NZ730806B2 - Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases - Google Patents

Abstract

The present invention describes compounds of formula (I) (I) Wherein: R1 is selected from H and CH3 R2 is selected from H, C4H9 alkyl, C6H13 alkyl and C3H6-phenyl, said phenyl optionally substituted by OH or OCH3, (1R,2S,5S)-5-methylcyclopent-3-ene-1,2-diol X is O or S Y is C, N or S. These compounds have been identified as novel compounds useful in the treatment of multiple sclerosis and other autoimmune diseases. s have been identified as novel compounds useful in the treatment of multiple sclerosis and other autoimmune diseases.

Description

Substituted Pyrimidine Derivatives useful in the ent of Autoimmune Diseases cal field The ion relates to novel substituted pyrimidine derivatives useful in the treatment of autoimmune diseases, particularly multiple sclerosis. This invention also s to the use of such compounds in the treatment of autoimmune diseases, particularly multiple sclerosis and to ceutical compositions containing such nds.

Background art Multiple sclerosis (MS) is a tating disease of the central nervous system (CNS) in which the body’s own immune system attacks the white matter of the brain and spinal cord. This triggers inflammation-induced damage to the CNS protective myelin layer causing demyelination. Loss of myelin exposes neurons to further attack leading to formation of multiple sclerotic lesions. This damage ts the ability of parts of the nervous system to communicate, resulting in a wide range of problems including fatigue, blurred vision, cognitive impairment, and spasticity. Many patients suffer from the development of irreversible motor disability. Long term prognosis is poor, within 15 years of disease onset approximately 50% of patients are unable to walk unassisted (Polman ancl aag, B.M.J., 2000, 321, 490-494).

MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).

There is at present no known cure for multiple sclerosis. Current treatments attempt to improve function after an attack and/or prevent subsequent s.

Medications used to treat MS, while modestly effective, can have adverse effects and be poorly tolerated. 3O There are a number of able front line therapies: . beta interferon 1a (Avonex) . beta interferon 1a (Rebif) . beta interferon 1b (Betaferon) . glatiramer acetate (Copaxone) erons may produce flu-like symptoms and some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, lessness, and y, which usually lasts less than thirty minutes. More dangerous but much less common is liver damage. Copaxone is associated with skin irritation at the site of injection Additional therapies include: . Natalizumab reduces the e rate more than line agents; however, due to issues of adverse effects such as progressive ocal leukoencephalopathy it is a second-line agent reserved for those who do not respond to other treatments or with severe disease.

. Fingolimod (Gilenya) - ed in March 2011 for people with rapidly evolving severe relapsing remitting MS (two or more relapses a year), and as a second line treatment for people whose MS remains active despite treatment with one of the beta eron drugs.

. Dimethyl fumarate (Tecfidera) was licenced by the FDA in 2013 and is an oral first line therapy for adults with relapsing remitting forms of MS.

. Teriflunomide (Aubagio) was approved by the FDA in September 2012, is an orally ble immunomodulatory drug for the treatment of relapsing forms of MS . Mitoxantrone, whose use is limited by severe adverse effects, systolic ction, infertility, and acute myeloid leukemia is a third-line option for those who do not respond to other tions.

Corticosteroids (or steroids) are sometimes given for a few days, either in the form of tablets or by intravenous drip. While there is no ce that steroids have any effect on the long-term course of the disease, they can be effective at speeding up recovery from relapse.

No treatment has been shown to change the course of primary progressive MS and as of 2011 only one medication, mitoxantrone, has been approved for secondary progressive MS. In this population, tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapse over two years.

There is ongoing research looking for more effective, convenient, and tolerable treatments for relapsing-remitting MS.

WO 50804 Monoclonal antibodies have raised high levels of interest. The CD52 onal dy alemtuzumab, CD25 monoclonal antibody daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments. Their use has also been accompanied by the appearance of potentially dangerous e effects, most importantly opportunistic infections.

Accordingly, there is a huge unmet medical need for the treatment of MS.

Summary of the invention The present invention provides new medicaments for the ent of autoimmune conditions, particularly multiple sclerosis. One embodiment of the invention describes compounds of formula (I) %§ / and ceutically acceptable salts and solvates thereof wherein: R1 is selected from H and CH3 R2 is selected from H, C4H9 alkyl, C6H13 alkyl and C3H6-phenyl, said Phenyl optionally substituted by OH or OCH3, X is O or S Y is C, N or S.

Preferably alkyl chains are straight chain.

In a preferred embodiment, R1 is H In a preferred embodiment R2 is selected from C4H9 alkyl, C6H13 alkyl and C3H6- phenyL In a particularly preferred embodiment R2 is C3He-phenyl In a preferred embodiment X is O In a preferred embodiment Y is C or N In a ularly preferred embodiment Y is N Particularly preferred are those compounds of formula (I) where: X is O Y is N R1 is H; and R2 is selected from C4H9 alkyl, C6H13 alkyl and C3H6-phenyl.

In a particularly preferred embodiment R2 is C3He-phenyl Particularly red compounds of the invention include: 2-amino((butylamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinone N—((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)butan aminium chloride 2-amino((hexylamino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinone N-((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)hexan m de Queuine; 2-amino((((1S,4S,5R)-4,5-dihydroxycyclopent-Z-en yl)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinone Queuine HCI 2-Amino[[[(15,45,5R)-4,5-dihydroxycyclopenten yl]amino]methyl]-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinone, monohydrochloride Most preferred is/are: 2-amino(((3-phenylpropyl)amino)methyl)-3,7-dihydro- 4H'|3\""’0'0[2,3-d]pyrimidinone N-((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl) phenylpropanaminium de; Suitable salts include salts of acidic or basic groups present in compounds of formula (I). The compounds of a (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare ceutically acceptable acid addition salts of such basic compounds of formula 1 are those that form non-toxic acid addition salts. Suitable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edentate, camsylate, carbonate, chloride, clavulanate, citrate, ochloride edentate, edisylate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, ate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide isothionate, e, lactobionate, laurate, malate, maleate, mandelate, te, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate and valerate salts.

Preferred salts include hydrochloride and aminium chloride.

The subject invention also includes isotopically-labelled compounds which are cal to those described, but for the tution of an atom for a corresponding isotope. es of isotopes include isotopes of hydrogen such as deuterium and tritium; isotopes of carbon such as 13C. Other examples are well known to those skilled in the art.

Where appropriate, compounds of the present invention include any cis/trans 3O isomers.

The compounds of the t invention may be synthesised by a number of synthetic routes. Scheme 1 bes a conventional synthetic protocol for the synthesis of nds of formula (I) where X & Y are as described herein. x x $3 aHN (i) HN l \ H2N \Y N PG\M \Y M (II) (III) //Ph x N (ii) —, HN ‘ \ \HN \Y H x N (iii) a I l \ H2N \Y N Scheme 1 Compounds of formula (III) may be prepared from compounds of formula (II) by process step (i) on of a suitable amine protecting group. The term ‘PG’ is used to denote any suitable protecting group. Suitable groups and conditions may be found in ‘Protective Groups in Organic Synthesis’ by Theodora W. Greene, Peter G. M. Wuts, 4th Edition, 2006, ISBN: 9784711 published by Wiley Particularly favoured protecting groups are octyl alkyl amides, which result in lower levels of by-products and isomers in subsequent steps. Compounds of formula (IV) may be produced from compounds of a (III) via s step (ii) which an ophilic aromatic substitution reaction occurs between compound (iii) and the m ion formed by the condensation of dibenzylamine with formaldehyde under the standard conditions of the Mannich-type reaction. nds of formula (I) may be produced by process step (iii) an amine exchange reaction followed by cleavage of the protecting group under acidic or basic conditions, or with a nucleophile.

An alternative route is described in scheme 2: 2N \Y H PG\Nj\Y‘ W) (VI) PG\HfigowpGeneral rocedure A H2N (VII) Scheme 2 nds of formula (VI) may be made by reacting compound of formula (V) with suitable amine protecting group under the conditions of process step (i).

Compounds of formula (VII) may be synthesised by steps consisting of the reduction and hydrolysis (in either order) of compounds of formula (VI).

Compounds of formula (I) may be made by reacting compounds of formula (VII) under the conditions of process (v) - a ive amination followed by removal of the protecting group. Suitable conditions are described under ‘General ure A’ in the experimental.

Compounds of formula (Ia) may also be synthesised as bed in Scheme 3.

(Vi) Nj\Y| HN General Procedure B X H2N Y (VIII) (la) Scheme 3 Compounds of formula (VIII) in which the PG is acid labile are treated under acidic conditions of process step (vi) to remove the acid labile protecting group and form acid addition salt of (I), described as (Ia) The invention also provides novel therapies for the treatment of disease.

Without being bound by theory, it appears the compounds of the present invention operate via a new drug pathway. They exploit an enzyme complex made of two proteins TGT (tRNA guanine transglycosylase) also known as queuine tRNA-ribosyltransferase 1, and Qvl (queuine tRNA transglycosylase domain containing 1). The effect is to increase the relative tions of Treg cells and/or decrease populations of Teff cells. Treg cells are a part of the immune system that are intricately involved in the determination of self from non-self proteins i.e. protecting proteins of the self being attacked by the immune system (which is the cause of many mune diseases). r data to demonstrate the efficacy of the compounds is provided in the experimental section.

The transfer RNA (tRNA) of y proliferating cells is ent (hypomodified) in queuine cation; examples include foetal liver, multiple tumour types and rating adult liver. By contrast, the tRNA of adult, fully differentiated cells contains high levels of queuine, which cannot be displaced once incorporated.

It could be expected that the tRNA of rapidly expanding immune cells (as occurs in an autoimmune response) are likewise deficient in the queuine modification.

Incorporation of novel Queuine Insertase substrates selectively into the queuine- deficient tRNA of immune cells could disrupt proliferation and cytokine production thereby modulating the immune response.

The present invention es new medicaments for the treatment of autoimmune es, particularly le sclerosis.

This invention also relates to compounds of Formula (I) X N/ ‘ \ H2N \Y N Wherein: R1 is selected from H and CH3 R2 is selected from H, C4H9 alkyl, C6H13 alkyl, (1R,ZS,SS)methylcyclopent ene-1,2-diol and C3H6-phenyl, said phenyl optionally substituted by OH or OCH3, X is O or S YisC,NorS. and pharmaceutically able salts and es f, for use as a medicament.

In a preferred embodiment R1 is ed from H and CH3 R2 is selected from H, C4H9 alkyl, C6H13 alkyl and C3H6-phenyl, said phenyl optionally substituted by OH or OCH3, XisOorS YisC,NorS.

The invention also es for compounds of formula (I) for use in the treatment of autoimmune conditions such as rheumatoid arthritis, ulcerative colitis, psoriasis, diabetes and inflammatory bowel disease, including crohn’s disease; and as agents to suppress transplant rejection.

This invention also relates to compounds of formula (I) as described above for use in the ent of multiple sclerosis.

The ion also relates to a method of treating multiple sclerosis in a mammal, particularly a human, comprising administering to said mammal an amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.

The term ‘treatment’ is intended to include curing, reversing, alleviating, palliative and prophylactic treatment of the condition.

The invention r relates to les of the invention in combination with other suitable agents, for use in the treatment le sclerosis.

Patients suffering from multiple sclerosis are commonly co-administered additional therapeutic agents. For patients suffering a severe attack, intravenous osteroids, such as methylprednisolone or techniques such as or plasmapheresis may be coadministered with any treatment.

The effects of nerve cell damage caused by le sclerosis result in diverse forms of damage to the patient. Nerve damage can lead to pain, difficulty with control of bladder and many other issues. For this reason, additional medicaments are often prescribed patients with multiple sclerosis to help treat the effects of MS damage. Suitable co-administrants would include: For Bladder problems . botulinum toxin (Botox) . desmopressin (Desmospray, abs) . oxybutynin (Ditropan, Lyrinel) . tolterodine (Detrusitol) For Depression . amitriptyline (Triptafen) . fluoxetine c) . imipramine (Tofranil) . pa roxetine at) For Erectile dysfunction . alprostadil (Caverject, MUSE, Viridal Duo) . sildenafil citrate (Viagra) o tadalafil (Cialis) . vardenafil (Levitra) For Fatigue . amantadine (Lysovir, Symmetrel) . modafinil (Provigil) For Optic neuritis steroids For Pain amitriptyline (Triptafen) carbamazepine tol) gabapentin (Neurontin) ibuprofen imipramine (Tofranil) Iamotrigine (Lamictal) phenytoin (Epanutim) pregabalin (Lyrica) For Problems with walking fampridine ra) For Psuedobulbar affect Nuedexta For Spasticity ancl spasms baclofen sal) botulinum toxin (Botox) carbamazepine (Tegretol) clonazepam (Rivotril) dantrolene (Dantrium) diazepam (Valium) gabapentin (Neurontin) phenol Tetrahydrocannabinol ancl cannabidiol (Sativex) tizanidine (Zanaflex) For Tremor epam (Rivotril) thalamotomy For Trigeminal neuralgia . carbamazepine (Tegretol) . gabapentin (Neurontin) . oxcarbazepine (Trileptal) . phenytoin (Epanutim) . alin (Lyrica) Other therapeutic agents are commonly administered to patients with MS. Other such medicaments are well known to ians and others d in therapy.

Such agents may be administered sequentially, simultaneously or itantly.

The invention also relates to a pharmaceutical composition comprising a molecule of the present invention and a pharmaceutically able diluent or carrier.

Pharmaceutical itions le for the delivery of nds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and s for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Compounds of formula (I) may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or gual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid ations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for e, from a sachet.

Compounds of formula (I) may also be used in issolving, fast-disintegrating dosage forms such as those described in Expert Opinion in eutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on close, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight °/o of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of egrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, , pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %. In one embodiment of the present invention, the egrant will comprise from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, , polyethylene glycol, l and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as e (monohydrate, spray-dried monohydrate, anhydrous and the like), ol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and rbate 80, and glidants such as n dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also lly contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl te. Lubricants generally comprise from 0.25 weight % to 10 weight %. In one embodiment of the present 3O invention, lubricants se from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed ly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Formulations of tablets are discussed in Pharmaceutical Dosage Forms: s, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film- forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The film-forming polymer may be selected from l polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range to 80 weight %. Other possible ients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary ating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti- foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically ed by evaporative drying of thin aqueous films coated onto a le backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and/or modified e. Modified release includes delayed, sustained, , controlled, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 3O 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve lled release is described in WO-A-00/35298. nds of formula (I) may also be administered directly into the blood stream, into , or into an internal organ. Such parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, entricular, rethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable s for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Compounds of the invention may also be administered topically to the skin or mucosa, that is, ly or transdermally.

The compounds of formula (I) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as atidylcholine) from a dry powder inhaler, as an aerosol spray from a rised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops.

For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. For intranasal use, the powder may se a bioadhesive agent, for example, an or cyclodextrin The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound of formula (I) comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the compound, a lant as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for e, from n or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the ion, a le powder base such as lactose or starch and a performance modifier such as l-leucine, ol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include n, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an er using electrohydrodynamics to produce a fine mist may contain from lug to 20mg of the compound of the invention per actuation and the actuation volume may vary from lul to 100ul. A typical formulation may comprise a compound of formula (I) propylene glycol, sterile water, ethanol and sodium chloride. Alternative ts which may be used instead of propylene glycol include ol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or ners, such as saccharin or saccharin , may be added to those formulations of the invention ed for intranasal administration. Formulations for intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release includes d, sustained, , controlled, targeted and programmed release.

Compounds of formula (I) may also be administered ly to the eye or ear, typically in the form of drops of a ised suspension or solution in isotonic, pH-adjusted, sterile saline.

Compounds of formula (I) may be combined with soluble olecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste, bioavailability and/or stability when using any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in ational patent publications WO-A-91/11172, WO-A-94/02518 and 3O WO-A-98/55148.

Experimental The synthesis of various molecules suitable for use in the present invention are described below.

All starting materials and reagents are commercially ble and were obtained from Aldrich with exception of 2-amino-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one which was purchased from Fluorochem. 2015/072486 Preparation 1: 2-octanoylamino-pyrrolo[2,3-d] pyrimidinone I \ MNkN H M A 50 cm3 round-bottomed flask containing a stirring bar was d with 2- amino-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (2.00 g, 13.33 mmol). The flask was fitted with a septum and placed under an Ar atmosphere. Freshly distilled pyridine (20.00 cm3) was added via syringe and the resulting suspension cooled on ice. The solution was allowed to equilibrate at this temperature (ca. 5 min) and then yl chloride (6.80 cm3, 39.99 mmol) was added dropwise. The resulting sion was heated at 85 °C for 30 min. After cooling to room temperature 6.5% lic ammonia (60 cm3) was added and the resulting suspension stirred at room temperature ght. The precipitate of product was removed via vacuum filtration and washed with ethanol followed by diethyl ether to yield the desired product (2.56 g, 70%) pure as a yellow solid, mp > 300 °C (decomposition). Procedure based on Akimoto et al. 1986 and Akimoto et al. 1988. am (400 MHz, DMSO-de): 0.86 (3H, t, J 5.1), 1.26 (8H, m), 1.58 (2H, app. quintet), 2.01 (1H, br 5, NH), 2.43 (2H, t, J 5.1), 6.40 (1H, d, J 2.0), 7.01 (1H, d, J 2.0), 11.43 (1H, br 5, NH), 11.67 (1H, br 5, NH) HRMS (m/Z ESI'): Found: 275.1517 ([M-H]' C14H19N4OZ; Requires: 275.1508) Preparation 2: 2-octanoylamino((dibenzyl)amino)methyl)- pyrrolo[2,3-d] pyrimidinone O N O HN)5:\< Q A 50 cm3 reaction vessel containing a stirring bar was charged with 2- octanoylamino-pyrrolo[2,3-d]pyrimidinone (1.00 g, 3.60 mmol), dibenzylamine (2.00 cm3, 10.80 mmol), formalin (349.00 uL, 12.60 mmol) and 80% aqueous acetic acid (36 cm3). The resulting suspension was heated at 60 °C for 20 h, cooled to room temperature, diluted with 0.5 M HCI (36 cm3) and stirred at room temperature for 30 min. The mixture was neutralised with conc. aq. ammonia (36 cm3) and extracted with form (3 x 50 cm3), The c extracts were combined, dried (MgSO4) and evaporated to s. The crude residue was purified by column chromatography (9:1 dichloromethane-MeOH — 7:3 dichloromethane-MeOH) to give the desired compound (1.45 g, 84%) as a yellow powder m.p. > 300 °C (decomposition). Procedure based on Akimoto et al. 1986 and o et al. 1988. 6H (400 MHz, DMSO-de): 0.86 (3H, t, J 7.1), 1.25 (8H, m), 1.57 (2H, m) 2.42 (2H, t, J 7.1), 3.57 (4H, s), 3.76 (2H, s), 6.88 (1H, s), 7.23 (2H, t,J 7.3), 7.31 (4H, app. t), 7.41 (4H, d, J 7.3), 11.34 (1H, 5, NH), 11.57 (1H, 5, NH), 11.68 (1H, 5, NH) HRMS(m/zESI+): Found: 486.2863 + C29H36N502; requires: 486.2869) Example 1: 2-amino(((3-phenylpropyl)amino)methyl)pyrrolo[2,3- d]pyrimidinone “1“\WW 2NNfi A large carousel tube containing a stirring bar was d with 2-octanoylamino- -((dibenzyl)amino)methyl)-pyrrolo[2,3-d]pyrimidinone (100.0 mg, 0.21 mmol), 3-phenylpropylamine (146.00 uL, 1.03 mmol) and 1:1 THF-methanol (2.00 cm3). The suspension was degassed and the reaction vessel sealed. The suspension was heated at 75 °C for 24 h, cooled to room temperature and treated with 5 M KOH (146.00 uL) and d at room temperature for 65 h. The solution was concentrated in vacuo and the crude residue purified by column chromatography (9:0.9:0.1 dichloromethane-MeOH-NH4OH). The resulting solid was washed with HPLC grade hexane ed by diethyl ether in order to remove trace impurities. This gave the desired compound (28 mg, 46%) as an orange powder, m.p. > 300 0C (decomposition). Procedure based on Akimoto et al. 1986 and Akimoto et al. 1988. 6H (600 MHz, DMSO-de): 1.24 (1H, br 5, NH), 1.66 (2H, app. quintet,), 1.91 (1H, 5, NH), 2.44 (2H, t, J 6.9,), 2.57 (2H, t, J 6.9,), 3.59 (2H, s,), 6.15 (2H, br s,), 6.45 (1H, s,), 7.15 (1H, t, J 7.4,), 7.16 (3H, m), 7.25 (2H, app. t,), 10.70 (1H, br s) 66 (600 MHz, DMSO-de): 30.6, 32.9, 45.2, 47.5, 48.6, 79.2, 98.7 (q), 113.6 (q), 125.5, 128.2, 128.3, 142.3 (q), 152.2 (q), 160.5 (C=O) Vmax (film)/cm'1: 697, 748, 749, 1080, 1420, 1596, 2927 HRMS (m/Z ESI+): Found: 298.1662 ([M+H]Jr C16H20N50; Requires: 298.1668) Preparation 3: 2-chlorooxopropanenitrile Cl CN In a dry round ed flask under a positive pressure of argon, a suspension of NaOMe (7.14g, l) in dry THF (90mL) was cooled to -5 0C. Methyl formate (9mL, 0.15 mol) was added dropwise over 1 min by e and stirring was continued at -5 0C for 20 min. Then chloroacetonitrile (8.33mL, 0.13 mol) was added dropwise via a dropping funnel over 45 min. The mixture turned from white to yellow and was stirred for a further 2 h at -5 0C at which point the reaction mixture was orange. The bath was removed and the reaction was allowed to warm up to room temperature. An aliquot of the on mixture was treated with a drop of concentrated HCI and analysed by TLC which indicated the ce of the desired product with an Rf = 0.45, eluting with 100% EtOAc. The mixture was cooled to 0 0C and concentrated HCI (12 mL) was added dropwise during which time the mixture reaction became cherry-red. The resultant suspension was filtered through a pad of celite, and the celite was washed with EtOAc until the te became colourless. The collected filtrates were concentrated at reduced pressure with the water bath at a temperature no higher than 40 0C to afford chloro(formyl)acetonitrile1 as a black oil, in quantitative yield, which was used without further purification. Procedure based on Brooks 2012. 6H (400 MHZ, CDCI3) 9.38 (s, 1H). 6c NMR (400 MHZ, DMSO-de) 6 168.2, 126.6, 67.8. 2015/072486 Preparation 4: 2-amino-4,7-dihydrooxo-3H-pyrrolo[2,3-d] pyrimidine- -carbonitrile “1W\ H2NNM 2,4-Diaminohydroxypyrimidine (3.00 g, 24 mmol) was added to a solution of sodium acetate (6.4g, 76 mmol) in millipore water (90 mL) and stirred at 50 °C for 1 hour. While still at 50 °C a solution of crude chloro(formyl)acetonitrile (3.00 g, 32 mmol) in mQ water (44 mL) was added dropwise with a dropping funnel, during which time the on turned beige and g continued for 18 h at 50 °C, after which time the reaction was heated to 100 °C for 3 h. The reaction mixture was allowed to cool to room temperature and the solid removed by tion. The solid was suspended in EtOH and 5M aqueous KOH solution was added until the solid dissolved. Charcoal was added to the solution and the mixture stirred for 30 minutes before removal of the solid by filtration. The pH of the filtrate was ed to pH=6 with concentrated aqueous HCI solution during which time a precipitate formed and was collected by filtration. In order to remove the final traces of water from the solid it was dissolved in a mixture of toluene/methanol 1/1 and then trated at reduced pressure. The resultant solid was dried over P205 to afford the desired compound (1.68 g, 9.6 mmol, 40% yield) as beige solid. Procedure based on Brooks 2012. 6H (400 MHz, DMSO-ds) 6 11.98 (br s, 1H) 10.74 (br s, 1H), 7.59 (s, 1H), 6.43 (s, 2H). 5c(100 MHZ, DMSO-ds) 5 158.0, 154.3, 152.1, 128.2, 116.4, 99.2, 86.0.

HRMS (m/Z ESI'): C7H5N50 [M-H]' Found 174.0415 Requires: 174.0416.

Preparation 5: 4,7-Dihydrooxo[(triphenylmethyl)amino]-3H- pyrrolo[2,3-d]pyrimidinecarbonitrile 0 O C.

O l I 3 H N In a dry round ed flask under an atmosphere of argon, trityl chloride (1.20 g, 4.28 mmol) was added to a solution of 2-amino-4,7-dihydrooxo-3H- pyrrolo[2,3-d]pyrimidinecarbonitrile (0.50 g, 2.85 mmol) in dry pyridine (29 mL). The mixture reaction was heated at 90 °C for 48 h. The reaction mixture was trated under reduced pressure then ed on silica gel and purified by flash chromatography on silica gel eluting with dichloromethane/MeOH with a gradient starting at 2% of MeOH and rising to 10%. The d compound was obtained as a brown solid (0.63 g, 1.5 mmol, 53% yield). ure based on Olgen 2008. am (400 MHz, DMSO-de) 5 11.80 (br s, 1H); 10.64 (br s, 1H), 7.56 (s, 1H), 7.41(s, 1H), 7.29-7.28 (m, 12H), 7.23-7.17 (m, 3H), 5.73 (s, 1H).

HRMS (m/Z ESI+): C26H18N50 [M-H]Jr Found 416.1514 Requires: 416.1511.

Preparation 6: 4,7-Dihydrooxo[(triphenylmethyl)amino]-3H- pyrrolo[2,3-d]pyrimidinecarboxaldehyde HMDS (6mmol, 1.3mL) was added to a mixture of 4,7-dihydrooxo [(triphenylmethyl)amino]—3H-pyrrolo[2,3-d]pyrimidinecarbonitrile (1.30 g, 3 mmol) with ammonium sulphate (397 mg, 0.3mmol) in dry toluene (8mL) in a round bottomed flask. A reflux condenser was fitted, and the flask was heated at reflux temperature overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. Under a positive pressure of argon, the crude reaction mixture was solubilised in dry dichloromethane (8mL) and cooled to -78 °C. At this temperature, DiBAL-H (4.5 mL, 1 M in dichloromethane, 4.5 mmol) was added dropwise. After 2 hours, analysis by TLC (EtOAc 100%) indicated that some starting material remained. So, a further 2mL DiBAL-H solution was added dropwise. After 1 hour, the reaction was complete and a mixture of H20/AcOH (9/1, 3.5 mL) was added at -78 °C. The reaction mixture was d to warm to room temperature slowly. A mixture of H20 (1/1, 300 mL) was added to the reaction e and stirring continued at room temperature for 2 hours. The layers were separated and the organic layer was washed with brine and the aqueous layers were extracted with EtOAc. The combined organic fractions were dried over MgSO4, ed and concentrated at reduced re. The crude reaction product was filtered through a pad of silica gel eluting with EtOAc to afford a yellow solid (1.01 g, 2.38 mmol, 76 %).

Procedure based on Brooks 2010 and Brooks 2012. 6H(400|WH2,[N480-d6)61JH82(s,1H),10.63(s,1H),9.99(s,1H),7.54(s,1H), 7.31-7.27 (nu 13H),7.23-7.19 (nL 3H).

HRMS (m/Z ESI'): C26H18N402 [M-H]' Found 419.1508 Requires: 419.1508.

Preparation 7: 5-((3-phenylpropylamino)methyl)(tritylamino)-3H— pyrrolo[2,3-d] pyrimidin-4(7H)-one o NH THHN N N General procedure A: To a sion of N-((4-oxo(tritylamino)-4,7-dihydro- 3H-pyrrolo[2,3-d]pyrimidinyl)methyl)formamide (200.0 mg, 0.48 mmol) and sodium sulphate (5.0 mg) in methanol (5 cm3) under an argon atmosphere was added 3-phenylpropylamine (74.00 uL, 0.52 mmol) and the resulting suspension stirred at room temperature for 2 h. Sodium dride (55.00 mg, 1.43 mmol) was then added and the reaction mixture stirred at room temperature for a r 1 h. Water (5 cm3) was added and the resulting suspension stirred for 10 min before being extracted with dichloromethane (3 x 5 cm3). The combined WO 50804 organic layers were dried (MgSO4) and concentrated in vacuo to yield the crude product which was purified by flash chromatography (9:1 dichloromethane- MeOH) to yield the desired nd as a white solid (210 mg, 41.8 %), m.p. > 300 °C (decomposition). Procedure based on Brooks 2010 and Brooks 2012. 1H (400 MHz, DMSO-de): 1.73 (2H, quintet, J 7.8), 2.56 (4H, m), 3.74 (1H, s), 6.42 (1H, s, H-6), 7.19 (20H, m), 7.45 (1H, bs, NH), 10.78 (1H, bs, NH) 13c (400 MHz, DMSO-de): 31.7, 32.8, 45.4, 47.8, 70.4 (q), 99.7 (q), 114.9, 117.6 (q), 125.9, 126.0, 126.9, 128.0, 128.6, 129.0, 142.6 (q), 145.4 (q), 150.0 (q), 150.4 (q), 159.7 (C=O) HRMS (m/z — ESI+): Found: 540.2757 [M+H]+ C35H34N50 Requires: 540.2765) vmax/cm‘l: 1542, 1611, 1670, 2868, 2951 Example 2: N-((2-aminooxo-4,7—dihydro-3H-pyrrolo[2,3-d]pyrimidin- 5-yl)methyl)phenylpropanaminium de H2NNM General procedure B: A 5 cm3 reaction vessel containing a stirring bar was charged with 5-((3-phenylpropylamino)methyl)(tritylamino)-3H-pyrrolo[2,3- d]pyrimidin-4(7H)-one (210.0 mg, 0.39 mmol) and 1.25 M methanolic HCI (3 cm3). The resulting solution was d at room temperature for 16 h. The precipitated product was removed by vacuum filtration and washed with dichloromethane to yield the desired compound as a white powder (84 mg, 68 %), m.p. > 300 °C position). Procedure based on Brooks 2010 and Brooks 2012. on (600 MHz, DMSO-de): 1.90 (2H, app. quintet), 2.63 (2H, t, J 7.8), 2.90 (2H, m), 4.13 (2H, t, J 5.2), 6.57 (2H, bs), 6.80 (1H, d, J 2.3), 7.16 (3H, m), 7.26 (2H, t, J 7.0), 9.11 (2H, bs), 11.05 (1H, m, NH), 11.31 (1H, broad doublet, NH) 2015/072486 66 (125 MHz, DMSO-de): 27.6, 32.1, 42.9, 45.6, 48.9, 98.6, 108.7 (q), 117.9 6.4, 128.6, 128.7, 140.9 (q), 152.9 (q), 160.5 (C=O) HRMS (m/z ESI+): Found: 298.1662 (M+ C16H20N50 Requires: 298.1664) Vmax (film)/cm'1: 1456, 1625, 2443, 2713, 2756, 2873, 2933, 3184 Preparation 8 5-((3-butylamino)methyl)(tritylamino)-3H—pyrrolo[2,3- d]pyrimidin-4(7H)-one O NH “1 I TrtHN N g Prepared as per general procedure A using N-((4-oxo(tritylamino)-4,7- dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)formamide (200.00 mg, 0.48 mmol), n-butylamine (95.00 uL, 0.95 mmol) and NaBH4 (55 mg, 1.43 mmol) to yield the desired product as a white powder (200 mg, 88%), mp. > 300 °C (decomposition). 6H (400 MHz, DMSO-de): 0.84 (3H, t, J 7.3), 1.30 (2H, app. sextet), 1.51 (2H, app. quintet), 2.82 (2H, t, J 7.3), 4.01 (2H, s), 6.62 (1H, s), 7.24 (15H, m), 7.57 (1H, bs), 11.07 (1H, bs) 66 (400 MHz, DMSO-de): 13.9, 19.6, 28.0, 42.9, 46.0, 70.6 , (q), 99.4 (q), 108.9, 118.0 (q), 127.0, 128.1, 129.0, 145.2 (q), 150.5 (q), 150.6 (q), 160.3 (C=O) Vmax /cm'1: 1545, 1613, 1672, 2870, 2956 HRMS(m/ZESI+): Found: 478.2600 ([M+H]+ cgngsto; Requires: 478.2607) Example 3 N-((2-aminooxo-4,7—dihydro-3H—pyrrolo[2,3-d]pyrimidin- -yl)methyl)butanaminium chloride WO 50804 H2NN N Prepared as per general procedure B using 5-((butylamino)methyl) lamino)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (108 mg, 0.39 mmol) and 1.25 M methanolic HCI (3 cm3) to yield the desired product as a white powder (72 mg, 67 %), m.p. > 300 0C position). 6H (400 MHz, DMSO-de): 0.86 (3H, t, J 7.4), 1.31 (2H, app. sextet), 1.57 (2H, app. quintet), 2.90 (2H, m), 4.12 (2H, t, J 5.3), 6.49 (2H, bs), 6.81 (1H, s), 9.01 (2H, bs), 10.98 (2H, bs), 11.29 (1H, bs) 6c (400 MHz, DMSO-de): 18.7, 24.7, 32.7, 47.4, 50.6, 103.6 (q), 114.0, 123.2 (q), 153.3 (q), 157.6 (q), 164.7 (c=0) HRMS (m/z ESI+): Found: 236.1518 (M+ C11H18N50 Requires: 236.1511) Vmax (film)/cm'1: 1456, 1625, 1668, 2443, 2713, 2756, 2873, 2933, 3184 Preparation 9 5-((3-hexylamino)methyl)(tritylamino)-3H—pyrrolo[2,3- d]pyrimidin-4(7H)-one O NH TrtHN N S Prepared as per general procedure A using N-((4-oxo(tritylamino)-4,7- dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)formamide (200.0 mg, 0.48 mmol), n-hexylamine (125.00 uL, 0.95 mmol) and sodium borohydride (55 mg, 2015/072486 1.43 mmol) to yield the desired product as a white powder (200 mg, 83.0 %), m.p. > 300 °C (decomposition). 6H (400 MHz, e): 0.82 (3H, t, J 7.4), 1.20 (6H, m), 1.34 (2H, app. quintet), 2.40 (2H, t, J 7.4), 3.60 (2H, s), 6.30 (1H, s), 7.23 (15H, m), 7.37 (1H, bs), 10.62 (1H, bs) 66 (400 MHz, DMSO-de): 14.4, 22.5, 26.8, 31.6, 29.6, 45.2, 48.3, 70.4 (q), 99.7 (q), 115.2, 116.7 (q), 127.0, 128.1, 129.0, 145.4 (q), 150.1 (q), 150.5 (q), 159.7 (c=0) Vmax (film)/cm'1: 1552, 1648, 1734, 2856, 2928 HRMS (m/Z ESI'): Found: 504.2769 ([M-H]' C32H34N50; Requires: 504.2763) Example 4 N-((2-aminooxo-4,7-dihydro-3H—pyrrolo[2,3-d] pyrimidin- -yl)methyl)hexanaminium chloride 0 [:le H2NN N H Prepared as per general procedure B using xylamino)methyl) (tritylamino)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (190 mg, 0.39 mmol) and 1.25 M methanolic HCI (3 cm3) to yield the desired product as a white powder (70 mg, 64.8 %), m.p. > 300 oC. 6H (400 MHz, DMSO-de): 0.83 (3H, t, J 7.2), 1.25 (6H, m), 1.59 (2H, app. sextet, J 7.2), 2.87 (2H, m), 4.11 (2H, t, J 5.3), 6.71 (2H, bs), 6.84 (1H, d,J 3.6), 9.11 (2H, bs), 11.25 (1H, bs), 11.46 (1H, bs) 66 (400 MHz, DMSO-de): 14.3, 22.3, 25.8, 25.9, 31.1, 42.6, 46.1, 98.9 (q), 109.3 (q), 118.5, 148.1 (q), 152.8 (q), 159.8 (c=0) Vmax(fi|m)/Cm'1: 1578, 1625, 1669, 2429, 2712, 2861, 2930, 2957, 3266 HRMS (m/Z ESI+): Found: 264.1830 ([M+H]Jr C13H22N50 Requires: 264.1824) H. Akimoto et al., J. Chem. Soc. Perkin Trans 1, 1998, 1627-1644.

H. Akimoto et al., J. Med. Chem., 1986, 29, 1749-1753.

S. Olgen et al., Arch. Pharm. Chem. Life Sci., 2008, 341, 113 — 120.

A.F. Brooks et al., Tetrahedron Lett., 2010, 51, 165.

A.F. Brooks PhD Thesis “Synthesis of Tritium Labeled Queuine, Prte and Related Azide Probes Toward Examining the Prevalence of e” University of Michigan, 2012.

To assess the potential of these compounds in vivo, a chronic monophasic EAE disease in mice was induced before treatment with the new chemical entity (NCE). EAE Disease was induced in 8-10 week old female mice (C57BL/6) by sub-cutaneous (s.c.) injection of 200 pl on containing 150 pg M0633- 55 peptide (Genscript) in Complete Freund’s Adjuvant (CFA; containing 5mg/ml heat-inactivated Mycobacterium tuberculosis). On the same day, mice were administered 500 ng Pertussis Toxin (Kaketsuken, Japan) intraperitoneally (i.p.) and again two days later. Disease ty was ed every 24 hours: 0- Normal; 1-flaccid tail; ried/wobbly gait; 3-complete hind limb weakness; 4-hind limb and forelimb sis; 5-moribund state/dead. Protocol is based on the Nature Protocols for Active induction of experimental allergic encephalomyelitis, which includes the scoring methodology: Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc. 1(4):1810-9.

Figure 1 shows the results of the in vivo testing for molecule N-((2-aminooxo- hydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)pheny|propanaminium chloride (Compound I). The EAE score relates to an assessment of disease progression with respect to issues like tail paralysis and limb paralysis, a higher score is a worse condition. A score of 1 indicates decreased tail tone, a score of 2 indicates hind leg weakness (paraparesis), a score of 3 tes hind limb paralysis and/or incontinence. Note that the untreated animals have a continuous and progressive worsening of disease. In st, the animals treated with N- 40 ((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl) propanaminium chloride (Compound I) exhibit rapid (within 24 hrs) reversal of symptoms at the highest dosage given (30 mg/kg, i.p.) and animals were scored as disease free after 4 daily treatments. At lower doses animals were slower to respond but in all cases disease progression was halted and Figure 2 shows that in agreement with the observed disability scores, treated animals showed a dramatic return to normal weight gain, reaching a weight level 96.6% that of ls (19.9 grams versus 20.6 grams), at 21 days post inoculation (dpi). This contrasts with the ned drop in body weight of non- treated EAE ed animals to a level 86.4% that of controls at 21 dpi (17.8 grams versus 20.6 grams). Motor coordination and hind-limb strength were also evaluated by the ability of mice to cross a horizontal bar (Figure 3). Non-diseased animals crossed the bar with an average time of 4.3 i 0.57 seconds. From 9 dpi, EAE mice showed a rapid deterioration in performance and were subsequently unable to maintain a grip on the apparatus. Strikingly, N-((2-aminooxo-4,7- dihydro-3H-pyrrolo[2,3-d]pyrimidinyl)methyl)phenylpropanaminium chloride (Compound I) treatment fully restored the performance of EAE diseased mice to control levels within 4 treatments.

Claims (10)

Claims 1.

1. A compound of formula (I) or pharmaceutically acceptable salt thereof wherein: R1 is selected from H and CH3; 10 R2 is selected from C4H9 alkyl and C3H6-phenyl, said phenyl optionally substituted by OH or OCH3; X is O or S; and Y is C, N or S. 15

2. A compound of Formula (I) according to claim 1 wherein X is O.

3. A compound of Formula (I) according to claim 1 or claim 2 wherein Y is C or

4. A compound of Formula (I) ing to any one of claims 1 to 3 wherein Y is 20

5. A Compound of Formula (I) according to any one of claims 1 to 4 wherein R1 is H.

6. A nd of Formula (I) according to any one of claims 1 to 5 wherein R2 is C3H6-phenyl.

7. A compound of formula (I) according to claim 1 where: 25 X is O; Y is N; R1 is H; and R2 is selected from C4H9 alkyl and C3H6-phenyl.

8. A compound of formula (I) as sed in claim 7 n R2 is C3H6-phenyl. 30

9. A compound of formula (I) according to claim 1 selected from: N-((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin yl)methyl)butanaminium chloride; 2-amino(((3-phenylpropyl)amino)methyl)-3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidinone; and N-((2-aminooxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidineyl)methyl- 3-phenylpropanaminium chloride. 5

10. A composition comprising a compound of formula (I) according to claim 1 and a ceutically acceptable carrier or diluent.