SK399A3 - Benzo[g]quinoline derivatives, process for their preparation, pharmaceutical composition containing same and their use - Google Patents

Abstract

The invention provides a compound of formula (I) wherein A, B, X, Y and R are as defined in the description, and a process for preparing them. The compounds of formula (I) are useful as pharmaceuticals for the treatment of glaucoma and myopia.

Description

Benzo [g] quinoline derivatives, process for their preparation, pharmaceutical composition containing them and their use

Area, techniques

The present invention relates to novel benzo [g] quinoline derivatives, their preparation, their use as medicaments and pharmaceutical compositions containing them.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I wherein

A and B are each hydrogen or together form another bond,

X is CH ₂ or CO,

Y is O, S, S = O, NR ¹ (wherein R ¹ is hydrogen or C 1 -C 4 alkyl), CH ₂ or O-CH ₂ , and R is a group of formulas (a), (b) , (c), (d), (e), (f), (g), (h), or (i) ·

wherein R ¹ is as defined above, R ² is a hydrogen atom or a trifluoromethyl group, Z _T is O, S or NH and Z ₂ is CH or N, provided that when X is CH ₂ , Y is S and R is a group of formula (a) wherein the free bond is adjacent to a nitrogen atom and R ² is a hydrogen atom, then A and B are not hydrogen atoms, in the form of a free base or in the form of an acid salt.

The above alkyl groups are preferably methyl. X is preferably CH _second Y is preferably O or S.

The compounds of the invention have asymmetric centers at the 3, 4a and 10a positions and optionally in the X-Y-R substituent. They can therefore be present in optically active form or in the form of mixtures of optical isomers, for example in the form of racemic mixtures. All optical isomers and mixtures thereof, including the racemic mixture, form part of the present invention.

In the group of compounds of formulas IA and B, both are hydrogen, X is CH ₂ , Y is O or S and R is the remainder of formulas (b) or (c).

In another group of compounds of formula IA and B together form another bond, X is CH ₂ , Y is O or S, and R is the remainder of formulas (a) or (e).

In yet another group A and B and X are as previously defined, Y is O, S, NR ¹ (where R ¹ is hydrogen or C 1 -C 4 alkyl), CH 2 or O-CH 2, and R is a radical of formulas (a), (b), (c), (d) or (g), wherein R ³ is as defined above and R ² is a hydrogen atom, or the remainder of formulas (e) or (f), wherein R ¹ is an atom hydrogen, Z 1 is O or S and Z 2 is CH.

When A and B are both hydrogen atoms, X-Y-R preferably represents the 3R configuration.

The present invention further provides a process for the preparation of the compounds of formula (I) and their acid addition salts, comprising:

wherein A, B, X, Y and R are as defined above and R ² is a C 1 -C 4 alkyl group, converts the alkoxy group to a hydroxy group, and the compound of formula I thus obtained is isolated as the free base or as an acid salt.

The reaction may be carried out by known methods, for example using hydrobromic acid or boron tribromide. In formula II, R is preferably methyl.

The reaction mixtures obtained according to the above process and the purification of the compounds thus obtained can be carried out according to known procedures.

Acid salts can be prepared from the free bases in a known manner and vice versa. Suitable salts for use according to the invention are, for example, hydrochlorides.

The starting compounds of formula II wherein A and B are both carbon atoms can be prepared from the corresponding compounds of formula IIIa.

wherein R ² is defined, for example as described in Example 1st

The compounds of formula (IIIa) are known or can be prepared analogously to known methods.

The starting compounds of formula II wherein A and B together form another bond can be prepared from the corresponding compounds of formula IIIb

wherein R is as defined above, for example as described in Example 24.

Compounds of formula IIIb can be prepared from compounds of formula X according to the following reaction scheme:

ΝΗ3, ch ₃ cooh dehydrating agent

NaBKj

CH ₂ = CHCOOMe

T

NaBH, (BOC-protected)

Hlb (VI)

SOCl

CH3Cl base

IN

(IV)

All reactions in this scheme can be carried out according to known procedures.

The compounds of formula I are known or can be prepared analogously to known methods.

The compounds of formula I and their physiologically acceptable salts, referred to herein as agents of the invention, exhibit valuable pharmacological properties in animal tests and are therefore useful as pharmaceuticals.

In particular, the agents of the invention act to reduce the intraocular pressure of rabbits at doses of 0.1 to 100 μπιοί. Male rabbits weighing about 3 to 6 kg are firmly fixed in cages, leaving their heads free. Solutions with the compound to be tested are applied to the right eye and placebo solutions (50 μΐ each) are applied to the left eye. The eyes are first anesthetized with a drop of a solution containing 0.4% Novesine (Ciba Vision Ophthalmics, Switzerland) and eye pressure is determined at various intervals after administration (10, 30, 60, 120, 180 and 240 minutes) using a pneumatonometer (Mentor). O&O Inc., Norwell, USA).

