Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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

Definitions

• the present invention relates to a series of novel Pyrazolo [3 ,4-b]pyridin-2-yl] -benzoic acid derivatives which inhibit HIV Integrase and that have been characterized by specific structural and physicochemical features.
• This inhibitory property may be advantageously used to provide compounds with antiviral properties against retroviruses such as HIV viruses, including the HIV-I and HIV-2 viruses.
• the Pyrazolo[3,4-b]pyridin-2-yl]-benzoic acid derivatives including pharmaceutical compositions thereof may be used to inhibit the activity of HIV integrase and therefore may be used to reduce HIV replication.
• the HIV (human immunodeficiency virus) retrovirus is the causative agent for AIDS (acquired immunodeficiency syndrome).
• the HIV-I retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in CD4 (+) T-helper lymphocytes and certain other cells (Lasky L. A. et al., Cell vol. 50, p. 975 - 985 (1987)).
• HTV infection is characterized by a period immediately following infection called "asymptomatic" which is devoid of clinical manifestations in the patient.
• AIDS-related complex characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS.
• viral RNA is converted into DNA, which is then integrated into the host cell DNA.
• the reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. vol 5, p. 2349 - 2360 (1991)).
• RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA
• RNase H ribonuclease H
• DNA-dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template
• provirus the viral genome now in the form of DNA (called provirus) is integrated into host genomic DNA and serves as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Roth et al.,1989).
• the preintegration complex consists of integrase, reverse transcriptase, pi 7 and proviral DNA (Bukrinsky M. L, Proc. Natn. Acad. Sci. USA vol. 89 p.6580 - 6584 (1992)).
• the phosphorylated pl7 protein plays a key role in targeting the preintegration complex into the nucleus of the host cell (Gallay et al., 1995).
• the primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II which is modulated by two virus-encoded proteins called tat and rev.
• the viral proteins are formed as polyproteins.
• Post-translational modifications of viral polyproteins include processing and glycosylation of Env (envelope) proteins, and niyristylation of the N-terminal residue of the pl7 protein in the Gag and Gag-Pol polyproteins.
• the viral protease is involved in processing polyproteins Gag and Gag-Pol into mature proteins, an essential step for virus infectivity.
• a number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV. These agents include compounds which interfere with viral binding to CD4 (+) T-lymphocytes (for example, soluble CD4), compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), budding of virion from the cell (interferon), or the viral protease (for example Ritonavir and Indinavir). Some of these agents proved ineffective in clinical tests. Others, targeting primarily early stages of viral replication, have no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of many of these agents in effective therapeutic doses has led to cell-toxicity and unwanted side effects, such as anemia, neurotoxicity and bone marrow suppression.
• Anti-protease compounds in their present form are typically large and complex molecules of peptidic nature that tend to exhibit poor bioavailability and are not generally consistent with oral administration. These compounds often exhibit side effects such as nausea, diarrhea, liver abnormalities and kidney stones. None of the known antiviral agents on the market target the HIV integrase.
• the present invention seeks to meet these and other needs.
• the present invention relates to a class of pyrazolo[3,4-b]pyridin-2-yl]-benzoic acid compounds as well as their pharmaceutically acceptable derivatives (e.g., salts).
• the present invention in a first aspect thereof provides a compound of formula I
• n may be, for example from 0 to 4 (0, 1, 2, 3 or 4)
• m may be, for example, from 0 to 4 (0,1, 2, 3 or 4)
• n and m may not exceed the number of available positions (i.e., 4),
• R 1 may be selected, for example, from the group consisting of -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, -F, -Cl, -Br, -I, -CN and - OR 3 (e.g. -OH),
• R 2 may be selected, for example, from the group consisting of -H, -CO 2 H, -CONR 3 R 4 and - COR 6 ,
• R 3 may be selected, for example, from the group consisting of -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, an allyl group, a cycloalkyl group of 3 to 8 carbon atoms, piperidine, pyrrolidine, morpholine and -R 3 -COOH, where R a may be a straight alkyl group of 1 to 6 carbon atoms,
• R b may be a cleavable unit (e.g., a physiologically cleavable unit), whereby upon cleavage of the unit, the compound releases an integrase inhibitor (an HIV integrase inhibitor).
• R b may be an enzymatically or metabolically cleavable unit or hydrolysable bond which may be cleaved under enteric and/or gastrointestinal conditions (pH) or other physiological conditions.
• R b may be (independently) selected, for example, from the group consisting of -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, an allyl group, a cycloalkyl group of 3 to 8 carbon atoms, R b -CO-, (HO) 2 P(O) and (MO) 2 P(O), wherein M is an alkali metal (e.g. Na, K, Cs, etc) or alkaline earth metal (Ca, Mg, etc.),
• M is an alkali metal (e.g. Na, K, Cs, etc) or alkaline earth metal (Ca, Mg, etc.)
• R b - may be selected, for example, from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, zso-propyl, butyl, wo-butyl, tert- butyl, ferr-butyl-CH 2 -, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl- , cyclohexyl- etc.) and a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH 2 -, cyclohexyl-CH2-, etc.),
• a straight or branched alkyl group of 1 to 6 carbon atoms e.g. methyl, ethyl, propyl
• R 4 may be selected, for example, from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, -CH 2 CH 2 OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-(l,2,3,4-tetrahydroquinolyl, - CO 2 R 3 , -CONR 3 R 3 , -COR 6 , 2-hydroxy-6-methyl nicotinyl, formyl, benzyl (substituted (e.g., with a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms) or unsubstituted) and phenyl (unsubstituted or mono-, di-, tri- hydroxysubstituted phenyl , o,
• R 5 may be selected from the group consisting of piperidine (1-, 2-, 3- piperidine), morpholine (e.g., 1 -morpholine),
• R 6 may be selected from the group consisting of -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, -NH 2 , phenyl, (unsubstituted or substituted phenyl such as mono, di, tri hydroxysubstituted phenyl, o, m, p straight (of 1 to 6 carbon atoms) and branched alkyl (of 3 to 6 carbon atoms) substituted phenyl, etc.), -CH 2 CH 2 OH, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- (1,2,3,4-tetrahydroquinolyl), o, m, p straight and branched alkyl substituted pyridyl, nicotinyl (substituted nicotinyl (mono, di,
• R 7 may be -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms.
• Cx may be more particularly selected, for example, from the group consisting of -CHO, -CHNO-CH 2 -COOH, -CHNO-Me, -CHNOEt, CHNO- allyl, -CHNO-t-Bu, -CHNOH, -CHNNH 2 , -CHN-1-piperidine, -CHN-1-morpholine, -CHN- NH-(CO-2-OH-6-Me nicotinyll), -CHN-NH-(CO-hydroxyphenyl) (e.g., -CHN-NH-(C0-2- OH-Phenyl)), -CHN-NH-(CO-di-hydroxyphenyl) (e.g., -CHN-NH-(CO-2, 3-Di OH-Phenyl)), -CHN-NH-(CO-tri-hydroxyphenyl) (e.g.
• Cx may be chosen for example among the group consisting of -CHO, -CHNO-CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, - CHNO-t-Bu, -CHN-NH-(CO-2-OH-6-Me nicotinyll), -CHN-NH-2-pyridine, -CHN-NH- formyl, -CHN-NH-(CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH-(4-t-Bu Bz).
• Cx may be selected from the group consisting of -CHO, CHNO-CH 2 -COOH, -CHNOEt, -CHN-NH-(CO-2-OH-6-Me nicotinyll) and -CHN-NH-(CO-hydroxyphenyl).
• the -CHN-NH-CCO-hydroxyphenyl) group may be more particularly selected from the group of, a -CHN-NH-CCO-mono-hydroxyphenyl), -CHN-NH-tCO-di-hydroxyphenyl), -CHN-NH- (CO-tri-hydroxyphenyl) etc., such as, for example, -CHN-NH-(CO-2-OH-Phenyl), -CHN- NH-(CO-3-OH-Phenyl), -CHN-NH-(CO-4-OH-Phenyl), -CHN-NH-(CO-5-OH-Phenyl), - CHN-NH-(CO-2, 3-Di-OH-Phenyl), -CHN-NH-(C O-2, 4-Di-OH-Phenyl), -CHN-NH-(CO-3, 4-Di-OH-Phenyl), -CHN-NH-(CO-2, 3,4 -Tri-OH-Phenyl
• compounds of formula I encompass those, for example, where -COOH or alternatively -H group may be found at position 3'.
• Exemplary embodiments of compounds which are encompassed herewith includes, for example, - compounds of formula I, where m may be 0, 1 or 2;
• n may be 0, 1 or 2;
• R b' may be, for example -H
• R b may be more particularly selected from the group consisting of -H, (HO) 2 P(O) and (MO) 2 P(O), where M may be, for example, an alkali metal or alkaline earth metal thereof;
• compounds of formula I where R 2 may be, more specifically H or -COOH are encompassed herewith.
• Other exemplary embodiments of the invention are compounds where n may be, for example, 0 or 1.
• compounds of formula I where R 1 may be more specifically, -H, -F, -Cl, -Br and -OH are encompassed herewith. More particularly, Cl may be found, for example, at position 2', 4' and/or 6'.
• m may more particularly be 0, 1 or 2.
• Compounds of the present invention also includes, for example, compounds of formula I, wherein R 1 may be -OH and R 2 may be -CO 2 H and wherein R 2 may be, more particularly CO 2 H at position 4'
• the present invention relates to compound of formula IA
• Cx, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 3 , R b , R b' may be as defined herein.
• Cx may be more particularly selected from the group consisting of -CHO, -CHNO-CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, - CHNO-t-Bu, -CHNOH, -CHNNH 2 , -CHN-1-piperidine, -CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyll), -CHN-NH-(CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN- NH-formyl, -CHN-NH-(COOMe), -CHN-NH-(CONH 2 ), -CHN-NH-Bz, and -CHN-NH-(4-t- Bu Bz).
• Cx may thus be selected from the group consisting of -CHO, -CHNO- CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH-(CO-2-OH-6- Me nicotinyll), -CHN-NH-2- ⁇ yridine, -CHN-NH-formyl, -CHN-NH-(CO-hydroxyphenyl), - CHN-NH-Bz, and -CHN-NH-(4-t-Bu Bz).
• Cx maybe selected from the group consisting of -CHO, CHNO-CH 2 - COOH, -CHNOEt, -CHN-NH-(CO-2-OH-6-Me nicotinyll) and -CHN-NH-(CO- hydroxyphenyl).
• Particular embodiments of compounds of the present invention includes those where Cx may be, for example, -CHO.
• compounds of formula IA encompassed by the present invention may include, for example, a compound where Cx may be -CHO, n may be 1 and R 2 may be - COOH at position 4' or 5'.
• Other embodiments of the present invention include compounds of formula IA where m may be O or Ri may be H.
• Compounds of formula IA where R b is, for example H are also encompassed by the present invention. Also encompassed are compounds of formula IA where R b - is, for example, H.
• the present invention provides compounds of formula IA where Cx may be -CHO, n may be 1, R 2 may be -COOH, for example, at position 5', m may be 1 and Ri may be -OH, for example, at position 4'.
• compounds of formula IA may include, for example, compounds where Cx may be -CHO, m may be 1 and R 1 may be -Cl, for example, at position 4' or 6'.
• compounds of formula IA where Cx may be -CHNO-CH 2 -COOH, where m may be O, n may be 1 and R 2 may be -COOH are also encompassed herein, hi accordance with the present invention, R 2 may be, for example, at position 5'.
• Cx may be -CHNO-CH 2 -COOH, where m may be 1, n may be O and R 1 may be -Cl.
• R 1 may be, for example, at position 4'.
• Cx may be, for example, - CHN-NH-(CO-2-OH-6-Me nicotinyll).
• compounds of formula IA where Cx may be -CHN-NH-(CO-2-OH-6-Me nicotinyll), where m may be 0, n may be 1 and R 2 may be -COOH are also encompassed herein.
• R 2 may be at position 5'.
• compounds of formula IA where Cx may be - CHN-NH-(CO-2-OH-6-Me nicotinyll), where m may be 1 , n may be 0 and R 1 may be -Cl are also encompassed herewith. Li accordance with the present invention, R 1 may be, more particularly at position 4'.
• Cx may be for example, -CHN-NH-(C0-2-0H- Phenyl), -CHN-NH-(CO-2, 3-Di OH-Phenyl) or -CHN-NH-(CO ⁇ , 3, 4 -Tri OH-Phenyl) or other hydroxyphenyl.
• m may be 0, n may be 1 and R 2 may be -COOH. R 2 may be found, for example, at position 5'.
• FIG. 1 For example, compounds of formula IA, where Cx may be -CHNO- AHyI, m may be 1 , R 1 may be Cl and n may be 0 or R 2 may be - H.
• Exemplary embodiments of compounds which are encompassed herewith includes, for example, - compounds of formula IA where R 2 may be more particularly, H or -COOH or even more particularly, -COOH;
• R 1 may be more specifically selected from the group consisting of -H, -F, -Cl, -Br and -OH or even more particularly, -Cl or - OH;
• m may be 0, 1 or 2;
• n may be 0, 1 or 2;
• R b may be selected, for example, from the group consisting of -H, (HO) 2 P(O) and (MO) 2 P(O), wherein M is an alkali metal or alkaline earth metal thereof;
• R 2 may be -COOH at position 4' or 5' and wherein m is 0 or 1 and n is lor 2; and/or,
• R 1 may be -Cl or -OH at position 4' or 6' and wherein m is 1, 2 or 3 and n is 0 or 1.
• Examples of compounds of formula IA encompassed by the present invention thus includes, without limitation;
• the present invention relates to compounds of formula IA'
• Cx may be more particularly selected from the group consisting of -CHO, -CHNO-CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, - CHNO-t-Bu, -CHNOH, -CHNNH 2 , -CHN-1-piperidine, -CHN-1-morpholine, -CHN-NH- (CO-2-OH-6-Me nicotinyll), -CHN-NH-(CO-hydroxyphenyl), -CHN-NH-2-pyridine, -CHN- NH-formyl, -CHN-NH-(COOMe), -CHN-NH-(CONH 2 ), -CHN-NH-Bz, and -CHN-NH-(4-t- Bu Bz).
• Cx may thus be selected from the group consisting of -CHO, -CHNO- CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, -CHNO-t-Bu, -CHN-NH-(CO-2-OH-6- Me nicotinyll), -CHN-NH-2-pyridine, -CHN-NH-formyl, -CHN-NH-(CO-hydroxyphenyl), - CHN-NH-Bz, and -CHN-NH-(4-t-Bu Bz).
• Cx maybe selected from the group consisting of -CHO, CHNO-CH 2 - COOH, -CHNOEt, -CHN-NH-(CO-2-OH-6-Me nicotinyll) and -CHN-NH-(CO- hydroxyphenyl) (e.g., -CHN-NH-(CO-mono-hydroxyphenyl), -CHN-NH-(CO-di- hydroxyphenyl), -CHN-NH-(CO-tri-hydroxyphenyl) etc.).
• R 3 may be selected, for example, from the group consisting of -H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms and an allyl group.
• compounds of formula IA' may include, for example, compounds where m is O or R 1 is -H.
• Compounds of formula IA' where R b is, for example H and Rb- is, for example, H are also encompassed by the present invention.
• Examples of compounds of formula IA' encompassed by the present invention thus includes, without limitation;
• Cx, n, R 2 , R 3 , R 4 , R 5 , R 6 , R7, R a , Rb, R b > are as defined herein.
• Cx may be selected, for example, from the group consisting of -CHO, CHNO-CH 2 -COOH, -CHNOEt, -CHN-NH-(CO-2-OH-6-Me nicotinyll) and -CHN-NH-(CO-hydroxyphenyl).
• exemplary compounds of formula IB may include, for example, a compound where n is 0 or R 2 is -H.
• Compounds of formula IB where R b is, for example H and R b ' is, for example, H are also encompassed by the present invention.
• R 1 may be one of, for example, -OH, -Cl, -F, -Br, -I etc.
• R 3 and R 4 may be as defined herein, for example, R 3 may be H and R 4 may be benzyl (unsubstituted or substituted) for example, -CHN-NH-Bz, CHN-NH-(4-t-Bu Bz), etc.
• the present invention also encompasses compounds of formula IC
• Cx, m, Ri, R 2 , R3, R 4 , Rs, RO, R7, Ra, R b , R b - are as defined herein.
• Cx may more specifically be selected from the group consisting of -CHO, -CHNO-CH 2 -COOH, -CHNO-Me, -CHNOEt, -CHNO-allyl, - CHNO-t-Bu, -CHN-NH-(CO-2-OH-6-Me nicotinyll), -CHN-NH-2-pyridine, -CHN-NH- formyl, -CHN-NH-(CO-hydroxyphenyl), -CHN-NH-Bz, and -CHN-NH-(4-t-Bu Bz).
• Cx may be selected from the group consisting of -CHO, CHNO-CH 2 - COOH, -CHNOEt, -CHN-NH-(CO-2-OH-6-Me nicotinyll) and -CHN-NH-(CO- hydroxyphenyl).
• R 1 may be selected from the group consisting of -H, -Cl, -F, -Br, -I and -OH and more particularly from the group consisting of -H, -Cl and -OH.
• R 2 may be as described herein and more particularly, may be, for example, -H or -COOH.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula I, IA, IA' IB and/or IC and a pharmaceutically acceptable carrier.
• the pharmaceutical composition may comprise, for example, a pharmaceutically effective amount of such one or more compounds of this invention.
• the pharmaceutical compositions may be used to inhibit integrase, including HIV integrase, thus providing protection against HIV infection.
• the present invention further relates to the use of at least one compound of formula I, IA, IA' IB and/or IC, for making a pharmaceutical composition, medicament or drug.
• the compound of formula I, IA, IA' IB and/or IC may be used in the making of a drug for the treatment and/or prevention of HIV infection and/or for the prevention of the apparition of acquired immunodeficiency syndrome (AIDS), and/or for reducing HIV replication and/or its cytopathic effects and/or inhibiting the HIV integrase enzyme etc.
• AIDS acquired immunodeficiency syndrome
• the present invention further relates to the use of the at least one compound of formula I, IA, IA' IB and/or IC, for treating and/or preventing HIV infection and/or AIDS for reducing HIV replication and/or its cytopathic effects and/or inhibiting the HIV integrase enzyme or else in an individual in need thereof.
• the invention also relates to a method of treating and/or preventing HIV infection and/or AIDS (e.g., for delaying the apparition of AIDS), for reducing HIV replication and/or its cytopathic effects and/or for inhibiting the HIV integrase enzyme or else in an individual in need thereof.
• the method may comprise administering a compound of formula I, IA, IA' IB and/or IC (or a pharmaceutical composition, drug etc.) to (in) an individual in need thereof.
• the present invention more particularly relates to a method of reducing the replication (e.g., integration) of HIV, the method may comprise providing a cell with a compound of formula I, IA, IA' IB and/or IC (or a pharmaceutical composition, drug etc.) or administering such compound to (in) an individual in need thereof.
• a method of reducing the replication e.g., integration
• the method may comprise providing a cell with a compound of formula I, IA, IA' IB and/or IC (or a pharmaceutical composition, drug etc.) or administering such compound to (in) an individual in need thereof.
• the present invention also relates to a process or method for preparing a compound of formula I, IA, IA' IB and/or IC and the use of intermediate compounds for that purpose.
• the compounds of this invention may include pharmaceutically acceptable derivatives of the compounds of formula I, IA, IA' IB and/or IC as defined above.
• a "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt (e.g., Na, K, Cs, etc), acetals (i.e., dimethylacetal, diethylacetal, etc), oxime, or ester (as for example, but not limited to methyl, ethyl, propyl, isopropyl esters, etc) of a compound of this invention.
• the expression "pharmaceutically acceptable derivative” is to be understood as referring to any other compound having a structure such that, upon administration to a recipient, it is capable of providing (directly or indirectly) a compound of this invention or an antivirally active metabolite or residue thereof.
• the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• the compounds of the present invention including where applicable their pharmaceutically acceptable derivatives have an affinity for integrase, in particular, HIV integrase. Therefore, these compounds may be useful as inhibitors of such integrase, i.e. they are in particular useful as HIV integrase inhibitors. These compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as antivirals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection or for reducing the probability of infection or reducing the probability of developing ARC and/or
• the compounds of this invention may be capable of inhibiting HIV viral replication in human CD4+ T-cells, by inhibiting the ability of HIV integrase to integrate the double stranded DNA into host genomic DNA for further virus replication by the host cell machinery (Sakai H., J. Virol. Vol. 67 p. 1169 - 1174 (1993)).
• These novel compounds may thus serve to reduce the production of infectious virions from acutely infected cells, and may inhibit the initial or further infection of host cells.
• HIV integrase and "integrase” as used herein are used interchangeably and refer to the integrase enzyme encoded by the human immunodeficiency virus type 1 or 2. In particular this term includes the human immunodeficiency virus type 1 integrase.
• pharmaceutically effective amount refers to an amount effective in treating or preventing HIV infection in a patient (e.g., reducing HIV replication, delaying the apparition of AIDS, lowering the probability of infection, lowering the probability of developing AIDS, etc.). It is also to be understood herein that a “pharmaceutically effective amount” may be interpreted as an amount giving a desired therapeutic effect, either taken into one dose or in any dosage or route or taken alone or in combination with other therapeutic agents.
• a "pharmaceutically effective amount” may be understood as an amount having an inhibitory effect on HIV (HIV-I and HIV-2 as well as related viruses (e.g., HTLV-I and HTLV-II, and simian immunodeficiency virus)) infection cycle (e.g., inhibition of replication, reinfection, maturation, budding etc.) and on any organism depending on integrase for their life cycle.
• HIV HIV-I and HIV-2
• related viruses e.g., HTLV-I and HTLV-II, and simian immunodeficiency virus
• prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient or preventing AIDS (e.g., delaying the apparition of AIDS, lowering the probability of infection, lowering the probability of developing AIDS, etc.).
• patient refers to a mammal, including a human.
• pharmaceutically acceptable carrier refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
• a "straight alkyl group of 1 to 6 carbon atoms” includes for example, methyl, ethyl, propyl, allyl, butyl, pentyl, hexyl.
• a "branched alkyl group of 3 to 6 carbon atoms” includes for example, without limitation, iso-butyl, tert-butyl, 2-pentyl, 3 -pentyl, etc. It is to be understood herein, that a "cycloalkyl group having 3 to 6 carbon” includes for example, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclocyclohexyl (i.e., C 6 H 11 ).
• Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N - (C 1-4 alkyl) 4 + salts.
• any specified range or group is to be understood as a shorthand way of referring to each and every member of a range or group individually as well as each and every possible subranges or sub-groups encompassed therein; and similarly with respect to any sub-ranges or sub-groups therein.
• a time of 1 minute or more is to be understood as specifically incorporating herein each and every individual time, as well as subrange, above 1 minute, such as for example 1 minute, 3 to 15 minutes, 1 minute to 20 hours, 1 to 3 hours, 16 hours, 3 hours to 20 hours etc.;
• the compound formulae each include each and every individual compound described thereby as well as each and every possible class or sub- group or sub-class of compounds whether such class or sub-class is defined as positively including particular compounds, as excluding particular compounds or a combination thereof; for example an exclusionary definition for the formula (e.g. I) may read as follows: "provided that when one of A and B is -COOH and the other is H, -COOH may not occupy the X' position".
• the compounds of this invention may be readily prepared using conventional techniques from commercially available and cheap starting materials.
• the derivatives of the present invention may be readily obtained from pyridoxal through sequences recognized by those knowledgeable in the art as straightforward, requiring readily available reagents and easy techniques.
• pyridoxal may be transformed to the desired HIV integrase inhibitors according to approaches as below.
• Scheme 1 illustrates a generic example for the coupling of aminoaryl carboxylic acid 1 with pyridoxal.
• Title compounds 3 may further be modified by reaction with appropriately O-substituted oximes , N'substituted hydrazines, N'substituted hydrazides, N', N'disubstituted hydrazines, or N', N'disubstituted hydrazides to give title compounds 4 or 5 (Scheme 2) Scheme 2
• novel compounds of the present invention are excellent ligands for integrase, particularly HIV-I, and most likely HIV-2 and HTLV-I integrase. Accordingly, these compounds are capable of targeting and inhibiting an early stage event in the replication, i.e. the integration of viral DNA into the human genome, thus preventing the replication of the virus.
• the compounds according to this invention may also be used as inhibitory or interruptive agents for other viruses which depend on integrases, similar to HIV integrases, for obligatory events in their life cycle. Such compounds inhibit the viral replication cycle by inhibiting integrase.
• integrase is essential for the production of mature virions, inhibition of that process effectively blocks the spread of virus by inhibiting the production and reproduction of infectious virions, particularly from acutely infected cells.
• the compounds of this invention advantageously inhibit enzymatic activity of integrase and inhibit the ability of integrase to catalyze the integration of the virus into the genome of human cells.
• the compounds of this invention may be employed in a conventional manner for the treatment or prevention of infection by HIV and other viruses which depend on integrases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
• a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
• a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against viral infections, such as HIV infection.
• novel integrase inhibitors of this invention may be administered as agents for treating or preventing viral infections, including HIV infection, in a mammal.
• the compounds of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other antiviral agents which interfere with the replication cycle of HIV.
• the coadministered antiviral agent may be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA.
• Antiviral agents targeting such early life cycle events include, didanosine (ddl), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT), polysulfated polysaccharides, sT4 (soluble CD4) - - which blocks attachment or adsorption of the virus to host cells ⁇ and other compounds which block binding of virus to CD4 receptors on CD4-bearing T-lymphocytes.
• Other retroviral reverse transcriptase inhibitors, such as derivatives of AZT may also be co- administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith.
• antiviral agents examples include ganciclovir, dideoxycytidine, trisodium phosphonoformiate, eflornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate.
• non-ribonucleoside inhibitors of reverse transcriptase such as TIBO, nevirapine or delavirdine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral protease. These compounds may also be co-administered with other inhibitors of HTV integrase.
• Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HFV replication.
• the use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent that would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
• These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents.
• These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
• These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
• Preferred combination therapies include the administration of a compound of this invention with AZT, 3TC, ddl, ddC, d4T, combivir, ziagen, sustiva, nevirapine and delavirdine.
• the compounds of this invention may also be co-administered with other HIV protease inhibitors such as saquinavir, indinavir, nelfinavir, ritonavir and amprenavir to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
• HIV protease inhibitors such as saquinavir, indinavir, nelfinavir, ritonavir and amprenavir to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
• the compounds of this invention may be administered as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT or HIV aspartyl protease inhibitors. Co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms.
• retroviral reverse transcriptase inhibitors such as derivatives of AZT or HIV aspartyl protease inhibitors.
• the compounds of this invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbante, tumor necrosis factor, naltrexone and rEPO); antibiotics (e.g., pentamidine isethionate) or vaccines to prevent or combat infection and disease associated with HIV infection, such as AIDS and ARC.
• immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbante, tumor necrosis factor, naltrexone and rEPO
• antibiotics e.g., pentamidine isethionate
• vaccines to prevent or combat infection and disease associated with HIV infection, such as AIDS and
• compositions according to this invention may be comprised of a combination of an integrase inhibitor of this invention and another therapeutic or prophylactic agent.
• the compounds of this invention may also be used as inhibitory agents for other viruses that depend on similar integrases for obligatory events in their life cycle. These viruses include, but are not limited to, other diseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I and HTLV-II.
• compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
• Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• compositions of this invention may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration or administration by injection are thus contemplated by the present invention.
• the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
• parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• suitable dispersing or wetting agents such as, for example, Tween 80
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• Suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solutions, hi addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. HeIv. or a similar alcohol.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspension and solutions, hi the case of tablets for oral and carriers which are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
• compositions of this invention may also be administered in the form of suppositories for rectal administration.
• These compositions may be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
• Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
• the pharmaceutical composition may be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
• Suitable carriers include, but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable neat formulation. Topically-transdermal patches are also included in this invention.
• compositions of this invention may be administered by nasal aerosol or inhalation.
• Such compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• Dosage levels of between about 0.01 and about 25 mg/kg body weight per day, between about 0.5 and about 25 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection.
• the pharmaceutical compositions of this invention may be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration may be used as a chronic or acute therapy.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form may vary depending upon the patient treated and the particular mode of administration.
• a typical preparation may contain from about 5% to about 75% active compound (w/w), for example, from about 20% to about 50% active compound.
• a maintenance dose of a compound, composition or combination of this invention may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of disease symptoms, especially for AIDS.
• the compounds of this invention are also useful as commercial reagents which effectively bind to integrases, particularly HIV integrase.
• the compounds of this invention, and their derivatives may be used to block integration of a target DNA molecule by integrase, or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications.
• HIV-I Human immunodeficiency virus type 1
• type 2 Human immunodeficiency virus type 1
• HTLV-I, -II Human T-cell lymphotropic virus type I, type II
• analytical plates may be treated with a 0.3% ninhydrin solution in ethanol containing 3% acetic acid and/or a CAM solution made of 20 g (NH 4 ) 6 Mo 7 O 24 and 8.3 g Ce(SO 4 ) 2 polyhydrate in water (750 mL) containing concentrated sulfuric acid (90 mL).
• Melting points (mp) were determined on a B ⁇ chi 530 melting point apparatus in capillary tubes and were uncorrected.
• Mass spectra were recorded on a Hewlett Packard LC/MSD 1100 system APCI either in negative mode or positive mode.
• NMR Nuclear magnetic resonance
• spectra were recorded on a Bruker AMX 500 equipped with a reversed or QNP probe.
• Samples were dissolved in deuterochloroform (CDCl 3 ), deuterium oxide (D 2 O) or deuterodimethylsulfoxide (DMSOd 6 ) for data acquisition using tetramethylsilane as internal standard.
• Chemical shifts (*) are expressed in parts per million
• the coupling constants (J) are expressed in hertz (Hz) whereas multiplicities are denoted as s for singlet, d for doublet, dd for doublet of doublets, t for triplet, q for quartet, quint for quintet m for multiplet, and br s for broad singlet.
• Method B 1 mmol of an aminobenzoic was dissolved in 2 mL 2N HCl (with 5 mL ethanol to help dissolution if necessary) and cooled to 0-5 0 C in an ice/salt bath. 1 mmol OfNaNO 2 was added portionwise and the diazonium salt was formed during 5 min. Then, 1 mmol (263 mg) of pyridoxal was dissolved in 2 mL of ice water with addition of 0.5 mL of saturated NaOH. The diazonium salt was the added portionwise over a 1 min period and the resulting orange red solution left for 15 min. The solution was then warmed to RT for 1-4 h. The red solution was then cooled in an ice bath until a yellow precipitate results. The precipitate was filtered and dried. The yield for this reaction ranged from 20 to 80%.
• a Pyrazolo[3,4-b]pyridin-2-yl]-benzoic acid derivative (0.1 mmol) was added to a 20% solution of hydrazine hydrochloride in 2-5 mL, pH 6 buffered water and stirred for 20 min. The pH was adjusted with hydrochloric acid until precipitation of the product was completed. The precipitate was filtered and dried ( ⁇ 65% yield).
• This product was obtained from commercially available 3, 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method B and B. The final product was obtained in 85% yield.
• This product was obtained from commercially available 2 Chloro 5 -amino-benzoic acid and pyridoxal as described in general procedures A, method A and B. The final product was obtained in 70% yield.
• This product was obtained from commercially available 4-Chloro, 5-amino-benzoic acid and pyridoxal as described in general procedures A, method A and B. The final product was obtained in 88% yield.
• This product was obtained from commercially available 4-amino-benzoic acid and pyridoxal as described in general procedures A, method A and B. The final product was obtained in 95% yield.
• This product was obtained from commercially available 3-amino-phthalic acid and pyridoxal as described in general procedures A, method A and B. The final product was obtained in 85% yield.
• This product was obtained from commercially available 2 Hydroxy, 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B. The final product was obtained in 65% yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with carboxy methoxyl amine by general procedure C and obtained in 80% yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with Ethoxyl amine by general procedure C and obtained in 80% yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and ⁇ pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with Allyloxyl amine by general procedure C and obtained in 80% yield.
• This product was obtained from commercially 2 Chloro 5 -amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2). The filtered product was then reacted with Allyloxyl amine by general procedure C and obtained in 80% yield.
• This product was obtained from commercially 2 Chloro 5 -amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2). The filtered product was then reacted with Carboxy methoxyl amine by general procedure C and obtained in 80% yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with Hydrazine by general procedure D and obtained in 80% yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with 1- amino piperidine by general procedure D and obtained in 69 % yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with 2-Hydroxy-6 Methyl nicotinyl hydrazide by general procedure D and obtained in 79 % yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with 2, 3- DiHydroxy-Benzoic hydrazide by general procedure D and obtained in 77 % yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with 2, 3, 4- TriHydroxy-Benzoic hydrazide by general procedure D and obtained in 77 % yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with 2-pyridyl hydrazine by general procedure D and obtained in 65 % yield.
• This product was obtained from commercially available 5-amino-isophthalic acid and pyridoxal as described in general procedures A, method A and B (Example 1). The filtered product was then reacted with Salicyl hydrazide by general procedure D and obtained in 88 % yield.
• This product was obtained from commercially 2 Chloro 5-amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2).
• the filtered product was then reacted with NH2NHCOOMe by general procedure D and obtained in 80% yield.
• This product was obtained from commercially 2 Chloro 5-amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2). The filtered product was then reacted with semicarbazide by general procedure D and obtained in 80% yield.
• This product was obtained from commercially 2 Chloro 5 -amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2).
• the filtered product was then reacted with Benzoyl hydrazide by general procedure D and obtained in 80% yield.
• This product was obtained from commercially 2 Chloro 5-amino-benzoic acid and pyridoxal as described in general procedures A, method A and B (Example 2).
• the filtered product was then reacted with 4-t Butyl- Benzoyl Hydrazide by general procedure D and obtained in 80% yield.
• HIV-I integrase inhibition assay was carried out following a known procedure (IGEN International, Inc. 2002; ORIGEN® HIV Integrase assay, A highly Sensitive and Rapid method to measure Integrase Activity and to Identify Inhibitors), Using an M8 Electroluminescence analyzer (IGEN International).
• Table 1 are shown compounds of formula I wherein carbon 2', 3', 4', 5'and in a case 6' are substituted as presented in Table 1.
• IC 5O , EC 5O as well as CCIC 50 results for compound of formula I and Ib are also presented in Table 1 illustrating their potential usefulness.
• Table 1 Anti-integrase activity of Pyrazolo[3,4-b]pyridin-2-yl]-benzoic acid derivatives of formula I
• R b and R b ' are both H.

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