SI8910395A - NEW STILBEN DERIVATIVES - Google Patents

Abstract

New compounds with a general formula and a process for their preparation. The compounds can be used as active ingredients in drugs for the treatment of diseases, e.g. neoplasias, dermatoses or skin aging.

Description

and a process for their preparation. The compounds can be used as active ingredients in medicaments for the treatment of diseases, e.g. neoplasias, dermatoses or skin aging.

F.HOFFMANN-LA ROCHE AG

NEW DERIVATIVES OF STILBENE

Field of technology

The invention is in the field of pharmaceutical chemistry and relates to new stilbene derivatives, as well as to a process for their production.

Technical problem

The technical problem solved by this invention is to find new compounds that would be effective in the treatment of benign and malignant neoplasias and lesions, as well as a suitable process for their production.

State of the art

The new stilbene derivatives obtained according to the invention represent completely new compounds that have not been produced so far, and the process for their production according to the invention is also completely new.

Description of the solution to the technical problem with implementation examples

The invention relates to new stilbene derivatives with the general formula

X ·

R'

I in which R and R independently of one another represent lower alkyl, or together alkylene with 3-5 C atoms in a straight chain; one of the radicals R and R denotes hydrogen, the other hydrogen or lower alkyl; R and R hydrogen or lower alkyl; R and R hydrogen, lower alkyl, lower alkoxy or halogen; X is -O-, -S-, -SO-, -SO2 or NR; r is hydrogen, lower alkyl or acyl; Y is -S(O) _m R or -NHet and, in the case that X stands for -NR-, -S-, -SO- or -SO2-, also -N(R) ² or -OR; R is lower alkyl; RH and R is hydrogen, lower alkyl or acyl; -NHet is a 5-8-membered, saturated or unsaturated, monocyclic heterocycle, bonded via an N atom; n denotes 2, 3 or 4; and m is 0, 1 or 2.

The invention further relates to a process for the production of compounds of formula I, pharmaceutical preparations based on compounds of formula I, compounds of formula I for the treatment and prophylaxis of neoplasias, dermatoses and skin aging, as well as to the use of compounds of formula I for the production of pharmaceutical preparations for the treatment and prophylaxis of such diseases.

The designation lower refers to groups with 1-6 C atoms. Alkyl and alkoxy groups can be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl or tertiary butyl, or methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy and tertiary butoxy. Examples of acyloxy groups are alkanoyloxy groups, preferably lower alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy, pivaloyloxy, and caproyloxy; or aroyloxy groups such as benzoyloxy, p-nitro-benzoyloxy and toluoyloxy; or aralkanoyloxy groups such as phenylacetoxy. Halogen includes fluorine, chlorine, bromine and iodine. Preferred heterocyclic radicals -NHet are those of the formula -N Y', in which Y' represents -CH2-, -CH=, -O-, -S-, -SO-, -SO2 or NR^ and R^ is hydrogen, lower alkyl or acyl, with a total of 3-6 carbon atoms between N and Y'. Examples of such radicals are piperidino, pyrrolidino, morpholino, piperazino, N-methyl-piperazino, thionorpholine, thiomorpholine-4-oxide, thio-morpholine-4,4-dioxide as well as imidazoline and pyrrole. Together with Rl and R^, an alkyl radical with 3-5 C atoms in a straight chain can represent branching. Examples of such alkylene radicals are 1,3-propylene, 1,4-butylene and 1,5-pentylene and lower alkyl substituted derivatives thereof, such as the radicals

-C(CH ₃ )2-CH ₂ -C(CH ₃ )2-, -(CH ₃ )2-CH ₂ -CH ₂ -C(CH ₃ )2- and

-CH ₂ -CH 2 -C(CH ₃ ) 2 -CH 2 -CH ₂ .

The compounds of formula I may be in the form of trans- or cis- isomers or cis/trans- mixtures of isomers. In general, the trans-compounds of formula I are preferred.

Preferred groups of compounds of formula I are those in which R1 and R2 together represent the residue -C( _CH3 )2-CH2-C( _CH3 )2- or -C( _CH3 )2-CH2-CH2-C( _CH3 )2,

^R4 , R5 and R8 are hydrogen and R1 represents methyl. Compounds of formula I in which R1 and

R ⁸ lower alkyl, especially tertiary butyl, are of particular importance. Furthermore, compounds of formula I in which X is -O- and Y is -NHet are preferred, such as 4-[2[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenoxy]-ethyl]-morpholine.

