WO2006052229A1 - Aminated polyamines - Google Patents
Aminated polyamines Download PDFInfo
- Publication number
- WO2006052229A1 WO2006052229A1 PCT/US2004/036485 US2004036485W WO2006052229A1 WO 2006052229 A1 WO2006052229 A1 WO 2006052229A1 US 2004036485 W US2004036485 W US 2004036485W WO 2006052229 A1 WO2006052229 A1 WO 2006052229A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polyamine
- alk
- cell
- nitrogen atoms
- human
- Prior art date
Links
- 0 COc1ccc(C2=NC(*)C*2)c(*)c1 Chemical compound COc1ccc(C2=NC(*)C*2)c(*)c1 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/13—Amines containing three or more amino groups bound to the carbon skeleton
Definitions
- the invention relates to novel animated polyamines having valuable therapeutic and other biological properties.
- polyamines particularly spermidine
- spermidine are required for cell proliferation: (i) they are found in greater amounts in growing than in non- growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth.
- polyamines by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules such as nucleic acids by anion neutralization. See Dkystra et al, Science, Vol.
- Anti-neoplastic analogues of the naturally occurring polyamines, pharmaceutical compositions and methods of treatment are also disclosed in the following pending patent application Ser. No. 08/231,692 filed Apr. 25, 1994, as well as in U.S. Pat. Nos. 5,091,576 issued Feb. 25, 1992; 5,128,353 issued JuI. 7, 1992; 5,173,505 issued Dec. 22, 1992 and 5,962,533, issued October 5, 1999.
- the disclosures of each of the foregoing applications and patents are incorporated herein by reference.
- Diethylhomospermine is an example of a polyamine recently found to have potent activity as an anti-neoplastic and anti-diarrheal agent. Its metabolic profile indicates the highest concentration of the polyamine and its principal metabolites, N.sup.l - ethylhomospermine (MEHSPM) and homospermine (HSPM), in the liver and kidney. N- deethylation is a key metabolic step in processing DEHSPM (see FIG. 2); however, HSPM does not undergo further metabolism. The accumulation and persistence of HSPM in the tissues of DEHSPM-treated animals is especially striking. Even three weeks after a seven day schedule of DEHSPM, 35% of the drug administered to mice remains in the liver and kidney as drug or metabolites.
- MEHSPM N.sup.l - ethylhomospermine
- HSPM homospermine
- the key to a less toxic DEHSPM-like therapeutic agent is one in which the metabolites can be quickly cleared from the tissues.
- this metabolite cannot be processed through the polyamine biosynthetic network; thus, it remains in the tissues for protracted periods of time.
- Neither the primary nor the secondary nitrogens of HSPM offer an opportunity for facile conversion to an easily cleared metabolite.
- the methylene backbones cannot be easily oxidized to an excretable metabolite.
- R 1 and R 4 may be the same or different and are alkyl, aryl, aryl alkyl or cycloalkyl, optionally having an alkyl chain interrupted by at least one etheric oxygen atom;
- R 2 and R 3 may be the same or different and are R 1 , R 4 or H;
- N 1 , N 2 , N 3 and N 4 are nitrogen atoms capable of protonation at physiological pH's;
- ALK 1 , ALK 2 AND ALK 3 may be the same or different and are straight or branched chain alkylene bridging groups having 1 to 4 carbon atoms which effectively maintain the distance between the nitrogen atoms such that the polyamine:
- (i) is capable of uptake by a target cell upon administration of the polyamine to a human or non-human animal or is capable of binding to at least one polyamine site of a receptor located within or on the surface of a cell upon administration of the polyamine to a human or non-human animal;
- the polyamine upon binding to the biological counter-anion in the cell, functions in a manner biologically different than the intracellular polyamines; and further wherein at least one of said bridging groups ALK 1 , ALK 2 and ALK 3 contains at least one -CH(NRH)- group which is not alpha- to either of the nitrogen atoms and R is H, alkyl, acyl or sulfonyl.
