WO2006101103A1 - 造血器腫瘍治療剤 - Google Patents
造血器腫瘍治療剤 Download PDFInfo
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- WO2006101103A1 WO2006101103A1 PCT/JP2006/305646 JP2006305646W WO2006101103A1 WO 2006101103 A1 WO2006101103 A1 WO 2006101103A1 JP 2006305646 W JP2006305646 W JP 2006305646W WO 2006101103 A1 WO2006101103 A1 WO 2006101103A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to a therapeutic and Z or preventive agent for hematopoietic tumors containing a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- antitumor agents such as taxanes, microtubule agonists such as vin power alkaloids, topoisomerase inhibitors and alkylating agents have been used for cancer chemotherapy. These anti-tumor agents have various problems such as limited indication of carcinoma, side effects such as bone marrow toxicity and neuropathy, and emergence of resistant tumors! ⁇ Levi Use 'Cancer (Nature Reviews Cancer), 3 ⁇ , p. 502 (2003)].
- M-phase kinesin is a protein involved in M-phase spindle regulation, and plays an essential role in the progression of the M phase of the cell cycle! /.
- M-phase kinesin Easy Five (Eg5)
- Eg5 M-phase kinesin Easy Five
- M-phase kinesin Easy Five is a homotetrameric bipolar molecule that bridges two microtubules in the same direction, toward the + (plus) end. Move and slide between two anti-parallel microtubules, separating the (minus) ends of the microtubules to separate the spindle poles and form a bipolar spindle structure Known to be involved [Cell, 8 3 (, p.
- Eg5 inhibitors are considered promising as therapeutic agents for diseases involving cell proliferation [WO200 1/98278, WO2002 / 56880, WO2002 / 57244, “Trends in Cell Biology”, 12 ⁇ , p. 585 (2002)].
- Eg5 inhibitors for example, quinazolin-4-one derivatives (WO200lZ30768, WO2003 / 039 460, etc.), trimethane derivatives (WO2002Z56880), thiadiazoline derivatives (see Patent Documents 1 to 3) and the like are known.
- Non-patent Documents thiadiazoline derivatives having a lower alkanoylamino group at the 2-position, a lower alkanol group at the 4-position, a substituted or unsubstituted aryl group and a lower alkyl group at the 5-position are known (Non-patent Documents). 1 to 3).
- thiadiazoline derivatives useful as antitumor agents are known (see Patent Documents 2 to 4).
- compounds represented by the following formulas (P) to (U) are known to suppress the growth of colon cancer cells (see Patent Document 4).
- Patent Document 1 International Publication No. 2004-092147 Pamphlet
- Patent Document 2 Pamphlet of International Publication No. 2004-111023
- Patent Document 3 Pamphlet of International Publication No. 2004-111024
- Patent Literature 4 Pamphlet of International Publication No. 2003—051854
- Non-Patent Document 1 “Journal 'Ob' Chemical 'Society' Chemical 'Communications (J. Chem. Soc. Chem. Comm.)”, 1982, p. 901
- Non-Patent Document 2 "Archives Pharm.Res", 2002, 25th, p. 250
- Non-Patent Document 3 CAS Registry Database (Registration Number: 352225-16-2, 332 389—23—8, 332389—24—9, 332389—25—0, 443105—83—7, 443105—73—5, 443105—51—9, 443105—46—2, 443105—41—7, 443105- 3 4-8, 443105- 88- 2, 443105- 78-0, 443105- 56-4, 432536- 58-8)]
- An object of the present invention is to provide a hematopoietic tumor containing a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient (for example, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphoma) Leukemia, leukemia such as plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma such as adult T-cell leukemia lymphoma, multiple myeloma, plasmacytoma, myelodysplastic syndrome, chronic myeloproliferative disease, etc.) And to provide Z or prophylactic agents.
- a thiadiazoline derivative or a pharmacologically acceptable salt thereof for example, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphoma
- Leukemia leukemia such as plasma cell leukemia, Hod
- the present invention relates to the following (1) to (19).
- n an integer from 1 to 3
- R 1 represents a hydrogen atom
- R 2 represents lower alkyl
- R 1 and R 2 together represent alkylene
- R 3 represents lower alkyl
- R 4 is a hydrogen atom
- R 7 is hydroxy, lower alkoxy, amino-substituted lower alkylamino and di-lower alkylamino group selected] Lower alkyl optionally having 1 to 2 substituents, COR 8 (Wherein R 8 is a group consisting of hydroxy, lower alkoxy, amino-containing lower alkylamino-containing di-lower alkylamino-containing carboxy, phenol, hydroxyphenol, imidazolyl, guazyl, methylthio, and lower alkoxycarboaminoamino groups. Selected from 1 to 2 substituents selected from! /, May! /, Substituted with lower alkyl, lower alkoxy carbo or oxo, and may be nitrogen-containing aliphatic hetero Represents a cyclic group, or a lower alkoxy) or a hydrogen atom] or
- R 9 represents a lower alkyl optionally having 1 to 2 substituents selected from the group consisting of hydroxy, lower alkoxy, amino-substituted lower alkylamino and di-lower alkylamino
- R 5 represents a halogen, hydroxy, lower alkoxy, nitro, amino-cyano and carboxy group forces that are also selected and a thiadiazoline derivative represented by A therapeutic and Z or prophylactic agent for hematopoietic tumors containing a pharmacologically acceptable salt thereof.
- R 4 is NHSO R 6 (wherein R 6 is as defined above)
- the hematopoietic tumor is leukemia, lymphoma, multiple myeloma, plasmacytoma, myelodysplastic symptom group and chronic myeloproliferative disease power is a selected tumor of (1) to (11)
- the therapeutic and / or preventive agent according to any one.
- Hematopoietic tumors are acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cell leukemia lymphoma, multiple myeloma, Plasmacytoma, myelodysplastic syndrome and patience (2)
- the therapeutic and Z or preventive agent according to any one of (1) to (11), which is a selected tumor.
- a method for the treatment and Z or prevention of hematopoietic tumor comprising administering an effective amount of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (11).
- the hematopoietic tumor is a tumor selected from leukemia, lymphoma, multiple myeloma, plasmacytoma, myelodysplastic syndrome group and chronic myeloproliferative disease group.
- Hematopoietic tumors are acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cell leukemia lymphoma, multiple myeloma,
- the plasma cell tumor, myelodysplastic syndrome and chronic myeloproliferative disease power are the group forces selected: The method according to (14), which is a selected tumor.
- the hematopoietic tumor is a tumor selected from leukemia, lymphoma, multiple myeloma, plasmacytoma, myelodysplastic syndrome group and chronic myeloproliferative disorder.
- Hematopoietic tumors are acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cell leukemia lymphoma, multiple myeloma, Use of plasmacytoma, myelodysplastic syndrome and chronic myeloproliferative disease power group power as described in (17).
- a hematopoietic tumor for example, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic
- a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- Leukemia leukemia such as plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma such as adult T-cell leukemia lymphoma, multiple myeloma, plasmacytoma, myelodysplastic syndrome, chronic myeloproliferative disease, etc.
- leukemia such as plasma cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma such as adult T-cell leukemia lymphoma, multiple myeloma, plasmacytoma, myelodysplastic syndrome, chronic myeloproliferative disease, etc.
- Examples of the lower alkyl moiety in are linear or branched alkyl having 1 to 10 carbon atoms, and more specifically methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl.
- the lower alkenyl includes, for example, linear or branched C2 to L0 alkenyl, and more specifically, bur, aryl, 1-probe, butyl, pentale, Examples include hexyl, heptul, octenyl, nonel, and desal.
- Aaryl includes, for example, aryl having 6 to 14 carbon atoms, and more specifically phenyl, naphthyl and the like.
- alkylene examples include linear or branched alkylene having 1 to 10 carbon atoms, and more specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, otatamethylene. , Nonamethylene, decamethylene, propylene, ethylethylene, methylmethylene, dimethylmethylene and the like.
- a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one nitrogen atom and a 3- to 8-membered ring are condensed.
- Bicyclic or tricyclic condensed aliphatic heterocyclic groups containing at least one nitrogen atom and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, perhydroazepinel.
- Halogen means each atom of fluorine, chlorine, bromine and iodine.
- R 1 is preferably a hydrogen atom.
- R 2 is preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec butyl, tert butyl and the like, more preferably methyl, tert butyl and the like.
- the alkylene formed by combining R 1 and R 2 together is preferably trimethylene, tetramethylene, pentamethylene and the like.
- R 3 is preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec butyl, tert butyl and the like, more preferably methyl, ethyl, isopropyl, tert butyl and the like.
- R 4 is preferably NHSO R 6B [wherein R 6B is methyl, ethyl, propyl, vinyl,
- Aminomethyl 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, methylaminomethyl, 1- (methylamino) ethyl, 2- (methylamino) ethyl, 1- (methylamino) propyl, 2 -(Methylamino) propyl, 3 (methylamino) propyl, dimethylaminomethyl, 1 (dimethylamino) ethyl, 2- (dimethylamino) ethyl, 1 (dimethylamino) propyl, 2- (dimethylamino) propyl, 3 (dimethylamino) propyl, Ethylaminomethyl, 1- (ethylamino) ethyl, 2- (ethylamino) ethyl, 1- (ethylamino) propyl, 2- (ethylamino) propy
- NHCOR 8B (wherein R 8B is as defined above), CONHR 9B (wherein R 9B is as defined above), and more preferably NHSO R 6B (wherein R is as defined above). 6B is the same as above
- NHCOR 8BB (wherein R 8BB represents methoxy, ethoxy, n-butoxy, sec butoxy, ter t butoxy, etc.), CONHR 9B (wherein R 9B is as defined above), etc. Even more preferably, NHSO R 6B (wherein R 6B is as defined above), NHCOR 8BB (wherein
- R 8BB is as defined above.
