DE2123834A1 - Phenothiazines, their acid addition salts, processes for their production and medicinal preparations - Google Patents

Description

"Phenothiazines, their acid addition salts, process for their
Manufacture and medicinal products ^Ir

Priority: May 15, 1'97Ö, V.St.A., No. 37 898

The invention relates to new phenothiazines of the general formula (I)

in which R is a halogen atom, the cyano, trifluoromethyl or
!!, N-dimethylamiriosulfonyl group, a C ^ -alkyl, C _1-0 -alkoxy or C ^ g-thioalkyl group, R ₁ and R _{2 are} identical or different

109848/1992

den and are a hydrogen atom, a C, "-alkyl- or C, ....- alkanoyl radical and m and η are identical or different and are an integer from 1 to 8, and their acid addi-. ionic salts.

The aforementioned hydrocarbon radicals can be straight-chain or branched.

Specific examples of alkyl radicals are the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, Amyl, isoamyl, hexyl, heptyl, octyl or isooctyl group. The methyl and ethyl groups are preferred.

Specific examples of alkoxy radicals are the methoxy, ethoxy, propoxy, butoxy or hexyloxy group, or others of the the aforementioned alkyl radicals derived alkoxy radicals.

Specific examples of thioalkyl radicals are the thiomethyl, Thioethyl or Thiopropy! Group, or others, of the aforementioned Thioalkyl radicals derived from alkyl radicals.

Possible halogen atoms are fluorine, chlorine, bromine or iodine atoms; bromine atoms and, in particular, chlorine atoms are preferred.

R. and R ₂ preferably represent hydrogen atoms. The alkyl radicals R .. and Rp ^ preferably contain ^{3 to} 5 carbon atoms and the alkanoyl radicals R ₁ and Rp up to 8 carbon atoms, in particular

7 carbon atoms and up to 3 carbon atoms «.

The alkylene residues of the empirical formula ~ ( ^GH 2 ^ m ~ ^{un <3} · "

be straight-chain or branched and preferably contain up to 4 G atoms. In particularly preferred compounds

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in "den Yiert 3 and η den Y / ert 1. Specific examples are the Methylene, ethylene, propylene, trimethylene, butylene or damsel ethylethylene group or others of the aforementioned alkyl radicals derived alkylene radicals.

In particularly preferred compounds of the general formula (I), R is the trifluoromethyl group or a chlorine atom, R ₁ and Rp are hydrogen atoms, m is an integer from 1 to 3,

preferably 3, and η an integer from 1 to 3 »preferably

^ R. meadow 1. The - (CH ^ -NC

-Rest can be bonded to any carbon atom of the piperidine ring, but the para position is preferred to the nitrogen atom.

Specific examples of phenothiazines of the general formula (I) are:

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-A-

(ch ₂ ) ₂ -n;

-H

Cl

CH.

NS.

JCH ₂ -N;

CH

CH.

(CH ₇ ) _A -N

I ⁴

CN

C H

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(CH ₂ ) ₃ -N

(CH ₂ ) ₃ -N '. C ₄ H ₉ ^C 2 ^H 5

NS,

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^c h-

¹ w

SO ₂ N (CH ₃ )

C ₄ H,

CN

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-V-

((JH ₂ ) 3-N

r ^N (3 ~ ^(cH ) ₂ -ΝΗ ₂

OCH, or

OCH.

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The salts of the phenothiazines of the general iVi'iwl (I) le-rittn different from inorganic or organic {corridors? .. ·;.;> v / ie Iialo ^ hydrogen acids, e.g. chlorine and broruv / aeüerP-to figure, Sulfur, nitric, boron, phosphorus, oxaline, v / oin, i-ialein, Fumar, parnoine, apple, lemon, vinegar, amberotein, benzene sulf on- or toluenesulfonic acid. The Söureadd j t: i onssulso be often used to isolate the phenothiazines. Here, the phenothiazines are converted into salts from suitable solvents failed. After separation, the salts are earthed by adding a base, such as barium or sodium hydroxide, to the compounds of the general formula (I) converted. Possibly other salts can be produced from this.

The invention also relates to a method for producing the Phenothiazines of the general formula (I), which is characterized is that you have an alkylene dihalide of the general. Formula (II)

Hal- (CH ₂ ) _m -Hal

(II)

in which m has the aforementioned meaning and Hai is a Halogenatoiri represents, initially with one of the two compounds of the general Formulas (III) and (IV)

(III)

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BAD OWQINAt

Π! Ϊ

ⁿ ^ R ₉ (IV)

in d & nen E, R ₁ , H ₀ and n have the aforementioned meaning, condensed and then reacting the reaction product with the other of the two compounds.

