WO2007032695A1 - New salts of olanzapine and method of their preparation - Google Patents
New salts of olanzapine and method of their preparation Download PDFInfo
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- WO2007032695A1 WO2007032695A1 PCT/PL2006/000025 PL2006000025W WO2007032695A1 WO 2007032695 A1 WO2007032695 A1 WO 2007032695A1 PL 2006000025 W PL2006000025 W PL 2006000025W WO 2007032695 A1 WO2007032695 A1 WO 2007032695A1
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- olanzapine
- acid
- reaction
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- salts
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical class C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 108
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 101
- 150000003839 salts Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims abstract description 25
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 20
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 19
- 239000011976 maleic acid Substances 0.000 claims abstract description 19
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 10
- 239000001530 fumaric acid Substances 0.000 claims abstract description 10
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 9
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 8
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 8
- 229960004365 benzoic acid Drugs 0.000 claims abstract description 8
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 8
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 7
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 7
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001991 dicarboxylic acids Chemical class 0.000 claims abstract description 5
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 5
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- -1 aliphatic alcohols Chemical class 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229960005137 succinic acid Drugs 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000013049 sediment Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 150000001450 anions Chemical class 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 238000002083 X-ray spectrum Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- LJVNYCDXBXGQIK-UHFFFAOYSA-N chembl440512 Chemical compound S1C(C)=CC2=C1NC1=CC=CC=C1N=C2N1CC[N+](C)([O-])CC1 LJVNYCDXBXGQIK-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the invention relates to hitherto unknown salts of olanzapine and carboxylic acids, new olanzapine salts obtained by reaction of olanzapine with selected anhydrides and the method of their preparation allowing to obtain an olanzapine salt of high purity, containing much less impurities than normal olanzapine obtained and used so far.
- Olanzapine (2-methyl-4-[4-methyl-l-piperazinyl)-lOH-thieno[2,3- b][l,5]benzodiazepine) (formula 1) is a known drug acting upon the central nervous system.
- olanzapine used most often so far is one of its polymorphic forms I or II. They have been described, among others, in the international patent application WO96/30375 and in the corresponding RP patent PL183723. These forms differ in their IR and X-ray spectra.
- Form I is obtained by dissolution of olanzapine or its hydrate and form II in methylene chloride at the temperature of boiling point, treatment with a hot active coal solution, hot filtering of the solution, crystallization of form I by cooling the solution and filtering off the product crystals.
- An international patent application WOOO/ 18408 describes pharmaceutically acceptable microspheres containing olanzapine, olanzapine palmoate or their solvates.
- the method of preparation of olanzapine palmoate described there is based on dissolution of olanzapine and other components in DMSO and their subsequent heating. This method allows for obtaining a product of average purity - ca. 99.6 % (HPLC).
- Olanzapine changes its color with time and influence of light and oxidation from yellow to orange-red; at the same time decomposition of olanzapine progresses and decomposition increases (Table 2). Neither reactions of olanzapine with carboxylic acids or their anhydrides nor products thereof have been described in the literature so far, with the exception of aforementioned olanzapine palmoate.
- New salts according to the invention comprise salts of olanzapine and carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, salicylic acid, acetylsalicylic acid or benzoic acid, preferably of olanzapine to acid ratio of 1: 1 or 1:2.
- New salts according to the invention comprise also salts of olanzapine and monoalkylesters of dicarboxylic acids (formula 4), selected from the group consisting of maleic acid, phtalic acid and succinic acid.
- New olanzapine salts may be obtained both in reaction with aforementioned acids and anhydrides of carboxylic acids selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride, in a suitable solvent in the presence of alcohol.
- the method of synthesis of new olanzapine salts according to the invention comprises carrying out the reaction of olanzapine in organic solvents with carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, succinic acid, benzoic acid, salicylic acid and acetylsalicylic acid.
- carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, succinic acid, benzoic acid, salicylic acid and acetylsalicylic acid.
- reaction of olanzapine is preferably carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
- reaction of olanzapine is also preferably carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
- reaction is carried out at temperature from -35 °C to +100 °C.
