Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to a method of treating HIV-1 positive individuals with a
• European Patent Publication Nos. 393 529 Al, 393 530 Al, 393,604 A2, 410 148 Al, 415 304 A2, 429 987 A2, 498 290 Al disclose dipyridodiazepinone derivatives including nevirapine (BI-RG-587) 6,11-dihydro-l l-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-
• 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,
• 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.
• 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
• nucleoside (AZT) and non-nucleoside reverse transcriptase inhibitors are known as being useful for the treatment of HIV infected individuals.
• non-nucleoside reverse transcriptase inhibitors see for example, European Patent Publication Nos. 484 071 A2, 462,800 A2, 462,808 A2, 481,802 Al, 393 529 Al, 393 530 Al, 393,604 A2, 410 148 Al, 415 304 A2, 429 987 A2, 498 290 Al, 417 840 Al, 0384 522 Al, 336,466 Al, 430 334 Al, 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).
• 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.
• the SENSITIZING HIV- 1 INHIBITOR compound be l-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridin- yl)piperazine (WO 91/09849, EXAMPLE 16) or l-[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.
• the MERCK COMPOUNDS be selected from the group consisting of 3- ⁇ [(4,7-dichloro-l,3-benzoxazol-2-yl)methyl]amino ⁇ -5-ethyl-6-methylpyridin-2(lH)-one, 3- ⁇ [(4,7-dimethyl-l,3-benzoxazol-2-yl)methyl]amino ⁇ -5-ethyl-6-methylpyridin-2(lH)- one,
• JANSSEN COMPOUNDS be selected from the group consisting of
• the JANSSEN COMPOUND be selected from the group consisting of (-)- -[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)- ⁇ -[(5-methyl-2nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, (-)- ⁇ -[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, (-)- ⁇ -[(2-acetyl-5-methylphenyl)amino]-2,6-dichlorobenzeneacetamide, ⁇ -[(2-acetyl-5-chlorophenyl)amino]-2,6-dichlorobenzeneacetamide, ⁇ -[(5-chloro-2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide, ⁇ -[(2-acetyl-5-fluoropheny
• 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.
• 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.
• the HIV positive individual will have increased sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG when resistance develops to the SENSITIZING HIV-1 INHIBITOR.
• 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.
• 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.
• ELISA enzyme-linked immunosorbent assay
• An alternative method of determining the HIV positive individual's increased sensitivity is by checking the HTV positive individual's reverse transcriptase for a mutation in the region known to confer resistance to the SENSITIZING HTV-l INHIBITOR and increased sensitivity to the NON-NUCLEOSIDE HTV TREATMENT DRUG. If a mutation from proline to leucine occurs at amino acid 236 of the HTV-l 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
• 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 HTV-l INHIBITOR is given for a period of about two to about 16 weeks, preferably about 8 to about 12 weeks before the HIV infected individual is treated with a NON-NUCLEOSIDE HIV TREATMENT DRUG. More preferably, the transition from administration of the SENSITIZING HTV-l INHIBITOR to the NON-NUCLEOSIDE HIV TREATMENT DRUG is measured either clinically and/or in vitro as discussed above.
• an HTV 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 l-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N- ethylamino)-2-pyridinyl)piperazine, an HTV 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 l-[2-(5-methoxyindolyl)carbonyl]-4-[3-(N- ethylamino)-2-pyridinyl)piperazine
• SENSITIZING HTV-l INHIBITOR is l-[2-(5-methanesulfonamidoindolyl)carbonyl]-4- [3-(N-isopropylamino)-2-pyridinyl]piperazine, an HTV 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 HIN TREATMENT DRUG. Following treatment with SENSITIZING HIV-1 INHIBITOR, the sensitized strains would then be more sensitive to the NON-NUCLEOSIDE HTV TREATMENT DRUG.
• the dosages of the NON-NUCLEOSIDE HTV 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.
• 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.
• the NON-NUCLEOSIDE HTV 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.
• 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.