- R 5 is preferably a file.
- n is preferably 1 or 2.
- the compound (I) or ( ⁇ ) is more preferably a compound in which the above-mentioned preferred substituents are combined.
- R 1 is a hydrogen atom and R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec butyl, tert butyl, or the like, or R 1 and R 2 together are trimethylene, tetra Represents methylene, pentamethylene, etc.
- R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec butyl, tert butyl, etc.
- R 4 is NHSO R 6B (wherein R 6B is as defined above) NHR 7B (where R 7
- N is 1 or 2 is preferred.
- R 1 is a hydrogen atom
- R 2 is methyl, tert butyl, etc. or R 1 and R 2 together are trimethylene Represents tetramethylene
- R 3 is methyl, ethyl, isopropyl, tert butyl, etc.
- R 4 is NHSO R 6B (wherein R 6B is as defined above)
- NHCOR 8B (wherein R 8B is as defined above), CONHR 9B (wherein R 9B is as defined above), R 5 is phenyl, and n is 1 or 2 Is more preferred R 1 is a hydrogen atom, R 2 force is a force such as tert-butyl, or R 1 and R 2 together represent trimethylene, tetramethylene, etc., and R 3 is methyl, ethyl, isopropyl, tert- But R 4 is NHSO R 6B (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHCOR 8BB (wherein R 6B is as defined above), NHC
- R 8BB is as defined above
- CONHR 9B wherein R 9B is as defined above
- R 5 is a file
- n 1 or 2.
- R 1 is a hydrogen atom
- a force is R 2, etc.
- R 4 is NHSO R 6B (wherein R 6B is as defined above), NHCOR TM (where R 8BB is
- R 5 is phenyl and n is 1 or 2.
- the asymmetric center to which R 5 is bonded is the R configuration
- n is 2 or 3
- the S configuration is preferred that the compounds (I) and ( ⁇ ) are preferably compounds having a configuration represented by the following formula (Z).
- the pharmacologically acceptable salts of compound (I) include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. To do.
- examples of the pharmacologically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, kenate, and the like.
- Examples of pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, Zinc salts, etc., and pharmacologically acceptable ammonium salts Examples thereof include salts such as ammonium and tetramethyl ammonium, and pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine.
- Examples of amino acid addition salts that are physically acceptable include addition salts of lysine, glycine, ferulalanin, aspartic acid, glutamic acid, and the like.
- Examples of the salt of compound (I) include trifluoroacetate and trifluoromethanesulfonate in addition to the pharmacologically acceptable salts shown above.
- Compound (I) is WO2003 / 051854, WO2004 / 092147, WO2004 / 11102
- Compound (II) is WO2003 / 051854, WO2004 / 092147, WO2004 / 11102
- racemate (la) obtained by the method described in 4 or the like is subjected to preparative high-speed liquid chromatography matography using an optical isomer separation column [for example, CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.)] It can be produced by resolving each stereoisomer.
- an optical isomer separation column for example, CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.)
- the compound ( ⁇ ) can also be produced according to the following steps.
- R 1Q is an optically active substituent having one asymmetric center, for example, optically active C alkyl, optically active
- C alkyl part of C alkyl and C alkoxy is, for example,
- Methyl pionyl, chloride)-(+)-2-phenylpropionyl, etc.] are reacted according to the method described in, for example, Shinkengaku Kagaku Koza, No. 14, p. 1142 (1978), Maruzen Co., Ltd.
- To obtain the compound (B; diastereomeric mixture) step 1).
- the diastereomers are separated by means of silica gel column chromatography, recrystallization or the like to obtain the compound (C; one diastereomer) (Step 2).
- the obtained compound (C) is treated with a reducing agent such as sodium borohydride according to the method described in, for example, WO2003Z051854 and converted to the compound (D) (step 3).
- the compound ( ⁇ ) can be produced by carrying out an acylation etc. according to the method described in WO2003Z051854 or the like (step 4).
- n is 1 and R 4 is NHSO R 6 (wherein R 6 is as defined above) or N Compound (Ila), which is HR 7 (wherein R 7 is as defined above), can be produced according to the following steps.
- R 1 ⁇ 2 is NHSO R 6 (wherein R 6 is as defined above) or NHR 7 (wherein R 7 is the same as before)
- a compound (Ic; one enantiomer) is obtained by subjecting it to preparative high performance liquid chromatography using (1). Next, the obtained compound (Ic) is treated with an acid such as hydrochloric acid or trifluoroacetic acid according to the method described in, for example, WO2004Z111024 to convert it into a compound (Id) (step 2), then the compound.
- Compound (Ila) can be produced by subjecting compound (Id) to sulfonation, silylation or alkylation according to the method described in, for example, WO2004Z111024 (Step 3).
- compound (IA) wherein R 1 is a hydrogen atom, R 2 is the same lower alkyl as R 3 and R 4 is tert-butoxycarbonylamino is produced according to the following steps: I will do it.
- Compound (XI) can be produced by reacting compound (X) with di-tert-butyl dicarbonate in the presence of a base in a suitable solvent.
- compound (X) is dissolved in a suitable solvent, di-tert-butyl dicarbonate and then a base are added, preferably at a temperature between 0 ° C. and 80 ° C.
- Compound (XI) can be produced by reacting at a temperature between 0 ° C. and 40 ° C. for 5 minutes to 72 hours, preferably 30 minutes to 4 hours.
- Di-tert-butyl dicarbonate is preferably used in an amount of 1 to 10 equivalents, more preferably 1 to 3 equivalents, and still more preferably 1 to 1.2 equivalents relative to compound (X).
- the solvent examples include hydrophilic solvents such as methanol, ethanol, acetonitrile, dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, Dichloromethane, chloroform, 1,2-dichloroethane, toluene, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, jetyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME ) And the like, water and the like, and these may be used alone or in combination.
- hydrophilic solvents such as methanol, ethanol, acetonitrile, dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (
- Preferable examples include non-hydrophilic organic solvents or mixed solvents of non-hydrophilic organic solvents and water, and more preferable organic solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, or the like.
- a mixed solvent of an organic solvent and water is preferably used, and more preferably, ethyl acetate and water (2: 1 to 1: 2, preferably 4: 3 to 3: 4, more preferably 5: 4 -1: 1, more preferably 1: 1).
- the total amount of the solvent is, for example, such an amount that the compound (X) has a concentration of 10 to 600 gZL, preferably 20 to 200 gZL, more preferably 30 to 80 gZL.
- Examples of the base include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropyl.
- Ethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and the like preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, carbonate
- Examples thereof include potassium, potassium hydroxide, sodium hydroxide and the like, and more preferable examples include sodium hydrogen carbonate and potassium carbonate.
- the base is preferably used in a large excess amount, more preferably 1 to 30 equivalents, still more preferably 1 to 5 equivalents, and even more preferably 1 to 1.2 equivalents, relative to compound (X).
- the base is dissolved in an appropriate amount of water, for example, the compound (X) and di-tert-butyl dicarbonate are dissolved in an aqueous solution having a concentration of 1 to 6 molZL, preferably 1.5 to 2.5 molZL.
- the solution is slowly added with vigorous stirring, preferably at a temperature between 0 ° C and 40 ° C, more preferably between 0 ° C and 10 ° C.
- Compound (X) can be obtained as a commercial product or as described in, for example, Journal of Med. Chem., 25 ⁇ , p. 1045 (1982); Synthesis, 28 ⁇ , p. 615 (1990) and the like.
- Compound (XII) can be produced by reacting compound (XI) obtained in Step 1 with thiosemicarbazide in a suitable solvent.
- the compound (XII) is obtained by dissolving the compound (XI) obtained in the above step 1 in an appropriate solvent, preferably ⁇ 10 ° C. and 60 ° C., more preferably 0 °
- an appropriate solvent preferably ⁇ 10 ° C. and 60 ° C., more preferably 0 °
- a solution of thiosemicarbazide in hydrochloric acid is added dropwise at a temperature between C and 20 ° C., preferably at room temperature for 5 minutes to 72 hours, preferably 30 minutes to 4 hours, and then ice-cooled for 30 minutes to
- the mixture can be produced by stirring for 24 hours, preferably 30 minutes to 4 hours, collecting the precipitated solid, washing the resulting solid, and drying.
- solvent for example, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, tert-butanol, acetonitrile, dioxane, DMF, D
- hydrophilic solvents such as MA, NMP, pyridine
- non-hydrophilic solvents such as dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, jetyl ether, THF, DME, and water.
- hydrophilic solvents such as MA, NMP, pyridine
- non-hydrophilic solvents such as dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, jetyl ether, THF, DME, and water.
- a hydrophilic solvent or a mixed solvent of a hydrophilic solvent and water is mentioned, more preferably methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, tert-butanol, etc., or these and water.
- examples thereof include a mixed solvent, more preferably methanol or ethanol, or a mixed solvent of these with water.
- a mixed solvent with water is particularly preferred, a mixed solvent of methanol or ethanol and water (for example, 9: 1 to 1: 9, preferably 8: 2 to 5: 5, more preferably 7: 3 to 6: 4 (methanol or ethanol: water)) is more preferable.
- the amount of the solvent used is, for example, such an amount that the compound (XI) has a concentration of 50 to 600 gZL, preferably 80 to 300 gZL, more preferably 100 to 200 g / L.
- Thiosemicarbazide is preferably used in an amount of 1 to 5 equivalents, more preferably 1 to 3 equivalents, and even more preferably 1.1 to 2.2 equivalents.
