WO1994014780A1 - Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors - Google Patents
Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors Download PDFInfo
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- WO1994014780A1 WO1994014780A1 PCT/GB1993/002556 GB9302556W WO9414780A1 WO 1994014780 A1 WO1994014780 A1 WO 1994014780A1 GB 9302556 W GB9302556 W GB 9302556W WO 9414780 A1 WO9414780 A1 WO 9414780A1
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- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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Abstract
The use of a compound which binds at the tetrahydrobiopterin site of NO synthase for the treatment of conditions where there is an advantage in inhibiting neuronal NO synthase with little or no inhibition of endothelial NO synthase is disclosed. Pharmaceutical formulations comprising such compounds, and processes, including a novel process, for their preparation are also disclosed.
Description
PYRIMIDINE, PYRIDINE , PTERIDINONE AND INDAZOLE DERIVATIVES AS ENZYME INHIBITORS
The present invention relates to neuronal nitric oxide (NO) synthase inhibitors, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use in diseases of the nervous system in which NO plays a part.
It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amyl nitrite, glyceryl trinitrite and other nitro vasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesised from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews, 43, 109-142 (1991)). It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve systemic hypotension such as toxic shock and therapy with certain cytokines.
It has recently become apparent that the neuronal NO synthase is a distinct protein from the endothelial NO synthase (Sessa et al, J.Biol.Chem., 267, 15274-15276, 1992).
We believe that NO synthesis plays an important part in the pathology of a range of diseases of the nervous system, eg. ischemia. However, non-selective inhibitors of NO syntheses cause profound changes in blood pressure and blood flow, including cerebral blood flow. Unfortunately, ischemic injury inherently reduces the blood supply to the brain and any further decrease in blood flow caused by a non-selective NO synthase inhibitor would have a deleterious effect, potentially opposing any beneficial effect of decreased NO production within the brain. Nevertheless, studies of middle cerebral artery occlusion in both rats and mice have demonstrated a substantial protection effect of low doses of NO synthase inhibitors (see for example Nowicki et al, Eur. J.Pharmacol., 1991 , 204, 339-340). At high doses, or in models of global ischemia, these inhibitors fail to provide protection. Thus,
there is a need for a potent inhibitor of neuronal NO synthase with preferably little or no activity against the vascular endothelial NO synthase.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue L-N- monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L- NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A- 0446699. Compounds like L-NMMA do not show selectivity for the neuronal NO synthase as opposed to the other NO synthases.
It is known that the presence of (6R)-5,6,7,8-tetrahydro-L-biopterin (hereinafter tetrahydrobiopterin) is necessary for activity of the NO synthase enzymes. We believe that tetrahydrobiopterin causes expression of the activity of the enzymes by binding to them. We have now found that compounds which competitively bind at the tetrahydrobiopterin sites of NO synthases inhibit neuronal NO synthase selectively over endothelial NO synthase.
Accordingly, the present invention provides the use of a compound which binds at the tetrahydrobiopterin site of NO synthase for the manufacture of a medicament for the treatment of a condition where there is an advantage in inhibiting neuronal NO synthase with little or no inhibition of endothelial NO synthase.
In another aspect, the present invention provides a method for the treatment or prophylaxis of a condition where there is an advantage in inhibiting neuronal NO synthase with little or no inhibition of endothelial NO synthase which comprises the administration of an effective amount of a compound which binds at the tetrahydrobiopterin site of NO synthase.
Suitable compounds which bind at the tetrahydrobiopterin site include those of formula (IA), formula (IC) or structural analogues of tetrahydrobiopterin and or salts thereof, as hereinafter defined.
T is oxygen. CH2 or nitrogen substituted by hydrogen or C1 -4 alkyl, and v and w are the same or different and each is 1 or 2 provided the sum of v and w is 3 or 4; X is nitrogen or CH; Y is nitrogen. CH or CNH2; D is a group S(O)x wherein x is 0, 1 or 2, a C1 -4 alkylene chain, or a C2-4 alkenylene or alkynylene chain; d is 0 or 1 ; Ar is a monocyclic or bicyclic ring system which may contain one or two heteroatoms and which contains at least one aromatic ring; R3 represents hydrogen or one to three substituents on the ring system Ar which may be the same or different and are chosen from halo, NR5 R6 wherein R5 and R6 are independently selected from hydrogen or S(O)X' R7 wherein x' is 0, 1 or 2 and R7 is C1 -4 alkyl; nitro, cyano, a C1 -4 carboxcylic acid group or an ester thereof, C1 -4 alkyl optionally substituted by one to three halo atoms; phenyl or a group -(A)mR8 wherein A represents oxygen, S(O)n wherein n is 0, 1 or 2, or NR9 wherein R9 is hydrogen or C1-4 alkyl optionally substituted by halo and m is 0 or 1, and R8 is hydrogen, or C1 -4 alkyl or phenyl each optionally substituted by one to three halo atoms; R4 is hydrogen, C1 -4 alkyl, hydroxy, halo, trifluoromethyl or a group NR10R1 1 wherein R10 and R11 are the same or different and each is hydrogen or C1 -4 alkyl, or NR1 0R1 1 forms a 5- or 6- membered heterocyclic group optionally substituted by a C1-4 alkyl group or R4 represents a C1-2 alkylene group linking the heterocyclic ring to Ar.
Preferred heterocyclic groups include morpholino, piperidino and methylpiperazino.
Formula (I A) includes compounds of formula (II)
or a salt thereof, wherein R1 ,R2 ,X,Y,R4 are as hereinbefore defined, Ar' is a monocyclic or bicyclic ring system containing at least one aromatic ring, and R3 ' represents hydrogen or one to three substituents which may be the same or different and are chosen from halo, amino, nitro, cyano, a C1 -4 carboxylic acid group or an ester thereof, a group -(A)mR8' wherein A and m are as hereinbefore defined and R8 ' is C1 -4 alkyl optionally substituted by halo;
Preferred compounds of the formula (I A) include those of the formula (III)
or a salt thereof wherein D, d, Ar, R3 , R1 , R2, X and R4 are as hereinbefore defined.
For formulae (IA), (II) and (III):
Suitably d is 0;
Suitably Ar is phenyl, naphthyl, tetrahydronaphthyl, or benzothienyl.
Preferably Ar is phenyl.
Suitably R3 is halo, most suitably chloro or bromo, C1 -4 alkyl or C1 -4 alkoxy, preferably methoxy. Preferably there are one or two substituents which are at the 3-, 4- or 5- positions of the phenyl ring (when Ar is phenyl) or at a position not α- to the linkage of the group Ar to the nitrogen containing aromatic ring when Ar is not phenyl. Preferably, when Ar is phenyl the. or one of the. subsituents is at the 4-position of the phenyl ring.
Suitably R1 and R2 are hydrogen, methyl, ethyl or NR1 R2 is a methyl-piperazino group. Preferably R 1 and R2 are hydrogen.
R4 is most suitably hydrogen or NH2 and preferably R4 is hydrogen.