• the JANSSEN COMPOUND is (+)-(5S)- 4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,l- jk][l,4]benzodiazepin-2(lH)-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 (-)- ⁇ -[(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 HTV TREATMENT DRUG has increased by the initial administration of the SENSITIZING HTV-l INHIBITOR, is to administer the SENSITIZING HTV-l INHIBITOR and NON-NUCLEOSIDE HTV 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 HTV-l INHIBITOR to increase the HIV positive individual's sensitivity to the NON-NUCLEOSIDE HIV TREATMENT DRUG, is to administer the
• the other method of treatment involves initially treating the HIV infected individual with a SENSITIZING HTV-l INHIBITOR concurrently with the NON- NUCLEOSIDE HIV TREATMENT DRUG. Using this method the HTV infected individual is given both the SENSITIZING HTV-l 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 HTV-l INHIBITOR, the only thing that is different is the sequencing of when the SENSITIZING HIV-1 INHIBITOR and NON-NUCLEOSIDE HTV TREATMENT DRUG are given.
• a modification of this process is that after a period of time when increased sensitivity to the NON-NUCLEOSIDE HTV TREATMENT DRUG is obtained, the SENSITIZING HTV-l INHIBITOR is given intermittently with the NON- NUCLEOSIDE HTV 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 HTV-l INHIBITOR and NON-NUCLEOSIDE HTV 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 HTV-l INHIBITOR in the patient's blood and/or the patient's response to the particular condition being treated.
• 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, "Z j " or "R j " 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 Z j would represent a bivalent variable if attached to the formula CH ⁇ -C ⁇ Z j . )H.
• Groups R_ j and R would represent monovalent variable substituents if attached to the formula CH ⁇ -C ⁇ - R j XR -H.
• variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
• each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
• both R j and R- are bonded to the preceding carbon atom.
• C j 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.
• R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
• the cyclic molecular fragment, 4-(ethyl)-l-piperazinyl can be represented by -N*-(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C*H 2 .
• 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.
• the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial equatorial.
• 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.
• a substituent (X j ) which is "below” another substituent (X 2 ) will be identified as being in the alpha ( ⁇ ) 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” (X 2 ) the other (X j ) is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
• variable substituents When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
• R j When a bivalent variable, R j , is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variabl is of the form " ⁇ -R j _ : ⁇ -R j _ k " or some variant thereof.
• both ⁇ -R j.j and ⁇ R j _ k are attached to the carbon atom to give -C( ⁇ -R j _:)( ⁇ -R j _ k )-.
• the two monovalent variable substituents are ⁇ -Rg_
• a ring substituent for which separate ⁇ and ⁇ orientations do not exist e.g. due to the presence of a carbon carbon double bond in the ring
• a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the ⁇ and ⁇ designations are omitted.
• 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.
• R j and R may be defined to be taken together to form (1) a second bond between C j and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
• R j and R: are taken together to form a more complex entity, such as the group - X-Y-, then the orientation of the entity is such that C j in the above formula is bonded to X and C 2 is bonded to Y.
• the designation "... R j and R are taken together to form -CH 2 -CH 2 -O-CO- " means a lactone in which the carbonyl is bonded to C 2 .
• the convention means a lactone in which the carbonyl is bonded to C j .
• 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 "C j - C 4 ", 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.
• C j -C 4 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.
• C 2 -C 4 alkoxycarbonyl describes a group H ⁇ - (CH 2 ) n -O-CO- where n is zero, one or two.
• 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.
• this optional convention (C j - C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C j -C " refers only to the carbon atom content of the alkoxy group.
• C 2 -C 6 alkoxyalkyl and (C j -C3)alkoxy(C j -C 3 )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.
• compositions 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) [Aryl/IeteroarylB-Ri-Z (I
• R O or R3.
• R3.2 where one of R 3 . j and R _ 2 is -H and the other of R _ j
• R4 is R 4 1 :R4_ 2 and R 5 is R 5 _ j .R 5 _ 2 where one of R 4 _ j and R4 2 is -H and the other of R 4 _ j and R 4 . 2 is -H or -CH3, where one of R 5 . j and R ⁇ . 2 is -H and the other -CH 3 ,
• R 4 is where one of R 4 _ 3 and R 4 4 and one of R 5 _ and R5.4 are taken together to form -CH 2 - and the other of R 4 _ 3 and R4.4, and R 5 _3 and R 5 ⁇ are -H, R 2 and R3 are -H:-H, (IE) R 2 is R2-5 ; R2-6 anc * ⁇ 5 * s ⁇ 5-5 : ⁇ 5-6 wnere one or" 2-5 anc ⁇ ⁇ 2-6 an ⁇ ⁇ one of R 5 _ 5 and R 5 _g are taken together to form -CH 2 -CH 2 - and the other of R 2 5 and R _£ . and R 5 . 5 and R 5 _g are -H, and R 3 and R 4 are -H:-H,
• R3 is an d
• R4 is R4_ 5 :R 5 _g where one of R 3 _g and R 3 _g and one of R 4 _ 5 and R 4 _ 6 are taken together to form -CH 2 -CH 2 - and the other of R 3.5 and R 3.6 , and R 4 _ 5 and R 4 _ 6 are -H, and R 2 and R 5 are -H:-H,
• Y j is -O-, -S-,
• Y j _ 2 and Y j . 3 are the same or different and are -H or C j -C 4 alkyl, Y 2 is -O-, -S-,
• Z 2 is nothing (a bond), -O-, -S-, -N(Z 2 . 1 )- where Z 2 . j is -H or C r C 4 alkyl,
• r j j is 1 only when Z 2 is nothing (a bond), -C ⁇ C-, -C(Z 2 _ 2 )(Z 2 _ )- or and (2) that when Y 2 is -O-, -S- or -N(Y 2.1 )-, then n 26 is 1 only when Z 2 is nothing (a bond), -C ⁇ C-, -C(Z 2 _ 2 )(Z 2 _3)- or
• n j2 is 1 or 2 and n J 3 is 1 or 2
• n 12 and n 13 are as defined above,
• R 7 is -COO-R ⁇ . j j where R7 . 11 is as defined above,
• R 7 _ 3 and R 7 _ 4 are the same or different and are -H or C r C 6 alkyl
• R 7 _ 5 is C r C 6 alkyl
• R7 . 5 and R ⁇ _i are the same or different and are -H or C1-C3 alkyl and where R7.17 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C «; alkynyl containing 1 triple bond,
• n j is 2 or 3 and where R7 . 7 and R 7 _ 8 are the same or different and are -H or C1-C4 alkyl, and where R7.7 and R 7 _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, 1- aziridinyl, and where R 7 _g is -H, C r C 6 alkyl,
• R7.5 and R _ 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,
• Rg. j is -H, -F, -Cl, -Br, -CF 3 , C r C 6 alkyl, C C 3 alkylthio, -OH,
• Rg_ 2 is C j -Cg alkyl, - ⁇ , -CO-R _3 where RQ ⁇ is C j -C 6 alkyl or - ⁇ ,
• R _7 and Rg_g are the same o different and are -H or C j -Cg alkyl and where R ,9 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C ⁇ 5 alkynyl containing 1 triple bond, -NRg_ 5 -CO-R 8 _ 6 where Rg_ 5 is -H or C j -C 6 alkyl and R g _ 6 is -H,
• R 9 . j is -H, -F, -Cl, -Br, C r C 6 alkyl
• Rg_ 2 is C ⁇ C ⁇ alkyl, - ⁇ , -CO-R ⁇ where Rg_ 3 is C j -Cg alkyl or - ⁇ , are the same or different and are
• R ⁇ _ and Rg_g are the same or different and are -H or C1-C3 alkyl and where alkenyl containing 1 or 2 double bonds or C 2 -C 5 alkynyl containing 1 triple bond,
• Rg_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, -NRp.g-CO-R ⁇ where Rg_ is -H or C r C 6 alkyl and R ⁇ is -H,
• R 10 _ 8 and R 10 _ 9 are the same or different and are -H or C ⁇ -C alkyl and where RIQ-IO - S ⁇ I' ⁇ S lk en yl containing 1 or 2 double bonds or C ⁇ C ⁇ alkynyl containing 1 triple bond,
• Aryl/Heteroaryl is a substituent selected from the group of substituents of formula (1)
• X 4 and X 5 are the same or different and are -H, C r C 4 alkyl,
• n ⁇ is 2 or 3 and where X4 . 1 and X 4 _ 2 are the same or different and are -H or C j -C 4 alkyl or where X 4 .
• j 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 X 4 and X ⁇ 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 X j and X 2 are as defined above, with the proviso that both X 4 and X 5 are not both -H; ... of formula (3)
• X 6.14 is -H, C r C 6 alkyl, - ⁇ , -CH 2 - ⁇ ,
• Xg.i Q and Xg . n 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 )(CH 2 ) n3 -N(X 6 .
