KR880001454B1 - Pyrmido (4,5-g) quinoline derivatives - Google Patents

Abstract

The title compds. of formula (I) and its pharmaceutically acceptable acid addn. salts are new. In the formula, R=C1-3 alkyl or allyl, R2=H, CH3, Cl or Br, R1=NH2, NHR3 or NR4R5 [R3=Me, Et, n-propyl or R6-CO (R6=C1-3 alkyl), R4 and R5=Me, Et or n-propyl independently . (I) have 2 chiral centers at 5a and 9a, so can exist for 4 stereoisomers. (I) are used for treating hypertension, parkinson syndrome, sexual functional disorder, etc..

Description

Pyrimido [4,5-g] quinoline derivatives

The present invention provides trans- (±) -2,4,6-optionally substituted-5,5a, 6,7,8,9 of the following general formula (I) useful as D-1 and D-2 dopamine agonists , 9a, 10-octahydropyrimido [4,5-g] quinoline, and a pharmaceutically acceptable acid addition salt thereof.

(여기에서 R⁷은 각기 H, CI, F, Br, CH_3,C₂H₅, CH₃O, C₂H₅O 또는 CF₃이고, m은 0,1 또는 2이다)이다] 또는 NR⁴R⁵(여기에서 R⁴및 R⁵는 각기 메틸, 에틸 또는 n-프로필이다)이다.Wherein R is C ₁ -C ₃ alkyl or allyl, R ² is H, CH ₃ , CI or Br, R ¹ is NH ₂ , NHR ³ wherein R ³ is methyl, ethyl, m-propyl or R ⁶ -CO, R ⁶ is C ₁ -C ₃ alkyl or

Where R ⁷ is H, CI, F, Br, CH _3, C ₂ H ₅ , CH ₃ O, C ₂ H ₅ O or CF ₃ , and m is 0,1 or 2) or NR ⁴ R ⁵ , where R ⁴ and R ⁵ are each methyl, ethyl or n-propyl.

The fact that various body tissues contain two dopamine receptors has recently been generally accepted. These receptors were named D-1 and D-2 receptors. There are a variety of D-2 dopamine receptor agonists, including ergotryl and pergolide, two ergolines and LY141865 (US Pat. No. 4,198,415) ergoline partial structures.

These D-2 agonists have proven to be useful in treating Parkinson's syndrome, as well as in conditions of excessive cyclic prolactin, such as lacusea.

LY 141865 [trans- (±) -5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] Quinoline] has been demonstrated to reduce mammalian hypertension without causing positional hypotension. This hypertension treatment is attributed to 4aR, 8aR-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-, one of the stereoisomers of trans- (±) racemates. It has been shown to exist only in trans-(-) isomers named 1H (and 2H) -pyrazolo [3,4-g] quinoline.

Various terms used herein are defined as follows. “C ₁ -C ₄ alkyl” includes methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl and tert-butyl. “C ₁ -C ₃ alkyl” is included within C ₁ -C ₄ alkyl. “C ₁ -C ₃ alkoxy” includes methoxy, ethoxy, n-propoxy and isopropoxy.

Pharmaceutically acceptable acid addition salts of the compounds of formula (l) include non-toxic organic acids, as well as salts derived from non-toxic inorganic acids (e.g. Salts derived from, for example, aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkano and alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, these pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, boramides, urine Amide, acetate, poropionate, caprylate, acrylate, formate, iso-butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate, sebacate, puma Latex, maleate, mandelate, butyne-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzo Eate, Phthalate, Lelephthalate, Benzenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylene Phonates, Phenyl Acetate, Phenylpropionate, Phenylbutyrate, Sight-rate, Lactate, β-hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate Naphthalene-2-sulfonate, and the like.

Compounds of formula (l) have two asymmetric carbons (optical centers) at 5a and 9a and are therefore in two racemic pairs, commonly named trans- (±) racemates and cis- (±) racemates. There may be four stereoisomers present. The trans racemates are trans-(-)-stereoisomers (5aR, 9aR stereoisomers) of the following general formula (II) and trans-(+)-(5aS, 9aS stereoisomers of the following general formula (IIa) )

Wherein R, R ¹ and R ² are as described above.

Trans-(-)-(5aR, 9aR) stereoisomers of formula (II) are D-2 agonists which are active dopases. The compound according to general formula (II) thus serves a second object of the present invention. Trans-(+)-(5aS, 9aS) stereoisomers of formula (IIa) are active dopamine D-1 agonists.

Therefore, the compound according to general formula (IIa) serves as a third object of the present invention. Since the trans-(+)-D-1 agonist is less active than the trans-(-) D-2 agonist in doses, it is active trans-(-) at trans- (±) -racemate (II + IIa). It is very useful to use stereoisomer as its contents.

Preferred groups of compounds are those of the general formulas (I), (II) and (IIa), wherein R is n-propyl. Another preferred group of compounds are compounds of formula (I), (II) and (IIa), wherein R ¹ is NH ₂ and / or R ² is H.

Compounds of formula (I), (II) and (IIa) are, for example, as follows:

5aR, 9aR-2-dimethylamino-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline sulfate,

Trans- (±) -2-methylethylamino-4-methyl-6-n-propyl-5,5a-6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline Monohydrophosphate,

Trans- (±) -2-m-propylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline maleate,

5aR, 9aR-2-amino-4-chloro-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline succinate,

Trans- (±) -2-amino-4-bromo-6-aryl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline phthalate,

Trans- (±) -2-n-propylamino-6-m-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline mesylate,

Trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline hydrochloride,

5aR, 9aR-2-amino-4,6-dimethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline tosylate,

5aR, 9aR-2-acetamino-6-methyl-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dihydrobromide ,

5aR, 9aR-2-benzamino-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline hexane-1,6-dioate,

Trans- (±) -2-n-propylamino-6-isopropyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dinitrobenzoate ,

5aS, 9aS-2-methylamino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline malteate,

5aS, 9aS-2-amino-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline sulfate,

5aS, 9aS-2-dimethylamino-4-methyl-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline succinate,

5aS, 9aS-2-ethylamino-4-chloro-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline mesylate,

5aS, 9aS-2-allylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline phosphate,

5aS, 9aS-2-methylethylamino-6-allyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline citrate,

5aS, 9aS-2-methylamino-6-allyl-4-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline laclate,

5aS, 9aS-2-amino-6-allyl-4-bromo-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline sulfate,

5aS, 9aS-2-dimethylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline maleate,

5aS, 9aS-2-dimethylamino-6-ethyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline maleate and the like.

Compounds of formula (I), (II) and (IIa) are prepared as follows:

(a) condensation of a compound of formula (V) with a compound of formula (VI) or a salt thereof to give a compound of formula (I), or

[Wherein R and R ₁ are as defined above and Y is CH ₃ CO or (R ¹⁰ ) ₂ NCH = (where R ¹⁰ is each C ₁ -C ₃ alkyl or one is H and the other is C ₁ -C ₃ 3 alkyl).

(b) alkylating the compound of formula (Ia) to afford a compound of formula (I), or

(Wherein R and R ¹ are as described above)

(c) halogenating the compound of formula (I f) to afford a compound of formula (I) wherein R ² is CI or Br,

(Wherein R and R ¹ are as described above)

(d) acylating the compound of formula (I) wherein R ¹ is NH ₂ to obtain a compound of formula (I) wherein R ¹ is NHR ³ , wherein R ³ is R ⁶ -CO;

(e) optionally chloride to form pharmaceutically acceptable acid addition salts of the product of formula (I), and / or the racemic product is cleaved to form the optically active product of formula (I).

Compounds of formula (I), (II) or (IIa) are used as medicaments in their free base form or in the form of pharmaceutically acceptable acid addition salts.

Compounds represented by formulas (I) and (II) are dopamine D-2 agonists with little other agonistic or antagonistic (blocking) action. The compounds of the present invention are useful for treating Parkinson's syndrome and sexual dysfunction as D-2 dopamine agonists, and for lowering blood pressure and suppressing prolactin secretion in mammals as antidepressants or anti-anxiety agents. The compounds of formulas (I) and (II) are therefore useful for the treatment of disease conditions characterized by hypertension, depression, anxiety, Parkinson's syndrome, sexual dysfunction, and excessive prolactin secretion, such as lacusea and inadequate milk secretion. .

The compound represented by general formula (IIa) is a dopamine D-1 agonist. When stimulated with D-1 agonists, dopamine D-1 receptors are characterized by increased cyclic AMP release. This effect is inhibited with D-2 agonists. Stoof and kebabiem discussed the effects of D-1 agonists in a paper in the following literature (Natmre, 294, 266 (1981) and Braim Res., 250, 263 (1982)). . Compounds of formula (IIa) are potentially useful as neovascular dilators and therefore useful for treating hypertension.

