DE1957957A1 - Novel pyrimido [5,4-d] pyrimidine derivatives - Google Patents

Description

DR. WALTER NIELSCH Patent attorney

2 Hamburg 70 SAIoMraß «112 · P.O. Box N * 65 * »7ö7

Yamanouchi Pharmaceutical Co., Ltd., Tokyo (Japan)

N ew PyrimidoT 5 ₁ 4-dJpyrimidind er i vat e

The present invention relates to new dine derivatives of the general formula

wherein E represents a nitrogen-containing heterocyclic group; R ^ and E ₂ each represent an alkyl group or

R aareteHt; R * and E · each denote a hydrogen · atom, an alkyl group, a hydroxyalkyl group, an alkylaminoalkyl group and Ro and R. can together with dom material atom form a heterocyclic ring which can contain an impurity in the ring; η is zero or one and

E | and R ₂ are: each -Νζ ' ^J if η is zero *

QQ 0.8 2.7 / 2 QO

The compounds of the present invention have recorded activity in inhibiting platelet aggregation *

As compounds similar to the compounds of the present invention, 2,6-bis (diethanolamino) 4jÖ-dipiperidinfti · pyrimidof S ^ - ^ lpy ¹ * ^111114111 (commonly known as "dipyridemol") * 2,6 ~ bis ( äthylmer capio} -4 J8 * -Dipiperidinopyr imido ^ 5 »4 ~ dJ pyr imidine known and the same show remarkable effects (cf. German patent i 116 676; ÜSA patent 3 031 450 and British patent 0 07 826).

Among these known compounds is, for example, from Dipyridamole known to be platelet aggregate ion ·? In addition to the aforementioned medicinal effect, it has an inhibitory effect

It has now been found that the compounds of the present Invention an excellent platelet aggregation * inhibitory effect in comparison with these known compounds owns. In addition, some compounds of this invention can serve as starting materials for the preparation of dipyridamole.

The compounds of the invention can .by Umsetaen imn Pyrimidol ^^ - djpyriraidin substituted with a halogen atom and / or a halogenosulfonyl group with an amine be to the halogen atom or the halogen atom of the Halogenosul = · to replace fonyl group with the amine

The preparation of the compound according to the invention is under Reference to the typical starting material, namely 2-chloro-6-chlorosulfonylpyrimidof5 | 4-d1pyrimidine derivative to be explained *

The reaction is illustrated by the following reaction picture:

009827/2007

(eüreh R ^?

Temperature) ^ \ _n «, ^^

^H 4

n »» 0 R ₁ = R ₂ -

(in) ,

where R,

ft. and R. have the meaning already mentioned

One mole of starting material (IX) is left in excess of 4 moles of an amine react at elevated temperature to form the compound

(I) to receive

The compound (J) can also go through the course of the reaction

(II) (III) (I) · Here, one mole of the starting material (II) becomes about 2 moles of one

reacted in a solvent such as dioxane, benzene, dimethylformamide and the like at room temperature or with cooling to prepare the compound (III). The compound (III) prepared in this way is mixed, with or without isolation, with about 2 fetch amine and the mixture is umgeietstι at an elevated temperature, preferably at a temperature below 150 ° C _{1 to} obtain the compound (I). By using different

009827/2007

Amines in the first stage and the second stage in the above reaction sequence, different amines can be in the 2- and 6-positions to be introduced.

The compounds of the present invention having alkylsulfonyl groups in the 2- and 6-positions can be obtained by reacting the starting material, which chlorine atoms in the 4- and Ö positions, with a heterocyclic amine, the chlorine atoms of these being substituted by the amines mentioned.

Additionally ^ when a liquid amine is used in the reaction is used, a large amount of the liquid amine is used to use a part of the liquid amine as a reaction solvent use.

AIa examples of compounds of the invention may be mentioned:

(IJ 2-diethanolamino-6-methylaminosulfonyl-4 | ό-dipiperidinopyrimidof 5 | 4-d pyrimidine;

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(2) E-diethanolamino-o-ethylaminosulfonyl-4, Ö-dipiperidinopyrimidoj " 5,4-dj pyrimidine:

(3) 2-diethanolamino-6-diethylaminoäthylaininosulfonyi-4, Ö dipiperidinopyriraidor5,4-dJpyrimidine!

