WO2013082476A1 - Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections - Google Patents
Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections Download PDFInfo
- Publication number
- WO2013082476A1 WO2013082476A1 PCT/US2012/067369 US2012067369W WO2013082476A1 WO 2013082476 A1 WO2013082476 A1 WO 2013082476A1 US 2012067369 W US2012067369 W US 2012067369W WO 2013082476 A1 WO2013082476 A1 WO 2013082476A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- pyrimidin
- thieno
- haloalkyl
- amino
- Prior art date
Links
- DUMSKQUKLVSSII-UHFFFAOYSA-N ICC1CCCC1 Chemical compound ICC1CCCC1 DUMSKQUKLVSSII-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- HIV-1 human immunodeficiency virus
- ABT synthetic nucleoside 3'-azido-3'-deoxythymidine
- these synthetic nucleosides After cellular phosphorylation to the 5'-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3'-hydroxyl group. They can also inhibit the viral enzyme reverse transcriptase.
- Drug-resistant variants of HIV-1 can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication, and most typically in the case of HIV-1, reverse transcriptase, protease, or DNA polymerase. Recently, it has been demonstrated that the efficacy of a drug against HIV-1 infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous pressures on the virus. However, drug resistance can still emerge, and no effective cure has yet been identified, such that a patient can ultimately stop treatment.
- HAART Highly Active Antiretroviral Therapy
- HAART typically involves various combinations of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and HIV-1 protease inhibitors.
- these multidrug therapies do not eliminate HIV-1 and long-term treatment often results in multidrug resistance.
- many of these drugs are highly toxic and/or require complicated dosing schedules that reduce compliance and limit efficacy. There is, therefore, a continuing need for the development of additional drugs for the prevention and treatment of HIV-1 infection and AIDS.
- Antiretro viral JAK inhibitors are provided.
- viruses that can be treated using the compounds described herein include HIV, including HIV-1 and HIV-2, Flaviviridae viruses, such as HCV and Dengue, and Alphaviruses such as Chikungunya virus.
- Representative JAK inhibitors include those disclosed in U.S. Patent No.
- Ruxolitinib Jakafi, Incyte
- JAK inhibitors also include those disclosed in U.S. Patent Nos. Re 41,783; 7,842,699; 7,803,805; 7,687,507; 7,601,727; 7,569,569; 7,192,963; 7,091,208; 6,890,929, 6,696,567; 6,962,993; 6,635,762; 6,627,754; and 6,610,847, an example of which is Tofacitinib (Pfizer), which has the structure shown below:
- the compounds have the formula:
- R 1 is a group of the formula
- R 4 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (Cr
- R 4 is (C3-C 1 o)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino; or R 4 is (C3-C 1 o)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((Cr C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino; or R 4 is (C3-C 1 o)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium
- R 5 is (C 2 -C9)heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (Q- C 6 )alkoxy-CO-NH, (Ci-C 6 )alkylamino-CO ⁇ , (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C
- Y is S(0) n wherein n is 0, 1 or 2; or carbonyl;
- Z is carbonyl, C(0)0-, C(0)NR- or S(0) composition wherein n is 0, 1 or 2;
- R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (Ci-C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (Ci-C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((Cr C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;
- R is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C - C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO--NH, (C 1 -C 6 )alkylamino-CO--, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (Ci-C
- R" and R J are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, trifluoromethyl, trifluoromethoxy, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (C 3 - C 1 o)cycloalkyl wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino (C - C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (Cs-Cc heteroaryl, (C 2 - 2 3
- R and R are each independently (C 3 -C 1 o)cycloalkyl, (C 3 -C 1 o)cycloalkoxy, (C 1 -C 6 )alkylamino, ((Q- C 6 )alkyl) 2 amino, (C 6 -C 1 o)arylamino, (Ci-C 6 )alkylthio, (C 6 -Cio)arylthio, (Q- C 6 )alkylsulfinyl, (C 6 -C 1 o)arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 1 o)arylsulfonyl, (Cr C 6 )acyl, (Ci-C 6 )alkoxy-CO-NH-, (Ci-C 6 )
- C 6 )alkylamino ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, ((Q- C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, carboxy, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy-CO--NH- -, (C 1 -C 6 )alkyl-CO-NH-, cyano, (C 5 -C 9 )heterocycloalkyl, amino-CO--NH-, (C C 6 )alkylamino-CO--NH-, ((C 1 -C 6 )
- the JAK inhibitors also include compounds of Formula B:
- a 1 and A 2" are independently selected from C and N;
- T, U, and V are independently selected from O, S, N, CR 5 , and NR 6 ; wherein the 5-membered ring formed by A 1 , A 2 , U, T, and V is aromatic;
- X is N or CR 4 ;
- Y is Ci- 8 alkylene, C 2 - 8 alkenylene, C 2 _ 8 alkynylene, (CR R ) p — (C3-W cycloalkylene)-(CR u R 12 ) q , (CR n R 12 V-(Ci-io heterocycloalkylene)-(CR n R 12 ) q , (CR 11 R 12 ) p -(heteroarylene)-(CR 11 R 12 ) q , (CR ⁇ p C CR 1 ⁇ 12 ⁇ , (CR 11 R 12 ) p S(CR 11 R 12 ) q , (CR 11 R 12 ) p C(0)(CR 11 R 12 ) q , (CR 11 R 12 ) p C(0)NR c (CR 11 R 12 ) q , (CR 11 R 12 ) p C(0)0(CR 11 R 12 ) q , (CR n R 12 ) p OC(0)( CR n R
- n 1;
- W is Ci- 8 alkylenyl, C 2-8 alkenylenyl, C 2-8 alkynylenyl, O, S, C(O), C(0)NR c' , C(0)0, OC(O), OC(0)NR c' , NR C' , NR c C(0)NR d' , S(O), S(0)NR c' , S(0) 2 , or S(0)2NR C' ;
- Q is H, halo, CN, N0 2 , C 1-8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, C 1-8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, C 1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy 2 , CN, N0 2 , OR a' , SR a'
- Cy 1 and Cy 2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, CN, N0 2 , OR a" , SR a" , C(0)R b “, C(0)NR c , R d" , C(0)OR a" , OC(0)R b" , OC(0)N R c 'R d , NR c 'R d , NR c , C(0)R b" , NR c" C(0)OR a" , NR c" S(0)R b" , NR c" S(0) 2 R b" , S
- R 5 is H, halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CN, N0 2 , OR 7 , SR 7 , C(0)R 8 , C(0)NR 9 R 10 , C(0)OR 7 , OC(0)R 8 , OC(0)NR 9 R 10 , NR 9 R 10 , NR 9 C(0)R 8 , NR 9 C(0)OR 7 , S(0)R 8 , S(0)NR 9 R 10 , S(0) 2 R 8 , NR 9 S(0) 2 R 8 , or S(0) 2 NR 9 R 10 ;
- R 6 is H, CM alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CM haloalkyl, OR 7 , C(0)R 8 ,
- R is H, Ci-6 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
- R is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
- R 9 and R 10 are independently selected from H, C 1-10 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 1-6 alkylcarbonyl, arylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
- R 9 and R 10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group
- R 11 and R 12 are independently selected from H and -E 1 -E 2 -E 3 -E 4 ;
- D 1 and E 1 are independently absent or independently selected from C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N0 2 , N 3 , SCN, OH, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 8 alkoxyalkyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, amino, C 1-6 alkylamino, and C 2 _8 dialkylamino;
- D 3 J and E 3 J are independently absent or independently selected from C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N0 2 , N 3 , SCN, OH, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 8 alkoxyalkyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, amino, C 1-6 alkylamino, and C 2 _8 dialkylamino;
- R a is H, Cy 1 , -(Ci-6 C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, or C 2 _ 6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R b is H, Cy 1 , -(Ci_6 Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, wherein said Ci_6 alkyl, Ci_6i-6 halo
- R a ' and R a " are independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Ci_6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, halosulf
- R b' and R b" are independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6
- R c and R d are independently selected from H, Cy 1 ,—(Ci-6 alky ⁇ -Cy 1 , C ⁇ o alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, wherein said C ⁇ o alkyl, C ⁇ haloalkyl, C 2 _ 6 alkenyl, or C 2 _ 6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 ,—(Ci-6 alky ⁇ -Cy 1 , OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, and halosulfanyl;
- R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 ,— (Ci_6 alky ⁇ -Cy 1 , OH, CN, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, and halosulfanyl;
- and R dl are independently selected from H, C O alkyl, Ci_6 haloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C ⁇ o alkyl, Ci_6 haloalkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 halo
- and R dl together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R c " and R d " are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, halosulf
- R c " and R d " together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R 1 is H, CN, N0 2 , or C 1-6 alkyl
- R e and R f are independently selected from H and C 1-6 alkyl
- R 1 is H, CN, or N0 2 ;
- n 0 or 1 ;
- n 0 or 1 ;
- p 0, 1, 2, 3, 4, 5, or 6;
- q 0, 1, 2, 3, 4, 5 or 6;
- r is 0 or 1 ;
- Additional JAK inhibitors include CEP-701 (Lestaurtinib, Cephalon Technology), a JAK 2 FL3 kinase, AZD1480 (Astra Zeneca), a JAK 2 inhibitor, LY3009104/INCB28050 (Eli Lilly, Incyte), a JAK 1/2 inhibitor, Pacritinib/SB1518 (S*BIO), a JAK 2 inhibitor, VX-509 (Vertex), a JAK 3 inhibitor, GLPG0634 (Galapagos), a JAK 1 inhibitor, INC424 (Novartis), a JAK inhibitor, R-348 ( Rigel), a JAK 3 inhibitor, CYT387 (YM Bioscience), a JAKl/2 inhibitor, TG 10138, a JAK 2 inhibitor, AEG 3482 (Axon), a JAK inhibitor, and pharmaceutically-acceptable salts and prodrugs thereof.
- TG 10138 has the following formula:
- CYT387 has the following formula: LY3009104 is believed to be (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl-3-cyclopentyl-propanenitrile
- the compounds include those described in U.S. Publication Nos. 20110020469; 20110118255; 20100311743; 20100310675; 20100280026; 20100160287; 20100081657; 20100081645; 20090181938; 20080032963; 20070259869; and 20070249031.
- the compounds also include those described in U.S. Publication Nos.
- the compounds also include those described in U.S. Publication Nos.
- the compounds also include those described in U.S. Publication Nos. 20110245256; 20100009978; 20090098137; and 20080261973.
- the compounds also include those described in U.S. Publication No. 20110092499.
- Representative compounds include:
- N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine 8.
- 2- (4- morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxylate 9.
- N-(4- morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine 10. 7-(4-amino-3- methoxyphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin— 2-amine 11.
- R348 (Rigel) is defined in Velotta et al., "A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection,” Transplantation. 2009 Mar 15;87(5):653-9.
- the present invention also relates to the use of pharmaceutically acceptable acid addition salts of compounds of Formulas A and B, as well as the additional JAK inhibitors described herein.
- the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate [i.e., l,l'-methylene-bis-(2-hydroxy-3-
- the invention also relates to the use of base addition salts of Formulas A and B.
- the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of Formulas A and B that are acidic in nature are those that form non-toxic base salts with such compounds.
- Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
- the JAK inhibitors described herein include all conformational isomers (e.g., cis and trans isomers. Those compounds which have asymmetric centers exist in different enantiomeric and diastereomeric forms.
- This invention relates to the use of all optical isomers and stereoisomers of the compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z configurations.
- the compounds of Formulas A and B can also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
- This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the Formulas A and B.
- This invention also encompasses methods of treating or preventing viral infections that can be treated or prevented by inhibitors of protein kinases, such as the enzyme Janus Kinase 1, 2, or 3 comprising administering prodrugs of compounds of the Formulas A and B.
- Compounds of Formulas A and B having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
- Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of Formulas A and B.
- the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone.
- Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of Formulas A and B through the carbonyl carbon prodrug sidechain.
- the JAK inhibitors can be used in combination with additional anti-retroviral agents, including reverse transcriptase inhibitors, such as nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI), non-nucleoside viral polymerase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors such as raltegravir (Isentress) or MK-0518, GS-9137 (Elvitegravir, Gilead Sciences), GS- 8374 (Gilead Sciences), or GSK-364735.
- reverse transcriptase inhibitors such as nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI)
- non-nucleoside viral polymerase inhibitors such as raltegravir (Isentress) or MK-0518, GS-9137 (
- the combinations include, in addition to a JAK inhibitor as described herein, at least one adenine nucleoside antiviral agent, at least one cytosine nucleoside antiviral agent, at least one guanine nucleoside antiviral agent, and at least one thymidine nucleoside antiviral agent.
- the therapeutic combinations include, and further include at least one additional agent selected from reverse transcriptase inhibitors, especially non- nucleoside viral polymerase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors such as raltegravir (Isentress) or MK-0518, GS-9137 (elvitegravir, Gilead Sciences), GS-8374 (Gilead Sciences), or GSK-364735.
- reverse transcriptase inhibitors especially non- nucleoside viral polymerase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors
- raltegravir Isentress
- MK-0518 g., MK-0518
- GS-9137 elvitegravir, Gilead Sciences
- GS-8374 Gilead Sciences
- JAK inhibitors are also inhibitors of CYP3A4, which means that they will significantly increase the C max plasma level of any anti-HIV drug that binds to CYP3A4, including HIV-1 protease inhibitors.
- this therapy particularly when administered at an early stage in the development of HIV-1 infection, has the possibility of eliminating HIV-1 infection in a patient. While not wishing to be bound to a particular theory, it is believed that the JAK inhibitors function in a way that is not likely to provoke resistance (i.e., does not involve inhibition of enzymes, or introduction of modified bases in a way that would provoke enzyme mutations).
- the combination minimizes the ability of the virus to adapt its reverse transcriptase and develop resistance to any class of nucleoside antiviral nucleosides (i.e., adenine, cytosine, thymidine, or guanine), because it would be susceptible to at least one of the other nucleoside antiviral agents that are present, and/or the additional non-NRTI therapeutic agent.
- nucleoside antiviral nucleosides i.e., adenine, cytosine, thymidine, or guanine
- hitting the same target such as the active site of the HIV-1 polymerase with different bases allows complete and thorough chain termination of all the possible growing viral DNA chains.
- NNRTI in addition to the four different nucleosides (ACTG analogs) can be even more effective, since NNRTI bind to the HIV-polymerase and cause the enzyme to change conformation preventing chain elogation by natural nucleosides interacting in the active site of the enzyme.
- additional therapeutic agents can be used in combination with these agents, particularly including agents with a different mode of attack.
- agents include but are not limited to: antivirals, such as cytokines, e.g., rIFN alpha, rIFN beta, rIFN gamma; amphotericin B as a lipid-binding molecule with anti-HIV activity; a specific viral mutagenic agent (e.g., ribavirin), an HIV-1 VIF inhibitor, and an inhibitor of glycoprotein processing.
- Representative anti-TNF alpha therapies include, but are not limited to, Infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), alone or with a circulating receptor fusion protein such as etanercept (Enbrel).
- the agents When administered in combination, the agents can be administered in a single or in multiple dosage forms. In some embodiments, some of the antiviral agents are orally administered, whereas other antiviral agents are administered by injection, which can occur at around the same time, or at different times.
- the compounds can be used in different ways to treat or prevent HIV, and, in one embodiment, to cure an HIV infection.
- the invention encompasses combinations of the two types of antiviral agents, or pharmaceutically acceptable derivatives thereof, that are synergistic, i.e., better than either agent or therapy alone.
- a combination of a JAK inhibitor as described herein, a macrophage depleting agent e.g., clodronate-loaded liposomes, gadolinium chloride (GdCl)
- a macrophage depleting agent e.g., clodronate-loaded liposomes, gadolinium chloride (GdCl)
- HAART therapy is used.
- HDAC inhibitor histone deacetylase inhibitor
- IL-7 interleukin 7
- the JAK inhibitors are administered to a patient before, during, or after administration of a vaccine or an immunomodulatory agent.
- antiviral combinations described herein provide means of treatment which can not only reduce the effective dose of the individual drugs required for antiviral activity, thereby reducing toxicity, but can also improve their absolute antiviral effect, as a result of attacking the virus through multiple mechanisms. That is, various combinations described herein are useful because their synergistic actions permit the use of less drug, and/or increase the efficacy of the drugs when used together in the same amount as when used alone.
- JAK inhibitors alone or in combination, provides a means for circumventing the development of viral resistance, thereby providing the clinician with a more efficacious treatment.
- the disclosed JAK inhibitors used alone or in combination or in alternation therapies, are useful in the prevention and treatment of HIV-1 infections and other related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma, thrombocytopenia purpurea and opportunistic infections.
- these compounds or formulations can be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HIV antibody or HIV-antigen positive or who have been exposed to HIV.
- the therapy can be also used to treat other viral infections, such as HIV-2.
- the invention includes methods for treating or preventing, and uses for the treatment or prophylaxis, of a Flaviviridae infection, including all members of the Hepacivirus genus (HCV), Pestivirus genus (BVDV, CSFV, BDV), or Flavivirus genus (Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus), as well as Alphaviruses, such as the Chikungunya virus.
- HCV Hepacivirus genus
- BVDV Pestivirus genus
- CSFV CSFV
- BDV Pestivirus genus
- Flavivirus genus Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus
- Alphaviruses such as the Chikungunya virus.
- Figure 1 is a chart showing the potency and toxicity of JAK inhibitors Tofacitinib or Jakafi versus FDA approved controls AZT and 3TC in acutely infected resting macrophages (M0), as well as in peripheral blood mononuclear (PBM) cells.
- Median effective antiviral concentration (EC 50 ) data is shown in terms of ⁇ concentration of the compounds.
- the IC 50 values (toxicity) ( ⁇ ) are also shown in PBM, M0 cells, CEM cells, and Vero cells.
- Figure 2 is a chart showing the effect of various concentrations of Tofacitinib and Jakafi on cellular proliferation [total cell number (10 6 cells) versus ⁇ drug] in activated PBM cells incubated for 5 days with the compounds. Cycloheximide is shown as a positive control, and a "cells plus media” control for each compound is also shown.
- Figure 3 is a chart showing the effect of various concentrations of Tofacitinib and Jakafi on cellular viability (% viability versus ⁇ drug) in activated PBM cells incubated for 5 days with the compounds. Cycloheximide is shown as a positive control, and a "cells plus media" control for each compound is shown as well.
- Figures 4a-f show the results of flow cytometric analysis of PHA+IL-2 stimulated primary human lymphocytes exposed to various concentrations of Jakafi or Tofacitinib for 5 days prior to assessment of viability using propidium iodide (flow cytometry). Histograms and scatter plots are representative data from at least 3 independent experiments conducted with pooled cells from 8 donors.
- Figure 4a is a scatter plot showing a Side Scatter (SSC) Gating strategy, where the X-axis in the first chart is Side Scatter Pulse Height (SSC-h) and the Y-axis is Side Scatter Pulse Width (SSC-w), and in the second chart, the forward-scattered light (FSC) is shown with the X axis being Forward Scatter Pulse Height (FSC-H) and the Y axis being Forward Scatter Pulse Width (FSC-W) and Gating strategy based on forward scatter (FSC) and side scatter (SSC) was established and used uniformly across all samples (A).
- SSC Side Scatter
- Figure 4B is a histogram showing the results of flow cytometry studies using Propidium Iodide stain, which is read by the phycoerythrin (PE-A) channel, looking at the cell counts of viable cells.
- Propidium iodide is a large molecule, which exclusively intercalates into the DNA of dead/dying cells and is detectable by PE fluorescence (flow cytometry). Living cells do not uptake Propidium Iodide, therefore they are not fluorescent or detectable by the PE channel.
- Figure 4c shows histograms comparing the cell viability for cells exposed to
- FIG. 4d shows histograms comparing the cell viability for cells exposed to Tofacitinib and to no drug (i.e., controls) for concentrations of 0.1 ⁇ Tofacitinib, 1.0 ⁇ Tofacitinib, ⁇ Tofacitinib, and 50 ⁇ Tofacitinib.
- Figures 4e and 4f are charts showing the mean and standard deviations from the experiments shown in Figures 4c (Jakafi) and 4d (Tofacitinib), respectively.
- Figures 5a and 5b are charts showing the percent inhibition of HIV-1 replication versus untreated control for the co-administration of jakafi and Tofacitinib in primary human lymphocytes (Figure 5a) and macrophages (Figure 5b). The data is shown in terms of percent inhibition (%) on the Y axis versus drug concentration ( ⁇ ) on the X axis.
- Figures 6a and 6b are charts showing the fold increase 50 (FI 50 ) and fold increase 90 (FI 90 ) for Jakafi and Tofacitinib against various NRTI-resistant HIV- 1 in primary human lymphocytes. Results with NRTI AZT, (-) FTC, 3TC, D4T, ddl, EFV, and TDF are also shown.
- FIGS 7a-7d are charts showing the effect of various Jak inhibitors
- Figures 8a and 8b are charts showing that Tofacitinib and Jakafi inhibit reactivation of latent HIV-1.
- Figure 8a shows the results in a primary central memory-based T cell latency model (Bosque and Planelles (2009) Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 113: 58-65), in terms of the % inhibition of reactivation of latent HrV - 1 versus concentration of Jak inhibitor ( ⁇ ).
- Figure 8b shows the results in a J-Lat latency T cell system (Jordan et al, (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. The EMBO Journal, Vol. 22 No. 8 pp. 1868+1877), in terms of the % inhibition of reactivation of latent HIV-1 versus concentration of Jak inhibitor ( ⁇ ). Diamonds represent results for Tofacitinib, and squares represent results for Jakafi.
- Figures 9a and 9b are charts showing that Tofacitinib and Jakafi inhibit reactivation of latent HIV-1 in primary human macrophages.
- Tofacitinib ( Figure 9a) and Jakafi ( Figure 9b) inhibit reactivation of latent HIV-1 in primary human macrophages when drug is applied to cells during reactivation but removed thereafter.
- Tofacitinib inhibits ⁇ 40 % of reactivation while Jakafi inhibits ⁇ 35 % of reactivation within 72 hr post reactivation.
- the present invention is directed to compounds, compositions and methods for treating viral infections, such as HIV infections, including HIV-1 and HIV-2 infections.
- the compounds are heteroaryl substituted pyrrolo[2,3- b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases (JAK inhibitors).
- any "R" group(s) such as, without limitation, R 1 , R la , R lb , R c , and R ld represent substituents that can be attached to the indicated atom.
- R groups include, but are not limited to, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, cyano, halogen, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- s
- R group may be substituted or unsubstituted. If two "R" groups are covalently bonded to the same atom or to adjacent atoms, then they may be "taken together" as defined herein to form a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
- R' and R" of an NR'R" group are indicated to be “taken together", it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen: Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent may be selected from one or more the indicated substituents.
- the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carbox
- C a to in which "a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
- the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a” to "b", inclusive, carbon atoms.
- a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 - CH 3 CH 2 - CH 3 CH 2 CH 2 - (CH 3 ) 2 CH- CH 3 CH 2 CH 2 CH 2 - CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
- alkyl can be straight or branched hydrocarbon chains that comprise a fully saturated (no double or triple bonds) hydrocarbon group.
- the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “ 1 to 20” refers to each integer in the given range; e.g., " 1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
- the alkyl group can also be a lower alkyl having 1 to 6 carbon atoms.
- the alkyl group of the compounds may be designated as "Q-Gs alkyl” or similar designations.
- “Ci-G* alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
- “Ci -C 6 alkyl” indicates that there are one to six carbon atoms in the alkyl chain.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
- the alkyl group may be substituted or unsubstituted.
- alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
- An alkenyl group may be unsubstituted or substituted.
- alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
- An alkynyl group may be unsubstituted or substituted.
- alkoxy includes O-alkyl groups wherein “alkyl” is defined above.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- cycloalkenyl refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi- electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.
- cycloalkynyl refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. Pf there is more than one triple bond, the triple bonds cannot form a fully delocalized pi- electron system throughout all the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.
- aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group is a C 6-14 aryl group, a C 6 -io aryl group, or a C 6 aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrim
- heteroalicyclic or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
- the heteroatoms are independently selected from oxygen, sulfur, and nitrogen.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heteroalicyclyl or heteroalicyclic groups may be unsubstituted or substituted.
- heteroalicyclic or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2- dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazoline, isox
- aralkyl is an aryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2- phenylalkyl, 3-phenylalkyl, and naphtylalkyl.
- heteroarylkyl is heteroaryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3- thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
- a "(heteroalicyclyl)alkyl” is a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (l ,3-thiazinan-4-yl)methyl.
- Lower alkylene groups are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and butylene (-CH 2 CH 2 CH 2 CH 2 -). A lower alkylene group may be substituted or unsubstituted.
- alkoxy refers to the formula -OR wherein R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl is defined as above. Examples of include methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso- butoxy, sec- butoxy, tert-butoxy, phenoxy and the like. An alkoxy may be substituted or unsubstituted.
- acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.
- hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by hydroxy group. Examples of hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
- haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl).
- halogen e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl.
- groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2-fluoromethyl, 2-fluoroisobutyl.
- a haloalkyl may be substituted or unsubstituted.
- haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
- halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
- groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2- fluoromethoxy, 2-fluoroisobutoxy.
- a haloalkoxy may be substituted or unsubstituted.
- a “sulfenyl” group refers to an "-SR" group in which R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.
- R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.
- a sulfenyl may be substituted or unsubstituted.
- a sulfinyl may be substituted or unsubstituted.
- a “sulfonyl” group refers to an “SO 2 R” group in which R is the same as defined with respect to sulfenyl.
- a sulfonyl may be substituted or unsubstituted.
- R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
- An O-carboxy may be substituted or unsubstituted.
- a “trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
- a “trihalomethanesulfonamido” group refers to an "X 3 CS(0) 2 RN-” group wherein X is a halogen and R defined with respect to O-carboxy.
- amino refers to a -NH 2 group.
- hydroxy refers to a -OH group.
- a “cyano” group refers to a "-CN” group.
- azido refers to a -N 3 group.
- An “isocyanato” group refers to a "-NCO” group.
- a “thiocyanato” group refers to a "-CNS” group.
- An “isothiocyanato” group refers to an " -NCS” group.
- a “mercapto” group refers to an "-SH” group.
- S-sulfonamido refers to a "-SOiNR A R B " group in which R A and R B are the same as R defined with respect to O-carboxy.
- An S-sulfonamido may be substituted or unsubstituted.
- N-sulfonamido refers to a "R B S0 2 N(R A )-" group in which R A and R B are the same as R defined with respect to O-carboxy.
- a N-sulfonamido may be substituted or unsubstituted.
- An O-carbamyl may be substituted or unsubstituted.
- An N-carbamyl may be substituted or unsubstituted.
- An O-thiocarbamyl may be substituted or unsubstituted.
- An N-thiocarbamyl may be substituted or unsubstituted.
- a C-amido can be substituted or unsubstituted.
- An N-amido can be substituted or unsubstituted.
- R' can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.
- An organylcarbonyl can be substituted or unsubstituted.
- alkoxycarbonyl refers to a group of the formula -
- An organylaminocarbonyl can be substituted or unsubstituted.
- halogen atom means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, i.e., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
- substituents there may be one or more substituents present.
- haloalkyl may include one or more of the same or different halogens.
- Q-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
- nucleoside refers to a compound composed of any pentose or modified pentose moiety attached to a specific portion of a heterocyclic base, tautomer, or derivative thereof such as the 9-position of a purine, 1 -position of a pyrimidine, or an equivalent position of a heterocyclic base derivative. Examples include, but are not limited to, a ribonucleoside comprising a ribose moiety and a deoxyribonucleoside comprising a deoxyribose moiety, and in some instances, the nucleoside is a nucleoside drug analog.
- nucleoside drug analog refers to a compound composed of a nucleoside that has therapeutic activity, such as antiviral, antineoplastic, anti-parasitic and/or antibacterial activity.
- nucleotide refers to a nucleoside having a phosphate ester substituted on the 5' -position or an equivalent position of a nucleoside derivative.
- heterocyclic base refers to a purine, a pyrimidine and derivatives thereof.
- purine refers to a substituted purine, its tautomers and analogs thereof.
- pyrimidine refers to a substituted pyrimidine, its tautomers and analogs thereof.