Also an embodiment of the present invention is the preparation of a pharmaceutical formulation in administering a medicament of general formulas (I), (II) and (IIa) in the above-described treatment method.

Pharmaceutical formulations containing the general formula (I), (II) or (IIa) or pharmaceutically acceptable salts thereof as active ingredients, together with one or more pharmaceutically acceptable carriers or diluents, are within the scope of the present invention. Belong.

Intermediates useful in the preparation of compounds of general formula (I), (II) or (IIa) are represented by the following general formulas (II), (IV) or (IVa) or acid addition salts thereof.

In the formula, R ¹ and R ² are as defined in general formula (I) and R ⁸ is H, CN or (C ₁ -C ₃ alkoxy) -CO.

Another group of intermediates useful for the preparation of compounds of general formula (I), (II) or (IIa) is represented by the following general formula (Va).

Wherein R ⁹ is H, CN, C ₁ -C ₃ alkyl or allyl, and R ¹² is methyl or C ₁ -C ₃ alkoxy.

Compounds of formula (I), (II) or (IIa), wherein R ² is H, can be prepared as shown in the following scheme:

Wherein R ¹ , R ⁹ and R ¹⁰ are as described above.

The process is similarly applicable to the synthesis of trans-(-)-stereoisomer (Ib) or trans-(+)-stereoisomer (Ic).

Wherein R ¹ and R ⁹ are as defined above. Suitable solvents are polar organic solvents, for example C ₁ -C ₄ alkanols, dimethylsulfoxide (DMSO), dimethylformamide (DMF), and acetonitrile. The reaction is carried out at reflux at room temperature, preferably under an uncertain air (eg nitrogen).

Optically active ketones (Xa and Xb below) are used to prepare the following optically active intermediates (Vb) and (Vc).

Wherein R ⁹ and R ¹⁰ are as described above. The preparation of optically active ketone Xa is described below and the preparation of stereoisomeric ketone Xb is also described below.

Similar synthetic methods are used for the preparation of compounds according to general formula (I), (II) or (IIa), wherein R ^X is not H.

Wherein R ¹ and R ⁹ are as described above, R ¹² is CH ₃ or C ₁ -C ₃ alkoxy and R ^11a is CH ₃ or OH.

At the end of the ring closure reaction, R ¹² of the ester group is substituted with OH to give a 4-OH derivative. This OH derivative is then halogenated to give a compound of formula (I) wherein R ² is CI or Br. Suitable halogenation reagents are POCI ₃ , PBr ₃ , SOCI ₂ or SOBr ₂ . The reaction is usually carried out at reflux temperature. Ether solvent may optionally be present.

Using the same process, compounds of the following general formula (I d) are produced from trans-(-) enantiomers, and compounds of the following general formula (I e) are respectively produced from trans-(+)-enantiomers. The product is converted to a compound wherein R ^11a is OH and converted to a compound of formula (II) or (IIa) by halogenation.

Starting material (Va) of Synthesis Method 2 was prepared according to the following process: Ketone (trans racemate X, trans-(-)-stereoisomo Xa and trans-(+)-stereoisomer Xb) For example, plated with C-7 with lithium diisopropylamide (LiN [CH (CH ₃ ) ₂ ]) to form an enol anion. This anion is then reacted with acetyl chloride or dialkyl carbonate to give the compound represented by general formula (Va). The latter compound is converted to the desired pyrimidine and purified from impurities.

Finally, compounds of formula (I), (II) or (IIa) are most readily prepared using ketones (X, Xa or Xb) as starting materials.

Wherein R is C ₁ -C ₃ alkyl or allyl. The ketone represented by general formula (X) preferably quaternizes the 6-alkoxyquinoline of general formula (XI) with a C ₁ -C ₃ alkyl halide when R is C ₁ -C ₃ alkyl, The quaternized salt is prepared according to the method for obtaining NC ₁ -C ₃ alkyl-6-alkoxy-1,2,3,4-tetrahydroquinoline of formula (XI a).

Wherein R ¹³ is C ₁ -C ₃ alkoxy and R ¹⁴ is C ₁ -C ₃ alkyl. In particular, the C ₁ -C ₃ alkyl group is preserved intact through two reduction steps: Birch reduction followed by sodium cyanoborohydride or borohydride reduction, eventually resulting in octa of Formula (X II) Obtain hydroquinoline.

Wherein R ¹³ and R ¹⁴ are as described above. Treatment with acid then yields enolether X (R is C ₁ -C ₃ alkyl), and X is partitioned as described above to yield Xa.

In addition, the compound according to general formula (I), (II) or (IIa), wherein R is allyl, can be prepared according to the following other steps. Optionally active ketones (Xa) and (Xb) are prepared by splitting trans- (±) -racemate as follows.

The ketone X or Xa is easily converted by treatment with dimethylformamide dimethylacetal to give a compound of formula (V) which is the starting material of Synthesis Method 1.

Another method for preparing the ketone X (where R is C ₁ -C ₃ alkyl) is described in US Pat. No. 4,198,415.

Another intermediate for V, Vb or Vc is 1-alkyl-6-oxo-7-formyldecahydroquinoline, which is described in European Patent Application No. 010496, from 6-oxo derivatives (X, Xa or Xb). A method of making this intermediate is also described.

In addition, intermediates, V, Vb- and Vc are 7-mono- or dialkylaminomethylene derivatives by treating the 1-alkyl-6-oxo-7-formyl-decahydroquinoline with a primary or secondary amine in the presence of a dehydrating agent. It can be prepared by obtaining.

As can be seen from the above description, the group R of general formula (X) remains as it is through the synthesis method. Therefore, to substitute one alkyl group with another alkyl group or allyl, an indirect synthesis method should be used. For example, when R in general formula (X), (Xa) or (Xb) is methyl or n-propyl, 1-cyano-6-oxodecahydroquinoline wherein R ¹⁵ is cyano when reacted with cyanogen bromide (XV), (XVa) or (XVb) is obtained. Hydrolysis of this cyano group affords secondary amines (XV), (XVa) or (XVb), wherein R ¹⁵ is H. Similarly, a compound of formula (X), (Xa) or (Xb), wherein R is methyl, is reacted with ethyl chloroformate to give an intermediate (XV), (XVa), wherein R ¹⁵ is C ₂ H ₅ -O-CO or (XVb) can be obtained and also hydrolyzed to give the corresponding compound (XV), (XVa) or (XVb), wherein R ¹⁵ is H.

Secondary amines (XV), (XVa) or (XVb) in which R ¹⁵ is H can then be optionally alkylated with the same or different alkyl groups, or allylated if the allyl group is intended to have cyclic nitrogen. The highly reactive allyl halides in this synthetic method can be used to obtain compounds (X), (Xa) or (Xb) in which R is allyl.

Further alternatively, R ¹⁵ is a compound (XV), (XVa) or (XVb) is reacted with guanidine, R ¹ is NH ₂ and R ² is H and R ⁸ is CN in the general formula (III) CN, New intermediates (IVb), (IVc) and (IVd) of (IV) or (IVa) can be obtained:

Hydrolysis of the cyano product affords compounds of formula (III), (IV) or (IVa), wherein both R ⁸ and R ² are H and R ¹ is NH ₂ . Hydrolysis is acidic hydrolysis using aqueous hydrochloric acid, zinc chloride in acetic acid, or zinc in acetic acid under standard conditions. This compound may then be optionally alkylated or allylated to afford a medicament of Formula (I), (II) or (IIa), wherein R ¹ is NH ₂ and R ² is H and R is as described above. . Alkylation (allylation) is carried out in a conventional manner. For example, alkyl halides (or allyl halides) in polar organic solvents such as DMF; Reductive amination reactions with aldehydes and catalytic hydrogenation (P ₂ on H ₂ / carbon), formaldehyde / formic acid, or aldehydes and sodium cyanoborohydride with trace acids in an alcohol or polar organic solvent; Amides formed by treating the secondary amines with an acid halide or anhydride and a base such as triethylamine or pyridine and a solvent such as ether, dioxane, tetrahydrofuran (THF) or dimethoxyethane (DME). Reduction of aluminum lithium hydride or diborane, and this process also involves labeling the R group at the last stage of the synthesis to avoid entailing uneconomical (isotopic or radioactive) labeling molecules through various lossy synthetic methods. It is a good way to introduce.

