MXPA98009960A - Process for preparing 2,2 '- (1-methyl-1,2-etanodyiliden) bis [hidrazincarboximidami - Google Patents
Process for preparing 2,2 '- (1-methyl-1,2-etanodyiliden) bis [hidrazincarboximidamiInfo
- Publication number
- MXPA98009960A MXPA98009960A MXPA/A/1998/009960A MX9809960A MXPA98009960A MX PA98009960 A MXPA98009960 A MX PA98009960A MX 9809960 A MX9809960 A MX 9809960A MX PA98009960 A MXPA98009960 A MX PA98009960A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- bis
- parts
- approximately
- solution
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 37
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims abstract description 33
- -1 1-methyl-1,2-ethanediylidene Chemical group 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000012535 impurity Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 9
- QDXQAOGNBCOEQX-UHFFFAOYSA-N 1-methylcyclohexa-1,4-diene Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- DWJDEJZHYRTMRR-UHFFFAOYSA-N 2,2-dimethoxypropanal Chemical compound COC(C)(OC)C=O DWJDEJZHYRTMRR-UHFFFAOYSA-N 0.000 claims description 6
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- 201000010099 disease Diseases 0.000 claims description 4
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- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000003211 malignant Effects 0.000 claims description 3
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- 238000001816 cooling Methods 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 4
- XEVRDFDBXJMZFG-UHFFFAOYSA-N Carbohydrazide Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims 1
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000005712 crystallization Effects 0.000 abstract 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 23
- 230000002194 synthesizing Effects 0.000 description 14
- ATHGHQPFGPMSJY-UHFFFAOYSA-N Spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 229920000768 polyamine Polymers 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 7
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- 229960003539 Mitoguazone Drugs 0.000 description 6
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- 239000008367 deionised water Substances 0.000 description 6
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- 239000000047 product Substances 0.000 description 6
- 229940063673 spermidine Drugs 0.000 description 6
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- 239000000126 substance Substances 0.000 description 4
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- VFXXTYGQYWRHJP-UHFFFAOYSA-N 4,4'-Azobis(4-cyanopentanoic acid) Chemical compound OC(=O)CCC(C)(C#N)N=NC(C)(CCC(O)=O)C#N VFXXTYGQYWRHJP-UHFFFAOYSA-N 0.000 description 3
- 108010070753 Adenosylmethionine Decarboxylase Proteins 0.000 description 3
- 102000005758 Adenosylmethionine Decarboxylase Human genes 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 231100000486 side effect Toxicity 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 2
- 230000036826 Excretion Effects 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N Putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 229920001949 Transfer RNA Polymers 0.000 description 2
- 108020004566 Transfer RNA Proteins 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- AKRQHOWXVSDJEF-UHFFFAOYSA-N heptane-1-sulfonic acid Chemical compound CCCCCCCS(O)(=O)=O AKRQHOWXVSDJEF-UHFFFAOYSA-N 0.000 description 2
- 125000005638 hydrazono group Chemical group 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
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- 238000006011 modification reaction Methods 0.000 description 2
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- 159000000000 sodium salts Chemical class 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 231100000759 toxicological effect Toxicity 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- FQQQSNAVVZSYMB-UHFFFAOYSA-N 1,1-diaminoguanidine Chemical compound NN(N)C(N)=N FQQQSNAVVZSYMB-UHFFFAOYSA-N 0.000 description 1
- JGGFDEJXWLAQKR-UHFFFAOYSA-N 1,2-diaminoguanidine Chemical compound NNC(N)=NN JGGFDEJXWLAQKR-UHFFFAOYSA-N 0.000 description 1
- VEXRMMJOMMTPKJ-ZVSIBQGLSA-N 1-methyl-3-[(E)-[(1E)-1-(methylcarbamothioylhydrazinylidene)propan-2-ylidene]amino]thiourea Chemical compound CNC(=S)N\N=C\C(\C)=N\NC(=S)NC VEXRMMJOMMTPKJ-ZVSIBQGLSA-N 0.000 description 1
- DCVQOLOVXUUDBR-XOBNHNQQSA-N 2-butyl-1-[(E)-[(1E)-1-[(N'-butylcarbamimidoyl)hydrazinylidene]propan-2-ylidene]amino]guanidine Chemical compound CCCCN=C(N)N\N=C\C(\C)=N\NC(N)=NCCCC DCVQOLOVXUUDBR-XOBNHNQQSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