009827/2007

(4) 2-diethanolamino-6-diethanolaminosulfanyl-if, 8 * -dipiperidino.-5 j 4 "dJ pyrimidine i

HIGH

HOH ₂ CH ₂ C

(5) 2-Diethanolamino-o- {N-methyl} ethanolaminosulfonyl-4> O-dipiperidinopyrimidope , 4-dJpyrimidines

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{6). 2-diethanolamino-6-morphonylsulfonyl-4, Ö-dipiperidinopyr imido Π> , 4-dlpyr imidine:

VJ

OJS

{ 7) 2 (H * methyl) äthanolamino-6 (K-methyl) äthanölamitiosulfony3- ■ 4,8-d! Piperidinopyrimidofs ^^, 4-dl ^^ pyrimidine:

009827/200 7 originally inspected

(δ) 2-diethanolamino-6-diethylaminosulfonyl-4, Ö-dimorph.olinopyrimidop, 4-dJ pyrimidine:

(9) 2,6-bis (methylsulfonyl) -4, O-dipiperidinopyrimidor5,4- ^ midin:

009827/2007

(10) 2, 6-bis (diäthanolaminosulfonyl) -4, east-dipiperidinopyrdUnido-Γ 5 j4-dl pyrimidin:

HOE

(17) 2-Diethanolaminosulfonyl-6-methylsulfonyl-4, O-dipiperidinopyrimidoT 5,4-dj pyrimidine:

H ₃ CNO ₂ S

009827/2007

- ίο - '

The following experiments were carried out. The results obtained show excellent medicinal effects for the compounds of this invention

Platelet Aggregation Inhibition Effect The effect for compounds of this invention to inhibit platelet aggregation was tested with adenosine phosphate \ md compared to the effect of dipyrimadol,

Carrying out the experiment

The blood obtained from the heart of a rat was mixed with 3 "oily sodium citrate solution" so that the citrate was present in the blood in an amount of 1/10 volume. The mixture was subjected to centrifugal separation for 15 minutes at 1,000 rpm to obtain a platelet-rich plasma (hereinafter, the plasma ^{M is called} PRP ^M ).

To 2.5 ml of PRP was added 10 moles of adenosine diphosphate, 10 "^ moles Compound of this invention having the general formula given below, 7x10 moles sodium chloride, 1.2x10 "* · * moles Potassium chloride and 9x10 "" ^ moles of calcium chloride are given, being a Total volume of 5 ml was obtained «

While vigorously shaking the mixture at 25 ° C using a Thermomlxers became aware of the extent of the lowering of the extinction coefficient caused by the aggregation of platelets who,. every 30 seconds with the help of a photoelectric Photometer EPO-B (filter 61) manufacturer Hitaohi AG, measured. The measurement of the extinction coefficient was carried out in such a way that that without the addition of compounds of this invention a corresponding? such approach served as the standard;

The extinction coefficient of the system reached the minimum value after 1-2 minutes from the start of the measurement and was then constant for about 5 minutes; the value was in this period of time

009827/2007

measured. From the extinction coefficient thus obtained, the platelet aggregation inhibition rate (%) was calculated and its relative value was calculated, so that in the case of using dipyridamole in place of the compound of this invention, it was also calculated. The results are shown in Table 1.

In addition, the test facilities for which the possibility consisted of coming into contact with the platelets, previously subjected to a silicone treatment.

The compounds of the invention used in the experiments are represented by the following general formula:

009827/2007

- 12 Table 1

Experimental
Raumner
I. link -MHCH, ^H 2 BipyridaJEol Enhancement
ratio (f Inhibition
relationship 1 -NHC ₂ H ₅ .CH ₉ CH ₉ OH
^ CH ₂ CH ₂ OH 26th 1.24 2 -MCH ₂ CH ₂ N ^ "° 2 ^H 5
N ₂ H ₅ CH ₉ CH OH
-IT ^ ^
^ CH ₂ CH ₂ OH 26th 1.24 3 CH CH OH
T) H ₂ CH ₂ OH / CH ₉ CH OH
^ CH ₂ CH ₂ OH 44 2.09 4th -JJ ^
^x CH ₂ CH ₂ OH / CH CH OH
Λ CH ₂ CH ₂ OH 47 2.24 5 O / CH ₉ CH ₉ OH
^ CH ₂ CH ₂ OH 29 1.37 6 - ^ CH ₂ CH ₂ OH / CH ₉ CH ₉ OH
^ -CHpCH ₂ OH 38 1.81 7th
L. / CH
^ CEL ^v CH ₂ CH ₂ OH 35 1.67 8th CH ₉ CH ₉ OH
^ CH ₂ CH ₂ OH 27 1.28 9 21 1.00

009827/2007

In addition, since the known compound 2,6-bis- (äthylmercapto) ~ 4, Ö-dipiperidinopyr.imidoj 5,4-dJpyrimidine was insoluble in water, the platelet aggregation inhibition effect, caused by this connection cannot be measured.

