CA2229024A1 - Use of fluconazole for inhibiting the growth of cancers - Google Patents
Use of fluconazole for inhibiting the growth of cancers Download PDFInfo
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- CA2229024A1 CA2229024A1 CA002229024A CA2229024A CA2229024A1 CA 2229024 A1 CA2229024 A1 CA 2229024A1 CA 002229024 A CA002229024 A CA 002229024A CA 2229024 A CA2229024 A CA 2229024A CA 2229024 A1 CA2229024 A1 CA 2229024A1
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
A pharmaceutical composition for the treatment of cancers or tumors in mammals is disclosed which comprises 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives. A chemotherapeutic agent can be used in conjunction with 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives as can potentiators. 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives can also be used to treat viral infections, either alone, in conjunction with other anti-viral agents or with a potentiator.
Description
Use of fluconazole for inhibiting the growth of cancers TECHNICAL FIELD
This i~ lion is a ph_ ~ ;c~l c~ that is useful for the v~dtl~ l of canoers and tumors, paulicuLuly in human and warm blooded animals cc ~ g 2-(2~4~ 1UUIU~
1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its de.ivdli.~ It can be used in co ~h;. ~I;o~ with 10 other e ' , agents and pùt~ The same ~ on can be used to treat vi~al BACKGROUND OF THE INVENTION
Canoers, ~ iing IP~ Pm;q, are the leading cause of death in animals and humans The exa~ cause of I ' is not known, but Unks between certain activities such as smolcing or 15 ~uau~; to c~n~ills;~' ~~ and the i~ :d~ of oertain types of le~ pmiq and tumors has been shûwn by a number ûf l-,s~-h_.a Many types of ~h~ ';c agents have been shown to be effective agaunst canoers, tumors and '~ ~ but not all types of cancer and tumor oells respond to these agents U~vrvl '~" many of these agents also destroy normal cells The exact . ~ for the 20 action of these ~ ' - agents are not always known De_pite a~ul~ in the field of canoer and It ~ Il~ll..~.-ta the leading ' , to dateare~ io~andrhPm~ ' , andbonem.~row1,~"~ h. ~ lvd~h~
are said to fight cancers that are pal~ uly a~;l~ _ Such cytocidal or ~lu~ , agents work best on canoers with large growth factors, i e., ones whose cells are rapidly dividing To date, ho.~ , in p~- t;~ estrogen, plUg_it~l - and ~ uat .une, and some ' ~ ed by a variety of microbes, aLt.~ldtil.g agents, and anti ~;tPC form the bulk of i' , available to --Y"" Ideally ~Iv~ic agents that have c~rifi~ity for I ' a, canoer and tumor oells while not affecting normal cells would be e,~ ,..lel~ d ' '- Ullrul: '~" none have been found and instcad agents which target especially rapidly dividing oells (both diseased and normal) 30 have been used Clearly, the d~ 1O~ of materials that would target canoer or hP~ Pm;~ oells due to some unique ~l~c~ for them would be a bl~ll--u..~ll. Alt~,-l~li~.~.ly, .-~ lc that were ~ylolu,~ic to IP~ Pmiq or cancer cells while exerting mild effects on normal cells would be ' '- Therefor0, it is an object of this hl~_~lvion to provide a ph~ ;l;on that~5 is effective in treating I~P~ Pmi~ with mild or no effects on normal blood oells WO 97/05873 PCT~US96/12474 More r~ific~lly, it is an object of this invention to provide a ~ nn C~ ;n~ a p~ l carrier and a 2-(2,4~1inuo-u~,hc..-~1)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its derivatives as defined herein along with a method for treating cancer, le~ mi~ and tumors.
The use of 2-(2,4~inuoruphe..~1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its S d~,.ivali-_o in co -~ with other chP~oth~ ic agents which are effective in d~,~h'~ .g the turnor is a novel method of l-e 2~2,4-Dinuo-uphc.~1)-1,3-bis(lH-1,2,4-triazol-1-yl)prop,an-2-ol and its derivatives can also be used to treat viral i~f ~ ~ either alone or in the presence of a p -.
SUMMARY OF TI~E rNVENTION
lû A ~ ""~r, ,~ u~ for l.~LI.. ~.ll of rnqn~n~ql~ and in ~>alLi~ ld~, wârrnblooded animals and humans, which are affected by le..t~Pmiq Cu--~ illg a ph~ ;ral carrier and an e~fective arnount of 2-(2,Willuùr~l,h~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)prop, n-2-ol ) and its dC~ivaLi~Cj. 2~2,4-Dinuu-uphcn.~1)-1~3-bis(lH-1~2~4-triazol-lyl)propan-2-ol has the formula:~5 l H
F~
These c~ can be used to inhibit the growth of le~ Pmiq tumors and canc_r oells in hurnans or animals by ~ h~ .. of an effective amount either orally, rectally, topically or ~. 'Iy, or i--L dv-.-ul~. These cu..l~,o:.iLions do not r~ ;ri~ ly affect healthy~0 cells.
r~ can also be used in ~.u-~ n with 2-(2,4~1illuo.uph.,~ 1)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its de~ivd~i~_s as can cl~ ;c agents.
These ~ .. c are ~KULi~ ~lhul~, effective against the i.~n.. --,~ virus.
~ =~ -W O 97/OS873 PCT~US96/12474 DETAnLED DESCRUPTION OF THE ~NVENl~ON
~u DEFLNIllONS:
As used herein, the term ~cc~ ,gu means various c~ l~n.~ can be COlljOi~ y . ' ,_i in the pl~u~ u~ cc~ o~l of this invention. Ac~ Ln~ly, the terms "~o~ g 5 Pccpn~ y of-U-and"c~ 1;ngof-Uare~ intheterm co ~ ; ug A~i used herei4 a ul,~ " ~ ~ .";, ~lly a: r ' ' " c~ is one that is suitable for use with hurnans and/or animals without undue adverse side effects (such as toxicity, irritatio4 and allergic response) t-~ with a ~ "c ~... rlL/.i~k ratio.
As used herein, the term "safe and effective amountU refers to the quantity of a10 ~ pQ ~r"l which is ~--ITi- ~-1 to yield a desired ~ l;u response without undue adverse side effects (such as ~oxicity~ irritatio4 or allergic response) co-----~r--~ t with a 1~
~..~r.l/.i~ ratio when used in the manner of this in~ on. The specific "safe and effective amountU will, ~ll,.iuu~l~, vary with such factors as the particular a7ntlitil~n being treated, the physical co~A;I;~ of the patient, the type of mammal being treated, the duration of the t-~ t, 15 the natwe of cor,.u.~ therapy (if any), and the specific ru, -~ ,~ and the structure of the r~ o~ lc or its d~ ali~
As used herein, a "2-(2,4-di~luu~u~k.~ yl)-l~3-bis(lH-l~2~4-triazol-l-yl)propan-2 d- -iVd~ " includes its esters and ethers and its pk~ ;. ~-lly 7 p' blr salts.
As used h.ereirl, a "~,h " ~ ;c~l addition salts" are salts of 2-(2,4~ 1uu~ulJh.,.lyl)-1,3-20bis(lH-1,2,4-triazol-1-yl)propan-2-ol with an organic or inul~u ic acid. These l". f .-. d acid addition salts are cl,lo-;dcs, I,-u",.~s, sulfates, nitrates, Fl "' '~ r tartrates, rn~1 malates, citrates, !r ~alh,y' ~c -; and the like.
As used herei4 a "I' ' carrier" is a ph~ lly a , ' ' solvent, - ~ ' g agent or velhicle for d~ _.i-.g the anti I ' ~ agent to the anirnal or human. The 25 carrier m ay be liqnid or solid and is selected with the planned manner of ~A; u ;~ ;nn in mind.
As used !herein, "cancer" or "le~ mi~ refers to all types of cancers or n~ - or disease which attack normal healthy blood cells or bone rnarrow which produces blood oells which are fonnd in ~ ------.~lc As used herein, "viruses" includes viruses which cause diseases in warm blooded animals 30~ ' ' G HIV, i.-~l--r -~_ ,I,i,.uvi,~s, herpes and the like.
