DD207544A1 - PROCESS FOR THE PREPARATION OF NEW BENZIMIDAZOLE DERIVATIVES - Google Patents

Abstract

New benzimidazole derivatives of general formula R above 1- (CH below 2) below nO-CH below 2-CHOH-CH below 2-graft 2 (I) can be prepared by reacting a compound of general formula R above 1- ( CH below 2) below nOR above 8 (VII) with a compound of general formula R above 9-R above 2 (VII), wherein one of R above 8 or R above 9 is a hydrogen atom and the other of R above 8 or R above 9 is an epoxide group of the formula -CH below 2-CH-CH below 2 (IX) or their chlorohydrin or a mixture of both and R is above 1, R above 2 and n have the meanings mentioned in the invention. The compounds of the general formula are suitable for the treatment of allergic diseases.

Description

Process for the preparation of new benzimidazole derivatives

Field of application of the invention

The invention relates to processes for the preparation of novel benzimidazole derivatives of the general formula T, in which R is one of the radicals of the general formula II or

2 ^:

III and R denote one of the radicals of the general formula IV, V and VI, wherein R and R, which may be identical or different, are a straight-chain or branched alkyl radical having 1 to 4 C atoms, an unsubstituted or an alkyl, alkoxy , Alkylthio, carbalkoxy or dialkylamino radicals in which the alkyl radicals each have 1 to 4 carbon atoms, or 'by an acyl, acylamino or a cyano radical, a halogen atom or a thio group <mono- or polysubstituted aryl radical, a Haphthylreat or an unsubstituted or in the aryl ring by an alkyl, alkoxy, alkylthio, carbalkoxy or dialkylamino radical in which the alkyl radicals each have 1 to 4 carbon atoms, or by an acyl, acylamino or a cyano radical, a halogen atom or a thio group mono- or polysubstituted aralkyl radical having 1 to 2 C atoms in the side chain, R ^ is also a hydrogen atom, R is a hydrogen atom or an acyl radical having 1 to 4 C atoms, R is a hydrogen or Ch laurel

7 '

atom, R is a hydrogen atom or an alkyl group

40 9 24 2

rest with 1 to 3 C atoms and η one of the numbers 0, 1, 2, 3 or 4 can mean. ι

These compounds cause new, high-potency pharinaka,

especially orally effective antiallergic and antihistamines and are useful in the treatment of allergic diseases such as bronchial asthma and hay fever. Partially own this

Compounds also have antihypertensive effects.

Characteristic of the known technical solutions

The orally applicable drugs introduced in the therapy of allergic diseases are characterized by insufficient efficacy, short duration of action and side effects such as sedation. ,

Although modern preparations such as di-sodium geromoglycate (DSCG) are well-acting and relatively poor in side-effects, they can not be used orally.

Object of the invention

The invention makes it possible to produce novel, highly active pharmaceuticals, in particular orally active antihistamines and antiallergics, in a technically simple manner which do not possess the described disadvantages of the previously known active ingredients.

Thus, the compounds of the general formula I have, in addition to an antihistaminic action, a strong anti-allergic effect. ^l '',

> 3In contrast to the disodium salt of cromoglycic acid (DSCG, 1,3-bis (2-carboxy-4-o2-ochromen-5-yloxy) -propan-2-ol)

0 9 24 2

the compounds of the general formula I are orally active, have a longer duration of action, inhibit the histamine price from human basophilic granulocytes, but have no tachyphylaxis and no cross tachyphylaxis with DSCG and have no sedative effect.

Some of these compounds also have antihyper-. tensive effects.

Explanation of the essence of the invention

The invention has the object of finding and producing new highly effective pharmaceuticals, in particular orally effective antihistamines and antiallergic drugs.

