EP1651647A1 - Derives de nicotinamide utiles en tant qu'inhibiteurs de pde4 - Google Patents

Derives de nicotinamide utiles en tant qu'inhibiteurs de pde4

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Publication number
EP1651647A1
EP1651647A1 EP04744024A EP04744024A EP1651647A1 EP 1651647 A1 EP1651647 A1 EP 1651647A1 EP 04744024 A EP04744024 A EP 04744024A EP 04744024 A EP04744024 A EP 04744024A EP 1651647 A1 EP1651647 A1 EP 1651647A1
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EP
European Patent Office
Prior art keywords
asthma
group
pyridine
formula
disease
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.)
Withdrawn
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EP04744024A
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German (de)
English (en)
Inventor
John Paul Mathias
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Pfizer Ltd
Pfizer Inc
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Pfizer Ltd
Pfizer Inc
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Publication of EP1651647A1 publication Critical patent/EP1651647A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to nicotinamide derivatives of general formula (I):
  • R 1 , R 2 and R 3 have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.
  • the 3',5'-cyclic nucleotide phosphodiesterases comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another.
  • the enzymes within each family are commonly referred to as isoenzymes, or isozymes, A total of more than fifteen gene products is included within this class, and further diversity results from differential splicing and post-translational processing of those gene products.
  • the present invention is primarily concerned with the four gene products of the fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family.
  • the PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram.
  • cAMP adenosine 3',5'-cyclic monophosphate
  • a number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models (see, e.g., Torphy et al., Environ. Health Perspect, ,1994, 102 Suppl. 10, p. 79-84 ; Duplantier et al., J. Med. Chem., 1996, 39, p 120-125 ; Schneider et al., Pharmacol. Biochem.
  • PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bronchial responsiveness occurring after allergen challenge.
  • PDE4 inhibitors also suppress the activity of immune cells (including CD4 + T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation.
  • immune cells including CD4 + T-lymphocytes, monocytes, mast cells, and basophils
  • eNANC excitatory nonadrenergic noncholinergic neurotransmission
  • iNANC potentiate inhibitory nonadrenergic noncholinergic neurotransmission
  • PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4 + T-lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and potentially interfere with the ability of airway epithelial cells to generate pro- inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema.
  • PDE4 inhibitors are particularly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions and for wounds and some of them are in clinical development mainly for treatment of asthma, COPD, bronchitis and emphysema.
  • the effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFa) release in eosinophils, neutrophils and monocytes.
  • TNFa tumor necrosis factor alpha
  • nicotinamide derivatives having a PDE4 inhibitory activity have already been synthetized.
  • the patent application WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme.
  • patent applications WO 01/57036 and WO 03/068235 also disclose nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory allergic and respiratory diseases and conditions.
  • PDE4 inhibitors that are good drug candidates.
  • preferred compounds should bind potently to the PDE4 enzyme whilst showing little affinity for other receptors and enzymes. They should also possess favourable pharmacokinetic and metabolic activities, be non- toxic and demonstrate few side effects. Furthermore, it is also desirable that the ideal drug candidate will exist in a physical form that is stable and easily formulated.
  • the present invention therefore provides new nicotinamide derivatives of formula (I) :
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halo and (C ⁇ -C 3 )alkyl;
  • R 3 is a 9- or 10-membered bicyclic heteroaryl containing from 1 to 4 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, halo, (C ⁇ -C 4 )alkyl, (C ⁇ -C 4 )alkoxy, hydroxy(C-i- C )alkyl and hydroxy(C 2 -C 4 )alkoxy.
  • R 1 is H, F, Cl or methyl, more preferably R 1 is F.
  • R 2 is H or F, more preferably R 2 is H.
  • R 3 is a 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heterocyclic ring system is optionally substituted by one or two groups selected from OH, halo, (C 1 -C )alkyl, (d- C 4 )alkoxy and hydroxy(C ⁇ -C 4 )alkyl.
  • R 3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, F, Cl, (C 1 -C 4 )alkyl, (C ⁇ - C 4 )alkoxy and hydroxy(C ⁇ -C )alkyl.
  • R 3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, (C ⁇ -C 3 )alkyl, (C-i-C 3 )alkoxy and hydroxy(C ⁇ -C 3 )alkyl.
  • R 3 groups are selected from the group consisting of: indole, isoindole, indolizine, indazole, benzoimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyhdine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, and naphthyridine.
  • R 3 groups are selected from the group consisting of: indazole, benzoimidazole, benzotriazole, imidazo[1 ,2-a]pyridine, pyrrolo[1 ,2-b]pyridazine and quinoline.
  • Preferred optional substitutent groups for the bicyclic ring system of R 3 are selected from OH, methyl, ethyl, propyl, hydroxymethyl and hydroxyethyl.
  • the present invention provides compounds of formula (I) wherein R 1 is H, F, Cl or methyl; R 2 is H or F; and R 3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or more groups selected from OH, halo, (C ⁇ -C )alkyl, (C-t-C 4 )alkoxy and hydroxy(C.-C 4 )alkyl.
