CH656382A5 - SULFOXIDES, METHOD FOR THEIR PRODUCTION AND THEIR USE. - Google Patents

Description

The invention relates to new sulfoxides of the formula (CH2) n-CORl

I I S s

I.

o where R, for the hydroxyl, the amino, a lower mono- or dialkylamino, a lower alkoxy or a MeO group, where Me is a metal equivalent and alkyl groups can be substituted by aryl, and n is an integer are from 0 to 10 or Rj is the cyclohexylmethylamino group and n = 0, and processes for their preparation and their use.

According to the invention, the compounds of the formula I are obtained by using compounds of the formula

•> /

(CH2> n-C ° Ri where R] and n have the above meaning, oxidized.

The process according to the invention can be carried out according to known oxidation methods, for example with m-chloroperbenzoic acid. The reaction can be carried out in a solvent which is inert under the reaction conditions, e.g. B. in a 5 chlorinated hydrocarbon such as dichloromethane, preferably at low temperature, e.g. B. run under ice cooling. The end product can be isolated from the reaction mixture by known methods and optionally purified. The compounds of formula I have immunostimulation activity; in particular, they not only stimulate the antigen-dependent proliferation of lymphocytes, but also the antibody formation (primary and secondary immune response), as well as cell-mediated immunity, and thus increase the immune response, in particular the antigen-dependent immune response. This immunostimulating effect can be demonstrated in vitro and in vivo. In vitro, for example, the Mishell-Dutton test can be used, which is based on eliciting a homoral immune response by immunizing mouse spleen 1 cells in suspension culture against heterologous, red blood cells [Science, 153, 1004 [1966] and J. Exp. Med., 126, 423 (1967)].

Another in vitro test is based on the stimulation of the antigen-dependent formation of immune interferon. Lymphocytes (spleen cells from Balb / c mice) are incubated for 5 days together with allogeneic spleen cells from irradiated mice (CBA), otherwise analogously to the Mishell-Dutton test, in the presence or absence of test substance. The supernatants are collected and checked for the levels of immune interferon (protection of virus-infected L929 fibroblasts), the measured interferon units being standardized using a human leukocyte interferon preparation. In these test methods, stimulation is observed at concentrations of compounds of the formula I of approximately 0.01-10 mg / ml II__.

In vivo, immune stimulation can be demonstrated using the delayed-type hypersensitivity test (cell-mediated immunity) [Dietrich, et al., Int. Arch. Allergy, 38, 246 [1970]).

Another in vivo test is the activation of "natural killer" cells. The test substance is administered intraperitoneally or by os to naked (thymus-free) mice (Balb / c or C57 / BL). After 16 hours, the spleens are removed and the spleen cells are incubated for 4 hours with chromium-labeled target cells (C'Cr YAK-1). Natural killer cells destroy the target cells, releasing 51Cr into the supernatant. The supernatant is collected and the amount of 51Cr released is measured in the scintillation counter. As a control, use is made of the release from target cells which had been incubated together with spleen cells from untreated mice. This release is reported as 100% and the release after substance administration is calculated as a percentage change compared to the control. The increase in the release of 51Cr is observed after administration of compounds of the formula I in the dosage range from 0.1 to 10 mg / kg.

The compounds of formula I can therefore be used as immunostimulants, i. H. as immunological adjuvants to systemically increase the immune response and to increase non-specific immunity. Compounds of formula I are thus indicated e.g. for treatment or supportive treatment t d. H. together with other specific or supportive forms of therapy) of conditions and reduced immunanuvori. especially in the case of reduced II homoral immune response and / or reduced hypersensitivity reaction of the delayed type and for the treatment of conditions in which an increase in the immune response is otherwise desirable. In particular, compounds of formula I are indicated for the treatment or supportive treatment of disease states due to idiopathic

35

40

45

50

55

60

f> 5

3rd

656 382

Immunodeficiencies or immunodeficiencies of the type that occur in geriatric patients or in those with severe burns or generalized infections. The compounds of the formula I are also indicated for the treatment or supportive treatment of viral diseases (such as disseminated herpes, progressive pox diseases and disseminated varicella diseases) and also of Hodgkin's disease and other malignant tumors.

For the applications mentioned, the indicated oral dose is between about 0.1 mg and about 70 mg, administered once to achieve an adjuvant effect, e.g. B. with supportive treatment, or daily, in the latter case the dose is divided into 2 to 4 administrations per day or given in sustained release. Indicated dose units for oral administration therefore contain between approximately 0.025 and approximately 35 mg of the formula I substance if administered daily, or up to 70 mg of the formula I substance if a single, adjuvant treatment is desired.

Because of their immunostimulating activity, compounds of the formula I are also suitable as adjuvants for vaccines. For this type of use, an indicated oral dose between 0.5 and 100 mg, preferably about 70 mg, is administered on the day of vaccination with a possible repetition at the same dose 2 to 4 weeks later.

Pharmaceutical preparations containing the compounds of the formula I can be prepared according to standard galenical methods, e.g. B. by mixing with conventional, pharmaceutically acceptable diluents or carriers. Such preparations are simply made in the form of tablets, capsules or injectable solutions.

The starting products of formula II are partly new and can be obtained as follows:

10th

I I

S S

(CH2) n * C00H

r'i

S s o

w /

(ch0) .coo-n 2. n. \

«11 •

//

+ hn

/ R2

\

r.

/ R2

(ch9) -co-n 1 n r.

In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all the temperatures are given in degrees Celsius.

Example 1:

syn- and anti-1,2-dithiolane-4-carboxylic acid-3,4-dimethoxy-benzylamide S-oxide:

0.3 g asparagic acid veratrylamide are taken up in 15 ml of dry methylene chloride and cooled to ice bath temperature. 0.21 g of m-chloroperbenzoic acid, dissolved in 15 ml of dry methylene chloride, is added. After 1 h, the reaction mixture is shaken against sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The crystalline residue is taken up in a little methylene chloride and separated on a medium pressure column (Merck LiChro-Sorb Si60, size C; eluent: ethyl acetate).

syn isomer: Rf = 0.23, mp 164-166 °

anti-isomer: Rf = 0.35, mp: 191-193 °

Analogously to that described in Example 1, the following compounds can also be obtained (Rj in the 4-position):

20th

25th

30th

Bp:

Ri n

Fp:

2nd

3rd

-NH.CHZ- / H \

-nh.ch2.c6h5

0 0

syn anti syn anti

103-105 ° 131-133 ° 99-103 ° 161-163 °

35

The required starting products can be obtained as follows:

A) Aspartic acid veratrylamide: a) N-hydroxysuccinimide ester of aspartic acid To 0.32 g asparagic acid, dissolved in 20 ml of dry methylene chloride, 0.62 g of di- (N-succinimidyl) carbonate, 0.3 ml of pyridine and 1 g of anhydrous magnesium sulfate are added. The mixture is heated to 50 ° with nitrogen flushing and stirred under reflux for 3 h. After this time, the reaction mixture is allowed to cool, filtered off from the magnesium sulfate and evaporated. The residue is purified on a medium pressure column (Merck LiChroSorb Si60, size C) (mobile solvent: toluene / ethyl acetate = 1/1, 45 Rf = 0.56), mp: 129 °.

b) Asparagus Acid Veratrylamide 0.062 g of N-hydroxysuccinimide ester of asparagic acid are dissolved in 5 ml of dry methylene chloride. 0.112 g of veratrylamine is added at 50 room temperature. After 20 min, the reaction mixture is evaporated and purified on a medium pressure column (Merck LiChroSorb Si60, size A; mobile phase: toluene / ethyl acetate = 1/1; Rf = 0.32), mp: 154 °.

Analogous to that described under A, the following 55 starting products can also be obtained (R, in the 4-position):

60

R; and k represent hydrogen or an alkyl group optionally substituted by aryl.

Ri n

Fp:

B

-NH.CHZ- / H

0

119-123 °

C.

-NH.CH2.C6H5

0

119-123 °

Ni

Claims (3)

656 382 i PATENT CLAIMS 1. Sulfoxides of the formula (CH ^) -COR, 2.n 1 I. S S i O wherein Rj for the hydroxyl, amino, a lower mono- or dialkylamino, a lower alkoxy or a MeO group, where Me is a metal equivalent and alkyl groups can be substituted by aryl, and n for an integer from 0 to 10 stand or R! the cyclohexylmethylamino group and n = 0. 2. Process for the preparation of new sulfoxides of the formula (CH0) -COR, 2 n 1 I. S. i O 20th 25th where Rj is the hydroxyl, the amino, a lower mono- or dialkylamino, a lower alkoxy or a MeO group, where Me is a metal equivalent and alkyl groups can be substituted by aryl, and n is an integer of 0 to 10, or R] is the cyclohexylmethylamino group and n = 0, characterized in that compounds of the formula (CH2) n-c ° Ri 30th I. S where Rj and n have the above meaning, oxidized. 3. Use of compounds of formula I for the preparation of agents with immunostimulating activity.