- thiosemicarbazide is used as an acidic aqueous solution of hydrochloric acid, for example 0.5 to 12 molZL, preferably 0.5 to 6 molZL, more preferably 2 to 3 molZL of thiosemicarbazide in hydrochloric acid such as lOOg to: LkgZL, Preferably, it is used by dissolving in a concentration of 150 to 300 gZL, more preferably 190 to 230 gZL.
- the solvent used in the reaction water or a mixed solvent thereof is used, and these washing solvents are preferably used after cooling.
- Ice-cold It is preferable to wash with water or a mixed solvent of ice-cooled water and methanol (1: 2 to 2: 1, preferably 1: 1).
- the obtained solid is dried, for example, under reduced pressure, preferably at a temperature between 10 ° C and 60 ° C for 30 minutes to 72 hours.
- Compound (IA) is compound ( ⁇ ) in the presence of a base in a solvent, R 3 COX (wherein R 3 and X are as defined above) or (R 3 CO) 0 (wherein R 3 Is the same as above)
- compound (IA) for compound (IA), compound (XII) is added to a suitable solvent, and R 3 COX (wherein R 3 and X are as defined above) or (R 3 CO) 0 (where R 3
- Isolation of compound (IA) is preferably carried out by adding hydrochloric acid to the reaction mixture and removing the aqueous phase as necessary, then adding water dropwise, collecting the precipitated solid, washing the resulting solid and drying. This can be done from the beginning.
- the solvent examples include hydrophilic solvents such as methanol, ethanol, acetone, methyl ethyl ketone, aceto-trinole, propio-trinole, dioxane, DMF, DMA, NMP, pyridine, dichloromethane, chloroform, 1, 2—
- hydrophilic solvents such as dichloroethane, toluene, ethyl acetate, diethyl ether, THF, DME, water, etc. can be mentioned, and these can be used alone or in combination.
- hydrophilic solvents more preferred are acetonitrile, propionitol, acetone, methyl ethyl ketone, pyridine and the like, and more preferred are acetonitrile.
- the amount of the solvent used is, for example, such an amount that the concentration of the compound (XII) is S30 to 600 gZL, preferably 50 to 300 gZL, more preferably 80 to 120 g ZL.
- Examples of the base include potassium acetate, sodium hydrogen carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine. , Pyridine, DBU, etc. Preferable examples include pyridine.
- the base is preferably used in an amount of 2 to 12 equivalents, more preferably 2.5 to 5 equivalents, relative to compound (XII).
- R 3 COX examples include R 3 COCl, R 3 COBr, etc., and preferably 2 to 10 equivalents, more preferably 2.5 to 3.5 equivalents, relative to compound (XII).
- (R 3 CO) O is
- the compound (:) is preferably used in an amount of 2 to: LO equivalent, more preferably 2.5 to 3.5 equivalent. These are preferably added dropwise to the mixture of compound (ii), base and solvent with stirring under ice cooling.
- a method such as filtration can be used to obtain the precipitated solid.
- a solvent used in the reaction for example, water, a solvent used in the reaction, or a mixed solvent thereof can be used, and these are preferably used after cooling. It is preferable to wash with a mixed solvent (30: 1 to 1: 1, preferably 15: 1 to 5: 1) of the solvent used for the chilled reaction, followed by cold water U.
- the obtained solid can be dried, for example under reduced pressure, preferably 1-7 at a temperature between 10 ° C and 70 ° C.
- R 1 is a hydrogen atom
- R 2 is the same lower alkyl as R 3
- R 4 force Stert-butoxycarbolamino is a compound ( ⁇ ) produced by the production method 5 etc.
- the compound (IA) obtained can be used, for example, according to the method described in Production Method 2.
- Compound (IB) or ( ⁇ ) can be produced by treating compound (IA) or ( ⁇ ) obtained by production method 1, 2, 3, 5, 6, etc. with an appropriate acid.
- the hydrochloride of the compound (IB) or ( ⁇ ) can be obtained from the compound (IA) or ( ⁇ ) obtained by the production method 1, 2, 3, 5, 6, etc., if necessary. It can be produced by dissolving in a suitable solvent and treating with a solution containing, for example, sodium chloride and hydrogen. The treatment is preferably carried out at a temperature between 0 ° C and 60 ° C, more preferably between 5 ° C and 40 ° C for 5 minutes to 72 hours, preferably 1 to 12 hours, optionally under ice cooling. It is carried out by stirring for another 10 minutes to 4 hours. Isolation of the hydrochloride salt of the compound (IB) or (IV) is preferably performed, for example, by solid solution precipitated in the mixture, and if necessary, washing and drying.
- hydrogen chloride for example, methyl chloride, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, dioxane, etc.
- hydrogen chloride is, for example, 1 to 12 molZL, preferably 1 to 8 molZL, more preferably 2 Examples include solutions dissolved at a concentration of ⁇ 6molZL.
- a solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, more preferably ethyl acetate has a hydrogen chloride salt of, for example, 1 to 12 molZL, preferably 1 to 8 molZL, more preferably 2 to 6 molZL. Examples thereof include 4 mol ZL salt-hydrogen-ethyl acetate.
- the solvent that dissolves the compound (IA) or (IV) include the same solvents as the above-mentioned solution containing hydrogen chloride, and specific examples include ethyl acetate.
- a technique such as filtration can be used.
- the resulting solid is washed preferably in the same solution as the cooled solution containing the salt and hydrogen. It is carried out using a medium, specifically preferably cold ethyl acetate.
- the obtained solid is dried, for example, under reduced pressure, preferably at 10 ° C and 120 ° C, more preferably at a temperature between 20 ° C and 100 ° C, and even more preferably at a temperature between 30 ° C and 80 ° C for 1 to 72 hours, Preferably it is performed for 1 to 24 hours.
- R 4 is NHSO R 6 (wherein R 6 is as defined above), NHR 7e (wherein,
- R 7C may have 1 to 2 substituents selected from the group consisting of hydroxy, lower alkoxy, amino-substituted lower alkylamino and di-lower alkylamino in the definition of R 7 V,
- a compound (ICa), (ICb) or (ICc) which is lower alkyl) or NHCOR 8 (wherein R 8 is as defined above) can also be produced according to the following steps.
- Compound (ICa) is compound (IB) obtained by production method 1, 2, 4, 7, etc. in an appropriate solvent in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents of R 6 SO X (wherein R 6 and X are the same as above.
- Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, and the like.
- Examples of the base include sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide.
- Compound (ICb) is compound (IB) obtained by production method 1, 2, 4, 7, etc., in an appropriate solvent, 1 to 20 equivalents of R 7e X (wherein R 7e and X are And is allowed to react at a temperature between 20 ° C. and 150 ° C. for 5 minutes to 72 hours, if necessary, in the presence of 0.5 to 20 equivalents of a base.
- solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, and the like. Or mixed.
- Examples of the base include sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tret butoxide, triethylamine, diisopropyl propylamine, N-methylmorpholine, pyridine, DBU and the like. Can be given.
- compound (ICb) may be prepared by subjecting compound (IB) obtained by production method 1, 2, 4, 7 etc. to a suitable solvent, preferably 1 to 20 equivalents, more preferably 1 to 5 equivalents of R.
- Ketone or aldehyde corresponding to rc eg, formaldehyde when R rc is methyl, acetoaldehyde when ethyl, acetone when isopropyl, etc.
- preferably 1 to 20 equivalents more preferably 1 to Produced by reacting for 5 minutes to 72 hours at a temperature between 20 ° C and 150 ° C in the presence of 5 equivalents of reducing agent, and preferably 1 to 20 equivalents, more preferably 1 to 5 equivalents of acid. can do.
- Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
- Examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid and the like.
- solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, DMA, NMP, water, and the like. These are used alone or in combination.
- Compound (ICc) is obtained by reacting compound (IB) obtained by production method 1, 2, 4, 7 or the like with 1 to 20 equivalents of R 8 COX in the absence of solvent or in a suitable solvent (wherein R 8 and X are as defined above Or (R 8 CO) 0 (wherein R 8 is as defined above), and if necessary, 0.5 to 20 equivalents
- It can be produced by reacting in the presence of a base at a temperature between -20 ° C and 150 ° C for 5 minutes to 72 hours.
- Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, DMA, NMP, pyridine, and the like. Or mixed.
- Examples of the base include sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tret-butoxide, triethylamine, diisopropyl propylamine, N-methylmorpholine, pyridine, DBU and the like. It is done.
- the compound (ICa) having the same configuration as the compound ( ⁇ ⁇ ⁇ ) can be obtained by performing the same operation as above by using the compound ( ⁇ ) obtained by the production methods 2 and 7 instead of the compound (IB).
- ⁇ (ICb) can be produced.
- R 4 is NHSO CH CH R 4B (wherein R 4B is a lower alkyl group defined by R 6)
- a compound containing an amino-substituted hydroxyami-substituted lower alkylami-substituted di-lower alkyl ami-substituted N-hydroxy-lower alkylami-substituted amino-substituted lower alkylthio, lower alkylamino-substituted lower alkylthio or di-lower alkylamino-substituted lower alkylthio) (ID) can also be produced according to the following steps.
- the compound (IDa) is obtained by reacting the compound (IB) obtained by the production method 1, 2, 4, 7 or the like in the absence of a solvent or in an appropriate solvent, preferably in the presence of 1 to 20 equivalents of a base. 1 to 20 equivalents, preferably 1 to 5 equivalents of C1CH CHSOC1, 20 ° C and 150 ° C, preferably -10 ° C to 30 ° C
- compound (IB) can be produced by reacting at a temperature of between 5 minutes and 72 hours, preferably between 5 minutes and 5 hours.
- compound (IB) can also be used as an acid addition salt such as hydrochloride, in which case the base is preferably used in an amount of 2 equivalents or more.
- Solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, DMA, NMP, N, N, monodimethylimidazolidinone (DMI), pyridine and the like, and these may be used alone or in combination. Ethyl acetate, acetonitrile, etc. are particularly preferred.