• X 6 _ 3 and Xg_ 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,
• n 24 is 1 thru 5, -(CH 2 ) n6 -N(X 6 . 5 )(X 6.6 ) where n 6 is 1 thru 5 and X 6.5 and X 6 . 6 are the same or different and are -H, C j -C 4 alkyl or where X ⁇ _- and Xg ⁇ 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,
• X 6.7 is C r C 4 alkyl, CyO j cycloalkyl, - ⁇ or
• Xg . g is C j -C 4 alkyl, C 3 -C cycloalkyl or - ⁇ and where X 6 _ 4 and Xg. 7 are as defined above, (b) Xg_ 7 and X 6 _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,
• Xg ⁇ and X ⁇ are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1- pyrrolidinyl or 1-piperidinyl,
• prodrug is -PO 2 -O " cation + , -CO-CH 2 -CO-NH-CH 2 -SO 2 -O " cation*,
• R51.1, R51.2 an d R51.3 are the same or different and are
• R 5 ⁇ 2 are as defined above,
• R5 .1 and R5i_ 2 are as defined above, -NXg .4 -prodrug where X ⁇ and prodrug are as defined above except that prodrug is not -PO 2 -O " , n 2 is 1 thru 3, the Xg's can be the same or can be different and where when n 2 is 2 and the two Xg groups are ortho to each other they can be taken together to form - O-CH 2 -O-; with the proviso that if n 2 is 2 or 3, only one of the X 6 's can be a prodrug, ... of formula (4)
• Q j is -NX j ⁇ where XJ J is -H, -SO 2 - ⁇ , -SO 2 -CH 3 , -CO-XU J where X j j j is C r C 4 alkyl, -CF 3 or - ⁇ ;
• X 12 . j is -H or C r C 4 alkyl, -CO-N(X j2 _ 2 )(X 12 _ 3 ) where X ⁇ 2 _ 2 and X j2 . are the same or . different and are -H, C j -C 4 alkyl or where X j . and X j2 -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,
• X j4 is -H
• R 14 _ 10 is -H, C r C 4 alkyl, - ⁇ or -CH 2 - ⁇ ,
• n 25 is 1 thru 5, -NO 2 , -NH 2 , -N 3 ,
• X 14 _! is C r C 6 alkyl, CyC- cycloalkyl or - ⁇ , -NX 14 _ 2 (CH 2 ) n3 -N(X 1 4_ 3 )(X 1 4_ 4 ) where n 3 is 2 thru 5, X 14.2 is -H or
• C ⁇ _4 alkyl, Xi4. 3 is -H or C ⁇ alkyl, X14 .
• 4 is -H or C j ⁇ alkyl, or where X j 4_ 3 and X j 4_ 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, -NXi4_ ⁇ 3 X j _i where X ⁇ 4 _ ⁇ 3 and X ⁇ 4 _i4 are the same or different and are
• X14 . 7 and X j 4_ are C j -Cg alkyl, C -C7 cycloalkyl or - ⁇ , where X14 . is as defined above,
• X14 . and Xi4_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,
• X j 4_4 and X14 . 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-X14 . where X14 . 7 is as defined above,
• prodrug is as defined above except that it is not
• X 2 J is -H, C1-C4 alkyl, -CO-(C -C 4 alkyl), -CH 2 - ⁇ , -CO- ⁇ or -prodrug where prodrug is as defined above,
• X 22 , X 23 and X 24 are the same or different and are -F, -Cl, Br, -OH, -O-CH 2 - ⁇ , -O-CF 3 , -O-CH 2 -COOH,
• X 22 . j is -H, C r C 4 alkyl or - ⁇ , -NO 2 , -NH 2 , -N 3 , -ON,
• -NX 22 _ 2 (CH 2 ) n9 -N(X 22 _ 3 )(X 22 _4) where rig is 2 thru 5, X 22 . 2 is -H or C j -C alkyl, X 22.3 is -H or C j -C alkyl, X 22 _ 4 is -H or C j -C 4 alkyl, and where X22-3 and X22-4 ⁇ 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,
• ⁇ JQ is 1 thru 5 and X 2 2-5 ar >d ⁇ 22-6 are the same or different and are -H, C1-C4 alkyl and where X22-5 anc ⁇ 2-6 are ta ⁇ en 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.