- purines include, but are not limited to, purine, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine.
- pyrimidines include, but are not limited to, cytosine, thymine, uracil, and derivatives thereof.
- An example of an analog of a purine is l,2,4-triazole-3-carboxamide.
- heterocyclic bases include diaminopurine, 8- oxo-N 6 -methyladenine, 7-deazaxanthine, 7-deazaguanine, N 4 ,N 4 -ethanocytosin, N 6 ,N 6 -ethano-2,6-diaminopurine, 5-methylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases.
- -O-linked amino acid refers to an amino acid that is attached to the indicated moiety via its main-chain carboxyl function group. When the amino acid is attached, the hydrogen that is part of the -OH portion of the carboxyl function group is not present and the amino acid is attached via the remaining oxygen.
- An -O-linked amino acid can be protected at any nitrogen group that is present on the amino acid.
- an -O-linked amino acid can contain an amide or a carbamate group.
- Suitable amino acid protecting groups include, but are not limited to, carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), and tosyl (Ts) groups.
- Cbz carbobenzyloxy
- Moz or MeOZ p-methoxybenzyl carbonyl
- BOC tert-butyloxycarbonyl
- FMOC 9- fluorenylmethyloxycarbonyl
- Bn benzyl
- PMB p-methoxybenzyl
- DMPM 3,4- dimethoxybenzyl
- Ts tosyl
- an -N-linked amino acid can be protected at any hydroxyl or carboxyl group that is present on the amino acid.
- an -N-linked amino acid can contain an ester or an ether group.
- Suitable amino acid protecting groups include, but are not limited to, methyl esters, ethyl esters, propyl esters, benzyl esters, tert-butyl esters, silyl esters, orthoesters, and oxazoline.
- amino acid refers to any amino acid (both standard and non- standard amino acids), including, but limited to, a-amino acids ⁇ -amino acids, ⁇ -amino acids and ⁇ - amino acids.
- suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
- protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons (1999), and in J.F.W.
- protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art.
- a non-limitmg list of protecting groups include benzyl, substituted benzyl; alkylcarbonyls (e g., t-butoxycarbonyl (BOC)); arylalkylcarbonyls (e.g., benzyloxycarbonyl, benzoyl), substituted methyl ether (e.g.
- methoxymethyl ether substituted ethyl ether, a substituted benzyl ether; tetrahydropyranyl ether; silyl ethers (e g , temethylsilyl, tnethylsilyl, tnisopropylsilyl, t-butyldimethylsilyl, or t- butyldiphenylsilyl), esters (e.g. benzoate ester), carbonates (e g.
- methoxymethylcarbonate sulfonates
- acyclic ketal e g dimethyl acetal
- cyclic ketals e.g., 1,3-dioxane or 1,3-dioxolanes
- acyclic acetal cyclic acetal, acyclic hemiacetal, cyclic hemiacetal, and cyclic dithioketals (e.g., 1,3- dithiane or 1,3-dithiolane).
- leaving group refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction hi some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids Examples of suitable leaving groups include, but are not limited to, tosylates and halogens Non-limitmg characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed , Francis Carey (1992), pages 328-331, Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169- 171; and Organic Chemistry, 5 ⁇ ed., John McMurry (2000), pages 398 and 408; all of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.
- prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Examples of prodrugs include compounds that have one or more biologically labile groups attached to the parent drug (e.g., a compound of Formula I and/or a compound of Formula II). For example, one or more biologically labile groups can be attached to a functional group of the parent drug (for example, by attaching one or more biologically labile groups to a phosphate).
- the biologically labile groups can be the same or different.
- the biologically labile group(s) can be linked (for example, through a covalent bond), to an oxygen or a heteroatom, such as a phosphorus of a monophosphate, diphosphate, triphosphate, and/or a stabilized phosphate analog containing carbon, nitrogen or sulfur (referred to hereinafter in the present paragraph as "phosphate").
- phosphate a stabilized phosphate analog containing carbon, nitrogen or sulfur
- the removal of the biologically labile group(s) that forms the prodrug can be accomplished by a variety of methods, including, but not limited to, oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, dephosphorylation, hydration and/or dehydration.
- An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water- solubility is beneficial.
- a further example of a prodrug might comprise a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized or cleaved to reveal the active moiety.
- the prodrug can be a carbonate.
- the carbonate can be a cyclic carbonate.
- the cyclic carbonate can contain a carbonyl group between two hydroxyl groups that results in the formation of a five or six memebered ring.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose of describing procedures and preparation of suitable prodrug derivatives.
- pro-drug ester refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions.
- pro-drug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4- yl)methyl group.
- Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S.
- esters useful as prodrugs for compounds containing carboxyl groups include esters useful as prodrugs for compounds containing carboxyl groups.
- pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- the salt is an acid addition salt of the compound.
- Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like.
- Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
- Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Q-G7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine, lysine, and the like.
- a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Q-G7 alkylamine, cyclohexy
- aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
- the aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et ah, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- purine or pyrimidine base includes, but is not limited to, adenine, N 6 - alkylpurines, N 6 -acylpurines (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6- thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C 5 -alkylpyrimidines, C 5 -benzy
- Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, 2-chloro-2-aminopurine, inosine, and 6- chloropurine.
- Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
- Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, i-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, C to C 4 alkyl or C to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl.
- Aryl groups in the esters optimally comprise a phenyl group.
- Acyl can also include a natural
- nucleoside composition that includes at least 95% to 98%, or more preferably, 99% to 100%, of the designated enantiomer of that nucleoside.
- isolated refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
- the term "host,” as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention.
- the term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including chimpanzees) and humans. Relative to abnormal cellular proliferation, the term “host” refers to unicellular or multicellular organism in which abnormal cellular proliferation can be mimicked.
- the term host specifically refers to cells that abnormally proliferate, either from natural or unnatural causes (for example, from genetic mutation or genetic engineering, respectively), and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as bovine viral diarrhea virus in cattle, hog cholera virus in pigs, and border disease virus in sheep).
- halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
- the compounds of this invention may contain double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
- the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy) may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties.
- halogen includes fluorine, chlorine, bromine, and iodine.
- Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, l,2-tetrahydrothiazin-2-yl, l,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazin-2-yl, 1,3-te
- Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4- triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-di
- (C6-Cio)aryl when used herein refers to phenyl or naphthyl.
- antiviral nucleoside agent refers to antiviral nucleosides that have anti-HIV activity.
- the agents can be active against other viral infections as well, so long as they are active against HIV.
- antiviral thymidine nucleosides refers to thymidine analogues with anti-HIV activity, including but not limited to, AZT (zidovudine) and D4T (2',3'- didehydro-3'deoxythymidine (stravudine), and 1- -D-Dioxolane)thymine (DOT) or their prodrugs.
- antiviral guanine nucleosides refers to guanine analogues with anti-HIV activity, including but not limited to, HBG [9-(4-hydroxybutyl)guanine], lobucavir ([lR(lalpha,2beta,3alpha)]-9-[2,3-bis(hydroxymethyl)cyclobutyl] guanine), abacavir ((l l S',4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1 -methanol sulfate (salt), a prodrug of a G-carbocyclic nucleoside) and additional antiviral guanine nucleosides disclosed in U.S. Patent No. 5,994,321
- antiviral cytosine nucleosides refers to cytosine analogues with anti-HIV activity, including but not limited to, (-)-2',3'-dideoxy-3'-thiacytidine (3TC) and its 5-fluoro analog [(-)-FTC, Emtricitabine], 2',3'-dideoxycytidine (DDC), Racivir, beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (DFC, D-d4FC, RVT, Dexelvucitabine) and its enantiomer L-D4FC, and apricitabine (APC, AVX754, BCH-10618).
- antiviral adenine nucleosides refers to adenine analogues with anti-HIV activity, including, but not limited to 2',3'-dideoxy-adenosine (ddAdo), 2',3'-dideoxyinosine (DDI), 9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-R-2- phosphonomethoxypropyl adenine (PMPA, Tenofovir) (K65R is resistant to PMPA), Tenofovir disoproxil fumarate (9-[(R)-2[[bis[[[isopropoxycarbonyl)oxy]-methoxy]- phosphinyl]methoxy] propyl] adenine fumarate, TDF), bis(isopropyloxymethylcarbonyl)PMPA [bis(poc)PMPA], GS-9148 (Gilead Sciences) as well as those disclosed in Balzarini, J.; De Cler
- AZT is used interchangeably with the term zidovudine throughout.
- abbreviated and common names for other antiviral agents are used interchangeably throughout.
- DAPD ((2R,4R)-2-amino-9-[(2-hydroxymethyl)-I, 3- dioxolan-4-yl] adenine) is also intended to include a related form of DAPD known as APD [(-)-P-D-2-aminopurine dioxolane], as well as all optically active forms of DAPD, including optically active forms and racemic forms and its phosphate prodrugs as well as dioxolane-G and the 6-methoxy or 6-chloro derivatives.
- pharmaceutically acceptable salts refers to pharmaceutically acceptable salts which, upon administration to the recipient, are capable of providing directly or indirectly, a nucleoside antiviral agent, or that exhibit activity themselves.
- prodrug in connection with nucleoside antiviral agents, refers to the 5' and N-acylated, alkylated, or phosphorylated (including mono, di, and triphosphate esters as well as stabilized phosphates and phospholipid) derivatives of nucleoside antiviral agents.
- the acyl group is a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl including phenoxymethyl, aryl including phenyl optionally substituted by halogen, alkyl, alkyl or alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl, or diphenylmethylsilyl.
- Aryl groups in the esters optimally comprise a phenyl group.
- the alkyl group can be straight, branched or cyclic and is preferably C 1-18 .
- resistant virus refers to a virus that exhibits a three, and more typically, five or greater fold increase in EC 50 compared to naive virus in a constant cell line, including, but not limited to peripheral blood mononuclear (PBM) cells, or MT2 or MT4 cells.
- PBM peripheral blood mononuclear
- the term “substantially pure” or “substantially in the form of one optical isomer” refers to a composition that includes at least 95% to 98%, or more, preferably 99% to 100%, of a single enantiomer of the JAK inhibitors described herein, and, optionally, to similar concentrations of a single enantiomer of a nucleoside.
- the JAK inhibitors are administered in substantially pure form.
- JAK inhibitors include those disclosed in U.S. Patent No. 7,598,257, an example of which is Ruxolitinib (Jakafi, Incyte), which has the structure shown below:
- JAK inhibitors also include those disclosed in U.S. Patent Nos. Re 41,783; 7,842,699; 7,803,805; 7,687,507; 7,601,727; 7,569,569; 7,192,963; 7,091,208; 6,890,929, 6,696,567; 6,962,993; 6,635,762; 6,627,754; and 6,610,847, an example of which is Tofacitinib, which has the structure shown below:
- Tofacitinib (Pfizer), and which has the chemical name 3- ⁇ (3R,4R)-4 methyl-3- [methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-l-yl ⁇ -3-oxo- propionitrile.
- the compounds have the formula:
- R 1 is a group of the formula
- y is 0, 1 or 2;
- R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (Q- C 6 )alkylsulfonyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((Q- C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino; or R 4 is (C3-C 1 o)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium,
- R 5 is (C 2 -Cc))heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy, halo, (C 1 -C 6 )acyl, (C 1 -C 6 )alkylamino, amino(C 1 -C 6 )alkyl, (Q- C 6 )alkoxy-CO-NH, (C 1 -C 6 )alkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C
- Z is carbonyl, C(0)0-, C(0)NR- or S(0) composition wherein n is 0, 1 or 2;
- R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 6 )acyloxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )alkylamino, ((Q- C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, nitro, nitro(C 1 -C 6 )alkyl or (C 1 -C 6 )acylamino;
- R is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C - C 6 )alkyl, trifluoromethyl(C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy, halo, (Ci-C 6 )acyl, (C C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-CO— NH, (C 1 -C 6 )alkylamino-CO--, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, hydroxy(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy(Ci-C 6 )alkyl, (Ci-C 6
- R" and R J are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, trifluoromethyl, trifluoromethoxy, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (C 3 - C 1 o)cycloalkyl wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino (C - C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C 5 -C 9 )heteroaryl, (C 2 -
- R and R are each independently (C 3 -C 1 o)cycloalkyl, (C 3 -C 1 o)cycloalkoxy, (C 1 -C 6 )alkylamino, ((Cr C 6 )alkyl) 2 amino, (C 6 -C 10 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -C 10 )arylthio, (Q- C 6 )alkylsulfinyl, (C 6 -C 1 o)arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 1 o)arylsulfonyl, (C - C 6 )acyl, (C 1 -C 6 )alkoxy-CO-NH-,
- the JAK inhibitors also include compounds of Formula B:
- a 1 and A 2" are independently selected from C and N;
- T, U, and V are independently selected from O, S, N, CR 5 , and NR 6 ; wherein the 5-membered ring formed by A 1 , A 2 , U, T, and V is aromatic;
- X is N or CR 4 ;
- Y is Ci-g alkylene, C 2 -8 alkenylene, C 2 _g alkynylene, (CR R ) p — (C3- 10 cycloalkylene)-(CR u R 12 ) q , (CR 11 R 12 ) p -(arylene)-(CR 11 R 12 ) q ,
- n 1;
- W is Ci_8 alkylenyl, C 2 _ 8 alkenylenyl, C 2 _ 8 alkynylenyl, O, S, C(O), C(0)NR c' , C(0)0, OC(O), OC(0)NR c' , NR C' , NR c C(0)NR d' , S(O), S(0)NR c' , S(0) 2 , or S(0)2NR C' ;
- Q is H, halo, CN, N0 2 , C 1-8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, Ci- 8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, C 1-8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, Ci_ 4 hydroxyalkyl, Ci_ 4 cyanoalkyl, Cy 2 , CN, N0 2 , OR a' , SR a
- Cy 1 and Cy 2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, CN, N0 2 , OR a" , SR a" , C(0)R b “, C(0)NR c , R d" , C(0)OR a" , OC(0)R b" , OC(0)N R c 'R d , NR c 'R d , NR c , C(0)R b" , NR c" C(0)OR a" , NR c" S(0)R b" , NR c" S(0) 2 R b"
- R 1 , R 2 , R 3 , and R 4 are independently selected from H, halo, C 1-4 alkyl, C 2 ⁇ alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N0 2 , OR 7 , SR 7 , C(0)R 8 , C ⁇ NR O, C(0)OR 7 OC(0)R 8 , OC(0)NR 9 R 10 , NR 9 R 10 , NR 9 C(0)R 8 , NR c C(0)OR 7 , S(0)R 8 , S(0)NR 9 R 10 , S(0) 2 R 8 , NR 9 S(0) 2 R 8 , and S(0) 2 NR 9 R 10 ;
- R 5 is H, halo, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CN, N0 2 , OR 7 , SR 7 , C(0)R 8 , C(0)NR 9 R 10 , C(0)OR 7 , OC(0)R 8 , OC(0)NR 9 R 10 , NR 9 R 10 , NR 9 C(0)R 8 , NR 9 C(0)OR 7 , S(0)R 8 , S(0)NR 9 R 10 , S(0) 2 R 8 , NR 9 S(0) 2 R 8 , or S(0) 2 NR 9 R 10 ;
- R 6 is H, CM alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CM haloalkyl, OR 7 , C(0)R 8 , C(0)NR 9 R 10 , C(0)OR 7 , S(0)R 8 , S(0)NR 9 R 10 , S(0) 2 R 8 , or S(0) 2 NR 9 R 10 ;
- R is H, Ci- 6 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
- R is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
- R 9 and R 10 are independently selected from H, C 1-10 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 1-6 alkylcarbonyl, arylcarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
- R 9 and R 10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group
- R 11 and R 12 are independently selected from H and -E 1 -E 2 -E 3 -E 4 ;
- D 1 and E 1 are independently absent or independently selected from C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N0 2 , N 3 , SCN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2 _ 8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2 _ 8 dialkylamino; 2 2 2
- D J and E J are independently absent or independently selected from Ci_6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the Ci_6 alkylene, C 2 _ 6 alkenylene, C 2 _ 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N0 2 , N 3 , SCN, OH, Ci-6 alkyl, Ci_ 6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, Ci_6 alkylamino, and C 2 _g dialkylamino;
- R a is H, Cy 1 , -(Ci_6 Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2 _6 alkenyl, or C 2 _6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, C ⁇ haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R b is H, Cy 1 , -(Ci_6 Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, wherein said Ci_6 alkyl, Ci-6i-6 haloalkyl, C 2 _ 6 alkenyl, or C 2 _ 6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R a ' and R a " are independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Ci_6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, halosulf
- R b' and R b" are independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Ci_6 alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6
- R c and R d are independently selected from H, Cy 1 ,—(Ci-6 alky ⁇ -Cy 1 , C ⁇ o alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, wherein said C O alkyl, Ci_6 haloalkyl, C 2 _ 6 alkenyl, or C 2 _ 6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 ,—(Ci-6 alky ⁇ -Cy 1 , OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, and halosulfanyl;
- R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 ,—(Ci-6 alky ⁇ -Cy 1 , OH, CN, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, and halosulfanyl;
- and R dl are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2 -6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-10 alkyl, Ci-6 haloalkyl, C 2 _ 6 alkeny
- and R dl together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R c " and R d " are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, halosulf
- R c " and R d " together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
- R 1 is H, CN, N0 2 , or C 1-6 alkyl
- R e and R f are independently selected from H and C 1-6 alkyl
- R 1 is H, CN, or N0 2 ;
- n 0 or 1
- n 0 or 1 ;
- p 0, 1, 2, 3, 4, 5, or 6;
- s is 0 or 1.
- Additional JAK inhibitors include CEP-701 (Lestaurtinib, Cephalon Technology), a JAK 2 FL3 kinase, AZD1480 (Astra Zeneca), a JAK 2 inhibitor, LY3009104/INCB28050 (Eli Lilly, Incyte), a JAK 1/2 inhibitor, Pacritinib/SB1518 (S*BIO), a JAK 2 inhibitor, VX-509 (Vertex), a JAK 3 inhibitor, GLPG0634 (Galapagos), a JAK 1 inhibitor, INC424 (Novartis), a JAK inhibitor, R-348 ( Rigel), a JAK 3 inhibitor, CYT387 (YM Bioscience), a JAKl/2 inhibitor, TG 10138, a JAK 2 inhibitor, AEG 3482 (Axon), a JAK inhibitor, and pharmaceutically-acceptable salts and rodrugs thereof.
- AEG 3482 has the following formula:
- TG 10138 has the following formula:
- CYT387 has the following formula: LY3009104 is believed to be (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl-3-cyclopentyl-propanenitrile
- the compounds include those described in U.S. Publication Nos. 20110020469; 20110118255; 20100311743; 20100310675; 20100280026; 20100160287; 20100081657; 20100081645; 20090181938; 20080032963; 20070259869; and 20070249031.
- the compounds also include those described in U.S. Publication Nos.
- the compounds also include those described in U.S. Publication Nos.
- the compounds also include those described in U.S. Publication Nos. 20110245256; 20100009978; 20090098137; and 20080261973.
- the compounds also include those described in U.S. Publication No. 20110092499.
- Representative compounds include:
- N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine 8.
- 2- (4- morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxylate 9.
- N-(4- morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine 10. 7-(4-amino-3- methoxyphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin— 2-amine 11.
- R348 (Rigel) is defined in Velotta et al., "A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection,” Transplantation. 2009 Mar 15;87(5):653-9.
- the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of Formulas A and B, as well as the additional JAK inhibitors described herein.
- the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate [i.e., l,l'-methylene-bis-(2-hydroxy-3- naph
- the invention also relates to base addition salts of Formulas A and B.
- the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of Formulas A and B that are acidic in nature are those that form non-toxic base salts with such compounds.
- Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
- the compounds of this invention include all conformational isomers (e.g., cis and trans isomers.
- the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
- This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z configurations.
- the compounds of Formulas A and B can also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
- This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the Formulas A and B, and their use in treating or preventing HIV.
- This invention also encompasses methods of treating or preventing viral infections that can be treated or prevented by protein kinase inhibitors, such as the enzyme Janus Kinase 1, 2, or 3, comprising administering prodrugs of compounds of the Formulas A and B.
- protein kinase inhibitors such as the enzyme Janus Kinase 1, 2, or 3
- Compounds of Formulas A and B having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
- Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of Formulas A and B.
- the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methioine sulfone.
- Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of Formulas A and B through the carbonyl carbon prodrug sidechain.
- compositions include antiretroviral JAK inhibitors as described herein and one or more additional antiviral agents.
- the JAK inhibitors and additional antiviral agents are administered in combination or alternation, and in one aspect, in a manner in which both agents act synergistically against the virus.
- the compositions and methods described herein can be used to treat patients infected with a drug resistant form of HIV, specifically, a form including the M184V/I, multidrug resistant viruses (e.g., Q151M), K65R mutation, Thymidine analog mutations (TAMS), and the like.
- TAMS include, but are not limited to, mutations at reverse transcriptase (RT) positions 41, 67, 70, 210, 215, and 219, which confer clinically significant resistance to each of the nucleoside RT inhibitors with the exception of 3TC.
- the JAK inhibitors described herein function in a way not associated with heretofore known antiretroviral therapy, in that the compounds do not act in the same way as NRTI, NNRTI, protease inhibitors, integrase inhibitors, entry inhibitors, and the like, all of which interfere directly with a step in the viral replication cycle. Rather, they act in an intracellular manner, in a way that is not likely to provoke resistance. More specifically, the mechanism is independent and distinct from direct modulation or interference with the viral replication cycle itself, and therefore lacks a selective pressure to confer emergence of drug resistant virus.
- the combination of the JAK inhibitors described herein, and one or more additional antiviral agents can help prevent the development of viral resistance to other antiviral agents. Therefore, co-formulation of the JAK inhibitors with these additional antiviral agents can function as a "resistance repellent" for the various mutations associated with conventional therapy, and provides better therapy than either alone.
- a combination therapy is administered that has the capability of attacking HIV in a variety of mechanisms. That is, the combination therapy includes an effective amount of at least one adenine, cytosine, thymine, and guanosine nucleoside antiviral, as well as one or more additional agents other than NRTI that inhibit HIV viral loads via a different mechanism.
- Examples include reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, polymerase inhibitors, and integrase inhibitors such as integrase inhibitors such as raltegravir (Isentress) or MK-0518, GS-9137 (Gilead Sciences), GS-8374 (Gilead Sciences), or GSK-364735.
- integrase inhibitors such as raltegravir (Isentress) or MK-0518, GS-9137 (Gilead Sciences), GS-8374 (Gilead Sciences), or GSK-364735.
- this therapy particularly when administered at an early stage in the development of HIV infection, has the possibility of eliminating HIV infection in a patient. That is, the presence of the different nucleosides and additional agents minimizes the ability of the virus to adapt its reverse transcriptase and develop resistance to any class of nucleoside antiviral nucleosides (i.e., adenine, cytosine, thymidine, or guanine), because it would be susceptible to at least one of the other nucleoside antiviral agents that are present, and/or the additional non-NRTI therapeutic agent. In addition the lipophilic character of certain agents would allow them to penetrate certain compartments where virus could replicate (e.g., brain, testicles, gut).
- nucleoside antiviral nucleosides i.e., adenine, cytosine, thymidine, or guanine
- the lipophilic character of certain agents would allow them to penetrate certain compartments where virus could replicate (e.g., brain, testicles, gut
- Attachment and fusion inhibitors are anti-HIV drugs which are intended to protect cells from infection by HIV by preventing the virus from attaching to a new cell and breaking through the cell membrane. These drugs can prevent infection of a cell by either free virus (in the blood) or by contact with an infected cell. These agents are susceptible to digestive acids, so are commonly delivered by break them down, most of these drugs are given by injections or intravenous infusion.
- Additional fusion and attachment inhibitors in human trials include AK602, AMD070, BMS-378806, HGS004, INCB9471, PRO 140, Schering C, SP01A, and TAK-652.
- AK602 is a CCR5 blocker being developed by Kumamoto University in
- AMD070 by AnorMed blocks the CXCR4 receptor on CD4 T-cells to inhibit HIV fusion.
- BMS-378806 is an attachment inhibitor that attaches to gpl20, a part of HIV.
- HGS004 by Human Genome Sciences is a monoclonal antibody CCR5 blocker.
- INCB 9471 is sold by Incyte Corporation.
- PRO 140 by Progenies blocks fusion by binding to a receptor protein on the surface of CD4 cells.
- SP01A by Samaritan Pharmaceuticals is an HIV entry inhibitor.
- TAK-652 by Takeda blocks binding to the CCR5 receptor.
- RT reverse transcriptase
- NRTIs chain terminating nucleoside analogs
- NRTIs allosteric non-nucleoside RT inhibitors
- the third class includes pyrophosphate mimetics such as foscarnet (phosphonoformic acid, PFA).
- the reverse transcriptase has a second enzymatic activity, ribonuclease H (RNase H) activity, which maps to a second active site in the enzyme.
- RNase H activity can be inhibited by various small molecules (polymerase inhibitors). Examples include diketo acids, which bind directly to the RNase H domain, or compounds like PFA, which are believed to bind in the polymerase domain.
- NRTIs Transcriptase Inhibitors
- NRTIs Transcriptase Inhibitors
- Integrase Inhibitors include globoidnan A, L-000870812,
- PK pharmacokinetic
- ritonavir or Gilead' s pharmacoenhancing agent also referred to as a PK booster
- Suitable integrase inhibitors include those described in:
- Additional integrase inhibitors include L-870,810 (Merck), INH-001 (Inhibitex), L870810 (Merck), PL-2500, composed of pryidoxal 1-5-phosphate derivatives (Procyon) monophores (Sunesis), V-165 (Rega Institute, Belgium), Mycelium integrasone (a fungal polyketide, Merck), GS 9224 (Gilead Sciences), AVX-I (Avexa), ITI-367, an oxadiazol pre-integrase inhibitor ⁇ George Washington University), GSK364735 ⁇ GSK/Shionogi), GS-9160 (GSK), S-1360 (Shionogi- GlaxoSmithKline Pharmaceuticals LLC), RSC 1838 (GSK/Shionogi), GS-9137 (taken alone or with Norvir) (Gilead), MK-2048 (Merck), S/GSK 1349572 and S/GSK 1265744 (no
- integrase inhibitors are peptides, including those disclosed in Divita et al., Antiviral Research, Volume 71, Issues 2-3, September 2006, Pages 260-267.
- integrase inhibitor that can be used in the methods of treatment described herein include 118-D-24, which is disclosed, for example, in Vatakis, Journal of Virology, April 2009, p. 3374-3378, Vol. 83, No. 7.
- integrase inhibitors include those described in McKeel et al., "Dynamic Modulation of HIV-1 Integrase Structure and Function by Cellular LEDGF Protein, JBC Papers in Press. Published on September 18, 2008 as Manuscript M805843200.
- DCQAs dicaffeoylquinic acids
- nucleoside compounds active as integrase inhibitors including those disclosed in Mazumder, A., N. Neamati, J. P. Sommadossi, G. Gosselin, R. F. Schinazi, J. L. Imbach, and Y. Pommier. 1996. Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase. Mol. Pharmacol. 49:621-628.
- Protease inhibitors treat or prevent HIV infection by preventing viral replication. They act by inhibiting the activity of HIV protease, an enzyme that cleaves nascent proteins for final assembly of new virons. Examples are shown in the table that follows. HIV Therapies: Protease Inhibitors (Pis)
- alternation therapy an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents is administered together.
- one or more first agents can be administered in an effective amount for an effective time period to treat the viral infection, and then one or more second agents substituted for those first agents in the therapy routine and likewise given in an effective amount for an effective time period.
- the dosages will depend on such factors as absorption, biodistribution, metabolism and excretion rates for each drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
- suitable dosage ranges for anti-HIV compounds including the JAK inhibitors described herein, can be found in the scientific literature and in the Physicians Desk Reference. Many examples of suitable dosage ranges for other compounds described herein are also found in public literature or can be identified using known procedures. These dosage ranges can be modified as desired to achieve a desired result.
- JAK inhibitors described herein are also inhibitors of CYP3A4, which means that they will significantly increase the C max plasma level of any anti-HIV drug that binds to CYP3A4, including HIV-1 protease inhibitors. This information can be taken into consideration when determining suitable dosages for such compounds.
