WO1994009781A1

WO1994009781A1 - Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection

Info

Publication number: WO1994009781A1
Application number: PCT/US1993/008354
Authority: WO
Inventors: William Gary Tarpley; Thomas Jerome Dueweke; Donald Herman M. D. Batts
Original assignee: The Upjohn Company
Priority date: 1992-10-28
Filing date: 1993-09-10
Publication date: 1994-05-11
Also published as: PL308551A1; MX9306031A; EP0666744A1; FI952018A0; HU9501218D0; FI952018A; NO951608D0; HUT72050A; KR950703958A; CA2145545A1; JPH08502745A; NO951608L; AU4848293A; CZ69695A3

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-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. 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-1 INHIBITOR concurrently with an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.

Description

USE OF BHAP COMPOUNDS IN COMBINATION WITH OTHER NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR THE TREATMENT OF HIV INFECTION

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a method of treating HIV-1 positive individuals with a

SENSITIZING HIV-1 INHIBITOR prior to, currently or intermittently with drugs for the treatment 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 A1 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 including nevirapine (BI-RG-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.

International 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 (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][l,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][l,4]benzodiazepin-2(1H)- thione, (-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(5-methyl-2- nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)-α-[(2-acetylphenyl)amino]-2,6- dichlorobenzeneacetamide, (-)-α-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzene- acetamide, α-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(5-chloro-2- nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(2-acetyl-5-fluorophenyl)amino]-2,6- dichlorobenzeneacetamide.

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 resistance altering the sensitivity to other drugs within the same 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 discussed the mutations in the RT gene which leads to amino acid changes in the reverse transcriptase of the resistant strains.

Bioorganic & Medicinal Chemistry Letters 2(12), 1745 (1992) disclosed various nevirapine-like compounds including various imidazo[2',3':6,5]dipyrido[3,2-b:2',3'-e]-1,4-diazepines which are HIV-1 reverse transcriptase inhibitors with greater enzyme affinity than nevirapine.

The present invention is a method of treating HIV infected individuals which increases the sensitivity of the HTV virus to treatment with various non-nucleoside drugs.

SUMMARY OF INVENTION

Dislcosed is 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.

A1so disclosed 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-1 INHIBITOR concurrently with an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.

Further 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 administration of a SENSITIZING HIV-1 INHIBITOR. Additionally, disclosed is the use of a NON-NUCLEOSIDE HIV TREATMENT DRUG to prepare a medicament for the treatment of HIV positive individuals concurrently receiving a SENSITIZING HIV-1 INHIBITOR.

DETAILED DESCRIPTION OF THE INVENTION

Various nucleoside (AZT) and non-nucleoside reverse transcriptase inhibitors are known as being useful for the treatment of HIV infected individuals. With regard to the non-nucleoside reverse transcriptase inhibitors, see for example, European Patent Publication Nos. 484 071 A2, 462,800 A2, 462,808 A2, 481,802 A1, 393 529 A1, 393 530 A1, 393,604 A2, 410 148 A1, 415 304 A2, 429 987 A2, 498 290 A1, 417 840 A1, 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 that resistance to the pharmaceutical agent rapidly develops reducing or eliminating the efficacy of NON-NUCLEOSIDE HIV TREATMENT DRUGs.

The SENSITIZING HIV-1 INHIBITOR compounds of the present invention sensitize the HIV infected individual's HIV to treatment with a NON-NUCLEOSIDE HIV TREATMENT DRUG. It is preferred that the SENSITIZING HIV-1 INHIBITOR, be a BHAP COMPOUND but other HIV-1 RT inhibitors which sensitize 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-methanesulfonamidoindolyl)-carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]piperazine (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-1 reverse transcriptase inhibitors are also operable.

It is preferred that the MERCK COMPOUNDS be 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 and

3-{[1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-pyridin-2(1H)-one.

It is preferred that the BOEHRINGER COMPOUND be 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.

It is preferred that the JANSSEN COMPOUNDS be 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,

(-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[ (5 -methyl -2nitrophenyl)amino] -2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide. It is more preferred that the JANSSEN COMPOUND be selected from the group consisting of (-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, α-[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(2-acetyl-5-fluorophenyl)amino]-2,6-dichlorobenzeneacetamide.

It is preferred that the PFIZER COMPOUND be

There are a number of ways the sensitizing process of the present invention can be used to treat HIN infected individuals (both asymptomatic and those with AIDS). One method involves treating the HIV infected individual with a SENSITIZING HIV-1 INHIBITOR followed by treatment with a NON-NUCLEOSIDE HIV TREATMENT DRUG. Another method involves concurrent administration of the SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG.

The first method involves treating the HIV infected individual with a

SENSITIZING HIV-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 until increased sensitivity to a NON-NUCLEOSIDE HIV TREATMENT DRUG develops. This is then followed by administering 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 occurred and the administration 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

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 administration 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 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-1

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-1 reverse transcriptase, then that individual will have increased sensitivity to the NON-NUCLEOSIDE 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 to about 275, more particularly at 233, 234 or 238, will confer resistance to the

SENSITIZING HIV-1 INHIBITOR and sensitization to the NON-NUCLEOSIDE HIV TREATMENT 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 Medical Virology, 37, 241 (1992).

The sensitizingly effective amount is an amount that achieves a sustainable blood level which can either be below the MIC of the HIV 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 sensitized strains will occur more quickly if the MIC of 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 sustainable blood level. The SENSITIZING HIV-1 INHIBITOR is administered in a dosage range of 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 SENSITIZING HIV-1 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 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-1 INHIBITOR is 1-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine, an HIV infected individual would be treated with a dose of 3-10 mg/kg orally three or four times daily for 8-12 weeks; if the

SENSITIZING HIV-1 INHIBITOR is 1-[2-(5-methanesulfonamidoindolyl)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 mg/kg/dose orally two to four times daily, this would be followed by a NON-NUCLEOSIDE HIV TREATMENT DRUG.

Following treatment with SENSITIZING HIV-1 INHIBITOR, the sensitized 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, preferably from about about 50 to about 2,000 mg. If the NON-NUCLEOSIDE HIV TREATMENT DRUG is a MERCK COMPOUND, it is preferably administered 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 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 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 administered continuously IV in a total daily dose of from about 50 to about 1,000 mg daily. More specifically if the JANSSEN COMPOUND is (-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzene- acetamide, it is administered orally in a total daily dose of from about 100 to about 2,000 mg in divided doses two to six times daily. With this method one or more than one SENSITIZING HIV-1 INHIBITOR can be used, likewise one or more than one NON-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 administration of the SENSITIZING HIV-1 INHIBITOR, is to administer the

SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG concurrently rather than terminate the SENSITIZING HIV-1 INHIBITOR.

Another alternative form of this method is after the initial administration of the

SENSITIZING HIV-1 INHIBITOR to increase the HIV positive individual's sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG, is to administer the

SENSITIZING HTV-1 INHIBITOR intermittently with administration of the NON-NUCLEOSIDE 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 individual with a SENSITIZING HIV-1 INHIBITOR concurrently with the NON-NUCLEOSIDE HIV TREATMENT DRUG. Using this method the HIV infected individual is given both the SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG simultaneously. The therapeutic dosage range and frequency of administration of both the SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG is the same as for administration of the NON-NUCLEOSIDE HIV TREATMENT DRUG following administration of the SENSITIZING HIV-1 INHIBITOR, the only thing that is different is the sequencing of when the SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV

TREATMENT DRUG are given.

A modification of this process is that after a period of time when increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG is obtained, the SENSITIZING HIV-1 INHIBITOR is given intermittently with the NON-NUCLEOSIDE HIV TREATMENT DRUG rather than continuously. The particular method to be utilized with an particular patient will depend on many factors as will be apparent to those skilled in the art. These factors include whether the patient is symptom free or has some symptoms. Further, if the patient has symptoms are they mild or severe. In addition, other diseases/conditions that affect the 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 administration depends on the particular SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HIV TREATMENT DRUG used, the particular condition being treated, the severity of the condition being 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 measuring the blood level or concentration of the SENSITIZING HIV-1 INHIBITOR in the patient's blood and/or the patient's response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as used throughout this entire 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 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, "Z₁" or "R_i" where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z₁ would represent a bivalent variable if attached to the formula CH₃-C(=Z_{1 -})H. Groups R_i and R_j would represent monovalent variable substituents if attached to the formula CH₃-CH₂-C(R_i)(R_j)-H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R_i and R_j are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C_j, 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 designated by those skilled in the art of steroid chemistry. Likewise the term "R₆" represents 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-O-CH₂-CH(R_i)-CH₃ represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol "=" represents a double bond, e.g.,

CH₂=C(R_i)-O-CH₃, and the symbol "≡" represents a triple bond, e.g., HC≡C-CH(R_j)- 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 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 represented by -N^*-(CH₂)₂-N(C₂H₅)-CH₂-C^*H₂.