  • the present invention provides compounds of formula (I) wherein R 1 is F; R 2 is F; and wherein the ring system of R 3 is an optionally substituted bicyclic heteroaryl selected from the group consisting of: indazole, benzoimidazole, benzotriazole, imidazo[1 ,2-a]pyridine, pyrrolo-[1 ,2- b]pyridazine and quinoline.
  • Preferred compounds according to the present invention are selected from the group consisting of:
  • Syn-lmidazo[1 ,2-a]pyridine-2-carboxylicacid (4- ⁇ [5-fluoro-2-(3-methylsulfanyl- phenoxy)-pyridine-3-carbonyl]-amino ⁇ -cyclohexyl)-amide
  • Syn-1 H-lndazole-3-carboxylic acid (4- ⁇ [5-fluoro-2-(3-methylsulfanyl-phenoxy)- pyridine-3-carbonyl]-amino ⁇ -cyclohexyl)-amide
  • Syn-3-Hydroxy-quinoline-8-carboxylic acid (4- ⁇ [5-fluoro-2-(3-methylsulfanyl- phenoxy)-pyridine-3-carbonyl]-amino ⁇ -cyclohexyl)-amide; and Syn-1 -(2-Hydroxy-ethyl)-1 H-indazole-3-carboxylic acid (4- ⁇ [5-fluoro-2-(3- methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino ⁇ -cyclohexyl)-amide and pharmaceutically acceptable salts, pro-drugs, solvates and polymorphs thereof.
  • More preferred compounds are selected from the group consisting of: Syn-2-Methyl-3H-benzoimidazole-4-carboxylic acid (4- ⁇ [5-fluoro-2-(3- methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino ⁇ -cyclohexyl)-amide;
  • the present invention additionally provides compounds of formula (I) wherein R 1 , R 2 , and R 3 are as previously defined and wherein the optional substituent groups of R 3 additionally comprise hydroxymethoxy.
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • (C ⁇ -C )alkyl or (C ⁇ -C )alkyl radicals denote a straight-chain or branched group containing respectively 1 to 3 and 1 to 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in (d- C )alkoxy radicals and hydroxy(C ⁇ -C )alkyl radicals.
  • suitable (C-r C 3 )alkyl and (C ⁇ -C )alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • Examples of suitable (C- ⁇ -C 4 )alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.
  • Hydroxy(C ⁇ -C )alkyl and hydroxy(C -C )alkoxy radicals may contain more than one hydroxy group (-OH). According to a preferred embodiment of said invention, such radicals contain one hydroxy substituent.
  • Examples of suitable hydroxy(C ⁇ -C 4 )alkyl radicals are hydroxymethyl, 1- hydroxyethyl or 2-hydroxyethyl.
  • 9- or 10-membered bicyclic heteroaryl means a radical of a bicyclic aromatic system having 9 or 10 ring members, which contains 1, 2, 3 or 4 nitrogen (N) atom(s) depending in number and quality of the total number of ring members.
  • additional, optional heteroatoms are oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be identical or different.
  • Heteroaryl radicals can also be unsubstituted, monosubstituted or polysubstituted, as indicated in the definition of R 3 hereabove for general formula (I) according to the present invention.
  • bicyclic heteroaryl is a bicyclic aromatic radical which contains 1 , 2 or 3 nitrogen (N).
  • suitable bicyclic heteroaryl radicals are the radicals derivated from indole, isoindole, indolizine, indazole, purine, napthyridine, phthalazine, quinoline, quinazoline, quinoxaline, cinnoline, isoquinoline, benzoimidazole, imidazo[1,2-a]pyhdine, benzotriazole, pyrazolo[1,5-a]pyridine and pyrazolopyrimidine.
  • bicyclic heterocyclic radicals selected from indole, isoindole, indolizine, indazole, benzoimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, and naphthyridine.
  • Nitrogen bicyclic heteroaryl radicals can also be present as N-oxides or as quaternary salts.
  • the nicotinamide derivatives of the formula (I) can be prepared using conventional procedures such as by the following illustrative methods in which R 1 , R 2 and R 3 are as previously defined for the nicotinamide derivatives of the formula (I) unless otherwise stated.
  • the compounds of formula (I) may be prepared by the methods disclosed hereunder, and exemplified in the Examples and Preparations. Other methods may be used in accordance with the skilled person's knowledge.