The connection will now be explained by the following examples, but it is not intended to be limited to them.

The starting material was prepared as follows:

a) In a suspension of 0.0 g of 2-chloro-6 ~ mercapto-4, & - dipiperidinopyrimidoj 5,4-d | pyrimidine in 25 ml of methanol-water mixture (1: 4), chlorine gas was passed in for one hour while stirring and cooling to 4 to 5 ° C. The reaction product which precipitated was collected by _filtration} washed with water and dried. The crude 2-chloro-6-chlorosulfonyl-4, O-dipiperidinopyrimidol 5,4-d1-pyrimidine was chromatographed on a silica gel column. Using chloroform as the eluent, 0.66 g (70%) of the product with a melting point of 220-230 ° C. was obtained.

b) A solution of 4.3 g of 2-chloro-6-chlorosulfonyl-4ιÖ-dipiperidinopyrimido [5.4-dj pyrimidine (prepared as described above) in 40 ml of chloroform was added dropwise to a Solution of 2.5 g of diethanolamine in 30 ml of chloroform under Stir added. After stirring for half an hour, the reaction mixture was washed with water and dried over anhydrous Dried magnesium sulfate. The residue, which was obtained after removing the solvent, was purified by means of a Silica gel column chromatographed using benzene and then ethyl acetate as the eluant. The eluate was under Concentrated under reduced pressure and there were 3.7 g ($ 74.6) of 2-chloro-6-diethanolamino-sulfonyl-4, Ö-dipiperidinopyrimido ^ 5,4-djpyrimidine obtained with a melting point of 160 ° C.

009827/2007

- 14 analysis as ^C 20 ^H 30 ^N 7 ° 4 ^SC1

C [fo) H (%) N (%) calculated 43.04 6.05 19.61 found 40.09 6.15 19.50

The following, represented by the general formula ^ Connections were made in a manner analogous to described above, but using other amines,

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Melting yield
(*) Elementaxanalys e H (fo) 19.84 found ö (50 6.51 Ci ($>) 208-210 67 calculated 6.54 23.02 55.48 5.71 1,." -MCH ,, 203-205 70.6 cW 5.68 21.60 47.99 6.31 23.12 -MC ₅ H ₇ 159-161 55.2 53.57 6.22 19.77 50.39 6.88. 21.48
19.71 " ¹ S ₃ H ₇ 161-164 68.2 47.93 6.91 20.95 53.31 6.38 20.93 -MC ₄ H ₉ 131-132 64.0 50.27 6.46 21.95 51.61 6.79 21.74 112-115 55 53.27 6.90 20.82 51.79 6.18 20.89 ^ CH ₂ CH ₂ CH 115-117 53.2 51.33 6.21 20.98 48.50 6.51 21.01 152-154 74.5 51.70 6.47 19.61 51.49 6.15 19:58 do do do iia 74.6 . 48.45 6.05 48.09 51.38 48.04

Example T

S-diethanolamino-o-diethanolaminosulfonyl-4, β-dipiperidinopyr A-mido [5 1 4-dJ pyrimidine:

009827/2 0 07

2 g of diethanolamine were added to a solution of 1.5 g of 2-chloro-6-diethanolaminosulfonyl-4, O-dipiperidinopyrimidor5,4- ^d ] pyrimidine, prepared as described above, in 30 ml of dioxane. The reaction mixture was refluxed for about 14 hours and then concentrated under reduced pressure. The obtained residue was poured into 50 ml of cold water to obtain an oily substance, which was dissolved in 30 ml of chloroform. The chloroform solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation. The residue obtained was chromatographed on a silica gel column using ethyl acetate as the eluent. The eluate was concentrated under reduced pressure to give 1.3 g ($ 76.5) of a product having a melting point of 140-141.5 ° C.

