DE2244761A1 - INDAN AND TETRALINE DERIVATIVES - Google Patents

Description

Berlin, September 8, 1972

Indane and tetralin derivatives

The invention relates to new indane and tetralin derivatives and a method for their production.

From the U.S. U.S. Patent No. 542,4-65 is known to have tetralin-substituted Imidazolcarboxylic acid derivatives have antifungal effects.

It has now been found that (benzyloxy-imidazolyl) - indan and -tetralin derivatives are more valuable than the above-mentioned compounds Pharmaceuticals are because they are equally or more effective against Derrr.atophytes, such as Tricnophyton rubrur. and Tricnophyton mentagrophytes, a good effect against Yeasts // ie Candida albicans.

Are the subject of the invention. Connections of the general Forrr.el I

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BATHROOM ORIGlNAt

wherein

- 2 - SCHERINGAG

Patent department

R, and Rp are identical or different and are hydrogen or mean halogen atoms,

R. ,, Rj., Rj-, R ^ and R are the same or different and Hydrogen atoms, halogen atoms, nitro groups, alkyl groups with 1-4 C atoms, alkoxy groups with 1-4 carbon atoms or phenyl groups or 2 adjacent substituents together with the aromatic ring form a naphthalene ring and

η is 1 or 2,

as well as their salts with pharmacologically acceptable acids, as trans and cis isomers and as mixtures of the two Isomers.

Examples of pharmacologically acceptable acids are in question: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, Tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid, and heptagluconic acid.

The production of the new compounds takes place by that one connections the more general! Formula II

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BATH ORIGINAL.

SCHERiNGAG

Patent department

22U761

II,

worxn

R ,, R and η have the meaning given above, with an alkali base and with a compound of the general

Formula III.

R-

5 V-

X-C

III,

R,

wherein

R_, Rj ₁ J R_, R ^ - and R _{7 have} the meaning given above and

X is halogen or a reactive ester group,

converts and then optionally the compounds obtained with pharmacologically acceptable acids into their salts

convicted.

A09811 / 1U0

BAD ORKaINAL

SCHERINGAG

Patent department

- * - 22U761

The reaction of a compound of the general formula II with an alkali base, v, <ie an alkali hydride, alkali metal arnide or an alkali alcoholate and with an optionally substituted benzyl halide of the general formula III, preferably the optionally substituted benzyl chloride * or an optionally substituted reactive ester of the general formula HX , such as tosylate, happens in a suitable organic solvent such as dimethylformamide, hexamethyl ^ phosphoric acid triamide, an aromatic hydrocarbon such as benzene or toluene, an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or a lower alcohol at temperatures .from 0 to 100 C, preferably at temperatures from JO to 60 ° C.

To increase the yield, the alkali base and the benzyl compound can be used in excess.

The production of the previously unknown raw materials of the general formula II can be carried out in two ways:

a) An am Benzolkcrii according to the general formula II substituted, 1-indanone or 1-tetr al on is initially used in a suitable solvent such as ether, chloroform or carbon tetrachloride with bromine in the bronze ketone transferred and this then with imidazole in a geeifr.eten

4 0 9 8 1 1/1 U 0

SCHERINGAG

Patent department

Solvents such as dimethylformamide, hexamethylphosphoric triamide or a lower alcohol. The α-imidazolyl ketone formed can be isolated or without isolation immediately in the reaction solution with a suitable reducing agents such as sodium borohydride for Alcohol of the general formula II can be reduced. The alcohol is purified by crystallization.

b) The a-Bromketcn described under a) is in a suitable Solvent such as lower alcohols with a suitable reducing agent such as sodium borohydride ;; to bromohydrin reduced and this then in a suitable solvent, such as dimethylformamide, hexamethylphosphoric acid triamide or a lower alcohol, reacted with imidazole to form the alcohol of the general formula II. The cleaning is carried out as described under a).

