EP0662829A1 - Derives de polyamine utiles comme agents anti-cytomegaloviraux - Google Patents

Derives de polyamine utiles comme agents anti-cytomegaloviraux

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Publication number
EP0662829A1
EP0662829A1 EP93921461A EP93921461A EP0662829A1 EP 0662829 A1 EP0662829 A1 EP 0662829A1 EP 93921461 A EP93921461 A EP 93921461A EP 93921461 A EP93921461 A EP 93921461A EP 0662829 A1 EP0662829 A1 EP 0662829A1
Authority
EP
European Patent Office
Prior art keywords
bis
compound
compounds
mixture
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP93921461A
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German (de)
English (en)
Inventor
A. Stanley Flat 8 59 Bassett Road Tyms
Ronald D. Snyder
Terry L. Bowlin
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Aventis Pharmaceuticals Inc
Original Assignee
Merrell Dow Pharmaceuticals Inc
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Publication of EP0662829A1 publication Critical patent/EP0662829A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
    • 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
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains

Definitions

  • CMV Human cytomegalovirus
  • CMV chronic myeloma
  • CMV chronic myeloma
  • Infected individuals may transmit the virus in urine, saliva, cervical secretions, semen, feces, milk, or infected blood and organs.
  • Molecular analysis of the DNA of CMV isolates reveals minor strain-specific differences that are useful markers in epidemiological investigation.
  • CMV is highly host- specific and cannot be propagated in laboratory animals or in most non-human cell cultures. Therefore, experiments designed to be predictive of CMV activity generally are restricted to human cell lines that have resident the CMV virus or have become infected with CMV.
  • aliphatic polyamines such as spermine and spermidine
  • spermine and spermidine play a role in cell growth and proliferation.
  • These naturally occurring polyamines are found in animal cells and are produced in a biosynthetic pathway involving putrescine as a precursor.
  • Putrescine is formed by a decarboxylation of ornithine by ornithine decarboxylase (ODC) and this is a highly regulated stage in the biosynthesis of spermidine and spermine.
  • ODC ornithine decarboxylase
  • the human cytomegaloviruses are a subgroup of agents within the herpes group of viruses, all of which have the propensity for remaining latent in man. No specific therapy is generally available for CMV infections.
  • CMV agents afford less cell and/or tissue toxicity compared to other agents in use.
  • CMV compared to other herpes viruses, herpes simplex type 1 and type 11 and varicella-zoster virus, is relatively resistant to the action of acyclovir. Research in this area is primarily focused toward identifying agents which would be therapeutically effective in humans.
  • a further feature of the present invention is that the compounds described herein provide a CMV agent that selectively acts against CMV compared to other Herpes viruses.
  • polyamine derivatives are effective therapeutic agents when used against cell cultures infected with CMV.
  • An object of the present invention is the use of the describe polyamine derivatives as therapeutic agents against CMV.
  • Synthesis of compounds of the present invention as anticancer agents has been described in part in U.S. Patent Application 07/602,530 which is herein incorporated by reference.
  • Synthesis of compounds of the present invention as antiprotozoal agents has been described in part in U.S. Patent Application 07/840,575 which is herein incorporated by reference.
  • Synthesis of compounds of the present invention as potentiating cell-mediated immunity has been described in part in U.S. Patent Application 07/856,818 which is herein incorporated by reference.
  • This invention relates to methods of use of certain polyamine derivatives in the treatment of patients suffering from CMV disease states and to pharmaceutical compositions containing these polyamine derivatives.
  • this invention relates to a method for the treatment of patients suffering from CMV infections which comprises administering a therapeutically effective amount of a compound of the formula (I): wherein Z is a
  • each R group independently is hydrogen, a Ci-C ⁇ saturated or unsaturated hydrocarbyl, or -(CH 2 ) x -(Ar)-X wherein Ar is phenyl or napthyl, X is H, Ci-C ⁇ alkoxy, halogen C 1 -C 4 alkyl, wherein x is an integer 0, 1, or 2; with the proviso that both R groups cannot be hydrogen; or said compounds of formula I can be a pharmaceutically acceptable acid addition salt thereof.
  • compounds of formulae (I) provide an anti- CMV effect in patients in need thereof.
  • Compounds of formuale I generally produce effective treatment without similar delayed toxicity effects produced by other agents.
  • the present invention relates to the use of novel compounds of the formula (I) for CMV infections, or more specifically to the novel compounds of formula (la) and (lb).
  • novel compounds of formula (la) are of the formula: HN-Zi-NH-(CH 2 ) m -NH-Z ⁇ -NH
  • Zi is a branched chain (C 2 -C 6 ) alkyl moiety; m is 7 or 8; and each R group independently is hydrogen, a Ci-C ⁇ saturated or unsaturated hydrocarbyl, or -(CH 2 ) x -(Ar)-X wherein Ar is phenyl or napthyl, X is H, Ci-C ⁇ alkoxy, halogen C 1 -C alkyl, wherein x is an integer 0, 1, or 2; with the proviso that both R groups cannot be hydrogen; or said compounds of formula la can be a pharmaceutically acceptable acid addition salt thereof.
  • novel compounds of formula (lb) are of the formula:
  • Z 2 is a straight chain (C 2 -C 6 ) alkyl moiety; m is 7 or 8; each R group independently is hydrogen, a Ci-C ⁇ saturated or unsaturated hydrocarbyl, or -(CH 2 ) x -(Ar)-X wherein Ar is phenyl or napthyl, X is H, Ci-C ⁇ alkoxy, halogen C 1 -C 4 alkyl, wherein x is an integer 0, 1, or 2; with the proviso that both R groups cannot be hydrogen; or said compounds of formula lb can be a pharmaceutically acceptable acid addition salt thereof.
  • the center alkylene moiety of compounds of the formula (I) is a saturated, straight-chain hydrocarbyl radical comprising 7 or 8 carbon atoms, i.e., "(CH2)7" or “(CH 2 ) 8 " «
  • Z is understood to mean a saturated hydrocarbylene radical of straight (Z 2 ) or branched-chain configuration (Zi) comprising 2 to 6 carbon atoms including, but not limited to, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 2 ) 2 CH 2 -, -CH 2 (CH 2 )3CH2-, -CH 2 (CH 2 ) CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH3)CH 2 - and the like.
  • R is an unsaturated hydrocarbyl moiety
  • compositions of the formula (I) can be used according to the present invention as pharmaceutically acceptable acid addition salts thereof.