As used herei4 "2-(2,4~ 1uu~u~L~.~yl)-1,3-bis(lH-1,2,4-tria_ol-l-yl)propan-2-ol and its d~,.i.,dti~ inclufles esters and ethers ac well as addition salts.
As used herein "~.n~ " are materials such as triprolidine and its cis-isomer or lH-R~n7i~ ' '~-2-l"u~dnoic acid which are used in ~.~....1~in~1i9n with 2-(2,4~ 1uu~u~,henyl)-1,3-35bis(lH-1,2,4-tria7o1-l-yl)propan-2-ol and its derivatives. Pu~ u~ can affect the immune system or enhance the c~li~ .sj of the drugs.
~ s used herein "- h~ tir agents" includes DNA~ Agents, Antime-tabolites, Tubulin-Interactive Agents. TT...,..,l-~l agents and others, such as ~p~ Y or h~Lu~u.~d.
B. 2-(2,4-DIFLUOROPHENYL)-I,3-BIS(IH-1,2,4-TRIAZOL-l-YL)PROPAN-2-OL
S AND ITS DERIVATIVES
2-(2,4 diIluu.uph~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its dc.;~ ~cs has the following ~LI u~,luuc.
~H
It is prepared a~,culding to the method cl~ ;l~d in U.S. 4,404,216 issued to R~
10 (1983).
The de.ivali~_~ include the lower WlJUA,~/lic acid esters of the propanol group, for . '~, acetyl, propanoyl, butyl, pentyl and hexyl esters. Pa~ ulauly p.~,f..-~,d are the esters of UA~IiC acids having less than seven carbons, and most p~f~abl~ propyl esters. Aryl ~bui~lic acids such as salicylic acid. benzoic acid, and related acids can also be used to esterify 15 the propanol group. AL~cyl eLhers having less than 7 carbons are also useful dc.ivàLi~_S.
The p~ 1 addition salts are salts of 2~2,4~1..~1luph~u~1)-1~3~is(1H-1~2~4-triazol-l-yl)propan-2-ol with an orgaluc or invl~anic acid. These ~ .f~ acid addition salts are rhlonr~ b~ul~ d~s, sulfates, nitrates, F~ r 5~ ~1 s, tartrates, tn~l s, malates, citrates, h~ .li~L~tes, ~u,' : and the like.
20 These ~-- - ,p-~--.. l~ are part of a more generic class of r -.~ d~ ~ with the formula:
lH
~ J R' ~N~
;
W O 97/0~873 PCTAUS96/12474 wherein Rlis an optionally T vl~ ut~;l alkyl, cycloaL~cyl, aryl (2,4-dichlo.uph,..~i) or aralkyl group, and yl and y2 are =CH- or =N-; and salts or metal . n, ' and ether or esters thereof.
While these materials are active against fungus disease, some have been found to be l ~ O
Therefore, those llldt~,.ials which exhibit this property are not useful herein.
S C CEIEMOT~ERAPEUTIC AGENTS
The c~ "~th--al~ ~t;c agents are generally grouped as DNA-h-t~"a~Agents, Tubulin-I.It ,.a.,li- _ Agents, T-Tn.~ l agents and others such as ~ or L.~.hu,~ a. Each of the groups of . ~ th . ~ agents can be further divided by type of activity or ~U-~ I The e1.. )~ ;f agents used in c~ h;~';o~ with 2~2,4-10 .li~luo.u~ I,3-bis(lH-1,2,4-triazol-lyl)propan-2-ol and its d~"ivali~ include .. ~ -, of all of these groups. For a detailed .1;~ n of the ch~mnthr-~ " ;r agents and their method of G h~ n, ~iee Dorr, et al, Cancer Chemotheropy Handbook 2d edition, pages 15-34, Appleton ~ Lange (CQn~r~ 1994) herein h.CCII~ol"!t~,d by ,ef~.~n~c;.
DNA-L4t~,~a~ _ Agents include the allylating agents, e.g. C~ in. Cy.,l~ph~
15 Al~ the DNA strand-breakage agents, wch as Blw.. ~ ; the ' og l~q~ I,jt,,,~. c.g., n~ i.. and DUAUIl ~ ~ ); the r.v. i--t.. ~hl;-.g l_p ~ II inhihit~i wch as, FtrpQri~ and T~ , and the DNA minor groove binder Pl~--ydii~.
The aLkyldlii.g agents form covalent chemical adducts with cellular DNA, RNA, and 20 protein ~ ~ and with smaller amino acids, ~h~-lhion~ and similar . h~ C GeneraUy, these alUylating agents react with a "",~l~phjljn atom in a cellular cn--~io ~ ~. such as an amino, carboAyl, p'- p~ . sulfhydryl group in nucleic acids, proteins, amino acids, or ~ 1-;onP The ,---- 1- ----~ and the lole of these aUcylating agents in cancer therapy is not well ,...
Typical alkylating agents include:
2S Nitroger,~ .. ~u~, such as Chlo~ u~ ;l Cy. ~}e~ e, T -' 'r;, M~hlor~t~ ~ e~ ' Uracil mustard;
Aziridine such as Thiotepa t; 1~h esters such as R--~..lr,---;
nitroso ureas, wch as C~U lllUa~ c. r platinum c ~ . ' ;, such as ['iq71~jn. CalbvplaLin;
~ eIUL~ - aL~cylator, such as MUc,....~i--, and ~u~ba~inc, Dà.,a b~i--c and Alll~ ~ , DNA strand breaking agents include Blec,---~_hl, DNA ln~ --.. -, ~ II inhibitnrs include the following:
I.~t~ aldtu-~, such as A~ a~,lh~_, Dactinomycin, Dau-~vll ' l, DUAUII~~
I kul ~ . and MUoA~u.~-unP, W O 97/05873 PCT~US96/12474 nolli.,tc.~lators, such as F~opo~i~lP and Te~ lr The DNA minor groove binder is PlicLun~
The ~ s interfere with the production of nucleic acids by one or the other of two major n~rl~ .. c Some of the drugs inhibit production of the de~ u~
S ~ .ho~.k ~t. c that are the - " p,~ UU~UI:~ for DNA sylllh~is~ thus inhihi'in~ DNA
rrrli~ion Some of the ru---~ k are ,--~ ly like purines or pynmiAintc to be able to _1 for them in the anabolic ~ cl~iAt palh~.a,~5. These analogs can then be ~.-h~ A
into the DNA and RNA instead of their normal c r Ls. The ~nli~ ~l~lit~c useful herein include:
folate: ~ such as Metht,L ~at~, and L~hu~,L~i ~ go~ c such as Flu~luu d~;L nuù-u.l~G~ uidine,CB3717,~ e, C~kudbi-.e, and Floxuridine purine ~ gl~ni~ include M~ uh~e, 6-l'hing~ inr, Fl A~h;~r r. -~ ;
sugar modified analogs include Cy~L abil e, Fhl~U~ I
lS ~ o(iAt l~dll-last~ inhihi-nrc include L~Lu~ d.
Tubulin T ~,_ agentc act by binding to specific sites on tubulin, a protein that pol,~ ,.i~5 to form oellular ulul,~l~,s. Mi~.-ului ul~.s are critical oell structure units. When t_e ~_ agents bind on the protein, the oell can not form uLul,ules Tubulin T tt ' ._ agentc include V - and Vinl-l ~li..t., both ~ and ~
TT.~ ,.. n-.31 agents are also useful in the L.~P of cancers and tumors. They are used in ht ...onally , ble tumors and are usually derived from natural souroes These include:
~ LIuo_.~, co ~ju~ UO_as and Ethinyl FctrAiol and Diethylctilh~e~ol,Chlo.Lii~iscn and Idenestrol;
~ ..ug_.ti~ such as II~u~,-oO~st~ . MP~UA~Y-L O ~ ~ and Mc~ L~ul;
2S '~ such as i u.le, I ~ r ~ ', nUU.~,~ ' u~14 Adrenal c~ ' are derived from natural adrenal cortisol or hy-LO~ O.Liau--_. They are used because of their anti i.. n~.. to.~ benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA aruth~s;s. These c~--~l~---- 1~ include, F~ ' o, D~
30 1~ 't o, and Fl. ' ' o T.-..l;l~;,;.,g hormone releasing hormone agents or ~gonadùLu~ releasing h~rmrn.-are used prirnarily the 11~ of prostate cancer. These include leuprolide acetate and ~LIill acetate. They pre~ent the ~ ~..LI.w; . of steroids in the testes.
