HUT68396A - Method for preparing pharmaceutical preparation containing isoflavone derivative or salt of it - Google Patents

Description

The present invention relates to a process for the preparation of a compound of formula (I)

- where in the formula r! represents a C 2 -C 18 alkyl group which may be optionally substituted with C 1 -C 6 alkoxy, hydroxy, C 1 -C 6 carbalkoxy, phenyl, benzoyl or halogen;

Phenylalkyl optionally substituted with C 1-3 alkyl, optionally substituted with halo or nitro, or C 2-6 alkenyl; ·.

2.3

R and R are hydrogen or C 1-6 alkoxy

R is hydrogen, (C 1 -C 6) -alkyl or carboxyl;

is hydrogen or alkyl,

R 4 is hydrogen or when hydrogen is R 4 is methyl or hydroxymethyl

3 may be provided, provided that when R, R, R ⁴ , R 4 and R 4 are hydrogen, R 4 is for the preparation of a pharmaceutical composition containing an isoflavone derivative or a salt thereof other than isopropyl, characterized in that an isoflavone derivative of the formula wherein R 1, R 1, R ⁴ and R 4 are as defined herein - or a salt thereof is admixed with fillers, diluents, and other excipients conventionally used in the pharmaceutical art and formulated as a pharmaceutical composition for treating osteoporosis.

Compounds of formula I wherein H is hydrogen may be prepared by:

the. ) Reacting the ketones of formula (II) (wherein R 1, R 1, R 4 and R 2 are as defined above) with an ortho-formic acid alkyl ester in the presence of a basic catalyst, or

b. ) Reacting the ketones of formula (III) (wherein R 1 and R 4 are as defined above) with hydrogen cyanide and / or cyanide salts in the presence of halogenated hydrochloric acid, or

1'2

c. ) Ketones of formula III (wherein R, R, R and

R 1 is as defined above) with an alkyl tannic acid ester in the presence of an alkali metal, or

d. ) Reacting the ketones of formula (III) (wherein R 1, R 1 and R 4 are as defined above) with an alkyloxalkyl halide, then optionally saponifying and / or decarboxylating the resulting isoflavone ester, or

12

e. ) Reacting ketones of formula (III) (wherein R, R, R and r3 are as defined above) with organic carboxylic anhydride1, or

17

f. ) Ketones of formula III (wherein R, R, R and

· R ⁵ is as defined above), Ν, Ν-dialkyl acid amide with phosphorous chloride in the presence or

g. ) Dehydrating the 2-hydroxyisoflavanone derivatives of formula (IV) (wherein R, R, R and R are as defined above) and optionally introducing a non-hydrogen group into the resulting compound of formula (I) wherein R is hydrogen optionally converting a group into another R 1 group and optionally converting the resulting compound of formula (I) to a salt or liberating a salt thereof. (Hungarian Patent No. 162377).

The compounds of formula (I) containing the methyl group at the 6-position may be prepared by reduction of the halomethyl isoflavones obtained by the halomethylation from the compounds (I) containing a hydrogen atom. The reduction is preferably carried out in the presence of metals, preferably zinc.

The compounds of formula (I) having the 6-position alkoxy or hydroxymethyl group can be obtained by replacing the halogen atom of the halomethyl isoflavones prepared by the above procedure with alcohols or by converting the sodium acetate to the O-acetyl group and converting the acetoxy group to OH. live.

According to Hungarian patent specification 162377, compounds of the formula I and their salts lower blood cholesterol

- They have 5 woods and have an effect on metabolism, most of them are anabolic and some of them are catabolic.

Osteoporosis is a known disorder that is very common in postmenopausal women. For the treatment of osteoporosis, estrogen preparations, calcitonin, vitamin D and other calcium preparations are used. However, none of the above formulations proved to be sufficiently effective.

We have found that the compounds of the formula I and their salts, when used in the appropriate dosage, are very useful in the prevention or treatment of osteoporosis (its mechanism of action is not clearly elucidated).

Based on in vitro experimental results, it can be demonstrated that

Compounds of formula I.

- increase the ATP-generating capacity of muscle tissue,

increase hepatic mitochondrial glycerophosphate dehydrogenase activity, and

- improve the efficiency of cellular respiration.

These effects are a consequence of the increased calcium content.

(See Biochem. 3, 119, 129-138 (1980); Biochemistry Vol.

It is known in the literature that there is a vice versa relationship between the formation of calcium and the calcium content.

(Biochemistry (1977) 279; Current Topics in Biogenetics Vol.

6 (1977)).

• · ·

- 6 Based on in vitro experiments, the following agents were shown to be effective (see Table 1)

The following results were observed in clinical trials:

20-20-20 patients were treated with FL-276, FL-253, or FL-305 for 6 months (7 untreated controls) at a dose of 15 mg / kg body weight / day.

Among the treated patients, 15-16-16 patients reported significant improvement (reduced spine and joint pain), and 5-6 and 4 subjects, respectively, felt completely healed.

There was no improvement in untreated patients.

The results of the X-ray examinations confirmed the subjective judgment.

In 60% of treated patients, radiographs showed improvement.

In the treatment process, the active ingredient is preferably administered in the form of a capsule, tablet, or sustained release tablet.

The active ingredients of the pharmaceutical compositions of the present invention can be prepared in a known manner. As used herein, the term "known" encompasses procedures known from the prior art to the day of priority.

Claims (2)

1.) Process as active ingredient of formula (I) - where in the formula r! is a C 2 -C 18 alkyl group which may be optionally C 1-6 alkyl; it may be substituted by a C 1 -C 6 alkoxy group, a hydroxyl group, a C 1 -C 6 carbalkoxy group, a phenyl group, a benzoyl group or a balogen atom; Phenylalkyl or C2-C6alkenyl optionally substituted with C1-C3 alkyl, optionally substituted with halo or nitro 2 3 R and R are hydrogen or (C 1 -C 6) alkoxy; R is hydrogen, C 1-6 alkyl or carboxyl · R 1 is hydrogen or alkyl) R 4 is hydrogen, or when R 4 is hydrogen R ⁶ is methyl or hydroxymethyl 2 3 may be used, provided that when R, R 1 is hydrogen, R ^ for the preparation of a pharmaceutical composition containing an isoflavone derivative or a salt thereof other than isopropyl, characterized in that: - 11 isofla derivatives of the general formula (I), in which R 1, R 1, R 1 and R 4 are as defined in the preceding art, or salts thereof, which are conventionally used in the preparation of drugs, diluents and gums; mixed with excipients and formulated as a pharmaceutical composition for the treatment of osteoporosis. The process according to claim 1, wherein the active ingredient is formulated as a capsule, tablet, prolonged-release tablet.