1) 69 g of 1-tetralone are mixed with 24.2 ml of bromine in 450 ml of ether while cooling. The ether phase is then washed several times with water and finally with saturated sodium bicarbonate solution, the organic phase is dried and the ether is evaporated in vacuo. A solution of 150 g of inidazole in 160 ml of dimethylformamide is added to the residue and the mixture is stirred are then added, the mixture I5 hours at 5O ⁰ C. under ice-cooling, 20 g of finely powdered sodium borohydride in portions over about 8 minutes and stirred J50 it still j; hours at room temperature, the mixture is then poured in bOO RR.L KiSV. / asnor, acidified with 5N H ₀ SO, at (pH 2-3) and extracted

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original

SCHERINGAG

/ - Patent Department

3 χ with ether. The aqueous phase then becomes 40 percent higher Brought potassium hydroxide solution to pH 12 and extracted 3 times with methylene chloride. The combined methylene chloride phases are dried and evaporated in vacuo. After recrystallizing the 40 g of pure crystalline crude product from benzene are obtained. trans-2- (l-imidazolyl) -l-tetralol with a melting point of 148 - 149 ° C. The cis isomer was not isolated in pure form.

2) 15.5 g of 7-chloro-l-tetralone are treated and worked up in 200 ml of ether and 50 ml of carbon tetrachloride with 4.4 rci of bromine as under l). "J) O g of imidazole in 120 ml of dinethylformamide are added to the 3rom compound, the mixture is stirred for 2 hours at room temperature and 2 hours at 50 ° C. and then 4 g of sodium borohydride are added and the mixture is stirred for 15 hours at room temperature. The work-up is carried out as under 1), only part of the product can be filtered off after adding potassium hydroxide to the aqueous phase.Recrystallization from acetonitrile gives 15 g of tran3-7-chloro-2- (l-imidazolyl) -l-tetralol with a melting point of 215 - 219 C. The cis isomer was not isolated in pure form.

3 · 50 g of 1-iidanone are reacted with 19 * 4 nil bromine as in 1) and worked up. The reaction of the bromine compound with IpO g of imidazole in 39Ο ml of ethanol at 50-55 ° C (2 hours) and then with 8 g of sodium borohydride at naurutane temperature (I-3 Hunac gives after work-up v / ie at l) 32.6 g of pure 2 - (l-Ii; .i-. ¹ : i .-. olyl) -1-tetralol, which is a mixture of dos eis- and trar.s-Ir.onjcren i «" ■ ·> - · -

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ÖAD ORKaINAL

SCHERINGAG

- "J - Patent department

The ratio is 1: 1, which can be separated into the components by chromatography on silica gel + 3 J>a'asser:

cis-2- (l-imidazolyl) -l-tetralol melting point 120 ° C trans-2- (l-imiaazolyl) -l-tetralol melting point 168-171. C.

The starting compound for further reactions was the Mixture used. '

7 * 3 g of 6-chloro-1-indanone are treated and worked up in 100 ml of ether and 25 ml of carbon tetrachloride with 2.2 ml of bromine as under l). The subsequent reaction with 13 g of imidazole in K5 Dimethylfojsraniid ml and then with sodium borohydride analogously to 1,5 S l) are 6.6 g of crude product, which fo by chromatography on silica eluting with chloroform /.3 water + ¹ P isopropanol 20-60 can be separated into the isomers:

cis-6-chloro-2- (l-imidazolyl) -l-indanol

Melting point 156-159 ° C

■ trans-ö-chloro ^ -Cl-imidazolylj-l-indanol

Melting point 193 - 19 '+ ° C.

This was used as a starting point for further reactions Mixture of isomers used.

! 5) 30 C ^, b-piciilor-l-indar.on (melting point II5 - 116 ° ^, i shown i: rc :. Peiuincilun.T of 2,4-DiChIOrPhCnYlPrOPiOnSUUi ¹ C-

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BAD ORfGiNAL

SCHERNGAG

Patent department

Chloride with aluminum chloride in methylene chloride) are treated and worked up with 7 * 7 ml of bromine in 5 °° ml of ether and 100 ml of carbon tetrachloride as in l). The bromine compound is first reacted with 43 g of imidazole in 170 ml of dimethylformamide, then with 12 g of sodium borohydride as in 1) and worked up in the same way. This gives 4.6 g of crude product which, after recrystallization from ethanol / water (3: 1), gives 3.1 g of pure 4,6-dichloro-2- (l-imidazoly) -l-indanol with a melting point of 191-201 . The cis-trans isomers are not separated.

The new compounds of general formula I are good effective against dermabophytes such as Trichophyton rubrum and Trichophyton mer.tag-'ophytes and against Candida albicans, as can be seen from Table I. Etonam and the commercially available Asteror ^ are given as comparison substances. The ί-IC values were determined in the tube test.