Another method of synthesis is useful in the manufacture of pharmaceuticals in which R is allyl. This method applies the karmfeld-Bach synthesis method described in Scheme 1 of US Pat. No. 4,198,415. Using allyl halide in step 2 of the process of this patent, trans- (±) -1-allyl-6-oxodecahydroquinoline is obtained. This N-allyl derivative is then converted to trans- (±) -1-allyl-6-oxo-7- (dimethylaminomethylene) -decahydroquinoline of formula (V) wherein R ⁹ is allyl. The racemate may then be split to yield trans-(−)-enantiomers or trans-(+)-enantiomers.

Compounds of general formula (I), (II) or (IIa) wherein R ¹ is NHR ³ , R ² is H, CH ₃ , CI or Br and R ³ is R ⁶ -CO, R ¹ is NH ₂ Compounds of formula (I a) (or 5aR, 9aR stereoisomers or 5aS, 9aS stereoisomers) with acid chlorides or anhydrides under standard reaction conditions, e.g. salts (e.g. pyridine), solvents (e.g. ether And acylation in the presence of a catalyst (dimethylamine in pyridine).

Finally, there are two methods of preparing trans-(-) or 5aR, 9aR derivatives (II), or trans-(+) or 5aR, 9aR derivatives (IIa).

The first method is a fragment such as d-(-)-tartaric acid, or trans- (±) -2-substituted-6-C ₁ -C ₃ alkyl (allyl) -5,5a, 6,7,8,9 The trans- (±) racemate (I) was prepared using another suitable optically active acid that forms a salt with the trans-(-)-component of the, 9a, 10-octahydropyrimido [4,5-g] quinoline. To divide. Similarly, 5aS, 9aS-stereoisomers are obtained using opposite coordinating splitting agents (e.g., 1-(+)-tartaric acid). Preferably, however, the cleavage is carried out on bicyclic ketone (X) or (XV) to give 4aR, 8aR-1-alkyl (or allyl) -6-oxodecahydroquinoline, and (-)-di-P- Form the salt with 4aR, 8aR-ketone using tulloyl tartaric acid, and salt with the 4aS, 8aS-ketone using (+)-di-P-toluoyl tartaric acid. The split ketones are then reacted with dimethylformamide dimethylacetal, tris (dimethylamino) methane or ethyl formate followed by (CH ₃ ) ₂ NH followed by 4aR, 8aR-or of formula (Vb) or (Vc) 4aS, 8aS) -alkyl (or allyl) -6-oxo-7- (disubstituted aminomethylene) decahydroquinoline can be obtained.

Wherein R ⁹ and R ¹⁰ are as described above. The general formula (Vb) or (Vc) can then be reacted with the following general formula (VI) to obtain the optically active derivative (II) or (IIa) directly or indirectly.

Wherein R ¹ is as defined above.

Salts can be obtained from this process. The conversion of the obtained salts to the corresponding free bases is easily carried out by dissolving the salts in water followed by addition of excess aqueous bases (NaOH, Na ₂ CO _3, etc.). The free base insoluble in the basic solution is separated and the water immiscible organic solvent is extracted. The organic extract is then separated and dried. A solution containing 1 equivalent of other non-toxic acid is then added to separate the salt obtained by filtration and the solvent is evaporated. Alternatively, the solvent may be removed from the dried organic extract to obtain a free base as a residue. The free base is then dissolved in a suitable solvent and nontoxic acid is added to the solution. Preferred salts are HCI salts, for example, which can be obtained by adding 1 equivalent of ethanolic hydrogen chloride to an ethanol solution of free base, followed by evaporation of ethanol and recrystallization of the residual salt. To prepare a dichloride, such as dihydrochloride, the HCI gas is placed in a free base solution to the saturation point and the dichloride is separated as described above.

The compounds represented by formula (I), (II) or (IIa) each have two or more basic centers. The most basic of these are octahydroquinoline cyclic amino groups. This group easily forms salts with pharmaceutically acceptable acids. There is also a less basic amine group, which will react with pharmaceutically acceptable strong inorganic acids (e.g. mines) or strong organic acids (e.g. P-toluenesulfonic acid) to form the bis salt. Pharmaceutically acceptable acid addition salts therefore include salts 1 or 2 derived from inorganic acids such as those previously described herein.

The invention is explained in more detail by the following specific examples.

Preparation of Starting Materials and Intermediates

Example A

Preparation of 4aR, 8aR-1-m-propyl-6-oxotecahydroquinoline.

=-107.49°(MeOH, C=1), 메탄올로부터 염을 재결정시켜

=-108.29°(MeOH, C=1)인 1.943g의 광학적으로 순수한 염을 수득하였다.10 g of (-)-di-P-toluoyltartaric acid is dissolved in 75 ml of warm methanol. This solution is added to a 5.05 g trans-dl-1-n-propyl-6-oxodecahydroquinoline solution in 15 ml of methanol. The reaction mixture is boiled and left to cool to ambient temperature. After standing overnight at ambient temperature, crystallization is carried out with the addition of seed crystals obtained beforehand. The crystalline tartarate salt is separated by filtration and the filter cake is washed with methanol; Yield = 2.813 g (18.7%) of white crystalline solid containing (a) -di-P-toluoyl tartrate of 4aR, 8aR-1-n-propyl-6-oxotecahydroquinoline;

= -107.49 ° (MeOH, C = 1), recrystallize salt from methanol

1.943 g of optically pure salt with = -108.29 ° (MeOH, C = 1) were obtained.

=-88.51°(MeOH, C=1)The obtained (-)-di-P-toluoyl tartrate salt is treated with dilute aqueous sodium hydroxide and the obtained alkaline solution is extracted with methylene dichloride. This methylene dichloride extract is dried and concentrated from which the solvent is removed in vacuo. The obtained residue was distilled off to obtain a colorless oil containing purified 4aR, 8aR-1-n-propyl-6-oxodecahydroquinoline;

= -88.51 ° (MeOH, C = 1)

Other 1- (alkyl, allyl, benzyl or cyano) -6-oxodecahydroquinolines can be cleaved in a similar manner.

Example B

Preparation of 4aS, 8aS-1-n-propyl-6-oxodecahydroquinoline

The partitioning of trans- (±) -1-n-propyl-6-oxo-decahydroquinoline is carried out according to the following procedure: 10 g of (-)-di-p-toluoyltartaric acid are dissolved in 75 ml of warm methanol. Let's do it. This solution is added to a 5.05 g trans- [±] -1-n-propyl-6-oxodecahydroquinoline solution in 15 ml of methanol. The reaction mixture is boiled and left to cool to ambient temperature. After standing overnight at ambient temperature, crystallization is carried out with the addition of seed crystals obtained beforehand. Crystalline tatarate is separated by filtration and the filter cake is washed with methanol;

=-107.49°(MeOH, C=1).4aR, yield containing (-)-di-p-toluoyl tartrate of 8aR-1-n-propyl-6-oxotecahydroquinoline = 2.813 g (18.7%) of white crystalline solid;

= -107.49 ° (MeOH, C = 1).

=+106.3°(메탄올, C=1.0) ;

=+506.7°(메탄올, C=1.0). 상기 화합물은 약 9%ee의 광학적 순도를 나타냈다. 모액으로부터의 두번째 수득물을 상기한 바와 같이 결정화시켜 융점이 약 166.0 내지 166.5℃(분해)인 2.3g의 백색 고체를 수득하였다 ;The free base formed by mixing the filtrate and mother liquor containing the tartrate obtained from the above process or similar larger scale process and treating the mixed filtrate with alkali, is rich in 4aS, 8aS-isomers, A 1-n-propyl-6-oxocatecahydroquinoline solution without 4aR, 8aR-isomer is obtained. This solution was treated with (+)-ditoluyl tartaric acid monohydrate according to the above procedure to obtain 4aS, 8aS-1-n-propyl-6-oxotecahydroquinoline-(+) of about 80% ee optical purity. Obtain ditoluoyl tartrate (excess of ee-enantiomer). 20 g of the salt was crystallized with 250 ml of methanol to obtain 12 g of a white crystalline powder having a melting point of 167.5 to 169.5 ° C. (decomposition);

= + 106.3 ° (methanol, C = 1.0);

= + 506.7 ° (methanol, C = 1.0). The compound showed an optical purity of about 9% ee. The second crop from the mother liquor was crystallized as above to yield 2.3 g of a white solid having a melting point of about 166.0 to 166.5 ° C. (decomposition);

=106.0°;=+510.8°

= 106.0 °; = + 510.8 °

=+86.2°;

=+376.6°(둘다 메탄올, C=1.0) ; 광학적 순도=약 98%ee,(Both methanol, C = 1.0) and had an optical purity of about 94% ee. The first and second crystals obtained are recrystallized from methanol to give a white solid from which a free base is obtained by standard processes. This free base was distilled off to obtain 4.14 g of colorless oil boiling at 82 to 86 DEG C and 0.13 Torr containing 4aS, 8aS-1-n-propyl-6-oxotecahydroquinoline;

= + 86.2 °;

= + 376.6 ° (both methanol, C = 1.0); Optical purity = 98% ee,

In contrast, trans- [±] -1-n-propyl-6-oxodecahydroquinoline was directly treated with (+)-di-p-toluoyltartaric acid to provide 4aS, 8aS-1-n-propyl-6 -Oxotecahydroquinoline-(+)-di-p-toluoyl tartrate can be obtained and purified according to the above process.

