JPH01503069A - Novel pharmaceutical compounds - Google Patents

Abstract

A compound of formula (I), wherein the radicals A, X, R<1>, R<2>, and R<3> are defined as follows: A: formula (a) or formula (b); X: (a) O; (b) S; (c) CH2; R<1>: H; alkyl containing 1-3 carbon atoms; -CH=CH2; -CH=CH-CH3; -CH2-CH=CH2; formula (II); -C=CH; R<2>: H; or R<2> constitutes together with R<3> a carbon-carbon bond; R<3>: H; F; Cl; Br; I; N3; CN; C=CH; OH; OCH3; CH2OH; and when R<3> is F; Cl; Br; I; N3; CN; C=CH; OH; OCH3 or CH2OH it may have either the cis-configuration or trans-configuration relative to the hydroxymethyl function at position 4', or R<3> constitutes together with R<2> a carbon-carbon bond, and therapeutically acceptable salts thereof, for use in therapy, in particular for the treatment of HIV virus infections.

Description

[Detailed description of the invention] Novel pharmaceutical compounds field of invention The present invention relates to acquired immunodeficiency syndrome (AIDS), an infection caused by human immunodeficiency virus. Therapeutic and prophylactic control of infection, hepatitis B virus infection and retroviral infection and the use of the compound and its physiologically acceptable salts for treatment and The present invention relates to such inhibition and treatment methods in animals and humans.

Background of the invention In the recent 1970s, a disease known as acquired immunodeficiency syndrome (AIDS) was introduced. A new disease has been reported. Currently, previously human) T-cell lymphocytophilic virus Type (HTLV-I) or known as linohepidosis-associated virus (LAV). A retrovirus called arv (human immunodeficiency virus), which had been It is generally accepted that it plays an essential role in the pathogenesis of DS.

AIDS is caused by the activation of Litz ξ-T-hell 12-cells, one target of HIV infection. It is characterized by marked immunodeficiency due to a low number of subpopulations. AIDS patients Significant immunodeficiency.

These patients may have a variety of bacterial, fungal, protozoan, or viral etiologies. Makes susceptible to opportunistic infections. The etiology of viral opportunistic infections is often virus (VZV), FB virus (F, BV) and special C: cytomegalo Found in viruses (CMI/). Other retroviruses that affect humans are , HTLV-1 and ■ Examples of retroviruses that affect animals are , feline leukemia virus and equine infectious anemia virus.

Hepatitis B virus infection causes a significant number of cases of acute, chronic, and severe hepatitis in humans. cause serious illnesses such as

It is estimated that there are 200 million patients with chronic hepatitis B infection worldwide.

A significant number of chronic cases progress to liver cirrhosis and liver ridge ulcers. In some cases Hepatitis infection also has a mortality rate of about 90%, as in severe hepatitis B. It progresses rapidly and vigorously. At present, there is no evidence of hepatitis B infection. Known Effective Treatments A number of nucleoside analogs each exhibit antimetabolic activity.

These nucleosides can be used in place of naturally occurring nucleosides. or by competing with naturally occurring nucleosides.

Recently, AIDS and AIDS-related complexes (ARR) have been studied in cell culture. Human immunodeficiency virus (HTLV-m, also known as LAV), which is the cause of Several nucleoside congeners have been described in the literature that inhibit the growth of . this Such compounds include, for example, azidothymidine, dideoxycytidine and dideoxycytidine. It is cyadenosine. HIV-Antimetabolites described in these and other publications Nucleoside congeners are the same nucleoside bases as naturally occurring nucleosides. It has a geometrical relationship with the glycoside moieties. That is, these compounds are It is a β-anomer.

Surprisingly, some nucleosides and nucleosides with opposing geometries The cleoside congener meanomer is not an inhibitor of cell division, but it inhibits HIV proliferation. It is a strong inhibitor. Anti-EIV activity is determined by the nucleoside base moiety and glycoside moiety. represented by such geometrical isomers modified in one or both parts. Ru. The structures of these compounds are disclosed in this invention.

Conventional technology The following compounds of formula (1) are known.

compound.

In the above formula, R5 is OH, and R1 is as follows.

R1 is Yo and CH3: T, NishN15hi, B, 5hi nizu.

1, Ivrai, C! hem, Pharm, Bull, (Tokyo ) 12 (1964), 1471R1 is C2H5: M, Swierko wski, D., Shugar, J., Med.