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BATH ORIGINAL

TABSLDi I

Substance *

^ = R "= Cl, η = 2

MIC (/ ß / ml) against
Candida albicans Trich. mentagroph. Drive, rubrun

50

Etonam
Asterol

inactive **

inactive

* All substituents not listed are hydrogen atoms

** at 100 / ßCg / ml. /

1.6

50

0.8

50-

¹¹ I. = 7-Cl, R ₅ 1 ! H ,, η = 2 ( .HCl) .HCl) 3, 1 3, 1 6th , 3 ^R l -. ι -v> l, xl- R ₇ = Cl, η = 2 ( 1, 6th 0. 8th 0 , δ ^R 5 = Cl, η = 25th 3, 1 β

SCHERNGAG

- 10 - Patent Department

As can be seen from Table I, the comparison substances no effect against Candida albicans. In contrast to the comparison substances, one of which The compounds according to the invention have no known effect v / continued to have a systemic effect. It can be used in the usual pharmaceutical administration forms take place. Tablets, coated tablets, capsules, pills and suspensions are particularly suitable for oral administration in question. For example, tablets contain 0.05 up to 0.50 g of active ingredient and 0.1 to 5 g of a pharniacological indifferent excipient. As auxiliary materials, for example used for tablets: lactose, starch, talc, gelatin, magnesium stearate, etc.

The new active ingredients should be in quantities between 0.1 and 4.0 g per patient and per day can be used.

The following examples are intended to demonstrate the method according to the invention explain in more detail.

example 1

1 g of 2- (l-imidazolyl) -l-tetralol are dissolved in 5 n: l Diraethylforr.ian.id dissolved and under a nitrogen atmosphere with 0.6 g of a Sodium hydride oil suspension (50, 1 sodium hydride) was added. Man stirs for 45 minutes at room temperature and then puts under egg.% cooling 1.16 g Benzy! Chloric! ^ u and stirs J> 0 minutes at iiuur.:-

utc.r. at ^: j0 ° C. Gut becomes' Jas mixture. 4098 1 1/1140 - 11 -

temperature and 00 Γ-Knutcn at ^: 0 ° C. Gut becomes' Jas mixture.

BATH ORIGINAL

SCHERING AG

Patent department

- 22447 # 1

given in 50 ml of 1 NH ₀ SOj ₁ and extracted with ether. The aqueous phase is made strongly alkaline with 40 percent potassium hydroxide solution and extracted with methylene chloride. The methylene chloride phase is evaporated after drying with sodium sulfate and the residue is recrystallized from cyclohexane. This gives 500 mg of l-eonzyloxy-2- (l-ircidazoiyl) ~ tetralin with a melting point of 89 - 90 ° C.

In an analogous reaction -rferden from the corresponding output- ■ isn the following substars:

Enamel ex. Substance P ^ '^ p _C J yield /% /

2) l- (benzyloxy) -> 2- (l-irrada- '

zolyl) «tetrslin 89 - 90 ■ 55

J5) 2 "(1-imidazolyi) -1-

(^ -tnethylbenzyloxy) tetralin 89 -'90 40

) (, 3Aw

oxy) -2- (l-imidazolyl) -

tetralin 103-106 27

5) 2- (l-iinidazo: iyl) ₇ l- (4 ~
methoxybenzyloxy) tetralin '115 ~ HS 58

6) 2- (l-inidazoly1) -1 - (>

nitr-obonzyloxy) -tetralin ID2 - II3 I5

7) 1- (ü -; · ¹ luorobensyloxy) -2- (imlda. ". Olyl) -tdral5n 89 -90 7

0) i - (? ~ F;? Acryy)

(3-5.w.l'ip. :: olyl) -t'Jtralin 94 - 96

Λ09811 / 1140 BATH ORIGINAL

Example 9) 10)

- 12 -

substance

SCHERING AG

Patent department

point / ⁰ C / yield

l-O-chloro'-benzyloxy) ^ - (l-imidazolyl) tetralin

l- (4-chloro-benzyloxy) -2- (l-imidazolyl) -tetralin - 75

- 121

1- (2,5-DichloiH ^ nzyloxy) - 126 2- (l-imidazolyl) -tetralin

1- (2,6-dichlorobenzyloxy) - 89 2- (l-imidazolyl) tetralin

l- (3,4-dichloro-benzyloxy) - _QQ 2- (l-imidazolyi) -tetralin ^J ^ "