- polyamines with asymmetric centers may occur as racemates, racemic mixtures and as individual enantiomers or diastereoisomers, with all isomeric forms of the compounds being included in the present invention.
- An additional embodiment of the invention relates to compositions comprising therapeutically effective amounts of polyamines of the above formula and suitable carriers therefor.
- a further embodiment of the invention concerns methods of exerting therapeutic actions on human or non-human animals requiring such action comprising administering thereto therapeutically effective amounts of polyamines of the above formula.
- Another embodiment of the invention concerns the use of the aminated polyamines of the invention to serve as vectors for the introduction of pharmacores into eukaryotes and prokaryotes.
- FIG. 1 depicts a reaction scheme for preparing the aminated polyamines of the invention.
- 6 amino-N ,N -diethylspermine (6-NH 2 DESPM).
- the protected diamine fragment 1 and 4-bromo-l,2-epoxybutane 2 underwent reaction to give the aminated epoxy butane 3; the ring-opening product 4 was subsequently generated in 80% yield at 70 .C.
- the secondary hydroxyl group was tosylated (5) and then converted into phthalimide 6, followed by releasing the amino group at C-6 with sodium, borohydride to result in the primary amine 7.
- the deprotection of the four secondary amines furnished the desired 6-NH 2 DESPM.
- This new method is very useful for the synthesis of hydroxylated or aminated polyamines.
- the multifunctional 4-bromo-l,2-epoxybutane, both enantiomers of which are easy to obtain, can undergo stepwise reactions at both the brominated carbon and the terminal carbon of the epoxide; thus, it is possible to use this method for the synthesis of unsymmetric polyamines at the two sides of the butane backbone.
- the successful transformation of the hydroxyl group to the amino group through the Gabriel synthesis makes it possible that many of the hydroxylated polyamines disclosed in US patent no. 5,962,533 can be converted into the corresponding aminated analogues by this method.
- Polyamines of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or non-racemic mixtures thereof.
- the optical isomers can be obtained by resolution of the racemic mixtures according to processes known to those skilled in the art, for example, by formation of diastereoisomeric salts by treatment with an optically active acid or base.
- appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and the like, followed by separation of the mixture of diastereoisomers by crystallization, then release of the optically active bases from these salts.
- optically active compounds of the present invention can also be obtained by utilizing optically active starting materials.
- IC50 was estimated from growth curves for L1210 cells grown in the presence of nine different extracellular concentrations of drug spanning four logarithmic units: 0, 0.03, 0.1, 0.3, 1.0, 3, 10, 30, and 100 DM. IC 50 data are presented as the mean of at least two experiments with variation from the mean typically 10-25% for the 96-h IC 50 values.
- K ⁇ determinations were made by following analogue inhibition of spermidine transport. All polyamine analogues exhibited simple substrate-competitive inhibition of [ 3 H]SPD transport by L1210 cells. Values reported in the table represent the mean of at least two or three experiments with a variation typically less than 10%.
- Enzyme activity is expressed as percent of untreated control for ODC (1 DM at 4 h), AdoMetDC (1 DM at 6 h), and SSAT (10 DM at 48 h).
- Each experiment included a positive control which had a known, reproducible impact on enzyme activities (mean ⁇ SD): 1 DM DEHSPM lowered ODC to 6.7 ⁇ 2.6% of the untreated control; 1 DM DEHSPM decreased AdoMetDC to 40.7 ⁇ 6.2% of the untreated control; and 2 DM DENSPM increased SSAT to 3877 ⁇ 76% of the untreated control.
- Data shown in the table represent the mean of at least three experiments and have variances consistent with those suggested by the positive control data presented above. ⁇ Reproduced from reference 1. Reproduced from reference 2. References:
- the polyamine derivatives were studied for their ability to compete with [ ⁇ H]SPD or
- tubes were centrifuged at 90Og for 5 min at 0-4 °C.
- the pellet was washed twice with 5 mL of cold RPMI-1640 containing 1 DM SPD, dissolved in 200 DL of 1 N NaOH at 60 0 C for 1 h, and neutralized with 1 N HCl.
- the material was transferred to a vial for scintillation counting. Lineweaver-Burke plots indicated a simple competitive inhibition with respect to SPD.
- Another valuable embodiment of the invention comprises the value of the aminated polyamines as potential vectors for the intracellular delivery of a pharmacore wherein the vector comprises a conjugate of a polyamine covalently attached, optionally indirectly attached via a linking group, to a pharmacore, the conjugate having a polyamine moiety, wherein the polyamine moiety comprises an aminated polyamine of the invention.
- the point of attachment of the pharmacore to the polyamine is at one of the -CH(RNH)- groups of either ALKl, ALK2, or ALK3.
- Suitable pharmacores for conjugation with the aminated polyamines of the invention include antibiotics, antivirals or chelating agents such as the following:
- the animated polyamines may be conjugated with the pharmacores according to the methods described in Bergeron et al, J. Med. Chem. 2003, 46, 5478-5483 and US provisional patent application serial no. 60/501,341, filed September 9, 2003.
- the articles of manufacture, method and composition of the present invention are predicated on administering to a subject (human or animal) an effective amount of one or more of the compounds described herein as being effective for the desired purpose. Administration may be accomplished either therapeutically or prophylactically by means of pharmaceutical compositions which are prepared by techniques well known in the pharmaceutical sciences.
- the polyamines of the present invention may be used either solely or jointly in pharmaceutically effective amounts for treating animals or humans.
- the polyamines of the invention can be used either solely or jointly together in pharmaceutically acceptable amounts with pharmaceutically effective amounts of other pharmaceutically active components in pharmaceutical compositions or preparations.
- the compounds of the invention are preferably administered orally, they may also be administered by a variety of other routes such as transdermally, subcutaneously, intranasally, intrarectally, intramuscularly and intravenously.
- the present invention is also directed to pharmaceutical compositions which include at least one compound as described above in association with one or more pharmaceutically acceptable diluents, excipients or carriers therefor.
- one or more compounds will usually be mixed with, diluted by or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
- the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 60% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
- pharmaceutically acceptable carriers such as an aqueous or nonaqueous solvent. Examples of solvents which may be used are distilled water for injection, physiological saline solution, Ringer's solution, plant oil, synthetic fatty acid glycerides, higher fatty acid esters, propylene glycol, etc.
- Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate and mineral oil.
- the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
- the compositions of the invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
- the dose of the compound is that amount effective for the desired purpose.
- effective amount By “effective amount,” “therapeutic amount” or “effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective treatment.
- the effective dose may vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the condition under treatment and the manner in which the pharmaceutical composition is administered.
- the compositions are formulated, preferably in a unit dosage form, such that each dosage contains from about 0.006 to about 12,000 mg., more usually about 0.06 to about 6,000 mg., of the active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with one or more of the above-described suitable pharmaceutical diluents, excipients or carriers.
- the term "effective amount" refers to a dosage range of from about 0.006 to about 500 mg/kg of body weight per day. In the treatment of adult humans, the range of about 0.06 to about 250 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of compound actually administered will be determined by a physician in light of the relevant circumstances, including (1) the condition to be treated, (2) the choice of compound to be administered, (3) the chosen route of administration, (4) the age, weight and response of the individual patient, and (5) the severity of the patient's symptoms. Therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
- active ingredient is meant a polyamine as described herein or a salt thereof with a pharmaceutically acceptable acid.
- salt is meant an addition salt between the polyamine of the invention and a sufficient amount of pharmacologically appropriate acid, such as hydrochloric, sulfuric, phosphoric, acetic, butyric, citric, maleic, lactic, valeric, tartaric, gluconic, succinic and the like, made by conventional chemical means.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004324870A AU2004324870A1 (en) | 2004-11-03 | 2004-11-03 | Aminated polyamines |
PCT/US2004/036485 WO2006052229A1 (en) | 2004-11-03 | 2004-11-03 | Aminated polyamines |
EP04800606A EP1812377A4 (en) | 2004-11-03 | 2004-11-03 | Aminated polyamines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2004/036485 WO2006052229A1 (en) | 2004-11-03 | 2004-11-03 | Aminated polyamines |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006052229A1 true WO2006052229A1 (en) | 2006-05-18 |
Family
ID=36336796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/036485 WO2006052229A1 (en) | 2004-11-03 | 2004-11-03 | Aminated polyamines |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1812377A4 (en) |
AU (1) | AU2004324870A1 (en) |
WO (1) | WO2006052229A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013081614A1 (en) * | 2011-11-29 | 2013-06-06 | University Of Florida Research Foundation, Inc. | Hydroxypolyamine salts |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5886050A (en) * | 1986-12-02 | 1999-03-23 | University Of Florida Research Foundation, Inc. | Sterically hindered tetraamines and method for their production |
US5962533A (en) * | 1996-02-06 | 1999-10-05 | University Of Florida Research Foundation, Inc. | Hydroxy polyamines |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991000853A1 (en) * | 1989-07-03 | 1991-01-24 | New York University | Use of polyamines as ionic-channel regulating agents |
-
2004
- 2004-11-03 AU AU2004324870A patent/AU2004324870A1/en not_active Abandoned
- 2004-11-03 WO PCT/US2004/036485 patent/WO2006052229A1/en active Application Filing
- 2004-11-03 EP EP04800606A patent/EP1812377A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5886050A (en) * | 1986-12-02 | 1999-03-23 | University Of Florida Research Foundation, Inc. | Sterically hindered tetraamines and method for their production |
US5962533A (en) * | 1996-02-06 | 1999-10-05 | University Of Florida Research Foundation, Inc. | Hydroxy polyamines |
Non-Patent Citations (1)
Title |
---|
See also references of EP1812377A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013081614A1 (en) * | 2011-11-29 | 2013-06-06 | University Of Florida Research Foundation, Inc. | Hydroxypolyamine salts |
Also Published As
Publication number | Publication date |
---|---|
EP1812377A1 (en) | 2007-08-01 |
AU2004324870A1 (en) | 2006-05-18 |
EP1812377A4 (en) | 2008-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5962533A (en) | Hydroxy polyamines | |
US6472426B2 (en) | Sterically hindered tetraamines and method for their production | |
US5886050A (en) | Sterically hindered tetraamines and method for their production | |
EP0349224B1 (en) | Anti-neoplastic, anti-viral or anti-retroviral spermine derivatives | |
Bergeron et al. | Antiproliferative properties of polyamine analogs: a structure-activity study | |
EP1940773B1 (en) | Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors | |
US20130197088A1 (en) | Compositions and Methods for Combinations of Oligoamines with 2-Difluoromethylornithine (DFMO) | |
US6342534B1 (en) | Analogs of biologically active, naturally occurring polyamines, pharmaceutical compositions and methods of treatment | |
CA1305425C (en) | Anti-neoplastic spermine derivative | |
US7425579B2 (en) | Methods for inhibiting activity of polyamine transporters | |
CA2154663C (en) | Polyamine derivatives as radioprotective agents | |
US20130137772A1 (en) | Hydroxypolyamine salts | |
AU617502B2 (en) | N-2,3-butadienyl tri- and tetraaminoalkane derivatives | |
US6235794B1 (en) | Biologically active spermidine analogues, pharmaceutical compositions and methods of treatment | |
US7423182B2 (en) | Aminated polyamines | |
US20090143456A1 (en) | Polyamine Analogs as Modulators of Cell Migration and Cell Motility | |
EP1812377A1 (en) | Aminated polyamines | |
US20130137706A1 (en) | Antimicrobial Molecules For Treating Multi-Drug Resistant and Extensively Drug Resistant Strains Of Mycobacterium | |
US5677351A (en) | Sterically hindered tetraamines and method for their production | |
US6583280B1 (en) | Polyamine analogues having antiproliferative activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2007540291 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004324870 Country of ref document: AU |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004800606 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004324870 Country of ref document: AU Date of ref document: 20041103 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004800606 Country of ref document: EP |