JPH07503966A - Novel therapeutic applications of pyridylpyrrolothiazole carboxamide derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Novel therapeutic applications of pyridylpyrrolothiazole carboxamide derivatives The present invention is based on the general formula: During the ceremony, R is a general formula.

represents the group of X is oxygen atom, carbonyl, hydroxymethylene, carboxamide, methylene carbonyl, carbonylvinylene or vinylenecarbonyl, and Y is a carbocyclic heterocyclic aromatic group, 3-(3-pyridine,)-18. 3H-pyrrolo [1. 2-c]Thia-nol-7-carboxamide derivative, In their stereoisomeric forms (as well as in their mixtures as well as their salts) Therapeutic applications of 1.

Conventionally, products of general formula (1) or analogs thereof and their production have been developed in Europe. State Patent (EP) No. 115,979, European Patent (EP) No. 388,309 and U.S. Patent No. 4,906.757 and U.S. Patent No. 4.783,472. in the treatment of allergies, inflammation and inhibition of platelet aggregation, as well as PAF-acetate Regarding their usefulness in the treatment of acether-related conditions Written.

Pyrrolo [1. 2-cl thiazole carboxamide derivatives, These stereoisomeric forms or mixtures thereof, as well as their salts, are Lovirus infections, especially AIDS (Acquired Immune Deficiency Syndrome) and related symptoms Prevention and/or treatment of the group [ARC (AIDS-related complex)] It is useful for the manufacture of medical products intended for medical treatment.

Prevention is for subjects exposed to HIV virus (human immunodeficiency virus) and - non-symptomatic seropositivity that represents a risk of disease development in subsequent years after infection means the treatment of the subject.

In the general formula (I), the symbol Y represents an aromatic group, preferably phenyl, chenyl or a pyridyl group.

Products of general formula (1) where X is carboxamide or hydroxymethylene group is a new product. These piroro [1. 2-cl thiazole carboxy Amide derivatives are prepared by methods similar to those described in the aforementioned references. can be built.

The activity of the halide product of general formula (1) was demonstrated by the following method.

Tumor necrosis factor (TNF) inhibits HIV virus production, especially in chronically infected cells. This causes the activation of rus.

pyrolo to the induction of HIV-1 virus [1. 2-cl thiazole carboxy The effects of mido derivatives were studied in chronically infected cell lines.

A U1 cell line was used, where the U1 cell line is a promonocytic U937. infected by a virus and infected with phorbol myristate acetate (Phorb ol Myristate Acetate (PMA), TNF and other selected for their ability to increase virus production in response to mediating factors. [Folks et al., 5science 238.800 (1987)]. reverse transcription enzyme The activity of the element is used as an indicator of virus production. In this way, the sting Analyze the effect of increasing the concentration of the entity to be studied on the stimulated cell line.

experimental research The product to be studied is dissolved in dimethylformamide (DMF).

Stock solutions are prepared on the day of the assay and kept at a temperature of 4°C. DMF concentration is one Perform dilution to obtain a constant (0.1%).

Cell cultures were collected during exponential growth phase and a final 1°C of 2X10' cells/ml was added. Re-inoculate in the presence of various concentrations of the product to be studied in proportions.

After 30 minutes, all cultures are supplemented with TNFα or PMA.

Each assay is performed in triplicate, excluding controls that are performed in quadruplicate. . After 3 days, a small portion of the supernatant from the culture was collected and used for measurement of reverse transcriptase. Freeze.

Reverse transcriptase activity measurements are performed by known techniques in duplicate experiments [S pyrolo[ 1,2-c]thiazole carboxamide derivatives at concentrations of 1.10 and 30 μM. Research at the degree.

TNFα is added at a rate of 100.10 or 1 unit/ml.

Some controls do not receive the activator. Other contrasts exist to be studied. Can not accept. Other controls receive neither product nor activator. .

result: Viruses caused by pyrrolo[1,2-c]thiazole-7-carboxamide derivatives The decrease in production was significant and for U1 cells treated with TNFα or PMA. is dose dependent. On the third day, treated with 10 units/ml TNFα. and for U1 cells supplemented with product at a concentration of 10 μM, at least 50% A decrease in reverse transcriptase activity is observed.

Moreover, pyrrolo[1,2-c]thiazole carboxamide derivatives of general formula (I) The conductor does not affect cell viability regardless of the concentration used.

The results are shown in Table I below.

The present invention provides a pyrrolothiazole carboxamide derivative of general formula (1) with its steric structure. in isomeric form or mixtures, optionally in salt form, in pure form, or one or more compatible and pharmaceutically acceptable diluents or agents; The present invention relates to the preparation of pharmaceutical compositions containing in combination with a dejuvant.