- the method of synthesis of new olanzapine monoesters according to the invention comprises carrying out the reaction of olanzapine in a suitable organic solvent in the presence of alcohol with anhydrides of carboxylic acids selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride.
- reaction of olanzapine is preferably carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
- reaction of olanzapine is also preferably carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
- reaction is carried out at temperature from -35 0 C to +100 0 C.
- Embodiments of the invention are presented below.
- Olanzapine (3.12 g - 0.01 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of methanol is added. After 20 minutes sediment begins to precipitate. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 1.22 g of precipitate of olanzapine salt, brick-red in color.
- Olanzapine (3.12 g - 0.01 mol) and maleic acid (2.32 g - 0.02 mol) are placed in a flask with a magnetic stirrer; 50 ml of methanol is added. After 5 minutes sediment begins to precipitate. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 4.77 g of precipitate of olanzapine salt, dark orange in color.
- Olanzapine (2.81 g - 0.009 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of ethanol is added. Dark orange sediment precipitates. The reaction is carried out for 24 hours. The sediment is filtered off and washed with ethanol. What is obtained is 3.48 g of precipitate of olanzapine salt, orange in color.
- Olanzapine (2.81 g - 0.009 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of hexane is added. The reaction is carried out for 24 hours. The precipitated sediment is filtered off and washed with hexane. What is obtained is 3.31 g of precipitate of olanzapine salt, orange in color (contaminated product).
- Olanzapine (3.12 g - 0.01 mol) and fumaric acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added.
- the reaction is carried out for 22 hours.
- the sediment is filtered off and washed with methanol. What is obtained is 2.02 g of precipitate of olanzapine salt, light yellow in color.
- Fumaric acid (1.16 g - 0.01 mol) and 10 ml of methanol are placed in a flask with a magnetic stirrer - the acid does not dissolve.
- Olanzapine (2.81 g - 0.009 mol) in 10 ml of methanol is then added.
- the components dissolve into a light yellow solution.
- the reaction is carried out for 4 hours.
- the sediment is filtered off and washed with methanol. What is obtained is 1.73 g of precipitate of olanzapine salt, light yellow in color.
- Olanzapine (2.81 g - 0.009 mol) and salicylic acid (1.38 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added. The components dissolve into an orange solution. After a few minutes yellow sediment begins to precipitate; the solution thickens quickly. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 3.30 g of precipitate of olanzapine salt, light yellow in color.
- Olanzapine (2.81 g - 0.009 mol) and acetylsalicylic acid (1.80 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added. The components dissolve into a light orange solution. After more than ten hours the solution becomes light yellow. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol.
- Olanzapine (2.81 g - 0.009 mol) and benzoic acid (1.22 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of acetone is added. The components dissolve after 10 minutes into a yellow solution. The reaction is carried out for 24 hours. The sediment is filtered off and washed with acetone. What is obtained is 1.93 g of precipitate of olanzapine salt, yellow in color.
- Olanzapine (3.13 g - 0.01 mol) is placed in a flask with a magnetic stirrer and dissolved in 20 ml of methanol. Then maleic anhydride (0.98 g - 0.01 mol) is added - substrates dissolve into a dark orange, clear solution. After ca. 10 minutes sediment begins to precipitate. The precipitate is filtered off after 19 hours and washed with methanol. What is obtained is: 1.87 g of precipitate of olanzapine salt, yellow in color. Structural analysis of the product confirmed that it is a salt of olanzapine and methyl monoester of maleic acid.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
New salts according to the invention are presented, which comprise salts of olanzapine and carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, benzoic acid, salicylic acid or acetylsalicylic acid, of olanzapine to acid ratio of 1: 1, 1:2 or other. New salts of olanzapine and monoesters of dicarboxylic acids obtained in reaction of olanzapine with anhydrides selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride are presented. The method of synthesis of new olanzapine salts according to the invention comprises carrying out the reaction of olanzapine in organic solvents with carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, succinic acid, benzoic acid, salicylic acid and acetylsalicylic acid. The method of synthesis of new olanzapine salts according to the invention comprises carrying out the reaction of olanzapine with an anhydride of a dicarboxylic acid selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride in the presence of alcohol in organic solvents.
