DE1906551A1 - New dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalogenobenzene and processes for their preparation - Google Patents

Description

PATENT LAWYERS

DIPL-CHEM. DR.-WERNER KOCH DR .-! NG. RfCHAKD GLAWE

DIPL.-ING. KLAUS DELFS DiPL-PHYS-DR-WALTERMOLL

HAMBURG MONCHfN

2000 Hemb.rg i2 · Waltsdro «« 18 · B »f IiZJSS
EtSOQ Manckän 22 · U * bk «rritr« f * 20 · tat33 <S4 ·

YOUR CHARACTER CONCERNS:

IHKE NACMUCHT FROM

OUR MARK

A 95

MONKS

d ¹ Etudes Seientiflques
et Industrielles de Li ¹ Ile-de-France
Paris, France

New dialkylaminoalkyl ethers des

2-Älteoxy-j5,5-dihalobenzene
and processes for their manufacture.

The invention relates to new dialkylarainoallcyl ethers of 2-alkoxy-3,5-dihalogenobenzene, their salts formed with an inorganic or organic acid, their quaternary ammonium salts, and a process for the production of these compounds, which are important in pharmaceuticals, in * b «i«? changer as spasmogen
own.

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_ORJ G, NAL

906551

The general formula for the compounds of the invention can be as follows; to be written:

R ₂

Here mean:;

η andLm integers between zero vma two,

R "Rj / R ₂ , R3 hydrogen or a finely shaped wheel with 1 to 5 carbon atoms (R), such as, for example, ethyl, propyl, _r

■ dl "Gruppe IT" ^ a heterocyclic radical, like Pyrolidyl, piperidyl, morpholyl * Pip «ra3; ynyl

] f and. γ; Halogens such as sB F ₃ , Cl ₃ bp.

Manufacture of inventive connections

consists in being a Konpäfcher des ^ röcafcechols aeetylated ^ Sann the compound obtained ha3, og "ni" iert, dan "this connection deaetylated

and then m %% an alkylamino> atlSgflöiilopl <l treated. ; --V ^ ^; ; V-- "■ '" ^ ■ ΐ -.''λ-ν -: ■ - ^ fe /.-''-

The manufacture of some of these successful ones

'^ 1'jConnections will- _: «lurch di« n & chsteh ^ nuen, it

ORiÖINÄL INSPECTED '

limiting examples to be understood.

example

L-3 chlorohydrate & ethylaminoethQ3cy-2-methoxy- 3, 5-dichlorobenzene

Level At 5.5- <0ichlorg.uaJak: ol

In a 250 ml balloon with a reflux condenser, 62 g of guaiacol (0.5 mol) are acetylated with acetic anhydride in the presence of a few drops of concentrated sulfuric acid. When the reaction is complete, the sulfuric acid is neutralized with sodium acetate. • After the solution has cooled down, the gaiacol acetate is chlorinated.

The solution obtained in the previous step is placed in a one liter balloon containing the is equipped with an agitator and a thermometer, and add 150 ml of acetic acid. You then give in Gradually add 16Ö g of chlorosuecinimide in small amounts. The suspension is then heated to 50 bis 55 ° C and then keep it in the heating cabinet. 117 hours at 55 ° G. .

After the reaction has ended, the mixture is cooled and added Add two liters of water, stirring constantly

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909834/1571

is maintained. The chlorinated compound crystallized. It is centrifuged, rinsed and deacetylated with 125 ml of Jojß sodium hydroxide solution.

The product is tfrd distilled and then recrystallized from petroleum ether. 66 g of 3> 5-Diehlorguajakol (F; 62-63 ⁰ C Rt: 68 $) are obtained.

Stage B: 1-diethylaminoethoxy-2-methoxy-3f5-dichlorobenzene

50 g of 3,5-dichloroguajakol (0.25 moles) are poured into a Given sodium ethylate solution, which consists of 6 g of sodium ± n 68 ml of pure * alcohol is produced.

