WO1994009781A1 - Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection - Google Patents
Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection Download PDFInfo
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- WO1994009781A1 WO1994009781A1 PCT/US1993/008354 US9308354W WO9409781A1 WO 1994009781 A1 WO1994009781 A1 WO 1994009781A1 US 9308354 W US9308354 W US 9308354W WO 9409781 A1 WO9409781 A1 WO 9409781A1
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- 0 C*1C*N(C)*C1 Chemical compound C*1C*N(C)*C1 0.000 description 5
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- 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
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- 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
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- 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
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- 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
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- 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 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.
- 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.
- 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.
- Dislcosed is a method of treating a HIV positive human which comprises
- 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.
- 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.
- 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 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
- 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 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
- 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,
- BOEHRINGER COMPOUND be 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4]diazepin-6-one.
- JANSSEN COMPOUNDS be selected from the group consisting of
- JANSSEN COMPOUND be selected from the group consisting of (-)- ⁇ -[(2-nitrophenyl)amino]-2,6-dichlorobenzeneacetamide,
- 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.
- 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
- 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
- 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.
- 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.
- 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.
- 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.
- 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 (-)- ⁇ -[(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
- Another alternative form of this method is after the initial administration of the
- 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
- 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.
- R i and R j would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(R i )(R j )-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 i and R j 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.
- CH 2 C(R i )-O-CH 3
- ⁇ represents a triple bond, e.g., HC ⁇ C-CH(R j )- CH 2 -CH 3
- Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
- the cyclic molecular fragment, 4-(ethyl)-1-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 1 ) 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 1 ) is identified as being in the beta (ß) configuration and is indicated by an unbroken line attachment to the carbon atom.
- variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
- R i 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 " ⁇ -R i-j : ⁇ -R i-k " or some variant thereof.
- both ⁇ -R i-j and ß R i-k are attached to the carbon atom to give -C( ⁇ -R i-j )( ⁇ -R j-k )-.
- the two monovalent variable substituents are ⁇ -R 6-1 :ß-R 6-2 , .... ⁇ -R 6- 9 .ß-R 6- 10, etc, giving -C( ⁇ -R 6-1 )(ß-R 6-2 )-, .... -C(a-R 6-9 )(B-R 6-10 )-, etc.
- a ring substituent for which separate ⁇ and ß 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 ß 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 i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
- 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 1 - 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 1 -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 CH 3 - (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 1 -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
- C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -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.
- A1l temperatures are in degrees Centigrade.
