TW550073B - Compounds and pharmaceutical compositions for treatment of disorders related to HIV and HTLV - Google Patents

Abstract

The subject invention is directed to a pharmaceutical composition for the treatment of disorders related to HIV and HTLV, comprising an effective amount of a compound of formula I, wherein Ar represents phenyl, which is unsubstituted or substituted with halo, hydroxyl or C1-6-alkoxy; A represents C1-6-alkylene or C2-6-alkenylene, m is an integer from 0 to 6; and B represents hydrogen, C1-6-alkyl or phenyl, said phenyl is unsubstituted or substituted with halo, hydroxyl or C1-6-alkyl; or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier. The invention is also directed to a pharmaceutical composition for use in the inhibition of HIV and HTLV replication and to a compound of formula II.

Description

550073 A7 B7 Printed by Xiao Gong Consumer Cooperative, Intellectual Property Bureau, Ministry of Economic Affairs. 5. Description of the invention (1) Field of the invention The present invention relates to a novel pharmaceutical composition containing a compound of formula I, which can be used to treat diseases related to HIV and HTLV viruses and Inhibits HIV and HTLV replication. In addition, the composition may be combined with other antiviral inhibitors as necessary. The invention further relates to novel compounds of formula II. BACKGROUND OF THE INVENTION Human diseases of acquired immune deficiency disease (AIDS) are caused by human immunodeficiency virus (HIV). Like other viruses, HIV cannot replicate without occupying its biosynthetic equipment that infects host cells. It causes this device to produce the structural proteins that make up the progeny of the virus. These proteins are encoded by the genetic material contained in the infected virus particles or virus particles. However, as a retrovirus, the transmitting substance of HIV is RNA, not as DNA in the host cell's genome. Therefore, viral RNA must first be converted into DNA, and then chimeric into the host cell's genome in order to make the host cell produce the desired viral protein. The conversion of RNA into DNA is achieved using the enzyme reverse transcriptase (RT), which is contained in the infected viral particles together with the RNA. Reverse transcriptase has three known enzyme functions: it functions as an RNA-dependent DNA polymerase, as a ribonucleic acid, and as a DNA-dependent DNA polymerase. First as RNA-dependent DNA polymerization, RT produces single-stranded DNA backups of viral RNA. As a ribonuclease, RT dissociates DNA from the original viral RNA and destroys the original RNA. Finally, as a DNA-dependent DNA polymerase, RT uses the first DNA strand as a template to make a second complementary DNA strand. The two strands of double-stranded DNA are integrated into the base of the host cell by another enzyme called an integrase. -4- The size of this paper applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the note on the back first) Matters "this page"