Furthermore, compounds of formula I in which X represents -S-, -SO-, are of particular importance.

-SO2- or -NR2 and Y is -S( _Om )R2 or -NHet. Typical representatives of the compounds of this invention are given in the given examples, as well as the compounds listed below:

4-[2-[p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenylanylinoethylmorpholine;

4-[2-[p-[[(E)-2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenylphenylthioethylmorpholine;

1-methyl-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxyethyl]piperazine;

cis-2,6-dimethyl-4-[2-[p-[2-(E)-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenylphenoxyethylmorpholine;

tetrahydro-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]-2H-1,4-thiazine;

tetrahydro-4-[2-[p-[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)propenyl]anilino]ethyl]-2H-1,4-thiazine;

1-[2-[p-[[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]pyrrole;

1-[2-[p-[[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenylphenoxyethylimidazole.

Compounds of formula I can be obtained according to the invention by reacting:

a) a compound with the general formula

II with a compound of general formula

R i

C k'

III or

b) a compound with the general formula

IV with a compound of the general formula 'RO).?

with

- OE

M

^R6i

c I 7

R' or

c) a compound with the general formula

VI with a compound with the general formula

n

VII and optionally in the compound of formula I thus obtained the sulfide group represented by X and/or Y is oxidized to a sulfoxide or sulfone group, where in the aforementioned formulas II-VII the radicals R1, r2 r3 _? r4, r5, r6, r7, r8 χ, γ j _n n have the above-mentioned meaning; Q represents aryl; A' represents an anion of an inorganic or organic acid; R represents a lower alkyl group; Z represents hydroxy, mercapto -NHR^ or -SO' 2M ⁺ ; M ⁺ represents a cation; L represents a leaving group.

The reaction according to process variant a) can be carried out under the usual process conditions of the Wittig reaction. In this case, the components react with each other in the presence of an acid-binding agent, e.g. in the presence of a strong base, such as e.g. butyllithium, sodium, in an aromatic hydrocarbon, such as e.g. benzene or toluene, and in a temperature range between room temperature and the boiling point of the reaction mixture.

Among the inorganic acid anions A', the chlorine, bromine or hydrosulfate ion is preferred, and among the organic acid anions, the tosyloxy ion is preferred. The aryl radical Q is in particular a phenyl radical or also a substituted phenyl radical, such as, for example, p-tolyl.

The reaction according to process variant b) can be carried out under the usual conditions according to the Homer reaction. In this case, the components can be condensed with the aid of a base and preferably in the presence of an inert organic solvent, e.g. with the aid of sodium hydride in benzene, toluene, dimethylformamide, DMSO, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, as well as with the aid of sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, at a temperature between 0 °C and the boiling point of the reaction mixture.

Alcohol residues RO are lower alkoxy residues with 1-6 carbon atoms, such as methoxy or ethoxy.

The reaction according to process variant c) can be carried out in an organic solvent, such as e.g. dimethylformamide, optionally with heating to the reflux temperature of the reaction mixture. Examples of leaving groups L are halogens, such as e.g. chlorine, mesyloxy and tosyloxy. The cation M+ in the compound of formula Vi is expediently an alkali metal cation, such as e.g. Na ⁺ .

The oxidation of the sulfide group X or Y to a sulfoxide group and the oxidation of the sulfoxide group X or Y to a sulfonyl group can be carried out using an oxidizing agent, such as a peracid, such as peracetic acid or m-chloroperbenzoic acid. The oxidation of the sulfide group to a sulfoxide group can be carried out using periodates, such as sodium periodate.

The starting compounds of general formulae II-VII can - insofar as this is not already known or described herein - be obtained analogously to known or described herein methods.

Compounds of general formulae II or IV and their preparation are described, for example, in German Patent Specification Nos. 2,414,619 and 2,819,213 or in European Patent Specification No. 2,742.