Chem, 12 (1969), 533R1 is n-C3H7: A, 5zaboles, J, Sagi%L, 6tv5sJ, Carbo hydrates II Nucleosides, Nucleotides 2 (1975)% 197-211 R1 is 1-c5a7: M, Craminski, A, Zgit -WrobleWskaPolish J, Chemistry 54 (1 980χ1o85R1 is OCH: P, J, Barr, A, S, J ones, P., Serainowski, R.I.Walker, J., Chem. , Soc, Perkin I (1978χ1263~ and R5 is N3 and R1 is OH3: M, Imezawa, F, Eckstei n, J, Org, C! hem, 45 (1978), 3044-3048 Compound of °.

R1 is saliva: P, J, Barr, A, S, Jones, P, Serafinowski, R. Walker, J. Chem., So. c, Perkin I (1978), 1263-R1 is H: J, J , FOX, N, C! , Yung, L. Wempen and M. Hof. fer, , T, Am, Chem, SOc,, Vol, 85 (19 61χ4066~4070° Groups 1 and 2 both contain 3'-groups and 4'-hydroxymers in the trans-configuration. Concerning only compounds having a chill group.

Disclosure of the invention According to the invention, the formula Compounds of and therapeutically acceptable salts thereof are effective for human immunodeficiency virus (HIV) It was found that it inhibits the growth of.

In the above formula, the groups A, X% R1, R2 and R5 are defined as follows.

R1:H, alkyl containing 1 to 6 carbon atoms, R2:H or R2 is R5 together with form a carbon-carbon bond R5: H%F, C1, Br, I, N5, I:iN, -c=cH, OH, ○cH5, CH20H or R5 together with R2 constitute a carbon-carbon bond. Ru.

Compounds of Formula I are useful for inhibiting and treating HIV virus infections in mammals and humans. It is useful as a therapeutic and/or prophylactic agent.

In a more general aspect, the compounds of formula I can be used to combat infections caused by salivary sores. Useful as a therapeutic and/or prophylactic agent in control and treatment.

In their natural cycle of replication, all retroviruses, including HIV, Requires reverse transcriptase.

Hepatitis B virus (HBV) has a unique circular double-stranded DNA that is partially single-stranded. It is a DNA virus with a genome.

It contains the specialized NA4 remerase necessary for viral replication. . This DNA polymerase also replicates HBV DNA via an RNA intermediate. During the process, it acts as a reverse transcription base.

Compounds of Formula I inhibit the activity of reverse transcriptase of retroviruses, including HIV; Inhibits hepatitis B virus DNA polymerase activity.

The present invention has the following several aspects.

1 Novel compound included in formula l.

2. Pharmaceutical compositions containing a compound of formula I as an active ingredient.

3. Compounds of formula I for use in therapy.

4.) Caused by retroviruses including HV or by hepatitis B virus. for use in the manufacture of medicaments for the therapeutic and/or prophylactic treatment of infections caused by A compound of formula ■.

5. Administering an effective amount of the compound of formula (■) to a host in need of such treatment. caused by retroviruses including HIV or hepatitis B virus. Therapeutic and/or prophylactic treatment of infections in mammals and humans How to do it.

Attacking HIV virus infection in humans is a preferred aspect of the invention.

The expression "alkyl containing 1 to 3 carbon atoms" for the radical R1 means CH3, 02H5, cH2cH2c dog, 0H(OH5)2 and cyclopropyl Ru.

R3 in formula I is F, O1! , Br%T, N3, ON, C=C! H1O H,0CH5 or CI (if 20H, it is the 4-hydroxymethyl It has a cis-configuration or a trans-configuration with respect to the le function.

Preferred compounds of formula (1) have the following radical definitions: (c) in the 3'-position; The hydroxymethyl group in the R5 and 4'-positions has a trans-configuration.

(CI) R1 is OH5 or C2H5.

(e) X is O or OH2.

(X is 0.

(g) R2 is H.

(→ R2 forms a carbon-carbon bond together with R5.

(i) R5 is H, F%N3, ○H, QCH3 or 0H20H, or It forms a carbon-carbon bond together with R2.

(j) R5 is H, F or N5.

(Assistant) A combination of the above-mentioned (a), (C), (d) and (e).

(1) Combination of the above (a), (C), (d), (e), (ω and (i)) Let me.

(→ Combination of the above-mentioned (a), (→, (gradient), (0, (β and (j)).

(→ Combination of the aforementioned (a), (c), (d), Ce) and (h).

(0) A combination of (b), (C), (, i) and (e) described above.