- - ⁇ refers to phenyl (C 6 H 5 ).
- 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 R 1 is -CH 2 -,
- R3 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,
- R 4 is R 4- 1 :R 4-2 and R 5 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 -CH 3 , 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
- R 4 is R 4-3 :R 4-4 and R 5 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 -CH 2 - and the other of R 4-3 and R 4-4 , and R 5-3 and R 5-4 are -H, R 2 and R3 are -H:-H,
- R 2 is R 2-5 ;R 2-6 an d R 5 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 -CH 2 -CH 2 - and the other of R 2-5 and R 2-6. and R 5-5 and R 5-6 are -H, and R 3 and R 4 are -H:-H,
- R 3 is R 3-5 :R 3 -6 and R 4 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 -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,
- n 26 is 1 thru 5
- Y 1 is -O-, -S-,
- Y 2 is -O-, -S-,
- Y 2-2 and Y 2-3 are the same or different and are -H or C 1 -C 4 alkyl
- Z 2 is nothing (a bond), -O-, -S-,
- Z 2-2 and Z 2-3 are the same or different and are -H or C 1 -C 4 alkyl
- n 12 is 1 or 2 and n 13 is 1 or 2
- n 12 and n 13 are as defined above,
- Y 3 is -N(Y 3-1 )- where Y 3- 1 is C 1 -C 4 alkyl and n 12 and n 13 are as defined above;
- R 7 is -COO-R 7-11 where R 7- 1 1 is as defined above,
- R 7-3 and R 7-4 are the same or different and are -H or C 1 -C 6 alkyl
- R 7-15 and R 7-16 are the same or different and are -H or C 1 -C 3 alkyl and where R 7-17 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C 5 ; alkynyl containing 1 triple bond,
- n 1 is 2 or 3 and where R 7-7 and R 7-8 are the same or different and are -H or C 1 -C 4 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,
- 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,
- -CR 8- 1 where R 8- 1 is -H, -F, -Cl, -Br, -CF 3 ,
- R 8-2 is C 1 -C 6 alkyl, - ⁇ , -CO-R 8-3 where R 8-3 is C 1 -C 6 alkyl or - ⁇ ,
- R 8-7 and R 8-8 are the same o different and are -H or C 1 -C 3 alkyl and where R 8-9 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C 5 alkynyl containing 1 triple bond,
- R 8-5 is -H or C 1 -C 6 alkyl and R 8-6 is -H
- -CR 9- 1 where R 9-1 is -H, -F, -Cl, -Br,
- R 9-2 is C 1 -C 6 alkyl, - ⁇ , -CO-R 9-3 where R 9-3 is C 1 -Cg alkyl or - ⁇ ,
- R 9-4 and R 9-5 are the same or different and are
- R 9-8 and R 9-9 are the same or different and are -H or C 1 -C 3 alkyl and where R 9-10 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C 5 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,
- R 9-6 is -H or C 1 -C 6 alkyl and R 9-7 is -H
- -CR 10- 1 where R 1 0-1 is -H, -F, -Cl, -Br, -CF 3 ,
- R 10-4 and R 10-5 are the same or different and are -H,
- R 10-8 and R 10-9 are the same or different and are -H or C 1 -C 3 alkyl and where R 10- 10 is C 2 -C 5 alkenyl containing 1 or 2 double bonds or C 2 -C 5 alkynyl containing 1 triple bond,
- R 10-6 is -H or C 1 -C 6 alkyl and R 10-7 is -H, C 1 -C 6 alkyl or C 1 -C 3 alkoxy;
- Aryl/Heteroaryl is a substituent selected from the group of substituents of formula (1)
- X 1 is -H, C 1 -C 6 or n- alkyl
- X 2 is -H, C 1 -C 6 or n -alkyl
- X 3 is C 1 -C 6 alkyl
- X 3- 1 is C 1 -C 4 alkyl or - ⁇
- n 5 is 2 or 3 and where X 4- 1 and X 4-2 are the same or different and are -H or C 1 -C 4 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 X 4 and X 5 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 6.14 is -H, C 1 -C 6 alkyl, - ⁇ , -CH 2 - ⁇ ,
- X 6- 1 is -H, C 1 -C 4 alkyl or - ⁇
- X 6 . 13 is -H, C 1 -C 4 alkyl, - ⁇ or -CH 2 - ⁇ ,
- X 6 - 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 )(CH 2 ) n3 -N(X 6-3 )(X 6-4 ) where n 3 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,
- n 3 is as defined above
- n 3 , X 6-3 and X 6-4 are as defined above,
- n 6 is 1 thru 5 and X 6-5 and X 6-6 are the same or different and are -H, C 1 -C 4 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,
- X 6-7 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, - ⁇ or
- X 6-8 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or - ⁇ and where X 6-4 and X 6-7 are as defined above,
- 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,
- 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,
- prodrug is
- R 5 1 - 1 and R 51-2 are the same or different and are -H or C 1 -C 3 alkyl
- R 53 's are the same or different and are C 1 -C 18 ,
- R 5 1-2 are as defined above,