  • pharmaceutically acceptable acid addition salt encompasses both organic and inorganic acid addition salts including, for example, those prepared from acids such as hydrochloric, hydrofluoric, sulfuric, sulfonic, tartaric, fumaric, hydrobromic, glycolic, citric, maleic, phosphoric, succinic, acetic, nitric, benzoic, ascorbic, p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, propionic, and the like.
  • the hydrochloric acid addition salts are preferred.
  • the selection and preparation of pharmaceutically acceptable non-toxic acid addition salts are within the ability of one of ordinary skill in the art utilizing procedures and techniques well known and appreciated in the art.
  • the compounds of formula (I) may be prepared by chemical reactions analogously known in the art.
  • the choice of any specific route of preparation is dependent upon a variety of factors. For example, general availability and cost of the reactants, applicability of certain generalized reactions to specific compounds, and so forth, are all factors which are fully understood by those of ordinary skill in the art and all contribute to the choice of synthesis in the preparation of any specific compound embraced by formula (I).
  • R is as defined in formula (I) except when R is X-(Ar)-(CH) x , x cannot be zero.
  • a Boc is the t-butoxycarbonyl protecting group, and Y is tert-butyl.
  • the initial step of this process entails an N- alkylation of the appropriate diamine with 2 equivalents of acrylonitrile by heating reactants, either in a suitable solvent or neat, according to standard conditions well known in the art.
  • the resulting cyano derivatives (2) are chemically reduced by reaction with hydrogen in the presence of a catalyst (Pt ⁇ 2 ) in a suitable solvent, such as acetic acid containing 8 equivalents of hydrochloric or hydrobromic acid, to produce the resulting hydrohalic salts according to standard procedures well known in the art.
  • a catalyst Pt ⁇ 2
  • a suitable solvent such as acetic acid containing 8 equivalents of hydrochloric or hydrobromic acid
  • hydrohalic salts are neutralized with base and the nitrogen atoms are protected, preferably with di-t-butyldicarbonate according to standard operating conditions well known in the art.
  • the tetra N-protected amines (4) are alkyiated by reacting (4) with the appropriate alkyl halides (chloro or bromo) in the presence of potassium butoxide according to standard alkylation procedures well known in the art.
  • alkyl halides chloro or bromo
  • monosubstitution of compounds of formula (4) is effected by reacting about 1 to about 1.5 equivalents of the alkyl halide with subsequent isolation of the monosubstituted compound according to standard procedures well known in the art and optionally further reacting the monosubstituted compound with the desired different alkyl halide.
  • the N-protective groups of compound (5) are removed by standard procedures, e.g., treatment with acid, preferably HCl, in the presence of a suitable solvent or solvent system, e.g., diethyloxide in ethanol, to obtain the desired products (6).
  • compounds of formula (3) and their otherwise prepared homologs may be subjected to a reductive alkylation using an appropriate aldehyde.
  • the reduction is effected by hydrogenation in the presence of Pt ⁇ 2 or sodium cyanoborohydride according to well known procedures. This procedure does not generally require protection of the nitrogen atoms of the intermediates.
  • n is an integer 2 to 6 describing a straight chain alkylene moiety
  • Boc is the t-butoxycarbonyl protecting group
  • R is as defined in formula (I)
  • Ms is mesyl and Ri is hydrogen, methyl or ethyl.
  • This synthesis is initiated by reductive alkylation techniques well known in the art using an amino alcohol (7) and an appropriate aldehyde to form R- substituted amino alcohols (8).
  • the nitrogen atom is protected, preferably with di-t-butyldicarbonate, according to standard operating conditions well known in the art, to yield the N-protected amino alcohols (9) which are converted to their mesylates (10) by known reaction conditions, e.g., reaction with mesylchloride in the presence of pyridine, preferably in a solvent such as CH 2 CI 2 .
  • the mesylate is subjected to alkylation with an N- protected diamine (i.e., BocNH(CH 2 ) m NHBoc) in the presence of potassium t-butoxide in a solvent such as DMF.
  • N- protected diamine i.e., BocNH(CH 2 ) m NHBoc
  • the so- produced tetra N-protected tetramines (11) are deprotected as in Scheme A.
  • the foregoing reductive alkylation, N-protection, mesylation, alkylation and deprotection procedures all employ techniques and reaction conditions which are well known in the art.
  • N-alkylation entails the reaction of an appropriate dihaloalkane (13) with excess quantities (lOx) of ethylene diamine (12) by heating the reactants at reflux temperatures in a suitable solvent, e.g., ethanol.
  • a suitable solvent e.g., ethanol.
  • Preparation of the final products bearing the desired R substituents on the terminal nitrogen atoms of the intermediates (14) may be effected by N-protection, alkylation with the appropriate alkyl halide, and deprotection in an analogous manner to that described for Reaction Scheme A.
  • the alkylation can be carried out by the reductive alkylation procedures without N-protection as alternatively described for Reaction Scheme A.
  • compounds of the formula (la) can be prepared in an analogous manner to that described in
  • the appropriate primary amino alcohol (15) containing a branched chain hydrocarbyl moiety is prepared by standard procedures well known in the art. If desired, the primary amine can at this point be converted to a secondary amine (16), by a reductive alkylation with the appropriate aldehyde.
  • the amino alcohol is reacted as described in Reaction Scheme A by standard conditions well known in the art to effect protection of the amines with an appropriate N-protecting group such as Boc (17).
  • the mesylates of the N-protected amino alcohols (18) are prepared and are alkyiated with the appropriate N-protected diamine (i.e., BocNH(CH 2 ) m NHBoc) using standard procedures well known in the art as discussed for Reaction Scheme B.
  • the so- produced tetra N-protected tetramines (19) are deprotected as in Scheme A to yield compounds of the formula (la).
  • the foregoing reductive alkylation, N-protection, mesylation, alkylation and deprotective procedures all employ techniques and reaction conditions which are well known in the art.
  • the substituted mesylates (18) are prepared separately and monoalkylation of the appropriate N-protected diamine (i.e., BocNH(CH 2 ) m NHBoc) is effected by reacting the diamine with about 1.0 to 1.5 equivalents of one of the mesylates (18) with subsequent isolation of the monosubstituted compound and optionally further reacting the monosubstituted compound with the desired differently substituted mesylate (18).
