DE2146340A1 - - Google Patents

Description

· W. ^ Diptlng P Wirffi

Dr. V. Sh

*. f. Weinhold, Dr. D.

t ' ^Gr · Eschenheimer Sfr. 3 <J

Sandoz AG. case 600-6395

Today's organic compounds and their processes Manufacturing

The invention relates to compounds of the formula I, R,

wherein X stands for a direct bond or for the groups

-0-, -S-, -CH ₂ -S- or -N-, in which R ₁₀ denotes methyl or ethyl, R denotes an alkyl group having 1-3 carbon atoms and R- to R _{Q are} identical or different and are each stand for hydrogen, chlorine or an alkoxy group with 1-3 carbon atoms, with the proviso that not more than 2 of the substituents R 1 to R _{Q have} a meaning other than hydrogen and a process for their preparation.

According to the invention, compounds of the formula I get by using compounds of the formula II,

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II

R -

wherein X, R and R, to R _{q have the} above meaning, reduced.

The reduction of compounds of the formula II is described in carried out in an inert organic solvent and in an inert gas atmosphere. As a reducing agent one uses those who are able to reduce an amidocarbonyl group to a methylene group, without causing reduction of an aromatic ring. It is preferred to use for this reduction Metal hydrides, for example lithium aluminum hydride, diisobutyl aluminum hydride or sodium bis * (2-methoxyethoxy) aluminum hydride or diborane. As an inert organic solvent, for example Use ethers such as diethyl ether or tetrahydrofuran, or hydrocarbons such as benzene or toluene. A nitrogen atmosphere is expediently used as the inert gas atmosphere. The reduction will expediently at temperatures between 50 ° and

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150 ° C, preferably carried out at the boiling point of the reaction mixture, the reaction time between 15 and 48 hours, preferably between 18 and 24 hours, should be.

The compounds of the formula I obtained in this way can be isolated and purified in a manner known per se, If desired, the basic compounds of the formula I can be converted into their acid addition salts in a manner known per se be convicted and vice versa.

The compounds of the formula II used as starting compounds in the above process can be obtained by using compounds of the formula III,

III

wherein X, R and R, to R _{Q have the} above meaning, subjects to a ring closure.

The ring closure of compounds of the formula III is carried out with the aid of a mineral acid or with the aid of an organic Acid or an acid anhydride. Aqueous or non-aqueous conditions can be adhered to here

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and it is advantageous if the reaction takes place in an inert gas atmosphere, for example in a nitrogen atmosphere. The presence of an inert organic solvent is beneficial, but not absolutely necessary. If inert organic solvents are to be used, ethers such as tetrahydrofuran or hydrocarbons such as heptane, hexane or benzene are preferred. The mineral acids suitable for ring closure are, for example, sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid and phosphoric acid. However, the ring closure is preferably carried out using organic acids or anhydrides of organic acids. Expediently, acetic acid, trifluoroacetic acid, acetic anhydride or trifluoroacetic anhydride are used here. When using a mineral acid, the ring closure is expediently carried out at temperatures between 70 ° and 120 ° C., preferably at the boiling point of the reaction mixture. The response time is between 24 and hours. When using an organic acid or an organic acid anhydride ring closure is preferably, for 1 to 24 hours, carried out conveniently at temperatures between -10 ° and + 10 ° C between -5 ° and + 5 ⁰ C. If compounds of the formula III which contain alkoxy substances are used as starting compounds, strongly acidic conditions should be avoided in order to avoid the possibility of

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to reduce the splitting off of these alkoxy groups. It is therefore advantageous, for example, to use an organic acid or the anhydride of an organic To use acid if it is assumed that compounds of the formula III contain alkoxy substituents.

However, it has been found that, if in the compounds of the formula III, X stands for a direct bond and in particular if o- (9-hydroxy-9-fluorenyl) -N-methylbenzamide is used as the compound of the formula III is used, the yield of compounds of the formula II can be increased if the reaction product, which is contaminated by some undesirable by-products, such as the corresponding iminophthalane with a mineral acid, preferably a hydrohalic acid such as hydrogen chloride acid treated. This treatment is expediently at temperatures between 40 ° and 100 ° C carried out for 12 to 24 hours.

The compounds of formula II obtained in this way can on can be isolated and purified per se known manner.

Compounds of the formula III can be obtained by adding compounds of the formula IV,

—R ₁ ,

IV

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wherein R, to Rg and X have the above meaning with

Compounds of formula V,
Li

R-M-C

is

y ^v

^U R
^R 9

in which R and R "to R _{Q have the} above meaning, are reacted in an inert organic solvent and the reaction product is then hydrolyzed.

The reaction of compounds of the formula IV with compounds of the formula V can conveniently at Temperatures between -10 ° and + 10 ° C, preferably between -5 ° and + 5 ° C are carried out, the The reaction time should expediently be between 1 and 3 hours. Suitable for this implementation Solvents are ethers, for example diethyl ether and tetrahydrofuran and hydrocarbons, for example Hexane, heptane and benzene and toluene. The subsequent hydrolysis can be carried out in a manner known per se, preferably carried out using an aqueous ammonium chloride solution or by adding the reaction mixture to water or applying it to ice will. The hydrolysis is expediently carried out at temperatures between 0 ° and 10 ° C.

The compounds of the formula III obtained can be isolated and purified in a manner known per se.

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However, the compounds of the formula III are expediently not isolated, but rather directly to compounds of the Formula II processed.

The compounds of the formula IV and V used as starting compounds in the above process are known.

The compounds of the formula I obtained according to the invention have extremely favorable pharmacodynamic properties and therefore can be used as remedies. In particular, the compounds of formula I show in which X stands for the groups -0-, -S- or -CHp-S-, an analgesic Effect that is evident when 25-100 mg / kg of active ingredient is administered to mice and rats using the so-called hot plate method according to Woolfe and McDonald [J. Pharmacol, and Exper. Therap. 80, 300 (1944)]. These compounds can therefore be used as analgesics.

The amount of compounds of the formula I to be administered daily should be between 6 mg and approx. 1000 mg, these amounts preferably in smaller doses between 1.5 and 500 mg 2-4 times daily or in sustained release form administered.

The compounds of formula I in which X is a direct

Bond or the group -N- have liypotive Properties, as can be seen from experiments, where

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the active ingredient i.v. administered to an anesthetized dog. These compounds of formula I can therefore be used as antihypertensive agents.

The amount of these compounds to be administered daily is between 350 ^and 2000 mg, this amount preferably being administered in smaller doses between 85 and 1000 mg 2-4 times daily or in sustained-release form.

The compounds of the formula I can be in the form of the free bases or in the form of their acid addition salts used together with pharmaceutically acceptable acids. The potency of the salts is in of the same order of magnitude as that of the free bases. Suitable acids for the preparation of the acid addition salts are mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and Phosphoric acid and organic acids such as succinic acid, benzoic acid, acetic acid, p-toluenesulfonic acid and benzenesulfonic acid.

The compounds of the formula I can be administered orally in the form of tablets, capsules, granules, elixirs, suspensions or syrups or parenterally in the form of injection solutions or suspensions. The manufacture of these forms of administration is known.

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Preferred compounds of the formula I are those in which R 1 to R _Q each represent hydrogen and in particular those in which X represents the groups -0- or -S-.

A representative composition suitable for oral administration is a capsule made using of the following components is produced in a manner known per se.

Components Weight (mg)

2-methylspiro [isoindoline-1,9'-

xanthene] 25

Inert fillers (such as starch,

Kaolin or lactose) 275

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Example 1: 2-methylspiro [isoindoline-1,9'-xanthene]

a) o- (9-Hydroxy-xanthen-9-yl) -N-methylbenzaniide

In one with stirrer, dropping funnel, reflux condenser and Flask fitted with gas inlet tube are under nitrogen atmosphere at room temperature 15.2 g (0.108 mol) of N-methylbenzamide and 150 ml of dry tetrahydrofuran given. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5 ° C. Thereafter is stirred and for about 1 hour 152 ml of a Ι, ό Μ

n-Butyllithium - solution in hexane dropwise

added, the temperature being kept below 8 ° C. The red dilithium salt formed is stirred for a further hour at 5 ° C and then a solution of 21.2 g (0.108 mol) of xanthen-9-one in 75 ml of anhydrous tetrahydrofuran is added dropwise over about 45 minutes, the temperature between - 10 ° and + 10 ° C is maintained. The resulting mixture is stirred for a further hour at 5 ⁰ C and then poured with stirring to 300 g of ice, maintaining the temperature below 10 ° C. The layers are then separated and the tetrahydrofuran layer is dried over anhydrous magnesium sulfate, filtered off and evaporated in vacuo. The oil obtained as residue is triturated with cold diethyl ether and the mixture is filtered off. The crude o- (9-hydroxy-xanthen-9-yl) -N-methylbenzamide is obtained as the residue.

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b) 2-methylspiro [isoindolin-1 ^^ - xanthene] -3-one

100 g of trifluoroacetic anhydride are placed in a flask equipped with a stirrer, reflux condenser and gas inlet tube at room temperature under a nitrogen atmosphere. The flask is cooled to an internal temperature of 0 ° C. and then 31 g of the crude o- (9-Hydroxyxanthen-9-yl) -N-methylbenzamide are added in several portions with stirring. The reaction mixture is kept at 0 ° C. for 1 hour and then at room temperature for 19 hours. The solvent is then evaporated in vacuo. The oily residue is dissolved in methylene chloride and the methylene chloride solution is washed with 100 ml of water, 100 ml of a 2N aqueous sodium hydroxide solution and again with 100 ml of water. After drying over magnesium sulfate, it is filtered off and the mixture is evaporated in vacuo. The solid residue obtained is triturated with cold diethyl ether and the portion which is insoluble in the ether is recrystallized from hot benzene. This gives the 2-methylspiro [isoindoline-l, 9'-xanthene] -3-one with a melting point of 19O-19I ⁰ C.

c) 2-methylspiro [isoindoline-l _i 9 ^t -xanthene]

In a flask equipped with a stirrer, reflux condenser and gas inlet tube, l _f l4 g (0.03 mol)

BATH ORIGINAL

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Lithium aluminum hydride and 50 ml of anhydrous tetrahydrofuran. The mixture is then stirred and a solution of 7.9 S (0.021 mol) of 2-methylspiro [isoindolin-l, 9'-xanthene] -3-one in 120 ml of anhydrous tetrahydrofuran added dropwise over about 30 minutes. The resulting mixture is heated to boiling for 18 hours and then cooled in an ice bath. After adding dropwise 6.8 ml of ethyl acetate over a period of about 10 minutes are added dropwise over a period of about 10 minutes, 2.3 ml of a 2N aqueous sodium hydroxide solution and 3.4 ml dropwise over about 10 minutes Water too. The resulting mixture is dried over anhydrous magnesium sulfate and then evaporated in vacuo. This gives a semi-solid material which is triturated with hot diethyl ether. After filtering off the filtrate is evaporated in vacuo and the residue is recrystallized from diethyl ether. The 2-methylspiro [isoindoline-l, 9'-xanthene] obtained in this way melts between 124 ° and 126 ° C.

Example 2:

a) Using the method described in Example la), but replacing the one used there Xanthene-9-one by approx. equivalent shares of j

10-ethyl-2-methoxy-acridan-9-one dibenzo [b, e] thiepin-11 (6H) -one
9-fluorenone

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thioxanthen-9-one

6-methoxy-thioxanthen-9-one or 3-chloro-10-methyl-acridan-9-one

one arrives at

(i) o- (10-Ethyl-9-hydroxy-2-methoxy-acridan-9-yl) -N-methylbenzamide

(ii) o- {6, II-dihydro-II-hydroxy-dibenzo [b, e] thiepin-11-yl} - N -methylbenzamide

(iii) o- (9-Hydroxy-9-fluorenyl) -N-methylbenzamide (iv) o- (9-Hydroxy-thioxanthen-9-yl) -N-methylbenzamide

(v) o- (9-Hydroxy-6-methoxy-thioxanthen-9-yl) -N-methylbenzamide and

(vi) o- (10-Methyl-9-hydroxy-3-chloro-acridan-9-yl) -N-methylbenzamide

Using the method described in Example la), but replacing the N-methylbenzamide used there by equivalent proportions of

o-chloro-N-methylbenzamide or
m-methoxy-N-ethylbenzamide

you get to the following connections:

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(vi i) o-chloro-S- (9-hydroxy-xanthen-9-yl) -N-methylbenzamide and

(viii) 2- (9-Hydroxy-xanthen-9-yl) -5-methoxy-N-ethylbenzamide

b) Using that described in Example Ib) Method, but with replacement of the o- (9-hydroxy-xanthen-9-yl) -N-methylbenzamide used there approximately equivalent amounts of compounds described under (i) to (viii) in process a) above you get to the following connections:

(i) 10-Ethyl-2-methoxy-2'-methylspiro [acridan-9, I ¹ -isoindolin] -3'-one

(ii) 2'-methylspiro- {dibenzo [b, e] thiepin-II (6H) ^{-1 T} -isoindolin] -3'-one, m.p. 202-204 ° C

(iii) 2 '-Methylspiro [f luor en-9,1 ^f} isoindolin -.3' -one, mp. 166 ⁰ C-I67

(iv) 2-methylspiro [isoindolin-1,9'-thioxanthene] -3-one of m.p. 241-242 ° C

(v) 6-methoxy-2-methylspiro [isoindolin-1,9'-thioxanthene-3-one of m.p. 207.5-209 ° C

(vi) 3-chloro-10-methyl-2'-methylspiro [acridan-9, I ¹ -isoindolin] -3'-one, mp 216-217 ° C

(vii) 4-chloro-2-methylspiro [isoindolin-1,9 ¹ -xanthene] 3-one and

(viii) 2-methyl-5-methoxyspiro [isoindoline-1,9'-xanthene] 3-on

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c) Using that described in Example Ic) Process, but with replacement of the 2-methylspiro [isoindolin-1,9'-xanthene] -3-one used there approx. equivalent proportions of the compounds described in section b) under (i) to (viii), you get to the following connections:

(i) 10-Ethyl-2-methoxy-2 ^l -methylspiro [acridan-9, l ^l isoindoline]

(ii) 2 ^f -Methylspiro- {dibenzo [b, e] thiepin-II (6H), l'-isoindoline}, mp 127-129 ° C

(iii) 2'-Methy1spiro [fluorene-9,1'-isoindoline] from M.p. 102-104 ° C

(iv) 2-methylspiro [isoindoline-l, 9'-thioxanthene] from

M.p. 139.5-141.5 ° C (v) 6-Methoxy-2-methylspiro [isoindoline-1,9'-thioxanthene] of m.p. Il8 ° -119.5 ° C

(vi) 3-Chloro-10-methyl-2 ^t -methylspiro [acridan-9, l ^l isoindoline], mp. 170-175 ° C

(vii) 4-chloro-2-methylspiro [isoindoline-1,9'-xanthene] and (viii) 2-methyl-5-methoxyspiro [isoindoline-1,9'-xanthene]

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Claims (4)

- i6 - 600-6395 Claims Process for the preparation of compounds of the formula I, R-N, wherein X stands for a direct bond or the groups -0-, -S-, flO
-CHp-S- or -N-, where R, - is methyl or ethyl, R is an alkyl group with 1-3 carbon atoms and R ₁ to R _{q are} identical or different and each represent hydrogen, chlorine or an alkoxy group 1-3 carbon atoms, with the proviso that no more than 2 of the substituents R. to _{R.sub.Q have} a meaning other than hydrogen, characterized in that compounds of the formula II, II R - 2098U / 182? - 17 - 600-6395 in which X, R and R ₁ to R "have the above meaning, reduced. 2. The method according to claim 1, characterized in that the reduction of compounds of formula II takes place in an inert organic solvent and in an inert gas atmosphere. 2098U / 1822 ' 600-6395 Germany 3 compounds of the formula I, 2U63A0 wherein X stands for a direct bond or the groups -0-, -S-, -CH ₂ -S- or -N-, in which R ₁ - denotes methyl or ethyl, R denotes an alkyl group having 1-3 carbon atoms and R to R _{q are} identical or different and each represent hydrogen or chlorine or an alkoxy group with 1- 3 carbon atoms, with the proviso that no more than 2 of the substituents R 1 to R _{Q have} a meaning other than hydrogen. 4. Therapeutic composition characterized by the content of compounds of the formula I. 3700 / ST / SE 209814/1022