CH665208A5 - 3-AMINOPROPOXYARYL DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM. - Google Patents

Description

DESCRIPTION The invention relates to 3-aminop.ropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them. The invention relates to the compounds of formula I.

OH

I.

OCH2CHCH2-B- (CO) p-R I

Ar wherein

Ar represents an aromatic or heteroaromatic group;

B represents group i), ii), iii) or iv) with the following meaning:

1J "1 r — n-

wherein

V and W represent hydrogen or together represent an additional bond; and

R 1 is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or phenyl disubstituted by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35;

ii) ï-Q "

R, -

J

wherein

Rj represents hydrogen or alkyl of 1 to 4 carbon atoms;

III) -f- (CH2) n-N-,

Rk K

where n is 2, 3 or 4,

Rk is hydrogen or alkyl having 1 to 4 carbon atoms and

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

665 208

Ri has the meaning given above for Rj; and ! V,

wherein m is 2 or 3;

p represents 0 or 1; and

R is the same or different disubstituted alkyl by aromatic, heteroaromatic and / or cycloaliphatic groups;

with the proviso that if a) Ar is a group of the formula A

H

means in which either

R 'means: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl or cyan and

R "represents hydrogen or methyl; or R 'hydroxy and

R "is hydrogen; and furthermore b) either p stands for 1 and

B means: a group i ') of the formula in which

R, has the above meaning and

V and W 'are hydrogen or, if R' is hydroxy and R "are hydrogen, V 'and W' are hydrogen or together represent an additional bond, or

a group ii) or iii) as defined above, or p is 0 or 1 and

/ - \

B is a group iv ') of the formula -N ^ ^ N-, then

R is not for diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number from 9 to 35 mono- or identically or differently disubstituted diphenylalkyl with 13 to 17 Carbon atoms, and their physiologically hydrolyzable derivatives, in which the hydroxyl group in the 2-position of the propoxy side chain is present in esterified form.

They are hereinafter referred to as “the compounds according to the invention”.

Physiologically hydrolyzable derivatives are derivatives which are split under physiological conditions to give the corresponding compounds which have a hydroxyl group in the 2-position of the propoxy side chain.

A group of derivatives in esterified form of the compounds of formula I consists e.g. from the compounds of formula E.

OCORe

I.

OCH: CHCH2-B- (CO) p-RE

Ar wherein

Ar, B, p and R have the above meaning, and

R4 for alkyl with 1 to 12 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, phenyl, phenylalkyl with 7 to 12 carbon atoms, in the phenyl ring with alkyl with 1 to 4 carbon atoms monosubstituted phenyl or phenylalkyl with 7 to 12 carbon atoms, in the phenyl ring with halogen with a Atomic number from 9 to 35 mono- or identical or different disubstituted phenyl or phenylalkyl with 7 to 12 carbon atoms, or in the phenyl ring by alkoxy with 1 to 4 carbon atoms mono- or identical or different di- or identical or different trisubstituted phenyl or phenylalkyl with 7 to 12 carbon atoms.

Preferred compounds are those in which the hydroxy group in the 2-position of the propoxy side chain is present in unesterified form.

If the compounds according to the invention can be recorded in a tautomeric structure, such tautomeric forms are also encompassed by the invention. For example, if Ar is an indole group substituted by hydroxy in the 2-position, the oxindole form is also included.

Compounds structurally related to the compounds of the present invention are disclosed in e.g. European Patent No. 25 111 and the U.K. Patent Specification No. 2 091 261 and their equivalents. These disclosures have been excluded from the scope of the present invention by the measure. The compounds of the present invention are neither specifically disclosed nor suggested by these disclosures.

Ar can be both mono- and polycyclic, e.g. consist of fused rings. It is preferably polycyclic. If it is polycyclic and heteroaromatic, it preferably represents a fused, completely unsaturated ring system with at least one nitrogen heteroatom. Ar means e.g. an indole, oxindole, 2,1,3-benzoxadiazole, benzimidazole, benzimidazol-2 (1H) -one, quinolin-2-one, 3,4-dihydroquinolin-2-one, carbazole, Spiro (cyclohexane-l, 2'-indan) -l'-one, phenyl, pyridyl or pyridine residue.

Ar can be substituted or unsubstituted. It preferably means an indole or oxindole radical, in particular an indole or oxindole radical bonded to the 4-position on the propoxy side chain; it means in particular 2-cy-an-1H-indol-4-yl.

Phenyl represents another preferred group Ar.

B is preferably a group iv). If it stands for a group i), ii) or iii), it preferably means a group i) or ii). V and W are preferably hydrogen. Rj, Rj and / or R preferably represent hydrogen or alkyl, in particular hydrogen, n preferably represents 2. Rk preferably represents hydrogen, m preferably represents 2. If Rj and / or Ri represents optionally substituted phenyl, they are preferably unsubstituted. If it represents substituted phenyl, the phenyl ring is preferably monosubstituted, in particular in the 4-position, or disubstituted, in particular in the 3 and 4 positions.

p is preferably 0 if B is a group iv). It preferably means 1 if B represents a group i), ii) or iii).

R preferably represents an alkyl radical which is substituted

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

665 208

is by at least one aromatic or heteroaromatic group and a further group which can be aromatic, heteroaromatic or cycloaliphatic. If Ar represents an indole radical, then at least one of the two groups in the radical R preferably denotes a group which is not phenyl. They can be substituted or unsubstituted.

The two groups which substitute the alkylene part in R are preferably bonded to the same carbon atom. They are preferably attached to the carbon atom in the co-position. Diphenylalkyl means e.g. preferably diphenylmethyl.

An aromatic group in R is preferably a phenyl group.

A heteroaromatic group in R is preferably pyridinyl, thienyl, furyl, pyrrolyl or imidazolyl, in particular thienyl or pyridinyl.

A cycloaliphatic group in R preferably contains 3 to 7 carbon atoms, in particular 5 or 6 carbon atoms, it preferably represents cyclohexyl. It can contain heteroatoms in the cycle, e.g. an oxygen atom or an oxygen and a nitrogen atom, e.g. a tetrahydropyran or morpholine.

If a substituent which is a phenyl ring can be both substituted and unsubstituted, it is preferably unsubstituted. If such a phenyl ring is nevertheless substituted, it is preferably monosubstituted. If it is monosubstituted, it is preferably substituted in the para position. If it is disubstituted, it is preferably substituted in the meta, para position. If it is substituted several times, the substituents are preferably identical.

A preferred group of compounds according to the invention consists of the compounds of the formula Ia

OH

1 .

OCH: CHCH: B (CO) p-R., Ia

Ar,

wherein

Ar stands for:

Phenyl: by hydroxy, benzyloxy, carboxy, alkoxycarbonyl with a total of 2 to 5 carbon atoms, trifluoromethyl, acetylmethyl, methylsulfonylamino, cyanomethylamino. Amino. Acetamido, (1-hydroxymethylcyclohexyl) methyl. (l-acetoxymethylcyclohexyl) methyl, l-dimethylamino-3-oxo-1-buten-2-yl or 3-cyano-1,2-dihydro-6-methyl-2-oxopyridin-5-yl monosubstituted phenyl; or phenyl disubstituted by: either nitro, amino, hydroxy or benzyloxy; or hydroxy and cyan; or benzyloxy and cyan: or acetyl and (2-methoxy) ethoxy; or cyan and (2-methoxy) ethoxy; or nitro and methyl;

Indolyl: in the 2-position by methyl. Hydroxymethyl, carboxyl. Alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl, cyano or acetyl monosubstituted indolyl: indolyl monosubstituted in the 3-position by methyl or cyano; indolyl monosubstituted in the 6-position by carboxyl or alkoxycarbonyl having a total of 2 to 5 carbon atoms; in the 7-position by fluorine or alkoxyalkyl with 1 to 4 carbon atoms in the alkyl and alkoxy part mono-substituted indolyl, depending on the tin: in the 1-position by alkyl with 1 to 4 carbon atoms. Alkoxycarbonyl with a total of 2 to 5 carbon atoms or alkoxycarbonylalkyl with a total of 3 to 9 carbon atoms and in the 2-position by cyan, or in the 2-or 3-position by cyan. or in the 2-position by methyl. Hydroxymethyl. Carboxyl, alkoxycarbonyl having a total of 2 to 5 carbon atoms, carbamoyl or cyan and in the 3-position by methyl, or in the 2-position by cyan and in the 3-position by dimethylaminomethyl disubstituted indolyl;