Analysis as ^C 24 ^H 40 ^N Ö ° 6 ^S

C (fo) H (fo) N (fo) calculated: 50.69 7.09 19.70 found 50.50 7.00 19.71

The compounds of the following general formula were obtained by a procedure analogous to that described above, but using different amines.

.009827 / 2007

* 2 Sinewy
i ° Cl Auabeui
(η Cemental analysis mi ι
22.65 found. 7.53 NW / CH ₉ CH ₉ OH
^! H ₂ CH ₂ OH 185
-187 78 te "calculated 7.52 21 * 44 CCf ₀ ) 7iO9 19.75 ^ CH ₂ CH ₂ OH
^ H ₂ CH ₂ OH 153
-155 76i2 6.93 19.84 55.20 7 * 40 22.75 -NHCH, / CH ₀ CH ₀ OH
^ CH ₂ CH ₂ OH; 186.5
-187 * 5 64 * 8 55 * 49 7 * 33 20.88 51jO4 7.87 21.17 -MC ₃ H ₇ CH ₀ CH ₀ OH
-N ^ ^ά
^ CH ₂ CH ₂ OH 122
-124 74.5 50 ^ 99 7.85 19.68 52 * 59 7.73 19.66 -η; ⁵ '
V ₇ ^ CH ₂ CH ₂ OB
^ CH ₂ CH ₂ OH 165
-167 82 52 * 85 7.51. 21 »74 55.38 7.08 20.46 -HHC ₄ H ₉ ^ ₂ CH ₂ OI
^ CH ₂ OB 140
-141.5 76.5 55.30 7.03 20.80 53.58 7.88 19.71 ^ CH ₂ CH ₂ OH
> DH ₂ CH ₂ OH / CH ₀ CH ₉ OH
- $ ^{ά ά}
^ CH ₂ CH ₂ OE 99.5
-101.5 75 53 * 71 7.82 50.50 7.01 21.52 -MCH ₀ CH-N ² ^ ^ CH ₂ CH ₂ OI
^ CHgCHgOEJ 109
-109.5 38 50.61 7.11 53.48 20.73 ^ ₂ CH ₂ OH 53.86 51.30 51.28

Example 2

2-diethanolamino-6-diethyleddnosilfonyl-4 _l d-dipiperidinopyrimido [5,4-d pyrimidine:

00 9 827/2007

A solution of Ο, δό g of 2-chloro-6-chlorosulfonyl-4, Ö-dipiperidinopyrimidop ^ -dlpyrimidine in 20 ml of benzene was mixed with a solution of 1.4 g of diethylamine in 30 ml of benzene while stirring at room temperature * After stirring for three hours was distilled off, the benzene * to the residue, 1.05 g of diethanolamine was added, and the mixture was kept for 1 ₄ 5 hours under reflux. The reaction mixture was extracted with ethyl acetate and the extract was chromatographed on a silica gel column using ethyl acetate as the eluent. The eluate * was concentrated under reduced pressure. 0.44 g ($ 41.4) of pure product with a melting point of 110-120 ° C. were obtained.

Analysis as ^C 24 ^H 40 ^N Ö ° 4 ^S

C (f ₀ ) HW. N OT

calculated 53.71 7.51 20.30

found 53.03 7.59 20.69

The compounds represented by the following general formula were obtained in an analogous manner to the above procedure, except that different amines f were used.

009827/2007

Elemental analysis

yield

(η

calculated

found

E (J)

.CH ₂ CH ₂

OH

oil

41.3

57.52

6.90

18.82

57.05

7.00

18.53

CH ₂ CH ₂ OH

160-162

48.6

52.35

6.96

20.35

52.05

6.87

20.12

^ CH ₂ CH ₂ O]

OH

IH

143

51.95

7.13

22.05

51.99

7.22

21.82

I ₂ H ₅ -

-JT.

