JP2010059099A - Proliferation inhibitor of human immunodeficiency virus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new proliferation inhibitor of human immunodeficiency virus. <P>SOLUTION: The proliferation inhibitor of human immunodeficiency virus (HIV) comprises 2-[2-(phenylmethylsulfonyl)ethylsulfanyl]-5,6,7,8-tetrahydroquinoline-3-carbonitrile or a salt thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a human immunodeficiency virus (HIV) growth inhibitor or a pharmaceutical composition for treating human immunodeficiency virus infection.

  Acquired immunodeficiency syndrome (AIDS) is a disease caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Early in HIV infection is usually asymptomatic, but after infection, the body's immune function gradually declines, causing opportunistic infections, cancer, generalized weakness, and progressive disease with central nervous degeneration. The period from HIV infection to the onset of AIDS is generally several years to several tens of years, but once AIDS develops, the fatality rate is very high. Therefore, in order to prevent the onset of AIDS, a search for a compound that inhibits the growth of HIV has been conducted.

  There are two types of HIV: HIV-1 and HIV-2. These HIVs have the following life cycle. First, when HIV infects cells, HIV gene RNA is reverse transcribed into DNA by reverse transcriptase contained in the virus particle and incorporated into DNA of infected cells by HIV integrase. Next, HIV RNA is transcribed from the promoter in the LTR at the 5 ′ end of the incorporated HIV gene to become gene RNA, and at the same time, a viral protein is synthesized using the RNA as a template. Some of the synthesized viral proteins are cleaved by HIV protease to become mature proteins and form next generation viral particles.

  Considering the above life cycle of HIV, HIV growth is inhibited by inhibiting reverse transcriptase, inhibiting HIV integrase, inhibiting RNA transcription from LTR, or inhibiting HIV protease. It is thought that it can be inhibited.

  Hitherto, HIV growth inhibitors that inhibit reverse transcriptase or protease are known (see, for example, Patent Documents 1 and 2).

Japanese Patent No. 3806990 Special table 2001-516350 gazette

  However, human immunodeficiency virus (HIV) can easily acquire resistance to these conventional HIV growth inhibitors. Accordingly, there is a need for new HIV growth inhibitors that can be used after HIV has acquired resistance to conventional inhibitors, or that can extend the period of time before HIV acquires resistance to conventional inhibitors.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a given compound has an HIV growth inhibitory activity and completed the present invention.
That is, the present invention is as follows.

(1) 2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7,8-tetrahydroquinoline-3-carbonitrile,
5,7-dimethyl-2- [2- (3-methylpiperidin-1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile,
N-cyclohexyl-2- (3-methylquinolin-2-yl) sulfanylacetamide,
N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide,
N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanylacetamide,
1-piperidin-1-yl-2- (3,5,7-trimethylquinolin-2-yl) sulfanylethanone,
2- (4-methylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide,
2- (2-oxo-2-piperidin-1-ylethyl) sulfanyl-6,7-dihydro-5H-cyclopentapyridine-3-carbonitrile,
4,6-dimethyl-2- (2-oxo-2-piperidin-1-ylethyl) sulfanylpyridine-3-carbonitrile,
2- (3-cyano-8-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide,
2- (3-cyano-7-methylquinolin-2-yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide,
2- (3-cyano-6-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide,
N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide,
2- (4-methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone,
2- [2- (azepan-1-yl) -2-oxoethyl] sulfanyl-5,7-dimethylquinoline-3-carbonitrile, and
At least one compound selected from the group consisting of 2-[(3-cyano-4-pyridin-4-yl-5,6,7,8-tetrahydro-quinolin-2-yl) sulfanyl] acetamide or a salt thereof, A human immunodeficiency virus (HIV) growth inhibitor comprising.
(2) A pharmaceutical composition for treating human immunodeficiency virus (HIV) infection, comprising the compound according to (1) above or a pharmaceutically acceptable salt thereof.
(3) Use of the compound of the above (1) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treating human immunodeficiency virus (HIV) infection.

  According to the present invention, a novel HIV growth inhibitor is provided. The inhibitor according to a preferred embodiment of the present invention can effectively inhibit the growth of HIV that has acquired resistance to conventional inhibitors. The inhibitor according to another preferred embodiment of the present invention can prolong the period until HIV acquires resistance to a conventional inhibitor.