For formulae (IA) and (II) Y is preferably CNH2
Suitable compounds of the formula (IA) include
2,4-diamino-6-(4-methoxyphenyl)pyrimidine
2,4-diamino-6-(3,4-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2-(4-methylphenyl)ethyl)pyrimidine
2,4-diamino-5-(4-methylphenylethynyl)pyrimidine
2,4-diamino-5-phenylethynylpyrimidine
2,6-diamino-3-(2,4,5-trichlorophenyl)pyridine
2,6-diamino-3-(4-methoxyphenyl)pyridine
2,6-diamino-3-(2-naphthyl)pyridine
2,6-bis(acetamido)-3-(3,4-dimethoxyphenyl)pyridine
2,6-diamino-3-(3,4-dimethoxyphenyl)pyridine
1-amino-2, 4-diaza-5, 6-dihydro-9-methoxy-3-(4-methyl-1-piperazinyl)phenanthrene
4-amino-9, 10-dihydro-7-methoxy-2-(4-methyl-1-piperazinyl)benzo [f] quinazaline
2-amino-5-((-naphthyl)pyrimidine
2-amino-5-(4-methoxyphenyl)pyrimidine
2-(4-methylpiperazinyl)-5-(2-naphthyl)pyrimidine
5-(3,4-dimethoxy)-2-(4-methyl-1-piperazinyl)pyrimidine
5-(1,3-benzo[d]dioxol-5-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5-(1,4-benzodioxan-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5-(3,4-dichlorophenyl)-2-(4-methylpiperazinyl)pyrimidine
2,4-diamino-5-(3-thienyl)pyrimidine
2,4-diamino-5-(3,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-biphenylpyrimidine
2,4-diamino-5-(3,5-bis(trifluoromethyl)phenyl)pyrimidine
2,4-diamino-5-(3,5-dichlorophenyl)pyrimidine
2,4-diamino-5-(2,5-dibromo-4-chlorophenyl)pyrimidine
2,4-diamino-5-( 4-chloro-3-methanesulphonamidophenyl)pyrimidine
2,4-diamino-5-(4-methoxy-3-methylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethoxyphenyl)pyrimidine
2,4-diamino-5-(3-amino-4-chlorophenyl)pyrimidine
2,4-diamino-5-(3-aminophenyl)pyrimidine
2,4-diamino-5-(4-chloro-3-nitrophenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-hydroxyphenyl)pyrimidine
2,4-diamino-5-(3-fiuorophenyl)pyrimidine
2,4-diamino-5-(3-trifluoromethoxyphenyl)pyrimidine
2,4-diamino-5-(3-bromo-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-fluoro-4-methoxyphenyl)pyrimidine
2,4-diamino-5-( 3-chloro-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-fluorophenyl)pyrimidine
2,4-diamino-5-(4-chlorophenyl)pyrimidine
1 ,3-diamino-5, 6-dihydro-7-methoxy-2, 4-phenanthroline
1 ,3-diamino-5, 6-dihydro-8-methoxy-2, 4-phenanthroline
1 ,3-diamino-5, 6-dihydro-9-methoxy-2, 4-phenanthroline
3-(2, 4-diamino-5-pyrimidinyl)phenol
2,4-diamino-5-(3-methoxyphenyl)pyrimidine
2,4-diamino-6-(4-nitrophenyl)pyrimidine
2,4-diamino-5-(3,4-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(3,4,5-trimethoxyphenyl)pyrimidine
2,4-diamino-5-(4-fluorophenyl)pyrimidine
2,4-diamino-5-(4-methoxyphenylthio)pyrimidine
2,4-diamino-5-phenethylpyrimidine
2,4-diamino-5-(4-chlorophenylthio)pyrimidine
2,4-diamino-5-(4-chlorophenylsulphonyl)-6-methylpyrimidine
or a salt thereof.
Preferred compounds of the formula (IA) include:
2, 4-diamino-5-(3, 4-dichlorophenyl)pyrimidine
2, 4-diamino-5-(4-methoxyphenyl)pyrimidine
2, 4-diamino-5-(4-methylphenyl)pyrimidine
2, 4-diamino-5-(4-chlorophenyl)pyrimidine
2, 4-diamino-5-(3-chlorophenyl)pyrimidine
2, 4-diamino-5-(2, 4-dichlorophenyl)pyrimidine
2,4-diamino-5-(3-trifluoromethylphenyl)pyrimidine
2,-4-diamino-5-(3-bromopheny l)pyrimidine
2,4-diamino-5-(3-methylphenyl)pyrimidine
2,4-diamino-5-(3,4-methylenedioxyphenyl)pyrimidine
2,4-diamino-5-(3,4-ethylenendioxyphenyl)pyrimidine
or a salt thereof
2) Structural analogues of tetrahydrobiopterin include those of the formula (IB):
and salts thereof wherein R12 is hydrogen, halo, C1 -4 alkyl optionally substituted by halo or alkoxy and preferably R12 is a substituent at 3, 4 or 5 position. (+-)-2-Amino-6-[[(4-
chlorophenethyl)oxy]methyl]-5, 6, 7, 8-tetrahydro-4(3H)-pteridinone is an example of a compound of the formula (IB). These compounds bind less strongly than those of formula (IA).
3)
wherein R13, R14, Rl 5 and R1 6 are each separately selected from hydrogen, halo, haloalkyl, formyl, carboxy, sulpho, cyano, nitro, COR18 and +NR1 8R1 9R20, wherein R18, R19 and R20 are each separately alkyl, aralkyl or aryl groups and R17 is selected form hydrogen, halo, haloalkyl, formyl, carboxy, sulpho, cyano, nitro, hydroxy, alkoxy, alkyl, COR18, NHCOR18 and +NR1 8R19R20 groups, wherein R1 8, R19 and R20 are each separately alkyl aralkyl or aryl groups.
The standard system of numbering is used herein for the indazole ring system as shown below
As regards the groups R13 , R14 , Rl 5 and Rl 6, the halo and haloalkyl groups may for example be a fluoro, bromo, iodo or particularly a chloro group or a C1 -12 particularly C1 -6, straight or branched chain alkyl group, for example an ethyl or especially a methyl group, substituted by one or more, for example three, such halo groups. Aralkyl and aryl groups R18 , Rl 9 and R20, may conveniently be or contain various forms of aromatic hydrocarbyl group but 1- or 2-naphthyl and particularly phenyl groups are of most interest. Alkyl and aralkyl group R18 , Rl 9 and R20 may conveniently be or contain alkyl group such as are described above in relation to the haloalkyl groups R13, R14 , R15 , Rl 6. Particular examples of groups COR18 and +NR 1 8R1 9R20 are thus propionyl and especially acetyl, and triethylamino and especially trimethylamino.
As regards the group R17, similar comments apply to halo, haloalkyl, COR1 8 and +NR1 8R1 9R20 groups as for R13, R14, R15 and R16 whilst the alkyl groups R1 7 may conveniently be selected similarly to the alkyl portion of the halo alkyl groups R13, R14, R15, R16 and R17 and the groups R18 in NHCO R18 may conveniently be selected as for the groups R1 8 in COR18 and +NR1 8R2 0 , the group NHCOR1 8 being for example propionamido or acetamido.
Although each of the groups R13, R14, R15 and R16 may be hydrogen it is preferred that at least one is other than hydrogen, particularly the group R14 or R15 or especially R13, although preferably two or three of R13,R14, R15 and R16 are hydrogen. As regards the groups which are other than hydrogen, the groups which are preferred are those which effect a significant degree of electron withdrawal from the benzene ring. Accordingly a nitro group is of particular interest. Other groups of interest, possibly together with another type of group such as nitro, are haloalkyl and especially halo groups.
Although groups +NR1 8R1 9R20, for example trialkylamino groups such as trimethylamino, also possess this ability their charged nature is a disadvantage in terms of entry into the brain across the blood/brain barrier.
It will be appreciated that where more than one of R13, R14, R15 and R16 is other than hydrogen the two or more substituents may differ from each other. Conveniently however at least one. for example R13, is one of the groups just indicated as being of interest.
Although R17 may be other than hydrogen, for example a halo group such as chloro. it is preferably hydrogen.
Moreover, when one or more of R13, R14, R15 or R16 is a group +NR1 8 R19 R20 the compounds will be a quaternary ammonium salt which contains one or more physiologically acceptable anions. Such anions may for example correspond to those present in the acid addition salts hereinafter described but halo groups such as chloro and bromo are preferred.
Furthermore, when an acid substituent R13, R14, R15, R16 or R17 such as carboxy or sulpho is present then the physiologically acceptable salt may be one formed with a suitable base, examples of which are the alkali metal hydroxides, for example sodium hydroxide, quaternary ammonium hydroxides and amines such as tris (tris representing 2-amino-2- hydroxymethyl propane 1,3-diol).
