DE2810801A1 - ESTER OF 1,4-AETHANO-10-HYDROXY-5-OXO-5H- SQUARE CLAMP ON 1 SQUARE CLAMP CLOSE - BENZOPYRANO- SQUARE CLAMP ON 3.4-B SQUARE CLAMP CLOSE -PYRIDINE - Google Patents

Description

DR.-ING. "WALTER ABITZ DR. DIETER F. MORF DIPL.-PHYS, M. GRITSCHNEDER

Patent Attorneys Cf.

Müniier,

March 13, 1978

Postal address Postfach 860109, 8O00 Munich 8Θ

PienzenauerstraiSe 28

Telephone 98322a

Telegrams: Chemindus Munich Telax: CO) 523992

3386

ABBOTT LABORATORIES North Chicago, Illinois, V.St.A.

Ester of 1,4-ethano -10 ~ hydro3cy-5-oxo-5H- [i] - "benzopyrano- [3,4-b ] pyridine

809838/0819

3385

The invention relates to compounds of the general formula A.

OR

(A)

. ' I CHCH-nCcH ,, ID 11!

in which R is a straight or branched-chain alkanoyl radical with 2 to 8 carbon atoms or a radical of the following general formula:

-C-Y-N X

< ^CH 2> bj

in which Y is a straight or branched-chain alkylene radical with 1 to 8 carbon atoms,

a is an integer from 1 to 4,
b is an integer from 1 to 4 and

X is CH ₂ , O, S or NR ₁ (where R _{1 is} a hydrogen atom or a lower alkyl radical),

with the proviso that when X is O, S or NR ₁ , the sum of a and b is 3 or 4,

and their pharmacologically acceptable acid addition salts.

809838/0819

The term "pharmacologically acceptable acid addition salts" refers to acid addition salts derived from derive the desired acid. Typical examples of these salts are the hydrochlorides, hydrobromides, sulfates, Bisulfate, Acetate, Valerate, Oleate, Laurate, Borate, Benzoate. Lactates, phosphates, tosylates, citrates, maleates, Succinates and tartrates.

The compounds according to the invention are suitable as active ingredients for medicaments for reducing the intraocular Intraocular pressure in mammals, including humans, particularly for the treatment of glaucoma. Besides that the compounds according to the invention act as mild tranquilizers.

The compounds of the invention can be prepared by the methods described in US Pat. No. 3,493,579. The synthesis of the starting compound, namely 1,4-ethano-10-hydroxy-8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-tetrahydro-5H- [1] -benzopyrano - [3,4-b] pyridine hydrochloride of formula B

OH

• HCl (B)

is described in Example 1 of U.S. Patent.

Some representative compounds and their preparation are described in the examples below.

-Z- 809838/0819

Example 1

ti

Compound of Formula A where R is -CCH;

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 g (0.0074 mol) of pyrone hydrochloride prepared according to US Pat. No. 3,493,579, together with 2.46 g (0.03 mol) of anhydrous sodium acetate and 30 ml of acetic anhydride, are placed in a flask and the mixture is boiled overnight Reflux. The reaction mixture is then cooled from _9, the acetic anhydride is evaporated, the residue is treated with about 100 ml of water . The aqueous solution obtained is extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated.

The hydrochloride is then prepared in the usual way. 2.3 g of a white solid are obtained which are recrystallized from an ethanol / ether mixture; mp = 237 to 239 ^° C. (yield 69 %).

Analysis for C ₂₅ B ₅₃ NO ^

C. 18th 7th H 3 N ber .: 67, 40 7th , 67 3 , 13 gef.i 67, , 92 , 16

The IR and NMR spectrum are consistent with the proposed structure.

Abbott Laboratories 3386

Example 2

Il

Compound of Formula A where R is -CC ₂ H ₅ :

1,4-Ethano-8- (3-methyl-2-octyl) -5-0x0-1,2,3,4-tetrahydro-5H- [1 ] Benzopyrano- [3,4-b] pyridine-10-propionate hydrochloride

3 g (0.0074 mol) of pyrone HCl are dissolved in chloroform. The solution is washed with dilute potassium bicarbonate solution and then with saturated sodium chloride solution over magnesium sulfate dried and evaporated to a yellow, glassy residue (the free base).

The free base is dissolved in 75 ml of anhydrous benzene, and 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 mixture is refluxed overnight and then cooled. The triethylamine hydrochloride is then filtered off and the filtrate is evaporated to a glassy solid, which is taken up in anhydrous ether. Essential HCl is added, causing the salt to precipitate out of solution. A quantitative yield of 3.6 g of a white solid which has a softening point of 86 to 88 ^° C. and then ^{melts at 130 °} C. is achieved.

Analysis for C ₂₆ H ₃₅ NO ₄ ^ HCl:

67 C. 7th H 3 N ber .: 67 , 59 7th , 854 3 , 032 found: , 53 , 81 , 00

The IR and NMR spectrum are consistent with the proposed structure.

809838/0819

Example 3

1,4-Ethano-8- (3-methyl-2-octyl) -5-0X0-1,2,3,4-tetrahydro-5H- [1 ] Benzopyrano- [3 ^ -bj-pyridine-IO-octanoate hydrochloride

Example 2 is carried out using octanoyl chloride

instead of propionyl chloride, the compound in which R 0

-C (CH ₂ ) gCH, is.

This gives 3.4 g (Ausbeite 86%) of a white, crystalline solid, mp. 143 to 145 ⁰ C.

Analysis for

69 C. 8th H 2 N ber .: 69 , 968 8th _S 713 2 , 632 found: , 21 , 68 , 56

The IR and NMR spectrum are in agreement with the suspected th structure.

example

1,4-lthano-8- (3-methyl-2-octyl) -5-0x0-1,2,3,4-tetrahydro-5H- [1] -benzopyrano- [3,4-b] -pyridine- 1O-trimethyl acetate hydrochloride

Analogously to Example 2, using trimethylacetyl chloride instead of propionyl chloride, the compound in which 0 ^

UI ^J

R -CC-CH, is produced.
CH ^

3.6 g (yield 99 %) of a white, crystalline material are obtained

809838/0819

Solids from melting point 178 to 180 ^° C.

Analysis for C ₂ qH, qN0a »HC1:

CHN

calc .: 68.622 8.190 2.858 found: 68.28 8.24 2.79

The IR and NMR spectrum are consistent with the proposed structure.

example

Compound of formula A, where R is -C (CH ₂ KN \ (where Y = (CH ₂ ) ,, a + b = 4 and X = CH ₂ ):

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

4.05 g (0.01 mol) of pyrone hydrochloride are dissolved in sodium bicarbonate solution and extracted with methylene dichloride, the extract was washed with saturated sodium chloride solution, dry it over magnesium sulfate and evaporate to a light yellow oil (free base).

The free base is then taken up in 155 ml of anhydrous methylene dichloride, and 2.07 g (0.01 mol) of γ-piperidinobutyric acid HCl (cf. Cruickshank and Sheehan, J. Am. Chem. Soc ., 83 (1961), 2891). The solution is then stirred for 5 minutes and 2.26 g (0.011 mol) of N ₁ N ¹ -dicyclohexylcarbodiimide are then added. The reaction mixture is then stirred overnight (18 hours) under nitrogen, it is cooled for 3 hours at 0 ^° C. and then the by-product (di-

- 6 809838/0819

³³⁸⁶

cyclohexylurea). Then the filtrate is evaporated until to be solvent-free, resulting in an oily residue which crystallizes immediately,

The solid residue is taken up in hot methylene dichloride and anhydrous ether is added to the solution until it just becomes cloudy. The solution is then left to stand at room temperature, a solid product precipitating out. The solid is isolated and dried in a vacuum oven. 4.1 g of a white solid with a melting point of 165 to 167 ^° C. (yield 73 %) are obtained.

The MMR and IR spectrum confirm that it is the desired product.

Analysis for C ₅₂ H ₄₅ N ₄ O ₄ * HCl.1 / 2

C. 642 8th H 4th N ber. % 67, 89 8th , 515 VJl , 930 gefcS 67, , 47 , 04

Example 6

"0

Compound of Formula A in which R is -C (CH ₂ ) ^ - N 0:

1,4-1thano-10- [4- (4-morpholino) -butyryloxy] -8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-tetrahydro-5H- [i.d. ] Benzopyrano- [3,4-b] pyridine hydrobromide

The free base of the compound of the formula B (4.05 gj 0.01 mol) is mixed with 2.54 g (0.01 mol) 4-morpholinobutyric acid.HBr [J. At the. Chem. Soc. 83 (196I), 2891] and 2.26 g (0 ₉ 01 mol) of NjN'-dicyclohexylcarbodiimide are reacted analogously to Example 5 to give the above compound.

- 7th

Example 7

I!

Γ ~ \

Compound of Formula A where R is -C (CH ₂ UN N-CH ^:

1,4-Ethano-IO- [4- (4-methylpiperazino) -butyryloxy] -8- (3-ethyl-2-octyl) -5-OXO-1 , 2,3,4-tetrahydro-5H- [i] -benzopyrano- [3,4-b] -pyridine hydrobromide

In the same way as in Example 6, the free base of the compound of the formula B (4.05 g; 0.01 mol) is added 2.67 g (0.01 mol) of 4-methylpiperazinobutyric acid. HBr "and 2.26 g (0.01 mol) of NjN'-dicyclohexylcarbodiimide analog Example 5 implemented to the desired compound.

One determines the intraocular eye pressure (intraocular pressure) lowering effect of the compounds of the formula A on New Zealand male albino rabbits with a Weight from 2 to 4 kg each. The test animals are placed in plastic inhibitors. With help of a Bausch-and-Lomb Applamatic Tonometer are used by everyone Eye three separated by at least 30 minutes Get control readings. Test readings are taken 30, 60, 90, 120 and 180 minutes after drug administration, respectively carried out in the same way as for the check-ups. All examinations are on Blind base carried out. As a statistical method for The one-sided Mann-Whitney two-sample U test is used to analyze the data. P values < 0.1 are considered to be indicative of statistical significance. The compounds and the comparison substances pilocarpine hydrochloride as well as epinephrine hydrochloride are in sterile water for topical, intravenous and intramuscular administration prepared. Gelatin capsules filled with dry powders are used for oral examinations. As control placebos use volume doses of the medium or an empty gelatin capsule. The for topical (local) sub-

· »S -

809838/0819

The volume of test substance instilled in the search is constant 0.1 ml. Each compound is tested in four eyes.

The compound of the formula A, applied topically in the form of a 0.05% and 0.1 % solution, in which R

0 y—-.

Il / \

) ^ - N> results in a dose-dependent reduction in intraocular intraocular pressure compared to the comparison sample. The maximum effects for the two concentrations are -9 % and -32 %, respectively. The 0.1% solution remains effective for at least 90 minutes. Pilocarpine hydrochloride is active at a concentration of 0.5 % and yields after 60 Mn. a 26 % decrease in intraocular pressure. Epinephrine is inactive at a concentration of 0.05 % , but at 0.1 $ causes a gradual decrease in intraocular pressure which becomes statistically significant 180 minutes after topical application.

When the aforementioned compound is administered intravenously, a dose-dependent reduction in intraocular intraocular pressure is also achieved. The maximum effects range from -20 % at a dose of 0.05 mg / kg to -45% at a dose of 1 mg / kg. At an intravenous dose of 1 mg / kg, pilocarpine leads to a non-significant increase in intraocular pressure and to signs of activity of the parasympathomimetic type, in particular to excessive salivation.

Within the oral dose range of 1 to 50 mg / kg, the compound does not show any decrease in intraocular pressure Effect, and even with intramuscular administration, it does not result in a statistically significant change in the intraocular Pressure.

- 9 8Ό9838 / 081Φ

ir

The compound of Formula A where R is -CCH gives when applied topically as a 0.1% solution, a 23% solution

Decrease in intraocular pressure. The connection 0

tion with R = -C (CH ₂ ) ^ CH, leads to a 6 # decrease

O CH ^

Il f ^J

of pressure. The compound where R -C-C-CH ,,

gives a 33 / £ increase in pressure (not confirmed). The basis of comparison for all percentages given is a placebo control sample.

When applied topically, the compounds according to the invention thus have a higher activity than a placebo control sample or the comparison compounds pilocarpine or epinephrine.

The compound of the formula A, in which R -C (CH ₀ ) -, - N)

²³ \ /

(Example 5) is effective as a tranquilizer. If this compound is administered orally to a monkey at a dose of 10 mg / kg, the aggressive behavior, which manifests itself in the animal biting, evading, running around and making noises a hooded rat is administered orally at a dose of 5 mg / kg, a 34 % ± ge reduction in the activity induced by Deoxyn is achieved.

End of description

809838/0819

Claims (5)

DR.-ING. WALTER ABITZ DR.DISTSH F. MOBF DIPL.-PHYS. M. GKITSCHNEDSB Patent Attorneys Munich, March 13, 1973 Postal address Postfach 860109. 8O0O Munich Pienzenauerstraße Telephone 98 3222 Telegrams: Chemindus Munich Telex: (O) S23992 3336 PATENT CLAIMS \\ y compounds of the general formula OR CH ₀
ί 3 "CHCH -nC c H ₁ , i 5 11 ι CH ₃ in which R is a straight or branched-chain alkanoyl radical having 2 to 8 carbon atoms or a radical of The following general formula means: 809838/0819 in which Y is a straight or branched chain alkyl ene with 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4 and CH ₂ , O, S or NR ₁ (where R _{1 is} a hydrogen atom or a lower alkyl radical), with the proviso that when X is O, S or NR ₁ , the sum of a and b is 3 or 4, and their pharmacologically acceptable acid addition salts. 2. Compounds of the general formula OR CH ₀ I 3 'CHCH-nCcH, τ I 5 11 CH ₃ in which R is a group of formulas 0 0 It » 0 CH, Il I ^J , -CC ₂ H ₅ , -C (CH ₂ ) ₆ CH ₃ , -CC-CH ₅ or -C (CH ₂ J ₅ -N ) CH, is, ^D and their pharmacologically acceptable acid addition salts. 0 π 3. The compound of claim 2, wherein R is -CCH,, and their Hydrochlorxd. 809838/0 819 Il 4. A compound according to claim 2, wherein R is -C (CH ₅ ), - CH, -. 5. A compound according to claim 2, characterized in that It / \ that R is -C (CH ₂ UN>, and its hydrochloride.