,~r~ihrlrr~-n~l antigens include:
3S ~Iti~i.L u~_nic agents such as Tamosifen, a,lti~lL~,~_.. agents such as Flutamide; and ~.Li~,d.~,nal agents such as Mitotane and ~ . II,imifl~
-W O 97/0~873 PCT~US96/12474 .
HydluA~Lu~d appears to aet primarily through inhihition of the enzyme ,;~ Ul,t vl;
.~J..~
A~p~ ~ is an enyme whieh converts ~ r to nf~--rl.. ~ l aspartic aeid and thus blocks protein :,y ' - ~ in the tumor.
S Taxol is p~ d ~ l --u~l~r ~ .. lir~ agent.
D. POTENTIATORS
The ~ can be any material which hlll~lU.e5 or increase the efficaey of the ph-.".~ - 'if~ C(~ - or acts on the immune system. One such F ~ is l~iylulidi~c and its cis-isomer whieh are used in ~c,--~h;~ o-~ with the ~k. --...lh- -_~ agents and 2~2,4-10 diil.. v-v~h~ 1)-1,3-his(lH-1,2,4-triazol-l-yl)propan-2-ol and its d~,~-vd~ Triprolidine is d~ in US 5,114,951 (1992). Another po~ r is p.ucc,~ .,'e, lII.~ ~ ~~ 2-IJ~ ,r r acid; [B-(2 ben7imi~ 7f'~ acid; 2-(2~dulv~ h~n~imi~ ~ propaZOI]
Proco~l- le is a mon-speeific aetive ;~ ul~ul~li~re agent ag~unst viral and bacterial ~ a~C
and can be used t~ith the c~---r~ l;f~nc elaimed herein. It is effeetive with 2-(2,4~1inuv-u~,h_..,l)-15 1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its derivatives alone in treating cancers, ~nors, ~ and viral ;.-f: ~I;O-- or .v~h;.-~ with ch~n r~ ;r agents.
Pl~, - - aeid and its salts and esters ean also be used in cc---l-:f ~ with the yU - ,.. ~.,tj~ ~ C~ p~ ...c claimed herein.
;u.~ vitamins such as vitamins A, C and E and beta~drotene can be added to 20 these cv~ul~;l;o-~c E. DOSAGE
Any suitable dosage may be given in the method of the h.~ ioll. The type of co-..l u---A
and the carrier a~d the amount will vary widely d~ g on the species of the warm blooded animal or human, body weight, and the type of caneer or tumor or viral infection being treated.
25 Generally a dosage of between about 1 milligrqm (mg) per kiho~yp~ (Icg) of body weight and about 1000 mg per lcg of body weight is suitable for either the 2-(2,4~ Lv-upl ~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its d~.ivd~ s or the ~h- -~h--~ agent. P-~f~ from lS mg to about 800 mg/lcg of body weight is used. Generally, the dosage in man is lower than for small warm blooded mqm~qlc sueh as miee. A dosage unit may eomprise a single c-~ v---~A or 30 mixtures thereof with other ,o~ c or other cancer inhihi~ing ~ k The dosage unit can also cr , ~ diluents, ~ carriers, hl~ and the lilce. The unit may be in solid or gel form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, i~ s injeetion or pa l ~ n~a;o~- or injeetion into or around the bone marrow. The range and ratio of 2~2,Winuu.o~l.e.-~1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its derivatives to cht - ' ~ - agent will depend on the type of cancer or tumor being treated and the ya Li-ulat ~ u~ c agent.
F. DOSAGE DELIVERY FORMS
The c~ ;c agents, 2~2,4~1inuv.u~h~ 1)-1,3-bis(lH-1,2,4-triazol~
5 yl)p}opan-2-ol and its d~_.ivaLi-_S and, optionally, the ~ ~ are typically mixed with a p~ p ,,~lly r pt ' ~- carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of ~ ; u ;~ io~ being used. The active agent can be c~ - ~cd in the form of a tablet or capsule, lircomp. as an a~l~ t ~I powder or in a liquid form.
F ,'~ of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets 10 can be easily r....- ~ i and can be made easy to swallow or chew; other solid forms include gr~nl~lPc~ and buL~c powders. Tablets may contain suitable binders, l~ a-.lc, diluents, r~,~ t~iug agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
F ,~ of suitable liquid dosatge forrns include solutions or ~ nC in water, pn~ ally a , ' ~ fats and oils, alcohols or other organic solvents, i..~lu!;nE esters,~S ~n ~ ;rnc syrups or elixirs, ~ o--~ c andlor r ~ 1~ l from ~on-granules and effervescent p~l,l-,.-.ql;onc ~~CO~ t~ d from c~ Such liquid dosage fonns may contain, for example, suitable solvents, y~ tLi~_S, emulsifying agents, g agents, diluents, ~ ll.;. L.r~.~ and melting agents. Oral dosage forms OyLio~âlly contain na~J-a~-~ and coloring agents. ra,. - ' and illha~ )u~ forrns would also 20 include minerals and other -- ~ ' to make them , ' 'e with the type of injection or delivery system chosen.
Specific ~ , ' of ph~u.~ i a ~ carriers and c . ~ that may be used to ru~ uht~ oral dosage forms of the present invention are df G I ;Ih.d in U. S. Pat. No. 3,903,297 to Robert, i sued Sept. 2, 1975. T~ tc and co ~ c for making dosage forms useful in 2S the present i .. -- are dcs~,-il~cd in the following lef. .~,. c;,. 7 Modern rhd~ liss.
Chapters 9 and 10 (13anker ~ Rhodes, Editors, 1979); ~ et al., Pl...-...~c~ l Dosa~e Fonns: Tablets (1981); and Ansel, I-~t~udu~liùn to Pha.~ ti~ ,1 Dosa~e Forms 2nd Edition (1976).
G. METEIOD OF TREATMENT
30 The method of ll~ .. l can be any suitable method which is effective in the Il~Lu-~,nt of t the p~uli..ll~ canoer or tumor type being treated. Treatment may be oral, rectal, topical, ~ .~ ' or i- l-.... a~ ;o~ or by injection into the tumor or cancer. The method of applying an effective amount also varies dcp~ ing on the le~bPmi~ cancer, tumor or virus being treated. It is believed that pa-c~lh.~ by h~ ,.,G~Iu_, ~ n~llC or ~ ~
3S ~ of the 2-(2,Winuu.u~h~ 1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its ~
W~ 97~5873 PCTAUS96/12474 d~-ivdli~_s, f~ ' ~ with an ip~lU~J~iaiG carrier, a~ tionql cancer inhihiti~ C~ d or ~~ v~ c or diluent to facilitate app~ ;o~ will be the pl.f~,..cd method of qrln i- g the r~ .o..-- k to warm blooded animals.
In addition to the use of .~ ;c agents and F ~ . 2~2,4-S ~lilluv~u~h~ 1,3-his(lH-1,2,4-triazol-lyl)propan-2-ol and its derivatives can be c~----l,;~ with fi~ df~, h~,-b: I or other antiviiral agents. P~f~ d h; ~ -1PC and r....g;~ tif~ include w~ ,;... n-- c~ .henomyl,~ v~ate and~
When the pl.~ ;r.ql C~ ln ~ c are used for Ll~atl.._.-l of viral inf~ti('n. they can be ~ with other anti-viiral agents.
10 ~NTI VIRAL E'VALUATION WIT~ IIUMAN INFLUENZA VIRUS
Female CD (mice Charles River Breeding Labulatul;~i., Portage, Ml) S to 7 weeks old of age at the time of reoeipt are used. Mioe are al~JIu~ dt~,ly 6 to 9 wee~C old and weigh a~ ~ ~ ly 20 to 28 grams at the time test i--~ All miioe used in the study do not valy in age by more than 10 days. The mioe are housed 6 per cage with bedding. The miioe are fed rodent lS diet S002 (PMI, Sit. Louis Missouri) q'ilihihtm Fresh water is supplied to the mice q~ll ' 'tl Human i..nn ~-,- vinls, strain AT2~raiwan/1/64 is used to rhqllPn~ the mioe. Thev~, ' is stored at a~ Iy -70~C. Prior to ;~-f ~ ch~liPng~ a vial of frozen stock is ~awed amd diluted to the ~pl~. ~ ~ c~ -c ~ ~ - in bu~fered saline solution. The mioe are ~ ~ ' with ~ql~thqnP and the virus ct~qliPng~ dose is ~ ~ ed intra-nasally in volume 20 of 50 ~ loli~
Test -' are - ' ~,d at the co~ a~nd volume as provided below. On days 1 through 14, 10 mioe per group receive the test articles by oral lavage. Saline control animals (10) reoeive a ~ Ir volume of saline as cvll~a~ to the test article-dosed mioe.