When a carboxy or sulpho substituent is present or when a hydroxy group is present the indazoles (IC) can be used in the form of physiologically acceptable ester. Such esters may be formed respectively with a suitable phenol or alcohol or with a suitable organic acid or even inorganic acid. Of particular interest are esters formed with a C 1 - 12, particularly C 1 - 6 alkanol. for example ethyl and especially methyl esters.
Examples of specific indazoles (IC) of use in the present invention are indazole and its 4-, 5-, 6- and 7-nitro derivatives together with their halogeno, for example chloro or bromo, analogues. Of these indazole and the last three mentioned nitro derivatives, especially 7- nitroindazole, are of particular interest.
The compounds of formula (IA) (IB) and (IC) may include a number of asymmetric centres in the molecule depending on the precise meaning of the various groups and formula (IA) (IB) and (IC) are intended to include all possible isomers.
The activity of a compound as a tetrahydrobiopterin-site inhibitor of neuronal NO synthase can be determined by an assay in which L-[14 C]-arginine is convened to [U14C]-citrulline by brain cytosol NO synthase (as described by Salter et al., FEBS Lett. 291, 1991 , 145-149) following a preincubation with the compound in the absence or presence of a saturating concentration (typically 10μM) of tetrahydrobiopterin). Such inhibitors also show activity in an intact cell system in which conversion of [14C]-L-arginine to [14C]-citrulline is measured in brain slices stimulated with veratrine. In these experiments, single coronal slices of adult rat forebrain are preincubated in Krebs-Henseleit buffer before transfer to fresh buffer containing L-[U-14C]-arginine. 10μg/ml veratrine and various concentrations of test compound (routinely 1- 100μM). The mixture of test compound and coronal slices is then incubated and the level of [U- 14C]-citrulline formed, then determined (essentially as described-previously, Salter et al. 1991). Selectively for the neuronal NO synthase can be determined by comparison with enzyme assays for other forms of NO synthase or by comparisons with intact cell preparation NO synthesis such as in rat aortic rings in which the basal tone of the tissue is used as an indication of the activity of the constitutive NO synthase.
Alternatively, the activity of the compounds can be determined by the method of Dwyer et al., Biochem. Biophys. Res. Commun. 1991, 176, 1 136-1 141.
Conditions in which there is an advantage in selectively inhibiting neuronal NO production include cerebral ischemia, CNS trauma, epilepsy, AIDS dementia, chronic neurodegenerative disease (eg Parkinson's disease), schizophrenia and chronic pain, and conditions in which non-adreneric non-cholinergic nerve may be implicated such as priapism, obesity and hyperphagia. They are also suitable for use as analgesics and in the treatment of acute neurodegenerative diseases, for example in the treatment of convulsions or particularly for prophylactic use in the prevention of an ischemic incident and possibly also in memory enhancement.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis.
The present invention includes neuronal NO inhibitors in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, citric, tartaric, phosphoric, phosphonic, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids. Salts of neuronal NO inhibitors can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. Esters are pharmaceutically acceptable esters, for example C1 -4 alkyl esters.
A further aspect of the present invention provides a compound of formula (IA), (IB) or (IC) or a salt thereof for use in medicine, with the proviso that R12 is not hydrogen, and that R 14 and R15 are not independently selected from hydrogen, nitro or carboxy when R13 , R16 and R17 are each hydrogen.
Many compounds of formula (IA), (IB) or (IC) or salts thereof are novel, and accordingly the invention also provides:
(i) novel compounds of formula (IA) and salts thereof. Such compounds include:
2,4-diamino-5-(3-trifluoromethylphenyl)pyrimidine
2,-4-diamino-5-(3-bromophenyl)pyrimidine
2,4-diamino-5-(3-methylphenyl)pyrimidine
2,4-diamino-5-(3,4-methylenedioxyphenyl)pyrimidine
2,4-diamino-5-(3,4-ethylenendioxyphenyl)pyrimidine
2,4-diamino-6-(4-methoxyphenyl)pyrimidine
2,4-diamino-6-(3,4-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2-(4-methylphenyl)ethyl)pyrimidine
2,4-diamino-5-(4-methylphenylethynyl)pyrimidine
2,4-diamino-5-phenylethynylpyrimidine
2,6-diamino-3-(2,4,5-trichlorophenyl)pyridine
2,6-diamino-3-(4-methoxyphenyl)pyridine
2,6-diamino-3-(2-naphthyl)pyridine
2,6-bis(acetamido)-3-(3,4-dimethoxyphenyl)pyridine
2,6-diamino-3-(3,4-dimethoxyphenyl)pyridine
1-amino-2, 4-diaza-5, 6-dihydro-9-methoxy-3-(4-methyl-1-piperazinyl)phenanthrene
4-amino-9, 10-dihydro-7-methoxy-2-(4-methyl-1-piperazinyl)benzo[f]quinazoline
2-amino-5-((-naphthyl)pyrimidine
2-amino-5-(4-methoxyphenyl)pyrimidine
2-(4-methylpiperazinyl)-5-(2-naphthyl)pyrimidine
5-(3,4-dimethoxy)-2-(4-methyl-1-piperazinyl)pyrimidine
5-(1,3-benzo[d]dioxol-5-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5-(1,4-benzodioxan-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5-(3,4-dichlorophenyl)-2-(4-methylpiperazinyl)pyrimidine
2,4-diamino-5- (3-thienyl)pyrimidine
2,4-diamino-5- (3,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-biphenylpyrimidine
2,4-diamino-5-(3,5-bis(trifluoromethyl)phenyl)pyrimidine
2,4-diamino-5-(3,5-dichlorophenyl)pyrimidine
2,4-diamino-5-(2,5-dibromo-4-chlorophenyl)pyrimidine
2,4-diammo-5-(4-chloro-3-methanesulphonamidophenyl)pyrimidine
2,4-diamino-5-(4-methoxy-3-methylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethoxyphenyl)pyrimidine
2,4-diamino-5-(3-amino-4-chlorophenyl)pyrimidine
2,4-diamino-5-(3-aminophenyl)pyrimidine
2,4-diamino-5-(4-chloro-3-nitrophenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-hydroxyphenyl)pyrimidine
2,4-diamino-5-(3-fluorophenyl)pyrimidine
2,4-diamino-5-(3-trifluoromethoxyphenyl)pyrimidine
2,4-diamino-5-(3-bromo-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-fluoro-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-fluorophenyl)pyrimidine
2,4-diamino-5-(4-chlorophenyl)pyrimidine
(ii) compounds of formula (IB) and salts thereof with the proviso that R1 2 is not
hydrogen; and
(iii) novel compounds of formula (IC) and salts thereof.
Whilst it may be possible for the neuronal NO synthase inhibitors of the present invention to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. According to a further aspect, the present invention provides a pharmaceutical formulation comprising a compound which binds at the tetrahydrobiopterin site of NO Synthase in combination with a pharmaceutically acceptable carrier therefor and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (IA), (IB) or (IC) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration my be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient: as a powder or granules: as a solution or a suspension in an aqueous liquid or a non-aqueous liquid: or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, saline, water- for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration mav include flavourins aeents.
The neuronal NO synthase inhibitors of the invention may be administered orally or via injection at a dose of from 0.1 to 500mg/kg per day. The dose range for adult humans is generally from 5mg to 35g/day and preferably 5mg to 2g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5mg to 500mg, usually around 10mg to 200mg.
The neuronal NO synthase inhibitors of the invention are preferably administered orally or by injection (intramuscular, intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration may vary depending on the condition and its severity.
The present invention also provides a process for the preparation of the novel compounds of formula (IA), (IB) and (IC) as hereinbefore defined
Compounds of the present invention are commercially available or may be made by analogous methods to those known in the art. More specifically:
(a) Compounds of formula (IA) may be prepared
(i) when X is nitrogen, by the cyclisation of a compound of the formula (IV)
wherein R21 is cyano or CO R23 wherein R21 is hydroxy, C1 -4 alkoxy or hydrogen and R22 is oxo or a group wherein L is a leaving group; with
amino guanidine or guanidine respectively. Suitable leaving groups include alkoxy and substituted secondary amino groups, eg. aniline and substituted aniline groups and heterocyclic amines such as morpholine.
The reaction conveniently takes place in a polar solvent, for example an alkanol. e.g. a C1 -4 alkanol such as ethanol, or a dipolar aprotic solvent such as
dimethylsuiphoxide at a non-extreme temperature, e.g. 20 ° to 150 ° C and conveniently 25° to 90 °C, with the guanidine or aminoguanidine present in the form of a salt. The free guanidine or aminoguanidine can then conveniently be liberated in-situ by the presence of base, for example an alkoxide such as sodium methoxide. When the guanidine or aminoguanidine is in the form of its carbonate/bicarbonate, base is not required.
These reactions are analagous to those described in UK patent 1261455, UK patent 002121 and European patent application EP 0372934 for the preparation of benzyl pyrimidines, trizines and phenyl pyrimidines respectively
(ii) when R1 and R2 are hydrogen the removal of one or more protecting groups
from N R1R2 and optionally from R4, when it is desired that R4 is NH2.
Suitable protecting groups are derived from carboxylic acids, for example acetic or benzoic acids.
(iii) by the conversion of one compound of the formula (IA) to a further compound of the formula (IA), for example when R1 and/or R2 are C1 -4 alkyl the alkylation of the corresponding compound wherein R1 and/or R2 are hydrogen; or when R1 and R2 are hydrogen, the amination, or chlorination and subsequent animation, of a compound of the formula (V):
wherein Q is chloro or bromo, preferably chloro, or hydroxy respectively and R4' is hydrogen, methyl, hydroxy, trifiuoromethyl or halo. Suitable chlorinating agents include phosphorous oxychloride which can also be used as solvent. The amination is conveniently carried out by reaction with ammonia in a suitable solvent such as a C1 -4 alkanol. e.g. ethanol. The reaction is suitably carried out at an elevated temperature, for example 50-200°C, in a sealed system, and preferably under pressure.
(iv) when X is CH and Y is a group CH or CNH2 the reaction of a compound of the formula (VI):
or a suitably protected derivative thereof, wherein R24 is hydrogen or NH2 with benzene boronic acid or benzene boronic acid substituted so as to give the desired substituent R11 in the compound of the formula (IA) so formed, followed by the removal of any protecting groups.
This reaction is conveniently carried out in the presence of a catalyst, for example a palladium catalyst. We have found that tetrakistriphenylphosphine palladium is a suitable catalvst for this reaction. The reaction is convenientlv carried out at a non- extreme temperature, for example 20° to 100° C and preferably 50° to 90° C in a solvent, for example a mixture of an aromatic hydrocarbon such as benzene and an alkanol such as ethanol under an inert atmosphere. Acyl groups, for example acetyl groups, are suitable protecting groups when R1b and/or R2b are hydrogen.
(b) Compounds of the formula (IB) may be prepared by the reduction of the
corresponding 8-oxide. This is conveniently accomplished by hydrogenation in the presence of a suitable catalyst. The catalyst will normally be a transition metal catalyst, for example containing palladium or platinum, and will be chosen so that it reduces the 8-N-oxide function without affecting any of the other groups in the molecule, unless it is desired to also reduce these. We have found that palladium
(as a 5% of a mixture with barium sulphate) is a suitable selective catalyst. The reaction is conveniently carried out in a solvent, for example a glacial acetic
acid/trifluoroacetic acid mixture, at a non-extreme temperature, for example between 0°- and 80°C and suitably at room temperature.
(c) Compounds of formula (IC) can be prepared using various routes to indazoles described in the literature, for example the process of U.S. Patent 3, 988, 347 which involves reaction of o-methylacetanilide containing the appropriate substituents R13 , R14, R15 and R16 or substitutents convertible thereto. Indazoles (IC) having a substituent at the 3-position. i.e. containing a group R17 other than hydrogen may be prepared by other procedures described in the art of indazole chemistry or by modification of those procedures.
The compounds may be prepared directly in salt form or converted thereto by reaction of the indazole with the appropriate acid or base. Esters may similarly be prepared directly or through acid or base. Esters may similarly be prepared directly or through reaction of the corresponding indazole containing a carboxy or sulpho group with the appropriate alcohol or of the corresponding indazole containing a hydroxy group with the appropriate acid.
The present invention also provides a novel process for the preparation of a compound of formula (IA) as hereinbefore defined, which comprises the reaction of a compound of formula (VII).
Preferably d is 0 and/or Ar is phenyl.
The reaction is conveniently carried out in a polar solvent, for example toluene, in the presence of aqueous sodium carbonate and tetrakistriphenylphosphine palladium, under an inert atmosphere, for example nitrogen. The reaction is preferably carried out at a non- extreme temperature of 20°C to 150°C, suitably 80°C to 120°C.
Compounds of formula (VII) may be prepared from a compound of formula (VIII)
or a suitably protected derivative thereof wherein R1 , R2 , R4, X and Y are as hereinbefore defined, by reaction with iodine monochloride. The reaction is carried out in a suitable solvent, such as glacial acetic acid, at non-extreme temperature for example room temperature.
The present invention will now be described by way of example only, and is not intended to be limiting thereof.
Example 1
Preparation of 5-(Benzo-[B]-thien-3-yl)-2,4-diaminopyrimidine
(a) 2-(Benzo-[B]-thien-3-yl)-3-methoxyacrylonitrile
To a solution of sodium ethoxide (from 1.1gms of Na) in ethanol (60ml) at room temperature was added benzo-[B]-thien-3-yl acetonitrile (7.79gms, Maybridge Chemicals Ltd) in a single portion. Stirring was continued for 15 minutes, ethylformate (6.66gms) added, and the mixture left to stir overnight at room temperature. The suspension was then refluxed for 3 hours during which time the solid completely dissolved. After cooling, the solvent was removed in vacuo and the residue triturated with diethyl ether. The solid was filtered off and dried in vacuo to leave the crude product as a tan coloured solid (6.93gms).
