Method of preparing purine derivatives or their salts

专利摘要:

公开号:SU858568A3
申请号:SU792713599
申请日:1979-01-26
公开日:1981-08-23
发明作者:Фрибе Вальтер-Гунар；Тиль Макс；Роэш Андроники；Вильхельмс Отто-Хеннинг；Шауманн Вольфганг
申请人:Берингер Маннхай Гмбх (Фирма)；
IPC主号:

专利说明:

Pharmacological acceptable salts are prepared in the usual way, for example by neutralizing compounds of the formula} with non-toxic mineral or organic acids, such as hydrochloric, sulfuric, phosphoric, hydrobromic, acetic, citric, block, salicylic, milky, malonic, maleic, or amber. The novel compounds of the formula I and their salts can be used in liquid and solid form for enteral and parenteral administration. All the usual forms of application are suitable for this, in particular tablets, capsules, dragees, syrups, solutions, suspensions, etc .. As the injection medium, water is used predominantly which may contain additives usual for injection solutions, as stabilizers, dissolving agents and buffers. These are, for example, tartrate or citrate buffer solution, ethanol, a complexing agent (like ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers (like liquid p-polyethylene oxide) to control viscosity. Liquid carriers for injection solutions should be sterile and should be preferably found to be visually sterile and should be found in ampoules. Solid carriers, for example starch, lactose, mannitol methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (like stearic acid) , gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable oils, solid high-molecular compounds (like polyethylene glycol) for the introduction of black mouth, can contain vkudovye and synthetic sugar substances. Preferred are the following compounds: (2-Chlorobenzamido) -piperi dino-propyl-adenine 9-3.4- (3-chlorobenzamide) -piperi dino-propyl 5-adenine (3-methoxybenzamido) -piperidinoZ-PROPIL-adenine 9- | 3-4- ( 4-methoxybenzamido) -piperidino-propyl5-adenine 9- | 3- 4- (2-acetoxybenzamido) -py-peridino-propi a-adenine (3-methylbenzamido) -piperndino-propyl-adenine 9- (benzylbenzamido) -piperi dino3-propyl adenine 4- (4-cyanobenzamido) -piper dino-propyl adenine (ethoxycarbonylbenzamido-piperidino -propyl-adenine (ethoxycarbonylbenzamido-piperidino -propyl-adenine) {3- 4- (4-carboxybenzamido) -pyridine -propyl} -adenine N-ethyl-9-3- (4-benzamido-piperidino) propyl-adenine M-phenyl-9- 3- (4- Benzamido-piperidino) -propyl-adenine b-pyrrolidino-9- 3- (4-benamido-piperidino) -propyl-purine 9- 3- (4-trifluoroacetamido-piperidino) -propyl-adenine 9-H - {4-butyralido - piperidino) - pryupil - adenine (4-cyclopentacarbonylamzo-piperidino) - propylJ-adenine, as well as their salts with pharmacologically tolerated acids. Example 1. (4-Benzamido-piperidino) -propyl-adenine. 4.7 g (0.035 mol) of adenine is added to a solution of 0.8 g (0.035 mol) of sodium in 125 ml of isopropanol, heated for 10 min with counter current, cooled, and 11.2 g (0.04 mol) is added - (4-benzamido-piperidino) -propyl chloride in 50 ml of isopropanol. After stirring for 6 hours with a countercurrent, the reaction mixture is evaporated in vacuo, poured into methylene chloride, washed with 2N. sodium hydroxide solution, then with water, evaporated and recrystallized from ethanol. Obtain 7.1 g (4-benzamidopiperidino) -propyl-adenine (54% of theoretical), so pl. 213-214 s. The 3- (4-benzamido-piperidino) propylchloride used as the reagent was prepared as follows. A mixture of 20.4 g (0.1 mol) of 4-benzamido-piperidine, 15.7 g (0.1 mol) of 1-bromo-3-chloropropane, 30.3 (0.3 mol) of triethylamine and 200 ml of tetrahydrofuran is heated for b with counterflow, filter, the filtrate is evaporated in vacuo, the residue is extracted with ethyl acetate and the extract is evaporated. Obtain 13.0 g of 3- (4-benzamido-piperidino) -propyl chloride (46.5% of theoretical), so pl. 128-130s Substituted acylamidopiperidinepropylchlorides used in the following examples are obtained accordingly. Example 2. In a manner similar to that described in Example 1, the following compounds were prepared. The results are presented in table 1. Example 3. 9-Sz- (4-cyannamoylamnzo-piperidico) -propyl-adenine. To a mixture of 6.2 g (0.02 mol) of 9-СЗ- (4-amino-piperidino) -propyl-adenine and 100 ml of 1 s. caustic soda solution was added dropwise 3.7 g (o, 022 mol) of cinnamic acid chloride, stirred at room temperature for 5 hours, filtered and recrystallized from isopropanol. 3.2 g (4-cyanamoyl-amido-piperidino) -propyl-adenine (39% of the theoretical) are obtained with a mp of 217219 ° C. 9-Gz- (4-amino-piperidino) -propyl-adenine used as a reagent can be prepared as follows. A mixture of 32.0 g (0.085 mol) (4-benes1mido-piperidino) -propyl-adenine and 500 ml of 5N. Hydrochloric acid is heated with a countercurrent for 6 hours. The mixture is cooled, washed with ether, 1 is set on a 1N medium and extracted with chlorine Tfcw with methylene. The extract is evaporated. After recrystallization of the residue from isopropanol, 14.6 g of 9-СЗ- (4-amino-piperidino) -propyl} -adenine are obtained (62% of the theoretical) with a mp of 140 (hydrochloride with a melting range of 318320 C). Example 4. In the manner similar to that described in Example 3, the following compounds were prepared. The results are presented in table 2. Example 