FI80679B - Trans-(±)-1-(alkyl or allyl)-6-oxo-7-alkoxycarbonyl decahydroquinolines which are useful intermediates in the preparation of pyrimido/4,5-g/quinolines which are useful dopamine agonists. - Google Patents

Description

1 80679

Trans - (+) - 1- (alkyl or allyl) -6-oxo-7-alkoxycarbonyldecahydroquinolines useful as intermediates in the preparation of pyrimido [4,5-g] quinolines useful as dopamine agonists 5

This invention relates to the preparation of novel pyrimido [4,5-g] quinoline derivatives which have been found to be potent D-1 and D-2 dopamine agonists.

The invention relates to trans - (+) - 1- (alkyl or allyl) -6-oxo-7-alkoxycarbonyldecahydroquinolines useful as intermediates in the preparation of pyrimido [4,5-g] quinolines useful as dopamine agonists and having the formula Va

~ OO

R I

R9 wherein R9 is C1-3 alkyl or allyl and R12 is C3-3 alkoxy, and their acid addition salts.

The view that various body tissues contain two types of dopamine receptor agonists, e.g. lergotril and pergolide, both of which are ergolines, and LY141865 (U.S. Patent 4,198,415), which is a substructure of ergoline. These D-2 agonists have been found to be useful in the treatment of Parkinson's disease and in the treatment of disease states, e.g., 30 milk leaks in which there is excessive prolactin in the circulation. LY141865, i.e. trans - (+) - 5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] Nolin has also been found to reduce blood pressure in mammals in the absence of posture-dependent low blood pressure. This antihypertensive effect is found only in the second stereoisomer of the trans - (+) - racemate, i.e. 4aR, 8aR-5-n-propyl-4,4a, 5,6,7,8,8a, 9- octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline.

The main application (FI publication 78 091) relates to 5 methods of trans - (+) - 2,4,6-permitted substitution-5,5a, 6,7,8,9,9a-10-octohydropyrimido [4,5 -g] for the preparation of quinolines of formula I

R1-10 J9a o

R2 I

R R

wherein R is C 1-3 alkyl or allyl, R 2 is H, CH 3 or Cl, R 1 is NH 2, NHR 3 or NR 4 R 5, wherein R 3 is methyl, ethyl, n-propyl or R 6 -CO, wherein R 6 is C 1-3 alkyl or phenyl, and R 4 and R 5 are independently methyl, ethyl or n-propyl, and pharmaceutically acceptable acid addition salts thereof.

The terms used in this patent application have the following meanings: The term "C 1-3 alkyl" means methyl, ethyl, n-propyl and isopropyl. The phrase "C 1-3 alkoxy" means methoxy, ethoxy, n-propoxy and isopropoxy.

By pharmaceutically acceptable acid addition salts of the compounds are meant salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, organic acid, phosphoric acid and the like, and the like, and the like. mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dive-5 phosphate, metaphosphate, pyrophosphate, chloride, bromide, propionate, iodide, acetate, acetate. , formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate-10thi, butyl 1,4-dioate, hexyl-1,6-dioate, benzoate benzoate, chlorobenzoate, methylbenzoate, dinitrobent-benzoate, hydroxybenzoate, methoxybenzoate, phthalate, acetate, terephthalate, benzenesulfonate, toluenesulfonic, sulfonate, chlorobenzenesulfonate, xylenesulfonate, 15 phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycoates, malate, tartrate , methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

The compounds of formula I have two asymmetric carbon atoms (optical center) in the 5a and 9 positions, so that the compounds may exist as four stereoisomers forming two racemic pairs. These are called trans - (+) - racemate and cis - (+) - racemate. The trans-ra-25 formate consists of the trans - (-) stereoisomer (5aR, 9aR stereoisomer, formula II, and the trans - (+) - (5aS, 9aS) stereoisomer, formula Ha h ~ ΐ TT) n N ) t nf Hl

R R R

(II) (Ha) 4 80679 wherein R, R1 and R2 are as defined above. These trans - (-) - (5aR, 9aR) stereoisomers of formula II are active dopamine D-2 agonists. The trans- (+) - (5aS, 9aS) -stereoisomers of formula IIa are active dopamine D-1 agonists. Because trans - (+) - D1 agonists are less active than trans - (-) - D-2 agonists on a dose basis, trans - (+) - racemates (II + Ha) are mainly used for the active trans - (-) due to the stereoisomer.

The compounds of formulas I, II and Ha are used as medicaments either as the free base or as a pharmaceutically acceptable acid addition salt thereof.

