were added. 21.6 g of plridine hydrochloride / chromium trioxide are then added. The reaction mixture was stirred at room temperature under nitrogen for 7.5 hours and then filtered. The filtrate was concentrated in vacuo and chromatographed on 150 g of florisil. The lump formed during growth (1-5% methanol) as eluent. The 6-oxo compound is dissolved in toluene, ml of dimethylformamide dimethylacetal. The rcak <

containing chloroform. Thus 3.2 g of the trans-dl-1-allyl-6-oxo-decahydroquinoline are added and the reaction mixture is refluxed for 24 hours under nitrogen and then cooled and the solvent is refluxed. The residue obtained is chromatographed on 150 g of florisil, eluting with chloroform containing increasing amounts (2-20%) of methanol. The fractions containing the desired trans-dl-1-allyl-6-oxo-7g-dimethylaminomethylene-decahydroxyquinoline formed by the reaction were combined and evaporated to give 1.5 g of the desired product. This material was dissolved in methanol (75 ml), to which had previously been added 0.5 ml of hydrazine hydrate. The reaction mixture is stirred for about 20 hours at room temperature and then the azillos are removed by vacuum evaporation. The residual chloroform solution was chromatographed on 35 g of florisil, eluting with increasing amounts of chloroform containing 2-4% methanol. The fractions which were found to be desired by TLC. trans-dl-5-allll-4,4a, 5,6,7, ti, 8a, 9-octahydro-2-II-pyrazolo [beta], 4 [beta] -quinoline and its 1 H tautomer are tax ^w , combine and remove the solvent by evaporation in a vacuum. The autumn copy of the remaining mass spectrum shows molecular ion / 151 + - 217 /. The residue (0.55 g) was dissolved in acetone (75 mL) and the acetone solution was heated to reflux. 0.5 ml of 12N aqueous hydrochloric acid solution are added dropwise. The reaction mixture is then allowed to cool. The trans thus obtained is trans-d1-5-allyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H and -11H-pyrazolo [epsilon] -g-quinoline dihydrochloride at about 215 ° C. melt

-19180234 during decomposition; yield: 495 mg »

Analysis: Calculated: 0 53.80%, 117.29%, N 1.48%, 0124.4%; .

Found: C 53.52%, H 7.13%, N 1.65%, Cl 24.17% '.

In examining the efficacy of the compounds of formulas Ia and Ib, it has been found that these compounds have an effect on the rotation of 6-hydroxyldolylamine-confused rats according to an assay method for the detection of compounds for the treatment of Pneumonia. For this experiment, nigroneostriatalls / confused rats prepared according to the method of Ungerstedt and Arbuthnott / Brain Slit, 24, 485/1970/./ were used. Upon administration of dopamyl agonist compounds, the rats rotate in opposite circles. After incubation for 1 period, which changes from compound to compound, the number of laps completed over a 15 minute period is counted.

Table 1 below shows the results obtained for some of the compounds Ia and Ib described above. The compounds were dissolved in water and the aqueous solution was injected intraperitoneally into the rat at doses of 1 mg / kg and 100 mcg / kg. In column 1 of the table the name of the compound, in column 2 the percentage of rotating animals and?. column shows the average rotations observed during the first 15-minute latency period.

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-21180234

The compounds of formulas Ia and Ib are also valuable prolactin inhibitors and are therefore useful in the treatment of unsatisfactory milk secretion such as postpartum milk secretion and galactorxhoea. The utility of these compounds for the treatment of conditions requiring lowering of prolactin levels in the art is demonstrated by the following method, which demonstrates that compounds of formulas Ia and Ib inhibit prolactin.

Adult male rats of about 200 g of Gpraguo-Dav.ley strain were kept in controlled light at 6 o'clock, extinguished at 20 o'clock, in an air-conditioned room and fed with synthetic nutrient and water. Each animal was given an aqueous suspension containing 2.0 mg reserpine by intraperitoneal injection 10 hours prior to administration of the test drug. The purpose of administering reserpine was to maintain a steady increase in the prolactin level. Each compound was administered in each dose to 10-10 rats of osopoxt, a control group of 10 untreated rats received the same amount of 10% ethanol. One hour after treatment, all rats were sacrificed and prolactin was assayed in 150 µl aliquots of serum.

The difference between the prolactin levels of the treated and control rats divided by the prolactin levels of the control rats gives the percentage inhibition of prolactin secretion induced by the compounds Ia and Ib. Give these percent inhibition values to g in Table 2 below, with the name of the compound in column 1, and 50 mog / kg and columns 0.5 and 5 mg / kg in columns 2 and 4, respectively. percent prolactin inhibition is shown.