- Oxindol or oxindolyl substituted in the 3-position by two methyl groups;

- 2, l, 3-benzoxadiazol-4-yl;

Benzimidazol-4-yl or 2-trifluoromethylbenzimidazol-4-yl:

- 1,2-dihydro-2-oxobenzimidazol-4-yl;

- [Quinolin-2 (1H) -one] -4-yl or [3,4-dihydroquinoline-

2 (1H) -on] -4-yl;

- l- (9H) -carbazol-4-yl;

- | Spiro {cyclohexane-l, 2'-indanH'on] -4'-yl;

B and p have the above meaning and

Ra means alkyl with 1 to 5 carbon atoms, identical or different, disubstituted by: phenyl; by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35, hydroxy-cyan, trifluoromethyl, nitro, amino, alkanoyl-amino with 2 to 5 carbon atoms or trifluoromethyl mono- or identical or different disubstituted phenyl; Pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl; imidazolyl mono-substituted by methyl in the 1-position; or cycloalkyl of 3 to 7 carbon atoms;

with the proviso that if a) Ar. stands for a group of the formula A as defined above in part a) of the stipulation given under formula I and also b) p and B the part in part b) of the stipulation given under formula I above have defined meaning, then

R: 1 not for diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings with alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35 mono- or identically or differently disubstituted diphenylalkyl with 13 is up to 17 carbon atoms, and their corresponding physiologically hydrolyzable derivatives.

In formula Ia, Ar; 1 preferably denotes an optionally substituted indolyl or oxindolyl group as defined above, preferably an optionally substituted 4-indolyl or 4-oxindolyl group, in particular an optionally substituted 4-indolyl group. Another preferred group Ar “represents optionally substituted phenyl, preferably phenyl substituted by hydroxy. R; preferably denotes alkyl disubstituted by: phenyl or substituted phenyl; or by phenyl or substituted phenyl and pyridinyl; or by pyridinyl; or by pyridinyl and thienyl; in particular disubstituted by pyridinyl or by pyridinyl and thienyl. A substituted phenyl radical in R 1 is preferably substituted by fluorine.

In a subgroup of compounds of the formula Ia and their corresponding physiologically hydrolyzable derivatives, Ar. Stands for 4-indolyl, optionally substituted as defined above.

A particularly preferred group of compounds according to the invention consists of the compounds of the formula laa

OH

OCH; C HCH: -B- (CO) p-R;

(krt2

H 1

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

665 208

'6

wherein either

R, hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl or cyan and

R; Are hydrogen or methyl, or R 1 is hydroxy and R: are hydrogen and B, p and R. have the above meaning,

with the proviso that if

B and p have the meaning defined in part b) of the measure given above under formula I, then

Ra is not diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number from 9 to 35 mono- or identically or differently disubstituted diphenylalkyl with 13 to 17 carbon atoms means, and their corresponding physiologically hydrolyzable derivatives.

In a subgroup of compounds of the formulas Ia and Iaa and their corresponding physiologically hydrolyzable derivatives, R means not hydroxy. In another subgroup, R: stands for cyan. In another subgroup, p stands for 0. In another subgroup, B has the meaning given above iv). In another subgroup, B has the meaning iv) given above, in which m represents 2. In another subgroup, B does not have the above meaning i). In another subgroup, p stands for 1. In another subgroup, Ra has the above meaning with the proviso that it does not stand for alkyl having 1 to 5 carbon atoms disubstituted by two phenyl groups which are optionally substituted as defined above. In another subgroup, Ra stands for alkyl with 1 to 5 carbon atoms disubstituted by a phenyl group which is optionally substituted as defined above and a further group from the series: pyridinyl; Thienyl; Furyl; Pyrrolyl; Imidazolyl; methyl 1-substituted imidazolyl; and cycloalkyl of 3 to 7 carbon atoms. In another subgroup, Ra denotes alkyl with 1 to 5 carbon atoms, identically or differently, disubstituted by: pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, in the 1-position methyl-imidazolyl or cycloalkyl having 3 to 7 carbon atoms. In another subgroup, R a is alkyl having 1 to 5 carbon atoms, identically or differently disubstituted by: phenyl which is mono- or identical or differently disubstituted by hydroxy, cyano, nitro, amino, alkanoylamino having 2 to 5 carbon atoms or trifluoromethyl; Pyridinyl, thienyl, furyl. Pyrrolyl, imidazolyl or imidazolyl monosubstituted by methyl; or cycloalkyl of 3 to 7 carbon atoms. In another subgroup, R 1 denotes alkyl having 1 to 5 carbon atoms, identically or differently disubstituted by phenyl, mono- or identically or differently disubstituted by hydroxyl, cyano, nitro, amino, alkanoylamino having 2 to 5 carbon atoms or trifluoromethyl. In other subgroups, the symbols have the above meanings in combination, individually or together.

Another group of compounds according to the invention consists of the compounds of the formula Ip

OH

OCH: CHCH: -Bp- (CO) pp-Rp R "

wherein

Rip is hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl or cyan;

5 R2p represents hydrogen or methyl; either pp stands for 1 and

Bp means: a group ip) of the formula -N N-,

io R,

wherein

Ri has the above meaning; or - a group ii) or iii) as defined above, or pp is 0 or 1 and

15

Bp is a group ivp) of the formula - A -; and \ /

Rp for alkyl, identical or different, disubstituted by 20 aromatic, heteroaromatic and / or cycloalkyl groups; with the proviso that Rp is not for diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings by alkyl with 1 to. 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 35 mono- or identically or differently disubstituted diphenylalkyl having 13 to 17 carbon atoms, and their corresponding physiologically hydrolyzable derivatives.

Another group of Verbin-30 fertilizers according to the invention consists of the compounds of the formula 1p '

OH

och.chch ^ n:

35

H "lp

Ip '

40 where

Rip, Rip and Rp have the above meaning, and their corresponding physiologically hydrolyzable derivatives.

Unless otherwise specified in other places, the following meanings are preferred:

45 - for alkyl: methyl or ethyl, especially methyl;

- For alkoxy: methoxy or ethoxy, especially meth-oxy;

- for halogen: chlorine or bromine, especially chlorine;

for cycloalkyl: cyclopentyl or cyclohexyl, in particular 50 cyclohexyl;

- For alkoxycarbonyl: methoxy or ethoxycarbonyl, especially methoxycarbonyl; if it contains more than 2 carbon atoms, it is preferably branched in the a position to the carbonyl part, e.g. in isopropoxycarbonyl;

55 - for alkoxyalkyl: methoxymethyl or (2-methoxy) ethyl;

- for alkoxycarbonylalkyl: ethoxycarbonylmethyl.

The compounds according to the invention are obtained

by using a process according to the invention which 60 comprises the step of expedient 3-amino-2-oxypropylation of corresponding compounds of the formula IV

(oncR2p

H] P

OH I

65 ares in

IV

Ip Ar have the above meaning, or their precursors.

7

665 208

The process step according to the invention can be carried out using conditions known for the preparation of analog 3-amino-2-oxypropoxyaryl compounds.

Of course, the most suitable variant should be chosen taking into account the reactivities of the substituents present.

The compounds of formula IV are preferably used rather than their precursors.

Precursors of the compounds of formula IV are compounds which can be converted into compounds of formula IV, e.g. by suitable acylation or deprotection. For example, Carbonyl represents a precursor group for alkoxycarbonyl, and vice versa. For hydroxy, e.g. Benzyloxy represents a precursor group. For a ring system e.g. the corresponding uncyclized group represents a precursor group. For a substituted amine residue, e.g. the corresponding unsubstituted amino residue represents a precursor group. For amino, e.g. Nitro is a precursor group.

