CA2127545A1 - New therapeutic application for pyridyl pyrrolo thiazole carboxamide derivatives - Google Patents

Abstract

2127545 9317027 PCTABS00163 Application of derivatives of (pyridyl-3) -3 1H, 3H-pyrrolo ¢ 1,2-c! Thiazole carboxamide-7 of general formula (I) in which R represents a radical of general formula (II) for which X is an oxygen atom, a carbonyl, hydroxymethylene, carboxamido radical, a radical -CH2-CO-, _CH = CH-CO- or _CO-CH = CH-, and Y is a carbocyclic or heterocyclic aromatic radical, under their stereoisomeric forms or their mixtures and their salts, for obtaining a medicament intended for the prophylaxis and / or the therapeutic treatment of retrovirus infections.

Description

Wo 93/17027? ~ r PCl / FR93 / 00173 NOtlVET ~ LF ~ APPLICATIO ~ I TUF ~ RAPF ~ UrIOlJE DE DERIVES nu PYRII) YT.PYRROLOTHIAZOLF ~ CARBOXAMTr) E

The present invention relates to a new application therapeutic of (pyridyl-3) -3 1H, 3H-pyrrolo [1,2-c] derivatives 5 thiazole carboxamide-7 of general formula::
CONH - R
~ ' in which R represents a radical of general formula:

~ X ~ II) for which X is an oxygen atom, a carbonyl radical, 10 h ~ droxymethyl ~ ne, carboxamido, methylenecarbonyl, carbonylvinylene: ~
or vinylenecarbonyl, and:
Y is an aromatic carbocyclic or heterocyclic radical, ~
in their stereoisomeric forms or their mixtures as well as their:
salts 15 Products of general formula (I ~ or their analogs as well that their preparation, have been previously described in the patents European EP 115 979, EP 388 309 ~ American US 4 906 757 and US 4,783,472 for their usefulness in the treatment of allergies, from.
inflammation and inhibition of platelet aggregation as well as in the treatment of ailments in them-that} is involved the physiological role of PAF-aceter.

The pyrrolo [1,2-c] thiazole carboxamide derivatives of formula general III) in their stereoisomeric forms or their mixtures, aingi that their salts are useful for obtaining a drug intended for the prophylaxis and / or the therapeutic treatment of WO93 / 17027 ~, ~ rj PCI / FR93 / 00173 ,, ,,,, 5 ,, :
retrovirus infections, and more particularly AIDS (syndrome acquired immunodeficiency) and associated syndromes [ARC (AIDS
related complex)].

By prophylaxis we mean the treatment of subjects who have been exposed to HIVs (human immunodeficiency virus), especially asymptomatic HIV-positive people risk of developing the disease in the coming months and years after the primary infection.

In the general formula (I) the symbol Y represents a radical aromatic which can advantageously be chosen from radicals phenyl, thienyl or pyridyl.

The products of general formula (I) for which X is a carboxamido or hydroxymethylene radicals are new products.
These pyrrolo [1,2-c] thiazole carboxamide derivatives can be 1 ~ prepared by analogy with the methods described in the references references cited above.

The activity of the products of general formula (I) has been evidence as follows:

The Tumor Necrosis Factor (TNF) is responsible for the activation - 20 of the HIV virus, especially in chronically infected cells.

The effects of pyrrolo [1,2-c] thiazole carboxamide derivatives on the induction of the HIV-1 virus have been studied on lines chronically infected cells.

U1 cell lines obtained after infection are used of the promonocyte line, U937, by the HIV-1 virus and selection-born according to the ability to increase viral production in response Phorbol Myristate Acetate (PMA), TNF and other mediators tFolks et al., Science, 2 ~, 800 (1987)]. Reverse activity transcr1ptase is used as an indicator of production vlrale, We thus analyze the effect of increasing concentrations of prodult to study on stimulated cell lines.

WO 93/17027 '~ j PCT / FR93 / 00173 ., ~ ~, i. :.

