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    • 专利摘要:
    A 1,3-disubstituted urea or 2-thiourea having the formula <IMAGE> wherein R1, R2, R3, R6, R7 and R8 represent independently a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkenyl radical containing 2 to 4 carbon atoms, an alkylene radical forming together with the carbon atom to which it is attached a cycloalkane ring having 5 or 6 carbon atoms, an aryl radical or a substituted aryl radical, R4 and R5 represent independently a hydrogen atom, an alkyl radical containing 1 or 2 carbon atoms or a phenyl radical, n and q are independently a whole number of from 3 to 7, m and p are independently 0, 1 or 2 and X is an oxygen or a sulfur atom, processes for the preparation thereof and pharmaceutical compositions containing the same.
    公开号:SU1097622A1
    申请号:SU782637643
    申请日:1978-07-17
    公开日:1984-06-15
    发明作者:Де Ланнуай Жан
    申请人:Zhan De Lannuaj；
    IPC主号:
    专利说明:

    biologically active chemical compounds, more specifically to the synthesis of 1,3-bivalent (2-thio) ureas5 possessing activity in mnestic processes, and can be applied in medicine.
    Known 1,3-bis (alkyl) urea or trie3 trec3 formula
    R xo
    1 II / i
    N-Aei-NH-C-NH--L | c-H R /, 2
    where X is oxygen or sulfur Alk is an alkylene radical; R., can form hetero (n,) ,.
     G T
    EZ-CH- (dHr) HU-d-NH - () p-dH-3 3. - hydrogen, methyl, butyl, phenyl, chlorophenyl; Rj is hydrogen, methylS allyl, Rj is hydrogen, methyl or ethyl; X is oxygen or sulfur; t O, 1, 2; , 4, 5, 6, 7, or when n 6, q 3, which have activity in case of mnetic processes. Example 1. 153-bis- (2-Oxo-pyrrolidino) methyl urea (Compound 1). Option I. To a solution of 802 g (7.03 mol) of 1-aminomethyl-2-pyrrolidone and 521.2 g (5.16 mol) of triztilamine in 5 l of anhydrous methylene chloride, which is maintained at -10 ° C, is slowly added with intensive stirring, taking care that the temperature does not exceed 5 ° C, the solution of 232, .2 g (2.334 mol of phosgene in 1 liter of methylene chloride, also cooled to -10 ° C. After the addition, leave the reaction mixture until slowly reaching room temperature, then cooled again to -10 ° C and gaseous ammonia is introduced into the medium in order to release the triethylamine from its chlorohydrate. The ammonium chloride is formed and the filter is removed and the remaining solution is evaporated.
    However, these compounds are ganglion blocking agents and are intended for the treatment of hypertension.
    Compounds are also known, in particular, piracetam C 2-oxo-1-pyrrolidine acetamide) G-, which has a favorable effect on memory disorders in elderly patients,
    However, the known compound has an effect only when used in an increased dose.
    The purpose of the invention is to expand the arsenal of means for affecting the organism.
    The goal is achieved by using 1,3-disubstituted (2-thio) urea of the general formula
    (,)
    EI
    N
    : kg
    I was dry at jnoHifflceHHOM pressure. The residue is recrystallized in 2 liters of isopropyl. 384 g (64.4%) of 1,3-bis (2-oxo pyrrolidino) methyl urea with m.p. 184.5 C. Calculated,%: C 51.9; H 7.1; N 22.0., (Mol. Weight. 254) Found,%: 51.9, H 7.0, N 21.9 Option C. K 20.6 g (0.18 mol) 1-aminomethyl- 2-pyrrolidinone in 100 ml of methylene chloride is added 50 ml of an aqueous solution saturated with sodium carbonate. The solution and, 5.95 g (0.06 mol) of phosgene in 50 ml of methylene chloride are added with vigorous stirring, Confirm that the temperature of the reaction medium remains below 10 ° C. After the addition, stirring is continued at room temperature for 4 hours. The aqueous phase is decanted, lyophilized, then extracted several times with chlorine fifth chloride. The organic extracts are combined and evaporated under reduced pressure. The residue is recrystallized from a minimum amount of isopropyl alcohol and then 7.2 g (0.0283 mol) of pure compound 1 are taken.