Hereinafter, the present invention will be described in detail.
It should be noted that all publications cited in the present specification, for example, prior art documents, publications, patent publications and other patent documents are incorporated herein by reference.

1. Compound The present invention provides the following compound or salt thereof having HIV growth inhibitory activity.
(1) 2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7,8-tetrahydroquinoline-3-carbonitrile <2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7, 8-tetrahydroquinoline-3-carbonitrile>: GFI99-043

(2) 5,7-dimethyl-2- [2- (3-methylpiperidin-1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile <5,7-dimethyl-2- [2- (3 -methylpiperidin-1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile>: GMI08-003

(3) N-cyclohexyl-2- (3-methylquinolin-2-yl) sulfanylacetamide <N-cyclohexyl-2- (3-methylquinolin-2-yl) sulfanylacetamide>: GMI08-024

(4) N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide <N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide>: GMI08-052

(5) N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanylacetamide <N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanylacetamide>: GMI08-073

(6) 1-piperidin-1-yl-2- (3,5,7-trimethylquinolin-2-yl) sulfanylethanone <1-piperidin-1-yl-2- (3,5,7-trimethylquinolin- 2-yl) sulfanylethanone>: GMI08-087

(7) 2- (4-Methylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide <2- (4-metylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide>: GMI08-096

(8) 2- (2-oxo-2-piperidin-1-ylethyl) sulfanyl-6,7-dihydro-5H-cyclopentapyridine-3-carbonitrile <2- (2-oxo-2-piperidin-1- ylethyl) sulfanyl-6,7-dihydro-5H-cyclopenta [b] pyridine-3-carbonitrile>: GMI08-003-002

(9) 4,6-Dimethyl-2- (2-oxo-2-piperidin-1-ylethyl) sulfanylpyridine-3-carbonitrile <4,6-dimethyl-2- (2-oxo-2-piperidine-1 -ylethyl) sulfanylpyridine-3-carbonitrile>: GMI08-003-042

(10) 2- (3-Cyano-8-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide <2- (3-cyano-8-methylquinolin- 2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide>: GMI08-003-066

(11) 2- (3-Cyano-7-methylquinolin-2-yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide <2- (3-cyano-7-methylquinolin-2 -yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide>: GMI08-003-123

(12) 2- (3-Cyano-6-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide <2- (3-cyano-6-methylquinolin- 2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide>: GMI08-003-170

(13) N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide <N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide>: GMI08-003-180

(14) 2- (4-Methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone <2- (4-methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone>: GMI08-003 -239

(15) 2- [2- (azepan-1-yl) -2-oxoethyl] sulfanyl-5,7-dimethylquinoline-3-carbonitrile <2- [2- (azepan-1-yl) -2-oxoethyl ] sulfanyl-5,7-dimethylquinoline-3-carbonitrile>: GMI08-102

(16) 2-[(3-Cyano-4-pyridin-4-yl-5,6,7,8-tetrahydro-quinolin-2-yl) sulfanyl] acetamide <2-[(3-cyano-4-pyridin -4-yl-5,6,7,8-tetrahydroquinolin-2-yl) sulfanyl] acetamide> ： GFI99-043-075

  Salts of the above compounds include inorganic acid addition salts such as hydrochloride, sulfate, or phosphate, organic acid salts such as acetate, propionate, citrate, tartrate, malate, or oxalate Or a salt such as a sodium salt, a potassium salt, or a calcium salt.

  The method for synthesizing the compound or a salt thereof is not particularly limited, and can be synthesized using a known method. Of the above compounds or salts thereof, for example, GFI99-043-075 can be synthesized as follows. N- (1-cyclohexenyl) -morpholine and 4-pyridinyl-methylenecyanothio (seleno) acetamide are stirred in absolute ethanol at 20 ° C. for 4 hours. Then, 10% aqueous potassium hydroxide solution is added to the reaction solution, and after 5 minutes, 2-Chloro-acetamide is added and stirred for 5 hours. Thereafter, the reaction solution is filtered, washed with water, ethanol, and hexane and then appropriately purified, whereby the target substance GFI99-043-075 can be obtained in a yield of 75%, for example. (Dyachenko, VD; Litvinov, VPTG Shevchenko, Single stage synthesis of 2-alkylthio (seleno) -4-heteroaryl-3-cyano-5,6,7,8-tetrahydroquinolines., Chemistry of Heterocyclic Compounds (New York) (Translation of Khimiya Geterotsiklicheskikh Soedinenii), 33 (10), 1203-1208; 1998).

