KR810001974B1 - Process for preparing esters of 1,4-ethano-10-hydroxy-5-oxo-5h-(1)-benzopyrano(3,4-b)pyridines - Google Patents

Abstract

Title compds. (I; R = C2-8 alkanoyl or formula Ia (Y = C1-8 alkylene; a,b = 1-4 integer; X = CH2, O,S, NR1 (R1 = H, lower alkyl; if X is one of O, S and NR1, the sum of a and b is 3 or 4), useful medicines for treating glaucoma, were prepared by reacting compd. II with III to give I (R = H), which was esterifyed with ROH to give title compd. I. Thus, pyrone HCl (I; R = H) was refluxed with anhydrous sodium acetate and acetic anhydride for overnight, extracted with ether, washed with satd. NaCl soln., and dehydrated with MgSo4 to give 1,4-ethano-8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-tetrahydro 5H-[1 benzopyrano[3,4-b pyridine-10-acetateHCl.

Description

Method for preparing 1,4-ethano-10-hydroxy-5-oxo-5H- [1] benzopyrano [3,4-b] pyridine ester

The present invention relates to the following compound of formula (I), which is effective under intraocular pressure in a mammalian patient, and to a pharmaceutically toxic acid addition salt thereof.

In the above structural formula

R is a straight or branched alkane oil group having 2 to 8 carbon atoms or the following structural formula:

From here

Y is a linear or branched alkylene group having 1 to 8 carbon atoms

a is an integer from 1 to 4

b is an integer from 1 to 4

X is CH ₂ 0, S or NR ₁

R ₁ is hydrogen or lower alkyl, provided that the sum of a and b is 3 or 4 when X is 0, S or NR ₁ . "Pharmaceutically toxic acid addition salt" means a salt to which the desired acid is added. Representative salts include hydrochloride, hydrobromide, sulfate, sulfite, acetate, valerate, oleate, laurate, borate benzoate, lactate phosphate, tosylate, citrate, malate, succinate, tartrate and the like. .

As the compound of the present invention, the intraocular pressure generated in a mammalian patient is lowered, and in particular, the drug used in the glaucoma drug material can be obtained.

The compound is also effective as a mild mental stabilizer.

According to the present invention, the ethyl-3-quinuclidinone-2-carboxylate of the following formula (II) is reacted with dimethylheptyl-resolecinol of the following formula (III), and then cooled and the reaction mixture is reacted with sulfuric acid for 4 to 5 hours. After dropping over, phosphorooxychloride is added and the reaction mixture is stirred for 4-5 days at room temperature, a strong base (eg sodium hydroxide or potassium hydroxide) is added and the pH is adjusted to 7 with sodium bicarbonate. The residue of the gums is isolated by treatment with chloroform or a suitable organic solvent, dehydrated with sodium sulfate, and then evaporated to obtain the chemical formula (VI), which is a chemical substance. It is characterized in that it is esterified with to convert the compound of formula (I) as necessary to obtain a compound of formula (I) to obtain a pharmaceutically toxic acid addition salt.

Where R is as defined above.

Representative compounds of the invention are illustrated in the following examples.

Example 1

인 구조식(I)의 화합물R is

Phosphorus Compound (I)

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 mole) of pylon-HCI of formula (VI) is added to a flask containing 2.4 g (0.03 mole) of anhydrous sodium acetate and 30 ml of acetic anhydride and heated at reflux overnight to cool the reaction mixture and evaporate the acetic anhydride. . About 100 ml of water is added to the residue, and the aqueous solution is extracted with ether. The ether is washed with saturated NaCI solution and then dehydrated with MgSO ₄ and evaporated.

HCI-salts are prepared by conventional methods. Recrystallization from ethanol / ether mixtures yields 2.3 g of a white solid. Melting point 237 to 239 ° C (69% yield)

Elemental analysis: C ₂₅ H ₃₃ NO ₄ . HCI

Calculated Value: C 67.18, H 7.67, N 3.13

Found: C 67.40, H 7.92, N 3.16

IR and NMR spectra are consistent with the structures shown.

Example 2

인 구조식(I)의 화합물R is

Phosphorus Compound (I)

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

3.0 g (0.074 mole) of the starting material pyron-HCI is dissolved in chloroform, washed with dilute potassium bicarbonate solution, washed with saturated NaCI solution, dehydrated with MgSO ₄ and evaporated to give a free transparent yellow base residue.

After dissolving this free base in 75 ml of anhydrous benzene, 0.68 g (0.0074 mol) of triethylamine (ET ₃ N) was added thereto. The reaction mixture is refluxed overnight, cooled and filtered to remove ET ₃ N. HCI. The filtrate is evaporated to give a clear solid which is treated with anhydrous ether and then etheric-HCI is added.

The salt is precipitated from the solution.

3.6 g of a white solid is obtained.

Softening Point 86 ~ 88 ℃, Melting Point 130 ℃

Elemental analysis: C ₂₆ H ₃₅ NO ₄ . HCI

Calculated Value: C 67.59, H 7.854, N 3.032

Found: C 67.53, H 7.81, N 3.00

IR and NMR spectra are consistent with the structures shown.

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-octane oate hydrochloride

CH₃인 화합물 3.4g(수득량86%)을 흰색의 결정성물질로 얻는다. 융점 143 내지 145℃According to the method of Example 2 using R-otanyl chloride instead of propionyl chloride,

3.4 g (86% yield) of CH ₃ phosphorus is obtained as a white crystalline substance. Melting Point 143-145 ° C

Elemental analysis: C ₃₁ H ₄₅ NO ₄ . HCI

Calculated Value: C 69.968, H 8.713, N 2.632

Found: C 69.21, H 8.68, N 2.56

The IR and NMR spectra correspond to the structural formula.

Example 4

1,4-ethano-8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-tetrahydro 5 ′-[1] benzopyrano [3,4-b] Pyridine-10-trimethyl acetate hydrochloride

인 화합물 3.6g(수득량99%)의 흰색결정성 고체물질을 얻는다. 융점 178 내지 180℃When trimethylacetylchloride is used instead of propionyl chloride, R

3.6 g (99% yield) of white phosphorus compound were obtained. Melting Point 178-180 ℃

Elemental analysis: C ₂₈ H ₃₉ NO ₄ . HCI

Calculated Value: C 68.622, H 8.190, N 2.858

Found: C 68.28, H 8.24, N 2.79

The IR and NMR spectra match the structural formula.

Example 5

이고 Y=(CH₂)₃, a+b=4, x=CH₂인 구조식(I)의 화합물.R is

And Y = (CH ₂ ) ₃ , a + b = 4, x = CH ₂ .

1,4-ethano-10- [4- (1piperadino) 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 Pyron-HCI is diluted in NaHCO ₃ solution and extracted with methylene chloride. The methylene chloride was washed with saturated NaCI solution, dehydrated with MgSO ₄ and evaporated to give a pale yellow oily substance.

The free base was treated with 155mml of methylene chloride and 2.07 g (0.01 mol) of √-piperidino butyric acid-HCI (Cruick-Shank and Shee-han, J. Am. Chem. Soc., 83, 2891, 1961) After addition to a portion, it was stirred for 5 minutes and 2.26 g (0.011 mol) of N, N'-dicyclohexylcarbodiimide was added thereto. The reaction mixture is stirred overnight under nitrogen atmosphere (18 hours), cooled at 0 ° C. for 3 hours and the byproduct (dicyclohexylurea) is filtered off. Concentrate and dry the filtrate to crystallize immediately, leaving an oily residue. The solid residue is treated with hot CH ₂ CI ₂ and anhydrous ether is added until the solution becomes cloudy. Leaving the solution at room temperature precipitates a solid product from the solution. The solids are collected and dried in vacuo to yield 4.1 g of a white solid.

Melting point 165 to 167 ° C (73% yield)

IR and NMR are consistent with the desired product.

Elemental analysis: C ₃₂ H ₄₆ NO ₄ . HCI 1/2 H ₂ O

Calculated Value: C 67.642, H 8.515, N 4.930

Found: C 67.89, H 8.47, N 5.04

Example 6

인 구조식(I)의 화합물R is

Phosphorus Compound (I)

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

N, N'-dicyclohex using 4.05 g (0.01 mol) of free base, a structural formula (IV) compound, in a manner similar to Example 6, using 2.67 g (0.01 mol) of 4-methylpiperazino butyric acid HBr and Reaction with 2.26 g (0.01 mol) of silk carbodiimide affords the title compound.

Example 7

인 구조식(I)의 화합물R is

Phosphorus Compound (I)

1,4-ethano-10- [4- (4-phytylmethrazino) butyryloxy] -8- (3-methyl-2-octyl) -5-oxo-1,2,3,4-ted Lahydro-5H- [1] benzopyrano [3,4-b] pyridine hydrobromide

N, N'-dicyclohex using 4.05 g (0.01 mol) of free base, the structural formula (IV) compound, in the same manner as in Example 6, and 2.67 g (0.01 mol) of 4-methylpiperazino butyric acid HBr. Reaction with 2.26 g (0.01 mol) of silk carbodiimide affords the title compound.

The intraocular pressure-lowering effect of the compound of formula (I) was evaluated in New Zealand rabbits and albino breeds weighing 2 to 4 kg. The animals are placed in plastic fixtures and three control measurements separated at least 30 minutes apart using a Bausch and Lomb Appla-matic Tonometer. These measurements were taken every 30, 60, 90, 120 and 180 minutes after drug administration and control experiments were performed in the same manner. All experiments are based on blind spots. The statistical method used to analyze the measurements is Mann-Whitney on one side and two sample U-tests. Values equal to or less than 0.1 are considered to indicate statistical significance.

Phylocarpine hydrochloride and epinephrine hydrochloride as the present compound and the reference standard are prepared in microtherapeutic sterile water for intravenous injection and intramuscular injection, and the dry powder is filled in gelatin capsules for oral administration. Liquid excipients or empty gelatin capsules are used for placebo controls. The amount of drug injected in topical therapy should be constant at 0.1 ml. Each compound was tested in four eyes.

인 구조식(I)의 화합물을 대조 샘플과의 비교로 안내압을 강하시키는 투여량으로 제조된 0.05% 및 0.1%용액을 국부적으로 투여했다. -각기 9% 및 -32%의 농도에서 초대효과가 있었다. 0.1% 용액에서는 최소한 90분 이상에서 효과가 지속되었다. 필로카핀 하이드로클로라이드는 60분에서 안내압 26%가 감소되는 0.5%농도에서 유효하다. 에피네피린은 0.05 농도에서 유효하지 않으나 0.1%에서는 안내압이 점차로 강하되는데 국소치료후 180분에서 통계적 유의성을 지닌다.R is

Phosphorus structural formula (I) was administered locally at 0.05% and 0.1% solutions prepared at a dose lowering intraocular pressure in comparison to the control sample. At the concentrations of 9% and -32%, respectively, they were super effective. The effect lasted for at least 90 minutes in 0.1% solution. Pilocarpine hydrochloride is effective at 0.5% concentration with a decrease in intraocular pressure of 26% at 60 minutes. Epinephrine is not effective at 0.05 concentration, but gradually decreases intraocular pressure at 0.1% with statistical significance at 180 minutes after topical treatment.

The compound is prepared intravenously in dosages that lower intraocular pressure. The maximal effect occurs in the range of -20% at 0.05 mg / kg to -45% at 1.0 mg per kg body weight. In addition to intravenous administration of 1 mg / kg intravenously, pilocarpine not only significantly increases intraocular pressure, but also results in a particularly abundant fluid secretion of signs of parasympathetic stimulatory action.

When administered orally at 1.0 to 50.0 mg / kg body weight, the compound is inactive to intraocular pressure and no statistically significant change in intraocular pressure occurs when administered intramuscularly.

인 구조식(I)의 화합물은 0.1% 용액을 국소적으로 투여하면 안내압 28% 감소되고 R이

인 화합물은 안내압 6%가 감소되며 R이

인 화합물은 안내압이 33%가 증가(확인안됨)되나 모든 시험은 위약을 대조하여 비교한 것이다.R is

Phosphorus compounds of formula (I) decreased intraocular pressure 28% when topically administered 0.1% solution and R

Phosphorus compound decreases intraocular pressure 6% and R is

Phosphorus compounds increase intraocular pressure by 33% (not identified), but all tests compare placebo.

Topical administration of a compound of this invention is more effective than a control placebo or reference compound pilocarpine or epinephrine.

(실시예 5)인 구조식(I) 화합물은 정신안정제로 유효함을 알게 되었다. 이 화합물을 체중 kg 당 10mg의 투여량을 원숭이에게 경구투여 하면 물고 도망치고 뛰고 소리지르는등의 공격행동이 감소된다. 이와 같은 화합물을 덮개를 한 토끼에게 체중당 5.0mg의 투여량을 경구투여하면 데속신(Desoxyn)을 유발하는 작용 34%가 감소된다.R is

Example 5 Compound (I) was found to be effective as a mental stabilizer. Oral administration of 10 mg / kg of this compound to monkeys reduces aggression such as biting, running, running and screaming. Oral doses of 5.0 mg per body weight to rabbits covered with these compounds reduced 34% of the action that causes desoxyn.

Claims (1)

The following compound of formula (I) is characterized by reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV) and esterifying the compound with a compound of formula (V). A process for preparing 4-ethano-10-hydroxy-5-oxo-5H- [1] benzopyrano [3,4-b] pyridine ester.

In the above structural formula R is a C2-C8 straight or branched alkane oil group or the group of the following structural formula.

From here Y is a straight or branched chain alkyl group having 1 to 8 carbon atoms a is an integer from 1 to 4 b is an integer from 1 to 4 X is X is CH ₂ 0, S or NR ₁ R ₁ is hydrogen or lower alkyl, provided that the sum of a and b is 3 or 4 when X is 0, S or NR ₁ .