CS235526B2 - Method of tetrahydronaphtalene and indane new derivatives production - Google Patents

Abstract

Tetrahydronaphthalene and indane derivs. of formula (I) and its pharmaceutically acceptable salts are new. (I) are prepd. by reacting (II) with (III). In the formula, n=1 or 2; Z= -SO3-M+, - SO2-M+, ower alkylthio, lower alkylsulfinyl(or sulfonyl); M+= cation; A=triarylphosphonium ethyl of formula H3C-CH-P[Q3 +Y- or acetyl; B=formyl or dialkoxyphosphonyl methyl of formula-CH2-P(=0) [T 2; Q=aryl, T=lower alkoxy, Y-=anion of inorg. or org. acids.

Description

The present invention relates to a process for the preparation of novel tetrahydronaphthalene and indane derivatives of the general formula I ‘'.

where n is 1 or 2,

Z is mercapto or -S (O) _m R wherein m is 0, 1 or 2,

R‘ represents an alkyl group having from 1 to 4 carbon atoms or, when m represents the number i or 2, also represents a hydrogen group, and the pharmaceutically acceptable salts of the sulfonic and sulfinic acids of the formula I.

Post ^{characterized} by ^p with ^p očívá finding that reacting 1.1- ^(d ro-5,6,7,8teetaahy b'5>"8,8-tetrameehy ^y NIFF ^ι2-yl) ethyl. ^| - ^p o ^{p y} i ^p and ^{DE [1} - (1, ^{1, 3,3-tetramethylene Tay} -5 ^- nčld ^{0yy |)} eh ^{Ay | and} -TT at phosphonium ^{yy y} i with ^y or methylbenzyl lketony formula II i-

with dialkoxyphosphonylbenzyl derivatives III

in which n is as defined above,

Z * is C 1 -C 4 alkylthio, C 1 -C 4 alkylaulfinyl or C 1 -C 4 alkylsulfonyl;

And denoted by the trirrylphosphouiurnttyylvouu group of the formula

H ₃ c-CH-P [4] ₃ ⁽ * ⁾ Y ^(_)

B stands for frrmyovvuu kkupnnu, or

A represents an acetyl group and

B downstream dialkfxrУfsfozrlsrβttrlovfu group of formula *

-CH 2 -P [T] _{2 t} wherein

Q is an aryl group,

T represents an alkoxy group having 1 to 4 carbon atoms,

Y ^(-) means an organic non-inorganic tyls,

M ^{(+) C} represents ati.vz ^{and p} lean ^p and ^d s is staring salt as ^L fvzové tyseli ^ ^b not a salt suiyinové sowed ^ky ny converted to the free acid. .

C 1 -C 4 alkyl groups may be straight-chain or branched. Preferred alkyl groups having 1 to 4 carbon atoms are methyl, ethyl and isopropyl.

Suitable pharmaceutically acceptable salts are the alkali metal and alkaline earth metal salts as well as the ammonium salts.

Of particular interest are the following compounds:

ethyl-p- [2- (5,6-tetrahydro-5,5,8,8-tetrahydro-ethyl-2-yl) -propyl] -benzene-10-ol, ethyl [2- (5,6,7, 8 8 ^^^^ ^^ _5.5> 8,8-tttrarethyr-22nzaoyl) oropotnr] 0tzylsjl0fn, ethyly- [2- (5,6,7,8-Ο ^^ γο-5,5,8, 8-tyl) propenyl] tetramethyl-tert-o- [2- (5,6,7,8-tetrahydro-4, 8,8-tetramethyl-2- (80-) -1) oropotyl] benzoyl, ig ^ ppy-β- [2- (5,6 ^ -tetrahydro-5,5,8,8-tetramethylh-22-nazaoyl) o -globyl] methylsulfonyl.

The reaction according to the invention can be carried out in a manner known per se for the Wiitig and Horner reactions, optionally under conditions known per se for these reactions.

In the reaction of a compound of formula II in which A is a triaryphosphorous (methyl group) with a compound of formula III (Mttig reaction), said components react with each other in an acid binding agent present, for example a strong base such as sodium hydride. or sodium salts of diretulphide, especially in the present tri-oxide, which is optionally substituted by a lower alkyl group, such as in the presence of 1, 1,2-butylene oxide, optionally in a solvent, for example an ether, such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon such as benzene and in the temperature range between room temperature and the boiling point of the reaction snow.