/ CH ₂ CH ₂ OH

164

OH

39.0

51.95

7.13

22.03

52.16

7.17

21.75

CJ

CH ₉ CH ₀ OH

108-110

55.6

56.73

8.16

18.90

8.21

18.74

- ^N v

141 '-143

59.5

54.72

7.35

20.42

55.08

7 # 40

20.29

The starting material was prepared as follows:

A solution of 3.06 g of dibutylamine in 30 ml of benzene was added with stirring to a solution of 3.0 g of 2-chloro-6-chlorosulfonyl-4, O-dimorpholinopyrünido [5 »4-d pyrimidine in 60 ml of benzene After stirring for two hours, the benzene was distilled off under reduced pressure. The residue was dissolved in chloroform. The chlorine solution was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation. The residue was recrystallized from ethanol-chloroform. There were 2.55 g (70 $) of 2-chloro-6-dibutylaminosulfonyl-4, E-dimorpholinopyr imido [5 _i 4-djpyrimidin having a melting point at 14Ö-149 ⁰ C,

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C (56) H (56) N. (56) 50.04 6.49 10.57 49.91 6.32 10.64

- 20 -

obtain.

Analysis as C ₂ 2 ^H 34 ^N 7 ° 4 ^SC1

calculated
found

Example 3

2-diethanolamino-6-dibutylaminosulfonyl-4, Ö-dimorpholinopyr imi ' do [5,4-dj pyrimidine *

A mixture of 2.55 g. 2-chloro-6-dibutylaminosulfonyl-4, # - dimorpholinopyrimidoj5,4-dJ pyrimidine and 20 g diethanolamine was heated to 160 ° C. for 35 minutes with stirring. The reaction mixture was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate. then the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-petroleum ether. There were 2.7 g ($ 94) of the product with a melting point at

05 ° C. VW ³ C. (36) H (56) N (56) Analysis as C ₂ ^ 52 , 33 7th , 43 1Ö, 7Ö 51 , 00 7th , 46 Ίβ, 5β calculated found Example 4

2-diethylamino-6-diethylaminosulfonyl-4, Ö-dimorpholinopyr imido [5,4-djpyrimidine:

A solution of 3 x 0 g of 2-chloro-6-chlorosulfonyl-4, β-dimorpholinopyrimido [5,4-dj pyrimidine in 60 ml of benzene was added to a solution of 1.0 g of diethylamine in 20 ml of benzene with stirring

009827/2007

Given room temperature.

After stirring for two hours, the benzene was distilled off under reduced pressure * The residue was dissolved in chloroform *. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation. 25 ml of diethanolamine were added to the residue thus obtained, and the mixture was heated to 160 ° C. for half an hour. The reaction mixture was dissolved in 50 ml of chloroform; washed with water and dried over anhydrous magnesium sulfate * Then the solvent was removed by evaporation. The resulting crystalline residue was recrystallized from ethyl acetate-petroleum ether with the addition of a small amount of petroleum ether. 2.1 g [52.5%) of the product with a melting point of 100 ° C. were obtained.

Analysis as ^G 22 ^H 36 ^N Ö ° 6 ^p C. (%) H (JP) N (*) 4Ö 6, 7V 20th , 73 calculated 4ö , 71 6, 72 20th , 36 found

Example 5

2- (N-methyl) ethanolamino-6- (N-methyl) ethanolaminosulfonyl-4, O-dipiperidinopyrimido [5,4-dJ pyrimidine: To a solution of 1.5 g of chloro-6-chlorοsulfonyl-4, tf-dipiperidinopyrimido ^ 5.4-g pyrimidine in 50 ml of benzene became 2.63 g N-methylethanolamine in 10 ml of benzene was added with stirring. After stirring for two hours, the benzene was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulfate »Then the solvent was removed by evaporation removed. The residue obtained was chromatographed on a silica gel column using ethyl acetate as

009827/2007

Eluent »The eluate was concentrated under reduced pressure * narrowed. The residue obtained was recrystallized from ethyl acetate-petroleum ether. There was 0.5 g ($ 42) of product obtained with a melting point of 115 ° C.

Analysis as ^C 22 ^H 36%% ^

G {%) H W. N (*) 51.95 7th , 13 22nd , 03 51.70 7th , 00 22nd , 03

calculated
found

The following compounds of the following general formula were prepared in an analogous manner to the above procedure but different amines were used.