1- (3> 5-dichloro-benzyloxy) - -. ^ o-, r-2- (l-imida? olyi) -tetralin ~

1- (4-Breadn-benzyloxy) -2- (limidazolyl) -tetralin 110 -

7-chloro-2- (imidazolyl) -1- (4-niethoxy-benzyloxy) -118 tetralin

7-chloro-1- (2-chloro-benzyloxy) -2- (imidazolyl) -tetralin 147 -

79

73 79

Tl 63

61

80

Example

18th

1 g of 2- (l-imidazolyl) -l-tetralol, 0.6 g of Natriu.T.hydridölsuspension and 1.5 g of diiricthylbenzylochloride are reacted and worked up as in Example 1. The crude product is dissolved in ethanol and approximately 1 N HCl in methanol is added until a strongly acidic reaction occurs. The solvent is removed in vacuo; ⁱ ; e: -o; -cn and di? r residue in? · ': ·. · -thy] encIUorU) and v: \ t

4 0 981 1/1 UO - ^Tl -

BAD ORfGfNAL

~ 1 "5 -

"* Pffientabuiiung

e! ,, ... _r ^, „.,. ■. _r . f. , «, fytfn ^ 5Λ / 7 jay} '-

Ether added until the onset of turbidity. 1.3 g of 1- (3 _i 4-Dlmethylbenzyloxy) -2- (l-imidazolyl) -tetraliri-hydrochloride with a melting point of 188-200 ° C. crystallize from this solution.

In an analogous reaction, the corresponding starting materials become the following substances are produced in the form of their salts. Acids other than hydrochloric acid ground for salt formation is used, approx. 1 normal solutions of these acids in methanol are added up to approx. pH 6.

Example Substance Schraelzp. / ° C_7 yield l ';'

19) l -. (3, ^ y
oxy) -2- (li; r.idazolyl) - I88 - 200 76 tetralin-r ^ drochloriü

20) 2- (l-Ir.iida: io? Lyl) -l- (2- 169-175 55 phenylbenzyloxy) tetralin hydrogen sulfate

21) 2- (ly) (

pheriylbenzyloxy) tetra- '194-20Λ 5k

lin-II hydrochloride

22) 2- (l

naphthylrne;: icxy) -tetralin-16.8-174 Hydrochloride

::: d.-xzQlyi) ~ I90 - 192 tetraline H; ^- 23) 1 (2,4-di- 0 h 1 1 or -her.zy Qxy) -2- (l ~;. 'D rogerisulfat -

? Λ) l- (2,6-Dictilor -bör.zyl- ·

oxy) -2- (l -:;: - i: ia :: olyl) - 3.69 - 170

? «; J Y-Ci ilor -2- (1 - ί nildar.oly 1)

i - (^ - i: -. otiiy.'h.T: '. yJo: -: y) - 160 .-- I65 51

tutv ': illn ~ ilvcli'v> chiorj.cl

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SCHERING AG

- 14 - PstMrtabteiking

Melting example substance point / ° q / yield 37

26) 7-Chloro -l- (2-chloro Hoenzyloxy) -2- (l-imidazolyl) tetra- 190-195 80 lin hydrochloride

27) 7-Chloro -l- (2,4-dichlorobenzyloxy) -2- (1-imidazoly1) tetralin hydrochloride I90 - 206 86

28) 7-chloro-l- (2,6-dichloro-benzyloxy) -2- (l-imidasolyl) -tetra 215 - 23O 89 lin hydrochloride

29) 2- (l-imidazolyl) -l- (4-methyl-

benzyloxy) -indan- 1? 6 - ΙδΟ 40

Hydrochloride

raethoxybenzyloxy) -indan- 150-153 50

Hydroch lorid

l- (2-chloro-dencyloxy) -2- (l-

imidazolyl) indan-hydro-145-153 ^ chloride

32) 1- (4-chloro-benzyloxy) -2-

(1-imidazolyl) -indan-l82-190 55 Hydrochloride

33) l- (2,4-dichloro-benzyloxy) -2- (l-irr.idazolyl) -indan- 169-175 30 hydrochloride

34) 1- (2,6-dichloro-benzyloxy) -2- (l-imidazolyl) -indan-17I - 178 10 hydrochloride

35) l- (4-dron-benzyloxy) -

2- (l-irr.idazolyl) -indan- l82 - I86 33

Hydrochloride

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BATH ORIGINAL

Ex.

