NO780880L - PROCEDURES FOR THE PREPARATION OF NEW PYRIDINE DERIVATIVES - Google Patents

Description

The present invention relates to the production of compounds

with the formula

wherein R is a branched or unbranched alkanoyl group with 2-8 carbon atoms or

in which Y is a branched or unbranched alkylene group with 1-8 carbon atoms, a is an integer in the range 1-4, b is an integer from 1-4, X is CI^, 0, X or NR-^ where is hydrogen or a lower alkyl group with the proviso that when -X is 0, S or NR^ the sum of a and b is 3 or 4, as well as pharmaceutically acceptable acid addition salts thereof.

The term "pharmaceutically acceptable acid addition salts" refers to an acid addition salt of the desired acid. Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate and the like.

The compounds prepared according to the present method provide medicaments for reducing the intra-ocular pressure in mammals, particularly for use in the treatment of glaucoma. The compounds are also active as mild sedatives.

The compounds produced according to the present methods can be produced as described in US Patent No. 3,493,579, and production of the starting material 1,4-ethane-10-hydroxy-8-(3-methyl-2-octyl)-5- oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4b]pyridine hydrochloride of the formula

is described in the following example 1.

Representative compounds that can be prepared are exemplified in the following examples.

EXAMPLE 1

Compound of formula A, where R is

Preparation of starting material, namely 1,4-ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-b] -pyridine-10-acetate hydrochloride.

3.0 g (0.0074 mol) of the pyrone hydrochloride of formula B, prepared as disclosed in US Patent No. 3,493,579, was introduced into a flask together with 2.46 g (0.03 mol) of anhydrous sodium acetate and 30 ml of acetic anhydride and heated under reflux overnight. The reaction mixture was then cooled and the acetic anhydride evaporated. To the residue was added approx. 100 ml of water, and the aqueous solution extracted with ether. The ether phase was then extracted with a saturated NaCl solution and then dried over MgSO4 and evaporated.

The hydrochloride salt was prepared in a conventional manner. 2.3 g of a white solid were obtained, which after recrystallization from an ethanol/ether mixture had a melting point of 237-239°C (69% yield).

Analysis: Calculated for C25H33N04 •HC1: C'67.1.8; H, 7.67;

N, 3.13.

Found: C, 67.40; H, 7.92;

N, 3,16..

Infrared and NMR spectra were consistent with the proposed structure.

EXAMPLE . 2

Compound of formula A, where R is

1,4-ethanol-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine-10-propionate hydrochloride .

The pyrone hydrochloride (3.0 g, 0.0074 mol) starting material was dissolved in chloroform, washed with a dilute potassium bicarbonate solution and then washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give the free base as a yellow glassy residue.

The free base was dissolved in 75 ml of dry benzene, and to this solution were added 0.68 g (0.0074 mol) propionyl chloride and 0.75 g (0.0074 mol) triethylamine (ET₂N). The reaction mixture was refluxed overnight, cooled and filtered to remove Et^N.HCl. The filtrate was then evaporated to give a glassy solid which was dissolved in solid ether, after which an ethereal solution of hydrogen chloride was added. The salt precipitated out and a quantitative yield of 3.6 was obtained

g of a white solid, which had a softening point of 36-88°C and which melted at 130°C.

Analysis: Calcd for C 26 H 35 NO 4 .HCl: C, 67.59; H, 7.854;

N, 3,032

Found: C, 67.53; H, 7.81;

N, 3.00.

Infrared and NMR spectra were consistent with the proposed structure.

EXAMPLE 3

1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine-10-octanoate hydrochloride

In the same way as stated in example 2, a compound was obtained

share, in which R is

^when octanoyl chloride was used

instead of propionyl chloride.

3.4 g (yield 86%) of a white crystalline solid with a melting point of 143-145°C were obtained.

Analysis: Calculated for C31H45N04.HC1:C, 69.968; H, 8.713;

N, 2,632 .

Found: C 69.21; H, 8.68; N, 2.56.

Infrared and NMR spectra were consistent with the proposed structure.

