CH628633A5 - Esters of 1,4-ethano-10-hydroxy-5-oxo-5H-[1]benzopyrano[3,4-b]pyridine derivatives which can be used especially in the treatment of glaucoma - Google Patents

Description

628633

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CLAIMS 1. Therapeutically active compounds, corresponding to the formula:

OR 5

The present invention relates to esters of 1,4-ethano-10 hydroxy-5-oxo-5H- [1] -benzopyranno [3,4-b] pyridine derivatives of formula:

(at)

CHCH-nCJH -3

5 11

where R represents a straight or branched alkanoyl radical containing 2 to 8 carbon atoms, or a radical of formula:

0

-C-Y-N

\

"V.

CHCH-nC ^ H ^ j where R represents a straight or branched alkanoyl radical containing 2 to 8 carbon atoms, or a radical of formula:

"Go.

r

X

., y

20

S f "A

-C-Y-N X

V, „., J

where Y represents a straight or branched alkylene radical having 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, X represents CH2, O, S or NRj, where Ra represents a hydrogen atom or a lower alkyl radical, provided that when X represents O, S or NRj, the sum of a and b is 3 or 4; and their acid addition salts suitable for pharmacy.

2. Compounds according to Claim 1, in which R represents a radical of formula:

OOO -CCH „. -CCJfï_, -C (CHjcCH

30

2 5 *

2 6 33

0 CH-

11 1 -C-C-CH

CH

3 or -C (CH2) 3

O

35

and their acid addition salts suitable for pharmacy.

3. Compound according to claim 2, characterized in that R represents

O

II

-cch3,

or its hydrochloride.

4. Compound according to claim 2, characterized in that R represents

O

II

-C (CH2) 6CH3.

5. Compound according to claim 2, characterized in that R represents

• (CH2> b where Y represents a straight or branched alkylene radical containing 1 to 8 carbon atoms; a is an integer from 1 to 4; b is an integer from 1 to 4; X represents CH2, O, S or NR15 where Ri represents a hydrogen atom or a lower alkyl radical, provided that, when X represents O, S or NRj, the sum of a and b is equal to 3 or 4; and the acid addition salts suitable correspondents in pharmacies.

The term “acid addition salt suitable in pharmacy” is understood to mean a salt formed by the addition of a suitable acid such as, for example, the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate and the like.

The compounds of the invention are medicaments useful for lowering intraocular pressure in mammals and, in particular, for treating glaucoma. These compounds are also useful as mild tranquilizers.

The compounds of the invention can be prepared according to the methods described in US Pat. No. 3,493,579, the preparation of 1,4-hydroxy-10 (1,2-dimethyl heptyl) hydrochloride - 8-oxo-5 tetrahydro-1,2,3,4 5H- [l] -benzopyranno [3,4-b] pyridine of formula:

45

50

(B)

HCl

C9H19

O

II

-C (CH2) sN

55

O-

or its hydrochloride.

6. Medicament useful in particular for lowering the intraocular pressure and as a mild tranquilizer, consisting of a compound of formula I according to claim 1 or an acid addition salt of said compound, suitable in pharmacy, alone or in admixture with a excipient or inert carrier.

7. Medicament according to claim 6, in which the active ingredient is one of the compounds according to one of claims 2 to 5.

8. The medicament according to claim 6 or 7, in a form suitable for local, intravenous, intramuscular or oral administration.

being described in Example 1.

Typical compounds which can be prepared are shown in the following examples.

Example 1:

Compound of formula A where R represents

O

II

"O -cch3.

1,4-Ethano-acetoxy-10 hydrochloride (1,2-dimethyl heptyl) -8 5-oxo tetrahydro. 2,3,4 5H- [1 J-benzopyranno [3,4-b] Pyridine

3.0 g (0.0074 mol) of pyrone hydrochloride 65 of formula B, prepared as described in the aforementioned United States patent, with 2.46 g (0.03 mol) are introduced into a flask. anhydrous sodium acetate and 30 ml of acetic anhydride and heated to reflux overnight. The reaction mixture is cooled and evaporated

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628633

acetic anhydride. About 100 ml of water are added to the residue, then the aqueous solution is extracted with ether. The ether is washed with a saturated sodium chloride solution, then dried over magnesium sulfate and evaporated.

The hydrochloride is prepared in the usual way. 2.3 g of a white solid are obtained which are recrystallized from a mixture of ethanol and ether; Mp 237-239 ° C; yield 69%.