  • PyBOP® means Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate
  • PyBrOP® means bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
  • GDI means N,N'-carbonyldiimidazole
  • WSCDI means 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Mukaiyama's reagent means 2-chloro-1 -methylpyridinium iodide
  • HATU means O-(7-Azabenzotriazol-1 -y ⁇ )-N,N,N'N -tetramethyluronium hexafluorophosphate
  • HBTU means O-Benzotriazol-1 -yl- ⁇ /, ⁇ /, ⁇ /7V -tetramethyluronium hexafluorophosphate;
  • H ⁇ nig's base means N-ethyldiisopropylamine
  • Et 3 N means triethylamine
  • NMM N-methylmorpholine
  • NMP 1-methyl-2-pyrrolidinone
  • DMAP 4-dimethylaminopyridine
  • NMO 4-methylmorpholine A/-oxide
  • KHMDS potassium bis(trimethylsilyl)amide
  • NaHMDS sodium bis(trimethylsilyl)amide
  • DIAD diisopropyl azodicarboxyiate
  • DEAD means diethyl azodicarboxyiate
  • DIBAL means diisobutylammonium hydride
  • Dess-Martin periodinane means 1 ,1 ,1-triacetoxy-1 ,1 -dihydro-1 ,2- benziodoxol-3(1 H)-one;
  • TBDMS-CI means terf-butyldimethylchlorosilane;
  • TMS-CI chlorotrimethylsilane
  • Boc means ferf-butoxycarbonyl
  • CBz means benzyloxycarbonyl
  • MeOH means methanol
  • EtOH means ethanol
  • EtOAc means ethyl acetate
  • THF means tetrahydrofuran
  • DMSO means dimethyl sulphoxide
  • DCM dichloromethane
  • DMF means N,N-dimethylformamide
  • AcOH means acetic acid
  • TFA means trifluoroacetic acid
  • RT room temperature; 3° means tertiary; eq means equivalents; Me means methyl; Et means ethyl; Bn means benzyl; other abbreviations are used in accordance with standard synthetic chemistry practice.
  • Nicotinic acids or acid derivatives of formula (II) are either available commercially or may be obtained by analogy with the methods of Haylor et. al. (EP 0634413 examples 9 and 10, pages 12-13), or Marzi et. al. (European Journal of Org. Chem. 2001 (7), 1371-1376).
  • the protected amines of formula (III) are either available commercially or may be prepared by analogy with the method of Oku et al (WO 99/54284, for example, at page 80, preparation 77(1 )).
  • R 1 , R 2 and R 3 are as previously defined
  • PG is a suitable amine protecting group, typically Boc, CBz or Bn, and preferably Boc
  • LG is a suitable leaving group, typically halo, and preferably Cl.
  • This acid/amine coupling may be undertaken by using either: (i) an acyl chloride derivative of acid or acid derivative (II) + amine (III), with an excess of acid acceptor in a suitable solvent; or
  • the preferred conditions are: either treatment of (II) with oxalyl chloride and catalytic DMF in DCM at RT for 3 hours followed by the addition of H ⁇ nig's base or Et 3 N and the amine and stirring at RT for 18 hours; treatment of (II) with GDI in DMF at RT for 1 hour followed by the addition of the amine and stirring at RT for 72 hours.
  • Compounds of general formula (V) can be prepared from compounds of general formula (IV) via treatment with an optionally substituted, 3-methylsulphanyl- phenol in the presence of a suitable base, in a suitable solvent.
  • a suitable base e.g. Cs 2 CO 3 , K 2 CO 3 , NaOH
  • MeCN dioxan, toluene or NMP are suitable solvents for use.
  • the reaction is carried out at elevated temperature.
  • Preferred conditions are: reaction of compound (IV), wherein the LG is chlorine, with an excess of optionally substituted, 3-methylsulphanyl-phenol in the presence of caesium carbonate in dioxan or MeCN at about 100°C, optionally at reflux temperatures, for from about 24 to about 72 hours.
  • Step (c)-Removal of protecting group Deprotection of the N protecting group (PG), from compounds of general formula (V) to provide compounds of general formula (VI) is undertaken using standard methodology, as described in "Protective Groups in Organic Synthesis” by T.W. Greene and P. Wutz.
  • PG is Boc
  • the preferred conditions are: treatment of compound (V) with a strong acid (e.g. TFA, HCI), in a suitable solvent such as for example dioxan or DCM at room temperature.
  • a strong acid e.g. TFA, HCI
  • Preferred conditions herein for removal of a Boc group are treatment with hydrochloric acid (preferably 4M HCI) in dioxan at RT for about 5 hrs. Exemplified herein as preparation 18.
  • Step (d)-Reaction of de-protected amino group with R 3 COQH Compounds of the general formula (I) may be prepared by reaction of amines of general formula (VI) via treatment with a suitable acid of formula R 3 COOH according to the general methods described previously for step (a).
  • the preferred conditions are: treatment of a solution of amine (VI) and acid R 3 COOH in NMP or DMF, with WSCDI, HOBT and NMM or H ⁇ nig's base, at RT for from about 18 to about 72 hours.
  • the transformation (VI) to (I) is exemplified by Examples 1 to 9.
  • the compound of formula (VII) may be prepared from the amine (III) by reaction with R 3 COOH according to the methods described previously in step (d), Route A.
  • Preferred conditions provide stirring a solution of amine (III) in DCM with H ⁇ nig's base, HOBT, WSCDI and acid R 3 COOH at RT for about 48 hours.