Description
New salts of olanzapine and method of their preparation
The invention relates to hitherto unknown salts of olanzapine and carboxylic acids, new olanzapine salts obtained by reaction of olanzapine with selected anhydrides and the method of their preparation allowing to obtain an olanzapine salt of high purity, containing much less impurities than normal olanzapine obtained and used so far.
Olanzapine (2-methyl-4-[4-methyl-l-piperazinyl)-lOH-thieno[2,3- b][l,5]benzodiazepine) (formula 1) is a known drug acting upon the central nervous system.
It may be predicted with high probability that new olanzapine salts according to the present invention will have similar properties to the basic active agent - olanzapine. It is indicated by similar solubility of these salts and olanzapine (Table 1).
The form of olanzapine used most often so far is one of its polymorphic forms I or II. They have been described, among others, in the international patent application WO96/30375 and in the corresponding RP patent PL183723. These forms differ in their IR and X-ray spectra.
There are known methods of preparation of polymorphic form I of olanzapine from raw olanzapine, olanzapine hydrate and polymorphic form II by means of crystallization from methylene chloride. Form I is obtained by dissolution of olanzapine or its hydrate and form II in methylene chloride at the temperature of boiling point, treatment with a hot active coal solution, hot filtering of the solution, crystallization of form I by cooling the solution and filtering off the product crystals.
During the process of crystallization of raw olanzapine, olanzapine hydrate or form II from methylene chloride, when the operation is prolonged in order to obtain the end product of adequate purity, especially during heating a to boiling point, additionally impurity of olanzapine is formed. This substance is a product of quaternarization of the basic nitrogen atom in the piperazine ring with methylene chloride - l-(chlormethyl)-l-methyl-4-(2- methyl-l-OH-thieno[2,3-b][l,5]benzodiazepin-4-yl)-piperazin-l-yl chloride (formula 2). Repeated crystallization from methylene chloride is not effective for removing this compound. On the contrary, repeated crystallization from methylene chloride leads to progressive accumulation of the contaminant to amounts non-complying with requirements concerning purity of pharmacological substances.
An international patent application WOOO/ 18408 describes pharmaceutically acceptable microspheres containing olanzapine, olanzapine palmoate or their solvates. The method of preparation of olanzapine palmoate described there is based on dissolution of olanzapine and other components in DMSO and their subsequent heating. This method allows for obtaining a product of average purity - ca. 99.6 % (HPLC).
According to International Conference of Harmonisation (ICH) requirements, the level of a single contaminant must not exceed 0.15%. Otherwise toxicological studies concerning the contaminating molecule must be performed. In most of the known methods removal of impurities is a major technical problem.
In U.S. Patent No. 6352984, methods and compositions for the use of olanzapine N-oxide in the treatment of psychosis in humans are described. This compound is characterized by less narcotic action and less interactions than olanzapine; therefore it allows for more predictable dosage than olanzapine.
Olanzapine changes its color with time and influence of light and oxidation from yellow to orange-red; at the same time decomposition of olanzapine progresses and decomposition increases (Table 2).
Neither reactions of olanzapine with carboxylic acids or their anhydrides nor products thereof have been described in the literature so far, with the exception of aforementioned olanzapine palmoate.
Unexpectedly new olanzapine derivatives (formula 3) prepared according to the method of the present invention turned out to be free of aforementioned drawbacks of olanzapine or its known derivatives; namely, they do not decompose under the influence of oxygen or light; at the same time the amount of impurities can be significantly reduced (Table 2). Moreover, they are prepared in a simple technological process and, depending on the reaction time and solvent used, various salts of different olanzapine cation to acid radical ratio (1: 1, 1 :2 or other) may be obtained.
Summary of the invention
New salts according to the invention comprise salts of olanzapine and carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, salicylic acid, acetylsalicylic acid or benzoic acid, preferably of olanzapine to acid ratio of 1: 1 or 1:2.
New salts according to the invention comprise also salts of olanzapine and monoalkylesters of dicarboxylic acids (formula 4), selected from the group consisting of maleic acid, phtalic acid and succinic acid.
