DE2209244A1 - New pharmaceutical preparations - Google Patents

Description

CIBA-GEIGY AG, BASEL (SWITZERLAND)

Case 4-7399

Germany

New pharmaceutical preparations

The invention relates to new pharmaceutical preparations, in particular for the treatment of the menopausal syndrome accompanying anxiety and tension states, as well as climacteric failure symptoms or climacteric complaints.

It has been found that such disorders are particularly advantageous by administering a pharmaceutical

209839/1157

Preparation containing a combination of an estrogen with dissociated peripheral and pronounced central effects treat with a 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -etheno-anthracene.

Anxiety and tension often occur together with menopausal syndrome and with menopause Failure symptoms and menopausal complaints. at the treatment of such disorders is caused by the tranquillizer of 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -ethenoanthracene Type has an anxiety- and tension-relieving effect through influences on subcortical structures and on the gamma fiber system, while the mentioned estrogen in the sense of a substitution of the estrogen deficiency present in the menopausal syndrome works. The estrogen component controls the so-called vegetative symptoms, such as hot flashes, sweating, Paresthesia, fatigue, etc. A prerequisite for the clinical acceptability of estrogens in this syndrome is one Dissociation of the various intrinsic effects. It is of one suitable for the treatment of menopausal symptoms Estrogen has a pronounced central gonadotropin-inhibiting effect, as well as a selective effect on the vaginal epithelium to demand directed peripheral effect if the effect on the endometrium is absent or as weakened as possible.

The combination according to the invention extends the applicability compared to the individual active ingredients in such a way that that anxiety and tension as well as the climatic

209839/1157

bacterial deficiency symptoms of the Syinptomenkomplexes can be mastered.

Suitable estrogens are, in addition to the so-called estrogen pairlings, as they can be extracted from mare's urine, in particular estrogenic steroids with a 7a-methyl group, such as 7a-methyl-estradiol, 7-methyl-estrone, 7a- Methyl-3, 16a, 17a-trihydroxy-A ¹ * - ⁵ ' ⁵ "^ ¹⁰ ' -estratriene, the 7a-methyl-3, 16a, 17ß-trihydroxy-A ¹ * - ^5j5 ^ ¹⁰ ^ -estratriene, the 7a -Methyl-3, 16ß, 17ß-trihydroxy-A ^lj5s5i ^ ¹⁰ ^ -estratriene and the 7a-methyl-3, 16ß, 17a-trihydroxy-A ¹ * ⁵³⁵ ^ ¹⁰ ^ -estratriene.

The 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -ethenoanthracenes are above all those of the formula

(III)

R ¹

wherein R is an amino group, in particular a mono- or di-lower alkylamino group, v / ie the diine thy! amino, diethylamino, Monoäthylamino- or especially Monomethylaminogruppo, means, R and R for lower alkyl radicals, in particular

JL £ m

Methyl, lower alkoxy radicals, especially methoxy, hydroxyl groups, halogen atoms, especially chlorine, trifluoromethyl groups, Nitro groups, amino groups or hydrogen atoms

209Β3Π / 1 1 Π7

stand, 'where R _{g is} preferably hydrogen and R is in the 3- or preferably 2-position, R ^{1 is} chlorine,

Methyl or preferably hydrogen, R_ is a water

atom, a hydroxyl group or a lower alkanoyl

■ χ

oxy group, for example acetoxy, R ^ denotes a hydrogen atom or Rj and Rg together represent an oxo group, R denotes a hydrogen atom or R ^ denotes a hydrogen atom and R _K and R "together represent a second bond stand.

From this group of compounds are in particular called:

9- (ethylaminomethyl) -12-hydroxy-9,10-dihydro-9 # 10-ethanoanthracene, 9- (diethylaminomethyl) -12-hydroxy-9 * 10-dihydro-9,10-ethanoanthracene, 9- (dimethylaminomethyl) - 12-hydroxy-9 # 10-dihydro-9,10-äthanoanthrazen, 9- (dimethylaminomethyl) -12-oxo-9,10-dihydro-9., 10-äthanoanthrazen, 9- ^(D ifn ^e thylaminomethyl) -12- acetoxy-9,10-dihydro-9,10-ethane anthracene, 9- (ethylaminomethyl) -12-oxo-9,10-dihydro-9,10-ethanoanthracene, 9- (diethylaminomethyl) -9,10-dihydro-9, 10-ethanoanthracene, 9- (Dimethylaminomcthy1) -9,10-dihydro-9,10-ethanoanthracene, 9- (N -methyl-lithylaminornethylJ ^ 10-dihydro-10-utanoanthracene, 2-chloro-9- (methylaminoraethyl) -9 ; 10-dihydro-9 * 10-ethano-anthracene, 1,5-dichloro-9- (dimethylaminomethyl) -9,10-dihydro-9-10-ethanoanthracene, 10-chloro-9- (ethylaminomethyl) -9, 10 -dihydro-9,10-ethanoanthracene, 10-chloro-9- (diethylaminomethyl) -9, 10-dihydio-9,10-ethanoanthracene, 2-chloro-9- (di-

