DE2026688A1 - Orthosubstituted phenoxyamines with antihistaminic effects - Google Patents

Description

The invention relates to compounds with antihistaminic activity, in particular to a new class of ortho-substituted phenoxyamines which have the property of blocking the action of the histamine on the so-called "H ₂ ^H receptors, ie those that influence gastric acid secretion which, however, block the effect of the histamine on the so-called "H ₁ " receptors, ie those that influence the bronchial constriction, little or not at all.

The new compounds according to the invention have the general formula

009851/2276

2026658

in which R is a saturated aliphatic or allcyclic hydrocarbon radical with 7 to 9 carbon atoms, Y either (Δ) an aminoalkyl radical of the formula -AIk-UR R,

2 3
in which R and R each represent a lower alkyl radical -

oaer together with the nitrogen atom to which they are bonded form a saturated heterocyclic radical, and "Alk" a divalent saturated aliphatic radical Represents hydrocarbon radical with 2 to 4 carbon atoms, whereby the free valenes are at different Carbon atoms are ^ or (B) an aminocyclicache

Radical of the formula -0, H ₀ -CH Z, in which η 0 to 3 and Z

H C-Zl Ν ^ _ ^

means a divalent radical, the one saturated heterocyclic ring with at least one nitrogen atom and at least 4 carbon atoms completed, each nitrogen atom from the oxygen atom to which the amino-

cyclic radical is bound, .by a chain from 2 to

_S is separated from carbon atoms and R is a hydrogen or halogen atom or a lower alkyl, alkoxy or alkanoyl radical or an α-oximino (lower) alkyl radical.

The invention also relates to those pharmaceutically acceptable Acid addition salts of the named Yora Links.

In the laimeia of this description, the expression ^M ai © used ^{for a subatituent residue means the © r '8} © inen eating with 1 to 4 cabbage @ astoffa% oa @ B. landl d © ^ Äusdnask "EaLo ₁ -g @ n ^M includes Fluor» GhIOr ₉ Bros oöer J © dL

In the general formula kaan R straight or ve ^ - ^ be chain-like or contain an eycliscfeea remainder. For example, R is. © in, gamd- oäar ¥ © rax-j © igtl £ ettig © r

2026689

Heptyl, ootyl or honyl radical, or a cyclohexyl methyl, Cyclohexyläthyl-, Cyclohexylpropyl- or Cycloheptyläthylreet. Preferably R is a primary hydrocarbyl radical, i.e. through a methylene radical on the Benaol ring bound, and in particular an n-heptyl or 2-Gyelohexyläthylrest.

If Y is a -1Ik-NR R radical, R and I * ^{5 can} each represent, for example, a methyl, ethyl, propyl or butyl radical, or together with the nitrogen atom, for example, a pyrrolidine, piperidine, morpholine, Thiomorpholine, piperazine, azepine or blaze.

"2""5
form pinrest. If R and R form a saturated heterocyclic radical with the nitrogen atom which contains a further nitrogen atom, then the further nitrogen atom preferably bears a lower alkyl or

Benzyl radical as a substituent. - ·.

2 "5

If Y is an -AIk-KR R radical, -Alk- can, for example an ethylene, propylene, ethyl-substituted ethylene, dimethyl-substituted ethylene, trimethylene or Be tetramethylene residue.

If T is a C _n H _2n -OHT -, C _n Hg _{n can be,} for example, a methylene, ethylidene, ethylene, propylene or trimethylene radical, and the heterocyclic RlQg completed by Z can be, for example, a pyrrolidine, piperidine, morpholine , Ihiomorpholn-, Piperazin-, Azepin-, or HLazepinrint, provided that each nitrogen atom in the ring is separated by at least 2 carbon atoms from the oxygen atom to which the remainder is attached.

As a result, the radical -C _n H _2n -CH Z can for example

009851/2271

^ aio © a S-Py ^ oüdiayl- or 3- or 4-piperidinylresi ₉ a 2- or 3 ~ 3? yrrolldinyl®ethyl "or 2-"", 3 = or 4 = piparidinylmethyl residue", & ΪΏ- 2- (2 = or 3 Pyrrolldinyl) -äthyi- or 2- (2- or 3-piperidinyl) -äthylrest or a 3- (2 "S ^l yrrolidinyl) = propyl or 3- (2-2? iperidinyl) propyl ~ = rest sieiiio Every nitrogen atom in Z is preferably with s.insra'aieclerea allsyl ^ sst © the bensyl radical subs-tituiarto if every carbon atom in which -QH Z ~ radical can be substituted by a sleclöPea alkyl radical ",

They are pharmaceutically compatible acidic addition salts, using compounds according to the invention, can be produced as acids "; the non-tosise addition sal se with aeiitisioh v@rtraglioh.ea Anioatn forms a ₀ s "B ₀ das Hydrochlor-idß HyteobrcaiÄD l ^ rdsO ^ Qßlido Sul-fato Bisulf ®, t _a , piiiat or saus ³ ® Hmsplast ;, A © @ tis.t " ₀ Eäaloatt, Pumarat ₈ © salat, Laetatt, Sartrat _D Gitnate'Gluconate, -Saocharat or p ~ 5? oluene sulfonatsalae"