00 9 8 27/2007

. - Enamel
Point
(° e) - 23 - Elemental analysis 6.67 N (/ _o ) found H- (JG) (n (0) 24.7ij T? = T? s 193-194 calculated 7.19 26.67 ■ 0 (56) 6,57J26,4i: -NHCH ₃ 161 yield
(*) C (^ JH (f ₀ ) 24.99 51.19 7.30 ^X CH ₃ ■ 35 51.43
■ £ 3.70 each 37 53.55

The starting material was prepared as follows:

a) A mixture of 4 g of 4,3-dihydroxy-2,6-dimercapfcopyrimidop ^ -djpyrimidin, 22 g of phosphorus penta chloride and 120 ml of phosphorus oxychloride was in an oil bath for 30 minutes ;: heated under reflux. The reaction mixture was taking concentrated under reduced pressure to recover the residue. Of this, phosphorus pentachloride was used as far as possible ■ sub ^ .imiert as possible at about 70 ° C under reduced pressure. 4, O-dichloro-2,6-bis (chlorosulfeno) pyrimido [5 »4-djpyrimidine was precipitated by adding 5 ml of chloroform to the residue and separated by filtration. the Yield was 5.1 g (# 7 $) and the product showed one Melting point of 190-199 ° C.

Analysis as C _A N, S ₉ Cl,
042 4 (*) N (fo) Cl , 40 S. (fo) C. , 67 16 , 77 42 . 05 - 19th , 20 calculated 21 , 57 16 , 57 42 19th , 40 found 21

b) Eu of a solution 70a 350 mg 4, Ö-dichloro-2,6-bis (chlorosulfeno) pyrimido [5,4-d ^ 3yrimidine, as obtained above, in 10 ml of dry dioxane was added dropwise 0.0 ml of piperidine . Added with stirring and cooling. The reaction mixture was

00982 7/20 07

stirred at room temperature for one hour and at 50 ° C. for 30 minutes and then concentrated. The residue was dissolved in 50 ml of chloroform and the solution was washed three times with 10 ml of water each time; After that, the solution was dried over anhydrous sodium sulfate. The chloroform was removed by evaporation under reduced pressure. The reaction product was precipitated in crystal form by the addition of 1 to 2 ml of ethyl acetate to the residue. The crystals were separated by filtration, washed with a small amount of ethyl acetate and dried. 370 mg ($ 67) 4, Ö-Dipiperidino-2,6-P bis (piperidinosulfeno) pyrimido [5,4-dIpyrimidine with a melting point of 165-167 ⁰ C were obtained «

Analysis as C ₂ ^ ^H 40 ^N Ö ^S 2 H (fo) N , 19th S. / 07 \
I / Q i C. (*) 7th , 62 21 , 76 12th , 13 calculated 59 , 06 7th , 36 20th 11th , 06 found 5Ö , 90

c) In a suspension of 100 mg of 4, Ö-Dipiperidino72,6-bis (piperidinosulfeno) pyrimido [5 | 4-d pyrimidine in 7 ml of water-methanol mixture (5ί2) chlorine gas was passed in for two hours with stirring and ice-cooling. The yellow crystals obtained were separated by filtration, washed with water and dissolved in 50 ml of chloroform. The solution thus obtained was successively washed three times with 10 ml of 3 # aqueous sodium bicarbonate solution, three times with 10 ml of water each time and dried over anhydrous sodium sulfate. From the solution, the crude product was obtained in crystal form by evaporating off chloroform under reduced pressure, separated by filtration and washed with a small amount of ethyl acetate. 90 mg ($ 96) of 2,6-bis (chlorosulfonyl) -4,3-dipiperidijiopyrimido [5 _f 4-dJpyrimidine were obtained.

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Analysis as C. 6 ^H 20 ^N 6 ^S 2 ° 4 ^C1 2

calculated 3Ö , 79 4th , 07 16 , 96 12th , 94 14th , 31 found 39 , 29 4th , 46 16 , 39 12th , 49 14th , 05 Example 6

2,6-bis (diethanolaminosulfonyl) -4, S-dipiperidinopyrimido- | 5.4-d pyrimidine:

d) In a solution of 100 mg of 2,6-bis (chlorosilfonyl) -4, O-dipiperidinopyrimido [5 _i 4-djpyriinidin in dry dioxane, 5 mg of diethanolamine was added with stirring and cooling. In addition, the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform, and the resulting solution was successively washed once with water, twice with 1N aqueous hydrochloric acid, twice with 5 # aqueous sodium bicarbonate solution, three times with water and dried over anhydrous sodium sulfate. The chloroform was removed from the solution by evaporation under reduced pressure. The slightly yellowish oily substance thus obtained was dissolved in a small amount of chloroform and purified by column chromatography on a silica gel column using a chloroform-methanol ( 13i 1) mixture as an eluent The resulting white needles of the product are separated by filtration and washed with a small amount of ethyl acetate. The yield of the product was 65 mg ($ 63) and had a melting point of 107-112 ° C (with decomposition)