• g are C j -Cg alkyl, C3-C7 cycloalkyl or
• X 7 is -H, -SO 2 - ⁇ , -SO 2 -CH 3 , -CO ⁇ . j
• X 7 .! is C r C 4 alkyl or - ⁇
• X 8 is -H, C r C 6 alkyl, -CH 2 - ⁇ , -SO 2 - ⁇ , -SO 2 -CH 3 , -CO-Xg. j where Xg. j is C r
• MERCK 1 refers to the aminopyrimmidones of claim 1 of European Publication 484 071 A2:
• MERCK 2 refers to the compounds of claims 1 and 11 of European Publication 462 800 A2, pyridones of the formula:
• Z is 0, S or NR ⁇ is H or C j. g alkyl, n is 0-4;
• Ri , R and R 4 are the same or different and are independently (i) H; (ii) C j _ alkyl, C j .g alkenyl, C 3.8 cycloalkyl, any of which is unsubstituted or substituted with one or two of C j _ 3 alkoxy, C j ⁇ alkylamino, di(C j _ 4 alkyl)amino, C j _ 3 alkylthio, hydroxy, amino, carbonyl, aminocarbonyl, or oximido, or one to five of halo; (iii) C j .6 alkylthio; (iv) C j _ 5 alkylsulfinyl; (v) C j _ 5 alkylsulfonyl; (vi) C j _ 5 alkoxy; (vii) C ⁇ _ 5 alkoxycarbonyl;
• R j and R 4 may together form a cycloalkyl ring containing 5-7 members; or Ri and R 2 may together form a cycloalkyl ring containing 5-7 members; and R 3 or R ⁇ are the same or different and are independently (i) H;
• 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(lH)- pyridinone,
• MERCK 3 refers to the compounds of claim 1 of European Publication 462 808
• X is NH, O, S, or C 2 ; Z is O or S; n is 1-4; R j is
• C j _galkyl unsubstituted or substituted with one or two of C j _ 3 alkoxy, halo, C 1 . 4 alkylamino, or C j .galkylthio; (ii) C j. galkylthio;
• MERCK 4 refers to the compounds of claim 1 of US Patent 5,124,327, indoles of the formula: wherein R is
• MERCK 5 refers to the compounds of claim 1 of European Publication 481
• R or R 2 or both are substituted at least once with OH;
• R is H, C- ⁇ .g alkyl, C j . alkenyl or Cg g cycloalkyl; Z is 0, S or NR ⁇ when ⁇ is H or C j. g alkyl; n is 0-4; R j , R 2 and R 4 are the same or different and are independently (i) H;
• Rg or Rg are the same or different and are independently (i) H;
• MERCK 6 refers to the compound of Antimicrobial Agents and Chemotherapy
• 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 Al, 5,ll-dihydro-6H-dipyrido[3,2-b:2'.3'-e][l,4]diazepin-6-ones of the formula:
• R 1 and R 9 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
• Z is oxygen or sulfur
• R is hydrogen, alkyl or fluoroalkyl of 1 to 4 carbon atoms, cyclopropyl, alkenyl or alkynyl of 3 to 4 carbon atoms, 2-halo-propen-l-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;
• R 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:
• R , R and R 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 R , R and R 5 is butyl, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl of 2 t 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
• R 6 , R 7 , R 8 and R 9 are hydrogen; or £* n Q Q one of R , R , R and R 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
• BOEHRINGER 3 refers to the compounds of claim 1 of European Publication 393,604 A2, 6,ll-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepin-5-ones and -thiones of the formula:
• Z is oxygen or sulfur
• R is hydrogen, alkyl or fluoroalkyl of 1 to 5 carbon atoms, cyclopropyl, alkenyl or alkynyl of 3 to 5 carbon atoms, 2-halo-propen-l-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:
• R 2 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;
• R , R , and R 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 R , R and R 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
• R 6 , R 7 , R and R 9 are each hydrogen; or, one of R 6 , R , R 8 and R 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,
• BOEHRINGER 4 refers to the compounds of claim 1 of European Publication 410 148 Al, 5,ll-dihydro-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-ones and -thiones of the formula: wherein,
• Z is oxygen or sulphur
• R is hydrogen, C j. galkyl optionally substituted by fluorine, trihalomethyl, Cg. 5 alkenyl or alkynyl, 2-halopropen-l-yl, arylmethyl (wherein the aryl moiety is phenyl, thienyl or furanyl and is optionally substituted by methyl, methoxy or halogen), C 2. g alkanoyl or C 2 _ 4 alkoxyalkyl or alkylthioalkyl;
• R is hydrogen, C j .g alkyl optionally substituted by fluorine, C 2 .galkenyl or alkynyl, C 2 _ alkoxyalkyl or alkylt hioalkyl, C 2 _4alkanoyl, C 2 _ghydroxyalkyl, arylmethyl (where in the aryl moiety is phenyl, thienyl or furanyl, and is optionally substituted by C j. g alkyl or alkoxy, hydroxyl or halogen), phenyl optionally substituted by C j .g alkyl or alkoxy groups, hydroxy or halogen or (C .galkoxy)carbonylmethyl; and