    Yield 47.2%.
    Option Y. To a solution of 27 g (0.145 mol) of 1-aminomethyl-2-pyrrolidinone and 57 g (0.72 mol) of anhydrous pyridine in 300 ml of methylene chloride is added dropwise, taking care that the temperature of the reaction medium did not exceed О С, solution from 3, .6 g (0.036 mol) of phosgene in 100 ml of methylene chloride. The reaction mixture is maintained under reflux for 2 hours, then is allowed to dry to dryness under reduced pressure. The residue is purified by chromatography on silica gel using chloroform-methanol (10: 1) as eluent. The resulting product is recrystallized from a minimum amount of isopropyl alcohol. 3.5 g (0.0138 mol) of Compound 1 are removed.
    Exit 38%.
    Example 2. 1- (2-Oxo-pyrrolidino) methyl1-3- 3- (2-oxo-pyrrolvdi H9) propyl urea (compound 2).
    In a solution of 5.55 g (0.056 mol). phosgene, cooled to -70 ° C, 12.42 g (0.123 mol) of triethylamine and 6.39 (0.056 mol) of 1-aminomethyl-2-pyrrolidinone dissolved in 20 ml of methylene chloride are successively introduced. The mixture is then stirred for 30 minutes, taking care that the temperature does not exceed -60 ° C, and a solution of 7.97 g (0.056 mol) of 1- (3-aminoprop 1) -2-pyrrolidinone in 20 ml of chloride is added. methylene. After the addition, the suspension is stirred for 1 hour at room temperature, then cooled to –60 ° C, i.e. to the temperature at which triethylamine hydrochloride crystallizes. The precipitate is filtered off and the solution is evaporated to dryness under reduced pressure. The residue is chromatographed on a silica column (eluent: acetone-methanol, 96: 4).
    Obtain 3.1 g of 1- (2-oksko-pprolidino) methyl-3-C3 -; (2-oko-pprolidino) propyl-urea in the form of oil (19.6%).
    Calculated,%: C 55.3, H 7.9, N 19.3
    C ,, (mol. Weight 28Z)
    Found,%: C 55.3, H 7.9, N 19.1
    The following compounds of formula (T) are prepared analogously.
    1,3-bis- (2-Oxo-piperidino) methyl urea (compound 3). yield 34%, so pl. 161-2 C. Calculated,%: C 55.3, H 7.8, N 19.8
    Found,%: C 55jO H 7.9,
    N 19.9
    1,3-bis (Hexahydro-2-oxo-1H-azepin-1-yl) methyl 3-urea (compound 4).
    Yield 34%, so pl. 169-70 s.
    Calculated. %: C 58.1; H 8.5j N 18.1.
    five
    Found,%: C 58.9; H 8.5;
    N 18.1
    1,3-bis- (Hexahydro-2-oxo-1 (2H) -azocinyl) methyl urea (compound 5).
    Yield 41%, so pl. 224-5 ° C.
    Calculated,%: C 60.3, H 8.9, N 16.5
    C.,
    five
    Found,%: C 60.4, H 8.8, .N 16.5.
    1,3-bis (Octagidro-2-oxo-1H-azonin-1-yl) methyl urea (compound 6).
    0
    m.p. 207-8 s.
    Yield 48%, C: 62.3 H, 9.4; Calculated 15.3
    N SPNZO "40Z
    Found,%: C 62, Oj H 9.4;
    5 N 15.3
    1,3-bis- | (4 - (- chlorophenyl-3-metsh1-2-oxo-pyrrolidino) methyl-urea (compound 7).
    Yield 36%, so pl. 202-3 C.