- Nonlimiting examples of additional agents include:
- HCV Protease inhibitors examples include Medivir HCV Protease Inhibitor (HCV-PI or TMC435) (Medivir/Tibotec); MK-7009 (Merck), RG7227 (ITMN-191) (Roche/Pharmasset/InterMune), boceprevir (SCH 503034) (Schering), SCH 446211 (Schering), narlaprevir SCH900518 (Schering/Merck), ABT-450 (Abbott/Enanta), ACH- 1625 (Achillion), BI 201335 (Boehringer Ingelheim), PHX1766 (Phenomix), VX-500 (Vertex) and telaprevir (VX-950) (Vertex).
- HCV-PI or TMC435 Medivir HCV Protease Inhibitor
- MK-7009 Merck
- RG7227 ITMN-191
- boceprevir SCH 503034
- SCH 446211 Schering
- protease inhibitors include substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al, Antiviral Chemistry and Chemotherapy 1999, 10, 259- 273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub.
- SCH 351633 isolated from the fungus Penicillium griseofulvum, was identified as a protease inhibitor (Chu M., et al., Bioorganic and Medicinal Chemistry Letters 9 : 1949- 1952).
- Eglin c isolated from leech, is a potent inhibitor of several serine proteases such as S. griseus proteases A and B, a-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36: 1598-1607, 1997.
- U.S. patents disclosing protease inhibitors for the treatment of HCV include, for example, U.S. Patent No. 6,004,933 to Spruce et al., which discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2; U.S. Patent No. 5,990,276 to Zhang et al., which discloses synthetic inhibitors of hepatitis C virus NS3 protease; U.S. Patent No. 5,538,865 to Reyes et a; WO 02/008251 to Corvas International, Inc, and US7, 169,760, US2005/176648, WO 02/08187 and WO 02/008256 to Schering Corporation.
- HCV inhibitor tripeptides are disclosed in U.S. Patent Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol Myers Squibb.
- Diaryl peptides as NS3 serine protease inhibitors of HCV are disclosed in WO 02/48172 and US 6,911,428 to Schering Corporation.
- Imidazoleidinones as NS3 serine protease inhibitors of HCV are disclosed in WO 02/08198 and US 6,838,475 to Schering Corporation and WO 02/48157 and US 6,727,366 to Bristol Myers Squibb.
- HCV serine protease inhibitors are provided in US 6,872,805 (Bristol-Myers Squibb); WO 2006000085 (Boehringer Ingelheim); US 7,208,600 (Vertex); US 2006/0046956 (Schering-Plough); WO 2007/001406 (Chiron); US 2005/0153877; WO 2006/119061 (Merck); WO 00/09543 (Boehringer Ingelheim), US 6,323,180 (Boehringer Ingelheim) WO 03/064456 (Boehringer Ingelheim), US 6,642,204(Boehringer Ingelheim), WO 03/064416 (Boehringer Ingelheim), US 7,091,184 (Boehringer Ingelheim), WO 03/053349 (Bristol-
- Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al, Antiviral Research, 1996, 32, 9-18), especially compound RD- 1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;
- HCV polymerase inhibitors including nucleoside and non-nucleoside polymerase inhibors, such as ribavirin, viramidine, clemizole, filibuvir (PF- 00868554), HCV POL, NM-283 (valopicitabine), MK-0608, 7-Fluoro-MK-0608, MK-3281, IDX-375, ABT-072, ABT- 333, ANA598, BI 207127, GS 9190, PSI-6130, R1626, PSI-6206, PSI-35938, PSI-7851, PSI-7977, RG1479, RG7128, HCV-796 VCH-759 or VCH-916, and salts and prodrugs thereof.
- nucleoside and non-nucleoside polymerase inhibors such as ribavirin, viramidine, clemizole, filibuvir (PF- 00868554), HCV P
- Interfering RNA (iRNA) based antivirals including short interfering RNA (siRNA) based antivirals, such as Sirna-034 and others described in International Patent Publication Nos. WO/03/070750 and WO 2005/012525, and U.S. Patent Publication No. US 2004/0209831.
- iRNA Interfering RNA
- siRNA short interfering RNA
- S-ODN Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 1 ⁇ '-717), or nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al, Archives of Virology, 1997, 142, 589-599; Galderisi U. et al, Journal of Cellular Physiology, 1999, 181, 251-257);
- Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP-08268890; Kai Y. et al, Prevention and treatment of viral diseases, Japanese Patent Pub. JP- 10101591);
- HCV entry inhibitors such as celgosivir (MK-3253) (MIGENIX Inc.), SP-30 (Samaritan Pharmaceuticals), ITX4520 (iTherX), ITX5061 (iTherX), PRO-206 (Progenies Pharmaceuticals) and other entry inhibitors by Progenies Pharmaceuticals, e.g., as disclosed in U.S. Patent Publication No. 2006/0198855.
- Ribozymes such as nuclease-resistant ribozymes (Maccjak, D. J. et al,
- Nucleoside analogs have also been developed for the treatment of Flaviviridae infections.
- the compounds provided herein can be administered in combination with any of the compounds described by Idenix Pharmaceuticals in International Publication Nos. WO 01/90121, WO 01/92282, WO 2004/003000, 2004/002422, WO 2004/002999, WO 10/014134 and WO 11/123586.
- WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001), WO 02/48165, WO 05/003147; US 2005/0009737; US 2005/0009737; 7,094,770, 6,927,291, WO 08/12163434, WO 10/077554, WO 09/152095, WO 10/075549, and WO 10/135569 by Pharmasset, Ltd.
- miscellaneous compounds that can be used as second agents include 1- amino-alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Pat. No.
- one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus interferon, such as Intron A ® (interferon alfa-2b) and Pegasys ® (Peginterferon alfa-2a); Roferon A ® (Recombinant interferon alfa-2a), Infergen ® (consensus interferon; interferon alfacon-1), PEG-Intron ® (pegylated interferon alfa-2b) and Pegasys ® (pegylated interferon alfa-2a), optionally in further combination with ribavirin.
- an anti-hepatitis C virus interferon such as Intron A ® (interferon alfa-2b) and Pegasys ® (Peginterferon alfa-2a); Roferon A ® (Recombinant interferon alfa-2a), Infergen ® (consensus interferon; interferon al
- the anti-hepatitis C virus interferon is infergen, IL-29 (PEG- Interferon lambda), R7025 (Maxy- alpha), Belerofon, Oral Interferon alpha, BLX-883 (Locteron), omega interferon, multiferon, medusa interferon, Albuferon or REBIF ® .
- one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus polymerase inhibitor, such as ribavirin, viramidine, HCV POL, NM-283 (valopicitabine), PSI- 7977, PSI-938, MK-0608, 7-Fluoro-MK-0608, PSI-6130, R1626, IDX-184, INX-189, PSI-6206, PSI-35938, R1479, HCV-796 or R7128.
- an anti-hepatitis C virus polymerase inhibitor such as ribavirin, viramidine, HCV POL, NM-283 (valopicitabine), PSI- 7977, PSI-938, MK-0608, 7-Fluoro-MK-0608, PSI-6130, R1626, IDX-184, INX-189, PSI-6206, PSI-35938, R1479, HCV-796 or R7128.
- one or more compounds provided herein can be administered in combination or alternation with an anti-HCVprotease inhibitor such as ITMN- 191, SCH 503034, VX950 (telaprevir), GNS-227, or Medivir HCV Protease Inhibitor.
- an anti-HCV vaccine such as TG4040, PeviPROTM, CGI-5005, HCV/MF59, GV1001, IC41 or INNO0101 (El).
- one or more compounds provided herein can be administered in combination or alternation with an anti-HCV monoclonal antibody, such as AB68 or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus polyclonal antibody, such as cicavir.
- an anti-HCV monoclonal antibody such as AB68 or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus polyclonal antibody, such as cicavir.
- one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus immunomodulator, such as Zadaxin ® (thymalfasin), NOV-205 or Oglufanide.
- an anti-hepatitis C virus immunomodulator such as Zadaxin ® (thymalfasin), NOV-205 or Oglufanide.
- one or more compounds provided herein can be administered in combination or alternation with Nexavar, doxorubicin, PI-88, amantadine, JBK-122, VGX- 4 IOC, MX-3253 (Ceglosivir), Suvus (BIVN-401 or virostat), PF-03491390 (formerly IDN- 6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI- 4065, Bavituxinab (Tarvacin), Alinia (nitraz
- the 5'- hydroxyl moiety in the nucleosides described herein, and hydroxy groups on the JAK inhibitors described herein, can be modified to be in prodrug form.
- V 1 is O or S
- R 1 and R 10 can combine to form a cyclic phosphate of the formula:
- R is selected from N-linked amino acid ester, OR a or OR , wherein
- R 20 is substituted aryl with 1-3 substituents, or substituted heteroaryl with 1-2 substituents, wherein each substituent is independently selected from R al and R dl .
- R 1 and R 10 can combine to form a cyclic phosphate of the formula: where R is selected from N-linked amino acid ester, OR a or OR , wherein
- R 20 is substituted aryl with 1-3 substituents, or substituted heteroaryl with 1-2 substituents, wherein each substituent is independently selected from R al and R dl , each R 12 and R 13 are, independently, -C ⁇ N or an optionally substituted substituent selected from Ci_8 organylcarbonyl, Ci_8 alkoxycarbonyl and Ci_8 organylaminocarbonyl; each R 14 is hydrogen or an optionally substituted C ⁇ alkyl; each m is independently 1 or 2, and if both R 10 and R 11 are
- each m can be the same or different.
- R al , R bl , R cl , and R dl are each independently selected from hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl and an optionally substituted heteroaryl- (Ci_6 alkyl).
- R 1 is a mono-phosphate, di-phosphate, tri-phosphate, or phosphate prodrug.
- Humans suffering from effects caused by any of the diseases described herein, and in particular, HIV infection can be treated by administering to the patient an effective amount of the compositions described above, in the presence of a pharmaceutically acceptable carrier or diluent, for any of the indications or modes of administration as described in detail herein.
- the active materials can be administered by any appropriate route, for example, orally, parenterally, enterally, intravenously, intradermally, subcutaneously, transdermally, intranasally or topically, in liquid or solid form.
- the active compounds are included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of compound to inhibit viral propagation in vivo, especially HIV propagation, without causing serious toxic effects in the treated patient. While not wishing to be bound to a particular theory, it is believed that the JAK inhibitors render the cellular milieu non-supportive of productive replication.
- inhibitor amount is meant an amount of active ingredient sufficient to exert an inhibitory effect as measured by, for example, an assay such as the ones described herein.
- a preferred dose of the compound for all the above-mentioned conditions will be in the range from about 1 to 75 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day.
- the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent nucleoside or other agent to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
- the compounds are conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 3,000 mg, preferably 70 to 1,400 mg of active ingredient per unit dosage form.
- An oral dosage of 50 to 1,000 mg is usually convenient.
- the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.02 to 70 micromolar, preferably about 0.5 to 10 micromolar. This may be achieved, for example, by the intravenous injection of a 0.1 to 25% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
- the concentration of active compound in the drug composition will depend on absorption, distribution, metabolism and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
- the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible bind agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
- a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
- the compounds or their pharmaceutically acceptable derivative or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories, protease inhibitors, or other nucleoside or non- nucleoside antiviral agents, as discussed in more detail above.
- Solutions or suspensions used for parental, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- preferred carriers are physiological saline or phosphate buffered saline (PBS).
- Liposomal suspensions are also preferred as pharmaceutically acceptable carriers, these may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
- liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
- appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
- aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container.
- the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
- the composition is a co-formulated pill, tablet, or other oral drug delivery vehicle including one or more of the JAK inhibitors described herein, and optionally including one or more additional antiviral agents.
- the JAK inhibitors described herein are co-formulated with ATRIPLA® (efavirenz 600 mg/emtricitabine [(-)-FTC] 200 mg/tenofovir disoproxil fumarate 300 mg), and, optionally, with a thymidine nRTI such as AZT and a guanine nRTI (or a compound such as DAPD which is deaminated in vivo to form a guanine nRTI, in this case, DXG).
- ATRIPLA® efavirenz 600 mg/emtricitabine [(-)-FTC] 200 mg/tenofovir disoproxil fumarate 300 mg
- a thymidine nRTI such as AZT
- a guanine nRTI or a compound such as DAPD which is deaminated in vivo to form a guanine nRTI, in this case, DXG
- efavirenz is an NNRTI
- tenofovir is an adenine nRTI
- (-)-FTC is a cytosine nRTI
- AZT is a thymidine nRTI
- DAPD is deaminated in vivo to form DXG (a guanine NRTI)
- the combination of the coformulated compounds will provide, in addition to the JAK inhibitors, all four bases (ACTG) plus an additional agent capable of interacting with HIV in a different mechanism.
- biodegradable polymers have developed rapidly since the synthesis and biodegradability of polylactic acid was reported by Kulkarni et al., in 1966 ("Polylactic acid for surgical implants," Arch. Surg., 93:839).
- polymers which have been reported as useful as a matrix material for delivery devices include polyanhydrides, polyesters such as polyglycolides and polylactide-co- glycolides, polyamino acids such as polylysine, polymers and copolymers of polyethylene oxide, acrylic terminated polyethylene oxide, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes. See, for example, U.S. Pat. Nos.
- Degradable materials of biological origin are well known, for example, crosslinked gelatin.
- Hyaluronic acid has been crosslinked and used as a degradable swelling polymer for biomedical applications (U.S. Pat. No. 4,957,744 to Delia Valle et. al.; (1991) "Surface modification of polymeric biomaterials for reduced thrombogenicity," Polym. Mater. Sci. Eng., 62:731 735]).
- Dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds.
- Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions.
- Suspensions are defined as solid particles ranging in size from a few manometers up to hundreds of microns, dispersed in a liquid medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.
- Emulsions are defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids.
- Emulsion formulations include water in oil and oil in water emulsions, multiple emulsions, microemulsions, microdroplets, and liposomes.
- Microdroplets are unilamellar phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, as defined in U.S. Pat. Nos. 4,622,219 and 4,725,442 issued to Haynes.
- Liposomes are phospholipid vesicles prepared by mixing water-insoluble polar lipids with an aqueous solution. The unfavorable entropy caused by mixing the insoluble lipid in the water produces a highly ordered assembly of concentric closed membranes of phospholipid with entrapped aqueous solution.
- U.S. Pat. No. 4,938,763 to Dunn, et al. discloses a method for forming an implant in situ by dissolving a nonreactive, water insoluble thermoplastic polymer in a biocompatible, water soluble solvent to form a liquid, placing the liquid within the body, and allowing the solvent to dissipate to produce a solid implant.
- the polymer solution can be placed in the body via syringe.
- the implant can assume the shape of its surrounding cavity.
- the implant is formed from reactive, liquid oligomeric polymers which contain no solvent and which cure in place to form solids, usually with the addition of a curing catalyst.
- U.S. Pat. No. 5,749,847 discloses a method for the delivery of nucleotides into organisms by electrophoration.
- U.S. Pat. No. 5,718,921 discloses microspheres comprising polymer and drug dispersed there within.
- U.S. Pat. No. 5,629,009 discloses a delivery system for the controlled release of bioactive factors.
- U.S. Pat. No, 5,578,325 discloses nanoparticles and microparticles of nonlinear hydrophilic hydrophobic multiblock copolymers.
- U.S. Pat. No. 5,545,409 discloses a delivery system for the controlled release of bioactive factors.
- U.S. Pat. No. 5,494,682 discloses ionically cross-linked polymeric microcapsules.
- U.S. Pat. No. 5,728,402 to Andrx Pharmaceuticals, Inc. describes a controlled release formulation that includes an internal phase which comprises the active drug, its salt or prodrug, in admixture with a hydro gel forming agent, and an external phase which comprises a coating which resists dissolution in the stomach.
- U.S. Pat. Nos. 5,736,159 and 5,558,879 to Andrx Pharmaceuticals, Inc. discloses a controlled release formulation for drugs with little water solubility in which a passageway is formed in situ.
- U.S. Pat. No. 5,567,441 to Andrx Pharmaceuticals, Inc. discloses a once-a-day controlled release formulation.
- U.S. Pat. No. 5,472,708 discloses a pulsatile particle based drug delivery system.
- U.S. Pat. No. 5,458,888 describes a controlled release tablet formulation which can be made using a blend having an internal drug containing phase and an external phase which comprises a polyethylene glycol polymer which has a weight average molecular weight of from 3,000 to 10,000.
- U.S. Pat. No. 5,419,917 discloses methods for the modification of the rate of release of a drug form a hydrogel which is based on the use of an effective amount of a pharmaceutically acceptable ionizable compound that is capable of providing a substantially zero-order release rate of drug from the hydrogel.
- U.S. Pat. No. 5,458,888 discloses a controlled release tablet formulation.
- U.S. Pat. No. 5,641,745 to Elan Corporation pic discloses a controlled release pharmaceutical formulation which comprises the active drug in a biodegradable polymer to form microspheres or nanospheres.
- the biodegradable polymer is suitably poly-D,L-lactide or a blend of poly-D,L-lactide and poly-D,L-lactide-co-glycolide.
- U.S. Pat. No. 5,641,515 discloses a controlled release formulation based on biodegradable nanoparticles.
- U.S. Pat. No. 5,637,320 discloses a controlled absorption formulation for once a day administration.
- U.S. Pat. Nos. 5,580,580 and 5,540,938 are directed to formulations and their use in the treatment of neurological diseases.
- U.S. Pat. No. 5,533,995 is directed to a passive transdermal device with controlled drug delivery.
- U.S. Pat. No. 5,505,962 describes a controlled release pharmaceutical formulation.
- JAK inhibitors as well as the nucleosides or other compounds which are described herein for use in combination or alternation therapy with the JAK inhibitors or their related compounds, can be administered as an acylated prodrug or a nucleotide prodrug, as described in detail below.
- any of the JAK inhibitors, nucleosides, or other compounds described herein that contain a hydroxyl or amine function can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
- a number of nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the hydroxyl group of the compound or of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide.
- substituent groups that can replace one or more hydrogens on the phosphate moiety or hydroxyl are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1 17. Any of these can be used in combination with the disclosed nucleosides or other compounds to achieve a desire effect.
- the active nucleoside or other hydroxyl containing compound can also be provided as an ether lipid (and particularly a 5'-ether lipid for a nucleoside), as disclosed in the following references, Kucera, L. S., N. Iyer, E. Leake, A. Raben, Modest E. K., D. L. W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.” AIDS Res. Hum. Retroviruses. 6:491 501; Piantadosi, C, J. Marasco C. J., S. L. Morris-Natschke, K. L. Meyer, F. Gumus, J. R. Surles, K. S.
- Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside or other hydroxyl or amine containing compound, preferably at the 5'-OH position of the nucleoside or lipophilic preparations include U.S. Pat. No. 5,149,794 (Sep. 22, 1992, Yatvin et al.); U.S. Pat. No. 5,194,654 (Mar. 16, 1993, Hostetler et al., U.S. Pat. No. 5,223,263 (Jun. 29, 1993, Hostetler et al.); U.S. Pat. No. 5,256,641 (Oct. 26, 1993, Yatvin et al.); U.S. Pat.
- nucleotide prodrugs are described in the following references: Ho, D. H. W. (1973) "Distribution of Kinase and deaminase of ⁇ -D- arabinofuranosylcytosine in tissues of man and muse.” Cancer Res. 33, 2816 2820; Holy, A. (1993) Isopolar phosphorous-modified nucleotide analogues," In: De Clercq (Ed.), Advances in Antiviral Drug Design, Vol. I, JAI Press, pp. 179 231; Hong, C. I., Nechaev, A., and West, C. R.
- Alkyl hydrogen phosphate derivatives of the anti-HIV agent AZT may be less toxic than the parent nucleoside analogue.
- S. Itoh, H. Ueda, S., Imamura, S., Kukukawa, K., Tsujino, M., Matsuda, A. and Ueda, T. (1988) Pharm. Bull. 36, 209 217.
- An example of a useful phosphate prodrug group is the S- acyl-2-thioethyl group, also referred to as "SATE".
- compositions described herein can be used to treat patients infected with
- HIV-1 and HIV-2 to prevent an infection by HIV-1 and HIV-2, or to eradicate an HIV-1 or HIV-2 infection.
- the HIV-1 or HIV-2 may already have developed one or more mutations, such as the Ml 84V, K65R mutation or TAMS.
- the second agent will ideally be selected to be active against HIV-1 or HIV-2 that has these mutations.
- the administration is to a patient who has not yet developed any resistance to these antiviral agents or has been off therapy for at least three months. In that case, it may be possible to actually cure an infected patient if the therapy can treat substantially all of the virus, substantially everywhere it resides in the patient.
- the combination therapy should be effective against all known resistant viral strains, because there is at least one agent capable of inhibiting such a virus in this combination therapy, and because the JAK inhibitors do not function in the same manner as the conventional NRTI, NNRTI, protease inhibitors, entry inhibitors, integrase inhibitors, and the like, and thus remain effective against strains that have mutated following exposure to these agents.
- the compounds can be used in different ways to treat or prevent HIV, and, in one embodiment, to cure an HIV infection.
- a combination of a JAK inhibitor as described herein, a macrophage depleting agent (e.g., clodronate- loaded liposomes, gadolinium chloride (GdCl)), plus HAART therapy is used.
- the strategy involves reducing viral loads with traditional HAART and JAK inhibitor therapy.
- macrophages are systemically depleted (typically without discrimination for infected versus infected macrophages).
- HAART and JAK inhibitor therapy would be maintained during macrophage depletion.
- treatment with the macrophage depleting agent is withdrawn, while treatment with HAART and the JAK inhibitor is maintained.
- HAART is then withdrawn, while JAK inhibitor therapy is maintained, optionally while monitoring viral rebound.
- both HAART and JAK inhibitor therapy are then withdrawn, optionally while monitoring viral rebound.
- viral loads are reduced with traditional HAART + JAK inhibitors, specifically one or both of Tofacitinib and Jakafi, as described herein.
- macrophages are systemically depleted (typically without discrimination for infected versus infected macrophages) with Boniva or Fosamax (both of these drugs are potent macrophage depleting agents).
- HAART + JAK inhibitor therapy is maintained during macrophage depletion.
- treatment with the macrophage depleting agent is withdrawn, while treatment with HAART and the JAK inhibitor is maintained.
- HAART is then withdrawn, while JAK inhibitor therapy with one or both of Tofacitinib and Jakafi is maintained, optionally while monitoring viral rebound.
- both HAART and JAK inhibitor therapy with one or both of Tofacitinib and Jakafi are then withdrawn, optionally while monitoring viral rebound.
- HDAC inhibitor histone deacetylase inhibitor
- IL-7 interleukin 7
- HAART histone deacetylase inhibitor
- JAK inhibitor histone deacetylase inhibitor
- panobinostate which is described, for example, in Lewin, et al., "HIV cure and eradication: how will we get from the laboratory to effective clinical trials?" AIDS:24 April 2011.
- HDAC inhibitors include Vorinostat, Romidepsin (trade name Istodax), Panobinostat (LBH589), Valproic acid (including Mg valproate and other salt forms), Belinostat (PXD101), Mocetinostat (MGCD0103), PCI-24781, Entinostat (MS-275), SB939, Resminostat (4SC-201), Givinostat (ITF2357), CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC- 202, sulforaphane, suberoylanilide hydroxamic acid (SAHA), BML-210, M344, CI- 994,; CI-994 (Tacedinaline); BML-210; M344; MGCD0103 (Mocetinostat); and Tubastatin A.
- Vorinostat Romidepsin (trade name Istodax), Panobinostat (LBH589), Valproic acid (including M
- HDAC inhibitors are described in U.S. Patent No. 7,399,787.
- the strategy involves reducing viral loads with traditional HAART and JAK inhibitor therapy. Then, the patient is treated with a reactivation agent (as defined in Lewin et al., supra), such as panobinostat.
- both HAART and JAK inhibitor therapy are maintained during reactivation, and in another aspect of this embodiment, HAART, but not JAK inhibitor therapy, is maintained during reactivation.
- Treatment with the reactivation agent is then withdrawn, while continuing treatment with HAART and one or more JAK inhibitors, such as Tofacitinib and Jakafi as defined herein.
- HAART is then withdrawn, while JAK inhibitor therapy is maintained, optionally while monitoring viral rebound.
- both HAART and JAK inhibitor therapy are then withdrawn, optionally while monitoring viral rebound.
- the JAK inhibitors are administered to a patient before, during, or after administration of a vaccine and/or an immunostimulant.
- immuno stimulants can provide an optimal antiretroviral regimen.
- the immuno stimulatory treatments include, but are not limited to, therapies from two functional classes: 1) agents that target actively replicating cells and 2) agents activating latently infected cells.
- HAART can also be provided.
- the JAK inhibitors optionally with co-administered HAART, can suppress virus to undetectable or virtually undetectable levels.
- the addition of an immunomodulatory therapy that specifically targets viral reservoirs can, ideally, lead to a cure, or at least remove virus from one or more viral reservoirs.
- immunomodulatory agent is used herein to describe a substance which evokes, increases and/or prolongs an immune response to an antigen. While the present application distinguishes between an "antigen” and an “immunostimulant” it should be noted that this is merely for reasons of clarity and ease of description. It should be understood that the immunostimulant could have, and in many cases preferably has, antigenic potential itself. Immunomodulatory agents modulate the immune system, and, as used herein, immunostimulants are also referred to as immunomodulatory agents, where it is understood that the desired modulation is to stimulate the immune system.
- immunostimulants There are two main categories of immunostimulants, specific and non-specific.
- Specific immunostimulants provide antigenic specificity in immune response, such as vaccines or any antigen
- non-specific immunostimulants act irrespective of antigenic specificity to augment immune response of other antigen or stimulate components of the immune system without antigenic specificity, such as adjuvants and non-specific immunostimulators.
- immunostimulants include levamisole, thalidomide, erythema nodosum leprosum, BCG, cytokines such as interleukins or interferons, including recombinant cytokines and interleukin 2 (aldeslukin), 3D-MPL, QS21, CpG ODN 7909, miltefosine, anti-PD-1 or PD-1 targeting drugs, and acid (DCA, a macrophage stimulator), imiquimod and resiquimod (which activate immune cells through the toll- like receptor 7), chlorooxygen compounds such as tetrachlorodecaoxide (TCDO), agonistic CD40 antibodies, soluble CD40L, 4-lBB:4-lBBL agonists, OX40 agonists, TLR agonists, moieties that deplete regulatory T cells, arabinitol-ceramide, glycerol- ceramide, 6-deoxy and 6-sulfono-myo-ins
- TCDO TCDO formulated for intravenous injection.
- WF 10 specifically targets macrophages, and modulates disease-related up-regulation of immune responses in vivo.
- 3D-MPL is an immuno stimulant derived from the lipopolysaccharide (LPS) of the Gram-negative bacterium Salmonella minnesota. MPL has been deacylated and is lacking a phosphate group on the lipid A moiety. This chemical treatment dramatically reduces toxicity while preserving the immunostimulant properties (Ribi, 1986). Ribi Immunochemistry produces and supplies MPL to GSK-Biologicals.
- LPS lipopolysaccharide
- QS21 is a natural saponin molecule extracted from the bark of the South American tree Quillaja saponaria Molina. A purification technique developed to separate the individual saponins from the crude extracts of the bark, permitted the isolation of the particular saponin, QS21, which is a triterpene glycoside demonstrating stronger adjuvant activity and lower toxicity as compared with the parent component. QS21 has been shown to activate MHC class I restricted CTLs to several subunit Ags, as well as to stimulate Ag specific lymphocytic proliferation (Kensil, 1992). Aquila (formally Cambridge Biotech Corporation) produces and supplies QS21 to GSK-Biologicals.
- CpG ODN 7909 is a synthetic single-stranded phosphorothioate oligodeoxy- nucleotide (ODN) of 24 bases length. Its base sequence, which is 5'- TCGTCGTTTTG-TCGTTTTGTCGTT-3 ', has been optimized for stimulation of the human immune system.
- CpG DNA or synthetic ODN containing CpG motifs are known to activate dendritic cells, monocytes and macrophages to secrete THl-like cytokines and to induce TH1 T cell responses including the generation of cytolytic T cells, stimulate NK cells to secrete IFNg and increase their lytic activity, they also activate B cells to proliferate (Krieg A et al.