  • the appropriate N-protected diamine i.e., BocNH(CH 2 ) m NHBoc
  • Reaction Scheme E can be used to obtain intermediates of the formula (25) which can be subjected to alkylation of the N-terminal groups in a manner analogous to that described in Reaction Scheme A prior to de-protection,
  • the initial step of the process entails a reductive alkylation wherein the appropriate diamine is reacted with hydrogen gas and 2 equivalents of benzaldehyde in the presence of a catalyst such as Pt ⁇ 2 to yield the N-protected diamine (21) under standard conditions well known in the art.
  • the N-protected diamine (21) is then alkyiated with 2 equivalents of the appropriate vinyl ketone (22) in a suitable solvent such as methanol using standard techniques.
  • the resulting N-substituted diamine (23) is further reacted under standard conditions with hydroxylamine hydrochloride in the presence of base such as NaOH in a suitable solvent such as ethanol/water.
  • the resulting oximes (24) are reduced to the corresponding N- protected di-primary amines (25) by reaction with lithium aluminum hydride (LAH) in the presence of AICI 3 in a suitable solvent such as THF according to standard procedures.
  • LAH lithium aluminum hydride
  • AICI 3 a suitable solvent such as THF according to standard procedures.
  • the N-protected di-primary amines (25) can be further alkyiated with an appropriate aldehyde prior to deprotection in a manner analogous to that described for Reaction Scheme A.
  • a preferred method for preparing compounds of formula [I] wherein -(CH)x-(Ar)-X represents phenethyl or naphthylethyl, particularly wherein Z is 3 and m is 8, is the reaction of an aroylchloride according to the method depicted in Reaction Scheme F wherein depicted in Scheme F Bn is benzyl, ⁇ is phenyl, and LAH is lithium aluminum hydride.
  • the foregoing reaction is a preferred method for the preparation of one particular compound which entails N-alkylation of a partially protected intermediate [27] with an arylacetyl chloride [28] in the presence of triethylamine, using an inert solvent, to form an amide [29] which is chemically reduced, preferably with LAH, and the resulting product [30] is catalytically de-benzylated (H 2 Pd/C) to form the desired end product [31].
  • These steps entail reaction techniques and procedures well known in the art.
  • the same reaction scheme can be applied for the preparation of other compounds of formula [I]; adoption of the technique being with the usual caveats well understood by those of ordinary skill in the art.
  • reaction scheme depicts the preparation of compounds wherein Ar is phenyl, the first step of which is a LAH reduction effected according to procedures published is the art (Bui. Soc. Chim. Fr., Part 2, 165-7 (1979)).
  • this reaction scheme can be expanded to include napthyl and X-substituted intermediates which will not be adversely affected by the reaction conditions.
  • the N-protection uses the t-butoxycarbonyl protecting groups which are put on and taken off according to standard techniques already mentioned hereinabove.
  • the N-protected compounds are alkyiated by reaction with an appropriate dihaloalkane using standard and well known procedures.
  • a dibenzylated diamine [36] is N-alkylated by a simple displacement reaction to form compounds [37] which are sequentially benzylated [38] and N-protected. These steps are effected according to well known and standard procedures.
  • the resulting bishydroxyamino-alkanes [39] are mesylated and the mesylates [40] are alkyiated with two equivalents of an N- protected amine bearing an appropriate unsaturated hydrocarbyl moiety, e.g., N-(t-butoxycarbonyl)-2,3- butadienylamine.
  • a so-obtained tetra protected tetramine [41] is then readily de-protected to produce the desired compounds [42] .
  • the alkyl thioether is treated with a peracid according to known conditions.
  • Suitable oxidizing agents are H 2 O 2 and NaI ⁇ 4 , but meta-chloroperoxybenzoic acid is preferred.
  • 1 molar equivalent per alkylthioether moiety
  • 2 molar equivalents of the peracid will yield the sulfonyl derivatives.
  • the oxidations are effected at temperatures of about OoC to room temperature in solvents which themselves are not susceptible to oxidation.
  • Preferred solvents are CH 2 CI 2 , CHCI3, acetic acid, and ethyl acetate.
  • reaction scheme I depicts a method of preparation of the compounds of formula I.
  • Ts is a tolunesulfonyl substituent
  • DEAD is diethyl azodicarboxylate
  • THF is tetrahydrofuran
  • TFA is trifluoroacetic acid
  • Boc is the t-butoxycarbonyl protecting group.
  • reaction scheme can be expanded to include the variations of Ts protecting group by various other arylsulfonyl groups beside toluenesulfonyl, such as mesitylenesulfonyl, benzylsulfonyl and the like.
  • Step (b) involves the reaction of two equivalents of Compound [44] with a suitably protected diaminoalkane, e.g., as shown a di-tolsyl protected alkylydiamine (TsNH(CH 2 )mNHTs) can be used to form intermediate [45].
  • a suitably protected diaminoalkane e.g., as shown a di-tolsyl protected alkylydiamine (TsNH(CH 2 )mNHTs) can be used to form intermediate [45].
  • step (g)) for forming intermediate [45] can be accomplished by reaction [43] with the approximately 1 equivalent of the alkyldiol shown in the presence of TPP and DEAD in a suitable solvent, such as THF to form intermediate [49].
  • Intermediate [49] can then be reacted with a protected diaminoalkane, e.g., as shown, the ditosyl protected alkyldiamine (TsNH(CH 2 )mNHTs) , to form intermediate [45].
  • This route of synthesis, step (g) is suitable in those instance when Z is not 4.
  • compounds of formula [45] can be reacted with a R-alkyl alcohol in the presence of TPP and DEAD in an appropriate solvent (step e).
  • intermediate [46] can be reacted with a R- alkyl halide in the presence of hydride ion and sodium iodide to give the compound of formula [47].
  • Compounds of formula [47] can then be deprotected upon treatment with acid, to form the compounds of formula [48], wherein R is other than hydrogen.
  • reaction scheme J depicts the preparation of N, '-Bis[3-(ethylamino)propyl]1,7-heptanediamine tetrahydrochloride.
  • certain parts of the reaction scheme can be expanded to include the variations of m and R of formula I, however, Z is generally limited to being propyl, wherein Z is 3.
  • the R group introduced in scheme J is shown as ethyl, but the reaction scheme is not limited only to ethyl derivatives but may include those R groups of formula I to form corresponding R substituted derivatives.
  • the initial step (a) of scheme J is a protection of the nitrogens of formula [50] by reaction with aqueous HCHO using standard and well known procedures to give the corresponding diaza ring systems in compound [51].
  • step (b) the N-protected amines [51] are alkyiated by reacting with the appropriate acid anhydride according to standard alkylation procedures known to those skilled in the art.