Only in the event that R ₁ and Rp do not represent hydrogen atoms, the compound of the general formula (IV) is preferably first condensed with the compound of the general formula (II).

In one embodiment of the method of the invention e.g. i-chloro-3-bromo-n-propane or chlorobromoethane initially with the compound of the general formula (III) to an intermediate of the general formula (V)

(V)

in the R and m have the aforementioned meaning and Hai a Halogen atom, preferably a chlorine or bromine atom, is condensed. The condensation can be carried out in an organic solvent, preferably a ketone such as acetone, i ^ ethyl ethyl ketone, i'.Iothyl-n-propyl ketone or I'.iethyl isobutyl ketone, in the presence an anhydrous base such as an alkali or alkaline earth hydroxide, e.g. sodium, calcium or barium hydroxide,

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at about the boiling point of the ljösun _c -smittel3, ie, i;:. Range from about 55 to 115 ° C, preferably about Ib to 85 ° C, can be carried out.

The intermediate of the general formula (Y) is then z.3. under the aforementioned conditions in a ketone solution / ^ sraittr. with the compound of general formula (IV) in the presence of an alkali metal iodide such as sodium iodide, in approximately equimolar i-ienge, based on the compound of general formula (V), converted sets w.

Another option is to connect the general Formula (V) in a hydrocarbon solvent, such as benzene, toluene or xylene, at temperatures of about 80 to 140 C in the presence of copper bronze and anhydrous potassium carbonate to implement with the compound of the general formula (IV). In this case, twice the stoichiometric value is preferably used Amount of potassium carbonate, based on the compound of the general formula (V), used.

In the other embodiment of the process according to the invention, the alkylene dihalide of the general formula (II) is used first with the compound of the general formula (IV) in which R .. and Ep have the aforementioned meaning, but not hydrogen atoms represent, to an intermediate of the general formula (VI)

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Hal- (ClI ₂ ) _m -N

- 11 -

(CH ₉ ) -N ^ f

in which R ₁ , R ,,, m and η have the aforementioned meaning, but R ₁ and Rp do not represent hydrogen. This intermediate product of the general formula (VI) is then reacted with the compound of the general formula (III) in the presence of a ketone as solvent under the aforementioned conditions. Sodium hydroxide, for example, can be used as a halogenated hydrogen acceptor.

The reaction of the alkylene dihalide of the general formula (II) with the compound of the general formula (IV) can be carried out in the presence of an organic solvent, such as methylene chloride, chloroform or benzene, at low temperatures, for example from about 0 to 20 ° C., the reaction product being generally precipitates as the hydrohalide. After the salt has been separated off, the phenothiazine of the general formula (I) can be set free, for example by treatment with a base such as sodium or potassium hydroxide.

The compounds of the general formula (IV) can be prepared, for example, by the process described in "Chemical Abstracts" 64, (1966) 19 602a by customary catalytic hydrogenation of pyridine alkanoic acids. The preparation of the pyridine alkanoic acids is described in "Pyridine and Derivatives", Part 3 (1962) 179-507, Interscience Publishers. In the case of those compounds of the general formula (IV) in which R ₁ and / or R ₂ do not represent a hydrogen atom, the two separated

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th reductions with lithium aluminum hydride sov.-ie './aoXerrutoff and Raney-Iiickel an alkylation with an R- and / or some Rp-IIalogenide can be carried out.

For the preparation of those phenothiazines of the general formula (i) in which R. is an alkanoyl radical and Rp is a hydrogen atom or an alkyl radical, that compound of the general formula (I) in which R _{2 is} a hydrogen atom or an alkyl radical is used , halide heated with the stoichiometric amount of formic acid or a Alkanoy! up to temperatures of about 60 ⁰ G.

For the preparation of those phenothiazines of the general formula (I) in which R ^ and Rp represent alkanoyl radicals, the corresponding compound of the general formula (I) in which R ₁ and Rp represent hydrogen atoms, with at least twice the stoichiometric amount of an alkanoic anhydride in heated presence of an acidic catalyst such as sulfuric acid or p-toluenesulfonic acid at 120 to 15O ⁰ C.