- CpG 7909 is not antisense to any known sequence of the human genome.
- CpG 7909 is a proprietary adjuvant developed by and produced on behalf of Coley Pharmaceutical Group, Inc., Mass., US. iNKT Agonists
- iNKT invariant natural killer T
- iNKT cells are defined by their expression of a restricted TCR repertoire, consisting of a canonical V-alpha-14-J-alpha-18 or V-alpha-24-J-alpha-18-alpha chain in mice and humans respectively.
- iNKT cells recognize and become activated in response to self or foreign antigenic lipids presented by non-polymorphic CD Id molecules expressed on the surface of APCs.
- iNKT cells are activated in response to a variety of infections, and during inflammatory and autoimmune diseases.
- iNKT cells provide a means of linking and coordinating innate and adaptive immune responses, as their stimulation can induce the downstream activation of DCs, NK cells, B and T cells. It has been demonstrated in vitro that iNKT cells stimulate B cell proliferation and antibody production.
- NKT cells can be activated by alpha-galactosyl-ceramide (alpha-GalCer) or its synthetic analog KRN 7000 (U.S. 2003/0157135).
- Alpha-GalCer can stimulate NK activity and cytokine production by NKT cells (U.S. 2003/0157135).
- Alpha-GalCer and related glycosylceramides not only function as antigens, but can also be used as soluble adjuvants capable of enhancing and/or extending the duration of the protective immune responses induced by other antigens.
- the immuno stimulant may be an iNKT cell agonist.
- the agonist may be an exogenous or endogenous agonist. It may be a glycosidic agonist (such as alpha-galactasylceramide) or a non- glycosidic agonist (such as threitolceramide).
- the immunostimulant may be a lipid or a glycolipid.
- Glycolipids presented by CDl can be grouped into different classes including for example diacylglycerolipids, sphingolipids, mycolates and phosphomycoketides (Zajonc and Krenenberg, Current Opinion in Structural Biology, 2007, 17:521-529).
- Microbial antigens from pathogenic mycobacteria such as glucose monomycolates (GMM), mannosyl phosphomycoketides and phosphatidylinositol mannosides are known to be potent ligands for human T cells when presented by group I CDl molecules (Zajonc an Kronenberg, supra).
- the immunostimulant can be a glycosylceramide, for example alpha-galactosylceramide (KRN 7000, US2003/0157135) or an analogue thereof, such as for example threitolceramide (IMM47) or other non-glycosidic iNKT cell agonists (as described in Silk et al. Cutting Edge J. Immunol, 2008).
- analogues which may be used in accordance with the invention and methods of producing such analogues are disclosed in WO2007/050668, which is incorporated herein by reference.
- Intracellular TLRs such as TLRs 3, 7, 8 and 9 recognize nucleic acids.
- synthetic oligodeoxynucleotides such as the TLR9 agonist CpG have previously been used as immuno stimulants.
- These TLR immuno stimulants operate by a different mechanism than that employed by lipids such as alphaGalCer. These immuno stimulants directly activate the cell that they are taken up by, culminating in, for example, the secretion of cytokines and chemokines that result in the further stimulation of immune responses.
- the TLR expression pattern is specific for each cell type (Chiron et al, 2009).
- TLR expression in human B cells is characterized by high expression of TLR 1, 6, 7, 9 and 10, with the expression pattern varying during B-cell differentiation.
- Soluble CpG ODNs are rapidly internalized by immune cells and interact with TLR9 that is present in endocytic vesicles.
- Cellular activation by most members of the TLR family involves a signaling cascade that proceeds through myeloid differentiation primary response gene 88 (MYD88), interleukin-1 (IL-1), receptor- activated kinase (IRAK) and tumor-necrosis factor receptor (TNFR)- associated factor 6 (TRAF6), and culminates in the activation of several transcription factors, including nuclear factor-kappaB (NF-kappaB), activating protein 1 (API), CCAAT-enhancer binding protein (CEBP) and cAMP-responsive element binding protein (CREB).
- MYD88 myeloid differentiation primary response gene 88
- IL-1 interleukin-1
- IRAK receptor- activated kinase
- TNFR tumor-necrosis factor receptor
- TRF6 tumor-necrosis factor receptor
- B cells and plasmacytoid dendritic cells are the main human cell types that express TLR9 and respond directly to CpG stimulation. Activation of these cells by CpG DNA initiates an immunostimulatory cascade that culminates in the indirect maturation, differentiation and proliferation of natural killer (NK) cells, T cells and monocytes/macrophages. Together, these cells secrete cytokines and chemokines that create a pro-inflammatory (IL-1, IL-6, IL-18 and TNF) and T.sub.Hl-biased (interferon-. gamma., IFN-. gamma., and IL-12) immune milieu (Klinman, 2004, Nature Reviews, 4:249).
- IL-1, IL-6, IL-18 and TNF T.sub.Hl-biased immune milieu
- the immuno stimulant is a TRL agonist.
- it is an endosomal TLR agonist, in particular a nucleic acid, such as for example DNA, RNA (either double or single stranded).
- the immunostimulant may, for example comprise a CpG oligodeoxynucleotide or a poly-U nucleic acid.
- Saponins are taught in: Lacaille-Dubois, M and Wagner H. (1996. A review of the biological and pharmacological activities of saponins. Phytomedicine vol 2 pp 363-386). Saponins are steroid or triterpene glycosides widely distributed in the plant and marine animal kingdoms.
- Saponins are known as adjuvants in vaccines for systemic administration.
- the adjuvant and haemolytic activity of individual saponins has been extensively studied in the art (Lacaille-Dubois and Wagner, supra).
- Quil A derived from the bark of the South American tree Quillaja Saponaria Molina
- fractions thereof are described in U.S. Pat. No. 5,057,540 and "Saponins as vaccine adjuvants", Kensil, C. R., Crit Rev Ther Drug Carrier Syst, 1996, 12 (l-2): l-55; and EP 0 362 279 Bl.
- ICOMS Immune Stimulating Complexes
- QS7 a non-haemo lytic fraction of Quil- A
- QS21 a potent adjuvant for systemic vaccines.
- Use of QS21 is further described in Kensil et al. (1991. J. Immunology vol 146, 431-437).
- Combinations of QS21 and polysorbate or cyclodextrin are also known (WO
- Particulate adjuvant systems comprising fractions of QuilA, such as QS21 and QS7 are described in WO 96/33739 and WO 96/11711.
- TH-1 type cytokines e.g., IFN-gamma, TNF-alpha, IL-2, IL-12, IL-18, etc
- Th2-type cytokines e.g., IL4, IL-5, IL-6 and IL- 10.
- IFNg interferon-gamma
- IL-18 has several bioactivities, including the ability to promote the differentiation of naive CD4 T cells into Thl cells, to stimulate natural killer (NK) cells, natural killer T (NKT) cells, and to induce the proliferation of activated T cells, predominantly cytotoxic T cells (CD8+ phenotype) to secrete gamma interferon (IFN-gamma) (Okamura H. et al. 1998, Adv. Immunol. 70: 281- 312). IL-18 also mediates Fas-induced tumor death, promotes the production of IL-la and GMCSF, and has anti-angiogenic activity. IFN-a 2a, including pegylated versions thereof (Pegasys), can also be used. Recombinant human Interleukin-7 (r- hIL-7 / CYT107) can also be used.
- vaccine includes all prophylactic and therapeutic vaccines.
- a vaccine includes an antigen or immunogenic derivative, and an adjuvant.
- the vaccines can be any vaccine that inhibits any of the viruses described herein, including anti-HIV vaccines which inhibit HIV through any mechanism.
- the vaccine is an anti-HIV vaccine, it ideally inhibits or stops the HIV virion replication cycle at any one of the following phases of the HIV virion cycle:
- HIV-derived antigens include HIV-1 antigen gpl20, tat, nef, reverse transcriptase, gag, gpl20 and gpl60, and various targets in pol
- HIV vaccine is the Derma Vir therapeutic HIV vaccine, currently in Phase II clinical studies.
- the vaccines of the present invention may additionally contain suitable diluents, adjuvants and/or carriers.
- the vaccines contain an adjuvant which can enhance the immunogenicity of the vaccine in vivo.
- the adjuvant may be selected from many known adjuvants in the art, including the lipid-A portion of gram negative bacteria endotoxin, trehalose dimycolate of mycobacteria, the phospholipid lysolecithin, dimethyldictadecyl ammonium bromide (DDA), certain linear polyoxypropylene-polyoxyethylene (POP-POE) block polymers, aluminum hydroxide, and liposomes.
- the vaccines may also include cytokines that are known to enhance the immune response including GM-CSF, IL-2, IL-12, TNF-cc and IFNy.
- the dose of the vaccine may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of antibody to elicit a desired response in the individual. Dosage regime may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. The dose of the vaccine may also be varied to provide optimum preventative dose response depending upon the circumstances.
- the vaccines may be administered in a convenient manner such as by injection (subcutaneous, intravenous, intramuscular, etc.), oral administration, inhalation, transdermal administration (such as topical cream or ointment, etc.), or suppository applications.
- the recombinant retrovirus of the present invention can be any retrovirus, including HIV-1, HIV-2, SIV, HTLV-1.
- the retrovirus is a human immunodeficiency virus selected from HIV-1 and HIV-2, more preferably, the retrovirus is HIV- 1.
- the vaccine can be an essentially non-cytolytic retrovirus, wherein the term "essentially non- cytolytic” means that the retrovirus does not significantly damage or kill the cells it infects.
- the natural signal sequence of HIV-1 envelope glycoprotein gpl20 (NSS) is modified to be essentially non-cytolytic, or is replaced with an essentially non-cytolytic signal sequence.
- the present invention provides an essentially non-cytolytic recombinant HIV-1 capable of highly efficient replication wherein the NSS of the virus' envelope glycoprotein is modified sufficiently to prevent cell damage by the virus, preferably by eliminating positively charged amino acids, even more preferably, such elimination or modification resulting in no more than one (1) and preferably zero (0) positively charged amino acids.
- the positively charged amino acids which may be modified or replaced include lysine and arginine.
- the present invention provides an essentially non-cytolytic recombinant HIV-1 capable of highly efficient replication wherein the NSS of the virus' envelope glycoprotein is replaced with an essentially non-cytolytic and more efficient signal sequence.
- replacement of the NSS of the envelope glycoprotein of HIV-1 with either the mellitin or IL-3 signal sequence decreases the cytotoxicity of the retrovirus.
- the present invention includes within its scope replacement of NSS with any signal sequence which renders the retrovirus essentially non-cytolytic.
- the inventors have also shown that replacement of the NSS with mellitin or IL-3 signal sequences results in a greater level of production and secretion of gpl20, in addition to the reduced cytotoxicity.
- the inventors have also shown that replacement of the NSS results in partial deletion the vpu gene. Studies have shown the vpu gene can be completely deleted without any measurable impact on the virus' ability to replicate (James et al. AIDS Res. Human Retrovirus 10:343-350, 1994).
- the retrovirus is rendered avirulent.
- the virus is rendered avirulent by deleting the nef gene.
- the present invention provides an avirulent, essentially non-cytolytic retrovirus which contains a sufficient deletion of the nef gene to render the virus non-pathogenic and wherein the virus' envelope glycoprotein gpl20 coding sequence is replaced with a more efficient signal sequence.
- "sufficient deletion” means deletion of enough of the sequence to prevent transcription and thereby production of the nef protein product.
- the retrovirus is rendered avirulent, essentially non- cytolytic, and contains a sufficient deletion of the nef gene and the vpu gene to render the virus non-pathogenic.
- Recombinant retroviruses be prepared using techniques known in the art.
- the retrovirus can be introduced in a host cell under conditions suitable for the replication and expression of the retrovirus in the host.
- the essentially non-cytolytic and avirulent retroviruses can typically be produced in large quantities and in a form that is non-pathogenic to the patient.
- the viruses can be used, in combination with the JAK inhibitors and, optionally, with HAART, for preventing or treating a retroviral infection.
- an effective amount of a killed recombinant essentially non-cytolytic avirulent retrovirus is administered to a patient in need of treatment or prophylaxis of a retroviral infection.
- the term "effective amount" as used herein means an amount effective and at dosages and for periods of time necessary to achieve the desired result.
- the natural signal sequence of the virus' envelope glycoprotein such as gpl20
- the virus' envelope glycoprotein is modified to provide an essentially non-cytolytic signal sequence, and/or the virus is rendered avirulent by deleting the nef gene.
- the modification to provide a non-cytolytic NSS results in no more than one positively charged amino acid in the NSS sequence, more preferably zero positively charged amino acids.
- the natural signal sequence of the virus' envelope glycoprotein, preferably gpl20 is replaced with an essentially non-cytolytic signal sequence, and, optionally, the virus is rendered avirulent by deleting the nef gene.
- the non- cytolytic signal sequence is selected from the group consisting of the mellitin sequence and the IL-3 signal sequence.
- the vaccines can comprise chimaeric antigens, for example, a chimaeric influenza-HIV vaccine.
- the vaccine comprises the A-antigenic loop of influenza haemagglutinin (HA- A), modified to resemble the principle neutralizing determinant (PND) of HIV envelope glycoprotein gpl20.
- the Chimaeric antigens can be presented as killed or attenuated virus.
- the antigen is typically combined with a pharmaceutically acceptable carrier, and, typically, an adjuvant, to make a composition comprising a vaccine.
- This vaccine composition is optionally combined with an immuno stimulant and administered to a patient in need of treatment or prevention of a viral infection.
- the vaccine includes antigens selected for more than one virus, particularly where co-infection rates are known to be high.
- antigens selected for more than one virus particularly where co-infection rates are known to be high.
- One example is HIV and HBV or HCV, or HIV and influenza.
- adjuvants may be administered in conjunction with the protein in the vaccine composition.
- adjuvants include, but are not limited to the following: polymers, co-polymers such as polyoxyethylene-polyoxypropylene copolymers, including block co-polymers; polymer PI 005; monotide ISA72; Freund's complete adjuvant (for animals); Freund's incomplete adjuvant; sorbitan monooleate; squalene; CRL-8300 adjuvant; alum; QS 21, muramyl dipeptide; trehalose; bacterial extracts, including mycobacterial extracts; detoxified endotoxins; membrane lipids; or combinations thereof.
- the vaccine formulations can be presented in unit dosage form, and can be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers.
- Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
- sterile liquid carrier for example, water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets commonly used by one of ordinary skill in the art.
- Preferred unit dosage formulations are those containing a dose or unit, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients, particularly mentioned above, the formulations of the present invention may include other agents commonly used by one of ordinary skill in the art.
- the vaccine may be administered through different routes, such as oral, including buccal and sublingual, rectal, parenteral, aerosol, nasal, intramuscular, subcutaneous, intradermal, and topical.
- the vaccine of the present invention may be administered in different forms, including but not limited to solutions, emulsions and suspensions, microspheres, particles, microparticles, nanoparticles, and liposomes. It is expected that from about 1 to 5 dosages may be required per immunization regimen.
- Initial injections may range from about 1 mg to 1 gram, with a preferred range of about 10 mg to 800 mg, and a more preferred range of from approximately 25 mg to 500 mg.
- Booster injections may range from 1 mg to 1 gram, with a preferred range of approximately 10 mg to 750 mg, and a more preferred range of about 50 mg to 500 mg.
- Intramuscular injections may range from about 0.1 ml to 1.0 ml.
- the vaccines can be administered before, during or after an infection.
- An infected individual can receive a vaccine directed to the virus infecting the individual, even though the levels are reduced via treatment with the JAK inhibitors and/or HAART, stimulating the immune system to fight the virus that remains in the individual.
- the vaccine may be stored at temperatures of from about 4C. to -lOOC.
- the vaccine may also be stored in a lyophilized state at different temperatures including room temperature.
- the vaccine may be sterilized through conventional means known to one of ordinary skill in the art. Such means include, but are not limited to filtration, radiation and heat.
- the vaccine of the present invention may also be combined with bacteriostatic agents, such as thimerosal, to inhibit bacterial growth.
- the invention includes methods for treating or preventing, and uses for the treatment or prophylaxis, of a Flaviviridae infection, including all members of the Hepacivirus genus (HCV), Pestivirus genus (BVDV, CSFV, BDV), or Flavivirus genus (Dengue virus, Japanese encephalitis virus group (including West Nile Virus), and Yellow Fever virus).
- HCV Hepacivirus genus
- BVDV Pestivirus genus
- CSFV Pestivirus genus
- BDV Flavivirus genus
- Dengue virus Japanese encephalitis virus group (including West Nile Virus)
- Yellow Fever virus Yellow Fever virus
- Flaviviridae is a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. They are enveloped viruses of approximately 40-50 nm. An overview of the Flaviviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Flaviviridae consists of three genera.
- Flavi viruses This genus includes the Dengue virus group (Dengue virus,
- Dengue virus type 1 Dengue virus type 2, Dengue virus type 3, Dengue virus type 4
- the Japanese encephalitis virus group Alfuy Virus, Japanese encephalitis virus, Kookaburra virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Stratford virus, Usutu virus, West Nile Virus
- the Modoc virus group the Rio Bravo virus group ( acea virus, Rio Brovo virus, Saboya virus), the Ntaya virus group, the Tick-Borne encephalitis group (tick born encephalitis virus), the Tyuleniy virus group, Kenya S virus group and the Yellow Fever virus group.
- Flaviviruses Apart from these major groups, there are some additional Flaviviruses that are unclassified.
- This genus includes Bovine Viral Diarrhea Virus-2 (BVDV-2),
- Pestivirus type 1 (including BVDV), Pestivirus type 2 (including Hog Cholera Virus) and Pestivirus type 3 (including Border Disease Virus).
- Hepaciviruses This genus contains only one species, the Hepatitis C virus (HCV), which is composed of many clades, types and subtypes. Chikungunya virus, an RNA virus of the genus Alphavirus, can also be treated using the compounds described herein.
- HCV Hepatitis C virus
- Example 1 Comparison of JAK Inhibitors to Conventional Antiretro viral Therapy
- HAART highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV-1) infections combines two nucleoside reverse transcriptase inhibitors (NRTI) together with either a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI). These drug combinations have markedly decreased mortality and morbidity from HIV-1 infections in the developed world.
- NRTI nucleoside reverse transcriptase inhibitors
- PI protease inhibitor
- NRTI non-nucleoside reverse transcriptase inhibitor
- HAART regimens are selected in part to minimize cross resistance, and thereby delay the emergence of resistant viruses, all regimens eventually fail, due primarily to lack of adherence to strict regimens, delayed toxicities and/or the emergence of drug-resistant HIV-1 strains, making it a major imperative to develop regimens that delay, prevent or attenuate the onset of resistance for second line treatments for infected individuals who have already demonstrated mutations.
- TAM thymidine analog mutations
- K65R and M184V need to be a continued focus in the rational design of HIV- 1 NRTI drug development.
- JAK inhibitors that do not appear to function in the same manner as NRTI, NNRTI, protease inhibitors, entry inhibitors, integrase inhibitors, and the like.
- JAK inhibitors that were evaluated were Jakafi (Incyte) and Tofacitinib (Pfizer).
- Macrophages were isolated as follows: Monocytes were isolated from buffy coats of HIV-1 negative, HBV/HCV-negative donors with density gradient centrifugation coupled with enrichment for CD 14+ monocytes with Rosette Sep antibody cocktail (Stem Cell Technologies, Vancouver, British Columbia). Cells were seeded at a concentration of 1.0 x 10 6 cells/well for 1 hr at 37°C and 5% C0 2 to confer plastic adherence prior to repeated washes with 1 x PBS.
- Macrophages were maintained in medium containing 100 U/ml macrophage colony- stimulating factor (m-CSF, R&D Systems, Minneapolis, MN), supplemented with 20% fetal calf serum (Atlanta Biologicals, Lawrenceville, GA) and 1% penicillin/streptomyocin (Invitrogen, Carlsbad, CA) for 7 days (37oC, 5% C02) prior to testing.
- m-CSF macrophage colony- stimulating factor
- Macrophage infections Macrophages were cultured as described above for 7 days. For acute infection, macrophages were serum starved for 8 hrs prior to infection and cultured for 2 hr in medium containing various concentrations of AZT (positive control) or Tofacitinib and Jakafi for 2 hr prior to removal of drug-containing medium and 4 hr infection with HIV-lBaL at 0.1 MOI in the absence of drug. 4 hrs after infection, virus was removed and drug-containing medium was returned to the cultures. Supernatants were collected on day 7 post-infection and HIV-1 p24 was quantified via ELISA (Zeptometrix Corporation, Buffalo, NY). EC50 analysis was performed using CalcuSyn software (BioSoft Corporation, Cambridge, UK).
- PBM cells were isolated as follows: Lymphocytes were isolated from buffy coats derived from healthy donors obtained from Life South Laboratories (Dunwoody, GA). Activated lymphocytes were maintained for 72 hrs in medium that was supplemented with 6 ⁇ g/ml phytohemagglutinin (PHA) (Cape Cod associates, East Falmouth, MA). Media was comprised of RPMI media supplemented with 20% fetal calf serum, 1% penicillin/streptomyocin and 2% L-glutamine (Sigma Aldrich, San Jose, CA). PBM cell infections: Testing was performed in duplicate with at least 3 independent assays.
- PHA phytohemagglutinin
- Cytotoxicity Assay The toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), as described previously (see Schinazi R.F., Sommadossi J.- P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob. Agents Chemother. 1990, 34, 1061-67), and also in M0 cells. Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to cell culture medium were included as negative controls.
- the cytotoxicity IC 50 was obtained from the concentration-response curve using the median effective method described previously (see Chou T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1-11).
- the potency and toxicity of JAK inhibitors Tofacitinib and Jakafi versus FDA approved controls AZT and 3TC was evaluated in acutely infected activated M0, as well as in PBM cells.
- the EC 50 data ( ⁇ ) is shown in Figure 1. Also shown in Figure 1 are the IC 50 values ( ⁇ ) for these compounds in PBM, M0 cells, CEM cells, and Vero cells.
- the data show a very large therapeutic window (ratio of toxicity/potency), and that the JAK inhibitor compounds have substantially the same EC 50 and substantially lower IC 50 values as AZT and 3TC.
- Tofacitinib and Jakafi are potent, sub-micromolar inhibitors of HIV-l replication in both PBM cells and M0 cells.
- the compounds do not affect viability or proliferation for PBM cells and M0 cells, or total cell number, up to around 10 ⁇ (2-3 logs above EC 50 ).
- the therapeutic window (ratio of toxicity:potency) is wide for both cell types (24- >100).
- the effect on the growth of HepG2 cells can be determined by incubating cells in the presence of 0 ⁇ , 0.1 ⁇ , 1 ⁇ , 10 ⁇ and 100 ⁇ drug.
- Cells (5 x 10 4 per well) were plated into 12- well cell culture clusters in minimum essential medium with nonessential amino acids supplemented with 10% fetal bovine serum, 1% sodium pyruvate, and 1% penicillin/streptomycin and incubated for 4 days at 37 °C. At the end of the incubation period the cell number was determined using a hemocytometer.
- HepG2 cells from a stock culture can be diluted and plated in 12-well culture plates at 2.5 x 10 4 cells per well.
- concentrations (0 ⁇ , 0.1 ⁇ , 1 ⁇ , 10 ⁇ and 100 ⁇ ) of the compounds can be added, and the cultures incubated at 37 °C in a humidified 5% C0 2 atmosphere for 4 days.
- lactic acid product can be considered a marker for impaired mitochondrial function, elevated levels of lactic acid production detected in cells grown in the presence of the compounds would indicate a drug-induced cytotoxic effect.
- This assay can be used to determine the effect of the compounds on mitochondrial DNA content.
- low-passage- number HepG2 cells are seeded at 5,000 cells/well in collagen-coated 96-well plates.
- the compounds are added to the medium to obtain final concentrations of 0 ⁇ , 0.1 ⁇ , 10 ⁇ and 100 ⁇ .
- cellular nucleic acids are prepared by using commercially available columns (RNeasy 96 kit; Qiagen). These kits co-purify RNA and DNA, and hence, total nucleic acids were eluted from the columns.
- the mitochondrial cytochrome c oxidase subunit II (COXII) gene and the ⁇ -actin or rRNA gene were amplified from 5 ⁇ of the eluted nucleic acids using a multiplex Q-PCR protocol with suitable primers and probes for both target and reference amplifications.
- COXII the following sense, probe and antisense primers are used, respectively: 5'- TGCCCGCCATCATCCTA-3', 5'-tetrachloro-6-carboxyfluorescein- TCCTCATCGCCCTCCCATCCC-TAMRA-3' and 5'-
- the sense, probe, and antisense primers are 5'- GCGCGGCT AC AGCTTC A- 3 ', 5'-6-FAMCACCACGGCCGAGCGGGATAMRA-3' and 5 '-TCTCCTTA ATGTC ACGC ACG AT-3 ' , respectively.
- the primers and probes for the rRNA gene are commercially available from Applied Biosystems. Since equal amplification efficiencies are obtained for all genes, the comparative CT method can be used to investigate potential inhibition of mitochondrial DNA synthesis.
- the comparative CT method uses arithmetic formulas in which the amount of target (COXII gene) is normalized to the amount of an endogenous reference (the ⁇ -actin or rRNA gene) and is relative to a calibrator (a control with no drug at day 7).
- the arithmetic formula for this approach is given by 2-AACT, where AACT is (CT for average target test sample - CT for target control) - (CT for average reference test -CT for reference control) (see Johnson MR, K Wang, JB Smith, MJ Heslin, RB Diasio. Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. Anal. Biochem. 2000; 278: 175-184).
- a decrease in mitochondrial DNA content in cells grown in the presence of drug would indicate mitochondrial toxicity.
- NRTI induced toxicity has been shown to cause morphological changes in mitochondria (e.g., loss of cristae, matrix dissolution and swelling, and lipid droplet formation) that can be observed with ultrastructural analysis using transmission electron microscopy (see Cui L, Schinazi RF, Gosselin G, Imbach JL. Chu CK, Rando RF, Revankar GR, Sommadossi JP. Effect of enantiomeric and racemic nucleoside analogs on mitochondrial functions in HepG2 cells. Biochem. Pharmacol.
- HepG2 cells Incubated with 10 ⁇ fialuridine (FIAU; l,2'-deoxy-2'-fluoro-l-D-arabinofuranosly-5-iodo-uracil) showed the presence of enlarged mitochondria with morphological changes consistent with mitochondrial dysfunction.
- FIAU fialuridine
- JAK inhibitor compounds promote morphological changes in mitochondria
- mouse Neuro2A cells (American Type Culture Collection 131) can be used as a model system (see Ray AS, Hernandez-Santiago BI, Mathew JS, Murakami E, Bozeman C, Xie MY, Dutschman GE, Gullen E, Yang Z, Hurwitz S, Cheng YC, Chu CK, McClure H, Schinazi RF, Anderson KS. Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'- dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 1994-2001).
- concentrations necessary to inhibit cell growth by 50% can be measured using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide dye-based assay, as described. Perturbations in cellular lactic acid and mitochondrial DNA levels at defined concentrations of drug can be carried out as described above.
- Example 4 Assay for Bone Marrow Cytotoxicity Primary human bone marrow mononuclear cells were obtained commercially from Cambrex Bioscience (WalkersviUe, MD). CFU-GM assays can be carried out using a bilayer soft agar in the presence of 50 units/mL human recombinant granulocyte/macrophage colony- stimulating factor, while BFU-E assays used a methylcellulose matrix containing 1 unit/mL erythropoietin (see Sommadossi JP, Carlisle R.
- AZT can be used as a positive control.
- Cells can be incubated in the presence of a JAK inhibitor compound for 14-18 days at 37°C with 5% C0 2 , and colonies of greater than 50 cells can be counted using an inverted microscope to determine IC 50 .
- the 50% inhibitory concentration (IC 50 ) can be obtained by least-squares linear regression analysis of the logarithm of drug concentration versus BFU-E survival fractions. Statistical analysis can be performed with Student's t test for independent non-paired samples.
- Example 5 Anti-HBV Assay
- the anti-HBV activity of the JAK inhibitor compounds can be determined by treating the AD-38 cell line carrying wild type HBV under the control of tetracycline (see Ladner S.K., Otto M.J., Barker C.S., Zaifert K., Wang G.H., Guo J.T., Seeger C. & King R.W. Antimicrob. Agents Chemother. 1997, 41, 1715-20).
- Removal of tetracycline from the medium [Tet (-)] results in the production of HBV.
- the levels of HBV in the culture supernatant fluids from cells treated with the compounds can be compared with that of the untreated controls. Control cultures with tetracycline [Tet (+)] can also be maintained to determine the basal levels of HBV expression.
- 3TC can be included as positive control.
- the toxicity of the compounds can be assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (see Schinazi R.F., Sommadossi J. -P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn E.F. Antimicrob. Agents Chemother. 1990, 34, 1061-67). Cycloheximide can be included as positive cytotoxic control, and untreated cells exposed to solvent can be included as negative controls. The cytotoxicity IC50 can be obtained from the concentration-response curve using the median effective method described previously (see Chou T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27- 55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994, 25, 1-11).
- Huh 7 Clone B cells containing HCV Replicon RNA can be seeded in a 96- well plate at 5000 cells/well, and the JAK inhibitor compounds tested at 10 ⁇ in triplicate immediately after seeding. Following five days incubation (37°C, 5% C0 2 ), total cellular RNA can be isolated by using versaGene RNA purification kit from Gentra. Replicon RNA and an internal control (TaqMan rRNA control reagents, Applied Biosystems) can be amplified in a single step multiplex Real Time RT-PCR Assay. The antiviral effectiveness of the compounds can be calculated by subtracting the threshold RT-PCR cycle of the test compound from the threshold RT-PCR cycle of the no-drug control (ACt HCV).
- ACt HCV no-drug control
- a ACt of 3.3 equals a 1-log reduction (equal to 90% less starting material) in Replicon RNA levels.
- the cytotoxicity of the compounds can also be calculated by using the ACt rRNA values. (2'-Me-C) can be used as the control.
- ACt values can first be converted into fraction of starting material 3 and then were used to calculate the % inhibition.
- Example 8 Assay for Effectiveness Against West Nile Virus
- West Nile virus drug susceptibility assays can also be done as previously described in: Song, G.Y., Paul, V., Choo, H., Morrey, J., Sidwell, R.W., Schinazi, R.F., Chu, C.K. Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J. Med. Chem. 2001, 44, 3985-3993.
- Example 9 Assay for Effectiveness Against Yellow Fever
- Yellow fever drug susceptibility assays can also be done as previously described in: Julander, J.G., Furuta, Y., Shafer, K., Sidwell, R.W. Activity of T-1106 in a Hamster Model of Yellow Fever Virus Infection. Antimicrob. Agents Chemother. 2007, 51, 1962-1966.
- Dengue virus (DENV) NS5 possesses methyltransferase (MTase) activity at its N-terminal amino acid sequence and is responsible for formation of a type 1 cap structure, m7GpppAm2'-0 in the viral genomic RNA.
- MTase methyltransferase
- Optimal in vitro conditions for DENV2 2'-0-MTase activity can be characterized using purified recombinant protein and a short biotinylated GTP-capped RNA template. Steady-state kinetics parameters derived from initial velocities can be used to establish a robust scintillation proximity assay for compound testing.
- Anti-Noro virus Activity Compounds can exhibit anti-norovirus activity by inhibiting norovirus polymerase and/or helicase, by inhibiting other enzymes needed in the replication cycle, or by other pathways.
- Both Norovirus replicons and Hepatitis C replicons require viral helicase, protease, and polymerase to be functional in order for replication of the replicon to occur.
- an in vitro cell culture infectivity assay has been reported utilizing Norovirus genogroup I and II inoculums (Straub, T. M. et al. (2007) Emerg. Infect. Dis. 13(3):396-403). This assay is performed in a rotating-wall bioreactor utilizing small intestinal epithelial cells on microcarrier beads. The infectivity assay may be useful for screening entry inhibitors.
- a cynomolgus monkey can be surgically implanted with a chronic venous catheter and subcutaneous venous access port (VAP) to facilitate blood collection and can undergo a physical examination including hematology and serum chemistry evaluations and the body weight recording.
- VAP subcutaneous venous access port
- Each monkey (six total) receives approximately 250 ⁇ of H activity with each dose of active compound at a dose level of 10 mg/kg at a dose concentration of 5 mg/mL, either via an intravenous bolus (3 monkeys, IV), or via oral gavage (3 monkeys, PO).
- Each dosing syringe is weighed before dosing to gravimetrically determine the quantity of formulation administered.
- Urine samples are collected via pan catch at the designated intervals (approximately 18-0 hours pre- dose, 0-4, 4-8 and 8-12 hours post-dosage) and processed. Blood samples are collected as well (pre-dose, 0.25, 0.5, 1,2, 3,6, 8, 12 and 24 hours post-dosage) via the chronic venous catheter and VAP or from a peripheral vessel if the chronic venous catheter procedure should not be possible.
- the blood and urine samples are analyzed for the maximum concentration (Cmax), time when the maximum concentration is achieved (TmaX), area under the curve (AUC), half life of the dosage concentration (TV,), clearance (CL), steady state volume and distribution (Vss) and bioavailability (F).
- the assay can be perforrmed essentially as described by Baginski, S. G.;
- MDBK cells (ATCC) are seeded onto 96-well culture plates (4,000 cells per well) 24 hours before use.
- test compounds After infection with BVDV (strain NADL, ATCC) at a multiplicity of infection (MOI) of 0.02 plaque forming units (PFU) per cell, serial dilutions of test compounds are added to both infected and uninfected cells in a final concentration of 0.5% DMSO in growth medium. Each dilution is tested in quadruplicate.
- MOI multiplicity of infection
- PFU plaque forming units
- Cell densities and virus inocula are adjusted to ensure continuous cell growth throughout the experiment and to achieve more than 90% virus-induced cell destruction in the untreated controls after four days post-infection. After four days, plates are fixed with 50% TCA and stained with sulforhodamine B. The optical density of the wells is read in a microplate reader at 550 nm.
- the 50% effective concentration (EC 50 ) values are defined as the compound concentration that achieved 50% reduction of cytopathic effect of the virus.
- the effective concentration is determined in duplicate 24- well plates by plaque reduction assays.
- Cell monolayers are infected with 100 PFU/well of virus. Then, serial dilutions of test compounds in MEM supplemented with 2% inactivated serum and 0.75% of methyl cellulose are added to the monolayers. Cultures are further incubated at 37°C for 3 days, then fixed with 50% ethanol and 0.8% Crystal Violet, washed and air-dried. Then plaques are counted to determine the concentration to obtain 90% virus suppression.
- the concentration to obtain a 6-log reduction in viral load is determined in duplicate 24-well plates by yield reduction assays.
- the assay is performed as described by Baginski, S. G.; Pevear, D. C; Seipel, M.; Sun, S. C. C; Benetatos, C. A.; Chunduru, S. K.; Rice, C. M. and M. S. Collett "Mechanism of action of a pestivirus antiviral compound" PNAS USA 2000,97 (14), 7981-7986, with minor modifications.
- MDBK cells are seeded onto 24- well plates (2 x 10 5 cells per well) 24 hours before infection with BVDV (NADL strain) at a multiplicity of infection (MOI) of 0.1 PFU per cell.
- Serial dilutions of test compounds are added to cells in a final concentration of 0.5% DMSO in growth medium. Each dilution is tested in triplicate.
- cell cultures (cell monolayers and supernatants) are lysed by three freeze-thaw cycles, and virus yield is quantified by plaque assay.
- MDBK cells are seeded onto 6- well plates (5 x 10 5 cells per well) 24 h before use.
- Cells are inoculated with 0.2 mL of test lysates for 1 hour, washed and overlaid with 0.5% agarose in growth medium. After 3 days, cell monolayers are fixed with 3.5% formaldehyde and stained with 1% crystal violet (w/v in 50% ethanol) to visualize plaques. The plaques are counted to determine the concentration to obtain a 6-log reduction in viral load.
- RT-PCR reverse transcription-polymerase chain reaction
- the Norwalk G-I strain (Chang, K. O., et al. (2006) Virology 353:463-473), the GIT4 strain replicon, as well other Norovirus replicons can be used in assays to determine the in vitro antiviral activity of the compounds described herein, or other compounds or compound libraries.
- the replicon systems are subgenomic and therefore allow evaluation of small molecule inhibitors of non- structural proteins. This can provide the same benefits to Norovirus drug discovery that Hepatitis C replicons contributed to the discovery of therapeutics useful for treatment of that virus (Stuyver, L. J., et al. (2006) Antimicrob. Agents Chemother. 47:244-254). Both Norovirus replicons and Hepatitis C replicons require viral helicase, protease, and polymerase to be functional in order for replication of the replicon to occur. It is believed that the compounds described herein inhibit viral polymerase and/or viral helicase.
- the in vitro cell culture infectivity assay reported using Norovirus genogroup I and II inoculums can also be used.
- This assay can be performed in a rotating- wall bioreactor utilizing small intestinal epithelial cells on microcarrier beads.
- the infectivity assay can be used for evaluating compounds for their ability to inhibit the desired virus.
- Example 18 Antiviral Potency and Toxicity of Jakafi and tofacitinib in Primary Human Lymphocytes and Macrophages
- the antiviral potency and toxicity of jakafi and tofacitinib was evaluated in primary human lymphocytes and macrophages, using the methodology outlined above.
- the antiviral potency against HIV-1LAI in primary human lymphocytes was 0.1-0.8 ⁇ (EC 50 ) and 4.7-15.1 ⁇ (EC 90 ).
- Antiviral potency against HIV-2 in primary human lymphocytes was 0.02-0.07 ⁇ (EC 5 o) and 0.4-1.8 ⁇ (EC 90 ).
- Antiviral potency against HIV-lBaL in primary human macrophages was approximately 0.3 ⁇ (EC 5 o) and 3.0 ⁇ (ECgo).
- AZT (control) demonstrated antiviral potency against HIV-1LAI, HIV-2, and HIV-lBaL as expected.
- Toxicity (IC 50 ) measured with the MTT assay ranged from 1.3 to > 100 ⁇ depending on the cell type tested.
- Propidium Iodide (primary human lymphocytes) demonstrated IC 5 o> 50 ⁇ . Data are mean and standard deviations from at least three independent experiments.
- Example 19 Therapeutic Index for Jakafi and Tofacitinib in primary human lymphocytes and macrophages.
- the therapeutic index (ratio of toxicity:potency) for Jakafi and Tofacitinib was evaluated in primary human lymphocytes and macrophages using the methodology described above.
- the therapeutic index ranged from 1.0-31.0 for HIV-1 infection in primary human lymphocytes when using MTT assay toxicity values, and were > 100 using propidium iodide toxicity values.
- the therapeutic Index ranged from 18 to > 100 for HIV-2 infection in primary human lymphocytes when using MTT assay toxicity values, and were > 100 using propidium iodide toxicity values.
- the therapeutic index for HIV-1 infection in primary human macrophages was > 100 (MTT assay toxicity values).
- AZT > 100 > 50 > 100
- Example 20 Viability of primary human lymphocytes exposed to various concentrations of Jakafi or Tofacitinib.
- the viability of primary human lymphocytes exposed to various concentrations of Jakafi or Tofacitinib was determined using the techniques discussed above.
- PHA and interleukin-2 (IL-2) stimulated primary human lymphocytes were exposed to various concentrations of Jakafi or Tofacitinib for 5 days prior to assessment of viability using propidium Iodide (flow cytometry).
- IL-2 interleukin-2
- Figures 4a-f show the results of flow cytometric analysis of PHA+IL-2 stimulated primary human lymphocytes exposed to various concentrations of Jakafi or Tofacitinib for 5 days prior to assessment of viability using propidium iodide (flow cytometry).
- FIG. 4a is a scatter plot showing a Side Scatter (SSC) gating strategy, where the X-axis in the first chart is Side Scatter Pulse Height (SSC-h) and the Y-axis is Side Scatter Pulse Width (SSC- w), and in the second chart, the forward-scattered light (FSC) is shown with the X axis being Forward Scatter Pulse Height (FSC-H) and the Y axis being Forward Scatter Pulse Width (FSC-W).
- the gating strategy based on forward scatter (FSC) and side scatter (SSC) was established and used uniformly across all samples.
- Histograms and scatter plots are representative data from at least 3 independent experiments conducted with pooled cells from 8 donors.
- Graphs (E, F) are mean and standard deviations compiled from each independent experiment.
- Figure 4B is a histogram showing the results of flow cytometry studies using Propidium Iodide stain quantified with the phycoerythrin (PE-A) channel. Only dead/dying cells will stain positive for Propidium Iodide, therefore only dead/dying cells will be detected by the PE channel using flow cytometry. Living, viable cells will not be stained by Propidium Iodide, therefore they will not be detected in the PE channel.
- PE-A phycoerythrin
- Figure 4c shows histograms comparing the cell viability for cells exposed to Jakafi and to no drug (i.e., controls) for concentrations of 0.1 ⁇ Jakafi, 1.0 ⁇ Jakafi, 10 ⁇ Jakafi, and 50 ⁇ Jakafi.
- Figure 4d shows histograms comparing the cell viability for cells exposed to Tofacitinib and to no drug (i.e., controls) for concentrations of 0.1 ⁇ Tofacitinib, 1.0 ⁇ Tofacitinib, 10 ⁇ Tofacitinib, and 50 ⁇ Tofacitinib.
- Figures 4e and 4f are charts showing the mean and standard deviations from the experiments shown in Figures 4c (Jakafi) and 4d (Tofacitinib), respectively.
- Example 21 Viability of primary human lymphocytes exposed to various concentrations of Jakafi or Tofacitinib.
- the antiviral potency of Jakafi and Tofacitinib was evaluated in primary rhesus macaque lymphocytes and macrophages using the techniques discussed above.
- the antiviral potency was approximately 0.4 ⁇ (EC 5 o) and 4.0 ⁇ (ECgo) for both Jakafi and Tofacitinib in primary rhesus macaque macrophages.
- the antiviral potency was 0.09 + 0.1 (EC 50 ) and 1.3 + 0.8 (EC 90 ) in primary rhesus macaque macrophages.
- An AZT control demonstrated antiviral potency as expected.
- the data (Shown in Table 5 below) are mean and standard deviations from at least three independent experiments . Table 5
- Example 22 Synergistic antiviral potency for co-administration of Jakafi and Tofacitinib in primary human lymphocytes and macrophages
- the synergistic antiviral potentency for co-administration of Jakafi and Tofacitinib was evaluated in primary human lymphocytes and macrophages, using the techniques described above.
- Example 23 Antiviral potency and of Jakafi and Tofacitinib against various NRTI-resistant HIV-1 in primary human lymphocytes.
- the antiviral potency of Jakafi and Tofacitinib against various NRTI-resistant HIV- 1 was evaluated in primary human lymphocytes using the techniques described above.
- the antiviral potency of Jakafi and Tofacitinib was not significantly different for wild- type HIV-lxxLAI versus that of HIV-1 containing mutations K65R, Ml 84V, L74V, A62V/V75I7F77L/F116Y/Q151M, or 4xAZT (D67N/K70R/T215Y/K219Q).
- Various controls for each mutation demonstrated potency or resistance as expected.
- Efavirenz (EFV) was similarly potent across all NRTI resistant strains as expected. Data are mean and standard deviations calculated from at least 4 independent experiments, with pooled cells from 8 donors and duplicates in each experiment.
- the EC 50 data is shown in Table 6, and the EC 90 data is shown in Table 7.
- Example 24 Fold increase 50 (FI 50 ) and fold increase 90 (FI 90 ) for Jakafi and Tofacitinib against various NRTI-resistant HIV-1 in primary human lymphocytes
- FI 50 is the ratio of EC 50 against mutant virus :EC 5 o against wild- type xxLAI.
- FI 90 is the ratio of EC 90 against mutant virus :ECgo against wild-type xxLAI. There was not significant increase in FI 50 or FI 90 for Jakafi or Tofacitinib treated cells. Controls of AZT, (-)-FTC, 3TC, d4T, ddl, Efavirenz (EFV), TDF demonstrated sensitivity or resistance as expected.
- Efavirenz Efavirenz
- Example 25 Tofacitinib and Jakafi inhibit reactivation of latent HIV-1.
- Tofacitinib and Jakafi were evaluated using the techniques described in Bosque and Planelles (2009) Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells; Blood 113: 58-65, and Jordan et al, (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro; The EMBO Journal, Vol. 22 No. 8 pp. 1868+1877.
- Tofacitinib (diamonds) and Jakafi (squares) inhibit reactivation of latent HIV-1 in a primary central memory- based T cell latency model (Figure 8a) and in the J-Lat latency T cell system ( Figure 8b).
- Jakafi was the more potent inhibitor across both systems, and inhibited > 50 % of reactivation at concentrations found during steady-state or C max in vivo (shaded boxes).
- Tofacitinib and Jakafi were also evaluated in primary human macrophages.
- Primary human monocytes were obtained by elutriation and differentiated to terminally differentiated macrophages in the presence of m-CSF for 5 days. Cells were subsequently infected with VSV- pseudotyped HIV-1 (envelope region), allowing for 100 % infection rate of cultures. Cells were further cultured for 40 days until cultures were no longer producing HIV- 1. At this time, all macrophages are now resting, latently infected cells.
- PMA phorbol myristate acetate
- Tofacitinib and Jakafi inhibit reactivation of latent HIV-1 in primary human macrophages when drug is applied to cells during reactivation, but removed thereafter. Tofacitinib inhibits ⁇ 40 % of reactivation while Jakafi inhibits ⁇ 35 % of reactivation within 72 hr post reactivation.
- Example 26 Tofacitinib and Jakafi inhibit a pro-HIV cytokine (IFN-a) induced activation of the Jak-STAT pathway.
- IFN-a pro-HIV cytokine
- Tofacitinib and Jakafi inhibit a pro-HIV cytokine (IFN-a) induced activation of the Jak-STAT pathway.
- Jakafi and Tofacitinib inhibit IFN-a induced phosphorylation of STAT1, 3, and 5 in primary CD4+ T lymphocytes at sub- micromolar concentrations (A, B, C).
- Example 27 Tofacitinib and Jakafi inhibit a pro-HIV cytokine (IFN-a) induced activation of the Jak-STAT pathway.
- IFN-a pro-HIV cytokine
- Tofacitinib and Jakafi to inhibit a pro-HIV cytokine (IFN-a) induced activation of the Jak-STAT pathway was evaluated using techniques described above. Jakafi and Tofacitinib inhibit IFN-a induced phosphorylation of STAT1, 3, and 5 in primary CD4+ T lymphocytes at sub-micromolar concentrations, as shown below in Table 10. Both drugs also inhibit pSTATl, 3, and 5 with similar EC 50 /90 in CD8 T cells and CD14 monocytes (data not shown).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12852554.0A EP2785184B1 (en) | 2011-11-30 | 2012-11-30 | Compositions comprising jak inhibitors and haart drugs for use in the prevention or treatment of hiv |
BR112014013224-0A BR112014013224B1 (en) | 2011-11-30 | 2012-11-30 | ANTIVIRAL JAK INHIBITORS USEFUL IN THE TREATMENT OR PREVENTION OF RETROVIRAL AND OTHER VIRAL INFECTIONS |
MX2014006479A MX2014006479A (en) | 2011-11-30 | 2012-11-30 | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections. |
CN201710317607.6A CN107898790B (en) | 2011-11-30 | 2012-11-30 | Antiviral JAK inhibitors for the treatment or prevention of retroviral and other viral infections |
CN201280068590.0A CN104185420B (en) | 2011-11-30 | 2012-11-30 | Antiviral JAK inhibitor for treating or preventing retrovirus and other virus infection |
CA2856722A CA2856722C (en) | 2011-11-30 | 2012-11-30 | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
EP20176195.4A EP3750544A3 (en) | 2011-11-30 | 2012-11-30 | Jak inhibitors for use in the prevention or treatment of viral infection |
AU2012345732A AU2012345732B2 (en) | 2011-11-30 | 2012-11-30 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US14/360,905 US9089574B2 (en) | 2011-11-30 | 2012-11-30 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US14/808,860 US9662332B2 (en) | 2011-11-30 | 2015-07-24 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
AU2016244212A AU2016244212B2 (en) | 2011-11-30 | 2016-10-11 | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
US15/594,796 US10022378B2 (en) | 2011-11-30 | 2017-05-15 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US16/036,670 US10821111B2 (en) | 2011-11-30 | 2018-07-16 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US16/815,383 US11065254B2 (en) | 2011-11-30 | 2020-03-11 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US16/816,901 US11045474B2 (en) | 2011-11-30 | 2020-03-12 | Antiviral JAK inhibitors useful in treating or preventing coronaviridae infections |
US17/362,103 US11744831B2 (en) | 2011-11-30 | 2021-06-29 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US18/242,317 US20240173322A1 (en) | 2011-11-30 | 2023-09-05 | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161564994P | 2011-11-30 | 2011-11-30 | |
US61/564,994 | 2011-11-30 | ||
US201161570813P | 2011-12-14 | 2011-12-14 | |
US61/570,813 | 2011-12-14 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/360,905 A-371-Of-International US9089574B2 (en) | 2011-11-30 | 2012-11-30 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US14/808,860 Continuation US9662332B2 (en) | 2011-11-30 | 2015-07-24 | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013082476A1 true WO2013082476A1 (en) | 2013-06-06 |
Family
ID=48536118
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/067369 WO2013082476A1 (en) | 2011-11-30 | 2012-11-30 | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
Country Status (8)
Country | Link |
---|---|
US (3) | US9089574B2 (en) |
EP (2) | EP2785184B1 (en) |
CN (2) | CN107898790B (en) |
AU (2) | AU2012345732B2 (en) |
BR (1) | BR112014013224B1 (en) |
CA (2) | CA2856722C (en) |
MX (1) | MX2014006479A (en) |
WO (1) | WO2013082476A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9630968B1 (en) | 2015-12-23 | 2017-04-25 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
US9708326B2 (en) | 2013-02-25 | 2017-07-18 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
US10259816B2 (en) * | 2015-04-24 | 2019-04-16 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof |
WO2020092015A1 (en) * | 2018-11-02 | 2020-05-07 | University Of Rochester | Therapeutic mitigation of epithelial infection |
US11020398B2 (en) | 2016-08-24 | 2021-06-01 | Arqule, Inc. | Amino-pyrrolopyrimidinone compounds and methods of use thereof |
CN113248518A (en) * | 2021-06-21 | 2021-08-13 | 山东大学 | Pyrimidine piperazine derivative and preparation method and application thereof |
AU2020210312B2 (en) * | 2015-02-17 | 2022-10-20 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
US11865120B2 (en) | 2013-08-23 | 2024-01-09 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9295754B2 (en) | 2011-02-24 | 2016-03-29 | Emory University | Noggin inhibitory compositions for ossification and methods related thereto |
US10821111B2 (en) * | 2011-11-30 | 2020-11-03 | Emory University | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
US9089574B2 (en) * | 2011-11-30 | 2015-07-28 | Emory University | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
CA2953862A1 (en) * | 2014-07-07 | 2016-01-14 | F. Hoffmann-La Roche Ag | Dihydropyridopyrazine-1,8-diones and their use in the treatment, amelioration or prevention of viral diseases |
WO2016023082A1 (en) | 2014-08-12 | 2016-02-18 | Monash University | Lymph directing prodrugs |
CN105777754B (en) * | 2014-12-16 | 2019-07-26 | 北京赛林泰医药技术有限公司 | Pyrrolopyrimidine compounds |
WO2017007712A1 (en) * | 2015-07-04 | 2017-01-12 | Emory University | Use of trem-1 inhibitors for treatment, elimination and eradication of hiv-1 infection |
CN118063537A (en) | 2015-09-08 | 2024-05-24 | 莫纳什大学 | Prodrugs of directed lymphatics |
EP3381896B1 (en) * | 2015-11-27 | 2023-01-18 | Taiho Pharmaceutical Co., Ltd. | Biphenyl compound or salt thereof |
JP7366544B2 (en) | 2016-04-26 | 2023-10-23 | アデア ファーマシューティカルズ ユーエスエー, インク. | Biodegradable polymer microsphere composition for parenteral administration |
US11883497B2 (en) | 2017-08-29 | 2024-01-30 | Puretech Lyt, Inc. | Lymphatic system-directing lipid prodrugs |
US11608345B1 (en) | 2017-12-19 | 2023-03-21 | Puretech Lyt, Inc. | Lipid prodrugs of rapamycin and its analogs and uses thereof |
US11304954B2 (en) | 2017-12-19 | 2022-04-19 | Puretech Lyt, Inc. | Lipid prodrugs of mycophenolic acid and uses thereof |
EP3930709A4 (en) * | 2019-02-28 | 2022-11-09 | PureTech LYT, Inc. | Lipid prodrugs of jak inhibitors and uses thereof |
WO2020176868A1 (en) * | 2019-02-28 | 2020-09-03 | Puretech Lyt, Inc. | Lipid prodrugs of btk inhibitors and uses thereof |
CN110151765A (en) * | 2019-05-08 | 2019-08-23 | 武汉威立得生物医药有限公司 | Application of the AZD1480 in the drug of preparation treatment influenza infection |
CN112336859A (en) * | 2019-08-06 | 2021-02-09 | 上海绿谷制药有限公司 | Methods of treating alzheimer's disease by inhibiting amino acid uptake by T cells |
WO2021025625A1 (en) * | 2019-08-08 | 2021-02-11 | Agency For Science, Technology And Research | Compounds for hepatitis b treatment |
IL295362A (en) | 2020-02-05 | 2022-10-01 | Puretech Lyt Inc | Lipid prodrugs of neurosteroids |
WO2021206766A1 (en) | 2020-04-09 | 2021-10-14 | Children's Hospital Medical Center | Sars-cov-2 infection biomarkers and uses thereof |
US11324750B2 (en) | 2020-04-09 | 2022-05-10 | Children's Hospital Medical Center | Compositions and methods for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection |
WO2022056092A1 (en) * | 2020-09-11 | 2022-03-17 | Cti Biopharma Corp. | Methods of treating viral infection |
CN113321650B (en) * | 2021-05-20 | 2022-04-12 | 厦门大学 | 3-substituent-5- (substituted aryl) -7-azaindole derivative and application thereof |
Citations (157)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3342205A (en) | 1965-07-28 | 1967-09-19 | Mario J Quinto | Slide valve |
US4092905A (en) | 1976-02-17 | 1978-06-06 | Teleflex Incorporated | Axial piston pump |
US4262808A (en) | 1979-04-12 | 1981-04-21 | Laporte Joseph L | Apparatus for storage and selection of suspended sheets |
US4363608A (en) | 1981-04-20 | 1982-12-14 | Borg-Warner Corporation | Thrust bearing arrangement |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
US4622219A (en) | 1983-06-17 | 1986-11-11 | Haynes Duncan H | Method of inducing local anesthesia using microdroplets of a general anesthetic |
US4722905A (en) | 1981-12-01 | 1988-02-02 | National Research Development Corporation | Semiconductors |
US4725442A (en) | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
US4767628A (en) | 1981-02-16 | 1988-08-30 | Imperial Chemical Industries Plc | Continuous release pharmaceutical compositions |
WO1989002733A1 (en) | 1987-09-22 | 1989-04-06 | The Regents Of The University Of California | Liposomal nucleoside analogues for treating aids |
US4891225A (en) | 1984-05-21 | 1990-01-02 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
EP0350287A2 (en) | 1988-07-07 | 1990-01-10 | NeXstar Pharmaceuticals, Inc. | Lipid derivatives of antiviral nucleosides, liposomal incorporation and method of use |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4938763A (en) | 1988-10-03 | 1990-07-03 | Dunn Richard L | Biodegradable in-situ forming implants and methods of producing the same |
US4957744A (en) | 1986-10-13 | 1990-09-18 | Fidia, S.P.A. | Cross-linked esters of hyaluronic acid |
EP0109942B1 (en) | 1982-10-18 | 1991-03-06 | Bror Morein | Immunogenic protein or peptide complex, method of producing said complex and the use thereof as an immune stimulant and as a vaccine |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
WO1991016920A1 (en) | 1990-05-07 | 1991-11-14 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
WO1991018914A1 (en) | 1990-05-29 | 1991-12-12 | Vical, Inc. | Synthesis of glycerol di- and triphosphate derivatives |
WO1991019721A1 (en) | 1990-06-13 | 1991-12-26 | Arnold Glazier | Phosphorous produgs |
US5149794A (en) | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
WO1993000910A1 (en) | 1991-07-12 | 1993-01-21 | Vical, Inc. | Antiviral liponucleosides: treatment of hepatitis b |
US5194654A (en) | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
US5256641A (en) | 1990-11-01 | 1993-10-26 | State Of Oregon | Covalent polar lipid-peptide conjugates for immunological targeting |
WO1994026273A1 (en) | 1993-05-12 | 1994-11-24 | Hostetler Karl Y | Acyclovir derivatives for topical use |
EP0362279B1 (en) | 1987-05-29 | 1995-01-11 | Cambridge Biotech Corporation | Saponin adjuvant |
US5411947A (en) | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
US5419917A (en) | 1994-02-14 | 1995-05-30 | Andrx Pharmaceuticals, Inc. | Controlled release hydrogel formulation |
US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
US5458888A (en) | 1994-03-02 | 1995-10-17 | Andrx Pharmaceuticals, Inc. | Controlled release tablet formulation |
US5463092A (en) | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
US5472708A (en) | 1992-11-27 | 1995-12-05 | Andrx Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
US5494682A (en) | 1990-10-05 | 1996-02-27 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5505962A (en) | 1988-05-27 | 1996-04-09 | Elan Corporation, Plc | Controlled release pharmaceutical formulation |
US5508040A (en) | 1992-05-04 | 1996-04-16 | Andrx Pharmaceuticals, Inc. | Multiparticulate pulsatile drug delivery system |
WO1996011711A1 (en) | 1994-10-12 | 1996-04-25 | Iscotec Ab | Saponin preparations and use thereof in iscoms |
WO1996015132A1 (en) | 1994-11-15 | 1996-05-23 | The Regents Of The University Of California | Improved antiviral prodrugs |
US5533995A (en) | 1991-11-13 | 1996-07-09 | Elan Corporation, Plc | Passive transdermal device with controlled drug delivery |
US5540938A (en) | 1990-11-02 | 1996-07-30 | Elan Corporation, Plc | Formulations and their use in the treatment of neurological diseases |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5543389A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
US5545409A (en) | 1989-02-22 | 1996-08-13 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
US5554728A (en) | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
US5558879A (en) | 1995-04-28 | 1996-09-24 | Andrx Pharmaceuticals, Inc. | Controlled release formulation for water soluble drugs in which a passageway is formed in situ |
US5567441A (en) | 1995-03-24 | 1996-10-22 | Andrx Pharmaceuticals Inc. | Diltiazem controlled release formulation |
WO1996033739A1 (en) | 1995-04-25 | 1996-10-31 | Smithkline Beecham Biologicals S.A. | Vaccines containing a saponin and a sterol |
US5578325A (en) | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
WO1997005185A2 (en) | 1995-07-28 | 1997-02-13 | Focal, Inc. | Multiblock biodegradable hydrogels for use as controlled release agents for drugs delivery and tissue treatment agents |
US5616345A (en) | 1983-12-22 | 1997-04-01 | Elan Corporation Plc | Controlled absorption diltiazen formulation for once-daily administration |
US5626863A (en) | 1992-02-28 | 1997-05-06 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
US5637320A (en) | 1990-01-15 | 1997-06-10 | Elan Corporation, Plc | Controlled absorption naproxen formulation for once-daily administration |
US5641515A (en) | 1995-04-04 | 1997-06-24 | Elan Corporation, Plc | Controlled release biodegradable nanoparticles containing insulin |
US5641745A (en) | 1995-04-03 | 1997-06-24 | Elan Corporation, Plc | Controlled release biodegradable micro- and nanospheres containing cyclosporin |
US5718921A (en) | 1987-03-13 | 1998-02-17 | Massachusetts Institute Of Technology | Microspheres comprising polymer and drug dispersed there within |
US5728402A (en) | 1994-11-16 | 1998-03-17 | Andrx Pharmaceuticals Inc. | Controlled release formulation of captopril or a prodrug of captopril |
US5736159A (en) | 1995-04-28 | 1998-04-07 | Andrx Pharmaceuticals, Inc. | Controlled release formulation for water insoluble drugs in which a passageway is formed in situ |
US5749847A (en) | 1988-01-21 | 1998-05-12 | Massachusetts Institute Of Technology | Delivery of nucleotides into organisms by electroporation |
WO1999010008A1 (en) | 1997-08-29 | 1999-03-04 | Aquila Biopharmaceuticals, Inc. | Compositions comprising the adjuvant qs-21 and polysorbate or cyclodextrin as excipient |
US5994321A (en) | 1993-12-20 | 1999-11-30 | Aronex Pharmaceuticals, Inc. | Antiviral guanine analogs |
US20030157135A1 (en) | 2001-07-25 | 2003-08-21 | New York University | Use of glycosylceramides as adjuvants for vaccines against infections and cancer |
US6610847B2 (en) | 1998-06-19 | 2003-08-26 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US20030162775A1 (en) | 1999-11-04 | 2003-08-28 | Cephalon, Inc. | Heterocyclic substituted pyrazolones |
US6627754B2 (en) | 1999-12-10 | 2003-09-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US6635762B1 (en) | 1998-06-19 | 2003-10-21 | Pfizer Inc. | Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use |
US6696567B2 (en) | 2000-06-26 | 2004-02-24 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US20040121316A1 (en) | 2002-04-26 | 2004-06-24 | Gilead Sciences, Inc. | Method and compositions for identifying anti-HIV therapeutic compounds |
US20040157804A1 (en) | 2002-10-16 | 2004-08-12 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
US20040186157A1 (en) | 1999-02-12 | 2004-09-23 | Cephalon, Inc. | Cyclic substituted fused pyrrolocarbazoles and isoindolones |
US20040224917A1 (en) | 2003-01-14 | 2004-11-11 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20050059637A1 (en) | 2003-07-30 | 2005-03-17 | Gilead Sciences, Inc. | Nucleobase phosphonate analogs for antiviral treatment |
US20050137199A1 (en) | 2003-09-19 | 2005-06-23 | Gilead Sciences, Inc. | Aza-quinolinol phosphonate integrase inhibitor compounds |
US20050239753A1 (en) | 2004-01-21 | 2005-10-27 | Gilead Sciences, Inc. | Methods of inhibition of MMTV-like viruses |
US20050282839A1 (en) | 2004-01-12 | 2005-12-22 | Gilead Sciences, Inc. | Pyrimidyl phosphonate antiviral compounds and methods of use |
US20060172973A1 (en) | 2005-01-31 | 2006-08-03 | Vasu Nair | Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase |
WO2006096270A1 (en) | 2005-02-03 | 2006-09-14 | Vertex Pharmaceuticals Incorporated | Pyrrolopyrimidines useful as inhibitors of protein kinase |
US7125855B2 (en) | 2001-01-22 | 2006-10-24 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US20060276466A1 (en) | 2004-05-28 | 2006-12-07 | Naidu B N | Bicyclic heterocycles as HIV integrase inhibitors |
US20060293334A1 (en) | 2001-03-01 | 2006-12-28 | Masahiro Fuji | Nitrogen-containing heteroaryl compounds having inhibitory activity against HIV integrase |
WO2007019098A2 (en) | 2005-08-04 | 2007-02-15 | Smithkline Beecham Corporation | Hiv integrase inhibitors |
US20070049754A1 (en) | 2004-07-27 | 2007-03-01 | Gilead Sciences, Inc. | Phosphonate analogs of HIV inhibitor compounds |
US20070072831A1 (en) | 2005-05-16 | 2007-03-29 | Gilead Sciences, Inc. | Integrase inhibitor compounds |
WO2007050668A1 (en) | 2005-10-25 | 2007-05-03 | Ludwig Institute For Cancer Research | Analogs of alpha galactosylceramide and uses thereof |
US20070111984A1 (en) | 2005-11-17 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20070111985A1 (en) | 2005-11-16 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20070112190A1 (en) | 2005-11-15 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20070123524A1 (en) | 2001-10-26 | 2007-05-31 | Benedetta Crescenzi | N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase |
US20070129379A1 (en) | 2005-12-01 | 2007-06-07 | Bristol-Myers Squibb Company | Hiv integrase inhibitors |
US20070161639A1 (en) | 2004-03-09 | 2007-07-12 | Philip Jones | Hiv integrase inhibitors |
US20070179196A1 (en) | 2004-03-09 | 2007-08-02 | Wei Han | Hiv integrase inhibitors |
US20070249031A1 (en) | 2005-11-03 | 2007-10-25 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20070281917A1 (en) | 2006-05-30 | 2007-12-06 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20080004265A1 (en) | 2006-06-28 | 2008-01-03 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20080009490A1 (en) | 2004-03-09 | 2008-01-10 | Williams Peter D | Hiv Integrase Inhibitors |
US20080015187A1 (en) | 2004-06-09 | 2008-01-17 | Wai John S | Hiv Integrase Inhibitors |
US20080021013A1 (en) | 2006-07-21 | 2008-01-24 | Cephalon, Inc. | JAK inhibitors for treatment of myeloproliferative disorders |
US20080020010A1 (en) | 2006-07-19 | 2008-01-24 | The University Of Georgia Research Foundation, Inc. | Pyridinone diketo acids: inhibitors of HIV replication |
US20080039487A1 (en) | 2005-12-21 | 2008-02-14 | Gilead Sciences, Llc | Processes and intermediates useful for preparing integrase inhibitor compounds |
US20080039457A1 (en) | 2006-08-07 | 2008-02-14 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
US20080058315A1 (en) | 2006-05-16 | 2008-03-06 | Cai Zhenhong R | Integrase inhibitors |
US20080070920A1 (en) | 2006-07-24 | 2008-03-20 | Hongyan Guo | Novel HIV reverse transcriptase inhibitors |
US20080125594A1 (en) | 2006-09-12 | 2008-05-29 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
US20080139579A1 (en) | 2004-03-09 | 2008-06-12 | Merck & Co., Inc. | Hiv Integrase Inhibitors |
US20080153783A1 (en) | 2004-01-12 | 2008-06-26 | Gilead Sciences, Inc. | Pyrimidyl Phosphonate Antiviral Compounds and Methods of Use |
US20080161350A1 (en) | 2002-05-17 | 2008-07-03 | Bioalliance Pharma Sa | Use of quinoline derivatives with anti-integrase effect and applications thereof |
US20080167287A1 (en) | 2006-11-22 | 2008-07-10 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
US7399787B2 (en) | 2002-03-04 | 2008-07-15 | Merck Hdac Research, Llc | Methods of treating cancer with HDAC inhibitors |
US20080188500A1 (en) | 2006-12-22 | 2008-08-07 | Incyte Corporation | Substituted heterocycles as janus kinase inhibitors |
US20080207618A1 (en) | 2006-06-23 | 2008-08-28 | Motohide Satoh | 6- (Heterocyclyl-substituted Benzyl) -4-Oxoquinoline Compound and Use Thereof as HIV Integrase Inhibitor |
US20080221154A1 (en) | 2002-10-31 | 2008-09-11 | Pfizer Inc | Hiv-integrase inhibitors, pharmaceutical compositions, and methods for their use |
WO2008109517A1 (en) | 2007-03-02 | 2008-09-12 | University Of South Florida | Neurodegenerative disease treatment using jak/stat inhibition |
US20080261973A1 (en) | 2005-12-22 | 2008-10-23 | Novartis Ag | Sulphonamidoaniline Derivatives Being Janus Kinase Inhibitors |
US20080287394A1 (en) | 2004-05-07 | 2008-11-20 | Merck & Co., Inc. | Hiv Integrase Inhibitors |
US20080306051A1 (en) | 2007-06-06 | 2008-12-11 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20080312259A1 (en) | 2007-06-13 | 2008-12-18 | Incyte Corporation | SALTS OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20080312258A1 (en) | 2007-06-13 | 2008-12-18 | Incyte Corporation | METABOLITES OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20090018162A1 (en) | 2006-02-01 | 2009-01-15 | Yuji Matsuzaki | Use of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or salt thereof for treating retrovirus infection |
US20090035324A1 (en) | 2007-07-09 | 2009-02-05 | Concert Pharmaceuticals, Inc. | Novel pyrimidinecarboxamide derivatives |
US20090047252A1 (en) | 2007-06-29 | 2009-02-19 | Gilead Sciences, Inc. | Antiviral compounds |
WO2009045975A1 (en) * | 2007-10-02 | 2009-04-09 | Rfs Pharma, Llc | Potent combinations of zidovudine and drugs that select for the k65r mutation in the hiv polymerase |
US20090093467A1 (en) | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
US20090093482A1 (en) | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
US20090099366A1 (en) | 2007-09-11 | 2009-04-16 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
US20090098137A1 (en) | 2006-04-05 | 2009-04-16 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
US20090175820A1 (en) | 2008-01-04 | 2009-07-09 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 |
US20090181959A1 (en) | 2005-12-13 | 2009-07-16 | Incyte Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
US20090181902A1 (en) | 2007-07-06 | 2009-07-16 | Gilead Sciences,Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20090186869A1 (en) | 2007-06-29 | 2009-07-23 | Gilead Sciences, Inc. | Antiviral compounds |
US20090197869A1 (en) | 2005-09-22 | 2009-08-06 | Incyte Corporation, A Delaware Corporation | Azepine inhibitors of janus kinases |
US20090215766A1 (en) | 2004-04-28 | 2009-08-27 | Incyte Corporation | Tetracyclic inhibitors of janus kinases |
US20090221571A1 (en) | 2005-10-04 | 2009-09-03 | Vincenzo Summa | Hiv integrase inhibitors |
US20090227621A1 (en) | 2004-02-04 | 2009-09-10 | Teruhiko Taishi | Naphthyridine derivatives having inhibitory activity against hiv integrase |
US20090233964A1 (en) | 2005-12-30 | 2009-09-17 | Gilead Sciences, Inc. | Methods for improving the pharmacokinetics of hiv integrase inhibitors |
US20090233903A1 (en) | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
US7593820B2 (en) * | 2005-05-12 | 2009-09-22 | Cytopia Research Pty Ltd | Crystal structure of human Janus Kinase 2 (JAK2) and uses thereof |
US20090257978A1 (en) | 2007-06-29 | 2009-10-15 | Gilead Sciences, Inc. | Antiviral coumpounds |
US20090286778A1 (en) | 2008-04-24 | 2009-11-19 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
US20090291952A1 (en) | 2006-07-07 | 2009-11-26 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20090291921A1 (en) | 2007-11-20 | 2009-11-26 | Gilead Sciences, Inc. | Integrase inhibitors |
US20090318405A1 (en) | 2007-11-16 | 2009-12-24 | Incyte Corporation | 4-pyrazolyl-n-arylpyrimidin-2-amines and 4-pyrazolyl-n-heteroarylpyrimidin-2-amines as janus kinase inhibitors |
US20100009978A1 (en) | 2006-09-15 | 2010-01-14 | Novartis Ag | Benzoxazoles and Oxazolopyridines Being Useful as Janus Kinases Inhibitors |
US20100081645A1 (en) | 2005-11-15 | 2010-04-01 | Vertex Pharmaceuticals Incorporated | Tricyclic heteroaryl compounds useful as inhibitors of janus kinase |
US20100081657A1 (en) | 2003-12-04 | 2010-04-01 | Vertex Pharmaceuticals Incorporated | Quinoxalines useful as inhibitors of protein kinases |
US20100160287A1 (en) | 2007-03-22 | 2010-06-24 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of janus kinases |
US20100190804A1 (en) | 2009-01-23 | 2010-07-29 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
US7803805B2 (en) | 2001-12-06 | 2010-09-28 | Pfizer Inc. | Cristalline 3-{(3R,4R)-4 methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt |
US20100280026A1 (en) | 2003-10-14 | 2010-11-04 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of protein kinases |
US20100311693A1 (en) | 2009-06-05 | 2010-12-09 | Cephalon, Inc. | Preparation and Uses of 1,2,4-Triazolo [1,5a] Pyridine Derivatives |
US20100311743A1 (en) | 2006-01-17 | 2010-12-09 | Vertex Pharmaceuticals Incorporated | Azaindoles Useful as Inhibitors of Janus Kinases |
US20110086835A1 (en) | 2004-12-22 | 2011-04-14 | Incyte Corporation, A Delaware Corporation | Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-5-yl-amines as janus kinase inhibitors |
US20110086810A1 (en) | 2009-10-09 | 2011-04-14 | Incyte Corporation | HYDROXYL, KETO, AND GLUCURONIDE DERIVATIVES OF 3-(4-(7H-PYRROLO[2,3-d] PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20110092499A1 (en) | 2007-11-15 | 2011-04-21 | Ym Biosciences Australia Pty Ltd | N-containing heterocyclic compounds |
US20110118255A1 (en) | 2007-12-19 | 2011-05-19 | Vertex Pharmaceuticals Incorporated | PYRAZOLO[1,5-a]PYRIMIDINES USEFUL AS JAK2 INHIBITORS |
US20110207754A1 (en) | 2010-02-18 | 2011-08-25 | Incyte Corporation | Cyclobutane and methylcyclobutane derivatives as janus kinase inhibitors |
WO2011109217A2 (en) | 2010-03-02 | 2011-09-09 | Immunodiagnostics, Inc. | Methods of treating or preventing rna polymerase dependent viral disorders by administration of jak2 kinase inhibitors |
US20110245256A1 (en) | 2010-03-30 | 2011-10-06 | Novartis Ag | Use of a pkc inhibitor |
US9785906B2 (en) | 2002-11-27 | 2017-10-10 | Accenture Global Services Limited | Content feedback in a multiple-owner content management system |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5026687A (en) | 1990-01-03 | 1991-06-25 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds |
ES2152922T3 (en) | 1990-04-06 | 2001-02-16 | Genelabs Tech Inc | HEPATITIS VIRUS VIRUS EPITHOPES. |
US5610054A (en) | 1992-05-14 | 1997-03-11 | Ribozyme Pharmaceuticals, Inc. | Enzymatic RNA molecule targeted against Hepatitis C virus |
WO1994019012A2 (en) | 1993-02-24 | 1994-09-01 | Wang Jui H | Compositions and methods of application of reactive antiviral polymers |
CA2167537A1 (en) | 1993-07-19 | 1995-02-02 | Tsuneo Ozeki | Hepatitis c virus proliferation inhibitor |
DE4447588C2 (en) | 1994-05-03 | 1997-11-20 | Omer Osama Dr Dr Med | Treatment of herpes and hepatitis virus infections and bronchitis |
DE4432623A1 (en) | 1994-09-14 | 1996-03-21 | Huels Chemische Werke Ag | Process for bleaching aqueous surfactant solutions |
JP3786447B2 (en) | 1995-03-31 | 2006-06-14 | エーザイ株式会社 | Preventive and therapeutic agent for hepatitis C |
EP0914421A2 (en) | 1996-02-29 | 1999-05-12 | Immusol, Inc. | Hepatitis c virus ribozymes |
US5633388A (en) | 1996-03-29 | 1997-05-27 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5830905A (en) | 1996-03-29 | 1998-11-03 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
US5990276A (en) | 1996-05-10 | 1999-11-23 | Schering Corporation | Synthetic inhibitors of hepatitis C virus NS3 protease |
US5891874A (en) | 1996-06-05 | 1999-04-06 | Eli Lilly And Company | Anti-viral compound |
US5837257A (en) | 1996-07-09 | 1998-11-17 | Sage R&D | Use of plant extracts for treatment of HIV, HCV and HBV infections |
JP3927630B2 (en) | 1996-09-27 | 2007-06-13 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Preventive and therapeutic agents for viral infections |
US5922757A (en) | 1996-09-30 | 1999-07-13 | The Regents Of The University Of California | Treatment and prevention of hepatic disorders |
CA2268391A1 (en) | 1996-10-18 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
IL119833A (en) | 1996-12-15 | 2001-01-11 | Lavie David | Hypericum perforatum extracts for the preparation of pharmaceutical compositions for the treatment of hepatitis |
US6004933A (en) | 1997-04-25 | 1999-12-21 | Cortech Inc. | Cysteine protease inhibitors |
EA002254B1 (en) | 1997-06-30 | 2002-02-28 | Мерц + Ко. Гмбх Унд Ко. | 1-amino-alkylcyclohexane nmda receptor antagonists |
ES2234144T3 (en) | 1997-08-11 | 2005-06-16 | Boehringer Ingelheim (Canada) Ltd. | ANALOGS OF INHIBITING PEPTIDES OF HEPATITIS C. |
KR100954390B1 (en) | 1998-02-25 | 2010-04-26 | 에모리 유니버시티 | 2'-Fluoronucleosides |
GB9806815D0 (en) | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
US6323180B1 (en) | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
US6566365B1 (en) | 1999-11-04 | 2003-05-20 | Biochem Pharma Inc. | Method for the treatment of Flaviviridea viral infection using nucleoside analogues |
WO2001060315A2 (en) | 2000-02-18 | 2001-08-23 | Shire Biochem Inc. | Method for the treatment or prevention of flavivirus infections using nucleoside analogues |
CN100457118C (en) | 2000-04-13 | 2009-02-04 | 法玛塞特有限公司 | 3'-or 2'-hydroxymethyl substd. nucleoside derivs. for treatment of hepatitis virus infections |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
NZ547204A (en) | 2000-05-26 | 2008-01-31 | Idenix Cayman Ltd | Methods and compositions for treating flaviviruses and pestiviruses |
CN1446201A (en) | 2000-07-21 | 2003-10-01 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
AR034127A1 (en) | 2000-07-21 | 2004-02-04 | Schering Corp | IMIDAZOLIDINONES AS INHIBITORS OF NS3-SERINA PROTEASA OF THE HEPATITIS C VIRUS, PHARMACEUTICAL COMPOSITION, A METHOD FOR THEIR PREPARATION, AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
AR029851A1 (en) | 2000-07-21 | 2003-07-16 | Dendreon Corp | NEW PEPTIDES AS INHIBITORS OF NS3-SERINA PROTEASA DEL VIRUS DE HEPATITIS C |
JP2004504407A (en) | 2000-07-21 | 2004-02-12 | コルバス・インターナショナル・インコーポレイテッド | Novel peptide as NS3-serine protease inhibitor of hepatitis C virus |
US20030008841A1 (en) | 2000-08-30 | 2003-01-09 | Rene Devos | Anti-HCV nucleoside derivatives |
CN1646141B (en) | 2000-10-18 | 2014-06-25 | 吉利德制药有限责任公司 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
AU2002248147B2 (en) | 2000-11-20 | 2006-04-06 | Bristol-Myers Squibb Company | Hepatitis C tripeptide inhibitors |
KR20030091946A (en) | 2000-12-12 | 2003-12-03 | 쉐링 코포레이션 | Diaryl peptides as NS3-serine protease inhibitors of hepatitis C virus |
US6727366B2 (en) | 2000-12-13 | 2004-04-27 | Bristol-Myers Squibb Pharma Company | Imidazolidinones and their related derivatives as hepatitis C virus NS3 protease inhibitors |
US6653295B2 (en) | 2000-12-13 | 2003-11-25 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus NS3 protease |
AU2002230763A1 (en) | 2000-12-13 | 2008-01-03 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
KR20030081343A (en) | 2000-12-15 | 2003-10-17 | 파마셋, 리미티드 | Antiviral agents for treatment of flaviviridae infections |
US7105499B2 (en) | 2001-01-22 | 2006-09-12 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
IL157478A0 (en) | 2001-03-01 | 2004-03-28 | Pharmasset Ltd | Method for the synthesis of 2', 3'-didehydronucleosides |
US20040209831A1 (en) | 2002-02-20 | 2004-10-21 | Mcswiggen James | RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA) |
GB0112617D0 (en) | 2001-05-23 | 2001-07-18 | Hoffmann La Roche | Antiviral nucleoside derivatives |
US7301023B2 (en) | 2001-05-31 | 2007-11-27 | Pfizer Inc. | Chiral salt resolution |
GB0114286D0 (en) | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
US7022323B2 (en) | 2001-06-26 | 2006-04-04 | Progenics Pharmaceuticals, Inc. | Uses of DC-SIGN and DC-SIGNR for inhibiting hepatitis C virus infection |
US6867185B2 (en) | 2001-12-20 | 2005-03-15 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
CA2369970A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
US6642204B2 (en) | 2002-02-01 | 2003-11-04 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
CA2370396A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
US7091184B2 (en) | 2002-02-01 | 2006-08-15 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
GB2397062B (en) | 2002-02-20 | 2005-06-15 | Sirna Therapeutics Inc | RNA interference mediated inhibition of hepatitis c virus (HCV) gene expression using short interfering nucleic acid (siNA) |