- Examples of the base include sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert butoxide, triethylamine, diisopropylpropylamine, N-methylmorpholine, pyridine, N-methylbiperidine, N, N ,-Dimethylbiperazine, DBU, etc.
- Compound (ID) is a compound (IDa) obtained in Step 1 above, in the absence of a solvent or in a suitable solvent, optionally in the presence of 1 to 10 equivalents of a base, 1 equivalent to a large excess, preferably 5 ⁇ 100 equivalents, more preferably 10-20 equivalents of R 4 4D NH (wherein R 4e and R 4D are the same or different and are substituted with a hydrogen atom, hydroxy or a lower alkyl substituent defined by R 6).
- R 4E SH wherein R 4E is a lower alkyl substituent as defined for R 6 in the lower alkyl substituent, lower alkylthio, lower alkyl).
- Amino-substituted lower alkylthio and di-lower alkylamino-substituted lower alkylthio amino-substituted lower alkyl, lower alkylamino-substituted lower alkyl and di-lower alkyl Represent the Ruamino substituted lower alkyl), 10 ° C and 0.99 ° C, preferably 10 ° C and 40 ° C It can be produced by reacting at a temperature between 5 minutes and 72 hours.
- Solvents include, for example, methanol, ethanol, propanol, 2-propanol, butanol, dichloromethane, chlorophenol, 1,2-dichloroethane, toluene, ethynole acetate, acetonitrile, jetyl ether, THF, DME, dioxane, DMF, Examples thereof include DMA, NMP, pyridine, water and the like, and these are used alone or in combination. Methanol, ethanol, etc., or a mixed solvent of these with water is preferred.
- Examples of the base include sodium hydrogen carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropyl tyramine, N-methylmorpholine, pyridine and DBU. It is done.
- Some of the compounds (I) and ( ⁇ ) may have stereoisomers such as geometric isomers and optical isomers, positional isomers, tautomers and the like. All possible isomers and their mixtures can be used for the treatment of hematopoietic tumors and Z or preventive agents.
- salt of compound (I) or ( ⁇ ) when the salt of compound (I) or ( ⁇ ) is obtained, when compound (I) or ( ⁇ ) is obtained in the form of a salt, it can be purified as it is, or when it is obtained in the free form.
- Compound (I) or ( ⁇ ) may be dissolved or suspended in an appropriate solvent, and a salt may be formed by adding an acid or base to isolate and purify.
- the compounds (I) and ( ⁇ ) and their pharmacologically acceptable salts may exist in the form of adducts with water or various solvents. Can be used for treatment of organ tumors and Z or prophylactic agents.
- Test Example 1 Cell growth inhibition test for hematopoietic tumor cell line
- Hematopoietic tumor cell lines include human acute lymphocytic leukemia RS4; 11 cells (ATCC number: CR L 1873), human chronic myelogenous leukemia K—562 cells (ATCC number: CCL 243) and human multiple myeloma NCI—H929 Cells (ATCC number: CRL-9068) were used.
- RS4 11 cells (20000 cells Z-well), K-562 cells (1000 cells Z-well) or NCI H929 cells (15000 cells Z-well) in each 96-well plate (Nunk, catalog number 167008) The seeds were seeded and cultured overnight. Test compounds diluted in stages were collected and incubated for a further 72 hours (final volume 100 LZ well). To each well, 50 / zL of a cell label mixture of Cell Prol iferation Kit II (XTT) (Roche Diagnostics, catalog number 1465015) was added and incubated at 37 ° C.
- XTT Cell Prol iferation Kit II
- the absorbance at 490 ⁇ m was measured with a plate reader (Molecular Device, SpectraMax 340PC 384 ).
- the growth rate of the cells of the wells treated with the test compound was calculated with the growth rate of the cells of the control wells treated with the solvent (dimethyl sulfoxide (DMSO)) at 72 hours as 100%.
- a 50% growth inhibitory concentration GI value was calculated from a plot of the concentration of the test compound and the cell growth rate at that time.
- Compound 1, 2, a, b, d, e, h, i, j, 1, m, n, and o are acute-induced lymphoblastic leukemia RS4; 1 1 cells, human chronic myeloid leukemia K — It showed inhibitory activity of 562 cells and human multiple myeloma NCI-H929 cells with a GI value of 10 ⁇ molZL or less. From the above, compound (I)
- Compound (ii) has cell growth inhibitory activity against human acute lymphocytic leukemia cells, human chronic myelogenous leukemia cells and human multiple myeloma cells, ie leukemia, multiple myeloma, etc. It is considered useful as a therapeutic and Z or preventive agent for hematopoietic tumors.
- Test Example 2 Cell growth inhibition test on acute myeloid leukemia cells and non-Hodgkin lymphoma cells
- each cell was seeded on each well of a 96-well plate (NUNK, catalog number 167008) (each 8000-16000 cells Z-well) and treated with the test compound. Growth rate was calculated. Absorbance was measured 3 to 4 hours after the addition of the XTT labeling mixture. A 50% growth inhibitory concentration GI value was calculated from a plot of the concentration of the test compound and the cell growth rate at that time.
- compounds (I) and (ii) have cell proliferation inhibitory activity against human acute myeloid leukemia cells and human non-Hodgkin lymphoma cells, that is, acute myeloid leukemia and non-Hodgkin lymphoma. It is considered useful as therapeutic and Z or prophylactic agent for treatment and Z or prophylactic agent.
- compounds (I) and ( ⁇ ) are useful as therapeutic and Z or preventive agents for hematopoietic tumors such as leukemia, lymphoma, multiple myeloma.
- Test Example 3 Inhibition test for Eg5 enzyme
- the recombinant human Eg5 motor domain protein was prepared with reference to the literature [Biochemi stry, 35 ⁇ , p.2365 (1996)].
- a plasmid expressing the human Eg5 motor domain was constructed and transformed into E. coli BL21 (DE3). Transformants at 25 ° C When cultivated and reach an OD force of .74, the final concentration is 0.5 mmol / L.
- ⁇ -D thiogalataside was added. Furthermore, after culturing for 4 hours, the culture solution was centrifuged to recover the cells. The cells were suspended in a buffer, subjected to ultrasonic disruption, and the supernatant was collected by centrifugation. The supernatant was purified by cation exchange column chromatography to obtain a partially purified sample. Further, the partially purified sample was purified by gel filtration column chromatography to obtain the final purified sample.
- Solution B consisting of ytitol (DTT), 5 ⁇ mol / L paclitaxel and 2.5 mmol / L ATP was prepared.
- Solution A was dispensed into a 96-well plate by 45 ⁇ L of each well.
- the test compound was diluted stepwise using solution ⁇ .
- Each 30 ⁇ L of the diluted test compound solution was mixed with the solution solution dispensed in the previous 96-well plate to start the enzyme reaction.
- the enzyme reaction was performed at 30 ° C for 30 minutes.
- Absorbance at 360 nm, which is an index of ATPase activity, was measured with a plate reader (Molecular Devices, SpectraMax 340PC 384 ). Absorbance is 100% in the presence of Eg5 and in the absence of the test compound. Test compound is absent in the absence of Eg5.
- the relative activity was calculated with the absorbance in the presence as 0%, and the IC value was calculated.
- the compound ( ⁇ ) which shows a negative specific rotation at 20 ° C for sodium D-line (wavelength: 589.3 nm) when dissolved in methanol, has a stronger Eg5 inhibitory effect than its racemic mixture. Therefore, it was suggested to have stronger physiological activity.
- the compound (I) or (ii) or a pharmacologically acceptable salt thereof can be administered as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
- the pharmaceutical preparation according to the present invention may contain compound (I) or (IV) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other pharmaceutical ingredient as an active ingredient.
- these pharmaceutical preparations can be prepared by any method that is well known in the technical field of pharmaceutics by mixing the active ingredient together with one or more pharmaceutically acceptable carriers. Manufactured.
- the route of administration can be oral or the parenteral, for example intravenously, as it is desirable to use the most effective treatment.
- Examples of the dosage form include tablets and injections.
- Suitable for oral administration such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, interfaces such as fatty acid esters It can be produced using an activator or a plasticizer such as glycerin.
- Formulations suitable for parenteral administration preferably comprise a sterile aqueous preparation containing an active compound which is isotonic with the blood of the recipient.
- a solution for injection is prepared using a carrier such as a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
- the excipients, disintegrants, lubricants, binders exemplified for oral agents are used. It is also possible to add one or more auxiliary ingredients that are also selected for their power, such as mixtures, surfactants, plasticizers and diluents, preservatives, flavors.
- Compound (I) or (IV) or a pharmaceutically acceptable salt thereof is usually administered systemically or locally in an oral or parenteral form when used for the above purpose.
- the dose and frequency of administration vary depending on the dosage form, patient age, body weight, nature of the symptom to be treated or severity, etc. It is administered at a dose of 1000 mg, preferably 0.05 to 500 mg, 1 to 1 or several times, or once every several to 1 or 2 weeks.
- parenteral administration such as intravenous administration, it is usually 0.001 to 1000 mg, preferably 0.01 to 300 mg per adult, once to several times, every few days, or for 1 to 3 weeks. Administer once at intervals.
- Examples of administration methods include rapid intravenous injection and intravenous continuous administration in the range of 1 to 24 hours per day. However, these doses and the number of doses vary depending on the various conditions described above.
- the therapeutic and Z or prophylactic agent for hematopoietic tumor of the present invention has an excellent ability to exhibit hematopoietic tumor and Z or prophylactic effect, and further, as described above, the compound (I) or ( ⁇ ⁇ ⁇ ⁇ ) or its A combination of a pharmacologically acceptable salt and one or more other pharmaceutical ingredients can also be used.
