DD236096A1 - PROCESS FOR THE PREPARATION OF 5,6,7,8-TETRAHYDROPYRIDO / 4 ', 3': 4,5 / THIENO / 2,3-D / PYRIMIDIN-4 (3H) -ONEE - Google Patents

Abstract

The invention relates to a process for the preparation of 5,6,7,8-tetrahydropyrido / 4,3: 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones with optionally functionalized alkylthioether groups in 2 -Position. It is the object of the invention to prepare these compounds in a simple manner in high yield. The task is to find a technically feasible synthetic route. The object is achieved by the reaction of 4,5,6,7-tetrahydro-2- (3-benzoyl-thioureido) -thieno / 2,3-c / pyridine-3-carboxylic acid alkyl ester or 4,5,6,7 Tetrahydro-2-thioureido-thieno / 2,3-c / pyridine-3-carboxylic acid alkyl ester with haloalkanes or functionalized haloalkanes in the presence of hydroxide ions. The compounds obtained have platelet aggregation-inhibiting properties.

Description

wherein R ^{1 is} an alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl or alkenyl radical and R ^{2 is} an Η-atom or other substituent such as alkyl, alkenyl, aralkyl or aryl and R ^{3 is} an Η-atom or other substituents such as alkyl or aralkyl. ^

2. The method according to item 1, characterized in that compounds of general formula II as reactants to compounds of formula I with R ² = H lead.

Field of application of the invention

The invention relates to a process for the preparation of 5,6,7,8-tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones of the general formula I. with optionally functionalized alkylthioether groups in the 2-position. Such substances can gain importance as biologically active compounds. Furthermore, such compounds can also be used as starting materials for the production of pharmaceuticals, herbicides and fungicides.

Characteristic of the known technical solutions

5,6,7,8-Tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones of the general formula I with optionally functionalized alkylthioether groups in the 2-position are virtually unknown. Only 3,7-dimethyl-2-methylthio-5,6,7,8-tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -one was from the correspondingly substituted 2-mercapto-pyrimidine and methyl iodide in only 42% yield (I. Lalezari, MH Jabari-Sahbari, J. heterocycl Chem 15 [1978] 873). There are no indications of any biological activity of this substance.

Object of the invention

The aim of the invention is to produce such compounds in a simple manner in high yield.

Explanation of the essence of the invention

The object of the invention is to provide a technically applicable synthesis route for the preparation of 5,6,7,8-tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones of the general formula I with optionally functionalized alkylthioether groups in the 2-position.

According to the invention, this object is achieved in that 4,5,6,7-tetrahydro-2- (3-benzoyl-thioureido) thieno / 2,3-c / pyridine-3-carboxylic acid alkyl ester of the general formula II,

-2- i * V3 it

II COOR *

wherein R ³ and R ^{4 may be the} same or different and R ^{3 represents} a Η-atom or other substituents such as alkyl or aralkyl and R ⁴ corresponds to an alkyl radical, or that 4,5,6,7-tetrahydro ^ thioureido thieno ^ Sc / pyridine-S-carboxylic acid alkyl ester of the general formula III

III

cocfV *

wherein R ^{2 represents} a Η-atom or another substituent such as alkyl, alkenyl, aralkyl or aryl and R ³ and R ^{4 have} the meanings given above,

in the presence of aqueous or aqueous-alcoholic or alcoholic alkali solutions with halogenated or functionalized haloalkanes of the general formula IV

R ¹ X IV

where R ^{1 is} an alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl or alkenyl radical and X is a chlorine, bromine or iodine atom, to the 5,6,7,8-tetrahydropyrido / 4 ', 3 ': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones of the general formula I with optionally functionalized alkyl thioether functions in the 2-position at room temperature, if appropriate also by heating,

R ³ *

wherein R ¹ , R ² and R ^{3 have} the meanings given above. Emanating from the compounds of general formula Il reactions provide under the indicated reaction conditions, compounds of general formula I with R ² = H.

embodiments

The invention will be explained in more detail below with reference to three exemplary embodiments.

example 1

7-Ben2yl-2- (2-hydroxy-ethylthio) -5,6,7,8-tetrahydro-pyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H R ¹ = (CH ₂ ) 2OH; R ² = H; R ⁼ CH ₂ CeH5

2.4 g (5 mmol) of the benzoylthiourea II (R ³ = CH ₂ C _e H ₆ ; R ⁴ = C ₂ H ₅ ; mp: 161-163 ° C (acetone), prepared from 2-amino-6-benzyl- 4,5,6,7-tetrahydro-thieno / 2,3-c / pyridine-3-carboxylic acid ethyl ester and benzoyl isothiocyanate), 20 ml EtOH and 12 ml 1N NaOH are refluxed for 90 min. After addition of 50 ml of 0.5N NaOH, the reaction solution is filtered. 1.2 g of 2-bromo-ethanol are gradually added to the filtrate with stirring and gentle heating. The batch is stirred with occasional stirring for 3h. stored at room temperature and brought to pH 7 with 5% acetic acid. The precipitate is filtered off with suction, washed with H 2 O and dried in air

Mp .: 204-205 ⁰ C (EtOH). Yield: 52%.

