DD268473A5 - A PROCESS FOR THE PREPARATION OF NEW THIENO-IMIDAZO (2,1-B) THIAZONE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel thienoimidazo (2,1-b) thiazole derivatives of the formula I in which A together with the two carbon atoms of the imidazole ring forms a group of the formulas IIa, IIb, R1 is hydrogen, C1-C4 Alkyl, halogen or CF 3, R 2 is hydrogen, halogen or CF 3 and R 3 is hydrogen or C 1 -C 4 -alkyl and, in the event that R 3 is hydrogen, of their pharmaceutically acceptable salts, by cyclizing an appropriately substituted 3- (1H-thienoimidazole -2-yl) thiobutansaeureesters with a dehydrating agent, optionally alkaline saponification of the ester and, if desired, conversion of the free acid into a pharmaceutically acceptable salt. The new compounds can be used to treat cancer or rheumatoid arthritis caused by a defective immune system. Formulas I, IIa and IIb

Description

Title of the invention

V for the preparation of new thieno-imidazo (2 _> lb) thiazolderivate

Field of application of the invention

The invention relates to a process for the preparation of novel thieno-imidazo (2, lb) thiazole derivatives, which can be used in medicaments for stimulating the immune system.

Field of application of the invention is therefore the pharmaceutical and chemical industry.

Characteristic of the known technical solutions

U.S. Patent 4,293,696 discloses 3-substituted phenylthiazolo (3'2 ^l : l, 2) inidazo (4,5-b) pyridine-2-alkanoic acids having immunomodulatory activity. However, since the pharmacological profile of action of these substances has not yet been tested, there is still a need for new compounds with immunostimulating action.

Aim of the invention

The aim of the invention is to provide a simple and economical process for the preparation of novel thieno-imidazo (2, lb) thiazole derivatives which can be used to treat diseases that are caused by a malfunction of the immune system, use ¹ to provide.

Explanation of the essence of the invention

The present invention was based on the object, starting from simple and easily accessible starting compounds by selecting suitable chemical methods to enable the preparation of compounds of general formula I of the formula sheet.

The invention therefore provides a process for the preparation of novel compounds of the formula I of the formula sheet, in which A together with the two carbon atoms of the imidazole ring forms a group of the formulas Ha or Hb of the Fonnelblattea, Ri is hydrogen, Ci - C4 alkyl, halogen or trifluoromethyl R 2 is hydrogen, halogen or trifluoromethyl and R 3 is hydrogen or C 1 -C 4 -alkyl and, in the case where R 3 is hydrogen, their pharmaceutically acceptable salts; the thieno-imidazo (2, 1-b) thiazole derivatives of the formula I and their salts are prepared according to the invention by

a) a compound of formula III of the formula sheet,

in which R 1 and R 2 have the abovementioned meaning and R 3 is C 1 -C 4 -alkyl, in the presence of dehydrating reagents to give a mixture of isomers of the formula I in which A is the groups of the formulas Ha and Hb and R 1, R 2 and R 3 have the abovementioned meaning have cyclized and the isomer mixture is separated, whereupon

b) optionally a compound of the formula I in which R 3 is C 1 -C 4 -alkyl, to give compounds of the formula I in which R 3 is hydrogen, alkaline saponified and

If desired, a free acid of the formula I obtained in process step b), in which R 3 is hydrogen, is converted with inorganic or organic bases into a pharmaceutically acceptable salt.

The term "C 1 -C 4 alkyl" as used in this specification refers to straight-chained or branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms, e.g. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl. The term "halogen" denotes chlorine, bromine or fluorine.

A preferred class of the compounds of the formula I is that in which R 1 is hydrogen, R 2 is chlorine and R 3 is hydrogen or methyl.

Particularly preferred single compound is:

5- (4-chlorophenyl) thieno (2 ^L , 3 ^L -4.5) imidazo (2, Ib) thiazole-6-es3-acetic acid methyl 7- 7- (4-chlorophenoxy) thieno (3 ', 2'-A , 5) imidazo (2, lb) thiazole-6-es-3-hydroxyethyl ether 5- (4-chlorophen> i) thieno (2 ', 3 ^l -4.5) imidazo (2, lb) thiazole-6-e4-isoic acid 7- ( 4-chlorophenyl) thleno (3 ^L , 2 ^L ~ 4.5) imldazo (2,] - b) thiazole-6-eic acid.