、 1T line 550073 A7 B7 V. Description of the invention (2 factors). I handle clothes _ (Please read the notes on the back first. Most of the compounds on this page are known to inhibit the enzyme function of HIV reverse transcriptase. —Mu of known HIV- 1 RT · inhibitor a 枋 li: From μ to this—Rizone is a ribo analogue. This class includes ziridine (ZldOVVdll, ZDV), 2, 3, _dideoxyinosine (ddI ) And 2,, 3, _ di: oxycytidine (ddC). The other is a non-nucleoside analog. This class includes neVlrapine, which is propyl but 5l dihydromethyl-6 Two bite ratios [3,2_b: 2,, 3,] [1,4]: aza ^ 6 ,. non-nuclear ^: similar ^ Verapie and other special appropriate compounds are in US Patent No. 5,366,972 And Hargrave et al., "ΗΙν] a novel non-nucleoside inhibitor of the reverse transcriptase L tricyclic pyridobenzo and dipyridodiazepines ", J. Med. Chem. 34, 223 1 (1991 ) However, because the HIV virus is susceptible to resistance to known antivirals (such as protease inhibitors and reverse transcriptase inhibitors), it often makes treatment less effective than expected. In addition, these antibiotics The dosage of the viral agent has adverse side effects for most patients, the most common is that it produces drug toxicity to normal cells. Therefore, people in the medical industry continue to continuously develop new antiviral agents and their effective doses, so that they can treat HIV more effectively. Caused by the disease. Intellectual property of the Ministry of Economic Affairs ^ Printed by employee consumer cooperatives in recent years' Industry found that chimeric enzymes required for virus replication may be the goal of the development of another class of antiviral agents, especially as anti-MVV inhibitors Potential. In HIV and other retroviruses, chimeric DNA replication of the rnA genome to the host cell chromosome is necessary for efficient viral replication and augmentation. Specifically, the enzyme works by first incorporating the virus DN A 3 Remove one dinucleotide unit (called 3, -treatment), and then move the 3, -treated strand from the cytoplasm to the nucleus. The host DNA in the nucleus corresponds to the strand -5- this paper. Standards are applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 550073 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (3) 5-base pair compensation cut It is then incorporated (called strand transfer). In addition, since chimeric enzymes have not been found to function similarly to human cells, chimeric enzymes may be used to treat retroviral infections. Although chimeric enzymes have been used in the retroviral life history It plays an important role, but little is known about compounds that selectively inhibit anti-HI V chimeric enzymes. Until now, the main classes of chimeric enzyme inhibitors include DNA binding agents, isomerase inhibitors, and golden red three Carboxylic acid, phenylethyl caffeate (CAPE), and catechin age. Although many compounds are reported to inhibit HIV chimeric enzymes in biochemical tests, most compounds are not active or only weakly active in tissue culture and are not specific in their mechanism of action. These results show that the activation of removing HIV chimerase with these compounds is non-specific or that compounds that inhibit HIV chimerase do not enter cells. In particular, although most of the compounds have the effect of inhibiting chimeric enzymes in in vitro enzyme analysis, they have not been confirmed to have anti-HIV activity in vivo. For example, both actinomycin D and CAPE have the effect of inhibiting chimeric enzymes in vitro, but they have not been reported to have anti-HIV activity. CAPE is a product of honeycomb wax. It is currently known to have anti-mitotic, anti-cancer, anti-inflammatory, and immunomodulatory properties. In addition, CAPE can selectively inhibit dentate animal cells and human tumor cells transformed by viruses and oncogenes, including intestinal adenocarcinoma (HT-29), melanoma (HU-1), SK-MEL-28 and SK-MEL-MO), human breast cancer (MCF-7), and Fischei mouse embryo fibroblasts (CREF). CAPE can also stop the growth of human leukemia HL-60 cells and inhibit the DNA of HL-60 cells, -6- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the back Note on this page)-Binding line 550073 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) RNA and protein generation. Activation of NF-Kappa B by tumor necrosis factor can be blocked by CAPE in a dose- and time-dependent manner. CAPE can also be used as a lipoxygenase inhibitor with antioxidant properties. SUMMARY OF THE INVENTION The object of the present invention is to provide a pharmaceutical composition for treating diseases related to HIV and HTLV virus. Another object of the present invention is to provide a pharmaceutical composition for inhibiting the replication of HIV and HTLV viruses. Yet another object of the present invention is to provide a combination of the composition of the present invention with a known antiviral agent. Another object of the present invention is to provide a novel compound for treating HIV and HTLV virus related disorders and inhibiting HIV and HTLV virus replication. Brief description of the figure Figure 1 represents that the phenethyl caffeate was treated with different concentrations of macrophage trend (1 ^ 1 ^ 43), D cell trend (1103?) And peripheral blood with dual trend (89.6) virus infection. The result of a single core ball. Figure 2 represents the results of methyl caffeate treatment of peripheral blood mononuclear spheres infected with macrophages (^ 1 ^ 43), T cells (111103), and dual tendencies (89.6) at different concentrations. Figure 3 represents the treatment of peripheral blood mononuclear spheres infected with macrophage tendency (NL-43), T cell tendency (JRCSF), and dual tendency (8 9.6) virus infection at different concentrations of phenethyl dimethyl caffeate. result. The representative symbol (+) indicates that the compound was maintained at the original concentration after the infection was completed. (Please read the notes on the back first