Both new salts according to the invention and new monoalkylesters according to the invention were synthesized, their basic physical and spectroscopic properties were estimated, their X-ray powder diffraction spectra were analyzed and DSC was performed. New olanzapine salts may be obtained both in reaction with aforementioned acids and anhydrides of carboxylic acids selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride, in a suitable solvent in the presence of alcohol.
It was shown beyond any doubt that the obtained salts are not a simple physical mixture of olanzapine and a specific acid as the infrared (IR) spectra of newly synthesized salts are different from the IR spectra of mixtures of these compounds mixed at adequate ratio.
DSC also did not confirm the presence of olanzapine hydrates or solvates. In the compounds of the invention only remains of solvents used in the reaction were found (GC, NMR).
The method of synthesis of new olanzapine salts according to the invention comprises carrying out the reaction of olanzapine in organic solvents with carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, succinic acid, benzoic acid, salicylic acid and acetylsalicylic acid.
In the method of the invention the reaction of olanzapine is preferably carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
In the method of the invention the reaction of olanzapine is also preferably carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
In the method of the invention the reaction is carried out at temperature from -35 °C to +100 °C.
The method of synthesis of new olanzapine monoesters according to the invention comprises carrying out the reaction of olanzapine in a suitable organic solvent in the presence of alcohol with anhydrides of carboxylic acids selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride.
In the method of the invention reaction of olanzapine is preferably carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
In the method of the invention reaction of olanzapine is also preferably carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
In the method of the invention the reaction is carried out at temperature from -35 0C to +100 0C.
Embodiments of the invention are presented below.
Example 1.
Synthesis of the salt of olanzapine and maleic acid (olanzapine to acid ratio 1 :2)
Olanzapine (3.12 g - 0.01 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of methanol is added. After 20 minutes sediment begins to precipitate. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 1.22 g of precipitate of olanzapine salt, brick-red in color.
Yield: 44 %
Tt = 210 - 212 0C (not corrected)
The following analyzes were performed :
1H NMR (olanzapine cation δ 2.43 [3H, s, 4'-CH3]; δ 2.86 [3H, s, 2- CH3]; δ 3.31 [4H, m, H-3']; δ 3.98 [4H7 m, H-2']; δ 6.63 [H, s, H-3]; δ 6.95[H, d, H-9]; δ 7.23[H, t, H-7];δ 7.24 [2H, m, H-8,6]; maleic anion δ 6.33 [2H7 s, =CH-COOH])
IR (1702 cm"1 w; 1623 cm"1 s; 1349 cm"1 s; 1285 cm"1 m; 865 cm"1 s; 766 cm"1 s; 572 cm"1 s)
X-ray powder diffraction (fig. 1 - NOBI2) DSC (fig. 2a).
Example 2.
Synthesis of the salt of olanzapine and maleic acid (olanzapine to acid ratio 1 : 2)
Olanzapine (3.12 g - 0.01 mol) and maleic acid (2.32 g - 0.02 mol) are placed in a flask with a magnetic stirrer; 50 ml of methanol is added. After 5 minutes sediment begins to precipitate. The reaction is carried out
for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 4.77 g of precipitate of olanzapine salt, dark orange in color.
Yield: 88 %
Tt = 208 - 211 °C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.43 [3H1 s, 4'-CH3]; δ 2.84 [3H, s, 2- CH3]; δ 3.28 [4H, m, H-3']; δ 3.36 [4H, m, H-2']; δ 6.63 [H, s, H-3]; δ 6.95[H, d, H-9]; δ 7.22[H, t, H-7];δ 7.24 [2H, m, H-8,6]; maleic anion: δ 6.33 [2H, s, =CH-COOH])
IR (1702 cm"1 m; 1623 cm"1 s; 1573 cm'1 s; 1623 cm"1 s; 1350 cm"1 s; 865 cm"1 m; 766 cm"1 s; 572 cm"1 m)
Example 3.