Test article dosing is ~c~ pl~hr-~ at a~ ~ 'y 24 hour intervals. On day 0 ap~ ~ 'y 4 2S hours after the second dosing of test articles or saline, all mioe are rh~lPngPd intra-nasally with an infe~ive dose of virus c~' ' ~ ' to produoe alJ~IUAillldt~,l)' 90% lethality. Animals are observed daily for 21 days after ;~ l;u~ ch~lhPn~e~ for mortality or .---~
TESTMATERIAL DOSE (mg/kg) PERCENT MORTALIl'Y
Fl - '- 3S0 0 Fl ~ 700 30%
7, Saline - 100%
~ _. .- 7S
..
IN VITRO HUMAN TUMOR COLONY FORMING UNITS TEST
Solid t unors removed from patients are minoed into 2 to S mrn r.,.~;.. ~C and 30 ;.-----~~ placed in McCoy's Medium SA plus 10% heat h~ at~d ne~oorn calf serum plus 1% p~on;r~ n/~ plu~ Within 4 hours, these solid tumors are ~''f~ lly ;1'- ~~~ ' ' ~
with scissors, forced through No. 100 stainless steel mesh, through 25 gauge needles, and then washed with McCoys medium as fl~ above. Ascitic, pleural, p~.i~ lial fluids and bone marrow are obtained by standard l~ c The fluid or marrow is placed in sterile ~ ~
S ~-~ g 10 units of p~ va~ free heparin per ml. of m~ n~ fluid or marrow. Afier ~ ~r~, ~ at IS0 x g for 10 minutes, the cells are l~_i,t~ and washed with McCoy's medium plus 10% heat ind~ ' calf serum. The viability of cell ~ is d~ .-..illcd on a he...o-,ytu..._t~,. with trypan blue.
Cells to be cloned are _ r - ~ed in 0.3% agar in enriched CMRL1066 --I r~0 with lS% heat inactivated horse serum, peni~ in (1OO units/ml), ~L.~,~Lu...~_i" (2mg/ml), (2mM), insulin (3 units/ml), aa~a-~ ;ine (0.6 mg/ml), and HEPES buffer (2mM). For the co ~;--- ----~ e~s.,l~ test each c--~r ~ is added to the above mixture. Cells are placed in 3S
mm petri dishes in a top layer of agar over an i~n~;h,-la,~ ~ of agar to prevent growth of Jil,-ulll~.
Three plates are prepared for each data point. The plates are placed in a 37~C: _l and are lS removed on day 14 for counting of the number of colonies in each plate. The number of colonioe (defined as S0 cells) for~ned in the 3 cc---po-~ treated plates is ~,ull~)al~,d to the number of colonies formed in the 3 control plates, and the percent colonies s~rviving at the . ~r ~ of e ~, ~ can be iaL ' ~ ~ Three positive control plates are used to d~ - survival rate.
O ' " v ' at 200 Il&/rnl is used as the positive control. If there is ~30% cells in the 20 positive control when wl~ to the I ~ ~ control, the test is c~ ' ~
At oen~ - -- - of O.S and S.0 llg/ml in a ~ u~ exposure t ~_ ' ' or single dose e r- ' ' Fl J!~ was not effective (0/3 and 0/13 ~ Li~-el~) against tumors. At c~ - --- of S0.0 ~ug/ml in a C~ ~t; O~ exposure f ~ Fl ~ was effective against lung, non-small cell, and ovarian cancers pal Li-,ulàl 1~. Over all 4/13 had sS0% survival.
This i~ lion is a ph_ ~ ;c~l c~ that is useful for the v~dtl~ l of canoers and tumors, paulicuLuly in human and warm blooded animals cc ~ g 2-(2~4~ 1UUIU~
1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its de.ivdli.~ It can be used in co ~h;. ~I;o~ with 10 other e ' , agents and pùt~ The same ~ on can be used to treat vi~al BACKGROUND OF THE INVENTION
Canoers, ~ iing IP~ Pm;q, are the leading cause of death in animals and humans The exa~ cause of I ' is not known, but Unks between certain activities such as smolcing or 15 ~uau~; to c~n~ills;~' ~~ and the i~ :d~ of oertain types of le~ pmiq and tumors has been shûwn by a number ûf l-,s~-h_.a Many types of ~h~ ';c agents have been shown to be effective agaunst canoers, tumors and '~ ~ but not all types of cancer and tumor oells respond to these agents U~vrvl '~" many of these agents also destroy normal cells The exact . ~ for the 20 action of these ~ ' - agents are not always known De_pite a~ul~ in the field of canoer and It ~ Il~ll..~.-ta the leading ' , to dateare~ io~andrhPm~ ' , andbonem.~row1,~"~ h. ~ lvd~h~
are said to fight cancers that are pal~ uly a~;l~ _ Such cytocidal or ~lu~ , agents work best on canoers with large growth factors, i e., ones whose cells are rapidly dividing To date, ho.~ , in p~- t;~ estrogen, plUg_it~l - and ~ uat .une, and some ' ~ ed by a variety of microbes, aLt.~ldtil.g agents, and anti ~;tPC form the bulk of i' , available to --Y"" Ideally ~Iv~ic agents that have c~rifi~ity for I ' a, canoer and tumor oells while not affecting normal cells would be e,~ ,..lel~ d ' '- Ullrul: '~" none have been found and instcad agents which target especially rapidly dividing oells (both diseased and normal) 30 have been used Clearly, the d~ 1O~ of materials that would target canoer or hP~ Pm;~ oells due to some unique ~l~c~ for them would be a bl~ll--u..~ll. Alt~,-l~li~.~.ly, .-~ lc that were ~ylolu,~ic to IP~ Pmiq or cancer cells while exerting mild effects on normal cells would be ' '- Therefor0, it is an object of this hl~_~lvion to provide a ph~ ;l;on that~5 is effective in treating I~P~ Pmi~ with mild or no effects on normal blood oells WO 97/05873 PCT~US96/12474 More r~ific~lly, it is an object of this invention to provide a ~ nn C~ ;n~ a p~ l carrier and a 2-(2,4~1inuo-u~,hc..-~1)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its derivatives as defined herein along with a method for treating cancer, le~ mi~ and tumors.
The use of 2-(2,4~inuoruphe..~1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its S d~,.ivali-_o in co -~ with other chP~oth~ ic agents which are effective in d~,~h'~ .g the turnor is a novel method of l-e 2~2,4-Dinuo-uphc.~1)-1,3-bis(lH-1,2,4-triazol-1-yl)prop,an-2-ol and its derivatives can also be used to treat viral i~f ~ ~ either alone or in the presence of a p -.
SUMMARY OF TI~E rNVENTION
lû A ~ ""~r, ,~ u~ for l.~LI.. ~.ll of rnqn~n~ql~ and in ~>alLi~ ld~, wârrnblooded animals and humans, which are affected by le..t~Pmiq Cu--~ illg a ph~ ;ral carrier and an e~fective arnount of 2-(2,Willuùr~l,h~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)prop, n-2-ol ) and its dC~ivaLi~Cj. 2~2,4-Dinuu-uphcn.~1)-1~3-bis(lH-1~2~4-triazol-lyl)propan-2-ol has the formula:~5 l H
F~
These c~ can be used to inhibit the growth of le~ Pmiq tumors and canc_r oells in hurnans or animals by ~ h~ .. of an effective amount either orally, rectally, topically or ~. 'Iy, or i--L dv-.-ul~. These cu..l~,o:.iLions do not r~ ;ri~ ly affect healthy~0 cells.
r~ can also be used in ~.u-~ n with 2-(2,4~1illuo.uph.,~ 1)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its de~ivd~i~_s as can cl~ ;c agents.