Ben Bai C-Packed ·

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 550073 5. Description of the invention (6 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs or replaced by Cm-based or medically acceptable Accepted so far. More preferred compounds of formula I, where = is phenyl, which is substituted by a prime, hydrazone or methoxy; A is C2_3 phenylene; m is an integer from 0 to 2; and B is methyl or Phenyl, or its medicaments can be stupid. The best compound of formula I is selected from the group consisting of: phenethyl caffeate (CAPE), phenethyl dimethyl caffeate (PEDMC), methyl caffeate (MC ), And 4- phenethyl bromocinnamate, or a pharmaceutically acceptable peptone. Since the chelate of formula I and its pharmaceutically acceptable salts have been found to have a significant inhibitory effect on the replication of p, v HTLV Chimeric enzymes are very similar to HIV. [Another aspect of the present invention is to provide a pharmaceutical composition for inhibiting HIV and htlv to produce I, comprising the compound of the above formula and a pharmaceutically acceptable carrier. Can have one or more palm centers, so it has various stereoisomeric forms. Compounds include all such isomers. The compound of formula 1 and the starting materials used for its preparation can be prepared by known methods' as described in the literature (eg He zhao et al., J. Med Chem. 1997, 40, 1186_1194, chlnthalapaUy v Ra〇 etc.-9- (Please read the note on the back page first)-The paper size of the binding and binding table applies the Chinese national standard (210X 297 mm) 550073 A7 B7 V. Description of the invention (8 Ministry of Economy Printed by the Consumer Property Cooperative of the Intellectual Property Bureau or prepared by the method provided in the example. Although the hard tail wine therapy is currently used to treat AIDS in the clinic, the HV virus in patients with γ, γ and I disease is still It is known that antiviral agents produce drug resistance and cannot achieve the purpose of effective treatment. Therefore, in order to effectively treat AIDS related diseases and inhibit virus replication, it is necessary to cooperate with other antiviral agents Z or Y, the present invention provides a A pharmaceutical composition comprising the above formula: and an additional antiviral agent. The antiviral agent is selected from a protease inhibitor (such as indinavir, ritonavir, or ritonavir) Nelfinavir), nucleoside reverse transcriptase inhibitors (such as zidovudine (ZDV), lamivudine (3TC), stavudine (d4T), 2 ', 3 '_ Dideoxyinosine (ddI) or 2,3, · dideoxycytidine (ddC)), non-nucleoside reverse transcriptase inhibitors (Ruchuan, xvirapine) and chimerism Enzyme inhibitor. The compound of formula 丨 and / or pharmaceutically acceptable salts thereof used in the present invention can be formed by forming at least one solid, liquid and / or semi-liquid excipient or adjuvant together to form an appropriate pharmaceutical agent. Useful excipients are organic or inorganic substances suitable for enteral (such as oral) or parenteral or topical application, which do not interact with the aforementioned compounds, such as water, vegetable oils, benzyl alcohols, alkenyl ethylene Alcohols, polyethylene glycol ^ \ 7 triacetin, sugar, gelatin, lactose or starch and other sugars, magnesium stearate 7 slip: and petroleum jelly. Specifically, lozenges, pills, coated lozenges, gums, powders, granules, syrups, juices, or drips are used for oral administration, pick-ups are used for rectal administration, and solvents (preferably oily or water) Liquid solution) and suspensions, emulsions, injections are for parenteral administration, while ointments, creams or powders-11-This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) (please Read the precautions on the back first ^ This page}-Binding 550073 A7, Description of the invention (9 B7 application. The compounds used in the present invention can also be dried, and can be used as preparations for injections. These Preparations can be sterilized, such as emollients, preservatives, stabilizers and / or wetting agents, emulsifiers, and other substances that affect osmotic pressure, buffer substances, colorants, fragrances, and tongues. Γ: Adjuvants such as quality. If necessary, it may also contain-or a variety of other / tongue compounds, such as one or more vitamins. In addition, since antiviral agents are administered to patients at high doses, they are prone to toxicity. The invention provides a medicine containing a compound of formula τ in a safe and effective amount The combined effective and safe doses are 0.1 to 1 μM, preferably i⑽ to 400 μM. The specific dose administered to individual patients depends on all possible factors and 2 such as the activity of the hydrazone compound used , Age, weight, general health, sex, eating status, time and route of administration, excretion rate, combination of medical music substances, and the severity of the disease to be treated, etc. Oral is a better method of administration. Examples Synthesis of _4-Phenylethyl Bromocinnamic Acid

(Read the precautions on the back before reading V-Packing-1Γ Ben 100 Ordering Line Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Industrial and Commercial Cooperatives, Approved Standards, Appropriate Sizes, Paper, Paper, SN Standard 4

550073 A7 B7 V. Description of the invention (10 +

Br,

HO

OH, ammonia ratio <, p ratio

S02C12 CHCls

Pyridine / CHC13

(Please read the precautions on the back page first)

