CA2106068A1 - Long chain antiviral compounds - Google Patents
Long chain antiviral compoundsInfo
- Publication number
- CA2106068A1 CA2106068A1 CA002106068A CA2106068A CA2106068A1 CA 2106068 A1 CA2106068 A1 CA 2106068A1 CA 002106068 A CA002106068 A CA 002106068A CA 2106068 A CA2106068 A CA 2106068A CA 2106068 A1 CA2106068 A1 CA 2106068A1
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- Prior art keywords
- formula
- compound
- methyl
- chain
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A long chain compound of formula Z-(A)n-Y, wherein each of Z
and Y is a polyheteroalkyl chain of 9 to 32 members or is a polyheterocyclic moiety having from 9 to 32 ring members, providing that one of Z and Y is a chain, and A is a linking atom or group and n is 0 or an integer from 1 to 6, is indicated as an antiviral compound and has shown activity against HIV in standard tests.
and Y is a polyheteroalkyl chain of 9 to 32 members or is a polyheterocyclic moiety having from 9 to 32 ring members, providing that one of Z and Y is a chain, and A is a linking atom or group and n is 0 or an integer from 1 to 6, is indicated as an antiviral compound and has shown activity against HIV in standard tests.
Description
WO 92/16494 ~ o ~ ~ PCT/GB92/00438 LONG CHAIN ANTIVIRAL COMPOUNDS
., .
This invention concems improvements in chemical compounds, more especially it concerns compounds and pha~maceutical compositions. ln 5 particular it concerns compositions and compounds having activity in in vitro tests on Human Immunodeficiency Virus-infected cells.
The disease known as Acquired lmmune Deficiency Syndrome (AIDS) caused by infection by HlV has attracted immense research efforl because of the effects of the disease on infected individuals and the dangers of the disease spreading to a wider section of the population. In general.
~- although various chemo-therapeutic treatments have been advocated. and some compounds have emerged as a potential basis ~or treatment. there is still a need for alten~atives. In particular, most treatments such as the compound . .
wo 92/16494 Pcr/GB92/00438 ii 8 - 2 -known as AZT have a high toxicity to cells, and it would be desirable to find compounds which are less toxic. In mam the development of resistance to AZT has been identified as an additional clinical problem.
We have found a group of compounds which show protective properties in m vitro screens of cells challenged with HIV- I and/or HIV-2 .
and are therefore indicated as having potential for the treatment of AIDS and AIDS Related Complex and other viral and especially retroviral infections.
Accordingly, the present invention provides the use of compoundls defined below, in pharrnaceutical compositions for treating HIV-infected patients. The invention further provides pharmaceutical compositions comprising a said compound in combination or association with a pharmaceutically acceptable diluent or carrier, for the treatment of HIV-infected patients. The invention may also be defined as the use of a said compound for the manufacture of a medicarnent for the treatment of HlV-infected patients. The invention further provides a process for the production of a phannaceutical composition for the treatment of a HlV-infected patient, comprising the combination of a compound as defined below with a phalmaceutically acceptable diluent or carrier, and forrnulating said composition into a form suitable for administration to said patient. The invention also provides a method of treatment of an HIV-infected patient, comprising administering to said patient an effective dose of a said compound. It is to be understood that treatment includes prophylactic treatment of patients at risk. in view of the protective properties observed. Whilst this description is especially directed to - 25 combating HIV, this invention includes other aspects in which other diseases may be treated, including for exarnple microbial infections.
,.
WO 92/l6494 ~ ; 8 PCr/GB92/00438 A 2.2'-dimer of cycla~n has been reported as being isolated as a 2% by-product in the synthesis of cyclam (1.4.8.11-tetraazacyclotetradecane) (Barefield et al . J C S Chem Comm (1981). 302). This compound was stated to be insoluble in water. We believe that the insoluble 2.2'-bicyclam is a rnixture of the 2R.2 R and 2S,2 S enantiomers: we have characterised a soluble dimer which we believe to be the meso 2R.2' S isomer. The 6.6-bicyclam isomer has been reported by Pabbrizi et al, lnorg Chem 25.
2671 (1986). C~rtain N.N'-linked bicyclic compounds have been reported by Ciampolini et a Inorg. Chem. 26, 3527 (1987). No biological activity has been suggested for such compounds.
US Patent 4,156,683 discloses monocyclic and bicyclic macrocyclic compounds, which are said to have biological activity in regulating sodium~ potassium and calcium levels in mamtnals. Additionally.
a specific group of N-alkylated monocyclic compounds are said to possess activity against A2 influenza viruses in a modified Hermann test on chick fibroblast tissue. The single example mentioned of such N-alkylates/
monocyclic compounds is 4,13-dimethyl-1,7,10.16-tetra~,13-diazacyclo-octadecane. It is also said that the preferred compounds, which form complexes of greater stability, are those having three blidging chains between bridgehead nitrogen atoms. that is fused bicyclic compounds.
It is also reported in Chemical Abstracts 88 1052925 (1978) that ;. certain fused triple ring heterocyclic compounds ha~te activity against A2 ~ngland influenza virus in chick embryos.
wo 92/1~94 pcr/GB92/oo438 j 3 ~ ~ 4 Rowe~t et al have reported in Biochem J 1987, 245(3) 641-7 that some simple cyclic polyarnines reduce the infectivity of bactenophages.
Bacteriophages infect bacteria but do not cause any human disease. and this paper does not discuss anti-viral activity in humans.
Certain tetrarnines have been synthesised and shown to be active in tests indicating antimalalial activity. (Edwards et al, J Med Chem. 34.
No 2, 56911991]).
l 0 Our US Patent 5 ,021,409 discloses that linked cyclic polyheterocyclic compounds have activity against HIV.
The present invention provides active compounds of the general formula 1, Z ~ ~)n ~ Y
in which each :Z and Y is independently a polyheteroalkyl chain having a chain length of 9 to 32 members or a polyheterocyclic moiety having 'from 9 to 32 ring members, and each having from 3 to 8 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen and sulphur, provided that at least one of Z and Y is a said chain, A is a linking atom or group, and n is O or an integer from I to 6.
The invention also encompasses acid addition salts and metal 2~ complexes of the compounds of formula 1.
., .
This invention concems improvements in chemical compounds, more especially it concerns compounds and pha~maceutical compositions. ln 5 particular it concerns compositions and compounds having activity in in vitro tests on Human Immunodeficiency Virus-infected cells.
The disease known as Acquired lmmune Deficiency Syndrome (AIDS) caused by infection by HlV has attracted immense research efforl because of the effects of the disease on infected individuals and the dangers of the disease spreading to a wider section of the population. In general.
~- although various chemo-therapeutic treatments have been advocated. and some compounds have emerged as a potential basis ~or treatment. there is still a need for alten~atives. In particular, most treatments such as the compound . .
wo 92/16494 Pcr/GB92/00438 ii 8 - 2 -known as AZT have a high toxicity to cells, and it would be desirable to find compounds which are less toxic. In mam the development of resistance to AZT has been identified as an additional clinical problem.
We have found a group of compounds which show protective properties in m vitro screens of cells challenged with HIV- I and/or HIV-2 .
and are therefore indicated as having potential for the treatment of AIDS and AIDS Related Complex and other viral and especially retroviral infections.
Accordingly, the present invention provides the use of compoundls defined below, in pharrnaceutical compositions for treating HIV-infected patients. The invention further provides pharmaceutical compositions comprising a said compound in combination or association with a pharmaceutically acceptable diluent or carrier, for the treatment of HIV-infected patients. The invention may also be defined as the use of a said compound for the manufacture of a medicarnent for the treatment of HlV-infected patients. The invention further provides a process for the production of a phannaceutical composition for the treatment of a HlV-infected patient, comprising the combination of a compound as defined below with a phalmaceutically acceptable diluent or carrier, and forrnulating said composition into a form suitable for administration to said patient. The invention also provides a method of treatment of an HIV-infected patient, comprising administering to said patient an effective dose of a said compound. It is to be understood that treatment includes prophylactic treatment of patients at risk. in view of the protective properties observed. Whilst this description is especially directed to - 25 combating HIV, this invention includes other aspects in which other diseases may be treated, including for exarnple microbial infections.
,.
WO 92/l6494 ~ ; 8 PCr/GB92/00438 A 2.2'-dimer of cycla~n has been reported as being isolated as a 2% by-product in the synthesis of cyclam (1.4.8.11-tetraazacyclotetradecane) (Barefield et al . J C S Chem Comm (1981). 302). This compound was stated to be insoluble in water. We believe that the insoluble 2.2'-bicyclam is a rnixture of the 2R.2 R and 2S,2 S enantiomers: we have characterised a soluble dimer which we believe to be the meso 2R.2' S isomer. The 6.6-bicyclam isomer has been reported by Pabbrizi et al, lnorg Chem 25.
2671 (1986). C~rtain N.N'-linked bicyclic compounds have been reported by Ciampolini et a Inorg. Chem. 26, 3527 (1987). No biological activity has been suggested for such compounds.
US Patent 4,156,683 discloses monocyclic and bicyclic macrocyclic compounds, which are said to have biological activity in regulating sodium~ potassium and calcium levels in mamtnals. Additionally.
a specific group of N-alkylated monocyclic compounds are said to possess activity against A2 influenza viruses in a modified Hermann test on chick fibroblast tissue. The single example mentioned of such N-alkylates/
monocyclic compounds is 4,13-dimethyl-1,7,10.16-tetra~,13-diazacyclo-octadecane. It is also said that the preferred compounds, which form complexes of greater stability, are those having three blidging chains between bridgehead nitrogen atoms. that is fused bicyclic compounds.
It is also reported in Chemical Abstracts 88 1052925 (1978) that ;. certain fused triple ring heterocyclic compounds ha~te activity against A2 ~ngland influenza virus in chick embryos.
wo 92/1~94 pcr/GB92/oo438 j 3 ~ ~ 4 Rowe~t et al have reported in Biochem J 1987, 245(3) 641-7 that some simple cyclic polyarnines reduce the infectivity of bactenophages.
Bacteriophages infect bacteria but do not cause any human disease. and this paper does not discuss anti-viral activity in humans.
Certain tetrarnines have been synthesised and shown to be active in tests indicating antimalalial activity. (Edwards et al, J Med Chem. 34.
No 2, 56911991]).
l 0 Our US Patent 5 ,021,409 discloses that linked cyclic polyheterocyclic compounds have activity against HIV.
The present invention provides active compounds of the general formula 1, Z ~ ~)n ~ Y
in which each :Z and Y is independently a polyheteroalkyl chain having a chain length of 9 to 32 members or a polyheterocyclic moiety having 'from 9 to 32 ring members, and each having from 3 to 8 heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen and sulphur, provided that at least one of Z and Y is a said chain, A is a linking atom or group, and n is O or an integer from I to 6.
The invention also encompasses acid addition salts and metal 2~ complexes of the compounds of formula 1.
3 ~
4 pcrtGB92/oo438 In the above forrnula, A may be alkylene, for example 1,3 propandiyl, unsaturated alkylene or a group selected from aryl, alkylaryl, alkylarylalkyl, fused aryl, polyoxoethylene, carboxylate, esters ancl arnides, or a nitrogen or sulphur atom. In a particularly preferred embodiment of the 5 invention, A is alkylene of I to 6 carbon atoms or is alkylphenylalkyl in which each alkyl is of I to 6 carbon atoms and the phenyl ring is unsubstituted or substituted by methoxy~ fluorine. chlorine, bromine or nitro~
and the alkyl groups are in the m- or p- positions relative to one another.
The chains or heterocycles Z and Y may be linked to the remainder of the molecule through carbon or heteroatoms, for example linked through C.C'~C,N' or N.N', Each of Z and Y may contain nitrogen and/or oxygen and/or 15 sulphur heteroatoms; preferably the moieties contain nitrogen atoms with optional further heteroatoms selected from oxygen and sulphur, A particular embodiment of the invention relates to compounds in which all the chain or nuclear heteroatoms are nitrogen atoms. A more preferred embodiment relates to compounds in which each of Z and Y contain four nitrogen atoms.
The chains or cyclic moieties may be substituted or unsubstituted, and may contain unsaturation. Suitable substituents may be selected from halogens, especially fluorine, chlorine or bromine. -NH2. -OH~
;. -COOH, ester groups~ -CONH2 and alkyl or aryl groups~ eg of up to 10 25 carbon atoms, which themsel~es may be substituted by the aforementioned substituents. Preferred chains are of 8 to 18 atoms. especially 8 to 16 atoms, preferably with 4 to 8 nitrogen heteroatoms; preferred cyclic moieties WO92/16494 ~ `?~j 3;(~ pcr/GB92/oo438 are those of 10 to 24 ring members. especially 12 to 18 ring members, and preferred numbers of nuclear nitrogen atoms are 4 ~o 6. It is convenient that if two chains are linked. they are identicah S The invention also includes what may be termed "pro-drugs".
that is protected forms of the linked compounds, which release the compound after adminis~ration to a patient. For exarnple, the compound may carry a protective group which is split off by hydrolysis in body fluids. e.g. in the bloodstrearn, thus releasing active compound. A discussion of pro-drugs may be found in "Smith and Williams' Introduction to the Principles of Drug Design ", H J Smith, Wright, 2nd Edition, London 1988 .
The compounds of general formula I are believed to be novel.
They may be prepared by the man skilled in organic syntheses, using a variety of methods analogous to those already known in the literature. Thus, Ciampolini et al ~Inorg Chem 26, 3527[19871) have demonstrated the syntheses of alkyl-linked bicyclams by condensation of N,N',Nn-tritosylcyclam with bis (tosyloxy)alkanes or with bis(acyl chlorides). The syntheses of C.N'-and N,N'-linked compounds of formula I may be perfonned in a similar `~ 20 manner by reacting activated precursors (eg compounds substituted with alkyl chains terminated with halides or activated carboxylates) with (N-l)-substitutedheterocycles (eg N,N'.N"-tritosylcyclam) or (N-l)-substituted polyazaalkanes followed by deprotection.
:
Thus~ the invention further provides a process for the production of compourlds of formula I. comprising reacting a compound of formula 11 or 111, wo 92/16494 ~ ~ d pcr/GB92/oo438 Z - (A),~ - X 11 Z _ Xl lll in which Z. A and n are as defined above. and Xl is a reac~ive atom or group S with a compound of forrnula IV or V. respectivelly, X2 ~A)n - Y V
in which Y. A and n are as defined above, and X2 is a reactive atom or group~
under conditions such that a compound of formula I is forrned and the reactive atoms or groups Xl and x2 are split off. It will be realised that it may be desirable to protect other react~ve sites on the moieties Z and Y, for example amino nitrogen atoms, from participation in unwanted reactions, and this may be done by methods well known to the skilled synthetic chemist, fol1Owed by deprotection. Such process variants are to be understood as being within the scope of the invention.
The compounds are indicated for the treatment of viral infections, especially retrovirus infections and particularly HIV infections, and the compounds of formula 1, are to be be considered as active compounds for the pharmaceutical compositions, processes for making the same and methods of treatment mentioned above. In these aspects of the invention.
it is to be understood that rneso forrns. enantiorners and resolved optically active forms of the compounds of formula 1. are included. Also. it is to be considered within the invention. compounds of forrnula I diluted with non-toxic or with other active substances. Acid addition salts, for example hydrochlorides. and non-toxic labile metal complexes of the compounds of WO 92/16494 ~ ~ PCr/GB92/00438 forrnula I are also active compounds according to the present invention.
Non-toxic in the present context has to be considered with reference to the prognosis for the infected patient without treatment. Zinc and nickel complexes are especial]y indicated. whereas less labile metal atoms such as cobalt and rhodium are less preferred because of likely lower selectivity.
The invention will now be described by way of example only.
- EXAMPLE I
a) N-TosYI-3-asnino~roPanoic acid To a mixture of 3-aminopropanoic acid ( 1 equivalent) in water/dioxane ( 1/1 ) was added a solution of NaOH (3 equivalents) in water (50% solution). To the vigorously stisred reaction mixture tosyl chloride (1.1 equivalents) was added portion-wise over 3 hours. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with ether and the aqueous phase was acidified to pH 2.0 with concentrated HCI. The acidffled solution was extracted with ethyl acetate three times.
The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated to give the desired product as a white solid: m p 118.5-120C; yield 85%.
b) SuccinimidYI N-tosyl-3-arninopropanoate To a solutiosl of N-tosyl-3-arninopropanoic acid ( I equivalent) and N-hydroxysuccinimide (I equivalent) in ethyl acetate was added dropwise a solution of dicyclohexylcarbodiimide (I equivalent) in ethyl acetate. The reaction mixture was stirred at room temperature for 4 hours during which time copious amounts of a white precipitate formed. The solids wO 92/16494 2 :~ ;v ~; t3 ~) ~ pcr/GB92/oo438 g (dicyclohexylurea by-product) were removed by filtration and the filtrate was concentrated to drynes~ to give a thick colourless viscous oil The oil was treated with ether/ethyl acetate ~2/1) tO cause precipitation of a white solid:
yield 72 %; m p 126-129 C .
c) rneso- 1,2~3 ~4-tetraaminobutane The tetraamine was synthesised from meso-elythritol according to the method of R L Weller, J Org Chem 49, 5150 ~1984).
d) meso-1,2,3,4-tetrakis~N-~N-(3-tosvlarnidolpro~anamid~)-butane To a solution of 1~2,3 ,4-meso-tetraaminobutane ( I equivalent) in dimethylforrnarnide was added dropwise a solution of succinirnidyl N-tosyl-3-aminopropanoate (8 equivalents) in dimethylformamide. The reaction mixture was heated at 50C for 5days. The DMF was removed under reduced pressure and disso1ved in THF/lN NaOH and stirred overnight during which time a white/yellow solid precipitated which was removed by filtration.
The filtrate was washed with water and dried over magneshlm sulphate to give 12.0g of a light yellow solid; m p 195-197C; yield 70%; mass spec.
e) meso- 1,2 , 3 ,4-tetrakis(N-mesyl-N ' -tosYl- 13 diarnino-proPYl)butane) To a solution of tetraarnide-tetratosylate ( I equivalent) as synthsised above in tetrahydrofuran was added borane.tetrahydrofuran complex (I M: 10 equivalents). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and excess borane was quenched by the addition of methanol. The solution was WO 92/16494 pcr/GB92/oo438 ~ ^; r~ 10 concentrated to dryness and more methanol was added and the solution was re-concentrated The residue was treated with 10 % HCl and then basified to pH 12 with 10 N ~laOH. The cloudy solution was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate.
S filtered and concentrated to give an off-white solid. This product is approximately 50% desired tetraa~nine and was used directly.
The solid was dissolved in dichloromethane and triethylamine (6 equivalents) was added. To the homogeous so}ution a solution of mesyl chloride (4.5 equivalent) in dichlorornethane was added dropwise and the reaction mixture was stirred overnight at room temperature. Dichloromethane and water were added and the phases were separated. The organic phase was washed with 10% HCI and brine, dried over magnesium sulphate and concentrated to give a white amorphous solid. The solid was dissolved in ethyl acetate and passed through a column of silica gel using ethyl acetate as eluant. The eluate was concentrated to dryness to give the desired product as an arnorphous solid; overall yield 30~; mass spectrum '1275 (14%), llg7 (100%), 559 (13%).
f) meso-1,2,3,4-tetrahs(N-1,3-diaminopropYl)butane The tetrarnesyltetratosylate was dissolved in 48% HBr/HOAc and heated at 100C for 48 hours. The solvents were removed under reduced pressure to give a brown oil. The oil was dissolved in a minimum amount of concentrated HCI and concentrated to give a brown amorphous oil. The product was characterised by its mass spectrum. and designated compound A.
WO 92/16494 ~, ~ iJ ~ 8 pcr/GB92/oo438 Other compounds considered to be significant in the present invention are:
4 ,4-( 1 . 3-propanediyl)-bis- 1 .4 . 8 ~ I I -tetraazadodecane 2~4' -( I ~3-propanediyl)-2-rac-tetraazacyclotetradecyl~ -(1~4~8.1 1 )-tetraazadodecane 1 .4 ' -( I . 3-propanediyl )- I -tetraazacyclotetradecyl-4 -~ I .4 . 8 . I I )-tetraa7aundecane 2.4' -(1 .3-propanediyl)-rac-2-eetraazacyclotetradecyl-4 -(1,4.8.11)-tetraazaundecane I .4 -(1 .3-propanediyl~ tetraazacyclotetradecyl-4 -( I .4, 8, I I )-tetraazadodecane Additionally, the following compounds may be synthesised using methods analogous to those illustrated above and those described in the literature, and are indicated for further testing in the biological fields described below.
4 ~4 ' -( I ,2-ethanediyl)-bis- 1 ,4, 8, I I -tetraazadodecane 4 ,4 ' -(1 ,4-butanediyl)bis- 1,4, 8 ,1 1 -tetraazadodecane 4.4' -( I ,5-pentanediyl)-bis- 1,4,8,1 1 -tetraazadodecane 4.4' -( I .6-hexanediyl)-bis- 1,4,8,1 I-tetraazadodecane 2 ,4 ' -( I ,2-ethanediyl)-rac-2-tetraazacyclotetradecyl-4 ' -( I ,4, 8, I I )-tetraazaundecane 2,4' -(1 ,4-butanediyl)-rac-2-tetraazacyclotetradecyl-4' -( I ,4,8, I I )-tetraazaundecane 2.4' -(1,5-pentanediyl)-rac-2-tetraazacyclotetradecyl-4 -(1.4.8.1 1)-tetraazaundecane 2.4' -( I .6-hexanediyl)-rac-2-tetraazacyclotetradecyl-4 ' -( I .4, 8 . I I )-tetraazaundecane 1.4'-( I ,2-ethanediyl)- 1 -tetraazacyclotetradecyl-4' -(1.4,8, I I )-tetraa~aundecane 1.4' -( I .4-butanediyl)- 1 -tetraazacyclotetradecyl-4' -(1,4,8.1 1 )-tetraazaundecane I ,4 -( I ,5-pentanediyl)- 1 -tetraazacyclotetradecyl-4 -( I ,4 ,8.1 1 )-tetraazaundecane 1.4' -( I .6-hexanediyl~- 1 -tetraazacyclotetradecyl-4 -( I .4.8.1 1 )-tetraazaundecane wO 92/16494 PCr/GB92/00438 ~`~33~ - 12 -2 ,4' -( I,2-ethanediyl)-2-rac-tetraazacyclotetradecyl-4' -~1 ,4~8. I 1 )-tetraazadodecane 2 .4 ' -( I .4-butanediyl )-2 -rac-tetraazacyclotetradecyl-4 ' -(1 .4 . 8, I I )-tetraazadodecane 2.4' -(1.S-pentanediyl)-2-rac-tetr~7acyclotetradecyl~'-(1.4.8.1 1)-tetraazadodecane 2.4' -( I .6-hexanediyl)-2-rac-tetraazacyclotetradocyl-4' -(1.4.8.1 1 )-tetraazadodecane s I .4 ' -( I .2-ethanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, 8 ,1 1 )-tetraazadodecane ! .4 ' -(1 ,4-butanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, B ,1 1 )-tetraazadodecane I .4 -( I .5-pentanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, 8 . I I )-tetraazadodecane 1 .4 -( I, 6-hexanediyl)- 1 -tetraa~acyclotetradecyl-4 ' -( I ,4 . 8 . I I )-tetraazadodecane a) To a solution of p-dibromoxylene (2.0g, 7.54mmol) and K2 CO3 (524mg, 3 . 77mmol) in 20ml dry CH3 CN was added tritosylcyclam (l.Og, 1.506mmol) in 10ml of dry CH3CN dropwise over 45 minutes at room temperature. After ~he reaction mixture had been stirred for 2 hours at room temperature, the solution was concentrated, taken up in CH2 Cl2 (ISOml), washed with H20 (10mi) and dried over MgSO4. The organic layer was concentrated and purified by chromatography on silica gel (elu~ion with 5% EtOAc/hexane to 60% EtOAc/hexane) to afford 980mg (77%) of 1-bromomethyl-4~ (4,8,1I-tritosyl-l,4,8,1I tetraazacyclotetradecyl)methyl)-benzene as a white solid.
b) To a solution of N.N'-Bis(3-aminopropyl)ethylenediamine (771mg. 4.42mmol) K2CO3 (17Smg. 1.26mmol) in 20ml of CH3CN was added 950mg. 0.532mmol of the product of step a) in 10ml of dry CH3CN
dropwise over I hour at room temperature. After the reaction mixture had been stirred for 3 hours at room temperature. the solution was filtered and wo 92/16494 ~ .~ U ~ pcr/GB92/oo43B
the filtrate was concentrated. The excess tetraamine was removed by distillation of the concentrated filtrate on a Kugel Rohr apparatus ( 100C:
O.lmm Hg) and the residual oil was then tal¢en up in lOOml of chloroforrn and washed with 10% sat Na2CO3 three times. The organic layers were combined~ dried over K2 C03 and concentra~ed to afford a white solid 950mg (90%), as an approximate 2:1 mixture of 1~ (4,8.1 I-tritosyl-I . 4 . 8 . I I -tetraazacyclotetradecyl )methyl)-4- ( I -( I ,5, 8, 1 2-tetraazadodecyl )-methyl)benzene and 1-(1-(4,8,11-tritosyl-1,4,8.1 I-tetraazacyclotetradecyl)-me~hyl)-4-(s-( 1.5 . 8 .1 2-tetraazadodecyl)methyl)benzene .
c) The mixture produced in step b) (420mg, 0.448mmol) was added to 1 2ml of acetic acid and 6ml of 48 %aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120C. The red solution was cooled to room temperature and concentrated to a paste. Acetic acid (lOml) was added and the resulting solid was collected by filtration through a sintered glass funnel. The tan-white solid was washed with acetic acid (20ml) and ether (20ml) and dried under vacuum overnight (60C/0.4mm Hg~. A tan-white solid was thus obtained (400mg, 80%) as an approxinate 2:1 mixture of 1-(1-(1,4,8,1 1-tetraazacyclotetradecyl)methyl)-4-(1-(1,5,8,12-tetraaza-dodecyl)methyl,~benzene octahydrobromide and 1-(1-(1,4,8,1 I-te~raazacyclotetra-decyl)methyl)~-(5-( 1 ,5, 8, 1 2-tetraazadodecyl)methyl)benzene octahydrobromide .
The products were separated by chromatography. and their structures were confirrned.
. .
WO 92/16494 ~ pcr/GB92/oo438 ~- ~g,`S~ ~'J 3 ~' 1 4 -~,, a) To a solution of triethylenetetraamine (346mg. 2.37mmol) and K2 C03 (83mg, 0.592mmol) in 20ml of dry CH3 CN was added Lhe S product of step a) of Example 2 (250mg. 0.296mmol) in I Oml of dr~
CH3 CN dropwise over 1 hour at room temperature. After the reaction mixture had been stirred for 16 hours at room temperature, the solution was filtered and the filtrate was concentrated. The excess tetraarnine was removed by distillation of the concentrated filtrate on a Kugel Rohr apparatus (100C:
O. Imm Hg) and the residual oil was taken up in lOOml of chlorofol'rn and washed with 10 % sat Na2 CO3 three times. The organic layers were combined, dried over K2C03 and concentrated to af~ord a white solid 220mg (82%), as an approximate 2:1 mixture of 1-(1-(1,4,7,10-tetraazadecy])methyl)-4-(1-(1-(4,8,1 1-tritosyl-1,4,8,1 1-tetraazacyclotetradecyl)methyl)benzerle and 1-(1-(4, 8, I I -tritosyl- 1,4, 8,1 1 -tetraazacyclotetradecyl)methyl)-4-(4-( 1 ,4,7,10-tetraazadecyl)methyl)benzene .
b) The product from step a) above (220mg, 0.242mmol) was added to 8ml of acetic acid and 6rnl of 48 % aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120C. The red solution was cooled to room temperature and concentrated to a paste. Acetic acid (lOml) was added and the resulting solid was collected by filtration through a sintered glass funnel. The solid was washed with acetic acid (20ml) and ether (30ml) and dried under vacuum overnight ~60C/0.4mm Hg). A tan-white solid was wo 92/16494 ~ 8 Pcr/Gs92/Oû438 thus obtained (120mg, 46%) as an approximate 2:1 mixture of 1-~1-(1,4,7,10-tetraazadecyl)methyl)-4-(1~ 4~8,11-tetraazacyclotetradecyl)methyl)benzene octahydrobromide and 1-(1-(1~4~8~11-tetra~7acyclotetradecyl)methyl)-4-(4-( I ~4 ~7 ~ 10-tetraazadecyl)methyl)benzene, The products were separated using S chromatography, and their structures were confinned.
a) To a solution of N,N'-Bis(3-~ninopropyl)ethylenediamine-tetratosylate (467mg, 0.592mmol) and KzC03 (33mg, 0~236mmol) in 15ml of dry DMF was added lOOrng (OH 18mmol) of the product of step a) of Example 2 in lOml of dry DMF dropwise over I hour at 60C. After the reaction mixture had been stirred for 2 hours at 60 C the solution was cooled to room temperature and concentrated~ The residual oil was taken up IS in CH2CI2 (50ml) and washed with (Sml)~ The organic layer was dried over MgS04 and concentrated~ The residue was purified by chromatography on silica gel (elution 2% MeOH; 98% CH2C12) to afford l lOmg (60%~ of I -( I -( I ,4.8.11 -tetratosyl- I ,4,8,11 -tetraazacyclote~radecyl)methyl)4-(1 -( I ,5,8,12-tetratosyl-1,5,8,12-tetraazadodecyl)methyl)benzene, a white solid~
b) 80mg (O.OSlrnmol) of the product of step a) above was added to 6m} acetic acid and 4ml of 48% aq HBr (Aldrich) and the solution was stirred for 48 hours at 110-120C. The brown solution was cooled to .? .. room temperature and concentrated to a paste. Acetic acid (8ml) was added and the resulting solid was collected by filtration through a sintered glass funneh The solid was washed with acetic acid ~lOml) and ether (lOml) and dried under vacuum overnight (60~/0~4mm Hg~ A tan-white solid 50mg Wo 92/16494 , ,~ ,3 - 16 - pcrlGBg2/oo438 t88%), of 1-(1-(1,4,8,11-tetraazacyclotetradecyl)meth~l)-4-(1-(1.5.8.12-tetraazadodecyl)- methyl)benzene octahydrobromide was thus obtained and its structure was confirrned.
Characterised samples of compound A were tested in the standard in vitro tests, described below.
The compound of the invention was tested in a screen by the Ml~ method (J.Virol. Methods 120: 309-321 [1988]). MT-4 cells (2.5 x 104 / well) were challenged with HIV-1 (HTLV-IIIB) or HIV-2 (LAV-2 ROD) at a concerltration of 100 CCID50 and incubated in the presence of various concentrations of the test compounds, which were added immediately after challenge with the virus. After 5 days culture at 37C in a CO2 incubator, the number of viable cells was assessed by the MTT (tetrazolium) method.
Antiviral activity and cytotoxicity of the compounds are expressed in the table below as ED50 (ug/ml) and CD50 (ug/ml), respectively. The potential therapeutic usefulness was assessed by cslculating a Selectivity Index (Sl~
corresponding to the ratio of CD50 to ED50. A control test was performed using the known anti-HIV treatment AZT.
In the table below, the compounds screened were sompound A
and the known compound AZT.
WO 92/16494 ~ J ~ pcr/GB92/oo438 TA}3LE
Compound Virus CDsoED50 Sl A HIV-I >50039 > 13 HIV-2 >50039 > 13 AZT (Comparison) HIV-I> I <0.008 > 125 In this field of study. i~ is considered that any compound exhibiting a Selectivity Index of greater than S has the potential for further study. HIV is one of the most challenging viruses to combat~ and the results given above provide. an indication of activity against other retroviruses and against other vimses in general. The compounds of the invention are also to be considered for activity against microorganisms, such as bacteria and especially against the organisms causing malaria.
The active compounds may be adminis~ered in the form of pharmaceutical compositions formulated according to well known principles and incorporated the compound, preferably in unit dose fonn, in combination with a pharmaceuticaily acceptable diluent or excipient~ Such compositions may be in the form of solutions or suspensions for injection, or irrigation or be in capsule, tablet. dragee, or other solid composition or as a solution or suspension for oral administration or forrnulated into pessaries or suppositories or sustained release fonns of any of the above for implantation. Suitable diluents, calTiers. excipients and other components are known. lt may be desirable also to fo~mulate a composition ~or topical administration such as an ointment or crearn. The compounds of the invention may be used, in the forrn of a composition or alone, and possibly carried on a finely divided WO 92/16494 ~ 3 - 18 - PCr/GB92/00438 form of a composition or alone. and possibly carried on a finely divided support. as a coating on devices which in use contact body fluids. to discourage transmission of viral infections. Exarnples of devices to be considered in this aspect of the invention are surgical devices and gloves and S contraceptions such as condoms. and other items. appliances. wound dressings and coverings. implements etc generally to be considered as devices according to this aspect of the invention.
The pharmaceutical compositions according to the invention may contain unit dosages deterrnined in accordance with conventional pharmacological methods. suitably to provide active compounds in the dosage range in humans of from 0.1 to 10û mg/kg body weight per day. in a single dose or in a number of smaller doses. Preferred dosage ranges are 1 to 30 mg/kg body weight per day. Other active compounds may be used in the i S compositions or such active compounds or supplernenta! therapy may be included in a course of treatrnent.
and the alkyl groups are in the m- or p- positions relative to one another.
The chains or heterocycles Z and Y may be linked to the remainder of the molecule through carbon or heteroatoms, for example linked through C.C'~C,N' or N.N', Each of Z and Y may contain nitrogen and/or oxygen and/or 15 sulphur heteroatoms; preferably the moieties contain nitrogen atoms with optional further heteroatoms selected from oxygen and sulphur, A particular embodiment of the invention relates to compounds in which all the chain or nuclear heteroatoms are nitrogen atoms. A more preferred embodiment relates to compounds in which each of Z and Y contain four nitrogen atoms.
The chains or cyclic moieties may be substituted or unsubstituted, and may contain unsaturation. Suitable substituents may be selected from halogens, especially fluorine, chlorine or bromine. -NH2. -OH~
;. -COOH, ester groups~ -CONH2 and alkyl or aryl groups~ eg of up to 10 25 carbon atoms, which themsel~es may be substituted by the aforementioned substituents. Preferred chains are of 8 to 18 atoms. especially 8 to 16 atoms, preferably with 4 to 8 nitrogen heteroatoms; preferred cyclic moieties WO92/16494 ~ `?~j 3;(~ pcr/GB92/oo438 are those of 10 to 24 ring members. especially 12 to 18 ring members, and preferred numbers of nuclear nitrogen atoms are 4 ~o 6. It is convenient that if two chains are linked. they are identicah S The invention also includes what may be termed "pro-drugs".
that is protected forms of the linked compounds, which release the compound after adminis~ration to a patient. For exarnple, the compound may carry a protective group which is split off by hydrolysis in body fluids. e.g. in the bloodstrearn, thus releasing active compound. A discussion of pro-drugs may be found in "Smith and Williams' Introduction to the Principles of Drug Design ", H J Smith, Wright, 2nd Edition, London 1988 .
The compounds of general formula I are believed to be novel.
They may be prepared by the man skilled in organic syntheses, using a variety of methods analogous to those already known in the literature. Thus, Ciampolini et al ~Inorg Chem 26, 3527[19871) have demonstrated the syntheses of alkyl-linked bicyclams by condensation of N,N',Nn-tritosylcyclam with bis (tosyloxy)alkanes or with bis(acyl chlorides). The syntheses of C.N'-and N,N'-linked compounds of formula I may be perfonned in a similar `~ 20 manner by reacting activated precursors (eg compounds substituted with alkyl chains terminated with halides or activated carboxylates) with (N-l)-substitutedheterocycles (eg N,N'.N"-tritosylcyclam) or (N-l)-substituted polyazaalkanes followed by deprotection.
:
Thus~ the invention further provides a process for the production of compourlds of formula I. comprising reacting a compound of formula 11 or 111, wo 92/16494 ~ ~ d pcr/GB92/oo438 Z - (A),~ - X 11 Z _ Xl lll in which Z. A and n are as defined above. and Xl is a reac~ive atom or group S with a compound of forrnula IV or V. respectivelly, X2 ~A)n - Y V
in which Y. A and n are as defined above, and X2 is a reactive atom or group~
under conditions such that a compound of formula I is forrned and the reactive atoms or groups Xl and x2 are split off. It will be realised that it may be desirable to protect other react~ve sites on the moieties Z and Y, for example amino nitrogen atoms, from participation in unwanted reactions, and this may be done by methods well known to the skilled synthetic chemist, fol1Owed by deprotection. Such process variants are to be understood as being within the scope of the invention.
The compounds are indicated for the treatment of viral infections, especially retrovirus infections and particularly HIV infections, and the compounds of formula 1, are to be be considered as active compounds for the pharmaceutical compositions, processes for making the same and methods of treatment mentioned above. In these aspects of the invention.
it is to be understood that rneso forrns. enantiorners and resolved optically active forms of the compounds of formula 1. are included. Also. it is to be considered within the invention. compounds of forrnula I diluted with non-toxic or with other active substances. Acid addition salts, for example hydrochlorides. and non-toxic labile metal complexes of the compounds of WO 92/16494 ~ ~ PCr/GB92/00438 forrnula I are also active compounds according to the present invention.
Non-toxic in the present context has to be considered with reference to the prognosis for the infected patient without treatment. Zinc and nickel complexes are especial]y indicated. whereas less labile metal atoms such as cobalt and rhodium are less preferred because of likely lower selectivity.
The invention will now be described by way of example only.
- EXAMPLE I
a) N-TosYI-3-asnino~roPanoic acid To a mixture of 3-aminopropanoic acid ( 1 equivalent) in water/dioxane ( 1/1 ) was added a solution of NaOH (3 equivalents) in water (50% solution). To the vigorously stisred reaction mixture tosyl chloride (1.1 equivalents) was added portion-wise over 3 hours. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with ether and the aqueous phase was acidified to pH 2.0 with concentrated HCI. The acidffled solution was extracted with ethyl acetate three times.
The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated to give the desired product as a white solid: m p 118.5-120C; yield 85%.
b) SuccinimidYI N-tosyl-3-arninopropanoate To a solutiosl of N-tosyl-3-arninopropanoic acid ( I equivalent) and N-hydroxysuccinimide (I equivalent) in ethyl acetate was added dropwise a solution of dicyclohexylcarbodiimide (I equivalent) in ethyl acetate. The reaction mixture was stirred at room temperature for 4 hours during which time copious amounts of a white precipitate formed. The solids wO 92/16494 2 :~ ;v ~; t3 ~) ~ pcr/GB92/oo438 g (dicyclohexylurea by-product) were removed by filtration and the filtrate was concentrated to drynes~ to give a thick colourless viscous oil The oil was treated with ether/ethyl acetate ~2/1) tO cause precipitation of a white solid:
yield 72 %; m p 126-129 C .
c) rneso- 1,2~3 ~4-tetraaminobutane The tetraamine was synthesised from meso-elythritol according to the method of R L Weller, J Org Chem 49, 5150 ~1984).
d) meso-1,2,3,4-tetrakis~N-~N-(3-tosvlarnidolpro~anamid~)-butane To a solution of 1~2,3 ,4-meso-tetraaminobutane ( I equivalent) in dimethylforrnarnide was added dropwise a solution of succinirnidyl N-tosyl-3-aminopropanoate (8 equivalents) in dimethylformamide. The reaction mixture was heated at 50C for 5days. The DMF was removed under reduced pressure and disso1ved in THF/lN NaOH and stirred overnight during which time a white/yellow solid precipitated which was removed by filtration.
The filtrate was washed with water and dried over magneshlm sulphate to give 12.0g of a light yellow solid; m p 195-197C; yield 70%; mass spec.
e) meso- 1,2 , 3 ,4-tetrakis(N-mesyl-N ' -tosYl- 13 diarnino-proPYl)butane) To a solution of tetraarnide-tetratosylate ( I equivalent) as synthsised above in tetrahydrofuran was added borane.tetrahydrofuran complex (I M: 10 equivalents). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and excess borane was quenched by the addition of methanol. The solution was WO 92/16494 pcr/GB92/oo438 ~ ^; r~ 10 concentrated to dryness and more methanol was added and the solution was re-concentrated The residue was treated with 10 % HCl and then basified to pH 12 with 10 N ~laOH. The cloudy solution was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate.
S filtered and concentrated to give an off-white solid. This product is approximately 50% desired tetraa~nine and was used directly.
The solid was dissolved in dichloromethane and triethylamine (6 equivalents) was added. To the homogeous so}ution a solution of mesyl chloride (4.5 equivalent) in dichlorornethane was added dropwise and the reaction mixture was stirred overnight at room temperature. Dichloromethane and water were added and the phases were separated. The organic phase was washed with 10% HCI and brine, dried over magnesium sulphate and concentrated to give a white amorphous solid. The solid was dissolved in ethyl acetate and passed through a column of silica gel using ethyl acetate as eluant. The eluate was concentrated to dryness to give the desired product as an arnorphous solid; overall yield 30~; mass spectrum '1275 (14%), llg7 (100%), 559 (13%).
f) meso-1,2,3,4-tetrahs(N-1,3-diaminopropYl)butane The tetrarnesyltetratosylate was dissolved in 48% HBr/HOAc and heated at 100C for 48 hours. The solvents were removed under reduced pressure to give a brown oil. The oil was dissolved in a minimum amount of concentrated HCI and concentrated to give a brown amorphous oil. The product was characterised by its mass spectrum. and designated compound A.
WO 92/16494 ~, ~ iJ ~ 8 pcr/GB92/oo438 Other compounds considered to be significant in the present invention are:
4 ,4-( 1 . 3-propanediyl)-bis- 1 .4 . 8 ~ I I -tetraazadodecane 2~4' -( I ~3-propanediyl)-2-rac-tetraazacyclotetradecyl~ -(1~4~8.1 1 )-tetraazadodecane 1 .4 ' -( I . 3-propanediyl )- I -tetraazacyclotetradecyl-4 -~ I .4 . 8 . I I )-tetraa7aundecane 2.4' -(1 .3-propanediyl)-rac-2-eetraazacyclotetradecyl-4 -(1,4.8.11)-tetraazaundecane I .4 -(1 .3-propanediyl~ tetraazacyclotetradecyl-4 -( I .4, 8, I I )-tetraazadodecane Additionally, the following compounds may be synthesised using methods analogous to those illustrated above and those described in the literature, and are indicated for further testing in the biological fields described below.
4 ~4 ' -( I ,2-ethanediyl)-bis- 1 ,4, 8, I I -tetraazadodecane 4 ,4 ' -(1 ,4-butanediyl)bis- 1,4, 8 ,1 1 -tetraazadodecane 4.4' -( I ,5-pentanediyl)-bis- 1,4,8,1 1 -tetraazadodecane 4.4' -( I .6-hexanediyl)-bis- 1,4,8,1 I-tetraazadodecane 2 ,4 ' -( I ,2-ethanediyl)-rac-2-tetraazacyclotetradecyl-4 ' -( I ,4, 8, I I )-tetraazaundecane 2,4' -(1 ,4-butanediyl)-rac-2-tetraazacyclotetradecyl-4' -( I ,4,8, I I )-tetraazaundecane 2.4' -(1,5-pentanediyl)-rac-2-tetraazacyclotetradecyl-4 -(1.4.8.1 1)-tetraazaundecane 2.4' -( I .6-hexanediyl)-rac-2-tetraazacyclotetradecyl-4 ' -( I .4, 8 . I I )-tetraazaundecane 1.4'-( I ,2-ethanediyl)- 1 -tetraazacyclotetradecyl-4' -(1.4,8, I I )-tetraa~aundecane 1.4' -( I .4-butanediyl)- 1 -tetraazacyclotetradecyl-4' -(1,4,8.1 1 )-tetraazaundecane I ,4 -( I ,5-pentanediyl)- 1 -tetraazacyclotetradecyl-4 -( I ,4 ,8.1 1 )-tetraazaundecane 1.4' -( I .6-hexanediyl~- 1 -tetraazacyclotetradecyl-4 -( I .4.8.1 1 )-tetraazaundecane wO 92/16494 PCr/GB92/00438 ~`~33~ - 12 -2 ,4' -( I,2-ethanediyl)-2-rac-tetraazacyclotetradecyl-4' -~1 ,4~8. I 1 )-tetraazadodecane 2 .4 ' -( I .4-butanediyl )-2 -rac-tetraazacyclotetradecyl-4 ' -(1 .4 . 8, I I )-tetraazadodecane 2.4' -(1.S-pentanediyl)-2-rac-tetr~7acyclotetradecyl~'-(1.4.8.1 1)-tetraazadodecane 2.4' -( I .6-hexanediyl)-2-rac-tetraazacyclotetradocyl-4' -(1.4.8.1 1 )-tetraazadodecane s I .4 ' -( I .2-ethanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, 8 ,1 1 )-tetraazadodecane ! .4 ' -(1 ,4-butanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, B ,1 1 )-tetraazadodecane I .4 -( I .5-pentanediyl)- 1 -tetraazacyclotetradecyl-4 ' -( I ,4, 8 . I I )-tetraazadodecane 1 .4 -( I, 6-hexanediyl)- 1 -tetraa~acyclotetradecyl-4 ' -( I ,4 . 8 . I I )-tetraazadodecane a) To a solution of p-dibromoxylene (2.0g, 7.54mmol) and K2 CO3 (524mg, 3 . 77mmol) in 20ml dry CH3 CN was added tritosylcyclam (l.Og, 1.506mmol) in 10ml of dry CH3CN dropwise over 45 minutes at room temperature. After ~he reaction mixture had been stirred for 2 hours at room temperature, the solution was concentrated, taken up in CH2 Cl2 (ISOml), washed with H20 (10mi) and dried over MgSO4. The organic layer was concentrated and purified by chromatography on silica gel (elu~ion with 5% EtOAc/hexane to 60% EtOAc/hexane) to afford 980mg (77%) of 1-bromomethyl-4~ (4,8,1I-tritosyl-l,4,8,1I tetraazacyclotetradecyl)methyl)-benzene as a white solid.
b) To a solution of N.N'-Bis(3-aminopropyl)ethylenediamine (771mg. 4.42mmol) K2CO3 (17Smg. 1.26mmol) in 20ml of CH3CN was added 950mg. 0.532mmol of the product of step a) in 10ml of dry CH3CN
dropwise over I hour at room temperature. After the reaction mixture had been stirred for 3 hours at room temperature. the solution was filtered and wo 92/16494 ~ .~ U ~ pcr/GB92/oo43B
the filtrate was concentrated. The excess tetraamine was removed by distillation of the concentrated filtrate on a Kugel Rohr apparatus ( 100C:
O.lmm Hg) and the residual oil was then tal¢en up in lOOml of chloroforrn and washed with 10% sat Na2CO3 three times. The organic layers were combined~ dried over K2 C03 and concentra~ed to afford a white solid 950mg (90%), as an approximate 2:1 mixture of 1~ (4,8.1 I-tritosyl-I . 4 . 8 . I I -tetraazacyclotetradecyl )methyl)-4- ( I -( I ,5, 8, 1 2-tetraazadodecyl )-methyl)benzene and 1-(1-(4,8,11-tritosyl-1,4,8.1 I-tetraazacyclotetradecyl)-me~hyl)-4-(s-( 1.5 . 8 .1 2-tetraazadodecyl)methyl)benzene .
c) The mixture produced in step b) (420mg, 0.448mmol) was added to 1 2ml of acetic acid and 6ml of 48 %aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120C. The red solution was cooled to room temperature and concentrated to a paste. Acetic acid (lOml) was added and the resulting solid was collected by filtration through a sintered glass funnel. The tan-white solid was washed with acetic acid (20ml) and ether (20ml) and dried under vacuum overnight (60C/0.4mm Hg~. A tan-white solid was thus obtained (400mg, 80%) as an approxinate 2:1 mixture of 1-(1-(1,4,8,1 1-tetraazacyclotetradecyl)methyl)-4-(1-(1,5,8,12-tetraaza-dodecyl)methyl,~benzene octahydrobromide and 1-(1-(1,4,8,1 I-te~raazacyclotetra-decyl)methyl)~-(5-( 1 ,5, 8, 1 2-tetraazadodecyl)methyl)benzene octahydrobromide .
The products were separated by chromatography. and their structures were confirrned.
. .
WO 92/16494 ~ pcr/GB92/oo438 ~- ~g,`S~ ~'J 3 ~' 1 4 -~,, a) To a solution of triethylenetetraamine (346mg. 2.37mmol) and K2 C03 (83mg, 0.592mmol) in 20ml of dry CH3 CN was added Lhe S product of step a) of Example 2 (250mg. 0.296mmol) in I Oml of dr~
CH3 CN dropwise over 1 hour at room temperature. After the reaction mixture had been stirred for 16 hours at room temperature, the solution was filtered and the filtrate was concentrated. The excess tetraarnine was removed by distillation of the concentrated filtrate on a Kugel Rohr apparatus (100C:
O. Imm Hg) and the residual oil was taken up in lOOml of chlorofol'rn and washed with 10 % sat Na2 CO3 three times. The organic layers were combined, dried over K2C03 and concentrated to af~ord a white solid 220mg (82%), as an approximate 2:1 mixture of 1-(1-(1,4,7,10-tetraazadecy])methyl)-4-(1-(1-(4,8,1 1-tritosyl-1,4,8,1 1-tetraazacyclotetradecyl)methyl)benzerle and 1-(1-(4, 8, I I -tritosyl- 1,4, 8,1 1 -tetraazacyclotetradecyl)methyl)-4-(4-( 1 ,4,7,10-tetraazadecyl)methyl)benzene .
b) The product from step a) above (220mg, 0.242mmol) was added to 8ml of acetic acid and 6rnl of 48 % aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120C. The red solution was cooled to room temperature and concentrated to a paste. Acetic acid (lOml) was added and the resulting solid was collected by filtration through a sintered glass funnel. The solid was washed with acetic acid (20ml) and ether (30ml) and dried under vacuum overnight ~60C/0.4mm Hg). A tan-white solid was wo 92/16494 ~ 8 Pcr/Gs92/Oû438 thus obtained (120mg, 46%) as an approximate 2:1 mixture of 1-~1-(1,4,7,10-tetraazadecyl)methyl)-4-(1~ 4~8,11-tetraazacyclotetradecyl)methyl)benzene octahydrobromide and 1-(1-(1~4~8~11-tetra~7acyclotetradecyl)methyl)-4-(4-( I ~4 ~7 ~ 10-tetraazadecyl)methyl)benzene, The products were separated using S chromatography, and their structures were confinned.
a) To a solution of N,N'-Bis(3-~ninopropyl)ethylenediamine-tetratosylate (467mg, 0.592mmol) and KzC03 (33mg, 0~236mmol) in 15ml of dry DMF was added lOOrng (OH 18mmol) of the product of step a) of Example 2 in lOml of dry DMF dropwise over I hour at 60C. After the reaction mixture had been stirred for 2 hours at 60 C the solution was cooled to room temperature and concentrated~ The residual oil was taken up IS in CH2CI2 (50ml) and washed with (Sml)~ The organic layer was dried over MgS04 and concentrated~ The residue was purified by chromatography on silica gel (elution 2% MeOH; 98% CH2C12) to afford l lOmg (60%~ of I -( I -( I ,4.8.11 -tetratosyl- I ,4,8,11 -tetraazacyclote~radecyl)methyl)4-(1 -( I ,5,8,12-tetratosyl-1,5,8,12-tetraazadodecyl)methyl)benzene, a white solid~
b) 80mg (O.OSlrnmol) of the product of step a) above was added to 6m} acetic acid and 4ml of 48% aq HBr (Aldrich) and the solution was stirred for 48 hours at 110-120C. The brown solution was cooled to .? .. room temperature and concentrated to a paste. Acetic acid (8ml) was added and the resulting solid was collected by filtration through a sintered glass funneh The solid was washed with acetic acid ~lOml) and ether (lOml) and dried under vacuum overnight (60~/0~4mm Hg~ A tan-white solid 50mg Wo 92/16494 , ,~ ,3 - 16 - pcrlGBg2/oo438 t88%), of 1-(1-(1,4,8,11-tetraazacyclotetradecyl)meth~l)-4-(1-(1.5.8.12-tetraazadodecyl)- methyl)benzene octahydrobromide was thus obtained and its structure was confirrned.
Characterised samples of compound A were tested in the standard in vitro tests, described below.
The compound of the invention was tested in a screen by the Ml~ method (J.Virol. Methods 120: 309-321 [1988]). MT-4 cells (2.5 x 104 / well) were challenged with HIV-1 (HTLV-IIIB) or HIV-2 (LAV-2 ROD) at a concerltration of 100 CCID50 and incubated in the presence of various concentrations of the test compounds, which were added immediately after challenge with the virus. After 5 days culture at 37C in a CO2 incubator, the number of viable cells was assessed by the MTT (tetrazolium) method.
Antiviral activity and cytotoxicity of the compounds are expressed in the table below as ED50 (ug/ml) and CD50 (ug/ml), respectively. The potential therapeutic usefulness was assessed by cslculating a Selectivity Index (Sl~
corresponding to the ratio of CD50 to ED50. A control test was performed using the known anti-HIV treatment AZT.
In the table below, the compounds screened were sompound A
and the known compound AZT.
WO 92/16494 ~ J ~ pcr/GB92/oo438 TA}3LE
Compound Virus CDsoED50 Sl A HIV-I >50039 > 13 HIV-2 >50039 > 13 AZT (Comparison) HIV-I> I <0.008 > 125 In this field of study. i~ is considered that any compound exhibiting a Selectivity Index of greater than S has the potential for further study. HIV is one of the most challenging viruses to combat~ and the results given above provide. an indication of activity against other retroviruses and against other vimses in general. The compounds of the invention are also to be considered for activity against microorganisms, such as bacteria and especially against the organisms causing malaria.
The active compounds may be adminis~ered in the form of pharmaceutical compositions formulated according to well known principles and incorporated the compound, preferably in unit dose fonn, in combination with a pharmaceuticaily acceptable diluent or excipient~ Such compositions may be in the form of solutions or suspensions for injection, or irrigation or be in capsule, tablet. dragee, or other solid composition or as a solution or suspension for oral administration or forrnulated into pessaries or suppositories or sustained release fonns of any of the above for implantation. Suitable diluents, calTiers. excipients and other components are known. lt may be desirable also to fo~mulate a composition ~or topical administration such as an ointment or crearn. The compounds of the invention may be used, in the forrn of a composition or alone, and possibly carried on a finely divided WO 92/16494 ~ 3 - 18 - PCr/GB92/00438 form of a composition or alone. and possibly carried on a finely divided support. as a coating on devices which in use contact body fluids. to discourage transmission of viral infections. Exarnples of devices to be considered in this aspect of the invention are surgical devices and gloves and S contraceptions such as condoms. and other items. appliances. wound dressings and coverings. implements etc generally to be considered as devices according to this aspect of the invention.
The pharmaceutical compositions according to the invention may contain unit dosages deterrnined in accordance with conventional pharmacological methods. suitably to provide active compounds in the dosage range in humans of from 0.1 to 10û mg/kg body weight per day. in a single dose or in a number of smaller doses. Preferred dosage ranges are 1 to 30 mg/kg body weight per day. Other active compounds may be used in the i S compositions or such active compounds or supplernenta! therapy may be included in a course of treatrnent.
Claims (15)
1. The use of compounds of general formula I, Z- (A)D - Y I
in which each Z and Y is independently a polyheteroalkyl chain having a chain length of 9 to 32 members or a polyheterocyclic moiety having from 9 to 32 ring members, and each of Z and Y having from 3 to 8 heteroatoms selected from nitrogen, oxygen and sulphur, provided that at least one of Z and Y is a said chain, A is a linking atom or group, and n is 0 or an integer from 1 to 6, and their acid addition salts and metal complexes, in the preparation of a medicament for the treatment of HIV infections.
in which each Z and Y is independently a polyheteroalkyl chain having a chain length of 9 to 32 members or a polyheterocyclic moiety having from 9 to 32 ring members, and each of Z and Y having from 3 to 8 heteroatoms selected from nitrogen, oxygen and sulphur, provided that at least one of Z and Y is a said chain, A is a linking atom or group, and n is 0 or an integer from 1 to 6, and their acid addition salts and metal complexes, in the preparation of a medicament for the treatment of HIV infections.
2. The use of claim 1, wherein one of Z and Y in formula I is a polyheterocyclic moiety as defined therein.
3. The use of claim 1 or 2, wherein in formula I all the heteroatoms in Z and Y are nitrogen atoms.
4. The use of claim 1, 2 or 3, wherein in formula I A is selected from the group consisting of alkylene, aryl, alkylaryl and alkylarylalkyl.
5. The use of any one of the preceding claims, wherein in formula I
when Z and/or Y is a chain, the chain length is of 9 to 16 atoms and when Z
and/or Y is a polyheterocyclic moiety, there are from 12 to 18 ring members.
when Z and/or Y is a chain, the chain length is of 9 to 16 atoms and when Z
and/or Y is a polyheterocyclic moiety, there are from 12 to 18 ring members.
6. The use of any one of the preceding claims, wherein in formula I the number of heteroatoms in a chain is from 4 to 8, and the number of heteroatoms in a cyclic moiety is from 4 to 6.
7. The use of claim 6, wherein in formula I each of Z and Y has four nitrogen atoms as the heteroatoms.
8. The use of any one of the preceding claims, wherein in formula I A
is alkylene of 1 or 6 carbon atoms or is alkylphenylalkyl in which each alkyl is of 1 to 6 carbon atoms and the phenyl ring is unsubstituted or substituted by methoxyl, fluorine, chlorine, bromine or nitro, and the alkyl groups are in the m-or p- positions relative to one another.
is alkylene of 1 or 6 carbon atoms or is alkylphenylalkyl in which each alkyl is of 1 to 6 carbon atoms and the phenyl ring is unsubstituted or substituted by methoxyl, fluorine, chlorine, bromine or nitro, and the alkyl groups are in the m-or p- positions relative to one another.
9. A compound active against HIV, having the formula I as defined in claim I and wherein one of Z and Y is a polyheterocyclic moiety as defined therein.
10. The compound of claim 9 which is meso-1,2,3,4-tetrakis(N-1,3-diaminopropyl)butane.
11. The compound of claim 9 which is 1-(1-(1,4,8,11-tetraazacyclotetra-decyl)methyl)-4-(1-(1,5,8,12-tetraazadodecyl)methyl)benzene octahydrobromide.
12. The compound of claim 9 which is 1-(1-(1,4,8,11-tetraazacyclotetra-decyl)methyl)-4-(5-(1,5,8,12-tetraazadodecyl)methyl)benzene octahydrobromide.
13. The compound of claim 1 which is 1-(1 (1,4,8,11-tetraazacyclotetra-decyl)methyl)-4-(4-(1,4,7,10-tetraazadecyl)methyl)benzene octahydrobromide.
14. A pharmaceutical composition comprising a compound according to any one of claims 9 to 13, in admixture with or in association with a pharmaceutically acceptable diluent or carrier.
15. A process for the production of a compound according to claim 9, comprising reacting a compound of formula II or III, Z - (Aa -X1 II
in which Z, A and n are as defined in claims 1 and 9, and X1 is a reactive atom or group with a compound of forrnula IV or V, respectively, X2 - (A)a - Y V
in which Y, A and n are as defined in claims 1 and 9, and X2 is a reacdve atom or group, under conditions such that a compound of formula I is formed and the reactive atoms or groups X1 and X2 are split off.
in which Z, A and n are as defined in claims 1 and 9, and X1 is a reactive atom or group with a compound of forrnula IV or V, respectively, X2 - (A)a - Y V
in which Y, A and n are as defined in claims 1 and 9, and X2 is a reacdve atom or group, under conditions such that a compound of formula I is formed and the reactive atoms or groups X1 and X2 are split off.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919105489A GB9105489D0 (en) | 1991-03-15 | 1991-03-15 | Improvements in chemical compounds |
| GB9105489.0 | 1991-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2106068A1 true CA2106068A1 (en) | 1992-09-16 |
Family
ID=10691614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002106068A Abandoned CA2106068A1 (en) | 1991-03-15 | 1992-03-11 | Long chain antiviral compounds |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH06505728A (en) |
| AU (1) | AU1372092A (en) |
| CA (1) | CA2106068A1 (en) |
| FI (1) | FI933828A0 (en) |
| GB (1) | GB9105489D0 (en) |
| HU (1) | HU9302596D0 (en) |
| NO (1) | NO933273L (en) |
| WO (1) | WO1992016494A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9126677D0 (en) * | 1991-12-16 | 1992-02-12 | Johnson Matthey Plc | Improvements in chemical compounds |
| GB9318550D0 (en) * | 1993-09-07 | 1993-10-20 | Nycomed Salutar Inc | Chelants |
| US5606053A (en) * | 1995-05-02 | 1997-02-25 | Johnson Matthey Plc | Process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane |
| GB9511357D0 (en) * | 1995-06-06 | 1995-08-02 | Johnson Matthey Plc | Improved antiviral compounds |
| US6506770B1 (en) | 1996-06-06 | 2003-01-14 | Anormed, Inc. | Antiviral compounds |
| AU6074599A (en) * | 1998-10-13 | 2000-05-01 | Synchem Reserach, Inc. | Biomimetic chelating agents and methods |
| EP1189609A4 (en) * | 1999-05-03 | 2002-10-30 | Smithkline Beecham Corp | Cxcr-4 receptor antagonists - thrombopoietin mimetics |
| CN100335478C (en) | 1999-12-17 | 2007-09-05 | 阿诺麦德股份有限公司 | Chemokine receptor binding heterocyclic compounds |
| LT2371361T (en) | 2001-07-31 | 2019-09-10 | Genzyme Corporation | Methods to mobilize progenitor/stem cells |
| JP2009504788A (en) | 2005-08-19 | 2009-02-05 | ジェンザイム・コーポレーション | How to strengthen chemotherapy |
| BR112013029482A2 (en) | 2011-05-16 | 2016-08-09 | Genzyme Corp | use of cxr4 antagonists |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4156683A (en) * | 1973-03-26 | 1979-05-29 | Schering Corporation | Complexes of macrocyclic compounds |
| CA1305425C (en) * | 1986-12-02 | 1992-07-21 | Raymond J. Bergeron | Anti-neoplastic spermine derivative |
| US5091576A (en) * | 1986-12-02 | 1992-02-25 | University Of Florida | Anti-neoplastic, anti-viral or anti-retroviral spermine derivatives |
| US4994560A (en) * | 1987-06-24 | 1991-02-19 | The Dow Chemical Company | Functionalized polyamine chelants and radioactive rhodium complexes thereof for conjugation to antibodies |
| DE3728525A1 (en) * | 1987-08-24 | 1989-03-16 | Schering Ag | MULTI-CORE SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
| DK0378146T3 (en) * | 1989-01-10 | 1995-05-01 | Merrell Pharma Inc | Polyamine derivatives as antineoplastic agents |
| JP3250220B2 (en) * | 1989-10-23 | 2002-01-28 | ニコムド サルター インコーポレーテッド | Multi-site metal chelators |
| US5021409A (en) * | 1989-12-21 | 1991-06-04 | Johnson Matthey Plc | Antiviral cyclic polyamines |
-
1991
- 1991-03-15 GB GB919105489A patent/GB9105489D0/en active Pending
-
1992
- 1992-03-11 JP JP4506034A patent/JPH06505728A/en active Pending
- 1992-03-11 HU HU9302596A patent/HU9302596D0/en unknown
- 1992-03-11 CA CA002106068A patent/CA2106068A1/en not_active Abandoned
- 1992-03-11 WO PCT/GB1992/000438 patent/WO1992016494A1/en active Application Filing
- 1992-03-11 AU AU13720/92A patent/AU1372092A/en not_active Abandoned
-
1993
- 1993-09-01 FI FI933828A patent/FI933828A0/en not_active Application Discontinuation
- 1993-09-14 NO NO93933273A patent/NO933273L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO933273D0 (en) | 1993-09-14 |
| AU1372092A (en) | 1992-10-21 |
| FI933828A (en) | 1993-09-01 |
| GB9105489D0 (en) | 1991-05-01 |
| HU9302596D0 (en) | 1993-12-28 |
| FI933828A0 (en) | 1993-09-01 |
| JPH06505728A (en) | 1994-06-30 |
| WO1992016494A1 (en) | 1992-10-01 |
| NO933273L (en) | 1993-09-14 |
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