209839/1 1K7

220924A

methylaminomethyl) -9 * 10-dihydro-9,10-ethanoanthracene, 2-chloro-9- (diethylaminomethyl) -9,10-dihydro-9,10-ethanoanthracene, 10-chloro-9- (raethylaminomethyl) -9 , 10-dihydro-9,10-ethanoanthracene, 10 ~ chloro-9- (dimethylaminomethyl) -9 _J 10-dihydro-9,10-ethanoanthracene, 2-hydroxy-9- (dimethylaminomethyl) -9 ^ 10-dihydro ^^ 10-ethanoanthracene, 2-hydroxy-9- (methylaminomethyl) -9,10-dihydro-9il0-ethanoanthracene _J 2-nitro-9- (methylaminomethyl) S, 10-dihydro-9,10-ethanoanthracene, 2-amino-9 - (methylaminomethyl) ^, 10-dihydro-9,10-ethanoanthracene, 2-nitro-9- (dimethylaminomethyl) -9, 10-dihydro-9,10-ethanoanthracene, 2-amino-9- (dimethylaminomethyl) -9, 10-dihydro-9,10-ethanoanthracene, 2-methoxy-9- (dimethylaminomethyl) -9,10-dihydro-9,10-ethanoanthracene, 2-methoxy-9- (methylaminomethyl) -9,10-dihydro-9, 10-ethanoanthracene, 9 .- ( ^Dimefcn y ^{; 1} - ^aminometn y ¹ ) ~ 9i- ^! - ⁰ ~ ^din y ^ciro "9,10-ethenoanthracene.

The compounds of the formulas are particularly valuable from this group of compounds

CH

(IV) and

V ⁷

v / orin R denotes a methyl radical or a hydrogen atom tet and especially 9- (M ° thylaminomethyl) -9,10-dihydro-9,10-ethenoanthracene, and above all the 9 ^ (Mcthy1

2098 3 9/1157

aminomethyl) -9, 10-dihydro-9,10-ethanoanthracene ^

The mentioned estrogens and tranquillizers ·, depending on the number of their asymmetric carbon atoms in In the form of isomer mixtures, pure isomers (racemates) or optical antipodes. Used preferably they are each in the form of the more effective or less toxic isomer or antipode.

The aforementioned tranquillizers with basic groups can also be used in free form or in In the form of their non-toxic salts. As such salts come, especially salts with organic or inorganic acids, v / ie e.g .: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, Perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, Vinegar, propion, amber, glycol, milk., Apple, Christmas, Citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenyl acetic, benzoin, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, monoboxylic acid, Methanesulfone, ethanesulfone, hydroxyethanesulfone, Ethylene sulfonic acid; Halobenzenesulfone, toluenesulfone, Naphthalenesulfonic acid or sulfanilic acid; Cyclohexyl sulfamic acid, Methionine, tryptophan, lysine or arginine.

The invention therefore relates to pharmaceutical preparations which contain an estrogen, in particular one of the above

209839/1157

together with a 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -ethenoanthracene, in particular one of the above-mentioned, as well as the production of these preparations, furthermore the Use of these active ingredients in the form of the preparations mentioned or by combined but separate application for treatment nervousness, irritability, sleep disorders, anxiety and states of tension, Hot flashes, sweats, dizziness, palpitations, headaches as an expression of neurovegetative and emotional disorders in menopausal patients or after surgical or radiological castration.

Pharmaceutical preparations containing an estrogenic steroid as an estrogen are particularly valuable a 7a-methyl group together with a tranquillizer of the formula III and in particular of the formulas IV and V and above all together with the 9- (methylaminomethyl) -9, lO-dihydro-9,10- -ethenoanthracene or 9- (methylaminomethyl) -9, 10-dihydro-9, 10-ethano-anthracene.

