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

Definitions

• This invention concerns improvements in chemical compounds, more especially it concerns compounds and pharmaceutical compositions. In particular it concerns compositions and compounds having activity in in vitro tests on Human Immunodeficiency Virus-infected cells.
• AIDS Acquired Immune Deficiency Syndrome
• chemo-therapeutic treatments have been advocated, and some compounds have emerged as a potential basis for treatment, there is still a need for alternatives.
• most treatments such as the compound known as AZT have a high toxicity to cells, and it would be desirable to find compounds which are less toxic. In man, the development of resistance to AZT has been identified as an additional clinical problem.
• the present invention provides the use of compounds defined below, in pharmaceutical 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 medicament for the treatment of HIV-infected patients.
• the invention further provides a process for the production of a pharmaceutical composition for the treatment of a HIV-infected patient, comprising the combination of a compound as defined below with a pharmaceutically acceptable diluent or carrier, and formulating 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 combating HIV, this invention includes other aspects in which other diseases may be treated, including for example microbial infections.
• 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 mammals. Additionally, a specific group of N-alkylated monocyclic compounds are said to possess activity against A 2 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-l ,7, 10,16-tetra-4, 13-diazacyclo- octadecane. It is also said that the preferred compounds, which form complexes of greater stability, are those having three bridging chains between bridgehead nitrogen atoms, that is fused bicyclic compounds.
• the present invention provides active compounds of the general formula I, Z - (A) n - Y I in which each Z and Y is independently a poiyheteroalkyl 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 1 to 6.
• A may be alkylene, for example 1 ,3 propandiyl, unsaturated alkylene or a group selected from aryl. alkylaryl. alkylarylalkyl, fused aryl. polyoxoethylene. carboxylate, esters and amides, or a nitrogen or sulphur atom. In a particularly preferred embodiment of the invention.
• A is alkylene of 1 to 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 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 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. -NH 2 . -OH. -COOH. ester groups, -CONH 2 and alkyl or aryl groups, eg of up to 10 carbon atoms, which themselves 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 are those of 10 to 24 ring members, especially 12 to 18 ring members, and preferred numbers of nuclear nitrogen atoms are 4 to 6. It is convenient that if two chains are linked, they are identical.
• the invention also includes what may be termed "pro-drugs", that is protected forms of the linked compounds, which release the compound after administration to a patient.
• the compound may carry a protective group which is split off by hydrolysis in body fluids, e.g. in the bloodstream, thus releasing active compound.
• a discussion of pro-drugs may be found in "Smith and Williams' Introduction to the Principles of Drug
• Ciampolini et al (Inorg Chem 26, 3527[1987]) have demonstrated the syntheses of alkyl-linked bicyclams by condensation of N.N' ,N"-tritosy ley clam with bis (tosyloxy)alkanes or with bis(acyl chlorides).
• C.N' - and N,N' -linked compounds of formula I may be performed in a similar manner by reacting activated precursors (eg compounds substituted with alkyl chains terminated with halides or activated carboxylates) with (N-l)-substituted heterocycles (eg N,N' ,N"-tritosylcyclam) or (N-l )-substituted polyazaalkanes followed by deprotection.
• activated precursors eg compounds substituted with alkyl chains terminated with halides or activated carboxylates
• heterocycles eg N,N' ,N"-tritosylcyclam
• the invention further provides a process for the production of compounds of formula I. comprising reacting a compound of formula II or III, Z - (A) n - X 1 II
• X 1 is a reactive atom or group with a compound of formula IV or V, respectively,
• X 2 is a reactive atom or group, under conditions such that a compound of formula I is formed and the reactive atoms or groups X 1 and X 2 are split off. It will be realised that it may be desirable to protect other reactive 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, followed 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 I, are to be be considered as active compounds for the pharmaceutical compositions, processes for making the same and methods of treatment mentioned above.
• meso forms, enantiomers and resolved optically active forms of the compounds of formula I. are included.
• compounds of formula I diluted with non-toxic or with other active substances include Acid addition salts, for example hydrochlorides, and non-toxic labile metal complexes of the compounds of formula 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 especially indicated, whereas less labile metal atoms such as cobalt and rhodium are less preferred because of likely lower selectivity.
• the tetraamine was synthesised from meso-erythritol according to the method of R L Weller, J Org Chem 49, 5150 (1984).
• N-tosyl-3-aminopropanoate (8 equivalents) in dimethylformamide.
• the reaction mixture was heated at 50° C for 5days.
• the DMF was removed under reduced pressure and dissolved in THF/1N NaOH and stirred overnight during which time a white/yellow solid precipitated which was removed by filtration.
• the solid was dissolved in dichloromethane and triethylamine (6 equivalents) was added. To the homogeous solution a solution of mesyl chloride (4.5 equivalent) in dichloromethane 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% HCl 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 amorphous solid; overall yield 30%; mass spectrum 1275 (14%), 1197 (100%), 559 (13%).
• step c) The mixture produced in step b) (420mg, 0.448mmol) was added to 12ml of acetic acid and 6ml of 48%aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120°C. The red solution was cooled to room temperature and concentrated to a paste. Acetic acid (10ml) 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 (60°C/0.4mm Hg). A tan- white solid was thus obtained (400mg.
• step b) The product from step a) above (220mg. 0.242mmol) was added to 8ml of acetic acid and 6ml of 48% aq HBr (Aldrich) and the solution was stirred for 30 hours at 110-120° C. 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 (60°C/0.4mm Hg).
• a tan-white solid was thus obtained (120mg, 46%) as an approximate 2: 1 mixture of 1 -(l-( 1 ,4, 7, 10- tetraazadecyl)methyl)-4-( 1 -( 1 ,4,8, 1 1 -tetraazacyclotetradecyl)methyl)benzene octahydrobromide and 1-(1-(1,4,8.1 l-tetraazacyclotetradecyl)methyI)-4-(4- (1.4,7.10-tetraazadecyl)methyl)benzene.
• the products were separated using chromatography, and their structures were confirmed.
• step b) 80mg (0.051mmol) of the product of step a) above was added to 6ml acetic acid and 4ml of 48% aq HBr (Aldrich) and the solution was stirred for 48 hours at 1 10-120°C. 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 funnel. The solid was washed with acetic acid (10ml) and ether (10ml) and dried under vacuum overnight (60°C/0.4mm Hg).
• the compound of the invention was tested in a screen by the MTT method (J.Virol. Methods 120: 309-321 [1988]).
• MT-4 cells 2.5 x 10 4 / well
• HIV-1 HIV-1
• LAV-2 ROD HIV-2
• Antiviral activity and cytotoxicity of the compounds are expressed in the table below as ED 50 (ug/ml) and CD 50 (ug/ml), respectively.
• the potential therapeutic usefulness was assessed by calculating a Selectivity Index (SI) corresponding to the ratio of CD 50 to ED 50 .
• SI Selectivity Index
• any compound exhibiting a Selectivity Index of greater than 5 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 viruses 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 administered in the form of pharmaceutical compositions formulated according to well known principles and incorporated the compound, preferably in unit dose form, in combination with a pharmaceutically 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 formulated into pessaries or suppositories or sustained release forms of any of the above for implantation.
• Suitable diluents, carriers, excipients and other components are known. It may be desirable also to formulate a composition for topical administration such as an ointment or cream.
• the compounds of the invention may be used, in the form of a composition or alone, and possibly carried on a finely divided 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.
• devices to be considered in this aspect of the invention are surgical devices and gloves and 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.
• compositions according to the invention may contain unit dosages determined in accordance with conventional pharmacological methods, suitably to provide active compounds in the dosage range in humans of from 0.1 to 100 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 compositions or such active compounds or supplemental therapy may be included in a course of treatment.

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• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Immunology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Bioinformatics & Cheminformatics (AREA)
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• Communicable Diseases (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (11)

Citations (8)

• 1991
  • 1991-03-15 GB GB919105489A patent/GB9105489D0/en active Pending
• 1992
  • 1992-03-11 JP JP4506034A patent/JPH06505728A/ja active Pending
  • 1992-03-11 HU HU9302596A patent/HU9302596D0/hu unknown
  • 1992-03-11 WO PCT/GB1992/000438 patent/WO1992016494A1/en active Application Filing
  • 1992-03-11 CA CA002106068A patent/CA2106068A1/en not_active Abandoned
  • 1992-03-11 AU AU13720/92A patent/AU1372092A/en not_active Abandoned
• 1993
  • 1993-09-01 FI FI933828A patent/FI933828A0/fi not_active Application Discontinuation
  • 1993-09-14 NO NO93933273A patent/NO933273L/no unknown

Patent Citations (8)

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