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WO1999002145A1 - Traitement associe a base d'aminosides et de guanidines n,n'-disubstituees - Google Patents

Traitement associe a base d'aminosides et de guanidines n,n'-disubstituees Download PDF

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Publication number
WO1999002145A1
WO1999002145A1 PCT/US1998/013640 US9813640W WO9902145A1 WO 1999002145 A1 WO1999002145 A1 WO 1999002145A1 US 9813640 W US9813640 W US 9813640W WO 9902145 A1 WO9902145 A1 WO 9902145A1
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Prior art keywords
guanidine
ethylphenyl
naphthyl
methyl
substituted
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PCT/US1998/013640
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English (en)
Inventor
David I. Gwynne
Graham J. Durant
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Cambridge Neuroscience, Inc.
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Application filed by Cambridge Neuroscience, Inc. filed Critical Cambridge Neuroscience, Inc.
Priority to AU82784/98A priority Critical patent/AU8278498A/en
Publication of WO1999002145A1 publication Critical patent/WO1999002145A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound

Definitions

  • the present invention relates to pharmaceutical therapies that comprise administration of an aminoglycoside antibiotic in combination with a substituted guanidine or other compound as specified herein, particularly for treatment of infections such as those caused by Gram-negative bacteria.
  • Aminoglycoside antibiotics have been widely used in the treatment of both Gram-positive and Gram-negative bacteria as well as against tuberculosis strains.
  • the aminoglycosides are particularly effective against serious infections involving Gram-negative bacilli such as pyelonephritis, endocarditis, pneumonia, drug- resistant tuberculosis and sepsis.
  • a wide variety of aminoglycosides have been previously reported. See, U.S. Patents Nos. 5,508,269; 4,645,760; and 4,380,625; and E.J. Begg et al., Br. J. Clin. Pharmacol, 39:597-603 (1995).
  • aminoglycosides pose substantial toxicity problems with to about a third of patients receiving aminoglycoside therapy experience some level of hearing loss. See R.E. Brummett et al., Arch. Otolaryngol Head Neck Surg., 116:406-410 (1990); S.P. Stringer et al., Otolaryngology (eds. M.M. Paparella et al., 1653-1669 (Saunders, Philadelphia, 1991).
  • the present invention includes methods for treatment of infections, including Gram-negative and Gram-positive bacterial infections, comprising administering a combination of 1) an aminoglycoside antibiotic, and 2) with a substituted guanidine or other compound as disclosed herein (that second component sometimes referred to herein as "compound or componds 2)").
  • Preferred methods and compositions of the invention will be effective against infections previously treated with aminoglycoside antibiotics, but with the significant advantage of decreased occurrence of ototoxicity relative to use of an aminoglycoside antibiotic alone.
  • PCT/US92/0105 Goldin et al.; International Publication No. WO 92/ 14697
  • PCT/US92/03554 Weber et al.; International Publication No. WO 92/ 19621)
  • PCT/US94/06008 Durant et al.; International Publication No. WO 94/27591
  • PCT/US94/ 13245 Durant et al.; International Publication No. WO 95/ 14461
  • PCT/US94/ 13541 Magnar et al.; International Publication No. WO 95/ 14467
  • PCT/US95/01536 Goldin et al.; International Publication No.
  • substituted guanidines include N,N'-disubstituted guanidines, N,N,N'- trisubstituted guanidines, N,N,N',N'-tetrasubstituted guanidines, hydrazinedicarboximidamide compounds, aminoguanidines, N,N- disubstituted guanidines, indolinyl and indolinyl derivative compounds, imine-substituted piperidine compound and others as disclosed below.
  • a wide variety of aminoglycoside antibiotics are suitable for use in the formulations of the invention.
  • suitable aminoglycoside antibiotics contain two or more amino sugars (aminoglycosides) connected to an amino- cyclitol nucleus.
  • exemplary aminoglycoside antibiotics preferred for use in formulations of the present invention include clinical agents such as gentamycin, amikacin, kanamycin, streptomycin, paromoycin, neomycin, netilmicin and tobramycin.
  • Suitable aminoglycosides include seldomycins, sisomycins, aurimycin, lividomycins, streptothricins, hybrimycins, coralinomycin, butirosin, strepomutins, nebramycins, tenebrimycins, ribostamycins, destomycins, trehalosamines, myomycins, fortimicins, mutamicins and kasugamycin.
  • Suitable aminoglycoside antibiotics are also disclosed in U.S. Patents Nos. 5,508,269; 4,645,760; and 4,380,625. It should be appreciated however that the present invention is not limited by any particular aminoglycoside antibiotic, and the invention is applicable to any aminoglycoside antibiotic now known or subsequently discovered or developed.
  • aminoglycoside and substituted guanidine or other active compound may be administered simultaneously, in the same or different pharmaceutical formulations, or sequentially.
  • the components of the combination of the invention are administered substantially simultaneously, e.g. in a unitary pharmaceutical composition containing the two components.
  • the invention also includes pharmaceutical compositions that comprise an aminoglycoside antibiotic in combination with a compound 2) such as a substituted guanidine or other compound as disclosed herein.
  • a compound 2 such as a substituted guanidine or other compound as disclosed herein.
  • Other aspects of the invention are disclosed infra. DETAILED DESCRIPTION OF THE INVENTION
  • N,N'-disubstituted guanidines including compounds of the following Formula I:
  • R and R' each are an alkyl group of at least 4 carbon atoms or carbocyclic aryl groups of at least 6 carbon atoms, or heterocyclic or heteroaromatic of having 1 to 3 rings, 3 to 8 ring members in each and 1 to 3 heteroatoms, e.g., R and R', which can be the same or different, are alkyl of 4 or more carbon atoms, e.g., a 4 to 12 carbon atoms, preferably a straight chain, alkyl group and more preferably a 4 to 8 carbon atom alkyl group, for example, butyl, isobutyl, tertbutyl, amyl, hexyl, octyl, nonyl and decyl; cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 1,
  • substituents may be present on the R and R' groups, e.g., alkyl of 1-8 carbon atoms, e.g., methyl, ethyl; halo, e.g., chloro, bromo, iodo, fluoro; nitro; azido; cyano; isocyanate; amino; lower- alkylamino; di-lower alkylamino; trifluoromethyl; alkoxy of 1-8 carbon atoms; e.g., methoxy, ethoxy and propoxy; acyloxy, e.g., alkanoyloxy of 1-8 carbon atoms, e.g., acetoxy and benzoxy; amido, e.g., acetamido, N- ethylacetamido; carbamido, e.g., carbamyl, N-methylcarbamyl, N,N'- dimethylcarbamyl;
  • R and R' each are phenyl groups, which need not necessarily be identical, substituted with one or more of the foregoing substituents, for example, in the o-, m- or p-position or the o-, p- or m,n ⁇ -position, when the phenyl group is disubstituted, or R is phenyl or otherwise defined herein and R' is adamantyl.
  • N,N'-disubstituted compounds for use in accordance with the invention include N,N'-di-m-tolylguanidine; N,N'-di-o- iodophenylguanidine; N,N'-di-o-ethylphenylguanidine; N,N'-di-m- ethylphenylguanidine; N,N'-bis(2-iodophenyl)guanidine; N,N'-bis(3- tolyl)guanidine;N,N'-bis(3-ethylphenyl)guanidine; N,N'-bis(2- isopropylphenyl) guanidine; N,N'-bis(3-isopropylphenyl)guanidine; N,N'-bis(l- naphthyl) guanidine; N,N'-bis(3-methoxyphenyl)guanidine; N,N'-bis(l
  • Asymmetrical N,N'-disubstituted guanidines are also preferred for use as compound 2) in methods and compositions of the invention, such as compounds of Formula I above wherein R and R' are different.
  • Particularly preferred are asymmetrical compounds of Formula I wherein R and R' each are nonidentical aryl groups, including aryl groups substituted with one or more of the substituents discussed above with respect to Formula I, for example, in the o-, - or p-position or the o-, p- or m,m' -position, when the phenyl group is disubstituted.
  • N,N,N'-trisubstituted guanidines are also preferred for use as compound 2) in the methods and compositions of the invention, including compounds of the following Formula II: NH
  • R, R' and R" are independently a Ci-Cs alkyl group, a C2-C8 alkenyl group, C2-C8 alkynyl group, cycloalkyl group, cycloalkyl group substituted by one or more substituents, cycloalkenyl group, cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted by one or more substituents, alkaryl group, alkaryl group substituted by one or more substituents, heterocyclic group, heterocyclic group substituted by one or more substituents, heteroaryl group, or a heteroaryl group substituted by one or more substituents; or a physiologically acceptable salt thereof; wherein said substituent is a halogen of chloro, fluoro, bromo, iodo, Ci-Cs alkyl, Ci-Cs alkoxy, cyano, C3-C15 dialkylaminoalkyl
  • preferred N,N,N'- trisubstituted guanidines are wherein R and R" are independently a cycloalkyl group, a cycloalkyl group substituted with one or more substituents, cycloalkenyl, cycloalkenyl substituted by one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted with one or more substituents, alkaryl group, alkaryl group substituted with one or more substituents, aralkyl group, aralkyl group substituted with one or more substituents, heterocyclic group, heterocyclic group substituted with one or more substituents, heteroaryl group, or a heteroaryl group substituted with one or more substituents; and R' is independently a Ci-Cs alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, an alkaryl group, or a substituted alkaryl group.