A very special object of the invention are pharmaceutical preparations that contain 7a-methyl-estradiol, the 7a-methyl-estrone or the 7a-methyl-3, l6a, l7a-trihydroxy

estatriene or 7a-methyl-3, 16ß, 17a-trihydroxy-A ¹ / - ⁵ ' ⁵ ' ¹⁰ '-estatriene together with 9- (methylaminomethyl) -9,10-dihydro-9,10-etheno-anthracene or 9- (Methylaminomethyl) -9, 10-dlhydro-9,10-ethano-anthracene.

2 0 9 B 3 9/1 1 5 7

Accordingly, the use of these preferred preparations or the use of the individual components in a combination therapy is a special subject of the invention. .

In the new preparations, the ratio of estrogen to the tranquillizer can be of the ethano or ethenoanthracic type vary within wide limits.

The dosage of the new preparations depends of course on the effectiveness of the estrogens and tranquillizers concerned and the individual needs of the patient. You can, for example, for the estrogenic component between half and twice the single dose are, preferably being half used to simple single dose. For example, the above-mentioned particularly preferred preparations can contain 0.1 to 0.5 mg, in particular 0.2 to 0.3 mg of 7o-methylestrone, 0.1 to 0.5 mg, in particular 0.1 to 0.2 mg of 7a -Methyl-3, 16a, 17a-trihydroxy-A ^li ^ ^{> 5} ^ ¹⁰ ^ -estratrien or 0.2 to 1.0, in particular 0.3 to 0.6 mg of comjugated estrogens. The dosage of the tranquillizer can be between half and double the individual dose, with half to single dose preferably being used. For example, the above-mentioned preferred preparations can contain 5 to 20 mg, in particular 5 to 10 mg of 9- (methylaminomethyl) -9, 10-dihydro-9,10-ethanoanthracene hydrochloride, or 5 to 20 mg, in particular 5 to 10 mg, 9-

3 9/1157

(Methylaminomethyl) -9ilO-dihydro-9,10-ethenoanthracene hydrochloride contain. .

The new pharmaceutical preparations are mainly suitable for oral application and can be used as such the usual carrier materials, such as lactose, starch, gelatin, colloidal silica, mesium stearate, Talc, polyvinylpyrrolidone, and the like. They can also contain other therapeutically valuable substances included mixed in. They are available, for example, as tablets, coated tablets or capsules. They will be received in the usual way.

The estrogens and tranquillizers used are known or can be produced in a manner known per se.

The invention is described in the following examples, without thereby impairing its scope in any way should be limited.

2 0 9 8 3 9/1157

example 1

Tablets contain 5 mg of 9- (methylaminomethyl) -9,10-dihydro-9,10-ethano-anthracene and 0.2 mg of 7α-methylestrone can be prepared, for example, in the following composition will:

Composition:

, 9- (methylaminomethyl) -9,10-

dihydro-9,10-ethano-anthracene 5.0 mg

7a-methyl-estrone 0.2 mg

Lactose, 88.0 mg

Wheat starch ^ 5.8 mg

Colloidal silica 5.0 mg

Talc 5.0 mg

Magnesium stearate 1.0 mg

150.0 mg

Manufacturing

The two active ingredients are made with the milk sugar, the colloidal silicic acid and part of the wheat starch mixed and the mixture forced through a sieve. Another part of the wheat starch is made with 5 times the amount of water gelatinized on the water bath and knead the powder mixture with this paste until a weakly plastic mass originated.

209839/1 157

The mass is driven through a sieve, dried and the dry granules are sieved again. The remaining wheat starch, the talc and the magnesium stearate are then mixed in and the mixture is made into tablets weighing 150 mg
pressed.

2 0 9 '< :'> 9/1 1 5 7

Example 2

Tablets containing 5 mg of 9- (methylaminomethyl) 9,10-dihydro-9ilO-ethano-anthracene and 0.1 mg of 7 <* - methyl-3, 16a, 17a-trihydroxy Δ ^jj5 > - ^ '-estratriene can be found in, for example the following composition:

Composition:

9- (methylaminomethyl) -9, 10-

dihydro-9,10-ethano-anthracene. 5.0 mg

trihydroxy-A ^lj5i5 ^ ¹⁰ ^ -estratriene 0.1 mg

Milk sugar 88.0 mg

Wheat starch ^ 5> 9 mg

Colloidal silica 5 * 0 mg

Talc 5.0 mg

Magnesium stearate 1.0 mg

150.0 mg

Manufacturing

The two active ingredients are made with the milk sugar, the colloidal silicic acid and part of the wheat starch mixed and the mixture forced through a sieve. Another part of the wheat starch is made with 5 times the amount of water gelatinized on the water bath and knead the powder mixture with this paste until a weakly plastic mass

2 0 JU * 3 0 / H B 7

originated.

The mass is driven through a sieve, dried and the dry granules are sieved again. Then the remaining wheat starch, the talc and the magnesium stearate are mixed in and the mixture is made into tablets weighing 150 mg
pressed.

209839/1157

Example 3

Tablets containing 5 mg of 9- (methylaminomethyl) -9,10-dihydro-9,10-ethano-anthracene and 0.5 mg conjugated estrogens (expressed as sodium estrone sulfate) can e.g. manufactured in the following composition:

Composition:

9- (methylaminomethyl) -9.10-

dihydro-9,10-ethano-anthracene 5.0 mg

Conjugated estrogens (expressed as sodium estrone sulfate) 0.5 mg

Milk sugar '88.0 mg

Wheat Sugar ^ 5.5 mg

Colloidal silica 5 * 0 mg

Talc 5.0 mg

Magnesium stearate - 1.0 mg

150.0 mg

Manufacturing

The active ingredients are mixed with the milk sugar, the colloidal silica and part of the wheat starch and the mixture is forced through a sieve. Another part of the wheat starch is pasted with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a slightly plastic mass

209839/1157 ORIGINAL INSPECTED

originated.

The mass is driven through a sieve, dried and the dry granulate sieved again. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is wiped into tablets of 150 mg
pressed.

2 0 9 P: ί ·] I 1 Ί 5 7

Claims (2)

Claims 1. Pharmaceutical preparation containing an estrogen of dissociated peripheral and pronounced central action and a 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -etheno-anthracene or a non-toxic salt thereof together with a pharmaceutical carrier material. 2. A pharmaceutical preparation according to claim 1, characterized in that it is so-called as estrogen estrogen pair compacts or estrogenic steroid with a methyl group, and sometimes as 9- (aminomethyl '^ ^1, lO-diliydro-g äthano- or -äthenoanthrazen such the formula CH_-R -R, (III) j where R denotes an amino group, R. and R ₂ denote lower alkyl groups, lower alkoxy groups, hydroxyl groups, halogen atoms, trifluoromethyl groups, nitro groups, amino groups ^{or hydrogen atoms, R 1} denotes chlorine, methyl or hydrogen, R ^ a hydrogen atom, a hydroxyl group or a lower alkanoyloxy group, R ^ a water 209839/1157 or R ^ and R / - together for an oxo group stand, R "denotes a hydrogen atom or -Rg a. V / hydrogen atom and R _c and R "together for one 5 7 second bond, or a non-toxic salt thereof contains. 3 · Pharmaceutical preparation according to claim 1, characterized characterized that the 7 ^a -methyl-estradiol, the 7o-methyl-estrone, the 7o-methyl-j5, 16a, 17o-trihydroxy-A 1,5,5, ( ¹⁰ ) _ostratriene, the 7a-methyl-3 , 16a, 17β-trihydroxy-A 7a_Methyl-3, 16ß, 17ß-trihydroxy-A 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -ethenoanthracene 9- (ethylaminomethyl) -12-hydroxy-9,10-dihydro-9,10-ethano-anthracene, 9- (diethylaminomethyl ) -12-hydroxy-9, 10-dihydro-9,10-ethanoanthracene, 9- (dirnethylaminomethyl) -12-hydroxy-9,10-dihydro-9,10-ethanoanthracene, 9- (dirnethylaminomethyl) -12-oxo- 9,10-dihydro-9,10-ethanoanthracene, 9- (dimethylaminomethyl) -12 ~ acetoxy-9,10-dihydro-9,10 ~ ethanoanthracene, 9- (ethylaminoniethyl) -12-oxo-9,10-dihydro- 9,10-ethanoanthracene, 9- (diethylaminornothyl) -9,10-dihydro-9,10-ethanoanthracene, 9 ~ (diinolhylamino-methyl) - <), 10-dihydro-9,10-ethanoanthracene, 9- (II ■ -Ki .'thyl-ÄfcliylarnLnorr.othyl) -9, 10-dihydro-9,10-Uthanoanthrazc-n, 2- chloro-9 ~ (msthyla: nlnoraothyl) -9, 10-dihydro-9,10-eth &i'io - anthi'itzon, 1,5-DI chlorine --9- (dirnothylaminofncthyl) -9,10- BAD ORIGINAL 2 0 9 ft Ί ') / 1 1 5 7 dihydro-9,10-ethanoanthracene, 10-chloro-9- (ethylaminoniethyl) -9,10-dihydro-9,10-ethanoanthracene, 10-chloro-9- (diethylaminomethyl) -9,10-dihydro ^: 9.10- ethanoanthracene, 2-chloro-9 - (dime thy laminome thy l) -9,10-dihydro-9,10-ethanoanthracene, 2- 'chloro-9- (d iäthylaminomethy1) -9,10-dihydro -9,10- ethanoanthracene, 10-chloro-9- (methy laniinomethyl) -9,10-dihydro-9,10-ethanoanthracene, 10-chloro-9- (dimethylaminomethyl) -9,10 -dihydro -9,10-ethanoanthracene, 2- Hydroxy-9- (dimethylaminomethyl) -9,10-dihydro-9,10-ethanoanthracene, 2-hydroxy-9- (methylaminomethyl) -9,10-dihydro-9 , 10-ethanoanthracene, 2-nitro-9- (methylaminomethyl) ) -9,10-dihydro-9,10-ethanoanthracene, 2-amino-9- (methy1-aminomethyl) -9,10-dihydro-9i10-ethanoanthracene, 2-nitro-9- (dimethylaminomethyl) S, 10-dihydro -9,10-ethanoanthracene, 2-amino-9- (dimethylaminomethyl) S, 10-dihydro ~ 9> 10-ethanoanthracene, 2-methoxy-9- (dimethylaminomethyl) -9, 10-dihydro-9,10-ethanoanthracene, 2-methoxy-9- (methylaminomethyl) -9,10-dihydro-9,10-ethanoanthracene or 9- (Dimet hylaminomethyl) -9,10-dihydro-9,10-ethenoanthracene or a non-toxic salt thereof. H. A pharmaceutical preparation according to claim 1, characterized in that it comprises ^a 7-methyl-estradiol-methylestrone 7c, the 7a-methyl-3, L6A, LTA-trihydroxy-A ¹ * - ⁵ * ⁵ -estratriene '' ^1O ' the 7a-methyl-3, L6A _J 17-trihydroxy-A ¹ '^ ^lO ^ ^V-j5 östratrien, the 7a-methyl-3, l6ß-17.beta.-trihydroxy-A ¹ "* ⁵ *' ^1O '-östratrlen or 7a-methyl-3, 17a-trihydroxy-l6ß-A ^1> - ⁵ 'to ^10' -estratriene 2 0 9 R Ί 9/1 1 5 7 and a compound of the formula CH (IV) or where R is a methyl radical or a hydrogen atom, or contains a non-toxic salt thereof. 5. Pharmaceutical preparation according to claim 1, characterized in that it contains the fa- methyl-estrone, the 7 ^a -methylj5, 16a, 17a-trihydroxy-A '- ^^ v' -estratriene or conjugated estrogens and the 9- (methyl -aminomethyl) -9 _J 10-dihydro-9,10-ethanoanthracene or a non-toxic salt thereof. 6. Pharmaceutical preparation according to one of claims 1-5, characterized in that it is half to double Single dose of estrogen and half to double the single dose of 9- (aminomethyl) -9,10-dihydro-9,10-ethano- or -etheno-anthracene or a non-toxic salt thereof. 7. Pharmaceutical preparation according to one of claims 1-5, characterized in that it contains half to simple 209833/115 Single dose of estrogen and half to simple single dose of 9- (Aminorr.ethyl) -9,10-dihydro-9,10-ethano- or -etheno-anthracene or a non-toxic salt thereof. 8. A pharmaceutical preparation according to any one of claims 1-7, characterized in that it contains 0.1 to 0.5 mg of "Ja-Kethyl estron" and 5 to 20 mg of 9- (methylaminomethyl) -9,10-dihydro-9,10 - Contains ethano-anthracene hydrochloride. 9. Pharmaceutical preparation according to one of claims 1-7, characterized in that it contains 0.1 to 0.5 mg of 7o-methyl- ^, loajlTa-trihydroxy-A ¹ '' 5 ( ¹⁰ ) oestratriene and 5 to 20 mg of 9 - Contains (methylaminomethyl) -9, 10-dihydro-9,10-ethano-anthracene hydrochloride. 10. 'Pharmaceutical preparation according to one of claims 1-7, characterized in that it conjugated 0.2 to 1.0 mg Contains estrogens and 5 to 20 mg of 9- (methylaminomethyl) -9, 10-dihydro-9, 10-ethano-anthracene hydrochloride. 2 0 9: , ^; / 1 ι