EP0973753A2 - 4,4-disubstituiert-3,4-dihydro-2(1h)-chinazolinone zur verwendung als hiv-reverse-transcriptase-hemmer - Google Patents
4,4-disubstituiert-3,4-dihydro-2(1h)-chinazolinone zur verwendung als hiv-reverse-transcriptase-hemmerInfo
- Publication number
- EP0973753A2 EP0973753A2 EP98913401A EP98913401A EP0973753A2 EP 0973753 A2 EP0973753 A2 EP 0973753A2 EP 98913401 A EP98913401 A EP 98913401A EP 98913401 A EP98913401 A EP 98913401A EP 0973753 A2 EP0973753 A2 EP 0973753A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- dihydro
- pyridyl
- quinazolinone
- trifluoromethyl
- och
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
Definitions
- TITLE 4 4-DISUBSTITUTED-3 , 4-DIHYDRO-2 (IH) -QUINAZOLINONES USEFUL AS HIV REVERSE TRANSCRIPTASE INHIBITORS
- This invention relates generally to 4, 4-disubstituted- 3 , 4-dihydro-2 (IH) -quinazolinones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.
- HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections .
- ARC AIDS related complex
- the disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle.
- the virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion ' s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA.
- the virion enzyme, reverse transcriptase directs the process of transcribing the RNA into single-stranded DNA.
- the viral RNA is degraded and a second DNA strand is created.
- the now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction. At this point, RNA polymerase transcribes the integrated DNA into viral RNA.
- HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.
- the typical human immune system response killing the invading virion, is taxed because the virus infects and kills the immune system's T cells.
- viral reverse transcriptase the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus .
- the virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators , or both, death may result.
- virus 's life cycle There are at least three critical points in the virus ' s life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT) , and (3) the processing of gag-pol protein by HIV protease.
- nucleoside analogs such as 3 ' -azido-3 ' -deoxythymidine (AZT), 2 ' , 3 ' -dideoxycytidine (ddC) , 2 ' , 3 ' -dideoxythymidinene (d4T) , 2 ' , 3 ' -dideoxyinosine (ddl) , and 2 ' , 3 ' -dideoxy-3 ' -thia- cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
- RT reverse transcriptase
- An active area of research is in the discovery of non- nucleoside HIV reverse transcriptase inhibitors .
- certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.
- Z may be 0.
- EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula A:
- G is a variety of groups
- R 3 and R 4 may be H
- Z may be O
- R 2 may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl
- R 1 may be a variety of groups including substituted alkyl.
- WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A.
- G is a variety of groups, R 3 and R 4 may be H, Z may be 0, R 2 is substituted alkenyl or substituted alkynyl, and R 1 is cycloalkyl, alkynyl, alkenyl, or cyano.
- WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)- ⁇ -)-6- chloro-4-cyclopropyl-3 , 4-dihydro-4 ( (2-pyridy) ethynyl) -2 (IH) - quinazolinone .
- R is a phenyl, carbocyclic ring, or a heterocyclic ring.
- Compounds of this sort are not considered to be part of the present invention.
- one object of the present invention is to provide novel reverse transcriptase inhibitors .
- compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
- R 1 , R 2 , R 3 , and R 8 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors .
- the present invention provides a novel compound of formula I:
- R 1 is C ⁇ - 3 alkyl substituted with 1-7 halogen
- R 2 is selected from C 1 - 5 alkyl substituted with 1-2 R 4 , C 2 - 5 alkenyl substituted with 1-2 R 4 , and C 2 - 5 alkynyl substituted with 1 R 4 ;
- R 3 at each occurrence, is independently selected from C 1 -. 4 alkyl, OH, C 1 -. 4 alkoxy, F, Cl, Br, I, NR 5 R 5a , N0 2 , CN, C(0)R 6 , NHC(0)R 7 , and NHC (0)NR 5 R 5a ;
- R 4 is selected from C 3 - 5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-5 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from 0, N, and S, substituted with 0-2 R 3 ;
- R 5 and R 5a are independently selected from H and C 1 -. 3 alkyl
- R 6 is selected from H, OH, C 1 -. 4 alkyl, C 1 - 4 alkoxy, and NR 5 R 5a ;
- R 7 is selected from C 1 -. 3 alkyl and C ⁇ _ 3 alkoxy
- R 8 is selected from H, C 3 - 5 cycloalkyl, and C 1 - 3 alkyl; and,
- n is selected from 0 , 1 , 2 , 3 , and 4.