Experimental study The product to be studied is dissolved in the dimethylformamide (DMF). Stock solutions are prepared during the day of the test and kept at a temperature of 4C. Dilutions S are carried out in such a way that the DMF concentration is constant (0.1%).

Cell cultures are collected during the growth phase exponential and re-cultivated ~ due to conc ~ ntration final of 2x105 cells / ml, in the presence of different concentra-the product to be studied. 30 minutes later, all of the cul-tures is supplemented with TNFα or PMA.

Each test is done in triplicate, except for the controls which are done in quadruple. Three days later, a fraction of the supernatant cultures are taken, and frozen for measurement of the reverse transcriptase.

Your measurement of the reverse transcriptase activity is done by known techniques, in duplicate [Strebel et al., Nature, 32 ~, 728 (1987)].

Pyrrolo [1,2-c] thiazole carboxamide derivatives are studied - 20 at concentrations of 1, 10 and 30 ~ M.

The NPT ~ is added ~ at the rate of 100, 10 or 1 Unit ~ s / ml.

Some controls do not receive the activator ~ Others controls do not receive the product to be studied. Others do not receive neither the product nor the activator.

~:
t _ -The decrease in viral production by pyr- derivatives rolo [1,2-c] thlazole carboxamide-7 is significant and dose-dependent dante dan ~ ca5 of U1 cells treated by TNFa or by PMA, On ~ our 3, we observe a decrease of at least 50% in the activity , "'i' 4 rate of reverse transcriptase for U1 cells treated with 10 Units / ml of TNF ~ and added with a concentration of 10 ~ M
some products.

Furthermore pyrrolo derivatives ~ l, 2-clthiazole carboxamide of general formula ~ I) have no effect on the viability of those; -lules whatever the concentration used.

The results are shown in Table I below.
Table I
,. . _ ~:
Example XY ~ of ~ ibition _ ~ _ 10 ~ M, ll -CO- ~ 1 23 1 72

2 -CO-CH'CH- ~ 3 6 7 5

3 _o_ ~ 33 71 . . , - ~ ..... ,,.

4 -CO- ~ 1 14 68 .-. . , S,.
-CH2-CO- ~ 14 69 r. . . _ 6 -CH5CH-CO-. - 3 2 8 5 ¦ 7 l -CHOH- ¦ ~ ¦ l O ¦ 50 WO 93/17027 ~ PCr ~ FR93 / 00173 ..

Example XY% inhibition 1 ~.
8 -CONH- -13 ~ 4 56 ¦ -O ~ 30 ¦ 47 The present invention relates to obtaining a com- ~ sition pharmaceutical containing a pyrrolothiazole c joxamide derivative of general formula (I) in its stereoisomeric forms or their nappies, possibly in the form of salt, in the pure state or in form of association with one or more diluents or adjuvants compatible and pharmaceutically acceptable.
. ~. .
The pharmaceutical compositions according to the invention are ca ~ -able to inhibit the replication of retroviruses and therefore reduce progression to the disease or to decrease its severity in 1 ~ infected subjects - ~

Particularly in the case of HIV infections, by inhibiting the replication of this virus, they are able to reduce the progress-Zion to AIDS or decrease its severity ~ in infected subjects your.

The pharmaceutical compositions according to the invention are suscep-tend to prevent or slow down the progress of infected subjects by retrovirus towards an aggravated stage of the disease.

~ They can be used for prevention ~ f or curative. By "preventive" means the act of preventing the development of ~ ets with immunodeficiency and / or infected with r ~ trovirus.

WO 93/17027 ~) PCT / FR93 / 00173 Of course, the constitution of these compositions will be adapted to the specific case of the di ~ estif tract of immunosuppressed.