  • N,N,N'-trisubstituted guanidines for use as compound 2) in accordance with the invention include N,N'-di-( 1 -naphthyl) - N-methylguanidine; N,N'-di-(l-naphthyl)-N-ethylguanidine; N,N'-di-(m- ethylphenyl)-N-methylguanidine; N-(o-isopropylphenyl)-N'-methyl-N'-(l- naphthyl) guanidine; N-(m-ethylphenyl)-N-methyl-N'-(l-naphthyl)guanidine; N-ethyl-N,N'-di-(m-ethylphenyl)guanidine; N-ethyl-N-(m-ethylphenyl)-N'-(4- indanyl)
  • N,N,N',N'-tetrasubstituted guanidines are also preferred for use as compound 2) in accordance with the invention, including compounds of the following Formula III:
  • R, R', R" and R'" are independently a Ci-Cs alkyl group, a C 2 - C ⁇ alkenyl group, C2-C8 alkynyl group, cycloalkyl group, cycloalkyl group substituted by one or more substituents, cycloalkenyl group, cycloalkenyl group substituted with one or more substituents, carbocyclic aryl group, carbocyclic aryl group substituted by one or more substituents, alkaryl group, alkaryl group substituted by one or more substituents, heterocyclic group, heterocyclic group substituted by one or more substituents, heteroaryl group, or a heteroaryl group substituted by one or more substituents; or a physiologically acceptable salt thereof; wherein said substituent is halogen such as chloro, fluoro, bromo, iodo, Ci-Cs alkyl, Ci-Cs alkoxy, cyano, C3-C15 dialkyla
  • guanidines of Formula III are those wherein R and R" are independently carbocyclic aryl groups, substituted cycloalkyl groups, cycloalkenyl groups, cycloalkenyl groups substituted with one or more substituents, carbocyclic aryl groups, substituted carbocyclic aryl groups, alkaryl groups, substituted aralkyl groups, heterocyclic groups, substituted heterocyclic groups, heteroaryl groups, or substituted heteroaryl groups; and R' and R'" are Ci-Cs alkyl groups.
  • N,N,N'N'-tetrasubstituted guanidines include N,N'-diethyl-N,N'-di-(m- ethylphenyl) guanidine; N,N'-diethyl-N,N'-di-( 1 -naphthyl) guanidine; N,N'- diethyl-N-(m-ethylphenyl)-N'-(4-indanyl)guanidine; N,N'-diethyl-N-(m- ethylphenyl)-N'-(4-indenyl)guanidine; N,N'-diethyl-N-(m-ethylphenyl)-N'-(o- iodophenyl)guanidine; N,N'-diethyl-N-(m-ethylphenyl)-N'-(o- isopropylphenyl
  • typical alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, heptyl and octyl.
  • typical cycloalkyl groups have 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 1,4-methylenecyclohexyl, adamantyl, norbornyl, isobornyl, menthyl, cyclopentylmethyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl.
  • typical cycloalkenyl groups have 5 to 12 carbon atoms and include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cycloctenyl groups.
  • typical carbocyclic aryl groups include phenyl, 1 -naphthyl, 2-naphthyl, biphenyl, phenanthracyl, and anthracyl groups.
  • typical alkaryl or aralkyl groups may contain 1-3 separate or fused aromatic rings, e.g., benzyl, C1-C3 alkylphenyl, nitrophenyl, naphthyl, 1- and 2-phenylethyl, 1-, 2-, or 3-phenylpropyl, o-, m-, or p-tolyl, m,m'- dimethylphenyl, o-, m-, or p-ethylphenyl, m,m'-diethylphenyl, m-methyl-m- ethylphenyl, o-propyl phenyl, and o-isopropylphenyl.
  • aromatic rings e.g., benzyl, C1-C3 alkylphenyl, nitrophenyl, naphthyl, 1- and 2-phenylethyl, 1-, 2-, or 3-phenylpropyl, o-, m-, or
  • typical heterocyclic aromatic rings include coumarinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzthiazolyl.
  • typical alkenyl groups include allyl, 2-butenyl, 2-pentenyl and 2-hexenyl groups.
  • typical alkynyl groups include 2-butynyl, 2-pentynyl and 2-hexynyl groups.
  • typical aroyl groups include carbonyl substituted by the above-listed aryl groups.
  • typical aralkoxy groups include Ci-Cs alkoxy groups substituted by the above-listed aryl groups.
  • typical heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl groups.
  • N,N'-disubstituted, N,N,N'-trisubstituted and N,N,N',N'-tetrasubstituted guanidines having a 2,5-substituted-phenyl substituent particularly compounds of the following Formula IV:
  • R, R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulf ⁇ nyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 carbon ring atoms, substituted or unsubstituted a
  • acyl or substituted or unsubstituted carboxy such as acid or ester groups of the formula -(CH2) q COOY where q is an integer of 0-8, Y is hydrogen or substituted or unsubstituted Ci- ⁇ alkyl; n is 0 (R 5 is hydrogen), 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • R and R 1 will typically be other than hydrogen.
  • Preferred compounds of Formula IV include trisubstituted compounds where one of the guanidine substituents R, R 1 and R 2 of Formula IV above is hydrogen and the other two substituents are other than hydrogen, more preferably where R or R 1 is heterocyclic aryl or carbocyclic aryl, still more preferably where R is substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted carbocyclic aryl and one of R 1 and R 2 is hydrogen and one of R 1 and R 2 is substituted or unsubstituted alkyl.
  • N,N'-disubstituted compounds i.e.
  • R and R 1 of Formula IV is hydrogen and R 2 is hydrogen, preferably where R is substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted carbocyclic aryl and R 1 and R 2 are hydrogen. Also preferred are N,N,N'N'-tetrasubstituted compounds, i.e.
  • each of R, R 1 and R 2 substituents of Formula IV is other than hydrogen, preferably where R or R 1 is substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted carbocyclic aryl, more preferably where R is substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted carbocyclic aryl and R 1 and R 2 are each substituted or unsubstituted alkyl.
  • Preferred phenyl ring substituents R 3 , R 4 and R 5 of compounds of Formula IV include halogen such as F, Cl, Br and I, hydroxyl azido, substituted or unsubstituted alkyl including halogenated alkyl, substituted or unsubstituted alkoxy including halogenated alkoxy and substituted and unsubstituted alkylthio.
  • halogen such as F, Cl, Br and I
  • hydroxyl azido substituted or unsubstituted alkyl including halogenated alkyl
  • substituted or unsubstituted alkoxy including halogenated alkoxy and substituted and unsubstituted alkylthio.
  • preferred phenyl ring substituents have 1 to 4 carbon atoms with methyl, ethyl and propyl including isopropyl being particularly preferred.
  • Halogen-substituted alkyl and alkoxy groups are also particularly preferred including fluoroalkyl having 1, 2, 3 or 4 carbon atoms such as trifluoromethyl and fluoro-substituted alkoxy having 1 , 2, 3 or 4 carbon atoms such as trifluoromethoxy (-OCF3).
  • Methylthio (-SCH3) and ethylthio (-SCH2CH3) are also particularly preferred phenyl ring substituents.
  • R and R 1 groups of Formula IV include phenyl substituted at least at the 2,5 ring positions.
  • R and R 1 groups of Formula IV include phenyl substituted at least at the 2,5 ring positions.
  • R and R 2 are the same as defined above for Formula IV; each R 3 , R 4 , R 5 , R 3 ', R 4 ' and R 5 ' substituent is independently selected from the same group of substituents as defined above for R 3 -R 5 of Formula IV; m and n are each independently 0 (R 5 and R 5' are hydrogen when m and n are respectively 0), 1, 2 or 3; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formula IVa include those compounds where at least one of R and R 2 is other than heterocyclic aryl or carbocyclic aryl, e.g.
  • R and R 2 are hydrogen or substituted or unsubstituted alkyl, particularly substituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms.
  • Preferred values of m and n of Formula IVa are 0 and 1.
  • Further preferred compounds of Formula IV include those compounds where the value n equals 1 , particularly where n equals 1 and the phenyl ring is substituted by a R 5 group at the 3- or 4-position, i.e. the phenyl ring is 2,3,5-substituted or 2,4,5-substituted.
