R-isomers of nonnucleoside inhibitors

Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent

Reexamination Certificate

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C544S159000, C544S162000, C544S170000, C544S224000, C544S238000, C544S322000, C544S358000, C544S382000, C546S192000, C546S205000, C546S208000, C546S216000, C548S196000, C548S214000, C548S251000, C548S253000, C548S330100, C548S330500, C548S469000, C548S483000, C549S029000, C549S069000, C549S480000, C564S017000, C564S032000, C564S048000

Reexamination Certificate

active

06545152

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to chiral derivatives of thiourea compounds, particularly of halopyridyl and thiazolyl thiourea compounds useful as potent non-nucleoside inhibitors of viral reverse transcriptase.
BACKGROUND OF THE INVENTION
Design of potent inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT) activity, an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA, has been a focal point in translational AIDS research efforts. Promising inhibitors include nonnucleoside inhibitors (NNI), which bind to a specific allosteric site of HIV-1 RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al.,
Science
, 1992, 256, 1783-1790). The inclusion of structural information in the drug design process should lead to more efficient identification of promising RT inhibitors.
A composite binding pocket constructed with the NNI binding site coordinates of multiple, varied RT-NNI structures was generated to facilitate the rational design of RT inhibitors (WO99/47501 published Sep. 23, 1999). This novel composite binding pocket, together with a computer docking procedure and a structure-based semi-empirical score function, provides a guide to predict the energetically favorable position of novel compounds in the NNI binding site of RT. Using this model, we have attempted to design a variety of novel, potent inhibitors of RT for therapeutic use.
The invention described herein recognizes a previously unknown preference for stereospecific isomers of certain NNI, and provides compounds, compositions, and methods comprising such stereospecific NNI.
SUMMARY OF THE INVENTION
The invention provides specific, potent stereospecific compounds as inhibitors of reverse transcriptase (RT) activity. The stereoisomers of the invention inhibit replication of retrovirus, such as human immunodeficiency virus (HIV). In one embodiment, the compounds and compositions of the invention are stereospecific, chiral derivatives of non-nucleoside inhibitors (NNI), specifically R-isomers. Preferred compounds are the R-isomers of carbocyclic or heterocyclic thiourea compounds. More preferred compounds include an electron withdrawing group, for example at R
1
of the compound shown as Formula I. Exemplary compounds of the invention are shown in the Examples below, and include R-isomers of halopyridyl and thiazolyl thiourea compounds.
The invention additionally provides compositions and methods for inhibiting reverse transcriptase (RT) activity of a retrovirus, such as HIV-I, by contacting the RT binding site of the retrovirus with a compound of the invention. The methods of the invention are useful for inhibiting replication of a retrovirus, such as HIV-1 and include treating a retroviral infection in a subject, such as an HIV-1 infection, by administering a stereospecific chiral compound or composition of the invention, for example, in a pharmaceutical composition.
The compounds of the invention may be combined with carriers and/or agents to enhance delivery to sites of viral infection, such as targeting antibodies, cytokines, or ligands. The compounds may include chemical modifications to enhance entry into cells, or may be encapsulated in various known delivery systems.


REFERENCES:
patent: 5593993 (1997-01-01), Morin et al.
patent: 5658907 (1997-08-01), Morin, Jr. et al.
patent: 5686428 (1997-11-01), Eriksson et al.
patent: 5714503 (1998-02-01), Morin, Jr. et al.
patent: 5786462 (1998-07-01), Schneider et al.
patent: 5998411 (1999-12-01), Vig et al.
patent: 0 420 763 (1991-04-01), None
patent: 0 540 143 (1993-05-01), None
patent: WO 93/03022 (1993-02-01), None
patent: 07025770 (1995-01-01), None
patent: WO 95/06034 (1995-03-01), None
patent: WO 99/29318 (1999-06-01), None
patent: WO 99/47501 (1999-09-01), None
Bosworth, N et al., “Scintillation Proximity Assay”,Nature International Weekly Journal of Science,vol. 341, No. 6238, pp. 167-168 (Sep. 14, 1989).
Burkett, U. et al., “Methods For The Computation Of Molecular Geometry”,Molecular Mechanics, ACS Monograph 177,pp. 59-78 (1982 American Chemical Society).
Erice, A. et al., “Anti-Human Immunodeficiency Virus Type 1 Activity Of An Anti-CD4 Immunoconjugate Containing Pokeweed Antiviral Protein”,Antimicrobial Agents&Chemotherapy,vol. 37, No. 4, pp. 835-838 (Apr. 1993).
Kohlstaedt, L. et al., “Crystal Structure At 3.5 Å Resolution Of HIV-1 Reverse Transcriptase Complexed With An Inhibitor”,Science,Vo. 256, pp. 1783-1790 (Jun. 26, 1992).
Marshall, G., “Computer-Aided Drug Design”,Annual Review of Pharmacology And Toxicology,vol. 27, pp. 193-213 (1987).
Remington's Pharmaceutical Sciences, RPS XIV, Chapter 43, pp. 764-786 (Date Unknown).
Uckun, F. et al., “TXU (Anti-CD7)-Pokeweed Antiviral Protein As a Potent Inhibitor Of Human Immunodeficiency Virus”Antimicrobial Agents&Chemotherapy,vol. 42, No. 2, pp. 383-388 (Feb. 1998).
Zarling, J. et al., “Inhibition of HIV Replication By Pokeweed Antiviral Protein Targeted To CD4+Cells By Monoclonal Antibodies”,Nature International Weekly Journal Of Science,vol. 347, No. 6288, pp. 92-95 (Sep. 6, 1990).
Ambinter: Exploratory Library,Database Chemcats 'Online!,Abstract XP-002184046 (May 31, 2001).
Ambinter: Exploratory Library,Database Chemcats 'Online!,Abstract XP-002184047 (May 31, 2001).
Breuzard, J.A.J. et al., “Thioureas as new chiral ligands for the asymmetric hydroformylation of styrene with rhodium(I) catalysts”,J. Mol. Catal. A: Chem,156(1-2), 223-232 (2000) Abstract.
Drefahl et al., “Stilbenes—(XXXIX) Wittig reaction with p-halomethylbenzaldehyde”,Database Caold 'Online!,Abstract XP-002184037 (date unknown).
Furdik et al., Synergists of pyrethrum—(VI) synthesis of endo-cis-N-substituted 7-diphenylmethylene-bicyclo[1,2,2]hept-5-ene-2,3-dicarboximides,Database Caold 'Online!,Abstract XP-002184038 (date unknown).
Glover, Edward E., et al., “Synthesis and quaternization of heterocyclic mono-and disulfides”,J. Chem. Soc., Perkin Trans.1 (21) 2595-9 (1973) Abstract XP-002184040.
Iliceto, A., et al., “Thiocyanates and isothiocyanates—(III) kinetics and mechanism of benzhydryl thiocyanates isomerization”,Database Caold 'Online!,Abstract XP-002184036 (date unknown).
Jung et al., “A study on the stability of 5,5-diamino-substituted-1,4,2-oxathiazoline derivatives”,Synth. Commun.28(10), 1879-1884 Abstract XP-002184044 (1998).
Mao, et al., “Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thioureaa (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus”Bioorg. Med. Chem. Lett. 9,1593-1598, (1999).
Nagai et al., “Bisarylthiourea fungicides”,Japan, Kokai,6 pp. Abstract XP-002184043 (Feb. 3, 1978).
Patel, P.R., et al., “Synthesis of 5-alkyl-3-benzyhydryl-2-arylimino-4-thiazolidones and 5-substituted benzal/cinnamal-3-benzhydryl-2-arylimino-4-thiazolidones”,J. Inst. Chem.,Calcutta 48, Pt. 2, 105-8, Abstract XP-002184041 (1976).
Sato et al., “Arylthioureas as microbicides”,Japan, Kokai,5 pp., Abstract XP-002184042 (Dec. 18, 1976).
Tonellato, U., et al., “Stereochemistry of ion-pair return. I. Resolution and isomerization of (-)-4-chlorobenzhydryl thiocyanate”J. Org. Chem.,34(12), 4032-4, (1969).
Vig, R. et al., 1998Bioorganic&Medicinal Chemistry,6:1789-1797 Rational Design and Synthesis of Phenethyl-5-bromopyridyl Thiourea Derivatives as Potent Non-nucleoside Inhibitors of HIV Reverse Transcriptase.
Weiner, S.J. et al., 1984,J. Am. Chem. Soc., 106,765-784 A New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Proteins.
Zhang, et al., 1996,Antiviral Chemistry&Chemotherapy,7(5):221-229 “Synergistic inhibition of HIV-1 reverse transcriptase and HIV-1 replication by combining trovirdine with AZT, ddl and ddC in vitro”.
Ahgren, C., et al., 1995,Antimicrob. Agents Chemotherapy,39, 1329-1335 The PETT Series, a New Class of Potent Nonnuc

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