The compositions can be used orally, teral or rectal ~

Sterile compositions for parenteral administration may wind be preferably ~ nce aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, use water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, organic esters injectable nicks, for example ethyl oleate or other sol-suitable organic wings. These compositions can also contain adjuvants, in particular wetting agents, isotonizing, emulsifying, dispersing and stabilizing. The sterilization can be done in several ways, for example by sanitizing filtration, incorporating agents into the composition sterilants, by irradiation or by heating. They can also be prepared in the form of solid compositions riles which can be dissolved at the time of use in a medium sterile place for injection.

As solid compositions for oral administration may - be used tablets ~ pills, powders or granules In these compositions, the active product according to the invention (possibly associated with another pharmaceutical product compatible) is mixed with one or more diluents or adjuvants inert, such as sucrose, lactose or starch. These compositions may also include substances other than di-brighteners, for example a lubricant such as magnesium stearate.

- As liquid compositions for oral administration, may use pharmaceutically acceptable emulsions, solutions, suspensions, syrups, ~ lixirs containing inert diluents such as water or paraffin oil. These co ~ posltion5 may also include substances other than WO 93 / l7027 '~ PCT / FR93 / 00173 diluents, for example wetting products, sweeteners or ~ -flavorings.

The compositions for rectal administration are the roofs or rectal capsules, which contain in addition to the principle S active, excipients such as cocoa butter, glycerides ~
semi-synthetic or polyethylene glycols. ;

In general, the doctor will determine the dosage which he considers most appropriate according to age, weight and factors specific to the product and the subject to be treated. Usually 10 in adults the doses are between 25 and 500 mg per day.
,,, ~.
The following example, given without limitation, illustrates a composition according to the invention. -- N- (3-phenoxyphenyl) (3-pyridyl) -3 1H, 3H-pyrrolo, -;
[1,2-clthiazolecarboxamide-7 .. ~ ........................ 5 mg - Magnesium stearate: 1 ~ ........................... 2 mg - ~
- ACD ~ SOL: t% ......................................... 2 mg - - Colloidal silica: 0.5% ...... ................ 1 mg - Lactose ............................................. 190 mg ~ es derivatives of pyrrolo [1,2-c] thiazole carboxamide can be prepared as described in the references cited above ~ demment. AT
By way of example, the products of Examples 5 to 8 can be prepared res as described below:

~ m ~

2 ~ 2 g of 7-chlorofor- are added at around 60C in approximately 10 minutes - - myl-3-l3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) to a solution of 1.4 g of 3-benzoylmethylan ~ line and 1.9 cm of tr ~ ethylamine in 50 cm of dioxane. ~ em ~ reaction mixture is heated 5 hours at 100C, cooled to 25C and the solvent is eliminated under reduced pressure (2.7 kPa) ~ a temperature close to 60C. The residue is taken up in 200 cm of dichloromethane and 80 cm of water ;:

WO 93/17027 `PCT / FR93 / 00173 ~ 8 distilled. The organic phase is decanted, washed by 180 cm at total of 1N soda then 300 cm of distilled water. Organ extracts 0.5 g of bleaching black is added, dried on anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure (2.7 kPa) at a temperature close to 45C.
The 2.9 g of resin obtained are dissolved in 300 cm of acetate ethyl, filtered through a column 3 cm in diameter containing 25 g of silica (0.02-0.045 mm). The column is washed by 75 cm at total ethyl acetate. The filtrates are collected and concentrated very dry under reduced pressure (2.7 kPa) at a temperature of around 50C. The 2.5 g of solid cream obtained are dissolved one first time in 25 cm of boiling acetonitrile. The solution obtained is filtered hot. The filtrate is cooled to a temperature close to 10C for 48 hours. The crystals are separated by filtration, washed with 10 cm3 in total of ice-cold acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature close to 50C. 1.4 g of a so-beige lide which is redissolved hot in 200 cm of acetate ethyl, and treated in the presence of 0.5 g of bleaching black, very hot. After evaporation of the solvent under reduced pressure (2.7 kPa), at a temperature in the region of 50 ~ C, the 1.2 g obtained are dissolved one last time in 25 cm of boiled acetonitrile - lant The solution is filtered hot ~. The filtrate is cooled to 20C for 48 hours. The crystals obtained are separated by filtration, rinsed with 10 cm total of acetonitrile and dried under reduced pressure (13.5 Pa) at a temperature close to 80C.
0.75 g of N- (3-phenacylphenyl) -3- (3-pyridyl) is thus obtained 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- ~ RS), in the form of a solid cream melting around 165C.