The agents of the invention are therefore useful in the treatment of glaucoma.

In addition, the agents of the invention increase blood flow in the optic nerve as exemplified by the experiments carried out and described in M. Rudin and A. Sauter Non-invasive determination of regional cerebral blood flow in rats using dynamic imaging with Gd (DTPA), Magnetic Res. in Med., 22, 32-46 (1991). In this test, rats are anesthetized with isoflurane. A cannula is injected into the femoral vein to inject the paramagnetic contrast agent Gd (diethylene triamine pentaacetate). Determination of blood flow (ml / 100 g / min) by NMR is performed immediately before and 30 minutes after subcutaneous drug administration. The experiments were performed twice blinded in groups of 8 to animals. In the first series of experiments, the entire optic nerve is measured. In the second series, the effect on the optic nerve subregions, including the proximal optic head portion, is determined.

In this test, the agents of the invention at doses of 0.1 to 0.5 mg / kg subcutaneously significantly improve blood flow in the optic nerve, but not in the striped body. In a second series of experiments, the agents of the invention preferably increase blood perfusion in the proximal part of the optic nerve, including the head and the distal part, at the indicated doses.

The agents of the invention are therefore useful in conditions where the prevention or retardation of progressive optic optic atrophy is desirable, for example in conditions where the field of vision deteriorates, and particularly in forms of glaucoma not characterized by an increase in intraocular pressure (low pressure glaucoma), whose standard glaucoma therapy including β-blockers is ineffective. _;

The agents of the invention further exhibit dopaminomimetic activity, as exemplified in vitro, for example by their ability to inhibit the electrically induced release of acetylcholine from striatal sections [R. Markstein et al., J. Neural. Transm., 103, 17-30 (1996)] at concentrations of 1 to 100 nM.

In addition to the permeable dopaminomimetic compound, it has been found that they prevent the occurrence of myopia in humans [P. M. Iuvone et al., Inv. OphtAal Vis Sci., 32, 1674-1677 (1991)].

The agents of the invention may therefore be used in the treatment of myopia, as evidenced by standard tests, such as the model of R. A. Stone et al., [Proc. Natl. Acad. Sci. (USA), 86, 704-706 (1989)], where experimental myopia of the chickens was induced after administration of about 0.1 to about 1 mg / kg in eye drops.

For the above indications, the appropriate dosage will, of course, vary depending upon, for example, the compound employed, the host, the route of administration, and the severity of the condition being treated. In general, however, sufficient results are obtained in animals at a daily dose of from about 0.1 to about 100 gmol in ophthalmic solution. In larger mammals, for example humans, the daily dosages are in the same range, preferably at a daily dose. from about 0.1 to about 10 μπιοί of the compound suitably administered once or twice daily or in sustained release form.

The agents of the invention may be administered in free form or in the form of a pharmaceutically acceptable salt. These salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.

The present invention also provides an agent of the invention for use as a medicament, for example for the treatment of glaucoma and myopia.

The present invention further provides a pharmaceutical composition comprising an agent of the invention together with at least one pharmaceutically acceptable diluent or carrier. These compositions may be formulated in conventional manner. Unit dosage forms contain, for example, from about 0.10 to about 2 mg of an agent of the invention.

The agents of the invention may be administered in a conventional manner, for example parenterally in the form of injectable solutions or suspensions, or enterally, for example in the form of tablets or capsules. Preferably, however, they are applied topically to the eyes in about 0.01 to 0.5% ophthalmic solutions.

The ophthalmic vehicle is such that the compound is maintained in contact with the eye surface for a sufficient period of time to penetrate the corneal and internal areas of the eye.

For example, the pharmaceutically acceptable ophthalmic vehicle may be an ointment, a vegetable oil, or an encapsulated material.

Preferred agents of the invention for the above uses are [3R, 4aR, 10aR] -1-methyl-3E- {4-methyl- (4H) -1,2,4-triazo-3-yl} -thiomethyl-6-hydroxy -1,2,3,4,4aa, 5,10,10aa-octahydrobenzo [g] quinoline (compound A), [4aS, 10aR] -1,2,4aa, 5,10,10aB-hexahydro-6- hydroxy-1-methyl-3- (2-pyridyloxymethyl) benzo [g] quinoline (compound B), [4aS, 10aR] -1,2,4aa, 5,10,10aS-hexahydro-6-hydroxy-1- methyl-3- (2-imidazolylthiomethyl) benzo [g] quinoline (compound C) and [3R, 4aR, 10aR] -1-methyl-3S- (2-pyridyl-N-oxide) thiomethyl-6-hydroxy-1, 2,3,4,4aa, 5,10, 10afi-octahydrobenzo [g] quinoline (compound D) in free base or acid salt form, especially compound C.