    0
    Calculated,%: C 59.6; H 5.6, 11, Ij C1 14.1
    N
    Found,%: C 59.2 -, - H 5.5,
    11.0, C1 14.7
    N
    five
    1,3-bis- (5-Methl-2-oxo-pyrrolidino) methyl urea (compound 8). Yield 7%, so pl. 120-1 C.
    %: C 55.3; H 7.9;
    Vyisleno,
    N 19.9
    С1.г «Л
    0
    Found,%: C 55.3-, H 7.8N 19.7
    1,3-bis- ((2-Oxo-5-phenylpyrrolidino) methyl urea (compound 9).
    Yield 33%, so pl. 190-2 C,
    five
    Calculated,%: C 67.9; H 6.4; N 13.8
    C, zNg, J Found,%: C 67.3, H 6.4; N 13.7 1, (2-Oxo-pyrrolidyl pea-urea (compound 10), Yield, 52%, mp. 130-1 C. Calculated,%: C 58.0, H 8.4 15 Found, %: C 57.9; H 8.5-, N 17.9 1,3-bIs- 1- (2-Oxo-pyrrolide ethyl} -urea (compound 11) Yield 15%, mp. 158-9 ° C. Calculated,%: C 55.3-, H 7.9 N 19.8 C, H, H403 55.2; And 7.9i Found,%: C N 19.7 153-bis (2 -Oxo-4-phenylpyr but) methyl 3-urea (compound Yield 60%, mp. 188–9 ° C.%: C 68.0; H 6.4 Calculated, 13.8 C, 3 Na N403 Found ,%: C 68, Oj H 6.5i N 13.8 1, 3-bis (4,5-Dimethyl-2-oxo; lidino) methylJ-urea (compound 13). Yield 22%. 1,3-bis (3-Allyl-2-oxo-3-f-pyrrolidino) methyl urea (as found in 14). Yield 36%, mp. 134-5 ° C. Calculated, C 71.6; H 7.0; N 11.5 CjgHj N Oj Found: C 71.5, H 7.0; N 11.5 1,3-bis (5-p-Chloro-1CHL-2-ca-peridino) methyl3-urea ( Compound 15), Yield 56%, mp 202-3 ° C. Calculated,%: C 59.6-; H 5.6 N 11.1; C1 14.1 C,; jH, gC1, N , 0, Found: C 59.6; H 5.7; N 11.1; C1 14.0 1,3-bis (3,5,5-Trimethyl-2-o-pyrrolidino) methyl urea ( 16). Yield 45%, mp. 156-9 C. Calculated,%: C 60.3; H 8.9 N 16.5 C ,, Found,%: C 60.3-; H 8.9-, 16, 5, 1, 3-bis 2 (2-Oxo-pyrrolidi-urea (compound 17). 2 Yield, 51%, mp. Calculated,%: C 55.3; H 7.8; N 19.8 C., Found: C 55.1, H 8.0, N 19.2 1,3-bis- 2- (2-0 x-pyrrolidino) propyl-urea (compound 18). Yield 43%. 1,3-bis- 2- (2-Oxo-pyrrolidino) butyl 3-urea (compound 19) is an unreacted oil. Yield 55%. 1,3-bis- 3- (2- Oxo-pyrrolidino) propyl urea (compound 20). Yield 41%, mp 87-8 p. Calculated: C 58.0; H 8.4; N 18.1 Cl5 2bN403 Found: C 58.0; H 8.5; 18.2 3. 1,3-bic-5-p-chloropryl; Enyl-2-oco-piperidino) methyl -2-tiouchevin (compound 21). To a solution of 6.9 g (0.029 mol) of 1-amInomethyl-5-p-chlorophenyl-2-piperinone and 2.34 g (0.023 mol) of triethylmine in 50 ml of methylene chloride, maintained at low temperature (-20 ° C ), a solution of 1.334 g (0.0166 mol) of thiophosgene in 10 ml of methylene chloride is added slowly with vigorous stirring. After the addition, the reaction mixture is left to reach room temperature, then cooled to -50 ° C to obtain triethnlamine hydrochloride in the precipitate, filtered, the filtrate is evaporated to dryness. The resulting solid is recrystallized from methanol. 4.1 g (0.0079 moL) of 1,3-bis- (5-p-Chlorfensch-2-oxO-Piperidino) methyl-3-thiourea (68%) are obtained with a mp. 212-3 ° C. Calculated,%: C 57.8, H 5.4, N 10.8; C1 13.7j S 6.2 C..S Found,%: C 57.8; H N 10.7, C1 14.0-j S 6.0 In a similar manner, the following compounds are obtained. 