NZ242562A

NZ242562A - An octahydro-3-[(2-pyridylthio)methyl]-1-methyl-6-hydroxy-benzo[g]quinoline derivative, preparation and pharmaceutical compositions

Info

Publication number: NZ242562A
Application number: NZ242562A
Authority: NZ
Inventors: Peter Gull; Rudolf Markstein
Original assignee: Sandoz Ltd
Priority date: 1991-05-02
Filing date: 1992-04-30
Publication date: 1994-08-26
Also published as: TW241262B; FI921957A0; HUT61011A; MY131278A; CS131192A3; KR920021533A; JPH05170762A; DE4114325A1; FI921957A; IE921374A1; NO921723D0; HU9201296D0; IL101735A0; AU1529192A; EP0512952A1; CA2067648A1; RO109333B1; MX9202024A; AU656768B2; NO921723L

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £42562 242562 r.izv/- -■ l.V: Clsiee; C<? Public.: :.;cr 1 P.O. Journ c— ...26 AU6 1994 -l k'a: t33?3 NEW ZEALAND PATENTS ACT, 1953 M7 PATENT OFFtCS 30 APR 1992 No.: Date: COMPLETE SPECIFICATION OCTAHYDROBENZO[G] QUI NOLINE We, SANDOZ LTD. 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) 242562 CASE 100-7771 OCTAHYDROBENZO[G]QUINOLINE The present invention relates to a new octahydro[g]quinoline, its production and its use in therapy. The compound of the invention is the (-)-(30,4aoc, 10a3)~ 1,2,3,4,4a,5,10,10a-octahydro-3-[(2-pyridylthio)methyl]-l-methyl-6-hydroxy-benzo[g]quinoline of formula I in free base form or in acid addition salt form. Structurally related compounds are known from European Patent No. 77754. However, the compound of formula I has never been specifically disclosed. It has now surprisingly been found that this compound exhibits a particularly interesting pharmacological activity profile. In accordance with the invention, the compound of formula I and its acid addition salts are obtained by methylating the compound of formula II (-) HO (I) 242562 - 2 - 100-7771 (-) HO (II) and if desired, converting the compound obtained into its acid addition salts. The process according to the invention may be carried out by known methods, for example using formaldehyde/NaBH4, as described in the following example under e). Working up of the reaction mixture obtained and purification of the compound of formula I thus produced may be carried out by known methods. Acid addition salts can be produced from the free bases in known manner, and vice versa. The starting compound of formula II may be prepared from the compound of formula VII in accordance with the following reaction scheme, for example as described in the example under a) to d): - 3 - 10-&2 5 6 2 VII Ms = mesyl VI Zn/AcOH III 242 56 - 4 - 100-7771 The starting compound of formula VII is known from literature. The compound of formula I and its physiologically acceptable acid addition salts, referred to hereinafter as compounds according to the invention, exhibit interesting pharmacological activities in animal tests and may therefore be used as pharmaceuticals. The compounds according to the invention have in particular dopaminergic activity in vivo on the central nervous system, which is detected by contra-lateral rotation when administered at doses of 1 to 20 mg/kg p.o. or 0.1 to 0.3 mg/kg s.c. to rats which have undergone unilateral lesions in the nigrostriatal dopamine tract through a 6-hydroxy-dopamine injection [U. Ungerstedt, Acta physiol. scand. Suppl. 367, 69 - 93 (1973)]. The compounds according to the invention can therefore be used as dopaminergic agents, e.g. in the treatment of Parkinson's disease. Furthermore, the compounds according to the invention effect a decrease on the intra-ocular pressure in rabbits, at concentrations of 10 to 100 yM. Male rabbits of ca. 2% kg are fixed in cages leaving their heads free. The solutions with the compound to be tested are applied to the right eye and the placebo solutions to the left eye (2 drops each, i.e. ca. 40 yl). The eyes are firstly anaesthetized with a solution containing Novesine (0.4 X) and Fluorescein (0.05 X) and the ocular pressure is determined at various intervals after