- compositions used in combination include, for example, low molecular weight, protein, or nuclear acid drugs. Specifically, clinical oncology, 3rd edition, edited by Japan Clinical Oncology Society (2003) And the like.
- Examples of the low molecular weight drug include DNA alkylating agents (for example, cyclophosphamide, iphosphamide, melphalan, dacarbazine, procarbazine, dimustine, carmustine, mouth mustine, estramustine, busulfan, tiotepa, etc.); DNA synthesis inhibitors (eg, bleomycin, pepromycin, mitomycin C, mitoxantrone, actinomycin D, etc.); platinum drug-type DNA cross-linking agents (eg, cisbratine, carbobratin, oxalibratin, nedaplatin, etc.); antimetabolites (eg, 5-Fluorouracil, tegafur, force pecitabine, methotrexate, gemcitabine, funoredarabine, cytarabine, cladribine, mercaptopurine, hydroxycarbamide, etc.); topoisomerase I inhibitor (for example,
- tyrosine kinase inhibitors ⁇ eg EGFR inhibitors (eg Gefitiv, L-mouth, etc.), Abl inhibitors (eg imatinib, etc.) VEGFR inhibitors [eg ZD6474 (Cancer Res., 62, p. 4645 (2002))], FGFR inhibitors [eg PD 173074 (EMBO J.), 17 P. 5896 (1998))], PDGFR inhibitors [eg SU11248 (Clin. Cancer Res.), 9 ⁇ , p. 327 (2003))], Flt3 inhibitor [eg MLN518 (Cancer ⁇ Cancer Cell, 1, p.
- IGF-1R inhibitors eg NVP—AEW541 (Cancer Cell, 5 ⁇ , p. 231 (2004) Etc)]; adenosine deaminase inhibitors (eg, pentostatin); Hsp90 inhibitors [eg, radicicol, 17-arylamino-17-demethoxygeldanamycin (Cancer Chemother. Pharmacol ), 42 ⁇ , p. 273 (1998))]; Angiogenesis inhibitors [eg, SU6668 (Cancer Res., 60 ⁇ , p.
- Targeting agents such as combretastatin A4
- histone deacetylase inhibitors eg, SAHA (Procedinas ⁇ The ⁇ National ⁇ Academia 1 »Ob. Science ( proc . Natl. Acad Sci. USA), 95 ⁇ , p. 3003 (1998)) etc.
- Lixmeta mouth protease inhibitor eg, marimastat
- prenyl Group transferase inhibitors eg Rl 15777 (Cancer Res., 61 ⁇ , p.
- M phase kinesin inhibitors eg Eg5 inhibitors (eg SB-715992 (WO200lZ98278, WO2003Z070701) etc.) etc.
- derivatives of these drugs are also included.
- protein drugs include cyto force-in and antibodies.
- site force-in examples include interferon- ⁇ ⁇ , ⁇ , y; tumor necrosis factor (TNF) — ⁇ ; lymphotoxin; interleukin—1, 2, 3, 4, 7, 8, 12, 15, 18, 21; granulocyte colony stimulating factor (G-CSF); macrophage colony stimulating factor ( ⁇ -CSF); condylar granule. Macrophage colony stimulating factor (GM-CSF); interferon gamma-inducible protein 10 (IP-10); Fractal power in and so on. Also included are protein preparations such as growth hormone receptor antagonists.
- TNF tumor necrosis factor
- IP-10 interferon gamma-inducible protein 10
- the antibody is not particularly limited as long as it is an antibody against an antigen expressed in tumor cells, or an antigen involved in tumor pathogenesis such as tumor cell proliferation or metastasis.
- interleukin 6 (IL- 6) Receptor GD2, GD3, GM2, HER2, CD20, CD22, CD33, CD52, MAGE, HM1.24, parathyroid hormone related protein (PTHrP), basic fibroblast growth factor, fibroblast growth factor 8, basic fibroblast growth factor receptor, fibroblast growth factor 8 receptor, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), insulin-like growth factor, insulin-like growth factor receptor And antibodies to prostate-specific membrane antigen (PSMA), vascular endothelial growth factor, vascular endothelial growth factor receptor, and the like.
- PTHrP parathyroid hormone related protein
- EGFR epidermal growth factor receptor
- EpCAM epithelial cell adhesion molecule
- PSMA prostate-specific membrane antigen
- Anticancer Res. 18 ⁇ , p.
- the antibody described in 1217 (1998), anti-GD2 antibody Anti-Cancer 'Research (13), p. 331 (1993), and anti-GD3 antibody is Cancer Immunol. Immunother. 36 P. 260 (1993), as an anti-GM2 antibody, Cancer Res., 54 ⁇ ⁇ ⁇ ⁇ , p. 1511 (1994), as an anti-HER2 antibody
- Anti-IL-6 receptor antibodies Anticancer Res., 18 ⁇ , p.
- anti-GD3 antibody is Cancer Immunol. Immunother. 36 P. 260 (1993), as an anti-GM2 antibody, Cancer Res., 54 ⁇ ⁇ ⁇ ⁇ , p. 1511 (1994), as an anti-HER2 antibody
- Dinda's ⁇ The ⁇ National ⁇ Aka ⁇ Demi-Ob 'Science Proc. Natl. Acad. Sci.
- anti-HM1.24 antibodies include molecular immunol., 36., p. 387 (1999).
- Parathyroid hormone-related protein antibodies are those described in Cancer, 88 ⁇ , p. 2909 (2000), and anti-fibroblast growth factor 8 antibodies are proceedings ⁇ of ⁇ the ⁇ national ⁇ academia The antibody described in Phys Science (Proc. Natl. Acad. Sci. USA), 8611, p. 9911 (1989), and the anti-fibroblast growth factor 8 receptor antibody Described in J. Biol. Chem., 265 ⁇ , p. 16455 (1990) Body, anti-epithelial cell The growth factor receptor antibody is described in Cancer Res., 59 ⁇ , p. 12 36 (1999).
- an anti-insulin-like growth factor antibody Is an antibody described in the journal 'Ob-Euroscience' Research (J. Neurosci. Res.), 40 p, p. 647 (1995), and as an anti-insulin-like growth factor receptor antibody, The antibody described in 'Neuroscience' Research (J. Neurosci. Res.), 40 ⁇ , p. 647 (1995), and the journal 'Ob' as an anti-prostate specific membrane antigen antibody Urology, 160 ⁇ , p.
- nucleic acid drugs include antisense, small interfering RNA (siRNA), and ribozyme.
- the nucleic acid is not particularly limited as long as it has a sequence complementary to a gene involved in tumor pathogenesis such as tumor cell proliferation or metastasis, but it is complementary to the gene sequence targeted by the above-mentioned small molecule or protein.
- a nucleic acid having a typical sequence is not particularly limited as long as it has a sequence complementary to a gene involved in tumor pathogenesis such as tumor cell proliferation or metastasis, but it is complementary to the gene sequence targeted by the above-mentioned small molecule or protein.
- compound (I) or ( ⁇ ) or a pharmaceutically acceptable salt thereof is used in combination with another pharmaceutical ingredient, compound (I) or ()) or a pharmacologically acceptable salt thereof
- the salt and other pharmaceutical ingredients may be administered at the same time, or may be administered separately at a time interval. These doses vary depending on the administration subject, administration route, disease, combination of pharmaceutical ingredients, etc., as long as they are in accordance with clinically used doses.
- compound (I) or ( ⁇ ) or a pharmacologically acceptable salt thereof is used in combination with other pharmaceutical ingredients
- compound (I) or ( ⁇ ) or a pharmacologically acceptable salt thereof is used in combination with other pharmaceutical ingredients
- compound (I) or ( ⁇ ) or the pharmacologically acceptable salt and other pharmaceutical ingredients may be combined.
- it can be used or administered as a single agent (mixture) or as a combination of a plurality of formulations.
- When administered as a combination of multiple formulations they can be administered simultaneously or separately over time.
- These preparations are preferably used in the form of tablets, injections, and the like. Further, these preparations are produced by any method well known in the technical field of pharmaceutics as described above.
- a first component containing compound (I) or (II) or a pharmacologically acceptable salt thereof for example, (a) a first component containing compound (I) or (II) or a pharmacologically acceptable salt thereof, and (b) other components
- the second component containing the medicinal component is formulated separately and prepared as a kit. Using this kit, each component can be used simultaneously or at the same time for the same subject to the same route or different. It can also be administered by different routes.
- kits there are no particular limitations on the material, shape, etc. of the kit as long as it is a container that does not show, for example, denaturation of components that are contents by external temperature or light and elution of chemical components such as container force during storage.
- containers eg, vials, nogs, etc.
- content force e.g., a force to administer the contents of the first and second components.
- kits such as tablets and injections.
- Treatment and Z or prevention of hematopoietic tumors by using a combination of Compound (I) or (I) or a pharmacologically acceptable salt thereof and one or more other pharmaceutical ingredients. Expected to improve effects and reduce side effects.
- a tablet having the following composition is prepared by a conventional method.
- Compound 3, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm, and tablets (2 Omg of active ingredient per tablet) were prepared. Containing).
- a tablet having the following composition is prepared by a conventional method.
- Compound 4, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm, and tablets (2 Omg of active ingredient per tablet) were prepared. Containing).
- Tablet (Compound 7) A tablet having the following composition is prepared by a conventional method. Compound 7, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. The obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. This was mixed with 1.2 g of magnesium stearate and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (2 Omg active ingredient per tablet) Containing).
- RT-15 type manufactured by Kikusui Co., Ltd.
- An injection having the following composition is prepared by a conventional method. Add 5 g of Compound 3, lg and D-Mantool to distilled water for injection, mix, add hydrochloric acid and aqueous sodium hydroxide solution to adjust pH to 7, and then add distilled water for injection. The total volume is lOOOmL. Aseptically fill the glass vial with 2 mL of the resulting mixture to obtain an injection (containing 2 mg of active ingredient per vial).
