EP0674627A1 - Derives de pyrimidine, de pyridine, de pteridinone et d'indazole utilises comme inhibiteurs enzymatiques - Google Patents

Derives de pyrimidine, de pyridine, de pteridinone et d'indazole utilises comme inhibiteurs enzymatiques

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Publication number
EP0674627A1
EP0674627A1 EP94902868A EP94902868A EP0674627A1 EP 0674627 A1 EP0674627 A1 EP 0674627A1 EP 94902868 A EP94902868 A EP 94902868A EP 94902868 A EP94902868 A EP 94902868A EP 0674627 A1 EP0674627 A1 EP 0674627A1
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European Patent Office
Prior art keywords
pyrimidine
diamino
compound
formula
hydrogen
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.)
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Application number
EP94902868A
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German (de)
English (en)
Inventor
Eric Cleveland Bigham
John Frederick Reinhard, Jr.
Philip Keith Moore
Rachel Cecilia Babbedge
Richard Graham Wellcome Foundation Ltd. Knowles
Malcolm Stuart The Wellcome Foundation Ltd Nobbs
Donald The Wellcome Foundation Ltd. Bull
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Priority claimed from GB929226377A external-priority patent/GB9226377D0/en
Priority claimed from GB939303221A external-priority patent/GB9303221D0/en
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Publication of EP0674627A1 publication Critical patent/EP0674627A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • NO neuronal nitric oxide
  • endothelium-derived relaxing factor a labile humoral factor termed endothelium-derived relaxing factor (EDRF).
  • NO nitric oxide
  • NO is the active component of amyl nitrite, glyceryl trinitrite and other nitro vasodilators.
  • EDRF endothelium-derived relaxing factor
  • 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, 23., 1709-1715 (1989) and Moncada et a], Pharmacological Reviews, 42, 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.
  • neuronal NO synthase is a distinct protein from the endothelial NO synthase (Sessa et al, J.Biol.Chem.. 267, 15274-15276. 1992).
  • NO synthesis plays an important part in the pathology of a range of diseases of the nervous system, eg. ischemia.
  • non-selective inhibitors of NO syntheses cause profound changes in blood pressure and blood flow, including cerebral blood flow.
  • 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.
  • 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.
  • L-NMMA L-arginine analogue L-N- monomethyl-arginine
  • L-NMMA L-N- monomethyl-arginine
  • 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.
  • tetrahydrobiopterin (6R)-5,6,7,8-tetrahydro-L-biopterin (hereinafter tetrahydrobiopterin) is necessary for activity of the NO synthase enzymes.
  • tetrahydrobiopterin causes expression of the activity of the enzymes by binding to them.
  • compounds which competitively bind at the tetrahydrobiopterin sites of NO synthases inhibit neuronal NO synthase selectively over endothelial NO synthase.
  • 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.
  • 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.
  • R ⁇ and R ⁇ are the same or different and each is hydrogen or a C ⁇ __ alkyl group or NR--R2 forms a 5- or 6-membered heterocvclic ⁇ roup — NJ ⁇ , 'T ⁇ ⁇ T wherein
  • T is oxygen.
  • 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;
  • R- represents hydrogen or one to three substituents on the ring system Ar which may be the same or different and are chosen from halo, NR- ⁇ R ⁇ wherein R? and R ⁇ are independently selected from hydrogen or S(O) x > R wherein x' is 0, 1 or 2 and R ⁇ is Cj_4 alkyl; nitro, cyano.
  • a C1.4 carboxcylic acid group or an ester thereof C ⁇ __ alkyl optionally substituted by one to three halo atoms
  • R ⁇ is hydrogen, C ⁇ __ alkyl, hydroxy, halo, trifluoromethyl or a group NRIORI * wherein R ⁇ and R-- 1 are the same or different and each is hydrogen or Cj_4 alkyl, or NRI ORI I forms a 5- or 6- membered heterocyclic group optionally substituted by a C ⁇ __ alkyl group or R ⁇ represents a C _2 alkylene group linking
  • Preferred heterocyclic groups include morpholino, piperidino and methylpiperazino.
  • R * * ,R- *** ,X,Y,R4 are as hereinbefore defined
  • Ar' is a monocyclic or bicyclic ring system containing at least one aromatic ring
  • R**-' 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) m R° wherein A and m are as hereinbefore defined and R***' is C 1.4 alkyl optionally substituted by halo;
  • Preferred compounds of the formula (I A) include those of the formula (III)
  • d is 0;
  • Ar is phenyl, naphthyl, tetrahydronaphthyl, or benzothienyl.
  • Ar is phenyl
  • R**- 1 is halo, most suitably chloro or bromo, C1.4 alkyl or C 1.4 alkoxy, preferably methoxy.
  • Ar is phenyl the. or one of the. subsituents is at the 4-position of the phenyl ring.