5. (4-aminobenzamido) -piperidino-propyl-adenine. A mixture of 3.0 g (0.007 mol) of (4-nitrobenzamido) -piperidine-6-propyl} -adenine, 50 ml of methanol, 25 ml of tetrahydrofuran and 1 g of Rene nickel is hydrogenated for 2 hours at room temperature and a hydrogen pressure of 1 bar. After that, the reaction mixture is filtered, evaporated and the residue triturated with Uxus-ethyl ether. According to Table 1, 2.4 g of (4-aminobenzamido) -piperidino-D-propyl-adenine is radiated (86% of the theoretical) with so pl. 247248 S. Example 6. N — H-butyl-9-C 3— (4-benzamido-piperidino) -propyl-adenine. To a solution of 12.0 g (0.03 mol) of 6-chloro-9-D-benzamido-piperidino) propyl-purine in 100 ml of H-propanol is added 50 ml of C-butylamine and heated for 6 hours with countercurrent . It is then evaporated in vacuo and the residue is extracted with ethyl acetate. After evaporation of the solvent and recrystallization from a mixture of isopropanol and ether, 6.8 g of M -M-butyl-9 (4-benzamido-piperidino) -propyl-adenine (52% of the theoretical) are obtained. 190-192s. PRI me R 7. Chlorohydrate 4- (4-tert-butylbenzamido) -piperidinoZ-propyl1-adenine. A suspension of 1.0 g of (4-butylbenzamido) -piperidino1-propyl-adenine, in 10 ml of ethanol is treated with an excess amount of ethereal hydrochloric acid. When adding an ether solution, 0.95 g of U4- (4-tert-butylbenzamido) -piperidino1-propyl-adenine hydrochloride is obtained (87% of the theoretical) with m.p. 285287 S.
(2-fluorobenzamido) piperidine propyl-adenine from adenine and (2-fluorobenzamido) -piperi Dino-propyl chloride
(4-fluorobenzamido) -piperidino-propyl-adenine from adenine and (4-fluorobenzamido) -piperidino-propyl chloride
9- | 3- (2-methoxybenzamide) -piperidino-propyl-j-adenine from adenine and (2-methoxybenzamido) -piperidinoz-Propylchloride
9- 4- (} -butoxybenzamido-piperidino1-propyl, -adenine from adenine and (4-; -butoxybenamido) -piperidino-3-propyl chloride
180-181 Isopropanol
203-204 Isopropanol
139-141 Ether 208-210 Isopropanol
9- 3- 4- (2-methylbenzamido) -piperidino3-propyl) -adenine from
adenine and (2-methylbenzamido) -piperidino-propylchloro-.
reed
9- 4- (4-methylbenzamido) -piperidino-propyl-adenine from adenine and (4-methylbenzamido) -piperidino-propyl chloride
(3-trifluoromethylbenzamido) -piperidino-propyl-adenine from adenine and (3-trifluoromethylbenzamido-propyl chloride
9- | 3-f4- (4-tert-butylbenzamido-piperidino-propyl | -adenine from adenine and (4-tert-butybenzamido) -piperidino-propyl chloride
N -methyl-9-s- (4-benzamido-piperidino) -propyl-adenine from N-methyladenine and 3- {4-benzamido-piperidino) -propyl chloride
N - 2-hydroxyethyl-9-L3- (4-benzamchdo-piperidino) -propyl-estenin from (2-oxystil) -adenins and 3- {4-5-benzamido-piperidino-propyl chloride
M-C-butyl-9-3- (4-benzamido-piperidino) -propyl-adenine from N-H-butyladenine and 3- (4-benzamido-piperidino) -propyl chloride
6-dimethylamino-9-z- (4-benzamido-piperidino) -propyl-purine from 6-dimethylaminopurine and 3- (4-benzamido-piperidino) -propyl chloride
6-piperidino-9- 3- (4-benzamido-piperidino) -propyl-purine from b-piperidinopurin and 3- (4-benzamido-piperidino) -propyl chloride
(4-acetamido-piperidino) -propyl-adenine from adenine and 3- (4-acetamido-piperidino) -propyl chloride
Continued table. one
I ;; :: L ;;:; :::; :.
I.
182-183 Isopropanol
220-222 Isopropanol
176-177 Acetic ester
186-187 Airtime
212-214
A mixture of isopropanol and ether
154-155 Isopropanol
190-192
A mixture of isopropanol and ether
105-107
A mixture of ethyl acetate and ether
144-145 Isopropanol
213-215
A mixture of isopropanol and ether
Title
9- 3- 4- {4-chlorobeneamido) -piperidino-propyl} -adenine from (4-amido-piperidino) -propyl-adenine and 4-chlorobenzoyl chloride
 4- (2-oksibenzam c o) -piperidino-propyl-adenine from 9 -3- (4-amino-piperidino) -propyl 1-adenine and salicylic acid chloride
 4- (4-nitrobenzamido) -piperidino-propyl {-adenine from (4-amino-piperidino -) - propyl-adenine and 4-nitrobenzoyl chloride
 4- (phenylacetamido) -piperidino-propyl j-adenine from 9-Z- {4-amino-piperidino) propyl J-adenine and phenylacetic acid chloride
9- 3- 4- (2-phenylpropionamides) -piperidino-propyl} -adenine from 9- > {4-amino-piperidi-o) -prolyl-adenine and 2-phenylpropionic acid chloride
 t4- (4-furan-2-carbonylamido) -piperidino-propyl J-adenine from (4-amino-piperidino) -propyl-adenine and furan-2-carboxylic acid chloride
9- | 3- 4- {thiophene-2-.carbonylamido) -piperidino-propyl} -adenine from 9-3-amino-piperidino) propyl-adenine and thiophene-2-carboxylic acid chloride
9- 3- 4- (pyridin-3-cargonylamndo) -piperidino-propyl | -g1denine from 9- | 3- {4-amine-piperidino) -propyl-adrenine and 3- (isobutcarbonyloxycarbonyl)) - pyridine
9- | 3 - 4- (4-aminocarboishyl amido) -piperidino-propyl-adenine from 9-Cs- (4-amioo-piperidino) -propyl-adenine and 4- {isobutoxycarbonyloxycarbonyl) -benzamide
(4-Benzolyl-amido-piperidinp) -propyl -addenine from 9- 3.- (4-amino-piperidino) -propyl-adenine and benzenesulfonyl chloride
Table
M.pl., "with 1. Solvent
203-205
A mixture of isopropanol and ether
41
193-195
19 Acetone
142-143
28 isopropanol
190-192
32 Acetic ester
185-187
27 Acetic sfir
201-202 isopropanol
39
210-212
55 isopropanol
303-205
A mixture of isopropanol and ether
29
278-28-0 Acetone
39
175-177 Acetic ester
- 23