These ~ .. c are ~KULi~ ~lhul~, effective against the i.~n.. --,~ virus.
~ =~ -W O 97/OS873 PCT~US96/12474 DETAnLED DESCRUPTION OF THE ~NVENl~ON
~u DEFLNIllONS:
As used herein, the term ~cc~ ,gu means various c~ l~n.~ can be COlljOi~ y . ' ,_i in the pl~u~ u~ cc~ o~l of this invention. Ac~ Ln~ly, the terms "~o~ g 5 Pccpn~ y of-U-and"c~ 1;ngof-Uare~ intheterm co ~ ; ug A~i used herei4 a ul,~ " ~ ~ .";, ~lly a: r ' ' " c~ is one that is suitable for use with hurnans and/or animals without undue adverse side effects (such as toxicity, irritatio4 and allergic response) t-~ with a ~ "c ~... rlL/.i~k ratio.
As used herein, the term "safe and effective amountU refers to the quantity of a10 ~ pQ ~r"l which is ~--ITi- ~-1 to yield a desired ~ l;u response without undue adverse side effects (such as ~oxicity~ irritatio4 or allergic response) co-----~r--~ t with a 1~
~..~r.l/.i~ ratio when used in the manner of this in~ on. The specific "safe and effective amountU will, ~ll,.iuu~l~, vary with such factors as the particular a7ntlitil~n being treated, the physical co~A;I;~ of the patient, the type of mammal being treated, the duration of the t-~ t, 15 the natwe of cor,.u.~ therapy (if any), and the specific ru, -~ ,~ and the structure of the r~ o~ lc or its d~ ali~
As used herein, a "2-(2,4-di~luu~u~k.~ yl)-l~3-bis(lH-l~2~4-triazol-l-yl)propan-2 d- -iVd~ " includes its esters and ethers and its pk~ ;. ~-lly 7 p' blr salts.
As used h.ereirl, a "~,h " ~ ;c~l addition salts" are salts of 2-(2,4~ 1uu~ulJh.,.lyl)-1,3-20bis(lH-1,2,4-triazol-1-yl)propan-2-ol with an organic or inul~u ic acid. These l". f .-. d acid addition salts are cl,lo-;dcs, I,-u",.~s, sulfates, nitrates, Fl "' '~ r tartrates, rn~1 malates, citrates, !r ~alh,y' ~c -; and the like.
As used herei4 a "I' ' carrier" is a ph~ lly a , ' ' solvent, - ~ ' g agent or velhicle for d~ _.i-.g the anti I ' ~ agent to the anirnal or human. The 25 carrier m ay be liqnid or solid and is selected with the planned manner of ~A; u ;~ ;nn in mind.
As used !herein, "cancer" or "le~ mi~ refers to all types of cancers or n~ - or disease which attack normal healthy blood cells or bone rnarrow which produces blood oells which are fonnd in ~ ------.~lc As used herein, "viruses" includes viruses which cause diseases in warm blooded animals 30~ ' ' G HIV, i.-~l--r -~_ ,I,i,.uvi,~s, herpes and the like.
As used herei4 "2-(2,4~ 1uu~u~L~.~yl)-1,3-bis(lH-1,2,4-tria_ol-l-yl)propan-2-ol and its d~,.i.,dti~ inclufles esters and ethers ac well as addition salts.
As used herein "~.n~ " are materials such as triprolidine and its cis-isomer or lH-R~n7i~ ' '~-2-l"u~dnoic acid which are used in ~.~....1~in~1i9n with 2-(2,4~ 1uu~u~,henyl)-1,3-35bis(lH-1,2,4-tria7o1-l-yl)propan-2-ol and its derivatives. Pu~ u~ can affect the immune system or enhance the c~li~ .sj of the drugs.
~ s used herein "- h~ tir agents" includes DNA~ Agents, Antime-tabolites, Tubulin-Interactive Agents. TT...,..,l-~l agents and others, such as ~p~ Y or h~Lu~u.~d.
B. 2-(2,4-DIFLUOROPHENYL)-I,3-BIS(IH-1,2,4-TRIAZOL-l-YL)PROPAN-2-OL
S AND ITS DERIVATIVES
2-(2,4 diIluu.uph~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its dc.;~ ~cs has the following ~LI u~,luuc.
~H
It is prepared a~,culding to the method cl~ ;l~d in U.S. 4,404,216 issued to R~
10 (1983).
The de.ivali~_~ include the lower WlJUA,~/lic acid esters of the propanol group, for . '~, acetyl, propanoyl, butyl, pentyl and hexyl esters. Pa~ ulauly p.~,f..-~,d are the esters of UA~IiC acids having less than seven carbons, and most p~f~abl~ propyl esters. Aryl ~bui~lic acids such as salicylic acid. benzoic acid, and related acids can also be used to esterify 15 the propanol group. AL~cyl eLhers having less than 7 carbons are also useful dc.ivàLi~_S.
The p~ 1 addition salts are salts of 2~2,4~1..~1luph~u~1)-1~3~is(1H-1~2~4-triazol-l-yl)propan-2-ol with an orgaluc or invl~anic acid. These ~ .f~ acid addition salts are rhlonr~ b~ul~ d~s, sulfates, nitrates, F~ r 5~ ~1 s, tartrates, tn~l s, malates, citrates, h~ .li~L~tes, ~u,' : and the like.
20 These ~-- - ,p-~--.. l~ are part of a more generic class of r -.~ d~ ~ with the formula:
lH
~ J R' ~N~
;
W O 97/0~873 PCTAUS96/12474 wherein Rlis an optionally T vl~ ut~;l alkyl, cycloaL~cyl, aryl (2,4-dichlo.uph,..~i) or aralkyl group, and yl and y2 are =CH- or =N-; and salts or metal . n, ' and ether or esters thereof.
While these materials are active against fungus disease, some have been found to be l ~ O
Therefore, those llldt~,.ials which exhibit this property are not useful herein.
S C CEIEMOT~ERAPEUTIC AGENTS
The c~ "~th--al~ ~t;c agents are generally grouped as DNA-h-t~"a~Agents, Tubulin-I.It ,.a.,li- _ Agents, T-Tn.~ l agents and others such as ~ or L.~.hu,~ a. Each of the groups of . ~ th . ~ agents can be further divided by type of activity or ~U-~ I The e1.. )~ ;f agents used in c~ h;~';o~ with 2~2,4-10 .li~luo.u~ I,3-bis(lH-1,2,4-triazol-lyl)propan-2-ol and its d~"ivali~ include .. ~ -, of all of these groups. For a detailed .1;~ n of the ch~mnthr-~ " ;r agents and their method of G h~ n, ~iee Dorr, et al, Cancer Chemotheropy Handbook 2d edition, pages 15-34, Appleton ~ Lange (CQn~r~ 1994) herein h.CCII~ol"!t~,d by ,ef~.~n~c;.
DNA-L4t~,~a~ _ Agents include the allylating agents, e.g. C~ in. Cy.,l~ph~
15 Al~ the DNA strand-breakage agents, wch as Blw.. ~ ; the ' og l~q~ I,jt,,,~. c.g., n~ i.. and DUAUIl ~ ~ ); the r.v. i--t.. ~hl;-.g l_p ~ II inhihit~i wch as, FtrpQri~ and T~ , and the DNA minor groove binder Pl~--ydii~.
The aLkyldlii.g agents form covalent chemical adducts with cellular DNA, RNA, and 20 protein ~ ~ and with smaller amino acids, ~h~-lhion~ and similar . h~ C GeneraUy, these alUylating agents react with a "",~l~phjljn atom in a cellular cn--~io ~ ~. such as an amino, carboAyl, p'- p~ . sulfhydryl group in nucleic acids, proteins, amino acids, or ~ 1-;onP The ,---- 1- ----~ and the lole of these aUcylating agents in cancer therapy is not well ,...