A red "solution is obtained to which 39 S

(0.26 mol + Io % excess) diethylaminoethyl chloride is added. -;:. ■■. ■;

One warms carefully and the solution becomes cloudy. The sodium chloride precipitates. It is then heated _ .. J hours in reflux. It is then cooled and 300 ml of water and 25 ml of concentrated hydrochloric acid are added. The aqueous solution is filtered and passed over charcoal, and the base is precipitated with 40 ml of ammonia and extracted with ether. To

909834/1571

Distillation of the ether obtained 51 g (72 $ Rt) of l-methoxy Diäthylaminoäthoxy ^ - ^, 5-dichlorobenzene (Eb./7mm:· 1β5 - 166 ⁰ C).

Stage C; L-diethylaminoathoxy-2-methoxy-3,5-dichlorobenzene hydrochloride

The base obtained in the previous process is dissolved in 100 ml of acetone and 6 g of 35 are added add dry hydrochloric acid in 2o ml acetone. The hydrochloride des l-Piäthylaminoäthoxy - ^ - methoxy- ^ jS-dichlorobenzene precipitates, is centrifuged, washed with acetone and then dried. You get 51 g of the product (F: I32-134 ° C).

Analysis .

Calculated %% C 47.49 H 6.09 Cl 32.42 N 4.26 Found % C 47.31 H 6.14 Cl 32.24 N 4.18

example

L ~ dimethylaminopropoxy ^ 2-methoxy-3 »5 · chlorohydrate dichlorobenzene

Stage A as described in Example 1.

909834/1571

6551

Stage Br l ~ Dimethylaminopropxy-2-metho xy - ^, 5 _g , .- ,, ·. dichlorobenzene - -...--

63 g of _3-i 5 DichlorgüäJakol (o, 32 mol) is added "IRI>: a Natriumäthylatlösung that one aus'7 5 ^ \ g of sodium, and loo ml of ethyl alcohol obtained are added 44 g (o, 326th mol + lo # excess) of added 1-dimethylamino-3-chiorpropan and heating the micro _obtained; Providence for 6 hours in the return will be noted .a precipitation of the sodium chloride mixture is cooled and pulls out with 300 ml of water and 30.. ml of concentrated hydrochloric acid. The aqueous solution is passed over charcoal. The base obtained is precipitated by adding ammonia. It is extracted with ether, the ether is expelled and the residue is distilled.

63 g (Rt. 70 ^) of 1-dimethylaminopropoxy-2-methoxy-3 _> 5-clichlorobenzene (Eb./25 mm: 190-195 ° C.) are obtained.

Stage C; Hydrochloride of 1-D.imethylaminopropoxy-2-methoxy-3 5 _{J-dichlorobenzene}

The base obtained in the previous step is dissolved in 180 ml of acetone. 7. 85 g are added

^: - 6 - / - - - ■■■■■.

909834/15

anhydrous hydrochloric acid dissolved in 70 ml of acetone; add.- The chlorohydrate of 1-dimethylaminopropoxy-2-methoxy-3,5-dichlorobenzene was cancelled. It is a white solid material (F: 1? 8 - 14o ° C).

Analysis;

Calculated % ; C 45.79 H 5.72 Cl 35.86 N 4.45 Found & C 45.59 H 5.79 Cl 33.72 N 4.40

Example St.

Hydrochloride of 1-methylamino-propoxy-2 ^ methoxy-3,5-dichlorobenzene

Stage A as described in Example I.

Stage Bg l-Päthylaminopropoxy- · 2 ■ -methoxy-3 _J 5 - dichlorobenzene

The 66 g obtained in the previous stage of 3.5-lÄGhlorguajakal (0.34 moles) are converted into a Given sodium ethylate solution, which is made from 7 δ sodium and 130 ml of pure alcohol. To the The red solution obtained is added to 55 g of diethylaminopropyl chloride (0.34 mol + lo # excess).

One warms carefully. After five minutes the solution becomes cloudy. The sodium chloride precipitates.

909-834 / 1571 "

The mixture is then refluxed for two hours.

It is cooled and water is addedί The amine was cancelled. It is decanted and extracted with methylene chloride repeated several times, and then washes the organic solution by means of a 4 # solution of sodium :; hydroxide solution and then with water. One dries over potassium carbonate and the solvent is distilled off. 96 g of 1-diethylaminopropoxy-2-methoxy-3,5-dichlorobenzene are obtained (Rt:

Stage Ct chlorohydrate of 1-diethyläminopropoxy-2-methoxy- "?, 5-dichlorobenzol ""-'■■>■;,.