Especially beforeaw, gt © salts of the

are the% -drochlorid © and di @ Qlt

M © erfladep ^ sgesüßea Vo2% iadusig © n lasssa see ay.s dea suitable © a © rthosiibstituies ^ en Phonol the general

lcT}, where (a) this with formation of the alkali

0098M / 2278

reacted _2n Hal-Alk-NR R or hai-C _n H -CHJZ means in the "hai" is a halogen atom · under direct obtain the desired product: metal phenate in an inert solvent with an alkali metal compound and then with the appropriate HaIogenid of formula is, (b) this (under basic conditions) with a compound of the formula hal-Alk-Q, in which Q is a halogen atom or another ^M * radical to be split off (leaving group), for example an arylsulfonyloxy radical, such as Benaolsulfonyloxy- or p- Toluenesulfonyloxy radical, forming a compound of the formula

O-alk-hal

is implemented, which in turn then with the appropriate secondary Amin HJSTR R is converted, (c) this with a Haloalkanol of the formula: Hai-AIk-OH under similar conditions as in (b) to form a compound of the formula

O-Alk-OH

is reacted, which is converted to the halide, for example by reaction with thionyl chloride, and then with the suitable secondary amine as in (b) is converted, or where (d) this initially as in (a) with an alkali metal compound-under Formation of the phenolate and started with

009851/2276

a lower alkyl ester of a halogen acid of the formula s

E C

hal-Alk-GOOR m, in the Sr of an aledoraa alkyl rust "means _P under the form of a bond of the

G-AIk-

_s which is then converted by reaction sit the HNR R * (optionally via di @ fi? eie acid or the acid chloride) also suitably @n isifi and then finally aur Erai © liiasag of the gawilasehten srodskts with lithium aluminum hydride redi » I © pt

In the case of processes 1 (a) and (d), the inert solvent can, for example, be toluene or dimethyl formamide. To form the ikenolate, the pkeaol solution is carefully treated with latriumiiydsld fersetat ^ oad daiaa © rMtat » M® reaction with the halide © der am feio ^ aas & ur © ester (e.g. the chloride or @ M, © re®ter) k © aa fe © i Mckflussti ^ iperatur be carried out.

With Üea ¥ 1 (b) and 1 (c) k & nn experience the reaction lÄsaole bit of the remote link feal- ^ Lk-Q or deffl felogen = ·

l _(e sB Bro-malkanol) in msthaaolischer potassium - hydroxide * = ₈ äthanolisoher latriumäthpsid- or Aeeton / potassium »earbonatlösung at reflux temperature who performed - the *.

The subsequent reactions with the secondary amine can be carried out in any suitable inert solvent. 2.B ₀

Xth & nol, perform under reflux conditions »As Modi-

Fication of this process lets you use a primary amine HgHR instead of the secondary amine NHR R and alkylate aas product according to the conventional quiet way of obtaining a compound according to the invention in which -I / and R each represent a lower alkyl radical

(2) The compounds according to the invention "in dsnen E" aeric hydrocarbyl radical means »let see (a)

R ^i: · 'aiii *; Yes as he st off atom or a nic-ieren «oily

or Alkoiiyrf a ^ ^ e-aoafcet * from one the-

XX

0-Y

through Grignard reaction with M & gnesiu® vinü. of a * halide of the formula Hal-R »in the R ^ -CHg, equal Ff i @ t _s achievement of a compound of the föi» * i

R ⁴

0-1

which are then reduced, for example, with hydrogen la in the presence of a suitable catalyst, or (b) if R is a hydrogen atom or a large alkyl radical, from a lower alkyl ether of salicylaldehyde itself by a similar reaction with the Grignarü- Reagent and subsequent reduction to achieve a connection of the following:

O..O9051 / 2276

2026683

7th
in the. R denotes a lower alkyl radical, the itfeer being converted into the free phenol by conventional methods and then converted by one of the processes (l) (a), (b) or (c) «

In processes (2) (a) and (b), the Srig nard reagent is formed in the usual way from magnesium and the suitable halide in a "suitable solvent _2o B", ether, and the ge®iga®te Md Kyd is then slowly added to the cooled solution of the Grgnard reagent in the same solvent, the mixture is then heated to terminate the reaction and the magnesium ^{complex is acidified at about 0} ° C. The subsequent reduction can be carried out with hydrogen the present © inea catalyst® from PallaÄ «~ ao.f-Kohl © in an acidic medium, for example«) at -50 ° C are 5552 kg / cm, in ethanolic salic acid or the presence τοπ Raney-Iiickel as a catalyst.

(3) Compounds in which R is a primary hydrocarbyl radical and R is a hydrogen atom, a halogen atom or a lower alkyl or alkoxy radical, leave derived from the ortho-eylphenols of the formula

CÖ-fi ⁵

009851/2276

(a) by reduction with zinc and hydrochloric acid, with hydrazine in a suitable solvent or with hydrogen in Presence of a suitable catalyst and subsequent reaction according to one of the processes (l) (a), (b) or (c), or

(b) initially by reaction according to one of the processes (l) (a), (b) or (c) to give a compound of the formula

0-T

and subsequent reduction as in (ft). '

The reduction with hydrogen can be carried out in each Pail as in process (2), and where R is a halogen atom, ka
Hydrogen atom to be replaced.

R denotes a halogen atom, R can simultaneously be replaced by a

The starting materials for process (3), i.e. the acylphenols of the above formula, can be from the corresponding phenyl carboxylate using Friesscher Rearrangement reaction with aluminum chloride or similar Lewis acids easy to manufacture.