A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents 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(X₁)(X₂)- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and 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 (X₁) which is "below" another substituent (X₂) will be identified as being in the alpha (α) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "- - - " or "...". The corresponding substituent attached "above" (X₂) the other (X₁) is identified as being in the beta (ß) 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 separately or both in the definition of the variable. For example, a variable R_i attached to a carbon atom as -C(=R_i)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R_i-j and B-R_i-k. When a bivalent variable, R_i, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variabl is of the form "α-R_i-j:β-R_i-k" or some variant thereof. In such a case both α-R_i-j and ß R_i-k are attached to the carbon atom to give -C(α-R_i-j)(β-R_j-k)-. For example, when the bivalent variable R₆, -C(=R₆)- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R_6-1:ß-R_6-2, .... α-R_{6- 9}.ß-R_{6- 10,} etc, giving -C(α-R_6-1)(ß-R_6-2)-, .... -C(a-R_6-9)(B-R_6-10)-, etc. Likewise, for, the bivalent variable R_{1 1}, -C(=R₁₁)-, two monovalent variable substituents are α-R_{11- 1}:ß-R_{1 1-2}. For a ring substituent for which separate α and ß 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, but the α and ß designations are omitted.

Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -C₁(R_i)H-C₂(R_j)H- (C₁ and C₂ define arbitrarily a first and second carbon atom, respectively) R_i and R_j may be defined to be taken together to form (1) a second bond between C₁ and C₂ or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide. When R_i and R_j are taken together to form a more complex entity, such as the group -X-Y-, then the orientation of the entity is such that C₁ in the above formula is bonded to X and C₂ is bonded to Y. Thus, by convention the designation "... R_i and R_j are taken together to form -CH₂-CH₂-O-CO- ..." means a lactone in which the carbonyl is bonded to C₂. However, when designated "... R_j and R_i are taken together to form - CO-O-CH₂-CH₂-the convention means a lactone in which the carbonyl is bonded to C₁.

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 "C₁- C₄", where both "1 " and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C₁-C₄ alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C₂-C₄ alkoxycarbonyl 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 "C_j-Cj" designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaning as C₂-C₄ alkoxycarbonyl because the "C₁-C₃" refers only to the carbon atom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl 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 defining variable substituents and the number of carbon atoms in various groups is used to define the BHAP COMPOUNDS, it must be realized that there are alternative methods which accomplish the same thing.

Admittedly, the specification and claims here are a composite of information obtained electronically from different 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/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.

II. DEFINITIONS

A1l temperatures are in degrees Centigrade.

-∅ refers to phenyl (C₆H₅).

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

MIC refers to minimum inhibitory concentration.

BHAP refers to bisheteroarylpiperazines.

BHAP COMPOUNDS refers to bisheteroarylpiperazines selected from the group consisting of compounds of formula (I)

where R₁ is -CH₂-,

-CO-,

-CO-CH₂-,

-SO₂-,

-CH=CH-CO-;

where Z is

where

(I) R₂ is =O or R_2-1:R_2-2 where one of R_{2- 1} and R_2-2 is -H and the other of R₂ ₁ and R_2-2 is -H or -CH₃,

R3 is =O or R_{3- 1}:R_3-2 where one of R_{3- 1} and R_3-2 is -H and the other of R_{3- 1} and R_3-2 is -H or -CH3,

R₄ is R_{4- 1}:R_4-2 and R₅ is R_{5- 1} :R_5-2 where one of R_{4- 1} and R_{4- 2} is -H and the other of R_4-1 and R_4-2 is -H or -CH₃, where one of R_5-1 and R_5-2 is -H and the other of R_5-1 and R_5-2 is -H or

-CH₃,

(II) R₄ is R_4-3:R_4-4 and R₅ is R_5-3:R_5-4 where one of R_4-3 and R_4-4 and one of R_5-3 and R_5-4 are taken together to form -CH₂- and the other of R_4-3 and R_4-4, and R_5-3 and R_5-4 are -H, R₂ and R3 are -H:-H,

(III) R₂ is R_2-5;R_2-6 an d R₅ is R_5-5:R_5-6 where one of R_2-5 an d R_2-6 an d on^e of R_5-5 and R_5-6 are taken together to form -CH₂-CH₂- and the other of R_2-5 and R_2-6. and R_5-5 and R_5-6 are -H, and R₃ and R₄ are -H:-H,

(IV) R₃ is R_3-5:R_{3 -6} and R₄ is R_4-5:R_5-6 where one of R_3-5 and R_3-6 and one of R_4-5 and R_4-6 are taken together to form -CH₂-CH₂- and the other of R_3-5 and R_3-6, and R_4-5 and R_4-6 are -H, and R₂ and R₅ are -H:-H,

-Y ₁-(CH₂)_n11-Z₂-(CH₂)_n26-Y₂- (Z-II) where n_{1 1} is 1 thru 5,

n₂₆ is 1 thru 5,

Y₁ is -O-, -S-,

-N(Y_{1- 1})- where Y_{1- 1} is C₁-C₇ alkyl,

-C(Y_1-2)(Y_1-3) where Y_1-2 and Y_1-3 are the same or different and are -H or C₁-C₄ alkyl,

Y₂ is -O-, -S-,

-N(Y_2-1)- where Y_2-1 is C₁-C₄ alkyl,

-C(Y_2.2)(Y_2-3) where Y_2-2 and Y_2-3 are the same or different and are -H or C₁-C₄ alkyl,

Z₂ is nothing (a bond), -O-, -S-,

-N(Z_2-1)- where Z_2-1 is -H or C₁-C₄ alkyl,

-C≡C-,

-C(Z_2-2)(Z_2-3)- where Z_2-2 and Z_2-3 are the same or different and are -H or C₁-C₄ alkyl,

cis and trans -C(Z_2-2)=C(Z_2-3)- where Z_2-2 and Z_2-3 are the same or different and are -H or C₁-C₄ alkyl, with the provisos (1) that when Y₁ is -O-, -S- or -N(Y_{1 - 1})-, then n_{1 1} is 1 only when Z₂ is nothing (a bond), -C≡C-, -C(Z_2-2)(Z_2-3)- or -C(Z_2-2)=C(Z_2-3)- and (2) that when Y₂ is -O-, -S- or -N(Y_2-1)-, then n₂₆ is 1 only when Z₂ is nothing (a bond), -C≡C-, -C(Z_2-2)(Z_2-3)- or -C(Z_{2 2})=C(Z_2-3)-,

where n₁₂ is 1 or 2 and n₁₃ is 1 or 2,

where n₁₂ and n₁₃ are as defined above,

where Y₃ is -N(Y_3-1)- where Y_{3- 1} is C₁-C₄ alkyl and n₁₂ and n₁₃ are as defined above;

R₆ is -N=,

-CH=,

-N(O)=,

R₇ is -COO-R_7-11 where R_{7- 1 1} is as defined above,

-CO-N(R_7-3)(R_7-4) where R_7-3 and R_7-4 are the same or different and are -H or C₁-C₆ alkyl,

-N(R_7-5)(R_7-6) where R_7-5 is

C₁-C₆ alkyl,

-C(R_{7- 15})(R₇-₁₆)-(R_{7- 17}) where R_7-15 and R_7-16 are the same or different and are -H or C₁-C₃ alkyl and where R_7-17 is C₂-C₅ alkenyl containing 1 or 2 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-OH,

-CH₂-CF₃,

-CH₂-cyclopropyl,

-CH₂-CH₂F,

-CH₂-CH₂-C≡N, -C^* R_7-18-(CH₂)_n14-C^*H₂ where R_7-18 is -H or -CH₃, n₁₄ 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)n₁-N(R_7-7)(R_7-8) where n₁ is 2 or 3 and where R_7-7 and R_7-8 are the same or different and are -H or C₁-C₄ alkyl, and where R_7-7 and R_7-8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl, 1-aziridinyl,

and where R_7-6 is -H,

C₁-C₆ alkyl,

-C(R_7-15)(R_7-16)-(R_7-17) where R_7-15, R_7-16 and _R7-17 are as defined above,