Compounds of general formula III can be prepared starting from a ρ-hydroxy-, ρ-mercapto-, p-amino-, p-alkylamino- or p-acylamino-substituted benzaldehyde or acetophenone, propiophenone or their homologues by reaction with a compound of formula Y(CR6, R^) _n Cl in the presence of a base, such as e.g. NaH, or by reaction of a p-halo-benzaldehyde with an amine of formula NHR9-(CR6, RO _n Y, or with a mercaptan of formula HS-(CR^, R^) _n Y in the presence of a base, such as e.g. K2CO3.

Compounds of general formula V can be produced starting from ρ-hydroxy-, p-mercapto- or ρ-amino-, alkylamino- or acylamino-substituted benzoic acid esters by reaction with a compound of formula Y(CR6, R^) _n Cl, by reduction of the ester group with Dibal or L1-AIH4 to the corresponding alcohols, by exchange of the hydroxy group with bromine, e.g. by reaction with ΡΒΓβ and by reaction of the bromide with a trialkylphosphite to give a phosphonate of general formula V.

Compounds of general formula VI, in which Z represents hydroxy, can be produced from a compound of general formula II and a compound of general formula

VIII where Z' represents a protected hydroxy group, e.g. an acetoxy group, by means of a Wittig reaction and then by cleavage of the protecting group. Compounds of general formula VI in which Z represents an SH group can be prepared from a compound of general formula II by means of reaction with S-(4-formylphenyl)-dimethylthiocarbamate (cf. EP 58370 BI) and cleavage of the thiocarbamate group by means of treatment with L1AIH4.

Compounds of general formula VI, in which Z represents the residue -NHR^, can be prepared by producing a compound corresponding to general formula VI with Z=NO2 from a compound of general formula II and p-nitrobenzaldehyde by a Wittig reaction, whereby the nitro groups are reduced, for example with Na2S2O4 or nascent hydrogen, to amino groups, which are finally alkylated or acylated to NHR^ groups.

Compounds of formula VI in which Z represents the radical -SO^M ^-1 can be prepared as described in European Patent Specification 58 370.

The biological activity of the compound according to the invention can be seen, for example, from German Patent Specification 3,715,955, in the order of the experiments. In the study of the action against breast tumors in rats, indicated by the chemical route (oral administration of dimethylbenzanthracene), with the compound of the formula I, 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]morpholine, the following data were obtained:

dose/mg/kg per day p.o. rats with tumor/% of control growth or reduction of average tumors per 1 rat growth or decrease in average tumor volume per 1 rat 50 100 + 91 +550 100 50 -73 -77 control 200 10 - 96 -99 group 100 + 242 +714

The compounds of formula I can be used for local (external) and systemic therapies of benign and malignant neoplasias, premalignant lesions and also for systemic and local prophylaxis of the aforementioned disorders.

The compounds of formula I are also suitable for local and systemic therapy of acne, psoriasis and other dermatoses associated with increased or pathological changes in keratinization, as well as for inflammatory and allergic dermatological disorders. The products according to the invention of formula I can also be used for the treatment of mucosal diseases with inflammatory or degenerative or metaplastic changes. The compounds of formula I can be used primarily in preparations for external use for the treatment and prophylaxis of skin discoloration (skin aging).

Preparations can be administered enterally, parenterally or externally. For enteral administration, preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are suitable. For parenteral administration, preparations in the form of infusion or injection solutions are suitable.

The dosages in which the preparations are administered vary according to the route and type of administration as well as the needs of the patients. In general, daily doses for adults are about 0.1-100 mg/kg and preferably 1-50 mg/kg.

The preparations may also contain inert and also pharmacodynamically active additives. Tablets or granules, for example, may contain a variety of binders, fillers, carriers or diluents. Liquid preparations may be, for example, in the form of sterile solutions that are miscible with water. Capsules may additionally contain fillers or thickeners in addition to the active ingredients. The preparations may also contain flavoring additives, as well as conventional preservatives, stabilizers, humectants or emulsifiers, as well as salts for changing the osmotic pressure, buffers or other additives.

The above-mentioned carriers and diluents may be made of organic or inorganic substances, such as water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols, and the like. The condition is that all excipients used in the manufacture of the preparations are non-toxic.

For local (external) administration, all active substances are used expediently in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Preference is given to ointments and creams, as well as solutions. The preparations specified for the above-described administration can be prepared by adding non-toxic preparations or carriers suitable for local (external) administration to the products according to the invention, in conventional forms in solid or liquid state.