administration (10, 20, 30, 60, 90, 120, 180 and 240 minutes), whereby an applanation tonometer according to Goldberg is used. The compounds according to the invention are therefore useful in the treatment of glaucoma. - 5 - 242562 100-7771 The compounds according to the invention also show activity in the behavioural despair test [R.D. Porsolt et al., Arch. Int. Pharmaco-dyn., 229, 327 - 336 (1977)] upon administering doses of 10 to 100 mg/kg p.o. The compounds for use according to the invention are therefore useful as antidepressants. In addition, the compounds according to the invention effect an inhibition of the dependency on cocaine when administered at doses of 0.1 to 10 mg/kg p.o. to monkeys which administer the drug themselves according to the method described in Psychopharmacologia (Berl.) 16, 30 - 48 (1969). The compounds according to the invention may therefore be used in the prevention, reduction or treatment of dependency (or for treatment after deprivation to avoid renewed dependency) arising from the abuse of cocaine. For these therapeutical activities, an indicated daily dosage lies in the range ca. 1 to 100 mg, especially ca. 10 to 80 mg, of the compound according to the invention, which is conveniently administered e.g. in part doses up to 4 times daily. The compounds according to the invention may be administered in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions. For the treatment of glaucoma, the compounds according to the invention are preferably applied topically to the eye in ca. 0.002 to ca. 0.02 X ophthalmological solutions. - 6 - 242562 100-7771 In accordance with the foregoing, the present invention also provides a compound according to the invention, for use as a pharmaceutical, e.g. for the treatment of glaucoma, depression, cocaine dependency or Morbus Parkinson. The present invention furthermore provides a pharmaceutical composition comprising a compound according to the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. In the following example, all temperatures are uncorrected and are in degrees Centigrade. 24 6 7 100-7771 EXAMPLE: (-)-(3g, 4act, 10ag)-l, 2,3,4,4a, 5,10,10a-octahydro-3-[ (2- a) (±)-(3f5,4aa, 10a3)-l,2,3,4,4a,5,10,10a-octahydro-3-[(2-pyridyl-thio)methyl]-1,6-dimethoxy-benzo[g]quinoline A solution of 11 g (30.9 mM) of (±)-(3P,4aa,lOa0)-1,2,3,4,4a,5,10,10a^octahydro-3-mesyloxymethyl-1,6-dimethoxy-benzo[g]quinoline and 11 g (100 mM) of 2-mercaptopyridine in 200 ml of dimethylformamide is mixed at 10 - 15° with 41 ml of 2 N NaOH and stirred at room temperature for 20 hours. The suspension is worked by by concentrating in a rotary evaporator, mixing with water and extracting with methylene chloride. The organic phases are dried over Na2S04, filtered and concentrated. Chromatography on silical gel with methylene chloride/3% ethanol yields 5.6 g of the title compound (49% of theory). NMR (CDCI3, 360 MHz) 6 0.94 (q, J = 12 Hz, H-C9ax), 2.74 (dd, Jx = 12 Hz, J2 = 18 Hz, H-C5ax), 3.61 (s, N-0CH3), 3.8 (s, C-0CH3). b) (± ) - ( 3 fi, 4aa, 10a fl) -1,2,3,4, 4a, 5,10, lOa-oc t ahydro-3- [ ( 2-pyridy1-thio)methyl]-6-methoxy-benzo[g]quinoline 10 g (27 mM) of the compound obtained under a) and 37.8 g (570 mM) of zinc are suspended in a solution of 55 ml of water and 110 ml of acetic acid and stirred at room temperature for 20 hours. The suspension is filtered through Hyflo, concentrated, adjusted to pH 7-8 with 2 N NaOH and extracted with methylene chloride. After drying over Na2S04, filtering and concentrating on a rotary evaporator, 8 g of crude product are obtained as a yellow oil, and this is chromatographed on silica gel with methylene chloride/2.5% methanol: 4.6 g of the title compound (50% of theory) are thereby obtained as a yellowish oil. pyridylthio)methyl]-l-methyl-6-hydroxy-benzo[glquinoline - 8 - 24*56? 