- n 2 is 1 thru 3, the X 6 's can be the same or can be different and where when n 2 is 2 and the two X 6 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) where Q 1 is -NX 1 1 - where X 1 1 is -H, -SO 2 - ⁇ , -SO 2 -CH 3 , -CO-X 11-1 where X 1 1- 1 is
- X 12-2 and X 12-3 are the same or different and are -H, C 1 -C 4 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,
- n 23 is 1 or 2
- X 14 is -H
- R 14-10 is -H, C 1 -C 4 alkyl, - ⁇ or -CH 2 - ⁇ , C 1 -C 6 alkyl,
- n 25 is 1 thru 5
- X 14- 1 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or - ⁇ ,
- -NX 14-2 (CH 2 ) n3 -N(X 14-3 )(X 14-4 ) where n 3 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,
- 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,
- n 6 is 1 thru 5 and X 14-5 and X 14-6 are the same or different and are -H, C 1 -C 4 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,
- X 14-7 and X 14-8 are C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or - ⁇ , where X 14-4 is as defined above,
- 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,
- 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,
- prodrug is as defined above except that it is not
- n 7 is 0 thru 2
- X 6 and Q 1 are as defined above;
- X 21 is -H, C 1 -C 4 alkyl, -CO-(C 1 -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
- X 22-1 is -H, C 1 -C 4 alkyl or - ⁇
- -NX 22-2 (CH 2 ) n9 -N(X 22-3 )(X 22-4 ) where n 9 is 2 thru 5, X 22-2 is -H or C 1 -C 4 alkyl, X 22-3 is -H or C 1 -C 4 alkyl, X 22-4 is -H or C 1 -C 4 alkyl, and where X 22-3 and X 22-4 ar ⁇ 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 9 is as defined above
- n 9 , X 22-3 and X 22-4 are as defined above,
- n 10 is 1 thru 5 and X 22-5 and X 22-6 are the same or different and are -H, C 1 -C 4 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,
- X 22-7 and X 22-8 are C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or
- X 6 and X 1 1 are as defined above;
- X 7 is -H, -SO 2 - ⁇ , -SO 2 -CH 3 , -CO-X 7-1 where X 7-1 is C 1 -C 4 alkyl or - ⁇ ,
- X 8 is -H, C 1 -C 6 alkyl, -CH 2 - ⁇ , -SO 2 - ⁇ , -SO 2 -CH 3 , -CO-X 8- 1 where X 8- 1 is C 1-
- 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 O, S or NR X is H or C 1-8 alkyl
- n 0-4;
- R 1 , R 2 and R 4 are the same or different and are independently
- R 1 and R 4 may together form a cycloalkyl ring containing 5-7 members;
- R 1 and R 2 may together form a cycloalkyl ring containing 5-7 members;
- R 3 or R 5 are the same or different and are independently
- C 3-8 cycloalkyl is aryl or heterocycle each unsubstituted or substituted with one or more of
- heterocycle is not phthalimide; or pharmaceutically acceptable salt, hydrate or ester thereof; and the following compounds:
- MERCK 3 refers to the compounds of claim 1 of European Publication 462 808
- B is C 1-6 alkoxy
- X is NH, O, S, or C 2 ;
- Z is O or S
- n 1-4;
- R 3 is H or C 1-8 alkyl
- Pht is phthaloyl, of the structure
- both R 1 and R 2 cannot be C 1-2 alkyl.
- 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 1 or R 2 or both are substituted at least once with OH
- X is -NR-, -O-, -S-, -CRH-, -SO-, -SO 2 -, -CO-, -CH(OR)-,
- 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;
- R 1 and R 4 may together form a cycloalkyl ring containing 5-7 members; or, R 1 and R 2 may together form a cycloalkyl ring containing 5-7 members; and
- R 3 or R 5 are the same or different and are independently
- 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 A1, 5,11-dihydro-6H-dipyrido[3,2-b:2'.3'-e][1,4]diazepin-6-ones of the formula:
- R 1 and R 2 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
- R 1 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;
- R 2 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 3 , R 4 and R 5 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 3 , R and R 5 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,
- 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,
- R 3 , R 4 and R 5 when Z is oxygen, one of R 3 , R 4 and R 5 is alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms with the proviso that the remaining two substituents are hydrogen or methyl;
- R 6 , R 7 , R 8 and R 9 are hydrogen; or one of R 6 , R 7 , R 8 and R 9 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, carb
- 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:
- Z is oxygen or sulfur
- R 1 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:
- 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 3 , R 4 , and R 5 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 3 , R 4 and R 5 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,
- 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,
- R 3 , R 4 and R 5 when Z is oxygen, one of R 3 , R 4 and R 5 is alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms, with the proviso that the remaining two substituents are hydrogrogen or methyl; and,
- R 6 , R 7 , R 8 and R 9 are each hydrogen; or,
- R 6 , R 7 , R 8 and R 9 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 dialkyla
- substituents are hydrogen and one is methyl, ethyl or halogen; or a
- 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
- R 1 is hydrogen, C 1-6 alkyl optionally substituted by fluorine, trihalomethyl, C 3-5 alkenyl 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;
- R 2 is hydrogen, C 1-5 alkyl optionally substituted by fluorine, C 2-5 alkenyl or alkynyl, C 2-4 alkoxyalkyl or alkylt hioalkyl, C 2-4 alkanoyl, C 2-5 hydroxyalkyl, 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
- 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 5 is an alkyl, alkoxy, alkylthio, alkoxycarbonyl, hydroxyalkyl, alkanoyl, alkanoyloxy, alkanoylamino, carboxyalkyl or aminoalkyl group containing up to 4 carbon atoms, or a (C 1-2 alkoxy)carbonyl(C 1-2 alkyl), mono- or di -(C 1-2 alkyl)amino, cyano, nitro, hydroxyl, carboxyl, amino, mono- or di- (C 1-2 alkyDaminotC 1 .galkyl) or azido group or a halogen atom and the remaining five of R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each hydrogen, or one of R 3 , R 4 , R
- R 3 , R 4 and R 5 are each independently hydrogen or C 1-3 alkyl with the proviso that at least one is hydrogen, or one of R 3 , R 4 and R 5 is butyl with the remaining two being hydrogen
- R 6 , R 7 and R 8 are each independently hydrogen or C 1-6 alkyl with the proviso that at least one is hydrogen, or one of R 6 , R 7 and R 8 is butyl with the remaining two being hydrogen
- R 1 and R 2 are each independently hydrogen or straight-chained or branched C 1-5 alkyl and R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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
- R 1 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;
- R 2 is hydrogen, methyl, ethyl, halogen, nitro or amino
- R 3 is hydrogen, methyl, or halogen
- R 4 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 4 is other than hydrogen, R 2 is hydrogen, methyl or chloro and R 3 is hydrogen;
- R 5 is hydrogen, methyl or h ⁇ dogen
- R 6 is hydrogen, methyl, halogen or amino
- R 7 is hydrogen, methyl or halogen; with the proviso that at least two of R 5 , R 5 and R 7 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,
- R 1 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
- R 2 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 3 , R 4 and R 5 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-alky
- R 3 , R 4 and R 5 are each hydrogen:
- R 6 , R 7 and R 8 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-
- R 6 , R 7 and R 8 are each hydrogen;
- R 10 , R 11 , R 12 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 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,
- R 2 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
- A is a fused ring of the formula or or or or
- A may additionally be
- R 1 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 1 -PR 14 R 15 , -P(OR 14 )(OR 15 ), -P(O)(OR 15 )(OR 15 ), -PO 3 H 2 ,
- 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 14 R 15 may be pyrrolidine, piperidine, or morpholine;
- R 2 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;
- R 3 , R 4 and R 5 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
- R 3 , R 4 and R 5 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,
- alkyl 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,
- R 3 , R 4 and R 5 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 NR 16 R 17 , with the remaining substituent being hydrogen, methyl or chloro;
- R 6 R 7 , R 8 and R 9 are each hydrogen; or
- R 6 , R 7 , R 8 and R 9 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 6 , R 7 and R 8 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 -NR 18 R 19 , with the remaining substituent being hydrogen;
- R 10 and R 11 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;
- 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 6 , R 1 7 , R 1 8 and R 19 , together with the nitrogen
- 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.