Synthesis of the salt of olanzapine and maleic acid (Olanzapine to acid ratio 1: 1)
Olanzapine (2.81 g - 0.009 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of ethanol is added. Dark orange sediment precipitates. The reaction is carried out for 24 hours. The sediment is filtered off and washed with ethanol. What is obtained is 3.48 g of precipitate of olanzapine salt, orange in color.
Yield: 88 %
Tt = 204 - 206 ° C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.42 [3H, s, 4'-CH3]; δ 2.68 [3H, s, 2- CH3]; δ 3.02 [4H, m, H-3']; δ 3.84 [4H, m, H-2']; δ 6.59 [H, s, H-3]; δ 6.91[H, d, H-9]; δ 7.14[H, t, H-7];δ 7.19 [2H, m, H-8,6]; maleic anion: δ 6.31 [2H, s, =CH-COOH])
IR (1697 cm"1 w; 1591 cm"1 s; 1468 cm'1 s; 1351 cm"1 s; 865 cm"1 m; 756 cm"1 m; 561 cm"1 w; 458 cm"1 w)
Example 4,
Synthesis of the salt of olanzapine and maleic acid (olanzapine to acid ratio 1 : 1)
Olanzapine (2.81 g - 0.009 mol) and maleic acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of hexane is added. The reaction is carried out for 24 hours. The precipitated sediment is filtered off and washed with hexane. What is obtained is 3.31 g of precipitate of olanzapine salt, orange in color (contaminated product).
Yield: 83 %
Tt = 130 - 131 °C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.40 [3H, s, 4'-CH3]; δ 2.75 [3H, s, 2- CH3]; δ 3.14 [4H, m, H-3']; δ 3.88 [4H7 m, H-2']; δ 6.58 [H, s, H-3]; δ 6.92[H, d, H-9]; δ 7.12[H, t, H-7];δ 7.19 [2H, m, H-8,6]; maleic anion: δ 6.31 [2H, s, =CH-COOH])
IR (1699 cm"1 w; 1590 cm"1 s; 1467 cm"1 s; 1351 cm"1 s; 864 cm"1 m; 766 cm"1 m; 561 cm"1 w; 458 cm"1 w)
Example 5.
Synthesis of the salt of olanzapine and maleic acid (olanzapine to acid ratio 1 : 1)
Maleic acid (1.16 g - 0.01 mol) and 25 ml of dioxane are placed in a flask with a magnetic stirrer; then olanzapine (2.81 g - 0.009 mol) and 25 ml of dioxane are added. The components dissolve into a dark yellow, clear solution. After 30 minutes sediment begins to precipitate. The reaction is carried out for 24 hours. The sediment is filtered off and washed with dioxane. What is obtained is 2.87 g of precipitate of olanzapine salt, light orange in color.
Yield: 75 %
Tt = 186 - 187 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.42 [3H7 s, 4'-CH3]; δ 2.85 [3H, s, 2- CH3]; δ 3.30 [4H, m, H-3']; δ 3.98 [4H, m, H-2']; δ 6.63 [H, s, H-3]; δ 6.94[H, d, H-9]; δ 7.18[H, t, H-7];δ 7.25 [2H, m, H-8,6]; maleic anion: δ 6.31 [2H, s, =CH-COOH])
IR (1700 cm'1 w; 1580 cm"1 s; 1467 cm"1 s; 1350 cm'1 m; 865 cm"1 s; 766 cm"1 m; 572 cm"1 w)
Example 6.
Synthesis of the salt of olanzapine and fumaric acid (olanzapine to acid ratio 1 :2")
Olanzapine (3.12 g - 0.01 mol) and fumaric acid (1.16 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added.
The reaction is carried out for 22 hours. The sediment is filtered off and washed with methanol. What is obtained is 2.02 g of precipitate of olanzapine salt, light yellow in color.
Yield : 74 %
Tt = 228 - 229 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.34 [3H, s, 4'-CH3]; δ 2.54 [3H, s, 2- CH3]; δ 2.85 [4H, m, H-3']; δ 3.70 [4H, m, H-2']; δ 6.47 [H, s, H-3]; δ 6.80 [H, d, H-9]; δ 7.03 [H, t, H-7]; δ 7.07 [2H, m, H-8,6]; fumaric anion: δ 6.68 [2H, s, =CH-COOH];)
IR (1702 cm"1 w; 1592 cm"1 s; 1468 cm"1 s; 1364 cm"1 s; 1220 cm'1 s; 984 cm"1 s; 767 cm"1 s; 665 cm"1 s; 453 cm"1 w)
Example 7.