ω) Combination of the above (b), (e), (→, (e), (q) and (1)) .

(Q) Combination of the above (b), (C), (d), (f), (ω and (, J) Match.

(r) A combination of the above-mentioned (b), (C), (d), (→ and (h)).

Examples of suitable compounds are:

R1 is OH5, R2 is H, and BS is H.

R'ktCH5 is present, R12 is H, and RA is OR.

11 is OH5, B2 is H, and static is 0CH5.

R1 is OR5, B2 is H, and B5 is ca2oa.

R1 is OH5, B2 is H, and B5 is F.

R1 is OH5, B2 is H, and R5 is N3.

R1 is OH5 and R2 and R5 together form a carbon-carbon bond .

R1 is "2H5," R2 is "■," and B5 is "H."

R'　hac2FI5teaI), R2haHteaS), Rs is OH.

R1 is C! 2H5, R2 has H Te, N5 Ha. cH5theal.

R1 has 02H5 tomorrow, R2 has H, and OR1 has R''HaC!H20H 02H5, R2 is H and B5 is F.

R1 is C2H5, 12 is H, R5 is N5, OR1 is C! 2H5 and R2 and R6 together constitute a carbon-carbon bond.

R2 is H and R5 is H.

R2 is H and R3 is OH.

R2 is H and R5 is 0CH5.

R2 is H and R5 is CH20H.

R2 is ■, and B5 is F.

R2 is H and R5 is N5.

R2 and R3 together constitute a chemical bond.

In all examples of suitable compounds, R5 at the 3'-position and hydroxy at the 4'-position Cymethyl has a trans configuration.

In clinical practice, nucleosides of formula I are usually in solid, semisolid or liquid form. together with a pharmaceutically acceptable carrier or ingestible capsule that is a diluent for activity in the form of the parent compound or optionally its pharmaceutically acceptable salts. Orally 1; by injection or by infusion in the form of a pharmaceutical preparation containing a sex ingredient; It is administered as follows.

The compounds can also be used without carrier substances.

Examples of pharmaceutical preparations include tablets, dragees, capsules, granules, suspensions, elixirs, and syringes. Examples include drops, solutions, etc. Usually, the active substance is designed for injection. between 0.05 and 20% for formulated formulations and designed for oral administration. For formulations containing between 10 and 90 -.

For the treatment of patients infected with retroviruses, especially HIV or hepatitis B virus. includes oral, parenteral, rectal, nasal, topical and vaginal methods. It is preferred to administer the compounds by any suitable method. Parenteral method Includes subcutaneous, intramuscular, intravenous and sublingual administration. Topical methods are Includes buccal and sublingual administration. The dosage at which the active ingredient is administered can vary over a wide range. and various factors such as the degree of infection, age of the patient, etc. must be adjusted according to the rules and individually. Should be administered per day. Preferred ranges for the amount of the compound of the invention or its physiologically acceptable salt include: about 10-10,0 OOQ, preferably 100-500q for intravenous administration and Preferably, 100 to 3000 q can be used for oral administration.

Examples of pharmaceutically acceptable salts of compounds of formula I include, for example, alkali metals (e.g. thorium), alkaline earth metal (e.g. magnesium) salts, ammonium and derived from a suitable base such as Nx4+ (wherein X is C1-4 alkyl) and base salts. Physiologically acceptable salts of hydrogen atoms or amino groups are Carboxylic acids such as acetic acid, lactic acid, gluconic acid, citric acid, tartaric acid, maleic acid, Malic acid, pantothenic acid, isethionic acid, succinic acid, phosphoric acid, ethane sulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-tol Ensulfonic acid and inorganic acids such as hydrochloric acid, hydriodic acid, sulfuric acid, phosphoric acid and sulfuric acid includes salts of amino acid. Physiologically acceptable salts of compounds with hydroxy group are Na'', NH4+ and NX4+ (wherein X is 01-4 alkyl group) the anion of the compound in combination with a suitable cation.

Compounds of formula ■, which are new, are summarized as compounds of formula I under the following conditions.

R2 is H If R5 is OH, X is O R2 is H If R5 is N3, R1 is H, alkyl containing 2 to 3 carbon atoms, X is 0; R2 is five If R3 is OH, R1 is alkyl containing 1 to 3 carbon atoms.

The compound administered may also be 9-((2-hydroxy-1-(hydroxymethyl) ) ethoxy) methylcoguanine, 9-(2-hydroxyethoxymethyl)guani /(acyclovir), 2-amino-9-(2-hydroxyethoxymethyl)propylene Phosphorus, interferons such as α-interferon, interleukins and and other medications such as phosphonoformates or bone marrow or phosphoryl transfer. Immunomodulatory therapy including transplantation or lymphocyte counts and/or function as appropriate used therapeutically with medications such as repamisole or thymosin, which increase can be used.

Production method A further aspect of the invention is that the compounds of the present invention have the structure The hydroxyl group is optionally removed by known methods described in the A3 literature. represents the protected glycoside contained in formula I with the pyrimidium corresponding to group A of formula I. condensation at the N-1 position of the gin derivative, followed by separation of the a-anomer and removal of the protecting group. leave Such a method can be used, for example, in Ba5ic Pr1ciples in Nucleic Ac1d 0hezistry” Volume 1 (Acadezic Press, 1974, Ed, P, O, P, Ts’oχ-Nucleos ideAnalogues, Chemistry, Biology a nd Medical Appli-catiOns” (Pharma Pr ess, 1979, Eds, R.T., Walker, LDeClier cq apd F, Eckstein) and Nucleic Ac1dsR esearch No. 1dsResearch pages 6827-6837 (A, J.

Hubbard, A.S., Jones and R.T., Walker) It is described in. An example of such a method is for the case of uracil base analogs. It can be shown as follows.

CdH,OR5,0CH5 or CH20R5, BS is a protecting group, R 1 and R2 are as described above. Various protecting groups are known. And the example is p-)le B0 formula [In the formula, A, X and R2 are as described above, and R4 is HlF, C1%Br, I, N3, (!N, OR5,0CH5 or 0H20R5, R5 is H or a hydroxy-protecting group]. ization) l, to obtain a mixture of a- and β-anomers, then a-a The polymers are separated and the protecting groups are removed. Anomerization is for example trimethylsilyl using catalysts such as trifluoromethanesulfonate and in some cases known methods using protected β-nucleosides e.g. silylated nucleosides. Therefore, it can be carried out.

In the above formula, 11, R2, R4 and R5 are as described above.

C,) transglycosylation reaction cation) to transfer one nucleoside base to an a base.

The reaction is carried out using a catalyst such as trimethylsilyltrifluoromethanesulfonate. and then separating and deprotecting the product.

+ other products In the above formula, B1, R2, R4 and R5 are as described above. The group B is It is a pyrimidine or purine base and there are no restrictions on its selection.

D, the precursor of the functional group R5 or R3 is replaced by a suitable leaving group R7. , introduced into the nucleosidome anomer and then deprotected.

In the above formula, R1 and R5 are as described above, and R7 is, for example, triflu It is like olomethanesulfonyloxy (synthos), and R9 is an appropriate preservation. It is a protection group.

Another method for introducing the R8 functionality is the reaction of the 2.3'-7-hydro a-anomer: :evening.

In the above formula, Hl, R5 and R8 are as described above.

Although the formula describing the reaction simply refers to the uridine congener, the methods A-D described above The principles can be applied to the synthesis of both uridine and cytidine congeners of formulas ■ and ■. Ru.

E, the uracil moiety of the 5-substituted or unsubstituted a-uridine compound is replaced with the corresponding a- Converts to the cytosine moiety of the cytidine homolog. This is carried out by conventional methods. It will be done.

This principle applies, for example, to W, L+, Sung (J, Chem, Soc, C hem.

(1!ommun, 1981, p. 1089 and J, Organic Ch. emistry 1982, Vol. 47, pp. 3623-3628];:Thus and P.

550-555].

The following examples are presented to further illustrate the invention: A, 3'F-3'-deoxy Production of C-5'-〇-7 Cecil Temiji 7 (VSB423) 5'F-3'-deoxythymidine 45g9 (o18) in acetic anhydride (20g) 4 mmol) are heated in an oil bath at 80° for 7 hours with stirring. vacuum the solution The evaporated and residual acetic anhydride and acetic acid were dissolved in benzene-toluene (1:1). Remove by several additions and reevaporation. Use the residue without further purification. use

Preparation of compounds of the invention Example 1.1-(3-F-2,3-dideoxy-a-D-ribofuranosyl)thymi (Method B) Thymine 23 my (o, 1a mmol) and 3'F-3'-deoxy-51 - Heacetertemidine suspended in acetonitrile (1,2 rnt) and N , O-bis(trimethylsilyl)-acetamide (0,35g). mixture Stir for 15 hours at room temperature. Trimethylsilyltrifluoromethanesulfone -) Add (0,05d). After stirring at room temperature for 192 hours, the mixture was stirred Pour into a 1:1 (v/v) mixture of 10% aqueous KHCO3-ethyl acetate 20- Add. The two phases were separated and the aqueous phase was diluted with ethyl acetate (3XI D mt). Extract.

The combined ethyl acetate phases are filtered and then evaporated in vacuo. Dilute the residue 1:1 with dichloromethane. A 1:1 diluted solution was dissolved in ethyl acetate and applied to a column of silica gel. Starting material (VSB 423) [TLC silica] eluted with lolomethane-ethyl acetate. Gel, 0R2C! j? 2-EtOAC (1:1), RfO, 37:128 Jlg(5i) and 1-(3-F-2,5-dideoxy-5-0-acetyl- a-D-ribofuranosyl)thymine (VSB424) CTLC silica gel, CH2 Cl2-EtOAc (1:1), Rfo, 29] obtain IBM9 (34%) .

NMR ((!D50D) δt95 (s, 3H-CIH3-5), 2.12 (S, 5H.

ca5co), 23-5.0 (IIL 2E, H-2' a, b), 4.1 5 (d, 2H,, T4'.

5' = 4.4 Hz, H-5' a, bχ4.81 (dt, 1H, J3 'F, 4' = 30. Ohz.

: f 4' 5' = 4.6 Hz, H-4'), 5.23 (dd, I H, 8'F, 3' = 55.7 Hz.

J2', 5' = 5J], H-5'χ6.56 (d, IH, J1', 2' =7.57 Hz, H-1'χ7.27 (d, IH,, T I (-6, C I (3=1.47. H-6) 150 (CD30D) δ12BO (CH3χ20 ．． 87 (CIH3O0), 39.40 (d.

J=2Q, 8 Hz, C-2')%63.37 (d-J=122Hz, C -5')%84.65Cde J=24.4Hz, O-4'), 8650 (s, (1!-1'χ93.82 (d, J=178 Hz, O-3' ), 11t12 (0-5), 1354)7 (d, J=6.1 Hz.

C-6χ15α48 C0-2), 16 Otsu 6B (CI-4), t70.30 (cH3c,o) Compound VSB 424 (1619) was added to a saturated methanolic anhydride. Dissolve in Monia (5-) and leave overnight at room temperature. Evaporate the solution and leave the residue The product was treated with acetone-benzene (1:4) to obtain crystals of the desired compound VSA419. (9,4ati, 69%) was obtained by NMR (DMSO-δ6) IHδ 1.79 ( d, 3H, J OH5, H-6 = 1.2 HzCH3), 2.16-2.90 (m, 2H, H-2'), 3.2-3.6 (m, 2H, H-5'), 4.61 (dt, 11(,,T5'Ft4'=23.4)EZI J4'15'% 4 Hz, H-4'), 5.06 (ts IH, J5', 0H=5.6H z, OH), 5.32 (dd, IH,, T3'F, 3' = 54.2 Hz J 2'3' = 4.9 Hz, H-3'χ 6.18 (dd, IH, J1'2 '=7.7Hz and 2.1Hz, H-1'), 7.39 (d, IH, J OH5, H-6 = 1.2 Hz.

H-6) 15C (DMSO-66) 6 12.4 + S CC: H5χ ~ 39 (0-2 'χ　6L17　(a.

J=11.0 Hz, C-5'), 85.85 (c-1'), 87.15 (d, J=20.8 Hz.

C-4'χ 94.75 (cl, J=173 Hz, C-5'), 109. 15 CC-5), 135.63 (d, J=6.1 R2, C-6), 15 0.53 (0-2χ 153.95 (0-4) Example 2.1-(3-F-2 ,3-dideoxy-a-D-ribofuranosyl)-5--! Lopiluracil (US) A409) production (method C) 5-propyluracil (56 mg) and 3'-F-5'-deoxythymidine y (47 mg) was suspended in acetonitrile (t2d) to obtain N,O-bis(t2d). Add trimethylsilyl)acetamide (O15d). Mixture at room temperature for 1.5 hours Stir for a while. trimethylsilyltrifluoromethanesulfone) (0.05mg ) was stirred at room temperature for 138 hours, and the mixture was evaporated in vacuo to give R20 ( 0.5 mj), filtered and washed with R20 (o, sy). combined water phase was applied to a 018-column (HPLC column) and methanol was added at a rate of 7.0 mg/min. Elute with water (55:65). The β-anomer will be eluted after 12.9 minutes. The desired a-anomer USA 409 is eluted after 18.0 minutes. Yield 93 mg(1H&). UV 2maX (H2O) 269nm, MS M" 272 ( 10%), 154 (I 00%), 119 (76chi).

Example 3.1-(3-F-2,'5-dideoxy-a-D-ribofuranosyl)- Production of 5-ethyluracil (VSA alt) (method C) 5-ethyluracil (5111 g) and 3’l”-3’-deoxythymidine (48 mg) was suspended in acetonitrile (12 mg) and Add limethylsilyl)acetamide (0.35 wj). The mixture was heated at room temperature for 15 minutes. Stir for an hour.

Add trimethylsilyltrifluoromethanesulfonate (O,0S-). room After stirring at room temperature for 161 hours, the mixture was evaporated in vacuo and added to water (0.5 mj). , then rinse with water (0,5-). The combined aqueous phases were transferred to a 018-column (HPL C) and eluted with methanol-water (1:3) at a rate of 8.0 d/min. Ru. The β-anomer eluted after 12.3 minutes and the desired a-anomer VSA4 11 elutes after 16.4 minutes.

Yield: 13.1 mg (26%). Takumi λBax (H2O) 267.5 nm oMS M1258 (9 inches), 140 (100 inches), 119 (67 inches).

Example 4.1-(2-deoxy-a-D-ribofuranosyl)-5-isopro Luuracil (VSA 175) manufacturing (method person) 5-isopro is niluracil (4,31), hexamethyldisilazane (50ml ), chlorotrimethylsilane (1d) is heated. Evaporate excess solvent in vacuo. The remaining bis-silylated 5-isoprobonyluracil (8,4F) was removed by dichloromethane. Dichloride dissolved in loethane (5M) and containing molecular sieves (4X, 15f) 2-deoxy-6,5-di0-p-)luo-D in loethane (150-) - Erythro is added to tosyl chloride (11, C1). Let the suspension cool at room temperature. Stir overnight, then heat it with F and evaporate the solvent. Dichloromethane residue This was washed with saturated aqueous NaHCO3 and H2O, and Na2SO 4 and then concentrated to a volume of approximately 70 m. Remove the formed precipitate and dichloromethane. The methane was evaporated from the solution and the residue was evaporated using hexane/ethyl acetate/distillate as eluent. Chromatograph on silica gel column using chloromethane (515/3') 1-(2-deoxy-3,5-di0-p-toluoyl- a-p-9 bofuranosyl)-5-isopro is niluracil (VSA174) 2 ．． 64 f (thin layer chromatography, silica gel, solvents as mentioned above) system, Rf=0.5).

Sodium metal (0,2!M) was dissolved in anhydrous methanol (265m) and the compound VSA 174 (2,64f) was added and the solution was stirred at room temperature overnight; Add water (35 td) afterwards. Transfer the solution to an ion exchanger (Dowex H”50vrx 2) Neutralize, evaporate and evaporate the solvent. The residue was cleaned with hexane and then eluted. Chromatographed on a silica RP180 column using 50% aqueous methanol as agent. It was purified by graphic treatment to give 1-(2-deoxy-a-1)- (ribofuranosyl)-5-isopro gives niluracil (TLC silica RP8 ．． 50% aqueous methanol, R1=0.5).

Exam　■ Agents and methods of compounds of formula I against HV) in H9 cells: H9 cells HXV-infected 10 pieces of beef tallow serum, 100μν9-streptomycin RPMI-medium containing 10 μmJ of polypropylene hydrochloride and 2 μg/ml of polyprene. H9 cells at 105 cells per well on a 24-well plate suspended in 2wIt are exposed to various concentrations of HIV (HTLV-I [lB) and test compound. P The rates are cultured for 6-7 days at 37°C in 5% CO2. Next, for each hole Homogenize the contents with a pipette and transfer to a centrifuge tube. 10 minutes at 1500 rpm After centrifugation, remove the supernatant and let the cells rest on a glass plate. Analyze by fixing in ethanol. Dilute 1:80 or 1:160 Add HIV-positive serum and incubate at 37° for 50 minutes. then the plate Wash with phosphate-buffered saline (PBS) containing Ca2+ and Mg2+.

sheep antihuman conjugate e) After adding (FITO) and fresh incubation, wash the plate again with PBS. Ru. After counterstaining with Evans blue and drying, the frequency of HIV antigen-containing cells was determined. Measured using a microscope Table 1 In Table 1, the test compound is an active inhibitor of HIV viral proliferation. I understand.

Test■ Cytotoxicity 2X10 H9 cells per plate in the absence or presence of test compound. Below, 10% beef tallow serum, rainbow lymph 0 Q/l, streptomycin RPMI-1640 medium containing Isin 1008971 and Hehasu 10mM The number of cells cultured per plate is determined after 48 hours. Next test Cells cultured in the absence of compound are subjected to two cycles of cell division.

F5000 human fetal cells were tested at 1xios cells per plate. Earle's salt (Earle's 5al t), non-essential amino acids, 10% beef fat serum, 10mM, -? Nijilymph Eagle minimum requirement supplemented with 0ay/l and streptomycin 100Q/l Cultivate in medium. The number of cells per plate is determined after 48 hours. test Cells cultured in the absence of compound undergo one cycle of cell division. Conclusion The fruit is given as TC5Q, which is the concentration of compound that gives 50% inhibition of cell proliferation. .

Table 2 Cytotoxicity against H9 and F500018 cells In Table 2, the test compound By far the concentration rcso according to Table 1 for 50% inhibition of HIV virus proliferation It can be seen that the 'rc50 value exceeded.

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Claims (17)

[Claims] 1. formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼I and therapeutically acceptable salts thereof. In the above formula, the groups A, X, R1, R2 and R3 are defined as follows. A: (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (b) ▲ Mathematical formulas, chemical formulas, tables, etc. etc.▼X:(a)O (b)S (c) CH2 R1: H, alkyl containing 1 to 3 carbon atoms (including cyclopropyl) ), -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲Formula , chemical formulas, tables, etc. ▼, -C≡CHR2:H, or R2 together with R3 form a carbon-carbon bond R3: H, F, Cl, Br, I, N3, CN, -C≡CH, OH, OCH3, C H2OH. R3 in formula I is F, Cl, Br, I, N3, CN, -C≡CH, OH , OCH3 or CH2OH, it is the hydroxyl at the 4'-position It can have a cis-configuration or a trans-configuration with respect to the methyl function. Alternatively, R3 together with R2 forms a carbon-carbon bond. However, the following conditions (a) to (c) are met. (a) When A, X, R2 and R3 are combined as follows, i.e. A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and X is O. R2 is H R3 is OH (OH at the 3'-position and hydroxymer at the 4'-position) chill has a trans-configuration), then R1 is -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲number There are formulas, chemical formulas, tables, etc. ▼ or cyclopropyl (b) If A, X, R2 and R3 are combined as follows: A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and X is O. R2 is H and R3 is N3 (N3 in the 3'-position and N3 in the 4'-position hydroxymethyl has a trans-configuration), then R1 is H, alkyl containing 2 to 3 carbon atoms (including cyclopropyl) ), -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲number There are formulas, chemical formulas, tables, etc. ▼ or -C≡CH and (c) A, X, R2 and and R3 are combined as follows, i.e. A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and X is O. R2 is H R3 is OH (OH at the 3'-position and hydroxymethyl at the 4'-position are trans-configuration), R1 is an alkyl group containing 1 to 3 carbon atoms. (including cyclopropyl), -CH=CH2, -CH=CH-CH3, - CH2-CH=CH2 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 2. A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R1, R2, R3 and 2. A compound according to claim 1, wherein and X are as defined in claim 1. 3. 3. A compound according to claim 2, wherein R1 is H, CH3 or C2H5. 4. R3 is H, OH, OCH3, CH2OH, F, N3 or R2 and and R3 together form a carbon-carbon bond and X is O or CH2 A compound according to claim 3. 5. R3 at the 3'-position and hydroxymethyl at the 4'-position are trans 5. The compound according to claim 4, having the configuration. 6. A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R1, R2, B3 and 2. A compound according to claim 1, wherein and X are as defined in claim 1. 7. 7. A compound according to claim 6, wherein R1 is H, CH3 or C2H5. 8. 8. The compound according to claim 7, wherein R1 is H. 9. R3 is H, OH, OCH3, CH2OH, F, N3 or R2 and and R3 together form a carbon-carbon bond and X is O or CH2 A compound according to claim 8. 10. R3 at the 3'-position and hydroxymethyl at the 4'-position are trans 10. The compound according to claim 9, which has a H-configuration. 11. Formula for use in treatment ▲There are mathematical formulas, chemical formulas, tables, etc.