• R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is each hydrogen, or one of R 3 , R 4 , R 5 , R 6 , R 7 and
• R is an alkyl, alkoxy, alkylthio, alkoxycarbonyl, hydroxyalkyl, alkanoyl, alkanoyloxy, alkanoylamino, carboxyalkyl or aminoalkyl group containing up to 4 carbon atoms, or a (C j _2alkoxy)carbonyl(C j _2alkyl), mono- or dHC j ⁇ alkyDamino, cyano, nitro, hydroxyl, carboxyl, amino, mono- or dMC j .galky aminotC j .gal yl or azido group or a halogen atom and the remaining five of R , R , R , R , R and R are each hydrogen, or R , R and R , are each independently hydrogen or C j .galkyl with the proviso that at least one is hydrogen, or one of R , R and R is butyl with the remaining two being hydrogen, and R , R and
• galkyl with the proviso that at least one is hydrogen, or one of R , R and R is butyl with the remaining two being hydrogen; with the proviso that when R 1 and R are each independently hydrogen or straight-chained or branched C j .galkyl and R , R , R , R and R 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][l,4]oxazepin (and thiazepin)-6(5H)-ones and -thiones of the formula:
• X is oxygen or sulfur
• Z is oxygen or sulfur;
• R 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 inylic 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 alky lmethyl of 2 to 4 carbon atoms;
• R is hydrogen, methyl, ethyl, halogen, nitro or amino
• R is hydrogen, methyl, or halogen
• R 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 R is other than hydrogen, R is hydrogen, methyl or chloro and R is hydrogen;
• R is hydrogen, methyl or h ⁇ dogen
• R is hydrogen, methyl, halogen or amino
• R is hydrogen, methyl or halogen; with the proviso that at least two of R , R and R is hydrogen, or a pharmaceutically acceptable salt thereof.
• BOEHRINGER 6 refers to the compounds of claim 1 of European Publication 429 987 A2, 5,ll-dihydro-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepines of the formula: wherein,
• R 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-l-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
• R 9 is hydrogen (with the proviso that R 1 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
• R , R and R are each hydrogen: one of R , R and R 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
• 1 1 ⁇ moiety contains 1 to 2 carbon atoms, a group of the formula -NR -R , halogen, cyano, nitro, azido or carboxyl, with the other two substituents being hydrogen; or, two of R 6 , R and R 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 -NR R , with the remaining substituent being hydrogen; or, R , R and R are each hydrogen; and,
• R 10 , R 11 , R and R 13 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 dihydroxyal- kylmethyl 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, R and R , and R and R , together with the nitrogen atoms between them, respectively and independently
• BOEHRINGER 7 refers to the compounds of claim 1 of European Publication 498 290 Al, compounds of the formula
• A may additionally be
• R is cyano, chloro, bromo, imidazolyl, phosphetanyl, phospholanyl, or phosphorinanyl, or a group of the formula -OR 14 , -SR 14 , -SOR 14 , -SO 2 R 14 , -NH 2 , -NHR 14 , -NR 14 R* -PR 14 R 15 , -P(OR 14 )(OR 15 ), -P(O)(OR 15 )(OR 15 ), -P0gH 2 , -P(NR 14 R 15 )(NR 14 )(R 15 ), or -P(O)(NR 14 R 15 )(NR 14 R 15 ), wherein R 14 and R 15 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 -NR
• R , R and R 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 R , R and R 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
• 1 ⁇ 1 7 contains 1 to 3 carbon atoms, a group of the formula -NR R , 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 R , R and R are independently alkyl or hydroxyalkyl of 1 to 2 carbon atoms, trihalomethyl, alkyloxy or alkylthio of 1 to 2 carbon atoms, halogen or a
• R fs R 1 , R R and R ⁇ ) are each hydrogen; or ⁇ V ft Q one of R , R , R and R is alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of
• 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-alkylaminocarbony
• R and R are chosen from hydrogen, alkyl of 1 to 4 carbon atoms, halogen, cyano, nitro and alkanoyl of 1 to 3 carbon atoms, and R 19 and R 1 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, halogen or nitro;
• R 16 , R 17 , R 18 and R 19 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 fi , R 17 , R 1 ft and R , together with the nitrogen
• BOEHRINGER COMPOUNDS refers to the compounds of BOEHRINGER 1,
• JANSSEN 1 refers to the compounds of claim 1 of International Public No.
