DE2040438A1 - New 1- (2-hydroxy-3-phenoxy- or -phenylthio-propyl) -4-phenylpiperazines - Google Patents

Description

LAWYERS

DR. JUiI. Dir-L -CiIEM. WALTSR BEIL ALFRED HOIPPENER

DR, JUR. DI? L.-C; 1-.M. H.-J. WOLFF DR. JUR. HANS CHR. AX

623 FRAN KFURT AM MAIN-HÖCHST

ADElONSIRASSfciB

Our no.16549

Pfizer Corporation Colon, Panama e

New l- (2-hydroxy- * 3-phenox.v- or -phenylthio-propyl) -4-

phenylpiperazine.

The invention relates to derivatives of 1- (2-hydroxy-3-phenoxy- or -phenylthio-propyl) -4-phenylpiperazines, the phenoxy or phenylthio group of which has a polar substituent or an amino group. The compounds according to the invention are useful for regulating the blood circulation, in particular for treating hypertension. They have the general λ- order

OR ^

109610/2264

204Q438

in which

R is an amino, amido, amoyl, lower alkoxycarbonyl or nitro residue,

R is a halogen atom or a lower alkyl group,

R is a hydrogen atom or a lower alkyl group,

R represents a halogen atom, a lower alkyl group or a lower alkoxy group,

η the number 0, 1 or 2, and

X is an oxygen or sulfur atom.

The invention also relates to the esters of the compounds

2 y

fertilize where R * is a hydrogen atom, the N-oxides and the pharmaceutically acceptable acid addition salts of these compounds.

In the formula given above, "amino" means the unsubstituted -NHp group, "amido" can be for an acylamido, ureido or sulfamido group, "Amo.yl ¹¹ for a carbamoyl or a sulfamoyl group, and" halogen "stand for fluorine, chlorine, bromine or iodine.

The acyl residue of an acylamino group can be from either a mono- or dicarboxylic acid or a sulfonic acid and the acylamino group can be one of the following formulas

R ⁴ CON (R ⁵ ) -, R ⁴ SO ₉ N (R ⁵ ) - or R ⁹ H-

^ά V ./

CO

have, in which R is a hydrogen atom or a lower one Alkyl group, lower alkenyl group, aryl group

10 981 n / 226

_ 3 - '

or aralkyl group, R is a hydrogen atom or a lower one Alkyl group and R is the best of an aliphatic or aromatic carboxylic acid which forms an imide "is capable.

Ureido and suIfamido groups can use the pormulas

R ⁶ R ⁷ N-COW (R ⁸ ) - and R ⁶ R ⁷ U-SOoN (B. ⁸ ) - near, and carbamoyl-

6 7 and sulfamoyl groups can have the formulas R R N-CO- and

RV-ii-SOg- hahen, in -which R, R and R are each hydrogen atoms, lower alkyl groups, aryl groups or lower Represent arylalkyl groups.

The term "lower" denotes alkyl, alkenyl or alkoxy groups containing 1 to 6 carbon atoms,

Examples of amido groups represented by R. are formamido, acetamido »propionamido, ϋϊ-otonamido, Benaamidö, Phenylaeetamido, Methanesulfon ataido, Paratoluenesulfonamido, as well as the N-methyl and N-ethyl berivate derselhen; Succinimido and phthalamidoi

gNCOiiH) »1- and 3-methylureido, 1,3-dimethyl I ₄ 3» 3 ^w -trimethylureido, 3-phenylureido; BuIf aaddo (H ₂ MO ₂ NH-), and 3,3-DLmethylsulfamido * Examples of amoyl groups that can be represented by R, I.

are: GärfcäJaoyl (H ₂ N-CO-), N-methyl- and N.Jr-dimethyl carbamoyl, 'N-phenylcarhamoyl, sulfamoyl (H ₂ N-SO ₂ -) and NrN-Btmethylsul ^ amoyl. R is preferably an unsubstituted tJareido group, a nitro group or a

(especially a JOrmamido or Acetin 4 position.

1098 10/2264

12 3

When either R, R or R is a lower alkyl radical

is, it is expediently a methyl group, and if R is a lower alkoxy group, it is convenient a methoxy group. When η = 2, then R can represent two similar or dissimilar substituents, e.g. two methoxy groups or one methyl group and one methoxy group. Preferably (R) is a single methoxy group or a chlorine atom in the 2-position.

The compounds according to the invention in which R is a

represents a group other than an amino group, and

nen R is a hydrogen atom, are preferably prepared, by a Bpoxide of the formula

R ¹

with an N-phenylpiperazine of the formula

N NH

is reacted with or without a solvent at 20 to 100 ° C for a period of 2 to 24 hours. Ethanol is a suitable solvent and the reaction is preferred carried out under reflux conditions.

109810/226 4

_ 5 -

In other ways, such compounds can be prepared by treating the N-phenylpiperazine with a halohydrin or ether of the same of the formula

- XGH ₂ GHCH ₂ HaIogen

R ¹ OR ²

is implemented, the reactants in a geeig ä

Neten solvents such as ethanol, which contains an alkali carbonate such as sodium carbonate, can be dissolved and for Reflux until the reaction is complete.

In yet another different manner, such compounds can be prepared using a phenoxy or Phenylthio-propanolamine or ether of the same of Foirael

- XCH ₂ CHGH ₂ NH ₂ ι

^R OR ²

with an N, N-bis (2-haloethyl) aniline of the formula ι

109810 / 72B

CH ₂ CH ₂ halogens

( _R 3 \ "'''' CH ₂ CH ₂ halves

is reacted, which is also heated in an alkali-containing solvent.

Another alternative to making those according to the invention Compounds consists in) that one is a halogen carbonyl of the formula

R r

Λ ^(X - X-CH ₂ C-CH ₂ -halogen

1 "

^R O

with an N-phenylpiperazine of the formula

HN N
\ / \ ^X (R ^? ) _N

converts, whereupon the carbonyl is reduced.

There is another alternative to the

10981Π / 72Β4

Preparation of the compounds of the invention therein Halide of the formula

Halo-CH ₂ CHOH ₂ Ii 1

OR ²
with an anion of the formula

R.

R ¹

to implement.

Compounds in which R. is an amino group can from those in which R is an acylamino group acid hydrolysis, such as by heating to reflux in aqueous hydrochloric acid. Links, in which R is an amino group, they are also valuable intermediates in the preparation of other compounds by acylation in which R is an acylamino group. This is especially true for manufacturing those compounds in which R is an iOnnamido group is, with 90 ^ -iger formic acid in a suitable Solvent is heated, those compounds in which R is an imido group, with an anhydride of a dicarboxylic acid is heated, or such compounds

10981 Π / 2264

where R is a sulfonamido group, with an ali phatic or aromatic sulfonyl chloride is heated.

ο Compounds of the present invention in which R

is an alkyl radical, and esters of compounds in which

R is a hydrogen atom, can by conventional Al-

kylation or esterification reactions produced, and

2
if R is an alkyl radical, this can be a water -

Fabric remnants are reduced.

pharmaceutically acceptable acid addition salts of Compounds according to the invention can be prepared from acids which have pharmaceutically acceptable anions Forming non-toxic addition salts containing, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulf ate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate or paratoluene sulfonate. The N-oxides according to the invention Compounds can be made by treating with a suitable oxidizing agent.

The compounds of the invention can be administered alone , but they are generally administered in admixture with a pharmaceutical carrier which is selected taking into account the intended route of administration and common practice. So can they are administered e.g. orally in the form of tablets which contain such excipients as starch or lactose, or in capsules, alone or in admixture with diluents, or in the form of elixirs or suspensions, which Contain flavorings or colorings. You can injected parenterally, e.g. intramuscularly or subcutaneously. For parenteral administration, they are available on best used in the form of a sterile, aqueous solution,

1098in / ?? 64

which other dissolved substances, such as so much salt or May contain glucose, since the solution is isotonic.

The invention is illustrated in more detail by means of the following examples.

Example 1:

1- (4-Acetamidophenoxy) -3- / "4- (2-methoxyphenyl) piperazin-lyl 7-P * opan-2-ol.

A solution of 76 g l- (4-acetamidophenoxy) -2,3-epoxypropane and 70 g of l- (2-I ^v lethoxyphenyl) piperazine in a mixture of 50 ml dioxane and 50 ml of ethanol for 16 hours was. Heated to reflux. The mixture was evaporated to dryness leaving the product as the free base which was converted to the fumarate salt by being dissolved in 2-propanol and treating with 20 g of fumaric acid in the same solvent. The resulting white precipitate was uxakriitalized from ethanol, 107 g of pure hemi-fumarate with a melting point of -200 ° C. being obtained.

Analysis; Found :

Calculated for

0 62.92; H 6.78; N 9.40 ^; C 63.00; H 6.83? N 9.19 #

sj), tele 2 bla 17;

J) Lf) listed in the following table fjn compounds were prepared according to the procedure of Example 1, where-

1 0 9 B 1 Π /? 2 6 / ·

where the corresponding l- (substituted) phenoxy-2, 3- epoxypropane and! - (substituted or unsubstituted) phenylpiperazines were used as starting materials.

1098 1 0 /

> -OCH ₂ OHCH ₂ N OH

Example R

II 4-CH

III 4-NH ₂ CONH-

IV 4-CH ₃ CONH-

V 3-CH ₅ CONH-

VII 4-CH ₅ CONH-

VIII 4-CH ₅ CH ₂ CONH-

IX 4-CH ₅ CONH-

X 4-NO ₀

'η

Isolated

as

Oxalate

2-ΟΗ, Ο-free base

M.p.

2-OH ₅ -

Oxalate

2-CH, 0-hemi-oxalate

⁰ 1 / 2H ₂ O

3-CH, 0-oxalate

4-CH-O-free base

189 ^υ 104-5 ⁽

87-9 163 °

2-CH, 0-hemi-fumarate 184

2-Cl

HCl

2-CH ₅ O-HCl

245 °.

190-4

contains 1.1 mol of HCl according to analysis; Analysis ("calculated)

<fo C

fo H

? ο Έ

60, Ö6 (60.12)

'62, 92 (62.98)

60.94 (60.87)

59.44 (59.7)

58.89 (58.88)

66.36 (66.14)

63.33 (63.34)

57.0 (56.8)

56.99 (56.67)

6.32 (6.36) 9.00 (9.15)

6.96 (7.05) 14.32 (15.99)

6.65 (6.60) 8.38 (8.83)

.6.84 (6.97) 9.41 (9.1)

6.23 (6.38) 8.81 (8.58)

6.97 (7.32) 10.45 (10.52) 6.94 (7.05) 8.83. (8.91). 6.02 (6.14) 9.30 (9.40) 6.35 (6.14) 9.63 (9.91)

Ca »OD

example

XI
XII

XIII

XIY

XY

XYI

XYII

4-CH, CONH-

4-CH ₃ CONH-4-CH ₃ O-CO-4-NH _n CONH-

4-HH ₂ CO

4-CH ₃ COHH isolated
as

Sohmp.

Analysis (calculated) 96 H # N

4-CH ₃ CONH 2 CH ₃ O-5-CH ₃ - 2 HCl 202-5 ° 56.44 (56.8) 6.88 (6.84) 8.38 (8.65)

2,6-di-CH, 0-hemi-

⁵ fumarate

5-CH ₃ -2-CH ₃ O-

2-C1-

• 2-CH, 0-2-C ₂ H ₅ O-200
Free base I45

° * 61.24 (61.53) 6.82 (7.02) 8.33 (8.36)

⁰ 68.63 (68.90) 7.39 (7.63) 10.77 (10.97)

Free base 108-9 ° 66.25 (65.98) 7.13 (7.05) 7.35 (7.00)

HCl 1/2 H ₂ O 228-9 ° 53.01 (52.90) 5.91 (5.79) 12.32 (12.33)

Free base 176-8 ⁰ 58.98 (59.14) 7.37 (7.39) 5.63 (5.75)

HCl 200 ¹

61.54 (61.3) 7.41 (7.16) 9.34 (9.34) '

According to analysis, contains 1/4 mole of solvent (isopropanol).

The epoxy starting materials used in Examples 1 to 17 are easily obtained from the appropriately substituted phenols by conventional methods, such as them for the reaction of phenols with 2,3-epoxypropyl chloride are common.

Example 18:

1- (4-Aminophenoxy) -3- / "4- (2-methoxyphenyl) piperazin-l-yl J-

propan-2-ol »

30 g of 1- (4-AGetamidophenoxy) -3- ^ 4- (2-methoxyphenyl) - |

piperaziin-1-yl J7-propan-2-ol hemifumarate _f prepared according to Example 1, in 300 ml of 5 aqueous hydrochloric acid η "were heated within 1 h. at reflux temperature and maintained for 1 hr. at this temperature. The mixture was cooled, adjusted to pH 10 with sodium hydroxide and extracted with dichlorine than. The extract was concentrated to dryness, the residue was recrystallized from aqueous ethanol and then from ethanol, the desired product being obtained in 36% yield; Mp. 124 C.

Analysis; Found C, 67.05; H 7.13; N $ 11.52;

Calculated for C ₂₀ H ₂₇ N ₅ O ₅ : C, 67.20; H 7.61; N 11.75 #

Example 19 :

1- (4-Formamidophenoxy) -3- / "4- (2-methoxyphenyl) piperazin-lyl J- propan-2-ol.

7.15 g of the product from Example 18, 7 ml 90 # -

1098in / 2264

aqueous formic acid and 30 ml of dioxane were 1 hour on Heated to reflux, cooled and poured into ether. The resulting The precipitate was recrystallized twice from isopropanol, where the desired product as Foimat from Sehmp. 133-135 ° C in an amount of 4.72 g.

The compounds according to the invention have anti-hypertensive properties Efficacy as evidenced by their ability to lower the blood pressure of hypertensive animals. So are they able, for example, to lower the blood pressure of non-anesthetized, hypertensive rats when they are subcutaneously in at a dose of 10 mg / kg, or that of non-anesthetized, hypertensive dogs when given orally in administered at a dose of 20 mg / kg. The compounds of Examples are particularly effective in this regard 1, 2, 9, 10, 15 and 19.

109810/2264

Claims (6)

Pat ent claims before ϊ (JL / Process for the preparation of ron l- (2-Hydroxy-3-phenoxy- or -phenylthiopropyl) -4-phenylpiperazines of the formula - XCH ^ GHCH ₂ Ii N - < in which R is an amido, ijnoyl, lower alkoxy carbonyl or Hitrograppe, R is a halogen atom or a lower alkyl group, 2
R is a hydrogen atom or a lower alkyl group, 3
R is a halogen atom, a lower alkyl or lower Alkoxy group, f η is the number. O, 1 or 2 and
X is an oxygen or sulfur atom, as well as the N-Qxide and the pharmaceutically acceptable Acid addition salts of these compounds, characterized in that one (a) an epoxide of the formula: 10-9818 / 2264 16 - O -XCH ₂ CHCH ₂ R ¹ or the corresponding halohydrin or an ester of this compound of the Foimel R ¹ -XCH ₂ CHCH ₂ HaI og en with an N-phenylpiperazine of the formula - N NH implements, or (b) a phenoxy- or phenylthiopropanolajnine of the formula 109810/2264 R- with an H, JN-Ms (2-haloethyl) aniline of the formula \ CH ₂ CH ₂ halogen irritates, or
(c) a halocarbonyl of the formula -X-CH ₂ C-CH ₂ -IIaI ti R ¹ 0 with a Üi-phenylpiperazine of the formula 1098T0 / 2264 (R ³ ) converts and then reduces the carbonyl, or (d) a halide of the formula hai-CH ₂ CHCH ₂ OR ' with an anion of the formula —Χ " converts and optionally converts the compound obtained into a pharmaceutically acceptable acid addition salt, by treating them with a suitable acid, or converting them to an N-oxide by treating them with a suitable one Treated oxidizing agent. 109810/2264 2. The method according to claim 1, characterized in that if R is an aeyl group, this re with Sau hydrolyzed to the corresponding amine group. 3. The method according to claim 1 or 2, characterized 2
draws that if R is a hydrogen atom, this is alkylated to an alkyl group or esterified to an ester group, and / or if R is an alkyl group, this is reduced to a hydrogen atom. 4. The method according to claim 1, characterized marked f net that one of an epoxide or phenoxy or phenylthiopropanolamine, in which R is an unsubstituted ureido group in the 4-position, or a nitro group in the 4-position, or an acylamino group in the 4-position, or is a formamide or acetamide group. 5. The method according to any one of claims 1 to 4 »characterized in that one of an epoxide or phenylthiopropanolamine starts out in which R is a hydrogen atom. 6. The method according to any one of claims 1 to 5 »thereby characterized in that one of a N-phenylpiperazine ^ or N, N-bis (2-chloroethyl) aniline goes out, in which " (R) _{n is} a single methoxy group or a chlorine atom in the 2-position. For: Pfizer Corporation Lawyer 109810/2264