权利要求:
Claims (1)
[1]
Claim
A method of obtaining derivatives of purine of General formula I
ClkClhCMi.-,
- hydrogen or lower alkyl group;
- hydrogen, an hydroxyethyl group or r4 and R ^ together with the nitrogen atom form a piperidine ring,
- an acyl group or hydrogen, salts, wherein - where
R ² or s i
R ³ them in that the compound of formula II where A is halogen, mainly chlorine or bromine, or a group of about 4 l
. where R ⁴ and I ² have the indicated values, are reacted with 3-piperidino-propyl chloride of the formula HI
GHSNhS / kSh, where R ^ has the above meanings, and in the case where A is a halogen atom, the resulting product is subjected to subsequent interaction with the compound, where R and R have the meanings, from the subsequent target product or or
VNIIIPI Order 7278/92 of the formula HN <
the aforementioned by the removal of an acyl group, by dilation of the target product in salt.

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DE2401254A1|1974-01-11|1975-11-27|Boehringer Mannheim Gmbh|NEW DERIVATIVES OF N HIGH 6 SUBSTITUTE ADENINES|

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DE2550000A1|1975-11-07|1977-05-12|Boehringer Mannheim Gmbh|NEW PURIN DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION|DE2922159A1|1979-05-31|1980-12-04|Boehringer Mannheim Gmbh|NEW XANTHINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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DE3529497A1|1985-08-17|1987-02-26|Boehringer Mannheim Gmbh|N6-DISUBSTITUTED PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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FR2699176B1|1992-12-11|1995-03-03|Adir|New bicyclic pyrimidine compounds, process for their preparation and pharmaceutical compositions containing them.|

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FR2741881B1|1995-12-01|1999-07-30|Centre Nat Rech Scient|NOVEL PURINE DERIVATIVES HAVING IN PARTICULAR ANTI-PROLIFERATIVE PRORIETES AND THEIR BIOLOGICAL APPLICATIONS|

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KR20010012316A|1997-05-08|2001-02-15|스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스|Protease Inhibitors|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19782804416|DE2804416A1|1978-02-02|1978-02-02|NEW PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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