In the above-mentioned intraocular pressure test, compounds A, B, C and D in the hydrochloride form reduce the intraocular pressure of normal rabbits to a maximum of 3.3, 3.8, 3.3 and 4.5 mm Hg (440, 517, 440 and 538 Pa) after administration of 0.9 μπιοί eye drops, while no decrease in intraocular pressure was observed with the same dose of standard Timolol β-blocker. In addition, the duration of action of these 4 compounds is unexpectedly long.

In said blood flow test compound. C hydrochloride increases blood flow by 30% after administration of 0.1 mg / kg subcutaneously, while at doses up to 0.5 mg / kg subcutaneously Timolol does not increase blood flow.

At the doses administered in the above assays, the agents of the invention are well tolerated. In addition, compounds A, B, C and D show no mutagenicity in Salmonella typhimurium (i.e. they are negative in the known Ames test).

Accordingly, the present invention also relates to an agent of the invention for use as a medicament in the treatment of glaucoma and myopia.

In addition, the invention relates to the use of an agent of the invention for the preparation of a medicament for the treatment of glaucoma and myopia.

The invention further provides a method of treating glaucoma and myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent of the invention.

The following examples illustrate the invention in more detail. Temperatures are given in degrees Celsius and are not corrected.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 [3R, 4aR, 10aR] -1-methyl-3S- {4-methyl- (4H) -1,2,4-triazo-3-yl} -thiomethyl-6-hydroxy-1,2,3, 4,4aa, 5,10,10aS-octahydrobenzo [g] quinoline

a) [3R, 4aR, 10aR] -1-methyl-3S-hydroxymethyl-6-methoxy-1,2,3,4,4aa, 5,10,10aa-octahydrobenzo [g] quinoline

To a solution of 5.78 g (20 mM) of [3R, 4aR, 10aR] -1-methyl-3S-methoxycarbonyl-6-methoxy-1,2,3,4,4aa, 5,10,10aS-octahydrobenzo [g] of quinoline in 100 ml of toluene was added dropwise a solution of 12 ml of SDBA (70% in toluene, 42 mM) under argon at room temperature over 1 hour. Then, 10 mL of NaOH (30%) was added dropwise to the ice-cooled reaction mixture. The precipitated crystals are filtered off, washed with water and toluene and dried. The resulting title compound has a melting point of 148 ° C, [α] ²⁰ D = -120 ^° (c = 0.425 in ethanol).

b) [3R, 4aR, 10aR] -1-methyl-3E-mesyloxymethyl-6-methoxy-1,2,3,4,4aa, 5,10,10aS-octahydrobenzo [g] quinoline

To a solution of 20 g (76.5 mM) of the compound obtained under a) in 150 ml of pyridine is added dropwise 12 ml (153 mM) of methanesulfochloride at room temperature. The temperature is kept below 45 ° C by ice cooling. The mixture was stirred at room temperature for 2 hours, the solution was adjusted to pH 7-8 with saturated KHCO 3 at 0 ° C and extracted with ethyl acetate. After drying over sodium sulfate, filtering and concentrating by evaporation under reduced pressure, the title compound is obtained in the form of beige crystals and used directly for the next step.

c) [3R, 4aR, 10aR] -1-methyl-3S- {4-methyl- (4H) -1,2,4-triazo-3-yl} -thiomethyl-6-methoxy-1,2,3,4 4aa, 5,10,10aS-octahydrobenzo [g] quinoline

A solution of 6 g (17.7 mM) of the compound obtained under b) and 3.1 g (27 mM) of 3-mercapto-4-methyl- (4H) -1,2,4-triazole in 60 ml of dimethylformamide is mixed with 6 mL of 2N NaOH and stirred at 65 ° C for 18 hours. The suspension thus obtained is concentrated by evaporation. The crude product crystallizes. The suspension is cooled to 5-10 ° C, washed with ethyl acetate and dried. Chromatography on silica gel eluting with ethyl acetate containing 10% ethanol and 0.01% NHg gave the title compound as beige crystals, mp 205-207 ° C, [α] ² % = -107 ⁰ (c = 0.70 in ethanol).