-CH₂-CH₂-OH,

-CH₂-CH₂-CH₂-OH,

-CH₂CF₃,

- CH₂-CH₂F,

-CH₂-CH₂- C≡N,

or where R_7-5 and R_7-6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, N-morpholinyl or 1-aziridinyl,

-(CH₂)_n4-N(R_7-9)(R_7-10) where n₄ is 1 or 2 and where R_7-9 and R_{7- 10} are the same or different and are -H or C₁-C₄ alkyl, and where R_7-9 and R_7-10 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl, R₈ is -N=,

-CR_{8- 1}= where R_{8- 1} is -H, -F, -Cl, -Br, -CF₃,

-NO₂, -COCF₃,

C₁-C₆ alkyl,

C₁-C₃ alkylthio,

-OH,

-O-R_8-2 where R_8-2 is C₁-C₆ alkyl, -∅, -CO-R_8-3 where R_8-3 is C₁-C₆ alkyl or -∅,

-NH(R_8-4) where R_8-4 is C₁-C₆ alkyl,

-C(R_8-7)(R_8-8)-(R_8-9) where R_8-7 and R_8-8 are the same o different and are -H or C₁-C₃ alkyl and where R_8-9 is C₂-C₅ alkenyl containing 1 or 2 double bonds or C₂-C₅ alkynyl containing 1 triple bond,

-NR_8-5-CO-R_8-6 where R_8-5 is -H or C₁-C₆ alkyl and R_8-6 is -H,

C₁-C₆ alkyl or C₁-C₃ alkoxy;

R₉ is -N=,

-CR_{9- 1}= where R_9-1 is -H, -F, -Cl, -Br,

-NO₂, -COCF₃,

C₁-C₆ alkyl,

C₁-C₃ alkylthio,

-OH,

-O-R_9-2 where R_9-2 is C₁-C₆ alkyl, -∅, -CO-R_9-3 where R_9-3 is C₁-Cg alkyl or -∅,

-N(R_9-4)(R_9-5) where R_9-4 and R_9-5 are the same or different and are

-H,

C₁-C₆ alkyl,

-C(R_9-8)(R_9-9)-(R_9-10) where R_9-8 and R_9-9 are the same or different and are -H or C₁-C₃ alkyl and where R_9-10 is C₂-C₅ alkenyl containing 1 or 2 double bonds or C₂-C₅ alkynyl containing 1 triple bond,

R_9-4 and R_9-5 are taken together with the attached nitroge atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1- piperidinyl, 1-piperazinyl or N-morpholinyl,

-NR_9-6-CO-R_{9 -7} where R_9-6 is -H or C₁-C₆ alkyl and R_9-7 is -H,

C₁-C₆ alkyl or C₁-C₃ alkoxy;

R₁₀ is -N=,

-CR_{10- 1}= where R_{1 0-1} is -H, -F, -Cl, -Br, -CF₃,

-NO₂, -COCF₃,

C₁-C₆ alkyl,

C₁-C₃ alkylthio,

-OH,

-O-R_10-2 where R_10-2 is C₁-C₆ alkyl, -∅, -CO-R_10-3 where R_10-3 is C₁-C₆ alkyl or -∅,

-N(R_10-4)(R_10-5) where R_10-4 and R_10-5 are the same or different and are -H,

C₁-C₆ alkyl,

-C(R_10-8)(R_10-9)-(R_10-10) where R_10-8 and R_10-9 are the same or different and are -H or C₁-C₃ alkyl and where R_{10- 10} is C₂-C₅ alkenyl containing 1 or 2 double bonds or C₂-C₅ alkynyl containing 1 triple bond,

-NR_10-6-CO-R_10-7 where R_10-6 is -H or C₁-C₆ alkyl and R_10-7 is -H, C₁-C₆ alkyl or C₁-C₃ alkoxy;

with the proviso that not more than two of R₆, R₈, R₉ and R₁₀ are -N=;

Aryl/Heteroaryl is a substituent selected from the group of substituents of formula (1)

where X₁ is -H, C₁-C₆ or n- alkyl,

X₂ is -H, C₁-C₆ or n -alkyl,

X₃ is C₁-C₆ alkyl,

-CO-X_{3- 1} where X_3- ₁ is C₁ -C₄ alkyl or -Φ,

-CH₂-∅,

-Φ;

... of formula (2)

where X₄ and X₅ are the same or different and are -H,

C₁-C₄ alkyl,

-(CH₂)_n5-N(X_{4- 1})(X_4-2) where n₅ is 2 or 3 and where X_{4- 1} and X_4-2 are the same or different and are -H or C₁-C₄ alkyl or where X_4-1 and X_4-2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-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-piperidinyl, 1-piperazinyl or N-morpholinyl,

and where X₁ and X₂ are as defined above, with the proviso that both X₄ and X₅ are not both -H;

... of formula (3)

where X₆ is -H,

C₁-C₆ alkyl,

-F, -Cl, Br,

-OH, -O-CH₂-∅, -O-CF₃,

-O-CH₂-COOX_{6- 14} where X_6.14 is -H, C₁-C₆ alkyl, -∅, -CH₂-∅,

-CHO,

C₁-C₃ alkoxy,

C₁-C₃ alkylthio,

-O-CO-X_6-1 where X_{6- 1} is -H, C₁-C₄ alkyl or -∅,

-O-SO₂-X_6-12 where X_6-12 is C₁-C₄ alkyl,

-COO-X_6-13 where X₆.₁₃ is -H, C₁-C₄ alkyl, -∅ or -CH₂-∅,

-C≡N,

-NO₂, -N₃,

-NX_6-10X_{6- 1 1} where X_6-10 and X_{6- 1 1} are tne same or different and are

-H or C₁-C₅ alkyl or where X₆-₁₀ and X_6-11 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, N-morpholinyl or 1 -aziridinyl, -N(X_6-2)(CH₂)_n3-N(X_6-3)(X_6-4) where n₃ is 2 thru 5, X_6-2 is -H or C_{1 -4} alkyl, X_6-3 is -H or C_1-4 alkyl, X_6-4 is -H or C_{1 -4} alkyl, or where X_6-3 and X_6-4 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, N-morpholinyl or 1-aziridinyl,

-O-CO-(CH₂)_n3-COOH, where n₃ is as defined above,

-O-(CH₂)_n3-N(X_6-3)(X_6-4) where n₃, X_6-3 and X_6-4 are as defined above,

-(CH₂)_n24-OH, where n₂₄ is 1 thru 5,

-(CH₂)_n6-N(X_6-5)(X_6-6) where n₆ is 1 thru 5 and X_6-5 and X_6-6 are the same or different and are -H, C₁-C₄ alkyl or where X_6-5 and X_6-6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-NH-SO₂-X_6-7 where X_6-7 is C₁-C₄ alkyl, C₃-C₇ cycloalkyl, -∅ or

-CH₂-∅,

-N=C(X_6-4)-N(X_6-7)(X_6-8) where

(a) X_6-8 is C₁-C₄ alkyl, C₃-C₇ cycloalkyl or -∅ and where X_6-4 and X_6-7 are as defined above,

(b) X_6-7 and X_6-8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

(c) X_{6 -4} and X_6-7 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl or 1-piperidinyl,

-NX_6-4-CO-X_6-9 where X_6-9 is -H, C₁-C₄ alkyl or -∅ and where X_6-4 is as defined above,

-O-prodrug where prodrug is

-PO₂-O- cation⁺,

-CO-CH₂-CO-NH-CH₂-SO₂-O- cation⁺,

-CO-(CH₂)_n21-R₅₁ where n₂₁ is 1-7 and R₅₁ is -COO- cation ⁺,

-NR_{51- 1}R_51-2 where R_{5 1 - 1} and R_51-2 are the same or different and are -H or C₁-C₃ alkyl,

-N⁺R_{51 -1}R_51-2R_51-3 halide- where R_51-1, R_51-2 and R_51-3 are the same or different and are

-H or C₁-C₃ alkyl, 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-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 resulting 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 C₁-C₃ alkyl and where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-(CH₂)_n21-CO-O-[C₆H₁₂O₆ sugars],

-CO-O-CH(CH₂-O-CO-R₅₃)₂ where the R₅₃'s are the same or different and are C₁-C₁₈,

-CO-(CH₂)₆-CO-N(CH₃)-CH₂-CH₂-SO₃- cation⁺,

-CH₂-O-CO-(CH₂)_n21-NR_51-1R_{51- 2} where n₂₁, R_{5 1 -1} and

R_{5 1-2} are as defined above,

-CO-NH-C₆H₄-R₅₅ where R₅₅ is -H or C₁-C₃ alkyl, -NO₂,

-NR_{51- 1}R_51-2 where R_51-1 and R_51-2 are as defined above,

-NX_6-4-prodrug where X_6-4 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 - 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)

where Q₁ is -NX_{1 1 -} where X_{1 1} is -H, -SO₂-∅, -SO₂-CH₃, -CO-X _11-1 where X_{1 1- 1} is

C₁-C₄ alkyl, -CF₃ or -∅;

Q₂ is -N= provided R₁ is not -CH₂-,

-CX₁₂= where X₁₂ is

-COO-X _{12- 1} where X_12-1 is -H or C₁-C₄ alkyl,

-CO-N(X_12-2)(X_12-3) where X_12-2 and X_12-3 are the same or different and are -H, C₁-C₄ alkyl or where X_12-2 and X_12-3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-CO-COO-X_{12- 1} where X_{12- 1} is as defined above,

C₁-C₃ alkyl,

-CO-∅,

-CO-X_{12- 1} where Xι_2-ι is as defined above,

-CO-CO-N(X₁₂-₂)(X_12-3) where X_12-2 and X_12-3 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)

... of formula (7)

where .... is a single or double bond,

X₁₄ is -H,

-O-CH₂-∅, -O-CF₃,

-O-CH₂-COOR_14-10 where R_14-10 is -H, C₁-C₄ alkyl, -∅ or -CH₂-∅, C₁-C₆ alkyl,

-F, -Cl, Br,

-O-SO₂-X_{14- 1 1} where X_{14- 1 1} is C₁-C₄ alkyl,

-C≡N,

-CHO,

-(CH₂)_n25-OH where n₂₅ is 1 thru 5,

-NO₂, -NH₂, -N₃,

-NH-CH₂-∅, -NH-SO₂-X_14-1 where X_{14- 1} is C₁-C₆ alkyl, C₃-C₇ cycloalkyl or -∅,

-NX_14-2(CH₂)_n3-N(X_14-3)(X_14-4) where n₃ is 2 thru 5, X_14.2 is -H or C_1-6 alkyl, X_14-3 is -H or C_1-4 alkyl, X_14-4 is -H or C_1-4 alkyl, or where X_14-3 and X_14-4 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-NX_{14- 13}X_14-14 where X_14-13 and X_14-14 are the same or different and are

-H or C₁-C₅ alkyl or where X_14-13 and X_14-14 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-(CH₂)_n6-N(X_14-5)(X_14-6) where n₆ is 1 thru 5 and X_14-5 and X_14-6 are the same or different and are -H, C₁-C₄ alkyl or where X14.5 and X^g are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-N=C(X₁₄₄)-N(X_14-7)(X_14-8) where

(a) X_14-7 and X_14-8 are C₁-C₆ alkyl, C₃-C₇ cycloalkyl or -∅, where X_14-4 is as defined above,

(b) X_14-7 and X_14-8 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1- piperidinyl, 1-piperazinyl or N-morpholinyl,

(c) X_14-4 and X_14-7 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl or 1-piperidinyl,

-CO-O-X_14-7 where X_14-7 is as defined above,

-CO-N(X_24-7)(X_14-8) where X_14-7 and X_14-8 are as defined above, -N(X_14-2)-CO-X_14-9 where X_14-9 is -H, C₁-C₄ alkyl or -∅ where X_14-2 is defined above,

-N(X_14-2)-prodrug, where prodrug is as defined above except that it is not

-PO₂-O-, and when X_14-2 is as defined above,

n₇ is 0 thru 2,

X₆ and Q₁ are as defined above;

... of formula (8)

where X₂₁ is -H, C₁-C₄ alkyl, -CO-(C₁-C₄ alkyl), -CH₂-∅, -CO-∅ or -prodrug where prodrug 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,

C₁-C₃ alkoxy,

C₁-C₃ alkylthio,

-O-CO-X_{22- 1} where X_22-1 is -H, C₁-C₄ alkyl or -∅,

-NO₂, -NH₂, -N₃,

-ON,

-NX_22-2(CH₂)_n9-N(X_22-3)(X_22-4) where n₉ is 2 thru 5, X_22-2 is -H or C₁-C₄ alkyl, X_22-3 is -H or C₁-C₄ alkyl, X_22-4 is -H or C₁-C₄ alkyl, and where X_22-3 and X_22-4 arε taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-O-CO-(CH₂)_n9-COOH, where n₉ is as defined above,

-O-(CH₂)_n9-N(X_22-3)(X_22-4) where n₉, X_22-3 and X_22-4 are as defined above,

-(CH₂)_{n 10}-N(X_22-5)(X_22-6) where n₁₀ is 1 thru 5 and X_22-5 and X_22-6 are the same or different and are -H, C₁-C₄ alkyl and where X_22-5 an d X_22-6 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl,

-N(X_22-7)(X_22-8) where X_22-7 and X_22-8 are C₁-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-),

Q₁ and .... are as defined above;

... of formula (9)

4

where X₁₀ is -H, -F, -Cl or -Br,

Q₃ is -CH= or Q₂ where Q₂ is as defined above,

X₆ and X_{1 1} are as defined above;

... of formula (10)

where X₆, X_{1 1} and Q₃ are as defined above; ... of formula (1 1)

where X₇ is -H, -SO₂-∅, -SO₂-CH₃, -CO-X_7-1 where X_7-1 is C ₁-C₄ alkyl or -∅,

X₈ is -H, C ₁-C₆ alkyl, -CH₂-∅, -SO₂-∅, -SO₂-CH₃, -CO-X_{8- 1} where X_{8- 1} is C_1-

C₄ alkyl or -∅,

.... is as defined above;

... of formula (15)

where Q₃ and X_{1 1} are as defined above;

... of formula (16)

where Q₃ and X_{1 1} are as defined above;

... of formula (17)

where Q₃ and X₁₁ are as defined above; ... of formula (18)

where Q₃ and X₁₁ are as defined above; ... of formula (19)

where Q₃ and X₁₁ are as defined above; ... of formula (20)

where Q₃ and X₁₁ are as defined above;

... of formula (21)

where Q₁, X₆ and n₇ are as defined above;

with the proviso that one of R_7-5 or R_7-6 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]-4-[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,

1-[5-methoxyindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2-pyridinyl]-piperazine,

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]-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,

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)ethylenediamine,

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-butylenediamine,

N,N'-dimethyl-N-(5-methoxyindolyl-2-carbonyl)-N'-[3-(l-methylethylamino)-2-pyridinyl]-2Z-butylenediamine,

1-(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]-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 1 of European Publication 484 071 A2:

3-{[(4,7-dichlorobenzoaxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H-pyridinone,

3-{ [(4,7-dimethylbenzoxaxazol-2-yl)methyl]amino}-5-ethyl-6-ethyl-2(1H)-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(1H)-pyridinone,

3-{ [(7-fluorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-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(1H)-pyridinone,

3-{ [(4-fluoro-7-chlorobenzoxazol-2-yl)methyl]lamino}-5-ethyl-6-methyl-2(1H)-pyridinone,

3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone,

3-[N-(5-ethyl-2-methoxy-6-methyl-3-pyridylmethyl)-amino]-5-ethyl-6-methyl-

2(1H)-pyridinone,

3-[N-(5,6-dimethyl-2-methoxy-3-pyridylmethyl)amino]-5-ethyl-6-methyl-2(1H)-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(1H)-pyridinone, 3-[N-(2,6-dimethoxybenzyl)amino]-5-ethyl-6-methyl-2(1H)-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 or esters thereof.

