WO2011159137A2 - 신규한 티오우레아 또는 우레아 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 aids 예방 또는 치료용 약학 조성물 - Google Patents
신규한 티오우레아 또는 우레아 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 aids 예방 또는 치료용 약학 조성물 Download PDFInfo
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- WO2011159137A2 WO2011159137A2 PCT/KR2011/004459 KR2011004459W WO2011159137A2 WO 2011159137 A2 WO2011159137 A2 WO 2011159137A2 KR 2011004459 W KR2011004459 W KR 2011004459W WO 2011159137 A2 WO2011159137 A2 WO 2011159137A2
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- thiourea
- benzoyl
- butyl
- tert
- methyl
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- 0 C*CC(C1)*1NC Chemical compound C*CC(C1)*1NC 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
- C07C275/58—Y being a hetero atom
- C07C275/62—Y being a nitrogen atom, e.g. biuret
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/21—Radicals derived from sulfur analogues of carbonic acid
Definitions
- the present invention relates to a novel thiourea or urea derivative, a preparation method thereof and a pharmaceutical composition for preventing or treating AIDS containing the same as an active ingredient.
- HIV Human Immunodeficiency Virus
- HIV belongs to the taxonomic retrovirus, among which it is subdivided into the lentivirus group. HIV particles are about 10 microns in diameter, the outer part is wrapped in phospholipids like normal cell membranes, and inside, two viral genomes of RNA are protected in a capsid (core protein).
- the HIV genome is made up of 10 genes, which contain many genes compared to the size of the genome.
- HIV infection is caused by conjugation of an envelope protein (gp120) on the surface of a virus to a receptor on the surface of a target cell.
- CD4 antigens cell surface protein molecules
- CD4 cells macrophage T cells
- macrophages which contain many of these CD4 antigens on the cell surface
- the virus's conjugation causes the virus's phospholipid shell to fuse to the cell surface, and the virus's genome and nuclear proteins enter the cell.
- the viral genome is changed from RNA to DNA by reverse transcriptase in the virus particles, then transported into the cell nucleus and inserted into the genome of the host cell. This process is one of the characteristics that only retroviruses have. HIV hides in this safest place in the host cell and receives all the mechanisms and resources needed to grow it. In addition, depending on the situation and conditions, while suppressing or promoting proliferation, and protects itself from the immune system and survives.
- HIV-1 The AIDS virus is largely divided into two types, HIV-1 and HIV-2. Since HIV-1 is found in patients in many countries, including Korea, it is synonymous with the AIDS virus. HIV-2 is mainly found in patients in West Africa, whose genome sequence is only 55% identical to HIV-1, and is more similar to Simian Immunodeficiency Virus (SIV), a monkey AIDS virus. The toxicity of HIV-2 is known to be generally weaker than HIV-1. HIV is very diverse, both genetically and biologically. The HIV sequences isolated from different AIDS patients are different, as well as from the same patient, depending on the disease progression. Even when a virus is separated from the same patient at a certain time, a virus having a different sequence is detected depending on the tissue region.
- SIV Simian Immunodeficiency Virus
- Viruses with different sequences have different infection preferences for specific cells, proliferation rate, virus production level, toxicity to cells, multinucleated giant cell formation rate, incubation and activation, and sensitivity to neutralizing antibodies.
- NBI multinuclear giant cells
- Syncytia-Inducing capacity increases and it becomes a virus that infects and prefers helper T cells instead of macrophages. This suggests that the biological characteristics of HIV and disease development are not related.
- viremia One week after infection with HIV, the virus proliferates so that the virus can be easily detected in the patient's blood. This stage is called viremia.
- the virus diminishes rapidly, making it difficult to isolate within a week or two.
- This incubation period is maintained for a considerable period of time, then progresses to AIDS, the virus proliferates again and becomes viremia.
- CD4 cells suddenly decrease in numbers during the initial viremia, then recover to a constant level as the virus proliferates (healthy people: 500-1000 CD4 cells / mm3).
- CD4 cells gradually decrease, dropping below 200 per kilogram of blood, leading to ARC (AIDS-related complex) or AIDS.
- ARC AIDS-related complex
- AIDS AIDS-related complex
- CD8 T cells are known to play a role in inhibiting cell growth or selecting and killing virus-infected cells.
- CD8 cells have been shown to exhibit significant immune effects against early infected viruses. Antibodies are produced after the virus has decreased in time.
- CD8 cells and antibodies continue to exist from the beginning of infection until the onset of AIDS, but have already lost or altered their function, and even promote viral infection. How the immune system, which had had a clear antiviral effect in the early stages of infection, loses its function is still a challenge. Because of the uniqueness of AIDS, which only affects humans, understanding the causes of HIV is a very rudimentary step. Although all researchers agree that the reduction of CD4 cells is a direct cause of immunodeficiency, there are many differences between how HIV reduces CD4 cells.