Typical alkylating agents include:
2S Nitroger,~ .. ~u~, such as Chlo~ u~ ;l Cy. ~}e~ e, T -' 'r;, M~hlor~t~ ~ e~ ' Uracil mustard;
Aziridine such as Thiotepa t; 1~h esters such as R--~..lr,---;
nitroso ureas, wch as C~U lllUa~ c. r platinum c ~ . ' ;, such as ['iq71~jn. CalbvplaLin;
~ eIUL~ - aL~cylator, such as MUc,....~i--, and ~u~ba~inc, Dà.,a b~i--c and Alll~ ~ , DNA strand breaking agents include Blec,---~_hl, DNA ln~ --.. -, ~ II inhibitnrs include the following:
I.~t~ aldtu-~, such as A~ a~,lh~_, Dactinomycin, Dau-~vll ' l, DUAUII~~
I kul ~ . and MUoA~u.~-unP, W O 97/05873 PCT~US96/12474 nolli.,tc.~lators, such as F~opo~i~lP and Te~ lr The DNA minor groove binder is PlicLun~
The ~ s interfere with the production of nucleic acids by one or the other of two major n~rl~ .. c Some of the drugs inhibit production of the de~ u~
S ~ .ho~.k ~t. c that are the - " p,~ UU~UI:~ for DNA sylllh~is~ thus inhihi'in~ DNA
rrrli~ion Some of the ru---~ k are ,--~ ly like purines or pynmiAintc to be able to _1 for them in the anabolic ~ cl~iAt palh~.a,~5. These analogs can then be ~.-h~ A
into the DNA and RNA instead of their normal c r Ls. The ~nli~ ~l~lit~c useful herein include:
folate: ~ such as Metht,L ~at~, and L~hu~,L~i ~ go~ c such as Flu~luu d~;L nuù-u.l~G~ uidine,CB3717,~ e, C~kudbi-.e, and Floxuridine purine ~ gl~ni~ include M~ uh~e, 6-l'hing~ inr, Fl A~h;~r r. -~ ;
sugar modified analogs include Cy~L abil e, Fhl~U~ I
lS ~ o(iAt l~dll-last~ inhihi-nrc include L~Lu~ d.
Tubulin T ~,_ agentc act by binding to specific sites on tubulin, a protein that pol,~ ,.i~5 to form oellular ulul,~l~,s. Mi~.-ului ul~.s are critical oell structure units. When t_e ~_ agents bind on the protein, the oell can not form uLul,ules Tubulin T tt ' ._ agentc include V - and Vinl-l ~li..t., both ~ and ~
TT.~ ,.. n-.31 agents are also useful in the L.~P of cancers and tumors. They are used in ht ...onally , ble tumors and are usually derived from natural souroes These include:
~ LIuo_.~, co ~ju~ UO_as and Ethinyl FctrAiol and Diethylctilh~e~ol,Chlo.Lii~iscn and Idenestrol;
~ ..ug_.ti~ such as II~u~,-oO~st~ . MP~UA~Y-L O ~ ~ and Mc~ L~ul;
2S '~ such as i u.le, I ~ r ~ ', nUU.~,~ ' u~14 Adrenal c~ ' are derived from natural adrenal cortisol or hy-LO~ O.Liau--_. They are used because of their anti i.. n~.. to.~ benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA aruth~s;s. These c~--~l~---- 1~ include, F~ ' o, D~
30 1~ 't o, and Fl. ' ' o T.-..l;l~;,;.,g hormone releasing hormone agents or ~gonadùLu~ releasing h~rmrn.-are used prirnarily the 11~ of prostate cancer. These include leuprolide acetate and ~LIill acetate. They pre~ent the ~ ~..LI.w; . of steroids in the testes.
,~r~ihrlrr~-n~l antigens include:
3S ~Iti~i.L u~_nic agents such as Tamosifen, a,lti~lL~,~_.. agents such as Flutamide; and ~.Li~,d.~,nal agents such as Mitotane and ~ . II,imifl~
-W O 97/0~873 PCT~US96/12474 .
HydluA~Lu~d appears to aet primarily through inhihition of the enzyme ,;~ Ul,t vl;
.~J..~
A~p~ ~ is an enyme whieh converts ~ r to nf~--rl.. ~ l aspartic aeid and thus blocks protein :,y ' - ~ in the tumor.
S Taxol is p~ d ~ l --u~l~r ~ .. lir~ agent.
D. POTENTIATORS
The ~ can be any material which hlll~lU.e5 or increase the efficaey of the ph-.".~ - 'if~ C(~ - or acts on the immune system. One such F ~ is l~iylulidi~c and its cis-isomer whieh are used in ~c,--~h;~ o-~ with the ~k. --...lh- -_~ agents and 2~2,4-10 diil.. v-v~h~ 1)-1,3-his(lH-1,2,4-triazol-l-yl)propan-2-ol and its d~,~-vd~ Triprolidine is d~ in US 5,114,951 (1992). Another po~ r is p.ucc,~ .,'e, lII.~ ~ ~~ 2-IJ~ ,r r acid; [B-(2 ben7imi~ 7f'~ acid; 2-(2~dulv~ h~n~imi~ ~ propaZOI]
Proco~l- le is a mon-speeific aetive ;~ ul~ul~li~re agent ag~unst viral and bacterial ~ a~C
and can be used t~ith the c~---r~ l;f~nc elaimed herein. It is effeetive with 2-(2,4~1inuv-u~,h_..,l)-15 1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol and its derivatives alone in treating cancers, ~nors, ~ and viral ;.-f: ~I;O-- or .v~h;.-~ with ch~n r~ ;r agents.
Pl~, - - aeid and its salts and esters ean also be used in cc---l-:f ~ with the yU - ,.. ~.,tj~ ~ C~ p~ ...c claimed herein.
;u.~ vitamins such as vitamins A, C and E and beta~drotene can be added to 20 these cv~ul~;l;o-~c E. DOSAGE
Any suitable dosage may be given in the method of the h.~ ioll. The type of co-..l u---A
and the carrier a~d the amount will vary widely d~ g on the species of the warm blooded animal or human, body weight, and the type of caneer or tumor or viral infection being treated.
25 Generally a dosage of between about 1 milligrqm (mg) per kiho~yp~ (Icg) of body weight and about 1000 mg per lcg of body weight is suitable for either the 2-(2,4~ Lv-upl ~ 1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its d~.ivd~ s or the ~h- -~h--~ agent. P-~f~ from lS mg to about 800 mg/lcg of body weight is used. Generally, the dosage in man is lower than for small warm blooded mqm~qlc sueh as miee. A dosage unit may eomprise a single c-~ v---~A or 30 mixtures thereof with other ,o~ c or other cancer inhihi~ing ~ k The dosage unit can also cr , ~ diluents, ~ carriers, hl~ and the lilce. The unit may be in solid or gel form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, i~ s injeetion or pa l ~ n~a;o~- or injeetion into or around the bone marrow. The range and ratio of 2~2,Winuu.o~l.e.-~1)-1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its derivatives to cht - ' ~ - agent will depend on the type of cancer or tumor being treated and the ya Li-ulat ~ u~ c agent.
F. DOSAGE DELIVERY FORMS
The c~ ;c agents, 2~2,4~1inuv.u~h~ 1)-1,3-bis(lH-1,2,4-triazol~
5 yl)p}opan-2-ol and its d~_.ivaLi-_S and, optionally, the ~ ~ are typically mixed with a p~ p ,,~lly r pt ' ~- carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of ~ ; u ;~ io~ being used. The active agent can be c~ - ~cd in the form of a tablet or capsule, lircomp. as an a~l~ t ~I powder or in a liquid form.
F ,'~ of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets 10 can be easily r....- ~ i and can be made easy to swallow or chew; other solid forms include gr~nl~lPc~ and buL~c powders. Tablets may contain suitable binders, l~ a-.lc, diluents, r~,~ t~iug agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
F ,~ of suitable liquid dosatge forrns include solutions or ~ nC in water, pn~ ally a , ' ~ fats and oils, alcohols or other organic solvents, i..~lu!;nE esters,~S ~n ~ ;rnc syrups or elixirs, ~ o--~ c andlor r ~ 1~ l from ~on-granules and effervescent p~l,l-,.-.ql;onc ~~CO~ t~ d from c~ Such liquid dosage fonns may contain, for example, suitable solvents, y~ tLi~_S, emulsifying agents, g agents, diluents, ~ ll.;. L.r~.~ and melting agents. Oral dosage forms OyLio~âlly contain na~J-a~-~ and coloring agents. ra,. - ' and illha~ )u~ forrns would also 20 include minerals and other -- ~ ' to make them , ' 'e with the type of injection or delivery system chosen.