EXAMPLE 4

1,4-Ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine-10-trimethylacetate hydrochloride When trimetyl acetyl chloride was used instead of propionyl

chloride, a compound was obtained in which R is

3.6 g (yield 99%) of a white crystalline solid, m.p. 178-180°C.

Analysis: Calculated for C 2 g H 3 g NO 4 .HCl: C, 68.622; H, 8.190;

N, 2,858.

Found: C, 68.28; H, 8.24;

N, 2.79.

Infrared and NMR spectra were consistent with the proposed structure.

EXAMPLE 5

A compound of formula A, wherein R is

where Y = (CH2)3, a + b = 4, X = CH2.

1,4-Ethano-10[4-(1-piperidino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-b]pyridine hydrochloride.

4.05 g (0.01 mol) of the pyrone hydrochloride was dissolved in a sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride was washed with a saturated sodium chloride solution, then dried over magnesium sulfate and evaporated to give a pale yellow oil.

The free base was then dissolved in 155 ml of dry methylene chloride and 2.07 g (0.01 mol) of γ-piperidino-butyric acid hydrochloride (Cruick-shank and Sheehan, J. Am. Chem. Soc., 83, 2891, 1961 ] was added in one portion to the solution which was stirred for 50 min before 2.26 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide was added to the solution.The reaction mixture was stirred under a nitrogen atmosphere overnight (18 h), cooled for 3 hours at 0° C., after which the dicyclohexylurea formed was filtered off.The filtrate was then evaporated to dryness, yielding an oily residue which immediately crystallized.

The solid residue was then dissolved in hot CH 2 Cl 2 and dry ether was added until the solution just became turbid. The solution was allowed to stand at room temperature, whereby a solid product precipitated from the solution. The solid was collected and dried in a vacuum oven, and 4.1 g of white solid was obtained, m.p. 165-167°C (yield 73%).

NMR and IR spectra were consistent with the desired structure.

Analysis: Calculated for C32H46N4°4 'HC1 *1//2 H20:

C, 67.642; H, 8.515; N, 4,930.

Found: C, 67.89; H, 8.47; N, 5.04.

EXAMPLE 6

Compound of formula A, wherein R is

1,4-Ethano-10[4-(4-morpholino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-b]pyridine hydrobromide

The free base of the compound of formula B (4.05 g, 0.01 mol) was reacted with 2.54 g (0.01 mol) of 4-morpholino-butyric acid hydrobromide [J . Am. Chem. Soc. 8_3, 2891 (1961)] and 2.26 g (0.01 mol of N,N<1->dicyclohexylcarbodiimide as described in Example 5 and the above-mentioned compound was obtained.

EXAMPLE 7

Compound of formula A, wherein R is

1,4-Ethano-10[4-(4-methylpiperazino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [3,4-b]pyridine hydrobromide.

In the same manner as described in Example 6, the free base of the compound of formula B, (4.05 g, 0.01 mol) was reacted with 2.67 g (0.01 mol) of 4-methylpiperazine-butyric acid hydrobromide and 2.26 g (0.01 mol) N,N<1->dicyclohexylcarbodiimide as described in example 5

and the above-mentioned compound was obtained.

The intraocular hypotensive properties of the compounds of formula A were determined in male New Zealand white rats weighing 2-4 kg. The test animals were placed in plastic holder devices and three control readings, separated by at least 30 min. was obtained for each eye using a Bausch and Lomb Applamatic Tonometer. Sample readings were taken at 30, 60, 90, 120 and 180 min. after administration of the compound and was performed in the same manner as for the control readings. All determinations were made on a blinded basis. The statistical method used to analyze the data obtained was the one-sided Mann-Whitney, two-sample U-test. P-values equal to or less than

.0.1 was considered to indicate statistical significance. The compounds and reference standards pilocarpine hydrochloride and epinephrine hydrochloride were prepared in sterile water for topical, intravenous and intramuscular administration. Dry powders were introduced into gelatin capsules for oral studies. Volume doses of the vehicle or an empty gelatin capsule served as placebo controls. The volume amount of the active ingredient intended for topical investigations was kept constant at 0.1 ml. Each compound was examined in four eyes. The compound of formula A, wherein R is

applied topically

as 0.05% and 0.1% solutions gave a dose-dependent lowering of the intraocular pressure compared to the control sample.