- AZT Zidovudine
- the inventors of the present invention while studying the AIDS therapeutic agent with less emergence of side effects and resistant virus, prepared a novel thiourea or urea derivative, and confirmed that the thiourea or urea derivative prepared above had excellent HIV inhibitory activity and the present invention. Completed.
- the present invention is to provide a novel thiourea or urea derivative, a preparation method thereof and a pharmaceutical composition for preventing or treating AIDS containing the same as an active ingredient.
- Thiourea or urea derivatives according to the present invention can be usefully used for preventing or treating AIDS due to excellent HIV inhibitory activity by inhibiting HIV virus expression.
- the present invention provides a thiourea or urea derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof.
- R 1 is H, a halogen atom, C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkyl substituted or unsubstituted, C 1 -C 4 straight or branched alkoxy, C 6- Aryloxy of C 20 , or Is,
- R2 and R3 are each independently the same or different and are H, C 1 -C 4 straight or branched alkyl, C 3 -C 8 cycloalkyl,-(C 2 -C 6 straight or branched alkyl) -N- ( C 1 -C 2 alkyl) 2 ,-(C 1 -C 4 straight or branched alkyl) -NH- (C 1 -C 4 straight or branched alkyl), , , 5,6,7,8-tetrahydronaphthalen-1-yl, (naphthylene-2-yl) -methyl, , (Pyridin-3-yl) -methyl, 2-chloro-pyridin-4-yl, pyrazin-2-yl, quinolin-5-yl, quinolin-8-yl, 4-hydroxy-biphenyl-3-yl Or R2 and R3 are linked to each other to form a ring or ego,
- n 0 or an integer of 1 to 4,
- n 1 or 2
- X is H, C 1 -C 4 straight or branched alkyl, C 6 -C 20 aryl, hydroxy or halogen atom,
- Y is H or hydroxy
- R2 is H
- R3 is -CH 2 -C (CH 3 ) 2 -CH 2 -N- ( Except for CH 3 ) 2 ,-(CH 2 ) 3 -N- (CH 3 ) 2 , phenyl, 4-methyl-benzyl, 4-chloro-benzyl, or (pyridin-2-yl) -ethyl
- R1 is tert-butyl , except when R2 is H and R3 is phenyl or (pyridin-2-yl) -methyl,
- R1 is methyl
- R2 is H and R3 is phenyl or pyridin-2-yl
- R1 is Cl , except when R2 is H and R3 is cyclohexyl and naphthalene,
- R 1 is H, Cl, methyl, tert-butyl, phenyl, (tert-butyl) -phenyl, isopropoxy, phenoxy, or Is,
- R2 and R3 are each independently the same or different, H, methyl, cyclohexyl, -CH 2 CH 2 -N- (CH 3 ) 2 , -CH 2 CH 2 CH 2 -N- (CH 3 ) 2 , -CH 2 -C (CH 3 ) 2 -CH 2 -N- (CH 3 ) 2 , -CH 2 CH 2 -N- (CH 2 CH 3 ) 2 , -CH (CH 3 ) CH 2 CH 2 -N -(CH 2 CH 3 ) 2 ,-(CH 2 ) 3 -NH- (CH 2 CH 2 CH 3 ), , Naphthalen-1-yl, 5-hydroxy-naphthalen-1-yl, 7-hydroxy-naphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, pyridin-2-yl , (Pyridin-2-yl) -methyl, (pyridin-2-yl) -ethyl
- n 0 or an integer of 1 to 4,
- X is H, methyl, tert-butyl, phenyl, hydroxy, F, Cl or Br.
- Compounds of formula (I) of the present invention include those selected from the group consisting of:
- Thiourea or urea derivatives of Formula 1 of the present invention may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
- Acid addition salts formed by free acid are useful.
- Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
- a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
- An equimolar amount of the compound and an acid or alcohol (eg, glycol monomethylether) in water can be heated and then the mixture is evaporated to dryness or the precipitated salts can be suction filtered.
- Organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc.
- Citric acid maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, Galacturonic acid, glutamic acid, glutaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like can be used.
- Bases may also be used to prepare pharmaceutically acceptable metal salts.
- An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
- the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
- Pharmaceutically acceptable salts of the thiourea or urea derivatives of the invention include salts of acidic or basic groups which may be present in the thiourea or urea derivative, unless otherwise specified.
- pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group
- other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.
- the present invention provides a method for preparing a thiourea or urea derivative of the formula (1), represented by Schemes 1-5.
- R1, R2 and R3 are as defined in Formula 1.
- the amine compound of formula (5) is stirred with sodium hydrogen carbonate in an organic solvent, and then reacted with thiophosphene and the amine compound of formula (6) to To prepare a compound, it is represented by the following scheme 2.
- the amine compound of formula (5) is stirred with sodium hydrogen carbonate in an organic solvent and then reacted with phosgene and an amine compound of formula (6) to give a compound of formula 1-3 It is characterized in that the preparation, and is represented by the following Scheme 3.
- R1, R2 and R3 are as defined in Formula 1.
