-(l ,2,3,4-TETRAHYDRONAPHTHALEN-l-YL)-l ,9-DIHYDROPURIN-6-ONE DERIVATIVES AS PDE7 INHIBITORS
Field of the Invention
The present invention relates to novel heterocyclic compounds and to their 5 formulation and use as pharmaceuticals. Background of the Invention
The cyclic nucleotides cAMP and cGMP are known to be responsible for the regulation of a variety of intracellular processes. The levels of these nucleotides are modulated by the stimulation of adenylate or guanylate cyclases and by the activity of
10 phosphodiesterase enzymes. Phosphodiesterases (PDEs) specifically convert cyclic nucleotides to inactive analogues. Eleven PDE gene families have been identified to date, based on substrate specificity and regulatory characteristics. PDE7 is a low KM cAMP specific enzyme which is insensitive to the standard PDE4 inhibitor, rolipram. PDE7 is thought to play an important role in T cell activation (Beavo et al, Science
15 (1999) 283: 848), which implies that inhibitors of PDE7 could have benefit in T cell- mediated diseases. In addition, PDE7 has been detected in airway epithelial cells (Barnes et al, Am. J. Respir. Cell Mol. Biol. (1999) 20:292), so inhibitors could be beneficial in diseases of the airway. Summary of the Invention
20 This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting PDE7. According to the invention, the compounds are of formula (i):
wherein X-Y-Z represents NR
4-C=N or N=C-NR
4;
R1 represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R2 represents OR8, NR8R9, SR13, alkyl or CF3;
R3 represents halogen, alkyl, CF3 or OR8;
R4, which can be attached to either X or Z, is a residue chosen from
in which attachment is through any position on the saturated ring, provided that the attachment is not at a position adjacent to V, and the saturated ring may be substituted at any position with one or more R6;
A, B, D and E are the same or different and each represents CL„R
5, N or N-O; V represents O, S, NR
7 or
Q and W are the same or different and each represents CL
nR
5 or N; T represents O, S or NR
7; L
1 and L
2 are the same or different and each represents C(R
15)
2;
m and n are the same or different and each represents 0, 1 , 2, 3, 4 or 5;
R5 represents H, halogen, alkyl, cycloalkyl, OR8, NR8R9, CO2R10, CONR"R12, CONHOH, SO2NRnR12, SONRπR12, COR13, SO2R13, SOR13, SR13, CF3, NO2 or CN;
R6 represents H, alkyl, cycloalkyl, OR8, NR8R9, CO2R10, CONRπR12, SO2NRπR12, SONRπR12, COR13, SO2R13, SOR13, SR13, CF3, CN or =O;
R7 represents H or alkyl;
R8 represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; and
R9 represents R8 or alkylcarbonyl, alkoxycarbonyl, alkylsulphonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylsulphonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylsulphonyl, arylcarbonyl, arylsulphonyl, heteroarylcarbonyl, heteroarylsulphonyl, heterocyclocarbonyl, heterocyclosulphonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulphonyl, heteroarylalkylcarbonyl, heteroarylalkoxycarbonyl, heteroarylalkoxysulphonyl, heterocycloalkylcarbonyl, heterocycloalkoxycarbonyl or heterocycloalkylsulphonyl; or
NRgRg represents a heterocyclic ring such as morpholine;
R10 represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
Ru and R12 are the same or different and are each R8 , or NRUR12 represents a heterocyclic ring such as morpholine;
R13 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; the R14s are the same or different and are each chosen from H, alkyl, cycloalkyl, OR8, NR8R9, CO2R10, CONRnR12, CONHOH, SO2NRπR12, SONRπR12, COR13, SO2R13, SOR13, SR13, CF3, NO2 and CN, provided that, when m and n both represent 0, if one R14 is OR8, NR8R9or SR13 , the other is not OR8, NR R9or SR13; and
R15 represents H, alkyl or F; or a pharmaceutically acceptable salt thereof.
This invention also provides a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE7 in a mammal in need thereof which comprises
administering to said mammal an effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof.
Description of the Invention
Certain compounds of the invention are preferred; see claims 2-8. The compounds of the Examples are particularly preferred.
Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
Certain of the compounds of formula (i) which contain an amino group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, α- ketoglutarate, α-glycerophosphate and glucose- 1 -phosphate. The pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
It will be appreciated by those skilled in the art that some of the compounds of formula (i) may exist in more than one tautomeric form. This invention extends to all tautomeric forms.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers, and diastereoisomers and mixtures including racemic mixtures thereof.
When used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms. Alkoxy means an alkyl-O- group in which the alkyl group is as previously described. Aryloxy means an aryl-O- group in which the aryl group is as defined
below. Heteroaryloxy means a heteroaryl-O- group and heterocyclooxy means a heterocyclo-O- group in which the heteroaryl and heterocyclo group are as defined below. Arylalkoxy means an aryl-alkyl-O- group. Heteroarylalkoxy means a heteroaryl-alkyl-O group and heterocycloalkoxy means a heterocyclo-alkyl-O- group. Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl-N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below). Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of 3 to 10 carbon atoms. Cycloalkoxy means a cycloalkyl-O- group in which the cycloalkyl group is as previously described. The cyclic alkyl may optionally be partially unsaturated. Aryl indicates carbocyclic radicals containing 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl- group wherein aryl and alkyl are as described herein. Heteroarylalkyl means a heteroaryl-alkyl group and heterocycloalkyl means a heterocyclo-alkyl group. Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described. Cycloalkylcarbonyl means a cycloalkyl-CO- group in which the cycloalkyl group is as previously described. Cycloalkylalkylcarbonyl means a cycloalkyl-alkyl-CO- group in which the cycloalkyl and alkyl groups are as previously described. Arylalkoxycarbonyl means an arylalkoxy-CO- group in which the arylalkoxy group is as previously described. Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described. Arylalkylcarbonyl means an arylalkyl-CO- group in which the arylalkyl group is as previously described. Arylalkoxycarbonyl means an arylalkoxy-CO- group in which the arylalkoxy group is as previously described. Heteroarylcarbonyl means a heteroaryl-CO- group and heterocyclocarbonyl means a heterocyclo-CO- group. Heteroarylalkylcarbonyl means a heteroarylalkyl-CO- group in which the heteroarylalkyl group is as previously described. Heterocycloalkylcarbonyl means a heterocycloalkyl-CO- group in which the heterocycloalkyl group is as previously described. Heterocycloalkoxycarbonyl means a heterocycloalkoxy group in which the heterocycloalkoxy group is as previously described. Heteroarylalkoxycarbonyl means a heteroarylalkoxy-CO- group in which the heteroarylalkoxy group is as previously described. Arylsulphonyl means an aryl-SO2- group in which the aryl group is as previously described. Heteroarylsulphonyl means a heteroaryl-SO2- group and heterocyclosulphonyl means a heterocyclo-SO2- group.
Alkoxycarbonyl means an alkyloxy-CO- group in which the alkoxy group is as previously desribed. Alkylsulphonyl means an alkyl-SO2- group in which the alkyl group is as previously described. Cycloalkylsulphonyl means a cycloalkyl-SO2- group in which the cycloalkyl group is as previously described. Cycloalkylalkylsulphonyl means a cycloalkyl-alkyl-SO2- group in which the cycloalkyl and alkyl groups are as previously described. Arylalkylsulphonyl means an arylalkyl-SO2- group in which the arylalkyl group is as previously described. Heteroarylalkylsulphonyl means a heteroarylalkyl-SO2-group in which the heteroarylalkyl group is as previously described. Heterocycloalkylsulphonyl means a heterocycloalkyl-SO2- group in which the heterocycloalkyl group is as previously described. Heterocyclic ring means a 4 to a 10 membered monocyclic or multicyclic ring system (which may be saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon, chosen from nitrogen, oxygen and sulphur atoms. Heteroaryl means a 5 to a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from nitrogen, oxygen and sulphur. Heterocyclo means a 4 to a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from nitrogen, oxygen and sulphur. Halogen means fluorine, chlorine, bromine or iodine.
PDE7 inhibitors may be useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, psoriasis, atopic dermatitis, rheumatoid arthritis, osteoarthritis, COPD, chronic bronchitis, allergic rhinitis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and pancreatitis, and also in transplant rejection, in graft v host disease, in pannus formation in rheumatoid arthritis, restenosis following angioplasty and atherosclerosis, and in osteoporosis.
The compounds of formula (i) are preferably in pharmaceutically acceptable form. By pharmaceutically acceptable form is meant, inter alia, a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding
normal pharmaceutical additives, preferably 75 % , more preferably 90% and still more preferably 95 % . When used herein the term "pharmaceutically acceptable" encompasses materials suitable for both human and vetinary use.
The invention further provides a process for the preparation of a compound of formula (i), in which R'-R15 and A, B, D, E, L1, L2, Q, T, V, W, X, Y, Z, m and n are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene.
In particular, a process for preparing compounds of formula (i) in which R5 contains a -CO2H comprises deprotecting (for example by hydrolysis) a compound of formula (i) in which R5 contains an appropriate -CO2P wherein P represents a suitable protecting group (e.g. benzyl or methyl).
A process for the preparation of a compound of formula (i) comprises reaction of an appropriate compound of formula (ii) with a suitable alkylating agent of formula R4aG, wherein R'a represents R1 as defined in relation to formula (i) or a group convertible to R1 and R2a-R4a similarly represent R2-R4 or groups convertible to R2-R4 respectively; and thereafter, if required, converting any group R'a to R1 and/or R2a to R2 and/or R3a to R3 and/or R4a to R4; and formula (ia) represents formula (i) containing groups R1a-R4a; and G represents a suitable leaving group such as a halogen. It will be appreciated that compounds of formula (ii) and (iii) may exist in two tautomeric forms. The reaction of a compound of formula (ii) with R4aG may be carried out under any suitable conditions known to those skilled in the art. Favourably the compound of formula (ii) is treated with an appropriate base, such as potassium carbonate in a suitable solvent such as dimethylformamide. In some cases a stronger base, such as sodium hydride will be required. Compounds of formula (ii) are either commercially available, previously described compounds, or are prepared using standard procedures
known to those skilled in the art, for example as described in J. Med. Chem. , 1990, 33 (1), 203-206.
R4aG R4aG
(ia) (iv)
Alternatively, compounds of formula (ia) may be prepared by hydrolysis of a compound of formula (iv) under any suitable conditions known to those skilled in the art, such as an aqueous solution of sodium hydroxide at an appropriate temperature (for example, the reflux temperature of the solvent). A compound of formula (iv) may be prepared by treatment of a compound of formula (iii) with a suitable alkylating agent of formula R4aG, where R4a and G are as described previously under any suitable conditions known to those skilled in the art, such as those described for the conversion of a compound of formula (ii) to a compound of formula (ia). Compounds of formula (iii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art, for example as described
in J. Med. Chem. , 1997, 40 (12), 1768-1770. Compounds of formula R4aG are either commercially available, previously described compounds or may be prepared using standard procedures known to those skilled in the art. For example a compound of formula R4aG where G represents a halogen may be prepared from a compound of formula R4aG where G represents a hydroxyl group. This transformation may be carried out using any standard conditions known to those skilled in the art, for example by treatment with bromine and triphenylphosphine in a suitable solvent such as dichloromethane. The conditions used for the preparation of compounds of formula (ia) from compounds of formula (ii) or (iii) may result in the formation of a compound of formula (ia) wherein X-Y-Z represents NR4a-C =N (7-alkylation) and/or N =C-NR4a (9-alkylation) . In the cases where a mixture of 7- and 9-alkylated products are obtained, the individual components may be separated by any standard means known to those skilled in the art, for example column chromatography.
A compound of formula (ia) wherein X-Y-Z represents N=C-NR4a and R3a represents an alkyl or CF3 group or a group convertible to an alkyl or CF3 group, may also be prepared from a compound of formula (ix) using a ring construction procedure, for example by treatment of a compound of formula (ix) with an amide R3aCONH2 using any standard conditions known to those skilled in the art, for example those described in Ind. J. Chem. B, 1985, 24, 952-958, at a suitable temperature, for example, the reflux temperature of the amide. When R3a represents OR8 then the transformation may be achieved by treatment of a compound of formula (ix) with, for example, phosgene or triphosgene followed by treatment with a suitable alkylating agent, for example trimethyloxonium tetrafluoroborate as described in Bioorg. Med. Chem. Lett. , 1999, 9, 967-972. A compound of formula (ix) may be prepared by reduction of a compound of formula (viii) using any standard conditions known to those skilled in the art, for example sodium dithionite in a suitable solvent such as dimethylformamide at an appropriate temperature, for example, 60°C. A compound of formula (viii) may be prepared by treatment of a compound of formula (vii) with an appropriate amine R4aNH2, where R4 is as defined previously, under any standard conditions known to those skilled in the art, such as those described in Tetrahedron, 1996, 52 (40), 13017-13026. Suitable conditions, for example, may involve the
presence of a base such as triethylamine in a suitable solvent such as ethanol at an appropriate temperature such as the reflux temperature of the solvent. Compounds of formula (vii) are either previously described compounds or may be made by any standard conditions known to those skilled in the art, for example by nitration of a compound of formula (vi) . Compounds of formula (vi) are either previously described compounds or may be made using any standard conditions known to those skilled in the art, for example by hydrolysis of a compound of formula (v) using, for example, an aqueous solution of sodium hydroxide at an appropriate temperature such as the reflux temperature of the solvent. Compounds of formula (v) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. Alternatively, a compound of formula (iv) may be prepared from a compound of formula (xi) by any standard procedure known to those skilled in the art, for example using the procedures described in J. Med. Chem. , 1992, 35 (10), 1882-1886.
Nitration R4aNH2 R4aNH2
Reduction
A compound of formula (xi) may be prepared from a compound of formula (x) using any standard conditions known to those skilled in the art, for example using the methods described in J. Med. Chem. , 1992, 35(12), 2191-2195. A compound of formula (x) may be prepared by treatment of a compound of formula (v) with an amine R
4aNH
2, where R
4a is as previously described, using any suitable conditions known to those skilled in the art. Alternatively, a compound of formula (xi) may be prepared by treatment of a compound of formula (xii) with an amine R
4aNH
2 using any standard conditions known to those skilled in the art, followed by reduction of the resulting compound (xiii) using any standard conditions known to those skilled in the art, for example sodium dithionite in a suitable solvent such as dimethylformamide at an appropriate temperature, for example, 60°C. Compounds of formula (xii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
Amines R4aNH2 are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art, for example by reductive amination of an appropriate carbonyl compound. This amination may be carried out under any suitable standard conditions known to those skilled in the art.
A compound of formula (ia) wherein X-Y-Z represents NR4a-C = N and R3a represents alkyl or CF3 may also be prepared from a compound of formula (xv) using any standard conditions known to those skilled in the art, for example by treatment of compound (xv) with phosphorus oxychloride. A compound of formula (xv) may be prepared form a compound of formula (xiv) using any standard conditions known to those skilled in the art, for example by treating a compound of formula (xiv) with an appropriate carboxylic acid R3aCO2H using conditions such as those described in J. Med. Chem. , 1997, 40 (14), 2196-2210. A compound of formula (xiv) may be prepared using any standard conditions known to those skilled in the art, for example by the procedures described in Aust. J. Chem. , 1980, 33 (8), 1611-1617. A compound of formula (ia) wherein R2a represents alkyl or CF3 may also be prepared from a compound of formula (xvii), by treatment of compound (xvii) wherein L represents a suitable leaving group such as alkoxy, with an appropriate amine R'aNH2 using any
standard conditions known to those skilled in the art, for example phosphorus pentoxide in N,N-dimethylcyclohexylamine at an appropriate temperature such as 140°C. A compound of formula (xvii) may be prepared from a compound of formula (xvi) by treatment of a compound of formula (xvi) with an appropriate reagent R2aCOL, wherein L is a suitable leaving group such as a halogen, using any conditions known to those skilled in the art. A compound of formula (xvi) may be prepared using any procedure known to those skilled in the art, for example by the procedures described in Tetrahedron, 1982, 38 (10), 1435-1442.
0 Some compounds of formula (ia) may be prepared from other compounds of formula (ia). For example, compounds in which R3a is a halogen such as bromine,
may be prepared from compounds in which R3a represents hydrogen using any suitable standard conditions known to those in the art. An example of such conditions is the use of bromine in a suitable solvent such as water. Compounds in which R5 represents a halogen may be prepared from a compound in which R5 represents hydrogen using any suitable standard conditions known to those in the art. Compounds of formula (ia) in which RJa represents an alkyl group may be prepared from a compound of formula (ia) in which R'a represents hydrogen using any suitable standard conditions known to those in the art. An example of such conditions is alkylation using an alkylating agent such as benzyl chloride in the presence of a suitable base in an appropriate solvent. Compounds of formula (ia) in which R2a represents NR8aR9a may be prepared from compounds in which R2a represents a halogen, for example chlorine, using any standard conditions known to those skilled in the art, for example by treatment with an amine R8aR9aNH in a suitable solvent at a suitable temperature such as the reflux temperature of the solvent. Any of the above transformations may be carried out either at the end of the synthesis or on an appropriate intermediate.
It will be appreciated that where a particular stereoisomer of formula (i) is required, this may be obtained by conventional resolution techniques such as high performance liquid chromatography or the synthetic processes herein described may be performed using the appropriate homochiral starting material. A compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
The active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer
to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc, the compounds of the invention are effective in the treatment of humans.
The compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
Compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1 % to 99% by weight, preferably from
10-60% by weight, of the active material, depending on the method of administration.
Compounds of formula (i), or if appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
Suitably, the compound of formula (i), or if appropriate a pharmaceutically acceptable salt thereof, will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5% .
The dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the compound. However, as a general guide suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to lOmg, for example 0.5, 1 , 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01 , 0.02, 0.04, 0.05, 0.06, 0.08, 0. 1 or 0.2 mg/kg/day, and such therapy may extend for a number of weeks or months.
Compounds of the invention have activity in an assay of PDE7 activity. The PDE7 assay is carried out using the Amersham Pharmacia Biotech phosphodiesterase scintillation proximity assay.
Selectivity against the other phosphodiesterases is determined by carrying out phosphodiesterase selectivity assays using the same procedure.
The following Examples illustrate the invention. Intermediate 1 2-Ainino-5-i-itro-6-(l,2,3,4-tetr^ydroiiaphthalen-l-ylaniino)- 3f/-pyrimidin-4-one
A mixture of 2-amino-4-chloro-5-nitropyrimidine (2.0g), 1 ,2,3,4-tetrahydro-l- naphthylamine (1.5ml) and triethylamine (3.0ml) in ethanol (80ml) under an atmosphere of nitrogen was heated to reflux for three hours and then left to stand overnight at room temperature. The reaction was stirred at room temperature for a further hour then filtered and washed with ethanol (20ml) to afford the title compound as a cream solid (2.7g).
TLC Rf 0.78 (20% methanol in dichloromethane)
Intermediate 2 6-Chloro-9-(l,2,3,4-tetrahydronaphthalen-l-yI)-9H-purin-
2-ylamine A mixture of 2-amino-6-chloropurine (2.7g), 1-bromo-l , 2,3,4- tetrahydronaphthalene (as a 3: 1 mix with 1 ,2-dihydro-naphthalene) (4.7g) and potassium carbonate (4.4g) in N,N-dimethylformamide (50ml) was stirred overnight at room temperature under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (100ml), washed with water (2 x 100ml) and washed with brine (50ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography on silica, eluting with 50% dichloromethane in ethyl acetate afforded the title compound as a white foam (3.6g). TLC Rf 0.55 (50% dichloromethane in ethyl acetate) Intermediate 3 (Method A) 2-Amino-9-(l,2,3,4-tetrahydronaphthalen-l- yl)-l ,9-dihydropurin-6-one
A mixture of 6-chloro-9-(l,2,3,4-tetrahydronaphthalen-l-yl)-9H-purin-2- ylamine (1.5g) and aqueous sodium hydroxide solution (100ml, 0.3M) in tetrahydrofuran (10ml) was heated at reflux overnight. The mixture was then cooled and a solid filtered off. The filtrate was acidified to pΗ4 and filtered; the filter cake
was washed with water and dried in a vacuum oven at 40°C to afford the title compound as a white solid (lJg). TLC Rf 0.55 (50% dichloromethane in ethyl acetate)
Intermediate 3 (Method B) 2-Amino-9-(l ,2,3,4-tetrahydronaphthalen-l- yl)-l,9-dihydropurin-6-one
Sodium dithionite (4.0g) was added portion wise over 30 minutes to a stirred suspension of 2-amino-9-(l ,2,3,4-tetrahydronaphthalen-l-yl)-l ,9-dihydropurin-6-one (0.50g) in N,N-dimethylformamide at 60°C under a nitrogen atmosphere. Water (25ml) was then added over one hour and the reaction left to stir for ten minutes before cooling and pouring onto ice (50ml). The mixture was then filtered to give a cream solid (275 mg) which was used without further purification.
The cream solid obtained above was heated to reflux in formamide (20ml) for 30 minutes under a nitrogen atmosphere. The mixture was diluted with ice water (60ml) and cooled in an ice bath before filtering to give a brown solid. Purification by column chromatography on silica eluting with 10% methanol in dichloromethane gave a yellow solid. Trituration with ethyl acetate afforded the title compound as an orange solid (66mg).
TLC Rf 0.33 (10% methanol in dichloromethane) Intermediates 4 and 5 2-Amino-l-methyl-9-(l ,2,3,4-tetrahydronaphthalen-l- yl)-l,9-dihydropurin-6-one and 2-Amino-l-methyl-7-
(l,2,3,4-tetrahydronaphthalen-l-yl)-l,7-dihydropurin- 6-one A suspension of N-methylguanine (0.20g) in N,N-dimethylformamide (10ml) was stirred at room temperature under an atmosphere of nitrogen. Sodium hydride (60% dispersion in mineral oil, 53mg) was added and the mixture heated at 50°C for 30 minutes. The resulting solution was cooled to room temperature and a solution of the 1-bromo-l ,2,3,4-tetrahydronaphthalene (as a 3: 1 mix with 1 ,2-dihydronaphthalene) (0.36g) in N,N-dimethylformamide (2ml) was added. The mixture was stirred for 3 days at room temperature before removal of the N,N-dimethylformamide in vacuo. The residue was taken up in ethyl acetate (50ml), washed with water (2x50ml) then brine (20ml), dried over magnesium sulfate and the solvent removed in vacuo to give a cream
solid. Purification by column chromatography on silica eluting with 10% methanol in ethyl acetate gave the title compounds as white solids.
2-Amino-l-methyl-9-(l, 2, 3, 4-tetrahydronaphthalen- l-yl)-l ,9-dihydropurin-6-one (0.23g) TLC Rf 0.49 (10% methanol in ethyl acetate) 2- Amino- 1 -methyl-7-( 1,2,3 , 4-tetrahydronaphthalen- 1 -yl)- 1 , 7-dihydropurin-6-one (0J5g) TLC Rf 0.33 (10% methanol in ethyl acetate)
Examples 1. 2 and 3 2-Amino-8-bromo-9-(l,2,3,4-tetrahydronaphthalen-l- yl)-l,9-dihydropurin-6-one, 2-Amino-8-bromo-9-(6-bromo- l,2,3,4-tetrahydronaphthalen-l-yI)-l,9-dihydropurin-6-one and 2-Amino-8-bromo-9-(8-bromo-l ,2,3,4-tetrahydro- naphthalen-l-yl)-l,9-dihydropurin-6-one A suspension of 2-amino-9-(l ,2,3,4-tetrahydronaphthalen-l-yl)-l ,9-dihydro- purin-6-one (0.50g) in water (20ml) was stirred at room temperature. A solution of bromine (0.60g) in water (20ml) was added and the resulting mixture stirred for 3 days at ambient temperature. Purification by preparitive HPLC on a Phenomenex Luna 2 C-18 column (100x4.6mm) eluting with water (pH2.2) and acetonitrile gave the title compounds as white solids.
2- Amino-8-bromo-9-(l, 2, 3, 4-tetrahydronaphthalen- l-yl)-l ,9-dihydropurin-6-one (54mg): TLC Rf 0.61 (10% methanol in dichloromethane) Mass spectrum (EI+) 361 (M+K)
2-Amino-8-bromo-9-(6-bromo-l, 2, 3, 4-tetrahydronaphthalen- l-yl)-l , 9-dihydropurin-6- one (24mg):
TLC Rf 0.61 (10% methanol in dichloromethane) Mass spectrum (El ) 438 (M-H)
2- Amino-8-bromo-9-(8-bromo- 1 ,2,3 , 4-tetrahydronaphthalen- 1 -yl)- 1 ,9-dihydropurin-6- one (27 mg):
TLC Rf 0.61 (10% methanol in dichloromethane) Mass spectrum (El ) 438 (M-H) Examples 4 and 5 2-Amino-8-bromo-9-(6-bromo-l,2,3,4-tetrahydro-naphthalen- l-yI)-l-methyl-l,9-dihydropurin-6-one and 2-Amino-8-
bromo-9-(8-bromo-l,2,3,4-tetrahydronaphthaIen-l-yl)-l- methyl-l ,9-dihydropurin-6-one
A suspension of 2-amino-l-methyl-9-(l ,2,3,4-tetrahydronaphthalen-l-yl)-l ,9- dihydropurin-6-one (0.23g) in water (10ml) was stirred at room temperature. A solution of bromine (0.14g) in water (2ml) was added and stirring continued overnight at room temperature. The mixture was filtered and the solid washed with water. The solid was taken up in dichloromethane (50ml), dried over magnesium sulfate and the solvent removed in vacuo to give an orange solid. Purification by preparitive HPLC using the conditions described in examples 1,2 and 3 gave the title compounds and 2- amino-8-bromo-l-methyl-9-(l ,2,3,4-tetrahydronaphthalen-l-yl)-l ,9-dihydropurin-6-one (5mg) as off white solids.
2- Amino-8-bromo-9-(6-bromo- 1 ,2, 3, 4-tetrahydronaphthalen- l-yl)- l -methyl- 1 ,9- dihydropurin-6-one (13mg): TLC Rf 0.60 (10% methanol in ethyl acetate) Mass spectrum (El ) 452 (M-H)
2-Amino-8-bromo-9-(8-bromo- 1 ,2, 3, 4-tetrahydronaphthalen- l -yl)- l -methyl- 1 ,9- dihydropurin-6-one (21mg):
TLC Rf 0.60 (10% methanol in ethyl acetate)
Mass spectrum (El ) 452 (M-H) Examples 6 and 7 2-Amino-8-bromo-7-(6-bromo-l,2,3,4-tetrahydro-naphthalen- l-yl)-l-methyl-l,7-dihydropurin-6-one and 2-Amino-8- bromo-7-(8-bromo-l,2,3,4-tetrahydronaphthalen-l-yI)-l- methy 1- 1 , 7-dihy dropurin-6- one A suspension of 2-amino-l-methyl-7-(l,2,3,4-tetrahydronaphthalen-l-yl)-l ,7- dihydropurin-6-one (0J5g) in water (10ml) was stirred at room temperature. A solution of bromine (89mg) in water (2ml) was added and stirring continued overnight at room temperature. The mixture was filtered and the solid washed with water. The solid was taken up in dichloromethane (30ml), dried over magnesium sulfate and the solvent removed in vacuo to give an orange solid. Purification by preparitive HPLC using the conditions described in examples 1 ,2 and 3 gave the title compounds as white solids.
2-Amino-8-bromo-7-(6-bromo- 1 ,2, 3, 4-tetrahydronaphthalen- l -yl)-l -methyl- 1 ,7- dihydropurin-6-one (8mg):
TLC Rf 0.40 (10% methanol in ethyl acetate)
*H NMR (400MHz, CD3OD) δ 1.85-1.92 (2H, m), 2.20-2.29 (IH, m), 2.37-2.45 (IH, m), 2.80-2.89 (IH, m), 2.98-3.05 (IH, m), 3.48 (3H, s), 6.00-6.05 (IH, m), 7.03
(IH, s), 7.18 (IH, d), 7.40 (IH, d), 7.63 (2H, bs)
2- Amino-8-bromo-7-(8-bromo-l , 2, 3, 4-tetrahydronaphthalen- l-yl)-l -methyl- 1 ,7- dihydropurin-6-one(4mg) :
TLC Rf 0.40 (10% methanol in ethyl acetate) Mass spectrum (El") 452 (M-H)
Example 8 2-Amino-8-bromo-9-(7-methoxy-l ,2,3,4-tetrahydronaphthalen-l-yl)- 1 ,9-dihydropurin-6-one Bromine (0.70ml) was added to a solution of triphenylphosphine (3.57g) in dichloromethane (45ml) at 0°C. After several minutes an orange precipitate was formed; a solution of 7-methoxy-l,2,3,4-tetrahydro-l-naphthol (2.02g) in dichloromethane (10ml) was then added and the reaction mixture was stirred at 0°C for 45 minutes. The solvent was removed in vacuo; the residue was triturated with hexane and the resulting solid was filtered off. The filtrate was concentrated in vacuo to furnish l-bromo-7-methoxy-l,2,3,4-tetrahydronaphthalene (2.33g) as a pale yellow oil which was used without further purification. Sodium hydride (60% dispersion in oil, 87 mg) was added to a suspension of 8-bromoguanine (500mg) in
N,N-dimethylformamide (30ml) under an inert atmosphere and the mixture was heated at 50°C for 0.5h. A solution of l-bromo-7-methoxy-l ,2,3,4- tetrahydronaphthalene (628mg) in NN-di ethylformamide (3ml) was then added and the reaction mixture was allowed to cool to room temperature and stirred overnight. The solvent was removed in vacuo and the mixture purified by column chromatography on silica, eluting with 10% methanol in dichloromethane to furnish the title compound (108mg) as a yellow powder.
TLC Rf 0.45 (10% methanol in dichloromethane) Mass spectrum (EI+) 390, 392 (M+H)
The following examples were prepared by a similar procedure.
Example 9 2-Amino-8-bromo-9-(5-methoxy-l,2,3,4-tetrahydronaphthalen-l- yl)-l ,9-dihydropurin-6-one l-Bromo-5-methoxy-l,2,3,4-tetrahydronaphthalene was prepared from 5- methoxy-l,2,3,4-tetrahydro-l-naphthol. The title compound was prepared from 8- bromoguanine (l .OOg) and l-bromo-5-methoxy-l ,2,3,4-tetrahydronaphthalene (1.31g). Purification by column chromatography on silica, eluting with 10% methanol in dichloromethane afforded the title compound (0.24g) as a yellow solid. TLC Rf 0.36 (10% methanol in dichloromethane) Mass spectrum (ES ) 388, 390 (M-l) Example 10 2-Amino-8-bromo-9-(7-nitro-l,2,3,4-tetrahydronaphthalen-l-yl)- 1 ,9-dihydropurin-6-one l-Bromo-7-nitro-l ,2,3,4-tetrahydronaphthalene was prepared from 7-nitro- 1,2,3,4-tetrahydro-l-naphthol. The title compound was prepared from 8- bromoguanine (600mg) and l-bromo-7-nitro-l ,2,3,4-tetrahydronaphthalene (800mg). Purification by column chromatography on silica, eluting with 10% methanol in dichloromethane afforded the title compound (150mg) as a beige solid. Mass spectrum (ES ) 403, 405 (M-l)
Example 11 8-(2-Amino-8-bromo-6-oxo-l ,6-dihydropurin-9-yl)-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid methyl ester 8-Bromo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester was prepared from 8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester. The title compound was prepared from 8-bromoguanine (690mg) and 8- bromo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (850mg). Purification by column chromatography on silica, eluting with 10% methanol in dichloromethane afforded the title compound (360mg). TLC Rf 0.39 (10% methanol in dichloromethane) Mass spectrum (ES ) 416, 418 (M-l)
Example 12 8-(2-Anιino-8-bromo-6-oxo-l,6-dihydropurin-9-yl)-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid A solution of lithium hydroxide monohydrate (138mg) in water (5ml) was added to a solution of 8-(2-amino-8-bromo-6-oxo-l ,6-dihydropurin-9-yl)-5,6,7,8-
tetrahydronaphthalene-2-carboxylic acid methyl ester (141mg) in tetrahydrofuran (20ml) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to 5 ml in vacuo. Aqueous hydrochloric acid was added dropwise; filtration and drying of the resulting precipitate gave the title compound (1 lOmg) as a white powder.
TLC Rf 0.2 (10% methanol in dichloromethane) Mass spectrum (ES ) 402, 404 (M-l)
Example 13 8-(2-Amino-8-bromo-6-oxo-l ,6-dihydropurin-9-yl)-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid hydroxamide l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30mg) was added to a suspension of 8-(2-amino-8-bromo-6-oxo-l,6-dihydropurin-9-yl)-5, 6,7,8- tetrahydronaphthalene-2-carboxylic acid (50mg) and 0-(tert- butyldimethylsilyl)hydroxylamine (20mg) in dichloromethane (5 ml) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with water (5 ml) and then with saturated aqueous sodium hydrogen carbonate solution (5ml). The organic phase was concentrated in vacuo and the residue treated with a solution of hydrogen chloride in diethyl ether (IN, 2ml). The resulting precipitate was collected by filtration and dried in vacuo to afford the title compound (5mg) as a white powder. TLC Rf 0.6 (20% methanol in dichloromethane) Mass spectrum (ES ) 417, 419 (M-l)