For topical (external) administration, 0.1-5% and preferably 0.3-2% solutions are suitable, as well as 0.1-5% and preferably 0.3-2% ointments or creams.

Optionally, an antioxidant agent can be added to the preparations, such as tocopherol, N-methyl-q-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene.

The Examples given below illustrate the invention in more detail. The temperatures are given in °C.

Example 1

332 g of 2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide were suspended in 1.2 liters of tetrahydrofuran. 406 ml of butyllithium (1.6 moles in hexane) were added dropwise at 0 °C while stirring. After stirring for 1 hour, 120 g of 4-(2-morpholinoethoxy)benzaldehyde in 400 ml of tetrahydrofuran were added dropwise at 0 °C to this dark red solution. After stirring for two hours at room temperature, the reaction mixture was poured into 3 liters of a methanol/water mixture (6:4) and extracted with hexane. The organic phase was washed with water, dried over sodium sulfate and evaporated. The yellowish crystalline residue was recrystallized from ethyl acetate/hexane to give 123 g of 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxyethyl-morpholine in the form of white crystals; mp 107-109 °C.

The starting material 4-(2-morpholino-ethoxy)benzaldehyde can be prepared as follows:

92.8 g of 4-hydroxybenzaldehyde was dissolved in 820 ml of dimethylformamide. After addition of 228 g of 4-(2-chloroethyl)-morpholine and 415 g of finely powdered potassium carbonate, the reaction mixture was heated to 100 °C overnight under argon and with vigorous stirring. The cooled solution was poured into 3 liters of ice water, extracted with ethyl acetate, washed with water, dried and evaporated. The resulting dark oil was distilled in high vacuum to give 132 g of 4-(2-morpholinoethoxy)-benzaldehyde as a yellowish oil with a boiling point of 145-150 °C/33 Pa.

Example 2

In a manner analogous to Example 1, from 26 g of triphenyl-[1-(1,1,3,3-tetramethyl-5-indenyl)ethyl]phosphonium bromide and 10 g of 4-(2-morpholinoethoxy)benzaldehyde, after recrystallization from hexane, 13.6 g of 4-[2-[p-[(E)-2-(1,1,3,3-tetramethyl-5-indenyl)propenyl]phenoxyethyl]morpholine were obtained in the form of white crystals with a melting point of 85-86 °C.

Example 3

0.75 g of a 50% suspension of sodium hydride in mineral oil was suspended in 10 ml of dimethylformamide. A solution of 5 g of p-[(E)2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol in 30 ml of dimethylformamide was added dropwise at 0 °C while stirring. After stirring for one hour at 0 °C, a solution of 3.6 g of N-(2-chloroethyl)pyrrolidine in 30 ml of dimethylformamide was added dropwise. The reaction mixture was then heated to 70 °C for 2 hours, then cooled, poured into ice water and extracted with ethyl acetate. The organic solution was washed several times with water, dried and evaporated. In this way, a yellow-brown oil was obtained, which was purified by filtration through silica gel (eluent ethyl acetate + 10% ethanol) and recrystallized from hexane. From this, 4.5 g of 1-[p-[2-[-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxyethylpyrrolidine were isolated as white crystals, m.p. 80-82 °C.

Example 4

Analogously to Example 3, 5.2 g of 1-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]piperidine were obtained from 5 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethyl]piperidine in white crystals, with a melting point of 91-93 °C.

Example 5

A mixture of 6 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenol,

4.8 g of 2-chloroethyl methylsulfide and 10.5 g of finely powdered potassium carbonate in 100 ml of dimethylformamide were heated for 20 hours at 100 °C. The cooled reaction mixture was diluted with water and extracted several times with ethyl acetate. After drying and evaporation of the organic phase, the resulting crystalline residue was recrystallized from hexane, thereby obtaining 5.5 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxyethylsulfide as colorless crystals, with a melting point of 94-96 °C.

Example 6

2.1 g of the compound obtained in Example 5 was dissolved in 50 ml of chloroform and slowly mixed at 0 °C with a solution of 1.2 g of m-chloroperbenzoic acid (90%) in 10 ml of chloroform. After stirring for 20 hours at 0 °C, it was washed with a dilute solution of soda (sodium carbonate) and water, dried and evaporated. The yellow oil thus obtained was filtered through a silica gel column (eluent hexane/acetic acid = 1:2) and recrystallized from acetic acid. In this way, 1.7 g of methyl-2-[p-[(E)-2-(5,6,7,8tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulfoxide was obtained, with a melting point of 134136 °C.