Example 2

3-allyl-7-benzyl-2-methylthio-5,6,7,8-tetrahydro-pyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) - on I; R ¹ = CH ₃ ; R ² = CH ₂ CH = CH ₂ ; R = CH 2 C 6 H 5

2.1 g (5 mmol) desThiohamstoffs III (R ² = CH ₂ CH = CH _2; R ³ = CH ₂ C ₆ H _5; R ⁴ = C ₂ H _5; m.p .: 70-71 ⁰ C (EtOH); prepared from 2-amino-6-benzyl-4,5,6,7-tetrahydro-thieno / 2,3-c / pyridine-3-carboxylic acid ethyl ester and allyl isothiocyanate), 5 ml EtOH, 5 ml 1N NaOH and 2 ml H ₂ O is heated briefly. The reaction solution is filtered and gradually added to the filtrate with stirring and gentle heating is 780 mg (5.5 mmol) of methyl iodide. The batch is stirred with occasional stirring for 3h. stored at room temperature. The precipitate is filtered off with suction, washed with EtOH / H ₂ O and dried in air. M.p .: 134-135 ⁰ C (EtOH / H ₂ O). Yield: 71%.

Example 3

2- (2-amino-ethylthio) -7-benzyl-3-phenyl-5,6,7,8-tetrahydropyrido / 4 ', 3': (4.5 / thieno / 2,3-d / pyrimidin-4 3H) -one I; R ¹ = (CH ₂ ) ₂ NH ₂ ; R ² = C ₆ H ₆ ; R ³ = CH ₂ C ₆ H ₅

2,3g (5mmol) of thiourea III (R ² = C ₆ H ₆ ; R ³ = CH ₂ C ₆ H ₅ ; R ⁴ = C ₂ H ₅ ; m.p .: 174-175 ° C (propan-1-ol) Prepared from 2-amino-e-benzyl ^ Be ^ -tetrahydro-thieno ^^ - c / pyridine-S-carboxylic acid ethyl ester and phenylisothiocyanate) are dissolved with warming in 10ml 1N NaOH and 10ml EtOH and filtered. To the filtrate, at room temperature, while stirring, is gradually added a solution prepared from 1.1 g (5.5 mmol) of 2-bromoethylammonium bromide and 5 ml of EtOH. After standing overnight, the precipitate is filtered off with suction, dissolved in 1 N HCl, filtered, the filtrate is neutralized with 1 N NaOH, the precipitate is filtered off with suction, washed with H 2 O and dried in air

 Mp: 92-94 ° C (EtOH). Yield: 65%.

The following compounds of the general formula I (R ³ = CH ₂ C ₆ H ₅ ) were prepared, inter alia: Table 1

R ¹ R ² mp. ⁰ C y.

(Umkrist.)%

(CH ₂ ) ₂ OH H 204-205 52 (EtOH) CH (CH ₃ ) COOC ₂ H ₅ H 193-195 94 (Propan-1-ol / H ₂ O) CH ₃ CH2CH-CH2 134-135 71 (EtOH / H ₂ O) (CH ₂ I ₂ OH CH ₂ CH = CH ₂ 121-123 83 (EtOH / H ₂ O) CH ₃ C ₆ H ₅ 205-206 93 (Methyl glycol) (CH ₂ I ₂ OH C ₆ H ₆ 158-160 71 (EtOH) (CH ₂ I ₂ NH ₂ C ₆ H ₅ 92-94 65 (EtOH) CH ₂ COOC ₂ H ₅ C ₆ H ₅ 157-158 87 (EtOH)

All of the compounds of the general formula I listed in Table 1 were tested for platelet aggregation-inhibiting properties.

This shows the aggregation-inhibiting effect of the substances, especially when the aggregation is triggered by ADP. Of the compounds of the general formula I listed in Table 1, the 7-benzyl-2- (2-hydroxyethylthio) -3-phenyl-5,6,7,8-tetrahydropyrido / 4 ', 3': 4, 5 / thieno / 2,3-d / pyrimidin-4 (3H) -one having a I ₆₀ -wide of 9 x 10 ^-6 mol / l for the ADP-induced aggregation of the most effective representatives.

The antiplatelet effect was determined experimentally as follows:

The studies were performed on human platelets in citrated plasma. The platelet-rich plasma was pre-incubated with the test substance for 3 minutes before addition of the aggregation-triggering substances. As aggregation causing substances ADP (final conc. 1 x 10 ^"5 mol / l) (collagen and collagen""Horm) were used. The aggregation was measured turbidimetrically at 37 ⁰ C. Percent inhibition was calculated from the maximum absorbance change after addition of ADP or collagen.

Literature on the method: E.Glusa, W. Koth, F. Markwardt, Dtsch. Ges.wesen 29 (1974) 1020

Claims (1)

- 1 - / HO II Invention claim: 1. A process for the preparation of 5,6,7,8-tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidin-4 (3H) -ones of the general formula I with optionally functionalized alkylthioether groups in the 2-position, characterized in that 4,5,6,7-tetrahydro-2- (3-benzoyl-thioureido) thieno / 2,3-c / pyridine-3-carboxylic acid alkyl ester of the general formula II ( R ⁴ = alkyl) II V NHCSMH CGC ^ H ₅
^ * or 4,5,6,7-tetrahydro-2-thioureido-thieno / 2,3-c / pyridine-3-carboxylic acid alkyl ester of general formula III (R ⁴ = alkyl) · »III NHCSNHR * ' CUCR ¹⁺ with haloalkanes or functionalized haloalkanes of the general formula IV (X = Cl, Br or I) R ¹ X IV in the presence of aqueous or aqueous-alcoholic or alcoholic alkali solutions at room temperature or optionally also by heating to the 5,6,7,8-tetrahydropyrido / 4 ', 3': 4,5 / thieno / 2,3-d / pyrimidine 4 (3H) -ones of the general formula I are reacted with optionally functionalized alkylthioether groups in the 2-position,