Moreover, the said compound or its salt may acquire a commercially available thing.
For example, GFI99-043 is commercially available from ASINEX under the trade name BAS03395143.
GMI08-003 is commercially available from ASINEX under the trade name ASN05588029.
GMI08-024 is commercially available from ASINEX under the trade name ASN03799878.
GMI08-052 is commercially available from ASINEX under the trade name ASN05546408.
GMI08-073 is commercially available from ASINEX under the trade name ASN03799909.
GMI08-087 is commercially available from ASINEX under the trade name ASN03221372.
GMI08-096 is commercially available from ASINEX under the trade name BAS03434505.
GMI08-003-002 is commercially available from ASINEX under the trade name BAS01862082.
GMI08-003-042 is commercially available from ASINEX under the trade name BAS01862079.
GMI08-003-066 is commercially available from ASINEX under the trade name ASN05546041.
GMI08-003-123 is commercially available from ASINEX under the trade name ASN05545884.
GMI08-003-170 is commercially available from ASINEX under the trade name ASN05545551.
GMI08-003-180 is commercially available from ASINEX under the trade name BAS03434499.
GMI08-003-239 is commercially available from ASINEX under the trade name BAS02617839.
GMI08-102 is commercially available from ASINEX under the trade name ASN05588113.
GFI99-043-075 is commercially available from ASINEX under the trade name BAS02589988.

2. Growth inhibitor of human immunodeficiency virus (HIV) The present invention relates to growth of human immunodeficiency virus (HIV) comprising the above compound or a salt thereof (sometimes referred to herein as the compound of the present invention). Inhibitors (sometimes referred to herein as inhibitors of the invention) are provided. That is, the compound contained in the inhibitor of the present invention or a salt thereof is GFI99-043, GMI08-003, GMI08-024, GMI08-052, GMI08-073, GMI08-087, GMI08-096, GMI08-003-002, From the group consisting of GMI08-003-042, GMI08-003-066, GMI08-003-123, GMI08-003-170, GMI08-003-180, GMI08-003-239, GMI08-102, and GFI99-043-075 At least one selected compound or a salt thereof. The compound or salt thereof included in the inhibitor of one embodiment of the present invention is GFI99-043, GMI08-003, GMI08-024, GMI08-052, GMI08-073, GMI08-087, GMI08-096, GMI08-003- 002, GMI08-003-042, GMI08-003-066, GMI08-003-123, GMI08-003-170, GMI08-003-180, GMI08-003-239, GMI08-102, or GFI99-043-075, or Its salt. In an inhibitor of one aspect of the invention, the salt in the compound of the invention is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, sulfate, or phosphate, acetate, propionate, citrate, tartrate, malate, or oxalate An organic acid salt or a salt such as a sodium salt, a potassium salt, or a calcium salt can be mentioned. The inhibitors of the present invention can inhibit the growth of HIV-1, preferably both HIV-1 and HIV-2.

  In one embodiment of the present invention, the inhibitor of the present invention is used for screening a compound that can be used in combination with the inhibitor of the present invention to enhance the HIV growth inhibitory effect of the inhibitor of the present invention. Specifically, the inhibitor of the present invention is contacted with an HIV-infected cell in the presence or absence of a candidate compound, and the cell viability is measured. “Contact” means that HIV-infected cells and the inhibitor of the present invention are present in the same reaction system or culture system. For example, HIV-infected cells are cultured in the presence of the inhibitor of the present invention. Etc. are included. At this time, the cell viability is preferably measured in the presence of various concentrations of candidate compounds. When the cell viability in the presence of the candidate compound is higher than the cell viability in the absence (for example, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more , 70% or more, 80% or more, 90% or more, 100% or more, 150% or more, or 200% or more)) when the candidate compound is used in combination with the inhibitor of the present invention. It selects as a compound which can heighten a growth inhibitory effect. The cell viability can be measured using a known method such as an MTT assay.

  In another embodiment of the present invention, the inhibitor of the present invention is applied to a mammal orally or parenterally to treat an HIV infection in a mammal (eg, human, monkey, etc.). In some embodiments of the invention, the mammal is a mammal other than a human.

  Moreover, the inhibitor of this invention may contain a support | carrier and an additive in addition to the compound of this invention according to the intended purpose. Such carriers and additives include water, acetic acid, organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin , Methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, surfactant, etc. Can be mentioned.

  The amount of the compound of the present invention used in the inhibitor of the present invention varies depending on the purpose of use. A person skilled in the art can appropriately select the amount of the compound of the present invention to be used according to the purpose of use.

  For example, when the inhibitor of the present invention is used to screen for a compound that can enhance the HIV growth inhibitory effect of the inhibitor of the present invention in combination with the inhibitor of the present invention, use of the compound of the present invention It is preferred to measure cell viability by varying the amount. In this case, the amount of the compound of the present invention to be used is, for example, 2 μg / mL to 200 μg / mL, preferably 10 μg / mL to 100 μg / mL.

  When the inhibitor of the present invention is used to treat mammalian HIV infection, the amount of the compound of the present invention used is, for example, 1 mg to 600 mg per day for a 20 kg animal, preferably 20 mg to 300 mg.

  The present invention also provides the aforementioned compound or a salt thereof (the compound of the present invention) for inhibiting HIV growth. The usage and dosage of the compounds of the present invention are the same as described for the inhibitors.

  The present invention also provides a method for inhibiting HIV growth using the compound or a salt thereof (the compound of the present invention). Here, “using the compound of the present invention” includes, for example, the compound of the present invention in order to screen for a compound that can enhance the HIV growth inhibitory effect of the compound of the present invention in combination with the compound of the present invention. And the use of the compounds of the invention to orally or parenterally apply the compounds of the invention to animals to treat HIV infection in mammals, etc. It is not limited to. The usage and dose of the compound of the present invention in the method for inhibiting HIV growth of the present invention are the same as those described for the inhibitor.

  Furthermore, the present invention provides the use of the above compound or a salt thereof (the compound of the present invention) for producing an HIV growth inhibitor. The usage and dosage of the compounds of the present invention in the use of the present invention are the same as described for the HIV growth inhibitor.

3. Pharmaceutical composition This invention provides the pharmaceutical composition containing the said compound or its salt (compound of this invention). The compounds or salts thereof included in the pharmaceutical composition of the present invention are GFI99-043, GMI08-003, GMI08-024, GMI08-052, GMI08-073, GMI08-087, GMI08-096, GMI08-003-002, GMI08 -003-042, GMI08-003-066, GMI08-003-123, GMI08-003-170, GMI08-003-180, GMI08-003-239, GMI08-102, and GFI99-043-075 At least one compound or a salt thereof. The compound or salt thereof contained in the pharmaceutical composition of one embodiment of the present invention is GFI99-043, GMI08-003, GMI08-024, GMI08-052, GMI08-073, GMI08-087, GMI08-096, GMI08-003. -002, GMI08-003-042, GMI08-003-066, GMI08-003-123, GMI08-003-170, GMI08-003-180, GMI08-003-239, GMI08-102, or GFI99-043-075 or Its salt. The salt in the compound of the present invention is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, sulfate, or phosphate, acetate, propionate, citrate, tartrate, malate, or oxalate An organic acid salt or a salt such as a sodium salt, a potassium salt, or a calcium salt can be mentioned. Since the compound of the present invention contained in the pharmaceutical composition of the present invention has an HIV growth inhibitory action, HIV infection can be treated by administering the pharmaceutical composition of the present invention.

  An HIV infection is a disease caused by HIV infection, and includes, for example, a disease caused by a decrease in the body's immune function. Diseases caused by reduced body immune function include opportunistic infections (such as tuberculosis, candidiasis, or pneumocystis pneumonia), cancer (Kaposi's sarcoma, non-Hodgkin lymphoma or primary brain lymphoma), generalized weakness, and central Examples include progressive diseases associated with neurodegeneration (such as dementia or subacute encephalitis). Treating HIV infection includes delaying the onset of these diseases.

  In addition, the pharmaceutical composition of the present invention may be used in combination with other pharmaceutical compositions for treating HIV infection to enhance the therapeutic effect or delay the emergence of resistant virus. Examples of other pharmaceutical compositions for treating HIV infection include known pharmaceutical compositions, such as zidovudine (trade names: Retrovir, Glaxo SmithKline), nevirapine (trade names: Viramune, Boehringer), and zalcitabine (trade names: Hivid , Chugai), Lamivudine (trade name Epivir, Glaxo SmithKline), Ritonavir (trade name Norvir, Abbott), Indinavir (trade name Crixivan, Universal), or Sanilvudine (trade name Zerit, Bristol) One pharmaceutical composition may be mentioned. Preferred is zidovudine (trade name Retrovir, Glaxo SmithKline), lamivudine (trade name Epivir, Glaxo SmithKline), or indinavir (trade name Crixivan, universal).