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-23180234

When used to inhibit prolactin secretion or to treat Farkinson's disease or to achieve other pharmacological activity, the compounds of formulas Ia and Ib are administered in an amount sufficient to treat Farkinson's disease or to reduce prolactin levels, or pharmaceutically acceptable carriers thereof. acid salts of a patient with Farklson's disease or a patient whose prolactin levels need to be reduced. Oral administration is preferred. When administered parenterally, the active compounds are preferably administered by subcutaneous injection in a suitable formulation. Other parenteral routes of administration such as intraperitoneal, intramuscular or intravenous administration are equally effective. For intravenous or intramuscular administration, a water-soluble pharmaceutically acceptable salt is used. In the case of oral administration, the compound, in the form of the free base or a salt thereof, may also be admixed with the usual pharmaceutical carriers and filled into gelatin capsules or compressed into tablets. The oral dosage range is about 0.01-10 mg / kg body weight and the parenteral dose range is about 0.0025-2.5 mg / kg. '

Intraperitoneal doses of 10-100 mg / kg of trans-dl-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro and 9H-pyrazolo [3,4-g] quinoline dihydrocloxy they cannot cause death, but doses of 300 mg / kg do. This indicates that = 100-300 mg / kg.

Claims (8)

Patent claims A process for the preparation of the compounds of formula Ia and Ib and pharmaceutically acceptable acid addition salts thereof, wherein: R 1 is C 1 -C 3 alkyl, or allyl, and R 4 is hydrogen, or -CH ₂ SCH, characterized in that a compound of formula VIIIa wherein R is hydrogen, cyano, (C 1 -C 3) alkyl or allyl; R ^{1 is} hydrogen or -C-O (C 1-2) -alkyl Reaction with a representative hydrazine hydroxide and, when cyano is R, reacting it with zinc and eoetsay to react the resulting compound wherein R is hydrogen with alkyl or allyl halide or reductive alkylation with the corresponding aldehyde and femhydride. RJ is not hydrogen - is reacted fémhldrlddel, Ia and Ib are obtained intermediates of formula ^R1 anelyekben CH20H group, a nucleophile, preferably tosyl chloride, / C1-3 / alkyl sulfonyl, phenyl azulfonil chloride there, such as the íoszfortrlklorlddal, phosphorus or tribxomiddal foszforoxlklórladal preferably under argon and the resultant, Ia and Ib as intermediates of formula wherein R ¹ -CII2C1 CHgBr osoportot group, -CH ₂ 0S0 ₂ phenyl group, -CH ₂ -0-tosyl or -CH ₂ -OSO ₂ / C 1 -C 3 alkyl -24180234 , .ox ;, ot j · '! τιϋ, uefi 1 ->·; obtained with αη-ir · trIvmi salt and thus ol, au J ;. l'lb produces a compound case of the formula: a.,: 01. ', ·'.ΐ> οη Irish - .31 I _o - Cd. and, if desired, the worn compound is converted into a pharmaceutically acceptable salt by a pharmaceutically acceptable acid. 2. A process according to claim 1 for the preparation of tautomers of the formulas Ia and Ib, wherein Y is a hydrogen atom, characterized in that a compound of the general formula VIIIa wherein R is 1.1; Reaction was carried out with hydrocyanic acid, as defined in point η; pirc.zolo 3 tg of quinolone tautomers, characterized by reacting the trs-dl-1-cyano-6-oxo-7-dinylaminomethylone decahydrochlorol with hydrazine followed by reaction with zinc and acetic acid to remove the 5-cyano group, followed by reaction with propionaldehyde and sodium cyanoborohydride · 4. The process of claim 2 for trans-dl-5 ~ n-pxopil-4, ^z )?, 5,6,7,8,8a * 9-octahydro-III / and - 2H / - pyrazole. For the preparation of 5,4-g'quinoline tautomers, the trans-dl-1-cyano-6-oxo-7-dimethylaminomethylene-decahydroxyoctnooline is reacted with hydrazine and then zinc and acetic acid is removed to remove and then reacted with n-propyl iodide. The method of claim 1, wherein the method is trans-d1-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,5,7,8,8a, 9-octahydro-ΙΠ and -2II / -. pixazolo 'for the preparation of 5,4-g quinolone tautomers, characterized in that trans-dl-ln-propyl-5-ethoxycarbonyl 11-G-o: o-7-dimethyl 1-amino-1-butene The h idxoquinoline is reacted with hi dr with 1 nhi drut, then reacted with lithium aluminum hydroxide to give compounds in which R1 is -C1-6 OII followed by reaction with methanesulfonyl chloride followed by methyl mercaptone. G. The process of claim 1, wherein the method is trans-dl-5-methyl-4,4a, 5, 6,7,8,8a _? 9-octahydro-1H and 2H-pyrazolo for the preparation of 5,4-g quinoline tautomers, characterized in that the trans z-dl-1-methyl-6-oxo-7-dinylaminomethylene decahydrides dr azi nh1wire plate reac tat un k. The process of claim 1 for preparing quinoline tautomers of trans-dl-5-allyl-1α, 4α, 5,6,7,8, 9α-octahydro-/ and 2H / -pyrazolo g. characterized in that trans-dl-l-allyl-O-oxo ^ -dimetilaminoEietilén-oxodecahydroquinoline diluting dr _Z z inhidrát bowl reacted. 8. A process for the preparation of a pharmaceutical composition comprising the compounds of the formulas Ia and Ib or the pharmaceutically acceptable acid addition salts thereof according to claims 1-7, wherein R and R ¹ are A preparation having the same meaning as defined in claim 1, alone or in a non-synergistic form, In combination with -25180234, and / or other dosage forms prepared conventionally in the preparation of a medicament with auxiliary agents to form a pharmaceutical composition.