The compounds of formulas I and II are dopamine D-2 agonists with almost no other agonist-15 or antagonistic blocking effect. As dopamine D-2 agonists, the compounds are useful in the treatment of Parkinson's syndrome, in the treatment of sexual dysfunction, as antidepressants, anxiolytics, as antihypertensives in hypertensive mammals, and as inhibitors of prolactin secretion. Thus, the compounds of formulas I and II may be used in the treatment of hypertension, depressive disorders, anxiety disorders, Parkinson's disease, sexual dysfunction and conditions characterized by hyperactivation of prolactin, e.g. in the treatment of milk leakage and impaired lactation.

The compounds of formula IIa are dopamine D-1 agonists. Stimulated with a D-1 agonist, dopamine D-1 receptors are characterized by increased secretion of cyclic AMP. D-2 agonists inhibit this phenomenon. Stoof and Keba-30 bian discuss these D-1 agonist effects in Nature, 294 (1981) and Brain Res., 250 (1982), p. 263. The compounds of formula IIa are potentially useful as renal vasodilators and thus can be used in the treatment of hypertension.

Il 5 80679

According to FI publication 78 091, the compounds of the formula I can be prepared, for example, by halogenating a 4-OH compound of the formula If 5 'f Y j i 1 M i if

OH R

10 wherein R and R 1 are as defined in formula I, to give a compound of formula I wherein R 2 is Cl.

The compounds of formula Va which are the subject of the invention are useful as intermediates in the preparation of compounds of formula I.

The following synthetic route can be used to prepare certain compounds of formula I:

synthetic route

20 1 ^ NH

~ Tl + R-C - »0 = cA λ J" NH2 R12 | (VI) R9 25 (Va) T | (IaM)

R 1a is R 9 wherein R 1 is as defined in formula I, R 9 and R 12 are as defined in formula Va and R 11 is OH. During the ring closure reaction, the ester group R12 is replaced by OH and a 4-OH derivative is obtained. This OH derivative is then halogenated to give a compound of formula I wherein R 2 is Cl. Suitable halogenating agents are POCl 3 and 6 80679 SOCl 2. The reaction is usually carried out at reflux temperature. Optionally, an ether solvent may be present.

The starting materials of formula 5 Va used in the above synthetic route are prepared as follows:

A ketone of formula X

° TX)

10 I

R

wherein R is C 3-3 alkyl or allyl, the metal is attached to the 7-carbon with a lithium amide, e.g. lithium diisopropylamide {Lin [CH (CH 3) 2]}, to form the enolate anion. This anion is then reacted with acetyl chloride or di-alkyl carbonate to give a compound of formula Va. These compounds of formula Va are then converted to the desired pyrimidine of formula I, which is purified.

Ketones of formula X wherein R is C 2-3 alkyl

li, is preferably prepared by a process wherein 6-alkoxy-quinoline of formula XI

25 L · XI

wherein R 13 is C 3-3 alkoxy, quaternized with a C 2-3 alkyl halide and the quaternized salt is reduced to N-C 3-3 alkyl-C 1-6 alkoxy-1,2,3,4-tetrahydroquinoline of formula Xia I! LJ XIa R 14 35 7 80679 wherein R 14 is (C 1-3 alkyl and R 13 is as defined above. The C 1-3 alkyl group remains intact in the following two reduction steps: Birch reduction followed by reduction with sodium cyanoborohydride or 5-borohydride; and is obtained; octahydroquinoline of formula XII

^ N 'XII

ίο | R14 wherein R13 and R14 are as defined above. Treatment with an acid from this enol ether gives compound X (wherein R is C3-3 alkyl).

An alternative method for preparing ketone X when R is C3-3 alkyl is described in U.S. Patent 4,198,415.

As can be deduced from the above, the group R of formula X remains intact during the synthetic procedure. So

If it is desired to replace one alkyl group with another alkyl or allyl, indirect synthetic routes must be used. For example, if the group R in formula X is methyl or n-propyl, the reaction with cyanogen bromide gives 1-cyano-6-oxodeca-hydroquinoline of formula XV

"C/O

L15 30 where R15 is cyano. Hydrolysis of the cyano group affords a secondary amine of formula XV wherein R 15 is H. Similarly, reacting a compound of formula X wherein R is ethyl with an ethyl chloroformate intermediate of formula XV wherein R 15 is C 2 H 5 -O-CO , 80809 which can be hydrolysed to the corresponding compound of formula XV wherein R15 is H.

The secondary amine of formula XV wherein R 15 is H may then be selectively alkylated with the same or a different alkyl group or may be allylated if an allyl group on the ring nitrogen is desired. Extremely reactive allyl halides can be used in this synthesis to ultimately provide a compound of formula X wherein R is allyl.