- An injection having the following composition is prepared by a conventional method. Add Compound 9, lg, and D-Mantool 5 g to distilled water for injection, mix, add hydrochloric acid and aqueous sodium hydroxide solution to adjust pH to 7, and then add distilled water for injection. The total volume is lOOOmL. Obtained Aseptically fill each glass vial with 2 mL of the mixed solution to obtain an injection (containing 2 mg of active ingredient per vial).
- An injection having the following composition is prepared by a conventional method.
- Compound 12, lg, and 5 g of D-manntol are added to and mixed with distilled water for injection. Further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 7, and then with distilled water for injection. The total volume is lOOOmL. Aseptically fill the glass vial with 2 mL of the resulting mixture to obtain an injection (containing 2 mg of active ingredient per vial).
- a tablet having the following composition is prepared by a conventional method.
- Compound a (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution of hydroxypropylcellulose (120 g) is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. This was mixed with 1.2 g of magnesium stearate, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (2 Omg active ingredient per tablet) Containing).
- a tablet having the following composition is prepared by a conventional method.
- Compound d, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (2 Omg active ingredient per tablet) Containing).
- a tablet having the following composition is prepared by a conventional method.
- Compound e, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (2 Omg active ingredient per tablet) Containing).
- a tablet having the following composition is prepared by a conventional method.
- Compound 40g, lactose 286.8g and potato starch 60g are mixed, and 120% 10% aqueous solution of hydroxypropylcellulose is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm, and tablets (2 Omg of active ingredient per tablet) were prepared. Containing).
- a tablet having the following composition is prepared by a conventional method.
- Compound m, 40 g, lactose 286.8 g and potato starch 60 g are mixed, and 10% aqueous solution of hydroxypropylcellulose 120 g is added thereto.
- the obtained mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
- This was mixed with 1.2 g of magnesium stearate, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm, and tablets (2 Omg of active ingredient per tablet) were prepared. Containing).
- An injection having the following composition is prepared by a conventional method. Add 5g of Compound a, lg and D-Mantool to distilled water for injection, mix, add hydrochloric acid and aqueous sodium hydroxide solution to adjust pH to 7, and then add distilled water for injection. The total volume is lOOOmL. The resulting mixture is aseptically filled into glass vials in 2 mL increments and injected (appropriately suitable for each vial)
- An injection having the following composition is prepared by a conventional method. Add 5 g of compound lg and D-Mantool to distilled water for injection, add hydrochloric acid and sodium hydroxide aqueous solution to adjust the pH to 7, and then add the total volume with distilled water for injection. lOOOmL. Aseptically fill the glass vial with 2 mL of the resulting mixture to obtain an injection (containing 2 mg of active ingredient per vial).
- An injection having the following composition is prepared by a conventional method. Add 5 g of compound m, lg and D-mannitol to distilled water for injection, mix, add hydrochloric acid and aqueous sodium hydroxide solution to adjust pH to 7, then add distilled water for injection. To lOOOmL. Aseptically fill the glass vial with 2 mL of the resulting mixture to obtain an injection (containing 2 mg of active ingredient per vial).
- Step 1 (S) — (+) —2 Dissolve phenolpropionic acid (4.88 g, 32.5 mmol) in dichloromethane (20 mL), and add salt (30 mL) to room temperature. For 4 hours. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (10 mL) (dichloromethane solution).
- ⁇ 6 ⁇ d ⁇ 4SZ base ⁇ U Z base
- Step 3 The optically active N— ⁇ 2— [5 amino-3- (2,2 dimethylpropionyl) 1-2 phenyl 1 2, 3 dihydro 1, 3, 4 thiadiazole 2— Ru] ethyl ⁇ methanesulfonamide (90 mg, 0.23 mmol) is dissolved in dichloromethane (4 mL), and pyridine (0.224 mL, 2.77 mmol) and trimethylacetyl chloride (0.288 mL, 2.33 mmol) are added at room temperature. Stir for 3.5 hours. Water and 1 mol / L hydrochloric acid were added to the reaction solution and extracted with ethyl acetate.
- Step 1 In the same manner as in Step 1 of Reference Example 14, N— [2— (5-Amino-2-phenol-Lu 3 propio-Lu 2,3 dihydro—1 obtained according to the method described in WO2003Z051854 , 3, 4-thiadiazol-2-yl) ethyl] methanesulfonamide (10.7 g, 30.0 mmol), and (R)-(-)-2 phenolpropionic acid (10.5 g, 69.9 mmol) and salt Chloride (R)-(I) — Prepared from thiol, from 2-phenolpropiool, N— [5- (2-methanesulfolaminoethyl) 5—phenol-4 propionyl 4,5 dihydride 1,3,4 Thiadiazole-2-yl] -2 phenolpropanamide was obtained as a diastereomeric mixture (13.3 g, 92%).
- Step 2 In the same manner as in Step 2 of Reference Example 14, N— [5
- Step 3 In the same manner as in Step 3 of Reference Example 14, the optically active N— [2 — (5 amino-1, 2 phenyl-1, 3 propionyl 1, 2, 3 dihydro 1, 3, 4, thiadi obtained in Step 2 above.
- [Azol-2-yl) ethyl] methanesulfonamide (0.0480 g, 0.135 mmol)
- pyridine (3 2.7 ⁇ L, 0.405 mmol)
- trimethylacetyl chloride (41.7 ⁇ L, 0.338 mmol)
- the compound b ⁇ ( -) -N- [5- (2 Methanesulfolaminoethyl) 5-Fu-Loop 4-loop Mouth Pioni Luo 4, 5 Dihydro 1, 3, 4-thiadiazol 2-yl]-2, 2 Dimethylpropane Amide ⁇ (0.0504 g, 84%) was obtained.
- the organic layer was washed with 0.5 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in dimethyl sulfoxide (DMSO) (6 mL) and add sodium acetate. (0.331 g, 4.04 mmol) was added and heated to 100 ° C. over 14 minutes with stirring. After allowing to cool, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
- DMSO dimethyl sulfoxide
- Step 1 N— [4 Isobutyryl-5- (2-methanesulfolaminoethyl) 5 phenol 1,5 Dihydro-1,3,4, thiadiazole-2-yl obtained according to the method described in WO2003Z051854 —2, 2 Dimethylpropanamide (2.32 g, 5.10 mmol)
- HPLC Preparative high performance liquid chromatography [Column: CHIRALPAK AD (manufactured by Daicel Chemical Industries); Elution solvent: 12% isopropyl alcohol Zn-hexane; Flow rate: 6 mL / min; force ram temperature: 25 ° C] and fractions with retention times of 10.2 min and 11.2 min were fractionated.
- N-methanesulfol 3 aminopropiophenone 388 mg, 1.71 mmol
- thiosemicarbazide 156 mg, 1.71 mmol
- N-methanesulfone -Lu-3 Aminopropiophenone thiosemicarbazone (219 mg, 45%) was obtained.
- Step 3 In the same manner as described in WO2003Z051854, N— [4 acetyl-5- (2-methanesulfuraminoethyl) 5-phenol- 4,5-dihydro-1, obtained in Step 2 above 3, 4 Thiadiazole 2-yl] acetamide (5.22 g, 13.6 mmol), water From sodium boron bromide (5.14 g, 136 mmol) and cerium chloride heptahydrate (5.07 g, 13.6 mmol), N— [2— (3 acetyl 1 5 amino 1 2 phenol 1 2, 3 dihydro 1 1,3,4-thiadiazol-2-yl) ethyl] methanesulfonamide was obtained.
- Step 4 In the same manner as in Step 2 of Reference Example 14, N— [4-acetyl-5- (2-methanesulfolaminoethyl) 5-phenol- 4,5 dihydride eluted after obtained in Step 3 above Mouth 1, 3, 4 Thiadiazole-2-yl] —2 Another diastereomer of phenol propanamide (0.632 g, 1.33 mmol), cerium chloride 7hydrate (0.496 g, 1.33 mmol) and hydrogenation From sodium boron (0.503 g, 13.3 mmol), optically active N— [2— (3—acetyl-1,5 amino-1,2 phenyl-1,2,3 dihydro-1,3,4, thiadiazole-2-yl) ethyl] methane Sulfonamide (232 mg, 51%) was obtained.
- Step 5 In the same manner as in Step 3 of Reference Example 14, the optically active N— [2 — (3 acetyl 1 5 amino 1 2 phenol 1, 3 dihydro 1 1, 3, 4 thiadiazo 1-ro 2-yl) ethyl] methanesulfonamide (0.0393 g, 0.115 mmol), pyridine (44.7 ⁇ L, 0.552 mmol) and trimethylacetyl chloride (56.7 ⁇ L, 0.460 mmol) from compound f ⁇ ( 1)
- One N— [4 Acetyl 5— (2-Methanesulfolaminoethyl) 5 Phenoluol 4, 5 Dihydro 1, 3, 4-thiadiazol 2-yl] — 2, 2 Dimethylprop Namide ⁇ (0.0420 g, 86%).
- HPLC high-performance liquid chromatography
- Step 2 The optically active [3— (2,2 dimethylpropionyl) -5— (2,2 dimethylpropionylamino) 2 obtained from Step 1 above, 2,3 dihydro 1, 3, 4— Thiadiazole- 2-methylmethyl] rubamic acid tert butyl ester (5.91 g, 12.4 mmol) was dissolved in ethyl acetate (20 mL), and then 1 mol / L hydrogen chloride solution in ethyl acetate (40 mL) was added. Stir for 1 hour.
