PH27190A - Antiviral nucleosides - Google Patents

Antiviral nucleosides Download PDF

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Publication number
PH27190A
PH27190A PH33532A PH33532A PH27190A PH 27190 A PH27190 A PH 27190A PH 33532 A PH33532 A PH 33532A PH 33532 A PH33532 A PH 33532A PH 27190 A PH27190 A PH 27190A
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Philippines
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formulation
active ingredient
coe
deoxythymidine
cee
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Application number
PH33532A
Inventor
Janet Litster Rideout
David Walter Barry
Sandra Nusinoff Lehrman
Martha Heider St Clair
Phillip Alen Furman
George Andrew Freeman
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Wellcome Found
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Priority claimed from GB858506869A external-priority patent/GB8506869D0/en
Priority claimed from GB858511774A external-priority patent/GB8511774D0/en
Priority claimed from GB858523881A external-priority patent/GB8523881D0/en
Priority claimed from GB868603450A external-priority patent/GB8603450D0/en
Application filed by Wellcome Found filed Critical Wellcome Found
Priority to PH35502A priority Critical patent/PH24360A/en
Publication of PH27190A publication Critical patent/PH27190A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Description

, oo ANTIVIRAL WUCLEQSIDLS — : ) Ch Ey a
This application is a division of patent application Serial No. 33532 filed Jarch 14,1986.
The present invention relates to 31-anido- 3t.deoxythymidine, its pharmaceutically acceptable derivatives and thelr use in the treatment or prophylaxis of human retroviral infections. - fletrovirusen forn a sub-group of RNA viru- sea which, in order to replicate must firet ‘ro- verae transcribe’ the REA of their genone into
DNA (transcription conventionally der: Lhe the
Syntheais of RNA from DHA). once in the form of
DNA, the viral genome {is incorporated into the host cell gename, allowing it to take full ad- vantage of the host cell's transcription/trans= ) lation machinery for the purposes of replication. énce incorporated, the viral DNA Le virtually } fadistinguishavle from the host's DNA and, in this ; otate, the virus nay persiet for as long as the cell lives. is it 1e virtually invulnerable to attack in this forn, any treatment must be direc ted at another abate of the life cyole and will, of necesaity, havo Fl be continued antil all te virus-carrying celle have died.
HTLY-I and HILV-I1 are both retroviruses and are Known to be causative agente of Leukae- mia in nan. MTLV-1 infections are especially 1 aso ORIGINAL 9d
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To ER: gE Eg SERRE tly. io "oy viral AID Rn Vio ob UR
Po E E te RO eg “he 3° h D8 v BL or TR of f i Hn 4 ol es Ba pr } do): Ri & ge Pq Se Al sonia oy lt RL! i ars Had BAT TO : Or “Nel a i ith in neumor result « i ai *e Sigal i £0 2% LRN Px a fd aa % as p ml direct g been - eR1Er xd Lv ~ Toe Co : . Ye Rf SEE such ot asi Bo also b Bros iiext pr eli LF ; : tad = ha “i 3 fo) ad not a vo has al . 4 ing B: RE Ca . et a i § HE rl oh fa and no » AIDV B 5 “Inoluc Cy VE EN Shi 2
I Hl Edge, eamtly, AID 84 dnolu on andy Tous Foo i { tok £2 gl Ai! eam ny pes Fo hag al ne is Ep Xo : ; on i o x TR Li: Re tissue tr = aorop o ral. i fe A Soar SE ; £ F 8 i i Wa J ; tie oe ker, m Co cent lg So ‘ EES den a : iG vo Bu BY er or Lid mar he. i we ER SE CO k i ny gl : hE go hd iY oth “ 4 na in 4 3 po Ta oo EE neOE om hy 3 323 Eon oth eT ue 1 ie : fon
SR EE ed Lo sing th ed tise p EA ORIGINAL 2% il yA ih Titus: olatied. ie laa ORIGIN a 3 FOR Ph nL oy 1 880C. ; “Re nt BAD SE Sr v “ 3.2 oo 5 TA a : ce Cy A : J: LEE ¥ & By Seed a Fie 00 In A bi: i : boo Sen
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Co AR Co . ;Bysten (ORS). This latter infeotion has ‘been “dincoverad in patients expressing classical AIDS ‘symptoms and is associated with progressive de~ ‘myelination, leading to wasting and such ‘symp- ; tome as encephalopathy, progressive dysarthria, : : “hata and dieorientation.
A There are at least four clinical manifest ablons of AIDV infection. In the initial ‘carrier! skate, the only indication of infection ‘1s the } ; 10 { gresence of anti-AIDV antibodies in the’ blood= » = . : dxrean. 1t is believed that such tcarri¥Es’ are :
Sr & wi Co » of paasing on the infedsion, o.gi by E 1 ig 0 i) {aod transfusion, sexual intercourse of used - - - ; } kL ¥ : } g oe needles. The carrier state nay often ne- ! Co 3 15 a i or progress to the second stage oharacfersed by
E fidratstent generallised lyaphadenophthy’ (P91). . : : | L &- currently estimated that about 208. of POL . he: : {'Batiente progress to a more advaaced condition
SN go “homn as 'AIDS related complex’ (ARC) A hyntonl
So . 20 faptons associated with ARC may include, general % : ge increased temperature and onrofto infeo- : ; So No pod HAE ; | a § > ;iidone. This oondition usually progresses to the :
E “i$ine1, fatal AIDS condition, when the patient a
Co oT oo "ydompletely loses the ability to fight inteotion. - : 3 2s Tg The existence of these human roteeviruses ; } pr L Lo “ie others has only recently been recognised and, | ; - - : Ch § the diseases with whioh they are 11aked are of : - : | 7 i: ) 5 {ssa smenstenig nature, there sxists an ur - ) = i : Chee RE So ST co Uh Ta -3-| < EE
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‘gent need to develop ways to comvat these virus- : es.
Various drugs have nov been proposed ns vgures' for AIDS. These include antimoniotung- state, suramin, rivavirin and {noprinosine, which are either toxlc or nave shown no marked antl- retroviral activity. As the AIDV genome is incoe- porated into the host cell DHA after infection and is virtually {nvulnerable to attack in this gtate, it will persist as Long as the host cell survives, cuus ing new infection in the meantime.
Thus, any treatment of AIDS would nave to be for an extended period, possibly 1ife, requiring substunces with an accpptuble toxicity jleports have described the testing of com= poun:is agu1nst varicus retroviruses, for example, . Briend Leukaemia Virus (FLV), a murine retro- virus. for instance Krieg eteale (EXP. Cell reB., , 116 (1978) 21-29) found 31.azido-3'-deoxythymidine to be active against FLV in in vitro experiments, '" "and Ostertag et al. (Proc. Jat. Acad Sci. (1974) 71, 4980-85) stated that, on the basis of antl- viral activivy related to FLV an! a lack of cel- lular toxicity, 3v-azido-3'-deoxy thymidine "might favouratly replace pbromodeoxyuridine for medical - - treatment of diseases cnused by DNA viruses”.
However, De Clergy et al. (Blochem. Pharm. (1960) 29, 1849-1851) established six years later, that / - ee + emer TR -4- aro ORIGINAL PD ee — ee —————————— ’ 27140 3¢ ap1do-3'-deoxythymidine had no appreciable activity against any viruses used tn their tests, including vaccinia HSVI and varicella zoster virus (VZV). Glinski gb al. (J. Ore. chem. (1973), 28, 4299-4305) discloeres certain derivatives of 3'- fnido~3'-deoxythynidine (infra) and their ability to block mamaalian exoribonuclease activity. se have nox discovered that 3'-gzido=-3"'- deoxythymidine han A surprisingly potent aotivity ‘10 pgainst Human retrovirus, with a particularly nish activity against AIDV as demonstrated by the cxperi- mental data referred to below. Such activity renders the compound useful {pn tha therapy of human reftro- viral infections. “15 Thus, in the first aspect of the present in- vention, there is provided = compound of formula (I): tL 0 oo ay” N™ oo .. | hn (1) a HO — 0 _ 7 [ ] - 3 (L.e., 31_ggido-3'~deoxythymidine) or a phurmaceu- tically acceptable derivative thereof, for use in the treatment or prophylaxis of human retro- virus infections. The compound of formula \ = aap Onigin- gf i
L
) Le LE i : fas HP a oo (1) and its pharmaceutically acceptable deriva- ~ dives are hereafter referred to as the compounds according to the invention.
Sak Activity of 3'-agldo~3'~deoxythymidine | against human retrovituses has been established in various in vitro assay systems. ror example, infection of the H9 human lymphoblastoid cell=- ) "Tine by AIDV is effedtively prevented by con=-
Qentrations of 3'-azido-3t=deoxythymidine as low 48 0.013 meg/ml up to 20 acurs atter infection. : Arey 1nfuvo tion of U937 human 1ymphoblastotd cells, : PHA-stimulated white blood celles and cultured paripheral blood lymphocytes is also prevented cE ot : | at similarly low concentratione. In addttion, 10= day challenge experiments using up to 5000 AIDY . _‘¥irions per cell and cloned 24, tetanus~specific, id S¥chelper lymphocytes, showed no decreass in cells . “rented with 31-antdo-3'-deoxy thynidindy: ¥nile | i dy | “dfitreated cells had decreased 5-fold. Oytophatic wo ) 20 “etrects were also completely blocked in" the same ;
I lge11-line transformed by HTLV-1 and super-infeoted : | Ln Obher studies using purified AIDV reverse Vdanscriptase have shown that the activity of this ensyme is blocked by the triphosphate of 3'- - o 481403" -deoxythynld1ne by a competitive lnhibi- a - TT “$1on mechaniam. Ti hr Phaselclinical trials have also shown that | i 4 EO LE oo
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Co wd wei . “UN Lp . be trea n include iy HTLV=-I, , { LTT RE ay tio ially :
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Ey gaa VIE 3 V-1 or } 1D8 er oo : ! vo & | oy Em be treated ude AIDS, A “‘I¥mphoma. REI gL $y . §that may ion inolu ia and dynp dae LL } 2h Ve Tg do no W bh Cn invent Co . leukaem olde th “1 f
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Lo Eo 7280 CREE ter, o dminis (dreds) or Ll an i . JF i] Eh : galt y €8 upon a (dire RIE B og LER Te fad : nb 5h | ar aE Nin FART SE GA so wR hh CR poun le of pro | idine0s Le SEE a or re at ol 23 is capable of deoxythyn dE Bidue i gE gi
TA FL dav iect, asido-3'-deoxy th Lite oF HEH: ie they mio 3 of 5 fh iv 5 Yr 4bJ ily) 3'-asid : 93aBsllite. op) > id is th LU ge eg 4 ly ig bi hy a y 3 f LR ly : em . ne Ee 1d CL Tu it PRLS Lo ard ¥ 5 EE go Cg air sot ly aotiy i ter compas g En i PEA
Vil vif FAR RRS irally a non-e# LEE are GE WS Lie ou! ¥ p 5 Rn rn EC Re A {eretroy : le of a n : 2 O-aiont OR 2 FE
EEE 2 We a TE ier : Re WE a A hrs LE ] ¥ . Le Rit Cp TIA An examp ‘<Q and. Fy 20 Vee i vm i £ BR ilhe ee Sg of. he 5] Si Lan feta) oo Ee SRR SR y : nS . Nd re t ; . ele wa BE EL ; : yo a. js” xy ie herein : to form an i I TAR Te : } Te 4 py GS 2 pre] Ah Si tive w tom to So Sp { d SETAE o Fa i 2 TE CE ged id 3 de iva oxygen & hE bk hE a HTL Shes 3 5 Jo LE So) oR : n ) Lp Bi wt 43h PER: eh 4 5 a gS BR EA aked' by a 0 ide] oA ORIGHIAL -& 1 ¢ wd ds EO } ’ CAE = Rr Bo a. Vai : ' 4 TH Ji go _ 419% BAD a CO ¥Y A e vl 3 PA : wn Si Cod . bo i RS 4 bo RL + Rp Cie rn ; # an Di%e 25 AT: Be a SL Taga 3 : SAE ¥ ¥% ER ek wt - Ew di, ys # fhe i CE Ag HRA eR f Lo i VA Cra a £0 “of fd : oh : TE op MR : Em fie 40 i Ao & x 2 i NE > = Gein ih) hy © RIT 1% i Ng FO Trad be re i a ? Cay WERE, Loe oy Te
Ph ter EE RR 2 Rd Lee Ea CE 3 = 3 en Ck Eon PA whee RSE neh ¥ } i a a 0k an df 303 2H \ ne i " ¥
To Pd on NG EY 3 XC aE Co At . fx i & £ Ei Bc ne 0 po 8 bo 2 a EER 1d ol Re A : CE gry oa TE - 26% forms 3 [I NE gy - pds Ce ound: of ke ¥ y oa ERY Lh camp Jie hich a
Cd DE iE of the e in-w CL : 4 i fa? : ) He oy re ers he 8 n poo cr Sp. red oste ac1d est ifing 10 : EH Hed refer lic er i - : 3 A v P carboxy the est cy Fr alkyl, wo L} i Velie wk yw . : Sa ha Jr de £ inte Viney *s : 0 SE inclu ty o chail & ' : vr . Rt I) ole hed rg ge *
Co Yi 1a ano yale
Lo pie bony r br 1ky dA co oo
CIE -car 0 | ralkyl> Se ;
CL {he non-¢C straight ethyl), a dy, aryl oo : ; of 3 HY om m iy -
LT doy ted Ir ethoxy oxymothy .. . x TE m n “45 ih Ny . oN 'gelec (e.g g. phe “haloge “
L . . * ' - * * SE kyl (es. by Ren 8 : ‘lxoxyal loxyalkyl vatituted diters :
EE Ry ary 11y su nate SR - : LW ’ “aul shone SUBL e : so " benzyl) 1 optiona J} ul pho gs methane oo
Eo i tis g. pheny 0, alkoxy onyl a esters,
So “les - cylsulp phite EE ; of ) Ha or 1 ) le a wh hl,
CE A alkyl or arhdky Zor tri-pho Ta unless
Co "Y 4 1- 1= 0 tate,
LL Lb 9 Lky da esterp . : 2. . SC EL. a -y ed CEES Sas .
Co ro “Bach as and mono deserid 4 present
Co om 1)i ove-d stief rent Co boo . 10 Coreg wlphony to the ab lkyl moi $a 18 v } ” 5 - : : } a 1 18 Can a Vv : . Ee A Sh rd: n .- in yd & or . [ : - : Card x Lon regsa ified, a y ay conta atoms * a bo
SI Ao speciiiet eoue rb atoms. SE
CL eT WEE erwise | dvanteg to 4 ca En ta= oo : : 4 a 70th rs & 1 a dvan i
RE E2s ste larly ters MOVE . oT i : WEA eh e ticular h es Heil noe. “Ce i oo oa CORES ar ; uo a: Tere SO gh
Coda ik To adh P 8 <le Lo Say :
Coa Fak ; EA atoms, sent in Any red “oc To ah HE i
CoH i 1ety pre yl group. olden a him
TT Ee RES Ha ER mo en 5 in Abe XE Cup Chad Co pS p15 BE Y aryl ises a ph nds also ray - ake. He : .