d) [3R, 4aR, 10aR] -1-methyl-3S- {4-methyl- (4H) -1,2,4-triazo-3-yl} -thiomethyl-6-hydroxy-1,2,3,4 4aa, 5,10,10aS-octahydrobenzo [g] quinoline

To a solution of 4 g (11.2 mM) of the product obtained under c) in 250 mL of methylene chloride is slowly added dropwise at -40 ° C 40 mL of boron tribromide (1 M in methylene chloride) dropwise. The suspension is stirred at room temperature for 2 hours, neutralized with NH 4 and extracted with the mixture

150 ml methylene chloride and 100 ml isopropanol. After drying over sodium sulfate, filtration and concentration by evaporation, the title compound crystallizes. The corresponding hydrochloride crystallizes out of the mixture of methanol and ethanol 1: 1 during evaporation. Mp 185 DEG C. (with decomposition), [a] ²⁰ D = -77 ⁰ (c = 0. 640 in ethanol-water 1: 1).

In a manner analogous to that of Example 1, the compounds of formula (I) shown in the following table were prepared, wherein A and B are both hydrogen.

Pr. X Y R mp (Dec.) 2 ch ₂ 0 3 (a) ^(R2 = H) 230 ° C 3 11 with 4 (a) ^(R2 = H) 260 ° C 4 n (f) (Z ¹ = S, Z ² = CH, R ¹ = H) 280 ° C 5 1) n "(Z ¹ = 0, Z = CH ^2, R ¹ = H) 270 ° C 6 i) n 2 (b) 260 ° C 7 n n (C) (R'-H) 275 ° C 8 »1 n (E) (R = H) 200 ° C 9 n n (G) 280 ° C 10 n NH 2 (a) ^(R2 = H) 275 ° C 11 n nch ₃ H 280 ° C 12 WHAT NH 11 220 ° C 13 1 » ch ₂ 11 215 ° C (1) 14 »> och ₂ 11 275 ° C 15 ch ₂ WITH (H) 265 ° C 16 n 0 2 (b) 250 DEG C. (l) 17 n WITH (f) (R 1 = H, Z 1 = S, Z ² = N) 270 ° C 18 n n (f), (R ¹ = 5-CH ₃ , Z ¹ = NH. Z ² = CH) 245 ° C 19 υ n (i) (R ^{1 =} CH ₃₎ 260 [deg.] C 20 n n 2 (a) (R ² -O-CF ₃₎ 255 ° C 21 n n 2 (a) ^(R2 = _p-CF3) 250 DEG C. (l) 22 at s = o 2 (a) (R ² = H) 240 ° C 23 11 1 » 2 (a) ^(R2 = H) ** 226 ° C (1)

* (+) - diastereomer ** (-) - diastereomer (1) hydrochloride (2) dihydrochloride

Example 24 [4aS, 10aR] -1,2,4aa, 5,10,10aE-hexahydro-6-hydroxy-1-methyl-3- (2-pyridyloxymethyl) -benzo [g] quinoline

a) [4aS, 10aR] -1,2,4aa, 5,10,10aE-hexahydro-3-hydroxymethyl-6-methoxy-1-methylbenzo [g] quinoline

To a suspension of 2.9 g of lithium aluminum hydride in 200 ml of tetrahydrofuran at 5 ° C is added dropwise a solution of 10 g of [4aS, 10aR] -3-methoxycarbonyl-1,2,4ace, 5,10,10aS-hexahydro-6-methoxy 1-methylbenzo [g] quinoline in 50 ml tetrahydrofuran and the reaction mixture was stirred at room temperature overnight. Excess lithium aluminum hydride is hydrolyzed by dropwise addition of a solution of water and tetrahydrofuran, the precipitate is filtered off, the filtrate is concentrated and the residue is triturated with ether. The title compound is obtained in the form of crystals, m.p. 142-143 ° C, [α] ² θ ₀ =. -222.8 ⁰ (c = 3.5 in dimethylformamide). ' ^!

b) [4aS, 10aR] -1,2,4ace, 5,10,10aS-hexahydro-6-methoxy-1-methyl-3- (2-pyridyloxymethyl) -benzo [g] quinoline

To a solution of 15 g of the compound obtained under a) in 500 ml of dimethylformamide was added portionwise 4.62 g of sodium hydride (60% emulsion in oil). The suspension is heated to 60 ° C until evolution of hydrogen ceases before the addition of 12 mL of 2-chloropyridine. The reaction mixture is stirred for 6 hours at 60 ° C, quenched with NH 4 Cl, concentrated by evaporation and extracted with a mixture of water and methylene chloride, followed by flash chromatography of the organic phase on silica gel eluting with methyl tert- butyl ether and MeOH (96: 4). The crude compound was converted to the hydrochloride salt, which crystallized from EtOH and Et ₂ O.Teplota mp 244-247 DEG C., [.alpha] = ^2% = -98.4 ° (c = 0.62 in dimethylformamide).

c) [4aS, 10aR] -1,2,4aa, 5,10,10aE-hexahydro-6-hydroxy-1-methyl-3- (2-pyridyloxymethyl) -benzo [g] quinoline

The cleavage of the methyl ether is carried out with boron tribromide analogously to Example 1d), starting from the compound obtained under b). The corresponding hydrochloride has a melting point of 223-225 ° C, [α] ²⁰ D = -125.6 ^° (c = 0.45 in dimethylformamide).

In a manner analogous to that in Example 1, the compounds of formula I shown in the following table were prepared, wherein A and B together form an additional bond.

Pr. X Y R mp 25 ch ₂ 0 2 (a) (R ^z = H) 223-225 ° C 26 » with (E) (R = H) 226 - 228 ° C 27 n n 4 (a) ^(R2 = H) 200-202 ° C 28 n n (C) (R = H) 230 ° C * (I) 29 n M (d) (R ¹ = CH ₃ ) 230-232 ° C 30 « 0 4 (a) ^(R2 = H) 235 ° C

Claims (10)

PATENT CLAIMS A compound of formula I wherein (I) A and B are each hydrogen or together form another bond, X is CH ₂ or CO, is O, S, S = O, NR ¹ (where R ¹ is hydrogen or C 1 -C 4 alkyl), CH ₂ or O-CH ₂ , and is a group of formulas (and ), (b), (c), (d), (e), (f), (g), N. Ό ,. (a) (f) 'xz w 9 where R is as defined above, R ⁶ is a hydrogen atom or a trifluoromethyl group, Z 1 is O, S or NH and Z ₂ is CH or N, provided that if X is CH ₂ , Y is S and R is a group of formula (a) wherein the free bond is adjacent to a nitrogen atom and R ² is a hydrogen atom, then A and B are not hydrogen atoms, in free base or salt form with acid. A compound of formula I as claimed in claim 1, wherein A and B and X are as defined in claim 1, Y is O, S, NR ¹ (wherein R ¹ is hydrogen or C 1 -C 4 alkyl) and R is the radical of formulas (a), (b), (c), (d) or (g), wherein R ¹ is as defined above and R ² is a hydrogen atom or formulas (e) and (f) wherein R ¹ is hydrogen, is 0 or S and Z 2 is CH, in the form of the free base or in the form of an acid salt. A compound according to claim 1 selected from the group consisting of [3R, 4aR, 10aR] -1-methyl-3S- (4-methyl- (4H) -1,2,4-triazo-3-yl} -thiomethyl-6). -hydroxy-1,2,3,4,4aa, 5,10,10aS-octahydrobenzo [g] quinoline, [4aS, 10aR] -1,2,4aa, 5,10,10aS-hexahydro-6-hydroxy- 1-methyl-3- (2-pyridyloxymethyl) benzo [g] quinoline, [4aS, 10aR] -1,2,4aa, 5,10,10afi-hexahydro-6-hydroxy-1-methyl-3- (2- imidazolylthiomethyl) benzo [g] quinoline and [3R, 4aR, 10aR) -1-methyl-3S- (2-pyridyl-N-oxide) thiomethyl-6-hydroxy-1,2,3,4,4aa, 5,10 10QaS-octahydrobenzo [g] quinoline, in free base or acid salt form. A process for the preparation of a compound of formula I as defined in claim 1, or a salt thereof, characterized in that it is carried out in a compound of formula II wherein A, B, X, Y and R are as defined in claim 1 and R ² is C 1 -C 4 alkyl, alkoxy to hydroxy, and the compound of formula (I) thus obtained is isolated as the free base or as an acid salt. A compound according to any one of claims 1 to 3 in free base or pharmaceutically acceptable acid salt form for use as a medicament. . A compound according to any one of claims 1 to 3 in free base or pharmaceutically acceptable acid salt form for use in the treatment of glaucoma and myopia. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 in the form of the free base or in the form of a pharmaceutically acceptable acid salt together with a pharmaceutical carrier or diluent. Use of a compound according to any one of claims 1 to 3 in free base or pharmaceutically acceptable acid salt form as a medicament for the treatment of glaucoma and myopia. Use of a compound according to any one of claims 1 to 3 in free base or pharmaceutically acceptable acid salt form for the preparation of a medicament for the treatment of glaucoma and myopia. A method of treating glaucoma and myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 3 in free base or pharmaceutically acceptable acid salt form.