The pharmaceutical composition according to the invention blocks the replication of retroviruses and thus prevents the progression of the disease. can reduce the severity of infection or reduce its intensity in infected subjects. ! : Especially in the case of HIV infection, by inhibiting this virus. , reduce the progression of AIDS or its severity in infected subjects be able to.

The pharmaceutical composition according to the present invention can reduce the severity of the disease in subjects infected with retroviruses. Progression to a stage can be prevented or delayed.

The composition can be used for prophylactic or curative purposes. "Prevention" means immunity progression in subjects with the defect and/or retroviral infection. It means to prevent.

Of course, the composition of these compositions depends on the particular case of the gastrointestinal tract of immunosuppressed subjects. will be adapted.

The compositions can be used orally, parenterally or rectally.

Sterile compositions for parenteral administration are preferably aqueous or non-aqueous suspensions. Or it can be a solution that is an emulsion. as a solvent or excipient, Water, propylene glycol, polyethylene glycol, vegetable oil, especially olive oils, injectable organic esters such as ethyl oleate or suitable organic solvents can be used. These compositions also contain adjuvants, especially moisturizers. agents, tonicity agents, emulsifiers, dispersants and stabilizers. sterile yes in several ways, for example, by sterile filtration, by incorporating sterilizing agents into the composition. , by irradiation or by heating. They are also in the form of a sterile solid composition that can be dissolved in a sterile injectable form at the time of use It can be prepared in

Use tablets, powders, powders or granules as solid compositions for oral administration You can obi. In these compositions, the active products according to the invention (if necessary) in combination with other pharmaceutically compatible products) with one or more inert Mixed with sexual diluents or adjuvants, e.g. sucrose, lactose or starch. match. These compositions also contain lubricants such as magnesium stearate. can be included.

pharmaceutically acceptable emulsions as liquid compositions for oral administration; Solutions, suspensions, syrups, containing an inert diluent, e.g. water or paraffin oil You can use an elixir that does this. These compositions also contain more than a diluent. Extraneous substances may be included, such as humectants, sweeteners or flavoring agents.

Compositions for rectal administration are layered formulations or rectal capsules, which are In addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyesters may be added. Contains ethylene glycol.

In the general method, the physician determines the age, weight and product and the subject to be treated. will determine the dosage determined to be most appropriate according to the particular factors.

Generally, in adults, the dosage is 25-50 mg/day.

The following examples illustrate compositions according to the invention but are not meant to be limiting.

cold dust twist N-(3-phenoxyphenyl)-3-(3-pyridyl)-1)1.3H-bi0 Mouth [1,2-cl thiazole-7-carboxamide 5mg Magnesium stearate 2mg 7ri') zok (ACDISQL): 1% 2mg colloidal silica: (martyrdom) 5% 1mg lactose 190mg Pyrrolo[1,2-c]thiazole carboxamide derivatives are described in the aforementioned references. It can be produced by methods analogous to those described. For example, implementation The products of Examples 5-8 can be prepared as described below using 2 g of (R3)-7-chloro Formyl-3-(3-pyridyl)-1H.

3H-pyrrolo[1,2-c]thiazole in 1.4 cm of dioxane g of 3-benzoylmethylaniline and 1.9 cm” of triethylamine. Add to the solution over about 10 minutes at about 60°C. The reaction mixture was heated to 100°C for 5 hours. heated for 20 minutes, cooled to about 25°C, and removed the solvent at a temperature around 60°C under reduced pressure (2 , 7 kPa). The residue was dissolved in 200 cm3 of dichloromethane and 80 cm3 of dichloromethane. Take up in cm3 of distilled water. The organic phase was decanted and a total of 180 cm3 of I Wash with N sodium hydroxide and then with 300 cm3 of distilled water. organic extraction Add 5 g of decolorizing charcoal to the effluent, dry with anhydrous magnesium sulfate, filter, and The solvent is then removed under reduced pressure (2.7 kPa) at a temperature around 45°C.

2.9 g of the resulting resin was dissolved in 300 cm” of ethyl acetate and 25 g of silica Filter through a column with a diameter of 3 cm containing powder (0.02-0.045 mm). child column with a total of 75 cm3 of ethyl acetate.

