Indole derivatives with antiviral activity

A compound of the formula: ##STR1## wherein PA1 R.sub.1 is hydrogen, lower alkyl, or optionally substituted arylsulfonyl, or the like, PA1 R.sup.2 is hydrogen, lower alkyl, or optionally substituted aralklyl, or the like, PA1 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is independently hydrogen, halogen, trihalogenated lower alkyl, or the like, PA1 X is hydroxy or optionally substituted amino, PA1 Y is COOR R is hydrogen or an ester residue), optionally substituted aryl, or optionally substituted heteroaryl, has integrase inhibition activity, and is useful as an anti-HIV drug.

TECHNICAL FIELD
 This invention relates to novel compounds having an antiviral activity, in
 detail indole derivatives having an inhibitory activity against viral
 integrase, and pharmaceutical compositions containing them, especially
 anti-HIV drugs.
 BACKGROUND ART
 Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is
 known to cause acquired immunodleficiency syndrome (AIDS). The drug for
 treatment of AIDS is mainly selected from the group of reverse
 transcriptase inhibitors (AZT, 3TC, and the like) and protease inhibitors
 (Indinavir and the like), but they are proved to be accompanied by side
 effects such as nephropathy and the emergence of resistant virus. Thus,
 the development of anti-HIV drugs having the other mechanism of action has
 been desired.
 In the above circumstance, integrase has recently been thought to be
 noteworthy, which is an enzyme relating to the site-specific insertion of
 viral DNA into chromosome in animal cells, and the research for anti-HIV
 drugs based on said enzyme inhibition activity is performed ((1) Proc.
 Natl. Acad. Sci. USA 61 (3), 1013-1020 (1968), KOURILSKY P et al.; (2) J.
 VIROL. METHODS (NETHERLANDS), 17/1-2(55-61) (1987), F Barin et al.; (3)
 Proc. Natl. Acad. Sci. USA 90: 2399 (1993), Fesen. MR (1993); (4) CDC AIDS
 Weekly Pagination:P2 (1990). DeNoon, D J). Some integrase inhibitors has
 recently been reported, for example, peptide derivatives described in U.S.
 Pat. No. 5,578,573, tetrahydronaphthyl derivatives described in GB
 2306476A, and acrydone derivatives described in WO 97/38999.
 Additionally, in the literature, Khim. Geterotsikl. Soedin. 1973, (11),
 1519, some kind of indole derivatives are described, but their therapeutic
 activity is not described. Moreover, in U.S. Pat. No. 5.475,109,
 non-condensed heterocyclic compounds substituted with dioxobutanoic acid
 are described to be useful as an anti influenza viral drug, whose
 mechanism of the action is the inhibition of cap-dependent endonuclease.
 DISCLOSURE OF INVENTION
 In the circumstance above, the development of a novel integrase inhibitor
 is desired. The present inventors have studied intensively to find out
 that novel indole derivatives have an inhibitory action on integrase, and
 are useful as antiviral drugs, especially anti-HIV drugs, to accomplish
 the present invention shown below.
 (1) A compound of the formula:
 ##STR2##
 wherein
 R.sup.1 is hydrogen, lower alkyl, cycloalkyl lower alkyl, lower
 alkylsulfonyl, lower alkylcarbonyl, optionally substituted aryl,
 optionally substituted aralkyl, optionally substituted arylsulfonyl,
 optionally substituted arylcarbonyl, optionally substituted heteroaryl,
 optionally substituted heteroaralkyl, optionally substituted
 heteroarylsulfonyl, lower alkoxycarbonyl, optionally substituted
 sulfamoyl, or optionally substituted carbamoyl;
 R.sup.2 is hydrogen, lower alkyl, lower alkylcarbonyl, optionally
 substituted aryl, optionally substituted aralkyl, optionally substituted
 arylcarbonyl, optionally substituted heteroaryl, optionally substituted
 heteroaralkyl, optionally substituted arylthio, optionally substituted
 arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted
 heterocyclyl lower alkyl, or optionally substituted heterocyclyl sulfonyl;
 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each is independently hydrogen,
 halogen, trihalogenated lower alkyl, hydroxy, lower alkoxy, nitro, amino,
 optionally esterified carboxy, optionally substituted aralkyloxy, or
 optionally substituted arytsulfonyloxy;
 X is hydroxy or optionally substituted amino;
 Y is COOR (R is hydrogen or an ester residue), optionally substituted aryl,
 or optionally substituted heteroaryl,
 provided that a compound wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, and RG
 each is hydrogen; R.sup.4 is hydrogen, methoxy, or chloro; X is hydroxy;
 and Y is COOC.sub.2 H.sub.5 is excluded, (hereinafter referred to as a
 compound (I)), a tautomer, or a pharmaceutically acceptable salt, or a
 hydrate thereof.