  • the de-protected amine compound of general formula (VIII) may be prepared from the protected amine compound of general formula (VII) via removal of the protecting group PG, preferably a Boc group, by analogy to the methods described previously in step (c), Route A.
  • Preferred conditions provide compounds of general formula (VIII) via treatment of a solution of (VII) in DCM at 0°C with bubbled hydrogen chloride gas for about 2 hours followed by stirring for about 90 minutes at RT.
  • the amide compounds of general formula (IX) may be prepared by reaction of the amine of general formula (VIII) with the acid (II) according to the methods described previously in steps (a) and (d), Route A. Preferred conditions provide amide (IX) via treatment of a solution of amine (VIII) and the appropriate nicotinic acid (II) in DCM with Hunig's base, HOBT and WSCDI with stirring for about 18 hours at RT.
  • Compounds of formula (I) may be prepared by substitution of the leaving group, LG, of the compounds of formula (IX) by an optionally substituted, 3- methylsulphanyl-phenol group as described previously in step (b), Route A.
  • Preferred conditions provide compounds of general formula (I) via treatment of compounds of general formula (IX) and optionally substituted, 3-methylsulphanyl- phenol in MeCN and DMF in the presence of caesium carbonate at reflux temperatures from about 18 to about 36 hours.
  • the compounds of formula (I) may also be prepared by the process outlined in Route C.
  • R alk represents a C C 4 alkyl group or Bn, preferably a C ⁇ -C 3 alkyl group and more preferably Et.
  • Compounds of formula (XI) may be prepared by reaction of the ester (X) with optionally substituted, 3-methylsulphanyl-phenol, as described previously in step (b), Route A.
  • Suitable optional catalysts for use in this reaction include Cul.
  • Preferred conditions for use herein are treatment with caesium carbonate in dioxan at about 100 Q C for about 48 hours. Exemplified herein by preparation 15.
  • Step (e.-Ester hydrolysis Hydrolysis of the ester (XI) may be achieved in the presence of acid or base, in a suitable solvent, optionally at elevated temperature to afford the acid (XII).
  • the ester (XI) is treated with a suitable base such as an alkali metal hydroxide (eg LiOH, NaOH) or a carbonate base (eg K 2 CO 3 , Cs 2 CO 3 ) in aqueous solvent (MeOH, EtOH, dioxan, THF) at RT, to give the acid (XII).
  • a suitable base such as an alkali metal hydroxide (eg LiOH, NaOH) or a carbonate base (eg K 2 CO 3 , Cs 2 CO 3 ) in aqueous solvent (MeOH, EtOH, dioxan, THF) at RT, to give the acid (XII).
  • Preferred conditions herein provide for treatment of ester (XI) in THF with a 1 M aqueous solution
  • compounds of formula (XII) may be prepared from compounds of formula (II) by reaction with optionally substituted 3-methylsulphanyl-phenol, as described previously in step (b), Route A.
  • step (a) provides the compounds of formula (I).
  • Preferred conditions herein for formation of compounds of formula (I) from the corresponding acid of formula (XII) are treatment of acid (XII) in DCM and DMF with oxalyl chloride for about 2 hours at RT (to form the acid chloride), followed by treatment with a solution of the amine (VIII) and Et 3 N in DCM at RT for about 48 hours.
  • R 3 groups may undergo further functional group interconversions (FGIs) and transformations, such as alkylation of a hydroxy substituent group, using a suitable alkylbromide, in the presence of a suitable alkali metal base (such as K 2 CO 3 ), optionally in the presence of a catalyst (eg Kl) in a suitable solvent such as acetonitrile and/or N,N-dimethylformamide at elevated temperature, or demethylation of a methoxy group by treatment with lithium iodide in pyridine or collidine, or by treatment with BBr 3 in dichloromethane.
  • FGIs functional group interconversions
  • transformations such as alkylation of a hydroxy substituent group, using a suitable alkylbromide, in the presence of a suitable alkali metal base (such as K 2 CO 3 ), optionally in the presence of a catalyst (eg Kl) in a suitable solvent such as acetonitrile and/or N,N-dimethylform
  • a suitable protecting group strategy may be employed.
  • a hydroxyl group may be protected using a tetrahydropyran group, and deprotection may be achieved by treatment with a solution of acetic acid:water:tetrahydrofuran (4:1:2 by volume) at RT for up to 18 hrs.
  • a benzyloxy group may be used and deprotected to give the corresponding hydroxyl compound, for example by using a reduction (e.g. with palladium black in acid).
  • reaction of amine (VI) with a carboxylic acid of the formula, QR 3 COOH, wherein Q is an alcohol protecting group (eg THP or phenyl, preferably THP), to provide a protected amide can be carried out as described in step (c) of Scheme A.
  • Preferred conditions for such reaction are: treatment of a solution of amine (VI) in NMP with the carboxylic acid, QR 3 COOH, HOBT, WSCDI and Hunig's base at RT for about 72 hours.
  • Removal of protecting group, Q, from the protected amide can be achieved by a standard method specific for that protecting group, as described in "Protective Groups in Organic Synthesis" by T.W. Greene and P. Wutz.