- R 1 is C ⁇ _ 3 alkyl substituted with 1-7 halogen
- R 2 is selected from C 1 -. 5 alkyl substituted with 1 R 4 , C 2 - 5 alkenyl substituted with 1 R 4 , and C 2 - 5 alkynyl substituted with 1 R 4 ;
- R 3 at each occurrence, is independently selected from C 1 -. 4 alkyl, OH, C 1 - 4 alkoxy, F, Cl, Br, I, NR 5 R 5a , N0 2 , CN, C(0)R 6 , NHC ⁇ 0)R 7 , and NHC (0)NR 5 R 5 ;
- R 4 is selected from C 3 - 5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from 0, N, and S, substituted with 0-1 R 3 ;
- R 5 and R a are independently selected from H, CH 3 and C 2 H 5 ;
- R 6 selected from H, OH, CH 3 , C 2 H 5 , OCH 3 , 0C 2 H 5 , and NR 5 R 5a ;
- R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;
- R 8 is selected from H, cyclopropyl, CH 3 and C 2 H 5 ;
- n is selected from 0, 1, 2, and 3.
- the present invention provides a novel compound of formula I, wherein:
- R 1 is selected from CF 3 , and C 2 F 5 ;
- R 2 is selected from C 1 -. 3 alkyl substituted with 1 R 4 , C 2 - 3 alkenyl substituted with 1 R 4 , and C 2 - 3 alkynyl substituted with 1 R 4 ;
- R 3 at each occurrence, is independently selected from C 1 -. 3 alkyl, OH, C 1 - 3 alkoxy, F, Cl, Br, I, NR 5 R 5 , NO 2 , CN, C(0)R 6 , NHC(0)R 7 , and NHC (0)NR 5 R 5a ;
- R 4 is selected from C 3 - 5 cycloalkyl substituted with 0-2 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from 0, N, and S, substituted with 0-1 R 3 ;
- R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;
- R6 is selected from H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;
- R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;
- R 8 is selected from H, CH 3 and C 2 H 5 ;
- n is selected from 0, 1, and 2.
- the present invention provides a novel compound of formula I, wherein:
- R 1 is CF 3 ;
- R 2 is selected from C 1 - 3 alkyl substituted with 1 R 4 , C 2 - 3 alkenyl substituted with 1 R 4 , and C 2 - 3 alkynyl substituted with 1 R 4 ;
- R 3 at each occurrence, is independently selected from C 1 -. 3 alkyl, OH, C 1 - 3 alkoxy, F, Cl, NR 5 R 5a , N0 2 , CN, C(0)R 6 , NHC(0)R 7 , and NHC (0)NR 5 R 5a ;
- R 4 is selected from cyclopropyl substituted with 0-1 R 3 , phenyl substituted with 0-2 R 3 , and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from 0, N, and S, substituted with 0-1 R 3 , wherein the heterocyclic system is selected from 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2- imidazolyl;
- R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;
- R6 i selected from H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;
- R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;
- R 8 is selected from H, CH 3 and C 2 H 5 ;
- n is selected from 1 and 2.