Synthesis of the salt of olanzapine and fumaric acid folanzapine to acid ratio 1 :3)
Fumaric acid (1.16 g - 0.01 mol) and 10 ml of methanol are placed in a flask with a magnetic stirrer - the acid does not dissolve. Olanzapine (2.81 g - 0.009 mol) in 10 ml of methanol is then added. The components dissolve into a light yellow solution. The reaction is carried out for 4 hours. The sediment is filtered off and washed with methanol. What is obtained is 1.73 g of precipitate of olanzapine salt, light yellow in color.
Yield: 84 %
Tt = 230 - 231 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.36 [3H, s, 4'-CH3]; δ 2.57 [3H, s, 2- CH3]; δ 2.91 [4H, m, H-3']; δ 3.76 [4H, m, H-2']; δ 6.49 [H, s, H-3]; δ 6.80 [H, d, H-9]; δ 7.01 [H, t, H-7]; δ 7.11 [2H, m, H-8,6]; fumaric anion: δ 6.71 [2H, s, =CH-COOH])
IR (1716 cm"1 w; 1592 cm"1 s; 1468 cm"1 s; 1364 cm"1 s; 1220 cm"1 s; 984 cm"1 s; 767 cm"1 s; 653 cm"1 s; 557 cm"1 m; 453 cm"1 w)
X-ray powder diffraction (fig. 1 - NOBI3)
DSC (fig. 2b).
Example 8.
Synthesis of the salt of olanzapine and salicylic acid folanzapine to acid ratio 1 : 1)
Olanzapine (2.81 g - 0.009 mol) and salicylic acid (1.38 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added. The components dissolve into an orange solution. After a few minutes yellow sediment begins to precipitate; the solution thickens quickly. The reaction is carried out for 24 hours. The sediment is filtered off and washed
with methanol. What is obtained is 3.30 g of precipitate of olanzapine salt, light yellow in color.
Yield: 82 %
Tt = 206 - 208 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation δ 2.40 [3H, s, 4'-CH3]; δ 2.61 [3H, s, 2- CH3]; δ 2.93 [4H, m, H-3']; δ 3.78 [4H, m, H-2']; δ 6.55 [H, s, H-3]; δ 6.88 [H, d, H-9]; δ 7.11 [2H, m, H-8,6]; δ 7.33 [H, t, H-7]; salicylic anion: δ 6.86 [3H, m, -CH]; δ 7.89 [H, m, -CH])
IR (1605 cm"1 s; 1464 cm"1 s; 1408 cm"1 s; 1327 cm"1 s; 1152 cm'1 s; 965 cm"1 m; 765 cm"1 s; 664 cm"1 s; 473 cm"1 m)
Example 9.
Synthesis of the salt of olanzapine and acetylsalicylic acid (olanzapine to acid ratio 1 : 1)
Olanzapine (2.81 g - 0.009 mol) and acetylsalicylic acid (1.80 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 20 ml of methanol is added. The components dissolve into a light orange solution. After more than ten hours the solution becomes light yellow. The reaction is carried out for 24 hours. The sediment is filtered off and washed with methanol. What is obtained is 2.66 g of precipitate of olanzapine salt, light yellow in color - NMR analysis shows that acetylsalicylic acid radical is deacetylated and the product is the salt of olanzapine and salicylic acid, identical to the salt obtained in Embodiment 8.