  • Especially preferred compounds of Formula IV are those where n is equal to zero (i.e., the 3, 4 and 6 positions of the phenyl ring are hydrogen- substituted), specifically compounds of the following Formula IVb:
  • Particularly preferred compounds of Formula IVb include those compounds where R is substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl or naphthyl and where at least one of R 1 and R 2 is other than heterocyclic aryl or carbocyclic aryl, e.g. where at least one of R 1 and R 2 is hydrogen or substituted or unsubstituted alkyl, particularly substituted or unsubstituted alkyl having 1 , 2, 3 or 4 carbon atoms.
  • a still further group of preferred compounds 2) for use in accordance with the invention have, in addition to a 2,5-substituted phenyl moiety, at least one guanidine substituent (i.e., R, R 1 or R 2 of Formula IV) that is a phenyl group substituted at the 3-position, preferably without substitution at other ring positions.
  • guanidine substituent i.e., R, R 1 or R 2 of Formula IV
  • Particularly preferred are N-(3-substituted phenyl)- N'-(2,5-disubstituted phenyl) guanidines of the following Formula IVc:
  • R, R 2 and n are the same as defined above for Formula IV; each R 3 ', R 4 ', R 5 ' and R 3" substituent is independently selected from the same group of substituents as defined above for R 3 , R 4 and R 5 for Formula IV; and pharmaceutically salts of said compounds.
  • Preferred compounds of Formula IVc include those compounds where at least one of R and R 2 is other than heterocyclic aryl or carbocyclic aryl, e.g. where at least one of R and R 2 is hydrogen or substituted or unsubstituted alkyl, particularly substituted or unsubstituted alkyl having 1 to about 4 carbon atoms.
  • compounds of Formula IVc are those where one of R and R 2 is hydrogen and the other is substituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms, more preferably where R is methyl, ethyl or propyl and R 2 is hydrogen.
  • Preferred values of n of Formula IVc are 0 and 1.
  • Specifically preferred compounds of Formula IV for use in the present methods include N-(3-ethyl ⁇ henyl)-N,N'-dimethyl-N'-(2,5- dichlorophenyl) guanidine; N-(3-ethylphenyl)-N-methyl-N'-(2,5- dichlorophenyl) guanidine ; N- (3-ethylphenyl) -N- (2 ,5-dichlorophenyl) -N'- methylguanidine; N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine; N-(3- ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine; N- (3-ethylphenyl) - N'- (2, 5-dibromophenyl) -N'-methylguanidine; N-(3-ethy
  • Preferred compounds of the above Formulae I through III also include those having a substituent of carbocyclic aryl with at least 6 ring carbons, particularly phenyl, and substituted at one or more ring positions by haloalkyl, substituted or unsubstituted thioalkyl having from 1 to about 3 carbon atoms, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl and haloalkyl.
  • Specifically preferred compounds include N-(l-naphthyl)-N'-(3-methylthiophenyl)-N'- methylguanidine; N-( l-naphthyl)-N-methyl-N'-(3- methylthiophenyl) guanidine; N-(l-naphthyl)-N,N'-dimethyl-N'-(3- methylthiophenyl) guanidine; N-( l-naphthyl)-N'-(3- methylthiophenyl) guanidine; N-(l-naphthyl)-N'-(3-methylsulfinylphenyl)-N'- methylguanidine; N- (1 -naphthyl) -N-methyl-N' -(3- methylsulfmylphenyl) guanidine ; N- ( 1 -naphthyl)
  • R is cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 1 ,4-methylenecyclohexyl, 1- or 2-adamantyl, exo or endo 2-norbornyl, exo or endo 2-isobornyl, menthyl, cyclopentylmethyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl; carbocyclic aryl, alkaryl, aralkyl or heterocyclic, e.g., of 6 to 18 carbon atoms and containing 1-3 separate or fused rings, and 0-5 O, N and/ or S ring atoms in an aryl, alicyclic or mixed ring system, e.g., phenyl, benzyl
  • R 1 and R 2 are the same or different and selected from the group consisting of hydrogen, lower C ⁇ -6 alkyl, lower C ⁇ -6 alkylamino, C5-10 aryl or substituted aryl; wherein R and the acenaphthyl group are optionally substituted by hydroxy, acetate, oxo, amino, lower Ci- ⁇ alkyl, lower C1-6 alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocyanato, halogen, amido, sulfonato or carbamido.
  • Formula V include N,N'-di-(l-acenaphthyl)guanidine; N,N'-di-(3- acenaphthyl) guanidine; N,N'-di-(5-acenaphthyl)guanidine; N,N'-di-
  • diadamantylguanidine compounds of the following Formula VI:
  • X 1 , X 2 , X 3 , and X 4 are the same or different and are selected from the group consisting of hydrogen, hydroxy, acetate, oxo, amino, lower C ⁇ -6 alkyl, lower Ci- ⁇ alkyl amino, alkoxy of 1-6 carbon atoms, lower Ci- ⁇ alkyl amino, alkoxy of 1-6 carbon atoms, di-lower C2-12 alkyl amino, nitro, azido, sulfhydryl, cyano, isocynato, halogen, amido, sulfonato or carbamido; wherein at least one of X 1 , X 2 , X 3 , and X 4 is other than hydrogen; x and y are the same or different and are 0, 1, 2, 3 or 4.
  • diadamantyl guanidines for use in the present methods include di-(3-nitroadamantan-l-yl)guanidine; N,N'-di-(3- hydroxyadamantan- 1-yl) guanidine, N,N'-di-(3-amino-adamantan-l- yl)guanidine; N,N'-di-(3-nitro-adamantan-2-yl)guanidine; N,N'-di-(3- hydroxyadamantan-2-yl)guanidine; N,N'-di-(3-aminoadamantan-2- yl)guanidine; N,N'-di-(5-nitroadamantan-2-yl)guanidine; N,N'-di-(5-hydroxy- adamantan-2-yl)guanidine; N,N'-di-(5-aminoadamantan-2-yl)guanidine;
  • a further preferred group of compounds for use as a compound 2) in accordance with the invention is hydrazinedicarboximidamide compounds of the following Formula VII: R-NH-C-NH-R 1
  • R, R 1 , R 4 and R 5 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 1 ,4-methylenecyclohexyl, 1- or 2-adamantyl, exo or endo 2-norbornyl, exo or endo 2-isobornyl, menthyl, cyclopentyl-methyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl; carbocyclic aryl, alkaryl, aralkyl or heterocyclic, e.g., of 6 to 18 carbon atoms and containing 1-3 separate or fused rings, and 0-5 O, N and/or S ring atoms in an aryl
  • Specifically preferred compounds of Formula VII for use in accordance with the invention include N,N',N",N'"- tetracyclohexylhydrazinedicarboximidamide; N,N',N",N'"- tetraphenylhydrazinedicarboximidamide; N,N'-di-(adamantan- 1 -yl)-N" ,N'"- dicyclohexylhydrazinedicarboximidamide ; N ,N ,N" ,N" ' -tetra- (adamantan- 1 - yl)hydrazinedicarboximidamide; N,N',N",N'"-tetra-(adamantan-2-yl)- hydrazinedicarboximidamide; N,N'-di- (adamantan- l-yl)-N",N"'-di- (adamantan-2-yl)-hydrazinedicar
  • hydrazinecarboximidamides of the following Formula VIII:
  • R and R 1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 1 ,4-methylenecyclohexyl, 1- or 2-adamantyl, exo or endo 2- norbornyl, exo or endo 2-isobornyl, menthyl, cyclopentyl-methyl, cyclohexyl- methyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl; carbocyclic aryl, alkaryl, aralkyl or heterocyclic, e.g., of 6 to 18 carbon atoms and containing 1-3 separate or fused rings, and 0-5 O, N and/or S ring atoms in an aryl, alicyclic or
  • R and R 1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 1,4-methylenecyclohexyl, 1- or 2-adamantyl, exo or endo 2- norbornyl, exo or endo 2-isobornyl, menthyl, cyclopentyl-methyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl; carbocyclic aryl, alkaryl, aralkyl or heterocyclic, e.g., of 6 to 18 carbon atoms and containing 1-3 separate or fused rings, and 0-5 O, N and/or S ring atoms in an aryl, alicyclic or mixed ring system
  • R 6 is hydrogen, Ci-C ⁇ alkyl, C3-C12 cycloalkyl, carbocyclic aryl, nitrile, Ci-C ⁇ alkoxycarbonyl, Ci-C ⁇ acyl or benzoyl.
  • aminoguanidines for use as compound 2) in accordance with the invention are compounds of the following Formula X:
  • R and R 1 are the same or different and are cycloalkyl of 3 to 12 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 1,4-methylenecyclohexyl, 1- or 2-adamantyl, exo or endo 2- norbornyl, exo or endo 2-isobornyl, menthyl, cyclopentyl-methyl, cyclohexyl- methyl, 1- or 2-cyclohexylethyl and 1-, 2- or 3-cyclohexylpropyl; carbocyclic aryl, alkaryl, aralkyl or heterocyclic, e.g., of 6 to 18 carbon atoms and containing 1-3 separate or fused rings, and 0-5 O, N and/or S ring atoms in an aryl, alicyclic or mixed
  • Specifically preferred compounds of Formula X include N,N'-dicyclohexyl-N"-aminoguanidine, N,N'-di-(adamantan- l-yl)-N"-aminoguanidine, N,N'-di-(adamantan-2-yl)-N"- aminoguanidine, N,N'-di-(2-norbornyl)-N"-aminoguanidine, and N,N'-di-(2- isobornyl) -N"-aminoguanidine .
  • n 2, 3, 4 or 5;
  • X and Y are independently a single bond, a branched or straight chain C1-C12 alkylene or a branched or straight chain alkenylene;
  • R and R' are independently hydrogen, substituted or unsubstituted a cycloalkyl group of at least 3 carbons, a substituted or unsubstituted carbocyclic group of at least 6 carbon atoms, particularly substituted or unsubstituted phenyl; substituted or unsubstituted aralkyl of at least 6 carbon atoms and containing 1-3 separate or fused rings, or a substituted or unsubstituted heterocyclic or heteroaromatic group having from 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms, and wherein each of R and R' may be substituted; or wherein R and R' together with the guanidine nitrogen to which they are attached form a saturated or unsaturated cyclic ring containing at least 2 carbon atoms exclusive of
  • Specifically preferred compounds of Formula XI include N,N'-di(m-ethylphenyl)-2- iminodazolidine; N,N'-bis-(4-tert-butylphenyl)-2-iminopyrimidazolidine; N,N'- bis-(4-pentylphenyl)-2-iminopyrimidazolidine; N,N'-bis-(4-hexylphenyl)-2- iminopyrimidazolidine; N,N'-bis-(naphthyl)-2-iminopyrimidazolidine; N,N'- bis- (5-acenaphthyl) -2 -iminopyrimidazolidine; N,N'-bis-(tetralinyl)-2- iminopyrimidazolidine.
  • a further group of compounds preferred for use as compound 2) in accordance with the invention are compounds of the following Formula XII:
  • R is hydrogen, C2-C6 acyl, C ⁇ -C 6 alkyl, aryl, C ⁇ -C& alkoxycarbonyl, C - C10 aralkyl, C2-C6 alkenyl, C3-C15 dialkylaminoalkyl, Ci-C ⁇ hydroxyalkyl, C2- C6 alkynyl, C3-C15 trialkylsilyl, C -C ⁇ o alkylcycloalkyl, or C3-C6 cycloalkyl; R 1 hydrogen, Ci-C ⁇ alkyl, C2-C6 alkenyl, C 7 -C ⁇ o aralkyl, C ⁇ -C 6 alkoxy, Ci-C ⁇ alkylamino, or C3-C15 dialkylaminoalkyl;
  • X and Y are independently selected from the group consisting of a halogen such as chloro, fluoro, bromo, iodo, C ⁇ -C 6 alkoxy, C2-C6 dialkoxymethyl, Ci-C ⁇ alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C ⁇ -C 6 haloalkyl, e.g.
  • a halogen such as chloro, fluoro, bromo, iodo, C ⁇ -C 6 alkoxy, C2-C6 dialkoxymethyl, Ci-C ⁇ alkyl, cyano, C3-C15 dialkylaminoalkyl, carboxy, carboxamido, C ⁇ -C 6 haloalkyl, e.g.
  • Z represents a group selected from
  • R 2 is hydrogen, C ⁇ -C 6 alkyl, C2-C6 alkenyl, aralkyl, C4-C15 dialkylaminoalkyl, heterocycloalkyl, C2-C6 acyl, aroyl, or aralkanoyl
  • R 3 is Ci-C ⁇ alkyl, C2-C6 alkenyl, phenyl, aralkyl or C3-C15 dialkylaminoalkyl
  • n is an integer selected from 0 (X or Y is hydrogen, respectively), 1, 2,
  • the compounds having Formula (XII) above may exist in racemic form or in the optically active stereoisomeric form.
  • typical C1-C6 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl t-butyl, i-butyl, pentyl, i-pentyl and hexyl groups;
  • typical C2-C6 acyl groups include acetyl, propanoyl, i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl;
  • typical aryl groups include phenyl, naphthyl, phenanthryl and anthracyl;
  • typical Ci-C ⁇ alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, n-
  • typical C2-C6 alkenyl groups include vinyl, allyl, 2-butenyl, 2- pentenyl and 2-hexenyl groups
  • typical C2-C6 alkynyl groups include ethynyl and proparyl groups
  • typical halo include fluoro, chloro, bromo and iodo
  • typical aroyl include carbonyl substituted by phenyl, naphthyl, phenanthryl and anthracyl
  • typical aralkanoyl groups include carbonyl substituted by the above-listed aralkyl groups
  • typical aralkoxy groups include the above- listed Ci-C ⁇ alkoxy groups substituted by phenyl, naphthyl, phenanthyl and anthracyl groups
  • typical substituted aryl groups include the above-listed aryl groups substituted by halo
  • Specifically preferred compounds of Formula XII for use in accordance with the invention are disclosed in PCT/US92/03554 and include (+) and/or (-) 10,5- (iminomethano)- 10, 11 -dihydro- 5H- dibenzo[a,d]cycloheptene; (+) and/or (-) 5-methyl-10,5-(iminomethano)- 10, l l-dihydro-5H-dibenzo[a,d]cycloheptene; (+) and/or (-) N-methyl-10,5- (iminomethano)-10, l l-dihydro-5H-dibenzo[a,d]cycloheptene; (+) and/or (-) 5-methyl-N-methyl- 10,5- (iminomethano)- 10, 1 l-dihydro-5H- dibenzo[a,d]cycloheptene; (-)-3-chloro-5-(iminomethano)- 10, 1
  • N,N-disubstituted guanidines are also preferred for use as compound 2) in accordance with the invention, including compounds of the following Formula XIII:
  • R and R 1 are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having
  • R 2 and R 3 each being independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, and substituted and unsubstituted aminoalkyl; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of Formula XIII also include those compounds having substituents with 1 to about 6 carbon atoms, particularly R 2 and/or R 3 groups that have 1 to 6 carbon atoms (where R 2 and/ or R 3 are other than hydrogen).
  • R 2 and R 3 substituents of compounds of Formula XIII include unsubstituted alkyl and heteroalkyl such as alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl.
  • Preferred R and R 1 groups include substituted and unsubstituted acenaphthyl, phenyl, biphenyl, naphthyl, fluorenyl and benzyl, particularly alkyl-substituted and alkoxy- substituted phenyl and benzyl.
  • R and R 1 groups include straight and branched chain C ⁇ -8-alkyl substituted phenyl and benzyl such as tert- butylphenyl, tert-butylbenzyl, sec-butylphenyl, sec-butylbenzyl, n- butylphenyl, n-butylbenzyl, iso-butylphenyl, iso-butylbenzyl, pentylphenyl, pentylbenzyl, hexylphenyl, hexylbenzyl and the like; straight and branched chain C ⁇ -8-alkoxy (including haloalkoxy, i.e.
  • alkoxy substituted by F, Cl, Br and/ or I) substituted phenyl and benzyl such as butoxyphenyl, butoxybenzyl, pentoxyphenyl, pentoxybenzyl, hexoxyphenyl, hexoxybenzyl, trifluoromethoxyphenyl, trifiuorobenzyl, fluoro and the like; alkaryl (including alkoxyaryl) substituted phenyl and benzyl, particularly substituted and unsubstituted benzyl and benzyloxy (especially - OCH2C6H5) .
  • Cycloalkyl and aryl such as substituted phenyl, benzyl and naphthyl are also preferred R and R 1 groups such as biphenyl, phenylbenzyl (i.e. -CH2C6H4C6H5), cyclohexylphenyl, cyclohexylbenzyl and the like.
  • Halo (i.e., F, Cl, Br and/or I) substituted R and R 1 groups are also preferred including halo-substituted phenyl, naphthyl and benzyl.
  • Specifically preferred compounds of Formula XIII above include N-(4-sec-butylphenyl)-N-benzylguanidine; N-(5-acenaphthyl)- N-benzylguanidine; N- (3-acenaphthyl) -N-benzylguanidine; N-(5- acenaphthyl) -N- (4-isopropylbenzyl) guanidine ; N- (3-acenaphthyl) -N- (4- isopropylbenzyl) guanidine; N-(4-cyclohexylphenyl)-N-(4- isopropylbenzyl)guanidine; N-(4-cyclohexylphenyl)-N-(4-tert- butylbenzyl) guanidine; N-(2-fluorenyl)-N-(4-tert-butylbenzyl)guanidine; N-
  • a still further group of preferred compounds for use in the present methods are guanidines having a substituent of substituted or unsubstituted fluorenyl, phenanthracenyl, anthracenyl and fluoranthenyl, including compounds of the Formulae I, II or III above and having at least one guanidine substituent of substituted or unsubstituted fluorenyl, substituted or unsubstituted phenanthracenyl, substituted or unsubstituted anthracenyl and substituted or unsubstituted fluoranthenyl.
  • Specifically preferred compounds include N,N'-bis(2-fluorenyl)guanidine; N,N'-bis(2-fluorenyl)-N-methylguanidine; N,N'-bis(2-fluorenyl)-N,N'- dimethylguanidine; N,N'-bis(anthracenyl)guanidine; N,N'-bis(anthracenyl)-N- methylguanidine; N,N'-bis(anthracenyl)-N,N'-dimethylguanidine; N,N'- bis(phenanthracenyl) guanidine; N,N'-bis(phenanthracenyl)-N- methylguanidine; N,N'-bis(phenanthracenyl)-N,N'-dimethylguanidine; N,N'- bis(fluoranthenyl)guanidine; N,N'-bis(fluoroanthenyl)-N-methylguanidine; N,
  • R and R 1 are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aryloxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aralkoxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atom
  • R 2 and R 3 are each independently hydrogen or a group as defined for R and R 1 above, and preferably are each substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, alkylthio or alkylsulfinyl; or R 1 and R 3 together form a ring having 5 or more ring members; n and n' independently are each equal to 1, 2, or 3; X and X' are each independently a chemical bond (i.e., a bond between the guanidine nitrogen and R or R 1 ), substituted or unsubstituted alkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted alkenylene having from 2 to about 8 carbon atoms, or substituted or unsubstituted alkynylene having from 2 to about 8 carbon atoms, substituted or unsubstituted heteroalkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted
  • Preferred compounds of Formula XIV include those where X is substituted or unsubstituted alkylene or alkenylene having 1 to about 3 carbon atoms.
  • Specifically preferred compounds of Formula XIV include N-5-acenaphthyl- N'-benzhydrylguanidine; N-5-acenaphthyl-N'-benzhydryl-N-methylguanidne; N-5-acenaphthyl-N'-benzhydryl-N'-methylguanidine; N-5-acenaphthyl-N'- benzhydryl-N,N'-dimethylguanidine; N-3-acenaphthyl-N'- benzhydrylguanidine; N-3-acenaphthyl-N'-benzhydryl-N-methylguanidine; N-3-acenaphthyl-N'-benzhydryl-N'-methylguanidine; N-3-acenaphth
  • Further preferred compounds for use as compound 2) in accordance with the invention are substituted guanidines (including compounds of Formulae I, II and III above) that have a phenyl substituent that is ring substituted by one or more branched groups such as branched alkyl e.g. sec-butyl or tert-butyl, and/ or one or more substituted or unsubstituted aralkoxy substituents, particularly substituted or unsubstituted benzyloxy.
  • the phenyl substituent is ring substituted by such branched or aryloxy groups at 1, 2 or 3 ring positions.
  • Specifically preferred compounds include N,N'-di-(4-sec-butylphenyl)guanidine; N,N'-di-(4-sec-butylphenyl)-N-methylguanidine; N,N'-di-(4-sec-butylphenyl)-N,N'- dimethylguanidine; N-(2-naphthyl)-N'-(4-isopropylphenyl)guanidine; N-(2- naphthyl)-N'-(4-isopropylphenyl)-N-methylguanidine; N-(2-naphthyl)-N'-(4- isopropylphenyl)-N'-methylguanidine; N-(2-naphthyl)-N'-(4-isopropylphenyl)- N,N'-dimethylguanidine; N,N,N'-dimethylguanidine; N,N,N'-
  • R and R 1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic
  • substituent of the 4, 5, 6 and 7 aromatic ring positions are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring
  • 3- benzothiazolinylcarboximidamide compounds -O- or substituted or unsubstituted -N-, and preferably is substituted or unsubstituted methylene; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • R and R 1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic
  • substituent of the 2 and 3 ring positions) and each R 3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or
  • X is -O- (i.e. 2,3-benzmorpholinyl compounds), -S- (i.e. 2,3- benzthiomorpholinyl compounds), substituted or unsubstituted -N-, or substituted or unsubstituted methylene (-CH2-); m and n are each independently 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • Formula XVII Further preferred for use in combination with an aminoglycoside antibiotic in accordance with the present invention are compounds of the following Formula XVII:
  • R and R 1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic
  • substituent of the 1, 3 and 4 tetrahydroisoquinolinyl ring positions) and each R 3 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substitute
  • the 1, 3 and 4 tetrahydroisoquinolinyl ring positions are each hydrogen- substituted), 1, 2, 3, 4, 5 or 6; n is 0 (i.e. the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • R and R 1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic
  • substituent of the aromatic positions 3-8) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms,
  • R and R 1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic
  • substituent of the aromatic positions 1-4) and each R 4 are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted
  • the 5,6-dihydrophenanthridinyl ring position is hydrogen- substituted), 1 or 2; and n and r are each independently 0 (i.e. the ring positions are each hydrogen- substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
  • R, R 1 , X, R 2 , R 3 and n are the same as defined above for Formula XVI, but where X can also be sulfinyl (i.e.-S(O)-) or sulfonyl (i.e. - S(O2)-), and m of Formula XX is an integer equal to 0-6, and preferably m is 0, 1 or 2; and pharmaceutically acceptable salts thereof.
  • Preferred substituents of Formula XVI also will be preferred substituents at corresponding positions of compounds of Formula XX.
  • R, R 1 , R 2 , R 3 and m are the same as defined above for Formula XVIII, and n of Formula XXI is an integer equal to 0-9, and preferably n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. It is understood that an R 3 substituent can be the same or different and may be present on either the non-aromatic or aromatic fused ring. Preferred substituents of Formula XVIII also will be preferred substituents at corresponding positions of compounds of Formula XXI.
  • R, R 1 , R 2 , R 3 , n and r are the same as defined above for Formula XIX, except R and R 1 each may be hydrogen, although preferably at least one of R and R 1 will be other than hydrogen, and m of Formula XXII is an integer equal to 0-4, and preferably m is 0, 1 or 2, and the dotted line in Formula XXII represents an optional carbon-carbon double bond (endocyclic bond); and pharmaceutically acceptable salts thereof.
  • Preferred substituents of Formula XIX also will be preferred substituents at corresponding positions of compounds of Formula XXII.
  • R 2 , R 3 , n and r are the same as defined above for Formula XIX; R and R 1 are also the same as defined above for Formula XIX, except R and R 1 each may be hydrogen, although preferably at least one of R and R 1 will be other than hydrogen; m of Formula IX is an integer equal to 0-6 (i.e. R 2 may be a substituent at any of the available three saturated ring positions), and preferably m is 0, 1 or 2.
  • R and R 1 are a carbocyclic aryl, aralkyl, or heteroaromatic or heteroalicyclic group, particularly substituted or unsubstituted phenyl or naphthyl. More preferably, for each of Formulae XV through XXIII, R is a carbocyclic aryl, heteroaromatic or heteroalicyclic group, and R 1 is a non-aryl group, particularly hydrogen or substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or aminoalkyl.
  • R groups of Formulae XV through XXIII are preferred R groups of Formulae XV through XXIII.
  • R 1 groups are hydrogen and substituted or unsubstituted alkyl such as substituted or unsubstituted alkyl having 1 to about 6 carbon atoms or 1 to about 3 carbon atoms.
  • Specifically preferred compounds of Formula XV include the following:
  • N- (1 -naphthyl) - 1 -indolinylcarboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula
  • Specifically preferred compounds of Formula XVI include the following:
  • Particularly preferred compounds of Formula XVI include the following structure and pharmaceutically acceptable salts thereof:
  • Specifically preferred compounds of Formula XVII include the following:
  • Specifically preferred compounds of Formula XVIII include the following:
  • N-(2-methylphenyl)- l-(benz[cd]indolinyl) carboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compound of Formula XVIII.
  • Specifically preferred compounds of Formula XIX include the following:
  • Specifically preferred compounds of Formula XXI include the following:
  • Specifically preferred compounds of Formulae XXII and XXIII include the following: l-(5,6, l l,12-tetrahydrodibenz[b,f azocin)-carboximidamide;
  • Additional preferred compounds for use in combination with an aminoglycoside antibiotic include imine-substituted compounds of the following Formula XXIV:
  • Z is sulfur, oxygen, carbon or nitrogen; m and n are each independently an integer from 0 to 4, and the sum of m and n is at least 2, preferably is 3, 4, 5 or 6, more preferably 3, 4 or 5; each X is independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylamino preferably having from 1 to about
  • substituted or unsubstituted methylene (-CH2-) is a generally preferred Z ring member.
  • Generally preferred X groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
  • particularly preferred X groups included substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio and ethylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
  • the imine-substituted ring nitrogen shown in the above Formula XXIV generally would not be substituted by an X group. It is further understood that the ring methylene (CH 2 ) groups (which include Z where Z is carbon) of the above Formula XXIV will include only a single hydrogen if the methylene unit is mono-substituted by an X group, i.e. the methylene unit will be (CHX), or the methylene unit will contain no hydrogens if di-substituted by X groups, i.e. the methylene unit will be
  • Formula XXIV include six-member ring compounds (i.e. where the sum of m and n above is four), particularly compounds of the following Formula XXIVa:
  • Particularly preferred compounds of Formula XXIV are substituted piperidines of the following Formula XXIVb:
  • X is the same as defined above for Formula XXIV; p" is an integer of from 0 (where the ring is substituted only by the depicted imine) to 10, more typically from 0 to about 4; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of the invention have at least two ring substituents (p>2 in Formula XXIV), particularly 2,6-substituted compounds of Formula XXIVa, such as the following substituted piperidine compounds of Formula XXI Vc:
  • W and Y are each independently substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsilyl preferably having 1 to about 20 carbon atoms and 1 or more Si atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms, including haloalkoxy; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl preferably having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfony
  • W and Y groups include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
  • W and Y groups included substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
  • imine-substituted compounds that are substituted by a group other than hydrogen on the imine or adjacent non-cyclic nitrogen.
  • Preferred are compounds of the following Formula XXV:
  • R, R 1 and R 2 are each independently hydrogen; hydroxy; substituted or unsubstituted alkanoyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkanoyloxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkyl preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl preferably having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio preferably having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylamino preferably having from 1 to about 20 carbon atoms;
  • compounds of Formula XXV that have at least two ring substituents (p>2 in Formula XXV), particularly 2,6-substituted compounds of Formula XXVa, such as the following piperidine compounds of Formula XXVb:
  • W and Y are the same as defined above for Formula XXIVc; R, R 1 and R 2 are each the same as defined above for Formula XXV; and pharmaceutically acceptable salts thereof.
  • R, R 1 and R 2 are each the same as defined above for Formula XXV; and pharmaceutically acceptable salts thereof.
  • XXV, XXVa and XXVb include substituted and unsubstituted alkyl, substituted and unsubstituted alkylsilyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylsulfinyl, substituted and unsubstituted alkylsulfonyl, substituted and unsubstituted aralkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaromatic or heteroalicyclic groups.
  • XXV, XXVa and XXVb include substituted and unsubstituted alkyl and substituted and unsubstituted carbocyclic aryl, particularly substituted or unsubstituted naphthyl or phenyl such as naphthyl or phenyl substituted by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio or ethylthio, and alkylsilyl preferably having 1 to about 15 carbon atoms.
  • R and R 1 groups of compounds of Formulae XXV, XXVa and XXVb include substituted and unsubstituted carbocyclic aryl and heteroaromatic and heteroalicyclic groups.
  • Particularly preferred R and R 1 groups are substituted and unsubstituted naphthyl and phenyl groups, such as naphthyl or phenyl substituted at one or more ring positions by alkyl or haloalkyl having 1 to about 6 carbons, halogen, alkylthio, particularly alkylthio having 1 to about 6 carbon atoms such as methylthio.
  • R and R 1 groups include hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylsulfinyl, alkylsulfonyl, substituted or unsubstituted alkanoyl and substituted or unsubstituted alkanoyloxy.
  • compounds of Formulae XXV, XXVa and XXVb are those where at least of one of R and R 1 is other than hydrogen, and R 2 is hydrogen.
  • R 2 is hydrogen.
  • the ring methylene groups (CH2) of the above Formula XXV will include only a single hydrogen if the methylene unit is mono-substituted by an X group, i.e. the methylene unit will be (CHX), or the methylene unit will contain no hydrogens if di-substituted by X groups, i.e. the methylene unit will be (CXX). It is also understood the range of p values will depend in part on the sum of m and n as well as the valence of the Z ring substituent. Specifically preferred compounds of Formulae XXIV and XXV include the following:
  • N-carboximidamide-r-2 c-6-di(4-methylphenyl)piperidine; N-carboximidamide-r-2, c-6-di(4-isopropylphenyl)piperidine; N-carboximidamide-r-2, t-6-di(4-methylphenyl)piperidine; N-carboximidamide-r-2, c-6-diphenylpyrrolidine; N-(N'-phenyl)carboximidamide-r-2, c-6-diphenylpiperidine; and pharmaceutically acceptable salts thereof. See General of Organic Chemistry, 56:4833-4840 (1991) for discussion of the nomenclature of these preferred compounds. The structural formulae of these preferred compounds are also shown in the examples, which follow.
  • suitable halogen groups of compounds for use in the present methods include F, Cl, Br and I; preferred alkyl groups include those having 1 to about 12 carbon atoms, more preferably 1 to about 10 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, etc.; and preferred alkenyl and alkynyl groups include those groups having one or more unsaturated linkages, preferably one or two unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms.
  • alkyl, alkenyl and alkynyl may refer to both cyclic and noncyclic groups, unless otherwise specified.
  • Preferred alkoxy groups of compounds for use in the present methods include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbons. Straight and branched chain butoxy, pentoxy, and hexoxy may be particularly preferred for some compounds. Methoxy, ethoxy and propoxy also may be preferred.
  • Preferred aryloxy groups of compounds for use in the present methods have 6 to about 20 carbon atoms or from 6 to about 12 carbon atoms and include an oxygen atom.
  • Substituted or unsubstituted phenoxy and naphthoxy are preferred aryloxy groups.
  • Preferred aralkoxy groups of compounds for use in methods of the invention from 6 to about 20 carbon atoms and include an alkoxy group as specified above that contains one or more aryl substituents, particularly one or more carbocyclic aryl substituents. Typically an oxygen will be the terminal group of the substituent.
  • Substituted or unsubstituted benzyloxy i.e., C6H5CH2O-
  • Preferred alkylthio groups of compounds for use in the present methods include groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbons.
  • Preferred aminoalkyl groups of compounds for use in the present methods include those groups having one or more primary, secondary and/ or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbons. Secondary and tertiary amine groups are generally more preferred than primary amine moieties.
  • Preferred alkylsulfinyl groups of compounds for use in the present methods have one or more sulfinyl (SO) groups, more typically one sulfinyl group, and from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbons, and even more preferably 1-3 carbon atoms.
  • Preferred alkylsulfonyl groups of compounds for use in the present methods have one or more sulfono (SO2) groups, more typically one sulfono group, and from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbons, and even more preferably 1-3 carbon atoms.
  • Preferred alkenylene and alkynylene groups of compounds for use in the present methods have one or two carbon-carbon multiple bonds.
  • Preferred heteroalkylene, heteroalkenylene and heteroalkynylene groups of compounds for use in the present methods contain 1 to about 3 heteroatoms consisting of N, O and/ or S atoms.
  • heteroatoms of substituent groups will be N, O or S.
  • Suitable heteroaromatic and heteroalicyclic groups of compounds for use in methods of the invention contain one or more N, O or S atoms and include, e.g., quinolinyl including 8-quinolinyl, indolinyl including 5-indolinyl, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl and phthalimido groups all of which may be optionally independently substituted at one or more available positions and/ or fused to a benzene ring; and substituted or unsubstituted tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl groups, pyrazinyl, coumarinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzo
  • Preferred carbocyclic aryl groups include those having about 6 to about 20 carbons, more preferably about 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms such as phenyl, naphthyl, acenaphthyl, phenanthryl, anthracyl and fluorene groups.
  • Suitable aralkyl groups contain 1 to 3 separate of fused rings and from 6 to about 18 carbon atoms such as benzyl and metJb.ylenenaphth.yl (-CH2-naphthyl).
  • Said substituted moieties or substituents of compounds for use in the present methods may be substituted at one or more available positions by one or more suitable groups such as, e.g., halogen such as F, Cl, Br, or I; cyano; hydroxyl; nitro; azido; carboxy; carbocyclic aryl; alkyl groups including alkyl groups having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups such as those groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylthio groups such as those groups having one or more thioether linkages and from 1 to about 12 carbon atoms or
  • Specifically preferred substituted groups include carboxylic acyl groups, preferably having from 1 to about 12 or 1 to about 6 carbon atoms such as acetyl, propanoyl, iso-propanoyl, butanoyl, sec-butanoyl, pentanoyl and hexanoyl groups.
  • alkaryl groups which include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups, e.g., above- mentioned aryl groups substituted by one or more Ci-Cio alkyl groups such as phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl groups as well as the branched chain isomers thereof such as tert-butylphenyl, sec-butylphenyl, etc.
  • Haloalkyl and haloalkoxy are also preferred, particularly fluoroalkyl and fluoroalkoxy such as trifluoromethyl and trifluoroalkoxy.
  • Aroyl groups are also preferred substituted groups such as carbonyl substituted by phenyl, naphthyl, acenaphthyl, phenanthryl, and anthracyl groups and carboxylic acyl groups substituted by one or more aryl groups, e.g., diphenylacetoxy and fluorenecarboxy groups.
  • Aralkanoyl groups are also preferred and include carbonyl substituted by the aralkyl groups described above.
  • Aralkoxy groups are also preferred substituted groups and include alkoxy groups substituted by phenyl, naphthyl, acenaphthyl, phenanthyl, and anthracyl groups.
  • Preferred substituted aryl groups include the above described aryl groups substituted by halo, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, amino, aminoalkyl, thioalkyl and the like.
  • Compounds 2) for use in combination with an aminoglycoside antibiotic can be prepared in accordance with disclosed procedures.
  • guanidine compounds useful in methods of the invention can be readily prepared by the reaction of an amine, typically an amine salt such as an amine hydrochloride, with a preformed alkyl or aryl cyanamide (see S.R. Safer, et al., J. Org. Chem., 13:924 (1948)) or the corresponding N-substituted alkyl or aryl cyanamide.
  • a preformed alkyl or aryl cyanamide see S.R. Safer, et al., J. Org. Chem., 13:924 (1948)
  • This is a particularly suitable method for producing N,N'-diaryl-N'-alkyl in which the substituents are not identical.
  • asymmetrical guanidines see G.J. Durant et al., J. Med. Chem., 28: 1414 (1985), and CA. Maryanoff et al., J. Org. Chem., 51: 1882
  • substituted guanidines can be prepared suitably by reaction of an appropriate amine salt such as an amine hydrochloride with a slight molar excess (e.g., ca. 1.1 molar equivalent) of a substituted cyanamide in a suitable solvent such as toluene or chlorobenzene under an inert atmosphere such as argon or nitrogen.
  • a suitable solvent such as toluene or chlorobenzene
  • the reaction is then heated, e.g. from about 110 to 120°C for 2 to about 16 hours until reaction completion, e.g. as indicated by thin layer chromatography.
  • the reaction solution is then cooled to room temperature, and suitably diluted with a solvent such as absolute alcohol.
  • the solvent is then removed under reduced pressure to provide the desired substituted guanidine.
  • the crude product then can be purified e.g. by recrystallization and/or chromatography.
  • the cyanamide and amine reagents with appropriate substituents are commercially available or can be readily prepared by known procedures.
  • the cyanamide starting material can be synthesized from the correspondingly substituted amine by treatment with cyanogen bromide (BrCN) in suitable solvent such as dry ethyl ether.
  • the amine hydrochloride can be obtained by treatment of an appropriate amine with an excess of HCl.
  • alkylsulfinyl-substituted or alkylsulfonyl- substituted reagent that can provide correspondingly substituted guanidines as described above, can be provided by oxidation (e.g., H2O2) of alkylthio- substituted reagents.
  • Compounds of Formula XV through XXIII can be prepared by reaction of a suitable precursor compound, e.g. indolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroquinolinyI (or derivative thereof) compound, 1,2, 3, 4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound, 5,6-dihydrophenanthridinyl compound, 2,3,4, 5-tetrahydro-[ 1,5]- benzothiazepine compounds (or derivative thereof, e.g.
  • a suitable precursor compound e.g. indolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroquinolinyI (or derivative thereof) compound, 1,2, 3, 4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound, 5,6-dihydrophenanthridinyl compound, 2,3,4, 5-tetrahydro-[ 1,5]- benzothi
  • compounds Formulae XV through XXIII can be suitably prepared by reaction of an appropriate indolinyl (or derivative thereof) salt (to prepare compounds of Formula XV) , 1,2,3,4- tetrahydroquinolinyI (or derivative thereof) salt (to prepare compounds of Formula XVI), 1,2, 3, 4-tetrahydroisoquinolinyl salt (to prepare compounds of Formula XVII), benz[cd]indolinyl salt (to prepare compounds of Formula XVIII), or 5,6-dihydrophenanthridinyl salt (to prepare compounds of Formula XIX) or other appropriate salt such as salts of above mentioned precursor compounds (to form compounds of Formulae XX-XXIII) with a substituted cyanamide in a suitable solvent such as toluene, chlorobenzene or the like under an inert atmosphere such as argon or nitrogen as exemplified in the Scheme below.
  • a suitable solvent such as toluene, chlorobenzene
  • reaction solution is then heated e.g. from about 110° to 120°C for 2 to about 16 hours until reaction completion, e.g. as indicated by thin layer chromatography.
  • reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention.
  • the crude product then can be purified by recrystallization and/ or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50x w/w) with suitable solvents.
  • the indolinyl (or derivative thereof), 1,2,3,4-tetrahydroquinoline (or derivative thereof), 1,2,3,4-tetrahydroisoquinoline, benz[cd]indolinyl or 5,6- dihydrophenanthridinyl or other precursor such as those mentioned above (for Formulae XX-XXIII) and cyanamide reagents with appropriate substituents are commercially available or can be readily prepared by known procedures.
  • the cyanamide starting material can be synthesized from the correspondingly substituted amine by treatment with cyanogen bromide (BrCN) in a suitable solvent such as dry ethyl ether or toluene at reduced temperatures (e.g. 0°C) or room temperature.
  • R moiety as defined above for Formulae XV through XXIII (in the Scheme, that R moiety is exemplified as phenyl which may be ring-substituted by groups Ri and R2).
  • R groups of compounds of Formula XV through XIII can be provided by use of suitable substituted amines that are reacted with BrCN, such as e.g. substituted and unsubstituted anilines as shown in the Scheme, substituted and unsubstituted 1-naphthylamine, 2-naphthylamine, acenaphthylamine, etc.
  • R 1 groups other than hydrogen of compounds of Formulae XV through XXIII can be readily provided by reaction of a substituted cyanamide with a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide).
  • a halide reagent e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide.
  • compounds of the invention having an R 1 group of methyl can be prepared by reaction of a mono- substituted amine (e.g., an aniline, naphthylamine or acenaphthylamine) with formic acid followed by treatment with lithium aluminum hydride to provide the corresponding methyl-substituted cyanamide (e.g., C6HsN(CH3)CN from unsubstituted aniline).
  • a mono- substituted amine e.g., an aniline, naphthylamine or acenaphthylamine
  • Alkylsulfmyl-substituted or alkylsulfonyl- substituted reagents that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g., H2O2) of alkylthio- substituted reagents.
  • Compounds of Formula XVI where R and R 1 are each hydrogen can be prepared by reaction of 1,2,3,4-tetrahydroquinoline compound with cyanamide.
  • R 2 substituents can be provided by reaction of a substituted or unsubstituted quinoline compound with a Grignard reagent followed by hydrogenation to provide the substituted 1,2,3,4-tetrahydroquinoline compound.
  • Compounds of Formulae XV, XVI and XX where X is -S(O)- or - S(O)2- can be prepared by oxidation (e.g. with H2O2 and/or with sodium periodate) of the corresponding preformed compounds where the ring member X is -S-.
  • amine starting materials are commercially available and/ or can be readily prepared.
  • benz[cd]indoline and 5,6- dihydrophenanthridine reagents can be prepared treatment of a benz[cd]indo-2(lH)-one compound or 5,6-dihydrophenanthridinone compound with a base such as diborane in a suitable solvent such as tetrahydrofuran.
  • Chiral compounds of the invention may be used as optically enriched or racemic mixtures.
  • An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomers.
  • Optically enriched mixtures can be obtained by known procedures, e.g., column chromatography using an optically active binding material or formation of a salt using an optically active material, particularly an optically active acid.
  • Particularly preferred optically enriched mixtures include sulfinyl- containing compound of the invention, e.g. compounds of Formulae XV, XVI or XX where X is -S(O)-, or compounds having an alkylsulfinyl or other sulfinyl substituent.
  • Such optically active mixtures of sulfinyl-containing compounds can be readily prepared, e.g. by column chromatography using an optically active binding material.
  • Compounds of Formulae XXIV and XXV can be prepared by several routes.
  • compounds of Formula XXIV or XXV can be suitably prepared by reaction of a precursor compound of Formula XXVI above with cyanamide to provide compounds of Formula XXIV, or a substituted cyanamide to provide compounds of Formula XXV, in a suitable solvent such as methanol, ethanol and chloroform or the like under an inert atmosphere such as argon or nitrogen.
  • a suitable solvent such as methanol, ethanol and chloroform or the like
  • an inert atmosphere such as argon or nitrogen.
  • an HCl or other acid addition salt of the precursor compound III is reacted with the cyanamide.
  • the reaction solution is suitably heated e.g. from about 100°C or greater for 2 to about 60 hours until reaction completion, e.g. as indicated by thin layer chromatography.
  • reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention.
  • the crude product then can be purified by recrystallization and/ or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50x w/w) with suitable solvents.
  • Precursor compounds of the above Formula XXVI may be commercially available or can be prepared by reduction of the corresponding unsaturated heterocyclic nitrogen compound, e.g. by use of a reducing agent such as sodium and ethanol. Hydrogenation also may be employed using palladium or other suitable catalyst.
  • the nitrogen may be suitably activated during hydrogenation, e.g. with an oxycarbonyl group such as t- butoxycarbonyl or the like, which group can be then removed such as by acidic hydrolysis prior to reaction with cyanamide or other reagent.
  • Substituted unsaturated cyclic amine compounds to employ in such reduction reactions can be prepared by several methods.
  • an organometallic reagent can be prepared (typically Group I or II metal, particularly Li or Mg) such as by a halogen-metal exchange reaction followed by reaction of that organometallic reagent with a halopyridine or other halogen-substituted cyclic amine.
  • a substituted pyridine or other unsaturated precursor compound can be prepared by cyclization of an intermediate compound that contains the ring substituents (i.e. groups X, W and Y in the above Formulae XXIV and XXV), e.g. by cyclization of a substituted 1,5- diketopentyl compound with hydroxylamine.
  • Compounds of Formulae XXIV and XXV also may be prepared by reaction of a precursor compound of Formula XXVI above with cyanogen bromide to provide the N-cyano derivative (i.e. compounds of Formula XXVI above substituted at the depicted ring nitrogen by cyano).
  • That cyano intermediate then may be suitably reacted an amine, particularly an ammonium salt such as an acetate salt, typically with heating to provide the N-imine substituted compound of Formula XXIV.
  • Compounds of Formula XXV may be prepared by reaction of the N-cyano derivative with a primary or secondary amine (to provide the desired R and R 1 groups as defined above for Formula XXV) in the presence of a Lewis acid such as AlCb and the like.
  • Alkylsulfinyl-substituted or alkylsulfonyl- substituted reagents that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g., H2O2) of alkylthio- substituted reagents.
  • oxidation e.g., H2O2
  • methods are provided for treatment of infections, including Gram-negative and Gram-positive bacteria such as Pseudomonas aeruginosa and other Pseudomonas strains, and tuberculosis strains.
  • the therapeutic methods of the invention can be employed in therapies wherever aminoglycosides have been previously employed as well as against other infections, e.g.
  • the methods and compositions of the invention exhibit reduced ototoxicity relative to use of an aminoglycoside alone.
  • the methods of the invention in general comprise administering an aminoglycoside antibiotic in combination with a compound 2) such as a substituted guanidine or other compound as disclosed herein.
  • the aminoglycoside and a compound 2) may be administered simultaneously, in the same or different pharmaceutical formulations, or sequentially. However, if administered sequentially, the aminoglycoside and compound 2) are preferably administered within a sufficient time to achieve the desired pharmacological effects of reduced ototoxicity.
  • a combination of an aminoglycoside antibiotic and a compound 2) may be administered to a subject by a variety of routes including oral, rectal, nasal, topical (including eye drops, buccal, sublingual), vaginal or parenteral (including subcutaneous, intramuscular and intradermal) administration.
  • Compounds 2) are suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi- sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc. It also should be appreciated that at least many of the compounds 2) may exist as any one of a number tautomeric forms. Each of such tautomeric forms is within the scope of the invention, including as defined by the above formulae. Additionally, compounds used in the methods and compositions of the invention may have asymmetric centers and occur as racemic mixtures or an optically enriched mixtures.
  • an organic or inorganic acid e.g., hydrochloride, sulfate, hemi- sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, me
  • An aminoglycoside and compound 2) can be employed, either alone or in combination with one or more other therapeutic agents, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for a desired route of administration which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for a desired route of administration which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/ or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/ or aromatic substances and the like which do not deleteriously react with the active compounds.
  • solutions preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are convenient unit dosages.
  • enteral application particularly suitable are tablets, dragees or capsules having talc and/ or carbohydrate carrier binder or the like, the carrier preferably being lactose and/ or corn starch and/ or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • a suitable effective dose of a active agents of a formulation of the invention will be in a range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day of each of an aminoglycoside antibiotic and a compound 2) , more typically in the range of from 0.01 to 50 milligrams per kilogram bodyweight of recipient per day of each of an aminoglycoside antibiotic and a compound 2) .
  • the desired dose is suitably administered once daily, or several sub- doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.

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Abstract

Cette invention se rapporte à des procédés et à des compositions de traitement des infections, et notamment des infections bactériennes à bacilles gram négatif et gram positif. Lesdits procédés consistent à administrer un aminoside en association à une guanidine substituée ou à un autre composé. Les compositions et procédés préférés de cette invention permettent de traiter efficacement, et avec un risque réduit d'ototoxicité, des infections qui étaient par le passé traitées par des aminosides.
PCT/US1998/013640 1997-07-07 1998-07-06 Traitement associe a base d'aminosides et de guanidines n,n'-disubstituees WO1999002145A1 (fr)

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WO2005004880A1 (fr) * 2003-07-04 2005-01-20 Chelsea And Westminster Nhs Tr Ameliorations apportees a des composes organiques
EP1468005A4 (fr) * 2001-12-26 2006-05-03 Yeda Res & Dev Procedes d'utilisation de conjugues de saccharides et de composes d'acetamidine ou de guanidine pour le traitement d'infections bacteriennes
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US7511175B2 (en) 2005-01-05 2009-03-31 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US20110201688A1 (en) * 2008-10-20 2011-08-18 University Of South Florida N,n'-di-p-bromophenyl guanidine treatment for stroke at delayed timepoints
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8633337B2 (en) 2010-05-14 2014-01-21 Ge Healthcare Limited Method and synthesis
US8716345B2 (en) 2005-01-05 2014-05-06 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
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US7345018B2 (en) 2002-04-25 2008-03-18 Reception Aps Method of treating side effects induced by therapeutic agents
WO2004084876A3 (fr) * 2003-03-26 2004-12-23 Recepticon Aps Utilisation de composes pour prevenir la toxicite cellulaire induite par un medicament
CN100441175C (zh) * 2003-03-26 2008-12-10 里斯普蒂康公司 化合物用于制备预防药物诱导的细胞毒性药物的用途
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US8148337B2 (en) 2003-07-04 2012-04-03 Hazem El-Refaey Vaginal compositions for treating pelvic tissue infections and traumas
US7880001B2 (en) 2004-04-29 2011-02-01 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US9133145B2 (en) 2004-04-29 2015-09-15 Abbvie Inc. Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8415354B2 (en) 2004-04-29 2013-04-09 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8372841B2 (en) 2004-04-29 2013-02-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7855308B2 (en) 2005-01-05 2010-12-21 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
US9290444B2 (en) 2005-01-05 2016-03-22 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
USRE41135E1 (en) 2005-01-05 2010-02-16 Abbott Laboratories Inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 enzyme
US8198331B2 (en) 2005-01-05 2012-06-12 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8314270B2 (en) 2005-01-05 2012-11-20 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7528282B2 (en) 2005-01-05 2009-05-05 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7511175B2 (en) 2005-01-05 2009-03-31 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8716345B2 (en) 2005-01-05 2014-05-06 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US8993632B2 (en) 2005-01-05 2015-03-31 Abbvie Inc. Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US7217838B2 (en) 2005-01-05 2007-05-15 Abbott Laboratories Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
US9464072B2 (en) 2006-04-07 2016-10-11 Abbvie Inc. Treatment of central nervous system disorders
US8940902B2 (en) 2006-04-07 2015-01-27 Abbvie Inc. Treatment of central nervous system disorders
US20110201688A1 (en) * 2008-10-20 2011-08-18 University Of South Florida N,n'-di-p-bromophenyl guanidine treatment for stroke at delayed timepoints
US8633337B2 (en) 2010-05-14 2014-01-21 Ge Healthcare Limited Method and synthesis
WO2016121862A1 (fr) * 2015-01-28 2016-08-04 国立大学法人九州大学 Médicament anti-inflammatoire et utilisations

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