  • any compatible protecting radical can be used.
  • methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by McOMIE (Protective Groups in Organic Chemistry, Plenum Press, 1973), can be used.
  • nicotinamide derivatives of formula (I) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • the present invention provides a process for the preparation of a nicotinamide derivative of the formula (I) as described in claim 1 comprising: (i) reaction of amines of general formula (VI) via treatment with a suitable acid of formula R 3 COOH; or (ii) substitution of the leaving group, LG, of the compounds of formula (IX) by an optionally substituted, 3-methylsulphanyl-phenol group; or (iii) reaction of the acid of formula (XII) with the amine of formula (VIII)
  • the present invention additionally provides compounds of the general formulae (VI), (IX) and (XII) as defined hereinbefore.
  • the present invention provides processes for the preparation of compounds of general formulae (VI), (IX) and (XII) wherein said processes are as illustrated by steps (a), (b) and (c) Route A, steps (c) and (a) Route B and steps (b) and (e) Route C herein.
  • the nicotinamide derivatives of formula (I) may also be optionally transformed in pharmaceutically acceptable salts.
  • these pharmaceutically acceptable salts of the nicotinamide derivatives of the formula (I) include the acid addition and the base salts (including disalts) thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodie, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L-tartrate, 1-hydroxy-2-naphtoate, 3-hydroxy-2-naphthoate and tosylate saltes.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of a nicotinamide derivative of the formula (I) may be readily prepared by mixing together solutions of the nicotinamide derivative of formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d ⁇ -DMSO.
  • clathrates drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are are present in non-stoichiometric amounts.
  • references to nicotinamide derivatives of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.
  • the invention includes all polymorphs of the nicotinamide derivatives of formula (I)-
  • prodrugs of the nicotinamide derivatives of formula (I).
  • certain derivatives of nicotinamide derivatives of formula (I) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to nicotinamide derivatives of formula (1) having the desired activity.
  • Such derivatives are referred to as "prodrugs”.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the nicotinamide derivatives of formula (I) with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985).
  • nicotinamide derivatives of formula (I) may themselves act as prodrugs of other nicotinamide derivatives of formula (I).
  • Nicotinamide derivatives of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a nicotinamide derivative of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the nicotinamide derivative contains, for example, a keto or oxime group, tautomeric isomerism ('tautomerism') may occur. It follows that a single nicotinamide derivative may exhibit more than one type of isomerism.
  • optical isomers including optical isomers, geometric isomers and tautomeric forms of the nicotinamide derivatives of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.
  • Conventional techniques for the preparation/isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.
  • the present invention also includes all pharmaceutically acceptable isotopic variations of a nicotinamide derivative of formula (I).
  • An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the nicotinamide derivatives of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 13 C and 14 C, nitrogen, such as 15 N, oxygen, such as 17 O and 18 O, phosphorus, such as 32 P, sulphur, such as 35 S, fluorine, such as 18 F, and chlorine, such as 36 CI.
  • isotopic variations of the nicotinamide derivatives of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopic variations of the nicotinamide derivatives of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.
  • the present invention concerns mixtures of nicotinamide derivatives of the formula (I), as well as mixtures with or of their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms and/or isotope forms.
  • the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutical active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the PDE4 enzymes are involved, in particular the inflammatory disorders, allergic disorders, respiratory diseases and wounds.
  • the nicotinamide derivatives of formula (I) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy or prophylaxis. They can be administered per se, in mixtures with one another or in combination with other drugs, or in the form of pharmaceutical preparations which permit enteral (gastric) or parenteral (non- gastric) administration and which as active constituent contain an efficacious dose of at least one nicotinamide derivative of the formula (I), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives.
  • excipient is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
  • the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.
  • nicotinamide derivatives of formula (I) their pharmaceutically acceptable salts and/or derived forms of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual 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, films (including muco- adhesive), ovules, sprays and liquid formulations.
  • 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, 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 example, from a sachet.
  • nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).
  • composition of a typical tablet in accordance with the invention may comprise:
  • a typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion.
  • the tablet formulation may comprise one or more layers and may be coated or uncoated.
  • excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti-oxidants, flavours and colourants.
  • carriers for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate
  • granulation binders for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin
  • disintegrants for example, sodium starch glycolate and silicates
  • lubricating agents for example, magnesium stearate and stearic acid
  • wetting agents
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Other modified release formulations are described in US Patent No. 6,106,864. PARENTERAL ADMINISTRATION
  • nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and/or derived forms of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of nicotinamide derivatives of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • the nicotinamide derivatives of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by iontophoresis, eiectroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • nicotinamide derivatives of formula (I) may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.
  • the nicotinamide derivatives 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 in anhydrous or monohydrate form, preferably monohydrate, mannitol, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose or trehalose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised 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 dichlorofluoromethane.
  • a dry powder either alone, as a mixture, for example, in a dry blend with lactose in anhydrous or monohydrate form, preferably mono
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.