The filtrates were combined and a Reduce to dryness. 2.5 g of the resulting cream-colored solid were first poured into a 25 cm3 boiling pot. Dissolve in acetonitrile. The resulting solution is filtered hot. filtrate for 48 hours Cool to 10°C. The obtained crystals were separated by filtration and the total amount], Ocm' of water-cooled acetonitrile and vacuum (13, Dry under 5 Pa). In this way, 1.4 g of a beige solid was obtained, which redissolved hot in 200 cm' of ethyl acetate and in the presence of 0.5 g of decolorizing charcoal. Work up and filter hot. The solvent was removed under reduced pressure (2, After evaporation under 7 kPa), the obtained 1.2 g is finally boiled in 25 cm3. Dissolve in acetonitrile. The solution is filtered hot. Bring the filtrate to approximately 20°C. Allow time to cool. The obtained crystals were separated by filtration, and a total of 10 cm3 of acetic acid was collected. Rinse with tonitrile and vacuum (13,5 Pa) at a temperature around 80’C. Dry underneath. 0.75g(7)(R3)-N-(3-phenanulfenyl)- 3-(3-pyridyl)-11-L 3H-pyrrolo[1,2-c]thiazole-7 - The carboxamide is thus obtained as a cream-coloured solid, which at around 165°C melt.

3-benzoylmethylaniline is G, G, 1. MOORE, J, K.

HARRINGTON, J. Med, Chem, 18.386 (1975 ).

Example 6 7.8 g of (R3)-7-chloroformyl-3-(3-pyridyl)-1H,3H -pyrrolo[1,2-c]thiazole in 165 cm', t-xane. In a solution of 6 g of 3-aminochalcone and 8.3 cmj of triethinogenine, approx. Add over about 10 minutes at 60°C. The reaction mixture was heated to 100°C for 6 hours. , cooled to about 25°C, and the solvent was heated to around 50°C a7! Reduce pressure at r4 (2, 7 kPa). The residue is 500 cm3 of OO methane and 200 cm3 cm' of distilled water. Decant the organic phase and evaporate a total of 450 cm3. Wash with distilled water, dry with anhydrous magnesium sulfate, and remove the solvent at a temperature around 40°C. and removed under reduced pressure (2,7 kPa). 3000 g of the resulting foam Dissolve in m3 boiling acetonitrile. Bring the filtrate to a temperature around 10℃ for about 3 hours. Cool over time. The resulting crystals were separated by filtration and placed in a water cooling chamber with a total area of 20 cm. Wash with setonitrile and reduce pressure (13,5 Pa) at a temperature around 50 °C. Dry underneath. 6.6 g of (R3)-N-[3-(3-phenyl-3-oxop Lopenyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2 -clthiazole-7-carboxinamide is obtained in the form of a cream-colored solid; This melts at around 180°C.

3-Aminochalcone can be produced by the following method.

42.5 in a mixture of 40 cm' of absolute ethanol and 16 cm3 of 12N hydrochloric acid. g of stannous chloride in 50 cm' of absolute ethanol. Add the entire amount to the Lochalcon suspension over approximately 50 minutes, maintaining the temperature at approximately 45°C. do. The reaction mixture is then refluxed for 2 hours 30 minutes and then cooled to about 20°C. . The precipitate was separated by filtration, washed with approximately 1000 m3 of ethanol, and Dissolve in cm3 of ION ammonium hydroxide. 200 cm3 of distilled water and Add 200 cm' of ethyl acetate. Decant the organic phase and add water Extract the phase with a total of 800 cm' of ethyl acetate. Combine organic extracts and add total Washed with 300 cm3 of distilled water, dried over anhydrous magnesium sulfate, and heated to 40°C. Concentrate to dryness under reduced pressure (2,7 kPa) at a similar temperature. Thus, 9. ! 531 3-aminochalcone was obtained in the form of a yellow solid, which was heated at around 156 °C. melt.

3-Nitrochalcone from Le Fevre and Pearson SJ.

Chem, Soc, 2807 (1932).

Example 7 Consisted of 0.42 cm' of 2N sodium hydroxide and 4 cm' of distilled water. A solution of 0.31 g of sodium borohydride in the mixture was added to 25 cm of methanol. 8.8g of (RS)N(3<:/Soy/Lzphenyl)-3-(3- pyridyl)-18,3H-piOD[1,2-c]thiazole-7-carboxya Add to the solution of Mido in full at a temperature around 25°C. After stirring for 48 hours, 3 cm' of 4N acetic acid, 250 cm' of distilled water and 250 cm3 of ethyl acetate. Added. Decant the organic phase and dilute the aqueous phase with 250 cm” of ethyl acetate. Extract. The organic phases were pooled and washed with a total of 200 cm’ of distilled water, then 10 Wash with 0 cm3 of saturated sodium bicarbonate solution and 100 cm’ of distilled water. Ru.

0.5 g of decolorizing charcoal was added, the mixture was dried over anhydrous magnesium sulfate, and The solvent is then removed under reduced pressure (2.7 kPa) at a temperature close to 40°C. 8. 2 g of the obtained orange foam was mixed with 800 g of silica (0°02-0.045 mm ) on a column with a diameter of 8.5 cm. eluted with a mixture of cyclohexane and ethyl acetate and a 80 cm” Collect the minutes. Discard the first 45 fractions, combine the next 32, and remove the solvent from 4 It is removed under reduced pressure (2,7 kPa) at a temperature around 0°C. 5.6g yield Dissolve the orange foam in 90 cm' of boiling acetonitrile. This melt Filter the liquid hot. Cool the i& to 10° C. for 12 hours. Separate the crystals by filtration , washed with a total of 10 cm3 of acetonitrile and at a temperature around 60°C. Dry under reduced pressure (12,5 Pa). Thus, 1.4 g of (R3)-N-[3 -(α-hydroxybenzyl)phenyl]-3-(3-pyridyl)-1it 31-1-biO[1,2-c cothiazole-7-carboxamide is a white solid It is obtained in the form of , which melts at temperatures around 182°C.

Example 8 6g of (R5)-7-chloroformyl-3-(3-pyridyl)-18゜3) (-pyrrolo[1,2-c]thiazole in 100 cm' of dioxane at 4.2 g of 3-aminochalcone and 5.5 cm3 of triethylamine, approx. Add over approximately 15 minutes at 0°C. The reaction mixture was refluxed for 6 hours and brought to approximately 25°C. Cool and remove the solvent under reduced pressure (2,7 kPa) at a temperature around 60 °C. do. The residue was taken up in 500 cm' of dichloromethane and the insoluble material was removed by filtration. and washed with a total of 60 cm3 of dichloromethane and 200 cm3 of distilled water. do. Decant the organic phase and add 100 cm3 of IN sodium hydroxide and and a total of 500 cm3 of distilled water. The solid obtained above was transferred to the chloromethylene phase. and 90-10 methylene chloride (by volume) of 100 cm3 /methanol mixture to obtain a clear solution. Add this solution to anhydrous magnesium sulfate. and filter through 50 g of silica (0,063-0° 200 mm). Ru. The solvent is removed under reduced pressure (2°7 kPa) at a temperature around 50°C. 8. 5 g of the solid obtained are dissolved in 150 cm 3 of the formulation butanol. obtained Filter the solution hot. The filtrate was mixed with a total of 30 cm3 of butanol and 40 cm” of Wash with ethyl ether and under reduced pressure (13.5 Pa) at a temperature around 100°C. to dry.

42.5 in a mixture of 40 cm' of absolute ethanol and 16 cm' of 12N hydrochloric acid. g of stannous chloride in 50 cm' of absolute ethanol. Add the entire amount to the Lochalcon suspension over approximately 50 minutes, maintaining the temperature at approximately 45°C. do. The reaction mixture is then refluxed for 2 hours 30 minutes and then cooled to about 20°C. . The precipitate was separated by filtration, washed with approximately 100 cm" of ethanol, and cm' of ION ammonium hydroxide. 200 cm3 of distilled water and Add 200 cm3 of ethyl acetate. Decant the organic phase and add water The sexual phase is extracted with a total of 800 cm3 of ethyl acetate. Combine organic extracts and add total Washed with 300 cm3 of distilled water, dried over anhydrous magnesium sulfate, and heated to 40°C. Concentrate to dryness under reduced pressure (2,7 kPa,) at a similar temperature. Thus, 5. 3 g of (R3)-N-(3-phenylcarbamoylphenyl)-3-(3-pyri zyl)-11-(,3H-pyrrolo[1,2-c]thiazole-7-carboxya Mido is obtained in the form of a cream-colored solid, which melts around 206°C.

Copy and translation of amendment) Submission (Article 184-8 of the Patent Law) August 23, 1994

Claims (5)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼In the formula (I), R is single stage: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ represents the group of X is oxygen atom, carbonyl, hydroxymethylene, carboxamide, methylene carbonyl, carbonylvinylene or vinylenecarbonyl group, and 3-(3-pyridyl)-1H, where Y is a carbocyclic or heterocyclic aromatic group, 3H-pyrrolo[1,2-c]thiazole-7-carboxamide derivative, that in the form of their stereoisomers or mixtures thereof as well as their salts, medical treatment intended for the prevention and/or therapeutic treatment of retroviral infections; Application in the manufacture of products. 2. The medical product is specifically intended for the prevention and/or treatment of AIDS. Application of Claim 1. 3.3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7 - The symbol Y of the carboxamide derivative represents a phenyl, thienyl or pyridyl group. Application of claim 1 or 2, characterized in that: 4. Compatible and pharmaceutically acceptable products of claims 1 or 3 characterized by being mixed with one or more diluents or adjuvants, Agents intended for the prophylactic and/or curative treatment of retroviral infections Method for producing the composition. 5. X is a carboxamide or hydroxymethylene group, and Y is a claimed The novel 3-(3-pyridine) of claim 1 as defined in claim 1 of )-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide derivative conductor.