Theoretical analysis for C2sH33N04, HC1:

Calculated: C 67.18 H 7.67 N3.13%

Found: C 67.40 H 7.92 N 3.16%

The infrared spectrum and the nuclear magnetic resonance spectrum conform to the proposed structure.

Example 2:

Compound of formula A where R represents

O

II

-cc2h5.

Ethano-1,4-propionyloxy-10 hydrochloride (1,2-dimethyl heptyl) -8 oxo-5 tetrahydro-1,2,3,4 5H- [l] -benzopyranno [3,4-b] pyridine

3.0 g (0.0074 mol) of the starting pyrone hydrochloride are dissolved in chloroform, washed with a dilute solution of potassium bicarbonate, then a saturated solution of sodium chloride, dried over magnesium sulfate and evaporates to obtain the free base in the form of a yellow glassy residue.

The free base is dissolved in 75 ml of anhydrous benzene, then 0.68 g (0.0074 mol) of propionyl chloride and 0.75 g (0.0074 mol) of triethylamine are added to the solution. The reaction is continued at reflux overnight, cooled and filtered to remove the triethylamine hydrochloride. The filtrate is evaporated to obtain a glassy solid which is taken up in anhydrous ether, then hydrochloric acid is added in ether. The salt precipitates out of the solution. A quantitative yield is obtained (3.6 g) of a white solid which softens at 86-88 ° C, then which melts at 130 ° C.

Theoretical analysis for C26H3SN04, HC1:

Calculated: C 67.59 H 7.854 N 3.032%

Found: C 67.53 H 7.81 N3.00%

The infrared spectrum and the nuclear magnetic resonance spectrum conform to the proposed structure.

Example 3:

1,4-Ethano-octanoyloxy-10 (1,2-dimethyl heptyl) -8 oxo-5 tetrahydro-1,2,3,4 5H hydrochloride [1] -benzopy ranno [3,4-bJpyridine

The procedure of Example 2 is repeated, replacing the propionyl chloride with octanoyl chloride and the compound where R represents

O

11

—C (CH2) eCH3.

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

Theoretical analysis for C31H45N04, HC1:

Calculated: C 69.968 H 8.713 N 2.632%

Found: C 69.21 H 8.68 N 2.56%

The infrared spectrum and the nuclear magnetic resonance spectrum conform to the proposed structure.

Example 4:

1,4-ethano-trimethylacetoxy-10 (1,2-dimethyl heptyl) -8 oxo-5 tetrahydro-1,2,3,4 5H hydrochloride [1 J-benzo-pyranno [3,4-b] pyridine

Trimethylacetyl chloride is used instead of propionyl chloride to obtain the compound where R represents

O CH3

II I -c-c-ch3.

ch3

3.6 g (99% yield) of a white crystalline solid having a melting point of 178-180 ° C. are obtained.

Theoretical analysis for C28H39N04, HC1:

Calculated: C 68.622 H 8.190 N 2.858%

Found: C 68.28 H 8.24 N 2.79%

The infrared spectrum and the nuclear magnetic resonance spectrum conform to the proposed structure.

Example 5:

Compound of formula A where R represents O

-C (CH2) 3 O '

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

Ethano-1,4 hydrochloride (4-piperidino-butyryloxy) -10 (1,2-dimethyl heptyl) -8 oxo-5 tetrahydro-1,2,3,4 5H- [1] -benzopyranno [3,4- b Jpyridine

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

The free base is then taken up in 155 ml of anhydrous methylene chloride and a portion is added to the solution of 2.07 g (0.01 mol) of y-piperidinobutyric acid hydrochloride [Cruicks-hank and Sheehan, “ J. Am. Chem. Soc. ”, 83,2891 (1961)]. Stirring is continued for 5 min, then 2.26 g (0.011 mol) of N, N'-dicyclohexylcarbodiimide is added to the solution. The reaction mixture is stirred under a nitrogen atmosphere overnight (18 h), cooled to 0 ° C for 3 h, then the dicyclohexylurea formed as a by-product is filtered off. The filtrate is concentrated to dryness to obtain an oily residue which immediately crystallizes.

The solid residue is taken up in hot methylene chloride and anhydrous ether is added until the solution begins to cloud. The solution is allowed to stand at room temperature for the solid product to precipitate. The solid is collected and dried in an oven under vacuum to obtain 4.1 g of a white solid; Mp 165-167 ° C (yield 73%).

The nuclear and infrared magnetic resonance spectra conform to the structure of the desired product.