O-CO-R ⁵

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2026683

- ίο -

However, if R is a hydrogen atom, then arises in the reaction a mixture of ortho- and para-isomers, which are necessary for the production of the desired ortho-acylphenol need to be separated.

In each process, the end product can be obtained as the free base by precipitation or removal of the solvent under reduced pressure and purified by adding water, extracting into a suitable solvent, drying, filtering and evaporating under reduced pressure. The acid addition seals can be obtained in the usual way by adding the appropriate acid in a suitable solvent or liquid Baäe or by dissolving them and collecting the precipitate. The purification is carried out in the usual way by recrystallization from a suitable solvent.

It has been found that the compounds according to the invention powerful Hp antagonists, i.e. blocking agents of Are histamine effects on the EL receptors. This was done in Experiments in which the inhibitory effect of the compounds according to the invention on those induced by histamine Gastric acid secretion measured in experimental animals has been shown. One of the tests were anesthetized Rats by intravenous injection of carbachol (carbamoyl chloride) sensitized; then they were injected intravenously with a standard dois of histamine and the pH

of stomach contents measured over a short period of time until it stabilized. Then the test compound, also administered intravenously. The pH of the stomach contents was measured over a further period of time, until the inhibitory effect of the compound is no longer

- li -

was delivered. It has been found that many of the compounds according to the invention at a dose of 10 mg / kg have a 50 % inhibition of the effect of histamine on the pH value b6, while the most potent compounds have a 100% inhibition at 5 mg / kg. t-day inhibition and at 2.5 mg / kg or even less a 50% inhibition. IkLe more potent compounds are still effective for 3 to 4 hours after injection. In a similar anaesthetized cat test, the histamine was continuously infused before and during administration of the test compound.

They are compounds of the invention due to their Hp-blocking effect to reduce the gastric Super acidity and therefore in the treatment of gastric ulcers and others caused by gastric superceidity or aggravated symptoms. They are also useful for facilitating the effects of others Histamines at the Hp receptors causing symptoms.

The compounds of the invention can be administered alone. In general, however, they are mixed with a pharmaceutical carrier which is suitable for the desired route of administration and the usual pharmaceutical Practice is chosen, administered. For example, they can be in the form of tablets containing such carriers - ' containing substances such as starch or lactose, in the form of Capsules, - either alone or in combination with carrier substances, or in the form of flavorings or coloring agents Administer elixirs or suspensions orally. They can be parenterally, e.g. intramuscularly or subcutaneously, inject. When administered parenterally, they will preferably be in the form of a sterile aqueous solution related to the other dissolved substances, e.g. enough salts

009851/2276

or glucose to make the solution isotonic.

The following examples serve to illustrate the invention. The temperatures are shown in C

give.

Example 1;

N.N-diethyl-2- / ~ 2- (2-cyclohexylethyl) phenoxy j'-ethylamine.

To a solution of 2- (2-cyclohexylethyl) phenol (5.0 g) in dry dimethylformamide (75 ml), a 50 % sodium hydride diaphragm (1.2 g) is added a little at a time; then the mixture was ^{heated to 100 °} C. for half an hour. Then 2- (diethylamino) ethyl chloride (3 »3 g) in dimethylformamide (25 ml) was slowly added. The mixture was refluxed for 3 hours, then cooled and water (10 ml) was added. After most of the solution had been evaporated under reduced pressure, water (100 ml) was added to the tank and the mixture was extracted twice with Xther. The organic extract was washed with water, dried over sodium sulfate and filtered. After evaporation of the solvent the product was obtained as the "in" ehwachgelbes oil were by the addition of an ethereal solution of citric acid 9.1 of the Citratsalζes g dee product as a white precipitate obtained was recrystallized from isopropyl alcohol, and its melting point at 130 -.. 131 ⁰ C lay.

Analysis: Calculated for - C2O H ^ NO.

009851/2276

2026683

C 63.0; H 8.3; H 2.8 + found: C 62.7; H "8.2; N 2.95

Examples 2-39S .

The compounds shown in labeile I were according to Example 1 from the appropriate substituted phenol and made from the chloride Cl-Y. BLe the analytical numbers required by the Suinmen formula of each compound are shown in brackets. IkLe salt formation was carried out in the usual manner using the appropriate acid. .

009851/2276

Table It '

Elemental analysis of salt produced at- RTR game and Sohaelzp.

(Sueeenf orme1)

2 2-Cyolohexyl-ethyl -CH ₂ CHCH ₂ -H (CHj) ₂ -oxalate 164-165 ° C 66.8 »H 8.7t H 4.0

CHj · (C ₂₀ H ₅₃ HO-C ₂ H ₂ O ₄ ) (C 67.1 »H 8.9» H 5.6)

-CH ₂ OH ₂ CI ₂ - "- citrate 127-128 ° C 61.8} H 8.2» H 3.1

CC ₆ H ₈ O ₇ ) (C 62.3 »H 8.2 | H 2.9)

n-Heptyl -CH ₉ CH, · - Oitrate 94-95 ° C 60.3 »H 8.3» H 2.6

^ (C ₁₇ H ₂₉ HO-C ₆ I ₈ O ₇ ) (C 60.6 »H 8.2} 13.1),

IO.