- the precipitated crystals are collected by filtration, and the obtained crystals are heated and dried under reduced pressure to give the compound j ⁇ N— [5 aminomethyl-4 (2,2 dimethylpropiol) 5 felt 4, 5 dihydro-1, , 3,4 Thiadiazole 2-yl] -2,2-dimethylpropanamide ⁇ hydrochloride (4.72 g, 92%).
- Step 1 In the same manner as in Reference Example 25, N— [4- (2,2 dimethylpropiol) 5 ethenesulfolaminomethyl-5-phenyl-4,5 dihydro 1,3 obtained according to the method described in WO2003Z051854 , 4 Thiadiazol-2-yl] —2, 2 From dimethylpropanamide (0.05 g, 0.11 mmol) and 2 mol / L dimethylamine-methanol solution (0.10 mL), N— [5— (2 Dimethylaminoethanesulfo -Luaminomethyl) 4— (2,2 Dimethylpropionyl) 1 5 Phenyl 4, 5 Dihydro 1, 3, 4 Thiadia Zole 2—yl] —2, 2-Dimethylpropanamide (0.02 g, 35 %).
- Step 2 N— [5— (2 dimethylaminoethanesulfolaminomethyl) -4- (2,2 dimethylpropiool) 5 obtained in Step 1 above, 4,5 dihydro 1 , 3, 4-thiadiazole-2-yl] -2,2 Dimethylpropanamide (50 mg)
- HPLC high performance liquid chromatography
- Step 1 Compound obtained in Reference Example 23 j ⁇ N— [5 aminomethyl-4- (2,2 dimethylpropyl diol) -5 fluor 4,5 dihydro 1,3,4 thiadiazole-2-yl] —2, 2 Dimethylpropanamide ⁇ hydrochloride (1.00 g, 2.42 mmol) was suspended in dichloromethane (25 mL) and ice-cooled with triethylamine (1.35 mL, 9.69 mmol) and salt. (0.442 mL, 3.63 mmol) was added and stirred at room temperature for 22 hours. Water and 1 mol / L hydrochloric acid were added to the mixture and extracted with black mouth form.
- Step 2 Optically active N— [5— (3-chloropropanesulfo-laminomethyl) obtained in Step 1 above 4 (2,2 dimethylpropiool) —5-Fueru 4,5 dihydro 1, 3, 4-thiadiazol 2-yl] -2, 2 dimethylpropanamide (1.50 g, 2.90 mmol), sodium iodide (8.69 g, 58.0 mmol) and sodium azide (1.89 g, 29.0 mmol) was suspended in DMF (20 mL) and stirred at 90 ° C. for 4 hours. Water was added to the mixture and extracted with ethyl acetate.
- the organic layer was extracted with an aqueous hydrochloric acid solution, and the aqueous layer was made basic by adding a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate.
- the obtained organic layer was concentrated under reduced pressure to give compound p ⁇ N— [5- (3-Aminopropanesulfonylamaminomethyl) 1-4- (2,2 dimethylpropiool) -1 5 4,5 dihydro-1,3,4 thiadiazol-2-yl] -2,2 dimethylpropanamide ⁇ (1.29 g, 89%).
- Step 1 In the same manner as described in WO2003 / 051854, in WO2003 / 051854 4 [3— (2, 2 Dimethylpropionol) 5— (2, 2—Dimethylpropionylamino) 2 Phenolic 2, 3 Dihydro-1, 3, 4-thiadiazo Yl] butanoic acid methyl ester (11.2 g, 25.9 mmol) and sodium borohydride (2.94 g, 77.6 mmol), 4- [5 amino-3- (2, 2 dimethylpropiol) -2 phenol 2,3 dihydro-1,3,4-thiadiazol-2-yl] butanoic acid methyl ester (1.54 g, 17%) was obtained.
- Step 2 In the same manner as in Step 1 of Reference Example 14, 4- [5 amino-3- (2, 2 dimethylpropiol) 2 phenol 2, 3 dihydro 1, 3, obtained in the above step 1 4-thiadiazol-2-yl] butanoic acid methyl ester (1.54 g, 4.24 mmol), (S)-(+) — 2-phenolpropionic acid (1.99 g, 13.2 mmol), thiol chloride (20 mL) A diastereomeric mixture was obtained from pyridine (1.80 mL, 22.0 mmol).
- Step 3 Sodium hydroxide (0.240 g, 6.01 mmol) was dissolved in water (4.0 mL). Next, dioxane (8.0 mL) was dissolved and stirred. N— [3— (2,2-dimethylpropiole) -2 phenol-5— (2 phenolpropioluamino) -2, 3 dihydro 1, 3 obtained in the above step 2 was added to the obtained solution. , 4-thiadiazol-2-yl] butanoic acid methyl ester, one diastereomer (0.992 g, 2.00 mmol) was added and stirred at room temperature for 5 hours.
- Step 4 4 [3— (2, 2 Dimethylpropiool) 2 Phenoluol 5 — (2 Phenylpropionolamino) — 2, 3 Dihydro 1, 3, 4 Thiadiazole 2— [Ill] butanoic acid (1.03 g, 2.14 mmol) was added with oxalyl chloride (0.223 mL, 2.57 mmol) and DMF (17 n 0.214 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure, dichloromethane (20 mL) was added to the residue, and the mixture was stirred at 0 ° C.
- Ethanolamine (1.2 mL, 21.4 mmol) was added, and the mixture was stirred at room temperature for 3 hr. To the mixture was added 1 mol / L hydrochloric acid (20 mL) and water (30 mL), and the mixture was extracted with black mouth form. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitated white solid was collected by filtration.
- Step 5 4— [3- (2,2 Dimethylpropiole) —2 Phenol —5— (2 Phenol Propiolumino) — 2, 3 Dihydro 1, 3, 4 obtained in Step 4 above Thiadiazol 2—yl] —N— (2 Hydroxyethyl) butanamide (1.21 g, 2.31 mmol) was added dichloromethane (20 mL) and stirred at 0 ° C, followed by pyridine (0.470 mL, 5.77 mmol). Then, tert-butyldimethylsilyl (869 mg, 5.77 mmol) was added and stirred at room temperature for 3 hours.
- Step 6 In the same manner as in Step 2 of Reference Example 14, N- [2- (tert-butyldimethylsiloxy) ethyl] -4 [3- (2,2 dimethylpropiool) obtained in Step 5 above was used. ) -2 Phenol-5- (2-Phenolpropio-Lumino) -2,3 Dihydro 1,3,4 Thiadiazol-2-yl] butanamide (0.376 g, 0.588 mmol) and sodium borohydride ( 0.
- Step 7 In the same manner as in Step 3 of Reference Example 14, the optically active 4- [5-amino-1- (2,2 dimethylpropiol) -1-2phenol-1 obtained in Step 6 above 2 , 3 Dihydro-1, 3, 4 —thiadiazole-2-yl] N— [2— (tert-butyldimethylsiloxy) ethyl] butanamide (0.0683 g, 0.135 mmol), pyridine (131 ⁇ L, 1.62 mmol) and From trimethylacetyl chloride (0.166 mL, 1.35 mmol), optically active N— [2— (tert-butyldimethyl) ethyl] -4 [3— (2, 2 dimethylpropiool) -5— (2 , 2 dimethylpropionylamino) -2 phenyl 2,3 dihydro 1,3,4 thiadiazole-2-yl] butanamide (68.0 mg, 83%).
- Step 8 Optically active N— [2- (tert-butinoresimetinoleoxy) ethyl] obtained in the above Step 7] -4- [3— (2,2 dimethylpropiool) -5— (2, 2 Dimethylpropio-Luamino) 2 Ferule 2, 3 Dihydro-1, 3, 4-thiadiazole-2-yl] butanamide (71.0 mg, 0.117 mmol) dissolved in THF (1 mL) A THF solution (0.16 mL) of mol / L tetraptylamine moum fluoride was added and stirred at room temperature for 50 minutes. Into the mixture Water (1 mL) was added and extracted with ethyl acetate.
- Step 1 Palladium acetate ( ⁇ ) (125 mg, 0.559 mmol) and triphenylphosphine (317 mg, 1.21 mmol) were dissolved in tetrahydrofuran (THF) (50 mL). To the resulting solution was added N-tert-butoxycarboru 13-alanine (2.07 g, 10.9 mmol), phenylboronic acid (1.61 g, 13.2 mmol), distilled water (0.477 mL, 26.5 mmol) and trimethylacetic acid. After anhydrous (3.23 mL, 15.9 mmol) was added, the mixture was stirred at 60 ° C for 24 hours.
- THF tetrahydrofuran
- Step 2 The (3 oxo-3-phenol) force rubamic acid tert butyl ester (513 mg, 2.06 mmol) obtained in Step 1 above was dissolved in methanol (40 mL). Thiosemicarbazide hydrochloride (562 mg, 4.40 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 8 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer is washed with saturated brine and anhydrous The extract was dried over sodium acid and concentrated under reduced pressure to give a pale yellow solid (513 mg). A part (198 mg) of the obtained solid was dissolved in dichloromethane (10 mL).
- Step 3 ⁇ 2— [3— (2, 2 Dimethylpropionol) -5— (2, 2-Dimethylpropionylamino) 2 Phenylol 2, 3 Dihydro 1, 3 obtained in Step 2 above , 4-thiadiazol-2-yl] ethyl ⁇ power rubamic acid tert butyl ester (274 mg, 0.557 mmo 1) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1.0 mL) was added to the resulting solution, and the mixture was stirred at room temperature for 3 hours, and then the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the residue and stirred for 3 hours.
- Step 4 N— [5- (2 aminoethinole) -4- (2,2 dimethylenoleporol) obtained in Step 3 above 5 Fueluo 4, 5 Dihydro 1, 3, 4 Thiadiazole-2— Il] —2, 2 Dissolve trifluoroacetate salt of dimethylpropanamide (0.25 g, 0.53 mmol) in methanol (5 mL) and fill with ion-exchange silica gel [SCX (Varian BONDESIL SCX 40 u M)] Supported on a column.