By the methods described above, salt and. The salt thus obtained can be easily converted into the corresponding free base by dissolving the salt in water and then adding an excess of an aqueous solution of the base (e.g. NaOH or Na 2 CO 3). The free base insoluble in the base solution precipitates and is extracted as a water-immiscible organic solvent. The organic extract is then isolated and dried. A solution containing one equivalent of the second, non-toxic acid is then added and the salt formed is isolated by filtration or evaporation of the solvent.

Alternatively, the solvent is removed from the dried organic extract and the free base remains. This can be dissolved in a suitable solvent and non-toxic acid is added to the solution. The preferred salt is the HCl salt, which can be prepared, e.g., by adding an equivalent amount of an ethanolic solution of hydrogen chloride to an ethanolic solution of the free base, after which the ethanol is evaporated and the remaining salt is recrystallized. If desired, a disalt salt such as the dihydrochloride salt can be introduced into the free base solution until HCl gas is saturated and the disalt salt is isolated as above.

The following examples illustrate this invention.

Example 1 illustrates the preparation of a compound of formula Va, Example 2 the preparation of a compound of formula If and Example 3 the preparation of a compound of formula I.

Il 9 80679

Example 1

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

A suspension of 790 g of sodium hydride (55% in mineral oil) was added to a 50 ml round bottom flask and the mineral oil was removed by three hexane washes. The remaining solid sodium hydride was suspended in 8 ml of THF and 1.45 ml (1.41 g) of diethyl carbonate and 1 drop of anhydrous ethanol were added. The resulting solution was heated to reflux and 1.1 g of trans - (+) - 1-n-propyl-6-oxodecahydroquinoline in 5 ml of THF was added over 5 minutes. The resulting mixture was heated at reflux overnight. At this time, TLC indicated that no starting material remained and a new, hi-15 rearward moving spot had formed.

The reaction mixture was poured into water, and the pH of the aqueous layer became about 14. The basic layer was extracted with methylene chloride. The pH of the aqueous layer was adjusted to about 9 and the basic layer was re-extracted with methylene chloride. The methylene chloride extracts were combined and the combined extracts dried, the solvent removed to give 1.56 g of a yellow oil which was the trans - (+) - 1-n-propyl-6-oxo-7-ethoxycarbonyl-decahydroquinoline formed in the reaction described above.

The residue was chromatographed on Woelm silica (100-200 mesh) eluting with a 1: 1 mixture of ether and hexane with a little 14 N aqueous ammonium hydroxide. Fractions containing the desired product were combined to give 880 mg (55% yield) of a yellow oil. According to NMR, the ketoester was in the enol form with the following structure: xo i

35 0C 0HC I

"C3« 7 10 80679

The NMR spectrum of the compound was as follows: NMR (CDCl 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 = 3H). Example 2 Preparation of Trans - (+) - 2-amino-4-hydroxy-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline

A reaction mixture was prepared from 2.0 g of trans - (+) - 1-n-propyl-6-oxo-7-ethoxycarbonyldecahydroquinoline 10 (prepared in Example 1), 20 ml of anhydrous ethanol and 0.67 g of guanidine carbonate. The reaction mixture was heated under reflux overnight under nitrogen. The white precipitate formed was isolated by filtration and the filter cake was washed with ethanol and dried; yield 1.36 g. The filter cake was dissolved in 52 ml of 0.1 N aqueous hydrochloric acid.

The acidic mixture was filtered and the filtrate was concentrated in vacuo. The solid residue was dissolved in boiling methanol. The methanol solution was filtered and the trans - (+) - 2-amino-4-hydroxy-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] thus prepared was prepared. quinoline hydrochloride was crystallized to give 0.79 g of product. The physical characteristics of the free base were as follows: mass spectrum: molecular ion at 262.

25 Analysis; calculated: C 64.09 H 8.45 N 21.36 found: C 64.18 H 8.51 N 21.13.

Example 3

Preparation of trans - (+) - 2-amino-4-chloro-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinolin-30

The 4-hydroxy product obtained in Example 2 and 4 ml of phosphorus oxychloride were heated to reflux. The reaction mixture containing the trans - (+) - 2-amino-4-chloro-6-n-propylate formed in the reaction described above

II

11 80679 5.5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline, was poured onto ice and the resulting aqueous mixture was basified. The basic mixture was filtered and the insoluble matter (30 mg) was dissolved in 0.1 N aqueous hydrochloric acid.

The hydrochloride salt thus prepared was recrystallized from ethanol to give 13.6 g of trans - (+) - 2-amino-4-chloro-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimidine. do [4,5-g] quinoline hydrochloride having the following physical characteristics: mass spectrum: molecular ion at position 280, minor peak at position 282.

Analysis; calculated: C 53.00 H 6.99 N 17.66 found: C 53.15 H 6.92 N 17.17.

Claims (1)

30 R * 9 K. color R9 är. 3-alkyl or allyl and R12 are C1-6-alkoxy, as well as the addition moiety.