ATE503764T1 (en) | 2002-05-20 | 2011-04-15 | Bristol Myers Squibb Co | HEPATITIS C VIRUS INHIBITORS |
MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
JP4271148B2 (en) | 2002-05-20 | 2009-06-03 | ブリストル−マイヤーズ スクイブ カンパニー | Substituted cycloalkyl P1 'hepatitis C virus inhibitors |
ES2350201T3 (en) | 2002-05-20 | 2011-01-20 | Bristol-Myers Squibb Company | HETEROCYCLIC SULPHAMIDES AS INHIBITORS OF HEPATITIS C VIRUS. |
MXPA04012709A (en) | 2002-06-28 | 2005-09-30 | Idenix Cayman Ltd | Modified 2' and 3' -nucleoside produgs for treating flaviridae infections. |
KR20050055630A (en) | 2002-06-28 | 2005-06-13 | 이데닉스 (케이만) 리미티드 | 1'-, 2' and 3'-modified nucleoside derivatives for treating flaviviridae infections |
JP2005533824A (en) | 2002-06-28 | 2005-11-10 | イデニクス(ケイマン)リミテツド | 2'-C-methyl-3'-OL-valine ester ribofuranosyl cytidine for the treatment of Flaviviridae infections |
TWI332507B (en) | 2002-11-19 | 2010-11-01 | Hoffmann La Roche | Antiviral nucleoside derivatives |
US7601709B2 (en) | 2003-02-07 | 2009-10-13 | Enanta Pharmaceuticals, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
WO2005003147A2 (en) | 2003-05-30 | 2005-01-13 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
JP2006527719A (en) | 2003-06-19 | 2006-12-07 | エフ.ホフマン−ラ ロシュ アーゲー | Method for preparing 4'-azidonucleoside derivatives |
US20050043266A1 (en) | 2003-07-25 | 2005-02-24 | Sumedha Jayasena | Short interfering RNA as an antiviral agent for hepatitis C |
RU2006115558A (en) | 2003-10-10 | 2007-11-20 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | SERINE PROTEASES INHIBITORS, ESPECIALLY HCV NS3-NS4A PROTEASES |
WO2006000085A1 (en) | 2004-06-28 | 2006-01-05 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
CA2577526A1 (en) | 2004-08-23 | 2006-03-02 | Joseph Armstrong Martin | Antiviral 4'-azido-nucleosides |
JP2008511633A (en) | 2004-08-27 | 2008-04-17 | シェーリング コーポレイション | Acylsulfonamide compounds as inhibitors of hepatitis C virus NS3 serine protease |
WO2007001406A2 (en) | 2004-10-05 | 2007-01-04 | Chiron Corporation | Aryl-containing macrocyclic compounds |
CA2606195C (en) | 2005-05-02 | 2015-03-31 | Merck And Co., Inc. | Hcv ns3 protease inhibitors |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
ES2458358T3 (en) | 2008-07-02 | 2014-05-05 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
CN101401807B (en) * | 2008-11-10 | 2010-09-29 | 广州医学院第一附属医院 | Uses of selective JAK3 restrainer VI in antiviral mediated acute lung damnification |
EP3222628A1 (en) | 2008-12-23 | 2017-09-27 | Gilead Pharmasset LLC | Nucleoside phosphoramidates |
US8155811B2 (en) | 2008-12-29 | 2012-04-10 | General Electric Company | System and method for optimizing a path for a marine vessel through a waterway |
TWI576352B (en) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | Nucleoside phosphoramidates |
WO2011123586A1 (en) | 2010-04-01 | 2011-10-06 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
US9089574B2 (en) * | 2011-11-30 | 2015-07-28 | Emory University | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
-
2012
- 2012-11-30 US US14/360,905 patent/US9089574B2/en active Active
- 2012-11-30 EP EP12852554.0A patent/EP2785184B1/en active Active
- 2012-11-30 CA CA2856722A patent/CA2856722C/en active Active
- 2012-11-30 AU AU2012345732A patent/AU2012345732B2/en active Active
- 2012-11-30 EP EP20176195.4A patent/EP3750544A3/en active Pending
- 2012-11-30 CN CN201710317607.6A patent/CN107898790B/en active Active
- 2012-11-30 BR BR112014013224-0A patent/BR112014013224B1/en active IP Right Grant
- 2012-11-30 WO PCT/US2012/067369 patent/WO2013082476A1/en active Application Filing
- 2012-11-30 CA CA3131037A patent/CA3131037A1/en active Pending
- 2012-11-30 MX MX2014006479A patent/MX2014006479A/en unknown
- 2012-11-30 CN CN201280068590.0A patent/CN104185420B/en active Active
-
2015
- 2015-07-24 US US14/808,860 patent/US9662332B2/en active Active
-
2016
- 2016-10-11 AU AU2016244212A patent/AU2016244212B2/en active Active
-
2017
- 2017-05-15 US US15/594,796 patent/US10022378B2/en active Active
Patent Citations (199)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3342205A (en) | 1965-07-28 | 1967-09-19 | Mario J Quinto | Slide valve |
US4092905A (en) | 1976-02-17 | 1978-06-06 | Teleflex Incorporated | Axial piston pump |
US4262808A (en) | 1979-04-12 | 1981-04-21 | Laporte Joseph L | Apparatus for storage and selection of suspended sheets |
US4767628A (en) | 1981-02-16 | 1988-08-30 | Imperial Chemical Industries Plc | Continuous release pharmaceutical compositions |
US4767628B1 (en) | 1981-02-16 | 1990-07-17 | Ici Plc | |
US4363608A (en) | 1981-04-20 | 1982-12-14 | Borg-Warner Corporation | Thrust bearing arrangement |
US4722905A (en) | 1981-12-01 | 1988-02-02 | National Research Development Corporation | Semiconductors |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
EP0109942B1 (en) | 1982-10-18 | 1991-03-06 | Bror Morein | Immunogenic protein or peptide complex, method of producing said complex and the use thereof as an immune stimulant and as a vaccine |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4725442A (en) | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
US4622219A (en) | 1983-06-17 | 1986-11-11 | Haynes Duncan H | Method of inducing local anesthesia using microdroplets of a general anesthetic |
US5616345A (en) | 1983-12-22 | 1997-04-01 | Elan Corporation Plc | Controlled absorption diltiazen formulation for once-daily administration |
US4891225A (en) | 1984-05-21 | 1990-01-02 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4957744A (en) | 1986-10-13 | 1990-09-18 | Fidia, S.P.A. | Cross-linked esters of hyaluronic acid |
US5718921A (en) | 1987-03-13 | 1998-02-17 | Massachusetts Institute Of Technology | Microspheres comprising polymer and drug dispersed there within |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
EP0362279B1 (en) | 1987-05-29 | 1995-01-11 | Cambridge Biotech Corporation | Saponin adjuvant |
WO1989002733A1 (en) | 1987-09-22 | 1989-04-06 | The Regents Of The University Of California | Liposomal nucleoside analogues for treating aids |
US5749847A (en) | 1988-01-21 | 1998-05-12 | Massachusetts Institute Of Technology | Delivery of nucleotides into organisms by electroporation |
US5505962A (en) | 1988-05-27 | 1996-04-09 | Elan Corporation, Plc | Controlled release pharmaceutical formulation |
US5223263A (en) | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
EP0350287A2 (en) | 1988-07-07 | 1990-01-10 | NeXstar Pharmaceuticals, Inc. | Lipid derivatives of antiviral nucleosides, liposomal incorporation and method of use |
WO1990000555A1 (en) | 1988-07-07 | 1990-01-25 | Vical, Inc. | Lipid derivatives of antiviral nucleosides, liposomal incorporation and method of use |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US4938763A (en) | 1988-10-03 | 1990-07-03 | Dunn Richard L | Biodegradable in-situ forming implants and methods of producing the same |
US5629009A (en) | 1989-02-22 | 1997-05-13 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
US5545409A (en) | 1989-02-22 | 1996-08-13 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
US5411947A (en) | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
US5194654A (en) | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
US5463092A (en) | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
US5637320A (en) | 1990-01-15 | 1997-06-10 | Elan Corporation, Plc | Controlled absorption naproxen formulation for once-daily administration |
WO1991016920A1 (en) | 1990-05-07 | 1991-11-14 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
WO1991018914A1 (en) | 1990-05-29 | 1991-12-12 | Vical, Inc. | Synthesis of glycerol di- and triphosphate derivatives |
WO1991019721A1 (en) | 1990-06-13 | 1991-12-26 | Arnold Glazier | Phosphorous produgs |
US5494682A (en) | 1990-10-05 | 1996-02-27 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
US5256641A (en) | 1990-11-01 | 1993-10-26 | State Of Oregon | Covalent polar lipid-peptide conjugates for immunological targeting |
US5149794A (en) | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
US5543390A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5543389A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
US5543391A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5580580A (en) | 1990-11-02 | 1996-12-03 | Elan Corporation, Plc | Formulations and their use in the treatment of neurological diseases |
US5540938A (en) | 1990-11-02 | 1996-07-30 | Elan Corporation, Plc | Formulations and their use in the treatment of neurological diseases |
WO1993000910A1 (en) | 1991-07-12 | 1993-01-21 | Vical, Inc. | Antiviral liponucleosides: treatment of hepatitis b |
US5554728A (en) | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
US5533995A (en) | 1991-11-13 | 1996-07-09 | Elan Corporation, Plc | Passive transdermal device with controlled drug delivery |
US5626863A (en) | 1992-02-28 | 1997-05-06 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
US5508040A (en) | 1992-05-04 | 1996-04-16 | Andrx Pharmaceuticals, Inc. | Multiparticulate pulsatile drug delivery system |
US5472708A (en) | 1992-11-27 | 1995-12-05 | Andrx Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
WO1994026273A1 (en) | 1993-05-12 | 1994-11-24 | Hostetler Karl Y | Acyclovir derivatives for topical use |
US5578325A (en) | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US5994321A (en) | 1993-12-20 | 1999-11-30 | Aronex Pharmaceuticals, Inc. | Antiviral guanine analogs |
US5419917A (en) | 1994-02-14 | 1995-05-30 | Andrx Pharmaceuticals, Inc. | Controlled release hydrogel formulation |
US5458888A (en) | 1994-03-02 | 1995-10-17 | Andrx Pharmaceuticals, Inc. | Controlled release tablet formulation |
WO1996011711A1 (en) | 1994-10-12 | 1996-04-25 | Iscotec Ab | Saponin preparations and use thereof in iscoms |
WO1996015132A1 (en) | 1994-11-15 | 1996-05-23 | The Regents Of The University Of California | Improved antiviral prodrugs |
US5728402A (en) | 1994-11-16 | 1998-03-17 | Andrx Pharmaceuticals Inc. | Controlled release formulation of captopril or a prodrug of captopril |
US5567441A (en) | 1995-03-24 | 1996-10-22 | Andrx Pharmaceuticals Inc. | Diltiazem controlled release formulation |
US5641745A (en) | 1995-04-03 | 1997-06-24 | Elan Corporation, Plc | Controlled release biodegradable micro- and nanospheres containing cyclosporin |
US5641515A (en) | 1995-04-04 | 1997-06-24 | Elan Corporation, Plc | Controlled release biodegradable nanoparticles containing insulin |
WO1996033739A1 (en) | 1995-04-25 | 1996-10-31 | Smithkline Beecham Biologicals S.A. | Vaccines containing a saponin and a sterol |
US5558879A (en) | 1995-04-28 | 1996-09-24 | Andrx Pharmaceuticals, Inc. | Controlled release formulation for water soluble drugs in which a passageway is formed in situ |
US5736159A (en) | 1995-04-28 | 1998-04-07 | Andrx Pharmaceuticals, Inc. | Controlled release formulation for water insoluble drugs in which a passageway is formed in situ |
WO1997005185A2 (en) | 1995-07-28 | 1997-02-13 | Focal, Inc. | Multiblock biodegradable hydrogels for use as controlled release agents for drugs delivery and tissue treatment agents |
WO1999010008A1 (en) | 1997-08-29 | 1999-03-04 | Aquila Biopharmaceuticals, Inc. | Compositions comprising the adjuvant qs-21 and polysorbate or cyclodextrin as excipient |
US6635762B1 (en) | 1998-06-19 | 2003-10-21 | Pfizer Inc. | Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use |
US6610847B2 (en) | 1998-06-19 | 2003-08-26 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US6890929B2 (en) | 1998-06-19 | 2005-05-10 | Pfizer, Inc. | Pyrrolo [2,3-D] pyrimidine compounds |
US7687507B2 (en) | 1998-06-19 | 2010-03-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US7569569B2 (en) | 1998-06-19 | 2009-08-04 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US20040186157A1 (en) | 1999-02-12 | 2004-09-23 | Cephalon, Inc. | Cyclic substituted fused pyrrolocarbazoles and isoindolones |
US20060128780A1 (en) | 1999-02-12 | 2006-06-15 | Cephalon, Inc. | Cyclic substituted fused pyrrolocarbazoles and isoindolones |
US20030162775A1 (en) | 1999-11-04 | 2003-08-28 | Cephalon, Inc. | Heterocyclic substituted pyrazolones |
US7601727B2 (en) | 1999-12-10 | 2009-10-13 | Pfizer, Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US6627754B2 (en) | 1999-12-10 | 2003-09-30 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US7091208B2 (en) | 1999-12-10 | 2006-08-15 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine compounds |
US7842699B2 (en) | 1999-12-10 | 2010-11-30 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine compounds |
USRE41783E1 (en) | 1999-12-10 | 2010-09-28 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine compounds |
US7192963B2 (en) | 2000-06-26 | 2007-03-20 | Pfizer Inc | Pyrrolo[2,3-d]pyrimidine compounds |
US6696567B2 (en) | 2000-06-26 | 2004-02-24 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US6962993B2 (en) | 2000-06-26 | 2005-11-08 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidine compounds |
US7125855B2 (en) | 2001-01-22 | 2006-10-24 | Merck & Co., Inc. | Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase |
US20060293334A1 (en) | 2001-03-01 | 2006-12-28 | Masahiro Fuji | Nitrogen-containing heteroaryl compounds having inhibitory activity against HIV integrase |
US20030157135A1 (en) | 2001-07-25 | 2003-08-21 | New York University | Use of glycosylceramides as adjuvants for vaccines against infections and cancer |
US20070123524A1 (en) | 2001-10-26 | 2007-05-31 | Benedetta Crescenzi | N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase |
US7803805B2 (en) | 2001-12-06 | 2010-09-28 | Pfizer Inc. | Cristalline 3-{(3R,4R)-4 methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt |
US7399787B2 (en) | 2002-03-04 | 2008-07-15 | Merck Hdac Research, Llc | Methods of treating cancer with HDAC inhibitors |
US20060128692A1 (en) | 2002-04-26 | 2006-06-15 | Gilead Sciences, Inc | Non nucleoside reverse transcriptase inhibitors |
US20050209197A1 (en) | 2002-04-26 | 2005-09-22 | Gilead Sciences, Inc. | Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds |
US20050197320A1 (en) | 2002-04-26 | 2005-09-08 | Gilead Sciences, Inc. | Non nucleoside reverse transcriptase inhibitors |
US20040121316A1 (en) | 2002-04-26 | 2004-06-24 | Gilead Sciences, Inc. | Method and compositions for identifying anti-HIV therapeutic compounds |
US20080161350A1 (en) | 2002-05-17 | 2008-07-03 | Bioalliance Pharma Sa | Use of quinoline derivatives with anti-integrase effect and applications thereof |
US20040167124A1 (en) | 2002-10-16 | 2004-08-26 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
US20040157804A1 (en) | 2002-10-16 | 2004-08-12 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
US20090029939A1 (en) | 2002-10-16 | 2009-01-29 | Chen James M | Pre-organized tricyclic integrase inhibitor compounds |
US20080221154A1 (en) | 2002-10-31 | 2008-09-11 | Pfizer Inc | Hiv-integrase inhibitors, pharmaceutical compositions, and methods for their use |
US9785906B2 (en) | 2002-11-27 | 2017-10-10 | Accenture Global Services Limited | Content feedback in a multiple-owner content management system |
US20090143314A1 (en) | 2003-01-14 | 2009-06-04 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20090036408A1 (en) | 2003-01-14 | 2009-02-05 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20040224917A1 (en) | 2003-01-14 | 2004-11-11 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20040224916A1 (en) | 2003-01-14 | 2004-11-11 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
US20050059637A1 (en) | 2003-07-30 | 2005-03-17 | Gilead Sciences, Inc. | Nucleobase phosphonate analogs for antiviral treatment |
US20050137199A1 (en) | 2003-09-19 | 2005-06-23 | Gilead Sciences, Inc. | Aza-quinolinol phosphonate integrase inhibitor compounds |
US20100280026A1 (en) | 2003-10-14 | 2010-11-04 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of protein kinases |
US20100081657A1 (en) | 2003-12-04 | 2010-04-01 | Vertex Pharmaceuticals Incorporated | Quinoxalines useful as inhibitors of protein kinases |
US20050282839A1 (en) | 2004-01-12 | 2005-12-22 | Gilead Sciences, Inc. | Pyrimidyl phosphonate antiviral compounds and methods of use |
US20080153783A1 (en) | 2004-01-12 | 2008-06-26 | Gilead Sciences, Inc. | Pyrimidyl Phosphonate Antiviral Compounds and Methods of Use |
US20050239753A1 (en) | 2004-01-21 | 2005-10-27 | Gilead Sciences, Inc. | Methods of inhibition of MMTV-like viruses |
US20070281911A1 (en) | 2004-01-21 | 2007-12-06 | Gilead Sciences Inc. | Use of Adefovir or Tenofovir for Inhibiting Mmtv-Like Viruses Involved in Breast Cancer and Primary Biliary Cirrhosis |
US20090227621A1 (en) | 2004-02-04 | 2009-09-10 | Teruhiko Taishi | Naphthyridine derivatives having inhibitory activity against hiv integrase |
US20070179196A1 (en) | 2004-03-09 | 2007-08-02 | Wei Han | Hiv integrase inhibitors |
US20080009490A1 (en) | 2004-03-09 | 2008-01-10 | Williams Peter D | Hiv Integrase Inhibitors |
US20070161639A1 (en) | 2004-03-09 | 2007-07-12 | Philip Jones | Hiv integrase inhibitors |
US20080139579A1 (en) | 2004-03-09 | 2008-06-12 | Merck & Co., Inc. | Hiv Integrase Inhibitors |
US20090215766A1 (en) | 2004-04-28 | 2009-08-27 | Incyte Corporation | Tetracyclic inhibitors of janus kinases |
US20080287394A1 (en) | 2004-05-07 | 2008-11-20 | Merck & Co., Inc. | Hiv Integrase Inhibitors |
US20060276466A1 (en) | 2004-05-28 | 2006-12-07 | Naidu B N | Bicyclic heterocycles as HIV integrase inhibitors |
US20080015187A1 (en) | 2004-06-09 | 2008-01-17 | Wai John S | Hiv Integrase Inhibitors |
US20090202470A1 (en) | 2004-07-27 | 2009-08-13 | Gilead Sciences, Inc. | Phosphonate Analogs of Hiv Inhibitor Compounds |
US20070049754A1 (en) | 2004-07-27 | 2007-03-01 | Gilead Sciences, Inc. | Phosphonate analogs of HIV inhibitor compounds |
US20110086835A1 (en) | 2004-12-22 | 2011-04-14 | Incyte Corporation, A Delaware Corporation | Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-5-yl-amines as janus kinase inhibitors |
US20070259823A1 (en) | 2005-01-31 | 2007-11-08 | The University Of Georgia Research Foundation, Inc | Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase |
US20060172973A1 (en) | 2005-01-31 | 2006-08-03 | Vasu Nair | Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase |
WO2006096270A1 (en) | 2005-02-03 | 2006-09-14 | Vertex Pharmaceuticals Incorporated | Pyrrolopyrimidines useful as inhibitors of protein kinase |
US7593820B2 (en) * | 2005-05-12 | 2009-09-22 | Cytopia Research Pty Ltd | Crystal structure of human Janus Kinase 2 (JAK2) and uses thereof |
US20070072831A1 (en) | 2005-05-16 | 2007-03-29 | Gilead Sciences, Inc. | Integrase inhibitor compounds |
WO2007019098A2 (en) | 2005-08-04 | 2007-02-15 | Smithkline Beecham Corporation | Hiv integrase inhibitors |
US20090197869A1 (en) | 2005-09-22 | 2009-08-06 | Incyte Corporation, A Delaware Corporation | Azepine inhibitors of janus kinases |
US20090221571A1 (en) | 2005-10-04 | 2009-09-03 | Vincenzo Summa | Hiv integrase inhibitors |
WO2007050668A1 (en) | 2005-10-25 | 2007-05-03 | Ludwig Institute For Cancer Research | Analogs of alpha galactosylceramide and uses thereof |
US20080032963A1 (en) | 2005-11-03 | 2008-02-07 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20090181938A1 (en) | 2005-11-03 | 2009-07-16 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20070259869A1 (en) | 2005-11-03 | 2007-11-08 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20110020469A1 (en) | 2005-11-03 | 2011-01-27 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20070249031A1 (en) | 2005-11-03 | 2007-10-25 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20100310675A1 (en) | 2005-11-03 | 2010-12-09 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
US20070112190A1 (en) | 2005-11-15 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20100081645A1 (en) | 2005-11-15 | 2010-04-01 | Vertex Pharmaceuticals Incorporated | Tricyclic heteroaryl compounds useful as inhibitors of janus kinase |
US20070111985A1 (en) | 2005-11-16 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20070111984A1 (en) | 2005-11-17 | 2007-05-17 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US20070129379A1 (en) | 2005-12-01 | 2007-06-07 | Bristol-Myers Squibb Company | Hiv integrase inhibitors |
US20100022522A1 (en) | 2005-12-13 | 2010-01-28 | Incyte Corporationn, a Delaware corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
US7598257B2 (en) | 2005-12-13 | 2009-10-06 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors |
US20110224157A1 (en) | 2005-12-13 | 2011-09-15 | Incyte Corporation, A Delaware Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
US20110223210A1 (en) | 2005-12-13 | 2011-09-15 | Incyte Corporation, A Delaware Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
US20090181959A1 (en) | 2005-12-13 | 2009-07-16 | Incyte Corporation | HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIDINES AS JANUS KINASE INHIBITORS |
US20080039487A1 (en) | 2005-12-21 | 2008-02-14 | Gilead Sciences, Llc | Processes and intermediates useful for preparing integrase inhibitor compounds |
US20080261973A1 (en) | 2005-12-22 | 2008-10-23 | Novartis Ag | Sulphonamidoaniline Derivatives Being Janus Kinase Inhibitors |
US20090233964A1 (en) | 2005-12-30 | 2009-09-17 | Gilead Sciences, Inc. | Methods for improving the pharmacokinetics of hiv integrase inhibitors |
US20100311743A1 (en) | 2006-01-17 | 2010-12-09 | Vertex Pharmaceuticals Incorporated | Azaindoles Useful as Inhibitors of Janus Kinases |
US20090018162A1 (en) | 2006-02-01 | 2009-01-15 | Yuji Matsuzaki | Use of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or salt thereof for treating retrovirus infection |
US20090098137A1 (en) | 2006-04-05 | 2009-04-16 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
US20080058315A1 (en) | 2006-05-16 | 2008-03-06 | Cai Zhenhong R | Integrase inhibitors |
US20070281917A1 (en) | 2006-05-30 | 2007-12-06 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20080207618A1 (en) | 2006-06-23 | 2008-08-28 | Motohide Satoh | 6- (Heterocyclyl-substituted Benzyl) -4-Oxoquinoline Compound and Use Thereof as HIV Integrase Inhibitor |
US20080004265A1 (en) | 2006-06-28 | 2008-01-03 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20090291952A1 (en) | 2006-07-07 | 2009-11-26 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20080020010A1 (en) | 2006-07-19 | 2008-01-24 | The University Of Georgia Research Foundation, Inc. | Pyridinone diketo acids: inhibitors of HIV replication |
US20080021013A1 (en) | 2006-07-21 | 2008-01-24 | Cephalon, Inc. | JAK inhibitors for treatment of myeloproliferative disorders |
US20080070920A1 (en) | 2006-07-24 | 2008-03-20 | Hongyan Guo | Novel HIV reverse transcriptase inhibitors |
US20080039457A1 (en) | 2006-08-07 | 2008-02-14 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
US20080125594A1 (en) | 2006-09-12 | 2008-05-29 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
US20100009978A1 (en) | 2006-09-15 | 2010-01-14 | Novartis Ag | Benzoxazoles and Oxazolopyridines Being Useful as Janus Kinases Inhibitors |
US20080167287A1 (en) | 2006-11-22 | 2008-07-10 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
US20110136781A1 (en) | 2006-11-22 | 2011-06-09 | Incyte Corporation | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
US20080188500A1 (en) | 2006-12-22 | 2008-08-07 | Incyte Corporation | Substituted heterocycles as janus kinase inhibitors |
WO2008109517A1 (en) | 2007-03-02 | 2008-09-12 | University Of South Florida | Neurodegenerative disease treatment using jak/stat inhibition |
US20100160287A1 (en) | 2007-03-22 | 2010-06-24 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of janus kinases |
US20080306051A1 (en) | 2007-06-06 | 2008-12-11 | Bristol-Myers Squibb Company | HIV Integrase Inhibitors |
US20080312258A1 (en) | 2007-06-13 | 2008-12-18 | Incyte Corporation | METABOLITES OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
WO2008157207A2 (en) | 2007-06-13 | 2008-12-24 | Incyte Corporation | Metabolites of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-lh-pyrazol-l-yl)-3- cyclopentylpropanenitrile |
WO2008157208A2 (en) | 2007-06-13 | 2008-12-24 | Incyte Corporation | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US20080312259A1 (en) | 2007-06-13 | 2008-12-18 | Incyte Corporation | SALTS OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20110082159A1 (en) | 2007-06-13 | 2011-04-07 | Incyte Corporation | METABOLITES OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20090047252A1 (en) | 2007-06-29 | 2009-02-19 | Gilead Sciences, Inc. | Antiviral compounds |
US20090257978A1 (en) | 2007-06-29 | 2009-10-15 | Gilead Sciences, Inc. | Antiviral coumpounds |
US20090093467A1 (en) | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
US20090093482A1 (en) | 2007-06-29 | 2009-04-09 | Gilead Sciences, Inc. | Therapeutic compositions and methods |
US20090186869A1 (en) | 2007-06-29 | 2009-07-23 | Gilead Sciences, Inc. | Antiviral compounds |
US20090181902A1 (en) | 2007-07-06 | 2009-07-16 | Gilead Sciences,Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20090035324A1 (en) | 2007-07-09 | 2009-02-05 | Concert Pharmaceuticals, Inc. | Novel pyrimidinecarboxamide derivatives |
US20090099366A1 (en) | 2007-09-11 | 2009-04-16 | Gilead Sciences, Inc. | Process and intermediates for preparing integrase inhibitors |