Example 7

Analogously to Example 6, from 2.8 g of methyl-2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]ethylsulfide and 3.1 g of m-chloroperbenzoic acid (90%) after filtration of the crude product through a silica gel column (eluent hexane/acetic acid = 1:1) and recrystallization from acetic acid, 1.7 g of methyl 2-[p-[(E)-2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenoxy]ethylsulfone was obtained, m.p. at 169171 OC.

Example 8

Analogously to Example 5, from 8.2 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol], 12 g of l-chloro-2-dimethylamino-ethane and 6.9 g of potassium carbonate, by heating for 3 hours at 60 °C in dimethylformamide, 3.5 g of N,N-dimethyl-2-[[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]thio]ethylamine were obtained after recrystallization from hexane, with a melting point of 57-59 °C.

Example 9

Analogously to Example 8, from 8.2 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol, 10.6 g of 2-chloroethyl-methylether and 6.9 g of potassium carbonate, 5 g of 2-methoxy-ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthyl)propenyl]phenylsulfide were obtained after recrystallization from hexane, with a melting point of 48-50 °C.

Example 10

Analogously to Example 8, from 8.2 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]thiophenol, 12.4 g of 2-chloroethyl methyl sulfide and 6.9 g of potassium carbonate, 3.5 g of 2-thiomethoxyethyl-p-[(E)-2-(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthyl]propenyl]phenyl sulfide were obtained after recrystallization from hexane, with a melting point of 65-67 °C.

Example 11 g of sodium p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfinate were suspended in 30 ml of dimethylformamide and 1.5 g of 2-chloroethyl methyl ether were added. After heating at 90 °C for 20 hours, it was diluted with water, extracted with ethyl acetate, dried and evaporated. The crude product was filtered through a silica gel column (eluent hexane/ethyl acetate = 4:1) and then recrystallized from hexane/ether to give

1.8 g of 2-methoxyethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfonate, melting point 104-106 °C.

Example 12

Analogously to Example 1, from 38.5 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide, 45 ml of butyllithium and 13.7 g of p-[[2-(dimethylamino)ethyl]methylamino]benzaldehyde, 9.2 g of N,N,N'-trimethyl-N-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthyl)propenyl]phenyl]ethylenediamine were obtained after filtration through silica gel (eluent ethyl acetate, then ethyl acetate/ethanol = 1:1 with the addition of 1% triethylamine) and after recrystallization from hexane, with a melting point of 46-48 °C.

The starting material p-[[2-(dimethylamino)ethyl]methylamino]-benzaldehyde was prepared as follows:

A mixture of 10 g of 4-fluorobenzaldehyde, 9.7 g of trimethylethylenediamine and 13.1 g of potassium carbonate in 20 ml of dimethylformamide was heated at 150 °C for 16 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed several times with water, dried and evaporated. The brownish oil (13.7 g) was dried under high vacuum and used without further purification.

Example 13

Analogously to Example 12, from 10.4 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide, 12.2 ml of butyllithium and 3.4 g of p-[[2-(dimethylamino)ethylamino]benzaldehyde, after recrystallization from hexane/acetic acid ester, 2 g of N,N-dimethylN'-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]ethylenediamine were obtained, with a melting point of 102-104 °C.

The starting p-[[2-(dimethylamino)ethyl]amino]benzaldehyde can be prepared as described in Example 12 from 4-fluorobenzaldehyde and 2-dimethylaminoethylamine as a brownish oil.

Example 14

2.1 g of [1-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)ethyl]-triphenylphosphonium bromide were suspended in 10 ml of toluene and 0.5 g of potassium tert. butylate were added at 0 °C. After stirring for 2 hours at room temperature, a solution of 2-morpholino-ethoxy)benzaldehyde in 5 ml of toluene was added dropwise and stirred at room temperature for 3 hours. After the main amount of solvent had evaporated, it was poured into a methanol/water mixture (6:4) and extracted several times with hexane. The organic phase was washed with water, dried and evaporated. Recrystallization of the residue from hexane gave 0.4 g of 4-[2-[p[(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl)propenyl]phenoxy]ethyl]morpholine, melting at 78-79 °C.