  • the drug product 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.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 /g to 20mg of the nicotinamide derivative of formula (I) per actuation and the actuation volume may vary from 1//I to 100 /I.
  • a typical formulation may comprise a nicotinamide derivative of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the nicotinamide derivative of formula (I), a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1 ⁇ g to 4000 ⁇ g of the nicotinamide derivative of formula (I).
  • the overall daily dose will typically be in the range 1 ⁇ g to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Sustained or controlled release can be obtained by using for example polyp, L-lactic-co-glycolic acid).
  • Flavouring agents, such as methol and levomethol and/or sweeteners such as saccharing or saccharin sodium can be added to the formulation.
  • the nicotinamide derivatives of formula (I) may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.
  • the nicotinamide derivatives of formula (I) may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and andial administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/andial administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted, or programmed release.
  • the nicotinamide derivatives of formula (I) may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability.
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • 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 International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the nicotinamide derivatives of formula (I) is typically in the range 0.001 mg/kg to 100 mg/kg depending, of course, on the mode of administration.
  • the total daily dose may be administered in single or divided doses. The physician will readily be able to determine doses for subjects depending on age, weight, health state and sex or the patient as well as the severity of the disease.
  • the nicotinamide derivatives of the formula (I), their pharmaceutically acceptable salts and/or their derived forms can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result.
  • the second and more additional therapeutic agents may also be a nicotinamide derivatives of the formula (I), their pharmaceutically acceptable salts and/or their derived forms, or one or more PDE4 inhibitors known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
  • the terms "co-administration”, “co-administered” and “in combination with”, referring to the nicotinamide derivatives of formula (I) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following : ⁇ simultaneous administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient, ⁇ substantially simultaneous administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient, ⁇ sequential administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times
  • Suitable examples of other therapeutic agents which may be used in combination with the nicotinamide derivatives of the formula (I), their pharmaceutically acceptable salts and/or their derived forms include, but are by no mean limited to:
  • LTRAs Leukotriene antagonists including antagonists of LTB4, LTC4, LTD4, and LTE4,
  • Histaminic receptor antagonists including H1 , H3 and H4 antagonists
  • Histaminic receptor antagonists including H1 , H3 and H4 antagonists
  • 1- and ⁇ 2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use
  • Adhesion molecule inhibitors including VLA-4 antagonists
  • MMPs matrix metalloproteases
  • q Tachykinin NK1 , NK2 and NK3 receptor antagonists
  • ⁇ muscarinic M3 receptor agonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine, ⁇ /?2-adrenoceptor agonists including albutarol, salbutamol, formoterol and salmeterol, ⁇ p38 MAP kinase inhibitors, ⁇ H3 antagonists, ⁇ glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone fur
  • ipratropium salts namely bromide
  • tiotropium salts
  • the nicotinamide derivatives of formula (I) inhibit the PDE4 isozyme and thereby have a wide range of therapeutic applications, as described further below, because of the essential role, which the PDE4 family of isozymes plays in the physiology of all mammals.
  • the enzymatic role performed by the PDE4 isozymes is the intracellular hydrolysis of adenosine 3',5'-monophosphate (cAMP) within pro-inflammatory leukocytes.
  • cAMP adenosine 3',5'-monophosphate
  • PDE4 inhibition plays a significant role in a variety of physiological processes.
  • a further aspect of the present invention relates to the use of the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, in the treatment of diseases, disorders, and conditions in which the PDE4 isozymes are involved.
  • the present invention also concerns the use of the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, in the treatment of diseases, disorders, and conditions selected from the group consisting of : ⁇ asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non- atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise- induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma and whez infant syndrome,
  • ⁇ obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) and exacerbation of airways hyper-reactivity consequent to other drug therapy
  • COPD chronic osinophilic pneumonia
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith
  • COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome
  • pneumoconiosis of whatever type, etiology, or pathogenesis, in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis;
  • bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, ⁇ bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bron
  • sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or sphenoid sinusitis,
  • rheumatoid arthritis of whatever type, etiology, or pathogenesis, in particular rheumatoid arthritis that is a member selected from the group consisting of acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and vertebral arthritis,
  • an eosinophil-related disorder of whatever type, etiology, or pathogenesis in particular an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia, pulmonary infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, granulomas containing eosinophils, allergic granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotizing vasculitis,
  • PAN polyarteritis nodosa
  • urticaria of whatever type, etiology, or pathogenesis in particular urticaria that is a member selected from the group consisting of immune-mediated urticaria, complement-mediated urticaria, urticariogenic material-induced urticaria, physical agent-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal dominant form or in the acquired form, contact urticaria, giant urticaria and papular urticaria,