So wR Lo eh I ou Lh aN San re ENT . . SR S i nr ke : comp comp pta dy: hl EE jth a BL o By . " Ch gov VL a coe 23H fis wr Sela Gant Co : qo i igeously f the aboV tically e : pa be an : . : i bh ) 5 Lh atl u Jy cui “ te » Lae Ari CL . i Cai i 11 Bay © pharmace a 40-3 co AE i i CRE Bo CB fl to t 3! ARIAT pn CEE :
Lo ois © “¥¥arence hown tha Hine aE i ear CE & of have 8h vivo br Sh i na pi ., iEhere riments tedy in Vivo bi dros Seo 1 3 i 3 I ks: Expe converte the >A rE wl Lo 1 gol 11420; Jig e is into Fi¥thes wo.
FF WY ol go To se hymidin : negymes then Iu¥ i ok fai: ad : ANA ¥ cw eh Shdeoxyt lular e te is Ry he 43 i id pr oF & Pog Xr a EEG 0 cel spha 8 { brs Lu § PR § i. a tn dg ytioh of onopho s to fo Biiaaion. wn ® a SE Pa em : me aoe, Co tag 3 vo RY alg A73.80 Th ensy 1d otk ph by a oA : EE ok Yo . is bh ed Ca ha nha! Ee : ge - pa
A LA 2 SE Sg horylat a diphopp e triphpA) . ‘be= 5 He Ea
E ; £ Sa Lidhhop ia the it ia th woiBREis Ce a An 3 Sa we Ealph y So whidy id gm Ru Hl : Er EC }: hoophate ted that 3% > midine vl Ht aL LE 3 = TE id “ig:ph nstra jeoxy thy CR ail 5 J Tples vo
H § rot CRUE i by 3 denot 3 Je } SE BEE Sa sn & Lowy CEE TE ave ido~ Lo vy ~ ar tho "i [A = hy YL + PY o~ ‘wag : ala rs ve 53 gE & 4 kn Cen Es ols £3 re . I AN z : Ee 3g nh A] orm O . Ci HER age Loo Li ! wo "4 * bl = Lip j&: ul ORIGIN Al a
PoE: Eo Tal | 44 BAD ORI iE ¥ n J HE . SE To 7 Cw oh Ta Lo gle % Ea Th EP & +9= gi 5 AER Lie EN Hyon
C8 Hh
Coal LaR i i 38 Eo Sd a EE hg Co ages A AD.
Cd CRIA i J ha ; Foe ok Se Cb
R : 11eved to be the effective chain terainato¥ in : - : the reverse tranecription of AIDV, as evidenced by ‘tte effect on avian myeloblastosis virus and Moloney Co murine jeukaemia virus. This form also inhibits : 5 AIDY ‘reverse transcriptase in vitro whilst having a negligible affect on human DNA polymerase aotivity. " Examples of pharmaceutically acceptable salts of the compound of formula (I) end its pharmaceu- t3eally acceptable derivatives {nolude base salts, +10 01g} derived from an appropriate base, auch 8p al- : ; LF kal} metal (e.g. sodium), alkaline earth metal (e.g
CN : naghesiun) galts, ammonium and rx,’ (wherein X is 7 - Ta gE The proesent invention thus further provides i ; 5 1s sheinovel pharmaceutically acceptable aerivatives : F : otiine compound of the formula (1), other than the : : ) co 2 following 51 derivatives, namely monophosphate, : Ee oe monophosphate, 2-cyanoethyl monéphosphate,
Lk vathosphate, p-toluene pulphonate, sootaté, triphe- : LJ 5 : 20 riylaethy1 and methanesulphonate derivatives: or where “2 Le this 'o is linked to a further nucleotide’ dr nucleo- - : + ky side derivative. Hd iN i FE ‘specific examples of oharmaceutically accept- : oo 5 I nbie derivatives of the compound of fornila (I) that 4 EE ERT ney; be used in accordance with the present’ invention . Ea “friolude tha monosodium salt and the following 5! . Satere: monophosphate] disodium monophosphate! - “ ‘d{ phosphate} triphosphate] acetate} Fo
EY Tl i ie : REE + moompn O)
4 A SRL Ese 0 REA Coe fib LL AR @0.. vik
CR anf SUE hort we a ; ; CPR AR fT gd WoC TRE Sy 1% ¥ TB Amc Nn ER dT rn Ae yo rg i how BEER ER : - : - ET JT, : i R) ¥ mid # ios ot 0 pA - | : eo CTR ; ! RR ne NA Xi so SE ; 5 a Sr J Cw ; 2
Ed CER ag CR
CL . SE FAY BS . : 5 a 3Jnathyl-butyrate; octanoate; palmitate} 3-ochloro- i
EEL aE fe '"% bensoate; benzoate} 4-methyl benzoate; hydrogen E : CEE i i fr : sucdinate; pivalate; and mesylate. £7 : :
Yeoh Ea Be %:f 3v.pgido-3'~deoxythymidine, or a phaimaceu- 9 co : Wo oo v . 3 tically acceptable derivative thereof (hereafter ° referred to as the active ingredient), may be ad- 3 ministered to humans for prophylaxis or treatment v of retwoviral infections by eny suitable route in- -
So cluding oral, rectal, nasal, topical (including - : ) i ©-10 buctal and sublingual), vaginal and parenteral :
Lh 7 (including subcutaneous, intramascular, intravenous :
Nt and; intradermal). It will be appreciated that the :
A bm : - Sagem preferred route will very with the condition and age = i a § rh AL Sh Lp Le Lo A i el y
Lot F a 50 a ol’ he recipient, the nature of the infection and So. :
Ch va RR Agpi Co ORE SE
EEE i cE TE) Doha En Clppanetp Cy ie ' k 5 Lo 40% 4 the :Ghosen active ingredient. a AR : : NY: BG CBee Pe wig = oe 8 Ho ey Lika in general a suitable dose will bein the Ca i
Goo Le mm leg vo, Cogen L hog ER i» 7 i gi of 3.0 to 120 mg per kilogram body ent: ; FE LC : oh : 2 7 kg ; can : Ca pl ; . . Bb NT “ wa ar ory ele Co p Bi 4 Hg , Lib of ot She patient per day, preferably. in thegrange of, i) E
Hh EE 6:10) 30 mg per kilogram body weight, per day and : Bide : 7 coh WEL iE : - ty Mba geal 0b i. Con) Ae TTR WE A HR : he dn 37% oh tf J io K 520 4 mo#¥! preferably in the range 15 %o 60 mg per kis ve 3 4 Reo AE vn ee mma Lig lai ddl lL # 3 3 EE ; Yogkam body weight per day: The desired dose ‘id SR fal : 8 LOE RE dekh cg gms) i 3 Sr on preferably presented as two, three, four, five, Bix <i HE Cod
H & hy TW LE } ; BER . SE i a Ee CHT I 34 a 59 ki (oe, ' . sw 2 1d ! LOT wr He 1-9 oe ok WW vo 2 rie bi} or soxe sub-doses administered at approprigie. me gf EL gd i oF opr Lo SEER nC She VabiheX Fy it : od ha tesvals throughout the day. These sub-doseg¥may ve, Blac] ! 4 Loads ECG SEE cer gir RR TY Ln
Boy EE 3 no ER : RG dl LE Ye af iu $00 - zii28 " ad@inistered in unit dosage formas, for. exanple oo LW, [EE 4 ’ SRR ane doh ol pT i ! 4 A ; containing 10 to 1500 mg, preferably 20,30:1300, So x i " 4.3 Lk ik, - hd . : cr Gn a ok Cp Ker Ce : i ‘ ’ vila “a © Ta yk YA dil a ho " ny 1 i m0 “ : as Pana most preferably 50 to 700 mg of adtive SEER ANRE A) oo 2H SH , CL AME oo BRS eat ¥ TE 3 ' ingredient per unit dosage form. £ ing 5H go it Lh
Eo He BE beg Gf A eT Eo $n pe eel kas TOS eg hn o we Lo . Ka om ’ Cort Lak FANN EADS Ww wi 4 fo Ea WEA AUREL nage elite LI i i a ¥ MVE 1" Co hE eg : an Ts ; 4 ; Fig ER == Sh Cpe Ly + oy 8 SCRA BAD ORIGINALS N.C mone ro) a SER | ae FE
Bi I Codd sons oo 27192 ' Experiments with 3t'eazido-3'deoxythymidine suggest ~ that “a dose ehould be administered to achiwe peak plasma concentrations of the active compound of from about 1 to about 75 )'M, prefer- ably about 2 to 50 HM, meat preferably about 3 to about 30 ;(M. This may be achieved, for exam- ple, by tae intravenous injection of a 0.1 to 5% solution oi tnc active ingreufent, optionally in : galine, or orally administered as & bolus con- taining about 1 to about 100 mg/kg, of the active ~ ingredient. Desirable blocd levels may be mein- tained by = continyoue infusion to provide about 0.01 to ambcut 5.0 mg/kg/hour or by intermittent
Lo oo ... infusions containing about 0.4 to about 15 mg/kg of the active ingredients. } While it is possible for the active ingre-~ : dient to ba administered alone it is preferable to present it as a phermaceutical formulations - ) The formulations of the present invention com-
J . 20 prise at least one active ingredient, as above " derined, together with one or more acceptable carriers thereof and optionally other therapeutic agents, Each carrier must be "acceptable in the ’ pense of veiling compatible with the other ingre- dients of the formulation and nct igjurious to the patient. Formulations include those suitntle for oral, rectal, nasal, topical (including buc- cal and sublingual), veglinal or parenteral -12- BAD GRIGINAL Bb) - i
+ CLE SE LT TE Pa ‘ ‘ ST ef REY . ny ry ide Wd : LO 4 Cl Re Sno Ty ASL,
EE CRE Co Co SAREE CO Nc RAE
JRE Hs : 3 AL EEE SEEN Pah
Lo Bi wo oR Su SRR SE . A Sy oT RE LE 3 AT HR al : ; AE Be WE ea
SE fi TO THER
So Be wh oak aa : oT TE SRE ATE oo (4noluding subcutaneous, intramascular intra=- rn waa es UE
FEE venous and intradermal) administration. The for- he ’ -. muiations may conveniently be presented ‘in‘unit EN -dosage form and may be prepared by any methods . Eg vo a ‘ > ‘well known in the art of pharmacy. Such methods
Cy Aya 1 ie \include the step of bringing into association the : : ‘apttve ingredient with the carrier which’gons- .
CR RE : titutes one Or More accessory ingredients; In ;
ANS hy yo vii r Fe . Sgeneral, the formulations are prepared by uni- : formly and intimately bringing into assdolation : = ~~ %he active ingredient with liquid carriers or oo non nh - finely divided solid carriers or both, and then oo wid dE :
FE i 4% necessary shaping the product. fi : abe » Singh Soir ;
Cop eno ed Se SF 4 '
Lo Fy of Ea Formulation of the present invenbidn suite oe . SCE aaa . ; vg 4 ’ HG)
ERT iaBle for oral administration may be prefisnted es
YL TYR eb ; eR CS : ao “4lsorete unite such as capsules, cachet or tab- hE REL so gidets each containing & predetermined amgunt of : WE ST Co ; 4:$N0e active ingredient; ae a powder or granules) Lo E +i"a# a solution or & suspension in an aqifeous or Te } ~~ 20 ‘ fion-aqueous liquid; or as an oil-in-water liquid . CE Boek 5 ''", dmalsion or a water-in=oil liquid emulsfion. The “agtive ingredient nay also be presented: as a bole
CA eh ‘ ue, electuary or paste. Oral formulations may further include other azenta conventional in the art, auch as sweeteners, flavouring agents and . “thickeners. my cE A tablet may be made by compreégion or ) ST Lr oimould Ang, optionally with one or more 80Ces8BOTY {ingredients Compressed tablets may ve. prepared
Le a 3 | :
EE i. BAD ORIGINAL D : \ eR eh ee | YF
Be nu
| | i. XA” a
CE wT fic Li
RE
By compressing in a suitable machine the active : ) oo ingredient in a free-flawing form suxh at a pow=- der or granules, optionally mixed with a binder (0480 povidone, gelatin, hydroxypropylmethyl 5 cellulose), lubricant, inert dilaent, preserva- tive, disintegrant (e.g. sodium gterch glycol- late, cross-linked povidone, cross-linked sodium ‘carboxyme thyl cellulose), surface-active or dis- spexeing agent. Moulded tablebs may be nade by ‘moulding in a sultable machine & mixvure of the : por 1 compound mcistened with an inert liquid ~ diluent. Phe taulets may optionally be goated or . - : agored and may be formulated so as to provide oo -N : slow or controlled release of tie active ingre-
Cen jen therein using, for example, hydroxy propyl- : i rE Fuoshyl cellulose in varying propertions $0 pro- : : f - igs ne desired release profile. Pe oo i; 5 rot Formulations sultable for topioal adi i CL 3 if ) Padorratton in the mouth include lozenges’ com- pL ag prising the active ingredient ih a flavoured ba- ” | Te " sis, usually sucrose and acacia or tragaganth
Fo ES + pastilles comprising the active ingredient in an iy | “ A300 inert basis such as gelatin and glycerin, or su- / | i 37 3 fap and acaciajand mouthwasnes comprising the
C Bibiive ingredient in a suitable 1iquidioarrier. oi i ! Sik Formilations for rectal administration may
Re >be presented as & suppository with a suitable : / | % vase comprising for example cocoa butter or a / iil ‘salicylate. Ho
SVAN = a : Ew YAR Si BAD ORIGINAL oi ,
pa . EA . el BE ed HaS gE
Ca Ee a Est - CW an El : che ooBR AE . VERGE ERR TT SA
CE Fo ges Cn ERE kn HE CEE : de Ro LR
Coweh SH Bh 4%. Formulations guitable for vaginal’sdmi- Td
CEE CL Lo : nistration may be presented as pespariesy tam-~ CL
Spt Ea TE pons, cream, gels, pastes, foams or spray formu- En
Co 1dttons ccnteining in addition to the active ing= Fo . Seo he sre 3 } OF Asis Ta : 5 ~ ‘redient such carriers as are known in the art to » ‘be ‘appropriate. ROI oe
Cas } 3 jes HN ad re Pu 2
SE Formulations .suitable for parenteral ad~ oo ministration include aqueous and non-aquedus iso= i
Se VE 7 ‘gonic sterile injection solutions which hey con- 2
Cd 8, di 2 tain anti-oxidants. buffers, bactérinatuta and . =
BY " Ww . i - . 5 / “1utes which render the formulation isotonic with
NE RE sn : he the blood of the intended recipients and; aqueous Ry - gy on Sei 5 i - fand non-aqueous sterile suspensions which may : i oe Agel en % ya CRE Ta ; : Cd eb © *f{nolude suspending agents and taiickening agents. - !