- R1, R2 and R3 are as defined in Formula 1.
- the organic solvent used in Schemes 1 to 5 includes one or more selected from the group consisting of methylene chloride, acetonitrile, tetrahydrofuran and toluene, but is not limited thereto.
- the present invention provides a pharmaceutical composition for preventing or treating AIDS containing thiourea or urea derivative of Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a pharmaceutical composition for preventing or treating AIDS, which contains a compound selected from the group consisting of the following compounds as an active ingredient:
- Thiourea or urea derivatives according to the present invention have excellent HIV inhibitory activity by inhibiting HIV virus expression. Therefore, thiourea or urea derivatives according to the present invention can be usefully used for preventing or treating AIDS.
- composition of the present invention may contain one or more known active ingredients having HIV inhibitory activity together with thiourea or urea derivatives.
- composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration.
- Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as an antioxidant, buffer And other conventional additives such as bacteriostatic agents can be added.
- Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
- it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.
- composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
- the daily dosage of the thiourea or urea derivative is about 0.1 to 50 mg / kg, preferably about 2 to 10 mg / kg, and more preferably administered once to several times a day.
- composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the prevention and treatment of AIDS.
- Example 75 the compound of Examples 76 to 77 was prepared.
- Structural formulas, MS data and 1 H NMR data of the compounds of Examples 76 to 77 prepared above are shown in Table 2.
- Tetrahydrofuran (224.4 mL, 0.05 M) and 1,1'-carbonyldiimidazole (2 g, 12.34 mmol) were added to 4-tert-butyl-benzoic acid (2 g, 11.22 mmol) at room temperature, followed by stirring for 12 hours.
- 28% ammonia water (56.1 mL, 0.2 M) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours.
- the reaction mixture was separated from the water layer and the organic layer to obtain an organic layer.
- the organic layer was dried over magnesium sulfate and distilled under reduced pressure.
- the obtained product was purified by silica gel column chromatography to obtain the title compound.
- Acetonitrile (22.44 ml, 0.5 M) and toluene (22.44 ml, 0.5 M) were mixed and mixed with 4- (tert-butyl) -benzoyl chloride prepared in 1, and then 1M tin chloride (SnCl 4 ) (0.56 ml , 0.56 mmol) and sodium cyanate (NaOCN) (0.88 g, 13.46 mmol) were added and refluxed for 8 hours. After distilling the reaction mixture under reduced pressure, 2-aminopyridine (1.06 g, 11.22 mmol) was added thereto and stirred at room temperature for 2 hours. The reaction mixture was separated from the water layer and the organic layer to obtain an organic layer. The organic layer was dried over magnesium sulfate and distilled under reduced pressure. The obtained primary compound was purified by silica gel column chromatography to give 66 mg (yield: 3.92%) of the title compound.
- SnCl 4 1M tin chloride
- Example 78 the compounds of Examples 80 to 84 were prepared. Structural formulas, MS data and 1 H NMR data of the compounds of Examples 80 to 84 prepared above are shown in Table 3.
- Example 94 The compound of Example 94 was prepared by the same method as described in Example 78 (Scheme 4). Structural formula, MS data and 1 H NMR data of the compound of Example 100 prepared above are shown in Table 5.
- PNL4-3 vector expressing the HIV genome was transduced into 293FT cells.
- the HIV genome of pNL4-3 is not infected by the human body because the EGFP gene is substituted at the nef position.
- 293FT cells of about 3.0 ⁇ 10 5 in 6-well plates were inoculated in DMEM containing 10% FBS without antibiotics and incubated for 48 hours. 90 ⁇ 95% of confluency was shown during transduction.
- DNA (pNL4-3) was added to 250 ⁇ l of Opti-MEM I (GIBCO TM, USA) medium , a low serum medium, to a final concentration of 10 ng / ml, and 4 ⁇ l of 250 ⁇ l of Opti-MEM I (GIBCO TM ) medium.
- Lipofectamine 2000 lipofectamine TM 2000, Invitrogen, USA was added. After 5 minutes at room temperature, DNA (pNL4-3) and lipofectamine were mixed 1: 2 and reacted at room temperature for 20 minutes.
- the culture medium was removed from the cell culture solution prepared above, followed by incubation for 4 hours in a carbon dioxide cell incubator with the addition of the DNA-lipopeptamine complex, and the cell culture was exchanged with an antibiotic-free DMEM medium containing 10% FBS. Then, incubated again for 48 hours. After the culture containing HIV was recovered by centrifugation at 1,500 rpm for 5 minutes, the virus supernatant was obtained.
- MT-4 cells were inoculated at 1.0 ⁇ 10 6 cells / ml in RPMI cultures containing 10% FBS in 6-well plates, and virus supernatants obtained above were infected at a 1: 1 ratio after 4 hours of incubation. After 48 hours of incubation in a carbon dioxide cell incubator, the cells were replaced with fresh medium and incubated again for 72 hours. The amplified virus supernatant was then collected by centrifugation at 1500 rpm for 5 minutes and virus concentration was measured using the Virononstika HIV-1 Antigen Microelisa system kit (bioMerieux, Inc. Netherland).