1. 1T printed 500 mg (1 equivalent) of 4-bromobenzaldehyde and 562 mg (2 equivalents) of malonic acid in 4 ml of a 0-bito solution of 1T printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and then added 2 6 6 microliters of hexahydro ρ than bite. The mixture was heated to 80 ° C and maintained at this temperature for 2 hours, and then heated to 1 15 t: 8 hours. After the reaction mixture was cooled, 250 ml of ice water was poured. 10 ml of hydrochloric acid was slowly added to acidify the mixture. The crystals were separated by filtration and washed 4 times with ice water. The crude acid was dissolved in a solution of 1 g of 20 ml of NaOH. The solution was filtered, diluted with 10 ml of ice-water and acidified with 1 ·· 1 hydrochloric acid. The mixture was filtered and the crystals were washed with 20 ml of ice water and extracted with chloroform. (77% yield). -13- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 revolutions) line 550073 Printed by the bone-eliminating cooperative of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 --__ B7 V. Description of the invention (M) Will 4-bromo Cinnamic acid (1 equivalent) was placed with 8 ml of chC13 and thionine chloride (3 equivalents). The mixture was heated to 70 ° C for 7 hours and concentrated to produce acid chloride. The acid chloride was then dissolved in CHC13 (10 ml) and the 'valley' was added dropwise to a mixture of phenethyl alcohol (2 equivalents) and pyridine (2 equivalents) in 10 ml of CHC13 < for 5 minutes. The mixture was stirred for 30 minutes and purified by column chromatography to give 4-bromocinnamic acid phenethyl ester (yield 88 6%). Example 2 Cytotoxicity of phenethyl caffeate (CAPE), methyl caffeate (MC), and phenethyl dimethyl caffeate (PEDMC) on peripheral blood mononuclear spheres (PbmC). PBMC Cells were exposed to CAPE, MC, and PEDMC at different concentrations of 〇1, 〇5, 1, 5, 10, 25, 50, 100, 200, and 400 μM for 48 hours. Cells were tested for survival by trypan blue exclusion. Specifically, in order to determine the growth inhibitory effects of CApE, MC, and PEDMC, the method places cells and several cytotoxic concentrations of the solvent in a 6-well plate for 48 hours. Adjust the DMS concentration to less than 0.5%. Cells from 4 plates were washed once with Hank's salt-balanced solution (HBSS). In this way, dead cells that emerge will be separated from living monolayer cells. It was then stained with cone blue and counted. The total number of viable cells in the control group was considered as 100% survival rate. The% survival rate of the drug-treated cells was calculated from the total of the control group and the drug-treated cells. The results are shown in the table below. Even with PBMC up to 400 μM < CAPE, ME, or PEDMC, the survival rate is not significantly different from low doses (such as 丄 丄 丄). It is shown that cells do not produce cells at this high dose Toxicity. The cytotoxicity of CAPE, MC and PEDMC to PBMC (please read the precautions on the back page). -14- This paper is suitable for household materials (CNS) 210x7 ^^ 7 3 07 ο 5 5 A7 --------- B7, Description of the invention (12) (Number of dead cells in 400 cell count, 9 cells in control group) Concentration (μM) ^ CAPE MC PEDMC 400 8 7 6 200 7 8 7 100 11 7 10 50 12 11 10 25 5 11 8 10 10 7 9 5 10 9 11 1 7 12 7 0.5 9 7 10 0.1 11 9 11 (Please read the precautions on the back first) · Example 3 Quantitative effect of P24 of HIV and HTLV-1. PBMCs were treated with CAPE, MC and PEDMC at the concentrations listed in Example 2 and infected with macrophage tendencies (NL-43), T cell-trends (JRCSF) or giant double After infection of the HIV-1 isolate with phages and T cells re-oriented (89.6), the added compound was washed off the next day or maintained at the same concentration. The supernatants of the two groups were collected on the 3rd and 7th days after infection, and compared with the control concentration of the compound without the addition of P24 timing EIA reagent group of Abbott Company. The results show (see Figures 1 to 3). MC and PEDMC Youming -15- This paper size applies the Zhongguanjia Standard (CNS) A4 specification (2ω × 297 male!) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 550073 A7 B7 V. The invention description (13) significantly inhibits virus replication Effect, especially at a concentration of 100 μM or lower, CAPE and MC can inhibit 100% of the virus replication effect on different HIV isolates while maintaining the compound concentration. When the compound concentration decreases, the virus replication inhibition effect also In addition, this effect does not differ between different HIV isolates (NL-43, JRCSF, or 89.6), suggesting that its suppression appears to occur not during the exposure step but after subsequent virus penetration Therefore, the results show that CAPE, MC, and PEDMC can inhibit the replication of HI V isolates with various tropisms. (Please read the precautions on the back page first.) The Bureau of Intellectual Property, Lu (Printed by the Industrial and Consumer Cooperatives) -16- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (2l0X 297 mm)