The use of phenothiazines, such as fluphenazine or trifluorpromazine, for the treatment of psychotic states of depression is already known. The phenothiazines according to the invention and their pharmacologically acceptable acid addition salts are effective ataractics which are suitable for the treatment of anxiety states. A particular advantage is that this effect is increased with increasing doze, without side effects on the central nervous system, such as states of depression, occurring, as is the case with known phenothiazines.

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BATH ORIGINAL

When used, the phenothiazines of the general formula (I) are administered orally or parenterally to animals, for example domestic animals or test animals, in doses of about 3 to 25 mg / kg / day or divided between 2 to 4 sharks.

■ An experiment with thirsty rats shows that the Animals after increasing the dose from 3 to 25 mg / kg drink more frequently with each drink despite punishment. There are no signs depression, which would make the rats unable to drink.

The phenothiazines of the general formula (I) and their acid addition salts are used together with carriers, lubricants (glidants) and other pharmacologically common additives and aids orally, e.g. in the form of tablets, Capsules or elixirs, or parenterally, in doses of about 10 Ms 250 mg / day all at once, or divided up to 4 times, administered.

The examples illustrate the invention.

example 1

10- / 3- / 4- (aminomethyl) -piperidino_ / -propyl / -2-trifluoroniethylphenothiazine dimaleate

A mixture of 8.6 g (0.025 Hol) 10- (3-chloropropyl) -2-trifluoromethyl-phenothiazine, 4.3 g (0.038 mole) 4-aminomethylpiperidine, 6.9 g (0.050 mole) microfine powdered anhydrous Potassium carbonate and 100 mg of copper bronze in 50 ml of toluene p.a. is stirred under reflux for 24 hours. The reaction geuiisch It is cooled to room temperature and the precipitate formed .will after filtering 2 times with 20 ml of freshly distilled

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. Toluene washed. The toluene filtrates are purified and concentrated using a high-speed evaporator. The dark oily residue is dissolved in 100 ml of ether and extracted with 2 times 50 ml of ice-cold 10 percent aqueous phosphoric acid ·. The cold acid extracts are mixed with an excess of 50 percent sodium hydroxide solution, thereby doing so

The resulting oil is extracted with 4 times 50 ml of ether. The ether extracts are washed twice with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and quickly filtered using Hyflo in order to prevent the solution from becoming cloudy due to CO absorption. After concentration, 9.3 g of the oily free base are obtained, which, after being dissolved in 90 ml of acetonitrile, are treated with a boiling solution of 5.1 g (0.044 mol) of maleic acid in 25 ml of acetonitrile. The crystalline precipitate which separates out immediately is filtered off after standing in the cold for 15 hours and dried in the air. 14.2 g (87 ^c p) of the crude product with a temperature of about 170 to 173 ° C. are obtained.

^ After recrystallization from 3100 ml Äthylaethylketon using activated charcoal and Hyflo are obtained 5.95 g '(39? £) of pure product, mp 173 to 176 ⁰ C.

Analysis C ₂₂ H ₂₆ F ₅ N ₅ S 2 (C ₄ H ₄ O ₄ )

£ -HNS, Ii.E. (KOCK ₃ ) calc .: 55.07 4.51 6.38 4.92 162 found J 55.31 5.37 6.61 5.15 159

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BATH ORIGINAL "

For π ρ ie 1 2

chlor-phenotTd a gin

According to Example 1, using 6.0 g of (O, O; -JB Hol) 3- (2-i-iethyläthylafinnoäthyl) piperidine instead of 4 - airrinomethylpiperidine and using 7.8 g (0.025 mol) of 10- (2-chloroethyl) -2-chloro-pheriothiazine instead of 10- (3-chloropropyl) -2-trifruomethyl-phenothiazine the desired connection.

Example 3

10- / 3- / A-- (Dimethylaminoiuethyl) -pi per idino / -propyl / -2-triflu.ormethyl-phenothiasin-dihydrochloride

9-3 g of the phenothiazine base prepared in Example 1 are dissolved in 20 ml of 98 to 100 percent formic acid. The resulting solution is cooled and 20 ml of ormaldehyde solution (37 percent) are added in portions. The reaction vessel is ^{then heated to 90 to 95 ° C. for} 18 hours and then concentrated under reduced pressure. The residue is suspended in 100 ml of water, and 100 ml of benzene and 20 ml of 50 percent sodium hydroxide solution are added. The mixture is shaken, then the benzene layer is separated, washed with saturated aqueous sodium chloride solution, dried and filtered. The cooled filtrate is treated with an excess of dry hydrogen chloride. After filtering off the formed hydrochloride precipitate and recrystallization from 2-propanol, the desired compound is obtained. . . "

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Example 4

10- / 3- / 4- / ~ A ffiiriOn eth.yl ·) -pro py ! / - piperidin o / -pro PV- ^ T - ^ - cihl or phenothiaz in-dim aleate

(a) 10- (3-Chloropropyl) -2-chloro-phenothi8.sin

A mixture of 4-6.8 g (0.1 mol) 2-chloro-phenothiazine, 1 liter Ethyl methyl ketone, 63.0 g (0.2 mol) i-chloro-3-bromo-n-propane and 40.0 g (1.0 mol) of granulated sodium hydroxide is stirred under reflux for 9 hours. After cooling down Another 40.0 g of granulated sodium hydroxide are added, then P becomes the reaction mixture. another 15 hours under

Stirred under reflux. After mixing, the precipitate is with washed freshly distilled ethyl methyl ketone. The filtrates are combined with saturated aqueous sodium chloride solution washed, dried and concentrated under reduced pressure. The oily residue is distilled off 10- (3-chloropropyl) -2-chloro-phenothiazine from b.p. about 130 to 135 ° C (0.1 torr).

(b) 10- / 3- / 4-A aminomethyl) -propyl / -piperidineq7-propy3 ^ -2-chloro w phenothiazine dimaleate

31.1 g (0.1 mol) of the phenothiazine from Example 4a are mixed with 22.6 g (0.2 mol) of 4-aminomethylpiperidine, 500 ml of ethyl methyl ketone and 15.0 g (0.1 mol) of sodium iodide were stirred under reflux for 18 hours. Ground after cooling 100 ml of water are added and the mixture is carried out until "two layers are formed. The organic layer is separated off, washed with saturated aqueous sodium chloride solution ^ dried and concentrated under reduced pressure. The residue obtained in this way is dissolved in 300 ml of ether, the solution

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After cooling, it is increased by 3 ßial 100 ml of cold 10 percent v / U of phosphoric acid extracted. The phosphoric acid extracts are combined, cooled and covered with a layer of 300 ml of ether and with 50 percent strength aqueous sodium hydroxide solution. up to 2ur strong alkaline reaction. After separating the ethereal layer, washing with saturated aqueous sodium chloride solution, Drying and concentration gives 40.3 g of the oily free base. This is dissolved in 200 ml of acetone and at the boiling point a hot solution of 23.2 g of maleic acid in 250 ml of acetone is added. The resulting mixture becomes thorough shaken and then cooled. When recrystallizing the crude dimaleate product from acetone he

one keeps the desired compound in pure form.

Examples 5-13

According to the example. 1 or Example 4b, the reaction scheme given in Table I gives the desired ones, as given in V / alternatively substituted end products »

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'Table I.

Output connections

Reaction product

HNl

, Λ

* · * At- (CH ₀ ) _ Hal R. (CH-J 2 R ₁ R, (CH) (CH ₀ ) R. ^R 1 R ₀ < OO ■ z. —M ~~ . 2 ' η 3 _JL (CH ₂ J ₃ 4- (CH ₂ J ₂ CN " 1
H 2
H " ¹ p. No. (CH ₂ »3 Br CN 4- (CH ₂ ) H H CH ₂ ³ -CH ₂
( ^CH 2> 2 2- (CH ₂ J ₃ Cl
^ CH,
" ^S ° ^2N > _W CH ₃
H CH ₃
^CH 3n (O
co 5 CH ₂
(CH ₂ »2 Cl
Cl Cl ₁
, CH ₃
- ⁵ ^ CH ₃ 3-CH ₂
2- (CH ₂ ) 2 CH ₃
H
CH ₃ -d- CH ₃
CH,
O (CH ₂ J ₄ , -CH ₂ CH,
-SC ₂ H ₅ CH ₃ -C- U
Il
CH ₃ C- 6th
7th (CH ₂ »4 Cl -SC ₂ H ₅ 4-CH ₂ C ₄ H ₉ CH ₃ -C- (CH ₂ J ₃ i- (CH ₂ J ₂ iC ₃ H ₇ C ₄ H ₉ CH ₃ 8th (CH ₂ > 3 F. 1-C ₃ H ₇ 4- (CH ₂ ) CN VO ^C 6 ^H 13 CH ₃ (CH ₂ J ₆ 2-CH ₂ CP ₃ ^C 6 ^H 13 ^C 6 ^H l3 ^ 9 (CH ₂ > 6 Cl CP ₃ 2-CH ₂ C ₀ H ₁ -C-
2 S ₆
^C 2 ^H 5 ^C 6 ^H 13 (CH ₂ J ₃ 4- (CH ₂ J ₂
(CH ₂ J ₅ 3- (CH ₂ J ₆ CF,
Br ^C 2 ^H 5 ^C "
0
^C 2 ^H 5 HK)
CO
C ₀ HcC- °°
2 5 ti co 10 (CH ₂
(CH ₂ »3
's Br
Cl CF ₃
Br 4- (CH ₂ )
3- (CH ₂ ) H H
C ₀ H ₁ -C-
2 5 II CH ₂ 4- (CH ₂ J ₃ -OCH ₃ H H ° _ ^ 11
12th (CH ₂ > 3 Cl -OCH ₃ 4-CH ₂ O
H 13th