  • conjunctivitis of whatever type, etiology, or pathogenesis, in particular conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis and vernal conjunctivitis,
  • uveitis of whatever type, etiology, or pathogenesis, in particular uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, blinking, cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis,
  • ⁇ psoriasis ⁇ multiple sclerosis of whatever type, etiology, or pathogenesis, in particular multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis and relapsing remitting multiple sclerosis,
  • autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis in particular an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases, ulcerative colitis, endocrin opthamopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type I, keratoconjunctivitis sicca, epidemic keratoconjunctivitis
  • IBD ⁇ inflammatory bowel disease
  • CD Crohn's disease
  • septic shock of whatever type, etiology, or pathogenesis, in particular septic shock that is a member selected from the group consisting of renal failure, acute renal failure, cachexia, malarial cachexia, hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia suprarenalis or Addison's disease, cancerous cachexia and cachexia as a consequence of infection by the human immunodeficiency virus (HIV),
  • HAV human immunodeficiency virus
  • pulmonary hypertension of whatever type, etiology or pathogenesis including primary pulmonary hypertension / essential hypertension, pulmonary hypertension secondary to congestive heart failure, pulmonary hypertension secondary to chronic obstructive pulmonary disease, pulmonary venous hypertension, pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension,
  • central nervous system disorders of whatever type, etiology, or pathogenesis, in particular a central nervous system disorder that is a member selected from the group consisting of depression, Alzheimers disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany Huntington's chorea, Wilson's disease, paralysis agitans, and thalamic atrophies,
  • viruses wherein such viruses increase the production of TNF- ⁇ in their host, or wherein such viruses are sensitive to upregulation of TNF- ⁇ in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1 , HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and Herpes viruses including Herpes zoster and Herpes simplex,
  • CMV cytomegalovirus
  • influenza adenoviruses
  • Herpes viruses including Herpes zoster and Herpes simplex
  • yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF- ⁇ r or elicit TNF- ⁇ production in their host, e.g., fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but are not limited to, polymixins, e.g. Polymycin B, imidazoles, e.g. clotrimazole, econazole, miconazole, and ketoconazole, triazoles, e.g. fluconazole and itranazole as well as amphotericins, e.g.
  • Amphotericin B and liposomal Amphotericin B ⁇ ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infections, lupus erythematosus, kidney and ureter disease, urogenital and gastrointestinal disorders and prostate diseases, ⁇ reduction of scar formation in the human or animal body, such as scar formation in the healing of acute wounds, and ⁇ psoriasis, other dermatological and cosmetic uses, including antiphlogistic, skin-softening, skin elasticity and moisture-increasing activities.
  • the present invention relates in particular to the treatment of a respiratory disease, such as adult respiratory distress syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma, emphysema, bronchiectasis, sinusitis and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis asthma
  • emphysema bronchiectasis
  • sinusitis rhinitis
  • the present invention relates in particular to the treatment of gastrointestinal (Gl) disorders, in particular inflammatory bowel diseases (IBD) such as Crohn's disease, ileitis, collagenous colitis, colitis polyposa, transmural colitis and ulcerative colitis.
  • Gl gastrointestinal
  • IBD inflammatory bowel diseases
  • the present invention relates also to the reduction of scars formation.
  • a still further aspect of the present invention also relates to the use of the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, for the manufacture of a drug having a PDE4 inhibitory activity.
  • the present inventions concerns the use of the nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, for the manufacture of a drug for the treatment of inflammatory, respiratory, allergic and scar-forming diseases, disorders, and conditions, and more precisely for the treatment of diseases, disorders, and conditions that are listed above.
  • the present invention provides a particularly interesting method of treatment of a mammal, including a human being, with a PDE4 inhibitor including treating said mammal with an effective amount of a nicotinamide derivative of formula (I), its pharmaceutically acceptable salts and/or derived forms. More precisely, the present invention provides a particularly interesting method of treatment of a mammal, including a human being, to treat an inflammatory, respiratory, allergic and scar-forming disease, disorder or condition, including treating said mammal with an effective amount of a nicotinamide derivative of formula (I), its pharmaceutically acceptable salts and/or derived forms.
  • Ethyl-2-chloro-5-fluoro-nicotinoate (may be prepared according to the method of J. Med. Chem., 1993, 36(18), 2676-88, page 2684, column 2, 3 rd example, ethyl-2-chloro-5-fluoropyridine-3-carboxylate) was dissolved in tetrahydrofuran, THF, (350mL) and a 2M aqueous solution of lithium hydroxide (247mL, 0.495mol) added. The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to pH1 by addition of 6M hydrochloric acid and then extracted with dichloromethane (x3).
  • reaction mixture was partitioned between ethyl acetate (250mL) and water (250mL) and the organic layer washed with water (3x200mL), dried over magnesium sulphate and concentrated in vacuo.
  • the residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 10:1 to 5:1 to 3:1 to 2:1 to 1 :1 to yield the title product, 1.88g.
  • Lithium hydroxide solution (2.5mL, 1 M in water) was added to a solution of the ester from preparation 8 (400mg, 2.27mmol) in methanol (5mL) and the solution stirred at room temperature for 90 minutes. The solution was concentrated in vacuo to remove the methanol, the aqueous solution acidified using 2M hydrochloric acid, and the mixture concentrated in vacuo to give the title compound as a yellow solid.