ChE op ay : ad } . CE tA CER ids CL. ' ues 7. The formulations may be presented in upitadose
Ie ‘ Pio Sige ak set ‘ : ce 7 o¥.multi-dose sealed containers, for example, am=~ pe -
Co Teg WE ;
So . XP : ; .poules and vials, md may be stored in a freese~ nd [a SLE RET 8 ’ ’ ' oo ge LONE : dhe id¥ied (1yophilized) conditlont requiringignly the : Co ~ #gddition of tie sterile liquid carrieriifor exam~ : wT SE rit, J : ; oy AS AEE EE ,
LJ 20 2iple water for Anjeations, immediately prior to EL
SA er sa CEE He wh iad. Extemporaneous injection soluticndidnd susp = “. DOE code Ce ; : AACE Da : i.pansions may be prepared from sterile powders,
Si Cap - vy : ERY LS . co ;, granules and tablets of the kind provigiialy dese... abt Ry Sahib, : i An SEATS ; bribed. A :
Eh ad
Cu 28 By Preferred unit dosage formula tifns are
Ca wl Cay Aa La
Gh vw © dvithose containing a daily dose or unit +daily Bubs.
CRETE 5-idose, as herein above recited, or an appropriate © es bogie SE Cu
So otfraction thereof, of an actlve ingredient, for © i : FS i Non h eno a ‘ Gang sc a fc iE ;
EE AS Fa i. 4 , Bb hal Coe “ : -15- wy
Co on {5 PAD ORIGINAL 2
: oo v & rt vi Rs va Cn RR ng fA
Co Re Clue Eo | Al ; oo exanple a unit dose of between 5 end 1500 ng)’ h Le preferably of between 10 and 1000 mg and most preferably of between 20 and 700 mg of active : ingredient per unit dosage form. i »
Cl the administered ingredients may alec be 2 used. in therspy in conjunction with other dedi- caments such ae g-[[2-hydroxy-1=(hydroxy-methyl)- othoxy]methyl] guanine, 9-(2-hyaroxyethoxynothyl)- guanine (acybbovir ), 2-amino~9-(2-hydroxyethoxy- nethyl)purine, interferon, e.g., X~interferon, interleukin 1I, and phosphonoformate (Fosocarnet) or ~ in gonjunction with other immune modulating the- rapy including bone marrow or lymphocyte trans-
SA plants or medications such as levanisol or. thy- nosin which serve to increase lymphocyte numbere and/or furotion as ise appropriate. dr {t should be understood that in addition to - . the! ingredients particularly mentioned above the ‘ formulations oi this invention may include other
JOE 20 agents conventional in the art of formulation.
CT The compound of formula (I) and 1ts phar- g | xaoeutioally gcceptable derivatives may be pre- : : TL pared in conventional manner, for oxample ‘as dee~ osived {n the following ruferences, or by methods analogous thereto: J.R. Horwitz et al., J ‘org.
Onem. 29, \Jjuly 1964) 2076-78; M. Imazawa etal.,
Jo: org. Chem. 43(15) (1578) 3044-3046; KeAs Watanabe otial., J. Org. Chem. 45, 3274 (1980); and BoP. Glineki etial., J. Chem. Soc. Chem. Commun. , 915 (1970),
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Po LR Ane d et RR LP > STR REE Lo LE Be: oh a a ARs TATRA TINA . VL ! oT rie 5 Et SRE ald a AE
Pon Ek ove oH SEER - CoE TE ; «GRR ON ie SL
Yoo oo ne Ah Ge 3% Rs : Coed len Bo hn LC Arh . gi i)
Tod Rr REE wT rE . Coote. by GL IRAGe Er iE
Voob 3 Yon TERETE so Ces Sportal ob
AE hn Lo NS oo a ag edb dg i # SORRY TE ERD Bens . 3 “ : Ce : A Popa 4 Te ae te ir EE . ) Fehr oA, At £4 AnE iy, . . i Cn he Le #1 i 0 Iopeied ‘ Von LA Foi ell pe Y ' 7 ! v ~ TL Wao mt ht Ar Bre TR no ! Ch £ i Tr WE 5 Yi, te : Lo “ 5 NR §: ah Fal a i NL Ee SE vo I SE NO UHL SRR : J \ Coo Co UE SE Od IRL pale \ vw Y i Fi, Eg WE : cod : Bb Aa Hg hy SHE $4 EE CRUE rar gt SR AERA LL ERE Be co he 3 pd a JARRE ‘ SI : : Lo Ra Sodas 1h Br ETE 3 3 Je : ah aged 145 Wn} $e LM ! ce ye Le rage" Es i 3 Ane SE] fda Lis ¢ LEE TE DECAL yr RE. iS. ed A ee RR, rts
Loh EE mek TRE Co Sop ne REAR i 05 ERR : PEE BCR oh OF pl RE Ae ie LE a i © riod gi Cem REN ga IrCC EY 55h ; VO CEY REE -17~ FR CER oA ; YN. i 3 Cie ips QR ~ ' SE UR ey an SE na SRE opi £ fl val. TR i YO WR Fy .. CL : : Ey a 5 XA 5 8 i = . 3 <r % penn Bi oe . a ‘re IRF D0 Regi At [RR ‘WER
A a Ag Violoy Ruki) ‘ } wr oe ue rk at SAS 5 od HTB nt A
J i CA *Eig 3 wn 3 : iN - ad HART coe i FR Ae 2 POSE ER LU toga Co Ch - ARR a RE av 1 “28 (Wk 0 5 iB aaa 3 CL : ' “ $e : ; ori Phe Ch Ng EE : & Pp Cael : p.. § ig - X39 So Te So : ii oh - Lo bey SI Bi REN Chi : Axl Ge MET aR
LI 3 Cy 3. RE ag . Co Sal ? = Se ; i: EE : we 3 Loa RRL. .: - n . 3s Ce We Cn oot C & . we x a
Ce —————————— EE ————————— ee ——— mmm ———————r————
Coe ik ae
LA we Pheer : mE RRS Lo wo HR | Rp a I : rep - ST I ger
Lo ge een oo Ce SEs Le
RO EG Co on
ET “Hneretn R represents a presursor group; for the uw ino Ee
En Ca Zhgdroxy group, or for a pharmaceutically. accept- } CTE
CG LEER Epa ES
EB 4'dble derivative grou thereof) with an dgent or Co RE . Ce oy LENE Stns A
Loo CRE al 4
La 2 al conditions serving to convert theijsald hn
EP Fk EY pl - a . Ci lL J BE a. Eat ry gE
Ce 5 7‘predursor group into the corresponding desired CR . ‘, ba Lo : HK LE A Loris
Se CL mE Betsy CE i 3 . ¢ 2 group } or ha . Ln
Se =e TE VE ES co gk | Chel :
Rt wR : : UE i Cv a ‘ {@) reacting a compound of formula SEE &
Like) nh 3
Tk vod 3 mi Li
CL © xe . Vl x 10 ¥ A (Iv) Ad
ETE ALES 0 N fy Sc
Nt EY Gh gay H Shee i n ) . } Lo
BRE A SLR mel ov . vo of f Lo gaat DPR CAE co Rend Eh 0 gel CERNE
Co TE Ei Ll : CORRES aden
CEA CBE a RYSRy oilik LOPE Te LE
CL a dre Age. 'a functional equivalent trereof, withi® eom~ "0 Uo
SB Ee Ai Lh al: ; “00h uEE Slush | | : Co CER aw. Loh ge Ene ent FER : ER pen RE oo br ih ET EG ound serving to introduce the desired pibofura-” .. CL ‘ Eo al 0 Saar : Eagle GT TE . we AY i. Sgt SA SE co ee
F015 7 sqgayl ring at the 1-position of the confi of A.
SE a GV SE . a4 - . He IS py . \ 3 2 ya : Siad¥nula (IV) or Aa wo iL : 9 Ln oy Besse Badge 0 LL oe : ; 2 BE § & : ei iE ; GhE Boy SL adel : CER Ll TE BN
J : EP Loo a NE FAN: } . i A 4 4 =: on Ll - : x & E : He ) reacting a compound of formula = Loyal
JE a Eas CL Thee oh EE
GEL EES : : Se LEREn
Coad iE Re Roles o SEER FROTE OS
SE JE Noles . SRST EE A L x WoOENE , nates : . OR - ed AR : ne . gd os : IIR 3 gl a py Sani : EE Re) : Li Cpe HR da i
Loan gl En : CE . LEAR
CR L207 Ey : EL Le Het pd L0H = : LEE , R | - wT en ] Dap Li > . bi . : CRY ~ LO (V) wn - vo ER ai
CTE Ra ¢ ‘(herein a! 1s hydroxy or R as defined above),
Ch BR HE with an agent or under conditions serviifig to ’ - CR hint dgonvert the said sompound into a compound accor-
BG Ll ’ ‘ding to the Anvention; SU : ged thereafter, or simultaneously, therewith, " Se Lal 1
Crgn pt . ,
AE EE | A
A "| 'BAD ORIGINAL &y : ce kp SN : . $n -18=~ Re SA ra Bug ol . Re CL i 9 A . ' ny ‘0 br fips Ea AT oS 3 7h ay : Jib Pn #5
Te Cadi fs _ Li ‘ : Ry : xb SL i§frecting one or more of the following @ptional ES
CHE i # : : /gonversions: CE ;
Cee Silt ye
Tae Cy Sn
Ek (1) when 3'-azido-3'~deoxythymidine is ie : fa HE Ari i "formed, converting it into a pharmaceutldally ace ol ky ati - {“gaptable derivative thereof, RO teed LIE i
Te Chany Si rh (i1) when a pharmaceutically acceptable Be : Lo ST «derivative of 31-azldo-3'-deoxythyalding: 1s formed, :.gonverting the said derivative into the! compound . teh Aeon el . or or 4 . oe 01 formula (1), or a different derivative. thereof, Ey -~ Gage eet Ln a x SC Sign ir ee
TOR In the above-descrihed procenc geodrdin . : I CRS g CL ~ . . L : hi a ~ Ui a “igo tre ‘ovension, it 2111 be appreciated’ that the 5 J] EN . RK _ - . JE cel Ya al ; i ak Siete I i LE ‘{iprecursor compounde of formulae (II) ands (111), .
So CER LS LL Ed RE Co = : Ss oo re . i LA or od
Sd 7 a@ well ag the above-mentioned agents and’ conditions, ih [i Lo wk Aree : i . ca BB ee to : ie
PE 7:will be selected from those that are kntwn in } ia i oe wat ge EE : Lo ERE “ tL
Re wa en Es . : : 3 en £5 : LAS ;: fe art of nucleoside synthetic Ehemist¥ys: Exam= - 3 : oo for co Ske . crea ; : ve nl ol i
Cn oo Tig . EER : 5 : Noe tiples of such c.nversion procedures ars Heborived ; Ci
So EE . AA oy 5 . EA filereinatter for guidance and it will beliderstood a : x Fey ‘i 4hat they can be modified in oonventiondl¥manner “ 5 : Bi J STERIL Eng mE 5
Chg AY ARR Lage NE JF md han on the desired compound of 1o¥ubla (I)e on™ fi
Li od : SAT CARER : S . Ha oJ aE SEE CS Hl ir
TT x ~ 20 i fB, parsioular, where & conversion is deseiribed CN i 1 JRd soon Se AUATINY - aml le - - aa ' Fo fo i Baten a TT PEE, : mies oo TW Hy ge i“ gfifoh would otherwise result in the undéslred ree a + » Ee EY Bs oo CE gre
CEL A RI AN lA ER \ . «Ki md ‘iagtion of labile groups then such group ay be o.oo tH
CO pd. EE : LR ors . CRs wo . EN : an 4 iE Gon BE . LF fk il “iprotected in conventional manner, «ith Yabo Eta : BREE Cd ri Soames y HEE ed ar ARE Co RE Re L
EA a removal of the protecting sree Ake come ld nhl . . apn Hs ov : CT ENTRIES EY.