The aryl groups in said triarylphosoonium groups, which are designated by Q, include all known aryl groups, especially one-core groups such as phenyl or lower alkyl or lower alkoxy substituted phenyl groups such as tolyl, xylyl, messtyl or p-methoxyphenyl.

Of the inorganic acid anions Ϊ, the chloride and bromide anion or the hydrosulfate anion are preferred, and the organic acid anion is the tosyloxy anion.

The alkoxy groups referred to in the dialkoxyphosphonylmethyl group of the formula

- ^CH 2-? ^(T) 2 'T is especially lower alkoxy groups having 1 to 6 carbon atoms, such as methoxy or ethoxy.

In the reaction of a compound of formula II in which A represents an acetyl group with a compound of formula III in which B represents a dialkoxyphosphonylmethyl group (Horner reaction), said components are condensed with a base and preferably in the presence of an inert organic solvent, e.g. benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or dimethoxyalkane, or also by treatment with sodium alkoxide in an alkanol such as sodium methoxide in methanol at temperatures between 0 ° C and the boiling point of the reaction mixture. . ·

A sulfonate or sulfite. i.e. a compound of formula I wherein Z represents a group of non ^{b g} S ° "* · ^{W, P} may Revest půsoMním acid to ^{p kl} of manufacture ad mineral ^alkyl petroleum jelly, such as hydrochloric acid, to a sulfone of ^p poídajjcí optionally sulfinic acid, i.e. to a compound of formula I in which Z is -SO 4 H or -S ° gH ·

The starting materials of the formulas II and III, if produced, are used; known or rooms ^ ^D, but does not describe ^{and cycloalkyl, wherein} R ^Abs ive out of five C ^alkyl analogues ^{gi p} ccording ^or velocity of the axis ^{P T beyond} the ^{original b} * not by analogy with the procedures described above ^gives le.

The reaction products of formula I and their farmaaBU ^ C ^ uppořebitelné salts are farrakfa ^{y y} oaInick valuable compounds. These compounds can be used for the topical and systemic therapy of benign and mmageal neoplasms, premmaigous lesions, as well as for systemic and topical prophylaxis of said affection.

These compounds are further suitable for the topical and systemic therapy of acne, isfriaia and other dermis, which are common by enhanced or pathologically altered corneal corners, as well as inflammatory and allergic derrajological diseases. The reaction products of the formula I and their pharmaceutically acceptable salts can furthermore also be used to combat mucosal diseases with inflammatory or degenerative and / or partial changes.

The novel compounds belonging to the group of rstiophils are distinguished, for example, from the known retinoadors by, for example, causing a slight loss of hormone in the test animals, which, as a side effect, occurs with the administration of rstinfia (hypervitradiol A).

The effect of the reaction products manifested by tumor suppression is significant. This can be observed in a papilloma test in mice [Europ. J. Cancer 10, 732 (1974)] regression of tumor-induced tumors. dimethylbenzanthracene and croton oil. For example, papilloma diameter decreases within 2 weeks with intraperitoneal administration of ethyl p- [2- (5,6,7,8-eetrahydro-5,5,8, β-tetrameehhy-2-naphthyl) propenyl] phenylsulfone

at 12.5 mm / kg / week o - 56% at 6 , 25 mm / kg / week 36% at 3 mmgkg / t.week 12%

For the treatment of these diseases, the compounds of the invention are administered orally, conveniently at a dose of about 5 to 200 mg per day, preferably 10 to 50 mg / day for adult patients. Possible overdose may occur. hypervitaminosis to vitamin'A and can be easily detected by its symptoms (peeling skin, hair loss).

This dose may be administered as a single dose or may be divided into several sub-doses. *

The compounds of formula I and their pharmaceutically usable salts can therefore be used as medicaments, for example in the form of pharmaceutical preparations.

Formulations for systemic administration may be prepared, for example, by adding to the compound of formula I or a pharmaceutically acceptable salt thereof as the active ingredient the non-toxic, inert solid or liquid carriers which are customary in such formulations.