Example 14

10- / 2- / 4- / iMliHrie thy larain ü) -IU phenoth j azin-d if uinar.a t

A mixture of 31.1 g (0.1 mol) of 2-chlorophenothiazine, 90.0 g (0.3 I'Iol) 2 - / ( 2-dimethylaminoethyl) piperidinoT-ethyl chloride hydrobroiaid and 625 ml of ethyl methyl ketone is mixed with 90 , 0 g of granulated sodium hydroxide are added and the mixture is refluxed for 18 hours with vigorous stirring. After cooling, the reaction mixture is mixed with 400 ml of cold water. After separation, the organic layer is washed first with water and then with saturated aqueous sodium chloride solution, dried and concentrated. After dissolving the residue in 1 liter of ether, the ethereal solution is cooled down and repeated 3 times with

200 ml of cold 10 percent hydrochloric acid extracted. According to Abound

cool the acid extracts add an excess of 50 percent Sodium hydroxide solution, 48.7 g of the free base are isolated by extraction with ether. After solving the obtained free base in 490 ml of boiling acetonitrile, this solution is rapidly mixed with a hot solution of 23.2 g of fumaric acid in 250 ml Acetonitrile added. The solutions are mixed thoroughly and, after cooling, refrigerated in the refrigerator. You get the desired compound as a crystalline product.

Examples 15-23

According to Example 14 is obtained according to that given in Table II Reaction scheme the desired, substituted in the manner indicated End products.

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Claims (1)

in which R is an Ilalogenatom, the cyano, trifluoromethyl or W, N ~ dimethylaminesulfonyl group, a -C. o-Alkyl, C, Q-alkoxy or C ₁ ″ -thioalkyl radical, R ₁ and Rp are identical or different and are a hydrogen atom, a C ₁ ″ -alkyl or C _1. ..- alkanoyl radical and m and η are the same or different and are an integer from 1 to 8, and their acid addition salts. 2. Phenothiazines of the general formula (I) (CH ₂ ) _n -N in which R, R ₁ , R ", m and η have the aforementioned meaning. · 3 phenothiazines according to claim 1 and 2, characterized in that that m and η represent integers from 1 to 4. 109848/1992 4. Phenothiazines according to Claim 1 to 3j, characterized in that that R represents the trifluoromethyl group. 5. Phenothiazines according to claim 1 to 3, characterized in that R represents a chlorine atom. 6. Phenothiazines according to claim 1 to 3, characterized in that R represents the Thiomethy! Group. ) _O -N> ³ v __ / 8. Process for the preparation of the phenothiazines according to Claims 1 to 7 and their acid addition salts, characterized in that that an alkylene dihalide of the general formula (II) HaI- (CH ₂ ) _m -Hal (H) in which m has the aforementioned meaning and Hai is a halogen atom represents, initially with one of the compounds of the general formulas (III) and (IV) (III) id / "y ^? in which H, R ^, R _? and η have the abovementioned meaning, condensed and then the reaction product is converted into: t the other of the two compounds and, if appropriate, the free bases are converted into the acid addition salts. 9. Arsneipreparations, consisting of a compound of the general mean formula (I) according to claim 1 and optionally customary pharmacologically acceptable carriers and diluents. 109848/1992 INSPECTS *