WO2009045975A1 (en) * | 2007-10-02 | 2009-04-09 | Rfs Pharma, Llc | Potent combinations of zidovudine and drugs that select for the k65r mutation in the hiv polymerase |
US20110092499A1 (en) | 2007-11-15 | 2011-04-21 | Ym Biosciences Australia Pty Ltd | N-containing heterocyclic compounds |
US20090318405A1 (en) | 2007-11-16 | 2009-12-24 | Incyte Corporation | 4-pyrazolyl-n-arylpyrimidin-2-amines and 4-pyrazolyl-n-heteroarylpyrimidin-2-amines as janus kinase inhibitors |
US20090291921A1 (en) | 2007-11-20 | 2009-11-26 | Gilead Sciences, Inc. | Integrase inhibitors |
US20110118255A1 (en) | 2007-12-19 | 2011-05-19 | Vertex Pharmaceuticals Incorporated | PYRAZOLO[1,5-a]PYRIMIDINES USEFUL AS JAK2 INHIBITORS |
US20090175820A1 (en) | 2008-01-04 | 2009-07-09 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 |
US20090233903A1 (en) | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
US20090286778A1 (en) | 2008-04-24 | 2009-11-19 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
US20110251215A9 (en) | 2009-01-23 | 2011-10-13 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
US20100190804A1 (en) | 2009-01-23 | 2010-07-29 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
US20100311693A1 (en) | 2009-06-05 | 2010-12-09 | Cephalon, Inc. | Preparation and Uses of 1,2,4-Triazolo [1,5a] Pyridine Derivatives |
US20110086810A1 (en) | 2009-10-09 | 2011-04-14 | Incyte Corporation | HYDROXYL, KETO, AND GLUCURONIDE DERIVATIVES OF 3-(4-(7H-PYRROLO[2,3-d] PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE |
US20110207754A1 (en) | 2010-02-18 | 2011-08-25 | Incyte Corporation | Cyclobutane and methylcyclobutane derivatives as janus kinase inhibitors |
WO2011109217A2 (en) | 2010-03-02 | 2011-09-09 | Immunodiagnostics, Inc. | Methods of treating or preventing rna polymerase dependent viral disorders by administration of jak2 kinase inhibitors |
US20110245256A1 (en) | 2010-03-30 | 2011-10-06 | Novartis Ag | Use of a pkc inhibitor |
Non-Patent Citations (118)
Title |
---|
"GenBank", Database accession no. E01094 |
"Surface modification of polymeric biomaterials for reduced thrombogenicity", POLYM. MATER. SCI. ENG., vol. 62, 1991, pages 731 735 |
ANTIVIRAL CHEM. CHEMOTHER., vol. 5, pages 271 277 |
BAGINSKI, S. G.PEVEAR, D. C.SEIPEL, M.SUN, S. C. C.BENETATOS, C. A.CHUNDURU, S. K.RICE, C. M.M. S. COLLETT: "Mechanism of action of a pestivirus antiviral compound", PNAS USA, vol. 97, no. 14, 2000, pages 7981 - 7986 |
BALZARINI, J.DE CLERCQ, E.: "Antiviral chemotherapy", 1995, JOHN WILEY & SONS, INC., article "Acyclic purine nucleoside phosphonates as retrovirus inhibitors", pages: 41 - 45 |
BELEN'KII M.S.SCHINAZI R.F., ANTIVIRAL RES., vol. 25, 1994, pages 1 - 11 |
BIOCHEM., vol. 11, 1972, pages 942 - 944 |
BOMFORD ET AL., VACCINE, vol. 10, no. 9, 1992, pages 572 - 577 |
BOSQUEPLANELLES: "Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells", BLOOD, vol. 113, 2009, pages 58 - 65 |
CHANG, K. O. ET AL., VIROLOGY, vol. 353, 2006, pages 463 - 473 |
CHOU T.-C.TALALAY P., ADV. ENZYME REGUL., vol. 22, 1984, pages 27 - 55 |
CHU R ET AL., J. EXP. MED., vol. 186, 1997, pages 1623 |
COONEY E L ET AL., PROC NATL ACAD SCI USA, vol. 90, 1993, pages 1882 - 86 |
CUI LSCHINAZI RFGOSSELIN GIMBACH JLCHU CKRANDO RFREVANKAR GRSOMMADOSSI JP: "Effect of enantiomeric and racemic nucleoside analogs on mitochondrial functions in HepG2 cells", BIOCHEM. PHARMACOL., vol. 52, 1996, pages 1577 - 1584, XP002968516, DOI: 10.1016/S0006-2952(96)00562-X |
DANIELS, M. D. ET AL., SCIENCE, vol. 258, 1992, pages 1938 |
DESROSIERS, R. C. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 6353 |
DIVITA ET AL., ANTIVIRAL RESEARCH, vol. 71, no. 2-3, September 2006 (2006-09-01), pages 260 - 267 |
GIBBS, J. S. ET AL., AIDS RES. AND HUMAN RETROVIRUSES, vol. 10, 1994, pages 343 |
GRAHAM B S ET AL., J INFECT DIS, vol. 166, 1992, pages 244 - 52 |
GRAHAM B S ET AL., J INFECT DIS, vol. 167, 1993, pages 533 - 37 |
HO, D. H. W.: "Distribution of Kinase and deaminase of 1Ø-D-arabinofuranosylcytosine in tissues of man and muse", CANCER RES., vol. 33, 1973, pages 2816 2820 |
HOLY, A.: "Advances in Antiviral Drug Design", vol. I, 1993, JAI PRESS, article "Isopolar phosphorous-modified nucleotide analogues", pages: 179 231 |
HONG, C. I.NECHAEV, A.KIRISITS, A. J.BUCHHEIT, D. J.WEST, C. R.: "Nucleoside conjugates as potential antitumor agents. 3. Synthesis and antitumor activity of 1-(p-D-arabinofuranosyl)cytosine conjugates of corticosteroids and selected lipophilic alcohols", J. MED. CHEM., vol. 28, 1980, pages 171 177 |
HONG, C. I.NECHAEV, A.WEST, C. R.: "Synthesis and antitumor activity of 1Ø-D-arabino-furanosylcytosine conjugates of cortisol and cortisone", BIOCHEM. BIOPHYS. RS. COMMUN., vol. 88, 1979, pages 1223 1229 |
HOSTELLER, K. Y.CARSON, D. A.RICHMAN, D. D.: "Phosphatidylazidothymidine: mechanism of antiretroviral action in CEM cells", J. BIOL CHEM., vol. 266, 1991, pages 11714 11717 |
HOSTELLER, K. Y.D. D. RICHRNAND. A. CARSONL. M. STUHMILLERG. M. T. VAN WIJKH. VAN DEN BOSCH: "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3'-deoxythymidine", ANTIMICROB. AGENTS CHEMOTHER, vol. 36, 1992, pages 2025 - 2029 |
HOSTELLER, K. Y.KORBA, B.SRIDHAR, C.GARDENER, M.: "Antiviral activity of phosphatidyl-dideoxycytidine in hepatitis B-infected cells and enhanced hepatic uptake in mice", ANTIVIRAL RES., vol. 24, 1994, pages 59 67 |
HOSTELLER, K. Y.RICHMAN, D. D.SRIDHAR. C. N.FEIGNER, P. L.FEIGNER, J.RICCI, J.GARDENER, M. F.SELLESETH, D. W.ELLIS, M. N.: "Phosphatidylazidothymidine and phosphatidyl-ddC: Assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in rauscher leukemia virus-infected mice", ANTIMICROBIAL AGENTS CHEMOTHER, vol. 38, 1994, pages 2792 2797 |
HOSTELLER, K. Y.STUHMILLER, L. M.LENTING, H. B. M.VAN DEN BOSCH, H.RICHMAN, J BIOL. CHEM., vol. 265, pages 6112 6117 |
HOSTETLER, K. Y.L. M. STUHMILLERH. B. LENTINGH. VAN DEN BOSCHD. D. RICHMAN: "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides", J. BIOL. CHEM., vol. 265, 1990, pages 61127 |
HUNSTON, R. N.JONES, A. A.MCGUIGAN, C.WALKER, R. T.BALZARINI, J.DECLERCQ, E.: "Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine", J. MED. CHEM., vol. 27, 1984, pages 440 - 444 |
IGARASHI, T. ET AL., J. GEN. VIROL., vol. 78, 1997, pages 985 |
JAMES ET AL., AIDS RES. HUMAN RETROVIRUS, vol. 10, 1994, pages 343 - 350 |
JI, Y. H.MOOG, C.SCHMITT, G.BISCHOFF, P.LUU, B.: "Monophosphoric acid esters of 7-0-hydroxycholesterol and of pyrimidine nucleoside as potential antitumor agents: synthesis and preliminary evaluation of antitumor activity", J. MED. CHEM., vol. 33, 1990, pages 2264 2270 |
JOHNSON MRK WANGJB SMITHMJ HESLINRB DIASIO: "Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction", ANAL. BIOCHEM., vol. 278, 2000, pages 175 - 184 |
JONES, A. S.MCGUIGAN, C.WALKER, R. T.BALZARINI, J.DECLERCQ, E.: "Synthesis, properties, and biological activity of some nucleoside cyclic phosphoramidates", J. CHEM. SOC. PERKIN TRANS., vol. I, 1984, pages 1471 1474 |
JORDAN ET AL.: "HIV reproducibly establishes a latent infection after acute infection of T cells in vitro", THE EMBO JOURNAL, vol. 22, no. 8, 2003, pages 1868 - 1877, XP002968599, DOI: 10.1093/emboj/cdg188 |
JULANDER, J.G.FURUTA, Y.SHAFER, K.SIDWELL, R.W.: "Activity of T-1106 in a Hamster Model of Yellow Fever Virus Infection", ANTIMICROB. AGENTS CHEMOTHER., vol. 51, 2007, pages 1962 - 1966 |
JUODKA, B. A.SMART, J.: "Synthesis of diribonucleoside phosph (P.fwdarw.N) amino acid derivatives", COLL. CZECH. CHEM. COMM., vol. 39, 1974, pages 363 968 |
KATAOKA, S., UCHIDA: "cAMP) benzyl and methyl triesters", HETEROCYCLES, vol. 32, pages 1351 1356 |
KATAOKA, S.IMAI, J.YAMAJI, N.KATO, M.SAITO, M.KAWADA, T.IMAI, S.: "Alkylated cAMP derivatives; selective synthesis and biological activities", NUCLEIC ACIDS RES. SYM. SER., vol. 21, 1989, pages 1 2 |
KENSIL ET AL., J. IMMUNOLOGY, vol. 146, 1991, pages 431 - 437 |
KENSIL, C. R.: "Saponins as vaccine adjuvants", CRIT REV THER DRUG CARRIER SYST, vol. 12, no. 1-2, 1996, pages 1 - 55 |
KESTLER III, H. W. ET AL., CELL, vol. 65, 1991, pages 651 |
KINCHINGTON, D.HARVEY, J. J.O'CONNOR, T. J.JONES, B. C. N. M.DEVINE, K. G.TAYLOR-ROBINSON D.JEFFRIES, D. J.MCGUIGAN, C.: "Comparison of antiviral effects of zidovudine phosphoramidate and phosphorodiamidate derivatives against HIV and ULV in vitro", ANTIVIRAL CHEM. CHEMOTHER., vol. 3, 1992, pages 107 112 |
KLINMAN, NATURE REVIEWS, vol. 4, 2004, pages 249 |
KODAMA, K.MOROZUMI, M.SAITHOH, K. I.KUNINAKA, H.YOSINO, H.SANEYOSHI, M.: "Antitumor activity and pharmacology of I-β-D-arabinofuranosylcytosine -5'-stearylphosphate; an orally active derivative of I-β-Darabinofuranosylcytosine", JPN. J. CANCER RES., vol. 80, 1989, pages 679 685 |
KORTY, M.ENGELS, J.: "The effects of adenosine- and guanosine 3',5' phosphoric and acid benzyl esters on guinea-pig ventricular myocardium", NAUNYN-SCHMIEDEBERG'S ARCH. PHARMACOL., vol. 310, 1979, pages 103 111 |
KRIEG A ET AL., NATURE, vol. 374, 1995, pages 546 |
KUCERA, L. S.N. IYERE. LEAKEA. RABENMODEST E. K.D. L. W.C. PIANTADOSI: "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation", AIDS RES. HUM. RETROVIRUSES, vol. 6, 1990, pages 491 501 |
KULKARNI ET AL.: "Polylactic acid for surgical implants", ARCH. SURG., vol. 93, 1966, pages 839 |
KUMAR, A.GOE, P. L.JONES, A. S.WALKER, R. T.BALZARINI, J.DECLERCQ, E.: "Synthesis and biological evaluation of some cyclic phosphoramidate nucleoside derivatives", J. MED. CHEM, vol. 33, 1990, pages 2368 2375 |
LACAILLE-DUBOIS, MWAGNER H.: "A review of the biological and pharmacological activities of saponins", PHYTOMEDICINE, vol. 2, 1996, pages 363 - 386, XP000993545 |
LADNER S.K.OTTO M.J.BARKER C.S.ZAIFERT K.WANG G.H.GUO J.T.SEEGER C.KING R.W., ANTIMICROB. AGENTS CHEMOTHER., vol. 41, 1997, pages 1715 - 20 |
LEBEC, C.HUYNH-DINH, T.: "Synthesis of lipophilic phosphate triester derivatives of 5-fluorouridine an arabinocytidine as anticancer prodrugs", TETRAHEDRON LETT., vol. 32, 1991, pages 6553 6556 |
LEWIN ET AL.: "HIV cure and eradication: how will we get from the laboratory to effective clinical trials?", AIDS, 24 April 2011 (2011-04-24) |
LEWIS WLEVINE ESGRINIUVIENE BTANKERSLEY KOCOLACINO JMSOMMADOSSI JPWATANABE KAPERRINO FW: "Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts", PROC NATL ACAD SCI USA., vol. 93, 1996, pages 3592 - 7, XP002115121, DOI: 10.1073/pnas.93.8.3592 |
LICHTENSTEIN, J.BARNER, H. D.COHEN, S. S.: "The metabolism of exogenously supplied nucleotides by Escherichia coli.", J. BIOL. CHEM., vol. 235, 1960, pages 457 465 |
LIM ET AL., ANTIVIRAL RESEARCH, vol. 80, no. 3, December 2008 (2008-12-01), pages 360 - 369 |
LIM ET AL.: "A scintillation proximity assay for dengue virus NS5 2'-O-methyltransferase-kinetic and inhibition analyses", ANTIVIRAL RESEARCH, vol. 80, no. 3, December 2008 (2008-12-01), pages 360 - 369, XP025684752, DOI: 10.1016/j.antiviral.2008.08.005 |
LUCTHY, J.VON DAENIKEN, A.FRIEDERICH, J.MANTHEY, B.ZWEIFEL, J.SCHLATTER, C.BENN, M. H.: "Synthesis and toxicological properties of three naturally occurring cyanoepithioalkanes", MITT. GEG. LEBENSMITTELUNTERS. HYG., vol. 72, 1981, pages 131 133 |
MAZUMDER, A.N. NEAMATIJ. P. SOMMADOSSIG. GOSSELINR. F. SCHINAZIJ. L. IMBACHY. POMMIER: "Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase", MOL. PHARMACOL., vol. 49, 1996, pages 621 - 628, XP002920204 |
MCELRATH M J ET AL., J INFECT DIS., vol. 169, 1994, pages 41 - 47 |
MCGIGAN, C.TOLLERFIELD, S. M.RILEY, P. A.: "Synthesis and biological evaluation of some phosphate triester derivatives of the anti-viral drug Ara", NUCLEIC ACIDS RES., vol. 17, 1989, pages 6065 6075 |
MCGUIGAN, C.DEVIN, K. G.O'CONNOR, T. J.KINCHINGTON, D.: "Synthesis and anti-HIV activity of some haloalkyl phosphoramidate derivatives of 3'-azido-3'-deoxythylmidine (AZT); potent activity of the trichloroethyl methoxyalaninyl compound", ANTIVIRAL RES., vol. 15, 1991, pages 255 263 |
MCGUIGAN, C.DEVINE, K. G.O'CONNOR, T. J.GALPIN, S. A.JEFFRIES, D. J.KINCHINGTON, D.: "Synthesis and evaluation of some novel phosphoramidate derivatives of 3'-azido-3'-deoxythymidine (AZT) as anti-HIV compounds", ANTIVIRAL CHEM. CHEMOTHER., vol. 1, 1990, pages 107 113 |
MCGUIGAN, C.NICHOLLS, S. R.O'CONNOR, T. J.KINCHINGTON, D.: "Synthesis of some novel dialkyl phosphate derivative of 3'-modified nucleosides as potential anti-AIDS drugs", ANTIVIRAL CHEM. CHEMOTHER., vol. 1, 1990, pages 25 33 |
MCGUIGAN, C.O'CONNOR, T. J.NICHOLLS, S. R.NICKSON, C.KINCHINGTON, D.: "Synthesis and anti-HIV activity of some novel substituted dialkyl phosphate derivatives of AZT and ddCyd", ANTIVIRAL CHEM. CHEMOTHER., vol. 1, 1990, pages 355 360 |
MCGUIGAN, C.PATHIRANA, R. N.BALZARINI, J.DECLERCQ, E.: "Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT", J. MED. CHEM., vol. 36, 1993, pages 1048 1052 |
MCKEEL ET AL.: "Dynamic Modulation of HIV-1 Integrase Structure and Function by Cellular LEDGF Protein", JBC PAPERS IN PRESS, 18 September 2008 (2008-09-18) |
MEYER, R. B., JR.SHUMAN, D. A.ROBINS, R. K.: "Synthesis of purine nucleoside 3',5'-cyclic phosphoramidates", TETRAHEDRON LETT., 1973, pages 269 272 |
NAGYVARY, J.GOHIL, R. N.KIRCHNER, C. R.STEVENS, J. D.: "Studies on neutral esters of cyclic AMP", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 55, 1973, pages 1072 1077 |
NAIR ET AL., J MED CHEM., vol. 49, no. 2, 26 January 2006 (2006-01-26), pages 445 - 447 |
NAMANE, A.GOUYETTE, C.FILLION, M. P.FILLION, G.HUYNH-DINH, T.: "Improved brain delivery of AZT using a glycosyl phosphotriester prodrug", J. MED. CHEM., vol. 35, 1992, pages 3039 - 3044 |
NARGEOT, J.NERBONNE, J. M.ENGELS, J.LESER, H. A., NATL. ACAD. SCI. U.S.A., vol. 80, 1983, pages 2395 2399 |
NELSON, K. A.BENTRUDE, W. G.STSER, W. N.HUTCHINSON, J. P.: "The question of chair-twist equilibria for the phosphate rings of nucleoside cyclic 3',5'-monophosphates. HNMR and x-ray crystallographic study of the diastereomers of thymidine phenyl cyclic 3',5'-monophosphate", J. AM. CHEM. SOC., vol. 109, 1987, pages 4058 4064 |
NERBONNE, J. M.RICHARD, S.NARGEOT, J.LESTER, H. A.: "New photoactivatable cyclic nucleotides produce intracellular jumps in cyclic AMP and cyclic GMP concentrations", NATURE, vol. 301, 1984, pages 74 76 |
NEUMANN, J. M.HERV_, M.DEBOUZY, J. C.GUERRA, F. I.GOUYETTE, C.DUPRAZ, B.HUYNY-DINH, T.: "Synthesis and transmembrane transport studies by NMR of a glucosyl phospholipid of thymidine", J. AM. CHEM. SOC., vol. 111, 1989, pages 4270 4277 |
OHNO, R.TATSUMI, N.HIRANO, M.IMAI, K.MIZOGUCHI, H.NAKAMURA, T.KOSAKA, M.TAKATUSKI, K.YAMAYA, T.TOYAMA K.: "Treatment of myelodysplastic syndromes with orally administered I-β-D-arabinouranosylcytosine -5' stearylphosphate", ONCOLOGY, vol. 48, 1991, pages 451 455 |
OKAMURA H. ET AL., ADV. IMMUNOL., vol. 70, 1998, pages 281 - 312 |
PAIS ET AL., J MED CHEM., vol. 45, no. 15, 18 July 2002 (2002-07-18), pages 3184 - 94 |
PALOMINO, E.KESSLE, D.HORWITZ, J. P.: "A dihydropyridine carrier system for sustained delivery of 2',3' dideoxynucleosides to the brain", J. MED. CHEM., vol. 32, 1989, pages 22 625 |
PAN-ZHOU X-RCUI LZHOU X-JSOMMADOSSI J-PDARLEY-USMER VM: "Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells", ANTIMICROB. AGENTS CHEMOTHER., vol. 44, 2000, pages 398,408 - 503 |
PERKINS, R. M.BARNEY, S.WITTROCK, R.CLARK, P. H.LEVIN, R.LAMBERT, D. M.PETTEWAY, S. R.SERAFINOWSKA, H. T.BAILEY, S. M.JACKSON, S.: "Activity of BRL47923 and its oral prodrug, SB203657A against a rauscher murine leukemia virus infection in mice", ANTIVIRAL RES., vol. 20, no. 1, 1993, pages 84 |
PIANTADOSI, C.J. MARASCO C. J.S. L. MORRIS-NATSCHKEK. L. MEYERF. GUMUSJ. R. SURLESK. S. ISHAQL. S. KUCERAN. IYERC. A. WALLEN: "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity", J. MED. CHEM., vol. 34, 1991, pages 1408 - 1414, XP002201556, DOI: 10.1021/jm00108a025 |
PIANTADOSI, C.MARASCO, C. J., JR.NORRIS-NATSCHKE, S. L.MEYER, K. L.GUMUS, F.SURLES, J. R.LSHAQ, K. S.KUCERA, L. S.IYER, N.WALLEN, : "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV-1 activity", J. MED. CHEM., vol. 34, 1991, pages 1408 1414 |
POMPON, A.LEFEBVRE, I.IMBACH, J. L.KAHN, S.FARQUHAR, D.: "Decomposition pathways of the mono- and bis(pivaloyloxymethyl) esters of azidothymidine-5'-monophosphate in cell extract and in tissue culture medium; an application of the ''on-line ISRP-cleaning HPLC technique", ANTIVIRAL CHEM CHEMOTHER., vol. 5, 1994, pages 91 98 |
POSTEMARK, T.: "Cyclic AMP and cyclic GMP", ANNU. REV. PHARMACOL., vol. 14, 1974, pages 23 33 |
PRISBE, E. J.MARTIN, J. C. M.MCGHEE, D. P. C.BARKER, M. F.SMEE, D. F.DUKE, A. E.MATTHEWS, T. R.VERHEYDEN, J. P. J.: "Synthesis and antiherpes virus activity of phosphate an phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine", J. MED. CHEM., vol. 29, 1986, pages 671 675 |
PUCCH, F.GOSSELIN, G.LEFEBVRE, I.POMPON, A.AUBERTIN, A. M. DIMIMBACH, J. L.: "Intracellular delivery of nucleoside monophosphate through a reductase-mediated activation process", ANTIVIRAL RES., vol. 22, 1993, pages 155 174 |
PUGAEVA, V. P.KLOCHKEVA, S. I.MASHBITS, F. D.EIZENGART, R. S.: "Toxicological assessment and health standard ratings for ethylene sulfide in the industrial atmosphere", GIG. TRF. PROF. ZABOL., vol. 14, 1969, pages 47 48 |
R. JONESN. BISCHOFBERGER, ANTIVIRAL RESEARCH, vol. 27, 1995, pages 1 17 |
RAY ASHERNANDEZ-SANTIAGO BIMATHEW JSMURAKAMI EBOZEMAN CXIE MYDUTSCHMAN GEGULLEN EYANG ZHURWITZ S: "Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine", ANTIMICROB. AGENTS CHEMOTHER., vol. 49, 2005, pages 1994 - 2001 |
REED IJMUENCH H: "A simple method or estimating fifty percent endpoints", AM. J. HYG., vol. 27, 1938, pages 497 |
ROBINS, R. K.: "The potential of nucleotide analogs as inhibitors of Retro viruses and tumors", PHARM. RES., vol. 11, 1984, pages 18 |
ROSOWSKY, A.KIM. S. H.ROSSJ. WICK, M. M.: "Lipophilic 5'-(alkylphosphate) esters of 1-P-D-arabinofiiranosylcytosine and its N4-acyl and 2.2'-anhydro-3'-O-acyl derivatives as potential prodrugs", J. MED. CHEM., vol. 25, 1982, pages 171 178 |
ROSS, W.: "Increased sensitivity of the walker turnout towards aromatic nitrogen mustards carrying basic side chains following glucose pretreatment", BIOCHEM. PHARM., vol. 8, 1961, pages 235 240 |
RYU, E. K.ROSS, R. J.MATSUSHITA, T.MACCOSS, M.HONG, C. I.WEST, C. R.: "Phospholipid-nucleoside conjugates. 3. Synthesis and preliminary biological evaluation of 1-P-D-arabinofuranosylcytosine 5'diphosphate [-], 2-diacylglycerols", J. MED. CHEM., vol. 25, 1982, pages 1322 1329 |
SAFFHILL, R.HUME, W. J.: "The degradation of 5-iododeoxyuridine and 5-bromoethoxyuridine by serum from different sources and its consequences for the use of these compounds for incorporation into DNA", CHEM. BIOL. INTERACT., vol. 57, 1986, pages 347 355 |
SANEYOSHI, M.MOROZUMI, M.KODAMA, K.MACHIDA, J.KUNINAKA, A.YOSHINO, H.: "Synthetic nucleosides and nucleotides. XVI. Synthesis and biological evaluations of a series of I-β-D-arabinofuranosylcytosine 5'-alky or arylphosphates", CHEM PHARM. BULL., vol. 28, 1980, pages 2915 2923 |
SASTRY, J. K.NEHETE, P. N.KHAN, S.NOWAK, B. J.PLUNKETT, W.ARLINGHAUS, R. B.FARQUHAR, D.: "Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection", MOL. PHARMACOL., vol. 41, 1992, pages 441 445 |
SCHINAZI R.F.SOMMADOSSI J.-P.SAALMANN V.CANNON D.L.XIE M.-Y.HART G.C.SMITH G.A.HAHN E.F., ANTIMICROB. AGENTS CHEMOTHER., vol. 34, 1990, pages 1061 - 67 |
See also references of EP2785184A4 |
SHAW, J. P.JONES, R. J.ARIMILLI, M. N.LOUIE, M. S.LEE, W. A.CUNDY, K. C.: "Oral bioavailability of PMEA from PMEA prodrugs in male Sprague-Dawley rats", 9TH ANNUAL AAPS MEETING. SAN DIEGO, CALIF. (ABSTRACT, 1994 |
SHUTO, S.ITOH, H.UEDA, S.IMAMURA, S.KUKUKAWA, K.TSUJINO, M.MATSUDA, A.UEDA, T., PHARM. BULL., vol. 36, 1988, pages 209 217 |
SHUTO, S.UEDA, S.IMAMURA, S.FUKUKAWA, K.MATSUDA, A.UEDA, T.: "A facile one-step synthesis of 5' phosphatidiylnucleosides by an enzymatic two-phase reaction", TETRAHEDRON LETT., vol. 28, 1987, pages 199 202 |
SILK ET AL., CUTTING EDGE J. IMMUNOL, 2008 |
SOMMADOSSI JPCARLISLE R: "Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl) guanine for normal human hepatopoietic progenitor cells in vitro", ANTIMICROB. AGENTS CHEMOTHER., vol. 31, 1987, pages 452 - 454 |
SOMMADOSSI, JPSCHINAZI, RFCHU, CKXIE, MY: "Comparison of Cytotoxicity of the (-) and (+) enantiomer of 2',3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells", BIOCHEM. PHARMACOL., vol. 44, 1992, pages 1921 - 1925, XP025541685, DOI: 10.1016/0006-2952(92)90093-X |
SONG, G.Y.PAUL, V.CHOO, H.MORREY, J.SIDWELL, R.W.SCHINAZI, R.F.CHU, C.K.: "Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus", J. MED. CHEM., vol. 44, 2001, pages 3985 - 3993 |
STRAUB, T. M. ET AL., EMERG. INFECT. DIS., vol. 13, no. 3, 2007, pages 396 - 403 |
STUYVER L ET AL.: "Ribonucleoside analogue that blocks replication or bovine viral diarrhea and hepatitis C viruses in culture", ANTIMICROB. AGENTS CHEMOTHER., vol. 47, 2003, pages 244 - 254, XP055169861, DOI: 10.1128/AAC.47.1.244-254.2003 |
STUYVER LJLOSTIA SADAMS MMATHEW JSPAI BSGRIER JTHARNISH PMCHOI YCHONG YCHOO H: "Antiviral activities and cellular toxicities of modified 2',3'-dideoxy-2',3'-didehydrocytidine analogs", ANTIMICROB. AGENTS CHEMOTHER., vol. 46, 2002, pages 3854 - 60 |
STUYVER, L. J. ET AL., ANTIMICROB. AGENTS CHEMOTHER., vol. 47, 2006, pages 244 - 254 |
VATAKIS, JOURNAL OF VIROLOGY, vol. 83, no. 7, April 2009 (2009-04-01), pages 3374 - 3378 |
VELOTTA ET AL.: "A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection", TRANSPLANTATION, vol. 87, no. 5, 15 March 2009 (2009-03-15), pages 653 - 9 |
ZAJONCKRENENBERG, CURRENT OPINION IN STRUCTURAL BIOLOGY, vol. 17, 2007, pages 521 - 529 |
ZHU ET AL.: "Irreversible Inhibition of Human Immunodeficiency Virus Type 1 Integrase by Dicaffeoylquinic Acids", JOURNAL OF VIROLOGY, vol. 73, no. 4, April 1999 (1999-04-01), pages 3309 - 3316, XP000916737 |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9708326B2 (en) | 2013-02-25 | 2017-07-18 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
US11865120B2 (en) | 2013-08-23 | 2024-01-09 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
AU2020210312B2 (en) * | 2015-02-17 | 2022-10-20 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
US10259816B2 (en) * | 2015-04-24 | 2019-04-16 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof |
US10611770B2 (en) | 2015-04-24 | 2020-04-07 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof |
US9630968B1 (en) | 2015-12-23 | 2017-04-25 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
US10245263B2 (en) | 2015-12-23 | 2019-04-02 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
US10933065B2 (en) | 2015-12-23 | 2021-03-02 | Arqule Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
US11020400B2 (en) | 2015-12-23 | 2021-06-01 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
US11020398B2 (en) | 2016-08-24 | 2021-06-01 | Arqule, Inc. | Amino-pyrrolopyrimidinone compounds and methods of use thereof |
WO2020092015A1 (en) * | 2018-11-02 | 2020-05-07 | University Of Rochester | Therapeutic mitigation of epithelial infection |
CN113248518A (en) * | 2021-06-21 | 2021-08-13 | 山东大学 | Pyrimidine piperazine derivative and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
BR112014013224A2 (en) | 2019-07-30 |
EP2785184B1 (en) | 2020-06-10 |
CA2856722C (en) | 2022-11-22 |
CN104185420A (en) | 2014-12-03 |
US20140328793A1 (en) | 2014-11-06 |
AU2016244212B2 (en) | 2018-02-15 |
EP3750544A2 (en) | 2020-12-16 |
CA3131037A1 (en) | 2013-06-06 |
CN107898790B (en) | 2024-06-21 |
MX2014006479A (en) | 2015-01-22 |
BR112014013224B1 (en) | 2023-03-07 |
EP2785184A1 (en) | 2014-10-08 |
US9662332B2 (en) | 2017-05-30 |
EP3750544A3 (en) | 2021-03-24 |
AU2016244212A1 (en) | 2016-11-03 |
EP2785184A4 (en) | 2015-08-05 |
AU2012345732B2 (en) | 2016-07-14 |
CN107898790A (en) | 2018-04-13 |
US20160051554A1 (en) | 2016-02-25 |
CA2856722A1 (en) | 2013-06-06 |
US10022378B2 (en) | 2018-07-17 |
CN104185420B (en) | 2017-06-09 |
AU2012345732A1 (en) | 2014-07-17 |
US20170312283A1 (en) | 2017-11-02 |
US9089574B2 (en) | 2015-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10022378B2 (en) | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections | |
US11969427B2 (en) | Use of TREM-1 inhibitors for treatment, elimination and eradication of HIV-1 infection | |
US20240238323A1 (en) | Modified nucleosides and nucleotides analogs as antiviral agents for corona and other viruses | |
EP3732180A1 (en) | Combined modalities for nucleosides and/or nadph oxidase (nox) inhibitors as myeloid-specific antiviral agents | |
US20240173322A1 (en) | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections | |
EP1382343B1 (en) | Combination therapy to treat hepatitis B virus | |
MXPA03005382A (en) | Dapd combination therapy with inosine monophosphate dehydrogenase inhibitor. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12852554 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2856722 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14360905 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/006479 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2012345732 Country of ref document: AU Date of ref document: 20121130 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014013224 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112014013224 Country of ref document: BR Kind code of ref document: A2 Effective date: 20140530 |