- Citrate 128-129 ° C 62.1 »H 8.2» H 2.7

(C ₁₉ I ₃₃ ICC ₆ H ₈ O ₇ ) (C 62, UH 8.51 K 2.5)

° C 615 »η '

-CH ₂ CH ₂ CH ₂ -H (CH ₃ ) ₂ - citrate 97-98 C 61.5 »H 8.3» H 3.1

(C ₁₈ H ₃₁ HO-C ₆ H ₈ O ₇ ) ($ 63 »O» H 8.3 »H 2.8)

-CH ₀ CH ₀ CH ₉ T - citrate monohydrate.

² I ^{2 2} 79-79.5 ° C 60.0 »H 7.6» H 2.85 £?

CH ₃ (C ₁₉ H ₃₃ HO-C ₆ H ₈ O ₇ -H ₂ O.) (C 60.0? H 8.6> H 2.8) g Table I (continued!

«Ο ο» cn

n-Htptyl

n-octyl

10 n-Honyl

11 1-ithyl-haxyl

-CH ₀ CH ₉ CH HI (CH,),

CH ₁

-CH ₂ CH ₂ CH ₂ -I (CHj) ₂

-CH ₂ CH ₂ CH ₂ -I (CH ₅ ) ₂

Manufactured SaIx elementary analysis,

and melting point

( Sum formula) _ »__« ____ «__.__.____» _

Oxalate 102-103 ° C 66.1} H 9.0 »N 3.4

(C ₁₉ H ₅₃ KO-C ₂ H ₂ O ₄ ) (C 66.1 »H 9.2 | H 5.7)

Oxalate 120-125 ° C 66.2j H 9t2i H 3 »2

(C ₁₉ H ₅₃ NO-C ₂ H ₂ O ₄ ) (C 66.1 | H 9.2, I 3.7)

Citrate 95-96 ° (C ₂₀ H ₅₅ ICC ₆ H ₈ O ₇ )

Cltrat 110-112 °

C 62.4! H 8.3L I 2.7

(C 62.75? H 8.7l N 2.8)

C 61.8, H 8.5; N 2.7

(C 62.1} H 8.5 »I 2.9)

12 Crolohaxyl-ethyl

13 4,4-diethyl-pantyl Citrate 121-123

C 61.6 »H 7.6» I 3.0 (C 61.65 »H 8.0» I 3.0)

Citrate 130-130.5 ° C 62.6 »H 8.4» H 2.7 (C ₁₉ H ₅₅ NO-C ₆ H ₈ O ₇ ) (C 62.1 »H 8.5» I 2.9 )

Table I (porting ι

At- E
apiel

14 n-heptyl

16 2-cycl.ohexyl-ethyl

17 n-heptyl

Manufactured salt elemental analysis

and camel fur

(Sumnenforael)

-CH ₂ CHpCH ₂ -Ii (CH,) ,, Cl Oialate 109-110 ° C 59.7j H 8.0} N 3.3 ° (C ₁₈ H ₃₀ ClNO-C ₂ E ₂ P ₄ ) (C 60.1; H 7.6j If 3.5)

-CH ₂ CH ₂ -

-CH ₂ CH ₂

CH, oxalate 114-115 ° C 66.6 | H 9.2 »N 3» 5

(C ₁₉ H ₃₃ HCC ₂ H ₂ O ₄ ) (C 66, I ₁ H 9.2 * N 3.7)

- Hjiroohlorid 164 ° C69, O | H 9.7H 4.2

(C ₁₈ H ₂₉ JCHCl) (C 69.31 H 9.7 * N 4.5)

Cl "Citrate 145 ° C 58.3 * I 7.7} H.2.6

(C ₁₉ H ₃₂ CUrCC ₆ H ₈ O ₇ ) (C 58.0 »H 7.7 |» 2.7)

18 2-propyl-pentyl

-CH ₂ CH |

H Citrmt 13I-I32 ⁰ C 63.2 >> I 8.5 I 2.5

(C ₂₀ H ₃₅ KCC ₆ H ₈ O ₇ ) (C 62.751 H 8.7 »H 2, β)

^% Table 1 (continued):

At- .HY ά Manufactured salt elemental analysis

game and melting point

( Molecular formula)

(C ₂₁ H ₅₅ NO. C ₂ H ₂ O ₄ ) (c 68.1; H 8.7; N 3.45)

19 2-Cyolohexyl-ethyl "H ') H Oxalate 151-152 ° C 68.5} H θ, β} Ν 3.0

20 """ N (C ₂ H ) ₂ Cl citrate 145-146 ° C 59.0} H 7.5} N 2.3

(C ₂₀ H ₅₂ NOCLC ₆ H ₈ O ₇ ) (C 58.9} H 7.6; N 2.6)

21 """HJ (CH ₂ CH) ₂ H citrate 95-96 ° C 64.0} H 8.3} N 3.0 - ^

(C ₂₂ H ₅₇ NO-C ₆ H ₈ O ₇ ) (C 64.2; H 8.7; N 2.7)

22 """- N (C ₂ H ₅ ) ₂ CH ₅ O- citrate 118-118.5 ° C 62.0, H 8.1, N 2.3

(C ₂₁ H ₅₅ NO ₂ -C ₆ H ₈ O ₇ ) (C 61.7} H 8.25} N 2.7)

Hydrochlorxd

162-162.5 ° C 71.35} H 9.6} N 3.7 (C ₂₁ H ₅₅ NO.HCl) (C 71.65} H 9.7} N 4.0)

24 n-Heptyl -CH ₂ CH ₂ - N (C ₂ HJ ₂ CH ₅ - citrate 135-136 ° C 63.0} H 8.3} N 2.35 ~

) ■

, .NO.C ₆ HoO ₇ ) (C 62.75; H 8.7} N 2.8)

Table I (continued) χ

1 4-

Sals produced at ETR as slementar analyzes

game and melting point

(Summenforae1

- wfPH- "3 B free base

25 2-Cyclohexyl-ethyl-CH ₂ CH ₂ * vwn _χ 202% mn (boiling point) C 79.4 »H 11.3» H 3.9

⁰ V2 (C ₂₂ H ₃₇ HO) ■ (C 79.7 »H 11.25» H 4.2)

S γ \ :

OO 26 »", "- I b H Citrate (Heeihydrate)

JJ, 106-107 ° C 60.2 »H 7.7» Ä 2.6

H citrate 97-99 ° C 62 ^ 6 »Ή 7.9» 12.8

27 «« ·· 1 ^

(C 63.3 »H 9.0» I 2.8)

_2fl """w> H free base 199-201 ° /

^ ⁸ * - ⁷ 0.5 λβ (boiling point) C 81.1 »H 11.2» I 3.8

3 (C ₂₃ H ₃₇ IiO) (C 80.4 »I 10.9» ■ 4.1)

I 1-CH ₃ H citrate 159 ° C 62.2 »H 7.7» I 5.6 °

(C ₂₁ H ₃₄ H ₂ CC ₆ H ₈ O ₇ ) (C 62.05 »H β, Ι» I 5.4) gj

Table I (continued) ι

Example & ■ Produced Sal *
and "Melt.
(Sum form1)

Elemental analyzes

2-cyclohexyl-ethyl -CHgCH-

n-nonyl

-CHCH ₂ -H (C ₂ Hj) ₂

^C 2 ^H 5 CH ^ ² CH ₂ - -CH ₂

H citrate 112-115

H citrate 139-140 °
( ^C 21 ^H 35 ^NO * ^C 6 ^H 8 ° 7)

H hydrochloride 187-188 ° (C ₂₂ H ₃₅ NO.HCl.)

C 63.5; H 8.4; N 2.8

(G 63.5; H 8.5; N 2.75)

C 63.6; H 8.4l H 2.75 (C 63.6 | H 8.51 N 2.75)

(C 72.2, H 9.91, N 3.8)

Oxalate 121-122 ° C 65.65 H 9, Of K 3.6 (C ₁₉ H ₃₅ NO-C ₂ H ₂ O ₄ ) (C 66.1; H 9.25; N 3.7)

2-cyclohexylethyl C 62.4l H 7.9; N 2.4 C ₂₂ H ₃₅ NCC ₆ H ₈ O ₇ ) (C 62.551 H 8, li N 2.6)

"CH, CO- citrate 118-119

Table I (continued):

Example λ Salt produced elemental analysis and melting point.
(Molecular formula)

35 2-cyolohexyl-ethyl

36

₅₇

^ - NC ₂ H - CH \ ^J

CH ₂ CH ₂

CH

_CH _ _C g ²

38 Cycloheptylmethyl -CH ₂ CH ₂ -H (C ₂ H ₅ J ₂ H

39 cyclohexylmethyl

-CH ₂ -CH

Hydrochloride
159-160 °

C 72.0} H 9.5? K 3.8 (C 71.7} H 9.7; N 4.0)

Citrate 129-130 ° C 61.0} H 8.1} N 2.4

(C ₂₀ H ₃₂ FNO.C ₆ H ₈ O ₇ ) (C 60.8} N 7.85; N 2.7)

Hydrochloride 170 ° C 71.3; H 9.7} N 3.9

(C ₂₁ H ₅₅ NO-HCl.) (C 71.65} H 9.7? N 3.9)

Citrate 149.5-150 ° C 63.0} H 8.1}. N 3.0

(C ₂₀ H ₃₃ NO-C ₆ H ₈ O ₇ ) (C 63.0? H 8.31 N 2.8)

^Citrate ^ ¹ ' ¹ ^ ^{C 64} ' ⁰ ' ^H ^> ⁸ * ^{Έ 2} ^

(C ₇ IJO ₁ CXO) (C 63.9? H 8.1; N 2.8)

Example 40:

(A) 1-bromo-3- (2-n-heptylphenoxy) propane.

2 n-Heptylphenol (48 g) was slowly added with stirring to a solution of I potassium hydroxide (14 g) in methanol (100 ml). Then 1,3-dibromopropane (20.2 g) was added in one portion; the mixture was refluxed on a steam bath for 2 hours before cooling and filtering off the precipitated potassium bromide. After evaporation of the solvent, a residue oil _{9 was obtained} which was distilled under reduced pressure, the pure product between 138 and 146 ° C. at 0.6 mm (36 g).

Fraction collected between 138 and 146 ° 0 at 0.6 mm Hg

(B) 4- / ~ 3- (2-h-heptylphenoxy) propyi_7-l-methylp ± perazine.

The product obtained under (A) (5.0 g) and N-methylpiperazine (6.4 g) in ethanol (100 ml) was refluxed for 6 hours. After cooling and removing the solvent under reduced pressure, water (100 ml) was added and the mixture was just made basic with 2N sodium hydroxide, followed by extraction with Atrier twice. The combined organic extracts were dried, filtered, and evaporated to give a residual oil which was used to remove the N-methylpiperaain excess.
Pressure was held.

Methylpiperain excess for 1 hour at 60 ° C. and 1 mm

The maleate salt was prepared in the usual way and recrystallized from ithanol. The yield was 3.5 g of dimaleate; Melting point; 191-192 ° C,

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Analysis:

Calculated for

C 61.7? H 7 ₀ 85 ?. I 5 "Q found? -Οβΐ.8? H 7 ₀ 7i 14y

Examples 41 bia 44 »

The compounds listed in Table II were in the manner described in Example 40 »® manner from the gseignet en substituted phenols l ₉ 3-fiibronipropan and manufactured dsm appropriate amine, wherein the Salsbildung was conducted using the appropriate acid in conventional manner. In Examples 41 and 44 "in which the Aiain (ßiäthylamin) was volatile, the reaction was rather than under reflux in a sealed bomb tube at 80 C.

009851/2276

* • —ν CM ir » κ \ Ό χ— ^ KN VO in in γ- \ KN * KN • rt CO KN - * t CM t— * s Φ • ΙΟ m r-i β t5 O S5 te to m Φ ο i-l K Ή ·· » ··· Λ «A Mh 1-4 O P!
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009851/2276

Example 45:.

The product obtained in Example 34 was a solution of hydroxylamine hydrochloride (1.0 g) and sodium acetate (2jO g) in ethanol (50 ml) was added. The mixture was stirred, heated on a steam bath for 1 1/2 hours and cooled. The ethanol was then evaporated off under reduced pressure. The Mickstand was filled with water (50 ml) added, extracted twice with ether (25 ml), evaporated and dried, N, N-diethyl-2- / ~ 2- (2-cyclohexylethyl) -4- (l-oximinoethyl) phenoxy ^ 7ethylamine was obtained as a colorless oil. After addition of ethereal citric acid, the nitrate salt was obtained, which is white solid (1.8 g) was recrystallized from methanol / ethyl acetate; Melting point; 111-113 C.

Analysis;

Calculated for C ₂ 2 ^H 36 ^N 2 ⁰ 2 * ^C 6 ^I % ⁰ 7 ^:

C 60.85; H 8.0; H 5.1 *; found: C, 60.8; H 7.8; N 4.9 *.

Example 46;

(l) sodium hydroxide (50 # dispersion; 4.8 g) was a solution of 2- (2-cyclohexylethyl) phenol (20 g) in dry dimethylformamide (100 ml) added in portions; the mixture was heated to 80 g for 1 hour. Then chloroethyl acetate (12.1 g) was added and heated under reflux in the usual way for 4 hours, cooled, poured into water, extracted with ether, a

009851/2276

_ 25 -

steamed and dried. The distillation in a high vacuum gave 14.1 g of ethyl 2- (2-cycloliexyl-ethyl) phenoxyacetate as a clear liquid.

(2) This ester (25 g) was added to ethanolic sodium hydroxide (150 ml) and placed on the steam bath overnight heated. Then he was au l / 3 of the volume evaporated, brought into water, extracted with ither, with Acidified hydrochloric acid, extracted three times with chloroform (50 ml) and evaporated, leaving 18.5 g of crude 2- (2-cyclohexylethyl) phenoxyacetic acid was obtained.

(3) The acid was treated with thionyl chloride and the acid chloride so obtained (4.0 g) was dissolved in benzene (30 ml) slowly of a solution of isobutylpiperasine (2.0 g) in benzene (40 ml) added. A rapid reaction took place and a gelatinous precipitate formed. The mixture was refluxed on a steam bath for 1 hour, cooled, and then under reduced pressure Pressure evaporated until nearly dry. Water (100 ml) and NaOH were added to the residue basified and the mixture extracted with chloroform (50 ml). After working up the chloroform extract in the usual way In this way, 4.0 g of 1-laobutyl-4- / -2- (2-cyclohexylethyl) phenoxyacetyl-7piperazine were obtained as a dark brown oil.

(4) This amide (4.6 g) slowly turned to lithium aluminum hydride (1.1 g) in dry ether (200 ml) added; the mixture was stirred and taken for 6 1/2 hours Heated to reflux. To decompose the excess LiAlH ^, The mixture was then washed with a 5N aqueous sodium hydroxide solution added and filtered. The filter cake was thoroughly washed with ether, the filtrates

009851/2278

were combined, dried and evaporated to give a mobile yellow oil. After adding more essential HGl, 2.8 g of 1-isobutyl-4- / ~ 2- (2- £ 2-cyclohexylethyl) were obtained phenoxy) äthyl_7piperazine dihydrochloride, which was recrystallized from isopropyl alcohol. Melting point: 255-256 ° C.

Analyzes

Calculated for C ₂₄ H ₄₀ N ₂ O 1 HCl: G 64.7; H 9.5; N 6.3 ^;

Found: C, 64.45; H 9.3; N £ 6.1.

Example 47:

(1) Cyclohexylmethylmagnesium bromide (35.4 g; 0.2 mol) was prepared in a conventional manner from cyclohexylmethyl bromide and magnesium in ether (610 ml). 2-Diethylaminoethoxy-benzaldehyde (44.2 g; 0.2 mol) in ether (60 ml) was slowly added to the cooled G-rignard reagent. The mixture was then refluxed for 3 hours and then decomposed with 5N hydrochloric acid in the presence of ice. BLe free base of the product was made by adding

released from ammonium chloride (42.8 g) and dilute ammonia; the separated ethereal layer was removed. The aqueous phase was extracted twice with ether (150 ml in total, after which the ether extracts were combined and washed with dilute ammonia. The ether was removed by evaporation on a water bath and the residual oil was distilled in vacuo. The temperature of 180-186 C / 0.3 miu boiling fraction (29 "β g) was collected and consisted of 95 i> pure N, N-diethyl-2 / ~ 2- (2-cyclohexyl-l- hydroxyätnyl) phenoxy J ethylamine free base.

009851/2276

(2) The product obtained under (l) (20 g) was in Dissolve ethanol (100 ml) and add 36% (w / w) Hydrochloric acid (8 ml) and a 5 # palladium on carbon catalyst (5 i.e. 2.5 g of the catalyst was with the equal parts by weight of water wetted). The suspension was hydrogenated at a pressure of 3.52 atmospheres and 50 G for 2 1/2 hours until no more hydrogen was taken up. The catalyst was filtered off and the piltrate with an excess of 20 # (w / v) sodium carbonate solution (50 ml) treated. Most of the remaining ethanol was carried over. Vacuum distillation removed; the kickstand was extracted with ether (3 x 50 ml). To Evaporation of the ether gave Ib, 4 g of N, N-I) ethyl-2- / ~ 2- (2-cyelohexylethyl) phenoxyJ'-ethylamine than oil. This oil was dissolved in ether (150 ml) and the solution slowly sampled while stirring with a solution of citric acid monohydrate in ethyl methyl ketone (11.4 g in 75 ml). A colorless voluminous precipitate precipitated out, was filtered,

washed with ether and dried at 40 C in vacuo, whereby 25.8 g of nitrate identical to the product of Example 1 were obtained. Melting point! 128-130 C.

Analysis ;

Calculated for C ₂₀ H ₅₅ KO.C ₆ HqO ₇ : C 63.01; H 8.34; Ii 2.83 t

found: 0 63.60; H 8.50; N 2.71 *.

Example 48;

(1) A suspension of a sodium hydride oil dispersion (48 g; 1 mol) in dimethylformamide (400 ml) was at 90 ° G within 1 hour with 2-cyclohexyl-4-chlorophenol

009851/2276

(252.5 g; 1.0 mol) were added. The mixture obtained is ^{further at 90-1OQ 0} C! Stirred for 1/2 hour. Then, at 90 ° C., 2-dimethylamine ethylchloride (142 g; 1.05 mol), in dimethyl form amide (200 ml), was added over the course of 1/2 hour; the reactants were ^{heated at 90-10O 0} C for 3 hours. Machdem the reaction mixture was cooled to 25 G -was "was it added carefully with water (1 L) and the resulting solution extracted with chloroform (4 x 750 ml)}, the chloroform solution washed with water (3 x 500 ml) and a Concentrated oil which was dissolved in dilute (5N) hydrochloric acid (750 ml) and washed with ether (3 x 250 ml). The pH of the aqueous solution was _{adjusted to pH 9 8} 5 with a sodium hydroxide solution and the aqueous solution was extracted with chloroform (3 × 250 ml). After concentration of the chloroform solution, 345 g of N, N-diethyl-2- (2-cyclohexyl acetal-4-chlorophenoxy) ethylamine were obtained as an oil. The product was purified by the formation of the citrate, which was converted twice from isopropanol
owned.

was recrystallized and has a melting point of 123-125 ° C

(2) The product obtained in (1) (11.2 g; 0.02 moles) in the form of citrate in ^ Brennapiritus (100 ml) and treated over a catalyst of 10 i »palladium on carbon (6 g) in 4.22 atm and 80 ° C hydrogenated until no more hydrogen was taken up (2 hours). The catalyst was filtered off and the solution concentrated to an oil which was suspended in water; the pH was adjusted to pH 9 »5 with a sodium hydroxide solution and the solution was extracted with chloroform (3 × 50 ml). The chloroform solution was dried over magnesium sulfate and concentrated to an oil. 5 g of N, N-diethyl-2 - ^ "2 (2-cyclohexyl- 'ethyl) -phenoxy_7äthylamin were obtained as free base, boiling point: 183-189 ° C at 3.5 mm Hg. The product was in

009851/2276

SAD ORIGINAL

conventionally converted to the hydrochloride. Melting point: 161-162 ° C.

Analysis:

Calculated for C ₂₀ H ₃₅ NO.HGl: 0 70.78? H 10.10; M 4.13?

. approx 10.4.5

found! C 70.92; H 10.12 s N 4.09 ;.

'Cl-- 10.75 5t.

The products of all examples were identified as BL-JL antagonists in experiments to determine the inhibitory effect on the

gastric acid secretion induced by histamine »as described above, examined. According to the results obtained , the most effective compounds are those

aer formula

0-Y

1 4

wherein R is a heptyl or 2-Cydohexyläthylreat, R a

Hydrogen or a Huoratoa or a methyl or

2 3

Methoxy radical and Y a heat of the formula -AIk-HR R or-

-CH - Z (as described above) which (a) a single tertiary nitrogen atom separated from the oxygen atom by a chain of only 2 carbon atoms, (b) a total of 6 to 9 carbon atoms, and (c) one bonded to the oxygen atom Contains methylene radical, mean.

0öS85i / £ 227>

T therefore means w-rsugsweis® s _o Bsplo oinea remainder of

? "3 2 3

Foriael -CHgCHg-MR ¹ R »where E cad R susonsisn 4 feie 7

Contains carbon atoms (s, B. The products of the examples I ₉ 5 _S 13 »19, 2I ₉ 22 _β .24, 25 _β 27, 28 and 36), a residue of the formula -GH _O -CH (CH,) -HR R ο wherein R and S ^ 3 to sassrnmen € carbon atom © © atlaalten (s «B. Prodiakt that of example 30) or a l» M] syl ~ 2 »p ± peridyl® © thyl? est ₀ vori.it the 1-alkylseastituent Ms on 3 soles contains atoms (eg. ■ '

009SS1 / 227 ^:

Claims (8)

Patent claims: in which R is a saturated aliphatic or alicyclic Is a hydrocarbon residue with 7 to 9 carbon atoms, 2 3 Y either (A) is an aminoalkyl radical of the formula -AIk-NR R 2 3 means in which R and R each represent a lower alkyl radical or together with the nitrogen atom to which they are bonded form a saturated heterocyclic radical, and "Alk" represents a divalent saturated aliphatic hydrocarbon radical having 2 to 4 carbon atoms, the free ones being Valences are located on different carbon atoms, Qder (B) is an aminocyclic Reph of the formula - ^G _n ^H 2n ~ ^CH ^, in which η 0 to 3 and Z is a divalent radical which is a saturated heterocyclic ring with at least one nitrogen atom and at least 4 carbon atoms completed, * · wherein either nitrogen atom from the oxygen atom to which the · aminocyclische residue is bonded is through a chain of 2 to 4 carbon atom Separated, and R is a water 'fabric or halogen atom or a lower alkyl, Alkoxyoaer alkanoyl or denotes an oc-oximino (lower) alkyl radical, as well as their pharmaceutically acceptable acid addition salts ze. 009851/2276 2. A compound according to claim 1, characterized in that R of the formula is a primary hydrocarbyl radical, in particular denotes an n-heptyl or 2-cyclohexylethyl radical. 3. Compound according to one of claims iodine ·! · 2, characterized characterized in that R of the formula denotes a hydrogen or a fluorine atom or a methyl or methoxy radical. 4. A compound according to any one of claims 1 to 3 «thereby characterized in that Y of formula (a) is a single tertiary nitrogen atom, daa from the oxygen atom through a chain of only two carbon atoms is separated, (b) a total of 6 to 9 carbon atoms, and (c) one on the oxygen atom contains bonded methylene radical. 5. A compound according to claim 4, characterized in that Y is a radical of the formula -CEL-CEU-NR ² R ³ , 2 3 cc in αer R and R have the meaning given in claim 1 and together contain 4 to 7 carbon atoms. 6. A compound according to claim 4, characterized in that Y is a radical of the formula ^ CH ₀ -CH (CH,) - BR ² R ⁵ 2 3 c ο interprets, in which R and R ^ the meaning given in claim 1 have and together contain 3 to 6 carbon atoms. 7. A compound according to claim 4, characterized in that that Y cter formula a l-alkyl * 2-piperidyl-metH.yl ^ Reet means in which the 1-alkyl substituent has up to 3 carbon atoms contains. 009851/2276 8. N, N-Diäfchyl ~ 2- [2- (2-cyclohexyl-ethyl) phenoxy> ethylamine, N, N-Di-n-propyl-2- [2- (2-cyclohexyl-ethyl)
phenoxy-ethylamine, N, N-diethyl-2- (2-n-hepfcyl-phenoxy)
äfchylamine, N, N-Diäfchyl-2- (2-n-hepfcyl-4-methyl-phenoxy) -äfchylamin, N, N-diethyl-2- [2- (4, M-dimethylpentyl) phenoxy> äfchylamin, 1- {2- [2- (2-cyclohexyl-ethyl) phenoxy ^ lfchyl ^ - piperidine, 1- £ 2- [2- (2-cyclohexyl-afchyl) phenoxy ^ lfchylJ-pyrrolidine, 1- (2- [2- ( 2-Cyclohexyl-afchyl) phenoxy ^ bthylj 2,6-diraethylpiperidine, N, N-Diäfchyl-2- [2- (2-cyclohexyläfchyl) -4-mefchoxyphenoxy 3äfchylamin, N, N -diäfchyl-2- [2- (2-cyclohexyl-αfchyl) -4-fluorophenoxy] ethylamine, N, N-diethyl-2- [2- (2-cyclohexyl-αfchyl) phenoxy> l-mefchylethylamine, 2- ΪΖ- (2-cyclohexylethyl) phenoxymethyl 3-1-ethylpiperidine, 2- [2- (2-cyclohexyl-αfchyl) -phenoxymethyl> 1-mefchylpiperidine. For Pfizer Corporation Lawyer 009851/2276