- the thiourea or urea derivatives prepared in Examples 1 to 94 were dissolved in DMSO, prepared as 10 mM or 20 mM stock solutions, and stored at -20 ° C.
- the stock solution thus prepared was diluted with DMSO to make a starting concentration of 200 ⁇ M and used for the experiment.
- MT-4 cells were suspended in 200 ⁇ l of RPMI1640 (Gibco, 10% FBS) medium and infected with 200 ⁇ l of 200,000 pg / ml virus solution to a total volume of 400 ⁇ l. .
- 200 ⁇ M stock solution or stock solution was treated with 2 ⁇ l of thiourea or urea derivatives, each diluted 10-fold with DMSO, to a final concentration of 1 ⁇ M or lower.
- 10 ⁇ M AZT azidothymidine, sigma, USA
- DMSO as a negative control was used to a final concentration of 0.5%.
- the HIV inhibitory activity concentration ( ⁇ M) of the thiourea or urea derivative of the present invention is shown in Table 6.
- a tablet was prepared by a direct tableting method.
- the powder was prepared by mixing the above components, the powder was filled in a hard capsule according to the conventional method for preparing a capsule to prepare a capsule.
- the amount of the above-mentioned ingredient was prepared per ampoule (2 ml).
- Each component was added and dissolved in purified water according to the conventional method for preparing a liquid, and lemon flavor was added appropriately, followed by mixing the above components. Then, purified water was added thereto to adjust the total volume to 100 ml, and then filled in a brown bottle and sterilized to prepare a liquid.
- Thiourea or urea derivatives according to the present invention can be usefully used for preventing or treating AIDS.
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Abstract
Description
실시예 | HIV 저해 활성 농도(μM) |
1 | 0.03 |
16 | 0.5 |
37 | 0.5 |
38 | 0.3 |
50 | 1.0 |
양성대조군(AZT) | 0.005 |
Claims (10)
- 하기 화학식 1로 표시되는 티오우레아 또는 우레아 유도체, 또는 이의 약학적으로 허용가능한 염:<화학식 1>상기 화학식 1에서,A는 -CH2 또는 -C(=O)이며,B는 -C(=O) 또는 -C(=S)이고,R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시 또는 할로겐 원자이며,Y는 H 또는 히드록시이고,단, A가 -C(=O), B가 -C(=S), 및 R1이 H이면, R2가 H이고, R3가 -CH2-C(CH3)2-CH2-N-(CH3)2, -(CH2)3-N-(CH3)2, 페닐, 4-메틸-벤질, 4-클로로-벤질, 또는 (피리딘-2-일)-에틸인 경우를 제외하고, 또한 R2가 H가 아니고 R3와 서로 연결되어 고리가 형성된 인 경우를 제외하며,A가 -C(=O), B가 -C(=S), 및 R1이 t-부틸이면, R2가 H이고, R3가 페닐 또는 (피리딘-2-일)-메틸인 경우를 제외하며,A가 -C(=O), B가 -C(=S), 및 R1이 메틸이면, R2가 H이고, R3가 페닐 또는 피리딘-2-일인 경우를 제외하고,A가 -C(=O), B가 -C(=S), 및 R1이 Cl이면, R2가 H이고, R3가 시클로헥실 및 나프탈렌인 경우를 제외하며,A가 -C(=O), B가 -C(=O), 및 R1이 H이면, R2가 H이고, R3가 벤질인 경우를 제외한다.
- 제 1항에 있어서, 상기 화학식 1에서,R2 및 R3은 각각 독립적으로 같거나 다르며, H, 메틸, 시클로헥실, -CH2CH2-N-(CH3)2, -CH2CH2CH2-N-(CH3)2, -CH2-C(CH3)2-CH2-N-(CH3)2, -CH2CH2-N-(CH2CH3)2, -CH(CH3)CH2CH2CH2-N-(CH2CH3)2, -(CH2)3-NH-(CH2CH2CH3), , 나프탈렌-1-일, 5-히드록시-나프탈렌-1-일, 7-히드록시-나프탈렌-1-일, 5,6,7,8-테트라히드로나프탈렌-1-일, 피리딘-2-일, (피리딘-2-일)-메틸, (피리딘-2-일)-에틸, (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,X는 H, 메틸, tert-부틸, 페닐, 히드록시, F, Cl 또는 Br인, 티오우레아 또는 우레아 유도체, 또는 이의 약학적으로 허용가능한 염.