 (2) The compound according to above (1) wherein R.sup.1 and R.sup.2 are not
 hydrogens at the same time when Y is COOR (R is as defined above).
 (3) The compound according to above (1) wherein R.sup.1 and R.sup.2 are not
 hydrogens at the same time when X is hydroxy and Y is COOR (R is as
 defined above).
 (4) The compound according to any one of above (1)-(3) wherein R.sup.1 is
 hydrogen or optionally substituted arylsulfonyl.
 (5) The compound according to any one of above (1)-(3) wherein R.sup.2 is
 hydrogen, optionally substituted aryl, or optionally substituted aralkyl.
 (6) The compound according to any one of above (1)-(3) wherein R.sup.3,
 R.sup.4, R.sup.5, and R.sup.6 each is independently hydrogen or halogen.
 (7) The compound according to above (6) wherein R.sup.3, R.sup.5, and
 R.sup.6 are all hydrogens.
 (8) The compound according to any one of above (1)-(3) wherein X is
 hydroxy.
 (9) The compound according to above (1) wherein Y is optionally substituted
 heteroaryl.
 (10) The compound according to above (9) wherein said heteroaryl is a 5- or
 6-membered ring containing at least one nitrogen atom.
 (11) The compound according to above (10) wherein said heteroaryl is
 tetrazolyl, triazolyl, or imidazolyl.
 (12) The compound according to any one of above (1)-(3) wherein R.sup.1 is
 hydrogen or optionally substituted arylsulfonyl; R.sup.2 is hydrogen,
 optionally substituted aryl, or optionally substituted aralkyl; R.sup.3,
 R.sup.4, R.sup.5, and R.sup.6 each is independently hydrogen or halogen; X
 is hydroxy.
 (13) The compound according to above (1) wherein R.sup.1 is hydrogen or
 optionally substituted arylsulfonyl; R.sup.2 is hydrogen, optionally
 substituted aryl, or optionally substituted aralkyl; R.sup.3, R.sup.4,
 R.sup.5, and R.sup.6 each is independently hydrogen or halogen; X is
 hydroxy; Y is optionally substituted heteroaryl. (14) The compound
 according to above (13) wherein R.sup.1 is hydrogen or phenylsulfonyl
 optionally substituted with halogen; R.sup.2 is hydrogen, phenyl
 optionally substituted with halogen, or phenylmethyl optionally
 substituted with halogen; R.sup.4 is halogen; R.sup.3, R.sup.5, and
 R.sup.6 are all hydrogens at the same time; X is hydroxy; Y is tetrazolyl.
 (15) A pharmaceutical composition containing, as an active ingredient, an
 incdole derivative having a group of the formula: --C(O)CH.dbd.C(X)Y
 (wherein X and Y are as defined above) at the 3-position.
 (16) A pharmaceutical composition containing the compound according to any
 one of above (1)-(14) as an active ingredient.
 (17) A composition for inhibiting integrase which contains the compound
 according to any one of above (1)-(14).
 (18) An antiviral composition which contains the compound according to any
 one of above (1)-(14).
 (19) An anti-HIV composition which contains the compound according to any
 one of above (1)-(14).
 (20) An anti-HIV medical mixture comprising a reverse transcriptase
 inhibitor and/or a protease inhibitor in addition to the integrase
 inhibitor according to above (17).
 The compound (I) of the present invention is characterized in that the
 indole ring has a group of the formula: --C(O)CH.dbd.C(X)Y at the
 3-position.