Claims (1)

550073 Patent Application No. 088107238 Shouting I ~ Chinese patent application scope replaces April this year) B8 f4. Day B I 1. A species that has the ability to inhibit HIV and replication within Aff, including an effective amount of a pharmaceutical combination of a compound of formula I II-Ar-AC- (CH2) mB wherein Ar is phenyl, which is unsubstituted or modified Halo; via A or Cl_6 alkoxy is A-based C! .6 alkylene or (^^ alkenyl; m is an integer from 0 to 6; and B is hydrogen, CN6 alkyl or phenyl; or A pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to item 丨 of the scope of the applied patent, wherein Ar = phenyl 'which is unsubstituted or substituted by a phenylene, phenylene, or C ". The radical is A is Ci-4 alkylene or c2 4 alkenyl; m is an integer from 0 to 3; and B is C 3 or a phenyl group, which is unsubstituted or halogenated, Substituted with oxo or Cu. &Amp; TU 3. The pharmaceutical composition according to item 2 of the scope of the patent application, wherein Ar is phenyl, which is substituted with dentin, hydroxyl or fluorenyloxy; A is C2-3 fluorenyl M is an integer from 0 to 2; and B is methyl or phenyl. 4. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the compound is selected from the group consisting of /, phenethyl caffeate (CAPE), phenethyl dimethyl caffeate (PEDMC), and methylphtalate ( MC), and phenethyl 4-bromocinnamate. 5. The pharmaceutical composition according to item 丨 of the scope of patent application, which is used to treat diseases related to HIV and HTLV virus. ‘, 6. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the condition is AIDS or AIDS-related complex (ARC). 7. The pharmaceutical composition according to item 5 of the application, wherein the condition is leukemia of adult T cells. 8. According to the scope of patent application! The pharmaceutical composition according to any one of items 7 to 7, further comprising an antiviral agent selected from the group consisting of a protease inhibitor, a ribonucleoside reverse transcriptase inhibitory W non-nucleoside reverse transcriptase inhibitor, and a chimeric enzyme inhibitor. 9. The pharmaceutical composition according to item 8 of the scope of patent application, wherein the protease inhibitor is selected from the group consisting of indinavir, ritonavir and nemnavir. 10. According to the application The pharmaceutical composition according to item 8 of the patent, wherein the nucleoside reverse transcriptase inhibitor is selected from the group consisting of Zidovudine (ZDV), lamivudine (3TC), and stavudine (d4T) ), 2, 3, dideoxymuscle (ddl) and 2, 3'-dideoxycyte: y: (ddC). 11. The pharmaceutical composition according to item 8 of the scope of patent application, wherein non-nuclear The reverse transcriptase inhibitor is selected from nevirapine. 8 8 8 8 ABC D 550073 6. Patent application scope 12. The pharmaceutical composition according to item 1 of the patent application scope, wherein the effective amount is 0.1 to 1000 μM. 13. The pharmaceutical composition according to item 12 of the patent application, wherein an effective amount is 100 to 400 μM. 14. The pharmaceutical composition according to item 12 of the patent application, wherein an effective amount is 100 to 400 μM. 15. —Species Compound of Formula II II Ar-AC-〇- (CH2) mB Ar is phenyl, which is substituted by dentin; A is Cu alkyl or C2_6 alkyl; m is an integer from 0 to 6; and B is hydrogen, (6_6 alkyl or phenyl; or pharmaceutically acceptable Accept salts. 16. Compounds according to item 15 of the scope of patent application, in which Ar is phenyl, which is substituted with halogen; A is C2_3 fluorenyl; m is an integer from 1 to 2; B is phenyl. 17. According to The compound under the scope of patent application No. 15 is a 4-bromocinnamic acid phenethyl ester. -3- The paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm)