CA2145545A1

CA2145545A1 - "sensitizing hiv-1 inhibitors" sensitize hiv infected individuals to "non-nucleoside hiv treatment drugs"

Info

Publication number: CA2145545A1
Application number: CA002145545A
Authority: CA
Inventors: William Gary Tarpley; Thomas Jerome Dueweke; Donald Herman Batts
Original assignee: Individual
Current assignee: Pharmacia and Upjohn Co
Priority date: 1992-10-28
Filing date: 1993-09-10
Publication date: 1994-05-11
Also published as: AU4848293A; NO951608L; PL308551A1; JPH08502745A; KR950703958A; MX9306031A; NO951608D0; EP0666744A1; CZ69695A3; HU9501218D0; HUT72050A; FI952018A0; WO1994009781A1; FI952018A

Abstract

The present invention are methods of treating a HIV positive human which Comprises (1) administering to the HIV positive individual a sensitizingly effective amount of a SENSITIZING HIV-I INHIBITOR until increased sensitivity to a NON-NU-CLEOSIDE HIV TREATMENT DRUG develops, (2) administering to the HIV positive individual an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG. An alternative method is a method of treating a HIV positive human which comprises administering to the HIV positive individual a sensitizingly effective amount of one or more SENSITIZING HIV-I
INHIBITOR concurrently with an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.

Description

W 0 94/09781 2 1 ~ 5 5 4 ~ PCT/~593/08354 USE OF BHAP COMPOUNDS IN COMBINATION WITH OTHER NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS FOR THE TREATMENT OF HIY INFECTION
BACKGROUND OF THE INVENTION
1. Field of the lnvention The invention relates to a method of treating HIV-1 positive individuals with a SENSITIZING HIV-1 INHIBITOR prior to, currently or i~ Lelllly with drugs for thetreatment of HIV (NON-NUCLEOSIDE HIV TREATMENT DRUG).

2. Description of the Related Art European Patent Publication Nos. 484 071 A2, 462,800 A2, 462,808 A2, US Patent 5,124,327, 481,802 Al and Antimicrobial Agents and Chemotherapy 36, 1019 (1992) [MERCK]
disclose a variety of pyridinone derivatives useful in the treatment of HIV-1 infection alone or in combination with other anti-virals.
European Patent Publication Nos. 393 529 A1, 393 530 A1, 393,604 A2, 410 148 A1,415 304 A2, 429 987 A2, 498 290 A1 disclose dipyridodiazepinone derivatives inrhl-lin~
nevirapine (BI-R(~-587) 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one of Boehringer Ingelheim [BOEHRINGER] are useful for in the treatment of HIV-1 infection alone or in combination with other anti-virals.
Intemational Publications Nos. WO 92/00952 and WO 92/00979, and European Patent Publication Nos. 417 840 A1, 0384 522 A1, 336,466 A1, 430 334 A1 of Janssen ~JANSSEN]
discloses various compounds which are useful in the treatment of HIV- 1 infection alone or in combination with other anti-virals. These compounds include (+)-(SS)4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1jk][1,4]benzodiazepin-2(1H)-thione, (+)-(5S)4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imicl~7O[4,5,1jk][1,4]benzodia7epin-2(1H)-thione, (-)-oc-[(2-nitrophenyl)amino]-2,6-dichloro~n7PnP~cet~midç, (-)-o~-[(5-methyl-2-nitrophenyl)amino]-2~6-dichlorobçn7PnP:~ret:lmide~ (-)-a-[(2-acetylphenyl)amino]-2,6-dichlorobçn7çn~acet~m i de, (-)-o~-[(2-acetyl -5 -methylphenyl)a~lino] -2,6-dichloroben_ene-acetamide~ a-[(2-acetyl-5-chlorul)l enyl)amino]-2,6-dichlorob~n7~n~cet~mide, o~-[(5-chloro-2-nIIluphellyl)amino]-2,6-dichlorobçn7çn~cet~mide, ol-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorob~n7~n~ et~mi(~
A major problem in treating HIV infected individuals with nucleoside and non-nucleoside compounds is that virus resistant to the compounds used for the treatment emerges, see J. Virol., 65. 4887 (1991) and Proc. Natl. Acad. Sci., (USA) 88, 11241 (1991).
The concept of HIV resi~t~nce altering the sensitivity to other drugs within the sarne chemical class has been reported, Science 353. 1557 (1991).
Virology 190, 269 (1992) discusses the antiviral properties of three BHAP compounds and the development of drug-resistant viruses. Further, the article ~ c~ ed the mutations in the WO 94/09781 ~ 1 4 5 5 ~ 5 -2- PCI/U593/08354 RT gene which leads to amino acid changes in the reve;se transcriptase of the resistant strains.
Bioorganic & Medicinal Chemistry Letters 2(12), 1745 (1992) disclosed various nevirapine-liKe compounds including various imida7O[2',3':6,5]dipy;ido[3,2-b:2',3'-e]-1,4-dia_epines which are HIV-I reverse transcriptase inhibitors with greater en_yme affLnity than S nevirapine.
The present invention is a method of treating HIV infected individuals which increases the sensitivity of the HIV virus to treatment with various non-nucleoside drugs.SUMMARY OF INVENTION
Dislcosed is a method of t;eating a HIV positive human which comp;ises (1) ~-lmini~t~ring to the HIV positive individual a s~nciti7ingly effective amount of a SENSITIZING HIV-l INHIBITOR until increased sensitivity to a NON-NUCLEOSIDEHIV TREATMENT DRUG develops, (2) a~lministe~ing to the HIV positive individual an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.
lS Also disclosed is a method of treating a HIV positive human which comprises ~flmini.~çring to the HIV positive individual a se~ ly effective amount of one or more SENSITIZING HIV-l INHIBITOR concu;rently with an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.
Fur~her disclosed is a NON-NUCLEOSIDE HIV TREATMENT DRUG to prepare a medicament for treatment of HIV positive individuals having strains of HIV showing increased sensivity thereto due to the a~lmini~t~.ation of a SENSITIZING HIV-I INHIBITOR.
Ad-lition~lly, disclosed is the use of a NON-NUCLEOSIDE HIV TREATMENT DRUG to p;epa;e a me(lic~ment for the treatrnent of HIV positive individuals concurrently receiving a SENSITIZING HIV-I INHIBITOR.
DETAILED DESCRIPTION OF THE INVENTION
Various nucleoside (AZT) and non-nucleoside reverse transcriptase inhibitors are knowll as being useful for the treatment of HIV infected individuals. Witn regard to the non-nucleoside reverse transc,iL~tase inhibitors, see for example, Eu~upe~l Patent Publication Nos. 484 071 A2, 462,800 A2, 462,808 A2, 481,802 Al, 393 529 Al, 393 530 Al, 393,604 A2, 410 148 Al, 415 304 A2, 429 987 A2, 498 290 A1, 417 840 Al, 0384 522 A1, 336,466 A1, 430 334 A1, US
Patent 5,124,327, International Publications Nos. WO 91/09849, WO 92/00952 and WO
92/00979 and Antimicrobial Agents and Chemotherapy, 36, 1019 (1992).
With the NON-NUCLEOSIDE HIV TREATMENT DRUGs, it has become apparent t'nat r~Ci~t:-n~e to the ph~m~reutic~l agent rapidly develops reducing or elimin~ting the efficacy of NON-NUCLEOSIDE HIV TREATMENT DRUGs.
Tne SEN~lll~lNG HIV-l INHIBITOR CCI"lpOu lds of t'ne present invention sen~i~i7e WO 94/U9781 ~ I 4 5 ~ 4 5 PCI/US93/083S4 the HIV infected individual's HIV to treatment with a NON-NUCLEOSIDE HIV TREATMENT
DRUG. It is preferred that the SENSITIZING HIV-l INHIBITOR, be a BHAP COMPOUND
but other HIV-l RT inhibitors which sen~iti7e HIV infected individuals to treatment with NON-NUCLEOSIDE HIV TREATMENT DRUGs are operable. The BHAP COMPOUNDS are known, see International Publication WO 91/09849. It is preferred that the SENSITIZING HIV-1 INHIBITOR compound be 1-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridin-yl)piperazine (WO 91/09849, EXAMPLE 16) or 1-[2-(5-meth~n~snlfon~midoindolyl)-carbonyl]-4-[3-(N-isc.p,~,l)ylamino)-2-pyridinyl]~i,uel~ille (WO 91/09849, EXAMPLE 105).
The NON-NUCLEOSIDE HIV TREATMENT DRUGs include the MERCK
COMPOUNDS, BOEHRINGER COMPOUNDS and JANSSEN COMPOUNDS, PFIZER
COMPOUNDS, but other non-nucleoside HIV-l reverse ~ ;d~ e inhibitors are also operable.
It is pl~;relled that the MERCK COMPOUNDS be selected from the group con~i~ting of

3- { [(4,7-dichloro- 1,3-benzoxazol-2-yl)methyl]amino } -5-ethyl-6-methylpyridin-2(1 H)-one, 3- { [(4,7-dimethyl- 1,3-benzoxazol-2-yl)methyl]amino } -5-ethyl-6-methylpyridin-2(1 H)-one, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one, 5-ethyl-6-methyl-3-(2-phth~limidQethyl)pyridin-2(1H)-one and 3- ( [1,3-benzoxazol-2-yl)methyl]amino ) -5-ethyl-6-methyl-pyridin-2( lH)-one.
lt is preferred that the BOEHRINGER COMPOUND be 6,11-dihydro- 11-cyclopropyl4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.
It is preferred that the JANSSEN COMPOUNDS be selected from the group consistingof (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imid~70[4,5,1-j~;][ l .4]benzodiazepin-2(1H)-thione, (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imid~zo [4,5,1-jk] [1,4]benzodiazepin-2(1 H)-thione, (-)-a-[(2-nitrophenyl)amino]-2,6-dichlorob~n7ene~ret:-mide, (-)-a-[(5-methyl-2",1,upllellyl)amino]-2,6-dichlorQbçn7e,n~ret~midç, (-)-a-[(2-acetylphenyl)amino]-2,6-dichlorob~n7t-nP~cet~mide.
(-)-a-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorob~n7P-n~acetamide, o~-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichloroken7~,nPa~etamide, a-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorok~menP~ret:-mi-le, a-[(2-acetyl-5-fluo,upllenyl)amino]-2,6-dichlorokçn7Pnçacetamide. It is more 35 ~ lc;d that the JANSSEN COMPOUND be selected from the group consisting of W O 94/09781 ~ 1 4 ~ ~ 4 ~ PC~r/US93/08354 (-)-a-[(2-nitrophenyl)amino] -2,6-dichlorobenzeneacetamide, (-)-a-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-a-[(2-acetylphenyl)amino] -2,6-dichlorobenzeneacetamide, (-)-a-[(2-acetyl-5-methylphenyl)amino]-2,6-dichloroben7ene~cetamide, a-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichloroben7ene~oet:~mi~1e, a-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobe.n7ene~cet~mi-1e, a-[(2-acetyl-5-fluorophenyl)amino] -2,6-dichlorobenzeneacetamide.
It is ~lc;rt;ll~d that the PFIZER COMPOUND be C~3 ~

There are a number of ways the senciti7ing process of the present invention can be used to treat HIV infected individuals (both asy"~c,-"a~ic and those with AIDS).
One method involves treating the HIV infected individual with a SENSITIZING HIV-1 INHIBITOR followed by tre~tment with a NON-NUCLEOSIDE HIV TREATMENT
DRUG. Another method involves concurrent arlmini~tration of the SENSITIZING HIV-20 1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG.
The first method involves treating the HIV infected individual with a SENSITIZING HTV-1 INHIBITOR followed by treatment with the NON-NUCLEOSIDE
HIV TREATMENT DRUG. Using this method the HIV infected individual is given a sensitizingly effective amount of one or more SENSITIZING HIV-1 INHIBITORs until25 increased sensitivity to a NON-NUCLEOSIDE HIV TREATMENT DRUG develops.
This is then followed by a~lmini~tering to the HIV positive individual of an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG. The increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG can be determined clinically and/or in vitro. Utilizing the clinical method, the HIV positive individual will ~() have increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG when resistance develops to the SENSITIZING HIV-1 INHIBITOR. Hence, when the clinician notices resistance developing to the SENSITIZING HIV-1 INHIBITOR, the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG will have ~ WO 94/09781 2 L ~ ~ 5 ~ ~ PCI/US93/08354 occurred and the ~mini.~tration of the SENSITIZING HIV-1 INHIBITOR can be stopped and the administration of the NON-NUCLEOSIDE HIV TREATMENT DRUG
can be started.
- Alternatively, the increased sensitivity to the NON-NUCLEOSIDE HIV
S TREATMENT DRUG can be measured in vitro by measuring the level of p24 antigen as determined by enzyme-linked immunosorbent assay (ELISA) using any of the number of commercially available ELISA kits. When ~dmini~tration of the SENSITIZING HIV-1 INHIBITOR begins, the level of p24 will decrease. When the level of p24 no longer decreases but begins to increase, the HIV positive individual has 10 become resistant to the SENSITIZING HIV-1 INHIBITOR and has increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG.
An alternative method of determining the HIV positive individual's increased sensitivity is by checking the HIV positive individual's reverse transcriptase for a mutation in the region known to confer resistance to the SENSITIZING HIV-l 15 INHIBITOR and increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT
DRUG. If a mutation from proline to leucine occurs at amino acid 236 of the HIV-l reverse transcriptase, then that individual will have increased sensitivity to the NON-NUCLEoSrDE HIV TREATMENT DRUG. It is also likely that other mutations in this region of reverse transcriptase, for example changes at the amino acid from about 200 20 to about 275, more particularly at 233, 234 or 238, will confer resistance to the SENSITIZING HIV-l INHrBrTOR and sen~iti7~tion to the NON-NUCLEOSIDE HIV
TF~EATMENT DRUG. These changes can be monitored or detected by means known to those skilled in the art, see for example J. Virol., 65, 4887 (1991); Proc. Natl. Acad.
Sci. (USA) 88,11241 (1991); Proc. Natl. Acad. Sci. (USA) 89, 1934 (1992); Journ. of 25 Medical Virology, 37, 241 (1992).
The senciti7ingly effective amount is an amount that achieves a s~st~in~ble blood level which can either be below the MIC of the I-rrV virus or above the MIC of the HIV virus. It is preferred that the amount be an amount that exceeds the MIC of the HIV virus since selection of the ~enciti7ed strains will occur more quickly if the MIC of 30 the organism is exceeded for most of the day. One skilled in the art knows how to monitor the blood level to determine if the amount given is above or below the MIC of the HIV virus and is able to then give an amount which will provide a sllst~in~lQle blood level. The SENSITI~rNG HIV-l INHIBITOR is administered in a dosage range of WO 94/0978~ ~ 1 4 5 5 4 ~ -6- PCI/U593/08354 about 50 to about 3,000 mg per day in a single or divided doses, preferably about 600 to about 2,100 mg per day in divided doses. The SENSIllGING HIV-l INHIBITOR is given for a period of about two to about 16 weeks, preferably about 8 to about 12 weeks before the HIV infected individual is treated with a NON-NUCLEOSIDE HIV
S TREATMENT DRUG. More preferably, the transition from administration of the SENSITIZING HIV-1 INHIBITOR to the NON-NUCLEOSIDE HIV TREATMENT
DRUG is measured either clinically and/or in vitro as discussed above. For example, if the SENSITIZING HIV-l INHIBITOR is 1-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine, an HIV infected individual would be treated with a 10 dose of 3-10 mg/kg orally three or four times daily for 8-12 weeks; if the SENSITIZING HIV-l INHIBITOR is 1-[2-(5-m~th~nesulfonamidoindolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]piperazine, an HIV infected individual could be treated with a dose of about 0.5 to about 5 mglkg/dose orally two to four times daily~
this would be followed by a NON-NUCLEOSIDE HIV TREATMENT DRUG.
15 Following treatment with SENSITIZING HIV-l INHIBITOR, the sen~iti7ecl strains would then be more sensitive to the NON-NUCLEOSIDE HIV TREATMENT DRUG.
The dosages of the NON-NUCLEOSIDE HIV TREATMENT DRUG are known to those skilled in the art. The dosage range is from about 50 to about 4,000 mg per day in either a single or divided doses depending on the particular compounds, 20 preferably from about about 50 to about 2,000 mg. If the NON-NUCLEOSIDE HIV
TREATMENT DRUG is a MERCK COMPOUND, it is preferably ~dmini~tered orally in a dosage range of from about 50 to about 2,000 mg, more preferably from about 200 to about 800 mg, one to three times daily. If the NON-NUCLEOSIDE HIV
TREATMENT DRUG is a BOEHRINGER COMPOUND, it is preferably administered 25 orally in a dosage range of from about 50 to about 2,000 mg, more preferably from about 50 to about 500 mg per day in a single or divided doses, still more preferably from about 100 to about 200 mg per day as a single dose. If the NON-NUCLEOSIDE
HIV TREATMENT DRUG is a JANSSEN COMPOUND it is preferably administered from about 50 to about 2,000 mg, more preferably from about 100 to about 2,000 mg ~0 per day either orally in divided doses or by continuous IV infusion depending on the particular compound. More specifically, if the JANSSEN COMPOUND is (+)-(5S)-

4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, it is ~Amini~tered continuously IV in a total daily WO 94/09781 ~ ~ ~ 5 ~ 4 ~ PCr/US93/08354 dose of frorn about 50 to about 1,000 mg daily. More specifically if the JANSSENCOMPOUND is (-)-oc-[(2-acetylphenyl)amino]-2,6-dichlorobenzene- acetamide, it isA~7mini~tered orally in a total daily dose of from about l00 to about 2,000 mg in divided -' doses two to six times daily. With this method one or more than one SENSITIZING
S HIV-1 INHIBITOR can be used, likewise one or more than one NOl~-NUCLEOSIDE
HIV TREATMENT DRUG can be used.
This method can involve a multiple of treatment cycles as is known to those skilled in the art. Further, a modified form of this method is after the sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG has increased by the initial 10 a~7mini.~tration of the SENSl'l l'~ G HIV-1 INHIBITOR, is to Ar7mini~ter the SENSITTZING T~V-1 TNHIBITOR and NON-NUCLEOSIDE HTV TREATMENT
DRUG con~ clllly rather than t~rminS7te the SENSITTZING HIV-1 INHIBITOR.
Another alternative form of this method is after the initial Ar7lmini~tration of the SENSITIZING HIV-1 INHIBITOR to increase the HIV positive individual's sensitivity 15 to the NON-NUCLEOSIDE HIV TREATMENT DRUG, is to ,7-7mini~ter the SENSITTZING HrV-l TNHIBITOR illLr,~ r~ y with Ar7mini~7Tation of the NON-NUCLEOSTDE HIV TREATMENT DRUG to reduce the probability that the increased sensitivity does not disappear.
The other method of treatment involves initially treating the HIV infected 20 individual with a SENSTTTZING HIV-1 INHTBITOR concurrently with the NON-NUCLEOSIDE HIV TREATMENT DRUG. Using this method the HIV infected individual is given both the SENSITIZING HIV-1 INHTBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG .~imnlt~7neously. The therapeutic dosage range and frequency of Admini.~7Tation of both the SENSTTIZING HIV-l INHTBITOR
25 and NON-NUCLEOSIDE HIV TREATMENT DRUG is the same as for ~r7mini~tration of the NON-NUCLEOSIDE HIV TREATMENT DRUG following 7dmini~tration of the SENSITIZING HTV-1 INHTBITOR, the only thing that is different is the sequencing of - when the SENSITTZTNG HIV-l TNHIBITOR and NON-NUCLEOSIDE HTV
TREATMENT DRUG are given.
~0 A modification of this process is that after a period of time when increased sensitivity to the NON-NUCLEOSIDE HTV TREATMENT DRUG is obtained, the SENSTTIZING HIV-1 TNHIBTTOR is given int~ ~iLLellLly with the NON-NUCLEOSTDE HIV TREATMENT DRUG rather than continuously.

WO 94/09781 2 ~ S PCI/US93/08354 The particular method to be utilized with an particular patient will depend on many factors as will be app~ellt to those skilled in the art. These factors include whether the patient is ~.yll,p~o"- free or has some sy"~to"~s. Further, if the patient has symptoms are they mild or severe. In addition, other ~i~e~ç~/conditions that affect the

5 patent can enter into the decision as to which method to use in a particular case as is known to those skilled in the art.
The exact dosage and frequency of a-lmini~tration depends on the particular SENSITIZING HrV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT
DRUG used, the particular condition being treated, the severity of the condition being 10 treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by me~ ring the blood level or concentration of the SENSITIZING HIV-l INHIBITOR in the patient's blood and/or the patient's responseto the particular condition being treated.
DEFrNTTIONS AND CONVENTIONS
The definitinns and explanations below are for the terms as used throughout thisentire document including both the specification and the claims.
I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES
The chemical formulas representing various compounds or molecular fragments 20 in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents may be identified by a letter or a letter followed by a numerical subscript, for example, ''Zl'' or "Rj" where "i" is an integer. These variable substitllent~ are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, 25 a group Zl would represent a bivalent variable if attached to the formula CH3-C(=ZI
)H. Groups Rj and Rj would represent monovalent variable substit--~nt~ if attached to the formula CH3-CH2-C(Rj)(Rj)-H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom imme(li~tely to the left of the variable substituent enclosed in parenthesis.
30 When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immeAi~tely preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R; and Rj are bonded to the preceding carbon atom. Also, for any molecule with an established ' WO 94/09781 ~ 1 ~1 5 ~ 4 5 PCI/I~S93/08354 system of carbon atom numbering, such as steroids, these carbon atoms are ~esignatçd as Ci, where "i" is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as tradition-ally (lç~ign~ted by those skilled in the art of steroid chemistry. Likewise the term "R6"
5 ~eylesellls a variable substituent (either monovalent or bivalent) at the C6 position.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus CH3-0-CH2-CH(Rj)-CH3 represents a 2-substituted-1-methoxypropanecompound. In a similar fashion, the symbol "=" represents a double bond, e.g., 10 CH2=C(Rj)-O-CH3, and the symbol "--" ,~iesellts a triple bond, e.g., HC-C-CH(Ri)-CH2-CH3. Carbonyl groups are represented in either one of two ways: -CO- or -C(=O)-, with the former being preferred for simplicity.
Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be 15 represented in linear fashion by N =C(CH3)-CH=CCl-CH=C H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be r~y~esented by -N -(CH2)2-N(C2Hs)-CH2-C H2-A rigid cyclic (ring) structure for any compounds herein defines an orientation 20 with respect to the plane of the ring for substit~-çnt~ attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(Xl)(X2)- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axiaVequatorial. However, the position of the two substituents relative to the ring and 25 each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (Xl) which is "below" another substituent (X2) will be identified as be~ng in the alpha (oc) configuration and is identified by a broken, dashed or dotted line ~0 attachment to the carbon atom, i.e., by the symbol "- - -" or "...". The corresponding substituent attached "above" (X2) the other (Xl) is identified as being in the beta (13) configuration and is indicated by an unbroken line attachment to the carbon atom.
When a variable substituent is bivalent, the valences may be taken together or WO 94/09781 i~ 1 4 ~ a 4 ~ PCI/US93/08354 separately or both in the definition of the variable. For example, a variable Ri attached to a carbon atom as -C(=Ri)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable cllbstit~lent~ a-Rij and ~-Ri k. When a bivalent variable, Rj, is defined to consist of S two monovalent variable substituents, the convention used to define the bivalent variable is of the form "a-R~ -Ri k" or some variant thereof. In such a case both a-Rij and 13-Ri k are attached to the carbon atom to give -C(a-R~ -Ri k)-. For example, when the bivalent variable R6, -C(=R6)- is defined to consist of two monovalent variable substit-uents, the two monovalent variable substituents are a-R6-1 B-R6-2~ --- a-R6-9 ~-R6-10 10 etc~ giving C(a R6 ~ -R6-2)-~ --- -C(a-R6 g)(~-R6-10)-~ etc- Likewise~ for the bivalent variable Rll, -C(=Rll)-, two monovalent variable substitllent~ are a-Rll l:~-Rl 1 2. For a ring substituent for which separate a and ~ orientations do not exist (e.g.
due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, 15 but the a and ~ design~tions are omitted.
Just as a bivalent variable may be defined as two separate monovalent variable substitlle~t~, two separate monovalent variable substitll~nt~ may be defined to be taken together to form a bivalent variable. For example, in the formula -Cl(Ri)H-C2(Rj)H-(Cl and C2 define a~ a-ily a first and second carbon atom, respectively) Ri and Rj 20 may be defined to be taken together to form (1) a second bond between Cl and C2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
When Ri and Rj are taken together to form a more complex entity, such as the group -X-Y-, then the orientation of the entity is such that Cl in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation "... Ri and Rj are 25 taken together to form -CH2-CH2-O-CO- ..." means a lactone in which the carbonyl is bonded to C2. However, when design~ted "... Rj and Ri are taken together to form -CO-O-CH2-CH2-the convention means a lactone in which the carbonyl is bonded to Cl.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "Cl-~0 C4", where both " 1 " and "4" are integers representing the minimum and maximumnumber of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "Cl-C4 alkyl" represents aLkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).

WO 94/09781 ;~ 1 4 ~ S 4 ~ Pcr/us93/n83s4 Whenever this single prefix is given, the prefix in-lic~tes the entire carbon atom content of the variable being defined. Thus C2-C4 aL~oxycarbonyl describes a group CH3-(CH2)n-O-CO- where n is zero, one or two. By the second method the carbon atom ' content of only each portion of the definition is indicated separately by enclosing the "Cj-Cj" design~tion in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)aL~oxycarbonyl has the same meaning as C2-C4 aL~oxycarbonyl because the "Cl-C3"
refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 aLkoxyalkyl and (Cl-C3)alkoxy(Cl-C3)aL~yl define alkoxyalkyl groups cont~ining from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the aL~coxy or aL~cyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
While the above method of clefining variable substinlent~ and the number of carbon atoms in various groups is used to define the BHAP COMPOUNDS, it must be realized that there are ~lt~rn~tive methods which accomplish the same thing.
~lmitteAly, the specification and claims here are a composite of information obtained electronically from (lirr~le~t sources and therefore represents various styles. Never-the-less, one skilled in the art will certainly know what is being disclosed and/or claimed.
When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/design~tion in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
II. DEFINITIONS
All temperatures are in degrees Centigrade.
-q) refers to phenyl (C6H5).
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacologicaVtoxicological point of view and to the manufacturing pharmaceutical chemist from a physicaVchemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
MIC refers to minimmn inhibitory concentration.
BHAP refers to bisheteroarylpiperazines.
BHAP COMPOUNDS refers to bisheteroarylpiperazines selected from the group consisting of compounds of formula (I) WO 94/09781 2 1 ~ 5 5 ~ 5 PCT/US93/08354 R~

[Aryl/~eterDaryl]-Rl-Z ~ R8 (I) s 6=Rl ~, where Rlis-CH2-, -CO-, -CO-CH2-.
-S02-, -CH=CH-CO-;
where Z is R2~4 (Z-I) where (I) R2 is =0 or R2 1:R2 2 where one of R2 1 and R2 2 is -H and the other of R2 1 and R2 2 is -H or -CH3, R3iS =O or R3 1:R3 2 where one of R3 1 and R3 2 is -H and the other of R3 and R3 2 is -H or -CH3, R4iS R4 1:R42 and R5 is R5 1:R5 2 where one of R4 1 and R4 2 is H an other of R4 1 and R4 2 is -H or -CH3, where one of R5 1 and R52is-H and the other of R5 1 and R5 2 is -H or -CH3, (II) R4iS R43:R44 and R5iS R53:R54 where one of R43 and R44 and one of R53 and R54 are taken together to forrn -CH2- and the other of R43 and R44, and R53 and R54 are -H, R2 and R3 are -H:-H, (III) R2is R2 s:R2 6 and R5is R5 5:R5 6 where one of R2 5 and R2 6 and one of R55 and R56 are taken together to forrn -CH2-CH2- and the other of R2 5 and R2 6 and R55 and R5 6 are -H, and R3 and R4 are -H:-H, (IV) R3 is R3 s:R3 6 and R4iS R4 5:R5 6 where one of R35 and R3 6 and one WO 94/09781 2 1 4 5 S 4 i - PCI`/U593/08354 of R4 5 and R4 6 are taken together to form -CH2-CH2- and the other of R3 5 and R3 6, and R4 5 and R4 6 are -H, and R2 and R5 are -H:-H, -Y1-(CH2)n~ 1~Z2~(CH2)n26~Y2~ (Z-II) - where n11 is 1 thru 5, n26 is 1 thru 5, Y I is -O-, -S-, -N(Y1 1)- where Yl l is Cl-C4 aL~cyl, -C(Yl 2)(Y1 3) where Yl 2 and Yl 3 are the same or different and are -H
or C1-C4 alkyl, Y2 is-O-, -S-, -N(Y2-l)- where Y2 1 is Cl-C4 alkyl, -C(Y2 2)(Y2 3) where Y2 2 and Y2 3 are the same or dirrc;1c1~t and are -H
or Cl-C4 alkyl, Z2 is nothing (a bond), -O-, -S-, -N(Z2 l)- where Z2-l is -H or Cl-C4 al~yl -C--C-, -C(Z2 2)(Z2 3)- where Z2-2 and Z2-3 are the same or di~r~1ent and are -H
or C1-C4 alkyl, nd trans -C(z2-2)=c(z2 3)- where Z2-2 and Z2 3 are the same or 20 dirre1~nt and are -H or Cl-C4 alkyl, with the provisos (1) that when Yl is -O-, -S- or -N(Y1 1)-~ then n11 is 1 only when Z2 is nothing (a bond), -C-C-, -C(Z2 2)(Z2 3)- or -C(z2 2)=C(Z2 3)- and (2) that when Y2 is -O-, -S- or -N(Y2 1)-, then n26 is 1 only when Z2 is nothing (a bond), -C-C-, -C(z2-2)(z2-3)- or -C(z2-2)=c(z2-3)-~

2) 12 (d~2)nl3 (Z-In) W O 94/09781 2 1 ~ ~ ~ 4 ~ PC~r/US93/08354 where nl2 is 1 or 2 and nl3 is 1 or 2, ~c~2)~ 12 (C~2)~1~ (Z-IV) S
where nl2 and nl3 are as defined above, Nr( C~_ y3 _ \ (C~2)~12 (Z-V) 3 ( 3-1) where Y3 1 is Cl-C4 alkyl and nl2 and nl3 are as defined above;
R6 is -N=, -CH=, -N(O)=, 7 is C-R7-1l where R7 11 is as defined above, -CO-N(R7 3)(R7 4) where R7 3 and R7 4 are the same or different and 20 are -H or Cl-C6 alkyl, -N(R7 s)(R7 6) where R7 5 is Cl-C6 aLlcyl, -C(R7-15)(R7-16)-(R7 17) where R7 15 and R7 16 are the same or dirr~ t and are -H or Cl-C3 alkyl and where R7 17 is C2-C5 aLkenyl cont~ining 1 or 2 25 double bonds or C2-C5 alkynyl containing 1 triple bond, -CH2-CH2-OH.
-CH2-CH2-CH2-OH.
-cH(cH3)cH2-o-cH3 ' -CH(CH3)cH2--CH2-CF3, -CH2-cyclopropyl, -CH2-CH2F.
-CH2-CH2-C-N.

21~5~5 -C R7-18~(CH2)nl4~C H2 where R7 18 is -H or -CH3, nl4 is 1 thru 5 and the carbon atoms marked with an asterisk ( ) are bonded to each other to resulting in the formation of a ring, -(CH2)nl-N(R7 7)(R7 8) where nl is 2 or 3 and where R7 7 and R7-8 are the same or different and are -H or Cl-C4 alkyl, and where R7 7 and R7 8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, 1-~7.irit1inyl,and where R7 6 is -H, Cl-C6 aL~yl, C(R7-l5)(R7-l6)-(R7-l7) where R7 15, R7 16 and R7 17 are as defined above, -CH2-CH2-OH, -CH2-CH2-CH2-OH, -CH2CF3~
-CH2-CH2F, -CH2-CH2-C--N, or where R7 5 and R7 6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-20 piperazinyl, N-morpholinyl or 1-aziridinyl, -(CH2)n4~N(R7 9)(R7 10) where n4 is 1 or 2 and where R7 9 and R7 10 are the same or dirr~rent and are -H or Cl-C4 alkyl, and where R7 9 and R7 10 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl, R8 is-N=, -CR8 1= where R8 1 is -H, -F, -Cl, -Br, -CF3, -NO2, -COCF3, Cl-C6 alkyl, Cl-C3 aL~ylthio, -OH, -O-R8 2 where R8 2 is Cl-C6 alkyl, -~, -CO-R8 3 where R8 3 is Cl-C6 aL~yl or-~, -NH(R8 4) where R8 4 is 2 1 ~ ~ ~ 4 ~ PCr/US93/08354 Cl-C6 aL~yl, -C(R8-7)(R8-8)-(R8 9) where Rg 7 and Rg 8 are the same or different and are -H or Cl-C3 alkyl and where R8 9 is C2-C5 aL~enyl containing 1 or 2 double bonds or C2-C5 alkynyl containing 1 triple bond, -NR8 5-CO-R8 6 where R8 5 is -H or Cl-C6 aL~cyl and R8 6 is -H, Cl-C6 alkyl or Cl-C3 alkoxy;
R9 is-N=, -CR9 1= where R9 1 is -H, -F, -Cl, -Br, -NO2, -COCF3.
Cl-C6 aL~yl, Cl-C3 aL~ylthio, -OH, -O-R9-2 where Rg 2 is Cl-C6 alkyl, -~, -CO-Rg 3 where Rg 3 is Cl-C6 alkyl or-~, -N(R94)(R9 5) where R94 and R9 5 are the same or different and are -H, Cl-C6 aL~yl, -C(R9 8)(R9 9)-(R9 10) where Rg 8 and R9 9 are the same 20 or different and are -H or Cl-C3 aL~yl and where Rg 10 is C2-C5 aL~enyl containing 1 or 2 double bonds or C2-C5 aL~ynyl cont~ining 1 triple bond, R9 4 and Rg 5 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl, 1-piperidinyl, l-piperazinyl or N-morpholinyl, -NR9 6-CO-Rg 7 where R9 6 is -H or Cl-C6 alkyl and R9 7 is -H, Cl-C6 aL~yl or Cl-C3 alkoxy;
Rlo is -N=, -CR 10-1 = where R 10-1 is -H, -F, -Cl, -Br, -CF3, -NO2, -COCF3.
Cl-C6 alkyl, Cl-C3 aL~ylthio.
-OH, -O-Rlo 2 where R10 2 is Cl-C6 alkyl, -~, -CO-Rlo 3 where R1o 3 WO 94/09781 ~14 5 ~ ~ 5 PCr/US93/083~4 is Cl-C6 alkyl or-~, -N(R104)(Rl0-5) where R104 and R1o 5 are the same or different and are -H, C1-C6 alkyl.
-C(R10-8)(RlO-9)-(Rlo-lo) where R10-8 and Rlo g are the same or difre~ t and are -H or Cl-C3 alkyl and where Rlo lo is C2-C5 alkenyl containing I or 2 double bonds or C2-C5 aL~cynyl containing 1 triple bond, -NR10-6-C-R10 7 where R10-6 is -H or Cl-C6 alkyl and Rlo 7 is -H, Cl-C6 alkyl or Cl-C3 alkoxy;
with the proviso that not more than two of R6, R8, Rg and Rlo are -N=;
AryVHeteroaryl is a substituent selected from the group of substihlent~ of formula ( 1 ) (1) ~3 ~1 where Xl is -H, Cl-C6 or n-aLkyl, X2 is -H, Cl-C6 or n-aL~cyl, X3 is Cl-C6 aLkyl, -C-x3-l where X3 1 is Cl-C4 aLkyl or -~, ~ ,;
... of formula (2) ~1 ~4~5N ~3 (2) ~a 30 where X4 and X5 are the same or different and are -H, Cl-C4 alkyl, -(CH2)n5-N(X4 1)(X4 2) where n5 is 2 or 3 and where X4 1 and X4 2 are the same or ~:lir~lent and are -H or Cl-C4 aLkyl or where X4 1 and X4 2 are taken O 94/09781 ;~, 1 45~ ~5 PCr/US93/08354 together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, and where X4 and X5 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-S piperidinyl, 1-piperazinyl or N-morpholinyl, and where Xl and X2 are as defined above, with the proviso that both X4 and X5 are not both -H;
... of formula (3) (~6 where X6 is-H, Cl-C6 alkyl, -F, -Cl, Br, -OH, -O-CH2-~, -O-CF3, CH2-COOX6 14 where X6 14 is -H, Cl-C6 aLkyl, -q), -CH2-~
-CHO, Cl-C3 alkoxy.
Cl-C3 aLkylthio, -O-CO-X6 1 where X6 1 is -H, Cl-C4 alkyl or ~, -so2-x6-l2 where X6 12 is Cl-C4 alkyl, -COO-X6 13 where X6 13 is -H, Cl-C4 aLkyl, -~ or -CH2-~, -CeN, -NO2, -N3, -NX6 10x6-ll where X6 l0 and X6 11 are the same or different and are -H or Cl-C5 aLkyl or where X6 10 and X6 11 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, l-piperazinyl, N-morpholinyl or l-a7.iri-1inyl, WO 94/09781 ~ 1 ~s a 5 4 5 PCI/US93/08354 ~N(X6-2)(CH2)n3~N(X6 3)(X6 4) where n3 is 2 thru 5, X6 2 is H or Cl 4 alkyl, X6 3 is -H or C14 alkyl, X64 is -H or C14 alkyl. or whe 6-3 X64 are taken together with the attached nitrogen atom to form a heterocyclic ring - selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, l-piperazinyl, N-5 morpholinyl or l-aziridinyl, -O-CO-(CH2)n3-COOH, where n3 is as defined above, (CH2)n3~N(X6-3)(X64) where n3, X6 3 and X64 are as defined above, -(CH2)n24-OH, where n24 is 1 thru 5, -(CH2)n6-N(X6 5)(X6 6) where n6 is 1 thru 5 and X6 5 and X6 6 are the same or different and are -H, Cl-C4 aL~yl or where X6 5 and X6 6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, -NH-S02-X6 7 where X6 7 is Cl-C4 alkyl. C3-C7 cycloalkyl, 15 or -CH2-~
-N=c(x64)-N(x6-7)(x6-8) where (a) X6 8 is Cl-C4 alkyl, C3-C7 cycloaL~yl or -~ and where X64 and X6 7 are as defined above, (b) X6 7 and X6 8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, (c) X64 and X6 7 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-25 pyrrolidinyl or l-piperidinyl, -NX64-CO-X6 9 where X6 9 is -H, Cl-C4 aLkyl or -~ and where X6 4 is as defined above, -O-prodrug where prodrug is -PO2-O- cation+, -CO-CH2-CO-NH-CH2-SO2-O- cation+, ~C~(CH2)n21~Rs 1 where n21 is 1-7 and R51 is -COO-cation+, -NR51 1R51 2 where R51 1 and R51 2 are the same or different and are -H or Cl-C3 WO 94/09781 ~ PCr/US93/08354 alkyl, -N+R51 1R51 2R51 3 halide~ where R51 ~, Rsl 2 and R51 3 are the same or different and are -H or Cl-C3 aL~yl, and where halide is -Cl or -Br, -CO-CH(amino acid)-NH2 where amino acid is -H, -CH3, -CH(CH3)2~ -CH2-CH(CH3)2. -CH2-OH, -CH(OH)(CH3), -CH2-~, -CH2-[p-hydroxyphenyl], -CH2-[3-indolyl], -CH2-S-S-CH2-CH(NH2)-COOH, -CH2-SH, -CH2CH2-S -CH3, -CH2-COOH, -CH2-CO-NH2, -CH2-CH2-COOH, -CH2-CH2-CO-NH2, -CH2-[2-HISTIDYL], -(CH2)3-o NH-c(NH)-NH2~-(cH2)4-NH2~-cH2-cH2-cH(oH)-cH2-NH2~-(cH2)3-NH2~-(cH2)3 NH-CO-NH2-CH2CH2-OH, -CO-CH=CH-CO-O- cation+, -CO-N -CH=CH-N=CH where the atoms marked with an asterisk ( ) are bonded to each other res~ ing in the formation of a ring, -CO-C =C[(CH2)n22-NH2~-CH=CH-CH=CH where n22 is 1 or 2 and where the atoms marked with an asterisk ( ) are bonded to each other resulting in the formation of a ring, -CO-C =CH-CH=C(-NR52)-CH=CH where R52 is -H or Cl-C3 aL~yl and where the atoms marked with an asterisk ( ) are bonded to each other resulting in the formation of a ring, ~Co-(cH2)n2~-co-o-[c6Hl2o6 sugars], -CO-o-cH(cH2-o-co-Rs3)2 where the R53's are the same or different and are Cl-Cl8, CO-(CH2)6-CO-N(CH3)-CH2-CH2-SO3- cation+, -cH2-o-co-(cH2)n2l-NR5l-lRsl-2 where n2l~ R5l 1 and R5l 2 are as defined above, -CO-NH-C6H4-Rs5 where Rss is -H or Cl-C3 alkyl, -N02, -NRsl lRsl 2 where Rsl ~ and R51-2 are as defined above, -NX6 4-prodrug where X6 4 and prodrug are as defined above except that prodrug is not -PO2-O-, n2 is 1 thru 3, the X6's can be the same or can be different and where when n2 is 2 and the two X6 groups are ortho to each other they can be taken together to form -21453~
W O 94/09781 PC~r/US93/08354 O-CH2-O-; with the proviso that if n2 is 2 or 3, only one of the X6's can be a prodrug, ... of formula (4) ~ (4) (~6)~a .

where Ql is -NXll where Xll is -H, -SO2-~, -SO2-CH3, -CO-Xll l where Xll l is Cl-C4 aL~cyl, -CF3 or -~; , Q2 is -N= provided Rl is not -CH2-, -CX12= where X12 is -C-X12 1 where X12 1 is -H or Cl-C4 aLlcyl, -C-N(X12-2)(X12-3) where X12 2 and X12 3 are the same or dirrelel~t and are -H, Cl-C4 aLIcyl or where X12 2 and X12 3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 15 l-pyrrolidinyl, l-piperidinyl, 1-piperazinyl or N-morpholinyl, C-C-X12-1 where X12 1 is as defined above, Cl-C3 alkyl, -CO-~, C-X12-1 where X12 1 is as defined above, CO CO N(X12-2)(X12-3) where X12 2 and X12 3 are as defined above, -(CH2)n23-OH where n23 is 1 or 2, and where X6 and n2 are as defined above, ... of formula (6) 25~L (6 ... of formula (7) 14~;L (7) (~6)n~

WO 94/09781 PCr/US93/08354 where .... .......is a single or double bond, X14 is -H, -O-CH2-~, -O-CF3, O-CH2-CR14-10 where R14 10 is -H, Cl-C4 aLkyl, -q) or -CH2-~
Cl-C6 aL~cyl, -F, -Cl, Br, S2-X14-11 where X14 11 is Cl-C4 alkyl, -C-N, -CHO, ~(CH2)n25~OH where n25 is 1 thru S, NO2. -NH2~ -N3--NH-CH2-~, -NH-SO2-X~4 ~ where X14 1 is Cl-C6 alkyl, C3-C7 cycloalkyl or -~, ~NX14-2(CH2)n3~N(x14-3)(xl44) where n3 is 2 thru 5, X14 2 is -H or C14 alkyl~ X14 3 is -H or C14 aL~yl, X144 is -H or C14 alkyl, or where X14 3 andX144 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group concicting of l-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, -NX14 13X14 14 where X14 13 and X14 14 are the same or different and are -H or Cl-C5 alkyl or where X14 13 and X14 14 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, l-piperidinyl, 1-piperazinyl or N-morpholinyl, -(CH2)n6-N(X14 5)(X14 6) where n6 is 1 thru 5 and X14 5 and X14 6 are the same or dirr~;le~lt and are -H, Cl-C4 alkyl or where X14 5 and X14 6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl, l-piperidinyl, l-piperazinyl or N-morpholinyl, -N=C(X 144)-N(X 14 7)(X 14-8) where (a) X14 7 and X14-8 are Cl-C6 alkyl, C3-C7 cycloalkyl or -~, where X144 is as defined above, (b) X14 7 and X14 8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-WO 94/09781 PCr/US93/08354 piperidinyl, l-piperazinyl or N-morpholinyl, (c) Xl4 4 and X14 7 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl or 1-piperidinyl, -CO-O-X14 7 where X14 7 is as def1ned above, -CO-N(X14 7)(X14 8) where X14 7 and X14 8 are as defined above, -N(X14 2)-CO-X14 9 where X14 9 is -H, Cl-C4 aLkyl or -~ where X14 2 is defined above, -N(X14 2)-prodrug, where prodrug is as defined above except that it is not -PO2-O-, and when X14 2 is as defined above, n7 is 0 thru 2, X6 and Ql are as defined above;
.... ..of formula (8) ~22 l~ (8) ~24 where X21 is -H, Cl-C4 aL~yl, -CO-(Cl-C4 aL~yl), -CH2-~, -CO-~ or -prodrug whereprodrug is as defined above, X22, X23 and X24 are the same or different and are -F, -Cl, Br, -OH, -O-CH2-~, -O-CF3, -O-CH2-COOH, Cl-C3 alkoxy, Cl-C3 alkylthio, O-CO-X22 1 where X22 1 is -H, Cl-C4 aL~yl or ~p NO2, -NH2, -N3--C-N, ~NX22-2(CH2)n9~N(X22-3)(X22 4) where ng is 2 thru 5, X22 2 is -H or Cl-C4 aL~yl, X22 3 is -H or Cl-C4 aL~cyl, X22 4 is -H or Cl-C4 alkyl, and where X22 3 and X224 are taken together with the attached nitrogen atom to form a heterocyclic ring WO 94/09781 ~ 5 PCI/US93/08354 selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl, -O-CO-(CH2)ng~COOH~ where n9 is as defined above, ~~(CH2)n9~N(X22-3)(X22 4) where ng, X22 3 and X22 4 are as defined 5 above, ~(CH2)nlO-N(x22-5)(x22-6) where n10 is 1 thru 5 and X22 5 and X22 6 are the same or different and are -H, Cl-C4 aLkyl and where X22 5 and X22 6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, l-~ a~ yl or N-morpholinyl, -N(X22-7)(x22-8) where X22 7 and X22 8 are Cl-C6 alkyl, C3-C7 cycloaLkyl or ~,, and where any adjacent two of -O-X21, X22, X23 or X24 are taken together to form a methylenedioxy group (-O-CH2-O-), Ql and ...... are as defined above;
.... of formula (9) ~10 ~6~ (9) lll where X10 is -H, -F, -Cl or -Br, Q~ is -CH= or Q2 where Q2 is as defined above, X6 and Xll are as defined above;
... of formula (10) ~6~4~ (10) I

~11 where X6, Xll and Q3 are as defined above;

W094/09781 21~5~5 PCI/US931U8354 ... of forrnula ( 1 1 ) ~8-N~L (11) S

~7 here X7 is -H~ -S02-~ -S02-CH3~ -CO-X7 1 where X7 1 is Cl-C4 aLkyl or -~
8 s H, Cl C6 aL~yl, -CH2-~. -S02-~, -S02-CH3. -C-X8 1 where X8 1 is C1-C4 aL~yl or-~, .... is as defined above;

15 ... of formula (15) N (15) ~11 where Q3 and X11 are as defined above;
... of forrnula (16) ~ (16) where Q3 and Xl 1 are as defined above;

... of forrnula (17) WO 94/09781 ~ 4 ~ PCr/US93/08354 ( 1 7) where Q3 and Xl 1 are as defined above;
... of formula (18) l 0 ~N~
(18) ~11 lS where Q3 and Xll are as defined above;
... of formula (19) ¢~Q3~ ( 19) ~11 where Q3 and Xl l are as defined above;
... of formula (20) ~N~ (2()) ~11 where Q3 and Xl 1 are as defined above;

... of formula (21) ~ WO 94/09781 2 1 4 ~ PCr/US93/08354 (~6,-7~1 (21) where Ql X6 and n7 are as defined above;
with the proviso that one of R7 5 or R7 6 must be -H when R6 is not -N=, enantiomers, pharmaceutically acceptable salts, hydrates and solvates thereof and anti-AIDS piperazines (II) selected from the group consisting of 1 -[4-methoxy-3,5-dimethylbenzoyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, 1-[4-methoxy-3,5-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, 1 -[4-hydroxy-3,5-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, 1 -[4-methoxy-3,5-dimethylbenzyl]~[3-(propylamino)-2-pyridinyl]piperazine, 1 -[4-methoxybenzyl] -4-[3-(ethylamino)-2-pyridinyl]piperazine, 1 -[5-methoxyindolyl-2-carbonyl] -4-[2-ethoxyphenyl]piperazine, 1-[5-methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, I -[5-methoxyindolyl-2-carbonyl]-4-[3-( 1-methylethylamino)-2-pyridinyl]-piperazlne, 1 -[5-methoxyindolyl-2-carbonyl] -4-[2-(ethylamino)phenyl]piperazine, 1 -[5-hydroxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, 1 -[5-hydroxyindolyl-2-carbonyl]-4-[3-( 1-methylethylamino)-2-pyridinyl]piperazine, 1 -[5-methoxy-4,6,7-trimethylindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl] -piperazine, 1 -[5-methoxyindolyl-2-carbonyl]-4-[3-( 1,1 -dimethylethylamino)-2-pyridinyl]-25 piperazine, 1 -(5-methoxyindolyl-2-carbonyl)-4-[3-(methylamino)-2-pyridinyl]piperazine, 1 -[3,5-dimethyl-4-methoxybenzoyl]-4-[3-(ethylamino)-2-phenyl]piperazine, 1 -[3,5-dimethyl-4-methoxybenzoyl]-4-[3-( 1-methylethylamino)-2-pyridinyl]-piperazine, ,0 1-[5-methoxyindolyl-2-methyl]-4-[3-(ethylamino)-2-pyridinyl]piperazine, 1-(5-fluoroindolyl-2-carbonyl)-4-[3-(1-methylethylamino)-2-pyridinyl]-1 ,4-diazepine, N,N'-dimethyl-N-(5-methoxyindolyl-2-carbonyl)-N'-(3-( 1 -methylethylamino)-2-pyridyl)ethylene~ mine., 1 -[4-methoxy-3,4-dimethylbenzyl] -4-(3-(2-propenylamino)-2pyridinyl]piperazine,N,N'-dimethyl-N-(5-methoxyindolyl-2-carbonyl)-N'-[3-( l -methylethylamino)-2-pyridinyl]-2E-butyleneAi~mine, S N,N'-dimethyl-N-(5-methoxyindolyl-2-carbonyl)-N'-[3-( 1-methylethylamino)-2-pyridinyl]-2Z-butylenefii~mine, l -(5-methoxyindolyl-2-carbonyl)-4-[3-methylamino-2-pyridinyl]piperazine, 1 -(5-methoxyindolyl-2-carbonyl)-4-[3-propylamino-2-pyridinyl]piperzine, 1 -(5-methoxyindolyl-2-carbonyl)-4-[3-(cyclo-propylmethylamino)-2-pyridinyl]-lO piperazine, 1 -(5-methoxyindolyl-2-carbonyl)-4-[3-( 1,1 -dimethylethylamino)-2-pyrazinyl] -piperazine and enantiomers, pharmaceutically acceptable salts, hydrates and solvates thereof.
MERCK 1 refers to the aminopyrimmidones of claim l of European Publication 484 071 A2:
3- { [(4,7-dichloroben70~x~7.ol-2-yl)methyl]amino }-5-ethyl-6-methyl-2( 1 H-pyridinone, 3- { [(4,7-dimethylbenzoxaxazol-2-yl)methyl]amino } -5-ethyl-6-ethyl-2( l H)-pyridinone, 3- ~ [(7-chlorobenzoxazol-2-yl)methyl]amino }-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- ~ [(7-methylbenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(4-fluorobenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(7-fluorobenzoxazol-2-yl)methyl]amino ~ -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-~ [(benzoxazol-2-yl)methyl]amino }-5-ethyl-6-methy-2(1H)-pyridinone, 3- ~ [(4-chlorobenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2(1 H)-pyridinone, 3- ~ [(4-fluoro-7-chlorobenzoxazol-2-yl)methyl]lamino } -5-ethyl-6-methyl-2( l H)-pyridinone, 3-[2-(benzoxazol-2-yl)ethyl] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(5-ethyl-2-methoxy-6-methyl-3-pyridylmethyl)-amino]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(5,6-dimethyl-2-methoxy-3-pyridylmethyl)amino]-5-ethyl-6-methyl-2( l H) pyridinone, w o 94/09781 ~ ~ 4~ Pc~r/us93/08354 3- [N-(5-ethyl-2-methoxybenzyl)amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone.
3- [N-(2-methoxy-4,5-dimethylbenzyl)amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone,3- [N-(2,6-dimethoxybenzyl)amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3 ' -azido-2,3 ' -dideoxythymidine, 2',3'-dideoxycytidine, 2 ' ,3 ' -dideoxyinosine, 2 ' ,3 ' -didehydro-2 ' ,3 ' -dideoxythymidine, 1 [(2-hydroxyethoxy)methyl]-6-phenyl-thiothymine, 3'-fluoro-2',3'-dideoxythymidine or pharmaceutically acceptable salts, hydrates 10 or esters thereof.
MERCK 2 refers to the compounds of claims 1 and 11 of European Publication 462 800 A2, pyridones of the formula:

R1x~ xX--(CH)n ~) where X is -NR-, -O-, -S-, -CRH-, -SO-, -SO2-, -CO-, -CH(OR)-, -CH2CH(OH)-, -CH2-CO-,-RC=CR-,-N(-CO-R)-,-N(-CH2-C02R)-,-NR-(SO)-, -NR-(SO2)-, or -NR-CO-, where R is-H, Cl 8a~yl, Zis0,SorNRXisHorCl 8aLlcyl, n is 0-4;
Rl, R2 and R4 are the same or different and are independently (i) H;
(ii) Cl 8 aL~cyl, Cl 8 alkenyl, C3 8 cycloaL~yl, any of which is unsubstituted or substituted with one or two of Cl 3 aL~coxy, C14 aL~ylamino, di(C14 aL~yl)amino, Cl 3 aL~ylthio, hydroxy, amino, carbonyl, aminocarbonyl, or oximido, or one to five of halo;

W O 94/09781 ~ ~ ~ S PC~r/US93/083~4 (iii) Cl 6 alkylthio;
(iv) Cl 5 aL~cylsulfinyl;
(v) Cl 5 alkylsulfonyl;
(vi) Cl 5 aLkoxy;
S (vii) Cl 5 alkoxycarbonyl;
(viii) cyano;
(ix) halo; or (x) aryl;
or Rl and R4 may together form a cycloalkyl ring containing 5-7 members;
or Rl and R2 may together form a cycloalkyl ring containing 5-7 members;
and R3 or R5 are the same or dirrt;~ t and are independently (i) H;
(ii) Cl 8 alkyl;
(iii) Cl 8 alkenyl;
(iv) C3 8 cycioalkyl;

is aryl or heterocycle each unsubstituted or substituted with one or more of (i) Cl 6 alkyl unsubstituted or substituted with one or more of A, wherein A is halo, hydroxy, hydroxy-CI 4 alkyl, amino, Cl 6 aL~cylamino, di(Cl 6 aL~cyl)amino, Cl 6 aL~oxy or aryl, (ii) Cl 6 alkenyl unsubstituted or substituted with one or more of A;
(iii) C3,6 cycloaLkyl unsubstituted or substituted with one or more of A;
(iv) Cl 6 aLkoxy unsubstituted or substituted with one or more or A;
(v) aryl;
(vi) amino, (vii) Cl 6 alkylamino;
(viii) di(Cl 6-aLlcyl)amino;
(ix) amino-Cl 8 alkyl;
(x) Cl 8 alkyl-amino-C, 1-8 alkyl;
(xi) di-(C, 6 alkyl)amino Cl 8 alkyl;

WO 94/09781 ~ 1 4 ~ ~ 4 ~ PCI/US93/08354 (xii) Cl 6 aL~oxycarbonyl;
(xiii) aminocarbonyl;
(xiv) Cl 6 aL~yl aminocarbonyl;
(xv) di(Cl 6 aL~cyl)aminocarbonyl;
S (xvi) Cl 6 aL~ylthio;
(xvii) Cl 6 aL~ylsulfinyl;
(xviii) Cl 6 aL~ylsulfonyl;
(xix) hydroxy;
(xx) halo~, (xxi) CN, or (xxii) NO2 with the provisos that (I) Rl, or R2 or both are not substituted with OH; and (II) heterocycle is not phth~limide; or pharmaceutically acceptable salt, hydrate or ester thereof; and the following compounds:
3- { [(4,7-dichlorobenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(4,7-dimethylbenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-{ [(7-chlorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-pyridinone, 3-~ [(7-methylbenzoxazol-2-yl)methyl]amino }-5-ethyl-6-methyl-2(1H)-pyridinone, 3- { [(4-fluorobenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(7-fluorobenzoxazol-2-yl)methyl]amino }-5-ethyl-6-methyl-2( lH)-pyridinone, 3- { [(7-fluorobenzoxazol-2-yl)methyl]amino }-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(benzoxazol-2-yl)methyl]amino }-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(4-chlorobenzoxazol-2-yl)methyl]amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-{ [(4-fluoro-7-chlorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[2-(4,7-dimethylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[2-(4-methylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 21~5~ 32-3-[2-(7-methylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- [N-(5 -ethyl-2-methoxy-6-methyl-3-pyridylmethyl)-amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(5-(2-hydroxyethyl)-2-methoxy-6-methyl-3-pyridylmethyl)amino] -5-ethyl-6-methyl-2(1H)-pyridinone, 3-[N-(5-( 1 -hydroxyethyl)-2-methoxy-6-methyl-3-pyridylmethyl)amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(5,6-dimethyl)-2-methoxy-3-pyridylmethyl)amino] -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(5-ethyl-2-methoxybenzyl)amino]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[N-(2-methoxy-4,5-dimethylbenzyl)amino]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[N-(2,6-dimethoxybenzyl)amino]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { [(4,7-dichlorobenzoxazol-2-yl)methyl]amino } -5-methylthio 6-methyl-2( 1 H)-pyridinone, 3-{ [(4,7-dichlorobenzoxazol-2-yl)methyl]thio }-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[N-(2-methoxy-5-methylbenzyl)amino]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[(5-ethyl-2-methoxy-6-methyl-3-pyridinylmethyl)-amino] -S-cyclopropyl-6-methyl-2(1H)-pyridinone, 3-[N-(2-methoxy-4-methylbenzyl)amino]-5-ethyl-6-methyl-2( 1 H)-pyridinone, 3- { N-[(4,7-dichlorobenzoxazol-2-yl)methyl-N-methyl-amino } -5-ethyl-6-methyl-2( 1 H)-pyridinone, 3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-propyl-6-methyl-2(1H)-pyridinone, 3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl] -5-ethyl-6-methyl-pyridin-2( 1 H)-thione, or, 3-[2-(7-fluorobenzoxazol-2-yl)ethyl]5-ethyl-6-methylpyridin 2(1H)-one or pharmaceutically acceptable ester thereof.
MERCK 3 refers to the compounds of claim 1 of European Publication 462 808 A2, pyridones of the formulae:
Rl ~A R1 ~A
or 11 1 R2~N ~ R2 N B
H

WO 94/0978l P~ 1 ~ 5 5 4 ~ PCI/US93/~83~4 wherein A is -X- (CH) n-Pht or - (CH) n-X-Pht B is Cl 6alkoxy;
X is NH, O, S, or C2;
Z is O or S;
n is 1-4;
Rl is (i) Cl 8aLkyl, unsubstituted or substituted with one or two of C
3alkoxy, halo, Cl 4alkylamino, Cl 4-diaLkylamino, or Cl 3alkylthio;
(u) C1 3alkylthio;
(iii) Cl 3aLkoxy; or (iv) halo;
R2 is (i) H;
(ii) Cl 2aLkyl, unsubstituted or substituted with one or two of methoxy, methylamino, dimethylamino or methylthio, R3isHorCl8alkYl;
Pht is phthaloyl, of the structure ~R1 )m o 3() wherein m is 0-2, with the proviso that when A is NHCH2-Pht, both Rl and R2 cannot be Cl 2aLkyl.
MERCK 4 refers to the compounds of claim 1 of US Patent 5,124,327, indoles 35 of the formula:

W o 94/09781 ~ PC~r/US93/08354 ~ N
H
wherein R is --CH2--~3 --CH2--N~ or CHO

MERCK 5 refers to the compounds of claim 1 of European Pl~hlic~t.ion 481 802 A1, hydroxy pyri-linon~.c of the formula:

Rl ~ X - (CH)n ~

where Rl or R2 or both are substituted at least once with OH;
where X is -NR-, -O-, -S-, -CRH-, -SO-, -SO2-, -CO-, -CH(OR)-, -CH2CH(OH)-, -CH2-CO-, -RC=CR-, -N(-CO-R)-, -N(-CH2-CO2R)-, -NR-(SO)-, -NR-(SO2)-, or-NR-CO-, where R is H, Cl 8 alkyl, Cl 8 alkenyl or C3 8 cycloalkyl;
Z is 0, S or NRX when Rx is H or C1 8 alkyl;
n is 0-4;

W O 94/09781 ~ 1 4 5 ~ 4 ~ PC~r/US93/08354 Rl, R2 and R4 are the same or dirrere.lt and are independently (i) H;
(ii) C1 8 alkyl, C1 8 alkenyl, C3 8 cycloalkyl; any of which is unsubstituted or substituted with one or two of C1 3 alkoxy, C1 4 alkylamino, dl(C1 4 S alkyl)amino, C1 3 alkylthio, hydroxy, amino, oxo, carbonyl, aminocarbonyl, or o~imi~o, or one to five of halo;
(iii) C1 5 alkylthio;
(iv) Cl 5 alkylsulfinyl;
(v) C1 5 alkylsulfonyl;
(vi) C1 5 alkoxy;
(vii) C1 5 alkoxycarbonyl;
(viii cyano; or (ix) aryl; or, Rl and R4 may together form a cycloalkyl ring cont~ining 5-7 members; or, Rl and R2 may together form a cycloalkyl ring cr~nt~ining 5-7 members; and R3 or R5 are the same or di~rere..t and are independently (i) H;
(ii) C1 8 alkyl;
(iii) C1 8 alkenyl;
(iv) C3 8 cycloalkyl;

is aryl or heterocycle, each unsubstituted or substituted with one or more of (i) C1 6 alkyl unsubstituted or substituted with one or more of A, wherein A
is halo, hydroxy, hydroxy-Cl 4 alkyl, amino, Cl 6 alkylamino, di(Cl 6alkyl)amino or aryl;
(ii) C1 6 alkenyl unsubstituted or substituted with one or more of A;
(iii) C3 6 cycloalkyl unsubstituted or substituted with one or more of A;
(iv) C1 6 alkoxy unsubstituted or substituted with one or more of A;
(v) aryl;
(vi) amino;
(vii) C1 6 aL~ylamino (viii) di(C1 6 alkyl)amino;
(ix) amino-C1 8 alkyl;

W094/09781 21~55~ PCr/US93/08354 (x) C1 8 alkyl-amino-Cl 8 alkyl;
(xi) di(C1 6 alkyl)amino C1 8 alkyl;
(xii) C1 6 alko2~ycafbonyl;
(xiii) aminocarbonyl;
(xiv) C1 6 alkyl ~minoc~rbonyl;
(xv) di(C1 6 alkyl aminocarbonyl;
(xvi) C1 6 alkylthio;
(xvii) Cl 6 all~ylsulf~myl;
(~vui) C1 6 aLkylsulfonyl;
(xix) hytL~ y, (xx) halo;
(xxi) CN; or (~;i) N02; with the proviso that heterocycle is not pht.h~limi~le; or pharmaceutically acceptable salt or ester thereof.
MERCK 6 refers to the compound of Antimicrobial Agents and Chemotherapy 36, 1019 (1992), 3-r2-(b~n7o~7nl-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one. MERCK COMPOUNDS refers to the compounds of MERCK 1, MERCK 2, MERCK 3, ... MERCK 6.
BOEHRINGER 1 refers to the compounds of claim 1 of European Pllhlic~tio 20 393 529 Al, 5,11-dihydro-6H-dipyrido[3,2-b:2'.3'-e][1,4]diazepin-6-ones of the formula:

O

where R1 and R2 are the same or Lrre~:nt and are hydrogen or straight or 3() brtanched aLkyl of 1 to 5 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
BOEHRINGER 2 refers to the compounds of claim 1 of European Pllhlic~tiQn 393 530 A1, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-ones and -thiones of the formula:

W O 94/09781 ~ 1 4 5 S ~ ~ PC~r/US93/08354 5 whereir, R4 ~ ~R7 Z is oxygen or R3 R2 R9 sulfur:
Rl is hydrogen, alkyl or fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl, alkenyl or alkynyl of 3 to 4 carbon atoms, 2-halo-propen-1-yl, arylmethyl (wherein 10 the aryl moiety is phenyl or thienyl, which is either unsubstituted or substituted by methyl, met~o~y or halogen), acetyl, or alkoxyalkyl or alkylthioalkyl of 2 to 3 carbon atoms;
R2 is alkyl or fluoroalkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 5~carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 15 to 3 carbon atoms, alkanoyl of 2 to 3 carbon atoms, hydlo~y~lkyl of 2 to 4 carbon atoms, arylmethyl (wherein the aryl moiety is phenyl, thienyl or fu~ yl, which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hyLo.~yl or halogen), phenyl (which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, halogen or hy~ Lyl) or alkoxy carbonylmethyl 20 wherein the alkoxy moiety cnnt~in~ 1 to 6 carbon atoms:
R3, R4 and R5 are each indep~n(l~ntly hydrogen or alkyl of 1 to 3 carbon atoms, with the proviso that at least one of these substituents is hydrogen; or one of R3, R4 and R5 is butyl, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, hyd~o2~y~1kyl of 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein 25 the alkoxy and alkyl moieties each cont~in 1 to 2 carbon atoms, halogen, trihalomethyl, hyLo~yl, alkoxy of 1 to 3 carbon atoms, alkylthio of 1 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, aL~anoylamino of 1 to 3 carbon atoms,~mino~lkyl of 1 to 3 carbon atoms, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 2 carbon atoms, carboxyalkyl of 2 to 3 carbon atoms, cyano,3() nitro, carboxyl, carbamyl, amino, azido, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, with the proviso that the rP.m~ining two substituents are hydrogen or methyl; or, when Z is oxygen, one of R3, R4 and R5 is alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms with the proviso that the r~m~ining two substituents are 35 hydrogen or methyl; and R6, R7, R8 and R9 are hydrogen; or W O 94/09781 ~ 1 4 5 ~ 4 ~ PC~r/US93/08354 one of R6, R7, R8 and R9 is alkyl of 1 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, aLko2~ycal1,0nyl of 2 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein the alkoxy and alkyl moieties each contain 1 to 2 carbon atoms, halogen, trihalomethyl, hyd~o~yl, alkoxy of 1 to 3 carbon atoms,S alkylthio of 1 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkanoylamino of 1 to 3 carbon ~tom~,~min-~lkyl of 1 to 3 carbon atoms, mono- or di-alkylaminowherein each alkyl moiety cont~in~ 1 to 2 carbon atoms, carboxyalkyl of 2 to 3 carbon atoms, cyano, nitro, carboxyl, carbamyl, amino, azido, mono- or di-alkyl~mino~lkyl wherein each alkyl moiety cont~in~ 1 to 2 carbon atoms, and the l0 r~m~ining three substituents are hydrogen or two of the r~m~ining three substituents are hydrogen and one is methyl, ethyl or halogen, or a ph:~rm~reutically acceptable acid addition salt thereo ~ OEHRINGER 3 refers to the compounds of claim 1 of European Publication 393,604 A2, 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-ones and -thiones of the formula:
R4 ~ ~R ~ R7 R R2 ~ R8 wherein, Z is oxygen or sulfur;
R1 is hydrogen, alkyl or fluoroalkyl of 1 to 5 carbon atoms, cyclopropyl, alkenyl or alkynyl of 3 to 5 carbon atoms, 2-halo-propen-1-yl, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubsbtuted or 30 substituted by methyl, methoxy or halogen), alkanoyl of 2 to 3 carbon atoms, or alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms:
R2 is alkyl or fluoroalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, alkenyl or alkynyl of 2 to 5 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hy~Lv~yalkyl of 2 to 5 carbon atoms, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, WO 94/09781 2 ~ PCI/US93/08354 hydroxyl, or halogen), phenyl (which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, halogen or hyLo~yl) or alko~yc~ubonylmethyl wherein the alkoxy moiety cont~in~ 1 to 5 carbon atoms;
R3, R4, and R5 are each independently hydrogen or alkyl of 1 to 3 carbon atoms, with the proviso that at least one of these substituents is hydrogen; or,one of R3, R4 and R5 is butyl, alkanoyl of 1 to 3 carbon atoms, hy~Loxy~lkyl of 1 to 4 carbon atoms, alko~yc~bonyl of 2 to 3 carbon atoms, aLko2~ycal1Jonylalkyl wherein both the alkoxy and alkyl moieties cnnt~in 1 to 2 carbon atoms, halogen, t.rih~lnmethyl, hyd~v~yl, alkoxy of 1 to 3 carbon atoms, alkythio of 1 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkanoylamino of 1 to 3 carbon atoms,~mino~lkyl of 1 to 3 carbon atoms, mono- or di-alkylamino wherein each alkyl moiety cnnt~in.~ 1 to 2 carbon atoms, carboxyalkyl of 2 to 3 carbon atoms, cyano, nitro, ca~rboxyl, carbamyl, amino, azido or mono- or dialkyl~mino~lkyl wherein the alkyl moieties each cont~in 1 to 2 carbon atoms, and the rem~ining two substituents are hyLu~ or methyl; or, when Z is oxygen, one of R3, R4 and R5 is alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms, with the proviso that the r~m~ining two substituents are hydrogrogen or methyl; and, R6, R7, R8 and R9 are each hydrogen; or, one of R6, R7, R8 and R9 is alkyl of 1 to 4 carbon atoms, alkanoyl of 1 to 3 carbon atoms, alko~ycarbonyl of 2 to 3 carbon atoms, hy(Lo~y~lkyl of 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein both the alkoxy and alkyl moieties contain 1 to 2 carbon atoms, halogen, trihalomethyl, hy~LùlLyl, alkoxy of 1 to 3 carbon atoms, alkylthio of 1 to 3 carbon atoms, alkanoyloxy of 2 to 3 carbon atoms, alkanoylamino of 1 to 3 carbon atoms, ~mino~lkyl of 1 to 3 carbon atoms, mono- or di-alkylamino wherein each alkyl moiety cont~in~ 1 to 2 carbon atoms, carboxyalkyl of 2 to 3 carbon atoms, cyano, nitro, carboxyl, carbamyl, amino, azido or mono- or di-alkyl~mino~lkyl wherein each alkyl moiety cont~in.~ 1 to 2 carbon atoms, and therPm~ining three substituents are hydrogen or two of the r~m~ining three 3() substituents are hydrogen and one is methyl, ethyl or halogen; or a pharmaceutically acceptable acid addition salt thereof.
BOEHRINGER 4 refers to the compounds of claim 1 of European Pnhlic~t.inn 410 148 A1, 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-ones and -thiones of the formula:

W O 94/09781 ~ ~ ~ r ~ ~ 5 PC~r/US93/08354 ~0-5wherein, R ~R7 Z is oxygen or R
sulphur;
R1 is hydrogen, C1 5alkyl optionally substituted by fluorine, trih~lomçthyl, C3 5alkenyl or alkynyl, 2-halopropen-1-yl, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl and is optionally substituted by methyl, methoxy or halogen), C2 3 alkanoyl or C2 4 alkoxyalkyl or alkylthioalkyl;
R2 is hyLog~ll, Cl 5 alkyl optionally substituted by fluorine, C2 5alkenyl or alkynyl, C2 4 alkoxyalkyl or alkylt hioalkyl, C2 4alkanoyl, C2 5hyLo2~yalkyl, arylmethyl (where in the aryl moiety is phenyl, thienyl or furanyl, and is optionally substituted by Cl 3 alkyl or alkoxy, hydro~yl or halogen), phenyl optionally substituted by C1 3 alkyl or alkoxy groups, hydroxy or halogen or (C1 5alkoxy)carbonylmethyl; and R3, R4, R5, R6, R7 and R8 is each hydrogen, or one of R3, R4, R5, R6, R7 and R8 is an alkyl, alkoxy, alkylthio, alkoxycarbonyl, hyL~y~lkyl, alkanoyl, alkanoyloxy, alkanoylamino, carboxyalkyl or ~mino~lkyl group containing up to 4 carbon atoms, or a (C1 2alkoxy)carbonyl(C1 2alkyl), mono- or di-(C1 2alkyl)amino, cyano, nitro, hyLo2~yl, carboxyl, amino, mono- or di-(Cl 2alkyl~amino(C1 2alkyl) or azido group or a halogen atom and the r~m~ining five of R3, R4, R5, R6, R7 and R8 are each hy~Loge~-, or R3, R4 and R5, are each indepçn~lçnt.ly hydrogen or Cl 3alkyl with the proviso that at least one is hydrogen, or one of R3, R4 and R5 is butyl with ther~m~ining two being hydrogen, and R6, R7 and R8 are each indepçnf~ntly hydrogen or C1 3alkyl with the proviso that at least one is hydrogen, or one of R6, R7 and R8 is butyl with the r~m~ining two being hydrogen; with the proviso that when R1 and R2 are each independently hydrogen or straight-rh~ine~l or branched Cl 5alkyl and R3, R4, R5, R6, R7 and R8 are all hydrogen then Z is sulphur) or an acid addition salts thereo BOEHRINGER 5 refers to the compounds of claim 1 of European Publication 415 304 A2, dipyrido[3,2-b:2',3'-e][1,4]oxazepin (and thiazepin~-6(~H)-ones and -thiones of the formula:

~14 ~ ~ 4 ~
W O 94/09781 PC~r/US93/08354 R4 R, Z R5 R~X~7 s wherein, X is oxygen or sulfur;
Z is oxygen or sulfur;
R1 is alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, fluoroalkylmethyl of 1 to 3 fluorine atoms and 2 to 4 carbon atoms, mono- or ~ih~lo~lk.?nyl of 2 to 4 carbon atoms wherein the halogen atoms are ~tt~he~ to the vinylic carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, aLkyloxyaLkyl or alkylthioalkyl of 2 to 4 carbon atoms, ~mino~rbonylmethyl, acetyl, cyanoalkyl and 15 wherein the alkyl moiety contD~in~ 1 to 3 carbon atoms, or hy-Lul~y~lkylmethyl of 2 to 4 carbon atoms, R2 is hydrogen, methyl, ethyl, halogen, nitro or amino;
R3 is hydrogen, methyl, or halogen;
R4 is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 3 20 carbon atoms, trihalomethyl, alkanoyl of 2 to 3 carbon atoms, cyano azido, amino, nitro, halogen, hy~llo~yl, alkyloxy or alkylthio of 1 to 2 carbon atoms, mono or di-alkylamino wherein each alkyl group cont~in~ 1 to 2 carbon atoms, aminoalkyl or mûno- or di-alkyl~minoalkyl wherein each alkyl group contains 1 to 2 carbon atoms, hy~Lo~yalkyl of 1 to 3 carbon atoms or alkylo~ycalbonyl of 2 to 3 carbon atoms;
25 with the proviso that when R4 is other than hydrogen, R2 is hydrogen, methyl or chloro and R3 is hydrogen;
R5 is hydrogen, methyl or halogen;
R6 is hydrogen, methyl, halogen or amino; and R7 is hydrogen, methyl or halogen; with the proviso that at least two of R5, 30 R6 and R7 is hydrogen, or a pharmaceutically acceptable salt thereof.
BOEHRINGER 6 refers to the compounds of claim 1 of European Publication 429 987 A2, ~,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepines of the formula:

WO 94/09781 ',;~ 1 45 ~ 45 PCI/US93/08354 R\ ~
S wherein, R3 N1' R8 Z is oxygen, R2 sulfur, = NCN, or a group of the formula = NOR9 wherein R9 is alkyl of 1 to 3 carbon atoms;
Rl is hydrogen, alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, 2-halo-2-propen-1-yl, mono- or di-halovinyl, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, metho~y or halogen), alkanoyl of 2 to 4 carbon atoms, aminoethyl, mono- or di-alkylaminoethyl wherein each alkyl moiety cont.~inq 1 to 2 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkylo~yc-~l,onal wherein the alkyl moiety cont~in.~ 1 to 4 carbon atoms, alkenyloxy-or alkynyloxycarbonyl wherein each alkenyl or alkynyl moiety cont~in.q 2 to 4 carbon atoms, hydroxy, alkyloxy of 1 to 4 carbon atoms, amino, mono- or di-aLkylamino wherein each alkyl moiety crnt~in.q 1 to 4 carbon atoms, ~minoc~rbonylmethyl, orcyanoalkyl wherein the alkyl moiety cont~in~ 1 to 4 carbon atoms;
R2 is hydrogen (with the proviso that R1 is not hydrogen), alkyl of 1 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, oxetanyl, thietanyl, tetrahy~Luful~lyl or tetrahydrothienyl, alkenyl or alkynyl of 2 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkanoyl of 2 to 5 carbon atoms, cyano, h.y~u~yalkyl of 2 to 6 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hyd~v2~yl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contqin.c 1 to 5 carbon atoms; and, one of R3, R4 and R5 is alkyl of 1 to 6 carbon atoms, cycloaLkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, trih~lr)methyl hy~Lu~yalkyl of 1 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkylo,~yca~l)onylalkyl wherein the alkyl moieties each cont~in 1 to 2 carbon atoms, h~Lw yl, alkyloxy or alkylthio of 1 to 5 carbon atoms, hyd~u2~yalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyloxycarbonyl wherein the ~ ~45~5 WO 94/09781 PCr/US93/08354 ~3-alkyl moiety cont~in~ 1 to 3 carbon atoms, mono- or di-alkylaminocarbonyl wherein each alkyl moiety cont.~in~ 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contg~in.C 1 to 3 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is S either unsubstituted or substituted by alkyl or alkyloxy of 1 to 3 carbon atoms, hy~lloxyl or halogen), a group of the formula -NRlRll, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen, methyl or chloro; or, two of R3, R4 and R5 are indepçn(l~ntly alkyl or hyd~o2~yalkyl of 1 to 2 carbon atoms, trih~lom~thyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or agroup of the formula -NRlRll, with the rçmzinin~ substituent being hydrogen or methyl; or, R3, R4 and R5 are each hydrogen:
one of R6, R7 and R8 is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, trih~lomethyl hy~l~u~y~lkyl of 1 to 4 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hyLu~yl, alkyloxy or alkylthio of 1 to 4 carbon atoms, hydloxyalkyloxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulf~myl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alko~yca~l,onyl wherein the alkyl moiety c~ntqin.C 1 to 3 carbon atoms, ~mino~lkyl of 1 to 4 carbon atoms, mono- or di-alkyl~mino~lkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the formula -NR12-R13, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen; or, two of R6, R7 and R8 are independently alkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio 1 to 2 carbon atoms, halogen or a group of the formula -NR12R13, with the r~m~ining substituent being hydrogen; or, R6, R7 and R8 are each hydrogen; and, Rl, Rll, R12 and R13 are each indep~n-lently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl of alkynylmethyl of 2 to 4 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by methyl, methoxy or halogen), mono- or dihydroxyal-kylmethyl of 2 to 4 carbon atoms, alkyoxy of 1 to 3 carbon atoms, hydroxy, alkyloxyethyl or alkylthioethyl of 3 to 4 carbon atoms, ~mino~lkylmethyl of 2 to 4 carbon atoms, mono- or dialkylaminoalkylmethyl wherein each alkyl moiety contains 1 or 2 carbon atoms, or alkanoyl of 1 to 4 carbon atoms; or, R1U and R11, and R12 and R13, together with the nitrogen atoms between them, respectively and indep.on~ntly form azetidin-l-yl or a 5, 6 or 7-membered W O 94/09781 ~ ~ ~ 5 ~ ~ 5 PC~r/US93/08354 ring which is either saturated or unsaturated, which optionally cont~inc up to one additional heteroatom which may be selected from O, S or N, or which optionally contains in place of a carbon atom a group of the formula =NR14 wherein R14 is hydrogen or alkyl or 1 to 2 carbon atoms, and which ring is optionally and 5 indep~nrient.ly substituted with hydlo2Lylllethyl, ~minomethyl, 1 to 4 methyl groups and 1 to 2 hydroxy groups; subject to the proviso that when a) Z is oxygen or sulphur b) R2 is hydrogen, aLkyl of 1 to 5 carbon atoms, aLkenyl or alkinyl of 2 to 5 carbon atoms, alkoxyaLkyl or aLl~ylthioalkyl of 2 to 4 carbon atoms, aL~canoyl of 2 to 4 10 carbon atoms, hy~ y~1kyl of 2 to 5 carbon atoms, phenyl (optionally substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), or aLko~yca~lJonylmethyl wherein the alkyl moiety cont~inc 1 to 5 carbon atoms.
BOEHRINGER 7 refers to the compounds of claim 1 of European Pllhlic~t.io~
498 290 A1, compounds of the formula ~R2 wherein, one of X and Y is -N = and the other is where A is a fused ring of the formula 2~ 455~
WO 94/09781 ~ . PCr/US93/08354 R6 R7 Rl R12 X~( ~R~1 r ~> or ~Rl R9 Rl3 or, when X is -N = and Y is ~R1 A may additionally be Rl is cyano, chloro, bromo, imi~ olyl, phosphetanyl, phospholanyl, or phosphorinanyl, or a group of the formula -oR14, -SR14, -SoR14, -So2Rl4, -NH2, -NHR14 -NR14Rl-PRl4Rl5, p(ORl4)(ORl5), P(o)(oR15)(oR15)~-P3H2~
P(NRl4Rl5)(NRl4)(Rl5) or p(o)(NRl4Rl5)(NRl4Rl5)~ wherein Rl4 and R15 are each independently alkyl of 1 to 4 carbon atoms, which may optionally be substituted by a cyano or alkoxycarbonyl group of 2 to 4 carbon atoms, cyclopropyl or cyclobutyl, or the group -NRl4Rl5 may be pyrroli~ine, piperidine, or morpholine;
R2 is hydrogen, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkanoyl of 2 to 5 carbon atoms, hydroxyalkyl of 2 to 6 carbon atoms, aryl or arylmethyl (wherein aryl means thiazolyl, 02azolyl or isoxazol, which is unsubstituted, or is phenyl, thienyl or furanyl, which is either 30 unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hy~ yl or WO 94/09781 ~ ; 4 ~ PCI/US93/08354 halogen), alkoxycarbonylmethyl wherein the alkoxy moiety cont.~in.~ 1 to 5 carbon atoms, oxetanyl, thiet~nyl~ tetrahydrothienyl, tetrahy~L.)ru~ yl, cyano;
R3, R4 and R5 are each independently hydrogen, alkyl of 1 to 3 carbon atoms or chloro, with the proviso that at least one of these substituents is hydrogen or methyl; or one of R3, R4 and R5 is alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alko~ycaflJonyl of 2 to 4 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, hy~o~yalkyl of 1 to 6 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, aLko~Lyca l,onylalkyl wherein the alkoxy and alkyl moieties each cont~in 1 to 2 carbon atoms, halogen, trihalomethyl, hy~ yl, alkoxy of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbonatoms, aryl or arylalkyl (wherein the alkyl moiety cont.~in~ 1 to 3 carbon atoms, and the aryl moiety is phenyl, thienyl, furanyl, pyridyl, or imidazolyl, which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hyLo2~yl or halogen), alkanoyl of 2 to 6 carbon atoms, alkoxycarbonyl wherein the alkyl moiety cont.~in~ 1 to 3 carbon atoms, hy~ yalkoxy of 2 to 4 carbon atoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 carbon atoms, alkanoylamino of 1 to 3 carbon atoms, ~mino~lkyl of 1 to 4 carbon atoms, mono- or di-alkylamino or mono- or di-alkylaminocarbonyl, wherein each alkyl moiety contains 1 to 3 carbon atoms, a group of the formula -NRl6Rl7, N-pyrrolidino, N-piperidino, N-morpholino, carboxyalkyl of 2 to 3 carbon atoms, cyano, nitro, carboxyl, carbamyl, amino, azido, mono- or di-alkyl~mino~lkyl wherein each alkylmoiety cont~in~ 1 to 3 carbon atoms, with the proviso that the r~m~ining two substituents are hydrogen, methyl or chloro; or two of R3, R4 and R5 are independently alkyl or hyLIJ~yalkyl of 1 to 2 carbon atoms, trih~lomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or agroup of the formula NRl6Rl7, with the r~m~ining substituent being hydrogen, methyl or chloro;
R6 R7, R8 and R9 are each hydrogen; or one of R6, R7, R8 and R9 is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, hyLokyalkyl of 1 to 4 carbon atoms, alko2~yc2lrl)0nylalkyl wherein the alkoxy and alkyl moieties each contain 1 to 2 carbon atoms, halogen, trihalomethyl, hy~ yl, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, hydlo~y~lkyloxy of 2 to 4 carbonatoms, alkanoyloxy of 2 to 4 carbon atoms, alkylsulfinyl or alkylsulfonyl of 1 to 4 WO 94/09781 ~ J ~ 4 ~ PCI/US93108354 ~7-carbon atoms, alkanoylamino of 1 to 3 carbon atoms, ~mino~lkyl of 1 to 3 carbon atoms, mono- or di-alkylamino or mono or di-alkylaminocarbonyl wherein each alkyl moiety contains 1 to 2 carbon atoms, carboxyalkyl of 2 to 3 carbon atoms, halogen, cyano, nitro, carboxyl, carbamyl, amino, azido, ~mino~lkyl of 1 to 4 carbon atoms, 5 mono- or di-alkyl~mino~lkyl wherein each alkyl moiety cont~in~ 1 to 2 carbon atoms, a group of the formula -NRl8Rl9, and the r~m~ining two or three substituents arehydrogen or two of the r.qm~ininF three substitutents are hydrogen and one is methyl, ethyl or halogen;
when only R6, R7 and R8 are present two of them are indep~n~l~ntly alkyl of l0 1 to 2 carbon atoms, t.rih~lnmethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen, or a group of the formula -NR18Rl9, with the r~m~ining substituent being hydrogen;
Rl and Rll are chosen from hydrogen, alkyl of 1 to 4 carbon atoms, halogen, cyano, nitro and alkanoyl of 1 to 3 carbon atoms, and lS Rl2 and Rl3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, halogen or nitro;
Rl6, R17, R18 and Rl9 are each indep~ntlently hydrogen, alkyl of 1 to 4 carbon atoms, alkenylmethyl or alkynylmethyl of 2 to 4 carbon atoms, aryl or arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl, which is either 20 unsubstituted or substituted by methyl, methoxy or halogen), mono- or di-hyd~u2~yalkylmethyl of 2 to 4 carbon atoms, alkyloxy of 1 to 3 carbon atoms, hydroxy, alkyloxyethyl or alkylthioethyl of 3 to 4 carbon atoms, ~mino~lkylmethyl of 1 to 4 carbon atoms, mono- or dialkylaminoalkyl-methyl wherein each alkyl moiety contains 1 to 2 carbon atoms, or alkanoyl of 1 to 4 carbon atoms; or Rl6, R17, R18 25 and Rl9, together with the nitrogen atoms between them, respectively and independently from ~7.eti-1in-l-yl or a 5, 6, or 7-membered ring which is eithersaturated or unsaturated, which optionally cnntqin.~ up to one additional heteroatom which may be selected from O, S or N, or which optionally cont~in~ in place of acarbon atom a group of the formula =NR20 wherein R20 is hydrogen or alkyl of 1 to 3U 2 carbon atoms, and which ring is optionally independently substituted with hy~ ymethyl, aminomethyl, 1 to 4 methyl groups and 1 to 2 hydroxy groups; or a pharmaceutically acceptable acid addition salt thereof.
BOEHRINGER COMPOUNDS refers to the compounds of BOEHRINGER 1, BOEHRINGER 2, BOEHRINGER 3, ... BOEHRINGER 7.
JANSSEN 1 refers to the compounds of claim 1 of Intern~t.i-ln~l Public No.
WO 92/009~2, HIV-inhihiting b~n7.~ne~ret~mi~1es of the formula:

WO 94/09781 ~ 5 3 ~ ~j PCI/US93/0835 ~8-Rl R2N X

Rs~ ~ n8 a ph~n~t-eutically acceptable acid addition salt form or a stereorhP.mic~lly isomeric form thereof, wherein R1 and R2 each indepen~lPntly are hydrogen, Cl 6alkyl or C3 6cycloalkyl; or R1 and R2 taken together with the nitrogen atom bearing said R1 and R2 may form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 4-C
4alkylpiperazinyl group;
lS X is O or S;
R3 is hydrogen or C1 6alkyl;
R4 R5 and R6 each indep~ntl~ntly are hydrogen, halo, Cl 6alkyl, Cl 6alkyloxy, nitro, trifluoromethyl, cyano, ~minomP.thyl, carboxyl, Cl 4alkylo~yca~1Jonyl, C
4alkylcarbonyl, aminocarbonyl or hy~J~y, R7 is hydrogen or halo; and R8, R9 and Rl each independently are hydrogen, halo, Cl 6aLkyl, C
6alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical C
6alkyl-(C=Y)- wherein = Y represents =O, =N-OH, =N-OCH3, =N-NH2 or =N-N(CH3)2;
provided that:
( 1) Rl is other than n-propyl when R2, R3, R4, R5, R6, R7, R9 and R10 represent hydrogen, R8 represents 4-ethoxy and X represents oxygen, and (2) X is other than sulfur, when Rl, R2, R3, R6, R7, R8, R9 and Rl0 represent hydrogen and R4 and R5 represent 3,4-dimethoxy.
JANSSEN 2 refers to the compounds of claim 1 of Intern~tion~l Public No.
WO 92/00979, antiviral tetrahydroimi~7.o[1,4]benzodiazeepin-2-(thio)ones of the formula:

WO 94/09781 2 1 4 ~ 5 4 ~ PCI/US93/083~4 Rs~ R2 a pharmaceutically R4 `R
acceptable acid addition salt or a stereo~h~mic~lly isomeric form thereof, wherein X is O or S;
Rl is a radical of formula:
Rl - Alk-C--C~R (a~ Alk~ 1HOz)n -Alk~ H2)n (a-3) or -Alk--S()m--R13 H \~R11 Alk is Cl 6~1k~nerliyl;
R6 is hydrogen, halo or Cl 4aLkyl;
R7 and R8 each indep~ntl~.ntly are hydrogen, halo, C3 6cycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, Cl 4alkyl optionally substituted with C
4alkyloxy;
R9 is hydrogen, halo or Cl 4alkyl;
each R10 independently is hydrogen or Cl 4alkyl; or both R10 taken together may form a Cl 6alkanediyl radical;
n is 2, 3, 4, 5 or 6;
R11 is hydrogen or C2 6alkenyl;

W O 94/09781 ~ 1 ~ 5 5 4 5 PC~r/US93/08354 each R12 indep~nrl~ntly is hydrogen or Cl 4alkyl; or both R12 taken together may form a Cl 6alkanediyl radical;
misO, 1 or2;
Rl3 is Cl 6alkyl, aryl, arylmethyl, C3 6cycloalkyl or (C3 6cycloalkyl) 5 Cl 4alkyl;
R2 is hydrogen or Cl 6aLkyl;
R3 is hydrogen or Cl 6aLkyl;
R4 and R5 each indep~nrl~ntly are hydrogen, Cl 6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, Cl 6alkyloxy, amino, mono- or di(Cl 6 alkyl)amino, C
l0 6alkylcarbonylamino or arylcarbonylamino; and each aryl is phenyl optionally substituted with from 1 to 3 substituents indep~n~ntly selected from Cl 6alkyl, halo, hydroxy, Cl 6alkyloxy, amino, nitro and trifluoromethyl;
provided that when R4 or R5 is other than Cl 6alkylcarbonylamino.or arylcarbonylamino, then Rl is other than C3 6alkenyl and (C3 6cycloalkyl)Cl 6alkyl.
JANSSEN 3 refers to the compounds of claim 1 of European Patent Pnhlicsltion No. 417 840 Al, antiviral tetrahy~Loi...irl~7.o[1,4]-benzodiazepines of the formula:
X
~$

2s a pharmaceutically acceptable acid addition salt or a stereo(h~mic~lly isomeric form thereof, wherein Rl is Cl 6alkyl optionally substituted with aryl; C3 6alkynyl; C3 6cycloalkyl;
30 or a radical of formula:

WO 94/09781 21 4 5 ~ ~ ~ PCI/US93/08354 Alk-C=C\ (a-l);

Alk-C C~H2)n (a-2);
R12 Wll Alk--& ( H2)n (a-3); or H W
Rl4 Alk--S()m Rl5 (a-4);

Alk is Cl 6~1k~n~rliyl;
R8 and R9 each indep~n~ntly are hydrogen, halo, C3 6cycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, Cl 4alkyl optionally substituted with Cl 4 alkyloxy;
R10 is hydrogen, halo or C1 4alkyl;
each Rll indep~n~ntly is hydrogen or Cl 4alkyl; or both Rll taken together may form a Cl 6~1k~ne~iyl radical;
R12 is hydrogen, halo or C1 4alkyl;
n is 2, 3, 4, 5 or 6;
each R13 indep~ntlently is hydrogen or Cl 4alkyl; or both R13 taken together may form a C1 6alkanediyl radical;
Rl4 is hydrogen or C2 6alkenyl;
mis 0, 1 or2;
R15 is C1 6alkyl, aryl, arylmethyl, C3 6cycloalkyl or (C3 5 cycloalkyl)C1 6alkyl;
R2 is hydrogen or C1 6alkyl;
R3 is hydrogen or C1 6alkyl;
R4 and R5 each independently are hydrogen, Cl 6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C1 6alkyloxy, amino, mono or di(C1 6alkyl)amino, C1 6alkylcarbonylamino or arylcarbonylamino; R6 is Cl 6alkyl;
R7 is hydrogen or C1 6alkyl;
X is OH, SH or NR16Rl7;
R16 is hydrogen, Cl 6alkyl, aryl, cyano, hydroxy, amino, nitro, C

WO 94/09781 2 ~ 4 5 ~ 4 ~ PCI`/US93/08354 6alkylo~y,;~bonyl, C1 6alkylcarbonyl, C1 6alkylsulfonyl or arylsulfonyl;
R17 is hydrogen, Cl 6alkyl or aryl; and each aryl is phenyl optionally substituted with from l to 3 substituents indep~nllently selected from Cl 6alkyl, halo, hydroxy, Cl 6alkyloxy, amino, nitro 5 and trifluoromethyl.
JANSSEN 4 refers to the compounds of claim 1 of European Patent Pl~hli( ~t,i- n No. 384 522 Al, antiviral tetrahydrnimi-l~7o[1,4]-benzodiazepin-2-thiones of the formula:

~ R

R~ ; R2 a pharmaceutically acceptable acid salt or a stereo-h~mic~lly isomeric form thereof, wherein R1 is Cl 6alkyl, C3 6alkenyl, C3 6alkynyl, C3 6cycloalkyl, or Cl 6alkyl 20 substituted with aryl or with C3 6cycloalkyl;
R2 is hydrogen or C1 6alkyl;
R3 is hydrogen or C1 6alkyl;
R4 and R5 each indep~nrl~ntly are hydrogen, Cl 6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C1 6alkyloxy, amino or mono-or di(Cl 6alkylamino); and25 aryl is phenyl optionally substituted with from 1 to 3 substituents indep~nrlf~nt.ly selected from Cl 6alkyl, halo, hydroxy, C1 6alkylo~y, amino, nitro and trifluoromethyl.
JANSSEN 5 refers to the compounds of claim 1 of European Patent Pllhlic~t.ion No. 336 466 A1, antiviral tetrahydroimi(1~7o[1,4]-benzodiazepin-2-ones of ~0 the formula '2~4~4~
w o 94/09781 PC~r/US93/08354 -s3-s ~ N\

a pharmaceutically acceptable acid addition salt or a stereorh.?mic~lly isomeric forms thereof, wherein R1 is hydrogen, Cl 8aLl~yl, C3 6alkenyl, Cl 6-alkynyl, Cl 6alkylcarbonyl, C
4cycloalkyl, or substituted with aryl, hydroxy, cyano or C3 6cycloalkyl;
R2 is hydrogen, Cl 6alkyl or C3 6alkenyl;
R3 is hydrogen, or C1 6alkyl;
R4 is hydrogen, Cl 6alkyl optionally substituted with hydroxy, cyano, 15 hy~ yca~bonyl or carbonyl Cl 6alkylcarbonyl; C3 6aLkenyl; C3 6cycloalkyl, C5 6cyrlo:~1k~nyl;
R5 is hydrogen, Cl 6aLkyl or halo; and aryl is phenyl optionally substituted with up to 3 substituents indep~nrl.?ntly selected from C1 6alkyl, halo, hydroxy, C1 6alkyloxy, amino, nitro and 20 trifluoromethyl.
JANSSEN 6 refers to the compounds of claim 1 of European Patent pnhlic~t.ion No. 430 334 A1, immunostimulating 6-aryl-~,6-dihydroimi(1~7:o[2,1-b]t.hi~ole.s of the formula:

2s Ar~ ~_ N S

~0 a pharmaceutically acceptable acid addition salt thereof or a stereorh~mir~lly isomeric form thereof, wherein Ar is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, Cl 6aLkyloxy, mercapto, Cl 6alkylthio, C1 6aL~cyl, nitro, amino, mono, and di(Cl 6alkyl)amino, Cl 6aLkylcarbonylamino, 35 arylcarbonylamino, C1 6alkylsulfonylamino, trifluoromethyl, cyano, aminocarbonyl, mono- and di(Cl 6aLkyl)aminocarbonyl, hyd~ y~;~lJonyl, Cl 6aLkyloxyamino, WO 94/09781 ~14 ~ PCI/US93/08354 carbo~ 1Rhyde and hyL~y~lethyl; pyridinyl; thienyl, furanyl or furanyl substituted with either C1 6alkyl or halo;
Rl and R2 each independently are C1 20alkyl, (C3 7cycloalkyl), C1 5alkyl, C3 7cycloalkyl, aryl or (aryl)-C1 6alkyl; and one of R1 and R2 may also be hydrogen; or 5 R1 and R2 taken together may also form a C3 6alk~nerliyl radical; each aryl indepRn-lRnt1y is phenyl optionally substituted with from 1 to 3 substituents each indepRn~1ently selected from halo, hydroxy, Cl 6alkyloxy, Cl 6alkyl, nitro, amino, trifluoromethyl or cyano.
JANSSEN COMPOUNDS refers to the compounds of JANSSEN 1, JANSSEN
10 2, JANSSEN 3, JANSSEN 6.
~ ;~ 1 refers to the compounds of the formula ~