3-Benzoylmethylanillne is prepared according to GGI MOORE, JK
HARRIN5TON, J. Med. Chem., 18, 386 (1975).

WO 93/17027 ~ PCT / FR93 / 00173 EmDl ~ 6 At about 60 ° C., 8.8 g of 7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-clthiazole- (RS) to a solution of 6.6 g of 3-aminochalcone and 8.3 cm of triethylamine in 165 cm of dioxane. The reaction mixture is heated 6 hours 30 minutes to 100C, cooled to 25C and the soil-is removed under reduced pressure (2.7 kPa) at a temperature close to 50C. The residue is taken up in 500 cm of dichlorome-thane and 200 cm of distilled water. The organic phase is decanted, l ~ washed with 450 cm total distilled water, dried over sulphate anhydrous magnesium and the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature close to 40C. The 13.9 g of me-ringues obtained are dissolved in 300 cm of boiling acetonitrile.
The solution obtained is filtered ~ e hot. The filtrate is cooled to a temperature close to 10C for approximately 3 hours. The crystals obtained are separated by filtration, washed with 20 cm at total of frozen acetonitrile and dried under reduced pressure ~ 13.5 Pa), ~ a temperature close to 50C. This gives 6.6 g of N- [3- ~ 3-phenyl-3-oxo-propenyl) phenyl] -3- (3-pyridyl) 1H, 3H-pyrrolo [1 ~ 2-c ~ thiazole-7-carboxamide- (RS) ~ in the form of a solid cream melting around 180C.

3-aminochalcone can be prepared as follows:

A solution of 42.5 g of stannous chloride in a mixture of 40 cm of absolute ethanol and 16 cm of 12N hydrochloric acid is added drop by drop, in about 50 minutes, to a suspension of 15 g of 3-nitrochalcone in 50 cm of absolute ethanol, maintaining the temperature around 45 ~ C. The reaction mixture is then heated 2 hours 30 minutes at reflux, then cooled to around 20C. The precipitate is separated by filtratior., washed with approximately 100 cm of ~ thanol and put 30 dissolved in 25 cm of 10N ammonia. We have ~ 200 cm of water di ~ tilled and 200 cm of ethyl acetate. The organic phase is d ~ canted and the aqueous phase is extracted by 800 cm in total ethyl acetate. The organic extracts are collected, washed WO 93/17027 ~ PCT / FR93 / 00173 ] O

per 300 cm in total of distilled water, dried over sulphate anhydrous magnesium and concentrated to dryness under reduced pressure t2.7 kPa) at a temperature close to 40C. 9.5 g of 3-aminochalcone, in the form of a yellow solid, melting towards 156C.

3-nitrochalcone is prepared according to Le Fevre and Pearson, J.
Chem Soc., 2807 ~ 1932).