- 제 1항에 있어서, 상기 화학식 1의 화합물은 하기 화합물로 이루어진 군으로부터 선택된 것을 포함하는 티오우레아 또는 우레아 유도체, 또는 이의 약학적으로 허용가능한 염:1) 1-(4-tert-부틸-벤조일)-3-(5-히드록시-나프탈렌-1-일)-티오우레아,2) 1-(4-tert-부틸-벤조일)-3-(3-디메틸아미노-프로필)-티오우레아,3) 1-(4-tert-부틸-벤조일)-3-(3-디메틸아미노-2,2-디메틸-프로필)-티오우레아,4) 4-tert-부틸-N-(4-에틸-피페라진-1-카보티오일)-벤조아미드,5) 3-(4-tert-부틸-벤조일)-1-(2-디에틸아미노-에틸)-1-메틸-티오우레아,6) 3-(4-tert-부틸-벤조일)-1-(2-디메틸아미노-에틸)-1-메틸-티오우레아,7) 1-(4-tert-부틸-벤조일)-3-(4-디에틸아미노-1-메틸-부틸)-티오우레아,8) 1-(4-tert-부틸-벤조일)-3-(4-메틸-벤질)-티오우레아,9) 1-(4-tert-부틸-벤조일)-3-(2-메틸-벤질)-티오우레아,10) 1-(4-tert-부틸-벤조일)-3-(3-프로필아미노-프로필)-티오우레아,11) 1-(4-tert-부틸-벤조일)-3-펜에틸-티오우레아,12) 1-(4-tert-부틸-벤조일)-3-(4-클로로-벤질)-티오우레아,13) 1-(4-tert-부틸-벤조일)-3-(3-클로로-벤질)-티오우레아,14) 1-(4-tert-부틸-벤조일)-3-(나프탈렌-2-일메틸)-티오우레아,15) 4-tert-부틸-N-[4-(4-플루오로-페닐)-피페라진-1-카보티오일]-벤즈아미드,16) 1-(4-tert-부틸-벤조일)-3-시클로헥실-티오우레아,17) 1-(4-tert-부틸-벤조일)-3-(2-플루오로-벤질)-티오우레아,18) 1-벤조일-3-(나프탈렌-2-일메틸)-티오우레아,19) 1-벤조일-3-[2-(4-클로로-페닐)-에틸]-티오우레아,20) 1-벤조일-3-(4-디에틸아미노-1-메틸-부틸)-티오우레아,21) N-[4-(4-플루오로-페닐)-피페라진-1-카보타오일]-벤즈아미드,22) 3-벤조일-1-(2-디에틸아미노-에틸)-1-메틸-티오우레아,23) N-(4-에틸-피페라진-1-카보티오일)-4-메틸-벤즈아미드,24) 1-시클로헥실-3-(4-메틸-벤조일)-티오우레아,25) 1-(4-클로로-벤질)-3-(4-메틸-벤조일)-티오우레아,26) 1-(3-디메틸아미노-프로필)-3-(4-메틸-벤조일)-티오우레아,27) 1-(4-메틸-벤조일)-3-(3-메틸-벤질)-티오우레아,28) 1-(4-메틸-벤조일)-3-(4-페닐-부틸)-티오우레아,29) 1-(4-메틸-벤조일)-3-(3-페닐-프로필)-티오우레아,30) 1-(3-디메틸아미노-2,2-디메틸-프로필)-3-(4-메틸-벤조일)-티오우레아,31) 1-벤조일-3-[2-(4-플루오로-페닐)-에틸]-티오우레아,32) 1-(4-메틸-벤조일)-3-(피리딘-3-일메틸)-티오우레아,33) 1-(4-메틸-벤조일)-3-(피리딘-2-일메틸)-티오우레아,34) 1-[2-(3-브로모-페닐)-에틸]-3-(4-메틸-벤조일)-티오우레아,35) 1-(4-메틸-벤조일)-3-(2-피리딘-2-일-에틸)-티오우레아,36) 1-(4-tert-부틸-벤조일)-3-(나프탈렌-1-일)-티오우레아,37) 1-(4-tert-부틸-벤조일)-3-(피리딘-2-일)-티오우레아,38) 1-(4-tert-부틸-벤조일)-3-(3-클로로-페닐)-티오우레아,39) 1-(4-메틸-벤조일)-3-(나프탈렌-1-일)-티오우레아,40) 1-(4-클로로-벤조일)-3-(3-디메틸아미노-2,2-디메틸-프로필)-티오우레아,41) 1-(4-클로로-벤조일)-3-(나프탈렌-2-일메틸)-티오우레아,42) 1-(4-클로로-벤조일)-3-(5-히드록시-나프탈렌-1-일)-티오우레아,43) 1-(4-페녹시-벤조일)-3-(피리딘-2-일)-티오우레아,44) 1-(바이페닐-4-카보닐)-3-(3-디메틸아미노-2,2-디메틸-프로필)-티오우레아,45) 1-(4'-tert-부틸-바이페닐-4-카보닐)-3-(3-클로로-페닐)-티오우레아,46) 1-(3-디메틸아미노-2,2-디메틸-프로필)-3-(나프탈렌-2-카보닐)-티오우레아,47) 1-(바이페닐-4-카보닐)-3-(3-클로로-페닐)-티오우레아,48) 1-(4-tert-부틸-벤조일)-3-(나프탈렌-1-일)-티오우레아,49) 1-(4-tert-부틸-벤조일)-3-(5,6,7,8-테트라히드로-나프탈렌-1-일)-티오우레아,50) 1-(4-tert-부틸-벤조일)-3-(퀴놀린-5-일)-티오우레아,51) 1-(4-tert-부틸-벤조일)-3-(4-tert-부틸-페닐)-티오우레아,52) 1-(3-디메틸아미노-2,2-디메틸-프로필)-3-(4-이소프로폭시-벤조일)-티오우레아,53) 1-(4-이소프로폭시-벤조일)-3-(나프탈렌-1-일)-티오우레아,54) 1-(5-히드록시-나프탈렌-1-일)-3-(4-이소프로폭시-벤조일)-티오우레아,55) 1-(4-이소프로폭시-벤조일)-3-(피리딘-2-일)-티오우레아,56) 1-(4-이소프로폭시-벤조일)-3-(m-톨릴)-티오우레아,57) 1-(4-tert-부틸-벤조일)-3-(4-페닐-부틸)-티오우레아,58) 1-(4-tert-부틸-벤조일)-3-(4-페닐-프로필)-티오우레아,59) 1-(4-tert-부틸-벤조일)-3-[2-(2-클로로-페닐)-에틸)-티오우레아,60) 1-(4-tert-부틸-벤조일)-3-(3-메틸-벤질)-티오우레아,61) 1-(4-tert-부틸-벤조일)-3-(퀴놀린-8-일)-티오우레아,62) 1-(4-tert-부틸-벤조일)-3-(m-톨릴)-티오우레아,63) 1-(4-tert-부틸-벤조일)-3-(피라진-2-일)-티오우레아,64) 1-(4-tert-부틸-벤조일)-3-(3-히드록시-페닐)-티오우레아,65) 1-(4-tert-부틸-벤조일)-3-(7-히드록시-나프탈렌-1-일)-티오우레아,66) 1-(4-tert-부틸-벤조일)-3-(2-클로로-피리딘-4-일)-티오우레아,67) 1-(4-tert-부틸-벤조일)-3-(4-히드록시-바이페닐-3-일)-티오우레아,68) 1-바이페닐-3-일-3-(4-tert-부틸-벤조일)-티오우레아,69) 1-(4-tert-부틸-벤조일)-3-(2-플루오로-페닐)-티오유레아,70) N-(2-플루오로페닐카바모티오일)-4-이소프로폭시벤즈아미드,71) N-(4-tert-부틸페닐카바모티오일)-4-이소프로폭시벤즈아미드,72) N-(바이페닐-3-일카바모티오일)-4-이소프로폭시벤즈아미드,73) N-(7-히드록시나프탈렌-1-일카바모티오일)-4-이소프로폭시벤즈아미드,74) 1-(4-tert-부틸-벤질)-3-(5-히드록시-나프탈렌-1-일)-티오우레아,75) 1-(4-tert-부틸-벤질)-3-(5-히드록시-나프탈렌-1-일)-우레아,76) 1-(4-tert-부틸-벤질)-3-(3-클로로-페닐)-우레아,77) 1-(4-tert-부틸-벤질)-3-시클로헥실-우레아,78) 1-(4-tert-부틸-벤조일)-3-(5-히드록시-나프탈렌-1-일)-우레아,79) 1-(4-tert-부틸-벤조일)-3-(피리딘-2-일)-우레아,80) 1-(3-디메틸아미노-2,2-디메틸-프로필)-3-(4-메틸-벤조일)-우레아,81) 1-시클로헥실-3-(4-메틸-벤조일)-우레아,82) 1-(4-메틸-벤조일)-3-(나프탈렌-2-일메틸)-우레아,83) 1-벤조일-3-(3-디메틸아미노-2,2-디메틸-프로필)-우레아, 및84) 3-벤조일-1-(2-디메틸아미노-에틸)-1-메틸-우레아.
- 1) 화학식 2의 카복실산 화합물과 옥살릴 클로라이드를 유기용매 하에서 반응시켜 화학식 3의 화합물을 제조하는 단계,2) 상기 1)단계에서 제조된 화학식 3의 화합물을 유기용매 하에서 티오시안산칼륨(potassium thiocyanate, KSCN)과 반응시켜 화학식 4의 화합물을 제조하는 단계, 및3) 상기 2)단계에서 제조된 화학식 4의 화합물을 유기용매 하에서 화학식 5의 아민 화합물과 반응시켜 화학식 1-1의 화합물을 제조하는 단계를 포함하여 이루어지며, 하기 반응식 1로 표시되는 제 1항의 화합물의 제조방법:<반응식 1>상기 반응식 1에서, R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시, 할로겐 원자이며,Y는 H 또는 히드록시이고,단, R1이 H이면, R2가 H이고, R3가 -CH2-C(CH3)2-CH2-N-(CH3)2, -(CH2)3-N-(CH3)2, 페닐, 4-메틸-벤질, 4-클로로-벤질, 또는 (피리딘-2-일)-에틸인 경우를 제외하고, 또한 R2가 H가 아니고 R3와 서로 연결되어 고리가 형성된 인 경우를 제외하며,R1이 tert-부틸이면, R2가 H이고, R3가 페닐 또는 (피리딘-2-일)-메틸인 경우를 제외하며,R1이 메틸이면, R2가 H이고, R3가 페닐 또는 피리딘-2-일인 경우를 제외하고,R1이 Cl이면, R2가 H이고, R3가 시클로헥실 및 나프탈렌인 경우를 제외한다.