  The pharmaceutical composition of the present invention can employ both oral and parenteral dosage forms.

  The dosage form can be formulated according to a conventional method, and may contain a pharmaceutically acceptable carrier or additive in addition to the compound of the present invention. Such carriers and additives include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, carboxymethyl. Sodium starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, pharmaceutical Examples of acceptable surfactants include additives.

  The additive is selected from the above alone or in appropriate combination depending on the dosage form of the pharmaceutical composition of the present invention. As for the dosage form, in the case of oral administration, it can be administered as a tablet, capsule, fine granule, powder, granule, solution, syrup or the like, or in an appropriate dosage form. In the case of parenteral administration, injections and the like can be mentioned. In the case of an injection form, it can be administered systemically or locally by intravenous injection such as infusion.

  For example, when used as an injectable preparation, the pharmaceutical composition of the present invention is dissolved in a solvent (for example, physiological saline, buffer solution, glucose solution, etc.), and an appropriate additive (human serum albumin, etc.) is added thereto. Things can be used. Alternatively, it may be freeze-dried to obtain a dosage form that dissolves before use. As the freeze-drying excipient, for example, sugar alcohols and saccharides such as mannitol and glucose can be used.

The dosage of the pharmaceutical composition of the present invention or the compound of the present invention varies depending on age, sex, symptom, route of administration, frequency of administration and dosage form. The administration method is appropriately selected depending on the age and symptoms of the patient. For example, in the case of an adult (60 kg), the dose is 50 to 2500 mg, preferably 300 to 1800 mg, more preferably 600 to 1200 mg per day. The administration method is appropriately selected depending on the age and symptoms of the patient. Administration may be divided, for example, once or 2-4 times per day.
In addition, when the pharmaceutical composition of the present invention or the compound of the present invention is used in combination with another pharmaceutical composition for treating HIV infection, the amount of the compound of the present invention is not particularly limited, and other drugs for treating HIV infection. For example, it is about 0.1 to 100 times (weight ratio) of other pharmaceutical compositions for treating HIV infection, depending on the individual combination with the composition. More preferably, it is about 1 to 10 times (weight ratio).

  The present invention also provides a method for treating HIV infection, comprising administering the compound or a salt thereof (the compound of the present invention) to a patient. Furthermore, the present invention provides use of the compound or a salt thereof (the compound of the present invention) for producing the pharmaceutical composition for treating HIV infection of the present invention. The method for administering the compound of the present invention in the method for treating HIV infection is the same as that described in the above pharmaceutical composition. In addition, the method for producing a pharmaceutical composition in the use of the compound of the present invention is the same as that described in the above pharmaceutical composition.

Hereinafter, the present invention will be specifically described by way of examples.
[Summary]
Cell line MT-4 derived from human T cells undergoes cell degeneration and is killed when infected with HIV. On the other hand, in the presence of a test compound having HIV growth inhibitory activity, HIV-infected MT-4 cells can survive without being killed. Therefore, if the survival rate of HIV-infected MT-4 cells in the presence of the test compound is high, it can be determined that the test compound has HIV growth inhibitory activity.
In the following, specifically, HIV-infected MT-4 cells and non-infected MT-4 cells were respectively added to the test compounds serially diluted in a 96-well microplate, and cultured for 5 days. The survival rate of non-test compound-added HIV-uninfected MT-4 cells was defined as 100% (control), and the cell viability at each concentration of the test compound was calculated by the MTT method (Nakashima et al. Antiviral Chemist Chemother 6; 271 -280,1995). The test compounds were evaluated for HIV growth inhibitory activity (or HIV infection inhibitory activity) and cytotoxic activity.

[Example 1]
2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7,8-tetrahydroquinoline-3-carbonitrile <2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7,8-tetrahydroquinoline -3-carbonitrile>: GFI99-043

  According to Nakashima et al. Antiviral Chmeist Chemother 6; 271-280,1995, the HIV growth inhibitory activity and cytotoxic activity of GFI99-043 (ASINEX) were evaluated.