Yield : 99 %
Tt = 206 - 208 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation: δ 2.40 [3H, s, 4'-CH3]; δ 2.62 [3H, s, 2- CH3]; δ 2.94 [4H, m, H-3']; δ 3.78 [4H, m, H-2']; δ 6.55 [H, s, H-3]; δ 7.10 [H, d, H-9]; 7.14 [2H, m, H-8,6]; δ 7.33 [H, t, H-7]; salicylic anion: δ 6.88 [3H, m, -CH]; δ 7.89 [H, m, -CH];)
IR (1605 cm"1 s; 1465 cm"1 s; 1408 cm"1 s; 1327 cm"1 s; 1152 cm"1 s; 965 cm"1 s; 859 cm"1 s; 765 cm'1 s; 664 cm"1 s; 473 cm"1 m)
Example 10,
Synthesis of the salt of olanzapine and benzoic acid (olanzapine to acid ratio 1 : 1)
Olanzapine (2.81 g - 0.009 mol) and benzoic acid (1.22 g - 0.01 mol) are placed in a flask with a magnetic stirrer; 50 ml of acetone is added. The components dissolve after 10 minutes into a yellow solution. The reaction is carried out for 24 hours. The sediment is filtered off and washed with acetone. What is obtained is 1.93 g of precipitate of olanzapine salt, yellow in color.
Yield : 35 %
Tt = 211 - 214 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation: δ 2.39 [3H, s, 4'-CH3]; δ 2.57 [3H, s, 2- CH3]; δ 2.87 [4H, m, H-3']; δ 3.73 [4H, m, H-2']; δ 6.53 [H, s, H-3]; δ 6.82 [H, d, H-9]; δ 7.10 [H, t, H-7]; δ 7.11 [2H, m, H-8,6]; δ 7.47 [2H, m, -CH]; δ 7.60 [H, m, -CH]; δ 8.04 [2H, m, -CH]; benzoic anion: δ 7.47 [2H, m, H- 3,5]; δ 7.60 [H, m, H-4]; δ 8.04 [2H, m, H-2,6])
IR (1605 cm"1 s; 1467 cm"1 s; 1410 cm"1 s; 1153 cm"1 s; 967 cm"1 s; 765 cm"1 s; 713 cm"1 s; 672 cm"1 s; 454 cm"1 m)
Example 11.
Synthesis of the salt of olanzapine in reaction of olanzapine with maleic anhydride in an alcohol-type solvent.
Olanzapine (3.13 g - 0.01 mol) is placed in a flask with a magnetic stirrer and dissolved in 20 ml of methanol. Then maleic anhydride (0.98 g - 0.01 mol) is added - substrates dissolve into a dark orange, clear solution. After ca. 10 minutes sediment begins to precipitate. The precipitate is
filtered off after 19 hours and washed with methanol. What is obtained is: 1.87 g of precipitate of olanzapine salt, yellow in color. Structural analysis of the product confirmed that it is a salt of olanzapine and methyl monoester of maleic acid.
Yield: 46 %
Tt = 179.3 - 183.1 0C (not corrected)
The following analyzes were performed:
1H NMR (olanzapine cation: δ 2.33 [3H, s, 4'-CH3]; δ 2.59 [3H, s, 2- CH3]; δ 3.92 [4H, m, H-3']; δ 3.73 [4H, m, H-2']; δ 6.51 [H, s, H-3]; δ 6.79[H, d, H-9]; δ 7.02[H, t, H-7];δ 7.05 [2H, m, H-8,6]; maleic monoester anion: δ 3.69[3H, s, -CH3]; δ 6.48 [2H, t, =CH-COOH];)
IR (1723 cm"1 s; 1598 αrf1 s; 1398 cm"1 s; 1215 cm"1 s; 1171 cm"1 s; 965 CIΎT1 m; 833 cm"1 m; 765 cm"1 s; 608 cm"1 s)
X-ray powder diffraction (fig. 1 - NOBIl).
DSC (fig. 2c)
Table 1. Solubility of salts and olanzapine
Claims
1. New salts comprising salts of olanzapine and carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, salicylic acid, acetylsalicylic acid or benzoic acid, preferably of olanzapine to acid ratio of 1 : 1 or 1 :2.
2. New salts comprising salts of olanzapine and monoalkylesters of dicarboxylic acids selected from the group consisting of maleic acid, phtalic acid and succinic acid.