The base obtained in the previous step becomes. dissolved in twice the weight of acetone »

Anhydrous hydrochloric acid is bubbled into the gieiohe amount of acetone and this solution is added to the base until the color of the methylene changes. V The chlorohydrate crystallizes »". " It is spun ■ out, washed and then _{dried in the air and:} in a heating cabinet at 30 °. It is recrystallized several times in isopropanol. EiHeH 51 g of chlorohydrate of l-ethylamino-

'.''■ ... .- - 8 - ■■■ ".."; ■ ^[■:'. \ :: ^{^:} ^^ 909834/1571

propoxy-2-methoxy-3,5-dlchlorobenzene (P: 142 ° C)

analysis

Calculated % \ C 49.05 H 6.42 Cl 31.09 N 4.09 Found % \ C 49.16 H 6.46 Cl 3o.9o N 4.19

Example IV

Chlorohydrate of 1-morpholinopropoxy-2-methoxy-3,5-dichlorobenzene

Stage A as described in Example I,

Level B; 1-morpholinopropoxy-2-methoxy-3,5- . dichlorobenzene

54 g of 3,5-dichloroguajakol (0.28 mol) are added to a sodium ethylate solution obtained by reacting 6.44 g of sodium with 84 ml of ethyl alcohol. 51 g (0.28 mol + lo% excess) of ve »1-chloro-1-morpholinopropane are added to the solution obtained. The mixture is refluxed for 8 hours. One notices the precipitation of the sodium chloride. The mixture is cooled, the mixture moves with j5o ml of water and Jo ml of concentrated hydrochloric acid. Man

- 9 -909834/1571

filter the resulting solution, add ammonia, to precipitate the base, which you then use ether moves out. The ether is driven out and distilled the residue in a vacuum, ----- ~~ -

73 g (Rt. 82 $) of 1-morpholinopropoxy-2-methoxy-3/5-dichlorobenzene (EbV / lo close: 197-2oo ⁰ C) are obtained.

Stage C; L-Morpholinopropoxy-2- chlorohydrate

tn e thoxy-3,5 - di chi ο rb enzol \

The base obtained in the previous step is dissolved in 150 ml of acetone. 8.32 g of anhydrous hydrochloric acid, which is dissolved in 50 ml of acetone, are added. The chlorohydrate of l-morpholinopropoxy-2-methoxy-3> 5-dichlorobehzole precipitates, is centrifuged, washed in the filter with acetone and dried (weight 73 s * Rt- 9W, P: 183-184 ° C.).

Analysis .

Calculated % i C 47.12 H 5.61 Cl 29.87 N 3.93: Found % \ C 4f, 33 H 5.72 Cl 29.77 N "3.92

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909834/1571

Example V

1-diethylaminosopropoxy ^ -methoxy ^ jS-dichlorobenzene oxalate

Stage A as described in Example I.

Level B; 1-Diethylaroinoisopropoxy ~ 2-methoxy-3f5-dichlorobenzene

63 g of 3 # 5-Di ° hlorguajakol (0.326 mol) become sodium ethylate added, which is obtained by dissolving 7.5 g of sodium in 100 ml of alcohol. The received

Solution is added 54 g (0.326 mol + lo # excess) of β-Chloropropyl diethylamine added. You heat them up Mix for 7 hours and obtain the precipitation of sodium chloride. One draws with 300 ml of water and 4.5 ml of concentrated acid. One filters the Solution and add 60 ml of ammonia. The precipitated base is drawn out with ether. One drives the ether and the residue is distilled.

70 g (rt. 1-10%) of 1-diethylaminoisopropoxy 3,5-dichlorobenzene (Eb./5 mm: 166-167 ° C.) are obtained.

Stage C: 1-diethylaminoisopropoxy-2-methoxy-3,5- , dichloropenzene oxalate

The base obtained above becomes pure in 130 ml

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909834/1571

Alcohol dissolved. 21 g of oxalic acid, which had previously been dissolved in 40 ml of alcohol, are added. The "oxalate of l-diethylaminoisopropoxy - ^ - methoxy-OiS-dichlorobenzene precipitates, is centrifuged, washed with alcohol and dried (Fs-128 ⁰ C).

Analysis *.

Calculated #: C 48.48 H 5.8L Cl 17.93 $:% 5 &: Found % \ C 48.28 H 5.98 Cl 17.8o N 3.59

Example VI - /;

1-Dlethylaminopropoxy-2-methoxy-3 ⁱ f 5-dlchlorobenzene bromomethylate . -. ■ · - "

The base is made as in ^ stages A and ' B of Example III.

A solution of methyl bromide in methanol (18 g of Br CH ^ to Ιβΐ ml of solution, d »h * ö, 17 mol + \ o% excess) in 51 g (0.17 mol) of 1-diethylaminopropoxy-2- ' methoxy-3 * 5-dichlorobenzene, which are dissolved in Ισο ml of methanol. The solution is kept at ambient temperature for about 90 hours. The alcohol is distilled under vacuum until the weight remains constant. The product obtained is recrystallized from acetone. The crystals are centrifuged, washed with acetone and heated to 55.degree

'' ■ - 12 "" - "- '-' .- ■■" · '- ■■ "■■ -909834 / 1571

dried. 43 gv © ä white crystals of the bromomethylate of 1-DAethylaminopropoxy-2-methoxy-3,5-dichlorobenzene are obtained. This substance is very hygroscopic (P: 114 - 115 ⁰ C, Rt: 63 $).

Analysis:

Calculated £: C 44.89 H 5.98 Br 19.95 Cl 17.7o N 3.49 Found %. C 44.76 H 6, Io Br 2o, o3 Cl 17.5β Ν 3.28

The severe toxicity tests carried out with mice have shown that the compounds of the invention have a toxicity which is entirely compatible with a therapeutic application. The following table is given as an example:

link D, L. "50 in mg / kg
Compound ^ in the basic state 181 SC PO IV 6o8 737 1- diethylaminopropoxy-2-
nethoxy-3,5-diochloro-
benzene 34.8
31.3

1) The spasmogenic effect of the compound according to the invention was determined on isolated guinea pig intestines examined.

On an insulated piece of guinea pig crooked

909834 / Ϊ.571.

90.6551

bowel (ileum) the level of contractions is measured, which is caused by increasing doses of the too un'tersü - chenxien substance: ö, -l o, 2 pg / ral - ο-Λ

Through this experiment, the strong spasmogenic (Cramp-inducing) properties of the erfindungsgetnäflen Medicines can be detected.

2) The counteraction against atropine was also on isolated guinea pig crawler arm examined. . '.

A piece of crooked darra is placed in a ventilated tyrode

Solution hung up. 1-Diethylaminopropoxy-2-methoxy-3,5-dichlorobenzene at a concentration of 2xl <r (0.2 µg / ml) is left in contact with the muscle for 10 seconds. The contractions caused by this are recorded and all of them Repeated 6 minutes until consistent response is reached.

The atropine is added to the bath J5o seconds before the Addition of the l-I ^ iäthylaiHinopropoxy-S-rinethoxy- ^ iS-dieiiiorbensolf added, and in such doses,

$ 1

that a suppression of the contraction of 2o Bo fl> is obtained, so that the counter dose related to 5o% can be determined graphically.

Spasmogenic substance Medium $ 50 counter dose
Atropine ^ g / ml) 1-diethylaminopropoxy
2-methoxy - ^, 5-dichloro-
benzene
Spasmogenic dose 2. Io ' 1.9 (a) Acetylcholine ₇
1 . lo ~ ' 0.010 (a) (a) Determined by 12 measurements, each bowel
piece first of the spasmogenic effects of 1-diethyl
aminopropoxy-2-methoxy-3,5-dichlorobenzene and
then exposed to acetylchloline.

Besides possessing their convulsive properties the medicaments according to the invention have various pharmacologically interesting properties that are in the are summarized in the following table:

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909834/1571

- - ■ - - ■ -
Type of attempt
and time of
Measurement (each
after entering the
Product ^ animal dose
ng / kg Type of
Feed 1-diethylamino
propoxy-2-methoxy-
3,5-dichlörbenzpl
- ■ """" -. ■ - Gastrointestinal
Passage 4aus DE 5o SvC ·· No effect ^v :
from 0, pol mg / kg
to 2oo mg / kg measured after 4o min
Test substance:
Biochar iund DE 5o S * C. ΛΜ effect
at 0.25mg / kg Antiemetic We
kung rat DE 5o ... . .
so yrf> effect "·
at 2Ö0 ing / fcg
--'-. · ■■ .- --- ". ^; - ■ --'- ^: ■ - '-'-...
: ----- " ^: ■" ■ ' measured after 5o min
(at SC) or after
1 hour (at PO)
Test substance
Apomorphine.
loo pg / kg SC Mouse . '; [ DE 5o Cataleptical effect ^ lousy index
^; 2 "". ■■ - ■. - ■ PO
■■ '■■' koi effect
at 150 rag / kg 0 measured in the
maximum or after
3oo to - "36o min. • f _e ^: Pv. ^: ■ '■; ..: . - "■ ■ - ^{■■■■:::;:.} -Ve
: \ 55Λ '- /' W ^ - ' ■ .-, ".- ■'; Tractlon attempt P. 0fr Index; 1.23;
at 200 mg / kg; . ■; measured according to
J) O min.
------ Potentialization
the barbiturate narcotic
kose measured after Jo min.
Test substance!
Pentobarbitoi
6o mg / kg IP

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909 834/1571

Type of attempt
and time of
Measurement (each
after entering the
Product.) Text after animal dose
mg / kg Type of
Feed - S.C. "- 1-D.iäthylamino-
propoxy-2-methoxy-
3,5-dichlorobenzene • 94.7 Spontaneous Winkler et al. _. - - 49.1 Motility RIATORS mouse DE 5o I. P. P.O. No effect
at 2oo mg / kg measured
after 15
min (at
IP) or.
60 min
(at PO; Activo-
graphics P.O. I.P. 16.1-19.7 Antimescaline effect mouse DE 5o I. P. • Io5 measured after 15 min,
Test substance:
Mescaline 50 mg / kg
IN THE mouse DE 5o .P.O. $ 3o effect Anti-apomorphine
effect I.P. at loo mg / kg (Janssen test)
measured according to
80 min.
Test substance:
Apomorphine
1.25 mg / kg IV rat DE 5o 3o # effect
at 600 mg / kg Anti-morbid effect (Straub test)
measured after 60
up to 12o min
Test substance:
Morphine 3o mg / kg
SC mouse DE 5o 313 Antitremorin effects mouse (Experiment after Chen)
measured after 60 min
Test substance:
Tremorin 7.5 mg / kg
IN THE. DE 5o

909834/1571

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1"

Type of attempt

and time of
Measurement (each
after entering the
Product)

animal

dose

Type of 1-diethylarnin feed propoxy-2-methoxy 3a5-dlchiorbenzene

Rotary rod t

mouse

DE 5o

I. P.

; measured according to Io
) is J5o min.

P.O.

71.5

# Effect at 2oo rag / kg

Evasion test

mouse

DE 5o

I. P.

75.9

(Try after
Kneipp)

measured after 1 hour

Antiserotonin effect;

dog

DE 5o

I. P.

19th

Reduction of the
through serotonin
(25f / kg IV)
produced experimental hypertension

anti-

convulsive

effect

Electric crisis

mouse

DE 5o

S. C.

27.1

measured at the height of the effect P.O.

Chem.
crisis

measured n.
3o min

Test substance:

Cardiazole

mouse

DE 5o

I. P.

84.9

P.O.

7ο mg / kg I.V.

No effect at 2oo mg / kg

Experimental

material:

Nicotine

mouse

DE 5o

I. P.

P.O.

92.9

2 mg / kg I.V.

Audiogenic crisis

mouse

DE 5o

I. P.

18.8-19.7

measured after 30 min.

P.O.

67

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909834/1571

Type of
and 2ei
Measurement
after egg
product Try it
point of
(respectively
indication of the animal dose Type of l-diethylamino
Supply propoxy-2-methoxy-
3,5-dichlorobenzene 7.1.5 Plant
fcisohe Mechanical
Stimuli JS mouse DE 5o I. P. M 179 effect (Haffner test)
measured in
Climax d.
Effect - P.O. 22? 6 effect
at 90 mg / kg More chemical
stimulus mouse DE 5o I. P. Jo ^ effect
at -jjoo jng (Test with
Phenylbenzo
chinone) P. O * 45JS effect Thermal House DE 5o SO. at 2oo mg / kg stimulus
U _n 4- Dl pfn P.O. M 295 nuif idleness
[Try after
Jacob, Woolfe
and McDonald)
measured in
Climax of the
Effect i * v.- R = 5o to 6o # «
HistaRin-Hypo- dog 32 R ^ 35 "55Ji anti- tension 16
G R = Jo "4o ^
R = Io "J> o%
R = OK " 25%
BrQ "lojf hista- percentage
reduction
the experimental 8th
4th
2
T R β 55 % nin-
Effect ^ hypotension 1 R = J> 2%
R = 5r ^
R = 16 %
R = O ^. Carotid dog 16 I. V. local okklu'slon 8th
2
1 sympathetic during 5osee.
percentage
reduction
d. Experimental
hypertension thi-
sches system

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909834/1571

190655T

Type of attempt

and time of measurement (after entering the Product /

animal

dose

Type of feed

1-diethylaminopropoxy-2-methoxy 5 , 5-dichlorobenzene

Ortho-

sympathetic

thl-

sches

system

adrenaline

dog

DE

I.V.

12th

percentage reduction or inversion d. Experimental hypotension ion

Norepinephrine

percentage reduction d. Test hypotension

dog

DE

I.V.

nicotine

percentage reduction d. Test hypothesis σ tension

dog

16 8 if 2 1

I.V.

⁴ ί

=

Acetylcholn

percentage reduction d. Test hypotension

dog

16 8 4 2 1

I.V.

Vagus irritation

dog

percentage reduction d. Experimental hypotension

16 8 4 2 1

I.V.

R R R R R

53 y

$ 15 5%

R R R R

⁵¹ % 21 %

ο %

The experimental results are through clinical trials has been confirmed, with the products in the form of Ta * tablets or ampoules of a pharmacologically harmless one Salt «were administered.

■ - - 2o - ■ "■■ '- ^; -;

909 8 34 / 1Sf 1

Claims (8)

.Pa t ent ans ρ r ü c h e 1. / Dialkylaminoalkyl ethers of 2-alkoxy ~ 3,5-dihalobenzene the general formula R ■ r »' • (CH ₂ ) _n -CH- (CH ₂ ) _{m -N} , X as well as their salts and their quaternary ammonium salts formed with inorganic or organic acids, in which: η and m integers between 0 and 2, R, Rij, R ₂ , Rz hydrogen or a lower alkyl radical with 1 to 5 carbon atoms, such as methyl, ethyl, propyl, A. ^: the group N is a heterocyclic radical, e.g. \ r2
Pyrrolidyl, piperidyl, morpholyl, piperazinyl and X and Y halogens such as Cl, Br., - 21 - 2. l ~ diethyla "minoethox3r-2-methoxy-3ii 5-diehlorbezolehlorhydrat» ^. 1-Dimethylaminopropoxy-2-πletiIoxy-3,5-dichlorobenzene chlorohydrate. 4. 1-Diethylaminopropoxy-S-methoxy- ^ S-dichlorobenzene chlorohydrate. 5 · l-morpholinopropoxy-2-raettlox2Γ- ■ 5,5-dichlorobenzene chlorohydrate. β. l-DiethylarainopΓöpoxy-2-raethoxy-5 _i 5-dlGi ^ lorbenzoloxalat. 7 · l-Diethylaminopropoxy-2-methoxy-3,5-dichloro ~ benzene bromomethylate. 8. A process for the preparation of the compounds according to claim 1 to 7, characterized in that a catechol monoether is ace.tyliert, the compound obtained is halogenated, then the acetyl group is split off and then the obtained. Compound treated with an alkylaminoalkylchlorisi - S2 - - ■ ■ '- SS34 / 1SI1