Specific ~ , ' of ph~u.~ i a ~ carriers and c . ~ that may be used to ru~ uht~ oral dosage forms of the present invention are df G I ;Ih.d in U. S. Pat. No. 3,903,297 to Robert, i sued Sept. 2, 1975. T~ tc and co ~ c for making dosage forms useful in 2S the present i .. -- are dcs~,-il~cd in the following lef. .~,. c;,. 7 Modern rhd~ liss.
Chapters 9 and 10 (13anker ~ Rhodes, Editors, 1979); ~ et al., Pl...-...~c~ l Dosa~e Fonns: Tablets (1981); and Ansel, I-~t~udu~liùn to Pha.~ ti~ ,1 Dosa~e Forms 2nd Edition (1976).
G. METEIOD OF TREATMENT
30 The method of ll~ .. l can be any suitable method which is effective in the Il~Lu-~,nt of t the p~uli..ll~ canoer or tumor type being treated. Treatment may be oral, rectal, topical, ~ .~ ' or i- l-.... a~ ;o~ or by injection into the tumor or cancer. The method of applying an effective amount also varies dcp~ ing on the le~bPmi~ cancer, tumor or virus being treated. It is believed that pa-c~lh.~ by h~ ,.,G~Iu_, ~ n~llC or ~ ~
3S ~ of the 2-(2,Winuu.u~h~ 1,3-bis(lH-1,2,4-triazol-l-yl)propan-2-ol and its ~
W~ 97~5873 PCTAUS96/12474 d~-ivdli~_s, f~ ' ~ with an ip~lU~J~iaiG carrier, a~ tionql cancer inhihiti~ C~ d or ~~ v~ c or diluent to facilitate app~ ;o~ will be the pl.f~,..cd method of qrln i- g the r~ .o..-- k to warm blooded animals.
In addition to the use of .~ ;c agents and F ~ . 2~2,4-S ~lilluv~u~h~ 1,3-his(lH-1,2,4-triazol-lyl)propan-2-ol and its derivatives can be c~----l,;~ with fi~ df~, h~,-b: I or other antiviiral agents. P~f~ d h; ~ -1PC and r....g;~ tif~ include w~ ,;... n-- c~ .henomyl,~ v~ate and~
When the pl.~ ;r.ql C~ ln ~ c are used for Ll~atl.._.-l of viral inf~ti('n. they can be ~ with other anti-viiral agents.
10 ~NTI VIRAL E'VALUATION WIT~ IIUMAN INFLUENZA VIRUS
Female CD (mice Charles River Breeding Labulatul;~i., Portage, Ml) S to 7 weeks old of age at the time of reoeipt are used. Mioe are al~JIu~ dt~,ly 6 to 9 wee~C old and weigh a~ ~ ~ ly 20 to 28 grams at the time test i--~ All miioe used in the study do not valy in age by more than 10 days. The mioe are housed 6 per cage with bedding. The miioe are fed rodent lS diet S002 (PMI, Sit. Louis Missouri) q'ilihihtm Fresh water is supplied to the mice q~ll ' 'tl Human i..nn ~-,- vinls, strain AT2~raiwan/1/64 is used to rhqllPn~ the mioe. Thev~, ' is stored at a~ Iy -70~C. Prior to ;~-f ~ ch~liPng~ a vial of frozen stock is ~awed amd diluted to the ~pl~. ~ ~ c~ -c ~ ~ - in bu~fered saline solution. The mioe are ~ ~ ' with ~ql~thqnP and the virus ct~qliPng~ dose is ~ ~ ed intra-nasally in volume 20 of 50 ~ loli~
Test -' are - ' ~,d at the co~ a~nd volume as provided below. On days 1 through 14, 10 mioe per group receive the test articles by oral lavage. Saline control animals (10) reoeive a ~ Ir volume of saline as cvll~a~ to the test article-dosed mioe.
Test article dosing is ~c~ pl~hr-~ at a~ ~ 'y 24 hour intervals. On day 0 ap~ ~ 'y 4 2S hours after the second dosing of test articles or saline, all mioe are rh~lPngPd intra-nasally with an infe~ive dose of virus c~' ' ~ ' to produoe alJ~IUAillldt~,l)' 90% lethality. Animals are observed daily for 21 days after ;~ l;u~ ch~lhPn~e~ for mortality or .---~
TESTMATERIAL DOSE (mg/kg) PERCENT MORTALIl'Y
Fl - '- 3S0 0 Fl ~ 700 30%
7, Saline - 100%
~ _. .- 7S
..
IN VITRO HUMAN TUMOR COLONY FORMING UNITS TEST
Solid t unors removed from patients are minoed into 2 to S mrn r.,.~;.. ~C and 30 ;.-----~~ placed in McCoy's Medium SA plus 10% heat h~ at~d ne~oorn calf serum plus 1% p~on;r~ n/~ plu~ Within 4 hours, these solid tumors are ~''f~ lly ;1'- ~~~ ' ' ~
with scissors, forced through No. 100 stainless steel mesh, through 25 gauge needles, and then washed with McCoys medium as fl~ above. Ascitic, pleural, p~.i~ lial fluids and bone marrow are obtained by standard l~ c The fluid or marrow is placed in sterile ~ ~
S ~-~ g 10 units of p~ va~ free heparin per ml. of m~ n~ fluid or marrow. Afier ~ ~r~, ~ at IS0 x g for 10 minutes, the cells are l~_i,t~ and washed with McCoy's medium plus 10% heat ind~ ' calf serum. The viability of cell ~ is d~ .-..illcd on a he...o-,ytu..._t~,. with trypan blue.
Cells to be cloned are _ r - ~ed in 0.3% agar in enriched CMRL1066 --I r~0 with lS% heat inactivated horse serum, peni~ in (1OO units/ml), ~L.~,~Lu...~_i" (2mg/ml), (2mM), insulin (3 units/ml), aa~a-~ ;ine (0.6 mg/ml), and HEPES buffer (2mM). For the co ~;--- ----~ e~s.,l~ test each c--~r ~ is added to the above mixture. Cells are placed in 3S
mm petri dishes in a top layer of agar over an i~n~;h,-la,~ ~ of agar to prevent growth of Jil,-ulll~.
Three plates are prepared for each data point. The plates are placed in a 37~C: _l and are lS removed on day 14 for counting of the number of colonies in each plate. The number of colonioe (defined as S0 cells) for~ned in the 3 cc---po-~ treated plates is ~,ull~)al~,d to the number of colonies formed in the 3 control plates, and the percent colonies s~rviving at the . ~r ~ of e ~, ~ can be iaL ' ~ ~ Three positive control plates are used to d~ - survival rate.
O ' " v ' at 200 Il&/rnl is used as the positive control. If there is ~30% cells in the 20 positive control when wl~ to the I ~ ~ control, the test is c~ ' ~
At oen~ - -- - of O.S and S.0 llg/ml in a ~ u~ exposure t ~_ ' ' or single dose e r- ' ' Fl J!~ was not effective (0/3 and 0/13 ~ Li~-el~) against tumors. At c~ - --- of S0.0 ~ug/ml in a C~ ~t; O~ exposure f ~ Fl ~ was effective against lung, non-small cell, and ovarian cancers pal Li-,ulàl 1~. Over all 4/13 had sS0% survival.
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for treating cancer and tumors and viral infections comprising from about 1 mg/kg to about 800 mg/kg body weight of a member selected from the group consisting of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives and mixtures thereof and a pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to claim 1 further comprising a safe and effective amount of a chemotherapeutic agent.
3. A pharmaceutical composition according to claim 1 or 2 wherein said chemotherapeutic agent is selected from the group consisting of DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents, Asparaginase or hydroxyurea.
4. A pharmaceutical composition according to claim 1, 2 or 3 wherein said chemotherapeutic agent is selected from the group consisting of Asparaginase, hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine, Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamydin.
5. A pharmaceutical composition according to claim 1, 2 or 3 wherein said chemotherapeutic agent is selected from the group consisting of Taxol, Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cyctrabine, and Fludarabine.