- HIV-inhibiting benzeneacetamides of the formula: a pharmaceutically acceptable acid addition salt form or a stereochemically isomeric form thereof, wherein
- R 1 and R 2 each independently are hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; or R 1 and R 2 taken together with the nitrogen atom bearing said R 1 and R 2 may form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 4-C 1- 4 alkylpiperazinyl group;
- X is O or S
- R 3 is hydrogen or C 1-6 alkyl
- R 4 R 5 and R 6 each independently are hydrogen, h ⁇ do, C 1-6 alkyl, C 1-6 alkyloxy, nitro, trifluoromethyl, cyano, aminomethyl, carboxyl, C 1-4 alkyloxycarbonyl, C 1 - 4 alkylcarbonyl, aminocarbonyl or hydroxy;
- R 7 is hydrogen or halo
- R 8 , R 9 and R 10 each independently are hydrogen, halo, C 1-6 alkyl, C 1- 6 alkyloxy, nitro, hydroxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,
- 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 8 represents 4-ethoxy and X represents oxygen, and
- 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
- X is O or S
- R 1 is a radical of formula: ;
- Alk is C 1-6 alkanediyl
- R 6 is hydrogen, halo or C 1-4 alkyl
- R 7 a nd R 8 each independently are hydrogen, halo, C 3-6 cycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, C 1-4 alkyl optionally substituted with C 1- 4 alkyloxy;
- R 9 is hydrogen, halo or C 1-4 alkyl
- each R 10 independently is hydrogen or C 1-4 alkyl; or both R 10 taken together may form a C 1-6 alkanediyl radical;
- n 2, 3, 4, 5 or 6;
- R 11 is hydrogen or C 2-6 alkenyl; each R 12 independently is hydrogen or C 1-4 alkyl; or both R 12 taken together may form a C 1-6 alkanediyl radical;
- n O, 1 or 2;
- R 13 is C 1-6 alkyl, aryl, arylmethyl, C 3-6 cycloalkyl or (C 3-6 cycloalkyl) C 1-4 alkyl;
- R 2 is hydrogen or C 1-6 alkyl
- R 3 is hydrogen or C 1-6 alkyl
- R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C 1-6 alkyloxy, amino, mono- or di(C 1-6 alkyl)amino, C 1- 6 alkylcarbonylamino or arylcarbonylamino; and each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkyloxy, amino, nitro and trifluoromethyl;
- R 4 or R 5 is other than C 1-6 alkylcarbonylamino or arylcarbonylamino, then R is other than C 3-6 alkenyl and (C 3-6 cycloalkyl)C 1-6 alkyl.
- JANSSEN 3 refers to the compounds of claim 1 of European Patent
- R 1 is C 1-6 alkyl optionally substituted with aryl; C 3-6 alkynyl; C 3-6 cycloalkyl; or a radical of formula: ;
- Alk is C 1-6 alkanediyl
- R 8 and R 9 each independently are hydrogen, halo, C 3-6 cycloalkyl
- R 10 is hydrogen, halo or C 1-4 alkyl
- each R 11 independently is hydrogen or C 1-4 alkyl; or both R 11 taken together may form a C 1-6 alkanediyl radical;
- R 12 is hydrogen, halo or C 1-4 alkyl
- n 2, 3, 4, 5 or 6;
- each R 13 independently is hydrogen or C 1-4 alkyl; or both R 13 taken together may form a C 1-6 alkanediyl radical;
- R 14 is hydrogen or C 2-6 alkenyl
- n 0, 1 or 2;
- R 15 is C 1-6 alkyl, aryl, arylmethyl, C 3-6 cycloalkyl or (C 3-6 cycloalkyl)C 1-6 alkyl;
- R 2 is hydrogen or C 1-6 alkyl;
- R 3 is hydrogen or C 1-6 alkyl
- R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C 1-6 alkyloxy, amino, mono or di(C 1-6 alkyl)amino,
- R 6 is C 1-6 alkyl
- R 7 is hydrogen or C 1-6 alkyl
- X is OH, SH or NR 16 R 17 ;
- R 16 is hydrogen, C 1-6 alkyl, aryl, cyano, hydroxy, amino, nitro, C 1- galkyloxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl or arylsulfonyl;
- R 17 is hydrogen, C 1-6 alkyl or aryl
- each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkyloxy, amino, nitro and trifluoromethyl.
- JANSSEN 4 refers to the compounds of claim 1 of European Patent
- R 1 is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, or C 1-6 alkyl substituted with aryl or with C 3-6 cycloalkyl;
- R 2 is hydrogen or C 1-6 alkyl
- R 3 is hydrogen or C 1-6 alkyl
- R 4 and R 5 each independently are hydrogen, C 1-6 alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C 1-6 alkyloxy, amino or mono-or di(C 1-6 alkylamino); and aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkyloxy, amino, nitro and
- JANSSEN 5 refers to the compounds of claim 1 of European Patent
- R 1 is hydrogen, C 1-8 5lkyl, C 3-6 alkenyl, C 1-6 - alkynyl, C 1-6 alkylcarbonyl, C 1- 4 cycloalkyl, or substituted with aryl, hydroxy, cyano or C 3-6 cycloalkyl;
- R 2 is hydrogen, C 1-6 alkyl or C 3-6 alkenyl
- R 3 is hydrogen, or C 1-6 alkyl
- R 4 is hydrogen, C 1-6 alkyl optionally substituted with hydroxy, cyano, hydroxycarbonyl or carbonyl C 1-6 alkylcarbonyl; C 3-6 alkenyl; C 3-6 cycloalkyl;
- R 5 is hydrogen, C 1-6 alkyl or halo
- aryl is phenyl optionally substituted with up to 3 substituents independently selected from C 1-6 alkyl, halo, hydroxy, C 1-6 alkyloxy, amino, nitro and
- JANSSEN 6 refers to the compounds of claim 1 of European Patent
- Ar is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyloxy, mercapto, C 1-6 alkylthio, C 1-6 alkyl, nitro, amino, mono, and di(C 1-6 alkyDamino, C 1-6 alkylcarbonylamino, arylcarbonylamino, C 1-6 alkylsulfonylamino, trifluoromethyl, cyano, aminocarbonyl, mono- and di(C 1-6 alkyl)aminocarbonyl, hydroxycarbonyl, C 1-6 alkyloxyamino, carboxaldehyde and hydroxymethyl; pyridinyl; thienyl, furanyl or furanyl substituted with either C 1-6 alkyl or halo;
- R 1 and R 2 each independently are C 1-20 alkyl, (C 3-7 cycloalkyl), C 1-5 alkyl, C 3- 7 cycloalkyl, aryl or (aryl)-C 1-6 alkyl; and one of R 1 and R 2 may also be hydrogen; or R 1 and R 2 taken together may also form a C 3-6 alkanediyl radical; each aryl independently is phenyl optionally substituted with from 1 to 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyloxy, C 1-6 alkyl, 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
- R 1 is C 1 -C 3 alkyl or cyclopropyl
- R 2 is -H or -CH 3 ;
- Rg is -H or -OR 3-1 where R 3-4 is C 1 -C 3 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 C 1 -C 4 alkyl.
- PFIZER COMPOUNDS refers to the compounds of PFIZER 1.
- NON-NUCLEOSIDE HIV TREATMENT DRUG refers to MERCK
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 (-)- ⁇ -[(2-acetylphenyl)amino]-2,6-dichlorobenzeneacetamide, 150 mg orally three times daily.
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93921364A EP0666744A1 (en) | 1992-10-28 | 1993-09-10 | Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection |
KR1019950701630A KR950703958A (en) | 1992-10-28 | 1993-09-10 | USE OF BHAP COMPOUNDS IN COMBINATION WITH OTHER NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR THE TREATMENT OF HIV INFECTION |
JP6511044A JPH08502745A (en) | 1992-10-28 | 1993-09-10 | Use of BHAP compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection |
AU48482/93A AU4848293A (en) | 1992-10-28 | 1993-09-10 | Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection |
FI952018A FI952018A (en) | 1992-10-28 | 1995-04-27 | Use of BHAP in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection |
NO951608A NO951608L (en) | 1992-10-28 | 1995-04-27 | Use of BHAP Compounds in Combination with Other Non-Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96763992A | 1992-10-28 | 1992-10-28 | |
US1711993A | 1993-02-12 | 1993-02-12 | |
US08/017,119 | 1993-02-12 | ||
US07/967,639 | 1993-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994009781A1 true WO1994009781A1 (en) | 1994-05-11 |
Family
ID=26689480
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/008354 WO1994009781A1 (en) | 1992-10-28 | 1993-09-10 | Use of bhap compounds in combination with other non-nucleoside reverse transcriptase inhibitors for the treatment of hiv infection |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0666744A1 (en) |
JP (1) | JPH08502745A (en) |
KR (1) | KR950703958A (en) |
AU (1) | AU4848293A (en) |
CA (1) | CA2145545A1 (en) |
CZ (1) | CZ69695A3 (en) |
FI (1) | FI952018A (en) |
HU (1) | HUT72050A (en) |
MX (1) | MX9306031A (en) |
NO (1) | NO951608L (en) |
PL (1) | PL308551A1 (en) |
WO (1) | WO1994009781A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996018628A1 (en) * | 1994-12-13 | 1996-06-20 | Pharmacia & Upjohn Company | Alkyl substituted piperadinyl and piperazinyl anti-aids compounds |
US6803362B2 (en) | 2001-03-09 | 2004-10-12 | Ortho-Mcneil Pharmaceutical Inc. | Heterocyclic compounds |
US7504426B2 (en) | 2002-09-06 | 2009-03-17 | Janssen Pharmaceutica N.V. | Heterocyclic compounds |
US8541407B2 (en) | 2010-03-31 | 2013-09-24 | Arqule, Inc. | Substituted benzo-pyrido-triazolo-diazepine compounds |
US8569331B2 (en) | 2010-11-01 | 2013-10-29 | Arqule, Inc. | Substituted benzo[f]lmidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds |
-
1993
- 1993-09-10 EP EP93921364A patent/EP0666744A1/en not_active Withdrawn
- 1993-09-10 JP JP6511044A patent/JPH08502745A/en active Pending
- 1993-09-10 HU HU9501218A patent/HUT72050A/en unknown
- 1993-09-10 PL PL93308551A patent/PL308551A1/en unknown
- 1993-09-10 CA CA002145545A patent/CA2145545A1/en not_active Abandoned
- 1993-09-10 KR KR1019950701630A patent/KR950703958A/en not_active Application Discontinuation
- 1993-09-10 WO PCT/US1993/008354 patent/WO1994009781A1/en not_active Application Discontinuation
- 1993-09-10 CZ CZ95696A patent/CZ69695A3/en unknown
- 1993-09-10 AU AU48482/93A patent/AU4848293A/en not_active Abandoned
- 1993-09-29 MX MX9306031A patent/MX9306031A/en unknown
-
1995
- 1995-04-27 NO NO951608A patent/NO951608L/en unknown
- 1995-04-27 FI FI952018A patent/FI952018A/en unknown
Non-Patent Citations (5)
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996018628A1 (en) * | 1994-12-13 | 1996-06-20 | Pharmacia & Upjohn Company | Alkyl substituted piperadinyl and piperazinyl anti-aids compounds |
US5866589A (en) * | 1994-12-13 | 1999-02-02 | Pharmacia & Upjohn Company | Alkyl substituted piperadinyl and piperazinyl anti-AIDS compounds |
US6803362B2 (en) | 2001-03-09 | 2004-10-12 | Ortho-Mcneil Pharmaceutical Inc. | Heterocyclic compounds |
US7504426B2 (en) | 2002-09-06 | 2009-03-17 | Janssen Pharmaceutica N.V. | Heterocyclic compounds |
US8541407B2 (en) | 2010-03-31 | 2013-09-24 | Arqule, Inc. | Substituted benzo-pyrido-triazolo-diazepine compounds |
US8569331B2 (en) | 2010-11-01 | 2013-10-29 | Arqule, Inc. | Substituted benzo[f]lmidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds |
Also Published As
Publication number | Publication date |
---|---|
PL308551A1 (en) | 1995-08-21 |
MX9306031A (en) | 1994-04-29 |
EP0666744A1 (en) | 1995-08-16 |
FI952018A0 (en) | 1995-04-27 |
HU9501218D0 (en) | 1995-06-28 |
FI952018A (en) | 1995-04-27 |
NO951608D0 (en) | 1995-04-27 |
HUT72050A (en) | 1996-03-28 |
KR950703958A (en) | 1995-11-17 |
CA2145545A1 (en) | 1994-05-11 |
JPH08502745A (en) | 1996-03-26 |
NO951608L (en) | 1995-06-28 |
AU4848293A (en) | 1994-05-24 |
CZ69695A3 (en) | 1995-12-13 |
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