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- ZSKAGXNTPRWVOR-UHFFFAOYSA-N NN=CNN=C(C=NNC(=N)NN=CC(C)=NNC=NN)C Chemical compound NN=CNN=C(C=NNC(=N)NN=CC(C)=NNC=NN)C ZSKAGXNTPRWVOR-UHFFFAOYSA-N 0.000 description 1
- 229960002460 Nitroprusside Drugs 0.000 description 1
- GRBHOGSBASDWSL-UHFFFAOYSA-N OCl.NN=C(N)N Chemical compound OCl.NN=C(N)N GRBHOGSBASDWSL-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000008881 Oenanthe javanica Species 0.000 description 1
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- 150000001241 acetals Chemical class 0.000 description 1
- PFCUZDIEKKTHCH-UHFFFAOYSA-N acetonitrile oxide Chemical compound CC#N=O PFCUZDIEKKTHCH-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 201000008286 diarrhea Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
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- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
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- 230000002218 hypoglycaemic Effects 0.000 description 1
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- 239000003999 initiator Substances 0.000 description 1
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- VVTBQCXLZQYGQE-PVTAQEPXSA-N mitoguazone hydrochloride Chemical compound Cl.Cl.NC(N)=N\N=C(/C)\C=N\N=C(N)N VVTBQCXLZQYGQE-PVTAQEPXSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000010927 mucositis Diseases 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
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- ASPOIVQEUUCDQT-UHFFFAOYSA-N nitroprusside Chemical compound O=N[Fe-2](C#N)(C#N)(C#N)(C#N)C#N ASPOIVQEUUCDQT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
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- BGUMNKICOFGUCP-UHFFFAOYSA-N sodium hexacyanoferrate(3-) Chemical compound [Na+].[Na+].[Na+].N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N BGUMNKICOFGUCP-UHFFFAOYSA-N 0.000 description 1
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Abstract
A process for the preparation of 2,2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] is described by: a) reacting aminoguanidine hydrochloride with methylglyoxaldehyde or methylglyoxal dimethylacetaldehyde; , 2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] by crystallization from an aqueous isopropyl alcohol medium
Description
PROCESS FOR PREPARING 2, 2 '- (1-METHYL-2-ETANODYYLIDEN) BIS [HYDRAZINCARBOXIMIDAMIDE] DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 2,2' - (1-methyl-1, 2- ethanediylidene) bis [hydrazine carboximidamide] which has greatly reduced impurities therein useful in a method for treating cancer or advanced malignancies. The compound 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboximidamide] is known by various names, such as 1,1' [(methyletandiylidene) dinitrile] diguamidine, pyruvaldehyde bis (amidinohydrazone), mitoguazone and methylglycoal bis-guanylhydrazone, methyl GAG or MGBG, represented by the formula
MGBG and its salts have been described in the prior art since 1950 for use against various diseases as illustrated by the following patents and publications. The antitumor activity of MGBB in leukemia L-1210 and adenocarcinoma 755 carried by rodents is reported by Freelander et al., 18 Cancer Res. 360 (1958). Japanese Patent 51044643 discloses MGBG and its acid addition salts as effective agents against viral diseases to prevent and treat infections, pancreatic necrosis and hematopoietic necrosis. Japanese Patent 50029520 describes MGBG and its salts for use against influenza viruses. U.S. Patent No. 4,201,788 describes MGBG for the treatment of non-malignant proliferative skin diseases. MGBG is known to inhibit S-adenosylmethionine decarboxylase (SMD), which is a key enzyme in the synthesis of polyamide, leading to the reduction of cellular polyamine. However, research with MGBG reveals unacceptable levels of toxicity. The toxicological effects of MGBG, some of which are peculiar to certain animal species, include gastrointestinal toxicity, delayed and fatal hypoglycemia, liver and kidney damage, bone marrow depression, diarrhea and phlebitis. These also have prevailed in human subjects suffering from treatment with MGBG. Additionally, several toxic effects are demonstrated which are unique to men. These include esophagitis, ulcerative pharyngitis, laryngitis, stomatitis, swelling of the genital mucosa, conjunctivitis, mucositis, erythema, edema, desquamative dermatitis, and deep anorexia as associated weight loss. Patients who are administered with MGBG in a daily program exhibit remission to acute leukemia only after a precarious struggle with some frequency of life of side effect treatments. In many patients, treatment has