SCHERiNG AG

Patent department

- 15 -

Subs dance

Melting point / ° C / yield β'J

6-chloro-2- (1-imidazolyl) -1- (4-methylbenzyloxy) -23O - 2-32 indane hydrochloride

6-chloro-2- (1-imidazolyl) -1- (4-methoxybenzylxy) -83 - 85 indan-hydroperchlorate

6-chloro-1- (2-chloro-benzyloxy) ^^ 1-imidazolyl) -156 indane hydrochloride

6-chloro -l- (2,4-dichloro or - benzyloxy) -2- (1-imidazolyl) -110 indan hydrochloride

- 120

6-chloro-1- (2,6-dichloro-186-190 benzyloxy) -2- (1-iniidazolyl) indane hydrochloride

- ¹ I-, 6-dichloro -1- (2,6-dichloro -
benzyloxy) -2- (1-imidazolyl) indane hydrochloride I86-202

17th

17th

17th

25th

Example 4-2

^{0.23 g of a sodium hydride oil suspension (50 c} fo sodium hydride) is added to g 2- (l-irnidazolyl) -l-tetralol in 5 ml of dimethylformamide. The mixture is stirred for 1 hour at room temperature and then 1.6 g of p-toluenesulfonic acid (p-bromobenzyl) ester are added while cooling with ice. The mixture is then stirred for a further hour at 50 ° C. The mixture is worked up as in Example 1. This gives 300 mg of 1- (4-brinbouzyloxy) -2- (1-imidazolyl) tetralin at the melting point

110-111 ° C.

- IC -

40981 1/1 UO

BATHROOM OBlGlNAL

SCHERINGAG

a - Patent Department

Example 4 "?

Ointment for external use of the following composition:

1.00 % 7-chloro-1- (2,6-dichloro-benzyloxy) -2-imidazolyltetralin hydrochloride

5.00 f> Beeswax, white, DAB 6 5.00 % wool fat, anhydrous, DAB6

20.00 fo Vaseline, white, DAB 6

25.00 fo Amphocerin K "Qehydag"

13.98 Ü paraffin, liquid, DAB 6

30.00 fo. Water, desalinated,

0.02 % Chypre No. 6466, Haarmann and Reimer

- 16 -

4098 1 1/1 1

Claims (1)

