DE2040441A1 - New phenyloxy and phenylthiopropylamines - Google Patents

Description

LEGAL LAWYERS

DR. JUR. DIPL-CHHM. WALTER BEIL

alfr: * d hoeppener

dr. jur. dipl-chem. h.-j. wolff

dr. jur. hans chr. ax

O Ätifl ¹ Q7fi FRANKFURT AM AAAlN-HOCHSf I «· ^HU » * ^lJiU

ADELONSIRASSt 50

Our Jwr. 16 544-

Pfizer Corporation
Colon / Panama

Iveue Phenyloxy-- and Phenylthiopropylamine

The present invention relates to new derivatives of 2-Bydro.xy-J-phenoxy- or -phenylthiopropylamins, which act as regulators of the cardio vesicular system, especially for the treatment of high blood pressure, as well as other heart conditions such as angina pectoris or cardiac arrhythmias are useful.

The compounds according to the invention are Tireido-phenoxy- and -phenylthio derivatives of 2-hydroxypropylamine of the general formula

^ in the R a Jreidogruope,

^ R (hydrogen, nelogen, or a lower 1> cyl group,

R ./hydrogen or a lower alkyl ^ ruvr <?, R ./hydrogen, a lower alkyl group or

R is a lower alicyl radical, hydroxy-lowest-alkyl radical, low-alkoxy-low-alkyl radical, aryloxy-low-alkyl radical, a cycloalkyl radical, lower AlKenyl radical or aryl-lower alkyl radical and

X represent oxygen or sulfur.

The invention also relates to esters of such compounds free hydroxyl groups, the aldehyde condensation products of

2 5

Compounds in which R and R // are hydrogen atoms, the

N-oxides of compounds in which R is not hydrogen, as well as the pharmaceutically acceptable acid addition salts.

The ureido group R, which is preferably in the 4-position, can have the formula R- ⁷ R NCON (R '), in which R ^ ₁ R and R are each hydrogen, a lower alkyl, aryl or aryl lower Mean alkyl radical.

In the present description, the term denotes

10 9 8 Q 9/2 2 5 ί

ORIGlNAL BATHROOM

"HHIIIIIIIHillllllllllllllni i'i | HI | ii ιμ ι

- 3 - 2040U1

If it is used for qualifying an Alley] -, alkoxy or alkenyl group, dai servant Λ to ή Ii ^; nst il> * "ffatome has. "Halogen" is understood to mean fluorine, chlorine, br-vii and iodine.

1st r ^'1, R "V R', R, R, B ^b or R ^ a lower alkyl radical, f ■"> icann he "vioh example" lietnyl-, ethyl, iso- "a. T0 [Y3 , η-butyl, tert-butyl or n-hexyl groups. If one of the grids R, R, R, R or R consists of an aryl-lower-alicyl radical, this can be, for example, in the form of a benzyl, phenyl or phenylprop-1 radical, where the pienyl ring has 1 or more substituents

Can, for example, contain lower alloys, lower e or halogen atoms. If R ⁷ , R or R ^ is an aryl group, this can consist, for example, of a phenyl group which can have one or more substituents in the form of low-alkoxy groups, lower alkoxy groups or halogen atoms.

If R is a hydroxy-lower alkyl radical or a lower alkoxy-lower alkyl radical, it can be, for example, a i-hydroxy-ethyl, 2-livaroxy , 1-dimethyl-ether or 2-methoxy-ethyl. Is R a

so it scans, for example, in the form of a 2-phenoxy-ethyl, 5-phen'-xy-propyl, i-methyl-2-phenoxy-ethyl or 1,1-dimethyl-3-phenoxy-ethyl radical, it being possible for the phenyl group to have one or more substituents, for example in the form of lower alkyl radicals, lower alkoxy radicals, halogen atoms, hydroxyl groups or alkylamino groups. In compounds having an antihypertensive effect, H is preferably a 2- (2-substituted-phenoxy) -ethyl radical _f , the substituents being, for example, ifethoxy, ethoxy or chlorine in the 2-position, while Br is a hydrogen atom.

109809/2254

BATH

2040U1

4 In association with the treatment of heart disease, R preferably a branched alkyl group, e.g. an isopropyl or tert-butyl group, or a 2- (4-acetamidο -phenoxy) -ethyl group, while R is hydrogen.

Compounds with free hydroxyl groups are particularly

2 4

those in which R is hydrogen and those in which R

is a hydroxyalkyl radical.

Aldehyde condensation products of compounds according to the present invention Invention are üxazolidine of the formula

those in the condensation of compounds in which R ~ and R

Represent hydrogen, with an aldehyde of the formula R (JHO, in which R 'represents Werseretoff or a low Alfeylreet, are formed.

ρ Invention gemäie compounds in which R is Waseeretoff, are preferably prepared by reacting a Bpoxyde the formula

1098G9 / 2254

with an amin of the formula RR NH, optionally in the presence of a solvent, at temperatures between 20 and 100 ° C. and reaction times between 1 hour at 100 ° C. and 7 days at 20 ° C. Suitable solvents are N, N-dimethylacetamide, in which the reaction can be carried out at room temperature for up to 7 days, or methanol or ethanol, which can also be used at room temperature, but also under reflux for reaction times of Λ 1 / 2 to 5 hours «

The amine of the formula RR NH can also be mixed with a halohydrin or corresponding ether of the formula

XCH ₂ CHCH ₂ hal OR

109809/22

in which hai denotes jhlor or bromine, in one Solvent, for example ethanol, which is an alkali wi e.g. contains sodium carbonate, can be reacted and cooked • Eat at the reflux until the reaction has ended.

Furthermore, a phenoxy or phenylthiopropanolanine or a corresponding ether of the formula

reacted with an aldehyde or ketone of the formula R'R CO and be reduced, e.g. with sodium borohydride or ax / oxygen in the presence of a »palladium / carbon catalyst, whereby one receives a compound in which R '.? as0erstioff and R is a

q
Represents a radical of the formula -JH-R or a cycloalkyl group.

q
Here R is an alkyl radical with up to 5 carbon atoms, which can be substituted by a hydroxyl group, alkoxy group, aryloxy group or an aryl radical, while R represents carbon or an alicyl radical with up to 4 carbon atoms.

, j Ίο
The alkyl radicals R and R together contain no more than

Q A _Q

5 carbon atoms, or R and R together with the adjacent carbon atom form an Oycloalkylidenrest.

109809/2254

The compounds of the formula I can also be prepared by men a halo carbonyl of the formula

X - JH ₀ - C - CH ₀ - hai

- II ¹ ^

with; an An in the Fornel RR HH and then the

2 ^

iJerbonylr, group reduced to group OR, in which R " tfesserstoff

means.

Furthermore, the compounds of the formula I can be prepared by reacting a halide of the formula

hai - JH ₂ - CH - CH ₀ - U

in which hai denotes chlorine or bromine and R a lower one represents, with an anion of the formula

10080 9/2254 bad original

in which X is oxygen or sulfur.

The conversion of the compounds of formula I in which R and /

or R * represent hydrogen, in compounds of the formula I,

2 5

in which R and / or R is one of the above *, of hydrogen have different meanings, can by known processes of O-alkylation; and / or H-alkylation take place.

Aldehyde condensation products of the compounds according to the invention are obtained by combining such a compound in which

2 3

R and R ^ represent water atony, mi *; an aldehyde of

Q Q

Formula R CHO, in which R "denotes hydrogen or a lower -kyl radical, in a diluent or solvent, e.g. ethanol, preferably in the presence of an 8sur3ketal ^ s8tore, e.g. hydrochloric acid or Hsacetic acid, and preferably at elevated temperature During the reaction, barrels can be removed by ezeotropic distillation using a liquid agent such as benzene or a de-hydrating agent such as anhydrous potassium carbonate.

Pharmaceutical-permissible acid addition salts of the substances according to the invention Compounds can be made with acids that form non-toxic addition salts such as the Hydrochloride, Hydiobroaid, Hydroiodide, Sulphate or Bieulphate, Phosphate or acid phosphate, acetate, maleet, funerate, oxalate, Lactate, lartrate, citrate, gluconet, saccharate and p-toluene sulfonate.

The compounds according to the invention can be administered as such However, in general, the administration takes place in the form of a mixture with a pharmaceutical carrier, which corresponds

1G9809 / 2254

BATH ORIGINAL

the type of administration is chosen. For example, the compounds can be in the form of tablets which contain excipients such as starch or lactose, or in the form of capsules which either contain the active ingredient alone or a mixture with excipients, or in the form of elixirs or suspensions which contain flavorings and colorings , administered orally. They can also be injected parenterally, for example intramuscularly or subcutaneously. For parenteral administration, it is best to use sterile aqueous solutions which may contain other dissolved substances, for example enough common salt or glucose to form an isotonic solution. - _

example 1

3- / 2- (2-methoxyphenoxy) -ethylamino7- ^/ 1- ( ^z <-ureidophenoxy) -propan-2-ol

A solution of 46.8 g of T, 2-u! Poxy-3- ( ^/ t-ureidophenoxy) propane and 234 g of 2- (2-methoxyphenoxy) ethylamine in 28o ml of dimethylacetamide was added for 2 hours at room temperature touched. During this time a white solid crystallized out. This was filtered off, slurried with 1000 ml of ether, filtered again and washed again with 1000 ml of ether. 54 g of the pure product were obtained as a free base, melting point 147 to 148 ° C.

Anal. {Found 0: 6o, 33; H: 6.59? H: 11.43%

B © r. for : G ₁₉ H ₂₅ N ₃ O ₅ JG: 60.55; H: 6.71 JN: 11.2o%

- 1ο -

Example 2

.I ₁₁ , ■ iii. — ii \ ■

L-4-ureidophen-

oxy) propan-2-ol

The solution of log 1,2-5-epoxy-3- (3-methyl-4-ureidophenoxy) propane and 2- (2-methoxyphenoxy) ethylamine in 100 ml of laethylacetamide was kept at room temperature for 72 hours as in Example 1. 15 »5 g of crude product with a melting point of about 172 ° C. were obtained. After two recrystallizations from 1-butanol, 6.3 g of the pure product with a melting point of 171 to 172 ^° C. were obtained.

Anal. : found: C: 62.04; H: 6.92; N: 1o

Ber. for - ₂ o ^H 27 ^N 3 ⁰ 5 ^{: C: 61} ' ⁶⁸ ' ^{H: 6} » ⁹⁹ » ^N: 1o

Example 3

1- / 2- (2-methoxyphenoxy) -äthylamlno7-3- / ~ ^/ > - (3-methylureido; -phenoxy 7 ~ propan-2-ol

A solution of 1.1 g of 1,2-Bpoxy-iJ- / ~ 4- (3- »ethylureido) -phenox27-propane and 4.4 g of 2- (2-Methoxyphenoa ^) ~ Mthyla! ain in 12 al Ν, Ν-Dimethylacetaaid was kept at room temperature for 7 days. The solution was then poured into 250 ml of Ither, and the precipitated white solid was filtered off. Repeated »crystallization from acetone / Ieopropyläther obtained di pure free Ba (1 g) with a melting point of 128 to 129 ° C

Anal .: found: Ci 61.56 | H: 7 _t 17 | Hi 1o, 75%

Ber. for ^c _2o ^H 27 ° 5 ^N 3 ^{: Ci 6} ^ ⁶⁸ S ^{Hl 6}

Od101 / 22β4

20404A1

heispie] «4 bip

Analogue; de · «Procedure of Examples 1» 2 and 5 earth the eae connections can be seen in the following table under use of the corresponding Rpoxyds and amine as ÄUBgang; smateriel manufactures. Product properties are shown in Table II see.

1CS809 / 225A

BATH ORIGINAL

i) ■ P ■ P

• Η Ή

«J

- 12 -

2 ^ 40441

¹ O 43 CO

O O O CM

• ο

4 *

co

JtT CM

υ ο

CM

1-1 O C

■ Ρ

α> TJ • • U) 4 * • Ü «5 CO 43 4 * Eh CO CO
■ he J3 " ΙΛ CM CM • ν » i • ν ,. CJ H τΗ ü O Vl O O O CM O % ^ CM id / 3
H «·>» G (C. H 3 O H υ δ 4) O Xi υ δ W 4- * CD XS *** CO X ιΗ >>, X OVO C tH 43
0) J3O B. 4X3 • Η OO Q se cm

ro

a a a a a a υ υ ο ο ο O CM
a
ο ο CM O ι I. O I. I.

ΚΛ

ι I. ι a a ζ ζ ο ο ο O CM Γ a ι

in

CM I

ro

vo

ο ι

CM

Z O O

CM

a ι

J3-

I CM I

X »OW

Λ υ

Οι

ΚΛ

I. I. CM a a a SB ο O O O ro '· Z a a CM ο Z a ι I. .ar

co

σ>

109809 / 225A

ORIGINAL INSPECTED

TABLE I (continued)

example

R ¹ R ³ solvent / conditions

12 4-H ₂ NCONH

H -CH ₂ CH ₂ O-

-NHCOCH ₃ methanol / 20 ⁰ C / 3 days

13 4-CH- (CH ₀ ) _NH. H CONH-

14 4-H ₂ NCONH-H

H -CH ₂ CH ₂ O- ^ y -NHCOCH ₃ dimethylacetamide / 20 ° C / 4 days

Cl

H -CH ₂ CH ₂

Oimethylacetamide / 20 ° C / 4 days

15th

H H -

16

H H, -CH,

CD ■■ -Ρ "»

Table II

ο to co

example UITlKI ⁴ is; aiiizes as / from
P. 112-114 ° 78-79 ° Base / ethanol 15 * -136 ° % σ analysis
(calculated value
Brackets
% H in
% N 4th free Base / ethyl acetate 128 ° 117-118 ° 59.55 (59.76) 5.00 (8.24) 14.59 (14.94) VJl It "/ Ethanol 156-158 ° Ho-141 ° 6o, 59 (6o, 55) 6.7o (6.71) Il, o9 (ll, 2o) 6th W. " /Water 147 ° 185-187 ° 58.45 (58.41) 7.73 (7.92) 15.37 (15.72) 7th dd "/ Methanol ¹¹ / tetrahydrofuran III 9-120 ° 198-200 ° 61.67 (61.68) 6.89 (6.99) lo, 82 (lo, 79) 8th ti / Isopropanol 165 ° 63.78 (64.02) 7.49 (7.72) 9.82 (9.74) 9 Oxalate Base / methanol Succinate / Ethanol ♦ Äjiherlo8-110 ⁰ 60.38 (60.53) 5.95 (5.99) 7.63 (7.56) 10 free "/ Ethyl acetate free 6l, 9K6l, 7o) 7.11 (6.99) lo, 91 (lo, 8o) 11 Il ¹¹ / water-based ethanol. 57.99 (58.41) 7.5o (7.92) 15.98 (15.72) 12th ft it ι tt π 60.14 (59.69) 6.63 (6.51) 13.89 (13.82) 13th It "/ Methanol 63.11 (62.86) 7.53 (7.47) 11.82 (12.22) 14th ff 52.42 (52.12) 5.11 (5.23) 9.99 (10.14) 15th 56.75 (56.75) 6.35 (6.55) 8.28 (8.27) 16 56.87 (56.9o) 5.77 (5.84) lo, 87 (11, o7)

2040Λ41

- 15 -

In all the examples that could used as Ausgangsmateriel oxide) slightly from the corresponding Ursidophenol by environmental se ~ / ren. with ^ - ^ chloro-S ^ -epoxypropane in aqueous alkali at h ° imuemperet ir, extraction in a suitable solvent, ζ- «, irtn-lanc'ilorid, and conventional work-up from the—

al.

jv, ^-en% hen skins is ntlich-GELEC 'obtain a mixture of Spox d ^ ini -Jhlorhvdrin, dos, v, ia -ie following B-jispiel illurtriati, nip such tcann be used.

1?

^ ^r 7-i roi'an-2-ol

(A · ¹ O c ' ¹ -Jhlor-2 ₁ , i-epoxypropane were asu a solution of 25 Z ü _ (* _ ph «n7 ·] ureide) -phenol in aqueous sodium hydroxide; -droxydlcBun £ (^""" C i ⁿ -oo ml) was added, and the mixture was stirred vigorously at room temperature for 20 hours, the Orange material was extracted with ethylene chloride, the extract was washed with Vipsrer and dried over sodium sulfate The excess ^ -Cnlcr - ^^ - epox ^ propane were removed on a drum evaporator, a mixture of 1,2-epoxy -. * - / ~ (5-phenylureido) -phenoxv7-prorane and 2- hydroxy -r -, / "" ^ - (3-phenvlur3ido) -phenoxv7-propyl chloride.

(B) That uh? (A) obtained mixture Oo r) was 4 hours l-an £ with 75 g 2- (2-ilethoxyphenoxy) -eth; 'lamin in 12o nl iiethancl am Reflux g3K0cht. The methanol was at reduced pressure .Distilled off, and the oily residue left behind resulted

BATH ORIGINAL 109809/2254

2U4Ü4A1

After repeated carcass precipitation with ether from Dimethylacetaiiidlöeung the semi-pure, fresh base in the form of a white solid. Wax repeated crystallization η us Jethanol the free BAEE was transferred to the Oxelat which front melting point 162 separated out from methanol in the form of white crystals ier (2.2 g) to 164 ⁰ G.

Anal .: found: U: 6o, o ^; H: 3.77 ', H: 7.8%

Ber. for C ₂₅ H ₂₉ N ₅ O ₅ -G ₂ H ₂ O ₄ : C: 60, ^ 0; H: 5.77; N: 7.7T / o

Many of the compounds according to the invention, including the compounds according to Examples 1, 2, 5, 5, 7, 8, 10, 12, 13 and 14, were found to have anti-hypertensive effects, demonstrated by lowering blood pressure in hypertensive test animals. For example, the compounds "reduce the blood pressure of the hypertensive rat in consciousness with eubeutan administration of 10 m <r per kg, or in conscious dogs with oral administration at a dose of 20 mg per kg. Particularly effective in this respect are Compounds of Examples 1, 2, 5, 7 and numerous compounds according to the invention, including the compounds prepared according to Examples 4, 6, 8, 11, 12, 15 and 17, block the 3-adrenergic receptors and are therefore suitable for corresponding Dosage for the treatment of heart disease and / or blood overdrack. For example, these compounds can block the stimulatory effect of isoprenaline on the adenyl cyclase enzyme present in rat heart muscle, and they can also suppress tachycardia produced by isoprenaline in experimental animals. In this regard, the Compounds according to Examples 4, 8 and 11.

109809/2254

ORIGINAL INSPECTED

Claims (2)

Claims in which H is an ureido group, R is a hydrogen atom, halogenated » ρ
or a lower alkyl radical, R a hydrogen atom or a lower alkyl radical, R * a hydrogen atom, a lower alkyl radical or an aryl-lower-alkyl radical, R a lower-alkyl-, hydroxy-lower-alkyl-, lower-alkoxy-lower- Alkyl, aryloxy-lower-alkyl, cycloalkyl, lower-alkanyl or aryl-lower-alkyl radical and X is oxygen or sulfur, Most of this type of bond to free hydroxyl groups, Aldehyde condensation product of such compounds in deaan R and R ^ are hydrogen, If-Oxyd © of such tar bonds, in which B / is not a hydrogen atom, and pharmaceutically to- ' casual acid addition salts thereof. 2. Compounds according to claim 1, characterized in that / 22S - ₁₈ - 2U4UU1 the Re3t R is based on the formula R ⁵ R ⁶ NC) ON (R?), in which R ⁷ , R ^b and 7th
R ', hydrogen atoms, lower alkyl radicals, Alpinste or Aryl-lower alkyl create mean. 3. Compounds according to claim 1 or 2, characterized net, that R is in the 4-position. 4. Connections according to claim 1 bie?, Dadurcn ^ e ^ ornzeicnnet, that R ^ is a 2-oxygen. 4 "5 that R is a 2- (2-substituted-phenoxy) -ethyl radical »and R» / as- 5 · connections according to claim 4, characterized in that that the ßubstituent in the 2-position of the phenoxy group ^ - Ä- or 2-chlorine. 6. Compounds geaäi Anepruch 1 to 3 _{t can} be characterized in that R is a branched ACyl group and η is hydrogen. 7 * connections g * mi3 claim 6, characterized in that j B is an isopropyl or tort.-butyl group 8. Connections according to Anepruch 1 to 3 »characterized in that that R is a 2- (4-AcetaaidO-phenoxy) -ätljylgruppe and R ^ is hydrogen. 9. 1- ^ ~ 2- (2-methoxyphenoxy) -äthylamino7-3- (4-ureidopheno3iy) -propan-2-ol. y) y7 ^ (3y-ureidophenoxy) propan-2-ol. phenoxy) prop © n-2-ol. 2Ü4ÜU1 Λ1 . Λ ~ £ ~ 2- \ .ί-i . 1- ^ ~ .-? - (^ -i.i9thox7'-phenoxy) ~ ethylamino7-3- _i / ~ ^/ i- (3-raethylureido) - Ί-iso ro; r-lanaino ^ -C ^ -ureidophenoxy) -propane - ^ - ol. 1-tert-butylamino-5- (4-jir3idophenoxy) -proan-2-ol. Displaced. for the production of compounds of the formula I. «Ii Anspri'Mi 1, daiarch marked, daiä nan" ? in ii ") o-r" d · rar Poriiel or an Hslosrenhydrin or a corresponding ether of the Forjiel XCH ₂ CHGHphal 1 λ 2040U1 - 2ο - 5 4-tn with an amine of the formula RR NH reacts to form a Compound of the formula I in which Λ ~ is hydrogen, and optionally the product obtained in this way is O-alkylated with formation 2 of a compound of the formula I in which R is a lower alkyl rest is b) a propanolamine derivative of the formula η " ¹ -" ^Or2 q I ₀ reacts with an aldehyde or ketone of the formula R'R CO and the product is reduced to form a compound in which R "^ is hydrogen and R -CHR R or a cycloalkyl group, where R 'is an alkyl radical with up to 5 carbon atoms , the .arch a hydroxyl, alkoxy, aryloxy or aryl group can be substituted, and R represent hydrogen or an alkyl radical having up to 4 carbon atoms, the M Ίο
Alkyl groups of R 'and R together do not have more than 5 carbon atoms, or add R and R form a cycloel-tylidene ring with the adjacent carbon atom, and optionally the compounds obtained in this way are O-alkylated and / or i \ i-al £ y] iert with the formation of compounds of the formula I, in which R '~ xnd / or R are different from hydrogen, c) a jia] o.ren "erbonyl d ^ r For ιοί 1Ü9ÜU9 / 225A 20 % 04Al X-CH _o -C-CH _D -hal - II ^ - Zk Il with an amine of the formula R ^ R NH and then the uarbonylgruppe reduced, and optionally the product 0-alkylated to form a compound of formula I in which 2
R is a lower alkyl radical, d) a halide of formula g ρ
in which R represents a lower alkyl radical, with an anion of the formula R ¹ converts, and optionally pharmaceutically acceptable acid addition salts of it forms 1'7 · Pharmaceutical composition containing a connector ^ according to any one of claims 1 to 15 and a pharmaceutical permissible carrier. For Pfizer Corporation Colon / ii-ana & a RechcsÄhwalfc 1C9809 / 2254