MERCK 2 refers to the compounds of claims 1 and 11 of European Publication 462 800 A2, pyridones of the formula:

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, C_1-8alkyl,

Z is O, S or NR_X is H or C_1-8 alkyl,

n is 0-4;

R₁ , R₂ and R₄ are the same or different and are independently

(i) H;

(ii) C_1-8 alkyl, C_1-8 alkenyl, C_3-8 cycloalkyl, any of which is unsubstituted or substituted with one or two of C_{1 -3} alkoxy, C_1-4 alkylamino, di(C_{1 -4} alkyl)amino, C_{1 -3} alkylthio, hydroxy, amino, carbonyl, aminocarbonyl, or oximido, or one to five of halo; (iii) C_{1 -6} alkylthio;

(iv) C_{1 -5} alkylsulfinyl;

(v) C_{1 -5} alkylsulfonyl;

(vi) C_1-5 alkoxy;

(vii) C_{1 -5} alkoxycarbonyl;

(viii) cyano;

(ix) halo; or

(x) aryl;

or R₁ and R₄ may together form a cycloalkyl ring containing 5-7 members;

or R₁ and R₂ may together form a cycloalkyl ring containing 5-7 members;

and R₃ or R₅ are the same or different and are independently

(i) H;

(ii) C_1-8 alkyl;

(iii) C_1-8 alkenyl;

(iv) C_3-8 cycloalkyl;

is aryl or heterocycle each unsubstituted or substituted with one or more of

(i) C_1-6 alkyl unsubstituted or substituted with one or more of A, wherein A is halo, hydroxy, hydroxy-C_1-4 alkyl, amino, C_1-6 alkylamino, di(C_1-6 alkyl)amino, C_1-6 alkoxy or aryl,

(ii) C_{1 -6} alkenyl unsubstituted or substituted with one or more of A;

(iii) C_3-6 cycloalkyl unsubstituted or substituted with one or more of A;

(iv) C_1-6 alkoxy unsubstituted or substituted with one or more or A;

(v) aryl;

(vi) amino,

(vii) C_1-6 alkylamino;

(viii) di(C_1-6-alkyl)amino;

(ix) amino-C_{1 -8} alkyl;

(x) C_1-8 alkyl-amino-C, _{1 -8} alkyl;

(xi) di-(C_1-6 alkyl)amino C_{1 -8} alkyl; (xii) C_1-6 alkoxycarbonyl;

(xiii) aminocarbonyl;

(xiv) C_1-6 alkyl aminocarbonyl;

(xv) di(C_1-6 alkyl)aminocarbonyl;

(xvi) C_1-6 alkylthio;

(xvii) C_1-6 alkylsulfinyl;

(xviii) C_1-6 alkylsulfonyl;

(xix) hydroxy;

(xx) halo;

(xxi) CN, or

(xxii) NO₂ with the provisos that

(I) R₁, or R₂ or both are not substituted with OH; and

(II) heterocycle is not phthalimide; 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(1H)-pyridinone,

3-{[(4,7-dimethylbenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-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(1H)-pyridinone, 3-{ [(7-fluorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-pyridinone, 3-{ [(7-fluorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-pyridinone, 3-{ [(benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-pyridinone,

3-{ [(4-chlorobenzoxazol-2-yl)methyl]amino}-5-ethyl-6-methyl-2(1H)-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(1H)-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(1H)-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(1H)-pyridinone, 3-[2-(7-methylbenzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone, 3-[N-(5-ethyl-2-methoxy-6-methyl-3-pyridylmethyl)-amino]-5-ethyl-6-methyl- 2(1H)-pyridinone,

3-[N-(5-(2-hydroxyethyl)-2-methoxy-6-methyl-3-pyridylmethyl)amino]-5-ethyl-6-methyl-2(1H)-pyridinone,

3-[N-(5-1l-hydroxyethyl)-2-methoxy-6-methyl-3-pyridylmethyl)amino]-5-ethyl-6-methyl-2(1H)-pyridinone,

3-[N-(5,6-dimethyl)-2-methoxy-3-pyridylmethyl)amino]-5-ethyl-6-methyl-2(1H)-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(1H)-pyridinone,

3-[N-(2,6-dimethoxybenzyl)amino]-5-ethyl-6-methyl-2(1H)-pyridinone,

3-{ [(4,7-dichlorobenzoxazol-2-yl)methyl]amino}-5-methylthio-6-methyl-2(1H)-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(1H)-pyridinone,

3-{N-[(4,7-dichlorobenzoxazol-2-yl)methyl-N-methyl-amino}-5-ethyl-6-methyl- 2(1H)-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(1H)-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: or

wherein A is

h or

B is C_1-6alkoxy;

X is NH, O, S, or C₂;

Z is O or S;

n is 1-4;

R₁ is

(i) C_1-8alkyl, unsubstituted or substituted with one or two of C_1- ₃alkoxy, halo, C_1-4alkylamino, C_1-4-dialkylamiiio, or C_1-3alkylthio;

(ii) C_1.3alkylthio;

(iii) C_1-3alkoxy; or

(iv) halo;

R₂ is

(i) H;

(ii) C_1-2alkyl, unsubstituted or substituted with one or two of methoxy, methylamino, dimethylamino or methyl thio,

R₃ is H or C_1-8alkyl;

Pht is phthaloyl, of the structure

wherein m is 0-2,

with the proviso that when A is NHCH₂-Pht, both R₁ and R₂ cannot be C_1-2alkyl.

MERCK 4 refers to the compounds of claim 1 of US Patent 5,124,327, indoles of the formula: wherein R is

or

MERCK 5 refers to the compounds of claim 1 of European Publication 481

802 A1, hydroxy pyridinones of the formula:

where R₁ 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, C_1-8 alkyl, C_1-8 alkenyl or C_3-9 cycloalkyl;

Z is O, S or NR_x when R_x is H or C_1-8 alkyl;

n is 0-4; R₁, R₂ and R₄ are the same or different and are independently

(i) H;

(ii) C_1-8 alkyl, C_1-8 alkenyl, C_3-8 cycloalkyl; any of which is

unsubstituted or substituted with one or two of C_1-3 alkoxy, C_1-4 alkylamino, dl(C_1-4 alkyl)amino, C_1-3 alkylthio, hydroxy, amino, oxo, carbonyl, aminocarbonyl, or oximido, or one to five of halo;

(iii) C_1-5 alkylthio;

(iv) C_1-5 alkylsulfinyl;

(v) C_1-5 alkylsulfonyl;

(vi) C_1-5 alkoxy;

(vii) C_1-5 alkoxycarbonyl;

(viii cyano; or

(ix) aryl; or,

R₁ and R₄ may together form a cycloalkyl ring containing 5-7 members; or, R₁ and R₂ may together form a cycloalkyl ring containing 5-7 members; and

R₃ or R₅ are the same or different and are independently

(i) H;

(ii) C_{1 -8} alkyl;

(iii) C_{1 -8} alkenyl;

(iv) C_3-8 cycloalkyl;

is aryl or heterocycle, each unsubstituted or substituted with one or more of

(i) C_1-6 alkyl unsubstituted or substituted with one or more of A, wherein A is halo, hydroxy, hydroxy-C_1-4 alkyl, amino, C_1-6 alkylamino, di(C_1-6alkyl)amino or aryl;

(ii) C_1-6 alkenyl unsubstituted or substituted with one or more of A;

(iii) C_3-6 cycloalkyl unsubstituted or substituted with one or more of A;

(iv) C_1-6 alkoxy unsubstituted or substituted with one or more of A;

(v) aryl;

(vi) amino;

(vii) C_1-6 alkylamino

(viii) di(C_1-6 alkyl)amino;

(ix) amino-C_1-8 alkyl; (x) C_1-8 alkyl-amino-C_1-8 alkyl;

(xi) di(C_1-6 alkyl)amino C_1-8 alkyl;

(xii) C_1-8 alkoxycarbonyl;

(xiii) aminocarbonyl;

(xiv) C_1-6 alkyl aminocarbonyl;

(xv) di(C_1-6 alkyl aminocarbonyl;

(xvi) C_1-6 alkylthio;

(xvii) C_1-6 alkylsulfinyl;

(xviii) C_1-6 alkylsulfonyl;

(xix) hydroxy;

(xx) halo;

(xxi) CN; or

(xxii) NO₂; with the proviso that heterocycle is not phthalimide; or pharmaceutically acceptable salt or ester thereof.

MERCK 6 refers to the compound of Antimicrobial Agents and Chemotherapy

36, 1019 (1992), 3-[2-(benzoxazol-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 Publication 393 529 A1, 5,11-dihydro-6H-dipyrido[3,2-b:2'.3'-e][1,4]diazepin-6-ones of the formula:

where R¹ and R² are the same or different and are hydrogen or straight or 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 Publication

393 530 A1, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-ones and -thiones of the formula: wherein,

Z is oxygen or

sulfur:

R¹ 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 the aryl moiety is phenyl or thienyl, which is either unsubstituted or substituted by methyl, methoxy 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 to 3 carbon atoms, alkanoyl of 2 to 3 carbon atoms, hydroxyalkyl of 2 to 4 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, hydroxyl or halogen), phenyl (which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, halogen or hydroxyl) or alkoxy carbonylmethyl wherein the alkoxy moiety contains 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, R and R⁵ is butyl, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl 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, hydroxyl, 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, aminoalkyl 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, nitro, carboxyl, carbamyl, amino, azido, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, with the proviso that the remaining 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 remaining two substituents are hydrogen or methyl; and

R⁶, R⁷, R⁸ and R⁹ are hydrogen; or one of R⁶, R⁷, R⁸ and R⁹ is alkyl of 1 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl 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, hydroxyl, 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,aminoalkyl 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, nitro, carboxyl, carbamyl, amino, azido, mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, and the remaining three substituents are hydrogen or two of the remaining three substituents are hydrogen and one is methyl, ethyl or halogen, or a

pharmaceutically acceptable acid addition salt thereof.

BOEHRINGER 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:

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 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, hydroxyalkyl 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, hydroxyl, or halogen), phenyl (which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, halogen or hydroxyl) or alkoxycarbonylmethyl wherein the alkoxy moiety contains 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, hydroxyalkyl of 1 to 4 carbon atoms, alkoxycarbonyl of 2 to 3 carbon atoms, alkoxycarbonylalkyl wherein both the alkoxy and alkyl moieties contain 1 to 2 carbon atoms, halogen,

trihalomethyl, hydroxyl, 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, aminoalkyl 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, nitro, carboxyl, carbamyl, amino, azido or mono- or dialkylaminoalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, and the remaining 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 remaining 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, alkoxycarbonyl of 2 to 3 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein both the alkoxy and alkyl moieties contain 1 to 2 carbon atoms, halogen, trihalomethyl, hydroxyl, 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, aminoalkyl 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, nitro, carboxyl, carbamyl, amino, azido or mono- or dialkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, and the remaining three substituents are hydrogen or two of the remaining three

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 Publication 410 148 A1, 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-ones and -thiones of the formula: wherein,

Z is oxygen or

sulphur;

R¹ is hydrogen, C_1-6alkyl optionally substituted by fluorine, trihalomethyl, C_3-5alkenyl 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), C_2-3 alkanoyl or C_2-4 alkoxyalkyl or alkylthioalkyl;

R² is hydrogen, C_1-5 alkyl optionally substituted by fluorine, C_2-5alkenyl or alkynyl, C_2-4 alkoxyalkyl or alkylt hioalkyl, C_2-4alkanoyl, C_2-5hydroxyalkyl, arylmethyl (where in the aryl moiety is phenyl, thienyl or furanyl, and is optionally substituted by C_1-6 alkyl or alkoxy, hydroxyl or halogen), phenyl optionally substituted by C_1-3 alkyl or alkoxy groups, hydroxy or halogen or

(C_1-5alkoxy)carbonylmethyl; and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ is each hydrogen, or one of R³, R⁴, R⁵, R⁶, R⁷ and R⁵ is an alkyl, alkoxy, alkylthio, alkoxycarbonyl, hydroxyalkyl, alkanoyl, alkanoyloxy, alkanoylamino, carboxyalkyl or aminoalkyl group containing up to 4 carbon atoms, or a (C_1-2alkoxy)carbonyl(C_1-2alkyl), mono- or di -(C_1-2alkyl)amino, cyano, nitro, hydroxyl, carboxyl, amino, mono- or di- (C_1-2alkyDaminotC₁.galkyl) or azido group or a halogen atom and the remaining five of R³ , R⁴, R⁵, R⁶, R⁷ and R⁸ are each hydrogen, or

R³, R⁴ and R⁵, are each independently hydrogen or C_1-3alkyl with the proviso that at least one is hydrogen, or one of R³, R⁴ and R⁵ is butyl with the remaining two being hydrogen, and R⁶, R⁷ and R⁸ are each independently hydrogen or C_1-6alkyl with the proviso that at least one is hydrogen, or one of R⁶, R⁷ and R⁸ is butyl with the remaining two being hydrogen; with the proviso that when R¹ and R² are each independently hydrogen or straight-chained or branched C_1-5alkyl and R³, R⁴, R⁵, R⁶ , R⁷ and R⁸ are all hydrogen then Z is sulphur) or an acid addition salts thereof.

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(5H)-ones and -thiones of the formula:

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 dihaloalkenyl of 2 to 4 carbon atoms wherein the halogen atoms are attached to the vinylic carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, aminocarbonylmethyl, acetyl, cyanoalkyl and wherein the alkyl moiety contains 1 to 3 carbon atoms, or hydroxy alkylmethyl 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 carbon atoms, trihalomethyl, alkanoyl of 2 to 3 carbon atoms, cyano azido, amino, nitro, halogen, hydroxyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, mono or di- alkylamino wherein each alkyl group contains 1 to 2 carbon atoms, aminoalkyl or mono- or di-alkylaminoalkyl wherein each alkyl group contains 1 to 2 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms or alkyloxycarbonyl of 2 to 3 carbon atoms; 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 hεdogen;

R⁶ is hydrogen, methyl, halogen or amino; and

R⁷ is hydrogen, methyl or halogen; with the proviso that at least two of R⁵, R⁵ 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, 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepines of the formula: wherein,

Z is oxygen,

sulfur, = NCN, or a

group of the formula = NOR wherein R is alkyl of 1 to 3 carbon atoms;

R¹ 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, methoxy or halogen), alkanoyl of 2 to 4 carbon atoms, aminoethyl, mono- or di-alkylaminoethyl wherein each alkyl moiety contains 1 to 2 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 4 carbon atoms, alkyloxycarbonal wherein the alkyl moiety contains 1 to 4 carbon atoms, alkenyloxy- or alkynyloxycarbonyl wherein each alkenyl or alkynyl moiety contains 2 to 4 carbon atoms, hydroxy, alkyloxy of 1 to 4 carbon atoms, amino, mono- or di-alkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms, aminocarbonylmethyl, or cyanoalkyl wherein the alkyl moiety contains 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, tetrahydrofuranyl 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, hydroxyalkyl 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, hydroxyl or halogen), or alkyloxycarbonylmethyl wherein the alkyl moiety contains 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, trihalomethyl hydroxyalkyl of 1 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkyloxycarbonylalkyl wherein the alkyl moieties each contain 1 to 2 carbon atoms, hydroxyl, alkyloxy or alkylthio of 1 to 5 carbon atoms, hydroxyalkyloxy 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 alkyl moiety contains 1 to 3 carbon atoms, mono- or di-alkylaminocarbonyl wherein each alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 3 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, hydroxyl or halogen), a group of the formula -NR ¹⁰R¹¹, halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen, methyl or chloro; or, two of R³, R⁴ and R⁵ are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula -NR¹⁰R ¹¹, with the remaining 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, trihalomethyl hydroxyalkyl 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, hydroxyl, alkyloxy or alkylthio of 1 to 4 carbon atoms, hydloxyalkyloxy 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, alkoxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the formula -NR¹²-R ¹³, 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

-NR¹²R ¹³, with the remaining substituent being hydrogen; or,

R⁶ , R⁷ and R⁸ are each hydrogen; and,

R¹⁰, R¹¹, R¹² and R¹³ are each independently 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 dihydroxyalkylmethyl of 2 to 4 carbon atoms, alkyoxy of 1 to 3 carbon atoms, hydroxy, alkyloxy ethyl or alkylthioethyl of 3 to 4 carbon atoms, aminoalkylmethyl 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,

R¹⁰ and R ^{1 1}, and R¹² and R ¹³, together with the nitrogen atoms between them, respectively and independently form azetidin-1-yl or a 5, 6 or 7-membered ring which is either saturated or unsaturated, which optionally contains 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 independently substituted with hydroxymethyl, aminomethyl, 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 alkylthioalkyl of 2 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, phenyl (optionally substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), or

alkoxycarbonylmethyl wherein the alkyl moiety contains 1 to 5 carbon atoms.

BOEHRINGER 7 refers to the compounds of claim 1 of European Publication 498 290 A1, compounds of the formula

wherein, one of X and Y is -N = and the other is

where A is a fused ring of the formula or or or

or, when X is -N = and Y is

A may additionally be

R¹ is cyano, chloro, bromo, imidazolyl, phosphetanyl, phospholanyl, or phosphorinanyl, or a group of the formula -OR¹⁴, -SR¹⁴, -SOR¹⁴, -SO₂R¹⁴, -NH₂, -NHR¹⁴, -NR¹⁴R¹ -PR¹⁴R¹⁵, -P(OR¹⁴)(OR¹⁵), -P(O)(OR¹⁵)(OR¹⁵), -PO₃H₂,

-P(NR¹⁴R¹⁵)(NR¹⁴)(R¹⁵), or -P(O)(NR¹⁴R¹⁵)(NR¹⁴R¹⁵), wherein R¹⁴ 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 -NR¹⁴R ¹⁵ may be pyrrolidine, 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, oxazolyl or isoxazol, which is unsubstituted, or is phenyl, thienyl or furanyl, which is either unsubstituted or substituted by alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl or halogen), alkoxycarbonylmethyl wherein the alkoxy moiety contains 1 to 5 carbon atoms, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, 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, alkoxycarbonyl of 2 to 4 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl or alkylthioalkyl of 2 to 5 carbon atoms, alkoxycarbonylalkyl wherein the alkoxy and alkyl moieties each contain 1 to 2 carbon atoms, halogen,

trihalomethyl, hydroxyl, alkoxy of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms, aryl or arylalkyl (wherein the alkyl moiety contains 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, hydroxyl or halogen), alkanoyl of 2 to 6 carbon atoms, alkoxycarbonyl wherein the alkyl moiety contains 1 to 3 carbon atoms, hydroxyalkoxy 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, aminoalkyl 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 -NR¹⁶R ¹⁷, N-pyrrolidino, N-piperidino, N-morpholino, carboxyalkyl of 2 to 3 carbon atoms, cyano, nitro, carboxyl, carbamyl, amino, azido, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 3 carbon atoms, with the proviso that the remaining two substituents are hydrogen, methyl or chloro; or

two of R³, R⁴ and R⁵ are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a group of the formula NR¹⁶R¹⁷, with the remaining 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, hydroxyalkyl of 1 to 4 carbon atoms, alkoxycarbonylalkyl wherein the alkoxy and alkyl moieties each contain 1 to 2 carbon atoms, halogen, trihalomethyl, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, hydroxyalkyloxy 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, aminoalkyl 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, aminoalkyl of 1 to 4 carbon atoms, mono- or di-alkylaminoalkyl wherein each alkyl moiety contains 1 to 2 carbon atoms, a group of the formula -NR¹⁸R ¹⁹, and the remaining two or three substituents are hydrogen or two of the remaining three substitutents are hydrogen and one is methyl, ethyl or halogen;

when only R⁶ , R⁷ and R⁸ are present two of them are independently alkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen, or a group of the formula -NR¹⁸R ¹⁹, with the remaining substituent being hydrogen;

R¹⁰ and R¹¹ are chosen from hydrogen, alkyl of 1 to 4 carbon atoms, halogen, cyano, nitro and alkanoyl of 1 to 3 carbon atoms, and

R^{1 2} and R^{1 3} are each independently hydrogen, alkyl of 1 to 4 carbon atoms, halogen or nitro;

R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each independently 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 unsubstituted or substituted by methyl, methoxy or halogen), mono- or di- hydroxyalkylmethyl of 2 to 4 carbon atoms, alkyloxy of 1 to 3 carbon atoms, hydroxy, alkyloxy ethyl or alkylthioethyl of 3 to 4 carbon atoms, aminoalkylmethyl 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 R^{1 6}, R^{1 7}, R^{1 8} and R¹⁹, together with the nitrogen atoms between them, respectively and independently from azetidin-1-yl or a 5, 6, or 7-membered ring which is either saturated or unsaturated, which optionally contains 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 =NR²⁰ wherein R²⁰ is hydrogen or alkyl of 1 to 2 carbon atoms, and which ring is optionally independently substituted with hydroxymethyl, 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 International Public No.

WO 92/00952, HIV-inhibiting benzeneacetamides of the formula:

a pharmaceutically acceptable acid addition salt form or a stereochemically isomeric form thereof, wherein

R¹ and R² each independently are hydrogen, C_1-6alkyl or C_3-6cycloalkyl; 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_1- ₄alkylpiperazinyl group;

X is O or S;

R³ is hydrogen or C_1-6alkyl;

R⁴ R⁵ and R⁶ each independently are hydrogen, hεdo, C_1-6alkyl, C_1-6alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, C_1-4alkyloxycarbonyl, C_{1 -} ₄alkylcarbonyl, aminocarbonyl or hydroxy;

R⁷ is hydrogen or halo; and

R⁸, R⁹ and R ¹⁰ each independently are hydrogen, halo, C_1-6alkyl, C_1- ₆alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,

(trifluoromethyl )carbonyl, aminocarbonyl, (cyclopropyl)carbonyl or a radical C_1- ₆alkyl-(C=Y)- wherein = Y represents =O, =N-OH, =N-OCH₃, =N-NH₂ or =N-N(CH₃)₂;

provided that:

(1) R¹ 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 R¹, R², R³, R⁶, R⁷, R⁸, R⁹ and R¹⁰ represent hydrogen and R⁴ and R⁵ represent 3,4-dimethoxy.

JANSSEN 2 refers to the compounds of claim 1 of International Public No. WO 92/00979, antiviral tetrahydroimidazo[l,4]benzodiazeepin-2-(thio)ones of the formula: a pharmaceutically

acceptable acid addition

salt or a stereochemically isomeric form thereof, wherein

X is O or S;

R¹ is a radical of formula: ;

or -Alk-S(O)_m—R¹³

Alk is C_1-6alkanediyl;

R⁶ is hydrogen, halo or C_1-4alkyl;

R⁷ a nd R⁸ each independently are hydrogen, halo, C_3-6cycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, C_1-4alkyl optionally substituted with C_1- ₄alkyloxy;

R⁹ is hydrogen, halo or C_1-4alkyl;

each R¹⁰ independently is hydrogen or C_1-4alkyl; or both R¹⁰ taken together may form a C_1-6alkanediyl radical;

n is 2, 3, 4, 5 or 6;

R¹¹ is hydrogen or C_2-6alkenyl; each R¹² independently is hydrogen or C_1-4alkyl; or both R¹² taken together may form a C_1-6alkanediyl radical;

m is O, 1 or 2;

R¹³ is C_1-6alkyl, aryl, arylmethyl, C_3-6cycloalkyl or (C_3-6cycloalkyl) C_1-4alkyl;

R² is hydrogen or C_1-6alkyl;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ each independently are hydrogen, C_1-6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C_1-6alkyloxy, amino, mono- or di(C_1-6 alkyl)amino, C_1- ₆alkylcarbonylamino or arylcarbonylamino; and each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C_1-6alkyl, halo, hydroxy, C_1-6alkyloxy, amino, nitro and trifluoromethyl;

provided that when R⁴ or R ⁵ is other than C_1-6alkylcarbonylamino or arylcarbonylamino, then R is other than C_3-6alkenyl and (C_3-6cycloalkyl)C_1-6alkyl.

JANSSEN 3 refers to the compounds of claim 1 of European Patent

Publication No. 417 840 Al, antiviral tetrahydroimidazo[1,4]-benzodiazepines of the formula:

a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein

R¹ is C_1-6alkyl optionally substituted with aryl; C_3-6alkynyl; C_3-6cycloalkyl; or a radical of formula: ;

);

; or

; Alk is C_1-6alkanediyl;

R⁸ and R⁹ each independently are hydrogen, halo, C_3-6cycloalkyl,

trifluoromethyl, 2,2,2-trifluoroethyl, C_1-4alkyl optionally substituted with C_1-4 alkyloxy;

R¹⁰ is hydrogen, halo or C_1-4alkyl;

each R¹¹ independently is hydrogen or C_1-4alkyl; or both R¹¹ taken together may form a C_1-6alkanediyl radical;

R¹² is hydrogen, halo or C_1-4alkyl;

n is 2, 3, 4, 5 or 6;

each R¹³ independently is hydrogen or C_1-4alkyl; or both R¹³ taken together may form a C_1-6alkanediyl radical;

R¹⁴ is hydrogen or C_2-6alkenyl;

m is 0, 1 or 2;

R¹⁵ is C_1-6alkyl, aryl, arylmethyl, C_3-6cycloalkyl or (C_3-6 cycloalkyl)C_1-6alkyl; R² is hydrogen or C_1-6alkyl;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ each independently are hydrogen, C_1-6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C_1-6alkyloxy, amino, mono or di(C_1-6alkyl)amino,

C_1-6alkylcarbonylamino or arylcarbonylamino; R⁶ is C_1-6alkyl;

R⁷ is hydrogen or C_1-6alkyl;

X is OH, SH or NR¹⁶R¹⁷;

R¹⁶ is hydrogen, C_1-6alkyl, aryl, cyano, hydroxy, amino, nitro, C_1- galkyloxycarbonyl, C_1-6alkylcarbonyl, C_1-6alkylsulfonyl or arylsulfonyl;

R¹⁷ is hydrogen, C_1-6alkyl or aryl; and

each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C_1-6alkyl, halo, hydroxy, C_1-6alkyloxy, amino, nitro and trifluoromethyl.

JANSSEN 4 refers to the compounds of claim 1 of European Patent

Publication No. 384 522 A1, antiviral tetrahydroimidazo[1,4]-benzodiazepin-2-thiones of the formula:

a pharmaceutically acceptable acid salt or a stereochemically isomeric form thereof, wherein

R¹ is C_1-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, or C_1-6alkyl substituted with aryl or with C_3-6cycloalkyl;

R² is hydrogen or C_1-6alkyl;

R³ is hydrogen or C_1-6alkyl;

R⁴ and R⁵ each independently are hydrogen, C_1-6alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C_1-6alkyloxy, amino or mono-or di(C_1-6alkylamino); and aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C_1-6alkyl, halo, hydroxy, C_1-6alkyloxy, amino, nitro and

trifluoromethyl.

JANSSEN 5 refers to the compounds of claim 1 of European Patent

Publication No. 336 466 Al, antiviral tetrahydroimidazo[1,4]-benzodiazepin-2-ones of the formula

a pharmaceutically acceptable acid addition salt or a stereochemically isomeric forms thereof, wherein

R¹ is hydrogen, C_1-85lkyl, C_3-6alkenyl, C_1-6- alkynyl, C_1-6alkylcarbonyl, C_1- ₄cycloalkyl, or substituted with aryl, hydroxy, cyano or C_3-6cycloalkyl;

R² is hydrogen, C_1-6alkyl or C_3-6alkenyl;

R³ is hydrogen, or C_1-6alkyl;

R⁴ is hydrogen, C_1-6alkyl optionally substituted with hydroxy, cyano, hydroxycarbonyl or carbonyl C_1-6alkylcarbonyl; C_3-6alkenyl; C_3-6cycloalkyl;

C_3-6cycloalkenyl;

R⁵ is hydrogen, C_1-6alkyl or halo; and

aryl is phenyl optionally substituted with up to 3 substituents independently selected from C_1-6alkyl, halo, hydroxy, C_1-6alkyloxy, amino, nitro and

trifluoromethyl.

JANSSEN 6 refers to the compounds of claim 1 of European Patent

Publication No. 430 334 Al, immunostimulating 6-aryl-5,6-dihydroimidazo[2,1-b]thiazoles of the formula:

a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein

Ar is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C_1-6alkyloxy, mercapto, C_1-6alkylthio, C_1-6alkyl, nitro, amino, mono, and di(C_1-6alkyDamino, C_1-6alkylcarbonylamino, arylcarbonylamino, C_1-6alkylsulfonylamino, trifluoromethyl, cyano, aminocarbonyl, mono- and di(C_1-6alkyl)aminocarbonyl, hydroxycarbonyl, C_1-6alkyloxyamino, carboxaldehyde and hydroxymethyl; pyridinyl; thienyl, furanyl or furanyl substituted with either C_1-6alkyl or halo;

R¹ and R² each independently are C_1-20alkyl, (C_3-7cycloalkyl), C_1-5alkyl, C_3- ₇cycloalkyl, aryl or (aryl)-C_1-6alkyl; and one of R¹ and R² may also be hydrogen; or R¹ and R² taken together may also form a C_3-6alkanediyl radical; each aryl independently is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C_1-6alkyloxy, C_1-6alkyl, nitro, amino, trifluoromethyl or cyano.

JANSSEN COMPOUNDS refers to the compounds of JANSSEN 1, JANSSEN 2, JANSSEN 3, ... JANSSEN 6.

PFIZER 1 refers to the compounds of the formula

where X and Y are the same or different and are -N=, -CR₄= where R₄ is -H or -CH₃;

where R₁ is C₁-C₃ alkyl or cyclopropyl;

where R₂ is -H or -CH₃;

where Rg is -H or -OR_3-1 where R_3-4 is C₁-C₃ alkyl, -N(R_3-2)(R_3-3) where R_3- ₂ and R_3-3 are the same or different and are -H or C₁-C₄ alkyl.

PFIZER COMPOUNDS refers to the compounds of PFIZER 1.

NON-NUCLEOSIDE HIV TREATMENT DRUG refers to MERCK

COMPOUNDS + BOEHRINGER COMPOUNDS + JANSSEN COMPOUNDS + PFIZER 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 as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

EXAMPLE 1 SENSITIZING HIV-1 INHIBITOR Followed By NON-NUCLEOSIDE

HIV TREATMENT DRUG

A 21 year old male, HIV positive patient with no symptoms is treated by administering 500 mg of 1-[2-(5-methoxyindolyl)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-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one (BI-RG-587,

nevirapine) administered orally in a dose of 200 mg once a day.

EXAMPLE 2 SENSITIZING 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-methanesulfonamidoindolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyljpiperazine, 50 mg orally three times daily for a period of 8 weeks, followed by 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one which is administered orally 250 mg three times daily.

EXAMPLE 3 SENSITIZING HIV-1 INHIBITOR Followed By NON-NUCLEOSIDE

HIV TREATMENT DRUG

A 2 month old child who is HIV positive with no symptoms is treated with 1- [2-(5-methoxyindolyl)carbonyl]-4-[3 -(N-ethylamino)-2-pyridinyl)piperazine, 1 mg/kg orally four times dafly for a period of 3 months followed by (+)-(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, 50 mg intravenously continuously daily.

EXAMPLE 4 SENSITIZING 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 daUy for 2 months concurrently with 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one given 500 mg orally twice daily indefinitely.

EXAMPLE 5 SENSITIZING HIV-1 INHIBITOR Concurrently With NON- NUCLEOSIDE HIV TREATMENT DRUG

A 17 year old male, symptomatic with HIV, is treated concurrently with 1-[2-(5-methanesulfonamidoindolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]-piperazine, 150 mg by mouth every 8 hours, concurrent with 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2^,,3'-e]-[1,4]diazepin-6-one, 400 mg by mouth daily.

EXAMPLE 6 SENSITIZING HIV-1 INHIBITOR Concurrently With NON- NUCLEOSIDE HIV TREATMENT DRUG

A 6 year old child symptomatic with HIV, is treated with 1-[2-(5-methanesulfonamidoindolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]piperazine at a dose of 0.5 mg/kg, four times daily concurrently with (-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, 150 mg orally three times daily.

Claims

1. Use of a NON-NUCLEOSIDE HIV TREATMENT DRUG to prepare a

medicament for treatment of HIV positive individuals having strains of HIV showin increased sensivity thereto due to the administration of a 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-methylethylamino)-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]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-phthaHmidoethyl)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]-[l,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-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione, (-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(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 SENSIΗZING HIV-1 INHIBITOR.

21. Use according to claim 1 where where after the initial administration of the

SENSITIZING HIV-1 INHIBITOR, the NON-NUCLEOSIDE HIV TREATMENT DRUG is administered concurrently with the SENSIΗZING 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 a SENSITIZING HIV-1 INHIBITOR.

24. Use according to claim 23 where the SENSIΗZING 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

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

(-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(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

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

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 SENSIΗZING 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-l,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

(-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(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 SENSIΗZING HIV-1 INHIBITOR concurrently with an effective amount of a NON-NUCLEOSIDE HIV TREATMENT DRUG.

64. A method of treating a HIV 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

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-[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-methyldipyrido[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

(-)-α-[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

(-)-α-[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,

α-[(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.