SCHERINGAG Patent department -Vf- If Claims LLJ compounds of the general formula I N- / - \ ^l 7 ^R 6 v; orin Around p are the same or different and are hydrogen or mean halogen atoms, , R _1. , R _r , Rg and R "are identical or different and. Hydrogen atoms, halogen atoms, nitro groups, alkyl groups with 1 - K C atoms, alkoxy groups with 1 - 4 C atoms or phenyl groups, or 2 adjacent substituents with the aromatic ring are a haphthane ring. form and 4 0981 1/1 UO - IY - BATH 22U761 SCHERINGAG Patent department η is 1 or 2, as well as their salts with pharmacologically acceptable acids, as trans and cis isomers and as mixtures of the two isomers. 2) l-Benzyloxy-2- (l-imidazolyl) tetralin. 3) 2- (1-Irnidazolyl) -i- (4-methylbenzyloxy) -tetralin. 4) 1- (2,5-dimethylbenzyloxy) -2- (1-imidazolyl) -tetralin. 5) 1- (3,4-Diir, ethylbenzyloxy) -2- (1-imidazolyl) tetralin. 6) 2- (1-imidazolyl) -1- (4-methoxybenzyloxy) tetralin. 7) 2- (1-imidazolyl) -1- (3-nitrobenzyloxy) tetralin. 8) 1- (4-Fluoro-benzyloxy) -2- (imidazolyl) -t e trali -. 9) 1- (2-chloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 10) 1- (3-chloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 11) 1- (4-chloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 12) 1- (2,5-dich] or -benzyloxy) -2- (l-imidazolyl) tetralin.
1- (3i 4-dichloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 1- (3> 4-dichloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 15) 1- (3,5-dichloro-benzyloxy) -2- (l-imidazolyl) -tetralin. 16) 1- (4.-Broin-ßenzyloxy) -2- (1-imidazolyl) -tetralin. 17) 7-chloro -2- (imidai-.olyl) -1- (4-metho: iybenzyloxy) -tetralin. / »098 1 1/1140 SCJHERiNGAG Patent department 18) 7-chloro-1- (2-chloro-benzyloxy) -2- (imidazQlyl) -tetralin. 19)! - (^^ - DxmethylbenzyloxjO - ^ - Cl-iniidazolylJ-tetralin hydrochloride. 20) 1- (5,4-dimethylbenzyloxy) -2- (1-imidazolyl) -tetralin hydrochloride 21) 2- (1-Imidazolyl) -1- (2-phenylbenzyloxy) -tetralin hydrogen 22) 2- (1-IrrtIdazolyl) -1- (4-phenylbenzyloxy) -tetralin hydrochloride 2 ^) 2- (1-Irnidazolyl) -l- (l-naphthylmetboxy) -tetralin hydrochloride 24) 1- (2,4-Biehlor »benzyloxy) -2 ~ {1-imidazolyl) -tetralin hydrochloride. 25) l- (2 _i 6-dichloro-benzyloxy) -2- (1-imidazolyl) -tetralin hydrochloride * 26) 7-chloro- 2- (l - :. rnidazolyl) -l- {4-methylbenzyloxy) -tetralin-hydr O'jhlorid. 27) 7-chloro-1- (2-chloro-benzyloxy) -2- (l-imidazolyl) -tetralin-hydr o .-; chloride. 28) 7-Chloro ~ 1- (2,4-dichloro-benzyloxy) -2- (1-iniidazolyl) -tetralin hydrochloride. 29) 7-chloro -! - (a ^ j-dichloro-benzyloxyj ^ -i 1-imidazolyl) tetralin hydrochloride. 2- (l-Iir.idazolyl) -l- (4-taethylbGnzyloxy) -indane hydrochloride. 2- (l ~ Ir:; idozv .- »ly L) -l- ( ^J l-! I5ethoxyben ^ yloxy) -indane hydrochloride - 19 409811/1140 22U761 SCHERINGAG _ τ * _ Patent Department XO 32) 1- (2-chloro-tjenzyloxy) -2- (l-imidazolyl) -indane hydrochloride. 23) 1- (4-chloro-ben3yloxy) -2- (l-imidazolyl) -indane hydrochloride. 34) 1- (2 _i ^ -Dichloro-benzyloxy) -2- (1-irnidazolyl) -indane hydrochloride. 35) 1- (2,6-dichloro-benzyloxy) -2- (1-imidazolyl) -indane hydrochloride. 36) 1- (4-Bromo-benzyloxy) -2- (l-imidazolyl) -indane hydrochloride. 6-chloro2- (l-imidazolyl) -l- ( ⁱ f-methylbenzyloxy) indane hydrochloride. 6-chloro-2- (1-imidazoly I) -I- (4-methoxybenzyloxy) indane hydroperchlorate. 39) 6-chloro-1- (2-chloro-denzyloxy) -2- (l-imida;: olyl) -indane hydrochloride. 40) 6-chloro-1- (2,4-dichlorobenzyloxy) -2- (1-iridazolyl) indane hydrochloride. 41) 6-chloro-1- (2,6-dichloro-benzyloxy) -2- (l-ir.! Idazolyl) -indane hydrochloride. 42) 4,6-dichloro-1- (2,6-d i-lor-benzy loxy) -2-1.1-imidazolyl) -indane · Hydrochlorld. 43) Process for the preparation of compounds of the general Formula I, characterized in that compounds of the general formula TI - 20 - 40981 1/1 UO SCHERINGAG Patent department OH N- II, , and Rp and η have the meaning given above with an alkali base and with a compound of the general formula III X - CH ₂ - III, R- ,, Uj ₁ , R ₁ -, R ^ and R have the meaning given above and Halogen or a reactive ester group means, converts, and then optionally the obtained ii'JuiVien with pharmacologically acceptable acids in their oal; ', o 'leads. - 21 - Α098117Ί-140 BATH 22U761 SCHERING AG Patent department - ai - 44) Medicines, characterized by the content of one or more compounds of claims 1 to 42 as active ingredient and those customary in galenic pharmacy Additives. 40981 1/1 UO