 The terms used in the specification are explained below. Each term by
 itself or as part of (an)other substituent(s) means the same unless
 particularly mentioned.
 The term "lower alkyl" is, for example, a C1-C6 straight or branched chain
 alkyl group, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl,
 isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
 tert-pentyl, n-hexyl, isohexyl, and the like. A preferable embodiment is
 C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
 isobutyl, and tert-butyl.
 The term "lower alkoxy" is, for example, a C1-C6 straight or branched chain
 alkoxy group, which includes methoxy, ethoxy, n-propoxy, isopropoxy,
 n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,
 n-hexyloxy, isohexyloxy, and the like. A preferable embodiment is C1-C4
 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
 isobutoxy, tert-butoxy, and the like.
 The term "cycloalkyl lower alkyl" is, for example, the above-mentioned
 lower alkyl group substituted with C3-C6 cycloalkyl, which includes
 cyclopropyl methyl, 2-cyclopropyl ethyl, 4-cyclopropyl butyl, cyclopentyl
 methyl, 3-cyclopentyl propyl, cyclohexyl methyl, 2-cyclohexyl ethyl, and
 the like. A preferable embodiment is C1-C4 alkyl substituted with
 cyclopropyl, for example, cyclopropyl methyl, 2-cyclopropyl ethyl, and
 4-cyclopropyl butyl.
 The term "lower alkylsulfonyl" is, for example, a sulfonyl group
 substituted with the above-mentioned lower alkyl, which includes
 methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,
 n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,
 n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl,
 tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, and the like. A
 preferable embodiment is sulfonyl substituted with C1-C4 alkyl, for
 example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,
 isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,
 and tert-butylsulfonyl.
 The term "lower alkylcarbonyl" is, for example, a carbonyl group
 substituted with the above-mentioned lower alkyl, which includes
 methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,
 n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl,
 n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl,
 tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, and the like. A
 preferable embodiment is carbonyl substituted with C1-C4 alkyl, for
 example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,
 isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,
 tert-butylcarbonyl.
 The term "lower alkoxycarbonyl" is an carbonyl group substituted with the
 above-mentioned lower alkoxy, which includes methoxycarbonyl,
 ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl
 isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
 n-pentyloxycarbonyl, isopentyloxycarbonyl, n-hexyloxycarbonyl,
 isohexyloxycarbonyl, and the like. A preferable embodiment is carbonyl
 substituted with C1-C4 alkoxy, for example, methoxycarbonyl,
 ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
 isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl.
 The term "aryl" is, for example, phenyl, naphthyl, or polycyclic aromatic
 hydrocarbone (phenanthry, and the like), and the like. A preferable
 embodiment is phenyl and naphthyl.
 The term "aralkyl" is, for example, the above-mentioned lower alkyl group
 substituted with the above-mentioned aryl, which includes benzyl,
 2-phenethyl, 1-naphthylmethyl, 2-(2-naphthyl)ethyl, and the like. A
 preferable embodiment is benzyl.
 The term "aralkyloxy" is, for example, an oxy group substituted with the
 above-mentioned aralkyl, which includes benzyloxy, 2-phenethyloxy,
 1-naphthylmethyloxy, 2-(2-naphthyl)ethyloxy, and the like.
 The term "arylcarbonyl" is, for example, a carbonyl group substituted with
 the above-mentioned aryl, which includes benzoyl, naphthylcarbonyl, and
 the like.
 The term "arylthio" is, for example, a thio group substituted with the
 above-mentioned aryl, which includes phenylthio, naphthylthio, and the
 like.
 The term "arylsulfinyl" is, for example, a sulfinyl group substituted with
 the above-mentioned aryl, which includes phenylsulfinyl, naphthylsulfinyl,
 and the like.
 The term "arylsulfonyl" is, for example, a sulfonyl group substituted with
 the above-mentioned aryl, which includes phenylsulfonyl, naphthylsulfonyl,
 and the like.
 The term "arylsulfonyloxy" is, for example, a sulfonyloxy group substituted
 with the above-mentioned aryl, which includes phenylsulfonyloxy,
 naphthylsulfonyloxy, and the like.