The maximum effects were respectively -9% and -32% for each of

the two concentrations. The effect of a 0.1% solution lasted for at least 90 min. Pilocarpine hydrochloride was active at a concentration of 0.5% dg and produced a 26% reduction in intraocular pressure for 60 min .. Epinephrine was not active at a concentration of 0.05%, but at 0.1% there was a gradual lowering of the intraocular pressure which became statistically significant at 180 min. after the topical application.

Intravenous administration of the compound also showed a dose-dependent lowering of intraocular pressure. Maximum effects ranged from -20% at a dose of 0.05 mg/kg to -45% at a dose of 1.0 mg/kg. Pilocarpine, at a dose of 1 mg/kg, i.v., produced a non-significant increase in intraocular pressure as well as signs of parasympathetic activity, particularly a strong salivation.

At oral doses in the range of 1.0 - 50.0 mg/kg, administered orally, the compound was inactive in lowering intraocular pressure and also did not result in a statistically significant change in intraocular pressure when administered in -tramuscular.

The compound of formula A, wherein R is

produced a 28% reduction in intraocular pressure when applied topically as a 0.1% solution. The compound in which R is gave a 6% reduction in pressure, and the compound in which R is

33% increase in pressure (not confirmed), compared to the placebo control.

It is obvious that the compounds prepared according to the invention are more active when applied topically than the placebo control or the reference compounds pilocarpine and epinephrine.

The compound of formula A, wherein R is

(example 5)

was found to be effective as a sedative. Aggressive behavior such as biting, avoidance, fleeing and screaming was attenuated when a monkey was orally administered at a dose level of 10 mg/kg.

Likewise, when the compounds were administered orally to a hooded rat at a dose level of 5.0 mg/kg, a 34% decrease in "Desoxyn" induced activity was obtained.

Claims (8)

1. Analogy method for the preparation of a therapeutically active compound with the formula wherein R is a branched or unbranched alkanoyl group with 2-8 carbon atoms or in which Y is a branched or unbranched alkylene group with 1-8 carbon atoms, a is an integer in the range 1-4, b is an integer from 1-4, X is CH2 , 0,X or Nr^ , where is hydrogen or a lower alkyl group with the proviso that when X is 0, S or NR^ the sum of a and b is 3 or 4, or a pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of the formula or the free base thereof is esterified with an acid of the formula ROOH or an active derivative thereof, wherein R has the above meaning, optionally in the presence of an acid acceptor or esterification promoter, after which the compound obtained is, if desired, converted into an acceptable acid addition salt in a manner known per se. 2. Method according to claim 1 in the preparation of 1,4-ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3, 4-b]pyridine-10-acetate hydrochloride, characterized in that the compound of formula B is reacted with acetic anhydride. 3. Process according to claim 1 in the preparation of 1,4-ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3, 4-b]pyridine-10-propionate hydrochloride, characterized in that the compound of formula B is reacted with propionyl chloride. 4. Method according to claim 1 in the preparation of 1,4-ethane-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano [ 3 4 -b] pyridine-10-octanoate hydrochloride, characterized in that the compound of formula B is reacted with octanoyl chloride. 5. Process according to claim 1 in the preparation of 1,4-ethano-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3, 4-b]pyridine-10-trimethylacetate hydrochloride, characterized in that the compound of formula B is reacted with a trimethylacetyl chloride. 6. Method according to claim 1 in the preparation of 1,4-ethano-10 [4-(1-piperidino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4 -tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine hydrochloride, characterized in that a compound of formula B is reacted with y-piperidino-butyric acid hydrochloride. 7 i Process according to claim 1 in the preparation of 1,4-eta'no-10[4-(4morpholino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4 -tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine hydrobromide, characterized in that a compound of formula B is reacted with 4-morpholinobutyric acid hydrobromide. 8. Method according to claim 1 in the preparation of 1,4-ethano-10[4-(4-methylpiperazino)butyryloxy]-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4 -tetrahydro-5H-[1]benzopyrano[3,4-b]pyridine hydrobromide, characterized in that a compound of formula B is reacted with 4-methylpiperaziro-butyric acid hydrobromide.