DE2411847A1 - SUBSTITUTED BENZOPYRANO SQUARE CLIP ON 3.4-C SQUARE BRACKET FOR PYRIDINE AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

PATENTANWÄLTE HENKEL - KERN - FEILER - HÄNZEL

MÜLLER

DR. PHIL.

TELEX: OS 29 802 HNKL D TELEPHONE: (08 II) 66 31 97. 66 30 91-92 TELEGRAMS: ELLIPSOID MUNICH

DIPI ..- ING.

DR. RER. NAT.

DIFL.-ING.

EDUARD-SCHMID-STRASSE 2 D-8000 MUNICH 90

DIPL.-ING.

BAVARIAN MORTGAGE AND EXCHANGE BANK MONCHLN NK. 313-85111 POSTAL CHECK: MCMN 1621 47-809

Warner-Lambert Company,
Morris Plains, NJ, V.St.A.

Substituted Benzopyrano .- / 5 «4-c7pyridines and medicinal products containing these compounds

The invention relates to a new class of benzopyrano- 13, 4-c7pyridines of the following general formula:

(D

where mean:

R ^ and R2 hydrogen atoms, hydroxyl radicals or short-chain Alkoxyl radicals having 1 to 6 carbon atoms;

R-z a hydrogen atom or a short-chain ' Alkyl radical with 1 to 6 carbon atoms and

an oxygen or sulfur atom, a methylene radical, one substituted by hydrogen Nitrogen atom, a short-chain alkyl radical

-2-

Dr F / jο

409841/1007

with 1 "to 6 carbon atoms or a short chain one Alkanoyl radical with 1 to 6 carbon atoms.

The compounds of the invention have an activity. acted as bronchodilators and are able to do so as such, for example Guinea pigs at an oral dose of 10 mg / kg up to 4th hrs before one by 'histamine, or serotonin Acetylcholine to preserve induced bronchospasm. Thus, the compounds according to the invention are more effective than the aminophylline known for the treatment of bronchial asthma and pulmonary edema, which at a dose of 100 mg / kg Guinea pigs only less than 2 hours before bronchospasm induced by histamine, serotonin or acetylcholine able to protect. In addition, they raise up to 1 hour in dogs at a daily dose of 10 mg / kg long a narrowing of the windpipe caused by pilocarpine or histamine. The bronchodilator activity of the N-substituted benzopyrano / 3,4-c7pyridines according to the invention is the result of a direct relaxation effect on the smooth muscles of the bronchial tree. This could be proven by in-vitro tests on guinea pig trachea. In these attempts were the N-substituted benzopyrano- / 3,4-c7pyridines according to the invention about 75 times more active than aminophytline in terms of relaxation of the smooth tracheal muscles.

The compounds according to the invention are suitable for the treatment of bronchial asthma. Usually it is in mammals and people weighing about 70 kg a dose of about 500 mg to 1000 mg several times a day indicated. The compounds of the invention can be administered orally or parenterally.

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For administration these compounds can be pharmaceutically harmless carriers or extenders such as lactose, starch, Eulverziicker and the like and converted into suitable administration forms such as tablets, capsules and the like. Depending on the Severity of the case to be treated * the dosage can be varied «

The compounds according to the invention are prepared according to the following reaction scheme:

COOC ₀ H

II

III

■ * i

/ \ I ³

X N-CH ₀ -CH-Cl

409841/1 Ü07

In the first stage, an R ₁ , ILj-substituted phenol is reacted with 3-carbethoxy-4-piperidone in the presence of an acid catalyst to give a benzopyrano / 3,4-c7pyridine intermediate corresponding to formula IV. The Ausgangspheno! Compounds (II), such as m-methoxyphenol, 3,4-dimethoxy phenol, 2,3-dimethoxy phenol, 3,5-dimethoxy phenol, and the like, are known and commercially available.

Examples of usable acid catalysts are sulfuric acid, phosphoric acid, phosphorus oxychloride, phosphorus pentoxide, Polyphosphoric acid, boron fluoride and the like.