The above product was divided into three equal portions. These were placed in separate Young tubes, methvl iodide (l.8gms) and DMF/18mls) added to each, and the tubes sealed. After stirring at 50°C for 4 hours the contents were cooled, combined, and the solvent removed in vacuo. The residue was then partitioned between ethyl acetate and water, and the organic phase again washed with water before drying over MgSO 4. After treating with activated charcoal, the solvent was evaporated to leave the desired product as a pale yellow waxy solid. (4.8 gms. 50% yield)
(b) 5-(Benzo-[B]-thien-3-yl)-2,4-diaminopyrimidine
To a solution of sodium ethoxide (from 1.03gms of Na) in ethanol (40ml) at room temperature was added guanidine HCl (4.26gms). After stirring for a further 5 minutes, the above intermediate was added in ethanol (40ml) and the resulting suspension refluxed for 5 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between chloroform and water. After washing the organic phase with water and drying over MgSO4, the solvent was removed in vacuo. The crude product was then purified by column chromatography (SiO2)
eluting with CHCl3 to 4% MeOH-CHCl3. Recrvstallization from ethanol gave the product as a white crystalline solid. (2.7gms, 50% yield, mp 193-4° C)
The following compounds were made by an analogous method:
2,4-diamino-5-(4-methoxy-3-methylphenyl)pyrimidine; mpt = 229-230°C
2,4-diamino-5-(4-trifluoromethylphenyl)pyrimidine; mpt = 218-219°C
2,4-diamino-5-(4-trifluoromethoxyphenyl)pyrimidine; mpt = 174-175°C
2,4-diamino-5-(3-fluorophenyl)pyrimidine; mpt = 215-217°C
2,4-diamino-5-(3-trifluoromethoxyphenyl)pyrimidine; mpt = 197.7-199.6°C
2,4-diamino-5-(3-bromo-4-methoxyphenyl)pyrimidine; mpt = 269.3-271.8°C
2,4-diamino-5-(3-fluoro-4-methoxyphenyl)pyrimidine; mpt = 243-245°C
2,4-diamino-5-(3-chloro-4-methoxyphenyl)pyrimidine; mpt = 337-339°C
2,4-diamino-5-(3-chloro-4-fluorophenyl)pyrimidine; mpt = 233-235°C
2,4-diamino-5-(3-methylphenyl)pyrimidine; mpt = 167-169°C
2,4-diamino-5-(3-bromophenyl)pyrimdine; mpt = 215.7-218.5°C
2,4-diamino-5-(3-trifluoromethylphenyl)pyrimidine; mpt = 260-261°C
2,4-diamino-5-(3-bromo-4-chloro)pyrimidine; mpt = 221-222°C
2,4-diamino-5-(3-chloro-4-methyl)pyrimidine; mpt = 281-282°C
Example 2
Preparation of 2,6-Diamino-3-( 3,5-dichlorophenyl)pyridine
(a) 2,6-Diaceτamido-3-(3,5-dichlorophenyl)pyridine
To a mixture of 3-bromo-2,6-diacetamidopyridine (2.00g, Alfred Bader Library of Rare Chemicals; Div. of Aldrich Chemical Company, INC.) in benzene (15ml), 2M aqueous sodium carbonate (7.36ml) and tetrakistriphenylphosphine palladium (0.25g), a solution of 3.5-dichlorobenzene boronic acid (1.52g) in absolute ethanol (3ml) was slowly added. The yellow biphasic reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between water and chloroform. The chloroform layer was washed once with saturated sodium bicarbonate, twice with water and dried over anhydrous magnesium sulphate. The solvent was removed under vacuo and the crude product was purified by column chromatography (SiO2) eluting with chloroform to 2% methanol-chloroform. The
product was triturated with ether, filtered and dried under vacuo at 60°C to give a white solid. (0.738g, mp 200-204°C.)
(b) 2,6-Diamino-3-(3.5-dichlorophenyl)pyridine
2,6-Diacetamido-3-(3,5-dichlorophenyl)pyridine was suspended in dilute hydrochloric acid (0.40ml, 12M HCl/lml H2O) and refluxed at 120°C for 1.50 hours. The reaction mixture was cooled in an ice-bath and basified with 0.880 ammonia. The white solid which precipitated was filtered, washed with water and dried under vacuo at room temperature. The crude product was purified by column chromatography [SiO2] eluting with ether. The product was triturated with petroleum ether, filtered and dried under vacuo at 70° C to give a cream solid.
(0.107g, mp 114-116°C.) Example 3 Preparation of 2, 4-diamino-5-(4-phenoxyphenyl)pyrimidine
(a) 2.4-diamino-5-iodopyrimidine
A soloution of iodine monochloride (16.24g, 0.1mol) in glacial acetic acid (5ml.) was added dropwise with stirring during 30 minutes to a mixture of 2,4- diaminopyrimidine (11g. 0.1mol) and glacial acetic acid (150ml). The mixture became homogeneous towards the end of the addition and then the product hydrochloride began to separate. The thick slurry was vigorously stirred for 4 hours then filtered. The filter cake was sucked as dry as possible then dissolved in hot water (400ml). Solid sodium sulphite was added in small portions until the iodine colour was completely discharged. The solution was filtered and the filtrate was basified with 10N.NaOH. Cooling in the refrigerator overnight gave the product as a cream cystalline solid (18.9g. 80% yield, m.p. 229-230).
(b) 2,4-diamino-5-(4-phenoxyphenvl)pyrimidine
A mixture of 2,4-diamino-5-iodopyrimidine (1.18g. 5mmol), 4-phenoxy- benzeneboronic acid (1.28g. 6mmol), toluene (40 ml), 2M aqueous sodium carbonate (10ml. 20mmol) and tetrakistriphenylphosphine palladium (400 mg. 0.35 mmol) was stirred and heated at 1 10°C under nitrogen for 6 hours. The reaction
mixture was evaporated to dryness in vacuo and the residue was washed with warm water and taken up in dichloromethane. The organic extract was dried (MgSO4) and evaporated to drynes in vacuo. The residue was purified by flash column chromatography (SiO2). Elution with CH2CI2 to 5% EtOH-CH2Cl2 gave a solid which after recrystallisation form EtOH afforded the product as a cream crystalline solid (860mg 62% yield, m.p. 149).
The following compounds were prepared by an analgous method:
2,4-diamino-6-(4-methoxyphenyl)pyrimidine; mpt. 220-222°C
2,4-diamino-6-[3,4-dimethoxyphenyl]pyrimidine; mpt 202-204°C
2,4-diamino-5-[2-(4-methylphenyl)ethyl]pyrimidine; mpt 187°C
2,4-diamino-5-(4-methylphenylethynyl)pyrimidine; mpt 197-199°C
2,4-diamino-5-phenylethynylpyrimidine; mpt 190°C
2,6-diamino-3-(2,4,5-trichlorophenyl)pyridine; mpt 173-175° C
2,6-diamino-3-(4-methoxyphenyl)pyridine; mpt 131°
2,6-diamino-3-(2-naphthyl)pyridine; mpt 193-194°C
2,6-Bis(acetamido)-3-(3,4-dimethoxyphenyl)pyridine; mpt 231-233°C
2,6-diamino-3-(3,4-dimethoxyphenyl)pyridine; mpt 190° C
2,4-diamino-5-[3,4-ethylenedioxyphenyl]pyrimidine; mpt 222-224°C
2,4-diamino-5-[3,4-methylenedioxyphenyl]pyrimidine; mpt 225-227°C
2-amino-5-(1-naphthyl)pyrimidine; mpt 155°C
2-amino-5-(4-methoxyphenyl)pyrimidine; mpt 183-184°C
2,4-diamino-5-(3-thienyl)pyrimidine; mpt 171-172°C
2,4-diamino-5-(3,5-dimethoxyphenyl)pyrimidine;
2,4-diamino-5-(2,5-dimethoxyphenyl)pyrimidine; mpt 157°C
2,4-diamino-5-biphenylpyrimidine; mpt 204-206°C
2,4-diamino-5-[3,5-bis(trifluoromethyl)phenyl]pyrimidine; mpt 201-203°C
2,4-diamino-5-(3,5-dichlorophenyl)pyrimidine; mpt 289-292°C
Example 4
The following compounds were made by conversion of a compound of formula (IA) according to the reaction scheme shown in Fig. 1.
(1 ) 2,4-diamino-5-(3-chloro-4-hydroxyphenyl)pyrimidine; mpt = 165-167°C
(2) 2,4-diamino-5-(4-chloro-3-nitrophenyl)pyrimidine; mpt = 245-246°C
(3) 2,4-diamino-5-(3-aminophenyl)pyrimidine: mpt = 156-157°C
(4) 2,4-diamino-5-(3-amino-4-chlorophenyl)pyrimidine; mpt = 189-190°C
(5) 2,4-diamino-5-(2,5-dibromo-4-chlorophenyl)pyrimidine; mpt = 245-248°C
(6) 2,4-diamino-5-(4-chloro-3-methanesulphonamidophenyl)pyrimidine;
mpt = 234-235°C
(7) 2,4-diamino-5-(4-chloro-3-cyanophenyl)pyrimidine; mpt > 300°C
Example 5
Preparation of (+-)-2-Amino-6-[[(4-chlorophenethyl)oxy]methyl]-5,6,7,8-tetrahy-dro- 4(3H)-pteridinone a) 2- Amino-6- [[(4-chlorophenethyl)oxy]methyl]-4(3H)- pteridinone 8-oxide
The title compound was prepared from 3-amino-6-chloromethyl- 2-pyrazinecarbonitrile 4-oxide and 4-chlorophenethanol by the method of Bigham et al, J.Med.Chem. 1987, 30, 40-45. b) (+-)-2-Amino-6-[[f4-chlorophenethvl)oxy]methyl]-5,6,7,8- tetrahydro-4(3H)- pteridinone
A mixture of 2-amino-6-[[(4-chlorophenethyl)oxy]methyl]-4(3H)- pteridinone 8-oxide monohydrate (0.600g), 5%Pd/BaSO 4 (0.200-0.300g), glacial acetic acid (40ml), and trifluoroacetic acid (20ml) was hydrogenated a total of three times for a total of 1h 23min. The total uptake of hydrogen was 111 ml. 6N HCl
(10ml) was added. After 3h, the mixture was filtered, and the yellow filtrate was evaporated to dryness. The crude product was dissolved almost completely in hot
6N HCl (100ml), and the solution was treated with charcoal, filtered, and cooled.
The resulting mixture was concentrated under vacuum to a solid that was dissolved in hot 6N HCl (70ml). The solution was allowed to cool, and the crystallized white solid was filtered, washed with 6N HCl (2x10 ml), and dried under vacuum at 50°C: yield 0.474g = mp 232-237°C (dec); IR(KBr) 1663 (CO) overlapping less intense
1700 cm- 1 ; NMR(Me2SO-δ6) d 2.81(t,2H,CH2 Cl); 3.1-3.2(m,1H,C-6H); 3.3-3.5(br d.2H.c-7 H2); 3.5-3.8(m. 4H, CH2OCH2); 5.6(br); 6.78(br s, 2H, NH2 ); 7.24-7.35
(AA'XX'. 4H, ArH); 7.42 (br s, 1H. NH); 1 10.0 (very br); 10.75 (br s, 1H. NH);
UV(0.1N HCl) λ max 265.5 nm (e 13800); Anal.C 15H1 8ClN5O2.2HCl.H2O
(C,H,N,Cl).
Example 6
Biological Activity of Compounds of the Present Invention
The activity of a compound as a tetrahydrobiopterin-site inhibitor of neuronal NO synthase was determined by an assay in which L-[U1 4C]-arginine is convened to [U1 4C]-citrulline by brain cytosol NO synthase (as described by Salter M. Knowles. R.G. and Moncada, S. (1991) FEBS Lett. 291, 145-149. following a 5 min preincubation with the compound in the absence or presence of a saturating concentration (typically 10μM) of tetrahydrobiopterin). Compounds were initially tested at a concentration of 10μM and the inhibition expressed as % control value at this concentration (see Table 1, column 2). Subsequent determinations of the effects of 0.01-30 μM compound permitted estimation of the maximum inhibition attainable under these conditions (see Table 1, column 3); maximal inhibition close to 100%) could be achieved following longer incubation with the compounds. Such inhibitors also show activity in an intact cell system in which conversion of [14C]- L-arginine to [ 14C]-citrulline is measured in brain slices stimulated with veratrine.
TABLE 1
Pterin-site Inhibitors of Neuronal NO Synthase
Example 7:
In vitro tests of 7-nitroindazole activity
Nitric oxide synthase (NOS) activity was determined in vitro by the method of Dwyer et al., Biochem. Biophys. Res. Commun. 1991. 176, 1 136-1 141. Mice (male, LACA, 28-32 g) were killed by cervical dislocation. Cerebella were removed, homogenized (1 :10 w/v in 20mM tris buffer containing 2mM EDTA, pH. 7.4) and aliquots (25μl) incubated (37°C) with L-arginine (120nM) containing 0.5 μCi [3H]- arginine (specific activity 62 Ci mmol -1), NADPH (0.5mM) and CaCb (0.75mM). Incubations also contained (a) 7-nitroindazole (MIM Research Chemicals Ltd.) in 0.5% w/v sodium carbonate solution (dissolution was effected by heating to 80°C and cooling when the 7-nitroindazole remained in solution), (b) for comparative puposes. L-NG-nitoarginine methyl ester (L-NAME) or L-NG-monomethyl arginine (L-NMMA) in distilled water, or, (c) as control, an equal volume (5μl) of 0.5% (w/v) sodium carbonate or distilled water. Final incubation volume was 105 μl. After 15 minutes the reaction was stopped by addition of 3 ml HEPES buffer (20mM containing 2 mM EDTA, pH 5.5. and [3H]-citrulline produced was separated by cation exchange chromatography on 0.5 ml columns of Dowex AG50- W8 Na+ form. [3H]-Citrulline was quantitated by liquid scintillation spectroscopy of duplicate 1 ml aliquots of the flow-through.
In some experiments mice were injected i.p. with 7-nitroindazole (25 mg kg -1) or L- NAME (50mg kg -1) and killed 15 minutes thereafter. Cerebella were removed, homogenized and NOS activity determined as described above.
It was found the 7-nitroindazole potently inhibited mouse cerebellar NOS in vitro (IC50 0.47 ± 0.01μM). For comparison, it was 1.8 times more potent than L-NAME (IC50 0.87 ± 0.02μM) and 5 times more potent than L-NMMA (IC50 2.37 ± 0.03μ M), the detailed results being presented in Figure 2. The results shown give the mean ± s.e. mean, n = 6 (statistical anlaysis carried out by Student's unpaired t test). Where no error bar is indicated the error lies within the dimensions of the symbol. In separate experiments, administration of 7-nitroindazole (25 mg kg- 1 , i.p.) decreased mouse cerebella NOS activity measured 15 minutes thereafter by over 55% (3.9 ± 0.06 nmol citrulline mg- 1- protein 15 min- 1 , cf. 9.1 ± 0.26 arachis oil- injected controls, n = 6, P<0 .01 ). For comparison, a higher dose of L-NAME (50 mg kg- 1 produced only 46.2 ± 1.6% inhibition of this enzyme under indentical
condition (4.46 ± 0.012 pmol citrulline mg- 1- protein 15 min- 1. cf. 8.33 ± 0.15. saline-injected controls, n = 6. P<0.01).
Example 8:
In vivo tests of 7-nitroindazole activity
Anti-nociceptive activity of 7-nitroindazole (10-50 mg kg - 1) administered i.p. to mice as a suspension in arachis oil produced by sonication was determined by the formalin-induced hindpaw licking assay as descrived by Moore et al., British Journal of Pharmacology, 1991, 102, 198-202. Control animals received 10ml kg- 1 of arachis oil or saline (0.9% w/v NaCl). This test shows hindpaw licking time (seconds) in the early (0-5 minutes) and late (15-30 minutes) phases on injection of 10μl formalin (5% v/v) administered 15 minutes after the 7-nitroindazole.
In separate experiments, again described by Moore et al. (ibid), the blood pressure of urethane-anaesthetized (10 g kg- 1) mice was monitored for 45 minutes after i.p. administration of 7-nitroindazole.
7-Nitroindazole (10, 25 and 50 mg kg- 1 ) produced a dose-related inhibition of late phase formalin-induced hindpaw licking without influencing the early phase response. The detailed results are presented in Figure 3 where open columns indicate the early phase (0.5 minutes) and hatched columns the late phase (15-30 minutes) hindpaw licking times. The mean ± s.e. mean is shown (statistical analysis by Student's unpaired t test), n = 6-12, **P<0.01. The control animals, identified by C. are those which received 10 ml kg- 1 arachis oil which, alone, did not influence hindpaw licking time. (The saline-injected mice gave an early phase value of 89.8 ± 7.0 seconds and a late phase value of 150.7 ± 1 1.5 seconds, n =15). The ED50 for the anti-nociceptive effect was 26 mg kg- 1 (equivalent to 159.5 μmol kg- 1 ).
Administration of 7-nitroindazole (25 and 80 mg kg- 1 ) did not increase mean arterial pressure (MAP) over the 45 minute experimental period (e.g. 25 mg kg- 1, 47.4 ± 5.1 mmHg, cf. 51.6 ± 4.4 mmHg, n = 4, before 7-nitroindazole administration. 80 mg kg- 1 , 43.9 ± 5.3 mmHg. cf. 49.5 ± 2.9 mmHg. n = 4. before 7- nitroindazole administration). In control experiments, i.p. administration of arachis oil failed to alter MAP.
Example 9:
In vitro and in vivo tests of other indazoles
The procedure of Example 7 was repeated for 7-nitroindazole and other indazoles but using rat cerebella. The IC50 values so obtained for inhibition of rat cerebella nitric oxide synthase (NOS) for various indazoles are shown in Table 2 below.
The procedure of Example 8 was repeated for 7-nitroindazole and other indazoles. The percentage inhibition of formalin-induced licking in the late phase following the administration of 50 mg kg- 1 i.p. of the indazoles is shown in Table 2 below. For the compound 5-nitroindazole. where an asterisk is shown, a pronounced sedative effect was produced which interfered with the determination of the anti-nociceptive effect so that it could not be quantitated. The other indazoles did not exhibit an overtly sedative effect.
Table 2
Example 10:
Formulation of medicaments
(A) Tablets of the following composition are prepared: mg/tablet
7-nitroindazole (micronised) 250
'Avicel' (microcrystalline cellulose) 38
polyvinylpyrrolidone 3
alginic acid 6 magnesium stearate 3
The 7-nitroindazole is mixed with 'Avicel' and polyvinylpyrrolidone is added, dissolved in sufficient industrial methylated spirits (74° OP) to produce a mass suitable for granulating. The mass is granulated through a 20 mesh sieve and the resultant granules are dried at a temperature not exceeding 50°C. The dried granules are passed through a 20 mesh sieve and the alginic acid and magnesium stearate are then added and mixed with the granules. The produce is compressed into tablets each weighing 300 mg on 3/8 inch flat bevelled edge divided punches.
(B) Tablets of the following composition are prepared: mg/tablet
7-nitroindazole (micronised) 250
lactose (300 mesh) 134
maize starch 4
gelatine 8
magnesium stearate 4
The tablets are prepared by essentially the same procedure as described in (A) and are compressed at a tablet weight of 400mg on 7/16 inch fait bevelled punches.
(C) Tablets of the following composition are prepared: mg/tablet
7-nitroindazole (micronised) 250
lactose (300 mesh) 19
maize starch 15
gelatine 10
magnesium stearate 6
The 7-nitroindazole is mixed with lactose and half the total quantity of maize starch required, and a 5% solution of gelatine in water is added to the mass. The product is granulated through a 16 mesh sieve, and the resultant granules are dried to constant weight
at a temperature not exceeding 50°C. The dried granules are passed through a 20 mesh sieve and mixed with magnesium stearate and the remainder of the maize starch. The product is compressed at a 300 mg tablet weight on 3/8 inch flat bevelled edge divided punches.
Claims
1. Use of a compound which binds at the tetrahydrobiopterin site of NO synthase for the manufacture of a medicament for the treatment of a condition where there is an advantage in inhibiting neuronal NO synthase with little or no inhibition of endothelial NO synthase.
2. Use of a compound according to Claim 1, wherein the compound is one of formula (I A), formula (IC) or a structural analogue of tetrahydrobiopterin or salts thereof
Wherein R1 and R2 are the same or different and each is hvdrogen or a C 1 -4 alkvl group or N R1 R2 forms a 5- or 6-membered heterocyclic group ' v \
wherein T is oxygen, CH2 or nitrogen substituted by hydrogen or C1 -4 alkyl, and v and w are the same or different and each is 1 or 2 provided the sum of v and w is 3 or 4; X is nitrogen or CH; Y is nitrogen, CH or CNH2; D is a group S(O)x wherein x is 0, 1 or 2, a C 1 -4 alkylene chain, or a C2 -4 alkenylene or alkynylene chain: d is 0 or 1 : Ar is a monocyclic or bicyclic ring system which may contain one or two heteroatoms and which contains at least one aromatic ring; R3 represents hydrogen or one to three substituents on the ring system Ar which may be the same or different and are chosen from halo, N R5 R6 wherein R5 and R6 are independently selected from hydrogen or S(O)x' R7 wherein x' is 0, 1 or 2 and R7 is C 1 -4 alkyl; nitro. cyano. a C 1 -4 carboxcylic acid group or an ester thereof. C 1 -4 alkyl optionally substituted by one to three halo atoms; phenyl or a group -(A)mR8 wherein A represents oxygen. S(O)n wherein n is 0. 1 or 2, or N R9 wherein R9 is hydrogen or C 1 -4 alkyl optionally substituted by halo and m is 0 or 1 , and R8 is hydrogen, or C 1 -4 alkyl or phenyl each optionally substituted by one to three halo atoms; R4 is hydrogen. C 1 -4 alkyl. hydroxy. halo, trifluoromethyl or a group N R10 R11 wherein R10 and R11 are the same or different and each is hydrogen or C 1 -4 alkyl, or N R10 R11 forms a 5- or 6- membered heterocyclic group optionally substituted by a C 1 -4 alkyl group or R4 represents a C 1 -2 alkylene group linking the heterocyclic ring to Ar; R13, R14, R15 and R16 are each separately selected from hydrogen, halo, haloalkyl, formyl, carboxy. sulpho, ,yano. nitro, CO R18 and +NR1 8 R19 R20, wherein R18, R19 and R20 are each separately alkyl, aralkyl or aryl groups and R17 is selected form hydrogen, halo, haloalkyl, formyl, carboxy, sulpho, cyano, nitro, hydroxy, alkoxy, alkyl, COR18, NHCOR18 and +NR18R19R20 groups, wherein R18, R19 and R20 are each separately alkyl aralkyl or aryl groups.
3) Use of a compound of formula (IA) according to Claim 2. which is a compound of formula (II)
or a salt thereof, wherein R1, R2,X,Y,R4 are as hereinbefore defined, Ar' is a monocyclic or bicyclic ring system containing at least one aromatic ring, and R3 ' represents hydrogen or one to three substituents which may be the same or different and are chosen from halo, amino, nitro, cyano, a C 1 -4 carboxylic acid group or an ester thereof, a group -(A)mR8' wherein A and m are as hereinbefore defined and R8' is C 1 -4 alkyl optionally substituted by halo.
4) Use of a compound of formula (IA) according to Claim 2. which is a compound of formula (III)
or a salt thereof wherein D, d, Ar, R3 , R1 , R2 , X and R4 are as hereinbefore defined.
5. Use of a compound according to Claim 4. wherein the compound is selected from 2, 4-diamino-5-(3, 4-dichlorophenyl)pyrimidine
2, 4-diamino-5-(4-methoxyphenyl)pyrimidine
2, 4-diamino-5-(4-methylphenyl)pyrimidine
2, 4-diamino-5-(4-chlorophenyl)pyrimidine
2, 4-diamino-5-(3-chlorophenyl)pyrimidine
2, 4-diamino-5-(2, 4-dichlorophenyl)pyrimidine
2,4-diamino-5-(3-trifluoromethylphenyl)pyrimidine
2,-4-diamino-5-(3-bromophenyl)pyrimidine
2,4-diamino-5-(3-methylphenyl)pyrimidine
2,4-diamino-5-(3,4-methylenedioxyphenyl)pyrimidine
2,4-diamino-5-(3,4-ethylenendioxyphenyl)pyrimidine
or a salt thereof.
6. Use of a tetrahydrobiopterin analogue according to Claim 2 which is a compound of formula (IB)
7. Use of a compound of formula (IC) according to Claim 2, wherein R13, R14, R15, R16 and R17 are independently selected from hydrogen, nitro or halo.
8. Use according to Claim 1 for the treament of cerebral ischemia.
9. Use according to Claim 1 for the treatment of CNS trauma.
10. Use according to Claim 1 for the treatment of AIDS dementia.
1 1. Use according to Claim 1 for the treatment of epilepsy.
12. Use according to Claim 1 for the treatment of chronic neurogenerative disease or chronic pain.
13. Use according to Claim 1 for the treatment of schizophrenia.
14 Use according to Claim 1 for the treatment of conditions in which non-adrenegic non-cholinergic nerve may be implicated.
15. Use according to Claim 1 as an analgesic.
16. Use according to Claim 1 for the treatment of acute neurodegenerative diseases.
17. A compound of formula (IA), (IB) or (IC) or a salt thereof for use in medicine, with the proviso that R12 is not hydrogen, and that R14 and R15 are not independently selected from hydrogen, nitro or carboxy when R13, R16 and R17 are each hydrogen.
18. A novel compound of formula (IA), (IB) or (IC) or a salt thereof as hereinbefore defined.
19. A compound according to Claim 18 which is selected from:
2,4-diamino-5-(3-trifluoromethylphenyl)pyrimidine
2,-4-diamino-5-(3-bromophenyl)pyrimidine
2,4-diamino-5-(3-methylphenyl)pyrimidine
2,4-diamino-5-(3,4-methylenedioxyphenyl)pyrimidine
2,4-diamino-5-(3,4-ethylenendioxyphenyl)pyrimidine
2,4-diamino-6-(4-methoxyphenyl)pyrimidine
2,4-diamino-6-(3,4-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2-(4-methylphenyl)ethyl)pyrimidine
2,4-diamino-5-(4-methylphenylethynyl)pyrimidine
2,4-diamino-5-phenylethynylpyrimidine
2,6-diamino-3-(2,4,5-trichlorophenyl)pyridine
2,6-diamino-3-(4-methoxyphenyl)pyridine
2,6-diamino-3-(2-naphthyl)pyridine 2,6-bis(acetamido)-3-(3,4-dimethoxyphenyl)pyridine
2,6-diamino-3-(3,4-dimethoxyphenyl)pyridine
1-amino-2, 4-diaza-5, 6-dihydro-9-methoxy-3-(4-methyl-1-piperazinyl)phenanthrene
4-amino-9, 10-dihydro-7-methoxy-2-(4-methyl-1-piperazinyl)benzo[f]quinazoline
2-amino-5-((-naphthyl)pyrimidine
2-amino-5-(4-methoxyphenyl)pyrimidine
2-(4-methylpiperazinyl)-5-(2-naphthyl)pyrimidine
5-(3,4-dimethoxy)-2-(4-methyl-1-piperazinyl)pyrimidine
5-(1,3-benzo[d]dioxol-5-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5-(1,4-benzodioxan-6-yl)-2-(4-methylpiperazin-1-yl)pyrimidine
5 -(3 ,4-dichlorophenyl)-2-(4-methylpiperazinyl)pyrimidine
2,4-diamino-5-( 3-thienyl)pyrimidine
2,4-diamino-5-( 3 ,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-(2,5-dimethoxyphenyl)pyrimidine
2,4-diamino-5-biphenylpyrimidine
2,4-diamino-5-(3,5-bis(trifluoromethyl)phenyl)pyrimidine
2,4-diamino-5-(3,5-dichlorophenyl)pyrimidine
2,4-diamino-5-(2,5-dibromo-4-chlorophenyl)pyrimidine
2,4-diamino-5-(4-chloro-3-methanesulphonamidophenyl)pyrimidine
2,4-diamino-5-(4-methoxy-3-methylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethylphenyl)pyrimidine
2,4-diamino-5-(4-trifluoromethoxyphenyl)pyrimidine
2,4-diamino-5-(3-amino-4-chlorophenyl)pyrimidine
2,4-diamino-5-( 3-aminophenyl)pyrimidine
2,4-diamino-5-(4-chloro-3-nitrophenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-hydroxyphenyl)pyrimidine
2,4-diamino-5-(3-fluorophenyl)pyrimidine
2,4-diamino-5-(3-trifluoromethoxyphenyI)pyrimidine
2,4-diamino-5-(3-bromo-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-fluoro-4-methoxyphenyl)pyrimidine
2,4-diamino-5-(3-chloro-4-methoxyphenyl)pyrimidine
2,4-diamino-5- (3-chloro-4-fluorophenyl)pyrimidine
2,4-diamino-5-(4-chlorophenyl)pyrimidine
20. A pharmaceutical formulation which comprises a compound which binds at the tetrahydrobiopterin site of NO synthase according to Claim 1, together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients.
21. A process for the preparation of the novel compounds according to Claim 17. which comprises:
(a) for a compound of formula (IA)
(i) when X is nitrogen, by the cyclisation of a compound of the formula (IV)
wherein R21 is cyano or CO R23 wherein R23 is hydroxy, C1 -4 alkoxy or hydrogen and R22 is oxo or a group 
C u wherein L is a leaving group; with amino guanidine or guanidine respectively.
(ii) when R 1 and R2 are hydrogen the removal of one or more protecting groups
from NR1R2 and optionally from R4, when it is desired that R4 is NH2.
(iii) by the conversion of one compound of the formula (IA) to a further compound of the formula (IA), for example when R1 and/or R2 are C1 -4 alkyl the alkylation of the corresponding compound wherein R1 and/or R2 are hydrogen; or when R1 and R2 are hydrogen, the amination, or chlorination and subsequent amination. of a compound of the formula (V):
wherein Q is chloro or bromo, preferably chloro. or hydroxy respectively and R4' is hydrogen, methyl, hydroxy, trifluoromethyl or halo. (iv) when X is CH and Y is a group CH or CNH2 the reaction of a compound of the formula (VI): /
or a suitably protected derivative thereof, wherein R24 is hydrogen or NH2 with benzene boronic acid or benzene boronic acid substituted so as to give the desired substituent R1 1 in the compound of the formula (IA) so formed, followed by the removal of any protecting groups;
(b) for a compound of formula (IB), the reduction of the corresponding 8-oxide; and
(c) for a compound of formula (IC), the reaction of O-methylacetanilide containing the appropriate substituents or substituents covertible thereto.
22. A process which comprises :-
(i) the reaction of a compound of formula (VIII)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP94902868A EP0674627A1 (en) | 1992-12-18 | 1993-12-15 | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
| AU57045/94A AU5704594A (en) | 1992-12-18 | 1993-12-15 | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
| JP6514909A JPH08504798A (en) | 1992-12-18 | 1993-12-15 | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9226377.1 | 1992-12-18 | ||
| GB929226377A GB9226377D0 (en) | 1992-12-18 | 1992-12-18 | Pharmaceutical compositions |
| GB939303221A GB9303221D0 (en) | 1993-02-18 | 1993-02-18 | Nitric oxide synthase inhibitors |
| GB9303221.7 | 1993-02-18 |
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| WO1994014780A1 true WO1994014780A1 (en) | 1994-07-07 |
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ID=26302179
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| PCT/GB1993/002556 WO1994014780A1 (en) | 1992-12-18 | 1993-12-15 | Pyrimidine, pyridine, pteridinone and indazole derivatives as enzyme inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0674627A1 (en) |
| JP (1) | JPH08504798A (en) |
| AU (1) | AU5704594A (en) |
| IL (1) | IL108075A0 (en) |
| MX (1) | MX9308199A (en) |
| WO (1) | WO1994014780A1 (en) |
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| US6465686B2 (en) | 2000-04-13 | 2002-10-15 | Pharmacia Corporation | Halogenated 2-amino-5,6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU5704594A (en) | 1994-07-19 |
| EP0674627A1 (en) | 1995-10-04 |
| JPH08504798A (en) | 1996-05-21 |
| IL108075A0 (en) | 1994-04-12 |
| MX9308199A (en) | 1995-01-31 |
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