- the compound of formula I is selected from:
- (+/-) -4-Cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3 , 4- dihydro-2 (IH) -quinazolinone;
- the present invention provides a novel compound of formula II :
- R 2 is C ⁇ C-R 4a ;
- R 3 is selected from C 1 - 4 alkyl, OH, C 1 - 4 alkoxy, F, Cl, Br, I, NR 5 R 5 , N0 2 , CN, C(0)R 6 , NHC(0)R 7 , and NHC (0)NR 5 R 5a ;
- R 4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl;
- R 5 and R 5a are independently selected from H and C1- 3 alkyl
- R 6 is selected from H, OH, C 1 - 4 alkyl, C 1 - 4 alkoxy, and NR 5 R 5a ;
- R 7 is selected from C 1 -. 3 alkyl and C 1 -. 3 alkoxy;
- R 8 is selected from H, C 3 -. 5 cycloalkyl, and C 1 - 3 alkyl; and,
- n is selected from 0, 1, 2, 3, and 4.
- the present invention provides a novel compound of formula II, wherein:
- R 2 is C ⁇ C-R 4a ;
- R 3 is selected from C 1 -. 4 alkyl, OH, C 1 - 4 alkoxy, F, Cl, Br, I, NR 5 R 5a , N0 2 , CN, C(0)R 6 , and NHC(0)R 7 ;
- R a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl; R 5 and R 5a are independently selected from H, CH 3 and C 2 H 5 ;
- R 6 is selected from H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;
- R 7 is selected from CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;
- R8 i s selected from H, cyclopropyl, CH 3 and C 2 H 5 ;
- n is selected from 0, 1, and 2.
- the compound of formula II is selected from:
- the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.
- the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.
- the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of :
- the reverse transcriptase inhibitor is selected from AZT, 3TC, ddl, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L- 697,661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI- 272, CGP-61755, U-140690, and ABT-378.
- the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and .indinavir.
- the reverse transcriptase inhibitor is AZT.
- the protease inhibitor is indinavir.
- the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
- the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I or II .
- the present invention to provides a novel a kit or container comprising a compound of formula I or II in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
- the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms . It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
- the processes of the present invention are contemplated to be practiced on at least a multigra scale, kilogram scale, multikilogram scale, or industrial scale.
- Multigram scale is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more.
- Multikilogram scale is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
- Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
- alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms .
- alkyl include, but are not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s- pentyl.
- haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl , pentafluoroethyl, and pentachloroethyl .
- Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s- pentoxy.
- Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or eye1openty1.
- Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like.
- Alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
- Halo or "halogen” as used herein refers to fluoro, chloro, bromo and iodo.
- Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
- aryl or “aromatic residue” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl.
- carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 5- membered monocyclic ring, which may be saturated or partially unsaturated. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
- heterocycle or “heterocyclic system” is intended to mean a stable 5- to 6- membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S.
- the nitrogen and sulfur heteroatoms may optionally be oxidized.
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized.
- the term "aromatic heterocyclic system” is intended to mean a stable 5- to 6- membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
- heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5- thiadiaziny1 , 2H, ⁇ H-1 , 5 , 2 -dithiaziny1 , furanyl , furazanyl , imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1,2,4- oxadiazolyl, 1, 2 , 5-oxadiazolyl, 1, 3 , 4-oxadiazolyl, oxazolidinyl .
- oxazolyl piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrroliny1 , pyrrolyl , tetrahydrofuranyl , 6H-1 , 2,5- thiadiazinyl, 1, 2 , 3-thiadiazolyl, 1, 2 , 4-thiadiazolyl, 1,2,5- thiadiazolyl, 1, 3 , 4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thioph
- Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- HIV reverse transcriptase inhibitor is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT) .
- nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddl, d4T, and 3TC.
- non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S) , TIBO derivatives, BI-RG-587, nevirapine (Boehringer Ingelheim), L-697,661, LY 73497, Ro
- HIV protease inhibitor is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538) , indinavir (Merck, MK-639) , VX- 478 (Vertex/Glaxo Wellcome) , nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy) , CGP-61755 (Ciba-Geigy) , U-140690 (Pharmacia and Upjohn), and ABT-378.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic , phenylacetic , glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
- organic acids such as acetic, propionic, succinic, glycolic, stearic,
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA,
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio .
- Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of the present invention for example formula (I) , are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
- Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively.
- prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.
- “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contempleted by the present invention.
- “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s) , provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host.