been discontinued before any beneficial results can be noticed. Knight et al., In Can. Treat. Rep. , £ 3 1933-1937 (1979) finds that the toxicity levels are dose-related programs and can be controlled. U.S. Patent 4,520,031 addresses the issue of such control related to the dose schedule in order to reduce toxicity. The control of the dose program, as described in the patent, is based on the postulation that MGBG exerts an inhibitory action in relation to the biosynthesis of polyamine. The physiologically achieved effects of MGBG can be related to the inhibition of the enzyme S-adenosyl methionine decarboxylase, which catalyzes the synthesis of polyamine, spermidine. It is believed that spermidine plays an important role in the initiation of DNA synthesis. Studies have shown that MGBG-mediated depression of DNA synthesis is associated with decreased spermidine and putrescine accumulation. Another area in which polyamines are thought to play a major role is in the synthesis of RNA, especially that of transfer RNA (t). TRNA methylation can be stimulated directly by polyamines, a finding of particular interest in the light of the reports is that neoplastic tissue differs from normal tissue with respect to the degree of methylated tRNA. Here, too, spermidine seems to play a critical role. The accumulation of polyamine seems to be a necessary requirement for DNA synthesis at an optimal speed, in both normal and neoplastic tissues. In this way, the toxicity of MGBG observed in rapidly changing tissues (skin, mucosa and bone marrow) may be related to the inhibition of polyamine synthesis and subsequent reduction of
RNA and DNA, the agents which ultimately regulate cell replication. There is, however, strong evidence that:
(1) polyamines are excreted in excess in most cancer patients; (2) polyamines, especially spermidine, are released from tumor cells during and after effective chemotherapy, with an initial increase in excretion and in serum levels and subsequent normal values decreasing; and (3) chemotherapy which produces only bone marrow toxicity (or other normal tissue), and has no antitumor efficacy, does not produce a significant increase in polyamine excretion. The latter observation may suggest either that cells with cancer have much higher levels of polyamines than normal cells, even those with higher proportions of DNA synthesis, or that which therapy is effective produces different specific effects in polyamine synthesis in cells with cancer. In this way, the decrease in spermidine is associated with the action of MGBG. In studies conducted in men, the toxicological effects observed clinically for the cumulative effects of repeated daily doses have been attributed. This accumulation or addition of toxicity is possibly explained by the unusual prolonged period required for urinary elimination of MGBG in man. Studies of bioavailability in man with MGBG-C14 have shown that following a simple intravenous infusion in a period of 20 minutes, the radioactivity disappears quickly from the plasma and that over a prolonged period of 3 weeks, 60 percent of the drug is excreted without changing in the urine. These data suggest that MGBG accumulates in the tissues and slowly filters out of tissue deposits to carry out the removal. In the patent, after a considerably large number of studies conducted with MGBG in the treatment of several tumors, it is concluded that a weekly administration schedule is more effective to achieve the higher therapeutic index while reducing the toxicity to an acceptable level. Accordingly, a dose range of 250 mg / m2 to 1000 mg / m2 of MGBG administered at intervals of weeks is established for the treatment of several tumors. While the dose range indicated above decreases toxicological side effects and produces treatments for several tumors, the long-term accumulation of MGBG is still a problem that requires additional studies and / or treatment modifications. In the present, there have been prolonged studies of MGBG in order to further reduce the toxic side effects thereof. In the course of these studies, it has been discovered that MGBG contains relatively large amounts of impurities, which may contribute to the toxicological side effects of MGBG. Accordingly, various efforts have been made to identify and reduce the amount of impurities present in MGBG and its salts. The process for preparing guanylhydrazones is described by Baiocchi et al., J. Med. Chem., 431 (1963) and Oliver, Denham., J. Pharm. Sci., 2 202 (1963). reacting the aminoguanidine salt with the corresponding carbonyl compound in an aqueous or aqueous-alcohol medium in the presence of a catalytic amount of acid The process uses commercially available aminoguanidine bicarbonate and is described as follows General Preparation of Guanilhydrazones To a solution of 0.11 moles (15 g) of aminoguanidine bicarbonate in 125 ml of water is slowly added the desired acid (add a few drops of amyl alcohol in order to avoid foam) until the pH of the solution is less than 7. It is filtered The solution of trace amounts of insoluble solids is then added to the appropriate carbonyl compound to a slightly acidic filtrate at a filtrate at 60 ° C. The amount of the carbonyl compound used is such that the proportion of aminoguanidine by carbonyl function is d 1: 1. If the carbonyl compound does not dissolve in the aqueous mixture, ethanol is added until the reaction mixture is homogeneous. The solution is then stirred at room temperature for 16 hours. If a precipitate forms, the solid product is isolated by filtration. Similarly, the reaction mixture is evaporated until a solid residue is obtained using methanol, ethanol and solvent combination. The recovery of guanilhidrazonas is low. In addition to the low yield it is found here that the products contain large amounts of impurities. Experimental Methods for the analysis of mitoguazone dichlorohydrate using various systems to identify and quantify their impurities have been developed in the present. U analysis system includes High Resolution Liquid chromatography. Considered in terms of determining chromatographic purity levels, a high degree of specificity provides confidence that all potential species of interest are detectable. Where these species, including impurities of degradation processes and products, are not available for injecting directly into the chromatographic system, the specificity test is usually performed on stressed samples using one or more techniques which can be placed in one of two categories. spacious. (a) Use of a specialized detection system to extract additional information from the peak of the analyte. (b) Some form of comparison between complementary separation techniques, the first being the low validation system and the second being a system which, by virtue of its different selectivity, can be expected to resolve co-elution of species in the first example. Examples of techniques in the first category include the use of diode array and mass spectroscopy detectors to obtain UV / Visible or mass spectra respectively from several positions across the analyte peak potentially allowing the detection of species co-eluents The techniques in the second category include the use of flux change apparatuses to invert the analyte peak in a second stationary phase with a different selectivity, or comparison of the results of the system that is validated with those of a second chromatography technique such as a thin layer chromatography (TLC).
Equipment and Chemicals HPCL data are generated using several Kontron (Watford, Herts) and Waters (atford, Herts) pumps, an autosampler, a column kiln and detector models. The HPLC data are processed using Multichrom ™ VI-82 (LabSystems, Altringham, Cheshire). The UV / visible absorption spectra are captured, using an HPO 1040 diode array detector (Hewlett Packard, Bracknell, Berks). Light tension (Xenon Source, filtered through window glass) is performed on a Haraeus Suntest ™ (Alplas Technology,
Oxford). The HPLC grade acetonitrile of chemicals is obtained
Rathburn (Walkerburn, Scotland), grade heptanesulfonic acid
HPLC (sodium salt), and inorganic chemicals from BHD limited
(Poole, Dorset) ACVA is obtained (4,4'-azobis (4-cyanovaleric acid), a radical initiator, exposure to which the oxidative contraction of Ajdrich (Gillingham, Dorset) is mimicked.) Mitoguazone dihydrochloride is obtained and purified water at home Stressed Sample Preparation Specimens of mitoguazone dichlorohydrate (approximately 370 mg, equivalent to one bq of 250 mg) are weighed out in 50 ml volumetric flasks and stressed, in accordance with the conditions given above. the tension continues for a maximum of 7 days or until the degradation has been achieved from 20 to 50% After the tension, the samples are neutralized, if necessary, and diluted to a volume with purified water to give solutions of approximately 5 m (base) / ml by TLC analysis The aliquots of these solutions are diluted with purified water to give solutions of about 1 mg / (base) / ml for use in HPLC impurity determinations. dilute aliquots of these solutions, either in the HPLC mobile phase to give a solution of approximately 0.01 mg (base) / ml for HPLC assay. Heat Tension Conditions: The sample is maintained at 80 ° C for 7 days.
Acidity: 10 ml of 0.1 M hydrochloric acid is added to the sample and the solution is kept at 70 ° C for 7 days. Basic: 10 ml of 0.1 M sodium hydroxide is added to the sample and the solution is maintained at 70 ° C for 2 days. Aqueous: 10 ml of purified water is added to the sample and the solution is maintained at 70 ° C for 7 days. Oxidative: 10 ml of a 0.1 M aqueous ACVA solution is added and the sample is kept at 40 ° C for 7 days. Light: The sample receives a total illumination of approximately 15,000 klx hours (with associated UV). Assay: The sample is chromatographed isocratically in columns of 25 cm x 0.46 d.i. Hypersil BDS C8 5 μm (Anachem, Luton, Beds.) Using a mobile phase consisting of 0.05 M potassium diacid orthophosphate buffer containing 1 g / 1 heptanesulfonic acid (sodium salt) and adjusted to pH 3.0 with acid concentrated orthophosphoric (89% by volume) and acetonitrile (11% by volume). The flow rate is 2 ml / minute, the wavelength of the detector is 283 nm, the injection volume is 20 μl and the temperature of the column is 40 ° C. The samples are quantified with respect to an accurately prepared external standard (nominally 0.01 mg (base) / ml) Impurity Method: The chromatographic conditions are com for the assay, except that a detector wavelength of 210 nm is used. uses a second HPLC system with a ratio of aqueous mobile phase to acetonitrile from 85% to 15% by volume, mainly to estimate the specific process impurities.The impurities are quantified with respect to a closely prepared external standard (nominally 0.005 mg (base ) / ml) TLC method 20 μl of each sample is placed on a silica gel TLC plate (Merck 60F254) The plate is developed at a height of 10 cm in acetone / ammonium hydroxide (SG 0.88) / water (90: 55.5% by volume) mobile phase The impurities are estimated against diluted mitoguazone dichlorohydrate stains, both with short wavelength ultraviolet light (254 nm), and after treatment with a reagent by aspersion Nitroprusside (sodium) -ferricyanide. Results Triplicate samples representing 0, 80%, 100% and 120% of the nominal mitoguazone dichlorohydrate concentration are analyzed. The results obtained in Table I are given. TABLE 1 Data Recovery
TABLE I (continued) Data Recovery
HPLC assay *. The Least Squares Regression analysis of the data gives an average accuracy of 99.8% (Coefficient d
Correlation 0.99935). Analysis of Stressed Samples Stressed samples are assayed by HPLC while the chromatographic impurity levels are determined by TLC HPLC. The chromatographic data is summarized in Table II. TABLE II Chromatographic Assays and Impurity Data for Stressed Mitoguazone Dichlorohydrate
Using HPLC, TLC and mass spectroscopy, they identify and quantify the impurities contained in the starting materials or formed during the process to manufacture the final product. It is found herein that purity related to diaminoguanidine is counted by more than 70 impurity level of MGBG-total dihydrochloride.
Then the general reaction scheme for the production of impurities and their chemical names.
1, 3 -Diaminoquanidine Impurity O: R1 = H, R2 = CH3 Impurity E ^ = CH3, R2 = H D v E
Impurity F: Rx = H, R2 = CH3, R3 = CH3, R4 = H Impurity G: RX = CH3, R2 = H, R3 = H, R4 = CH3 Impurity H ^ = H, R2 = CH3, R3 = H, R4 = CH3 wherein D [2- [(aminoiminomethyl) hydrazonojpropiliden-carbonimidicdihydrazid. E = [2- [(Aminoiminomethyl) hydrazono-1-methylethylidene] -carbonimidic dihydrazide. F = Bis [2- [(Aminoiminomethyl) hydrazono-1-methylethylidene-carbonimidic dihydrazide. G = Bis [2- [(Aminoiminomethyl) hydrazono] propylidene] -carbonimidic dihydrazide.