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- 26 Analysis as C ₂ 4 ^H 40 ^N £ ° Ö ^S 2

U \ / o) H (%) N (56) S {%) calculated 45.56 6.37 17.71 10.13 found 45.23 6.26 17.42 9.97 Example 7

2-diethanolaminosulfonyl-6-methylsulfonyl- * 4, Ö-dipiperidinopyrimidoj5,4-dJpyrimidine:

A solution of 1.4 g of 2-chlorosulfonyl-6-methylsulfonyl-4, & · dipiperidinopyriraido [5,4-dj pyrimidine in 10 ml of chloroform dropwise into a solution of 0.95 g of diethanolamine in 20 ml Chloroform added with stirring. After stirring an additional hour, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure. The oily residue was in Added water and left to stand over Nachb, with the reaction product became solid. The crude product was separated off by filtration and recrystallized from ethyl acetate were 1.45 g (# 9.7 $) of the product with the melting point at 152-153 ° C obtained.

Analysis as ^C 21 ^H 33 ^N 7 ° 6 ^S 2

G , 39 H W. ν m 46 .17 6th , 12 10.03 46 6th , 14 17.96

calculated
found

The starting material was prepared as follows:

a) A mixture of 2.9 g 4 »Ö-dihydroxy-6-mercapto-2-methyl <thiopyriraido [5i4-d] pyrimidine and 33 ml of 5 # sodium hydroxide solution was heated until a clear solution was obtained

001827/2007

After cooling, 0.9 ml of methyl iodide was added to the reaction mixture added with vigorous stirring to obtain a crude

4,8 ~ Dihydroxy-2,6-bis (methylthio) pyrimido [5,4- ^d J pyrimidine deposited as yellow crystals. After stirring for an additional half hour, the pH of the reaction mixture was adjusted to 4 to 5 by adding acetic acid and left to stand for a while left. The crude product was separated by filtration, with. Washed water, dissolved in dilute aqueous ammonia and treated the solution with activated charcoal. When the pH of the solution was adjusted to 4 to 5 by the addition of acetic acid, the product precipitated. It was separated by filtration * The yield was 2.76 g ($ 90) with a melting point above 300 ° C.

Analysis as ^C Ö ^H Ö ^N 4 ° 2 ^S 2 C. Λ9 H (*) N {%) 37 , 30 3 , 15 21, 06 calculated 37 3 , 22 found

b) In a suspension of 6.4 g of 4, Ö-dihydroxy-2,6-dimethylthio ~ pyrimidol 514-dJ pyrimidine (prepared as described above) in 320 ml of water, chlorine gas was introduced at 0 ° to 5 ° C with stirring. Crude crystals were separated out. After standing for a while, the crystals were separated off by filtration and washed with water. 7/6 g (95%) of crude 4,5-dihydroxy-2,6-bis (methylsulfonyl) pyrimido [5,4-dJpyrimidine were obtained. The crude product was dissolved in dilute aqueous ammonia. The solution was treated with activated charcoal; then the pH of this was adjusted to 4 by adding acetic acid. This caused the product to fall over. The product was separated by filtration and a new product was obtained.

009827/2007

N [fo) S (fo) 10.47 20.02 10.29 19.00

..; ■■ - 28 - analysis as CgHgN, OgS ₂

calculated
found

c) A mixture of 5 _} 6 g of 4, Ö-dihydroxy-2,6-bis (methylsulfonyl) pyriraidol 5} 4 ~ -dJpyrimidin (prepared as described above), 14.5 g of phosphorus pentachloride and 28 ml of phosphorus oxychloride was added for one hour heated with stirring. After the reaction was completed, phosphorus oxychloride was evaporated under reduced pressure. The residue was extracted with 30 ml of hot chloroform and the extract cooled. The crude product which had separated out was washed with water. There were 4.65 g ($ 74.5) of 4, Ö-dichloro-2,6-bis (methylsulfonyl) pyrimidoΓ5,4-d] pyrimidine in crystal form. obtained with a melting point of 270-272 ° C (decomposition).