Theoretical analysis for C32H46N404, HC1,1 / 2H20:

Calculated: C 67.642 H 8.515 N 4.930%

Found: C 67.89 H 8.47 N 5.040%

Example 6:

Compound of formula A where R represents °

—C (CH2) 3N p

Ethano-1,4-hydrobromide (4-morpholino-butyryloxy) -10 (1,2-dimethyl heptyl) -8 oxo-5-tétrahydro-1,2,3,4 5H- [1] -benzopy ranno [3,4 -b Jpyridine

4.05 g (0.01 mol) of the free base of the compound of formula B is reacted with 2.54 g (0.01 mol) of 4-morpholino butyric acid hydrobromide ["J. Am. Chem. Soc. ”, 83.2891 (1961)] and 2.26 g (0.01 mol) of N, N'-dicyclohexylcarbodiimide, as described in Example 5 to obtain the above compound.

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628,633

Example 7:

Compound of formula A where R represents O

- c (ch2) 3 - n yn - ch 3.

1,4-Ethanol hydrobromide [4-methyl-1-piperazinyl) -4 butyryloxy] -10 (1,2-dimethyl heptyl) -8 5-oxo-1,2,3,4 5H- [1] -benzopyranno [3,4-h Jpyridine

As in Example 6, 4.05 g (0.01 mol) of the free base of the compound of formula B is reacted with 2.67 g (0.01 mol) of acid hydrobromide (4-methyl piperazinyl-1) -4 butyric acid and 2.26 g (0.01 mol) of N, N'-dicyclohexylcarbodiimide, as described in Example 5, to obtain the desired compound.

The lowering properties of the intraocular pressure of the compounds of formula A are evaluated on male New Zealand albino rabbits weighing between 2 and 4 kg. The animals are placed in plastic restraints and three eye pressure measurements are made, each at least 30 min apart, with an Applamatic Tonometer Bausch and Lomb. Measurements are made 30, 60, 90, 120 and 180 min after administration of the drug and parallel readings are carried out in the controls. All studies are performed using a blind method. The statistical analysis of the data is carried out according to the U test with two samples from Mann and Whitney, with only one condition for t. We consider that probabilities P equal to or less than 0.1 are significant. The compounds and the reference standards, consisting of pilocarpine hydrochloride and epinephrine hydrochloride, are prepared in sterile water for local, intravenous or intramuscular administration, and the dry powders are introduced into gelatin capsules for oral administration. Corresponding volumes of the vehicle or empty gelatin capsules serve as placebo for the controls. The volume of drug instilled in topical studies is always 0.1 ml. Each compound is studied on four eyes.

The compound of formula A where R represents

O

He / \

-c (ch2) 3nY

when applied locally as 0.05% and 0.1% solutions, produces a dose-related decrease in intraocular pressure compared to the control. The maximum effects are respectively - 9% and - 32% for each of the two concentrations. The effect of the 0.1% solution lasts at least 90 min. Pilocarpine hydrochloride is active at a concentration of 0.5% and produces a decrease in intraocular pressure by 26% after 60 min. Epinephrine is not active at a concentration of 0.05%, but at 0.1% it produces a gradual lowering of the intra-

ocular which corresponds to a statistically significant difference, 180 min after the local application.

Intravenous administration of the above compound also produces a dose-related decrease in intraocular pressure. The maximum effects are between —20% at the 0.05 mg / kg dose and —45% at the 1.0 mg / kg dose. Pilocarpine, at a dose of 1 mg / kg, intravenously, produces a non-significant increase in intraocular pressure as well as signs of parasympathicomimetic activity, in particular profuse salivation.

In the oral administration range of 1.0 to 50.0 mg / kg, the compound is inactive for lowering intraocular pressure and does not produce a statistically significant change in intraocular pressure when 'it is administered intramuscularly.

The compound of formula A where R represents

O

II

-cch3

causes a 28% decrease in intraocular pressure when applied locally as a 0.1% solution; the compound where R represents

O

II

—C (ch2) 6ch3

produces a 6% decrease in pressure; and the compound where R represents o ch3 II I -c-c-ch3 I

ch3

causes an unconfirmed increase in pressure of 33%, these values all being expressed relative to the controls receiving a placebo.

Therefore, the compounds of the invention, when applied locally, are more active than a placebo or standard compounds, such as pilocarpine or epinephrine.

The compound of formula A where R represents

O

- & CH2) 3nq>

(example 5) is active as a tranquilizer. Its oral administration to a monkey, at a dose of 10 mg / kg, causes a decrease in aggressive behavior resulting in biting, escape, running and screams. Also, when administered orally to a hooded rat at a dose of 5.0 mg / kg, it causes a 34% decrease in the increase in activity caused by Desoxyn.

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