  • R-* and R ⁇ are hydrogen, methyl, ethyl or NR--R**-- is a methyl-piperazino group.
  • R* 1 and R- are hydrogen.
  • R4 is most suitably hydrogen or NEb and preferably R ⁇ is hydrogen.
  • Y is preferably CNH2
  • Suitable compounds of the formula (IA) include
  • Preferred compounds of the formula (IA) include:
  • R ⁇ , R ⁇ , Rl5 a ⁇ j R16 ⁇ Q eac h separately selected from hydrogen, halo, haloalkyl, formyl, carboxy, sulpho, cyano, nitro, COR --8 and + NR18R19 20 ?
  • R 1 ⁇ , R 9 and R-® are each separately alkyl, aralkyl or aryl groups and R-* ⁇ is selected form hydrogen, halo, haloalkyl, formyl, carboxy, sulpho, cyano, nitro, hydroxy, alkoxy, alkyl, COR18, NHCOR 18 and +NR18R19R20 groupSj wherein R 18 5 R 19 and R2° are each separately alkyl aralkyl or aryl groups.
  • the halo and haloalkyl groups may for example be a fluoro, bromo, iodo or particularly a chloro group or a C ⁇ _i2 > particularly C ⁇ _ ⁇ , 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 R * • **, Rl9 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 R** ** - * , Rl9 and R****0 may conveniently be or contain alkyl group such as are described above in relation to the haloalkyl groups R ⁇ , R ⁇ , R-*- ⁇ Rl6.
  • each of the groups R-* 3 , R-* 4 , R**- 5 and R-* ⁇ may be hydrogen it is preferred that at least one is other than hydrogen, particularly the group R-* 4 or R*-5 or especially R-* 3 , although preferably two or three of R 3 , R* , R***** and Rl° " are hydrogen.
  • the groups which are other than hydrogen 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.
  • R ⁇ , R-* 4 , R! *** and R1 ° " is other than hydrogen the two or more substituents may differ from each other. Conveniently however at least one. for example R ⁇ 3 , is one of the groups just indicated as being of interest.
  • R ⁇ 7 may be other than hydrogen, for example a halo group such as chloro. it is preferably hydrogen.
  • R* 3 , R ⁇ 4 , R ⁇ or R--6 when one or more of R* 3 , R ⁇ 4 , R ⁇ or R--6 is a group + NR1 R-* R 0 the compounds will be a quaternary ammonium salt which contains one or more physiologically acceptable anions.
  • 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.
  • 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).
  • the indazoles (IC) can be used in the form of physiologically acceptable ester.
  • esters may be formed respectively with a suitable phenol or alcohol or with a suitable organic acid or even inorganic acid.
  • 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.
  • halogeno for example chloro or bromo, analogues.
  • 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-[-* C]-arginine is convened to [U ⁇ 4 C]-citrulline by brain cytosol NO synthase (as described by Salter et al., FEBS Lett. 221, 1991 , 145-149) following a preincubation with the compound in the absence or presence of a saturating concentration (typically lO ⁇ M) of tetrahydrobiopterin).
  • a saturating concentration typically lO ⁇ M
  • Such inhibitors also show activity in an intact cell system in which conversion of [ ⁇ 4 C]-L-arginine to [ ⁇ 4 C]-citrulline is measured in brain slices stimulated with veratrine.
  • single coronal slices of adult rat forebrain are preincubated in Krebs-Henseleit buffer before transfer to fresh buffer containing L-[U- ⁇ 4 C]-arginine. lO ⁇ g/ml veratrine and various concentrations of test compound (routinely 1- lOO ⁇ M). The mixture of test compound and coronal slices is then incubated and the level of [U--* 4 C]-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.
  • 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.
  • SUBSTITUTE SHEET 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.
  • 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.
  • preferred salts include those formed from hydrochloric, hydrobromic.
  • 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 R 2 i s not hydrogen, and that R-* 4 and R--5 are not independently selected from hydrogen, nitro or carboxy when R-* 3 , R ⁇ ⁇ and R ⁇ are each hydrogen.
  • novel compounds of formula (IA) and salts thereof include:
  • the neuronal NO synthase inhibitors of the present invention 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.
  • 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.
  • active ingredient a pharmaceutically acceptable salt or solvate thereof
  • 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 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.
  • 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 0J 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 lOmg to 200mg.
  • the neuronal NO synthase inhibitors of the invention are preferably administered orally or by injection (intramuscular, intravenous or subcutaneous).
  • 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
  • R21 is cyano or COR2 3 wherein R 3 is hydroxy, C1.4 alkoxy or hydrogen and R22 is oxo or a group C ⁇ H 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 C ] _4 alkanol such as ethanol. or a dipolar aprotic solvent such as