Analysis as CgH ^ 'Cl ₀ N ₁ O ₁
3 2 4 4 ^S 2 Cl (fo) S (fo) N (fo) 19th , 05 17.93 calculated 15.69 20th , 04 17.74 found 15.52

d) To a suspension of 0.36 g of 4,8-dichloro-2,6-bis (methylsulfonyl) pyrimidor5,4-dJ pyrimidine (prepared as described above) in 3.6 ml of chloroform was added dropwise Stirring added 0.4 ml of piperidine. A clear, yellow-brown solution was formed with little VJärme development. After stirring for an additional half hour, the solution was washed twice with water. The chloroform layer was over dried dehydrated sodium sulfate, treated with activated charcoal and concentrated under reduced pressure. It was 0.38 g (83 #) of crude 2,6-bis (methylsulfonyl) 4,8-dipiperidinopyrimido [5,4-dJ pyrimidine obtained. By recrystallization

009827/2007

Acetone turned into fine, slightly yellowish needles with a Melting point obtained at 210-220 ° C.

Analysis as ^c -j £ ^H 26 ^ 6 ^O / j ^S 2

C. (fo) H (fo) N (fo) Η, 00 47 , 56 5 , 77 10.49 14, 10 47 Λ9 5 , 69 10.25

calculated found

The starting material * was prepared as follows: In a stirred suspension of 1.2 g of 6-mercapto-2-methyl ~ thio-4, # - dipiperidinopyrimidof5,4-djpyrimidine (prepared as described above) in 2 ml of methanol and 12 ml of water Chlorine gas introduced for 2 hours below 5 ° C and ice cooling. During this, white crystals were deposited. The crystalline precipitate was separated off by filtration, washed with water and dissolved in ethyl acetate. The solution was treated with activated charcoal and then concentrated. 1.3 g (& 5) lf °) 6-chlorosulfonyl-2-methylsulfonyl-4, δ-dipiperidinopyrimidoj 5,4-d] pyrimidine with a melting point of 174-176 ° C. was obtained.

Analysis as Ο., -, ΗοοΝ

calculated found

C. (%) H (fo) N (fo) 42 , 99 4th 17th , 69 43 , 23 5 , 09 17th , 42

009827/2007

Claims (11)

DR. WALTER NIELSCH _t . Patent attorney 2 Hamburg ^70j patent claims ; Schioßstrasse 112. P.O. Box 10914 Telephone: 652 97 07 Γ iy) Pyrimido J5,4-dl pyrimidine derivatives of the general formula wherein R represents a nitrogen-containing heterocyclic group; R- and Rp each represent an alkyl group or -N ^ "> means: R ₀ and R ₁ mean a hydrogen atom, ^X R, '34 an alkyl group, a hydroxyalkyl group, an alkylaminoalkyl group, and Ro and R may bond with the nitrogen atom to form a heterocyclic ring which may contain an impurity in the ring; η is. zero or one and R ₁ and R ^ mean each only -N ^J if η is zero. 2.) 2-Diethanolamino ~ 6-diethanolaminosulfonyl-4 | O-dipiperidinopyrimido [5.4 " ^d ] pyrimidine. 3.) 2-Diethanolamino ~ 6-diethylaminoethylaminosulfonyl-4 | O-dipiperidinopyrimidof5,4 "" ^ pyrimidine. 009827/2007 4.) 2-Diethanolamino-6-inorpholinosulfonyl-4, O-dipiperidinopyrimidoL 5, 4-dJ pyrimidine. 5.) 2- (N-methyl) ethanolamino-6- {N-methyl) ■ ethanolaminosulfonyl- , 4-q pyrimidine " 6.) 2-Diethanolamino-6-diraeth.ylaminosulfonyl-4, O-dipiperidino-pyrimido j 5,4-d.jpyrimidine. 7.) 2-Diethanolamino-6- (N-methyl) -ethanolaminosulfonyl-4, edipiperidinopyrimido \ 5 , 4-dt pyrimidine. Ö.) 2-Diethanolarainosulfonyl-6-methylsulfonyl-4, Ö-dipiperidinopyrimidoj 5} 4- < 9.) 2 _} 6-bis (diethanolaminosulfonyl) -4, O-dipiperidinopyrimido [5,4-dl pyrimidine. 10.) 2,6-bis (methylsulfonyl) 4, Ö-dipiperidinopyrimido [5,4-d] midin. 11.) Use of the _IV> ,,,. Compounds as an active ingredient with platelet aggregation ■ Inhibitory effect in drugs for the treatment of Human and animal. 009827/2007