H = [2- [(Aminoiminomethyl) hydrazono] -l methylethylidene] [2- [(aminoiminomethyl) hydrazono] propylidene] ~ carbonimidic dihydrazide. In the co-pending application D.N. 70493, Seri No. 08/655, 512 on the date with the present application, the reaction parameters are studied and modified in order to reduce the impurities in the final product. The copending application, which is incorporated by reference in its entirety, describes a process for the preparation of 2,2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carbsximidamine] which comprises the steps of: a) removing impurities of bicarbonate d aminoguanidine by suspending bicarbonate d aminoguanidine in water and filtering the suspension; b) reacting the filtered aminoguanidine bicarbonate with methylglyoxal dimethylacetal in an aqueous reaction medium to yield 2,2 '(methyl-1,2-ethandylidene) bis [hydrazine carboximidamide]; and c) purifying 2, 2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide by recrystallization from a d-isopropanol-aqueous acidic medium. An essential step in the process is the removal of the impurities from the bicarbonate d aminoguanidine starting material by suspending the aminoguanidine bicarbonate in water or by filtering out the impurities from the filtration. It has now been discovered that instead of using aminoguanidine bicarbonate as a starting material, the aminoguanidine hydrochloride can be used to react with methylglyoxal dimethylacetal in an aqueous reaction medium to produce 2, 2 '- (1- methyl-l, 2-ethandylidene) bis [hydrazine, caroximidamide]. The process including a subsequent purification step provides a final product which is at least 95.5% pure. The process for obtaining highly purified 2, 2 '- (1-methyl-1,2-ethandylidene) bis [hydrazine carboximidamide] involves reacting aminoguanidine chlorohydrate with methylglyoxal dimethylacetal comprising the steps of: a) dissolving a part of aminoguanidine hydrochloride in a mixture of about 0.5 to 3 parts, preferably about 0.93 parts of water, and about 0 to 3 parts of a miscible organic solvent, preferably about 0.75 of isopropyl alcohol. b) adjusting the pH of the solution to about 0 5, preferably 0 to 1 with concentrated hydrochloric acid.
c) adding to the solution about 0.25 part of methylglyoxaldehyde, preferably about 0.5 part of methylglyoxa dimethylacetal, at a temperature of about 0 to 50 ° C, preferably of 25-30 ° C; d) stirring the reaction mixture for about 48 hours, preferably about 1 to 1 hours at room temperature. e) adding approximately 0.5 to 20 parts of a water miscible organic solvent, preferably about 5 parts of isopropyl alcohol to the reaction mixture to produce 2,2 '- (1-methyl-1,2-ethandylidene) bis [hydrazine] carboximidamide]; f) collecting 2, 2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carboximidamide] without purifying solid and washing the same with 1 to 10 parts of an organic solvent, preferably with 1 to 2 parts of alcohol isopropyl; and g) optionally drying the final product without purification before purification in a vacuum oven at 45 ° C. The purification process of 2, 2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carboximidamide] without purification comprises the steps of: h) dissolving the unpurified compound from about 0.5 to 4 parts of deionized water, preferably about 3 parts of deionized water; 5) add approximately 0.5 to 2 parts of a water miscible organic solvent, preferably about 1 part isopropanol; j) adjusting the pH of the solution to about 0 to 5, and preferably 0 to 1 with concentrated hydrochloric acid; k) stir the solution for approximately 0.5 to 2 hours while adding 0.1 to 2 parts of deionized water and maintaining the temperature of the solution at approximately 28-32 ° C. 15 1) filter the solution to remove insoluble impurities; m) adding to the filtered solution about 0.5 to 10 parts of a water miscible organic solvent, preferably about 5 parts of
isopropyl alcohol to precipitate the compound; n) cooling the mixture to about 0 to 25 ° C, preferably about 10 ° C; o) collecting the final product by filtration and washing the filtrate with 0.5 to 10 parts of an organic solvent, preferably with a part of isopropyl alcohol; and p) drying the purified product. As used herein the process for synthesizing and purifying 2, 2 '- (1-methyl-1,2-ethandylidene) bis [carboximid hydrazine] includes synthesis and purification of its various forms including its hydrochloride, monohydrate, dihydrate and hemihydrated. In the process for synthesizing and purifying 2,2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carboximidamide] the use of isopropyl alcohol is preferred. However, other organic solvents miscible in water may be used which include methanol, ethanol, n-propyl alcohol, tetrahydrofuran, acetic acid, dimethylformamide, acetonitrile and dimethyl sulfoxide or mixtures thereof. Aminoguanidine hydrochloride, methylglyoxaldehyde and methylglyoxal dimethylacetal are commercially available such as from Aldrich Chemical Co. , and can also be prepared by processes known in the art. A representative example (Example 1) for synthesizing and purifying 2, 2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] illustrates the invention. Example 1 (A) Synthesis 60.0 grams of aminoguanidine hydrochloride is dissolved in 56 milliliters of deionized water and 36 grams of isopropyl alcohol. The pH of the solution is adjusted to approximately 0 to 1 by adding concentrated hydrochloric acid. 30.96 grams of methylglyoxal dimethyl acetal are added in 1.5 to 3 hours while maintaining the reaction temperature between 25 and 30 ° C. The reaction mixture is then stirred at room temperature for an additional 16 hours. 240 grams of isopropyl alcohol are added and the reaction mixture is cooled to 10 ° C. The unpurified product which is formed during the reaction process is collected by filtration and washed with 90 milliliters of isopropyl alcohol. The washed filtrate is then dried in an oven at 45 ° C overnight. The yield is 87% of the theoretical yield. (B) Purification Dissolve 79.3 grams of the unpurified product obtained (A) in 159 grams of deionized water at 37 ° C. Add 60.7 grams of isopropyl alcohol and adjust the pH to 0-1 by adding concentrated hydrochloric acid. The pH-adjusted solution is stirred for 1 hour while maintaining its temperature at 28-32 ° C, and adding 10 ml of deionized water. The mixture is filtered to remove impurities, such as dirty mechanical particles. 312 grams of isopropyl alcohol are then added to the solution to precipitate the product. The mixture containing the precipitated product is cooled to 8-12 ° C and stirred for about 15 minutes. The purified product is then washed with 68 milliliters with isopropyl alcohol and dried in a vacuum oven for 45 ° C. The yield of the purified product was 67.5 of the theoretical yield. Samples of 2, 2 '- (1-methyl-1, 2-ethanediidine) bis [hydrazine carboximidamide] produced ,: 1 reacting aminoguanidine bicarbonate with methylglyoxamethyl acetal or 2) Purify by HPLC to react aminoguanidine hydrochloride with dimethylglyoxamine dimethyl acetal . The comparative results are shown in l Taba II and Table III. TABLE II Test Results for Batch of Bicarbonate
Aminoguanidine used in the Production of MGBG and Test Results of MGBG Produced by the same.
TABLE III Test Results for Lots of Aminoguanidine Hydrochloride used in the Production of MGBG and MGBG Test Results Produced by the same.
Aminoguanidine hydrochloride contains lower levels of impurities than aminoguanidine bicarbonate gives a superior quality of MGBG. The purity of MGBG produced by the use of aminoguanidine hydrochloride and according to the present invention is found to be as high as 99.9%. Highly pure MGBG is well suited for pharmaceutical compositions for the treatment of cancer and other diseases. The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications may be made within the spirit and scope of the invention.