1,3-bis- (2-Oxo-pyrrolidino) methyl 3-2-thiourea (compound 22). Yield 68%, mp. 183-4 s. Calculated,%: C 48.9; H 6.7 N 20.8; S 11.9, S Found,%: C 48.8; H 6.8; N 20.8; S 11.7 1,3-bis-t (3-l-Butyl-2-oxo-pyrro-leadino) methyl -2-thiourea (compound 23). Yield 7%, mp. 119-20 ° C 1,3-bis- (3-1-Butyl-2-oxo-pyrrole-dino) methyl -2-thiourea (compound 24). Output 1%, so pl. 148-9 s. Compounds 23 and 24 are two diastereoisomers, which are separated by chromatography on a column of silica. Example 4. 1- (Hexagilro-2 oxo-1H-azepin-1-yl) methyl -3-2-ox-pyrrolidino) methyl -2-thiourea (compound 25). To a solution of 3.8 MP (0.05 mol) thiophosgene and 10.1 g (0.1 mol) of triethylamine in 50 ml of methylene chloride maintained at -70 ° C, a solution of 6.27 g (0.035 g) is added slowly and with vigorous stirring. mol) 1-aminomethyl-2-pyrrolidinone in 50 ml of methylene chloride. After the addition, the reaction was left to reach room temperature and 7.8 g (0.055 mol) of 1-aminomethyl-hexahydro-2H-azepin-2-one was slowly added. Stirring is continued for 15 minutes, then the mixture is cooled to -50 ° C to precipitate triethylamine hydrochloride, filtered and the filtrate is evaporated to dryness. The residue obtained is purified by chromatography on a silica column (eluent: chloroform). Obtain 5.9 g (39%) of 1- (hexahydro, .- oxo-1H-azepin-1-yl) methyl3-3 - (2-oxg; -pyrrolidino) metshtZ-2-thiouchevine with m.p. 147-8 C. Calculated,%: C 52.3; H 7.4; 18.8 N 10.7 C ,, H ,, N, 0; Found,%: C 52.2; H 7.4, 18.7J N 10.1 Example 5. 1- (Octagidro-2-oxo-1H-azonin-1-yl) methylJ-3- f (2-oxo-pyrrolidino) methyl urea (compound 26 ). To a solution of 5.7 g (0.05 mol) of 1-aminomethyl-2-pyrrolidinone in 20 mp of methylene chloride, cooled to -70 ° C, a solution of 8.1 g (0.05 mol) is added with vigorous stirring 1,1-Carbonyldiimidazole in 20 ml of methylene chloride, then 1 2 8.5 g (0.05 mol) of 1-aminomethyl-octahydro-2H-azonin-2-one in 20 ml of methylene chloride. After addition, the reaction medium is heated under reflux for 2 hours. After evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a column of silica (eluant: chloroform). 5.7 g (0.0184 mol) of 1- (octahydro-2-oxo-1H-azonin-1-yl methyl-3- (2-oxo-pyrrolidino) methyl} urea are obtained. The yield is 36.7%, t mp 149-50 ° C. Calculated,%: C 58.0; H 8.4; N 18.1., Found,%: C 57.6, H 8.1 j N 18.3 In the same way, the following are obtained. 1,3-bis- (3-P-Butyl-2-oxo-pyrro-leadino) methyl 3-urea (compound 27). Yield 65%, mp 186-7 0. Calculated,% 62.3; H 9.4} N, 15.3 CigH., Found,%: C 61.7i H 9.2; N 15.6 1- (Hexahydro-2-oxo-1H-azepin-1-yl) methyl-3- (2-oxo-pyrrolidino) methyl 3-urea (compound 28). Yield 34%, mp 114-5 ° C. Calculated,%: C 55.3; H 7.9; N 19, 8 С ,, Н ,, N, 0, Found,%: С 55.3, H 7.9; N 19.5 H (Hexahydro-2-oxo-1 (2H) -azocinyl) methyl -3- (2-oxopyrrolidino) Methyl1-urea (compound 29). Yield 18%, mp 118-9 C. Calculated,% f C 56.7; H 8.2- N 18.9 Found: C 56.5} H 8.1 18.3 Example 6. To a solution of 14.25 g (0.125 mol) of 1-aminomethyl-2-pyrrolidinone in 100 ml of anhydrous methylene chloride, maintained at a low temperature (-40 ° C), a solution of 8.9 g (0.05 mol) of 1,1-thiocarboni pdiimidazole in 60 ml of tetilene is added with stirring. Allow the reaction medium to reach room temperature and distill off the solvent under reduced pressure. The residue is recrystallized from methanol in the presence of active carbon. 