The method step according to the invention can therefore be carried out in more than one operation. You can e.g. implement a compound of formula IV in protected form, or introduce a 3-amino-2-oxypropyl radical in protected form, and then, after the 3-amino-2-oxypropylation has taken place, carry out a supplementary reaction step. e.g. split off any protective group (s).

Benzyl, methyl or tetrahydropyranyl, preferably benzyl, are examples of protective groups.

According to one embodiment of the process step according to the invention, the 3-amino-2-oxypropylation is carried out in two main work steps.

In a first main operation, a group -CH2-RX, in which Rx stands for a group which gives a 2-amino-1-hydroxyethyl group by reaction with a primary or secondary amine, is introduced into compounds of the formula IV by O-alkylation, where corresponding compounds of formula II

OCH.-R, II

I.

Ar wherein

Rs and Ar have the above meaning can be obtained.

In a second main operation, the compounds of formula II with corresponding compounds of formula III

H- (CO) p-R

III

wherein p and R have the above meaning, implemented and, if necessary, the compounds of the formula I obtained in this way appropriately esterified in the 2-position of the 3-aminopropoxy side chain.

The main O-alkylation step can be carried out using conditions known for the preparation of analog ethers. The compounds of formula IV are preferably used in anionic form.

The main amination step can be carried out using conditions known for the preparation of analog 3-amino-2-hydroxypropoxyaryl compounds. The group Rx is, for example, the group -CH-CH2 or a derivative of this group, for example

V

have a group of the formula -CH (OH) CH2L, where L is

Chlorine, bromine or a group Ry -S02-0-, where Ry is phenyl, tolyl or lower alkyl. L stands in particular for chlorine. The procedure is preferably in ethanol or in a suitable ether, such as dioxane. If necessary, ar-5 is processed in an excess of the amine as solvent. The reaction is expediently carried out in the melt. Suitable temperatures are about 20 ° to about 200 ° C, it is convenient to work at the reflux temperature of the reaction mixture if a solvent is present.

Any esterification of the hydroxy group in the 3-amino-propoxy side chain can be carried out analogously to the methods known for the preparation of analogous esters of 3-amino-2-hydroxypropoxyaryl compounds, 15 if necessary under selective conditions, if other reactive groups, e.g. Amino.

The compounds according to the invention can be used in free form, i.e. normally as a base, or in salt form, e.g. in acid addition salt form. Salts can be obtained in a known manner from the compounds 20 in free form and vice versa. Suitable acids for the extraction of acid addition salts are e.g. Hydrochloric, malonic and fumaric acid.

In the compounds according to the invention the carbon atom is e.g. 2-position of the propoxy side chain substituted asymmetrically. The compounds can therefore occur in the form of racemates or the individual enantiomers. Preferred enantiomers are those in which the S configuration is on the asymmetrically substituted carbon atom of the propoxy side chain. The individual enantiomers can be obtained in a manner known per se, e.g. by using the corresponding enantiomers of the starting compounds, or by fractional crystallization of diastereoisomeric salts prepared with optically active acids.

If R e.g. means alkyl substituted by two different groups, there is another center of asymmetry. These compounds can therefore occur as a mixture 40 or as two separate racemates or in pure enantiomer form. The individual diastereoisomeric forms can also be obtained in a known manner as described above, e.g. by

1) Chromatography using optically active adsorbents, e.g. acylated cellulose or polymer

Amino acid derivatives;

2) fractional crystallization of salts using optically active acids or bases for salt formation; or

50 3) Use of corresponding optically active starting products; in this case the separation can be carried out at an intermediate stage.

Insofar as the production of the required starting materials is not specifically described, they are known 55 or can be prepared by processes known per se or as described in the example section or analogously to the processes described in the example section.

In the following examples, all temperatures are given in degrees Celsius without corrections.

60

example 1

(S) -4- [3- [4- (3,3'-Dithienylmethyl) piperazin-l-yl] -2-hy-hydroxypropoxy] -IH-indole-2-carbonitrile

1.5 g of (S) -4- (2,3-epoxypropoxy) -lH-indole-2-carbonitrile 65 and 1.85 g of l- (3,3'-dithienylmethyl) piperazine are melted together at 70 °. The melt is chromatographed on silica gel. The title compound is obtained (foam; [a] D20 = −15.4 °, c = 1% in chloroform).

665 208

8th

The epoxy used as the starting product is obtained as follows:

a) 80 g of (S) -2,2-dimethyl-1,3-dioxolane-4-methanol dissolved in dimethylformamide are reacted at 0C with potassium hydroxide and then with benzyl bromide. The (S) -4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (light oil; [a] D20 = + 9.6 :, c = 2% in methanol) is obtained.

b) 93.3 g of the above product in aqueous hydrochloric acid solution and acetone are reacted for two hours at reflux. The (R) -3-benzyloxypropan-l, 2-diol (colorless oil; [a] D20 = - 1.2e, c = 2% in methanol) is obtained.

c) 118 g of the above product in pyridine are reacted at 0 ° with p-toluenesulfonyl chloride in benzene and the mixture is stirred for 72 hours at room temperature. The (S) -l-benzyloxy-3-tosyloxy-2-propanol is obtained (oil; [a] D: o = +8.3, c = 2% in methanol).

d) 41.5 g of 4-hydroxy-1H-indole-2-carboxamide are reacted with sodium hydride to give the corresponding sodium salt and this is reacted in dimethylformamide with 87.8 g of the product obtained under c) above. The mixture is stirred for 40 hours at 100 ° oil bath temperature. After working up and chromatographic purification on silica gel, the (S) -4- (3-benzyloxy-2-hydroxypropoxy) -lH-indole-2-carboxamide (mp 115-117; [a] D20 = -1.5 " , c = 2% in methanol).

e) 62.2 g of the above product are hydrogenated with 10% palladium on carbon in methanol for 6 hours. The (S) -4- (2,3-dihydroxypropoxy) -IH-indole-2-carboxamide (mp. 183-185c; [a] D20 = +6.15 ", c = 2% in methanol) is obtained.

f) 36.65 g of the above product are dissolved in pyridine at -15 to -5 with a solution of p-toluenesulfonic acid chloride in pyridine for 1 hour and the mixture is stirred for 3 more hours at 0: You get that

(R) -4- (2-hydroxy-3-tosyloxypropoxy) -1 H-indole-2-carbox-

amide (mp 162-168 "; [a] D20 = -13.5 °, c = 2% in methanol).

g) A solution of 44.2 g of the above product in methanol / tetrahydrofuran 1: 1 is at 0C a solution of

5 2.76 g of sodium in methanol were added dropwise over 1/2 hour and the mixture was stirred for 1 hour. The (S) -4- (2,3-epoxypropoxy) -1 H-indole-2-carboxamide (mp.

125-135; [cc] D20 = + 26 :, c = 2% in methanol).

h) 7.9 g of the above product are suspended in dioxane and pyridine, a solution of 7.8 ml of trifluoroacetic anhydride in dioxane is added dropwise at 10 "over the course of 1 hour and stirring is continued for 1 hour ) -4- (2,3-Epoxypropoxy) -1 H-indole-2-carbonitrile (m.p. 123-125 '; [a] D20 = +40.0 ", c = 1% in methanol).

15 The amine used as the starting product is obtained as follows:

a) 8.2 g of 3,3'-dithienylcarbinol in methylene chloride and 8.45 g of triethylamine are cooled to -70 °, a solution of 4.79 g of methanesulfonic acid chloride is added dropwise

20 methylene chloride. After 1 hour, a solution of 6.62 g of N-ethoxycarbonylpiperazine in methylene chloride is added, the mixture is stirred for 1 hour and the temperature is allowed to rise to room temperature. After chromatography on silica gel, the 4- (3,3'-dithienylmethyl) -l-piperazinecarboxylic acid is obtained.

25 reethylester (oil).

b) 10.35 g of the above ester are boiled with 60 ml of methanol, 60 ml of dimethyl sulfoxide and 120 ml of 30% aqueous sodium hydroxide solution for 2 hours. The l- (3,3'-dithienylmethyl) piperazine (mp 102-104) is obtained.