The cell line MT-4 derived from human T cells was used. The virus used was HIV-1 IIIB strain. As the medium, RPMI1640 medium (Invitrogen) containing 10% FCS was used. Test compounds were serially diluted in 2-fold series using 2 to 11 rows of 96-well microplates (Falcon) (100 μL / well, final concentrations 500 μM, 250 μM, 125 μM, 62.5 μM, 31.25 μM, 15.625 μM, 7.8125μM, 3.90625μM, 1.953125μM, or 0μM). MT-4 cells were prepared to 3 × 10 ⁵ cells / mL, and the upper half of the plate (lines B to D) was MT-4 cells infected with HIV-1 IIIB strain at moi = 0.01. Non-infected (mock-infected) cells were added to each of lines E to G) at 100 μL / well. After culturing at 37 ° C. for 5 days in the presence of 5% CO ₂ , MTT reagent (0.75%) was added, and further cultured for 2 hours. The medium 120 μL / well was removed so as not to suck the dye settled on the bottom of the well, and 100 μL / well dye solution was added. Absorbance (wavelength 540 nm, control 690 nm) was measured, and the viability of HIV-infected and uninfected cells at each drug concentration was calculated. That is, assuming that the absorbance value of non-infected cells when the concentration of the test compound was 0 μM was the cell viability 100%, the cell viability of virus-infected cells and non-infected cells at each concentration was calculated from the absorbance ratio. The result is shown in FIG. In FIG. 1, the vertical axis represents the cell viability (% viabilility), and the horizontal axis represents the concentration of the test compound. Moreover, HIV inf. MT-4 is a virus-infected cell, and Mock inf. MT-4 is an uninfected cell. As shown in FIG. 1, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.

The HIV growth inhibitory activity of the test compound was expressed as a 50% effective concentration value EC ₅₀ and a 90% effective concentration value EC ₉₀ . The cytotoxic activity of the test compound was expressed as a 50% cytotoxic concentration CC ₅₀ . Moreover, the effectiveness of the test compound was expressed by an effectiveness factor (SI = CC ₅₀ / EC ₅₀ ).
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the table below.

[Example 2]
5,7-dimethyl-2- [2- (3-methylpiperidin-1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile <5,7-dimethyl-2- [2- (3-methylpiperidin- 1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile]>: GMI08-003

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 2, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 3]
N-cyclohexyl-2- (3-methylquinolin-2-yl) sulfanylacetamide <G-08-024

  Evaluation was performed in the same manner as in Example 1 except that GMI08-024 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 3, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 4]
N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide <N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide>: GMI08-052

  Evaluation was performed in the same manner as in Example 1 except that GMI08-052 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 4, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 5]
N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanyl acetamide <N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanylacetamide>: GMI08-073

  Evaluation was performed in the same manner as in Example 1 except that GMI08-073 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 5, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 6]
1-piperidin-1-yl-2- (3,5,7-trimethylquinolin-2-yl) sulfanylethanone <1-piperidin-1-yl-2- (3,5,7-trimethylquinolin-2-yl ) sulfanylethanone>: GMI08-087

  Evaluation was performed in the same manner as in Example 1 except that GMI08-087 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 6, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 7]
2- (4-Methylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide <2- (4-metylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide>: GMI08-096

  Evaluation was performed in the same manner as in Example 1 except that GMI08-096 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 7, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

  [Example 8]

  2- (2-oxo-2-piperidin-1-ylethyl) sulfanyl-6,7-dihydro-5H-cyclopentapyridine-3-carbonitrile <2- (2-oxo-2-piperidin-1-ylethyl) sulfanyl -6,7-dihydro-5H-cyclopenta [b] pyridine-3-carbonitrile> ： GMI08-003-002

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-002 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 8, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

  [Example 9]

  4,6-Dimethyl-2- (2-oxo-2-piperidine-1-ylethyl) sulfanylpyridine-3-carbonitrile <4,6-dimethyl-2- (2-oxo-2-piperidine-1-ylethyl) sulfanylpyridine-3-carbonitrile>: GMI08-003-042

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-042 (ASINEX) was used as a test compound.