Example C

Preparation of trans- (±) -1-n-propyl-6-oxo-7-ethoxycarbonyldecahydroquinoline

A suspension of 790 mg of sodium hydride (55% in mineral oil) is placed in a 50 ml round bottom flask and the mineral oil is removed with three hexane washes. The solid residue, sodium hydride, is suspended in 8 ml of THF and 1.45 ml (1.41 g) of diethylcarbonate is added together with a drop of anhydrous ethanol. The resulting solution is heated to reflux and 1.1 g of trans- (±) -1-n-propyl-6-oxo-ethoxycarbonyldecahydroquinoline in 5 ml of THF is added over 5 minutes. The resulting mixture is heated to reflux overnight.

TLC showed no residual starting material and there was a new slower moving spot. The reaction mixture is poured into water to bring the pH of the aqueous layer to about 14. The alkaline layer is extracted with methylene chloride. After adjusting the pH of the aqueous layer to about pH = 9, the alkaline layer is extracted again with methylene chloride. The methylene dichloride extract was mixed and the mixed extract was dried and the solvent was removed therefrom to form trans- (±) -1-n-propyl-6-oxo-7-ethoxycarbonyl-decahydroquinoline formed in the reaction. 1.56 g of a yellow oil containing were obtained. The residue is chromatographed on woelm silica (100-200 mesh) using a 1: 1 ether / hexane solvent mixture containing traces of 14N aqueous ammonium hydroxide as eluent. Fractions containing the desired product were mixed to finally yield 880 mg (55% yield) of yellow oil. The keto ester was present in the form of yen represented by the following structural formula by nmr.

The compound has the following nmr spectrum: nmr (CDCI ₃ ): 12.20 (s, 1H); 4.28 (q, J = 7.2H); 3.20-1.10 (m, 16H); 1.36 (t, J = 7, 3H); 0.95 (t, J = 7, 3 H).

Example D

Preparation of trans- (±) -1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline

4 g of trans- (±) -1-n-propyl-6-oxo-decahydroquinoline is added to 5.6 g of potassium tert-butoxide solution of tetrahydrofuran strain of about 50 ml of anhydrous distillation. The reaction mixture is stirred for 30 minutes under a nitrogen atmosphere. Then 3.6 ml of ethyl formake is added dropwise while the reaction mixture is cooled in an ice-alcohol bath. After completion of the addition, the reaction mixture is stirred overnight at ambient temperature under nitrogen. The reaction mixture in the solid slurry state is neutralized with ice acetic acid. Methanol is added to this slurry, followed by 1 ml of dimethylamine. 3A molecular sieve is added to facilitate dehydration. The reaction mixture is stirred under nitrogen atmosphere for 48 hours and then filtered. The filtrate is evaporated to dryness in vacuo. Water is added and the aqueous mixture is extracted three times with the same volume of methylene chloride. The methylene dichloride extract is mixed and the mixed extract is washed with water and then dried. Methylene dichloride was evaporated to yield 4.15 g (81.4%) of trans- (±) -1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline.

Example E

Preparation of trans- (±) -2-amino-6-cyano-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

A reaction mixture was prepared from 16 g of trans- (±) -1-methyl-6-oxodecahydroquinoline (by the process of Bark and Confeld of US Pat. No. 4,198,415), 26 g of cyanogen bromide and 450 ml of methylene chloride do. The reaction mixture is stirred overnight at room temperature and then extracted three times with 1N aqueous hydrochloric acid. The reaction mixture extracted with acid is washed with saturated aqueous sodium bicarbonate and then dried. Any volatiles are evaporated off under vacuum. The residue obtained was a semi-solid oil containing 18,8 g of trans- (±) -1-cyano-6-oxodecahydroquinol formed in the reaction. This oil is chromatographed on Florisil using chloroform as eluent to give a total of 11.5 g (66%) of the purified material fraction. This oil was left to crystallize to give white crystals.

4. Prepare a reaction mixture from 18 g of trans- (±) -1-cyano-6-oxodecahydroquinol, 5.0 g of tris-dimethylaminomethane and 50 ml of toluene. The reaction mixture is refluxed under nitrogen atmosphere for 5 hours and then concentrated in vacuo. 5/100 and 76 g of a pale yellow solid containing trans- (±) -1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline is obtained. This crude product is mixed with 2.25 g of guanidine carbonate in 100 ml of absolute methanol. The reaction mixture is heated to reflux overnight under nitrogen and then concentrated in vacuo. The solid residue obtained is triturated with hot methanol and filtered. This filter cake is washed twice with methanol and once with ethanol. 4.11 g (78%) of trans- (±) -2-amino-6-cyano-5,5a, 6,7,8,9,9a, 10-octahydropyrimidine with the following physical properties [4,5-g] quinoline was obtained. Molecular ions at mass spectrum, 229; IR spectral peaks (cm ⁻¹ ) at 3307.18, 3157.70, 2202.87, 1660.83, 1599.10, 1564.38, 1486.26.

Elemental analysis

Calc .: C, 62.86; H, 6. 59; N, 30.54

Found: C, 63.18; H, 6. 70; N, 30.24.

Example F

Preparation of trans- (±) -2-amino-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

The reaction mixture is prepared from 1.66 g of the 6-cyano compound of Example E, 9.7 g of zinc powder, 200 ml of acetic acid and 50 ml of water. The reaction mixture is heated to reflux temperature under nitrogen atmosphere for about 24 hours and then stirred at room temperature for 48 hours. Any volatiles are removed from the reaction mixture under vacuum and the residue obtained is dissolved in water. This aqueous mixture is made basic with 50% aqueous sodium hydroxide (final pH is 10-11). A cloudy white precipitate forms. The basic solution is filtered and the filtrate is extracted three times with a solvent mixture of 3: 1 volume ratio of chloroform / isopropane. The organic extracts are mixed and dried. The solvent is removed in vacuo to contain trans- (±) -2-amino-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline free base 0.43 g of a light yellow powder was obtained. This free base was converted to hydrochloride and recrystallized from a methanol / acetate solvent mixture to yield a crystalline material having a melting point of at least 230 ° C.

Elemental Analysis (after drying at 150 ℃)

Calc .: C, 47.66; H, 6.55; N, 20.21

Found: C, 47.37; H, 6.65; N, 19.91

Alkylation or allyl halide of the prepared trans- (±) -2-amino-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline with lower alkyl halides Allylation can be carried out to obtain a compound within the range of the general formula (I).

Some of these preparations are carried out with racemates. This is known to those skilled in the art, and these chemical steps can be performed on isolated trans-(-)-or trans-(+) stereoisomers to obtain optically active intermediates and final products.

Example G

Of trans- (±) -2-amino-4-hydroxy-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline Produce

The reaction mixture was prepared from 2.0 g of trans- (±) -1-n-propyl-6-oxo-7-ethoxycarbonyldecahydroquinoline (prepared in Example C), 20 ml of absolute ethanol and 0.67 g of guanidine carbonate. Manufacture. The reaction mixture is heated to reflux overnight under nitrogen atmosphere. The white precipitate formed is collected by filtration and the filter cake is washed with ethanol and then dried; Yield = 1.36 g The filter cake is dissolved in 52 ml of 0.1N aqueous hydrochloric acid. The acidic mixture is filtered and the filtrate is concentrated in vacuo. The solid residue is dissolved in boiling methanol. This methanol solution was obtained by filtration. Trans- (±) -2-amino-4-hydroxy-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [ Crystallization of 4,5-g] quinoline hydrochloride gave 0.79 g of free base product having the following physical properties: Molecular ions at mass spectrum, 262.

Elemental analysis

Calc .: C, 64.09; H, 8. 45; N, 21.36

Found: C, 64.18; H, 8.51; N, 21.13.

Preparation of the final product

Example 1

Preparation of trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

The reaction mixture is prepared from 1.8 g of trans- (±) -1-methyl-6-oxodecahydroquinoline and 2.2 g of tris-dimethylaminomethane in 18 ml of toluene. The reaction mixture is refluxed for about 12 hours under vacuum. 0.8 g of tris-dimethylaminomethane is added and refluxed further under nitrogen for 5 hours. The reaction mixture is then concentrated to dryness in vacuo. The obtained residue containing trans- (±) -1-methyl-6-oxo-7- (dimethylaminomethylene) decahydroquinoline formed in the reaction was dissolved in 40 ml of ethanol, and 1.5 g of guanidine carbonate was added thereto. do. The resulting mixture is heated to reflux overnight under a nitrogen atmosphere. While cooling, the crystalline precipitate formed is collected by filtration and the filter cake is washed with ethanol; Yield = 0.68 g (38%) of light yellow powder. This material is dissolved in 1N aqueous hydrochloric acid. The acidic solution is then made basic using 10% aqueous sodium hydroxide.

Trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline free base insoluble in the alkylic layer Is separated and extracted with chloroform. This chloroform extract is dried and the chloroform is removed in vacuo. The residue containing trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline is suspended in ethanol And ethanol solution is saturated with hydrogen chloride gas.

The solvent was removed in vacuo and the resulting residue, trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5 -g] dihydrochloride of quinoline is recrystallized from hot ethanol. 66 mg of dihydrochloride were obtained having a melting point of 262 to 275 ° C. (decomposition) and having the following elemental analysis value (after drying at 150 ° C.):

Theoretic value: C, 49.49; H, 6.92; N, 19.24

Found: C, 49.61; H, 7.03; N, 18.92

Drying at high temperatures is necessary because the dihydrochloride crystallizes as a solvent compound after drying at low temperatures, and the solvent must be removed by drying to obtain reproducible analysis.

Example 2

Preparation of trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

Example 1 reaction except 1 g of trans- (±) -1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline was reacted with 0.4 g of guanidine carbonate in 20 ml of absolute ethanol Repeat (trans- (±) -1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline is trans- (±) -1-n-propyl-6-oxodecahydroquinoline and tris Prepared according to the above process from dimethylaminomethane). The reaction mixture is heated overnight at reflux temperature until a precipitate is observed. The reaction mixture is cooled in an ice bath to form trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4 formed in the reaction. A light yellow crystalline precipitate containing, 5-g] quinoline was obtained. The filter cake was washed with ethanol and dried: melting point = 260 ° C. or higher, yield = 0.6 g (61%)

Calc .: C, 68.26; H, 9.00; N, 22.74

Found: C, 68.45; H, 8. 87; N, 22.26

Trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline in 1N aqueous hydrochloric acid The acidic solution is extracted with ether. The acidic solution is then made basic with 10% aqueous sodium hydroxide. Precipitated trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline was isolated by filtration Let's do it. The free base is dissolved in 1N aqueous hydrochloric acid and the water is removed in vacuo. The obtained residue is recrystallized from hot ethanol.

Yield = 0.54 g (40%). The resulting trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dihydrochloride is It had a melting point of 225 to 270 ° C. and the following analysis.

Elemental _{analysis: (C 14 H 22 N 4} · 2HCI · H 2 O)

Calc .: C, 49.74; H, 7.75; N, 16.57; CI, 20.97

Found: C, 49.88; H, 8.03; N, 16.81; CI, 20.87.

After drying at 120 ° C., water and 1.5 moles of hydrogen chloride due to hydration are removed to give trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8 having the following analytical value , 9,9a, 10-octahydropyrimido [4,5-g] quinoline sesquihydrochloride was obtained.

Elemental _{analysis: (C 14 H 22 N 4} · 1.5HCI)

Calc .: C, 55.86; H, 7.87; N, 18.61; CI, 17.30

Found: C, 55.49; H, 7.83; N, 18.35; CI, 17.03

Example 3

Preparation of 5aR, 9aR-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

4aR, 8aR-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline (4aR, 9aR-1-n-propyl-6-oxodecahydroquinoline and tris-dimethyl according to the process of Example 1 Prepared according to Example A from aminomethane) is reacted with guanidine carbonate in anhydrous ethanol solution. The reaction was carried out and the reaction mixture was finished as in Example 1 to give 2.4 g of 5aR, 9aR-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octa Hydropyrimido [4,5-g] quinoline is obtained.

This product is suspended in ethanol and hydrogen chloride gas is bubbled into the suspension. The resulting solution is evaporated to dryness in vacuo and the residue yellow oil is dissolved in about 10 ml of ethanol. Ether is added to the starting point of precipitation and the mixture is heated in a steam bath. While cooling, the fine powdery crystals formed are separated by filtration. The filter cake was washed with ethanol to give 72 g of 5aR, 9aR-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g ] Dihydrochloride of quinoline was obtained.

Elemental Analysis: (after drying at 180 ℃)

Calc .: C, 52.67; H, 7. 58; N, 17.55

Found: C, 52.81; H, 7.75; N, 17.65

Molecular ions at 246;

=-99.6°;Optical intensity

= -99.6 °;

=-374.8°

= -374.8 °

Example 4

Preparation of trans- (± -2-dimethylamino-6-n-propyl-5,5A, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

The reaction mixture is prepared from 4.7 g of trans- (±) -2-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline and 2.5 g of N, N-dimethylguanidine hydrochloride in 50 ml of anhydrous ethanol. The reaction mixture is heated under nitrogen atmosphere overnight then cooled and the volatiles are removed in vacuo. The residue obtained is dissolved in ethyl acetate and the ethyl acetate solution is reacted with excess 10% aqueous sodium hydroxide.

Trans- (±) -2-dimethylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4], insoluble in the basic layer formed in the reaction. , 5-g] quinoline remains in the ethyl acetate layer. The aqueous layer is separated and the ethyl acetate layer is extracted once with water and once with saturated aqueous sodium chloride. The ethyl acetate layer is dried and ethyl acetate is removed in vacuo to separate 0.75 g of orange oil. The oily residue is chromatographed on Florisil using hexane containing a gradient (1-50 vol%) of ethyl acetate as eluent. Trans- (±) -2-dimethylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline as desired by TLC Fractions shown to contain are mixed and the solvent is removed from the mixed fractions in vacuo. The obtained residue is dissolved in ethanol and hydrogen chloride gas is passed through the solution to form the corresponding hydrochloride. From this ethanol was removed in vacuo and the dihydrochloride was crystallized from a methanol-ethyl acetate solvent mixture to yield 0.170 g of a white solid with molecular ions at 274 and a melting point of at least 250 ° C.

Elemental analysis

Calc .: C, 55.33; H, 8.13; N, 16.13

Found: C, 55.67; H, 8. 19; N, 16.19

Example 5

Preparation of trans- (±) -2-methylamino-6-n-propyl-5,5A, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

According to the process of Example 4, except for replacing N-methylguanidine with N, N-dimethylguanidine, trans- (±) -2-methylamino-6-n-propyl-5,5A, 6,7 Prepare 8,9,9a, 10-octahydropyrimido [4,5-g] quinoline. The compound is purified by chromatography on florisil using methylene dichloride containing a gradient (0 to 10% by volume) of methanol as the eluent; Yield = 0.66 g. .1 equivalent of 0.1N hydrochloric acid is added to the solid to form monohydrochloride, and the product is recrystallized from methanol; Yield = 599 mg, Melting Point = 240 deg.

Elemental analysis

Calculated Value: C, 60.69; H, 8. 49; N, 18.87; CI, 11.94

Found: C, 60.96; H, 8.53; N, 19.07; CI, 11.74

In Examples 1, 2, 4 and 5 above, the optically active 5aR, 9aR or 5aS, 9aS derivatives are the desired 4aR, 8aR- (or 4aS, 8aS) -C ₁ -C ₃ alkyl-6-oxo-7-dimethyl It can be prepared from aminomethylenedecahydroquinoline and appropriate guanidine.

Example 6

Preparation of trans- (±) -2-amino-4-methyl-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

13.7 ml of 1.6 M n-butyllithium in hexane is added to a solution containing 3.1 ml of diisopropylamine and 22 ml of THF at about 0 ° C. under a nitrogen atmosphere to prepare a reaction mixture. The reaction mixture is stirred for about 30 minutes and then 2.0 g of trans- (±) -1-n-6-propyl-oxodecahydroquinoline in a small amount of THF is added while maintaining at about -78 ° C. The solution is stirred for 2 hours and 1.1 ml of acetyl chloride is added. The fresh reaction mixture is stirred at about −78 ° C. for about 30 minutes and then at room temperature for 2 hours. The reaction mixture is then placed in water and the aqueous mixture is acidified to pH 9-10 with 1N aqueous hydrochloric acid. This aqueous solution is extracted three times with the same volume of methylene dichloride. The methylene dichloride extract is mixed and the mixed extract is dried. Evaporate the solvent to afford 2.7 g of trans- (±) -1-n-propyl-6-oxo-7-acetyl-decahydroquinoline. This crude reaction product is mixed (with no further purification) with about 0.9 g of guanidine carbonate. 40 ml of ethanol are added and the reaction mixture is refluxed under a nitrogen atmosphere. The reaction mixture is then evaporated to dryness and the crude product is chromatographed on Florisil. Trans- (±) -2-amino-4-methyl-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g formed in the reaction ] Quinoline-containing fractions are mixed to give 270 mg of free base, to which 10 ml of 0.1N aqueous hydrochloric acid is added. The dihydrochloride formed was recrystallized from ethanol; Melting point = 240 ° C. or higher; Mass spectrum, molecular ion at 260, small peak at 268.

Elemental analysis

Calculated: C, 54.05; H, 7.86; N, 16.81

Found: C, 53.93; H, 7.98; N, 16.61

Example 7

Preparation of trans- (±) -2-amino-4-chloro-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

The 4-hydroxy product obtained in Example G is refluxed with 4 ml of phosphorus oxychloride. Trans- (±) -2-amino-4-chloro-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido formed in the reaction [4,5-g ] The reaction mixture containing quinoline is placed on ice and the aqueous mixture obtained is made basic. The basic mixture is filtered and insoluble matter (30 mg) is dissolved in 0.1N aqueous hydrochloric acid. The hydrochloride formed was recrystallized from ethanol to give 13.6 mg of trans- (±) -2-amino-4-chloro-6-n-propyl-5,5a, 6,7,8,9,9a having the following physical properties , 10-octahydropyrimido [4,5-g] quinoline hydrochloride was obtained. Mass spectrum, molecular ion at 280, small peak at 282

Elemental analysis

Calc .: C, 53.00; H, 6. 99; N, 17.66

Found: C, 53.15; H, 6.92; N, 17.77

In the above reaction, POCI ₃ may be replaced with PBr ₃ to similarly prepare 4-bromo derivatives.

Example 8

Preparation of trans- (±) -2-acetylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

0.75 g of trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido in 20 ml of pyridine [4,5-g ] Prepare a solution containing quinoline and dropwise add 0.34 g of acetic anhydride. The reaction mixture is heated to reflux overnight under a blanket of nitrogen. TLC then showed that the starting material was still present; Thus, about 1.5 ml of acetic anhydride is added and the reaction mixture is again heated to reflux under a blanket of nitrogen. TLC using a 9: 1 volume ratio chloroform / methanol solvent system containing ammonia showed that the reaction was nearly complete but there was still some starting material present. The reaction mixture is therefore concentrated in vacuo and the residue obtained is triturated with hot ethyl acetate. While cooling, the formed crystals were separated by filtration and 340 mg of trans- (±) -2-acetylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline was obtained. At 0.7 R _f ; Molecular ion at 288; nmr and IR spectra were consistent with the structure predicted.

Example 9

Preparation of trans- (±) -2-benzoylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

According to the process of Example 8, trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g ] Quinoline is reacted with benzoyl chloride in pyridine solution. 450 mg of a yellow oil residue obtained after finishing the reaction mixture as described above is chromatographed on Florisil using floroform and gradient (0-10% by volume) of methanol as eluent. Tenth fraction was indicated by TLC as containing the desired 2-benzoylamino compound. From this the solvent is removed in vacuo. The obtained residue is dissolved in ethanol and hydrogen chloride gas is passed through ethanol solution. Ether was added to the start of precipitation, trans- (±) -2-benzoylamino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5- g] quinoline dihydrochloride; Molecular ions at 350

Elemental Analysis (after drying at 130 ℃)

Calc .: C, 59.57; H, 6.67; N, 13.23

Found: C, 59.35; H, 6. 85; N, 12.99

Example 10

Preparation of 5aS, 9aS-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

A solution is prepared from 3.37 g of 4aS, 8aS-1-n-propyl-6-oxodecahydroquinoline (prepared in Example B) in 60 ml of toluene. 6/100 and 26 g (7.5 ml) of tris (dimethylamino) methane are added dropwise. The resulting mixture was heated to reflux for about 4 hours, with tlc showing no spots corresponding to the starting material. The reaction mixture was concentrated to give 4.813 g of yellow oil, which was chromatographed using 8% methanol in methylene dichloride containing ammonium hydroxide concentrated on a 50 mm x 30 cm silica gel column as the eluent. Fractions indicated by tlc to contain 4aS, 8aS-1-n-propyl-6-oxo-7-dimethylaminomethylcarhydroquinoline were mixed to yield 3.651 g of yellow oil. This material is dissolved in 30 ml of ethanol without further purification and the solution is added to a 2.56 g guanidine carbonate suspension in 70 ml of absolute ethanol.

The reaction mixture is heated to reflux for about 18 hours and then cooled in an ice bath. The precipitate formed was collected by filtration to obtain 5aS, 9aS-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline. 3.506 g of fine bright yellow acicular crystals containing salt are obtained. The salt obtained is converted to dihydrochloride according to standard procedures. The acidic aqueous solution obtained by dissolving dihydrochloride in water is made basic using aqueous sodium hydroxide. The free base insoluble in the alkaline layer is separated and extracted with methylene dichloride. The extract is evaporated to dryness to afford a white foam, which is dissolved in a 1: 1 methanol / methylene dichloride solvent mixture and the solution is saturated with HCI gas. The solution was concentrated to give a yellow foam which was recrystallized from methanol / ethyl acetate to give 5aS, 9aS-2-amino-6-n-propyl-5,5a, 6,7,8,9 having the following elemental analysis A white powder containing the dihydrochloride of, 9a, 10-octahydropyrimido [4,5-g] quinoline was obtained:

Calc .: C, 52.67; H, 7. 58; N, 17.55; CI, 22.21

Found: C, 52.39; H, 7. 36; N, 17.31; CI, 22.40

-+108.3°,

=+405.2°

-+ 108.3 °,

= + 405.2 °

(Both methanol, C = 1.0)

As mentioned above, the compounds of formulas (I) and (II) are dopamine D-2 agonists without any other significant pharmacological action. One such D-2 agonist action is the inhibition of floractin secretion, as shown by the following process.

Mature male rats of Sprague-Dawley, weighing about 200 grams, are bred by random feeding of experimental food and water in a controlled light (6 am to 8 pm) and in an air-conditioned room. Each rat is intraperitoneally injected with 2.0 mg of selselpin in an aqueous suspension 18 hours before the test drug administration. This is to evenly raise the rat prolactin concentration. Test compounds are dissolved in 10% ethanol and injected intraperitoneally at a dose of 1 μg / kg to 100 μg / kg. The test compound is administered to 10 rat groups at each dose level and an equal amount of 10% ethanol is fed to the control of 10 untreated rats. One hour after treatment, all rats are killed by a head lice and analyzed for prolactin with 150 ul of serum.

The prolactin concentration difference between the treated and control rats showed that the prolactin concentration in the control rats provided a prolactin secretion rate due to the previous dose. Inhibition rates are shown in Tables 1 and 2 below for compounds of formula (I) or (II), respectively. In these tables, columns 1, 2 and 3 represent substitutions in the basic formula above, column 4 forms (salt or free base-FB), column 5 represents the route of administration, 6, 7, 8, 9 and 10. The heat represents the rate of prolactin inhibition at specific dose concentrations. In some instances, one compound was tested at least once at a particular dosage, and the prolactin levels in the table are averaged from several tests.

TABLE 1

TABLE 2

In addition, the compounds of the general formulas (I) and (II) are also orally active. The second compound in Table 1, trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline Inhibition of 74% when the oral administration of dihydrochloride at 10 μg, and 91% when oral administration at 50 μg / kg was shown.

Compounds of formulas (I) and (II), a dopamine D-2 agonist, have been shown to affect treatment in rats with 6-hydroxydopamine removed in a test process designed to find compounds suitable for treating Parkinson's syndrome. In this study, black nigroneostriatal-damaged mice use those made by the Ungerstedt and Arbuth-nott processes (Brain Res, 24, 485 (1970)). Compounds with a dopamine agonist action cause a cycle change on the opposite side of the injury site of the rat. After the incubation period, the number of treatments for the rats is shown after 15 minutes with varying doses of the compound.

The test results are described in Table 3 below. In this table, columns 1 and 2 represent the substitution form of the compound on the table, column 3 represents the percentage of test animals indicating treatment of the disease, and column 4 represents the mean size of treatment for the rats observed 15 minutes after the end of the incubation period.

TABLE 3

* 5aR, 9aR-isomers

In addition, the compounds of formulas (I) and (II) are active for their therapeutic effect even by oral administration, although some higher doses are required to obtain effective results.

Compounds of Formulas (I) and (II) reduce blood pressure in naturally occurring hypertensive rats, as demonstrated by the following experiments: Naturally occurring hypertensive rats (SHR), about 300 g of mature male (Taconic Farm) Germantown, New York) is anesthetized with pentobarbital sodium (60 mg / kg, intraperitoneally). Insert the trachea to breathe the SHR into the room air. Arterial blood pressure is measured from the inserted carotid artery using a statam transducer (P 23 ID). Average arterial blood pressure is calculated as diastolic blood pressure plus 1/3 pulse pressure. The heart rate is monitored by a long-term heart rate meter braked by a contraction pressure pulse. The drug solution is administered intravenously via a catheter placed in the femoral vein. Arterial blood pressure and heart rate are recorded on a multichannel oscillogram (Beckman, Model R 511A). After 15 minutes to equilibrate the drug, the next operation is performed.

Table 4 below shows trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline for Test result. In Table 4, column 1 represents dose, column 2 represents changes in mean arterial blood pressure and standard error, and column 3 represents percent change in heart rate and standard error, respectively.

TABLE 4

* Changes were measured immediately after injection.

Vaseline average arterial blood pressure is 181 ± 1.0 mmHg, and average heart rate is 366 ± 15 beats / minute.

** Average response to 4SHR

Also, trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline and trans- (-)-Stereoisomers are also potent activators of cholinergic neurons that lead to elevated acetylcholine levels in the rat striatum.

A substituted 6-alkyl (or allyl) -octahydropyrimido [4,5-g] quinoline that is trans- (±) or trans-(-)-2-amino-4 affecting mammalian sexual behavior or The ability of its salts (compounds of formulas (I) and (II), respectively) is illustrated by the following experiment.

Use male rats that require at least five minutes to ejaculate. Sexually soluble rats are introduced into the intestinal tract to initiate testing and immediately stop after the first mount after assessment. The following behavior indices were measured.

Behavior index definition

Mount latency (ML): time from introduction of the rat to the first mount

2. Insertion incubation period (IL): The time from the mouth to the first insertion of the female

3. Ejaculation incubation (PEL): time interval from insertion to ejaculation

4. Transfer interval (PEI): Time interval from assessment to next mount

5. Mount Frequency (MF): The total number of mounts required to get the situation.

6: Frequency of Insertion (IF): Total number of inserts and mounts required to obtain ejaculation

Vehicle singlets in water (1 mmol acetic acid + 1 mmol ascorbic acid) or trans-(-)-2-amino-6-n-propyl-5,5a in the same vehicle prior to the test. 25 mcg / kg of 6,7,8,9,9a, 10-octahydropyridodo [4,5-g] quinoline dihydrochloride is administered by subcutaneous injection for 30 minutes. One week after the drug test, the vehicle alone is retested.

The experimental results are shown in Table 5 below. Column 1 in the table represents the treatment, and columns 2 through 7 represent the behavioral index (X ± SE for 9 mice) for treatment in column 1.

TABLE 5

* Seconds like ML, EL, and PEL.

** MF and IF values are expressed in number of mounts.

The results of repeated tests of 0.25 mcg are shown in Table 6 below (values represent X ± SE for 11 rats).

TABLE 6

According to the data in Table 5 above, the drug is used in vehicle incubation period (EL) and mount frequency (MF) when the compound is compared with vehicle treatment before or after treatment and in incubation period (IL). Statistically significant improvement compared to before treatment. These data indicate remarkable improvements in sexual behavior, especially related to the effectiveness of the agent. According to the data in Table 6 above, in the incubation period (EL) by subcutaneous administration of the drug at 250 mg / kg, a statistically significant improvement compared to before the vehicle treatment was calculated. Although there was no statistically significant difference in the comparison of the mean performance between drug and subsequent vehicle response, 6 of 11 rats showed better performance at each performance index according to drug treatment compared to vehicle treatment, It is important that 8 to 9 of the 11 showed improvements in mount frequency and insertion frequency, respectively. These data show trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dihydrochloride It supports the view that even a dose as low as 250 mg / kg has a behavioral effect. Similar behavioral experiments were performed with subcutaneous administration of 2.5 mg / kg doses, but no behavioral effects were observed.

Trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline for sexual activity in male rats The effect of dihydrochloride was also evaluated in rats that showed no mating behavior or did not ejaculate within 30 minutes of testing. The effect of drug subcutaneous administration of 25 mcg / kg on the mating behavior of this animal is summarized in Table 7.

The agent has been shown to have the ability to induce sexual activity in animals that do not exhibit sexual activity and to promote sexual activity in animals that do not obtain ejaculation. The mating behavior of rats from these groups, which could be assessed after drug treatment and subsequent vehicle treatment, was evaluated. These animals showed a significant decrease in the number of mounts (mount frequency) required for ejaculation by drug treatment compared to vehicle treatment.

TABLE 7

Effect of Drug (25mcg / kg, Subcutaneous) Alone Administration on the Breeding Behavior of Inability Rats

Percent of rats indicating mating behavior

Vehicle (1 week ago) 0.0% (0/8)

Pharmaceutical 87.5% (7/8)

Vehicle (1 week later) 37.5% (3/8)

Percentage of weeks that can get matters to 30 minutes

Vehicle (front) 0.0% (0/14)

Pharmaceutical 92.9% (13/14)

Vehicle (after) 50.0% (7/14)

Male's ability to ejaculate

* Much bigger than a drug. (P <.003)

Trans- (±)-and trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyritic for sexual activity of stray animals in females The effect of dominant [4,5-g] quinoline dihydrochloride is evaluated in ovarian retreated estrogen-treated mice. The change in lordosis-to-mount ratio was measured (increase indicated by females to mount by males per mount).

Forman and Morse's protocol were used (Physiology and Behavior, 22,283 (1979)). Table 8 below provides the results of this experiment. In the table, column 1 represents the name of the drug used, column 2, if any, dose (mcg / kg), and column 3 represents changes in spinal deformity-to-mount ratio and standard error.

TABLE 8

* Much larger than vehicle (P <.05)

** Much greater than trans- (±) (P <.05)

Similar experiments were carried out with two stereoisomers, trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5 -g] quinoline and trans-(+)-isomers. The response to the trans-(+)-isomer was not much larger than the response to the vehicle alone (.093 ± .063 vs .035 ± .018), while the trans-(-)-isomer provided a very large change. (753 ± .031).

Table 9 below shows trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9 for spinal lordosis-to-mount ratio in estrogen-treated strains , 9a, 10-octahydropyrimido also provides the effect of a series of [4,5-g] quinoline doses.

TABLE 9

* All values are X ± SE for 19 (subcutaneous) and 8 (oral) (use water as vehicle). The behavioral response to the vehicle is much lower at each dose and route of administration than the response to the drug (P <.01).

Trans-(+)-stereoisomer or 5aS, 9aS-stereoisomer, which is a compound of formula (IIa), is a D-1 agonist. The compound represented by general formula (IIa) shows its dopamine D-1 agonist action in various ways; For example, one method is to stimulate the periodic AMP formation of the rat Stratul membrane.

For their measurement, the process of Wong and Reid (Communications in Psychopharmacology 4,269 (1980)) was used. 5aS, 9aS-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline (formula (IIa)), Adenylation cyclase of rat progenitor body membranes, measured as an increase in cyclic AMP concentrations relative to its 5aR, 9aR enantiomers (formula (II)) and their corresponding racemates (formula (I)) Their ability to activate adenylate cyclase) was tested. The measurement results are given in Table 10. Dopamine was used as a positive-control. In this table, column 1 represents the drug used, column 2 the concentration of the drug in the reaction mixture, column 3 the periodic AMP formation as a control percent, and column 4 the reliability or significance.

TABLE 10

In the presence of 10 micromoles of GIP, the basal adenylation cyclase action of the mouse striatum has a mean ± standard error value of 196.2 ± 20.3 Pmole / min / protein. The test was repeated three times with the compound.

According to the information shown in Table 10, 5aS and 9aS enantiomers of formula (IIa) significantly increased cyclic AMP formation, while exhibiting significant D-1 dopamine agonist action. The increase in cyclic AMP induced by 4aR, 9aR enantiomers of general formula (II) is much more effective than racemates, while clearly meeting the required significance.

Second, indicators of particularly sensitive D-1 agonist action include processes based on stoof and kebaian (Nature, 294,266 (1981) and Brain Res.) 250, 263 (1982)). Measurement of periodic AMP release in tissue slices used. In this process the striatal tissue is dissected from the rat brain and cut into 0.3 mm x 0.03 mm fragments. Tissue fragments are suspended in an appropriate buffer system (eg Earl's parallel salt solution) and continued to vent with O ₂ / CO ₂ of 95: 5 while maintaining the suspension at 37 ° C. Immediately before use, tissue fragments are transferred to a fresh medium to which bovine serum albumin (2.5 mg / ml) and 3-isobutyl-1-methylxanthine (1 mmol) are added to prevent sensitivity of the periodic AMP. Tissue fragments are incubated in drug free buffer and then transferred to the same medium to which the drug is added. Periodic AMP levels are analyzed by specific radioimmunoassay using aliquots of drug-free and drug-free cultures. The release effect of the agent or agents is expressed as a percentage of resting release.

The following medium was used.

Medium component concentration (mg / ι

NaCI 6800

KCI 402.6

NaHCO ₃ 2201.1

NaH ₂ PO ₄ 137.99

MgSo ₄ · 7H ₂ O 147.88

d-glucose 1009

CaCI ₂ · 2H ₂ O 191.1

Phenolic Red 10

In these experiments, Stopes and Kevavin used sulfiride to inhibit the negative (anti-D-1) effect of any drug that acts as a dopapine D-2 agonist. The fact that it inhibits (the opposite effect of the calculated D-1 agonist) has been transmitted. Sulphilides are known as antagonists for the pituitary D-2 receptor. The addition of sulfide to the test system prevents any D-2 effects of agents that reduce cyclic AMP production as described above. Stoves and kebabins are pure D-1 agonists that do not contain D-2 receptors and have no D-2 agonist action. SKF 38393 (1,2,3,4-tetrahydro-7,8-dihydride Oxy-1-phenyl 1H-3-benzezepine) can be used to eliminate the sulfide effect on cyclic AMP production in striatum tissue.

To 5aS, 9aS-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dihydrochloride (Compound A) The measurement results for the above are shown in Table 11. In this table, column 1 represents the drug added, column 2 represents the concentration of the drug, column 3 represents the concentration of the periodic AMP present, and column 4 represents the percent increase in the periodic AMP concentration.

TABLE 11

Compounds of formula (I), (II) or (IIa) are administered in various formulations for therapeutic purposes, as described below. However, trans- () is a dopamine D-2 agonist of formulas (I) and (II). It should be noted that the doses of ±)-and (5aR, 9aR) -stereoisomers are much less than the doses of (5aS, 9aS) -stereoisomers of the dopamine D-1 agonist of formula (IIa).

Hard gelatine capsules are prepared using the following ingredients:

Amount (mg / capsule)

Active Compound .1-2mg

Dried Starch 200

Magnesium Stearate 10

The ingredients are mixed and filled into hard gelatin capsules.

Tablet formulations are prepared using the following ingredients:

Amount (mg / tablet)

Active Compound .1-2mg

Cellulose (Fine Crystal) 400

Silicon Dioxide (Fumigation) 10

Stearic acid 5

The ingredients are mixed and compressed into tablets.

In contrast, tablets each containing .1-2 mg of active ingredient are prepared as follows.

Active ingredient .1-2 mg

Starch 45 mg

Microcrystalline Cellulose 35 mg

4 mg of polyvinylpyrrolidone (10% solution in water)

Sodium carboxymethyl starch 4.5 mg

0.5 mg magnesium stearate

Talc 1 mg

The active ingredient, starch and cellulose were added to U.S. Pass through a sieve and mix thoroughly. A solution of polyvinylpyrrolidone was mixed with the powder obtained above, followed by the U.S. Pass it through a sieve. The granules obtained were dried at 50-60 ° C. and the U.S. Pass it through a sieve. The sodium carboxymethyl starch, magnesium stearate and talc were described in U.S. After passing through a sieve, it is added to the granules, mixed and compressed on a tableting machine to obtain a tablet.

Each capsule containing 0.1 to 2 mg of the drug is as follows.

Active ingredient .1-2mg

Starch 58mg

Microcrystalline Cellulose 59mg

2 mg magnesium stearate

The active ingredient, cellulose, starch and magnesium stearate were mixed to make Messier 45 mesh. Pass through the sieve and fill into hard gelatin capsules.

Suspensions containing .1-2 mg each of 5 ml are prepared as follows:

Active ingredient .1-2mg

Sodium Carboxymethyl Cellulose 50mg

Syrup 1.25ml

0.10ml benzoic acid solution

Spice desired amount

Desired amount of dye

5 ml of tablet water

The agent was treated with U.S. Pass through a sieve and mix with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, antimicrobial agent and dye are diluted with a little water with stirring. Sufficient water is then added to the desired volume.

For oral administration, tablets, capsules or suspensions containing from about 1 to about 2 mg of active D-2 agonist per dose are administered to 75 kg of human body at a daily dose of 3 to 8 mg or about 4.0 to about 107 mcg / kg per day. To four times.

For D-1 agonists, the dosage level sufficient to stimulate the D-1 receptor will vary depending on the active compound used from .01-15 mg / kg / day. In the above, a formulation using .01-15 mg of active ingredient was used.

Claims (12)

A compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Wherein R is C ₁ -C ₃ alkyl or allyl, R ² is H, CH ₃ , C1 or Br, R ¹ is NH ₂ , NHR ³ or NR ⁴ R ⁵ where R ³ is methyl, ethyl, n-propyl or R ⁶ -CO [here R ₆ is C ₁ -C ₃ alkyl or

(Wherein R ⁷ is independently H, C1, F, Br, CH ₃ , C ₂ H ₅ , CH ₃ C, C ₂ H ₅ O or CF ₃ , n is 0,1 or 2) and , R ^{4 4} and R ⁵ are independently methyl, ethyl, or n-propyl. The acid addition salt according to claim 1, wherein the trans-(-)-stereoisomer of formula (II) or a pharmaceutically acceptable salt thereof.

Wherein R, R ¹ and R ² are as defined in claim 1. The Thans-(+)-stereoisomer of formula (IIa) or a pharmaceutically acceptable acid addition salt thereof according to claim 1.

Wherein R, R ¹ and R ² are as defined in claim 1. The compound of claim 1, 2 or 3, wherein R is n-propyl. The trans- (±) -2-amino-6-methyl-5,5a, 6,7,8,9,9a, 10-octahydropyridodo [4,5-g] quinoline, trans -(±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline, 5aR, 9aR-2- Amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline, trans- (±) -2-dimethylamino-6- n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline, trans- (±) -2-methylamino-6-n-propyl- 5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline, trans- (±) -2-amino-4-methyl-6-n-propyl-5 , 5a, 6,7,8,9,9a, 10-octahydropyrido [4,5-g] quinoline, trans- (±) -2-amino-4-chloro-6-n-propyl--5 , 5a, 6,7,8,9,9a, 10-octahydropyrido [4,5-g] quinoline, trans- (±) -2-acetylamino-6-n-propyl-5,5a, 6 , 7,8,9,9a, 10-octahydropyrido [4,5-g] quinoline, trans- (±) -2-benzoylamino-6-n-propyl-5,5a, 6,7,8 , 9,9a, 10-octahydropyrido With [4,5-g] quinoline and 5aS, 9aS-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline A compound selected from the group consisting of pharmaceutically acceptable acid addition salts thereof. The trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyridodo [4,5-g] quinoline according to claim 5 Dihydrochloride. Compounds of formula (II) or acid addition salts thereof.

Wherein R ¹ is NH ₂ , NHR ³ or NR ⁴ R ⁵ , R ₂ is H, CH ₃ , CI or Br and R ⁸ is H, CN or (C ₁ -C ₃ alkoxy) -CO. The trans-(-)-stereoisomer or acid addition salt thereof according to claim 7.

Wherein R ¹ , R ² and R ⁸ are as defined in claim 7. The trans-(+)-stereoisomer of formula (IVa) or an acid addition salt thereof.

Wherein R ¹ , R ² and R ⁸ are as defined in claim 7. Trans- (±) -compound of formula (Va) or acid addition salt thereof.

Wherein R ⁹ is C ₁ -C ₃ alkyl, CH, H or allyl, and R ¹² is methyl or C ₁ -C ₃ alkyloxy. The trans-(-)-stereoisomer compound of claim 10. The trans-(+)-stereoisomer compound of claim 10.