30 Analogously to Example 1 (unless stated otherwise in the footnotes), starting from the corresponding compounds of the formula II, in which Rx for 0

-CH-CH0

35

stands by reaction with the corresponding compounds of formula III, the following compounds of formula I:

Example Ar no.

B

P

R

Config. of the OH-bearing C * of the propoxy chain

If appropriate: config. of the C * of the group R

M.p.

Mon20

1. Ar = an indole group 1.1. B = piperazine

2U)) 2-CN -1 H-indol-4-yl

Piperazin-1,4-diyl

0

Di (2-thienyl) methyl rac.

n.p.

b foam n.p.

3 "2-CN -1 H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-NO2-phenyl) methyl rac.

n.p.

deh 205-208 °

n.p.

43) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

(Phe) (cyclohexyl) CHCH2-

S

rac.

b foam

-17.3 ° (c = 1% in CHC13)

4a3il) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

(Phe) (cyclohexyl) CHCH2-

S

A

b foam

-

4b3a) 2-CN -1 H-indol-4-y 1

Piperazin-1,4-diyl '

0

(Phe) (cyclohexyl) CHCH2-

S

B

b foam

-

52> 2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-CN-phenyl) methyl

S

n.p.

at 170-472 °

-2.8 ° (c = 2% in CH3OH)

64) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-NH2-phenyl) methyl

S

n.p.

b foam

-

75) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-MeCONH-phenyl) methyl s

n.p.

b foam

-

86) 2-CN -1 H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-pyridinyl) methyl s

n.p.

b foam

-

97) 2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

(4-OH-Phe) (Phe) methyl rac.

rac.

b foam

-

9a3a) 2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

(4-OH-Phe) (Phe) methyl

S

A

b foam

-

9b3a) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

(4-OH -Phe) (Phe) methyl

S

B

b foam

-

10 2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

(Dicyclohexyl) methyl

S

n.p.

b foam

-

II1 »2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

Di (4-CF3-phenyl) methyl

S

n.p.

b foam

- 8.8 ° (c = 1% in CH3OH)

1 la14) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

(Phe) (pyridin-4-yl) methyl

S

rac.

b foam

-

123a) 2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

(Phe) (pyridin-4-yl) methyl

S

A

b foam

+ 6.8 ° (c = 1% in ethanol)

133a) 2-CN-1H-indol-4-yl

Piperazine-1,4-diyl

0

(Phe) (pyridin-4-yl) methyl

S

B

b foam

+ 8.0 ° (c = 1%

Example No.

Ar

B

P

R

Config. of the OH-bearing C * of the propoxy chain

If appropriate: config. of the C * of the group R

M.p.

[a] D20

14 <»

2-CN-1H-indol-4-yl

Piperazine

, 4-diyl

0

Di (2-pyridinyl) methyl

S

n.p.

b foam

+ 7.3 "(c = 1% in CH3OH)

14al4)

2-CN-1H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (pyridin-3-yl) methyl

S

rac.

b foam

-

153a>

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (pyridin-3-yl) methyl

S

A

b foam

+4.5 "(c = 1% in ethanol)

163al

2-CN -1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (pyridin-3-yl) methyl s

B

b foam

+ 3.6 "(c = 1% in ethanol)

17151

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(3-thienyl) (4-pyridinyl) methyl s

rac.

b foam

-

17a3a)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(3-thienyl) (4-pyridinyl) methyl s

A

b foam

-

17b3a)

2-CN-1H-indol-4-yl

Piperazine

, 4-diyl

0

(3-thienyl) (4-pyridinyl) methyl s

B

b foam

-

188)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

Dicyclohexyl-methyl s

n.p.

zml159-161

- 8.5 "(c = 1% in CH3OH)

1916)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (2-thienyl) methyl s

rac.

b foam

+ 6.2 "(c = 1% in CH3OH)

19a3a)

2-CN-1H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (2-thienyl) methyl s

A

b foam

-

19b1a)

2-CN-1H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (2-thienyl) methyl s

B

b foam

-

20l6)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (3-thienyl) methyl s

rac.

b foam

+ 5.5 '(c = 1% in CH3OH)

20a3a)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (3-thienyl) methyl s

A

b foam

-

20b3a)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(Phe) (3-thienyl) methyl s

B

b foam

-

20c121

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(3-pyridinyl) (3-thienyl) methyl s

rac.

b foam

-

213al

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(3-pyridinyl) (3-thienyl) methyl s

A

b foam

+ 6.8 '(c = 1% in CH3OH)

2-CN-1 H-indol-4-yl

Piperazine

, 4-diyl

0

(3-pyridinyl) (3-thienyl) methyl s

B

b foam

+ 4.9 "(c = 1%

in CHjOH)

E.g.

Ar

B

P

No.

23 '')

2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

23a131

2-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

243ll)

2-CN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

253 "1

2-CN -1 H-indol-4-y 1

Piperazin-1,4-diyl

0

25a

2-CN-1 H-indol-5-yl

Piperazin-1,4-diyl

0

25b

2-CN-1 H-indol-6-yl

Piperazin-1,4-diyl

0

26

2-acetyl-1H-indol-4-yl

Piperazin-1,4-diyl

0

271s)

3-CN-1H-indol-4-yl

Piperazin-1,4-diyl

0

28 | c,)

6-COOH-1 H-indol-4-yl

Piperazin-1,4-diyl

0

29- ")

6-COOMe-1 H-indol-4-yl

Piperazin-1,4-diyl

0

30- »

7-CH: CH2OEt-1H-indol-4-yl

Piperazin-1,4-diyl

0

31— »

7-CH2CH2OMe-1 H-indol-4-yl

Piperazin-1,4-diyl

0

32231

2,3-diCN-1 H-indol-4-yl

Piperazin-1,4-diyl

0

3324)

2-CN-1-Me-1H-indol-4-yl

Piperazin-1,4-diyl

0

342?)

2-CN-1 -CH2COOEt-indol-4-yl

Piperazin-1,4-diyl

0

35-1

2-CN-1-COOEt-IndoI-4-yl

Piperazin-1,4-diyl

0

35a3'1 2-CN-3-CH2NMe2-1H-indol-4-yl piperazin-1,4-diyl

0

35b

2-CN-3-Me-1 H-indol-4-yl

Piperazine-1,4-diyl

0

35c3a | 2-CN-3-Me-1 H-indol-4-yl

Piperazin-1,4-diyl

0

R

Config. of the OH-bearing C * of the propoxy chain

If appropriate:

Config. of mp. C * of group R

Md

20th

Di (3-pyridinyl) methyl S

(Phe) (1 -Me-2-imidazolyl) methyl S

(Phe) (l-Me-2-imidazolyl) methyl S

(Phe) (l-Me-2-imidazolyl) methyl S

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

Diphenylmethyl rac.

(Phe) (pyridin-4-yl) methyl rac.

(Phe) (pyridin-4-yl) methyl S

n.p.

rac. A

B

n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p rac A

b foam b foam b foam b foam b foam b 167-168 b 186-188 fu 230-231 b 145-148 b 110-111 mo 107-110 hml 105-107 b foam b150-152 b 142-144 b 149- 151 tch 203 'b 169-170 b foam

+ 6.2 (c = 1% in CH, OH)

+ 7.0 (c = 1% in CHjOH)

+ 5.2 (c = 1% in CHjOH)

n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p n.p.

n.p.

Example Ar no.

35di '"2-CN-3-Me-1 H-indol-4-yl 35e411 7-F-1H-indole-4-vl

1.2. B = piperidine

36 2-CN-1 H-indol-4-yl

37 2-CN-1 H-IndoI-4-yl

1.3. B = another group

38 2-CN-1 H-indol-4-yl 39:71 2-CN-1 H-indol-4-yl

40: si 2-CN-1H-indol-4-yl 41-1 "2-CN-1H-indol-4-yl 42 2-CN-1H-indol-4-yl

42a 2-CN-1 H-indol-4-yl

2. Ar = an oxindole group

43: s) 2,3-dihydro-2-oxo-1H-indol-4-yl

442l) | 2,3-dihydro-2-oxo-1H-indol-4-yl

45: 7) 2,3-Dihydro-2-oxo-1H-indol-4-yl

B p R

Piperazin-1,4-diyl 0 (Phe) (pyridin-4-yl) methyl piperazin-1,4-diyl 0 diphenylmethyl

-O-

-O

-N N-

-NCH-.CHUN-

I "I

Me me

-N ^) - N (Me) - | Q »NH - N (Me) - ^ Sl-

-NH- ^ fV \ /

-N

■ N ^ -NH-

0 diphenylmethyl

0 di (4-F-phenyl) methyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

'y ~ N (Me) - 0 diphenylmethyl

0 diphenylmethyl

-N (Me) CH2CH-.N- 0 diphenylmethyl (Me) -

Config. of the OH-bearing C * of the propoxy chain rac.

If appropriate:

Config. of mp. C * of group R

B

n.p.

[«Lo

20th

b foam bml 154-156 'n.p.

ON ON Ul N> O 00

rac.

n.p.

n.p.

b foam

- 19.4 "(c = 1% in CHC1,)

b 179-181 "n.p.

rac.

rac.

n.p.

n.p.

b foam n.p. b 156-159 "n.p.

rac. rac. S

n.p. n.p. n.p.

n.p.

b 125-128 "n.p.

zml 192-194 n.p.

b foam - 33.2 (c = 1% in CHClj)

b foam

-8.5 "(c = 1% in CHCI3)

rac.

rac.

rac.

n.p. b 170-172 n.p.

n.p. b 154-156 "n.p.

n.p. b 140-142 "n.p.

E.g. Ar

No.

45a 2,3-dihydro-2-oxo-1H-indol-4-yl

462,3-dihydro-3,3-diMe-2-oxo-1H-indol-4-yl

46aU) 2,3-dihydro-2-oxo-1H-indol-4-yl

46b3 '"2,3-dihydro-2-oxo-1H-indol-4-yl

46c3 "1 2,3-dihydro-2-oxo-1H -indol-4-yl

B

/ <N-

Piperazin-1,4-diyl Piperazin-1,4-diyl Piperazin-1,4-diyl Piperazin-1,4-diyl

3. Ar = another polycyclic aryl group 473: i 4834)

4934)

5034 '

2,1,3-benzoxadiazol-4-yl 2-CF3-benzimidazol-4-yl benzimidazol-4-yl

1,2-dihydro-2-oxo-benzimidazol-4-yl

51 [Quinolin-2 (1H) -one] -4-yl

Piperazin-1,4-diyl Piperazin-1,4-diyl Piperazin-1,4-diyl Piperazin-1,4-diyl

P R

0 diphenylmethyl

0 diphenylmethyl

0 (Phe) (pyridin-4-yl) methyl

0 (Phe) (pyridin-4-yl) methyl

0 (Phe) (pyridin-4-yl) methyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

0 diphenylmethyl

52

53

54

55

56

[3,4-dihydroquinolin-2 (1 H) -one] -4-yl

[3,4-dihydroquinolin-2 (1H) oxo] -4-yl

1- [9H] carbazol-4-yl

Piperazin-1,4-diyl 0 diphenylmethyl

Piperazin-1,4-diyl 0 diphenylmethyl

Piperazin-1,4-diyl 0 di (4-F-phenyl) methyl

Piperazin-1,4-diyl 0 diphenylmethyl

Piperazin-1,4-diyl 0 diphenylmethyl

-NH

-c

N-

0 diphenylmethyl

Config. of the case OH-wearing - fitting:

the C * of the config. of mp. [a] D20 propoxy-C * of the chain group R

rac. n.p. b 106-108 n.p.

rac. n.p. zml 108-112 "n.p.

rac. rac. b 154-155 "-S Ab foam S B b foam rac. n.p. b 125-126 ° n.p. ^

U>

rac. n.p. fu 222 "n.p.

rac. n.p. b 176-178 "n.p.

rac. n.p. ch 265-267 "n.p.

rac. n.p. fu 214-217 n.p.

(Dec.)

rac. n.p. fu 218-219 n.p.

rac. n.p. - n.p.

rac. n.p. b 200-2021 n.p.

rac. n.p. hfu 169-170 n.p.

rac. n.p. zml 165-168 n.p.

O

00

Example No.

Ar

B

P

R

57

0

= a phenyl group

"nO

NH-

1

Diphenylmethyl

4. Ar

57a

4-OBz-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

583 ("

4-OH-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

58a

3-OBz-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

5936)

3-OH-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

59a

3-COOMe-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

6035)

3-COOH-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

61

3-CFrPhenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

62-, 7>

4-MeCOCH2-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

62a3s>

3-N H2-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

63-W)

3-N HSO: Me-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

64-to)

3-NHCH2CN-phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

65

3-N HCOMe phenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

66 '"

2- (1-hydroxymethylcyclohexyl) methylphenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

67

2- (1-acetoxymethylcyclohexyl) methylphenyl

Piperazine

, 4-diyl

0

Diphenylmethyl

67a171

ù

r ^ -COMe

Piperazine

, 4-diyl

0

Diphenylmethyl

ìJMe2

Config. of the OH-bearing C * of the propoxy chain rac.

If appropriate:

Config. of mp. C * of group R

n.p.

b 201-202 "

Md:

n.p.

20th

On ON 'J1 K »O 00

rac. rac. rac. rac. rac. rac. rac. rac. rac. rac. rac. rac. rac.

n.p, n.p. n.p. n.p. n.p. n.p. n.p. n.p. n.p. n.p. n.p. n.p. n.p.

b 106-108 n.p.

fu 155-159 "n.p.

b 01 n.p.

b 183-185 "n.p.

b 01 n.p.

b 190-191 ° n.p.

fu 180-182 "n.p.

b 108-110 ° n.p.

b 01 n.p.

b foam n.p.

bfu 131-133 "n.p.

mo 117-119 "n.p.

fu 154-156 "n.p.

rac.

n.p.

fu 162-164 "n.p.

rac.

n.p.

b foam n.p.

B

P R

Piperazin-1,4-diyl 0 diphenylmethyl

68a

3,5-di-OBz-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

692hl

3,5-di-OH-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

69a

2-CN-4-OBz-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

703 ,,)

2-CN-4-OH-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

71

2-acetyl-4-OCH2CH2OMe-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

72

2-CN-4-OCH2CH2OMe-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

73

2-Me-3-NOrPhenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

74

2,3-di-NO 2 phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

7533)

2,3-di-N H2-phenyl

Piperazin-1,4-diyl

0

Diphenylmethyl

Config. of the OH-bearing C * of the propoxy chain

If appropriate:

Config. of mp. C * of group R

Md:

20th

rac.

n.p.

b177-180

n.p.

rac. rac. rac. rac. rac.

n.p. n.p. n.p. n.p. n.p.

b foam b183-184 b 01

fu 196-198 fu 161-163

n.p. n.p. n.p. n.p. n.p.

rac. rac. rac. rac.

n.p. n.p. n.p. n.p.

b107-109 b149-150 b foam n.p. n.p. n.p.

deh 133-135 n.p.

665 208

16

Dictionary:

C *

=

asymmetric carbon atom

Config.

=

Configuration rac.

=

racemic n.p.

=

not suitable

Bz

Benzyl

Me

=

methyl

Phe

=

Phenyl

Et

=

Ethyl bml

=

in bis [maleinate] salt form deh

=

in dihydrochloride salt form b

=

in free form fu

=

in fumarate salt form mo

=

in malonate salt form zml

=

in bis [hydrogen maleate] slaz form hml

=

in hydrogen maleinate salt form ch

=

in hydrochloride salt form hfu

=

in hydrogen fumarate salt form bfu

=

in bis [fumarate] salt form tch

=

in trihydrochloride salt form

A

=

in one of the two possible stereoisomers

to form

B = in the other of the two possible stereo isomeric forms

Decay = Decomposition mp. = Melting point

Regulations and manufacture of intermediates:

hl- [bis (4-nitrophenyl) methyl] piperazine is obtained by acetylating 1-diphenylmethylpiperazine with subsequent nitration of the acetylpiperazine thus obtained and subsequent cleavage of the acetyl group from the dinitro derivative thus obtained.

: 'l- [bis (4-cyanophenyl) methyl] piperazine is obtained by reduction of di- (p-cyanophenyl) ketone with NaBH4 with subsequent mesylation of the alcohol thus obtained and subsequent reaction of the mesylate thus obtained with N-formylpiperazine and subsequent hydrolysis of the N-formylpiperazine derivative thus obtained.

'' [- [(Z-Cyclohexyl ^ -phenyOethyljpiperazin is obtained by acylation of 1-benzylpiperazine with 2-phenyl-2-cy-clohexylacetic acid chloride with subsequent reduction of the derivative thus obtained with LiAlH4 with subsequent N-debenzylation of the derivative thus obtained by hydrogenation with palladium on charcoal.

"•" The corresponding mixture of diastereoisomers of the formula I is separated into its two optically pure components by chromatography on silica gel.

4ll- [bis (4-aminophenyl) methyl] piperazine is obtained by reducing the nitro derivative described under 1).

Nl- [bis (4-acetaminophenyl) methyl] piperazine is obtained by acetylating the amino derivative described under 4).

The corresponding l- [bis (pyridinyl) methyl] piperazine is obtained by reducing the corresponding (dipyridylnyl ketone with NaBH4 with subsequent mesylation of the alcohol thus obtained with subsequent reaction of the mesylate thus obtained with N-formylpiperazine with subsequent cleavage of the formyl group from N-formylpiperazine derivative thus obtained.

'l- [4-H_ \ dro. \ yphenyl) -phenylmethyl [piperazine is obtained by reduction of phenyl- (p-benzyloxyphenyl) ke-ton with NaBH4 with subsequent bromine substitution with PBr, the free hydroxy group in the alcohol thus obtained with subsequent reaction the bromine derivative thus obtained with benzylpiperazine with subsequent cleavage of the benzyl and benzyloxy groups from the N-benzylpiperazine derivative thus obtained by hydrogenation with palladium on carbon.

N | l- [bis (cyclohexyl) methyl] piperazine is obtained by mesylation of dicyclohexylcarbinol with subsequent reaction of the mesylate thus obtained with formyl piperazine with subsequent cleavage of the formyl group from the N-formylpiperazine derivative thus obtained.

1.11 - [bis (4-trifluoromethylphenyl) methyl] piperazine is obtained by bromine substitution with PBr3 of the free hydroxyl group in di- (p-trifluoromethylphenyl) carbinol with subsequent reaction of the bromo derivative thus obtained with formylpiperazine with subsequent elimination of the formyl group from the N thus obtained -Formylpiperazine derivative.

"" The corresponding l- [bis (thienyl) methyl] piperazine is obtained as described in Example 1, starting from the corresponding di- (thienyl) ketone.

11 'The title compound is obtained by alkaline hydrolysis of the compound of Example 67.

l: 'l - [(3-pyridinyl) - (3'-thienyl) methylJpiperazine is obtained in a manner analogous to that described in footnote 15).

1311 - [(1-Methyl-2-imidazolyl) (phenyl) methyl] piperazine is obtained in an analogous manner to that described in footnote 16). The carbinol is obtained by reacting 2-lithio-l-methylimidazole with benzaldehyde.

l4lThe corresponding l - [(pyridinyl) (phenyl) methyl] piperazine is obtained by reacting the corresponding carbinol with ethoxycarbonylpiperazine at elevated temperature with subsequent hydrolysis of the carbethoxy compound thus obtained.

L "" l - [(4-pyridinyl) (3'-thienyl) methyl] piperazine is obtained in two stages as described in footnote 8), starting from the corresponding carbinol. The carbinol is obtained by reacting 3-thienyllithium with pyridine-4-carboxalde-hyd.

"" The corresponding l - [(phenyl) (thienyl) methyl] piperazine is obtained by reacting the corresponding carbinol with thionyl chloride with subsequent condensation of the chloride thus obtained with ethoxycarbonylpiperazine with subsequent hydrolysis of the carbethoxy compound thus obtained.

| 7The title compound is obtained by reacting the compound of Example 62 with N, N-dimethylformamide di-methylacetyl.

Is'4- (2.3-epoxypropoxy) -lH-indole-3-carbonitrile (mp. 125 126) is obtained by reacting 4- (2,3-epoxypropoxy) -lH-indole with chlorosulfonyl isocyanate with subsequent reaction of the obtained 3-cyan compound with benzhydrylpiperazine.

By hydrolysis of the compound of Example 29 with aqueous sodium hydroxide solution.

: "'4-Hydroxy-6-methoxycarbonyl-1H-indole (mp. 80 81) is obtained by the following reaction sequence: Stub-be condensation of pyrrole-2-aldehyde with dimethyl succinate followed by cyclization of the compound thus obtained with acetic anhydride sodium acetate to 4-acetoxy-6-methoxycarbonylindol with subsequent reaction with sodium methoxide in methanol.

2'The title compound is obtained by reacting the compound of Example 67a with cyanoacetamide in sodium ethylate.

:: i4-Hydroxy-7- (2-methoxyethyl) -IH-indole (oil) and

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

17th

665 208

4-Hydroxy-7- (2-ethoxyethyl) -IH-indole (oil) is obtained by formylating ethyl 4-benzyloxy-1H-indole-2-carbonate followed by hydrolysis of the 4-benzyloxy-7-formyl thus obtained. 1 H-indole-2-carboxylic acid ethyl ester (mp. 113-114) with subsequent decarboxylation of the 4-benzyloxy-7-formyl-1H-in-dol-2-carboxylic acid thus obtained (mp. 203-206) Subsequent NABH4 reduction of the 4-benzyloxy-7-formyl-lH-indole thus obtained (mp. 129-131) with subsequent acetylation of the 4-benzyloxy-7-hydroxymethyl-1H-indole thus obtained (mp. 82-84 ) with subsequent reaction of the 4-benzyloxy-7-acetyloxymethyl-1H-indole (mp. 70-71) thus obtained with NaCN with subsequent hydrolysis of the 4-benzyloxy-1H-indole-7-acetonitrile thus obtained (mp. 152-154 ) with subsequent reduction of the 4-benzyloxy-1H-indole-7-acetic acid thus obtained (mp. 133-136 °) with subsequent, corresponding etherification of the 4-benzyloxy-7- (2-hydroxyethyl) -IH-i thus obtained ndols (m.p. 62-64) with diazomethane or diazoethane with subsequent debenzylation of the ether thus obtained.

23) 4- (2,3-Epoxypropoxy) -1 H-indole-2,3-dicarbonitrile (mp. 172-174) is obtained by reacting 4- (2,3-epoxypropoxy) -lH-indole-2- carbonitrile with chlorosulfonyl isocyanate in dimethylformamide.

24) The title compound is obtained by methylation with dimethyl sulfate of 4- [3- (4-diphenylmethylpiperazin-1-yl) -2-hydroxypropoxy] -lH-indole-2-carbonitrile with tetrabutylammonium iodide in a solution of methylene chloride and aqueous sodium hydroxide for 30 minutes and then chromatography of the compound thus obtained on silica gel using methylene chloride / 5% methanol as eluent.

25) The title compound is obtained by reacting 4- [3- (4-diphenylmethylpiperazin-1-yl) -2-hydroxypropoxy] -1H-indole-2-carbonitrile with ethyl chloroacetate [example 34] or ethyl chloroformate (example 35).

26) The title compound is obtained by debenzylating the compound of Example 68a.

27) N-Diphenylmethyl -N, N'-dimethylethylenediamine (oil) is obtained by reacting MeCON (Me) CH2CH2Cl with N-diphenylmethyl-N-methylamine in dioxane and subsequent hydrolysis of the acetamide thus obtained with sodium hydroxide / ethanol.

28) 4- (N-diphenylmethyl-N-methylamino) piperidine (mp. 116-120 °) is obtained by hydrogenation of 1-carbethoxy

4-piperidone over platinum oxide with subsequent N-methylation of the amine thus obtained (mp. 78-80 °) with formaldehyde in formic acid with subsequent hydrolysis of the compound thus obtained (mp. 146-148 °) with potassium 5 hydroxide / ethanol .

29) 4- (Diphenylmethylamino) piperidine (mp. 67-69 °) is obtained by hydrolysis of the amine intermediate with mp. 78-80 °, described in footnote 28), with potassium hydroxide / ethanol.

io 30> The title compound is obtained by debenzylating the compound of Example 69a.

3 "The title compound is obtained by reacting 4- [3- (4-diphenylmethylpiperazin-1-yl) -2-hydroxypropoxy] -lH-indole-2-carbonitrile with formaldehyde and dimethylamine. 15 32> 4-hydroxy-2, 1,3-benzoxadiazole is obtained by reacting 2,6-dichloroaniline with hydrogen superoxide with subsequent reaction of the 2,6-di-chloronitrosobenzene (mp. 162-163 °) thus obtained with sodium azide with subsequent reaction of the 4-chloro 20 2,1,3-benzoxadiazole (mp. 75-79 °) with sodium methylate with subsequent acidic hydrolysis of the 4-methoxy-2, l, 3-benzoxadiazj> ls thus obtained (mp. 76-78 °).

The title compound is obtained by hydrogenating the compound of Example 74 with palladium on carbon. 25 34) The title compound is obtained by cyclization of the compound of Example 75 with trifluoroacetic anhydride (Ex. 48) or HC (OEt), (Example 49) or COCL (Example 50).

35) The title compound is obtained by alkaline hydrolysis of the compound of Example 59a.

The title compound is obtained by debenzylating the corresponding compound which carries a benzyl group instead of hydroxy (compounds of Examples 57a and 58a).

35 37 | [(4-Hydroxy) benzyl] methyl ketone is obtained by demethylation of [(4-methoxy) benzy!] Methyl ketone with hydrobromic acid.

3S) The title compound is obtained by alkaline hydrolysis of the compound from Example 65.

40:, l) | The title compound is obtained by reacting the compound of Example 62a with CH3S02C1.

40I3-cyanomethylaminophenol (oil) is obtained by reacting 3-aminophenol with chloroacetonitrile.

41'The starting material is obtained according to the following reaction sequence:

4-fluorophenol -ÜÜ, 2-bromo derivative »2-bromobenzyloxy derivative CuCN f 2-cyanobenzyloxy derivative *

2-formylbenzyloxy derivative »2- (CH = CCOOEt) -benzyloxy derivative 4-benzyloxy-7-fluoro-lH-in-

Aj dol-2-carboxylic acid ethyl ester »corresponding acid decarbonylation ^ 7-fluoro-4-benzyloxy-1 H-indole

Debenzylation ^ 7-fluoro-4-hydroxy-1 H-indole »corresponding epoxide.

The compounds according to the invention in free form or in the form of their pharmaceutically acceptable salts are distinguished by interesting pharmacological properties. They can be used as a medicine.

They have cardiotonic properties, as can be seen from standard tests. They effect on those anesthetized with Numal. normotonic dog [R. Salzmann et al., J. Cardiovasc. Pharm. 7 (1985)] at a dose of about 0.01 mg / kg to about 2 mg kg IV. and from about 0.02 mg / kg to about 2 mg / kg intraduodenally, an increase in the contraction force of the left ventricle.

The test method is as follows:

The experiments are carried out on bastard dogs of both sexes with a weight of 10 to 15 kg. Numal is used as a narcotic in a dose of 65 mg / 'kg IV. The animal is fixed on its back on an operating table. After the usual preparatory work, a 65 heparinized catheter is inserted into the left ventricle under X-ray control over the carotid artery and the transfer of pressure to a donor membrane is recorded (Gould Statham P 23 Gb). With the help of an HSE physiological differential, the increase in pressure processes in

665 208

18th

Calculated and recorded depending on the time. The pressure increase in the left ventricle is a measure of the contraction force of the heart. The dimension of the differentiated pressure is in mm hg, / sec. specified. An adequate body temperature (approx. 36 to 37 C) is maintained. After a control phase of about 40 minutes has ended, the test substance is injected into the femoral vein and its influence on the registered or calculated parameters is observed.

This effect can be seen in similar doses on the rat test anesthetized with inactin [method as indicated above, but using rats anesthetized with inactine instead of Numal dogs), on the test of the "pithed open-chest" cat [R. Salzmann et al., J. Car-diovasc. Pharm. 7 (1985) with direct measurement of the contraction force] and on the test of the spontaneously beating, acutely inefficient rabbit heart [G. Scholtysik et al., Naunyn Schmiedeberg's Arch. Pharmacol. (1985) 1.

The compounds are therefore suitable for use as cardiotonics. e.g. to treat heart failure. In this indication, they have a more balanced activity profile than known cardiotonic compounds with a similar structure.

The compounds of Examples 1.3 are preferred in this indication. 12, 13, 14, 15, 17, 21, 36, 38, 43 and 59, in particular Examples 12 and 21.

A suitable daily dose is from about 1 mg to about 500 mg. conveniently administered in 2 to 4 portions, e.g. orally, in unitary dosage forms containing from about 0.25 mg to about 250 mg, or in sustained release form.

In addition, the compounds have antiarrhythmic properties, as can be seen from standard tests. In this way they prolong the functional refractory period in the left guinea pig atrium at bath concentrations of approximately 10 "M to 10" 4 M [R. Hof and G. Scholtysik, J. Car-dioyasc. Pharm. 5 (1983) 176-183],

The compounds are therefore suitable for use as antiarrhythmics. e.g. for the treatment of cardiac arrhythmia. such as supraventricular tachycardia or fibrillation.

The compounds also have an a-adrenergic blocking effect, as can be seen from standard tests. They inhibit e.g. the a-adrenoceptors in isolated spiral strips of the femoral vein of dogs (E. Müller-Schweinitzer and E. Stürmer, Br. J. Pharmacol [1974] 5L, 441-446) at bath concentrations of approximately 10 ~ 7 M to 10-? M .

The compounds are therefore suitable for use as an a-adrenoceptor blocker, ZÌE. for the prophylaxis and treatment of conditions associated with paralysis of intestinal motility, e.g. from the paralytic ileus.

They also have a beta-adrenoceptor blocking effect, as is evident from standard tests. They inhibit e.g. in the isolated, spontaneously beating guinea pig atrium the positive inotropic adrenaline effect (A. Bertholet et al., Postgrad. Med. J. [1981] 57 (Suppl. 9-17) at a bath concentration of about IO-9 M to about IO-6 M .

The compounds are therefore suitable for use as β-adrenoceptor blockers, e.g. for the prophylaxis and therapy of coronary diseases, such as angina pectoris, of conditions associated with sympathetic overstimulation, e.g. nervous heart problems, from hypertension, from myocardial infarction, to the interval treatment of migraines and to the treatment of glaucoma and thyroid-toxicosis.

A suitable daily dose in the antiarrhythmic and α and β blocking indications is from about 0.1 mg to about 500 mg, conveniently administered in 2 to 4 portions, e.g. orally, in unitary dosage forms containing from about 0.025 mg to about 250 mg, or in sustained release form.

They also show typical effects for calcium antagonists. They have a pronounced muscle relaxant effect, especially on smooth muscles, as can be seen from the determination of vasodilating and hypotensive activity in standard tests. So they effect e.g. in the anesthetized cat test using "tracer" microspheres (R. Hof et al., Basic. Res. Cardiol. 75/1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J Cardiovasc. Pharmacol. 4 [1982] 352-362) coronary vasodilation, an increase in blood flow in the skeletal muscles and a decrease in blood pressure after intravenous administration of approximately 3 μg / kg to approximately 300

Hg, kg. *

A decrease in blood pressure is also seen in the awake, spontaneously hypertensive rat (method of Gerald M. Tschirki, Arzneimittelforsch. 18 [1968] 1285) after administration of about 1 ng / kg to about 100 jag / kg s.c. detected.

They are therefore suitable as calcium antagonists for the prophylaxis and therapy of

Coronary insufficiency, e.g. Angina pectoris;

- disorders of blood flow to the brain, such as cerebral vascular insufficiency; cerebrovascular insults, e.g. Stroke; and cerebrovascular spasms;

- other peripheral circulation disorders, e.g. in the limbs, such as intermittent limping and spasms, e.g. cholic; and _

Asthma, e.g. exercise-related asthma.

A suitable daily dose in the calcium antagonist

indications is from about 5 mg to about 500 mg, conveniently administered in 2 to 4 portions, e.g. orally, in unitary dosage forms containing from about 1.25 mg to about 250 mg, or in sustained release form.

In general, the 2 (S) optical isomers are more active than the 2 (R) optical isomers with respect to the propoxy side chain as cardiotonics, antiarrhythmics and β-adrenoceptor blockers.

Preferred as β-adrenoceptor blockers are the compounds according to the invention in which in B the nitrogen atom bonded to the propoxy side chain is part of a secondary amino group.

It should be appreciated that it may be appropriate, before carrying out the above in vitro tests to determine the activity, to take the compounds in which the hydroxyl group in the 2-position of the 3-aminopropoxy side chain is in esterified form into the corresponding un to implement esterified compounds.

The preferred use of the compounds is as cardiotonics.

The compounds can be administered in a pharmaceutically acceptable salt form. Such salt forms have an effect of the same order of magnitude as the free forms and can easily be produced in a known manner.

The invention also relates to pharmaceutical preparations which contain a compound according to the invention in free form or in a pharmaceutically acceptable salt form, together with a pharmaceutical carrier or diluent. Such preparations can be in the form of e.g. a solution or a tablet.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Claims (7)

665 208 -1,2-dihydro-2-oxobenzimidazol-4-yl; - [quinolin-2 (1H) -one] -4-yl or [3,4-dihydroquinolin-2 (1H) -one] -4-yl; - l- (9H) -carbazol-4-yl; - jSpiro (cyclohexan-l, 2'-indan) -l'-on} -4'-yl; B and p have the above meaning and Ra represents alkyl having 1 to 5 carbon atoms, the same or different disubstituted by: phenyl; by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35, hydroxy, cyano, trifluoromethyl, nitro, amino, alkanoyl-amino with 2 to 5 carbon atoms or trifluoromethyl mono- or identical or different disubstituted phenyl; Pyridinyl, thienyl, furyl, pyrrolyl, imidazolyl; methyl 1-substituted imidazolyl; or cycloalkyl with 3 to 7 carbon atoms; with the proviso that if a) Ara is a group of the formula A which has the meaning defined in part a) of the condition given above under formula I, and also b) p and B that in part b) of the above have defined meaning under formula I, then Ra is not diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number from 9 to 35 mono- or identically or differently disubstituted diphenylalkyl with 13 to 17 carbon atoms means, and their corresponding physiologically hydrolyzable esters in free form or in salt form. - 2, l, 3-benzoxadiazol-4-yl; Benzimidazol-4-yl or 2-trifluoromethylbenzimidazole 2nd PATENT CLAIMS 1. The compounds of formula I OH l OCHiCHCHi-B- (CO) p-R. I. Ar wherein Ar represents an aromatic or heteroaromatic group; B represents group i), ii), iii) or iv) with the following meaning: in N- I. Ri wherein V and W represent hydrogen or together represent an additional bond; and R is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 35, phenyl mono- or identical or differently disubstituted; ü) lO iv) -t / V 10th means wherein either R 'means: hydrogen, methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl or cyan and R "is hydrogen or methyl; or R 'is hydroxy and R" is hydrogen; and also b) either ' p stands for 1 and B means: a group i ') of the formula 15 2C where c £ v Rj has the above meaning and V 'and W' are hydrogen or, if R 'is hydroxy and R "are hydrogen, V' and W 'are hydrogen or together represent an additional bond, or - a group ii) or iii as defined above ), or p stands for 0 or 1 and 30th wherein Rj represents hydrogen or alkyl having 1 to 4 carbon atoms; üi) -N- (CH2) n-N-, K R1 where n is 2, 3 or 4, Rk is hydrogen or alkyl having 1 to 4 carbon atoms and Ri has the meaning given above for Rj; and 25th B is a group iv ') of the formula -N ^ N-, Hann R is not for diphenylalkyl with 13 to 17 carbon atoms or in one or both phenyl rings by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number of 9 to 35 mono- or identically or differently disubstituted di-35 phenylalkyl 13 to 17 carbon atoms, and their physiologically hydrolyzable esters, in which the hydroxy group in the 2-position of the propoxy side chain is in esterified form, in free form or in salt form. 2. Compounds according to claim 1 of formula Ia 40 OH I. OCH2CHCH2- I. B- (CO) "- R Yes 45 macaw wherein m is 2 or 3; p represents 0 or 1; and R is the same or different disubstituted alkyl by aromatic, heteroaromatic and / or cycloaliphatic groups; with the proviso that if a) Ar is a group of the formula A wherein Macaw stands for: - phenyl; by hydroxy, benzyloxy, carboxy, alkoxy-50 carbonyl with a total of 2 to 5 carbon atoms, trifluoromethyl, acetylmethyl, methylsulfonylamino, cyanomethylamino, amino, acetamido, (1-hydroxymethylcyclohexyl) methyl, (l-acetoxymethylcyclohexyl) methyl, 1 -Dimethylamino-3-oxo-l-buten-2-yl or 3-cyano-l, 2-dihydro-6-me-55thyl-2-oxo-pyridin-5-yl monosubstituted phenyl; or phenyl disubstituted by: either nitro, amino, hydroxy or benzyloxy; or hydroxy and cyan; or benzyloxy and cyan; or acetyl and (2-methoxy) ethoxy; or cyan and (2-methoxy) ethoxy; or nitro and methyl; 60 - indolyl; indolyl monosubstituted by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl, cyan or acetyl; indolyl monosubstituted in the 3-position by methyl or cyano; indolyl monosubstituted in the 6-position by carboxyl or 65 alkoxycarbonyl with a total of 2 to 5 carbon atoms; in the 7-position by fluorine or alkoxyalkyl with independently 1 to 4 carbon atoms in the alkyl and alkoxy part monosubstituted 3. The compounds according to claim 1, in which Ar represents 2-cyano-1H-indol-4-yl. 3-position by methyl, or 2-position by cyan and 3-position by dimethylaminomethyl-disubstituted indolyl; - Oxindolyl or oxindolyl substituted in the 3-position by two methyl groups; 3rd 665 208 Indolyl; in the 1-position by alkyl with 1 to 4 carbon atoms, alkoxycarbonyl with a total of 2 to 5 carbon atoms or alkoxycarbonylalkyl with a total of 3 to 9 carbon atoms and in the 2-position by cyan, or in the 2-and 3-position by cyan, or in 2- Position by methyl, hydroxymethyl, carboxyl, alkoxycarbonyl with a total of 2 to 5 carbon atoms, carbamoyl or cyan and in 4. A process for the preparation of the compounds defined in claim 1, characterized in that corresponding compounds of the formula II OCH2-Rx II I. Ar wherein Ar has the meaning given in claim 1 and Rx represents a group which, when reacted with a corresponding primary or secondary amine, gives a 2-amino-1-hydroxyethyl group, with corresponding compounds of the formula III H- (CO) p-R III wherein p and R have the meaning given in claim 1, and the compounds thus obtained are obtained in free form or in salt form. 4-yl; 5. A process for the preparation of the compounds defined in claim 1, characterized in that the compounds obtained according to the process of claim 5 are esterified in the 2 position of the 3-aminopropoxy side chain, and the compounds thus obtained in free form or in salt form wins. 6. Medicaments, characterized in that they contain the compounds defined in claim 1 in free form or in the form of their pharmaceutically acceptable salts. 7. Use of the compounds defined in claim 1 in free form or in the form of their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of cardiac arrhythmias, of disease conditions which are associated with paralysis of intestinal motility, of angina pectoris, of conditions which are associated with sympathetic overstimulation, hypertension, myocardial infarction, migraine, glaucoma, thyrotoxicosis, coronary insufficiency, disorders of cerebral and peripheral circulation or asthma.