Example 7 A drop is added dropwise at a temperature close to 25C.
solution of 0.31 g of sodium borohydride in a mixed applied 0.42 cm of 2N soda and 4 cm of distilled water to a solution 8.8 g of N- (3-benzoylphenyl) -3- (3-pyridyl) 1H, 3H-pyrrolo ~ 1,2-c] thiazole-7-carboxamide ~ (RS) in 2 ~ cm of methanol. After 48 hours with stirring, we have ~ 3 cm of 4N acetic acid, 250 cm of distilled water and 250 cm of ethyl acetate. The organ-decanted, the aqueous phase is extracted by 250 cm ethyl acetate. The organic extracts are combined, washed with 200 cm in total of distilled water, then with 100 cm of a solution saturated with sodium bicarbonate and per 100 cm of distilled water.
0.5 g of bleaching black is added, dried over magnesium sulfate.
- anhydrous sium, and the solvent evaporates under reduced pressi ~ n (2.7 kPa) at a temperature close to 40C The 8.2 g of meringue orange obtained are chromatographed on a 8.5 cm column of diameter containing 800 g of silica (0.02-0.045 mm), eluted with a mixture of cyclohexane and ethyl acetate 20-80 (by volume) in collecting 80 cm fractions. The first 45 fractions are eliminated, the next 32 are combined and the solvent is evaporated under reduced pressure ~ 2.7 kPa) at a room temperature sine of 40C. The 5.6 g of orange meringue obtained are dissolved in 90 cm of boiling acetonitrile. The solution is filtered at hot. The filtrate is cooled for 12 hours at 10C ~ The crystals are separated by filtration, washed with a total of 10 cm of acetonitrile and dried under reduced pressure (1 ~, 5 Pa) at a temperature WO 93 / l7027. ,, ..................... ~, ~ ................... PCT / FR93 / OOt73. ~
"'ll`;' ~. ............................

sine of 60C. 1.4 g of N- [3- (u-hydroxyben-zyl) phenyl] -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxa-mide- (RS), in the form of a white solid, melting around 182C.

Example 8 Around 60C, 6 g of 7-chloroformyl-3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole- (RS) to a solution of 4.2 g of 3-aminobenzanilide, 5.6 cm of triethyla-mine in 100 cm of dioxane. The reaction mixture is heated 6 hours at reflux, cooled to 25C and the solvent is removed under reduced pressure (2.7 kPa) at a temperature close to 60C.
The residue is taken up in 500 cm of dichloromethane, the insoluble is separated by filtration, washed with a total of 60 cm of dichlorome-.
thane and 200 cm of distilled water. The organic phase is decanted, washed with 100 cm of 1N soda and 500 cm in total of distilled water.
The solid obtained above is added to the chloromethyl phase.
picnic and ajou, .- 100 cm of a mixture of methyl chloride- ~
lene / methanol 90-10 (by volume) to have a clear solution. .
The solution is dried over anhydrous magnesium sulfate and filtered on 50 g of sil_ce (0,063-0,200 mm). The solvent is evaporated under reduced pressure (2.7 kPa) at a temperature close to 50C. The 8.5 g of solid obtained are dissolved in 150 cm of butanol boiling. The solution obtained is filtered hot. The filtrate is cooled to a temperature close to 10C for 24 hours. The crystals obtained are separated by filtration, washed with 30 cm at total butanol and 40 cm of ethyl ether and dried under pressure reduced pressure (13.5 Pa) at a temperature close to 100C. We ob-thus holds 5.3 g of N- (3-phenylcarbamoylphenyl) -3- (3-pyridyl) 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide- (RS), in the form of a solid cream ~ melting around 206C.
. ''' . .

Claims (4)

Claims 1 - Application of (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c] derivatives thiazole carboxamide-7 of general formula:

in which R represents a radical of general formula:

for which X is an oxygen atom, a carbonyl radical, hydroxymethylene, carboxamido, methylenecarbonyl, carbonylvinylene or vinylenecarbonyl, and Y represents a phenyl, thienyl or pyridyl radical, in their stereoisomeric forms or their mixtures, as well as their salts, for obtaining a medicament intended for the prophylaxis and/or the therapeutic treatment of retrovirus infections. 2 - Application according to claim 1, characterized in that the medicinal product is intended for the prophylaxis and/or treatment of AIDS. 3 - Process for preparing a pharmaceutical composition intended for the preventive and/or curative treatment of infections due to retrovirus characterized in that a product according to the claim 1 with one or more diluents or adjuvants compatible and pharmaceutically acceptable. 4 - A new derivative of (pyridyl-3)-3 1H,3H-pyrrolo[1,2-c)thia-zole carboxamide-7 according to claim 1, wherein X is a carboxamido or hydroxymethylene radical and Y is defined as in claim 1.