  • R and R2 are hydrogen the removal of one or more protecting groups from NR*R and optionally from R 4 , when it is desired that R 4 is NK .
  • Suitable protecting groups are derived from carboxylic acids, for example acetic or benzoic acids.
  • 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
  • reaction is suitably carried out at an elevated o temperature, for example 50-200 C. in a sealed system, and preferably under pressure.
  • This reaction is conveniently carried out in the presence of a catalyst, for example a palladium catalyst.
  • a catalyst for example a palladium catalyst.
  • tetrakistriphenylphosphine palladium is a suitable catalvst for this reaction.
  • the reaction is convenientlv carried out at a non- o o o o 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 ⁇ in inert atmosphere.
  • Acyl groups for example acetyl groups, are suitable protecting groups when R-* ⁇ and/or R b are hydrogen.
  • 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.
  • palladium for example containing palladium or platinum
  • a suitable selective catalyst (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 o o
  • SUBSTITUTE SHEET 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).
  • R 3 -Ar-(D) c j-B(OH)2 wherein R-*, R2, R 3 , R 4 , Ar, D, d, X and Y are as hereinbefore defined, followed by deprotection if necessary.
  • 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.
  • a polar solvent for example toluene
  • 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.
  • R*, R , R 4 , 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 above product was divided into three equal portions. These were placed in separate Young tubes, methvl iodide (l. ⁇ gms) and DMF/18mls) added to each, and o 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 drvin ⁇ over MgSO . After treating with activated charcoal, the solvent was
  • 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 (Si ⁇ 2) eluting with chloroform to 2% methanol-chloroform.
  • 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 [SiO?] elutin ⁇ with ether.
  • the product was triturated with o petroleum ether, filtered and dried under vacuo at 70 C to give a cream solid.
  • 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, 3 ⁇ , 40-45.
  • the activity of a compound as a tetrahydrobiopterin-site inhibitor of neuronal NO synthase was determined by an assay in which L-[U-- 4 C]-arginine is convened to [U*- 4 C]-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 lO ⁇ M) of tetrahydrobiopterin).
  • a saturating concentration typically lO ⁇ M
  • 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 (25 ⁇ l) incubated (37°C) with L-arginine (120nM) containing 0.5 ⁇ Ci [ 3 H]- arginine (specific activity 62 Ci mmol"-*), 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.
  • mice were injected i.p. with 7-nitroindazole (25 mg kg"-*) or L- NAME (50mg kg"-*) and killed 15 minutes thereafter. Cerebella were removed, homogenized and NOS activity determined as described above.
  • Anti-nociceptive activity of 7-nitroindazole (10-50 mg kg "') 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'-- 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 lO ⁇ l formalin (5% v/v) administered 15 minutes after the 7-nitroindazole.
  • the ED50 for the anti-nociceptive effect was 26 mg kg"' (equivalent to 159.5 ⁇ mol kg"').
  • Example 7 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.
  • Example 8 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"' i.p. of the indazoles is shown in Table 2 below.
  • Table 2 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.
  • 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.
  • 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.
  • 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
  • SUBSTITUTE SHEET 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.

Abstract

L'invention concerne l'utilisation d'un composé qui se lie au site de tétrahydrobioptérine de la NO synthétase pour le traitement d'états dans lesquels il est bénéfique d'inhiber la NO synthétase neuronale avec peu ou pas d'inhibition de la NO synthétase endothéliale. L'invention concerne également des formulations pharmaceutiques contenant de tels composés et des procédés, y compris un nouveau procédé, pour leur préparation.
EP94902868A 1992-12-18 1993-12-15 Derives de pyrimidine, de pyridine, de pteridinone et d'indazole utilises comme inhibiteurs enzymatiques Withdrawn EP0674627A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9226377 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 1993-02-18
PCT/GB1993/002556 WO1994014780A1 (fr) 1992-12-18 1993-12-15 Derives de pyrimidine, de pyridine, de pteridinone et d'indazole utilises comme inhibiteurs enzymatiques

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