- the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv.
- Enzyme Regul. 22:27-55 (1984) occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
- a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components .
- the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis .
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
- Each of the references cited below are hereby incorporated herein by reference .
- Scheme 1 illustrates a method of preparing keto-anilines from an appropriately substituted 2-aminobenzoic acid.
- the acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R ⁇ -substituted ketone.
- the keto-anilines are useful intermediates for the presently claimed compounds.
- Scheme 2 describes another method of preparing keto- anilines, this time from an appropriately substituted aniline.
- a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides the keto- aniline.
- Additional means of preparing keto-anilines are known to one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35 (37) , 6811-6814, the contents of which are hereby incorporated herein by reference.
- SCHEME 3 Houpis et al, Tetr. Lett. 1994, 35 (37) , 6811-6814, the contents of which are hereby incorporated herein by reference.
- Keto-aniline 1 which may be prepared by the methods desribed in Schemes 1 and 2, is treated with trimethylsilyl isocyanate in dry tetrahydofuran in the presence of dimethylaminopyridine followed by tetrabutylammonium fluoride to give the hydroxy- urea 2 .
- the hydroxy-urea 2 is then dehydrated with a dehydrating agent such as 4A molecular sieves in refluxing toluene or xylenes to give the ketimine 3.
- a dehydrating agent such as 4A molecular sieves in refluxing toluene or xylenes
- a lithium acetylide which is prepared in a separate vessel by reacting the corresponding substituted acetylene with n- butyllithium in dry tetrahydrofuran, to give the 4,4- disubstituted 3 , 4-dihydro-2 (IH) -quinazolinone __, a compound of formula I .
- the acetylenic bond of the compound 4 may be reduced, e.g., by catalytic hydrogenation, to give the corresponding alkenyl group (not shown) or the saturated compound 5..
- R 2 groups may also be introduced by directly reacting the imine 3. with a lithiate R 2 Li or a Grignard reagent R 2 MgX in the presence or absence of Lewis acid catalyst, such as BF 3 etherate. See also Huffman et al, J. Org. Chem. 1995, 60, 1590-1594, the contents of which are hereby incorporated herein by reference.
- one enantiomer of a compound of Formula I or II may display superior activity compared with the other.
- separation of the racemic material can be achieved by HPLC using a chiral column as exemplified in Examples 27-34 (Scheme 4) or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444.
- a chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem . 1995, 60, 1590-1594.
- Step 1 Synthesis of Vl-a from V-a.
- a solution of V-a (0.50 g, 2.28 mmol) was treated with dimethylaminopyridine and trimethylsilyl isocyanate as described in Step 1 of Example 1 to afford 0.58 g (97%) of the desired product:
- 1 H NMR 300 MHz, acetone-d 6 ) ⁇ 8.81 (br s, 1 H) , 7.17 (br s, 1 H) , 7.11 (br s, 1 H) , 7.00-6.92 (m, 2 H) , 6.83 (s, 1 H) , 3.76 (s, 3 H) ;
- Step 3 Synthesis of Xll-a from Xl-a.
- a solution of XI-a (6.28 g, 25.1 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (24.9 mL of 30 wt% solution in toluene/THF/hexanes, 0.113 mol) according to the procedure of Step 3 of Example 1.
- the resulting crude yellow oil was dissolved in acetone and concentrated under reduced pressure to deliver a yellow solid. Crystallization from acetone afforded 5.98 g (75%) of the desired material: mp 86.5-88.5 °C; ⁇ ⁇ .
- NMR 300 MHz, acetone-d 6 ) ⁇ 9.01 (br s, 1 H) , 7.46 (br s, 1 H) , 7.44-7.35
- Step 1 Synthesis of XV-a from XlV-a.
- Step 3 Synthesis of XVII-a from XVI-a.
- a solution of XVI-a (100 mg, 0.431 mmol) was treated with the the lithium acetylide derived from cyclopropylacetylene (1.43 mL of 30 wt% solution in toluene/THF/hexanes, 1.94 mmol) according to the procedure of Step 3 of Example 1.
- the material was purified by regular phase HPLC chromatography (41.4 mm Rainin Dynamax® column using 60 A silica @ 25 mL/min): 2.5% MeOH/CH 2 Cl 2 for 24 min, increase to 30% MeOH/CH 2 Cl 2 over 4 min, 30% MeOH/CH 2 Cl2 for 10 min, and ramp back to 2.5% MeOH/CH2Cl2 over 2 min.
- the yield of the protected intermediates was 47% and 32%, respectively.
- Example 36 was synthesized in an analogous manner to deliver the title compound in 88% yield.
- Example 37 The title compound was prepared as described for Example 37 (starting from IV-b) , except that it was purified using a Chiralcel OD column at 1.5 mL/min in 0.5% EtOH/20% CH 2 Cl 2 /79.5% hexanes. Mp 87-89 °C; ⁇ -H NMR (300 MHz, acetone- dg) d 9.08 (br s, IH) , 7.40-7.25 (m, 2H) , 7.04-6.90 (m, 2H) ,
- stereochemisty is (+/-) .
- OJ J J LO LO to to to to to to to to to to to t- F> I- 1 H P» O O o o o o o O o ⁇ P- LO to H O VO 00 -J cn L ⁇ ⁇ P- LO to O VO 00 ⁇ J cn L ⁇ OJ tO P» VO 00 o ⁇ i L ⁇ ⁇ P- LO to P 1
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Application Number | Priority Date | Filing Date | Title |
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US83854097A | 1997-04-09 | 1997-04-09 | |
US838540 | 1997-04-09 | ||
US7132298P | 1998-01-14 | 1998-01-14 | |
US71322P | 1998-01-14 | ||
PCT/US1998/006733 WO1998045276A2 (en) | 1997-04-09 | 1998-04-07 | 4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitors |
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EP0973753A2 true EP0973753A2 (de) | 2000-01-26 |
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EP98913401A Withdrawn EP0973753A2 (de) | 1997-04-09 | 1998-04-07 | 4,4-disubstituiert-3,4-dihydro-2(1h)-chinazolinone zur verwendung als hiv-reverse-transcriptase-hemmer |
Country Status (19)
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EP (1) | EP0973753A2 (de) |
JP (1) | JP2002504095A (de) |
KR (1) | KR20010006146A (de) |
CN (1) | CN1252063A (de) |
AR (1) | AR012340A1 (de) |
AU (1) | AU734928B2 (de) |
BR (1) | BR9808513A (de) |
CA (1) | CA2284996A1 (de) |
EA (1) | EA001991B1 (de) |
EE (1) | EE9900452A (de) |
HR (1) | HRP980143A2 (de) |
HU (1) | HUP0001446A3 (de) |
IL (1) | IL132188A0 (de) |
NO (1) | NO314936B1 (de) |
NZ (1) | NZ500592A (de) |
PL (1) | PL336305A1 (de) |
SK (1) | SK137899A3 (de) |
TW (1) | TW587078B (de) |
WO (1) | WO1998045276A2 (de) |
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CA2322203A1 (en) * | 1998-03-27 | 1999-10-07 | Jeffrey W. Corbett | 4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinthione derivatives, their preparation and their use as hiv reverse transcriptase inhibitors |
WO2000021565A1 (en) | 1998-10-13 | 2000-04-20 | Du Pont Pharmaceuticals Company | Selective eradication of virally-infected cells by combined use of a cytotoxic agent and an antiviral agent |
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HRP990359A2 (en) * | 1998-11-19 | 2000-08-31 | Du Pont Pharm Co | A process for the preparation of quinazolinones |
US6175009B1 (en) | 1999-11-18 | 2001-01-16 | Dupont Pharmaceuticals Company | Process for the preparation of quinazolinones |
US6759410B1 (en) | 1999-11-23 | 2004-07-06 | Smithline Beecham Corporation | 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors |
US6982270B1 (en) | 1999-11-23 | 2006-01-03 | Smithkline Beecham Corporation | 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors |
US6555686B2 (en) * | 2000-03-23 | 2003-04-29 | Bristol-Myers Squibb Pharma | Asymmetric synthesis of quinazolin-2-ones useful as HIV reverse transcriptase inhibitors |
WO2001070707A2 (en) * | 2000-03-23 | 2001-09-27 | Bristol-Myers Squibb Pharma Company | Asymmetric synthesis of quinazolin-2-ones useful as hiv reverse transcriptase inhibitors |
ZA200300255B (en) | 2000-07-20 | 2004-09-28 | Bristol Myers Squibb Pharma Co | Tricyclic 2-pyridone compounds useful as HIV reverse transcriptase inhibitors. |
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US8579831B2 (en) | 2002-04-19 | 2013-11-12 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
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WO2004060370A1 (en) * | 2002-12-16 | 2004-07-22 | Boehringer Ingelheim Pharmaceuticals, Inc. | Treatment of hiv infection through combined administration of tipranavir and capravirine |
US8574895B2 (en) | 2002-12-30 | 2013-11-05 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus using optical techniques to measure analyte levels |
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US8440693B2 (en) | 2009-12-22 | 2013-05-14 | Novartis Ag | Substituted isoquinolinones and quinazolinones |
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CN102060786A (zh) * | 2011-01-20 | 2011-05-18 | 天津大学 | 4-(取代-1,3-二炔基)-4-(三氟甲基)-3,4-二氢取代喹唑啉-2-酮类化合物及其制备方法和应用 |
DK2694101T3 (en) * | 2011-04-06 | 2017-01-09 | Biovaxim Ltd | Pharmaceutical compositions for the prevention and / or treatment of HIV disease in humans |
CN104321325B (zh) | 2012-05-24 | 2016-11-16 | 诺华股份有限公司 | 吡咯并吡咯烷酮化合物 |
EP2948451B1 (de) | 2013-01-22 | 2017-07-12 | Novartis AG | Substituierte purinonverbindungen |
WO2014115080A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction |
KR20160012194A (ko) | 2013-05-27 | 2016-02-02 | 노파르티스 아게 | 이미다조피롤리디논 유도체 및 질환의 치료에서의 그의 용도 |
PL3004112T3 (pl) | 2013-05-28 | 2018-02-28 | Novartis Ag | Pochodne pirazolo-pirolidyn-4-onu oraz ich zastosowanie w leczeniu choroby |
EP3004108B1 (de) | 2013-05-28 | 2017-10-18 | Novartis AG | Pyrazolo-pyrrolidin-4-on-derivate als bet inhibitoren und ihre verwendung bei der behandlung von krankheiten |
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1998
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Publication number | Publication date |
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WO1998045276A2 (en) | 1998-10-15 |
HUP0001446A3 (en) | 2001-11-28 |
NO994904D0 (no) | 1999-10-08 |
KR20010006146A (ko) | 2001-01-26 |
EE9900452A (et) | 2000-04-17 |
NZ500592A (en) | 2001-09-28 |
IL132188A0 (en) | 2001-03-19 |
EA001991B1 (ru) | 2001-10-22 |
HRP980143A2 (en) | 1999-02-28 |
HUP0001446A2 (hu) | 2001-05-28 |
JP2002504095A (ja) | 2002-02-05 |
TW587078B (en) | 2004-05-11 |
AU734928B2 (en) | 2001-06-28 |
NO314936B1 (no) | 2003-06-16 |
CN1252063A (zh) | 2000-05-03 |
SK137899A3 (en) | 2000-05-16 |
AU6796098A (en) | 1998-10-30 |
AR012340A1 (es) | 2000-10-18 |
CA2284996A1 (en) | 1998-10-15 |
WO1998045276A3 (en) | 1999-01-14 |
NO994904L (no) | 1999-12-01 |
PL336305A1 (en) | 2000-06-19 |
EA199900907A1 (ru) | 2000-04-24 |
BR9808513A (pt) | 2000-05-23 |
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