- SCX Variarian BONDESIL SCX 40 u M
- Step 5 N— [4 (2,2 dimethylpropiol) 5— (2-ethenesulfolaminoethyl) 5 obtained in Step 4 above 5 4,4 dihydro 1,3,4 Zol-2yl] 2, 2 Dimethylpropanamide (0.16 g, 0.33 mmol) was dissolved in acetonitrile (10 mL), 70% aqueous ethylamine (1.0 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 3 hours. did.
- Step 2 2- (tert-Butoxycarbo-amino) acetophenone (610 g) obtained above was dissolved in methanol (4.0 L) and cooled on ice. Thiosemcarbazide (425 g, 4.66 mol) was dissolved in dilute hydrochloric acid (concentrated hydrochloric acid (388 mL) and water (1612 mL)), and about half of the solution (1 L) was added dropwise over 10 minutes. Next, after seeding 2- (tert-butoxycarbonylamino) acetophenone thiosemicarbazone (400 mg) prepared in Reference Example 38, the remaining thiosemicarbazide solution was added dropwise over 30 minutes.
- Step 3 The 2- (tert-butoxycarbo-lumino) acetophenone thiosemicarbazone (690 g, 2.24 mol) obtained above was suspended in acetonitrile (6.9 L), pyridine (619 g) was added, and the mixture was ice-cooled. Salt and pivalol (809 g) were added dropwise to the mixture over 25 minutes. room temperature Then, 1 mol / L hydrochloric acid (1.2 L) was added and stirred for several minutes, and then the aqueous phase was removed. While stirring the organic layer, water (690 mL) was added dropwise over 40 minutes. A solid precipitated during the dropwise addition, and the resulting suspension was further stirred at 5 ° C for 1 hour.
- the precipitated solid was collected by filtration, and washed with cooled acetonitrile Z water (10: 1) (2.0 L) and then with cold water (1.4 L). The resulting solid was dried at 25 ° C under reduced pressure for 32 hours to give the compound 15 ⁇ [3— (2,2 dimethylpropionol) —5— (2,2 dimethylpropionylamino) — 2 phenyl 2,3 dihydro-1, 3, 4 thiadiazole-2-ylmethyl] power rubamic acid tert butyl ester ⁇ was obtained as a white solid (1031 g, yield 95.4%).
- T3 ⁇ 4 (louiui ⁇ 8 ⁇ 0 ⁇ ⁇ s m os) / —
- Step 1 Compound obtained in Reference Example 11 11 ⁇ N— [5 Aminomethyl— 4— (2, 2 dimethylpropionyl) 5 Phenol 4, 5 Dihydro-1, 3, 4-thiadiazol-2-yl] 2 , 2 Dimethylpropanamide ⁇ hydrochloride (4.00 g, 9.69 mmol) was dissolved in dichloromethane (100 mL). Under ice-cooling, triethylamine (4.05 mL, 29.1 mmol) and chloromethanesulfuryl chloride (1.12 mL, 12.6 mmol) were dissolved. ) was added and stirred at room temperature for 4 hours. Water and 1 mol / L hydrochloric acid were added to the mixture and extracted with black mouth form.
- Step 2 N— [5 Chloromethanesulfo-laminomethyl 4- (2, 2 dimethylpropiool) 5 phenol 4, 5 dihydro [1, 3, 4] thiadiazole obtained in Step 1 above —2—yl] —2, 2 Dimethylpropionamide (3.818 g, 7.807 mmol) was dissolved in DMF (70 mL) and tert-butyl-N— (2 mercaptoethyl) force rubamate (13.3 mL, 78.1 mmol) And a saturated aqueous sodium hydrogen carbonate solution (15 mL) were added, and the mixture was stirred at 70 ° C for 5.5 hours.
- Step 3 [2 — ( ⁇ [3-(2,2 dimethylpropionyl) -5- (2,2 dimethylpropio-lamino)] 2 phenol-2,3 dihydro obtained in step 2 above [0115] 1, 3, 4] thiadiazol-2-ylmethyl] sulfamoyl ⁇ methylsulfayl) ethyl] powered rubamic acid —tert-butyl ester (1.926 g, 3.058 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was added and stirred at room temperature for 1 hour.
- the mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 4 Treat the free base (51 5 mg, 0.972 mmol) of Compound 19 obtained in Step 3 above with Step 4 of Reference Example 35 with 4 mol / L ethyl chloride solution (0.5 mL) in hydrogen chloride.
- hydrochloride of Compound 19 (490 mg, 89%) was obtained.
- a therapeutic and Z or preventive agent for hematopoietic tumors containing a thiadiazoline derivative or a pharmacologically acceptable salt thereof as an active ingredient can be provided.
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JP2007509286A JPWO2006101103A1 (ja) | 2005-03-22 | 2006-03-22 | 造血器腫瘍治療剤 |
EP06729613A EP1870404A4 (en) | 2005-03-22 | 2006-03-22 | MEANS FOR THE TREATMENT OF A HEMATOPOIETIC TUMOR |
CA002602559A CA2602559A1 (en) | 2005-03-22 | 2006-03-22 | Agent for treatment of hematopoietic tumor |
US11/909,324 US20080262049A1 (en) | 2005-03-22 | 2006-03-22 | Therapeutic Agent for Hematopoietic Tumor |
AU2006225637A AU2006225637A1 (en) | 2005-03-22 | 2006-03-22 | Therapeutic agent for hematopoietic tumor |
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Cited By (6)
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EP1867640A4 (en) * | 2005-03-22 | 2010-07-14 | Kyowa Hakko Kirin Co Ltd | MEANS FOR TREATING SOLID TUMORS |
US7759371B2 (en) | 2001-12-11 | 2010-07-20 | Kyowa Hakko Kinn Co., Ltd. | Thiadiazoline derivative |
US7851635B2 (en) | 2003-04-18 | 2010-12-14 | Kyowa Hakko Kirin Co., Ltd. | Mitotic kinesin inhibitor |
JP4875205B2 (ja) * | 2007-07-12 | 2012-02-15 | イーライ リリー アンド カンパニー | チアジアゾール誘導体の安定な製剤 |
JP2014139249A (ja) * | 2004-10-19 | 2014-07-31 | Array Biopharma Inc | 有糸***キネシン阻害剤およびその使用方法 |
US8796460B2 (en) | 2007-10-19 | 2014-08-05 | Mercky Sharp & Dohme Corp. | Compounds for inhibiting KSP kinesin activity |
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EP1908755A4 (en) * | 2005-06-24 | 2009-06-24 | Kyowa Hakko Kirin Co Ltd | THERAPEUTIC AGENT AGAINST RESTENOSIS |
CN103601699A (zh) * | 2013-11-04 | 2014-02-26 | 南京大学 | 一类1,3,4-噻二唑-2-酰胺衍生物及其制备方法 |
Citations (6)
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WO2003051854A1 (en) * | 2001-12-11 | 2003-06-26 | Kyowa Hakko Kogyo Co., Ltd. | Thiadiazoline derivative |
WO2003079973A2 (en) * | 2002-03-08 | 2003-10-02 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
WO2004039774A2 (en) * | 2002-05-23 | 2004-05-13 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
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- 2006-03-22 KR KR1020077024037A patent/KR20070114822A/ko not_active Application Discontinuation
- 2006-03-22 CN CNA2006800167906A patent/CN101193877A/zh active Pending
- 2006-03-22 JP JP2007509286A patent/JPWO2006101103A1/ja not_active Abandoned
- 2006-03-22 AU AU2006225637A patent/AU2006225637A1/en not_active Abandoned
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US7759371B2 (en) | 2001-12-11 | 2010-07-20 | Kyowa Hakko Kinn Co., Ltd. | Thiadiazoline derivative |
US7902234B2 (en) | 2001-12-11 | 2011-03-08 | Kyowa Hakko Kirin Co., Ltd. | Thiadiazoline derivative |
US7851635B2 (en) | 2003-04-18 | 2010-12-14 | Kyowa Hakko Kirin Co., Ltd. | Mitotic kinesin inhibitor |
US8318782B2 (en) | 2003-04-18 | 2012-11-27 | Kyowa Hakko Kirin Co., Ltd. | Mitotic kinesin inhibitor |
JP2014139249A (ja) * | 2004-10-19 | 2014-07-31 | Array Biopharma Inc | 有糸***キネシン阻害剤およびその使用方法 |
US9499503B2 (en) | 2004-10-19 | 2016-11-22 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
US10017482B2 (en) | 2004-10-19 | 2018-07-10 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
EP1867640A4 (en) * | 2005-03-22 | 2010-07-14 | Kyowa Hakko Kirin Co Ltd | MEANS FOR TREATING SOLID TUMORS |
JP4875205B2 (ja) * | 2007-07-12 | 2012-02-15 | イーライ リリー アンド カンパニー | チアジアゾール誘導体の安定な製剤 |
US8796460B2 (en) | 2007-10-19 | 2014-08-05 | Mercky Sharp & Dohme Corp. | Compounds for inhibiting KSP kinesin activity |
Also Published As
Publication number | Publication date |
---|---|
AU2006225637A1 (en) | 2006-09-28 |
US20080262049A1 (en) | 2008-10-23 |
CA2602559A1 (en) | 2006-09-28 |
KR20070114822A (ko) | 2007-12-04 |
CN101193877A (zh) | 2008-06-04 |
EP1870404A1 (en) | 2007-12-26 |
JPWO2006101103A1 (ja) | 2008-09-04 |
TW200720265A (en) | 2007-06-01 |
EP1870404A4 (en) | 2010-07-14 |
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