Claims (6)
1. A process for preparing 2, 2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] characterized in that it comprises the steps of: a) dissolving a part of the chlorohydrate d aminoguanidine in a mixture of approximately 0.5 to 3 parts, of water and about 0 to parts of an organic solvent miscible with water; b) adjusting the pH of the solution to about 0 5; with concentrated hydrochloric acid; c) adding to the solution about 0.25 to parts of methylglyoxaldehyde or methylglyoxa dimethylacetal, at a temperature of about 0 to 50 ° C to obtain a reaction mixture; d) stirring the reaction mixture for approximately 48 hours, at room temperature. e) adding about 0.5 to 20 parts of a water-miscible organic solvent to the reaction mixture, to produce 2,2 '- (1-methyl-1,2-ethandylidene) bis [hydrazine carboximidamide]; f) collecting 2, 2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carboximidamide] if purifying by filtration and washing the same with 1 10 parts of an organic solvent; g) dissolving 2, 2 '- (1-methyl-1,2-ethanediylidene) is [hydrazine carboximidamide] if purifying in about 0.5 to 4 parts of water; h) adding approximately 0.5 to the solution to parts of a water-miscible organic solvent; and) adjusting the pH of the solution to about 0 5; 10 j) stir the solution for approximately 0.5 to hours while adding approximately 0 to parts of water and maintain the temperature of the solution at approximately 28 to 32 ° C; k) add approximately 0.5 to 1 to the solution 15 parts of an organic solvent miscible in agu to precipitate 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboximidamide], - 1) cool the mixture to about 0 to 25 ° C; m) collecting the 2, 2 '- (1-methyl-1, 2- 20 ethandylidene) bis [hydrazine carboximidamide] solid by filtration and washing with 0.5 to 10 parts of an organic solvent; and n) drying purified 2,2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboxamide].
2. 2,2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] prepared by the process according to claim 1.
3. A method for treating cancer or malignant disease in a mammal characterized because it comprises administering to the mammal an effective amount of a pharmaceutical composition containing the compound d according to claim 2.
4. A process for preparing 2,2 '- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide] characterized because it comprises the steps of: a) dissolving a part of the chlorohydrate d aminoguanidine in a mixture of approximately 0.93 parts, water and approximately 0.75 part isopropyl alcohol; b) adjust the pH of the solution to approximately 0 1, with concentrated hydrochloric acid; c) adding approximately 0.5 d methylglyoxal dimethylacetal to the solution at a temperature of about 25 to 30 ° C; d) shaking the solution for about 1 to 1 hours at room temperature; e) adding approximately 5 parts of isopropyl alcohol to the reaction mixture to produce 2,2'- (1-methyl-1,2-ethanediylidene) bis [hydrazine carboximidamide]; f) collecting 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboximidamide] without purification by filtration and washing the same with 1 to 2 parts of isopropyl alcohol; 5 g) dissolving 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboximidamide] without purification in about 2 parts of water; h) add approximately one part of isopropyl alcohol; 10 i) adjust the pH of the solution to 0 to 1 with concentrated hydrochloric acid; ) stirring the solution for approximately 0.5 to 2 hours while adding approximately 0 to 2 parts of water and maintaining the temperature of the solution at approximately 28-32 ° C; k) filter the solution to eliminate the soluble impurities thereof; 1) add approximately 5 parts of isopropyl alcohol to the filtered solution to precipitate 2,2 '- (1-methyl-1,2-ethoylidene) bis [hydrazine carboximidamide]; m) cooling the mixture to about 10 ° C; n) collecting the 2, 2 '- (1-methyl-1, 2-ethandylidene) bis [hydrazine carboximidamide] solid 25 by filtration and washing it with a portion of isopropyl alcohol; and o) drying 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboxamidamide].
5. The 2, 2 '- (1-methyl-1, 2-ethanediylidene) bis [hydrazine carboximidamide] prepared by the process of compliance with claim 4.
6. A method for treating cancer or malignant diseases in a mammal, characterized because it comprises: administering to the mammal an effective amount of a pharmaceutical composition containing the compound according to claim 5.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US08655518 | 1996-05-30 |
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MXPA98009960A true MXPA98009960A (en) | 1999-04-27 |
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