7.1 g (0.0263 mol) of 1,3-bis- (2-oxo-pyrrolidino) methyl -2-thiourea (Compound 22) are taken away. Yield 52.6%. Example 7. To a solution of 3.42 g (0.03 mol) of 1-amynomethyl 2 pyrrolidinone and 4.6 ml (0.032 mol) of triethylamine in 50 ml of anhydrous toluene is added slowly, taking care that the temperature does not exceed 10 ° C, a solution of 1.63 g (0.015 mol) of ethyl chloroformate in 30 ml of anhydrous toluene. After the addition, the reaction medium is stirred for 2 hours at 50 ° C. The mixture is then cooled to ambient temperature and the precipitate formed is filtered, which is suspended in methylene chloride and treated with gaseous ammonia. 5 Ammonium chloride is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from isopropyl alcohol. Obtain 0.3 g (0,002 mol) 1,3-bis (2-oxo-pyrrolidino) methyl urea (compound 1). Yield 13.3%. Example 8. To a solution of 16.15 g (0.1 mol) of 2-oxo-1-pyrrolidine acetyl chloride in 300 ml of benzene, 14.3 g (0.124 mol) of trimethylsilyl lasene were added with vigorous stirring at room temperature. The reaction medium is then heated under reflux until the end of the nitrogen gap. The solution is evaporated to dryness and the resulting (2-oxo-pyrrolidino) methyl isocyanate is dissolved in benzene, to which a few milliliters of water is added. The mixture is stirred for 1 h at room temperature. After evaporation under reduced pressure, the residue is recrystallized from isopropyl alcohol. 1.0 g (0.0039 mol) of 1,3-bis- (2-oxo-pyrrolidino) methyl 3-urea is obtained (compound 1). Yield 8%. Example 9. To a solution of 2550 g (30 mol) of 2-pyrrolidinone and 22.5 g (0.12 mol) of L-toluene sulfate lots, heated to 120 ° C, was added 900 g (7.5 mol) 1, 3-bis (hydroxymethyl) 1 urea. After dissolution, the mixture is heated at 120 ° C for another 5 minutes. The reaction mixture is then cooled (80 ° C) and poured over 5 liters of a mixture of ethyl acetate and isopropanol (77:23) with stirring. Filter the resulting solid, wash it with 2 L of ethyl acetate / isopropanol mixture and dry under reduced pressure. Selected 763 g of product, which is recrystallized from 3.5 liters of isopropanol. 650 g (2.56 mol) of 1,3-bis {(2-hydroxy-pyrrolidino) methyl urea are obtained (compound 1). Yield 34%. The following compounds are prepared analogously. Connection 4. Output 16%. 1,3-bis- (3-methyl-2-oxo-pyrrolidino) methyl urea (compound 30). Yield 49.6%, m.p. 145-6 ° C. Calculated,%: C 55.3; N. 7.8; N 19.8 s., N ,, K, Oz (mol. Weight 282) Found,%: C 55.2; H 7.8; N 19.8 1,3-bis- (5,5-Dimethyl-2-oxo-pyrrolidino) methyl urea (compound 31). The output of 32.1%, so pl. 180-1 C. Calculated,%: C 58.1 H 8.4; N 18.0 C15 And Found,%: C 57.7, - H 8.2 N 19.0 Example 10. To a solution of 34 g (0.4 mol) of 2-pyrrolidinone and 0.3 g (0.00l6 mol) p-toluenesulfonic acid, heated to 60.degree. C., -14.8 g (0.1 mol) of 1,3-bis- (1-hydroxyethyl) urea are added. The mixture is heated for 0.5 h. The residue is recrystallized from ethyl acetate / ethyl ether. 4 g (0.0124 mol) of 1,3-bis-Cl- (2-oxo-pyrrolidino) ethyl urea are obtained (compound 11). Example 11. To a solution of 34 g (0.4 mol) of 2-pyrrolidinone and 0.3 g (0.0016 mol) of p-toluenesulfonic acid heated to 120 ° C was added 13.6 g (0.1 mol) 1,3-bis- (hydroxymethyl) -2-thiourea. The mixture is heated for 1 hour at this temperature, cooled to 60 seconds and poured into 80 ml of methanol. The resulting suspension is filtered in a hot state and separated from the medium by crystallization 11109.7622 G, 3-bis-C (2-oxo-n "rrolidino) methyl 3-mouth -2-thiourea (compound 22). Zhit Obtain 5.3 g ( 0,0196 mol). You call 19.6%. Home Similarly, 1,3-bis-C (hex-5car sagidro-2-oxo-1N.-azepin-1-yl) methyl-con -2-thiourea (compound 32) is obtained. The output of 18.5%, T, pl. 213-14 C. Calculated,%: C 55.2; H 8.0; N 17.2; S 9.8 (mol. Weight 326) Found,%: C 55.5, H 8.1; N 17.1 S Example 12. A mixture of 17 g (0.2 mol) of 2-pyrrolidinone, 6 g (0.1 mol) of urea and 21 g (0.2 mol) of formaldehyde (35%) in the presence of 0.5 g p-toluenesulfonic acid in 120 ml of water is gradually heated to 70 ° C. The solution becomes cloudy and gas is observed. The reaction mixture is then heated under reflux for 4 hours, then cooled and filtered. The filtrate is evaporated to dryness and purified by chromatography on a silica column, using a mixture of chloroform and 5% methanol as the solvent. 3.4 g (0.0134 mol) of 1,3-bis- (2-oxo-pyrrolroschino) methyl} - 0 urea (compound 1) is taken away. Yield 13.4%. . Action on memesic processes. Determination of the ability of products to improve rat memory latency. A reduction reaction was observed in rat paws, the pressure on which has increased dramatically. The pressure that causes the reaction is called the reaction threshold, expressed as a number on the scale, graduated in centimeters, of the apparatus used and corresponds to the minimum pressure that is applied in the paw of animals and causes a contraction. In experiments conducted over 24 hours, the control animals did not show any visible delay in previous experience: a delay is made for the intensity of stimulation compared with the intensity of stimulation during the waking period. The animals that were treated with a substance that has a positive effect on melanic processes (for example, pyra-5S chains) showed a significant degree of delay: an irritant that rats responded to in doses of 11 din serv. tab 12, was statically lower than the control animals. A minimum of 20 rats were used in a hoard (10 rats, which were given, and 10 rats, which are crooks), and as an active dose, they had a minimum dose that reduced the stimulus below graduations. Subcutaneous administration of some soyions of formula (T) gave the effects listed in p. 1. Table 1 As can be seen from table. 