Said preparations may be administered enterally, parenterally or topically. Preparations in the form of tablets, capsules, dragees, syrups, suspensions, etc. are suitable for enteral administration. . - solutions and suppositories. For parenteral administration, preparations in the form of injection solutions or injectable solutions are suitable.

The doses in which they are applied. The compounds of the invention may be administered according to the mode of administration and the type of formulation as well as the requirements of the patients.

The compounds of the invention may be administered in single or multiple doses. A preferred dosage form is a capsule containing about 5, 20 or 50 mg of active ingredient.

These preparations may contain inert but also pharmacodynamically active ingredients. The tablets or granules comprise, for example, binders, fillers, carriers or diluents. Liquid preparations may be present, for example, in the form of a sterile solution which is miscible with water. The capsules may contain, in addition to the active ingredient, fillers or thickeners. Furthermore, these preparations may contain taste-improving additives as well as conventional substances used as preservatives, stabilizers, humectants and emulsifiers, as well as salts for altering the osmotic pressure, buffers and other additives.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, for example water, gelatin, lactose, starch, magnesium stearate,. It is assumed that all excipients used in the manufacture of these preparations are not toxic.

For local use, the compounds according to the invention are conveniently used in the form of masses, elixirs, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These topical formulations can be prepared by providing the compounds of the invention as an active ingredient with inert solid or liquid carriers customary in such formulations which are suitable for topical treatment.

About 0.05 to about 5%, preferably 0.1 to 1% of solutions, ointments or creams are suitable for topical use.

These preparations may optionally be treated with admixtures of antioxidants, for example tocopherol, N-mehehl-tocopheramide as well as butylated hydroxyaaisol or butylated hydroxytoluene.

The following examples illustrate the invention.

Example! _t

4.05 g of sodium hydride (50% suspension in mineral oil) are washed with absolute pentane, dried in a water pump vacuum and suspended in 100 ml of dimethylformamide. At 0 ° C was added dropwise a suspension of 43 g [1- (5,6,7, ^θ-, tet, rshaddOo5,5,8,8 tetrseethya-2-naphthyl) eth ^and L '] trffin ^f Offoiouiembooe ^id ua reaction the mixture was stirred at ⁰ ° C for 1 hour. At the same temperature, a suspension of 16 g of p-formylbenzene uonium potassium salt in 200 ml of dimethylformamide is added dropwise to the deep red solution thus obtained. After stirring at room temperature for 3 hours, the brown-red reaction solution was poured onto ice and the mixture was evaporated to dryness in a water pump vacuum. The crystalline, gray residue was suspended in ethyl acetate, the mixture was filtered, and the residue on the filter was washed several times with ethyl acetate. Twice překrystslóváníe of ^the TKU from boiling in the ^soil of, ISK: and ¹⁰ g of sodium p- [2- ^{(5, 6,} 7,8-tetra ^{HA d} ROF 5, ^5, 8,8-te ^r saeethyl- 2-naftyOprope lybenzensulfodtu melting dec ^ u, ^{the Ter} is higher than ^00? 3 ° C

Example 2

2.0 g of sodium sulfonate obtained according to Example 1 'is suspended in 70 ml of dilute hydrochloric acid (1: 1), the suspension is heated briefly and then cooled in an ice bath. The precipitate was filtered off, washed with dilute hydrochloric acid (1: 1) and water and dried under high vacuum at ⁵⁰ ° C. ZIS ^{ka 1.9} g of p- [2- ^{(5, 6, 7, 8-d} tetrsha rOf5, ^5, 8,8-2-terraeethyl iSftyl) poopeiLal '] benzenesulfonic acid, mp 103-110 ° C (decomposition).

Example 3. .