- 화학식 5의 아민 화합물을 유기용매 하에서 탄산수소나트륨과 교반시킨 후, 티오포스젠 및 화학식 6의 아민 화합물과 반응시켜 화학식 1-2의 화합물을 제조하는 것을 특징으로 하며, 하기 반응식 2로 표시되는 제 1항의 화합물의 제조방법:<반응식 2>상기 반응식 2에서, R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시, 할로겐 원자이며,Y는 H 또는 히드록시이다.
- 화학식 5의 아민 화합물을 유기용매 하에서 탄산수소나트륨과 교반시킨 후, 포스젠 및 화학식 6의 아민 화합물과 반응시켜 화학식 1-3의 화합물을 제조하는 것을 특징으로 하며, 하기 반응식 3으로 표시되는 제 1항의 화합물의 제조방법:<반응식 3>상기 반응식 3에서, R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시, 할로겐 원자이며,Y는 H 또는 히드록시이다.
- 1) 화학식 2의 카복실산 화합물과 1,1'-카보닐디이미다졸을 유기용매 하에서 반응시켜 화학식 7의 화합물을 제조하는 단계, 및2) 화학식 5의 아민 화합물을 유기용매 하에서 탄산수소나트륨과 교반시킨 후, 포스젠 및 상기 1)단계에서 제조한 화학식 7의 화합물과 반응시켜 화학식 1-4의 화합물을 제조하는 단계를 포함하여 이루어지며, 하기 반응식 4로 표시되는 제 1항의 화합물의 제조방법:<반응식 4>상기 반응식 4에서, R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시, 할로겐 원자이며,Y는 H 또는 히드록시이고,단, R1이 H이면, R2가 H이고, R3가 벤질인 경우를 제외한다.
- 1) 화학식 2의 카복실산 화합물과 옥살릴 클로라이드를 유기용매 하에서 반응시켜 화학식 3의 화합물을 제조하는 단계, 및2) 상기 1)단계에서 제조한 화학식 3의 화합물을 유기용매 하에서 틴클로라이드(SnCl4), 소듐시아네이트(NaOCN) 및 화학식 5의 아민 화합물과 반응시켜 화학식 1-4의 화합물을 제조하는 단계를 포함하여 이루어지며, 하기 반응식 5로 표시되는 제 1항의 화합물의 제조방법:<반응식 5>상기 반응식 5에서, R1은 H, 할로겐 원자, C1~C4의 직쇄 또는 측쇄 알킬, C1~C4의 직쇄 또는 측쇄 알킬이 치환 또는 비치환된 페닐, C1~C4의 직쇄 또는 측쇄 알콕시, C6~C20의 아릴옥시, 또는 이며,R2 및 R3은 각각 독립적으로 같거나 다르며, H, C1~C4의 직쇄 또는 측쇄 알킬, C3~C8의 시클로알킬, -(C2~C6의 직쇄 또는 측쇄 알킬)-N-(C1~C2의 알킬)2, -(C1~C4의 직쇄 또는 측쇄 알킬)-NH-(C1~C4의 직쇄 또는 측쇄 알킬), , , 5,6,7,8-테트라히드로나프탈렌-1-일, (나프텔렌-2-일)-메틸, , (피리딘-3-일)-메틸, 2-클로로-피리딘-4-일, 피라진-2-일, 퀴놀린-5-일, 퀴놀린-8-일, 4-히드록시-바이페닐-3-일, 또는 R2 및 R3가 서로 연결되어 고리가 형성된 또는 이고,n은 0, 또는 1 내지 4의 정수이며,m은 0, 1 또는 2의 정수이고,X는 H, C1~C4의 직쇄 또는 측쇄 알킬, C6~C20의 아릴, 히드록시, 할로겐 원자이며,Y는 H 또는 히드록시이고,단, R1이 H이면, R2가 H이고, R3가 벤질인 경우를 제외한다.
- 제 1항의 티오우레아 또는 우레아 유도체, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 AIDS 예방 또는 치료용 약학 조성물.
- 하기 화합물로 이루어진 군으로부터 선택된 화합물을 유효성분으로 함유하는 AIDS 예방 또는 치료용 약학 조성물:85) 4-tert-부틸-N-(4-메틸-피페라진-1-카보티오일)-벤즈아미드,86) 1-벤조일-3-(3-디메틸아미노-2,2-디메틸-프로필)-티오우레아,87) 1-벤조일-3-(4-메틸-벤질)-티오우레아,88) 1-벤조일-3-(3-디메틸아미노-프로필)-티오우레아,89) N-(4-에틸-피페라진-1-카보티오일)-벤즈아미드,90) 1-벤조일-3-(4-클로로-벤질)-티오우레아,91) 1-벤조일-3-페닐-티오우레아,92) 1-벤조일-3-(2-피리딘-2-일-에틸)-티오우레아,93) 1-(4-tert-부틸-벤조일)-3-페닐-티오우레아,94) 1-(4-tert-부틸-벤조일)-3-(피리딘-2-일메틸)-티오우레아,95) 1-(4-tert-부틸-벤조일)-3-(피리딘-4-일메틸)-티오우레아,96) 1-(4-메틸-벤조일)-3-(피리딘-2-일)-티오우레아,97) 1-(4-메틸-벤조일)-3-페닐-티오우레아,98) 1-(4-클로로-벤조일)-3-티오헥실-티오우레아,99) 1-(4-클로로-벤조일)-3-(나프탈렌-2-일메틸)-티오우레아, 및100) 1-벤조일-3-벤질-우레아.
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DE3615763A1 (de) * | 1986-05-10 | 1987-11-12 | Celamerck Gmbh & Co Kg | Verwendung von bezoylharnstoffen zur bekaempfung von pilzen, protozoen und nematoden |
FR2612187B1 (fr) * | 1987-03-12 | 1989-07-21 | Sanofi Sa | Derives du thiazole actifs sur le systeme cholinergique, leur procede de preparation et compositions pharmaceutiques en contenant |
US5593993A (en) * | 1991-08-02 | 1997-01-14 | Medivir Ab | Method for inhibition of HIV related viruses |
JPH07206822A (ja) * | 1994-01-25 | 1995-08-08 | Nippon Paper Ind Co Ltd | 新規な非対称チオ尿素化合物及びそれを有効成分とする抗ヒト免疫不全症ウイルス剤 |
GB9719530D0 (en) * | 1997-09-12 | 1997-11-19 | Smithkline Beecham Plc | Novel compounds |
US6545152B1 (en) * | 2000-07-18 | 2003-04-08 | Parker Hughes Institute | R-isomers of nonnucleoside inhibitors |
MXPA03001535A (es) * | 2000-08-21 | 2004-12-13 | Pacific Corp | Derivados de tiourea novedosos y las composiciones farmaceuticas que contienen los mismos. |
EP1945208A4 (en) * | 2005-10-06 | 2011-08-03 | Univ Massachusetts | COMPOSITION AND SYNTHESIS OF NEW REAGENTS TO INHIBIT HIV REPLICATION |
KR101535678B1 (ko) * | 2006-01-23 | 2015-07-09 | 조셉 피. 에리코 | 표적 약물 개발의 방법 및 조성물 |
US8183236B2 (en) * | 2007-04-12 | 2012-05-22 | University Of Southern California | Compounds with HIV-1 integrase inhibitory activity and use thereof as anti-HIV/AIDS therapeutics |
WO2009009041A2 (en) * | 2007-07-06 | 2009-01-15 | Kinex Pharmaceuticals, Llc | Compositions and methods for modulating a kinase cascade |
WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
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2011
- 2011-06-17 CN CN2011800301874A patent/CN103003236A/zh active Pending
- 2011-06-17 US US13/805,334 patent/US20130096138A1/en not_active Abandoned
- 2011-06-17 JP JP2013515272A patent/JP2013530182A/ja active Pending
- 2011-06-17 EP EP11796003.9A patent/EP2583962A4/en not_active Withdrawn
- 2011-06-17 WO PCT/KR2011/004459 patent/WO2011159137A2/ko active Application Filing
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2013111798A1 (ja) * | 2012-01-27 | 2015-05-11 | 国立大学法人富山大学 | セリンラセマーゼ阻害剤 |
CN104395421A (zh) * | 2012-06-27 | 2015-03-04 | 汉高美国知识产权有限责任公司 | 用于两步法粘合剂体系的促进剂 |
US9365750B2 (en) | 2012-06-27 | 2016-06-14 | Henkel IP & Holding GmbH | Accelerators for curable compositions |
US9371473B2 (en) | 2012-06-27 | 2016-06-21 | Henkel IP & Holding GmbH | Accelerators for two step adhesive systems |
Also Published As
Publication number | Publication date |
---|---|
EP2583962A4 (en) | 2013-11-13 |
US20130096138A1 (en) | 2013-04-18 |
EP2583962A2 (en) | 2013-04-24 |
WO2011159137A3 (ko) | 2012-05-03 |
KR20110137941A (ko) | 2011-12-26 |
CN103003236A (zh) | 2013-03-27 |
JP2013530182A (ja) | 2013-07-25 |
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