The intermediate products of the formula (IV) are converted into the end products of the formula (I) by treatment of the intermediates with an appropriate 2-aminoalkyl halide of formula (V), wherein R, is a. Hydrogen atom or a short-chain alkyl radical with 1 to 6 carbon atoms and X represents an oxygen or sulfur atom, a methylene radical or a hydrogen-substituted one Nitrogen atom, a short-chain alkyl radical with 1 to 6 carbon atoms or a short-chain alkanoyl radical with 1 to 6 carbon atoms.

For the preparation of N-aminoalkylbenzopyrano / B ^ -c / pyridines of the formula (I), in which R ₁ and Rp are ethoxy radicals and Rz and X have the meaning given in the previous section, the corresponding dimethoxy analogs, ie compounds of the formula (I ), in which R ₁ and R _{2 represent} methoxy radicals and R and X have the meaning given, with 48% strength hydrobromic acid to give the dihydroxy derivatives of the formula (I), in which R ₁ and Rp represent hydroxyl radicals, demethylated and the +) or higher alkoxy radicals

40984 1 / 1UU7

obtained dihydroxy derivatives with diethyl sulfate in the presence a base, such as potassium carbonate, ethylated or alkylated with other suitable alkylating agents.

The following examples are intended to illustrate the invention in more detail .

Example 1

Preparation of 1,2,3,4-tetrahydro-8-methoxy-5H- / T7benzopyrano- / 3,4-c7pyridin-5-one the formula:

A mixture of 31.0 g of m-methoxyphenol (0.25 m) and 41.5 g of 3-carbethoxy-4-piperidone hydrochloride (0.2 m) was cooled in an ice bath and with stirring and with exclusion of moisture for 20 minutes with 50 ml concentrated H ₂ SO ^ treated. After stirring at room temperature for 20 hours, the reaction mixture was cooled and made up to 250 ml with ice water. When the pH was increased to 9 by adding concentrated ML OH, a precipitate formed which was filtered off, washed with water and dried in vacuo. 41.0 g of crude product were obtained in an 88% yield. Recrystallization from ethanol an analytically pure · product was obtained with a constant melting range of 171 ° to 180 ⁰ C.

An elemental analysis of the compound C ^ H ^ NO ^ gave the following Values:

-6-

409841/1007

Calculated: C 67.52; H 5.67; N, 6.06 Found: C, 67.71; H 5.72; N 6.19.

Further, also the final product-HCl was coupled was a melting point of 248 ° to 250 ⁰ C.

An elemental analysis of the compound C ₁ , H ₁ , NOJKCT-1 / 4C gave the following values:

Calculated: C, 57.86; H 5.93; N 5.00; Cl 12.65 Found: C 57.51; H 5.66; N 5.11; Cl 12.65.

Example 2

Preparation of 1,2,3,4-tetrahydrp-5H- / T7benzopyrano / 3,4-c7-pyridin-5-one the formula:

A mixture of 18.8 g (0.2 m) phenol and 20.7 g (0.1 m) 3-carbethoxy-4-piperidone * HCl was cooled in an ice bath and treated with 75 ml of 73% HpSO ^ for 30 minutes while stirring and excluding moisture. After stirring for 4 days at room temperature, the reaction mixture was quenched and added an additional 10 g Treated (0.106 m) phenol. After 5 days a further 10 g of phenol were added. After stirring for 6 days, the 100 g of ice are added to the reaction mixture and the pH is adjusted to 8 to 9 by adding concentrated NH »OH

-7-409841 / 1007

brought. The gummy mass formed in this way was stirred for 30 minutes with 100 ml of CHCl 4 and then filtered off. After evaporation of the filtrate, the gummy mass obtained was washed with petroleum ether and then Triturated with ethyl ether. The solid obtained in this way was recrystallized from 100 ml of 3N HCl, with in 10biger yield 2.3 "g end product of a melting point from 330 ° to 335 ° C.

An analysis of the compound C-pHy., NOpHCl gave the following Values:

Calculated: C, 60.64; H 5.09; N 5.89; Cl 14.92 Found: C 60.87; H 5.08; N 5.78; Cl 14.69,

Example 3

Preparation of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H- / T7-benzopyrano / 3,4-c7pyridin-5-one hydrochloride the formula:

^CH 3 °

Example 2 was with 46.0 g (0.3 m) 3,4-dimethoxyphenol, 41.7 g (0.2 m) 3-carbethoxy-4-piperidone hydrochloride and 100 ml of a 73 volume -! & Lgen sulfuric acid repeated, with 33.4 g of the pyridin-5-one hydrochloride in a 63-6 yield with. a melting point of 254 ° to 256 ° C.

An elemental analysis of the compound C ₁ ^ H ₁ ^ NO ^ HCl gave the following values:

409841/1007

Calculated: C, 54.82; H 5.59; N 4.57; Cl 11.56 Found:. C 54.735 H 5.91; .N 4.38; Cl 11.64,

Example 4

Preparation of 1,2,3,4-tetrahydro-8-methoxy-3- (2-morpholinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

A mixture of 10 g (0.043 m) 1,2,3,4-tetrahydro-8-methoxy-5H- / T7t ⁾ enzopyrano / 3,4-c7pyridin-5-one, 11.2 g (0.06 m) N - (2-chloroethyl) morpholine «HCl and 14.2 g of triethylamine (0.14 m) in 170 ml of absolute ethanol were heated to reflux for 4 hours with stirring and with exclusion of moisture. The reaction mixture was then filtered hot, cooled slightly and treated with dry HCl. The precipitate obtained in this way was filtered off and washed first with ethanol and then with ether, 14.6 g of crude product being obtained in 81% yield. When recrystallizing from methanol, an analytically pure material with a melting point of 237 ° to 240 ° C. was obtained.

An elementary analysis of the compound C. "lip, MpO _- , -2HC1" resulted in the following values:

Calculated: C, 54.68; H 6.28; N 6.71 J-Cl 16.99 Found: C, 54.42; H 6.47; N 6.65; Cl 17.09,

409841 / 1UU7

Example 5

Preparation of 1,2,3,4-tetrahydro-8,9-dimethoxy-3- (2-morpholinoethyl) -SH-ZT ^ benzopyrano ^, 4-c7pyridin-5-one the formula:

A mixture of 7.85 g «(0.03 m) 1 ^^^ methoxy ~ 5H- / T7'benzopyrano / 3,4-c7pyridin-5-one, 6.15 g (0.033 m) N <2-chloroethyl ) morpholine-HCl and 7.08 g (0.07 m) triethylamine.in 250 ml of ethanol was heated to reflux temperature for 6 hours and then filtered hot. When the hot reaction solution was treated with excess HCl for 6 hours and cooled to room temperature, a crude product was obtained. Recrystallization from 75% ethanol an analytically pure material was obtained having a melting point of 238 ° to 24O ⁰ C.

An elemental analysis of the compound CpgHpgNpOc · 2HCl showed the following values:

Calculated: C, 53.70; H 6.31; N 6.26; Cl 15.85 Found: - ■ 'C53.60; H 6.47; N 6.35; -Cl 15.66,

Example 6

Preparation of 1,2,3,4-tetrahydro-8,9-dimethoxy-3 - (imethyl-2-morpholinoethyl) -5H- ^ j [7benzopyrano / 3,4-c7pyridin-5-one the formula:

-10-A09841 / 1007

CEL ₃ Q CH ₃ O

In the ¥ ice described in Example 5, 0.02 m 1,2,3,4-tetrahydro-8,9-dimethoxy-5H- / T7benzopyrano / 3,4-c7-pyridin-5-one with N- (2 chloropropyl) morpholine alkylated to give 1.3 g of final product were obtained with a melting point of 228 ° to 230 ⁰ C after recrystallization from 95? 6igem ethanol.

An analysis of the compound C ₂₁ ^H 28 ^N 2 O 5 ^{"2HBr he} g ^a b the following values:

Calculated: C, 53.62; H 6.43ϊ N 5.95; Br 16.98 Found: C 53.70; H 6.39; N 6.02; Br 16.97.

Example 7

Preparation of 1,2,3,4-tetrahydro-8,9-dimethoxy-3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

, CII ₃ O

A solution of 14.4 g (0.055 m) 1,2,3, * - tetrahydro-8,9-dimethoxy-5H- / i7benzopyrano / 3,4-c7-pyridin-5-one, 11.18 g (O, O6O5 tn) N- (2-chloroethyl) piperidine hydrochloride and 12.2 g (0.121 m)

- 11 409841/1007

Triethylamine in .500 ml of absolute ethanol was 17.5 hours heated to reflux temperature for a long time. After hot filtration and immediate treatment with excess gaseous HCl, 19.5 g of the crude DiHCl salt were obtained. After dissolving in 1.4 liters of 95% ethanol, filter off and concentration to 400 ml, an analytically pure material with a melting point of 233 ° to 239 ° C. was obtained.

An analysis of the compound Cp.H ₂₈ NpO, '2HCl gave the following values:

Calculated: C, 56.63; H 6.79ϊ 6.29; Cl 15.92 Found: C, 56.37; H 6.99; N 6.24; Cl 16.01.

Example 8 "

Preparation of 1,2,3,4-tetrahydro-8,10-dimethoxy-3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

οσί

In the manner described in Example 5, 0.02 m of 1,2,3,4-tetrahydro-8,10-dimethoxy-5H- / T7benzopyrano / 3,4-c7-pyridin-5-one alkylated with N- (2-chloroethyl) piperidine, 3.0 g of reaction product after recrystallization from methanol a melting point of 190 ° to 224 ° C were obtained.

An elemental analysis of the compound Cp.HpgNpO, ^# 2HC1 gave the following fourth:

40 9841 / 1UU7 " ¹² ~

Calculated: C, 56.63; H 6.79; N 6.29; Cl 15.92 Found: C 53.69; H 6.30; N 6.26; Cl 14.74,

Example 9

Preparation of 1,2,3,4-tetrahydro-7,8-dimethoxy-3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

, OCiI ₃

: 0

In the manner described in Example 5, 5.7 mmoles 1,2,3,4-tetrahydro-7,8-dimethoxy-5H- / T7benzopyrano / 3,4-c7-pyridin-5-one alkylated with N- (2-chloroethyl) piperidine, wherein after recrystallization from methanol 0.5 g of reaction product a melting point of 236 ° to 239 ° C was obtained.

An elemental analysis of the compound Cp ^ HpgNpOr ^ HCl showed the following values:

Calculated: C, 56.63; H 6.79; N 6.29; Cl 15.92 Found: C 55.58; H 6.77; N 6.30; Cl 15.68.

Example 10

Preparation of 1,2,3,4-tetrahydro-8,9-dih3> -droxy-3 - (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

-13-

409841/1007

~ 13 -

A solution of 4.7 g of 1 ^^^
3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one in 70 ml of 48% hydrobromic acid was heated to reflux temperature for 17 hours and then cooled. The precipitate formed was recrystallized from water, 2.8 g of reaction product having a melting point of 291 ° to 295 ° C. being obtained.

An elemental analysis of the compound gave the following values:

Calculated: C 45.08; H 5.18; Found: C, 45.06; H 5.30;

2 : 4 ^N 24 • 2HBr he- 57 N- 5, 53; Br 31, 39 N 5, 38; Br 31,

Example 11

Preparation of 1,2,3,4-tetrahydro-8,9-dihydroxy-3- (2-morpholinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

-14-

409841 / 1Ü07

- I ** -

A solution of 8.7 g of 1,2,3,4-tetrahydro-8,9-diniethoxy-3- (2morpholinoethyl) -5H / T7benzopyrano / 3Y4-c7pyridin-5-one in 60 ml of 48% strength hydrobromic acid was 17 hours long heated to reflux temperature and then cooled. The resulting precipitate was recrystallized from water, 5.5 g of reaction product having a melting point of 299 ° to 302 ° C. were obtained.

An elementary analysis of the connection gave the following values:

Calculated: C, 42.54; H 4.76; Found: C, 42.29; H 4.72;

N 5.51; N 5.53;

^he ~

Br 31.45 Br 31.42.

BeisDiel 12

Preparation of 8,9-diethoxy-1, 2,3,4-tetrahydro-3 - (2-morpholinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the formula:

C ₂ H ₅ O

C ₂ H ₅ O

A mixture of 0.01 m 1,2,3,4-tetrahydro-8,9-dihydroxy-3- (2-morpholinoethyl) -5H- / T7benzopyrano / 3,4 ~ c7pyridin-5-one, 0.022 m diethyl sulfate and 0.1 M K ₂ CO ₅ in 500 ml of acetone was heated to reflux temperature for 18 hours, then filtered while hot and concentrated. The residue was dissolved in CHCl ₅ and washed with 3% strength liaOH solution. The CHCl ^ -soluble material was recrystallized from methanol containing excess gaseous HCl, whereby

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409841/1007

1 g reaction product with a melting range of 240 ° to 260 ° C was obtained.

An elemental analysis of the compound ^ 22 ^H 30 ^N 2 ° 5 * ^ HCl gave the following values:

Calculated: C 55.58; H 6.78; N 5.89; Cl 14.91 Found: C 55.38; H 6.86; N 5.98; Cl 14.09.

Example 15

Preparation of 8,9-diethoxy-1,2,3,4-tetrahydro-3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one the Fl

Formula:

C ₂ H ₅ O

C ₂ H ₅ O

A mixture of 0.01 m 1,2,3,4-tetrahydro-8,9-dihydroxy-3- (2-piperidinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one, 0.022 m diethyl sulfate and 0.1 M K ₂ CO ₃ in 250 ml acetone was heated to reflux temperature for 20 hours and then filtered hot. After evaporation, the evaporation residue was recrystallized twice from ethyl acetate, 0.6 g of reaction product having a melting point of 144 ° to 146 ° C. being obtained.

An elemental ^{analysis of} the compound ^ p - ^ - x ^ o ^ h ^er S aD gende values:

Calculated: C, 68.97; H 8.05; N 7.00; Found: C, 68.62; H 8.07; N 7.03.

40984Ί / 1ϋϋ7 " ¹

Example 14

Preparation of 3- / 2- (4-acetyl-1-piperazinyl) ethyl7-1,2,3,4-tetrahydro-8,9-dimethoxy-5H- / T7benzopyran / 3,4-c7pyridin-5-one the formula:

CiI ₃

u ⁰ ^

In the manner described in Example 5, 0.02 m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H- / T7'benzopyrano- / 3,4-c7pyridin-5-one with N-acetyl -N '- (2-chloroethyl) piperazine is alkylated to give 5.8 g of reaction product were obtained with a melting point of 234 ° to 235 ⁰ C after recrystallization from methanol.

An elemental ^{analysis of the compound C} 22 ^H 29 ^N 3 ° 5 "2HC1 gave the following values:

Calculated: C, 54.10; H 6.40; N 8.60; Cl 14.52 Found: C, 54.09; H 6.42; N 8.75; Cl 14.50.

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4098A1 / 1Ü07

Claims (8)

Claims / i / compounds of the formula: where mean: R ^ and R-2 hydrogen atoms, hydroxyl radicals or short-chain ones Alkoxyl radicals having 1 to 6 carbon atoms; FU a hydrogen atom or a short chain Alkyl radical with 1 to 6 carbon atoms and X is an oxygen or sulfur atom, a methylene radical or a hydrogen-substituted nitrogen atom, a short-chain alkyl radical with 1 to 6 carbon atoms or a short-chain alkanoyl radical with 1 to 6 carbon atoms, 2. Compounds according to claim 1, characterized in that they consist of 1,2,3,4-tetrahydro-8-methoxy-3- (2-morpho-. Linoäthyl) -5H- / T7benzopyrano / 3,4-c7pyridine-5 -one, 1,2,3,4-tetrahydro-8,9-dimethoxy-3- (2-morpholinoethyl) -5H- / T7-benzopyrano / 3,4-c7pyridin-5-one, 1,2 ₁ 3, 4-Tetrahydro-S, 9-dimethoxy-3- (1-methyl-2-morpholinoethyl) -5H- / T7benzopyrano / 3,4-c7pyridin-5-one, 8,9-diethoxy-1,2,3,4 -tetra- -18- 409841/1007 1R hydro-3- (2-morpholinoethyl) -5H- ^ T7benzopyrano / 3,4-c7-pyridin-5-one, 1,2,3,4-Tetrahydro-8,9-dimethoxy-3- (2-piperidinoethyl) -SH-Z ^ benzopyrano ^, 4-c7pyridin-5-one, 1,2,3,4-Tetrahydro-8,1O-dimethoxy-3- (2-piperid: Lnoäthyl) -5H - /] 7benzopyranoZ3,4-c7pyridin-5-one, 1,2,3,4-Tetrahydro-7,8-dimethoxy-3- (2-piperidinoethyl) -5H- / T7-benzopyrano / 3,4-c7pyridin-5-one, 8,9-diethoxy-1,2,3,4-tetrahydro-3- (2-piperidinoethyl) -5H- / T7benzopyrano- ^ 3,4-c7pyridin-5-one or 3- / 2- (4-acetyl-1-piperazinyl) -ethyl7-1,2,3,4-tetrahydro-8,9-dimethoxy-5H- / T7benzopyrano ^ 3 , 4-c7pyridin-5-one exist, 3. Medicines for the treatment of bronchial asthma, thereby characterized in that it is a compound of the formula: ! .H-CH ₂ -N where mean: and R «hydrogen atoms, hydroxyl radicals or short-chain ones Alkoxyl radicals having 1 to 6 carbon atoms; a hydrogen atom or a short-chain alkyl radical with 1 to 6 carbon atoms and an oxygen or sulfur atom, a methylene radical or a hydrogen-substituted one Nitrogen atom, a short-chain alkyl radical with 1 to 6 carbon atoms or a short-chain alkanoyl radical with 1 to Carbon atoms, contains. 409841/1007 -19- - 19 - 241184? 4. Medicament according to claim 3, characterized in that that there are 1,2,3,4-tetrahydro-8,9-dimethoxy-3- (2-morpholinoethyl) -5H- / 77t> enzopyrano / 3,4-c7pyridin-5-one and / or 1,2,3,4-tetrahydro-8,9-dimethoxy-3- (2-piperidinoethyl) -5H- / T7benzppyraho-3,4-c'7pyridin-5-one contains. 5. Medicament according to claim 4, characterized in that that it is administered orally three to four times a day at a dose of 10 mg / kg of body weight. 6. Process for the preparation of compounds according to Claims 1 or 2, characterized in that a compound is used the formula OH - II ^v wherein R ₁ and R _{9 have} the meaning given, in the presence of an acidic catalyst with a compound of the formula N-H III. to an intermediate of the formula - 20 - 409841/1007 where R. and Rp have the meaning given,
converts that the intermediate obtained with
a compound of the formula I ³ N-CH ₂ -CH-Cl wherein X and R-. have the meaning given, allowed to react and that, if appropriate, those compounds of the given formula I in which R. and Rp are alkoxy radicals
are converted into the corresponding hydroxy compounds with the aid of a demethylating agent. 7. The method according to claim 6, characterized in that the starting compound of the formula II is m-methoxyphenol, 3,4-dimethoxyphenol, 2,3-dimethoxyphenol or 3 * 5-dimethoxyphenol used. 8. The method according to claim 6, characterized in that the acid catalyst used is sulfuric acid, phosphoric acid, phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or
Boron fluoride used. 409841/100 7