1, all of these compounds exhibited activity that exceeds that of piracetam. In addition, the effect on many processes is also manifested by a reduction in the time of spinal fixation as an elementary memory model, showing pharmacological reactivity with good correlation with clinical physiopathology. In the rat after unilateral damage to the cerebellum, asymmetry was observed in the position of the hind paws. This asymmetry can continue even after spinal. section, if the animal was in this situation for quite a long time. This time, called spinal fixation, was 45 minutes under experimental conditions. If the spinal section was carried out before this interval expired, for example, after 35 minutes not; lu ustanapeni asymmetry, then .n disappears. No animal to which placebo was given asymmetry did not retain asymmetry under these conditions. Any product that allows Krygmm to maintain asi metry (therefore, realizing spinal fixation), when the spinal section has been performed after 35 minutes, is considered active. Introduction inside the peritoneum of some of the compounds of formula (I) gave the results given in table. 2. All products were tested at a dose of 0.32 mmol. Minimum active doses were not investigated, excluding compound 1 and piracetam. For these two compounds, the minimum dose is indicated in Table. 2. ItTable2
    权利要求:
    Claims (1)
    [1]
    1,3-TWO-SUBSTITUTED (2-THIO) UREA ACTIVITIES IN MNESICAL PROCESSES.
    (57) 1 H-disubstituted (2-thio) ureas of the formula 3 - CH- (Yong) m -nk · - d-NH ~ (dHz ) p- dH -to 3 where R 1 - is hydrogen, methyl, butyl, phenyl, chlorophene il-,
    R 2 is hydrogen, methyl, allyl;
    R 3 is hydrogen, methyl or ethyl;
    x is oxygen or sulfur;
    w = p = 0, 1, 2;
    n = q = 3, 4, 5, 6, 7, or for η = 6, q = 3, which are active in mnemic processes.
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    同族专利:
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    ZA78793B|1979-01-31|
    FR2380262A1|1978-09-08|
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    IT1102355B|1985-10-07|
    IL54011D0|1978-04-30|
    PH14362A|1981-06-03|
    IN148262B|1980-12-27|
    ATA92578A|1980-03-15|
    GR66187B|1981-01-21|
    NZ186425A|1980-04-28|
    BG29571A3|1980-12-12|
    PT67637A|1978-03-01|
    CA1078858A|1980-06-03|
    NO780431L|1978-08-11|
    US4216221A|1980-08-05|
    JPS53101366A|1978-09-04|
    LU79047A1|1978-09-28|
    FI66601B|1984-07-31|
    FR2380262B1|1982-04-23|
    YU29778A|1983-01-21|
    SU936810A3|1982-06-15|
    AT359080B|1980-10-27|
    FI66601C|1984-11-12|
    DE2805769A1|1978-08-17|
    AU516765B2|1981-06-18|
    ES466815A1|1978-10-01|
    DK57778A|1978-08-11|
    PL112570B1|1980-10-31|
    BG29646A2|1981-01-15|
    IT7848004D0|1978-02-10|
    HU176033B|1980-11-28|
    IL54011A|1981-05-20|
    OA05883A|1981-05-31|
    DD134097A5|1979-02-07|
    JPH0140027B2|1989-08-24|
    DE2805769C2|1989-10-26|
    GB1582351A|1981-01-07|
    CH632999A5|1982-11-15|
    PT67637B|1979-09-20|
    SE426593B|1983-01-31|
    AU3315578A|1979-08-16|
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    RU2589056C2|2008-11-04|2016-07-10|Галдерма Ресерч Энд Девелопмент|Melanocortin receptor modulators, method for production thereof and use thereof in medicinal and cosmetic preparations for human use|US2850529A|1955-03-28|1958-09-02|Pfizer & Co C|Bis quaternary ammonia alkyl ureas|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB5494/77A|GB1582351A|1977-02-10|1977-02-10|Disubstituted ureas and thioureas|
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