Example 15

Analogously to Example 1, from 22 g of 2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]triphenylphosphonium bromide and 9.5 g of p-[[-2-(morpholino)ethyl]methylamino]-benzaldehyde, after recrystallization from hexane, 7 g of 4-[2-[N-methyl-p-[(E)-2-(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthyl)propenyl]anilino]ethyl]morpholine were obtained, in the form of white crystals with a melting point of 86-88 °C.

The starting material p-[[2-(morpholino)-ethyl]methylamino]-benzaldehyde was obtained in the manner described in Example 12 from 4-fluorobenzaldehyde and 4-(2-(N-methylamino)ethyl)morpholine as a brownish oil which crystallizes in the cold.

Example 16

Analogously to Example 1, tetrahydro-4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenoxy]-ethyl]-2H-1,4-thiazine 1,1-dioxide with a melting point of 144-145 °C was obtained from 2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and 4-[2-(tetrahydro-4'H-1,4-thiazin-4'-yl)ethoxy]-benzaldehyde Γ,1'dioxide after 16 hours of stirring at room temperature, with further work-up, by flash chromatography on silica gel with hexane/acetic acid ester (1:2) and crystallization from acetic acid ester/hexane.

4-[2-(tetrahydro-4’H-1,4-thiazin-4’-yl)ethoxy]benzaldehyde Γ,1’dioxide can be obtained as follows:

11.6 g of 4-hydroxybenzaldehyde in 160 ml of dimethylformamide was heated with 15.6 g of 4-(2chloroethyl)-tetrahydro-2H-l,4-thiazine 1,1-dioxide and 21.6 g of powdered potassium carbonate for 2 hours under argon at 100 °C. After cooling, the whole was poured onto 150 g of ice, extracted three times with 300 ml of ethyl acetate and the organic phases were washed twice more with 150 ml of water, dried over sodium sulfate and evaporated in vacuo. The thus obtained beige crystalline residue (22.1 g) was directly used for the above-mentioned Wittig reaction. The sample was chromatographed on silica gel with ethyl acetate/hexane (4:1) and colorless crystals were obtained from ethyl acetate/hexane, with a melting point of 101-102 °C.

The preparation of useful forms of the compounds of formula I can be carried out in a conventional manner, e.g. according to one of the Examples described below.

Example A

Hard gelatin capsules can be produced in the following way: Ingredients mg/capsule 1. spray-dried powder, which contains 75% of compound I 200 2. Sodium dioctyl sulfosuccinate 0.2 3. sodium carboxymethyl cellulose 4.8 4. microcrystalline cellulose 86.0 5. talc 8.0 6. magnesium stearate 1.0

total 300

A spray-dried powder consisting of the active ingredient, gelatin and microcrystalline cellulose, with a mean active ingredient grain size <1 μτη (measured by autocorrelation spectroscopy), is moistened with an aqueous solution of sodium carboxylmethyl cellulose and sodium dioctylsulfosuccinate and kneaded. The resulting mass is granulated, dried and sieved, and the resulting granulate is mixed with microcrystalline cellulose, talc and magnesium stearate. The powder is filled into size 0 capsules.

Example B

The tablets can be obtained in the following way:

Ingredients mg/tablet

1. Compound 1 as finely ground powder 500

2. powdered milk sugar 100

3. cornstarch, white 60

4. Povidone K30 8

5. cornstarch, white 112

6. talc 16

7. magnesium stearate 4 total

800

The finely ground substance is mixed with milk sugar and one part of corn starch. The mixture is moistened with an aqueous solution of Povidone K30 and kneaded. The resulting mass is granulated, dried and sieved. The granulate is mixed with the rest of the corn starch, talc and magnesium stearate and compressed into tablets of suitable size.

Example C

Soft gelatin capsules can be produced in the following way:

Ingredients

1. compound I

2. triglyceride mg/capsule

450 A total of 500 g of compound I are dissolved in 90 g of medium chain triglyceride with stirring under an inert gas atmosphere and protected from light. This solution is processed as a capsule filling mass for filling soft gelatin capsules containing 50 mg of active ingredient.

Example D

Lotion can be produced in the following way:

Ingredients

1. Compound I, finely ground 3.0 g

2. Carbopol 934 9.6 g

3. sodium hydroxide q.s. to pH 6

4. ethanol, 94% 50.0 g

5. demineralized water up to 100.0 g

The active substance is added to a mixture of 94% ethanol and water under protection from light. Carbopol 934 is mixed until completely gelled and the pH value is adjusted with sodium hydroxide.

For:

F.HOFFMANN-LA ROCHE AG

AURELIJA GRm-GORIUP

Claims (12)

in which R, and R ² independently of one another represent lower alkyl, or together represent alkylene with 3-5 straight chain C atoms; one of the radicals R ² and R 4 denotes hydrogen and the other represents hydrogen or lower alkyl; R and R ² are hydrogen or lower alkyl; R4 and R4 are hydrogen, lower alkyl, lower alkoxy or halogen; X is -O-, -S-, -SO-, -SO2 or NR4; R4 is hydrogen, lower alkyl or acyl; Y is -S (O) _m R ^ or -NHet and, if X stands for -NR ^ -, -S-, -SO- or -SO2-, so is -N (R11) 2 or -ORl ² ; R 10 is lower alkyl; RH and R ² are hydrogen, lower alkyl or acyl; -NHet is a single, N-linked, 5-8 membered, saturated or unsaturated, monocyclic heterocycle; n is 2, 3 or 4; m is 0.1 or 2. Compounds according to claim 1, characterized in that R ^ and R ² together represent a residue - (C ^ hC-CH ^ CH ^ CHs) 1 - or - (CH ₃ ) ₂ C-CH 2 -C (CH 3) 2 . Compounds according to claims 1 and 2, in which X represents -O- and Y represents -NHet. Compounds according to claim 3, in which -NHet is as defined in claim 1 a heterocycle of formula - NY ', wherein Y' represents -CH 2 -, -CH =, -O-, -S-, -SO-, - SO 2 or NR ² is _n is R ^{1 is} hydrogen, lower alkyl or acyl, with 3-6 carbon atoms between N and Y '. Compounds according to claims 1 and 2, in which X is -S-, -SO-, -SO 2 - or -NR 4 and Y is -S (O) _m R 10 or -NHet. Compounds according to claim 1, wherein R1 and R4 are lower alkyl. 7. 4- [2- [p - [(E) -2- (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenoxy] ethylmorpholine. 8. 4- [2- [p - [(E) -2- (1,1,3,3-tetramethyl-5-indenyl) propenyl] phenoxy] ethyl] morpholine, 1- [p- [2- [2 - (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] phenoxy] ethyl] pyrrolidine, 1- [[2-p - [(E) -2- [2- (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] phenoxy] ethylpiperidine , 4- [2- [p - [(E) -2- (6,7,8,9, -tetrahydro-7,7-dimethyl-5H-benzocyclohepten-2-yl) -propenyl] phenoxy] ethyl] morpholine, 4- [2- [p - [(E) -2- (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propenyl] phenoxy] ethyl] (2H -l, 4) thiazine-1,1-dioxide, 4- [2- [N-methyl-p - [(E) -2- (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] anilino] ethyl ] morpholine. 9. Methyl 2- [p - [(E) -2- (5,6,7,8, -tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenoxy] ethylsulfide, methyl 2- [p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenoxy] ethylsulfoxide, methyl 2- [p - [(E ) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenoxy] ethylsulfone, N, N-dimethyl-2 - [[p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylthioethylamine, 2-methoxyethyl p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl sulfide, 2-thiomethoxyethyl p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl sulfide, 2-methoxyethyl p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylsulfone, N, N, N′-trimethyl-N- [p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylethylenediamine, N, N-dimethyl-N '- [p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenylphenylethylenediamine. Compounds characterized in that they have the general formula wherein R1, r6, r7, χ, γ and n are as defined in claim 1 11. Compounds characterized in that they have the general formula In which R ^, R ^ r7 _? X, yj _{nn is as} defined in claim 1 and R is a lower alkyl group. A process for the production of compounds of general formula I according to claim 1, characterized in that it reacts: with a compound of the general formula p ⁺ (q) ₃ A ~ II X - I R R I C I l R *