  • the appropriate acid anhydride according to standard alkylation procedures known to those skilled in the art.
  • monosubstitution of compounds of formula [52] is effected by reacting about 1 to about 1.5 equivalents of the acid anhydride with subsequent isolation of the monosubstituted compound according to standard procedures well known in the art and optionally further reacting the monosubstituted compound with the desired different acid anhydride or alkyl or aryl halide.
  • step c The resulting acetylated derivatives of [52] are then chemically reduced (step c) by reaction with lithium aluminum hydride in anhydrous conditions according to standard procedures well known in the art.
  • reducing systems e.g., reduction with H 2 and Pt ⁇ 2
  • the N-protective groups of compound [53] are removed by standard procedures, e.g., treatment with acid, preferably HCl, in the presence of a suitable solvent or solvent system, to obtain the desired products of formula [54].
  • the term "patient” refers to a warm ⁇ blooded animal such as a mammal which is afflicted with a neoplastic disease state. It is understood that dogs, cats, rats, mice, horses, bovine cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
  • cytomegaloviral infection refers to an abnormal state or condition characterized by an active or latent CMV infection or state whenever the patient has virus residing active or dormant in the patients tissues, fluids, or body cavities.
  • Treatment of a patient afflicted with a CMV disease state comprises administering to such patient an amount of a compound of the formula (I) which is therapeutically effective in controlling the symptomatic and/or associated viral states of CMV beyond that expected in the absence of such treatment.
  • control CMV infection refers to slowing, interrupting, arresting or stopping a CMV infection and does not necessarily indicate a total elimination of the virus. It is believed that the prolonged survivability of a patient with the instant compounds indicates control of a CMV infection.
  • a compound of formula (I) in effecting treatment of a patient afflicted with a CMV infection or prophylatic treatment to prevent infection a compound of formula (I) can be administered parenterally in any manner which makes (I) bioavailable in effective amounts including for example, by intraperitoneal (i.p.), subcutaneous (s.c), or intravenous (i.v.) injection. Administration by intravenous injection is preferred.
  • a therapeutically effective dose or amount can readily be determined by the attending diagnostician and is a function of a number of factors including, but not limited to, the species of mammal, its size, age and general health, the specific CMV infection involved, the stage of the CMV infection, the compound selected and mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, and use of concomitant medication.
  • the correct amount for any specific situation can be readily determined by those skilled in the art using conventional range finding techniques and analogous results observed under other circumstances.
  • a therapeutically effective amount of (I) will vary from about 1 milligram per kilogram of body weight per day (mg/kg/day) to about 500 mg/kg/day and preferably will be about 5 mg/kg/day to about 50 mg/kg/day.
  • compounds of the formula (I) administered at the above doses to a patient suffering from a CMV infection are therapeutically effective in con-trolling the growth of one or more disease states a patient may have so as to prolong the survivability of the patient beyond that expected in the absence of such treatment.
  • compositions for parenteral administration for compounds of the formula (I) comprise a therapeutically effective amount of one or more compounds of the formula (I) in an admixture with one or more pharmaceutically acceptable excipients, Such compositions are prepared in conventional manner well known in the art of pharmaceutical science. The amounts of the active ingredient(s) in a unit dosage form and the dosage regimen are adjusted to provide a sustained pharmacologic effect at the dose regimen selected.
  • compositions are substances that are chemically inert to the active compound(s) and have no detrimental side effects or toxicity to mammals under the conditions of use.
  • Suitable excipients include solvents such as water, alcohol, and propylene glycol, surface active agents, suspending agents, lubricants, flavors, colorants, and the like.
  • Such carriers and excipients are known to those in the art and are disclosed, for example, in texts such as Remington's Pharmaceutical Manufacturing, 13th Edition, Mack Publishing Co., Easton, PA (1965).
  • Injectable dosage forms of a solution or suspension of (I) can be prepared, for example, in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • oils which can be employed in these preparations are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil and mineral oil.
  • water, saline, aqueous dextrose and related sugar solution ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • N,N'-bis[3- (ethylamino)propyl]-l,7-diaminooctane and N,N'-bis[3- (ethylamino)propyl]-l,7-diaminoheptane are most preferred.
  • the following examples are provided. The examples are illustrative only and are not intended to limit the invention in any way.
  • Step A N, '-Bis(2-(cyano)ethyl)-1,8-octanediamine Dissolve 14.4 g (0.1 mol) of 1,8-diaminooctane and 14.5 ml (0.22 mol) of acrylonitrile in 100 ml of ethanol and reflux overnight. Remove the solvent at reduced pressure. Analysis showed the title compound to be >98% pure.
  • Step B N,N'-Bis(3-(amino)propyl)1,8-octanediamine tetrahydrochloride
  • Step A Combine 14.4 g (0.057 mol) of the product of Step A, 200 ml of acetic acid, 30 ml of cone. HCl, and 1.2 g Pt ⁇ 2 and treat the mixture with H 2 at 45 lbs/in2 in a shaker flask until H 2 is no longer being reacted. Filter the mixture and remove the solvent at reduced pressure. 22.5 g of the title compound is obtained after purification. (R f is 0.17 for TLC on silica gel developed with 40% cone, ammonia/methanol) . Step C: 1,5,14,18-Tetra(t-butoxycarbonyl)-1,5,14,18- tetraazaoctadecane
  • Step D 1,18-Bis(methyl)-1,5,14,18-tetra(t-butoxy ⁇ carbonyl)-1,5,14,18-tetraazoctadecane
  • Step E N,N'-Bis(3-(methylamino)propyl)-1,8-octanediamine tetrahydrochloride
  • Step A 1,18-Bis(ethyl)-1,5,14,18-tetra(t-butoxy ⁇ carbonyl)-1,5,14-18-tetraazaoctadecane Combine 9.5 g (0.0144 mol) of the product of Step C in
  • Example 1 2.91 g (0.026 mol) of potassium t-butoxide, and 45 ml of DMF and cool to 0°C. Add 2.1 ml (0.026 mol) of iodoethane and stir at 0°C for 4 hours. Allow the mixture to warm slowly to room temperature and stir overnight. Remove the solvent at reduced pressure and partition the residue between 1400 ml ethyl acetate and 200 ml H 2 O. Wash the organic layer with 100 ml H 2 O (2x) and dry over anhydrous MgSO_j.
  • Step B ,N'-Bis(3-(ethylamino)propyl)-1,8-octanediamine tetrahydrochloride hemihydrate
  • Step A 1-Ethyl-l,5,14,18-tetra-(t-butoxycarbonyl)-
  • Step B N-(3-Aminopropyl)-N'-(3-(ethylamino)propyl)-1,8- octanediamine tetrahydrochloride Dissolve 2.5 g (0.0036 mol) of the product of Step A in 5 ml of ethanol and treat with 60 ml of 2 N HCl in diethyl ether stirring overnight. Filter the mixture and dry the residue to yield 1.35 g of the title compound, mp >300°C.
  • Step A N,N'-Bis[ (phenyl)methyl]-1,7-heptanediamine Combine 1,7-diaminoheptane (65.0 g, 0.5 mol), benzaldehyde (106 gm, 1 mol) and platinum oxide (Pt ⁇ 2 )[2.0 g] in ethanol (800 ml) and treat the mixture with hydrogen gas (45 lb/in2) until the uptake of gas ceases. Remove the catalyst by filtration and remove the solvent in vacuo. Purify the residue by bulb to bulb distillation to yield 99.4 g of the title compound (bp 191-195°C @ 1.0 mm/Hg).
  • Step B N,N'-Bis[ (3-oxo)butyl]-N,N'-bis[ (phenyl)methyl] - 1,7-diaminoheptane
  • Step C N,N'-Bis[ (3-hydroxyimino)butyl]-N,N'-bis[ (phenyl) methyl]-1,7-diaminoheptane Cool the reaction mixture obtained in step B to 0°C and to this mixture add a solution of hydroxylamine hydrochloride (4.38 g, 0.063 mol) and sodium bicarbonate (5.54 g, 0.066 mol) in water (40 ml). Stir the mixture at 0°C for 30 minutes and then stir at ambient temperature for 2 hours. Remove the solvent in vacuo and partition the residue between water (200 ml) and dichloromethane (200 ml).
  • Step D ,N'-Bis[3-(amino)butyl]-N, '-bis[ (phenyl) methyl]-1,7-diaminoheptane
  • Step E 2,16-Bis(methyl)-l,5,13,17-tetra(t- butoxycarbonyl)-l,5,13,17-tetraazaheptadecane Combine N,N'-bis[3-(amino)butyl]-N,N'-bis[ (phenyl)methyl]- 1,7-diaminoheptane (13.4 g, 0.029 mol), Pearlman's Catalyst (2.0 g) and ethanol (90 ml) and treat the mixture with hydrogen gas at 45 lb/in 2 until gas uptake ceases.
  • Step F l,2,16,17-Tetramethyl-l,5,13,17-tetra(t- butoxycarbonyl)-1,5,13,17-tetraazaheptadecane Combine 2,16-bis(methyl)-l,5,13,17-tetra(t-butoxycarbonyl)- 1,5,13,17-tetraazaheptadecane (8.5 g, 0.0126 mol) and sodium hydride (60% in oil) [1.21 g, 0.03 mol] in DMF (75 ml) and stir until hydrogen evolution ceases.
  • Step G N, '-Bis[3-(methylamino)butyl]-1,7-diaminoheptane tetrahydrochloride
  • Step A l,17-Diethyl-2,16-dimethyl-l,5,13,17-tetra(t- butoxycarbonyl)-1,5,13,17-tetraazaheptadecane Combine 2,16-bis(methy1)-1,5,13,17-tetra(t-butoxycarbonyl)- 1,5,13,17-tetraazaheptadecane (8.5 g, 0.0126 mol), made as described in Example 5, and sodium hydride (60% in oil) [1.21 g, 0.03 mol] in DMF (75 ml) and stir until hydrogen evolution ceases. To this mixture add ethyl iodide (4.68 g, 0.03 mol) and stir for 2 hours.
  • Step B N,N'-Bis[3-(ethylamino)butyl]-1,7-diaminoheptane tetrahydrochloride
  • Steps A and B 1,5,13,17-Tetraazaheptadecane tetrahydrochloride
  • Step C 1,5,13,17-Tetra(t-butoxycarbonyl)-1,5,13,17- tetraazaheptadecane
  • Step D 3,7,15,19-Tetra(t-butoxycarbonyl)-3,7,15,19- tetraazaheneicosane
  • Step E N,N'-Bis[3-(ethylamino)propyl]-1,7-heptanediamine Treat 3,7,15,19-tetra(t-butoxycarbonyl)-3,7,15,19- tetraazaheneicosane (1.68 gm, 0.0024 mol) with HCl in methanol (50 ml, 1.0 N) and stir overnight. Filter the mixture and recrystallize the title compound from methanol/water (20:80, v/v) to yield 0.5 gm of the title compound.
  • R f is 0.39 on silica gel plates eluted with 40% ammonia (concentrated) in methanol; mp 322-23°C with degradation.
  • Step A ,N'-Bis-[2,2'-bis(cyano)ethyl]-1,8-diamino-octane Dissolve 28.8 gm (0.2 mol) of 1,8 diaminooctane in 250 ml of EtOH. Add 27 ml (0.41 mol) of acrylonitrile and gently reflux the mixture overnight. Remove the solvent at reduced pressure. Analysis shows desired material to be >95% pure.
  • Step B 1,5,14,18-Tetraazaoctadecane tetrahydrochloride Combine 50.0 gm of the product of Example 1, 2.0 gm Pt ⁇ 2 , 133 ml of cone. HCl at 45 lbs./sq. in. in a shaker flask until hydrogen is no longer taken up. Filter the resulting mixture, evaporate the solvent and triturate the product with 1 liter of EtOH. Filter and dry the product to obtain 51.6 gm of the title compound, Rf is 0.17 (silica gel plates eluted with 40% cone. NH 3 /CH 3 OH) .
  • Step C 1,5,14,18-Tetra(t-butoxycarbonyl)-1,5,14,18- tetraazaoctadecane
  • Step D 1,18,-Bis[ (phenyl)methyl]-1,5,14,18-tetra(t- butoxycarbonyl)-1,5,14,18-tetraazaoctadecane Dissolve 20.0 gm (0.03 mol) of the product from Step C in 30 ml DMF and treat with 7.5 gm (0.067 mol) KtBuO and 7.96 ml (0.067 mol) BnBr, with stirring for 18 hours. Evaporate the volatiles (0.5 mm and 45°C) and take up the resulting residue in 1400 ml of EtOAc and water-wash (2x, 500 ml). The organic layer is then dried (MgS ⁇ 4 ) and the solvent is evaporated (in vacuo).
  • Step E l,18-Bis-[ (phenyl)methyl]-l,5,14,18-tetraaza- octadecane»4HCl
  • Step A N,N'-Bis(t-butoxycarbonyl)-1,8-octanediamine Dissolve 10.8 gm (0.075) of diaminooctane in 200 ml CH 2 CI 2 and 100 ml CH 3 OH, add 32.7 gm (0.156 mol) of di-t- butyldicarbonate and stir the mixture overnight. Evaporate, in vacuo, and crystallize the residue from hexane to obtain 20.2 gm of the desired compound, mp 96-97°C.
  • Step B 4-[ [ (Phenyl)methyl]amino]-butan-l-ol Combine 4-amino-butan-l-ol (8.9 gm - 0.1 mol), benzaldehyde (10.6 gm - 0.1 mol), EtOH (100 ml) and Pt ⁇ 2 (0.3 gm) , and hydrogenate the mixture at 45 lbs./sq.in. until H2 is no longer taken up. Filter, evaporate the solvent ( in vacuo) to yield 17.7 gm of the desired compound. Rf is 0.70 (eluted from silica gel with 10% cone. NH3/CH30H) .
  • Step C 4-[N-(t-butoxycarbonyl)-N-[ (phenyl)methyl]amino] butan-1-ol
  • Step B Combine the butanol of Step B (17.7 g - 0.1 mol) and di- tbutyldicarbonate in 100 ml of CH 2 CI 2 and stir the mixture overnight. Evaporate off the solvents, in vacuo, and flash chromatography of the residue, eluting from silica gel with 25% EtOAc/hexane to obtain the desired compound. Rf is .27 (silica gel plates eluted with 20% EtOAc/hexane).
  • Step D 4-[N-(t-butoxycarbonyl)-N-[ (phenyl)methyl]-amino]- lnethansulfonyl butane Cool (ice-bath) a mixture containing the product of Step C (21.8 gm - 0.078 mol), 250 ml CH 2 CI 2 and 9.7 ml pyridine (0.12 mol), add in a dropwise fashion (20 minutes) mesylchloride (6.65 ml - 0.086 mol) in 6.6 ml CH 2 CI 2 and allow the mixture to warm to room temperature, stirring the mixture for 2 hours.
  • Step E 1,20-Bis[ (phenyl)methyl]-l,16,15,20-tetra-(t- butoxycarbonyl)-1,6,15,20-tetraazaeicosane
  • Step E 1,20-Bis[ (phenyl)methyl]-l,16,15,20-tetra-(t- butoxycarbonyl)-1,6,15,20-tetraazaeicosane
  • Step E 1,20-Bis[ (phenyl)methyl]-l,16,15,20-tetra-(t- butoxycarbonyl)-1,6,15,20-tetraazaeicosane
  • Step E 1,20-Bis[ (phenyl)methyl]-l,16,15,20-tetra-(t- butoxycarbonyl)-1,6,15,20-tetraazaeicosane
  • Step E 1,20-Bis[ (phenyl)methyl]-l,16,15,20-tetra-(t- butoxycarbon
  • Step F 1,20-Bis[ (phenyl)methyl]-l,6,15,20-tetraeicosane «4 HCl Dissolve the product of Step E (4.7 gm) (0.0054 mol) in 5 ml EtOH and treat with 54 ml of 2N HCl in Et0 2 , stir the mixture overnight, filter and recrystallize to so-obtained solids from isopropanol/water. Cool, filter and dry the desired product, mp >300°C, Rf is 0.47 (eluted from silica with 10% cone. NH 3 /CH 3 OH) .
  • Step A N,N'-Bis( (phenyl)methyl)-1,8-octanediamine
  • Step B N,N'Bis( (3-oxo)butyl)-N,N'-bis( (phenyl)methyl)- 1,8octanediamine
  • Step A Dissolve the product obtained in Step A in 1400 ml of methanol and introduce 21.6 of methyl vinyl ketone on a stream of 2 gas. Stir for 16 hours to yield the title compound.
  • Step C N,N'-Bis( (3-hydroxyimino)butyl)-N,N'-Bis- ( (phenyl)methyl)-l,8-octanediamine Combine 18.07 g hydroxylamine hydrochloride, 10.4 g of NaOH and 40 ml of H 2 O and add to the solution obtained in Step B. Reflux the mixture for 3 hours, then cool and evaporate the solvent. Pour the reaction mixture into 300 ml of ethyl acetate and wash with 300 ml H 2 O. Wash the aqueous layer with 300 ml of ethyl acetate (2x). Combine the organic layers and dry over anhydrous MgS ⁇ 4 . Remove the solvent at reduced pressure. Purify the product by flash chromatography (silica gel), eluting with ethyl acetate to yield 34.8 g of the title compound (Rf is 0.42 for TLC on silica gel developed with ethyl acetate).
  • Step D N,N'-Bis( (3-amino)butyl)-N,N'-Bis( (phenyl)-methyl)-
  • Step E N,N'-Bis( (3-amino)butyl)-l,8-octanediamine Combine 5.0 g (0.01 mol) of the product of " Step D, 0.5 g of 20% Pd(OH) 2 on carbon (Pearlman's Catalyst), and 50 ml or ethanol and treat the mixture with H 2 at 45 lb/in2 in a shaker flask until no more gas is taken up. Remove the catalyst by filtration and remove the solvent at reduced pressure. Subject the residue to short path distillation to yield 1.59 g of the title compound (bp 145-148°C at 0.012 mmHg) .
  • Step A N,N'-Bis[ (phenyl)methyl]-1,7-heptanediamine Combine 1,7-diaminoheptane (65.0 g, 0.5 mol), benzaldehyde (106 gm, 1 mol) and platinum oxide (Pt ⁇ 2 )[2.0 g] in ethanol (800 ml) and treat the mixture with hydrogen gas (45 lb/in 2 ) until the uptake of gas ceases. Remove the catalyst by filtration and remove the solvent in vacuo. Purify the residue by bulb to bulb distillation to yield 99.4 g of the title compound (bp 191-195°C @ 1.0 mm/Hg) .
  • Step B N,N'-Bis[ (3-oxo)butyl]-N,N'-bis[ (phenyl)methyl]- 1,7- diaminoheptane
  • Step C N,N'-Bis[ (3-hydroxyimino)butyl]-N,N'-bis[ (phenyl) methyl]-1,7-diaminoheptane Cool the reaction mixture obtained in step B to 0°C and to this mixture add a solution of hydroxylamine hydrochloride (4.38 g, 0.063 mol) and sodium bicarbonate (5.54 g, 0.066 mol) in water (40 ml). Stir the mixture at 0°C for 30 minutes and then stir at ambient temperature for 2 hours. Remove the solvent in vacuo and partition the residue between water (200 ml) and dichloromethane (200 ml).
  • Step D N,N'-Bis[3-(amino)butyl]-N,N'-bis[ (phenyl) methyl]-
  • Step E 2,16-Bis(methyl)-1,5,13,17-tetra(t-butoxycarbonyl)- 1,5,13,17-tetraazaheptadecane
  • Step G N,N'-Bis[3-(methylamino)butyl]-l,7-diaminoheptane tetrahydrochloride
  • Add IN HCl in methanol (SO ml) to 1,2,16,17-tetramethyl- 1,5,13,17-tetra(t-butoxycarbonyl)-1,5,13,17-tetraazahepta- decane (3.8 g, 0.0054 mol) and stir overnight.
  • Rf is 0.31 for TLC on silica gel developed with 40% cone, ammonia in methanol.
  • ethyl iodide (4.68 g, 0.03 mol) and stir for 2 hours.
  • Step B , '-Bis[3-(ethylamino)butyl]-1,7-diaminoheptane tetrahydrochloride
  • 1,4,13,16-Tetra(t-butoxycarbonyl)-1,4-13,16-tetraazahexa- decane Combine 4.75 g 1,8-dibromooctane (0.017 mol), 20 ml EtOH and 9.32 ml of ethylene diamine and reflux the mixture overnight. Cool and treat the mixture with 1.4 gm NaOH. Evaporate off the solvent and triturate the residue with CH 2 CI 2 (200 ml 2x), filter. Treat the filtrate with 66.6 gm of di-t-butyldicarbonate and stir the mixture overnight. Remove the solvent and subject the residue to flash chromatography, eluted with 25% EtOAc/hexane to yield the desired product. Rf is 0.64 eluted from silica gel with 50% EtOAc/hexane.
  • Step A l,18-Bis[ [ (phenyl)methyl]carbonyl]-5,14-bis- [ (phenyl)methyl]-1,5,14,18-tetraazaoctadecane Chill a solution of 5,14-bis[ (phenyl)methyl]-l,5,14,18- tetraazaoctadecane (2.2 g, 5 mmole) and triethylamine (2 g, 20 mmole) in chloroform (100 ml) in an ice bath. Add a solution of phenylacetyl chloride (2.3 g, 15 mmole) in chloroform (10 ml) dropwise. Remove the ice bath and stir the mixture at ambient temperature for 18 hours.
  • Step B Add a solution of the product of Step A in THF (150 ml) dropwise to a suspension of LAH (0.5 g) in THF (500 ml). Stir the mixture for 48 hours at ambient temperature. Decompose the excess reducing agent by dropwise addition of 1 ml of water, 1 ml of 15% NaOH then 3 ml of water. Filter the mixture and evaporate the filtrate.
  • Step A N-(Phenyl-N,N'-bis(t-butoxycarbonyl)propanediamine Cool 200 ml of anhydrous Et 2 ⁇ in an ice bath and add lithium aluminum hydride (8.74 gm -0.23 mol). Add, in a dropwise fashion over 30 minutes, 3-anilinopropionitrile (14.6 gm) in 50 ml of Et 2 ⁇ , remove the ice bath, and reflux the resulting mixture overnight. Sequentially add 8.7 ml of water, 1.5 g of NaOH (in 10 ml of water) and 25 ml of water.
  • Step B N-(t-Butoxycarbonyl)-2,3-butadienylamine Reflux a mixture containing N-(t-butoxycarbonyl)- propargylamine (70 gm) , 93.5 ml of 32% formaldehyde, 76.4 ml of diisopropylamine, 19.66 gm of cuprous bromide and 860 ml of p-dioxane for 12 hours. Cool and dilute the resulting mixture with 3000 ml of Et 2 ⁇ , wash with 500 ml of water, 1000 ml acetic acid, 500 ml of water (2x), 200 ml sat'd.
  • Step C N,N-Bis[ (phenyl)methyl]-l,8-diaminooctane Combine 14.4 gm of diaminooctane, 20.3 ml of benzaldehyde and 0.66 gm of Pt 2 ⁇ in 100 ml of ethanol. Treat the resulting mixture with hydrogen at 45 lbs./sq.in. until no further hydrogen is taken up. Filter, evaporate the solvent (in vacuo), and distill the rendered material to obtain 25.5 gm of the desired product, bp 185-190°C at 0.1 mm.
  • Step D 1,18-Bis(hydroxy)-5,14-bis[ (phenyl)methyl]-5,14- diazaoctadecane Reflux a mixture containing 25.5 g of the product of Step
  • Step E 1,18-Bis(hydroxy)-5,14-diazaoctadecane Hydrogenate a mixture containing 3.0 gm of the product of Step D, 30 ml of AcOH and 0.6 gm of palladium oxide at 45 lbs./sq.in. until no further hydrogen is taken up. Filter and remove the solvent (in vacuo) to yield 1.77 gm of the desired product, Rf is 0.37 (eluted from silica gel with 10% cone. NH 3 /CH 3 OH)-.
  • Step F 1,18-Bis(hydroxy)-5,14-bis-(t-butoxycarbonyl)-5,14- diazaoctadecane
  • Step G 1,18-Bis(methanesulfonyl)-5,14-bis(t- butoxycarbonyl)- 5,14-diazaoctadecane
  • Step H l,18-Bis(2,3-butadienyl)-l,5,14,18-tetra-(t- butoxycarbonyl)-1,5,14,18-tetraazaoctadecane
  • Step I l,18-Bis(2,3-butadienyl)-1,5,14,18-tetraazaocta ⁇ decane * 4HC1
  • Step B 1,7-Bis(3-acetylhexahydropyrimidin-1-yl)heptane (MDL 44868) A stirred solution of crude bis(hexahydropyrimidine) MDL
  • Step C l,7-Bis(3-ethylhexahydropyrlmldln-l-yl)heptane (MDL 45692)
  • a solution of crude bis(acetylhexahydropyrimidine) MDL 44868 (2.0 g, 5.7 mmol) in anhydrous THF (40 mL) was added to a stirred suspension of LAH (0.85 g, 22.7 mmol) in anhydrous THF (60 mL) under N 2 .
  • the reaction mixture was heated at reflux for 16 h and then allowed to cool to room temperature.
  • the reaction mixture was stirred vigorously and quenched by the cautious addition of saturated aqueous Na 2 S ⁇ 4 (5 mL) at room temperature.
  • Step D N,N'-Bis[3-(ethylamino)propyl]-1,7-heptanediamine tetrahydrochloride (MDL 28314QA)
  • MeOH MeOH
  • HCl 5 mL
  • the reaction solution was heated at reflux for 3 h, using a nitrogen sweep to remove HCHO/MeOH distillate (MDL 28314QA precipitated from the reaction solution shortly after heating began) .
  • the loss in reaction volume was periodically adjusted to the original level by addition of MeOH.
  • Step A N-t-Butyloxycarbonyl-N-4-chlorobutyl-p- toluenesulfonamide
  • Step B 1,7-bis-p-Toluenesulfonamidoheptane
  • Step C 1,6,14,19-Tetraaza-l,19-bis-t-butyloxycarbonyl- 1,6,14,19-tetra-p-tol-uenesulfonylnonadecane
  • Sodium hydride 0.8 g, 16.8 mmol, 50% mineral oil dispersion
  • 27 3 g, 8.4 mmol
  • Sodium iodide 0.1
  • 26 5.2 g, 16.8 mmol
  • DMF 50 mL
  • Step D 1,6,14,19-Tetraaza-l,6,14,19-tetra-p- toluenesulfonylnonadecane
  • Step E 1,6,14,19-Tetraazanonadecane Tetrahydrobromide
  • NMR (D20) 1.4 (s, 6H), 1.6-1.85 (m, 12H) and 3.0-3.1 (m, 12H) .
  • Test compound numbers relate to the following compounds:
  • MDL27,393 CH3CH2-NH-(CH2)3-NH-(CH2)8-NH-(CH2)3-NH-
  • MDL28,314 CH3CH2-NH-(CH2)3-NH-(CH2)7-NH-(CH2)3-NH-
  • MDL28,454 CH3CH2CH2-NH-(CH2)3-NH-(CH2)7-NH-(CH2)3-
  • gaciclovir 9-[ (2-ydroxy-l-hydroxymethylethoxy)- methyl]guanine
  • polyamine analogues The antiviral effects of, polyamine analogues was determined by a standard plaque reduction assay as described by Tyms et al. (J. Antimicrobial Chemotherapy 8, 65-72, 1981). Monolayers of human embryo fibroblasts (MRC- 5 strain) were formed in the presence or absence of varying concentrations of compound and infected with CMV strain AD169 or Towne (100 pfu/105 cells) in the presence or absence of compound and incubated in the presence or absence of compound for ten days at 37°C.
  • Virus production was inhibited by the preferred compound, MDL27,393, by 90% at 1 nmoles/litre and 95% at lOnmoles/litre with a corresponding reduction in the synthesis of the three major "late” viral proteins the major capsid protein (153KD) tegument protein (69KD) and a DNA-binding protein (51KD).
  • This was confirmed in experiments in which numbers of CMV infected cells expressing the "late” antigens under these conditions, identified by a specific monoclonal antibody to a late protein, were shown to be reduced.
  • MRC-5 cells were seeded at low plating density and grown in the presence or absence of the preferred compound, MDL 27,393, or MDL 28,314 and cell numbers were determined at five days postseeding. The results showed that growth of these cells was not inhibited at concentrations of 0.5 ⁇ moles/litre or less although the time to confluency of the monolayers was longer compared to untreated controls at concentrations between 1 and 5 ⁇ moles/litre (data not shown) .
  • the therapeutic window for the preferred compound MDL 27,393, established by the amount of compound required to inhibit virus growth by 50% compared to the concentration required to inhibit cell growth by 50%, was greater than 10,000.

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Abstract

La présente invention se rapporte au traitement des infections à cytomégalovirus (CMV) à l'aide de composés de polyamine de la formule (I) dans laquelle Z représente une fraction alkylène (C2-C6) saturé ou à chaîne ramifiée; m représente 7 ou 8; chaque groupe R représente indépendamment hydrogène, un hydrocarbyle C1-C6 saturé ou insaturé, ou -(CH2)x-(Ar)-X où Ar représente phényle ou naphtyle, X représente H, alcoxy C1-C6; C1-C4 alkyle halogéné; x est un nombre entier, 0, 1 ou 2; à condition que les deux groupes R ne puissent représenter hydrogène; ou lesdits composés de la formule (I) peuvent être un sel d'addition d'acide pharmaceutiquement acceptable.
EP93921461A 1992-10-05 1993-09-10 Derives de polyamine utiles comme agents anti-cytomegaloviraux Ceased EP0662829A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB929220921A GB9220921D0 (en) 1992-10-05 1992-10-05 Polyamine derivatives as anticytomegaloviral agents
GB9220921 1992-10-05
PCT/US1993/008517 WO1994007480A1 (fr) 1992-10-05 1993-09-10 Derives de polyamine utiles comme agents anti-cytomegaloviraux

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KR (1) KR950703335A (fr)
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US5831001A (en) * 1990-10-24 1998-11-03 Allelix Biopharmaceuticals Inc. Treatment of herpesvirus infection
AU7723794A (en) * 1993-10-07 1995-05-01 Merrell Dow Pharmaceuticals Inc. Novel process for preparing polyamine derivatives and intermediates thereof
FR2749845B1 (fr) * 1996-06-18 1998-08-21 Oreal Nouveaux derives benzyl substitue(s) de polyalkylene-polyamines et leur utilisation dans des compositions cosmetiques et pharmaceutiques
WO2003013245A1 (fr) 2001-08-07 2003-02-20 Wisconsin Alumni Research Foundation Polyamines et analogues assurant une protection des cellules a l'occasion des chimiotherapies et radiotherapies anticancereuses
JP2005506354A (ja) 2001-10-16 2005-03-03 スリル バイオメディカル コーポレイション 癌治療のためのオリゴアミン化合物およびその誘導体
EP4257581A1 (fr) * 2018-01-30 2023-10-11 Panbela Therapeutics, Inc. Procédés de production de (6s,15s)-3,8,13,18-tétraazaicosane-6,15-diol

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AU628174B2 (en) * 1989-05-23 1992-09-10 Merrell Dow Pharmaceuticals Inc. A method of potentiating cell-mediated immunity utilizing polyamine derivatives

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Title
See references of WO9407480A1 *

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JPH08512279A (ja) 1996-12-24
GB9220921D0 (en) 1992-11-18
NZ256254A (en) 1997-04-24
KR950703335A (ko) 1995-09-20
HUT72663A (en) 1996-05-28

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