6. A pharmaceutical composition according to claim 1, 2, 3, 4 or 5 which furthercomprises a potentiator.
7. The use of a safe and effective amount of a composition of claim 1, 2, 3, 4, 5 or 6 for treating cancer or tumors in warm blooded mammals.
8. The use of a safe and effective amount of a composition of claim 1, 2, 3, 4, 5 or 6 for treating viral infections in warm blooded mammals.
9. The use according to claim 7 or 8 wherein said 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol or its derivatives comprises a dosage formsuitable for administration orally, enterically, intravenously, peritoneally, or by injection into the tumor.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US188995P | 1995-08-04 | 1995-08-04 | |
| US60/001,889 | 1995-08-04 | ||
| US08/674,180 US5908855A (en) | 1996-07-16 | 1996-07-16 | Compositions for treating viral infections |
| US08/674,180 | 1996-07-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2229024A1 true CA2229024A1 (en) | 1997-02-20 |
Family
ID=26669622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002229024A Abandoned CA2229024A1 (en) | 1995-08-04 | 1996-07-30 | Use of fluconazole for inhibiting the growth of cancers |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0841921A2 (en) |
| JP (1) | JPH11510187A (en) |
| KR (1) | KR19990036138A (en) |
| CN (1) | CN1195288A (en) |
| AR (1) | AR003175A1 (en) |
| AU (1) | AU711966B2 (en) |
| BR (1) | BR9609966A (en) |
| CA (1) | CA2229024A1 (en) |
| CZ (1) | CZ33798A3 (en) |
| HU (1) | HUP9903420A3 (en) |
| IL (1) | IL123095A0 (en) |
| MX (1) | MX9800998A (en) |
| NO (1) | NO980473L (en) |
| NZ (2) | NZ503921A (en) |
| PL (1) | PL324904A1 (en) |
| SK (1) | SK14198A3 (en) |
| TR (2) | TR199800270T1 (en) |
| WO (1) | WO1997005873A2 (en) |
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|---|---|---|---|---|
| US6177460B1 (en) | 1995-04-12 | 2001-01-23 | The Procter & Gamble Company | Method of treatment for cancer or viral infections |
| US6479526B1 (en) | 1995-04-12 | 2002-11-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US6262093B1 (en) | 1995-04-12 | 2001-07-17 | The Proctor & Gamble Company | Methods of treating cancer with benzimidazoles |
| US5770616A (en) | 1995-06-07 | 1998-06-23 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| US6265427B1 (en) | 1995-06-07 | 2001-07-24 | The Proctor & Gamble Company | Pharmaceutical composition for the method of treating leukemia |
| US6686391B2 (en) | 1995-08-04 | 2004-02-03 | University Of Arizona Foundation | N-chlorophenylcarbamate and N-chlorophenylthiocarbamate compositions |
| FR2742405B1 (en) * | 1995-12-13 | 1998-02-27 | Cgea Comp Gen Entre Auto | DRIVE UNIT COULD BE COUPLED TO A ROLLING SPEAKER AND RESULTING VEHICLE |
| US5900429A (en) | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| PE11499A1 (en) * | 1997-05-16 | 1999-03-01 | Procter & Gamble | TREATMENT OF HIV AND CANCER |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
| WO2000027428A1 (en) * | 1998-11-09 | 2000-05-18 | Idec Pharmaceuticals Corporation | Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-cd20 antibody |
| US6423734B1 (en) | 1999-08-13 | 2002-07-23 | The Procter & Gamble Company | Method of preventing cancer |
| US6407105B1 (en) | 2000-09-26 | 2002-06-18 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6380232B1 (en) | 2000-09-26 | 2002-04-30 | The Procter & Gamble Company | Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof |
| US6462062B1 (en) | 2000-09-26 | 2002-10-08 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6608096B1 (en) | 2000-09-26 | 2003-08-19 | University Of Arizona Foundation | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US7004915B2 (en) * | 2001-08-24 | 2006-02-28 | Kci Licensing, Inc. | Negative pressure assisted tissue treatment system |
| EP1895012A1 (en) | 2006-08-30 | 2008-03-05 | Universitätsklinikum Freiburg | Method for inducing tumor apoptosis by increasing nitric oxide levels |
| US20120071539A1 (en) * | 2006-12-12 | 2012-03-22 | Emory University | Compounds and methods for modulating the silencing of a polynucleotide of interest |
| WO2019185521A1 (en) * | 2018-03-26 | 2019-10-03 | Westfälische Wilhelms-Universität Münster | Ergosterol-biosynthesis inhibitor and influenza virus infection |
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|---|---|---|---|---|
| EP0196855A3 (en) * | 1985-03-29 | 1989-04-12 | Pfizer Inc. | Tioconazole and related compounds for prevention of sexually transmitted diseases and control of herpetic infections |
| BE1004029A6 (en) * | 1990-11-22 | 1992-09-08 | Mol Omer De | Pharmaceutical compound and pharmaceutical set for the treatment of cancer |
| US5565478A (en) * | 1994-03-14 | 1996-10-15 | The United States Of America As Represented By The Department Of Health & Human Services | Combination therapy using signal transduction inhibitors with paclitaxel and other taxane analogs |
| US5665751A (en) * | 1995-06-07 | 1997-09-09 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
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1996
- 1996-07-30 WO PCT/US1996/012474 patent/WO1997005873A2/en not_active Application Discontinuation
- 1996-07-30 SK SK141-98A patent/SK14198A3/en unknown
- 1996-07-30 CZ CZ98337A patent/CZ33798A3/en unknown
- 1996-07-30 NZ NZ503921A patent/NZ503921A/en unknown
- 1996-07-30 CA CA002229024A patent/CA2229024A1/en not_active Abandoned
- 1996-07-30 TR TR1998/00270T patent/TR199800270T1/en unknown
- 1996-07-30 BR BR9609966A patent/BR9609966A/en not_active Application Discontinuation
- 1996-07-30 TR TR1998/01739T patent/TR199801739T2/en unknown
- 1996-07-30 EP EP96926806A patent/EP0841921A2/en not_active Withdrawn
- 1996-07-30 CN CN96196682A patent/CN1195288A/en active Pending
- 1996-07-30 IL IL12309596A patent/IL123095A0/en unknown
- 1996-07-30 KR KR1019980700806A patent/KR19990036138A/en not_active IP Right Cessation
- 1996-07-30 NZ NZ315184A patent/NZ315184A/en unknown
- 1996-07-30 PL PL96324904A patent/PL324904A1/en unknown
- 1996-07-30 AU AU66833/96A patent/AU711966B2/en not_active Ceased
- 1996-07-30 JP JP9508494A patent/JPH11510187A/en active Pending
- 1996-07-30 MX MX9800998A patent/MX9800998A/en not_active Application Discontinuation
- 1996-07-30 HU HU9903420A patent/HUP9903420A3/en unknown
- 1996-08-02 AR ARP960103860A patent/AR003175A1/en not_active Application Discontinuation
-
1998
- 1998-02-03 NO NO980473A patent/NO980473L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9903420A2 (en) | 2000-03-28 |
| IL123095A0 (en) | 1998-09-24 |
| TR199800270T1 (en) | 1998-05-21 |
| JPH11510187A (en) | 1999-09-07 |
| SK14198A3 (en) | 1999-03-12 |
| NO980473L (en) | 1998-04-03 |
| BR9609966A (en) | 1999-02-02 |
| CN1195288A (en) | 1998-10-07 |
| PL324904A1 (en) | 1998-06-22 |
| MX9800998A (en) | 1998-04-30 |
| EP0841921A2 (en) | 1998-05-20 |
| AR003175A1 (en) | 1998-07-08 |
| CZ33798A3 (en) | 1998-06-17 |
| NO980473D0 (en) | 1998-02-03 |
| TR199801739T2 (en) | 1998-12-21 |
| NZ315184A (en) | 2000-05-26 |
| HUP9903420A3 (en) | 2001-12-28 |
| WO1997005873A3 (en) | 1997-03-27 |
| AU711966B2 (en) | 1999-10-28 |
| AU6683396A (en) | 1997-03-05 |
| KR19990036138A (en) | 1999-05-25 |
| NZ503921A (en) | 2002-03-01 |
| WO1997005873A2 (en) | 1997-02-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |