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WO1994022841A1 - Triazinediones, triazinemonothiones et triazinedithiones alkylamino substitues - Google Patents

Triazinediones, triazinemonothiones et triazinedithiones alkylamino substitues Download PDF

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Publication number
WO1994022841A1
WO1994022841A1 PCT/GB1994/000674 GB9400674W WO9422841A1 WO 1994022841 A1 WO1994022841 A1 WO 1994022841A1 GB 9400674 W GB9400674 W GB 9400674W WO 9422841 A1 WO9422841 A1 WO 9422841A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
group
reacting
triazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1994/000674
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English (en)
Inventor
Jeffrey Clifton Watkins
David Edward Jane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tocris Cookson Ltd
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Tocris Cookson Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tocris Cookson Ltd filed Critical Tocris Cookson Ltd
Priority to AU63811/94A priority Critical patent/AU6381194A/en
Publication of WO1994022841A1 publication Critical patent/WO1994022841A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/20—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with no nitrogen atoms directly attached to a ring carbon atom

Definitions

  • the invention relates to new organic compounds and more particularly new alkylamino substituted
  • triazinediones and the corresponding mono- and dithiones, their use as agents influencing the central nervous system, their preparation, their use as research tools and as pharmaceuticals, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use in methods of treatment practised in the human or animal body.
  • X and Y are each independently an oxygen or sulphur atom; E and G are each independently a nitrogen or carbon atom but E is not the same as G; Z is either substantially completely the (S) enantiomeric form, or substantially completely the (R) enantiomeric form or (R,S) mixtures where appropriate of the group which is
  • each A is independently
  • R 1 , R 2 , R 3 , R 4 and R 5 which may be the same or different, are hydrogen or a C1 to C6 alkyl, C2 to C6 alkenyl, C1 to C6 alkynyl, C6 to C12 aryl, C7 to C12 aralkyl, hydroxy, C1 to C6 alkoxy, C6 to C12 aryloxy, C1 to C6 haloalkyl, C6 to C12 haloaryl, C7 to C12 haloaralkyl, amino, C1 to C6 alkylamino, C6 to C12 arylamino, C1 to C6 aminoalkyl, C6 to C12 aminoaryl, C8 to C12 haloalkylaralkyl group, or R 1 and R 2 together constitute a double bond or an oxo group; and R 6 represents a hydrogen atom or a small alkyl (C1 to C3), carboxy, C1 to C6 alk
  • R 7 and R 8 which may be the same or different, and when not representing the residue Z, are hydrogen, or a C1 to C6 alkyl, C6 to C12 aryl, C7 to C12
  • aralkyl C1 to C6 haloalkyl, C6 to C12 haloaryl, C7 to C12 haloaralkyl or C8 to 12 haloalkylaralkyl group;
  • R 9 and R 10 (where structurally feasible) which may be the same or different and when not representing the residue Z are hydrogen or an electron withdrawing group, or represent the same moieties as R 4 and R 5 as defined above; and in which any suitable combination of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 together with the atoms to which they are attached form one or more carbocyclic or heterocyclic ring systems (where
  • hydrogen atoms in the compound may be a heavy isotope of hydrogen and any sulphur and any iodine atoms may be present in the form of a radioactive isotope of those atoms; and pharmaceutically acceptable salts thereof.
  • EAA excitatory amino acid
  • Substances of the application that block EAA receptors are useful as research tools for investigating central nervous mechanisms, and also as drugs for the treatment of disorders of the CNS due to hyperactivity of the CNS (as in epilepsy and spasticity) and for the treatment of those neurodegenerative disorders of the CNS which are due to excessive activation of EAA receptors as is known to occur in ischaemic conditions such as those arising in stroke, heart failure, traumatic head injury, or which are due to ingestion of certain neurotoxic substances.
  • substances with this depressant activity include those which block the N-methyl-D-aspartate type (NMDA-type) of EAA receptor as well as those that have antagonist action at non- NMDA-type receptors.
  • Examples of the invention that depress central nervous activity by activating IAA receptors are likewise useful as research tools for investigating mechanisms of CNS activity and as drugs for the treatment of disorders of the CNS which require a depression of the nervous system activity such as in epilepsy, spasticity and other conditions involving hyperactivity of the CNS.
  • X or Y represent an oxygen atom but useful activity is also envisaged in compounds where either or both X and Y is a sulphur atom (Formula I).
  • sulphur in the molecule can make a more favourable hydrophilic/lipophilic balance to aid penetration of the substances from the bloodstream into the brain, and also provides a centre for introduction of radioactivity into the molecule which is of use in metabolic receptor radioligand binding studies.
  • a single group Z is present in the molecule though two such groups may be present in the molecule.
  • receptor sites may possess multiple centres capable of interacting with amino acid residues, so that more than two amino acid residues may also be present in active compounds. Whether a certain substance acts at excitatory or inhibitory amino acid receptors depends on the nature of the group R 6 .
  • R 6 is a hydrogen atom, a small alkyl group, or part of a ring structure involving any other substituent such that it carries no acidic or negatively polarizable character, the substances are expected to act as agonists or
  • R 6 is a carboxylic acid moiety or represents another negatively polarizable group, the substances are expected to act at excitatory amino acid receptors.
  • R 6 is not a carboxylic or other negatively polarizable moiety activity resulting from interaction with inhibitory amino acid receptors is expected to depend on the position of attachment of Z to the ring, and the length of the chain A n . Highest agonist activity is expected when A represents a chain of one or two atoms .
  • the -CR 3(NR 4 R 5)CO 2 H group is attached directly to the ring system.
  • Z is attached to N1, N3 or E5 (where structurally feasible) and A is absent or A represents a single methylene group activity is usually of a neuro-excitatory nature when R 6 is CO 2 H.
  • Longer A chains of 3 to 6 carbon atoms produce mainly compounds with antagonist activity at excitatory amino acid receptors resulting in depression of neuronal synaptic activity when R 6 is CO 2 H.
  • Substances with intermediate A n chain length of 2 atoms and R 6 as CO 2 H have sometimes excitatory and sometimes depressant actions and the nature of the activity may depend on other features of the molecule.
  • Z is attached to Gg (where structurally feasible) and R 6 is CO 2 H
  • activity is usually similar to that seen when Z is attached to N1, N3 or E5 (where structurally feasible), but is more often of an excitatory amino acid
  • chain A is absent when some excitatory action may also be seen.
  • the stereochemistry of the asymmetric carbon atom (denoted * in the formulae) in the side chain Z is important to the activity observed.
  • Excitatory activity is seen most often in substances in which R 6 is CO 2 H and A n is a chain of 0 - 2 carbon atoms and the stereochemistry is substantially completely of the S configuration.
  • Antagonist activity can also be seen in some compounds of S configuration, especially where A is a chain of 2-6 carbon atoms, but is often a feature of molecules in which the stereochemistry of the amino acid moiety is of the R configuration. It is expected, however, that whether a substance is an agonist or antagonist at excitatory amino acid
  • R 1 , R 2 , R 3 , R 4 and R 5 when not each representing a hydrogen atom, are introduced to affect the hydrophilic/lipophilic balance of the molecule in order to assist absorption from the gut and/or passage from the blood into the central nervous system. This is the case also for Rg when this group is not a carboxylic acid moiety or similar negatively
  • R 9 and R 10 represent preferably those groups which have an electron-withdrawing influence on the triazinedione or triazinethione ring system which is preferred for interaction with both excitatory and inhibitory amino acid receptors.
  • R 9 and R 10 may be halogen, nitro, azido, hydroxy, cyano, C2 to C7 ketoalkyl, C7 to C12 ketoaryl, carboxy, C1 to C6 alkoxycarbonyl, C1 to C6 haloalkyl, sulphonyl, phosphonyl, tetrazolyl, C1 to C6 tetrazolyalkyl, C2 to C7 alkenyl, C2 to C7 haloalkenyl, C6 to C12 aryl, C6 to C12 heteroaryl, C6 to C12
  • R 7 or R 9 or R 10 (where structurally feasible) be Z.
  • each A be carbon, and that the chain A n be either fully saturated or have some degree of unsaturation. Unsaturated A chains are particularly useful as they allow for the easy introduction of labelled atoms.
  • R 1 and R 2 are each preferably hydrogen, alkyl, alkenyl or alkynyl.
  • R 3 is preferably hydrogen or forms a ring system with one of the R 1 R 2 , R 4 , R 5 , R 6 , R 9 and R 10 .
  • R4 and R 5 are preferably hydrogen, aryl or
  • haloaryl or form a ring system with each other or one of R 1 , R 2 , R 6 , R 9 and R 10 .
  • R 1 , R 2 , R 3 , R 4 , R 5 R 6 , R 7 , R 8 , R 9 or R 10 are or contain a chain with a haloatom or amino at the end they are useful in allowing the compound to be linked to a spacer arm (see below).
  • ring system that ring system is preferably unsaturated or saturated and may be aromatic.
  • ring systems include R 9 and R 10 forming together a 5 or 6 membered aromatic carbocyclic or heterocyclic ring, R 3 and R 1 /R 2 forming a 3 to 7 membered preferably saturated
  • the compounds of formula I may exist in tautomeric forms and these tautomeric forms are included in the definitions of the compounds of formula I.
  • radioactivity can be introduced as S in the triazinedithione moiety, as 125 I or another isotope of iodine or as isotopes of fluorine in the R 9 or R 10 substituents (where
  • the substances will be useful also for the isolation of receptors from central nervous tissue, for example, by linking the molecules via a spacer molecular chain to an affinity
  • chromatography support material of the sepharose or agarose type This can be done by using one or more of the group R 1 , R 2 , R 3 , R 4 , R 5 , R 6 ,
  • R 7 , R 8 , R 9 or R 10 as a reactive substituent for linking into the spacer arm, which would carry at its other end a group capable or reacting with sepharose, agarose, or like affinity chromatography support material.
  • a compound for use in the isolation of receptors from central nervous tissue which comprises a compound of formula I as defined above in which one or more of the group R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 (where structurally feasible), is linked to a spacer arm having at its free end a group capable of reacting with an affinity chromatography support material.
  • the compounds of the invention may contain a centre of asymmetry in the Z group and possibly
  • the compounds of the present invention include both RS mixtures, including racemic mixtures, and compounds in which the carbon atom bearing the NR 4 R 5 , R 3 , and R 6 substituents in the Z group is substantially completely in the R or substantially completely in the S configuration.
  • the compounds of the invention may be prepared inter alia as follows.
  • salt may be tertiary ammonium salt or a metallic salt, for example, a lithium, sodium, mercury or silver salt, in which the groups X, Y (Formula II), E, G, R 8 , R 9 and R 10 are as defined above with the (R) or (S) form of a compound of formula III
  • a n is as defined above and Prot is an amine protecting group followed where necessary or desirable by deprotection, for example, in trifluoroacetic acid and purification, for example, by resin column
  • R 8 may also be Z group.
  • substitution is at N3 i.e.
  • R 8 is Z.
  • a n , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above and L is a leaving group, for example, a chloro, bromo, iodo, or p-toluenesulphonyloxy group
  • R 6 is optionally protected by a suitable protecting group, for example, a tertiary-butyl or a benzyl group
  • the NR 4 R 5 group is optionally protected by a suitable protecting group, for example, a benzyloxycarbonyl or tertiary-butyloxycarbonyl group followed where desired or necessary by purification, for example, by column chromatography and removal of any protecting groups.
  • R 3 , R 4 , R 5 , R 7 , R 9 and R 10 are as defined above can be prepared by reacting a salt as defined above, e.g. the sodium salt, of a triazine of formula VI
  • hydrochloric acid and purification, for example, by ion-exchange chromatography.
  • G is a carbon atom
  • E is a nitrogen atom
  • R 3 , R 4 , R 5 , R 7 , R 8 , X, Y and An are as defined above and the CO 2 H group may be protected or be in the form of a derivative, for example, as an ester, can be prepared by reacting a triazine of formula VIII.
  • X, Y, R 7 , R 8 , An, L, E and G are as defined above, with a salt as defined above, for example, the sodium salt, of a glycine equivalent, for example, diethyl acetamidomalonate followed, where necessary or desired, by hydrolysis, for example, in hydrochloric acid, and purification, for example, by ion exchange chromatography.
  • a salt as defined above for example, the sodium salt
  • a glycine equivalent for example, diethyl acetamidomalonate
  • E is a carbon atom
  • G is a nitrogen atom
  • An, X, Y, R 7 and R 8 are as defined above and the CO 2 H group may be protected or be in the form of a derivative, for example, as an ester, may be prepared by reacting a triazine of formula X
  • G is a nitrogen atom
  • E is a carbon atom
  • R 7 is a carbon atom
  • R 8 , An, X, Y and L are as defined above, with a salt as defined above, for example, the sodium salt, of a glycine derivative, for example, diethyl
  • the (R) or (S) enantiomers of compounds of formulae VII or IX can be prepared from triazinediones in which the oxygen atoms are protected, for example, trimethylsilyl protected triazinediones, of formula VIII or X by reaction with the anions of chiral glycine equivalents such as Schollkopf 's reagent XI or
  • E, G, R 3 , R 4 , R 8 , R 9 , R 10' X, Y, and An are as defined above can be prepared by reacting a salt as defined above, for example, the sodium salt, of a triazine of formula II with a compound of formula XIV
  • R 3 , An and L are as defined above and Prot is an amine protecting group, followed where desired or necessary by silica gel chromatography, acid hydrolysis and purification, for example, by ion exchange
  • R 3 , R 4 , R 7 , R 9 , R 10, X, Y, A n , E and G may be prepared by reacting a salt as defined above, for example, the sodium salt, of a triazine of formula VI with the compound of formula XIV followed where desired or necessary by silica gel chromatography, and hydrolysis and purification, for example, by ion exchange chromatography.
  • compositions of the invention can also be prepared in the form of salts of the basic amino group present in the Z group and/or elsewhere in the molecule and here, salts of interest are
  • physiologically acceptable acid addition salts such as salts with hydrochloric acid, acetic acid, succinic acid, tartaric acid, or citric acid.
  • a pharmaceutical composition comprising a compound of formula I as defined above but in association with a pharmaceutically acceptable diluent or carrier.
  • Compounds of the invention act on the central nervous system and may be administered parenterally or orally, for example, intravenously for acute treatment, or subcutaneously or orally for chronic treatment.
  • preparations of low water solubility may be used for depot administration.
  • compositions of the invention might contain the active compound in a concentration such that a conventional dosage volume would provide the subject with up to about 200 mg/kg body weight although, when the compounds are to be administered by the intravenous or subcutaneous route, dosages in the region of about 1-20 mg/kg body weight are to be expected for the more active compounds and/or for those substances with a high lipophilic or
  • the compounds for use in the pharmaceutical compositions may be in the form of prodrugs, i.e. so modified that they enter the body in a modified
  • compounds of the invention have been found to stimulate or antagonize EAA receptors, or to activate IAA receptors, and to stimulate or depress spontaneous and evoked synaptic activity in the central nervous system.
  • Amino acid receptors mediate or modulate synaptic excitation and inhibition of many synapses in the brain.
  • the compounds of the present invention can modify abnormal central nervous system activity involving amino acid receptors and
  • the compounds of formula I have one or more of the following advantages. They are more potent excitatory compounds at the AMPA and kainate receptors than known compounds, they are able as a group of compounds to affect a greater variety of receptors than known groups of compounds, they have an improved lipophilic balance allowing for better absorbance at the blood/brain barrier, and they are more useful as research tools than known compounds of similar structure/function.
  • the compounds of formula I may provide insights into the existence and role in central nervous function of both AMPA and kainic acid receptor sub-types, as defined using molecular biology.
  • the compounds of the invention have agonist, partial agonist and/or antagonist action at excitatory or inhibitory amino acid receptors in the central nervous system.
  • excitatory or inhibitory amino acid receptors There are several different types of these receptors, some or all of which are intimately involved in central nervous function.
  • Three types of ionotropic excitatory amino acid receptors that have been described in the neuroscientific literature are known as N-methyl-D-aspartate (NMDA), kainate (K) and - amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and other types of excitatory amino acid
  • NMDA, K and AMPA receptors are also known, including metabotropic glutamate receptors.
  • the NMDA, K and AMPA receptors when activated, produce electrochemical changes in neurones which are important in transmission and metabotropic glutamate receptors additionally cause metabolic changes which are important in longer term changes in receptor function. Additionally, recent advances in molecular biology have revealed the
  • the compounds of the invention have differential actions at these amino acid receptors.
  • Compounds which act at amino acid receptors can affect the action of natural amino acid transmitter substances and thereby influence the electrical activity of the central nervous system.
  • the substances may be tested on spinal cord neurones, which have similar characteristics to nerve cells in the brain.
  • the isolated spinal cord of the 1-5 day old rat is used, and compounds are tested for their ability to affect the activity of spinal neurones induced by amino acids or electrical stimulation of afferent fibres.
  • Table 3 shows the excitatory activity of some invention compounds relative to the previously known excitatory amino acid of another structural series (S)- ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid, (S)-AMPA.
  • Table 4 shows the depressant effect of another invention compound on the spontaneous synaptic activity of neonatal rat motoneurones.
  • Potencies refer to depolarization induced in motoneurones in the hemisected isolated spinal cord preparation of the neonatal rat 1

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule générale (I) où X et Y sont chacun indépendamment un atome d'oxygène ou un atome de soufre; E et G sont chacun indépendamment un atome d'azote ou un atome de carbone, mais E diffère de G; Z représente presque complètement soit la forme énantiomère (S) soit la forme énantiomère (R) ou, lorsque cela convient, des mélanges (R, S) du groupe (Z) qui est accolé à un ou plusieurs des atomes N1, N3, E5 ou G6 du cycle, où n vaut de 0 à 6, où chaque A représente indépendamment CR1R2, NR1, S, SO ou SO2 de telle façon qu'An constitue une chaîne de 0 - 6 atomes saturés ou insaturés. R1-10 représente i.a. H, des groupes hydrocarbures pouvant contenir des hétéroatomes spécifiques, ou bien deux éléments parmi R1-10 peuvent se lier pour former des systèmes cycliques.
PCT/GB1994/000674 1993-03-30 1994-03-30 Triazinediones, triazinemonothiones et triazinedithiones alkylamino substitues Ceased WO1994022841A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63811/94A AU6381194A (en) 1993-03-30 1994-03-30 Alkylamino substituted triazinediones, triazinemonothiones and triazinedithiones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9306639.7 1993-03-30
GB939306639A GB9306639D0 (en) 1993-03-30 1993-03-30 Organic compounds

Publications (1)

Publication Number Publication Date
WO1994022841A1 true WO1994022841A1 (fr) 1994-10-13

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PCT/GB1994/000674 Ceased WO1994022841A1 (fr) 1993-03-30 1994-03-30 Triazinediones, triazinemonothiones et triazinedithiones alkylamino substitues

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AU (1) AU6381194A (fr)
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WO (1) WO1994022841A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247892A1 (fr) * 1986-05-30 1987-12-02 The Wellcome Foundation Limited Sels de triazine
EP0459829A1 (fr) * 1990-06-01 1991-12-04 The Wellcome Foundation Limited Composés pharmacologiques actifs sur le système nerveux central

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247892A1 (fr) * 1986-05-30 1987-12-02 The Wellcome Foundation Limited Sels de triazine
EP0459829A1 (fr) * 1990-06-01 1991-12-04 The Wellcome Foundation Limited Composés pharmacologiques actifs sur le système nerveux central

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Publication number Publication date
AU6381194A (en) 1994-10-24
GB9306639D0 (en) 1993-05-26

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