ι -

According to the present invention daa is achieved by reacting a compound of general formula VII with a compound of general formula VIII, wherein the radicals E to R have the abovementioned meaning

8 9, one of the radical R or R- ^{7 is} a hydrogen atom

8 9 and the other of the radicals R or R ^{J is} an eposide of the formula IX or its chlorohydrin or a mixture of, both means, and the resulting compounds of the general formula I, if desired, with physiologically acceptable inorganic or organic acids in their acid addition salts or transferred obtained acid addition salts of compounds of general formula I releases the bases,

The reactions can be carried out in solvents such as ζζΒ hydrocarbons (xylene, toluene, benzene, hexane), halohydrocarbons ,. ^? Alcohols having 1 to 9 carbon atoms, ethers and aliphatic ketones or in their mixtures at room temperature to boiling point (under atmospheric pressure)

-4- τ /, η Q? 4

ι.

take place of the solvent.

Under the same conditions, but in the presence of acid-binding agents, e.g. Soda can also be the acid addition salts of the compounds of. general formula X, ZE or XIX are converted to compounds of general formula I.

If the compounds of the general formula I in the workup as difficult to crystallize oils or greases, so by reacting these products in suitable LosungsmitteH with physiologically acceptable inorganic or organic acids such. Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, dichloroacetic acid, benzilic acid, succinic acid, salicylic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid or ascorbic acid, the corresponding crystalline acid addition salts are obtained of these salts also crystallize with defined amounts of solvent.

The compounds of the general formula I possess one or more asymmetric carbon atoms and are therefore generally obtained as acetates. These racemates; may, if desired, be separated into their stereoisomeric forms. However, it is also possible for the starting compounds, if they have one or more asymmetric C-atoins, to be used in their optically active forms in the reaction.

, 3Sl = ^> W <> • sow »» · ** -? ie "

example 1

A) '* 1- (2-Phenethoxy) -2,3-epo2: ipropane

1 Ιοί (122.2 g) of 2-phenylethyl alcohol is dissolved in 1.6 l of dry toluene and treated with 1.1 mol / (60 g) of sodium methylate (solid or in solution) with stirring and heated to reflux, distilled through a column the toluene-methanol mixture from the boiling point of toluene. It is then cooled to about 30 ⁰ C and 2 mol (185 g) of epiehlorohydrin is added dropwise with stirring. Within one hour, heat slowly until the beginning of reflux. After 9 hours, the reaction is complete. It is cooled to 30 ⁰ G and stirred with 300 ml of concentrated sodium hydroxide solution for 1 hour. The layers are separated. The toluene phase is washed three times with water and dried over sodium sulfate. In vacuo, the solvent is removed. The residue is fractionated in an oil pump vacuum. Yield: 73 g (41 % of theory)

100 ⁰ C n ^ ° = 1.5130

B) D, I 1-1- / 2-hydroxy-3- (2-phenethoxy) -propyl_7-4-piperidyl-2-benzimidazolinone iumarate

To a mixture of 900 ml of toluene and 350 ml of methanol are added 0.67 mol (182 g) of 1- (4-piperidyl) -2-benzimidazolinone hydrochloride monohydrate and 0.67 mol (119 g) of 1- (2-phenethyl ) 2,3-epo2: ipropane and 1.34 moles (142 g) of sodium carbonate. The G _e mixture is heated for 8 hours under stirring to reflux. It is filtered off with suction from the inorganic salt and treated with a solution of 0.4 mol (47 g) of pumaric acid in 500 ml of ethanol. The crystallized fumarate is

24 2

filtered off with suction and recrystallized from 1.1 l of ethanol.

Yield: 234 g ι (77V82 % of theory)

Mp:: 174-175 ⁰ CC ₂₃ H ₂₉ I ₃ O ₃ X 0.5 Fumaric acid

Example 2

D, L 1-1-7- "2-hydroxy-3- (2-phenethoxy) -propyl_7-4- (1,2,3,3-tetrahydropyridyl) J -2-benzimidazolinone

13.6 g of 1- (1,2,3,3-tetrahydropyridyl) -2-benzimidazolinone hydrochloride, 10.8 g of 1- (2-phenethylpoxy) -2,3-epoxypropane and 15.9 g of soda are added in one Mixture of 100 ml of toluene and 40 ml of methanol is heated with stirring and reflux for 8 hours. The mixture is then filtered off with suction and the filtrate is concentrated. Trituration of the residue with isopropanol and crystallization from butanol gives the title compound

 Yield: 10 ', 8 g (55% of theory)