18.1 g of [1- (5,6,7,8-tetrahydro-4, 5,8,8-tetrseeehya-2-iaphthal) ethyl] triphenylphosphinium bromide are heated with 5.0 g of p-ethylsulfinyleinsadaddehyde in 250 g. ml of butylene oxide at reflux for 3.5 hours. The reaction mixture is then cooled, taken up in 500 ml of a 6: 4 mixture of methanol and water, extracted three times with hexane, the organic phase is washed with water, dried over sodium sulphate and evaporated. The crude product was filtered through silica gel (eluent: hexane / ethyl acetate 1: 1) and recrystallized from a mixture of hexane and ethyl acetate. ^9.2 g ethyl. p- [2- ^{(5, 6, 7, 8} - ^t etrsh ^yd ro-5, ^{5, 8, 8 and} -tetraeethy ^-2-f i t ^l) prfpen ^IAL - ^f eiylsulfonu as colorless crystals, mp 158-161 ° C.

The p-ethanalsulonylonyl benzyl diethylene used as starting material is prepared as follows:

7.8 g of sodium hydride (50% suspension in mineral oil) are washed with absolute pentane, dried under a water pump vacuum and suspended in 100 ml of dieethalforeaeide. Under ice-cooling, 11.3 g of ethyl mercaptan was added dropwise, the mixture was stirred at room temperature for 1 hour, and then a solution of 25.0 g of 4-bromobenzaldehyde in 100 ml of dimethylforeaide was added dropwise. After 10 minutes c · ^N, the reaction mixture poured onto ice, extracted with ethyl acetate, · organic phase washed

2N hydrochloric acid solution and water, dried over sodium sulfate. and evaporate. Filtration of the oily residue through silica gel (eluent: hexane / ether 4: 1) gave

17.5 g of 4-thioethylbenzaddehyde as a thin, slightly yellow oil.

g-4-thioethylbenzaldehyde is dissolved in 150 ml of methylene chloride and 22 g of m-chloroperbenzoic acid are gradually added under ice-cooling. The reaction mixture was diluted with methylene chloride, then extracted twice with ice-cold potassium carbonate solution and water, dried over sodium sulfate and evaporated. . After recrystallization from a mixture of hexane and ether, 9.1 g of 4-ethylamino-benzene aldehyde is obtained in the form of colorless crystals. Melting point 107-109 ° C.

Example.

In a manner analogous to that described in Example 3, the following compounds can be prepared:.

starting from 1- (1,1,3,3-tetramethyl-5-Oddaoyl) -ethylthiophenylphosphonicoumbboomide and 4-ethylaulfonylbenzaldehyde to give tthyl-p- [2- (1 _> 1,3> 3-tettameteyl-5-Ondtoyl) propenol] phthylsulfoo, m.p. 125-127 ° C, from [1- (5,6,7,8-tetrahydro-5,5,8,8-trimethyl-2-naphthyl) ethyl] trifluorophenium boomide and 4-o-propylsulfonylbenzaddehyde to give prooyl -p- [2- (5,6,7, -8-tetrothiazole-5, 5, 6, 6-tetramethyl-2-nottyl) ptopenol] phenyl salt, m.p. 151-152 ° C, from [1- (5,6,7) 8-tetrahydro-5,5,8,8-tetrafluoro-2-naphthyl) ethyl] triphonylphenoniuetoouid and 4- (8-propylsulphonylbenzaddehyde) afford isopropopylp- [2- (5,6,7,8-tethoeydro-5,5,8), 146-147 ° C, from [1- (5,6,7,8-tetrteydroo5,5,8,8-tetrafamethyde-2-octyl) -ethyl] -phenophenone] -butamide and 4- (8-methyl-2-naphthyl) phenydsudfone, m.p. isobutyl-8-fluorophenone adadide, yielding 1-methylpropyl-β- [2- (5,6,7,8-tetrteydro-5,5,8,8-tetrafmethyl-2-oaphthyl) ptopexole] phenoxysulfone, m.p. 143-144 ° C, from [1- (5,6,7,8-tetrteydro-5,5,8,8-tetra 2-ethyl-2-octyl) ethyl] -thiophenophenoxy-benzoidide and 4- (2-eyedoxyethylsulfonyl) bonzaddehyde to give 2 - [[p- [2- (5,6,7,8-tetrteydro-5,5,8,8-tetrahydro-2-)] - naphthyl) prope ^[ f] ^[ b] wl] 8-sulfooyl] -ethanol, m.p. 131-133 ° C, from [1- (5,6,7, 4-tetrazol-2-yl) -hydroxy-5,5,8, 8-Tetrafluoro-2-n-phthyl) ethyl] -fluorophenoxyethanol and 4-ethylthio-benzaddehyde gave ethyl-p-O, 7,8-tetramethyl-2, 5-tetramethylthi-2-oaphthyl) -propenol] phenol-88-sulfide, m.p. 89 ° C, from [1- (5,6,7,8-tetrteydro-5, 5,8,8-tetrameteyl-2-octyl) ethyl] trfennyph ocofonium roomide and 4-uutyl · thiobeoztldeeyde, methanol-P is obtained. [2- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydro-2-ylmethyl) -propyl] -phenyl] -amide, m.p. 9-120 ° C.

Benzaldehyde derivatives can be prepared as described in Example 3 'by reacting the propylene aldehyde with the corresponding mercaptan followed by oxidation with m-chloroperbenzoic acid.

Example A

Maat with 1% active ingredient - can be made from the following ingredients:

an active ingredient, for example ethyl-β-β-tetramethyl (o-5,5,8,8-tetramethyl) propenyl] ool, white wax, white paraffin oil 'thick

DEHYMJLUS E (high-molar aliphatic ester) benzoic acid water, deminoralic acid

1.0 g 35.0 g

4.0 g 18.0 g

7,0 g

0.2 g to 100.0 g

Cleaning Β

Ointment with 0.1% active ingredient can be prepared from the following ingredients:

active substance, for example ethyl-β- 2- (5,6,7,8-tetrahydro-5,5,8,8-tetrameehhy-2-naphthyl) propenyl] phenylsulfone 0.1 g vaseline, white 35.0 g wax, white 10.0 g paraffin oil, viscous 18.0 g

DEHYMULUS E (high molecular weight aliphatic ester) 7.0 g benzoic acid 0.2 g water, demineealised to 1.0> 0 g

4.

Example 1 C d

Suspension ointment may be prepared from the following ingredients:

active substance, such as ethyl p- [2- (5,6,7,8-tetrahydro-5 _l 5 »8 & - 2-tetrametthl neatyl) propenyljfeellsulfoe. 0.3 g paraffin oil, ¹ viscous. 36,7 g vaseline, white. 45.0 g Lunacera tó (hydrocarbon-based wax) 15.0 g castor oil, hardened 3.0 g

Claims (3)

A process for the preparation of novel tetrahydronaphthalene and indane derivatives of formula (I) wherein * n is 1 or 2, Z represents a mercapto group or a group of formula -S (O) _m R in which m is 0, 1 or 2, R is C 1 -C 4 alkyl. or, when m is 1 or 2, also a hydroxy group, and pharmaceutically acceptable salts of sulfonic and sulfenic acids of formula I, characterized in that they are reacted with [1- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-4-naphthyl-ethyl] - optionally [1- (1,1,3,3-tetramethyl-5-neo-yl) -thiyl] -triaryl-f-sf-e-salt or -methyl ket- ey of formula II (II), 2. The process of claim 1 wherein the starting material is a compound of formula (II) wherein n is 2 and A is as defined in point 1. 2 35526 β with dialkoxyphosphonylbenzyl derivatives of the general formula III in which n is as defined above, ^Z * represents a C1-C4 alkylthisacin group, a C1-C4 alkylsulphinyl group or a C1-C4 alkylsulfonyl group and either, And. represents a tarylphosphinium ethyl group of the formula H ₃ C-h-P [4] ₃ ⁽⁺⁾ Y ⁽ ·) B represents a formyl group, in or A represents an acetyl group and B is a known dialkoCyrosoonylmethyl group of formula h '. -cH ₂ -p [T] ₂ , wherein 4 represents an aryl group, T represents a C 1 -C 4 alkoxy group, an anion of an organic or inorganic acid and is a cation, and optionally the sulfonic acid salt or sulfonic acid salt obtained is converted to the free acid. 3. Method according to claim 1 or 2, vyzanaujicí in that as the starting material used is a compound of formula III, wherein Z ^ alkylsuiooaylovou general represents a group having 1 to 4 carbon atoms, a group not ^b -ЗД М * ^ A 'and B M * maai meanings Uve en ^{d s} in ^b of ^DE of the first