3. Method for synthesis of new olanzapine salts, in which the reaction of olanzapine is carried out in organic solvents with carboxylic acids selected from the group consisting of: maleic acid, fumaric acid, phtalic acid, succinic acid, benzoic acid, salicylic acid and acetylsalicylic acid.
4. Method of claim 3, wherein the reaction of olanzapine is carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
5. Method of claim 3, wherein the reaction of olanzapine is also carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
6. Method of claim 3, wherein the reaction is carried out at temperature from -35 0C to +100 0C.
7. Method for synthesis of salts of olanzapine and monoesters of dicarboxylic acids, in which the reaction of olanzapine with anhydrides of dicarboxylic acids selected from the group consisting of maleic anhydride, phtalic anhydride and succinic anhydride is carried out in organic solvents in the presence of alcohols.
8. Method of claim 7, wherein the reaction of olanzapine is carried out in organic solvents selected from the group consisting of methanol, ethanol, isopropanol and higher aliphatic alcohols, acetone and higher aliphatic ketones.
9. Method of claim 7, wherein the reaction of olanzapine is also carried out in organic solvents selected from the group consisting of esters, ethers and aliphatic or aromatic hydrocarbons.
10. Method of claim 7, wherein the reaction is carried out at temperature from -35 0C to +100 0C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL377084A PL377084A1 (en) | 2005-09-15 | 2005-09-15 | New olanzapine compounds and method for their manufacture |
| PLP.377084 | 2005-09-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/PL2006/000025 WO2007032695A1 (en) | 2005-09-15 | 2006-05-04 | New salts of olanzapine and method of their preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018057968A1 (en) * | 2016-09-23 | 2018-03-29 | Delpor, Inc. | Compositions for small molecule therapeutic agent compounds |
| CN115836074A (en) * | 2020-05-05 | 2023-03-21 | 心悦生医股份有限公司 | Salts of neurological drugs and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004089313A2 (en) * | 2003-04-01 | 2004-10-21 | Transform Pharmaceuticals, Inc. | Novel olanzapine forms and related methods of treatment |
| WO2005070938A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | Stable salts of olanzapine |
| WO2005070939A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | Synthesis of olanzapine and intermediates thereof |
| WO2005090359A2 (en) * | 2004-03-18 | 2005-09-29 | Lek Pharmaceuticals D.D. | Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof |
| WO2006010620A2 (en) * | 2004-07-28 | 2006-02-02 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Olanzapine salts and their conversion to olanzapine free base |
-
2005
- 2005-09-15 PL PL377084A patent/PL377084A1/en not_active Application Discontinuation
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2006
- 2006-05-04 WO PCT/PL2006/000025 patent/WO2007032695A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004089313A2 (en) * | 2003-04-01 | 2004-10-21 | Transform Pharmaceuticals, Inc. | Novel olanzapine forms and related methods of treatment |
| WO2005070938A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | Stable salts of olanzapine |
| WO2005070939A1 (en) * | 2004-01-27 | 2005-08-04 | Synthon B.V. | Synthesis of olanzapine and intermediates thereof |
| WO2005090359A2 (en) * | 2004-03-18 | 2005-09-29 | Lek Pharmaceuticals D.D. | Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof |
| WO2006010620A2 (en) * | 2004-07-28 | 2006-02-02 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Olanzapine salts and their conversion to olanzapine free base |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018057968A1 (en) * | 2016-09-23 | 2018-03-29 | Delpor, Inc. | Compositions for small molecule therapeutic agent compounds |
| CN109890365A (en) * | 2016-09-23 | 2019-06-14 | 戴尔普尔有限公司 | Compositions of Small Molecule Therapeutic Compounds |
| AU2017331340B2 (en) * | 2016-09-23 | 2023-09-28 | Delpor, Inc. | Compositions for small molecule therapeutic agent compounds |
| CN115836074A (en) * | 2020-05-05 | 2023-03-21 | 心悦生医股份有限公司 | Salts of neurological drugs and uses thereof |
| EP4146656A4 (en) * | 2020-05-05 | 2024-06-26 | Syneurx International (Taiwan) Corp. | NEUROCEUTICAL SALTS AND USES THEREOF |
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