▼I and therapeutically acceptable salts thereof. In the above formula, the groups A, X, R1, R2 and R3 are defined as follows. A: (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼X: (a) O (b)S (c) CH2 R1: H, alkyl containing 1 to 3 carbon atoms (including cyclopropyl) ), -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲Formula , chemical formulas, tables, etc. ▼, -C≡CHR2:H or R2 together with R3 form a carbon-carbon bond R3: H, F, Cl, Br, I, N3, CN, -C≡CH, OH, OCH3, C H2OH and R3 are F, Cl, Br, I, N3, CN, C≡CH, OH, O If CH3 or CH2OH, it is the hydroxymethyl function at the 4'-position. or R3 can have a cis- or trans-configuration with respect to R2 together with form a carbon-carbon bond. 12. Formula as active ingredient ▲There are mathematical formulas, chemical formulas, tables, etc.▼I and a therapeutically acceptable salt thereof. In the above formula, the groups A, X, R1, R2 and R3 are defined as follows. A: (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (b) ▲ Mathematical formulas, chemical formulas, tables, etc. etc. ▼X: (a) O (b)S (c) CH2 R1: H, alkyl containing 1 to 3 carbon atoms (including cyclopropyl) ), -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲Formula , chemical formulas, tables, etc. ▼, -C≡CHR2:H or R2 together with R3 to form a carbon-carbon bond R3: H, F, Cl, Br, I, N3, CN, C≡CH, OH, OCH3, CH 2OH and R3 is F, Cl, Br, I, N3, CN, C≡CH, OH, OCH 3 or CH2OH, it is related to the hydroxymethyl function at the 4'-position. may have a cis- or trans-configuration or R3 is identical to R2. Together they form a carbon-carbon bond. 13. Treatment of infections caused by retroviruses or by hepatitis B virus Formulas used in the manufacture of medicaments for therapeutic and/or prophylactic treatment ▲There are mathematical formulas, chemical formulas, tables, etc.▼I and therapeutically acceptable salts thereof. In the above formula, the groups A, X, R1, R2 and R3 are defined as follows. A: (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (b) ▲ Mathematical formulas, chemical formulas, tables, etc. etc. ▼X: (a) O (b)S (c) CH2 R1: H, alkyl containing 1 to 3 carbon atoms (including cyclopropyl) ), -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, ▲Formula , chemical formulas, tables, etc. ▼, -C≡CHR2:H or R2 together with R3 form a carbon-carbon bond R3: H, F, Cl, Br, I, N3, CN, -C≡CH, OH, OCH3, C H2OH and R3 are F, Cl, Br, I, N3, CN, C≡CH, OH, OO If H3 or CH2OH, it is a hydroxymethyl function at the 4'-position. or R3 can have a cis- or trans-configuration with respect to R2 together with form a carbon-carbon bond. 14. For use in the therapeutic treatment of human infections caused by the HIV virus 14. The compound according to claim 13. 15. Effect of a compound of formula I as defined in claim 11 on a host in need of treatment. retroviruses including HIV or hepatitis B virus by administering Therapeutic and/or preventive treatment of mammalian and human infections caused by How to treat it defensively. 16. Request for therapeutic treatment of human infections caused by the HIV virus The method according to claim 15. 17. A. Glycosides as encompassed by formula I are represented by pyri corresponding to group A in formula I. condensation at the N-1 position of the midine derivative, and then the compound I thus obtained. Either the α-anomer is separated and the protecting group is removed, or the R. formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼III (in the formula, A, X, R2, R4 and R5 (as described above) is anomerized to produce α- and β-anomers. - and then separating the α-anomer and removing the protecting group, or C. formula ▲There are mathematical formulas, chemical formulas, tables, etc. ▼IV (in the formula, X, R2, R4 and R5 are the same as above) and B is a pyrimidine or purine base) is transglycosylated to produce the above-mentioned nucleoside containing the pyrimidine group A. D. formation followed by separation of the α-anomer and removal of the protecting group. formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼V (wherein A, X and R5 are as described above and R7 is a leaving group) Substituting group R7 of the compound with group R3 and then removing the protecting group E. Uracil moiety in compounds of formula I ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is as described above) to the cytosine part ▲ There are mathematical formulas, chemical formulas, tables, etc. Masu▼ (where R1 is as described above) and then, if desired, this by converting the compound of formula I thus obtained into a therapeutically acceptable salt. expression ▲There are mathematical formulas, chemical formulas, tables, etc.▼I (wherein A, X, R2 and R3 are as defined in claim 1) or A method for producing therapeutically acceptable salts thereof.