 The term "heteroaryl" is, for example, a 5- or 6-membered aromatic cyclic
 group containing 1 to 4 same or different hetero atoms selected from the
 group of N, O and S. which includes furyl, thienyl, pyrolyl, oxazolyl,
 thiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl,
 pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl, thiazolyl, and the like.
 The term "heteroarylsulfonyl" is, for example, a sulfonyl group
 substituted with the above heteroaryl, which includes furylsulfonyl,
 thienylsulfonyl, pyrolylsulfonyl, oxazolylsulfonyl, thiazolylsulfonyl,
 imidazolylsulfonyl, pyrazolylsulfonyl, triazolylsulfonyl, pyridylsulfonyl,
 pyridazinylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl,
 triazinylsulfonyl, tetrazolylsulfonyl, and the like.
 The term "heteroaralkyl" is, for example, the above-mentioned lower alkyl
 group substituted with the above-mentioned heteroaryl, which includes
 furylmethyl, thienylmethyl, 2-thienylethyl, pyrolylmethyl, 2-pyrolylethyl,
 oxazolylmethyl, 3-thiazolylpropyl, 4-imidazolylbutyl, pyrazolylmethyl,
 2-triazolylethyl, pyridylmethyl 2-pyridinylethyl, 3-pyridazinylpropyl,
 pyrimidinylmethyl, 2-pyrazinylethyl, 3-triazinylpropyl, 4-tetrazolylbutyl,
 and the like.
 The term "heterocyclyl" is a 5- to 7-membered non-aromatic cyclic group
 containing 1 to 3 same or different hetero atoms selected from the group
 of N, O, and S, which includes, for example, morpholinyl, piperadinyl,
 dioxanyl, piperidinyl, pyrolidinyl, thiazolidinyl, oxazolidinyl,
 imidazolidinyl, thiazolinyl, oxazolinyl, imidazolinyl, and the like.
 The term "heterocyclyl lower alkyl" is the above-mentioned lower alkyl
 group substituted with heterocyclic, preferably, morpholinomethyl, and the
 like.
 The above-mentioned "aryl", "arylcarbonyl", "arylsulfonyl",
 "arylsulfonyloxy", "aralkyl", "aralkyloxy", "heteroaryl",
 "heteroarylsulfonyl", "heteroaralkyl", "arylthio", "arylsulfinyl",
 "arylsulfonyl", "heterocyclyl lower alkyl", and "heterocyclyl sulfonyl",
 if substituted, each may be substituted with same or different 1 to 4
 substutuent(s) at any substitutable position (ortho, meta, and/or para),
 which includes, for example, hydroxy, carboxy, halogen (e.g., F, Cl, and
 Br), trihalogenated lower alkyl (e.g., CF.sub.3, CH.sub.2 CF.sub.3), lower
 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkoxy (e.g.,
 methoxy, ethoxy, propoxy, butoxy), lower alkoxycarbonyl (e.g.,
 methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, amino, amino
 substituted with lower alkyl (e.g., methylamino, ethylamino,
 dimethylamino), azido, aryl (e.g., phenyl), aralkyl (e.g., benzyl), an
 amino-protective group (e.g., trityl), and the like.
 "Halogen" includes F, Cl, Br, and I.
 "Trihalogenated lower alkyl" includes trifluoromethyl, trichloromethyl,
 tribromomethyl, trifluoroethyl, and the like.
 The substituent of "optionally substituted sulfamoyl" and "optionally
 substituted carbamoyl" in R.sup.1 includes optionally substituted phenyl
 and lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl).
 The substituent of "optionally substituted amino" in X includes lower alkyl
 (e.g., methyl, ethyl), lower alkoxyalkyl (e.g., ethoxymethyl,
 ethoxyethyl), aralkyl (e.g., benzyl), and the like.
 The ester residue of R in Y, or that of "optionally esterified carboxy" in
 R.sup.3, R.sup.4, R.sup.5, and R.sup.6 includes lower alkyl (e.g., methyl,
 ethyl, tert-butyl), aralkyl (e.g., benzyl, diphenylmethyl), and the like.
 Preferable examples of each substituent of the compound (I) are shown
 below.
 A preferable example of R.sup.1 includes hydrogen, methyl, n-butyl,
 cyclopropylmethyl, dimethylsulfamoyl, dimethylcarbamoyl,
 isopropylsulfonyl, morpholinosulfonyl, tert-butoxycarbonyl, optionally
 substituted phenylcarbamoyl (the substituent; e.g., halogen), optionally
 substituted phenylsulfonyl (the substituent; e.g., trifluoromethyl,
 methyl, isopropyl, benzyl, halogen, methoxy, carboxy, methoxycarbonyl),
 optionally substituted benzyl (the substituent; azido, halogen, phenyl,
 carboxy, methoxycarbonyl, nitro, amino), 2-phenethyl, 1-naphthylmethyl,
 pyridylmethyl, optionally substituted thienyl (the substituent; e.g.,
 carboxy, methoxycarbonyl), and the like. More preferable example includes
 hydrogen or optionally substituted phenylsulfonyl.
 A preferable example of R.sup.2 includes hydrogen, n-butyl, optionally
 substituted phenyl (the substituent; e.g., halogen, methoxy,
 dimethylamino), optionally substituted benzyl, or phenylpropyl (the
 substituent; e.g., halogen, methoxy, carboxy, methoxycarbonyl),
 phenylcarbonyl, optionally substituted phenylthio (the substituent: e.g.,
 halogen, methoxy), optionally substituted phenylsulfinyl (the substituent:
 e.g., halogen), optionally substituted phenylsulfonyl (the substituent:
 e.g., halogen, methoxy), morpholinomethyl, and the like. More preferable
 example includes hydrogen, optionally substituted phenyl, and optionally
 substituted benzyl.
 A preferable embodiment of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is that
 all are hydrogens or that R.sup.4 is halogen (especially, chlorine) and
 the others are hydrogens.
 Preferable example of X is hydroxy.
 Preferable example of Y includes COOR (R is hydrogen or an ester residue),
 or optionally substituted heteroaryl. Preferable example of R is hydrogen
 in light of the anti viral activity. Moreover the compound wherein R is an
 ester residue is useful as a synthetic intermediate. Preferable example of
 heteroaryl in Y is a 5- or 6-membered cyclic group containing at least one
 nitrogen atom in the ring, more preferably, tetrazolyl, triazolyl,
 imidazolyl, and thiazolyl, especially, tetrazolyl.
 The compound (I) usually shows chemical equilibrium in a solution and the
 like as shown below.
 ##STR3##
 wherein R.sup.7 is hydrogen or the substituent on the imino group.
 In the chemical equilibrium shown above, the compound (I', wherein Z=O) is
 the diketone derivative of the compound (I, wherein X=OH), and the
 compound (I") and the compound (I) are cis-trans isomers with respect to
 the olefin part of the 3-side chain. All the theoretically possible
 tautomers of the compound (I) including these compounds are in the scope
 of the present invention. In the specification, the term "the compound
 (I)" may be merely used as general term of the compound (I) and its all
 tautomers. Moreover, most of N.M.R. data in the following examples
 correspond to the above-described form (I) depending on the measuring
 condition.
 As a salt of the compound (I), any of pharmaceutically acceptable salts can
 be used, including base addition salts, for example, alkali metal salts
 such as sodium or potassium salts; alkaline-earth metal salts such as
 calcium or magnesium salts; ammonium salts; aliphatic amine salts such as
 trimethylamine, triethylamine, dicyclohexylamine, ethanolamine,
 diethanolamine, triethanolamine, or procaine salts; aralkylamine salts
 such as N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine
 salts such as pyridine, picoline, quinoline, or isoquinoline salts;
 quaternary ammonium salts such as tetramethylammonium, tetraethylammonium,
 benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium,
 methyltrioctylammonium or tetrabutylammonium salts; and basic amino acid
 salts such as arginine or lysine salts. Acid addition salts include, for
 example, mineral acid salts such as hydrochlorides, sulfates, nitrate,
 phosphates, carbonates hydrogen carbonates or perchlorates; organic acid
 salts such as acetates, propionates, lactates, maleates, fumarates,
 tartrates, malates, succinates, or ascorbates; sulfonates such as
 methanesulfonates, isethionates, benzenesulfonates, or
 p-toluenesulfonates; and acidic amino acid salts such as aspartates or
 glutamates.
 Furthermore, hydrates and various solvates of the compound (I) are in the
 scope of the present invention.
 The method of the preparation of the compound (I) is explained below.
 The compounds (I) are novel indole derivatives, on the other hand, known
 compounds having indole structure as a basic skeleton have already been
 reported (Hetrocyclic Compounds, Indoles Part 1-3, (Wiley Interscience),
 The chemistry of Indoles (Academic Press), etc). Accordingly, a person
 skilled in the art can easily prepare the compounds (I), for example, by
 applying these known compounds as starting materials to widely known
 organic reactions. The representative general method of the preparation of
 the compound (I) is shown below.
 (1) Forming of the 3-side Chain (The Basic Synthetic Route)
 ##STR4##
 (A) In case of X=OH
 For example, various 3-acetylindole derivatives (II) obtained in accordance
 with the methods described in the literature (Tetrahedron 48, 10645(1999))
 and the like, react with the above compound (III) (wherein L is a leaving
 group, for example, a halogen or OR.sup.8 (R.sup.8 is a lower alkyl and
 the like) and the like), preferably in the presence of base, to give the
 compound (Ia).
 Examples of the reaction solvent include tetrahydrofuran (THF), dlioxane,
 and the like. Examples of the base include sodium ethoxide, potassium
 t-butoxide, lithium bis(trimethylsilyl)amide (LHMDS), and the like. The
 reaction temperature is approximately -100 to 100.degree. C. preferably
 -70 to 60.degree. C.
 Examples of the compound (III) include dimethyl oxalate, (diethyl oxalate),
 methyl oxalyl chloride, (ethyl oxalyl chloride),
 2-trityl-2H-tetrazole-5-carboxylic acid ethyl ester,
 1-trityl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester,
 1-tritylimidazole-2-carboxylic acid ethyl ester, phthalic anhydride,
 o-methoxybenzoly chloride, and the like.
 (B) In case of X=NHR.sup.7
 The above compound (Ia) reacts with the above compound (TV) (R.sup.7 is a
 hydrogen or the substituent on the amino group) or their acid addition
 salt to give the compound (Ib).
 Examples of the reaction solvents include methanol, ethanol, and the like.
 The reaction temperature is approximately -10 to 100.degree. C.,
 preferably room temperature to 100.degree. C.
 (2) The Introduction of the Substituent (R.sup.1) at the 1-positon
 ##STR5##
 For example, the above compound (V) obtained in accordance with the method
 described in (1) can react with the compound (VI) (wherein L is a leaving
 group), or isocyanate derivatives which can be introduced as R.sup.1, or
 the like, if desired in the presence of base, to give the compound (I).
 Examples of the bases include NaH, K.sub.2 CO.sub.3, and the like. Examples
 of the solvents include THF, dioxane, and the like.
 Examples of the compound (VI) include various kinds of sulfonyl chloride
 (e.g., (substituted) benzenesulfony 1chloride, 2-thiophenesulfonyl
 chloride, (substituted) aminosulfonyl chloride, alkylsulfonyl chloride,
 and the like), halogenated alkyl (e.g., methyl iodide, butyl bromide,
 cyclopropyl bromide, and the like), halogenated aralkyl (e.g.,
 (substituted) benzyl, picolyl, naphthyl, biphenylmethyl, and the like),
 carbamoyl chloride (e.g., dimethylcarbamoyl chloride and the like),
 halogenated acyl (e.g., p-p-fluorobenzoyl chloride and the like), and the
 like.
 Examples of isocyanate derivatives include (substituted) aryl isocyanate
 (e.g., phenyl isocyanate and the like), and the like.
 The reaction temperature is approximately -100 to 100.degree. C.,
 preferably -20 to 60.degree. C. Moreover, this reaction is suitable for
 the case of X=OH.