FIG. 9 shows the cell viability of virus-infected cells and non-infected cells at each concentration. As shown in FIG. 9, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 10]
2- (3-Cyano-8-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide <2- (3-cyano-8-methylquinolin-2-yl ) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide> ： GMI08-003-066

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-066 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 10, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 11]
2- (3-Cyano-7-methylquinolin-2-yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide <2- (3-cyano-7-methylquinolin-2-yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide>: GMI08-003-123

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-123 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 11, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 12]
2- (3-Cyano-6-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide <2- (3-cyano-6-methylquinolin-2-yl ) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide> ： GMI08-003-170

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-170 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 12, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 13]
N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide <N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide>: GMI08-003-180

  Evaluation was performed in the same manner as in Example 1 except that GMI08-003-180 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 13, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 14]
2- (4-Methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone <2- (4-methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone>: GMI08-003-239

Evaluation was performed in the same manner as in Example 1 except that GMI08-003-239 (ASINEX) was used as a test compound.
The cell viability of virus-infected and non-infected cells at each concentration is shown in FIG. As shown in FIG. 14, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 15]
2- [2- (azepan-1-yl) -2-oxoethyl] sulfanyl-5,7-dimethylquinoline-3-carbonitrile <2- [2- (azepan-1-yl) -2-oxoethyl] sulfanyl- 5,7-dimethylquinoline-3-carbonitrile>: GMI08-102

  Evaluation was performed in the same manner as in Example 1 except that GMI08-102 (ASINEX) was used as a test compound.

The cell viability of virus-infected cells and non-infected cells at each concentration is shown in FIG. As shown in FIG. 15, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

[Example 16]
2-[(3-Cyano-4-pyridin-4-yl-5,6,7,8-tetrahydro-quinolin-2-yl) sulfanyl] acetamide <2-[(3-cyano-4-pyridin-4- yl-5,6,7,8-tetrahydroquinolin-2-yl) sulfanyl] acetamide> ： GFI99-043-075

  Evaluation was performed in the same manner as in Example 1 except that GFI99-043-075 (ASINEX) was used as a test compound.

The cell viability of virus-infected and non-infected cells at each concentration is shown in FIG. As shown in FIG. 16, all MT-4 cells were killed by viral infection in the absence of the test compound. However, it was confirmed that the cell viability increased when the test compound was added.
EC ₅₀ , EC ₉₀ , CC ₅₀ and SI are shown in the following table.

2 is a graph showing the HIV growth inhibitory activity of a test compound (GFI99-043). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-024). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-052). 3 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-073). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-087). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-096). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-002). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-042). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-066). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-123). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-170). 3 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-180). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-003-239). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GMI08-102). 2 is a graph showing the HIV growth inhibitory activity of a test compound (GFI99-043-075).

Claims (3)

2- [2- (phenylmethylsulfonyl) ethylsulfanyl] -5,6,7,8-tetrahydroquinoline-3-carbonitrile,
5,7-dimethyl-2- [2- (3-methylpiperidin-1-yl) -2-oxoethyl] sulfanylquinoline-3-carbonitrile,
N-cyclohexyl-2- (3-methylquinolin-2-yl) sulfanylacetamide,
N-cyclohexyl-2- (3-ethylquinolin-2-yl) sulfanylacetamide,
N-cyclopentyl-2- (3-methylquinolin-2-yl) sulfanylacetamide,
1-piperidin-1-yl-2- (3,5,7-trimethylquinolin-2-yl) sulfanylethanone,
2- (4-methylquinolin-2-yl) sulfanyl-N- (oxolan-2-ylmethyl) acetamide,
2- (2-oxo-2-piperidin-1-ylethyl) sulfanyl-6,7-dihydro-5H-cyclopentapyridine-3-carbonitrile,
4,6-dimethyl-2- (2-oxo-2-piperidin-1-ylethyl) sulfanylpyridine-3-carbonitrile,
2- (3-cyano-8-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide,
2- (3-cyano-7-methylquinolin-2-yl) sulfanyl-N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide,
2- (3-cyano-6-methylquinolin-2-yl) sulfanyl-N- [2- (1H-indol-3-yl) ethyl] acetamide,
N-cyclopentyl-2- (4-methylquinolin-2-yl) sulfanylacetamide,
2- (4-methylquinolin-2-yl) sulfanyl-1-piperidin-1-ylethanone,
2- [2- (azepan-1-yl) -2-oxoethyl] sulfanyl-5,7-dimethylquinoline-3-carbonitrile, and
At least one compound selected from the group consisting of 2-[(3-cyano-4-pyridin-4-yl-5,6,7,8-tetrahydro-quinolin-2-yl) sulfanyl] acetamide or a salt thereof, A human immunodeficiency virus (HIV) growth inhibitor comprising.   A pharmaceutical composition for treating human immunodeficiency virus (HIV) infection comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.   Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of human immunodeficiency virus (HIV) infection.

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