CE ter AER REE Ar LA i
Loo 2% ivPletion of the convereion. Thus, in prodens (A), Sekt CH
Po Bd And A 5 To, EN So ] Lo . 5 cre be DER cM eet ca Lr ~ H%%he group M in the compound of formila (1) may So Rp kh N. 2 In "ha ry Peg . A Pr . a ER n J t 3 ee : ATRL : i veo ve
So Ty $preseat, for example, a halogen (e.g/“thlorine), Co o : ” = Vy 2 * Adi a . . te
PE Lo WT rs : CRE ey ., ; ¥ihydroxy or organosulphonyloxy e.g. trifluoro- Ly Ld . gs 2% . ¢ Te ) ] | ;
SA £3; PN EE Lo 2 nb wp wih a nd : HE £1 Ch aE | Nie are amy
; on oo N J
Lod Ge methylsul phonyloxy, methanesulphonyloxy or p= Te : toluene sulphonyloxy radical. > For the preparation of tne compound of for- mula (I), a compound of formula (II) in which the group W ie a halogen (e.g. chloro) group in the threo configuration (in wnlch the S'-hydcoxy 1s advantageous- 1y protected, eg with a trityl group) may ‘be, treated fof, example with lithium or sodlum azide. The 3'- » hreo~halogen (eg chlorine) starting material may he obtained for example by reaction of the corres- a sonding 3t-erythro-hydroxy compound with for example
J ; - trdphenylrhosphine and carbon tetrachloride, or alter- . a : natively by treatment with organosulphonyl hallde . o (eg. trifluoronethanesul phonyl chloride) to" form a . BRE : s6xTesponding 31-erythro-organosul phonyloxy dompound L : ) ; «high 1s Iu¥p halogenated. Alternatively ® 3'~threo-
Co nydFéxy compound of formula (I1) may be treated, for example with triphqnylphosphine, carboy totrabromide : | : LC and’ 14thiun aside to forn the corresponding 3'- Lo ; J L 20 esythro anldo compound. Removal of any prdbseting IE . % grobp may then subsaenuently be effected, eis at above. ) : EY 7ith regard to procees (B), R may Fepresent a . - a protected hydroxy group e.g. an ester groliping of the * 3 . > - type ‘referred to above in relation to foraula (I) Co - 3 | 2s peckioulacly acetoxy, or an ether group such as oo E 3 : : Co x fFnieiyios group, €.g. $-butyldinsthyl- Co - don 3 s11lyloxy or an 8ralkoxy 4roup 8.8. tripheriyluethoxy. ay 5 vo RE * | 4 i { ty Ch vy Gl n g oo k i re Cg | or 20 ORIGIN lr) Cn %
. Ce | dal CL he ) RR . . Tv 2 wy * * ' i ! : AH * i Eee 3 - & oo FRE =e : poe Cg CT mR 4 ‘ Sg - La Ceri CS EEE RE
Cd wen A : CER Ce Died lr BE i IN a ; Bes CAE eR TEE
Co : cE : Co LA Su on ELE iE Mk ow : aan GEE ak Een if
EE gtich groups may be converted for exampldi by hydrouifid Te PEE
ERE Co BRE ' Cx oe Se TE RE ye Wy Ens \ . 83 Sep es aia CP . PEAT oo AY a . 3 A gr > rare Lo a cn Ld SG io. 21ysie to the desired hydroxy group or, Ho iraneenic LE gE
Pot ER SAE : So hw ‘yerification, be converted to an al terngtive ester’ . .'. op br . LE Aw fer Create : i) LE Ca Ee v EE ki gids. Ser Cg . Cate EF p¥oup of 3t-agido-3'-deoxythymidins. ty ha ‘8 wR CEREAL HEE EAR CTE ; ad nt a A Mra } ' - . or 4 Big : EER CATI ATS TE wi - with regard to process (0), this say be Eo EE : Ty eps Cad el i t So Vv ry ws ve; i 3 - CE i! ! 3 : ! ’ 5 Til vo } effected for example vy treating the appidpriate: HL ‘ ~ 3 na, ie or ol 3 pie ; ' _ - EE grintdine of formula (IV) or a salt or. protected By i . ' LTR ’ Ey ‘ : . A : a CUA " Fa . i v derivative thereof, with a compound of formula, Ck . eo Neon . Saat . . see ’ Coby wo i ¥ * Lr
Co A i f Ll
Ts suk AA oo Lo 5H 0 GEE 3 oo A <_ A ae 5
Loh ERR aq = . Lh C Lay ry Sa B Pn
CL peti cade Lek; \ add or end jE
CLA ges ge Co (EAA TA eg EE wh Bed PLA hal po nuks : : i Lo CE erein A represents a leaving group, ei: an aces © ET
NE has CAPER, STA el CoE RE . Tah Te } Hug ge ARAN ' REE CATT
CL i FE vo foxy or benzoylyxy or halo, eg chloro group and Bits pd go
Bw dd odd i THRE CHA
Poe nde TT ae REPEC ee
Co B15 | i¥presents an optionally protected hydr Ey. group; ER rh
SE ERT raed : : CER et GEE iH . a gt aioe } AMEE Cig mnt td ga
Coe ke eg e ptoluenesulphonyloxy group), and Gogh pquently & bE fi - A aE B bh A : ARN te i aR A CARA TL eT . : 4 Bl fa Be: po £ 2 Fos CS LH Ty A owt ah
LE ah “idgioving any protecting groups: Regardif Iprovess on flo al i Sawin Ede Sepa v ea Co nt Ee SE
CAE BE BREE 1 OR on SEER UT CELE Lge: EES : Co TRE Wee C0) R} may represent a precursor groupfa@; des TER gpa: oo i A AE CR 2h oo TL Lome Ie with # fo ARE CARE ade ‘bed above for R in formuha (III). 315481403 «0 hire * Toa aR RIN Chae AER CER LR od : ; Sek Dasha "5 AREF : Lo Ch 4 AREA e iF righ E RINE EE
Coa TE Too Si'4oxythymidine may then, for example, b 20 tained = gE ir Si 7 Vos hel. ERR EL eh GLY ERT ’ Poor BUR 00 Rl ' a a CNOA Ce TT SR REL , iA PE B.creaction witn an alkali metal azide; aig: 11 Ji Tp Am a
Coo we SER Co : Challe. ollie ; © 3 fh o-oo w¥ifum aside, advantageously in an appeogitiie Je a aot = SER Lng oo Sa er ee Bd rE LE ; : ” : EE : . Hr x CL ma . ne So -
EA ‘dd1vent such &8 mois. DMF followed by a¢id or base .
N « nt Np ; y Cn EL . ew : .
SE ~ hydrolycin ndvantigeoudly uhder mid conditions. 3 Ee 3t.Azido=-3'~deoxythymidine may. Y& Bonver- a Saas RT
SO LAR fer
Poy Uy . Jed into a pharmaceutically acceptable phosphate wo Sls Fi! a Edy Ad 8r other ester by reaction with respectively a ko ] gi ‘.phosphorylutirg sgent, e.g. FOC1,4 or an. appropriate . : ER nl
CLs ee
LE, , : NEE
Chel in ) wh LC — Pc le At . Le A Toe — Pa
Ss Je
Te Bh En ) Co a EL at so gE ~21= Wi - “ To iE 0 BAD ORIGINAL. £5
Co : J hy ‘ Lo : REN
— ~ TT cg - ce NAT ins 3 - : . Yoo Ps mil. BANA 7 5 . , 3 . Ar Aged Ho ab ERT Ag Ha Rpm bd Se cae iE j By. eg 7
Lor war Tn dis hes EEE EEL re ob £1 ; Boo dn Fs 5 ER las nT dh Alas
FI EE x. - ! oo ga - LPT OR E: : >on ER Tay an i 50 So CdR ER Lt RE Te
Lo WE owe EE x Co Tabs fag ok omy dE EE ¢ or anhydrides’ UU CE
Xo 4 Sle, Es il y . ons esl Th oR
Too 8 is ; 3 BN F ‘ g an acid hal ide Jor anhyd oh a Ad hi on afi
CR wn Cah . +€., 80 Pooh cml bo TR ait 1 shes : : A ent, ©.£. 80 %° Eo ERRL Eu EL
I jigeserity ing agent o: wy foluding ‘enters theres: : he ia . 3 egy he 4 Toy 1,0, By Tt . i . p nr A Opidaadi wo i | Chk Sef
CE gee 4 of formula (I) aE TRL
Cn EER RL gh @ compoun Da on aR gcep= ‘oolong so BELT ama Te harmaceutica 1 aocep= Gna
Coal Eg verted into p TES Lo Th
SE {lof may be converieg if wanRery e.gc v SR : wr dig conventional m EC Ce J : oii gre thereof in iY (A Cohen EE vitdble salts tate basefAniesger UC EY
To Boies opriate CIE Le Ee i : vy 23 3alie th an approp . CMA .. CTE, } Tt i Sak SE t t ant wi EAT I tow Co . Pe oe SY Rep treatm . Rg 4 cone L fos 5 i by } 1do=3" deoxythymidine ay be Toe nh He : oo CoahEl : LT -) RICA cr Hn : : 5 1 salt of 3'-az ‘B¥hydrolysis Cet
Loo rR sound, e.g. Dy. Qyd el Fe
Ca WE the parent comy ! sak A to Co Rt
Co i yerted into i are intefded for 1llus- . th : TN oo i Lo . a ; les are CSS ae oor F fi The following Examp ate the soope ; . . : TA 1 tended to 1! al Jat . :
SL AY re not in CELE SE Hs fp, and a "du 4s Vi . i ‘tration only term ‘motive in-' i : : ayes o : I ays The @ Taye . Lo rs
Sra in any w ETE : Lo . i ’ef the invention in ar Se compound Lr ; 10 ha Examples means. & oon Cen ’ co rN n gan } a CT dei oof, {8 3 em we gred harmaceutically agceptu eink 8
Cae gl em a pha bod ifm EN Sn BEE
Jee goth \ wi ag 1a I) or AN AR FEE SNE + Hom gh ink ag
VA Ba ie formula ( Cole ERE gp el a digs Pe ln i GEE Ro JR
CC Read ads ooh BE x meof. . Re Cs 5 hy 1 Hi i - i Al HE giderivative the LT SER oa 3 ol TRAE EE HEE SU etn TIE
I Seg RTE Rr ad SOREL Le om Set Sere
CE oak RE Cie BUYS. ; EA. EERE TN Jie RE
Poa FO SE AR Lge 1 Tablet Formulations fer dw LE & 2 0 2ER Te fo Spal ny ey le 3 ET wee : a A aoe nll Fes ri vo ERASER tl AR Bia ; LTE EL AR nan Wg ia 7 aed les gf a iY at A angi were : ARERR
HE b: CARER DT Cua i ps . . ? 1lowing formulations Fy M8 hi Jas fly [ARE wi : A digfea REIMER AEE AiR LE han oy
Cou Eo i he gE The fo ny ry Ae CeRy RE
FL EOaR YE Wk of the ingiédient ®. igs DER cl
PLA dR aa 4 by wet granulation vot iiadatsionldy Hii 1b 3 £0 Bg ghd la Ei hg pare Co i ved hyiisdaltlio Sal ase i i rel VAAN SA = LEY Pp . Lo . owed 2 by ech no EEN EET EATS
WL hs LAY FR. ‘ ‘a A ERR Deh rs EASE NT
Eo io, aE A wor iid , pr 5 vie. olution of povidone; Soll Cn i) Go nf i 1 po i Hen Lg
Lo ETE 3 i Jee 41 has Ce ea ee To so haRER ata A Ye ge Bh 3 Eo SE - ATER : CT Ad compress Lon FERAL | GR LE 3 i boat, LAgEL sium stearate and © + Cy op Bi Ty iF kh MR, Te oy COR ER ta hE SERN se gd Sl i om RL ET
Po uA a bE og if : AE a0 £ magne y CENT we = oY ng/ tablet vid ng/ tal SA Te Sol
RI. SE ARLE Tike kee. } - f ; LL . REED C0 7 RY CEE EE ; Ao Tam TENET uy meer Lo + Nimes Fa TE PAG
EER. el IEEE i 3 hoa eg EST hE FL 1 $16 SE E BE A ETRE ye
Cy heEB UME rahi a : Cn cE Co RRR yl : AIRE pat LAE ‘2Fdrmulation A , Co " 5 pid SECRET TE TD : RS TL 28 Raia Co . aE CE EE fii feeling ; PoE ORY 0 EE ag : CRE hl ROE
Cb dd pg | » Hae 250 HERE rE Es Pass 4 edient ~~ ° 250° iu “relent Paria, Col i vo Ce SEER e ingr : Co Co rE Pole Laken be : Ed . Gila) Ac v - N 210 : 24 SEAL - 2 . LR oak v Toa ERNE an Len TEOY - Co CR odin Dn Fh yo
Sas Ek ES B.P. EE & NEE Cdr : btaEhl Eh Ls RG Laotose . - : YEE 9 TA RR SE ge Lh : go vers Wo oth Ey he bv) a “15 le 30% = Abe pe EG : BoE Lg "25 i ANY SO Cie gn de El : Toad ALL #0 Sadak e B.Ps A RRR <1) 7 Ee ne 5 $ i; gy Hi © wie) Povidon collate 20 oe RY Fa nie Ei : cE JW to ker a LR) TN A
CLE Hh Sodium Itarch Glycoll SEEL eh : wo gk Tene, RAS : 5. ier To URE
YW y fe RAE ty . Sr 5 NL glum Stearate ie ve “a 2 = 300i 4 HE Ny = 3 LoomE Ey by { i Nagnse Co Co gd AVY NE Cp FRET 0
Poe Ea Ta) 8) 500: oR id Si EEL a ! cap Fade ve Sy 20 : Ak EINE Ee FEV CRE Cn } 3 nak Ger . SE . : SRE ges ih EE §n : <8 Fee 0 pad ‘ wa od VELL Te
PoE EE a Rig CREE ore ERR bie ¥ iu gk ACR LTR Cre Rel 8 . Boe and CPLR : TOSERSE RT v RT: 4 ob 3 Bagh ; ’ coo bo Loh Fakat a= i £ on
I NEES -22~ | Ls 0 eh gi
Too he ws BA GINAL ea nl hn THREES i RE AiR BAD ORIGiA. fife UHR gE
Lo AmAy sgh be, EEE oT BIRR
TL EE ox no TEAR EE Le ve WUT ERS
IE CEE Lot . ro wm ag Gale VSR Pe
Pom RR dame
Cw a . 23
A * fn 4 ‘a i vt : * . . t - . = : - .
Co : Formulation B mg/tablet - mg/tablet 3 \ : Sh ~ 7 ! , . : (a) Active ingredient §00 250 : / (b) Lactose 150 x = fo +(e) Avigel PH 101 60 26 i * (4) Povidone B.P. 15 ©: 9 yo i fe) Sodium Starch @Glycollate 20 12 - te “ oF & x ! i LY : iy : Cn {0 Magnesium Stearate 5 wl 2 “ng, oo Ci Tks ol
Co LR 500 le 300 Sl
EY The - so rE POE “A
CL “Formulation © _mg/tablet™. =
Lo i. Sm ep alge ST [IC
Co ge ®Ftive ingredient 100 70 i
Loy Hd For ER “ i
Lo Co ih FO Ly Lo Be . Ct yl Td gtose 200 Ese CL a
EET Rely a B i ] End $i8tarch 50 CE So i
CF Iw 5 NEE. : Coe age Ri Phvidone he Coie A ony Hb Xa, : ! dk £3 Magnesium steurate —Aa oo :
Lo CE Sead : o oR 5 i 359 a So a
Ct Coo BREE noooEET Ce ve hol Ee Ca Cg i ~ # vo Rand What Jed i : JE. wid tne following formulutions, D and Fj were voi i i“
Po EEA lama Lo AH Cy A Ci
TL EG :- co BR Cdr cg J sree. iw Fepared by direct compression of the ‘dllgixed Lt CE
LNA ERO Riel on Bi wlan Re : ours NE Lah Pa TE Me SN Vu fr SS Ey Oy hd - i 3 Sd NE ngredients. The lactose used in formulgtion Bow or 3 tS oe a Sl ¥ \ Ea Vora > A gh | ef Son : CE Ele Cl ede 00 BRE Br 3 4 Cen 4 ae of the direct compression type (vathyiOseat HE %
Logg tn anle CMe oo feb orl
GE Pigg ") ER mE cE ; weg in @@paroXT J. Coed Griese
BE EE Cogan To TTR
Eo RE ERR ER el ! uy “ ' or aN ’ .- Ey A aN cee ¥ it wr i i ge Pr . ny
Eo SRE oo Ci Ley BE + =% a5 si Formulation D mg/ca e. So a; : CTT Eee : ~ CHEE SN CE so tae wo EEe . wh na a Adin lA i : Coon CTE fi 12S SS Lh To Ey
Eo. vAQttve Ingredient 250 ASS SEE : IAN Th CIR J 0 Fi
Tao S40 Ag oe Ch i no vi Pregelatinised Sterch NFP 15 : 188 rE SL : ; AA $00 iw ooo TL : : ETE EEE Co
Co | 2 he "i : : ward las - ie :
Ey hee oo a oy
Co Crd Cd No . oo LUE . — ChE IS =
Lo 2g BAD ORIGINAL Qj: =r CN, v he TELE - SAY . oe . :
Sk CURE | EER LT ra
: Cy wy E i + fg BD ' oi i Sha X¥1q0 “ : a wo am 3 Cop pERBERL fo. Cee Ce oo ey Ee cor Be eB Kgl mh FRE Ces ER con RE TR ON ghee oo El Wedel. Dive ilo oan on gs nT CE Ch " ov yo . : SEAR oo Cre
Ls Lo - AR :
EE .. Boxmulation B | mg/cagsule Co } TE . v end So “ . £ i P » Care iy wo Sag oo NEE oT Tet pe
Lk bin il - Adtive Ingredient 230% . : SUE Sy en rr ott CL . ~ . , ‘Lactose 150.
Avidel 120
Ce 500: } Fdrmulation F(Controlled lHelease Formulriion) i } 10 "". The formulation was prepared by wet granula- - too. ‘t{on of the Ingredients (below) with a solution of
Co t ~ . A. So
EE povidone followed by the addition of magnesium he IE HE oo SE Se . a ~ 'sfearate and compression. AES ah ae aE LO a Ty SE Ti : & a hg La: Active ingredient 500 EVEL Se a 3 a 3 : ne pt . . : AEE SL Fon : ’ ’ A AB) Hydroxypropylmethylcellulose 112 : NN yet’ (Methocel K4M Premium) SL . 0 J\ (8) lactose B.P. 53 1.4
TL ha Fuk i od Co ErgR oo \ . fn
ER {di}: Povidone B.P.C. 28 4 i © gl Som dv li { LNT EL . wi 4 : Lo € pa Huguesium Stearate lA 3 : Cae Go i gel { ep te TE 0 700 nts : Fn Ea Seton BN . \ } of pe 20 RELY LS
R on + HEN tat : : -b a Sl : . ET ) - + CoE av on i wih
TE ~ CENT ppug relesse took place OVer & peridgd: of : : shah NEY ’ : Le Sra Aa - i ree “about 6-8 hours and was compleie alver 42 hours. E i Ln AER I
CoE SR Ry ’ = Lie Tei : : Ho CRtgRy Lee
I gy .
S25 “R¥ample 2: QapsubFormmdadtions a co “ AR . 7 ne te-aarn etn Be : DE Ar 5 Po . . do SA ei : a ag A . # pad JAD : ulation A_ Go
Cd iH A capsule formulation was prepared “by. admixdng
SE silks DIE E
VL PEE OA das LO Bay
Co EE ~24~ | ki ’ ur hn So oo REN . SY
Sh to BAD ORIGINAL 9 iN : . n Lo A
’ - Ad a ; . : way . : ad ’
EEA. RE HMI co Ge | "i Co,
SRE i SI the ingredients of Formulation D in Example 1 above and filling into a two-part hard _elatin capsule. ‘Porumulation B (infra) was prepared in a similar
SE by ‘m@gnner. “Formulation DB ng /oupsule (a) Active ingredient 250
CE - (vb) Lactose B.P. 143 ¢ 5 L . 10 ‘{c) sodium Starch Glycollate 25 (a) Mugnesiun Yteara.e 2
A no. Lo - } Cyn 420 : -'pdrmulation C mg/cupsule
Ye gn 5 . = . 1 5 + a wo ! ik ie (a) Active ingredient 250 i (b) Macrogol 4000 BP = 350 x od —— : . . awit of : LE 7 . olen, : 600 , ¥ CT Ph £4 oo Sy co Bains Sa i 20 digit Capsules were prepared by melting the Macro- oo figol 4000 BP, dispersing the active ingredient in uo . he ot } 5 ; i; 4he melt and filling the melt into a tWo=part hard oi Co . ley ede “oy gelatin caps le. Tan
Co ak f #0
Ai Ha :
EA : a Soh
OE lad SE 25 Fr Formulation D ng capsule - o Ag er : : v Ld Ka i 7 or SE * = LL to “i Active ingredient 250 : on He : - CL ¥i7 Lecithin 2300
A op Lo .'IiArachis Oil £100 cl EE el | 430
EEE EE SL BAD ORIGINAL of a : . + 8 Aan i | v Eg : . . ow oo hh ota - We ga SE ~25 wn 3] x Lh dra 5 ; wal SHES fig J
————— ee ————— ee ER —— ;
Ca LL | = 711° . | Bl kd - : I 4 ; , oe CN ighdly Vk - ‘ :d fn Corie Benn EES
LAE = BER ga : Crepes CE soo fap Co SES) alk ST CE : ap oy WLI pore Ls EE
Do Tf een CLR ce be
Nn if Capsules were prepared Ly dispersing ithe ac=- La : Fox RE = Bp
Lo A CEE : BE ©. "i¥i¥e ingredient in the lecithin and araciis old oo Ge : : pT 3 (np ,% RHINE De
Ry SUED Sed “i . AE TEN CE So
X ‘ahd filling the dispersion into soIt, elutic ge- CE i. hE FE 50 lain capsules. Cy =e
To SNE CR Ee
Ce REA vale =
Lae Sl co : BE Wey ; ~~ .Fp¥mulation F (Controlled Releas® Capsule). pn : co way: The following controlled release capsule for- ou : SEE CARS ti : A imilation was preparcd by extruding ingr dients a, = i : ; Eh: ih * . ; iz > , : rT Cah . S . . ATL : oN LN fei
Cs brand © wing an extruder, followed by spheronisa- : i ax danny : oi
Co : eke EGE : SL ition of the extrudate and drying. The dpfed pellets I . aoa aA Se ] : Ll
LON : TES Fenty . . oe = we Ti Che } . ; ra . i
Pon EE ryere then coated with releasé-conbrolling membrane oo ih
C8 mE Soh Co Bai : NAT TE Pa wr geelER . ek FT I. vio Ce Ci
Loan i : g () and filled into a two-plece , hard gelatin ocap= = ... Po . ; . wo : Jn g: te . aL NA oo ; 5 2 Ln . A ., pi RE Ra
LT ¥ = EB BE. ATR. TN - ‘. “A £35 : ol wikia CEE 5 gasEE NER “LBYAe ; 1 or CY ES SELEY En ET RE
A Ba se | RA ENED he
Eo laEoodeR on #RRE oo : CAREERS Tee eT
Loeb EER 41] rt . 3 Code ie RET boy OB RRR Sage Cn oo Cori Ee Te RE ’ 0 of REEL & Wh ir CL - ; CL $A dre \ Ce dee chi
LORE Ws mes Ce cabpule. oo sme EE : Cong Rl dE . ER ELE aoa TE
Vom ed EERE ow Coe LST ; Coop EE Ft Ch “RA a. EE CE : SE alam CT RL Co - JARRE a es een a : de ad 5 3 2 1 Active Ingredient ' ’ 250i. Jan wd Helipd i rel 2 on Cs EER Cd Lrg a oo : © Lug ri vo fhe aes i i v SOA : Co Hp CE Ea a . : : oo A 1 VEE rE ¢ Cove Te (y 7 Microcrystalline Cellulose 1295080, pe Tl CA : ig uh sobs Le po EE OH ee ah pd : Load miu ad So EET VE Rn { ioe ak aE HE laotoss BP ~;, Co 12855 MIR a dh i
Poel MER pr hg Qe ye LSA ACT Ee $ 5 J ak a AS wt " TEE ty, Comes TE “ . “r Le a abs FNAL Wh nh UH ER x VEEN yoo GEE ESA en aE Co CE x ROEETRER OT ar EAE ag
CLS TE Rg Uo mY sthyl Cellulose Cow JASWL Mg SAE $ od Th a) cD uh Rees : . De i Moa Lo i] SA ns rR dd CURRY { non CU RAEN SL he TLE ot wi ERR eed ER te i Cen ARE Spgs = : \ ' CG WERE YA AFCA Gon ITER ; a on Pay ENC Ls na eB So TRE LER. TR g ' Ce : Rc : . ROR At ER EE * Ag i ok Shih cn CoE AR coe CEBETRRRGL EE
Tu Fb mE ET Lo pOUSBIISG Cis Rgl o go ARE dm oh Sele ped CE PURER SERRA % a at ¢ tlxpmple 31 Injectable Formulation . LEERE TL hg Sotoltingr Ci * Co Ee Dh - TL CREE SRG ea ! Cd LE As AR fede no Mbeeadbia Ton 4, Lo GLE vo mE , PAE pl TORRE i CoE aber gE Cy 3 pda ES Bg 3 LOWER oI no S TRE : i: Co : co age le SERA We ER : [ ® pp op jEpEmulation Ad. Co aE CIBER a i bog 425 Ty Reade yn TE ad ee TE AE EL eg io al da cr ar [on SRE RE q Py whe i STEN CoE Ll, penn ole tent pe of S A , . SE NA Loh . HER FUN. ie i Alt RL AT a i . oa 2g vn ERB Cl co I gi . Calg 5 3 Low Ed 5 so EE FL Ne Pate | be we f y ANE ne rf & HR 7 ndive {ngredient a 0.2808 Eo EE JURE o Ags Ho 4 oe , " : ar] OE Pf yids IRE a 7
T En ' eR | Ct : ak wo Ser Th gdh : ne CNR . oh Bl Gea ig dR ST : SRE i drochloric acid sdlution,0.1M 4.03 9:7.0 i ps te ; ; SE Lg to Toon ERe le fir : TAs Es q.8.:%0 pH BRE eR en i ' Loh dE BL Chr : wor LER . g CREE pr pn i = Eo . Sal Cpl SRT SE . ) RK | ° P. 2 AEE DS Ls We £ & ' - JE
Ce TE I WE SEER
Cor ’ ri CL w@df- 3 : a Sod o Co TIERI oR
YL CER i Fare CWE gE A
Loy CPE LE | AD ORIGINAL <, Trae Cano it 2 Co MRE SRL nha
Che ie ; EE x : CRT Cpt mG mh “ FBR : CREAN CEE CE : : r,t < ey da , vo % ph RG Cs
. we FE MEST Le Trg / g 2 ew ~~ 3 oo Sodium hydroxide solution, 0.1H q.8. topH 4.,0t07.0
Cet RE SE --3terile water 1.8.%0 10ml : Rs The active ingredient was dissolved: in mest of the water (35°-40°C) and the pH adjusted to “between 4.0 and 7.0 with the hydrochloris acid or the sodiun hydroxide as appropriate. The batch was then made up to volume with the water und filtered £0 through a sterile micropore filter into a sterile 10ml amber gi.ss vial (type 1) and sesledwith ste- ‘file closures and overse:ls, A
Ca 3 : bo or i
Cu 8 a
Poms “Po¥mulation B. oo
Soo. E wm Saga Le
RE EE SE Ang Lo
CME oy ga. : SEEN : es) dk WES i : i . ca Te 7ABtive ingredient 04125 ¢g
BT TE HE - ;
CL 15 :8%erile, pyrogen-free,pH 7 phosphate +25 ml : ‘ ‘ od i Fi bufier, 7.8, to EL
Toa ands Hey hE is
EE Li SE pa “EXx8mple 4: Intrumuscular injection oo
EE ChE ph i CURE Le
LJ 20 “Adbive Ingredient 0120 & oo ; : LAT re Cue re oo * EE kay Alcohol “ado g EER A 3 : SE ig A : IR : 3 SR “al¥sorurol 15 Aids g8
Dt ons GEES No ) eo BE Hath” CEA Yo tT : ddter for Injectién Gest tO 3400 nl “25 14% The active ingredient was &lesolvediin the
EL ks € obi
Co J CER a Co ’ bE nT ‘gliyoofurol. The benzyl alcohol was then added ar COLE pat Lt
Lr eB agd @issolved, and water added to 3 ml, The mix- tr oo ture was then filtered through a sterile micro- . lh a . pare filter apd sealed in sterile 3 ml amber glass i : HS 2 SE fr wo ‘glass vials (type 1). ho : che SE A x
LA Hip, SL Co : Ts Lge -27-| ) Lo SE oo LEY BAD ORIGINAL Ci PT
, Te i wT CE Si IRD
TL Ege mE 2911 by ; , ! Jil = 54 i Co v } . - fp hn B . . By ) 4 ue
Goad oh MER THEE ee ol ek 8s . Tae Co Lorn En : Seo 8 yo : Bat oad. ee iL .? SE (Fat cet, we dl wl COSTE Whe, TOT
A bE ’ HER EET Pu ‘igxample 5: Ingredients nk Col he
Sh SG Cd vl NE
Co Lak SHE C3 “Active ingredient *012500¢ i. . HY Sen } Ea
I’86rbitol Solution 1450008 = : 5 ‘Glycerol 2:10000g nr
Come CAI ie + Sodium Benzoate '0,20050g ith
Lo “Flavour, Peach 17.42.3169 0,0125 ml A : Lp . A \
Se SL iy {Purified Water q.s. to 5,0000 ml pe y on ROL -
Cd TTA : hy hak PAE Ne qo Sar a ol
Hh kee La 10 . #4 The mctive ingredient was dissolved dn a i yo : HELE ; i : i LEY Sai ne , mixture of the glycerol and most of the purified foe ; wo Fendi ; Cue CT hE
J Ld 54 “gel. * CORSE : CU eh . LT a inWater. An aqueous solution of the sod u;fensoate Ld EE
Lo. ae as ck : Cpe Som males TLL wig
Foose uh fi i : : . NE wn TER ier ~ 4-gds then added to the solution’ followe by addiw >: vo ET od ak CE Spel CET he TE pr Med : CIE - ano Save Em s ¥ LE ! ah Pre : KJ oF LT I) ol Er . co he he jon of the sorbitol solution and finally; the Co
Co Cogs ER sora es “Aad oh SLE Ee iH | a 2 LEE RL . nee wed E 2ouht gi
NHS “Havour. The volume was made up with pUELfied wa~ 3: Ea : Platte } ARE : Roe Ty wy obey
CA +1¥er and mixed well. Cake So gd.
PoE : ae SAeEs cL Tepanthoe. TES
Ce Re | dda Weve
DE OnE REIN hat Yes
GC 8 AR he he i : Ci NS 2 gc Co TE ; tag F Cl + Ay Ex8mple 63 Sup posi tory . Fr : TE fir Hit Pk EE : Tel Ter EE Ch fe CM
COUPEE aL “wy ER : yp obEily CEST SE : 0 Toa 3k By : mg /sipposi tory ot on bi yuk A Sigh | Lo Cala on SEER a : CAR iE Se He AF : oo eS Eh LTR Ea «J 2 no 20 £33 3 ' Si ll Cv Ca TEN, Yo fe n Pa go oo ma Lo t “2 3 Sh Veit Bel aan » bi. - cEn TT RE : CE Ke ‘ny en iy ge : a oh] iAgtive Ingrodient (63 mm)* : Cig 250 Clog fd in dE - ray : SCANS Cpl Dane ho
SELB : SRR Copel CEE Ae ket
Goa Co ne : Sa CHIE AR J
Cot | “Hara Fat,bP(Witepsol R15-Dynamit NoBel J2:i: A119 Ja wi pe
J: ou ES Po . ool fie nhl ne
BE : TL t Fad . : Cn EEA Se diEdab En ’ co 1 Ted 5 2% bg , . . by ya 2020 EAE ekg & ried Tg Sele CL . DL RR 1 SIE Cen HAE ; ce DE es ; ER Ce LEER nook - Sia ' #The actlve Ingredient was used ag, gipowdex so Glin wT : Be ana Co RDEEY ; Lo madera A vt ja
CET ol . LEER gE Papell LS i ‘ Cn 028 nF 245 harein at least 90% of the putioles Webs of AE Ee 7 a SA : BE Re : n “TY Te 5 : SAY 3 Fl fr 3 ’
Ce LE : KR Upm diameter or less. - Cras LS Ce x. : goEe 0 aReeT : : } HE Fey nD ae
No AN CoE FEE eer
RE Ba One-fifth of the Witepsol H15 was ine ted in se st LE
CR ERE Ee DAE SE Coiawlig 3 aE Co LASER : oo AT el The NG
ROE LER : a LEY gant
LE TRE ‘ Egy fo Tn EER oy
J GP Hii wat der $ . NY: Ph : Le, a RE 2 B= } Rs ' Sat A - bE od ep Ah alded . fy : Cy a erg wrod
Fo % CME WE | CEE Cd pA
SRT eR Cha Cor
BR . em en 3 vin ar Yds wl ; Cg : BAD ORIGINAL £080 | dara BE
ELT CEMEN ( A Je ail 0 we SEE : i CER 2g Tak ThE Co TEE Sh
SE TRE CEE Co TR
; . Co NEN 20 oe 1 Hi eT 2 A, Ce a BEX ' SEE v0 ‘ ; & a ak Lo TEE Peano cle .
A doz - Lhert e SU ; Eo ALY : e Te I: SPR : PE SEE SEER rae po ZIRE mi a Loa Cla 0 TEE kK so . ! von bo ‘steam-jacketed pan at 45 C maximum. The-active oh eo Fhe Ay EE pas La h CE coh wo oo “‘Ihgredient was sifted through a 200um slave and - « ° vi dln a : : { . LH HE , : : , Se to the molten basewith mixing, using'a Bilvers - ro CME i x \ 5 fitted with a cutting head, until avemooth ~~ f : AER ut : fo 's . tdigpersion was achieved. Maintaining the mixture . i hl heli : : RISEN FRI : bi 48°00 the remalning #itepsol H15 wae’ added to 2 . ’ eer > : BNE Ho ? 4 suspension and stired to ensure a homogenous
RAL : ie: ! ~ ry The entire suspension was passed through a - ' - } eR ern co Co A stainless nteel screivn and, with continuous -
Ein wh : : SE en
Bhd . 0 NL 10 :§tirring, was allowed to cool to 40°C. At'a tem- : : Sy wag 0 0 . SL i» : 4 - ;.géruture of 38°C to 40°C 2.,02g of the mixture was 2 eS ki Balen CAE n ; Coot Ue es hi : Tt . Ch . . oN Bn TY i "{91ed into suitable plastic moulds. Th¥' Buppo- SU i Fogle ved Cp Abedin ig So by - 4 = hg yw ¥ RE: 8 at ahd $R pe a o - { Tos se FAIS were allowed to cool to room teip: fature, Ml 3 AEE wal Beg EER Popa 4s io GSE Rr ; Ae ada iate Lo At iE i or koe ER 0 Se CR SE eb Le £0 oad ace Tn Xia pa # BH SRED Ji oan ow ud lite wo : : Conn Cela Ls 3 i z 2 i] 5 ate i ample 7: Pessaries : Ps Cs Spar. Ln - CL $0 PE ye —————————————— Manet Coe co to = Sd ea Apes helen i we Be wr fie wg/p agary Rh ey i : fod BE Ri rar CLL ‘
Eo 0 mR Bk pov Eid EASE eo - . SoH Lk CRE SEW . { Snow! : apd Es oo TE { do haw ou FLEA, Eoh oh a0 § : is ce Bb HY 02 CA ! ce LL a : Lok ono Hive ingredient 63 pm el 0 Cah : ol nk Co fobs Ry woo TL : A SAE “Regn Sho Tw § 3. 7 SER “hyurare Dextrose 5980 LE : TOUGH Ee oe Silo CoRR
Cy as, EiER Se I ET 4 J wr 20 “iPdsato Starch 363 fe Wea nb ’ BE veadpite Cine GF at eRe ten ! pA DE iad Wee el 3 wee xb . wifagnesium Steauvate ag EE a DO : : : an Xo Paige res : SG agg cl a ok Hl ae
LiL ine NBR. 0 WEE : We nt CL ERE meas Cl ww w I 0 Cu taken : ie gt eed ha : fe al gu es fe 2. Go rend SUE EEL i wa of ion 3 he The above ingredients were mixed di¥eetly ES Lg - He ; ooTeEr En Eo TH SEE ; SHEAR WLC pid EE fe © EL x Co gs En 3 - Lo a EEE ks FAT A dean 3 Ts S25 et & d pesaarles prepared by direct comprgSuion of or) A HE ; wo bat wid 6 SE TATA : - CER Sep AFT eT id i *OH ee £: E Rie: “. ; SE CoE Ee LR, i 2 CEE WE SMEHG resulting mixture. r Hi FE eR A bo so 5 Chl EER : Co wh A Cee Et oon ue mls Ng wR Ee . HY igh WT ete oo Ten ow ¥ Ou 2a Coe ER ig ahh ha toy 7 eR oo Tee gp dU Tuan eri CRE aE Ug § oo Wor Ea I Aon oo LE a Lg
Yodel oh Re ‘ | CORRE RL ER LE
LOR RE TNE 28 =-29- de . CE apne ote / kK $a A Bi 78 ; 2x, 2 SERA I, pL CT = A A Sh ‘ £0 AMARA. hE ' alpen le Ta i SR RE hyn ARE Ty BRE Nor Ly EE
A J Fi EIR visidAL CEBEGL Lael aR dy ES Ady BAD ORIGINAL gt To ogy o 1 i we Ha sage oi ERT : . Fig So an ik : : ; + lr gree co Lo ; Ah Cok Lh uh t SI if iE TEE a : Her Ce an Ye HE oR ’ vl RR CUI te RAE oe donde a SY CLL TE eee J 3 heal Rl CE Sen fer it lar RES EE co PA
Brample 8: 3'-Azido=3'-deoxy-5'-0-octanoylthymidine
To 5 solution ol Z'-usido-3'-deoxy thymialne ‘in. pyridine (oc), octanoyl chloride (1,2 equiva- : Fars a 5. Lents) was added. The reaction was allowed ito warm bE C3 Lo to room temperature. When tlc (CHC151MeOH} 2041, on silica gel) indicated conplete reaction y ‘the BO= lution xas coured onto ice water. The aqueous phase was. decunmted. The resulting oll was chromatographed : Sake NT ‘on pilica gel eluted with CHCl iideOH. The, title ), eo 2 Co i ie .compound was obtained as an oll by evaporation of : ~~ the solvent trom the appropriate fractions. : oo [ON oul. 0-54.95 1i-6.92 N=17.80 br
ER oad Fo ; : Toa per ow : ro HE Tm CoE Rg ud RE 167,46(a, 11,35 ¢=18z,6H)86.13¢ t,1H,1 'B), 84.5 -4.2 : Co TE A ge Cy i
BE gimme, and 5'0H,) 84.0-3.8(m, 1H,4'H), §2.3-2.1 . - # oo E PML 3 ve i so (non? '# and (OH,)1 of @ctanoyl)),61 JB1(d, 3,05 6 : cm i GHz, 5CH5),81.5-0.6(m,13H,5 ‘octanpyl{QHy )5CHs) i
TE Reh Ea
EF A :20 ALE py gov Ean Penk Sa
JF ila i Exemple 9: Sl-Acelbyl- t‘-azido-3'-deoxyihymidine
CE Bho § AY Ce
Ey I sy EE Bad ve TI
Lo = bE wy 4%, To a solution of 312ugido-3'~aeoxy thymidine 7 om i - ary i op SE 7 To HE. 16208) in pyridine (50 ml) at ambient temperature, . / St Eee chloride (2.1 equivalents) was 84452, The *
Loam E ©. ¢, Jekpeaction was stirred for two hours and ‘kept at Fo : ET Ee WI wo
Cong #ibfo 5°C for 20 hours. It was poured ontd ice wa- a
PLY Fhe HE So
Toe fiber with stirring. The aqueous phuse was decanteds . wv . i Lo ) re A A . ae i .
CL ihe , Se J ! 7 oo . # t Bo ' \
Sot en i
Cn Ey | A» so CEE -30- BAD ORIGINAL EJ. ; coo Loh ood co
Ce BE He poe Re : 4 Gin @ WoL . Cet tan Lee
Lo CHE eg CRE es Fe ET A 2 ERY GY ‘ hn
' . " L1 190 iThe oily product nas siancalved in water and ex- groated vtih roter (5 tics), 9.5 WN Rydrozhloric acid, water (2+), ~nt arid over magnesium salchate.
The aclution was filtered and eviroroted in vocun.e
The r@=14n-l oi! wns Aicubdved in chloroforu, «a= plied to voeilico ce) ¢nlarn, anntl.sh ehromnto- gravhed uni 27 methoncl in chloroform. Frachions pith prolvct were cunpop hod and the il wos Chro- mata rephed oenin using, ebh 1 eet: Ler hexane 96:4 v/v). Yroctions «jth pendnel were vvouvorated in vocug to on white and ld,
MeDe 16-0820 cal. U=45.60 1=4.80 N.22.065 fra. U-45.087 11-4.94 W=-27.59
Brannle 19 50 The Inllowine comnounds wer” prenzred acror- ,dins to tne procedure of Example f ror 9 as ajuro=- © printe trom tae appropriate acid halide or anhy- arida, : 3% _as1ldo-5'-0O=-benzoyl-3'-deoxy thymidine : eal. 0-53.68 Hed .TTE=18.41 m.p. 54-59°¢C 3 3- 3
BAD ORIGINAL § -
. 1 190 Yi
EE ——,, . ‘ . . ; * : Coty ; yi RD ox $ I : Ss : Es Ri Xi 8 cl . co Looe } wr Lo - Cr Te Ree TET
Sw DE WEEE A [a ) : on mt = Ser ay 4 i 5 F i wo iy i an 5 b % : - ’ ) ee ’ Tn pe ! ut =o he EA rive Wan : ik on ss ve Lt i ¢ #5 5 2M RE GA ho Fe i } ) ! rn He Lar [io
LF ak cE ory : EE TET Le
PEE TR ho Sotid a gk : } : ro a 3
CT ane ah %y ” oe whe Ye i
EE iy fr Ha Can eh cal (0<51427H~6 492 REE jo
Cy i’ Fk no jiy-5i0-pivaloyls . oal.0=5 F199 ln tI wg J RE : 'edeoxy~3"'0=] Cr oe Me ag oi
Clg wm DE 1oAgido~3. : Ce as
Ca br + i 33 =Anlde ‘thymidine £44V0-51,07H-6/05 Lo el ¥ ik 2 ER . LE 5 . el . i : no “ Re 9 83. ee En a § ; ck Fe boo . : pms og be [
By “ 5 ud ges Co he ; % vA, ; ap 9. Le CE
IRR SET mi mids 8 3 br x RT, » oH ) J . } . § . . 5
ERT ia110-501248-61 13819133 oom h Ln 5 VaQw cali ye 4 ! 6 a 9 <= ; HE Mem . VUE Xy=o ! N=-18. Ng
Pog EL a 12Asldo=3'=deo thymidine C-50.27H~6411 4 ky ! i a id - OF is ethyltutyryl)thy fnd. - 2 ni Ee ; CY Be 1804 1H, 1H); CE ; : 3X ge noni oo, } 5 6H) 86 . 1 3( ) t
Ey EX. a boo Hidg gti 2Hz 6H),20 1 1.15(m, 11,4 'H) 2 ‘ ; v XE FLA rh k rn" : } 4 oo 3 CER Tee ok ’ 'H an : - :
Pog B4.35-4. 150m, 30, 3TH 5'netnase),81,80(¢,38: 5 =. ot i : ; an Lh ol : og t ‘RB and m Lo Vv CBr ine wl row { rd gn Lo RUE 78(m, 30,2 Bo EEN
Loon * wo ET i. & 4-1 » J . al B La She oh
CLF 0 28a, Lf VEER SCHL oh . : 2 Sho SE ai way Crh 2 , IO A RAE) Fe ie ¢ + EB i gt i SEE . 2 J i : ‘ a a in | on 5 "butyryl ): Lor i EY 3 get SH - AE
Cy REE Fike o J=6.4H8) aethyls Cote bak vi i - A BY is ) 6H,J=6. Ca Toth on no BERL ee He TER ENN hE 8 a NOT 3 RELA iy § 0. 9 (d, 1409 Boo EE dr hi i won Bo BOE SORT Lo ihe Kany A LE 3 8% iia oy EE 1 Jo DE Tg 8 oH i i gras A ng poh $i w 27 a Ale the, gE » 3 (Glows Hi i x A LR OY our hE Ce LL ELE TY . LE 6 TH=8 Vy, Tis FT ER , 5 8 Roki in 201 4 hoe mitoyls" eal 2 C= eT whan ft ot 3 1 HH Si ba IR A Cay deoxy-5!=0-palm Ck Ja) if Rr LE
EE a ACEI ev Ak 3% . 3 de A -. PO Rg ange by Re AAT f EE SA pc 31eKzido= @ i. uy LF a Nr SH Bi59 yet ] fF B SE ag : ERY 5 Co % \ SF je “-» tra A PE i § LEAS Sale thymidin aad & Cg nd 0 6 «89 aR ne ) cE REEREES 5 co Lo id yn : by Pept : ° fa sv a i bei Co ! 4 BF dee SO ig gn ne CEA g- Che REV EINER ad GE SY i £2 VPI A To APR ER vf Sh Eo ow ! CTY \ : Se TE Ding ha Ek be ah
CC Rs Le PES Sh J: ER HE iy i , . 7 A VEN WT i y ) El Co Ri £y ne SR £0 i fT Su a ri ~ Rt OHs{6H) 464120) 14) 'H) co pd lp
CH Soe RCE AE : 1% ’ TT Cio ER A'R) Hope i Z 5 3 im ow CL 1 d 1H, 6 SA gly } (alu 1H y BI pe AR fie
EWE i Yd 3% 454 I ie “and $'0H,) 384 10-348 andi. ro A ole CB 119 § £4.5-4.05(n, 51,378 ents ail); seldboriTi iby y Ng iy Yh RoR -4 oe ET ERE : tier SRRCIRRERER Li
ER A TN CER su 4.3 Q 02 CL 5 ot Rad ox) = ofp Sib 3 0 hh LH ll i
F od 1 Fake Se Og J Th gaa fy de Aa i 1 ! : 43 Ee , 8 ; , Sa ig i Hy HN £ So bo { a NER bit SH 2i35- ra wo ER ag hl a Sg ee i we 4 ss Ari Cig {Rad Sea Tg :
A = ; Ap o GH PR Fh) We. Xs J gi Co gt rd ca: 3 i : Fl gli i: or fv 3 Hy ‘x STi wl Jl hs be) ay Si bE IE .
JLEENE oh Tpjeet net da aR Ran ui
CE ORLA Sg Ae On cl yo) \ wipe Te “i “yy ‘3 AEP [Tie Ta iB ay
Foy Bk Sl BR Eh 8 Vaaliplt 2y. Yo & 13 LAA) 3 hi, Ge ROE Fant | a ov denn %.5s00 16(m, 29H)5} palpls famed ote & [i El ; ¥ ba gE: he i his Ih ba iE 5 nq | fu SAR wr te a Lr un : ; ie i § SER 0 Wa CR te JF Fe 4 © ENE ty gihg nog a TIE pm py nC ones [| DE Sar i Tp Fon du ECD Gf Wars 3rd 14{ne Regt 148 Seb atl nl 2 i ) io sl fred 4 A Lu sl V6 5% Tuyl thysiding gp: FA : LA PRR SEVER as pT , RE oy Re FRE LF og BE HE ro § EER lo 1d0-3"-deoxy=5 “OF {5 Gul. Bas6; 101 RELY TREAT 3 td & Ra be a | ah IRL nh SER Gade “2 RI A fo i » 14 RH oo EN ra bond 2 " 20% i M5 gL Dro Fo i - aad dy al EL - 18] oy oe § ns ae Sr eet Qk
EE ike beoarml pats TEE He PEER A a
Cl d Be FE Ig BEE Yo Fogo lo mR Bf GOEL de AES iL Re Ror gh 1
F 4 Bc ) ) ca Se ko ENT "os a ; ah Pe EE 0 4 & ow Se ah Sil atnls J00 § HIN hives 5 be j § OF based REE 0 mr fr Rud 0-354 RIN 2 Bons bo
BE ie FRE Coda wl EE A SR TEST © i Pe ig gis, 0. on ne dhe N418.09 1 5 Sega
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Txaapds 112 2,5 =umannuro=) =anidos)=deoxy shige
TVepnl do=D tein nny Shy Ltiine(3.0m, 11.2 aTel) was neeyl.teldl Ly tne .d.iltion of methanesulkphonyl ¢clo=- ride (2.7 ai) lo a solution ot the a-arting mate- rial in dry syriilae (2 ml). Tha rection was nl. lowed to procesd at 5°0 tor one nour, then poured onto Lue water. The precipitate was collected by filtr tion. Theproduct (3'-azido-5'-mesylthynidine) wag reacted with potausium ¢ Thong ¢ (UC.T8B gy He6 a¥ol) in DWE (9 nl. lhe reactents were healed in an 20°20 oll Lath tor six hours, then poured into toe winter. The product was ex!racued from the w ter , with eth, ] acetulie. the solvent was removed in vie cis and the sesul th ob oll wn f1-0h chronatogriphed on silica cel vy elution witn CHUL ite OH: v/v).
The title compound was obtained as a solid wfter gvapolr. Livn of the solvent fram the cyppropricte fractions. mep.= 164-146°C ~34- | oN
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Co. av ,Lrxample 1e3 3lepuido=3'=deoxythymiuine So wu) 2,3'-Anhydesthynidine
Thymidine (85.4 g: 0.353 mol) was disselved sn 500 wl ary WAR and ad.ed to He(Z-chtoro=1,1,2-- trifluoroethyl )dlethylonine (100.5 ji 0.529 aol) (prejynred necord ln, to the method of D.F. Ayer,
J. tod. Coome Lo,tud (1262)). hts solution ar heated at 7207¢ ior 30 awaruues then poured into 950 ml etnsnol (vol) with vigorous autirring. The nrodaact (reclipdbuted from this soiuticon end wae filtered. The zZtOH gupernatint was refri;er.tel then filtered to yleld che title compound. mp.= 228-230C. ro bp) Idisido-j!=deoxythynidine 2st =U-anhy aro bi: futne (2H giL.1110 aol ) anu lig 30 A (£9 ¢ Ua. A446 nel) weg Fug pended in a mixture of 2H0 rl Dud end 28 nl vnter. he resctlion wirture was. refluxed for > nours «tf which time it wespoured into 1 liter of w.ler. Ing a fuw04s solution was evtracied with atone, (3 x JuO al). The LtLsc elt- tracts wore cried over Na,bl,, tilternd wid phi
Kt0OAc wom regoved in Vacug to yleld ou viscous oil.
This o¢ll was stirred with £00 ml wal pr provicing the title compounds i gopia whicn wig coiected py filbrocion, oe 11n=11800 ~ 35m \ A
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Co i 7 pm ERE EEE ¥ ve ih : y Sn Le Grd re | hos ph. Goats TIRE id a pi Ado 2 1% + GE Bad 0 Arn ted. Py rop : wat Sts LAP Lgl He . i . ol LR Bi i 5 Bur elu in 30 mL of «+E Ati he Sh WB iar ie iE
Y . SI Hn . Ry ;! NET Lo aR ey B Le hi) ch) Ean rs RE 3 . . JE . SAAC ed Fob a fe + rr OT bias Ch
Po Lo To 10 oo i Fo ¥) wag d {ss0lv ’ or eluted; widhi ik Su ht iy 5 ig ig
DE Tw AN si Ay 1 nm) ’ Co wag el A a ARE Bites 4 YS aE ati A 3 Loo al Ln ; EY 2351 dlumn SAL =. LYRE Youn a age t SNARES fe psiay bE ; Tee AIRS hy 0d So ¢ So ea + 4 5 . & ol AAR nM nL
LS oR A Coon ER pat oc he column. The YL fluent which RE TR jo 1 i . = Ap RG a ig rr ol - ) . Some x do 8 wo J 1 ig i gi To Cb ‘ io % 2 ik hy Wo Ar As i a ionwof the e. ue “ Po vaita ee : bl i se AE ihe vik i Lh i ens Cok ) . XQ wT ave Giro gnd; 3 € Le “Ra boi ye iE Koa mL £ ract. “ collected. The CATER oly iE ve! : pre 3 a Eg wi CN SAR] 6 Co u + O Co Nw PORES ah @ ahi BeAr Lape ‘ ALFIE TR CULE ES Rgil® J . | 3 : 4 i i . 4 wor ip & lie * isk Li Rif ' terial wug : b {~~ [J REY, x fr AT ST a Eh ¥ & 3 °F a TEE CTA Shoring ma it rol ’ and tr ely AVORIE Eh AR x Loa a Eh L : rg § Hr dilate AR HYG “ol . « an pI "ry MAN RYZ015 prs SY i, FE ak Sei Th pn
Ci EE LrEaR SERN | . } cuo ti Sa Si 4 '
Li 1 fy Pegk 10 mb in Lik a red yyw Jan uo IR bl 1 Hk nN SLT uced to 10 ml — volume wee A SS Jka ER
YL NE a0 ELSI “idgauce Coa The volum CE Lopes hh oe pn jo % ue Loo ae dE - cn eT PR Bo i added. Te ET RI y FE gi ge aii ada HE a 3 "gh: § 3 4) ol on Deg ‘E HEY mL) wag Lo a by soevaph Ji a fo Thi . iss aN RG : 7% 1 I i SEY of 1) Co od RORY Ha ahi a IR i i: ; So | 8 . 1 3 PAY - Y be ww Ay . 3 3 la Ae ) i ve Ss dri 8 hae SEE , # HAN a AF 4 hole 5 i Ho to & Sag THE Ji bd . slduee was Gat dee was s Lexy 3 in fo ERT pe 3 ¥ EE Ni Ed aT Pe WARE ¥ the re ’ Talia SR lay oH roduct " A EN at iy gery pid Rar 4 fa Ar ol LI Vina Reh. WA18 We s The p Val PERN PRED. CER Re ag %
Ton Y ive nf OM 3 7 TA Ch imens. cee ETA SH Am ad, Ie RT 4 i wl : pe pg Cage. C 5d CET four ¢ SORE ER Ch REE Ge aE heals og 1 {dn ge Aine 10 IE Cho hoe i oH Spa aed p y v E ind dE oo Ea RET fe 2 Co Ce A EE Te Ce ns ET 5 @ % sid 3 A i ERE Iery C SU Co Jd SN SN a) « <n ERNIE Lo Hee ho TH Cb Re | Caan E g :; X TARE irs “pnd te WA [OSs -5 wl LE . into EA ln in EEA ra AH SET Ei 3 2 AES 8 Aaah g SE SR ez29r . 2A oo Lana Hr Mg HH a hii Hi I 7 : 24 rE | ny a eo Ea vA Bi tapi Jiao sy it bh G3 Lo AA SER ETE a i hl A hes “8 3 a - Cyan hg oo CAE ERAS x rh See ies ol = fo a dR Love - iT Bry, Co i. won Die OB TA | ORS Ha LEAS Hg A 1 Fr or vo ARE wn IEE AS Tay A 3 JE . 3 Tg = rE nh . aa | Cah Loan SEES pps Xe EIEN 4 FB. RE SSE cy, FOE > Co TT tupzidowh =i = Pe a iy i ERE Nil : ri SRE A Tad A? nd : . : LO AMG ner i on i hw one 1 i i) AE Q i 5 TH form of 3'= aa A er SR oC ppl ae wd
C3 en A EEN Jp oh eu, ANU aac R68 XOX CAE prot een gs a > iol : } ~~ GF ide ve ¥ 33 Page 3 R FORADK GI sora Lo TUL = or wad RE \ d< we Amy IE) § wo ot. HE PS : wo [He 3 a = oo. ry e = : : “hs siBAte was pr na A ES i ICN Su AE) No PE \ So EL . #3 Ca hide re bf Fo. ss Ley th idin Rk ; - nophos Res Co fo li & He ; : 2 pe iE £0 Ah 2 160X : e mo TE sta. : g He : : 3 J, i : amr on i * form of . : hy Vl Gre 9 i in Ex 1 gn AE pd Lo RNa SEY Co LORE . Chagoo leh 3 n= 4g Ta sr gt : i £ oo Yife The hydrogen Cok Moo oh salt abt ES CG ri pd : 2 5 Shee’ als , BER - . A ri wa in = SE 40 ons . red The wt } : o 3 : A he ammoniym Tew tn |; Briml, of 3 $i Ses
Poa bo Ey Tae d by passing CRRA “dissolved, n. SHE + hig § 0 Poko ov i gare ihe 283 miol) ¢ .. un oEp0w Son%s Se 1 we Lk Cad LAO - wl of do
CLR 3 ol nn RE (0.1 gy Oo oe i) column RAGE 3 i 4 Le be td Ly 5 1a 14 : L (10eq. Hah Co i. & 0s A ug¥ a ~3e x JP gn 1.5 m : ede T ; ua Ee Dama through a co Sob Ea
Pog eM ‘Hater, Cig Lo & Jo EC Taki . a % £N wpe , hat so
Po yon wi Fuga Chen A ; - Th Eg EI PE of bred a wo + i ho JE Ct : iia J ae i \ a ig i ti: 6 " ! Bie : i . : .
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LE i $y ‘ «38= mie a 3 LE 8 LR ie. - | ad = i
ET A sg aly vg Gl
Cow § a Fg og ' INAL ¢ Ne Daas vio ” CL I. sv Cris dn Lay TY : ; LE 8 " WE ¥: BAD ORIG Sha At ra 1 TE CEE | Cha CHER :
Toeg ovo TR FRE ed , Coorgr : RN Casali i . sadn J CAR TE ; bg Io CR 4
Pi v =z % 4. Ji i a iy i ian i » 5 : oA 5 2 ES . i i Vi » 2 A) i # i «ude y Ys : ; : nuh A ¢ ¥
(6) Phosphoromorpholidate Derivative of 3'-Asido~ . 3t~deoxythymidine in 9 ml of water was dissolved 0.283 mMol of the hydrogen form of the monophosphate obtain- ed in stage b). Morpholine (99m 1.13 mMol,4 eqs) was added anithe solution heated to reflux. Di- cyclohexyl carbodiimide (0.234 g, 1.13 mMol, 4 eq.) dissolved in t-butanol (5 ml) was added over a three hour period. The reaction was refluxed over- night. The: reaction was coaled to room tempe-~ rature, filtered, and the solvents removed in yacuo. Ethanol was added and evaporated in vacuo four times. The r sidue was dissolved in methanol and the phos phoromorpholidete precipitated by ‘the addition of ether. The precipitate was . tsisurated with ether four times and dried on a rotary evaporator. The title compound was ob=- tained. : 20 (a) 31-pAzido-3"'~deoxythymidine-5'-triphosphate .. '... The phosphoromorpholidate derivative ob- gaindd in stage c¢), was dried by a removal of pyridine in vacuo four times. The bis(n=Bu),N pyrophosphate obtained in stage a) was also dried by removal of pyridine in vacuo. The phosphoro-
A morpholidate was diosolved in pyridine, 5 ml, and added to the vessel containing the pyrophos- phate reagent. The reaction was allowed to ocon- ' tinue overnight at room temperature. The pyri- : -39- 2)
BAD ORIGINAL [3
Co. ~ 1190
Aine was removed in vacuo. Water was added to the : residue and removed in vacuo three times. The ‘pesidue was frozen.
The residue was thawed and dissolved in 50 ml of water. The solution was applied to a column (1 x 10 cm) of DE AE Saphadex A-25 which had been equilibrated with 50 mM ammonium bicarbonate. The : phosphates were eluted with a 300 ml linear ; gradient of 50-800 m¥ ammonium bivarbonate, The 7 fractions containing the diphosphate nucleotide were pooled as were those ontaining the tri- 3 oo | phos phate nucleotide. The pooled diphosphate and ) ‘triphosphate fractions were each dried ‘in vacuo, a redissolved in water, dried again, redissolved : in water and lyophilized. RE - -
Example 16: Ensymatic Synthesis of 3'~Asido- 51_triphosphate-3'-deoxy thymidine it The 5'-triphosphate was synthesised from the ~ 20 | 51-d1phosphate using pyruvate kinase and nucleoside ‘a4 phosphate dinase. The reaction aixtue consin= eds 6 mM 3'-azido TDP, 12 mM adenosine triphosphate, 40 mN MgCl, 40 mM potassium piperazine-N,N'~ bss(2-ethanesul phonic acid) PIPES buifer (pH 648), mM phosphanolpyruvate, 40 1U/ml nucleoside ¥ diphosphate dinase and 100 1U/ml pyruvate kihase : in a final volume of 5 mls Tne reaction mixture was ~incui ated at 37°C for 5 days. The reaction
Co 17140 mixture wag applied to a column (2.9% x 10 cm) of DE AL Sephadex A-25 which had been equili- brated with ammonium bicerbonate. The nucago=- tides were eluted with a gradient of 100 - 1060 mM ammonium bicarbonate. Fractions containing the triphosphate were pooled, and evaporated to dryness in vacuo. The comuound was further purified using a preparative HPL column (¥hat- man, Inc., Magnum 9 SAX) eluted with a gradient of 10 - 100 mM potassium phospate, pH 3.5. The resul ting compound was further purified using a
DEAR Sephadex A=25 column as above. The fractions contdaning the tetraammonium 31_azido-3'~deoxy- thymidine-5'-triphosphate were pooled, dried in vacuo, redissolved in water and lyophilliged to yield the title compound.
Example 17: Antiviral Activity (a) (1) Retrovirus-Induced Malignancy """ 34_pzido-3'-deoxythymidine was administered - | to female BALB/c mice infected with 1.5x104 pfu of the RVB3 strain of Rauscher Murine
Leukaemia Virus. Treatment was started 4 hours after infection at dosages of 80 mg/ kg intraperitoneally every 8 hours Or 0.5 or 1.0 mg/ml orally in drinking wate:. Such treatment was found to prevent infection of - A - - ORIGINAL aE 5 - IHD. Ee se Loh lh od? AE ve r
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FRE hv ol v ie ; oh Son ¥ oo nd su seed RA,
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Co i Fe aa ;
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LR WB gna i ard lo Be PS Ul
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EI p ak 1. iaisation in Ce J Co
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= BE
TTT [ir fr i gi Ri = 4 gr Sy 4 ev : Tes
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Ww Ea Te : Coe IE i 3 or Rn ES
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Pot rd CE E a $e : Co TE he id EN Ci TR CE
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By ek ;| fe ig 3 le £6 5 en He
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Nt CER dn ex wp on ¥ : oo 2 ud an lete A SE : : ¢ . afl ’ : i Sei oN Bo ’ . So ihe virus ting comp She oo “ir, YW E - : § re ndica ed vith. wr, fo we
Fie e) 1 1so probed h/aktrong Co & . } ; fe WL a + Ld Sern Po Ll so ERS “ LP 8 als 1th, AY oe DY : 5 3 {rus lture wa onan, w 07 Bhow- Le “%
Poa i9 ch ou soeptor 1taresy: aa = Cb i Ea 11 recep or Ail ou i ARS du £3 CR : wl : LRG T-ce for 1 RoR ati, h&
Co SoA or ted M1 Ca SE Gn eit ANE : Co #5%ove z ing genera nce of T HR Lt RS BL £6
K oe i" : Ey rd n e cou i ok Ce EE dim ES : -: wn SEE e es a 2 fonts AE Lata Y rt } tk LET & Bignal 5 nued pr : pA Hl ee Wo
Tw EE 3 i contd iment. Co SH CE SNE 2 en Lo CoRR the per RE CER Gi ; ok Ak a] oh a. : oe ~ Fy ng ex Fe FL wi HIE fn : ro Do Ta. EI 3 5 of the i id ye wo ak Ho LXE
Foo Es i te SG The ' 3. Jind 3 a sh Eg CTE LE
Co 0 | 2. BL Vt: eg wy § i Tr Sh - Bas LH TE Aoti RN x EE ak : : at EE no bh 2 Ha Ch ; oR c: 5 . EE fio A Yo § 3 wl of Ch ee | | opi n4 -— - Revs ce ine : FAN Ab Co AE yl - dik TLE i Ska Iranso} ea SRR LA mL r- : fg [ra : A ta }) AIDV verse: ee on diy thynid Lo his ER : A 3 A Eo EEE Lhe $i pile © Re %tade Sean Cb Je ie Soh Haak. I HAE L (1) 3t= Fk Re we Ee yi 0 + hel AB hd EEE te~ | IE Fan ee
Fu § fi . La hospha rn Tf Ar oo i Ch a + ae oil 3 HN Slatrip i inst | fy vt Ce j
L a i Th 51 i ER wb Hee! 0=H T° 886 Tos EY ’ : ' i i 2h E Wy pe vo wh Sage: Agid “vitro IN i jon { § woof ES nw Se pa 3 ed in vi a Ih and ox Fa SE \ xo 3 TW ery Lew xg, “ : vo Es EE aly i LE we Fh or HE Jo Tas tested RT). 118%va LAE 3 . W so Fa i Ce A a = oF, Bel . : -- nd
PI Ls EE a (AIDV RT d trom pé 23a phos ; k Toe ih es ra tase rified CoE B AR: i Yo : bk : Eo BE ER iS cup 8 pu vo h D A EEL ‘was vo :
Plog CRE DV RT was “throug $4vity was st ! i i 7 Co . z ‘ A I ion y ac ai lea : CR ig TER fracte column ® and and 1 , { PR 7. uk se utes rol am feo
Eo. 4 ry NO Te 1llulo min . lyce SS -18) “i
Hh EES ce h 60 $8 ASDAT (15 vi 3 5 3 Lo (aaph oug 60, ‘rAspd So
Cx ; w . thd at thr in £ TS ) i mum 3 aE po bo 20 Rs Yinear stored + Usin PH opt * n a Lo IY mk ¥ No pi an Cd
A WR 71 EE when per had PS otivid, CF ; Hg . ok the min RT Uity od e A x vo : I : He mon albu AIDY M {Bn Co : oo i) 5 perum imer, ! of Sn gts 1d i ! : i. A gd Sovine ate~pr timum 10310 bo “ a yr a] ro e templ gol, op Ol, was he gin of 043 wr Co won “ER h 2 sdhde . Che : SE Io wi A * and a 5 mM Mg reséiig 4 Cho be cL
FA x = Uo i A 0.3 mM nce of in’ the p To foun ip Jy! po
Lo Ya » 8 be prese tvity was i9lac Ch an La
Co as 25: %y in the the ack etivity HE CB il : - we 82 ThE an ms a op at ar) ; i WE Eo YF th sy iM Shel , is i. wh - i ; Te . - wb Max AIGINA od : WE ol Cob
PN oe Tye MnCl, BAD © SIRE or a wae ‘ , a a ot M Lo end Ep ton ur Hig 5 | Hin i Po y i eg 2 -43- 4 . Gv Le LC - / RE i in kas
Af : oo : CU G4 b He v1 JLRS i i Ef ARE bit
ZF Eo ke Td LL eA
SN WBE 5m, Cele a . Lo Lo RLRN ta le a we : Bn
Co, EE Sob le he i 4 A fabil Sn A : 1 : - ERR LA oo RT : ‘ CERT Hedy Th
Hn: 80 to 140 mM KCl and 60 to 100 aM Kalli : ‘Ingorporation of (’H) 4TTP was lineab with res- waded r wor : - Say CE “pedt to enzyme concentration. When tested; 3'~
TE SRE
. - wo. Jon AE So cam ve pm Es
Ca Jaiid0-5'-trphosphate-3'-deéxythyaidine wis found
Hobo, Dil Tw oe ” 5 :%0,be a competitive inhibitor of AIDV RT; giving oo Fi A 2 ar of 0.04 4M using rA-0dT(q,_1g)3® the ‘tem~ _ 'plate-primer. The enzyme had a Xm for ATTP of
Comm te So - ; . igis1/'M, suggesting that 31.agido-5'~triphos~ gy nn ‘phate-3'-deoxythymidine binde tighter to the en- syne than does ATTP, Purther experiménts with
Co ge of avian myeloblastosis virus, Moloney mu-
To Fo ed i : x : vis 4 NE Tn .
CoN fa oi oy Jeulemia virus and AIDV, showed 3'+agido~ 1
Pow i LE eh $545 ’ We EB
STR am Te i Zuflgriphos hate-3'-dsoxythymidine to be;a:ter- yo aR Id ides Cy £2 1 P P Sep :
Cog wig EE kainstor of DNA chain elongation. Rie - .
To FINE OE Wh (41) In Vitro Anti-AIDV Activity: 1 yoo . A sod kd by AE th Lo
INERT. TEE SNE v4 TH Ler i 3 Wo hg ix “3 wid : oomink Ra. .
L000 Don 8F C80 Yong 5 ent von B ae EC + . Sis 3t-Azido=3'~-deoxythymidine was tented and o.oo 4 pL hE hE ge BE boy SN Coe fdund to possess activity in a number ofiin vitro. Come 4 p § hs. LH 3h i H Bi so i : et ” To Lin i. WA ot hs
PO fe STEER Cen DY oy EE . a ag EEE 4 § Wa 250 HAR systema. Drug effects were measured by” Come ot 5 ke Rk. Bm Ly ee Ee ou he : : oy fos % CA E34 shaying reverse transcriptase (RT) activity in PL : Zo os on E | LE Er i ie: . : hada id . Co a Fe i
How CF aed Ruhl 8 LL JERE Lore Raedn ; 8 i a A 138 8 supiinates from infected, uninfected Zand cu ire § ov god dh cL ghd TT gE - i 3 id FE Cn yaEug treated ‘cells. 3'uApido=3'-deoxyiliyaidine Co 2 Hid ‘effectively blooked the infection by AIDY: of the CM,
FN BORA Ci an . 1 OR si, i H9 and U937 human lymphoblastoid cell linés at
BE 5 fil d fii rh ss § # Ss VR nd A ooncentrations from 2.7 to 0.0013 mog/aly; 8imilar- uo
OUD RUE NAL et mg : ; gw A Ce y ¥ i a $i, infection of normal PHA stimulated white
CRE ERE he 1 ; SE Ye
Co oe URE 3 food cells and cultured peripheral blgod’ lym- : *y 3 gy Age Ni r Gr !
To RR TE ET Toes ‘ gt :
Lol EE EER WL i WBE ged BAD ORIGINAL: gg}
OME ghd 4-H ORGINAL Lge
SC SR MeL AY a i ’ cgay EE en : : Af 5 2 0 Woy IEEE .
Co 2410 ‘phocytes wan ‘nhibited at drug concentrations ag lov ag 0.013 meg/ml. Drugs additlon and sube- traction experiments In H9 cells revealed thot 3teazido-3'=aeoxy thymidine was most effective when procent ot lhe tlie of virus infection of susce.tible cells, but still retained moet of ite «ac Liviral activity even when added as late as 20 hours after AIDV infection. Inhibition of viral replic«tion wes also evident when the drug was present Iv the media only during the 20 hour period of virus ubsurption. Eiiects were x scen at 0.15 and 0,013 meg/ml. 3'-Azido-3'- - deoxythynidine exhibited no dl.:ect anti-RT acti- : vity egainnt purified AILV virions. Similarly, iE the dmug had little or no effect on the produc- tion and release of virions from the chronically infected 19 AIDV cell line. . (111) Preventing infection by AIDV . veoh The ability of 3'-azido-3'-deoxythymidine "to block iniszctlon of cells by LiDV was detar=- mined ag follows.
Cloned T4 positive tetanus specific T helper lympiocytes were jnfccted with a pool . of AINV isnlutcs (at challenge doses of up to 5000 virions/cell) and cell survival after in- fection wus ronktored. After 10 days in culture aD ORIGiiNAL 2 =45- \ a :
Co J7 0 mo viral cytophatic effcotes were seen in infeoted
T .cells treated with 8.6 and 1.3 mcg/ml 3'- agido-3'-deoxythymidine, while untreated, infect- ed celle were 5-fo’d decreased, Cell survival was also evaluated in an NTLV-1 transformed,
AIDV superinfected cell line derived from the cells above. 3'~azido-3'-deoxythymidine at concen- trations of 2.7, 0.27, and 0.13 mge/ml totally blocked cyvtppalhlc effects at 7 days. Frotect- ive effects were seen in infections induced hy both cell free virions and cell associated virus. 3taazido~3"'-deoxythymldine at 0.27 mcg/ml con- centration also effectively prevented cytopathic effect #nduction by a less velated Haltian iso- late of AlIDV,
Example 18 : Toxicity issay 3t-pzido-3'-deoxythymidine wae administer- ed to both mice and ruts. 'The 1Dg value wae in rn gxeess of 750 mg/kg in Loth species. ono ORIGINAL 9

Claims (1)

  1. Lon | 2719 .. RT7lyg ’ CLAL%S
    1. A pharmaceutical formulation adapted for human administration for the treatment or prophylaxis of a human retroviral infection comprising, 58 active ingredient an anti- hnan retrovirus infection eflective amount of 3'-azido-3'~deoxythymidine in a unit dose form containing 20 - TUO mg of the sald active ingredient, together wlth a pharmaceutically acceptable carrier therefor.
    2. A formulation zccording to claim 1 wnerein the carrier is a liquid ca.rier, a finely divided solid ca:zrlier or beth, 3, A formulation accoidang to claim 1 walch is sterile.
    4. A formulation according to claim 3 adapted for adaminirtration by injection. 5: A formulation zccording to claim 3 contalned in a vealed vial. ({ 20 6. A formulation according to claam 3 wherein the " parrier is sterile waler. T+: A formulation according to claim 1 adpated for oral adaninistration.
    8. po formulation according to claim 2 in the forn of » tablet or capsule.
    9. A formulation accoidang Lo claim 1 providing gustzined release of tie active ingredient after oral administration.
    10. A formulation accordug to claim 7 further comprising a Ilavouring agent. -47- oo ORIGINAL, dD ly ’ oe Kv . ' 27190 . y JANET LIT3TSR IDEOUT Davin wana Ba RY SAHRA NUSINOFF LAHUAN MadTia Hi Ibee 30. CLalk IHILLIS 2h oh PURIAN GHOCGT AYR broanaial Inventors / -18-
    i . 2 : BAD ORIGINAL PD
PH33532A 1985-03-16 1986-03-14 Antiviral nucleosides PH27190A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PH35502A PH24360A (en) 1985-03-16 1987-07-02 Antiviral nucleosides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB858506869A GB8506869D0 (en) 1985-03-16 1985-03-16 Antiviral compound
GB858511774A GB8511774D0 (en) 1985-05-09 1985-05-09 Antiviral compounds
GB858523881A GB8523881D0 (en) 1985-09-27 1985-09-27 Antiviral compounds
GB868603450A GB8603450D0 (en) 1986-02-12 1986-02-12 Antiviral compounds

Publications (1)

Publication Number Publication Date
PH27190A true PH27190A (en) 1993-04-16

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PH33532A PH27190A (en) 1985-03-16 1986-03-14 Antiviral nucleosides

Country Status (5)

Country Link
KR (1) KR860006987A (en)
AU (2) AU587739B2 (en)
ES (2) ES8800257A1 (en)
HU (2) HU197209B (en)
PH (1) PH27190A (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5276019A (en) * 1987-03-25 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE73219B1 (en) * 1985-03-16 1997-05-07 Wellcome Found Therapeutic nucleosides
US4852127A (en) * 1985-03-22 1989-07-25 American Telephone And Telegraph Company, At&T Bell Laboratories Universal protocol data receiver

Also Published As

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HU199501B (en) 1990-02-28
AU587739B2 (en) 1989-08-24
AU1215988A (en) 1988-06-23
HUT40570A (en) 1987-01-28
ES8800257A1 (en) 1987-11-01
ES8802469A1 (en) 1988-07-16
ES557209A0 (en) 1988-07-16
KR860006987A (en) 1986-10-06
ES553013A0 (en) 1987-11-01
HU197209B (en) 1989-03-28
AU574620B1 (en) 1988-07-07

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