 Before the reaction described in any one of (1) or (2), if desired, the
 functional group may be protected in accordance with methods widely known
 to a person skilled in the art, and after that, if desired, ester
 hydrolysis or deprotection may be carried out.
 Use of the compounds of the present invention is explained below.
 The compounds (I) are useful as pharmaceutical compositions such as
 antiviral drugs. The compounds (I) have remarkable inhibition activity
 against viral integrase. Accordingly, the compounds (I) can be used for
 the prevention or treatment of various diseases caused by virus which at
 least produce integrase to grow in infected animal cells. For example, the
 compounds are useful as integrase inhibitors against retrovirus (e.g.,
 HIV-1 and the like) and as anti-HIV drugs.
 Furthermore, the compounds (I) can be used in the combination therapy with
 anti-HIV drugs having a different mechanism of action such as reverse
 transcriptase and/or protease inhibitor.
 The compounds (I) of the present invention can be administered orally or
 parenterally. For oral administration, the compounds of the present
 invention can be used in any form of usual formulations, for example,
 solid formulations such as tablets, powders, granules, capsules; aqueous
 formulations; oleaginous suspensions; solutions such as syrup or elixir.
 For parenteral administration, the compounds of the present invention can
 be used as an aqueous or oleaginous suspension injection, or nose drops.
 In the preparation of such formulations, conventional excipients, binding
 agents, lubricants, aqueous solvents, oleaginous solvents, emulsifying
 agents, preservatives, stabilizers, and the like can be optionally used.
 Although an appropriate dosage of the compound of the present invention
 varies depending on the administration route, age, body weight, conditions
 of the patient, and kind of disease, in the case of oral administration,
 the daily dosage can be between approximately 0.05-3000 mg, preferably
 approximately 0.1-1000 mg, an adult a day. The daily dosage can be
 administered in divisions. In the case of parenteral administration, the
 daily dosage can be between approximately 0.01-1000 mg, preferably
 approximately 0.05-500 mg.
 Furthermore, all kinds of indole derivatives having the group of the
 formula: --C(O)CH.dbd.C(X)Y wherein X and Y are defined above, at the
 3-position of the indole can be used as pharmaceutical compositions such
 as antiviral drugs, as well as the compound (I). In said indole
 derivative, a wide variety of substituents can be introduced at any
 position other than the 3-position, as far as they do not have a negative
 effect on the pharmacological activity. The above indole derivatives can
 be prepared in accordance with the preparation of the compound (I).
 The compound (I) are useful as intermediates of drug, starting materials of
 the preparation, and the like. For example, the compounds (I) wherein R
 defined in Y is an ester residue can be easily derived to the compound
 wherein R is a hydrogen by deprotection.
 BEST MODE FOR CARRYING OUT THE INVENTION
 Examples of the present invention are shown below. Reactions are usually
 carried out under nitrogen atmosphere, and reaction solvents are used as
 dried over molecular sieve and the like. Extracts are dried over sodium
 sulfate or magnesium sulfate and the like.
 (Abbreviation)
 Me=methyl; Et=ethyl; iPr=isopropyl; Ph=phenyl; Bn=benzyl; Ac=acetyl;
 Boc=t-butoxycarbonyl; MeOH=methanol; EtOH=ethanol; MEK=methyl ethyl
 ketone; EtOAc=ethyl acetate; CHCl.sub.3 =chloroform; MeCN=acetonitrile;
 DMF=N,N-dimethylformamide; DMA=N,N-dimethylacetamide; Et.sub.2
 O=ethylether; i-Pr.sub.2 O=isopropylether; LHMDS=lithium
 bis(trimethylsilyl)amide; Hex=n-hexane; THF=tetrahydrofuran;
 DMSO=dimethylsulfoxide; aq.dioxane=aqueous dioxane; Tet=2-H-tetrazol-5-yl;
 Tri=1H-[1,2,4]-triazol-3-yl; Imi=2-imidazolyl. Furthermore, as an example
 for expression of the substituents, Ph(2,5-Cl) represents phenyl group
 substituted with Cl at 2- and 5-position.