• R 1 and R 9 each independently are hydrogen, C j .galkyl or Cg.gcycloalkyl; or
• R and R taken together with the nitrogen atom bearing said R and R may form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 4-C j. 4 alkylpiperazinyl group;
• X is O or S;
• R is hydrogen or C j .galkyl
• R R and R each independently are hydrogen, h ⁇ do, C j .galkyl, C j .galkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, C j ⁇ alkyloxycarbonyl, C j ⁇ alkylcarbonyl, aminocarbonyl or hydroxy;
• R' is hydrogen or halo
• R 1 is other than n-propyl when R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 and R 10 represent hydrogen, R represents 4-ethoxy and X represents oxygen, and
• X is other than sulfur, when R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 10 represent hydrogen and R and R 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;
• R is a radical of formula:
• Alk is C j .galkanediyl
• R is hydrogen, halo or C j _ 4 alkyl
• R ⁇ uid R each independently are hydrogen, halo, Cg.gcycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, C j _ 4 alkyl optionally substituted with C j . 4 alkyloxy;
• R is hydrogen, halo or C j _ 4 alkyl; each R independently is hydrogen or C . 4 alkyl; or both R taken together may form a C j. galkanediyl radical; n is 2, 3, 4, 5 or 6; R is hydrogen or C 2.6 alkenyl; each R independently is hydrogen or C j _ 4 alkyl; or both R taken together may form a C j. galkanediyl radical; m is O, 1 or 2; R ⁇ ⁇ ⁇ is C j. galkyl, aryl, arylmethyl, Cg . gcycloalkyl or (Cg . gcycloalkyl) C j . 4 alkyl;
• R is hydrogen or C 1 _ 6 alkyl
• R is hydrogen or C j .galkyl
• R and R each independently are hydrogen, C j. galkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C j .galkyloxy, amino, mono- or di(C j .g alkyl)amino, C j galkylcarbonylamino or arylcarbonylamino; and each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C j.
• JANSSEN 3 refers to the compounds of claim 1 of European Patent
• R is C j .galkyl optionally substituted with aryl; Cg.galkynyl; Cg.gcycloalkyl; or a radical of formula:
• Alk is C j .galkanediyl
• R and R each independently are hydrogen, halo, Cg . gcycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, C j . 4 alkyl optionally substituted with C j _ 4 alkyloxy;
• R is hydrogen, halo or C j . 4 alkyl; each R independently is hydrogen or C j . 4 alkyl; or both R taken together may form a C j .galkanediyl radical;
• R 19 is hydrogen, halo or C j . 4 alkyl; n is 2, 3, 4, 5 or 6; each R independently is hydrogen or C j . 4 alkyl; or both R taken together may form a C j .galkanediyl radical;
• R is hydrogen or C 2.6 alkenyl; m is 0, 1 or 2;
• R is C j .galkyl, aryl, arylmethyl, Cg.gcycloalkyl or (Cg.g cycloalkyDC j. galkyl;
• R is hydrogen or C j. galkyl
• q R is hydrogen or C j. galkyl
• R and R each independently are hydrogen, C j. galkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C j. galkyloxy, amino, mono or di(C j _ 6 alkyl)amino, g C j galkylcarbonylamino or arylcarbonylamino; R is C j .galkyl; n
• R is hydrogen or C j. galkyl
• X is OH, SH or NR 16 R 17 ;
• R is hydrogen, C j .galkyl, aryl, cyano, hydroxy, amino, nitro, C j . galkyloxycarbonyl, C j .galkylcarbonyl, C j .galkylsulfonyl or arylsulfonyl;
• R 17 is hydrogen, C j .galkyl or aryl; and each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C j .galkyl, halo, hydroxy, C j. galkyloxy, amino, nitro and trifluoromethyl.
• JANSSEN 4 refers to the compounds of claim 1 of European Patent Publication No. 384 522 Al, antiviral tetrahydroimidazo[l,4]-benzodiazepin-2- thiones of the formula:
• R is C j .galkyl, Cg.galkenyl, Cg.galkynyl, Cg.gcycloalkyl, or C j .galkyl substituted with aryl or with Cg.gcycloalkyl;
• R is hydrogen or C j .galkyl;
• R is hydrogen or C j. galkyl;
• R and R each independently are hydrogen, C j .galkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C j. galkyloxy, amino or mono-or di(C j .galkylamino); and aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C j .galkyl, halo, hydroxy, C j .galkyloxy, amino, nitro and trifluoromethyl.
• JANSSEN 5 refers to the compounds of claim 1 of European Patent Publication No. 336 466 Al, antiviral tetrahydroimidazo[l,4]-benzodiazepin-2-ones of the formula
• R is hydrogen, C j .galkyl, Cg.galkenyl, C j .g- alkynyl, C j .galkylcarbonyl, C j
• R is hydrogen, C j. galkyl or Cg.galkenyl; o
• R is hydrogen, or C j .galkyl
• R is hydrogen, C j .galkyl optionally substituted with hydroxy, cyano, hydroxycarbonyl or carbonyl C j .galkylcarbonyl; Cg.galkenyl; Cg.gcycloalkyl; Cg.gcycloalkenyl;
• R is hydrogen, C j .galkyl or halo; and aryl is phenyl optionally substituted with up to 3 substituents independently selected from C j .galkyl, halo, hydroxy, C j galkyloxy, 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,l- b]thiazoles of the formula:
• Ar is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C j .galkyloxy, mercapto, C j. galkylthio,
• C j .galkyl nitro, amino, mono, and di(C j galkyDamino, C j .galkylcarbonylamino, arylcarbonylamino, C j .galkylsulfonylamino, trifluoromethyl, cyano, aminocarbonyl, mono- and di(C j .galkyl)aminocarbonyl, hydroxycarbonyl, C j. galkyloxyamino, carboxaldehyde and hydroxymethyl; pyridinyl; thienyl, furanyl or furanyl substituted with either C j. galkyl or halo;
• R and R each independently are C j .g Q alkyl . (Cg . ycycloalkyl), C j .galkyl, Cg ycycloalkyl, aryl or (aryl)-C j .galkyl; and one of R and R may also be hydrogen; or
• R and R taken together may also form a Cg.galkanediyl radical; each aryl independently is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C j .galkyloxy, C j .galkyl, 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
• PFIZER COMPOUNDS refers to the compounds of PFIZER 1.
• NON-NUCLEOSIDE HIV TREATMENT DRUG refers to MERCK COMPOUNDS + BOEHRINGER COMPOUNDS + JANSSEN COMPOUNDS + PFIZER COMPOUNDS.
• EXAMPLE 1 SENSITIZING HIV-1 INHIBITOR FoUowed By NON-NUCLEOSIDE HIV TREATMENT DRUG
• a 21 year old male HIV positive patient with no symptoms is treated by administering 500 mg of l-[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.
• EXAMPLE 2 SENSITIZING HIV-1 INHIBITOR FoUowed By NON-NUCLEOSIDE HIV TREATMENT DRUG
• a 45 year old female HIV positive who is symptomatic is treated with l-[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-l,3-benzoxazol-2-yl)methyl]amino ⁇ -5-ethyl-6-methylpyridin-2(lH)- one which is administered orally 250 mg three times daily.
• EXAMPLE 4 SENSITIZING HIV-1 INHIBITOR Concurrently With NON- NUCLEOSIDE fflV TREATMENT DRUG A 29 year old female, HIV positive with no symptoms is treated with l-[2-(5- methoxyindolyl)carbonyl]-4-[3-(N-ethylamino)-2-pyridinyl)piperazine, 400 mg by mouth four times da y for 2 months concurrently with 3-[2-(benzoxazol-2-yl)ethyl]-5- ethyl-6-methyl-pyridin-2(lH)-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 l-[2-(5-methanesulfonamidoindolyl)carbonyl]-4-[3-(N-isopropylamino)-2-pyridinyl]- piperazine, 150 mg by mouth every 8 hours, concurrent with 6,11-dihydro-ll- cyclopropyl-4-methyldipyrido[2,3-b:2 , ,3'-e]-[l,4]diazepin-6-one, 400 mg by mouth daily.

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• 1993
  • 1993-09-10 JP JP6511044A patent/JPH08502745A/ja active Pending
  • 1993-09-10 AU AU48482/93A patent/AU4848293A/en not_active Abandoned
  • 1993-09-10 WO PCT/US1993/008354 patent/WO1994009781A1/en not_active Application Discontinuation
  • 1993-09-10 EP EP93921364A patent/EP0666744A1/en not_active Withdrawn
  • 1993-09-10 CA CA002145545A patent/CA2145545A1/en not_active Abandoned
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• 1995
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