Fp .:, 130-135 ⁰

Example 3

Analogously to Example 1B, by reacting a compound of general formula YII in which R is a group of general formula II and R is a spoxide group of general formula IX or a chlorohydrin thereof or a mixture of both, with an amine of general formula 2, the following Compounds of the general formula I are obtained (see page 8, Table 1), in which R represents a radical of the general formula IV

Λ0 9 24 2

- 7 - Example 4 .... '

Analogously to Example 1 B were by reacting a

1 compound of general formula VII, wherein R is a

Group of the general formula Ii and R is an epoxide group of the general formula IX or a chlorohydrin thereof or a mixture of both, with an amine of the general formula XU the following compounds of the general formula I obtained (see page 9, Table 2), in the R represents a radical of the general formula VX.

Table 1 (for example 3, R ¹ £ Formula II, R ² £ Formula IV)

R ⁴ R- ³ R η empirical formula Fp ⁰ C

yield

b

6 4-Cl-C ₆ H ₄ -CH ₂ -

7 2-CH 1 -G / -H λ - OHp-

8 3-CH ₃ -C ₆ H ₄ -CH ₂ -

9 4-CH ₃ -C ₆ H ₄ -CH ₂ -

2-CH ₃ OC ₆ H ₄ -CH ₂ -4 -CH ₃ OC ₆ H ₄ -CH ₂ - C ₆ H ₅ -

H - H ,H II H H CH ₃ - H H ° 6 ^H 5- H H H -. H H H H H H- H H H H H H H H H H H II ' H H II ' H H H H H II H H

PumaraäurexHgO

, 5 fumaric acid

0 C ₂₂ H ₂ ^ N ₃ O

OC ₂₃ H ₂ QN ₃ O

O ^Ö 23 ^H 29 ^N 3 ° 3

OC ₂ qH ₃ -jN ₃ O ₃ XO, 5 fumaric acid

OC ₂₃ H ₂ OFN ₃ O ₃ XO ₁ S fumaric acid

OC ₂₃ H ₂₈ CIN ₃ O ₃ XO, 5Fumaraic acid xH ₂ 0

^G 24 ^ 31 ^ 3 ⁰ 3 ^x0 »^ Fumaric acid

C ₂ JI ₃ .N ₃ O ₃ XO, 5 fumaric acid

C ₂₄ Ho ₁ N ₃ O ₃ XO fumaric acid

C ₂₄ H ₃₁ N ₃ O ₄ Xi oxalic acid

C ₂₄ H ₃₁ N ₃ O ₄ XO ^ Fumaraäure

C ₂₄ H ₃₁ N ₃ O ₃ XO, fumaric ^ χ H ₂ O

3 C ₂₅ H ₃₃ N ₃ O ₃

C ₂₇ H ₂₇ N ₃ O ₃ XO, 5 fumaric acid

119-122 197-200

163-167

226-228

159-161

172

111-113

131-132

129-132

183-185

188-189

164-165

oil

112-116

70 73 61 80 69 76

87 76 85 74 70 92 90

Table 2 (for example 4; R ¹ f Hr. R ³ R ⁴ RR? Η empirical formula Fp ° C Yield

1O ₆ H ₅ -GH ₂ -HH 'CH ₃ --OF ₂₄ H ₃₁ H ₃ O ₂ ^ ₁₃₄ ^

2 C ₆ H ₅ -CH ₂ - H Cl CH ₃ -OC ₂₄ H ₃₀ Cl ₃ O ₂ XO, 5 fumaric acid 130-133 65

  ". 10 - * »** w s3 *> ^ 4

Example 5.

D, L 1-ff - / "2-hydroxy-3- (3-phenyl-2-propen-yloxy) -pro-

9.5 g of 1 - / - 3-phenyl-2-propenyloxy-7-2,3-e-poxi per pan and 11 g of 1- (4-piperidyl) -2-benzimidazolinone are added together with 140 ml of toluene and 60 ml Methanol kept under reflux for 6 hours, lan narrows .ein, takes up the Rückatand in 50 ml of acetone and treated with a solution of 3.5 g of fumaric acid in 40 ml of ethanol. The precipitated pumarate is filtered off with suction and recrystallized from 100 ml of butanol

Yield: 18 g (67 % of theory) mp 164-168 ⁰ CC ₂₄ H ₂₉ H ₃ O ₃ χ 0.5 fumaric acid

HlerzuZSeitoformeln

 DEZ. 1982 * 053 590

· - # _ 24

R ¹ - (CH ₂ ) _n - O - CH ₂ - CHOH - CH ₂ -

CH -

II

C = C-

III

II ¹

.c

ο Il C,

Έ -

R ¹

-H

V.

VI

21.M1382 * Oi? 527

45- 9 24 2

R ¹ - (CH _O ) "- O - R ⁸

711

R? - R ²

I ₉ -GH-CH ₀

VIII

II

Il c

- "IT H - R-

HH / Y * ^Έ

/ Y

XI

R ¹

TST

XII

21st JULY1982 * 017

Claims (6)

claims: 1 7 · '" ^: wherein the radicals R to R are the above / 1 _ -1 p - / /! a 1 - i j £ _ * 4 · '* "» have the meaning mentioned, one of the radicals R or Q 8 R is a hydrogen atom and the other of the radicals R or R _ is an epoxide group of the formula IX or its chlorohydrin or a mixture of both, and the resulting compounds of the general formula I erfunschtenfalla with physiologically acceptable inorganic or organic acids in their Säureadwendungaaalze or from resulting acid addition salts of compounds of general formula I, the bases releases. , 1. Process for the preparation of novel benzimidazoles Derivatives of the general formula I in which R is one of the radicals of the general formulas II or III and R is one of the reagents of the general formulas IV, V or VI, where R and R, which are identical or different and have a straight-chain or branched alkyl radical having 1 to 4 C atoms, an unsubstituted or an alkyl, alkoxy, Alkylthio, Carbalkoxy- or Dialkylaminorest in which the alkyl radicals each have 1 to 4 carbon atoms, or by an acyl, acylamino or a cyano radical, a halogen atom or a thio group mono- or polysubstituted Aryirest, a Uaphthylrest or an unsubstituted or in the aryl ring by an alkyl, alkoxy, alkylthio, carbalkoxy or dialkylamino radical in which the alkyl radicals have in each case 1 to 4 C atoms, or by an acyl, acylamino or cyano radical, a halogen atom or a otrogroup. or polysubstituted aralkyl radical having 1 to 2 C atoms in the side chain, R 2, Process according to item 1, characterized in that the compositions in organic solvents or diluents such as aromatic hydrocarbons such as benzene, toluene, Paraffinkohlenwaaaeratoffen such as n-Hesan, Halogenkohlenwaaaerstoffen such as! Carbon tetrachloride or trichlorethylene; lower aliphatic ketones, such as acetone or methyl ethyl ketone, or alcohols having 1 to 9 carbon atoms or their mixtures, 3 · Method according to points 1 and 2, characterized in that one uses the compounds of general formulas 1, XI or XII ala acid addition salts ir ^ presence of Säuraeaceeptoren. 4 *. A process as claimed in 1 to 3, characterized in that physiologically compatible inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid are used to form the acid addition salts of compounds of general formula I 240924 2 Acetic, propionic, dichloroacetic, benzilic, succinic, salicylic, oxalic, malonic, adipic, maleic, fumaric, tartaric, citric or ascorbic acid used, 5 · Procedure according to points 1 to 4 characterized thereby. characterized in that the Ausgangsaverbindungen having one or more asymmetric carbon atoms, as optically active forms in the reaction begins ·   5 also a hydrogen atom, R 1 is a hydrogen atom or an acyl radical having 1 to 4 C atoms, R is a hydrogen atom, 7 '
or a chlorine atom, R is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms and η one of the numbers 0, 1, 2, 3 or 4 and their salts with physiologically acceptable inorganic or organic acids, characterized in that a compound of general formula VII with a compound of general formula VIII, 6 · Process according to items 1 to 4, characterized in that the racemic mixtures of compounds of general formula I are decomposed into stereoisomeric forms ·