where X and Y are the same or dirrer~slt and are -N=, -CR4= where R4 is -H
or-CH3;
where Rl is Cl-C3 aLkyl or cyclopropyl;
where R2 is -H or -CH3;
where R3 is -H or -OR3 1 where R3 1 is C1-C3 alkyl, -N(R3 2)(R3 3) where R3 2 and R3 3 are the same or LLrere.lt and are -H or C1-C4 alkyl.
~ ~ COMPOUNDS refers to the compounds of ~
NON-NUCLEOSIDE HIV TREATMENT DRUG refers to MERCK
COMPOUNDS + BOEHRINGER COMPOUNDS + JANSSEN COMPOUNDS +
;~ COMPOUNDS.
EXAMPLES
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent.
The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed asmerely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize a~pru~. ;ate variations from the procedures both as to re~rt~nt.~ and as to reaction con-lition~ and W094/0978l 55 PCI`/IIS93/~8354 techni ques.
.XAMPLE 1 SEN~;l'l`l~l~G HIV-l INHIBITOR Followed By NON-NUCLEOSIDE
HIV TREATMENT DRUG
A 21 year old male, HIV positive patient with no symptoms is treated by S ~lmini.~tering 500 mg of 1-[2-(5-met~ o~yindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine orally three times daily for 3 months. The patients blood is monitored to insure that a sustainable blood level is achieved which is above the MIC of the HIV virus. This initial sensitizing course is followed by 6,11-dihydro-11-cyclo~lù~yl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one (BI-RG-587, 10 n~vi d~ e) ~r~mini~tered orally in a dose of 200 mg once a day.
EXAMPLE 2 SEN~l'l'l:!lNG HIV-1 INHIBITOR Followed By NON-NUCLEOSIDE
HIV TREATMENT DRUG
A 45 year old female, HIV positive who is symptomatic is treated with 1-[2-(5-methaneslllfon~mir~oinrlnlyl)carbonyl]-4-[3-(N-isopropyl~mino)-2-pyridinyl]piperazine, 50 mg orally three times daily for a period of 8 weeks, followed by 3-{[(4,7-dichloro-1,3-ben~n~7.nl-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one which is ~rlmini~tered orally 250 mg three times daily.
EXAMPLE 3 SEN~;l'l`l~lNG HIV-l INHIBITOR Followed By NON-NUCLEOSIDE
HIV TREATMENT DRUG
A 2 month old child who is HIV positive with no syl.lptoms is treated with 1-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine, 1 mg~g orally four times daily for a period of 3 month~ followed by (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imifl~7 o[4,5,1-jk]L1,4]benzodiazepin-2(1H)-thione, 50 mg intravenously continnously daily.
li'XAMPLE 4 SEN~l'l'l;~lNG HIV-1 INHIBITOR Concurrently With NON-NUCLEOSIDE HIV TREATMENT DRUG
A 29 year old female, HIV positive with no symptoms is treated with 1-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine, 400 mg by mouth four times daily for 2 months concurrently with 3-[2-(b~n7o~ol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one given 600 mg orally twice daily intl~finitely.
.XAMPLE 5 SEN~l'l'l~l~G H~V-1 INHIBITOR Concurrently With NON-NUCLEOSIDE HIV TREATMENT DRUG
A 17 year old male, symptom~tic with HIV, is treated concurrently with 1-[2-(5-methanes~llfnn~mitloin~lnlyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]-piperazine, 150 mg by mouth every 8 hours, concurrent with 6,11-dihydro-11-cyclo~, u~yl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one, 400 mg by mûuth 2145~5 ~

daily.
hxAl\/rpLE 6 SEN~l'11;~l~G HIV-1 INHIBITOR Concurrently With NON-NUCLEOSIDE HIV TREATMENT DRUG
A 6 year old child symptomatic with HIV, is treated with 1-[2-(5-5 methaneslllfon~mi~oinrlolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]piperazine at a dose of 0.5 mg/~g, four times daily concurrently with (-)-a-[(2-acetylphenyl)amino]-2,6-dichlorob~n7.~ne~etamide, 150 mg orally three times daily.

Claims

-57-

1. Use of a NON-NUCLEOSIDE HIV TREATMENT DRUG to prepare a medicament for treatment of HIV positive individuals having strains of HIV showing increased sensivity thereto due to the administration of a non-nucleoside SENSITIZING HIV-1 inhibitor.

2. Use according to claim 1 where the SENSITIZING HIV-1 INHIBITOR is selected from the group consisting of BHAP COMPOUNDS.

3. Use according to claim 2 where the where the BHAP COMPOUND is 1-[5-methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]-piperazine and 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-1-methylethyl-amino)-2-pyridinyl]piperazine.

4. Use according to claim 1 where the sensitizingly effective amount of the SENSITIZING HIV-1 INHIBITOR is from about 50 to about 3,000 mg per day.

5. Use according to claim 1 where more than one SENSITIZING HIV-1 INHIBITOR
is used.

6. Use according to claim 1 where more than one NON-NUCLEOSIDE HIV
TREATMENT DRUG is used.

7. Use according to claim 1 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured by clinical resistance to the SENSITIZING HIV-1 INHIBITOR.

8. Use according to claim 1 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured in vitro by an increase in p24 antigen.

9. Use according to claim 1 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured in vitro by a measurement which detects a change in the amino acid 236 of the reverse transcriptase.

10. Use according to claim 1 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is selected from the group consisting of MERCK COMPOUNDS, BOEHRINGER COMPOUNDS, JANSSEN COMPOUNDS and PFIZER
COMPOUNDS.

11. Use according to claim 10 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of MERCK COMPOUNDS.

12. Use according to claim 11 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a MERCK COMPOUND selected from the group consisting of 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]mino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one, 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one, 3-{[1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-pyridin-2(1H)-one.

13. Use according to claim 10 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of BOEHRINGER
COMPOUNDS.

14. Use according to claim 13 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.

15. Use according to claim 10 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of JANSSEN
COMPOUNDS.

16. Use according to claim 15 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a JANSSEN COMPOUND selected from the group consisting of (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (-)-.alpha.-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide.

17. Use according to claim 10 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of PFIZER COMPOUNDS.

18. Use according to claim 17 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is

19. Use according to claim 1 where an effective amount of a NON-NUCLEOSIDE
HIV TREATMENT DRUG is from about 50 to about 4,000 mg per day.

20. Use according to claim 1 where administration of the NON-NUCLEOSIDE HIV
TREATMENT DRUG follows administration of the SENSITIZING HIV-1 INHIBITOR.

21. Use according to claim 1 where where after the initial administration of theSENSITIZING HIV-1 INHIBITOR, the NON-NUCLEOSIDE HIV TREATMENT
DRUG is administered concurrently with the SENSITIZING HIV-1 INHIBITOR.

22. Use according to claim 1 where after the initial administration of the SENSITIZING HIV-1 INHIBITOR, the NON-NUCLEOSIDE HIV TREATMENT
DRUG is administered intermittently with the SENSITIZING HIV-1 INHIBITOR.

23. Use of a NON-NUCLEOSIDE HIV TREATMENT DRUG to prepare a medicament for the treatment of HIV positive individuals concurrently receiving non-nucleoside SENSITIZING HIV-1 inhibitor.

24. Use according to claim 23 where the SENSTTIZING HIV-1 INHIBITOR is selected from the group consisting of BHAP COMPOUNDS.

25. Use according to claim 23 where the BHAP COMPOUND is 1-[5-methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]-piperazine and 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine.

26. Use according to claim 23 where the sensitizingly effective amount of the SENSITIZING HIV-1 INHIBITOR is from about 50 to about 3,000 mg per day.

27. Use according to claim 23 where more than one SENSITIZING HIV-1 INHIBITOR
is used.

28. Use according to claim 23 where more than one NON-NUCLEOSIDE HIV
TREATMENT DRUG is used.

29. Use according to claim 23 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is selected from the group consisting of MERCK COMPOUNDS, BOEHRINGER COMPOUNDS, JANSSEN COMPOUNDS and PFIZER
COMPOUNDS.

30. Use according to claim 23 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of MERCK COMPOUNDS.

31. Use according to claim 30 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a MERCK COMPOUND selected from the group consisting of 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one, 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one, 3-{[1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-pyridin-2(1H)-one.

32. Use according to claim 23 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of BOEHRINGER
COMPOUNDS.

33. Use according to claim 32 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.

34. Use according to claim 23 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of JANSSEN COMPOUNDS.

35. Use according to claim 34 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a JANSSEN COMPOUND selected from the group consisting of (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (-)-.alpha.-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide.

36. Use according to claim 23 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is a compound selected from the group consisting of PFIZER COMPOUNDS.

37. Use according to claim 36 where the NON-NUCLEOSIDE HIV TREATMENT
DRUG is

38. Use according to claim 23 where an effective amount of a NON-NUCLEOSIDE
HIV TREATMENT DRUG is from about 50 to about 4,000 mg per day.

39. Use according to claim 23 where after the initial concurrent administration of the SENSITIZING HIV-1 INHIBITOR and the NON-NUCLEOSIDE HIV TREATMENT
DRUG, the concurrent administration of the SENSITIZING HIV-1 INHIBITOR and the NON-NUCLEOSIDE HIV TREATMENT DRUG is continued.

40. Use according to claim 23 where after the initial concurrent administration of the SENSITIZING HIV-1 INHIBITOR and INHIBITOR and the NON-NUCLEOSIDE HIV
TREATMENT DRUG are administered intermittently.

41. A method of treating a HIV positive human which comprises (1) administering to the HIV positive individual a sensitizingly effective amount of a SENSITIZING HIV-1 INHIBITOR until increased sensitivity to a NON-NUCLEOSIDE HIV TREATMENT DRUG develops, (2) administering to the HIV positive individual an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.

42. A method of treating a HIV positive human according to claim 41 where the SENSITIZING HIV-1 INHIBITOR is selected from the group consisting of BHAP
COMPOUNDS.

43. A method of treating a HIV positive human according to claim 42 where the BHAP COMPOUND is 1-[5-methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]-piperazine and 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine.

44. A method of treating a HIV positive human according to claim 41 where the sensitizingly effective amount of the SENSITIZING HIV-1 INHIBITOR is from about 50 to about 3,000 mg per day.

45. A method of treating a HIV positive human according to claim 41 where more than one SENSITIZING HIV-1 INHIBITOR is used.

46. A method of treating a HIV positive human according to claim 41 where more than one NON-NUCLEOSIDE HIV TREATMENT DRUG is used.

47. A method of treating a HIV positive human according to claim 41 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured by clinical resistance to the SENSITIZING HIV-1 INHIBITOR.

48. A method of treating a HIV positive human according to claim 41 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured in vitro by an increase in p24 antigen.

49. A method of treating a HIV positive human according to claim 41 where the increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured in vitro by a measurement which detects a change in the amino acid 236 of the reverse transcriptase.

50. A method of treating a HIV positive human according to claim 41 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is selected from the group consisting of MERCK COMPOUNDS, BOEHRINGER COMPOUNDS, JANSSEN COMPOUNDS
and PFIZER COMPOUNDS.

51. A method of treating a HIV positive human according to claim 50 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of MERCK COMPOUNDS.

52. A method of treating a HIV positive human according to claim 51 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a MERCK COMPOUND selected from the group consisting of 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one, 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one, 3-{[1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-pyridin-2(1H)-one.

53. A method of treating a HIV positive human according to claim 50 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of BOEHRINGER COMPOUNDS.

54. A method of treating a HIV positive human according to claim 53 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.

55. A method of treating a HIV positive human according to claim 50 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of JANSSEN COMPOUNDS.

56. A method of treating a HIV positive human according to claim 55 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a JANSSEN COMPOUND selected from the group consisting of (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (-)-.alpha.-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide;

57. A method of treating a HIV positive human according to claim 50 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of PFIZER COMPOUNDS.

58. A method of treating a HIV positive human according to claim 57 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is

59. A method of treating a HIV positive human according to claim 41 where an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG is from about 50 to about 4,000 mg per day.

60. A method of treating a HIV positive human according to claim 41 where administration of the NON-NUCLEOSIDE HIV TREATMENT DRUG follows administration of the SENSITIZING HIV-1 INHIBITOR.

61. A method of treating a HIV positive human according to claim 41 where after the initial administration of the SENSITIZING HIV-1 INHIBITOR, the NON-NUCLEOSIDE HIV TREATMENT DRUG is administered concurrently with the SENSITIZING HIV-1 INHIBITOR.

62. A method of treating a HIV positive human according to claim 41 where after the initial administration of the SENSITIZING HIV-1 INHIBITOR, the NON-NUCLEOSIDE HIV TREATMENT DRUG is administered intermittently with the SENSITIZING HIV-1 INHIBITOR.

63. A method of treating a HIV positive human which comprises administering to the HIV positive individual a sensitizingly effective amount of one or more SENSITIZING
HIV-1 INHIBITOR concurrently with an effective amount of a NON-NUCLEOSIDE
HIV TREATMENT DRUG.

64. A method of treating a HlV positive human according to claim 63 where the SENSITIZING HIV-1 INHIBITOR is selected from the group consisting of BHAP
COMPOUNDS.

65. A method of treating a HIV positive human according to claim 63 where the BHAP COMPOUND is 1-[5-methoxyindolyl-2-carbonyl]-4-[3-(ethylamino)-2-pyridinyl]-piperazine and 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine.

66. A method of treating a HIV positive human according to claim 63 where the sensitizingly effective amount of the SENSITIZING HIV-1 INHIBITOR is from about 50 to about 3,000 mg per day.

67. A method of treating a HIV positive human according to claim 63 where more than one SENSITIZING HIV-1 INHIBITOR is used.

68. A method of treating a HIV positive human according to claim 63 where more than one NON-NUCLEOSIDE HIV TREATMENT DRUG is used.

69. A method of treating a HIV positive human according to claim 63 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is selected from the group consisting of MERCK COMPOUNDS, BOEHRINGER COMPOUNDS, JANSSEN COMPOUNDS
and PFIZER COMPOUNDS.

70. A method of treating a HIV positive human according to claim 63 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of MERCK COMPOUNDS.

71. A method of treating a HIV positive human according to claim 70 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a MERCK COMPOUND selected from the group consisting of 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one, 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one, 3-{[1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-pyridin-2(1H)-one.

72. A method of treating a HIV positive human according to claim 63 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of BOEHRINGER COMPOUNDS.

73. A method of treating a HIV positive human according to claim 72 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is 6,11-dihydro-11-cyclopropyl-4-methyldipyridor[2,3-b:2',3'-e]-[1,4]diazepin-6-one.

74. A method of treating a HIV positive human according to claim 63 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of JANSSEN COMPOUNDS.

75. A method of treating a HIV positive human according to claim 74 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a JANSSEN COMPOUND selected from the group consisting of (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (-)-.alpha.-[(2-nitrophenyl)amino]-2,6-dichlorobeneanceacetamide, (-)-.alpha.-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-.alpha.-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, .alpha.-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide.

76. A method of treating a HIV positive human according to claim 63 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is a compound selected from the group consisting of PFIZER COMPOUNDS.

77. A method of treating a HIV positive human according to claim 76 where the NON-NUCLEOSIDE HIV TREATMENT DRUG is

78. A method of treating a HIV positive human according to claim 63 where an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG is from about 50 to about 4,000 mg per day.

79. A method of treating a HIV positive human according to claim 63 where after the initial concurrent administration of the SENSITIZING HIV-1 INHIBITOR and the NON-NUCLEOSIDE HIV TREATMENT DRUG, the concurrent administration of the SENSITIZING HIV-1 INHIBITOR and the NON-NUCLEOSIDE HIV
TREATMENT DRUG is continued.

80. A method of treating a HIV positive human according to claim 63 where after the initial concurrent administration of the SENSITIZING HIV-1 INHIBITOR and INHIBITOR and the NON-NUCLEOSIDE HIV TREATMENT DRUG are administered intermittently.