As dehydrating reagents in the cyclization of compounds of formula IiI all commonly used dehydrating agents can be used. Preferably, polyphosphoric acid or phosphorus oxychloride come into question, which can be used at the same time as a solvent. The cyclization temperature should be about 60 ⁰ C to 110 ⁰ C. Phosphorus oxychloride is best cyclized at reflux. The reaction time, depending on the temperature and the cyclization agent, is between about 10 minutes and 4 hours.

The Anellierungsisomerengemisch thus obtained, consisting of Jen esters of the formula I meaning A = Ha and Hb, by all ükhen methods of isomer separation such as recrystallization, column chromatography, partition chromatography, extraction u.a. we are separated. The esters of the formula I with the meaning A = Ha are preferably replaced by several times? Recrystallization from methanol obtained isomer-free. From the combined mother liquors, the esters of formula I with the meaning A = Hb can then be obtained isomer-free by column chromatography on silica gel, wherein elution mixtures in which the ester mixture dissolves well, such as. Mixtures Au3 to methylene chloride, chloroform, benzene or toluene on the one hand and ethers on the other hand, are suitable. The esters of the formula I where A = Hb are thus eluted first.

Optionally, the esters of formula I may be prepared by boiling with bases, preferably with equivalent amounts of alkali hydroxide solutions and with the addition of a solubilizer such as e.g. Methanol or ethanol, in almost quantitative yield to compounds of formula I, in which R3 is hydrogen, saponified.

468 ϊ? 3

The compounds of the formula I which have a free carboxyl group in the reaction in process b) b) can be converted into their pharmaceutically acceptable salts in the usual way with inorganic or organic bases. The salt formation can be carried out, for example, by dissolving the above-mentioned precursor compounds of the formula I in which R 3 HH b r " ^{f f f} ,,, in a suitable solvent, for example water or a 3m lower aliphatic alcohol, e Add an equivalent amount of the desired base, ensure good mixing and, after completion of the salt formation, the solvent is distilled off in vacuo. Optionally, the salts can be recrystallized after isolation.

Pharmaceutically acceptable salts are e.g. Metal salts, in particular alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium aza. Other pharmaceutically acceptable salts include, for example, easily crystallizing ammonium salts. The latter are derived from ammonia or organic amines, e.g. Mono-, di- or Triniedoralkyl (cycloalkyl or -hydroxyalkyD-amines, lower alkylenediamines or (hydroxy lower alkyl or ArylniederalkyO-lower alkylammonium bases, for example methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) -amino-methane, benzyl-trimethylammonium hydroxide and the same.

The compounds of the formula III can be obtained starting from the compounds of the formula IV (EP-A 201 094) known from the literature and V (CF.H. Allen, 0.3. Normington and CV Wilson, Can. J. Research, 11, 382 (1934 )), according to the following reaction scheme and the specific details in the examples, according to customary and familiar to any person skilled in the chemical working methods.

scheme

COO CrWkyl

Bra

IY

COO-Ci-CiAlkyl

VI

III

The novel compounds of formula I and their pharmaceutically acceptable salts show excellent stimulation of the immune system in in vitro models.

Because of these pharmacological properties, these compounds may be used alone or in admixture with other active ingredients in the form of common g. Cancer or rheumatoid arthritis, to be used as a drug.

The compounds of formula I are for human use and can be administered in a conventional manner, such as orally or parenterally. Preferably, they are administered orally, the daily dose being about 0.1 to 10 mg / kg of body weight, preferably 0.2 to 20 mg / kg of body weight. However, depending on the general condition and age of the patient, the subject compound of formula I, the nature of the disease, and the nature of the formulation, the attending physician may prescribe doses above or below.

If the substances according to the invention are used for prophylaxis, the doses move approximately in the same frame as in the case of treatment. Oral administration is also preferred in the case of prophylaxis.

The compounds of the formula I can be administered alone or in combination with other pharmaceutically active substances, the content of the compounds of the formula I being between 0.1 and 99%. In general, the pharmaceutically active compounds are in a mixture with suitable inert adjuvants and / or carriers or diluents, e.g. pharmaceutically acceptable solvents, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable, p.Vilkylenkol, Vaseline and the like.

The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules and the like, in semisolid form, for example as ointments or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and

contain auxiliary substances such as preservatives, stabilizers or emulsifiers, salts for varying the osmotic pressure and the like.

In particular, pharmaceutical preparations may contain the compounds according to the invention in combination with other therapeutically valuable substances. With these, the compounds according to the invention can be formulated, for example, together with the abovementioned additives and / or excipients or diluents to form combined preparations.

EXEMPLARY EMBODIMENTS example 1

5- (4-chlorophenyl) -thieno (2 ', 3'-4,5) imidazo (2 _t lb) thiazol-6-e33ig8äuremBthyle8ter

11.0 g (28.9 mmol) of methyl 4- (4-chlorophenyl) -4-oxo-3- (1H-thleno ( _2f 3-d) -imldazn ·.:> YlHiobutansäuremethylester (formula IH, Rj = H, R2 - Cl, R3 = CH3) are suspended in 99.0 g of phosphorus oxychloride and heated to boiling for 10 minutes, the excess phosphomethylchloride is distilled off and the residue is neutralized with saturated sodium hydrogencarbonate solution, which is extracted once with 300 ml and three times with 100 ml of ethyl acetate The combined organic phases werdfm dried over sodium sulfate, stirred with a h.ilben teaspoon activated carbon, filtered and evaporated to dryness

 The residue is recrystallized three times from methanol.

Yield: 6 ,. ¹ g of yellowish crystals (58.2% of theory) m.p .: 159-161 ⁰ C (methanol)

¹ H-NMR: (DM: 50)

delta (ppm): 7.70 (3; 4H, Ph-H), 7.31; 7.25; 7.22; 7.16 (AB; 2H; Th-H), 3.92 (35 2H;

¹³ C-NMR: (DMSO)

delta (ppm): 169.6 (s) 152.2 (s) 150.9 (s) 135.0 (s) 130.7 (d) 129.4 (d) 127.2 (s) 126.0 (s) 122.6 (3) 121.5 (d) 117.0 (3) 115.4 (d) 52.2 (q) 32.6 (t)

The starting material can be prepared as follows: 3-bromo-4- (4-chlorophenyl) -4-oxo-butanoic acid methyl ester

50.0 g (0.221 mol) of 4- (4- ^ 1θφΓΐβη> · 1) -4-oxy-Η'ΐΐ8η3ΜυΓβπΓ »Ιη> · Ιβ3ΐβΓ (CF.H. Allen, JB Normington and ^ CV Wilson, Can. Research, 11, 382 (1934)) are dissolved in 250 ml of glacial acetic acid and three drops of a solution of hydrogen bromide in glacial acetic acid are added. While stirring, 35.3 g (0.221 mol) of bromine are added dropwise,

that no noticeable browning can form in the reaction mixture.

After completion of the addition, stirring is continued for 15 minutes and then the glacial acetic acid is distilled off to a large extent.

The residue is neutralized with saturated NatrlrTihydrogencarbonatlöeung and extracted three times with a total of 600 ml of methylene chloride. The combined organic phases are yetrocknat over sodium sulfate, filtered and evaporated (67.2 g of yellow oil).

It is triturated with methanol and recrystallized from Metharoi.

Auebeute: 65.2 g of colorless crystals M.p .: 48 - 49 ⁰ C (methanol)

4. (4-Chloro-phenyl-4-oxo-3- (1H-thleno (2,3-d) -mida-2-ol-2-vi) -thiobutanoic acid methyl ester

3.60 g (23.0 mmol) of 1,3-dihydro-thieno (2,3-d) imidazole-2-thione (prepared according to EP-A 201 094) and 6.40 g (20.9 mmol) of 3 Bromo-4- (4-chlorophenylM-oxo-butanoic acid meth) ester are dissolved in 100 ml of absolute methanol and heated for one hour under reflux. Thereafter, the solvent is distilled off and the oily residue is triturated with 5 r.l ether. The crystals thus obtained are filtered off, digested with a little cold ether and dried (50 ° C / 50 mbar).

Yield: 9.25 g of yellow crystals; Hydrobromide.

The hydrobromide is suspended in 20 ml of EtNyl acetate and stirred with saturated sodium bicarbonate solution until gas evolution ceases. Thereafter, the protein is distilled off in vacuo. The crystals are filtered off with suction, washed with cold, distilled water and poured (80 ° C./50 mbar).

Yield: 6.45 g blaOgelbe Krislalle (81% of theory) m.p .: 170-172 ⁰ C (ethanol)

Example 2 5- (4-chiourphen> J) -thienoC2 ^l _> 3'-4 _> 5) imidazo (2 _> Jb) thiazoJ-g-es3ig8ijremeth> Je8ter

6, AO g (16.8 mmol) of methyl 4- (4-chlorophenyl) -4-oxo-3- (1H-thieno (2,3-d) imidazol-2yl) -thio-butanoate are dissolved in 30 g of polyphosphoric acid suspended and heated to 80 ⁰ C with stirring. After 2.5 hours, the reaction mixture is poured into 100 ml of water and stirred. The aqueous solution is treated with 100 ml of ethyl acetate, heated to 70 ⁰ C and suction filtered through HYFLO biphasic. The filter cake is rewaxed several times with boiling ethyl acetate. The phases werdan separated and the aqueous phase extracted three more times with a total of 300 ml of ethyl acetate. The combined organic phases are extracted with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated.

The mixture of the two isomeric esters is recrystallized three times from methanol.

Yield: 1.20 g yellowish crystals (19.7% of theory) m.p .: 159-161 ⁰ C (methanol) NMR: as in Example 1

Example 3

7- (4-ChloΓphenyl) -thieno (3 ^l, 2 ^t -4,5) in ^ imidazole (2, lb) tl · iazol-6-me thy es8igsäure! Ester

Evaporation of the combined mother liquors of the obtained according to Example 1 5- (4-chlorophenyl) thieno (2 ', 3'-4,5) imdazo (2, lb) thi iZol-o-acetic acid methyl ester are 2.7 g mixture of Anellierungsisorneren won. This mixture is separated by column chromatography (150 g of silica gel 60, 0.04-0.063 mm, eluent: chloroform: ether = 3: 1). The title compound is eluted as the first fraction and recrystallized from methanol.

Yield: 1.10 g of yellowish crystals (10.5% of theory, based on 4- (4-chlorophenyl) -4-oxo-3- (1H-thieno (2,3-d) imidazol-2yl-) thiobutanoic acid methyl ester from Example 1)

Mp: 131-133 ⁰ C (methanol)

¹ H-NMR: (DMSO)

delta (ppm): 7.69 (s, 4H, Ph-H), 7.20; 7.14; 6.57; 6.51 (AB; 2H; Th-H), 3.88 (s; 2H; -CH2-)

¹³ C-NMR: (DMSO)

delta (ppm): 169.7 (s) 150.8 (s) 148.2 (s) 135.0 (s) 131.1 (d) 129.3 (d) 128.8 (s) 128.3 (s ) 126.1 (s) 120.2 (d) 116.5 (s) 109.9 (d) 52.2 (q) 32.6 (t)

Example 4 7- (4-Chlorophenyl) thieno (3 ', 2'-4 _> 5) imidazo (2, lb) thiazole-6-acetic acid, methyl ester

Evaporation of the combined mother liquors of the obtained according to Example 2 5'-4-chlorophenyl) thieno (2 ^l , 3 ^l -4 _> 5) imidazo (2, lb) thiazole-6-acetic acid methesters are 0.60 g of the mixture Anellierung3isomeren won. This mixture is separated by column chromatography (150 g of silica gel 60, 0.04-0.063 mm, eluent: chloroform: ether = 3: 1). The title compound is eluted as a first fraction and recrystallized from methanol.

Yield: 0.25 g of yellowish crystals (4.1% of theory, based on 4- (4-chlorophenyl-4-oxo-3- (1H-thieno (2,3-d) imidazol-2yl) -thiobutanoic acid methyl tester from Example 2).

M.p .: 131-133 ⁰ C (methanol) NMPR as in Example 3

Example 5 5- (4-Chlorophenyl-thieno (2 '_>3' ^/ ! ₎ 5) imidazo (2, 1b) -thiazole-6-acetic acid

1.70 π (4.69 mmol) of 5- (4-chlorophenyl) -thieno (2 ^1, 3 '- <:, 5) irpidazo (2, lb) thiazol-6-methyl acetate are (in a solution of 270 mg 4.81 mmol) potassium

_l2

hydroxide in 8 ml of water and 20 ml of methanol and heated for 20 minutes under reflux. The solvent is distilled off and the residue taken up in 15 ml of water. The resulting suspension is acidified to pH = 1 with 2N hydrochloric acid and filtered with suction after stirring for 15 minutes. The residue is washed with distilled water, recrystallised from ethanol using activated charcoal and dried (50 ° C / 2 mbar).

Yield: 1.60 g of colorless crystals (98% of theory) m.p .: 239-240 ⁰ C (ethanol)

¹ H-NMR: (DMSO)

deltas (ppm): 7.71 (s; 4H, Ph-H), 7.32; 7.26; 7.23; 7.16; (AB, 2H, Th-H), 3.82 (s, 2H, -CH ₂ -).

¹³ C-NMR: (DMSO)

delta (ppm): 170.6 (s) 152.1 (s) 151.2 (s) 135.0 (s) 130.7 (d) 129.3 (d) 126.8 (s) 126.2 (β) 122.5 (s) 121.4 (d) 117.9 (s) 115.5 (d) 33.1 (t)

Example 6 7- (4-chlorophenyl) -thieno (3 ^l, _2'-4> 5) imidazo (2, lb) thiazol-6-es3igsäure

0.30 g (0.33 mmol) of 7- (4-chlorophenyl) thieno (3 ', 2'-4,5) imidazo (2, lb) thiazole-6-acetic acid methyl ester are dissolved in a solution of 50 mg (0 , 89 mmol) of potassium hydroxide in 5 ml of water and 10 ml of methanol and heated under reflux. It creates a clear solution. The solvent is distilled off and the residue taken up in 15 ml of water. It is acidified with 2N hydrochloric acid (pH = 1) and filtered with suction after 15 minutes of stirring. The residue is washed with distilled water, recrystallised from ethanol using activated charcoal and dried (50 ° C / 2 mbar).

Yield: 0.28 g of colorless crystals (97% of theory) mp: 235-238 ^° C. (ethanol)

iH-NMR: (DMSO)

delta (ppm): 7.70 (35 4H; Ph-H), 7.20; 7.14; 6.59; 6.53 (AB; 2H; Th-H), 3.78 (35 2H;

¹³ C-NMR: (DMSO)

delta (ppm): 170.7 (s) 151.1 (s) 148.2 (s) 134.9 (s) 131.1 (d) 129.3 (d) 128.8 (s) 127.9 (3) 126.4 (s) 120.1 (d) 117.4 (s) 110.0 (d) 32.9 (t)

Claims (7)

14,266 <f? 3 claims 1. A process for the preparation of novel thieno-imidazo (2, lb) thiazole derivatives of the formula I of the formula sheet in which A together with the two carbon atoms of Imidazolrings forms a group of formula Ha or Hb of the formula sheet, Rj is hydrogen, Cj C4 alkyl, halogen or CF3, R2 is hydrogen, halogen or CF3 and R 3 is hydrogen or C 1 -C 4 alkyl and, in the event that R 3 is hydrogen, of their pharmaceutically acceptable salts, characterized in that a) a compound of the formula IH of the formula sheet, in which R 1 and R 2 have the abovementioned meaning and R 3 is C 1 -C 4 alkyl, in the presence of dehydrating reagents, to form a mixture of isomers of the formula I in which A is the group of formulas Ha and IIIb and R 1, R 2 and R 3 are those mentioned above Meaning have cyclized and the isomer mixture separates, whereupon b) optionally, a compound of the formula I in which R 3 is C 1 -C 4 -alkyl, to give compounds of the formula I where R 3 is hydrogen, are alkali-saponified and c) if desired, converting the free acid of formula I of the formula sheet obtained in Verrichtungsachritt b) with inorganic or organic bases in a pharmaceutically acceptable salt. 2. The method according to claim 1, characterized in that one carries out the cyclization in step a) with phosphorus oxychloride or Poiyphosphorsäure at 60 - 110 ⁰ C for 10 minutes to 4 hours. 3. The method according to any one of claims 1 or 2, characterized in that one carries out the cyclization with phosphorus oxychloride at reflux temperature. 4. A process as claimed in any of claims 1 to 3 for the preparation of isomerically pure compounds of the formula I in which R 3 is C 1 -C 4 -alkyl and A is either a group of the formula IIs or a group of the formula Hb, characterized in that Anellierung3isomerengemisch of formula I, in which A represents the groups Ha and Hb, the esters of formula I, in which A represents the group Ha, isolated by isomer pure by repeated recrystallization in methanol and from the combined mother liquors, the esters of formula I, in the A the group Hb is isolated isomerically pure by column chromatography on silica gel. 5. The method according to any one of claims 1 to 4, characterized in that one uses as eluent in column chromatography on silica gel mixtures of methylene chloride, chloroform, benzene or toluene on the one hand and ethers on the other hand. 6. The method according to any one of claims 1 to 5 for the preparation of Ver-Dindungen of formula I in which R3 has the meaning of hydrogen, characterized in that one carries out the alkaline saponification of step b) with alkali metal hydroxide solutions with the addition of a solubilizer. 7. The method according to any one of claims 1-6, characterized in that the solubilizer in step b) methanol or ethanol 'is. OZ 853
10.03.1988