100-7771 NMR (CDC13, 360 MHz) 6 1.03 (q, J = 12 Hz, H-C9ax), 2.67 (t, J = 12, H-C5ax), 2.88 (b, N-H), 3.8 (s, C-0CH3). c) (-)-(3(3,4aa, 10a{3)-l,2,3,4,4a,5,10,10a-octahydro-3-[ (2-pyridyl-thio)methyl]-6-methoxy-benzo[g]quinoline In order to split the racemate, the racemic sec. amine obtained under b) is converted using (-)-camphanic acid chloride into the two diastereoisomeric amides, which are separated by fractional crystallization from diisopropyl ether. The two diastereoisomeric amides possess the following rotational values (CHC13): [a]D20 = - 108° resp. [a]o20 = + 86°. In order to carry out amide hydrolysis, 3.4 g (6.5 mM) of the amide with [a]D20 = - 108° are stirred for 16 hours at 105° in 135 ml of conc. HC1, diluted with water, neutralized at 10° with 10 N NaOH and extracted with methylene chloride/10% isopropanol. The organic phases are dried with Na2S04, filtered and concentrated on a rotary evaporator. The yield is 2 g of crude product, which is chromatographed on silica gel with methylene chloride/7% methanol. The resulting 1.6 g of pure enantiomer are used further without characterization. d) ( - ) - ( 3 0,4aa,10a{5) -1,2,3,4, 4a, 5,10,lOa-oc tahydro-3-[(2-pyridy1-thio)methyl]-6-hydroxy-benzo[g]quinoline 1.6 g (4.7 mM) of the pure enantiomer obtained under c) in 14 ml of HBr (47%) are stirred for 6 hours at 100°. The mixture is subsequently concentrated, neutralized with 2 N NaOH and extracted with methylene chloride/10% isopropanol. After drying over Na2S04, filtering and concentrating by evaporation, 1.8 g of crude hydroxy derivative are obtained, which is chromatographed on silica gel with methylene chloride/7% methanol. The resulting 1 g of pure hydroxy derivative is immediately N-methylated. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 9 - 5 6 (-)-(3(5, 4aa, 10a(5)-l, 2,3,4, 4a, 5,10,10a-octahydro-3- [ (2-pyridyl-thio)methyl]-l-methyl-6-hydroxy-benzo[g]quinoline A solution of 1 g (3.06 mM) of the hydroxy derivative obtained under d) and 8 ml of aqueous 35% formaldehyde solution in 80 ml of methanol is stirred for 30 minutes at room temperature, and subsequently mixed slowly in portions at 0° with 2.2 g of NaBH4. After stirring for 2 hours at room temperature, it is concentrated, mixed with NaHC03 solution and extracted with chloroform. Drying over Na2S04, filtering and concentrating by evaporation yield 1 g (99% of theory) of pure title compound, which is crystallized from acetone/ethyl acetate: [a]D20 = - 162° (pyridine). Following recrystallization from acetone/ethyl acetate: [a]D20 = -160° (pyridine). M.p. = 186 - 187°. 2425 - 10 WHAT WE CLAIM IS: A process for the production of the (-)-(3$,4acc, 10af3)-1,2,3,4,4a,5,10,lOa-octahydro-3-[(2-pyridylthio)methyl]-1-methyl-6-hydroxy-benzo[g]quinoline of formula I (-) (I) in free base form or in acid addition salt form, which comprises methylating the compound of formula II (-) HO (II) and, if desired, converting the compound obtained into its acid addition salts.
2. A process for the production of the compound of formula I in free base or acid addition salt form, substantially as hereinbefore described with reference to the Example:. 2425621
3. A compound of formula I in free base or acid addition salt form, whenever produced by the process of claim 1.
4. A compound of formula I in free base or acid addition salt form, as defined in claim 1.
5. A compound of claim 4 in free base form.
6. A compound of claim 4 in form of the hydrochloride.
7. A compound of any one of claims 3 to 6 in physiologically acceptable form, for use as a pharmaceutical.
8. A compound of any one of claims 3 to 6 in physiologically acceptable form, for use in the treatment of Morbus Parkinson, depression or cocaine dependency.
9. A compound of any one of claims 3 to 6 in physiologically acceptable form, for use in the treatment of glaucoma.
10. A pharmaceutical composition comprising a compound according to any one of claims 3 to 6 in physiologically acceptable form, in association with a pharmaceutical carrier or diluent. DATED THIS D/Y/ A. J. PER AGE 8.®-1 SO 3 APPUOAisnrs </div>