  • the nitro compound of preparation 12 (6.0g, 33.0mmol) was dissolved in methanol (150mL) and the solution treated with 10% Pd/C (300mg) and stirred for 18 hours under 60psi of hydrogen.
  • the reaction mixture was filtered to remove the catalyst and the filtrate concentrated in vacuo.
  • the residue was taken up in methanol (150mL) and treated with charcoal (5.0g) and the mixture stirred at room temperature for 1 hour.
  • the mixture was filtered and the filtrate concentrated in vacuo to yield the title product, 3.0g.
  • the ester of preparation 15 (27.1 g, 88.2mmol) was dissolved in tetrahydrofuran (300mL) and the solution treated with a 1 M aqueous solution of lithium hydroxide (220mL, 220mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to remove the tetrahydrofuran and the aqueous was cooled to 0°C before being acidified to pH 1 with hydrochloric acid. The resulting pink precipitate was removed by filtration and washed with iced water. The solid was dissolved in dichloromethane (800mL) and washed with acidified brine solution (200mL).
  • the acid of preparation 16 (5g, 17.9mmol) and N,N-dimethylformamide (5 drops) were dissolved in dichloromethane (100mL) and the solution cooled to 0°C. This was treated dropwise with oxalyl chloride (3.1mL, 35.8mmol) over 15 minutes and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue taken up in dichloromethane (100mL). The solution was cooled to 0°C and treated with triethylamine (7.5mL, 54mmol) and the amine of preparation 2 (4.2g, 19.6mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 48 hours.
  • the reaction mixture was diluted with dichloromethane (100mL) and washed with water (70mL), 10% citric acid solution (2 x 70mL), saturated sodium hydrogencarbonate solution (2 x 70mL) and water (70mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo to yield the title product, 8.0g.
  • the carboxylic acid of preparation 4 (145mg, 0.50mmol) was dissolved in 1- methyl-2-pyrrolidinone (3mL) and the solution treated with 1- hydroxybenzotriazole hydrate (74.3mg, 0.55mmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115mg, 0.60mmol). The mixture was stirred for 10 minutes and was then treated with amine of preparation 18 (200mg, 0.48mmol) and N-ethyldiisopropylamine (155mg, 1.20mmol) and stirred at room temperature for 72 hours.
  • reaction mixture was partitioned between ethyl acetate (75mL) and water (75mL) and the organic layer washed with water (2 x 75mL) and 5% sodium carbonate solution (75mL), dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with ethe ⁇ pentane 1:1 to yield the title product as a white solid, 218mg.
  • the mixture was then treated with the amine of preparation 18 (200mg, 0.48mmol) and N-ethyldiisopropylamine (155mg, 1.20mmol) and the reaction mixture stirred at room temperature for 48 hours.
  • the reaction mixture was partitioned between ethyl acetate (75mL) and water (75mL) and the organic layer washed with water (3x50mL) and 0.880 ammonia in water (100mL), dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with ether to yield the title product as a white solid, 223mg.
  • Example 2 The carboxylic acid of preparation 11 was used. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:1 to 50:1 to 25:1 to 15:1.
  • Example 3 The carboxylic acid of preparation 7 was used. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:1 to 50:1 to 25:1 to 15:1.
  • Example 4 1 H-indazole-3-carboxylic acid, which is available from Fluka was used.
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:1 to 50:1 to 25:1 to 15:1 and then with pentane:ethyl acetate 10:1 to 3:1 to 2:1 to 1:1 to 1:2 to 1 :3.
  • Example 5 2-methyl-3H-benzoimidazole-4-carboxylic acid (J. Med. Chem., 43, 2000, 4084-4097, at page 4090, column 2, 6 th compound) was the carboxylic acid used. The organics were washed with 10% citric acid before a basic wash.
  • Example 6 Syn-lmidazoM ,2-alpyridine-8-carboxylic acid (4- ⁇ r5-fluoro-2-(3-methylsulfanyl- phenoxy)-pyridine-3-carbony ⁇ -aminol-cvclohexyl)-amide
  • the amine of preparation 18 (250mg, 0.60mmol) was dissolved in N,N- dimethylformamide (7mL) and the solution treated with 1 -hydroxybenzotriazole hydrate (84mg, 0.60mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124mg, 0.69mmol), 4-methylmorpholine (205 ⁇ L, 1.88mmol) and the carboxylic acid of preparation 9 (90mg, 0.55mmol).
  • the reaction mixture was stirred at room temperature for 18 hours.
  • the mixture was diluted with ethyl acetate:water 3:1 (28mL) and the aqueous extracted with ethyl acetate (x2).
  • the title compound was prepared by a method similar to that described for example 6 using the carboxylic acid of preparation 14.
  • the amine of preparation 18 (150mg, 0.36mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (91 mg, 0.47mmol), 1-hydroxybenzotriazole hydrate (72mg, 0.47mmol), N-ethyldiisopropylamine (0.25mL, 1.40mmol) and 8- quinolinecarboxylic acid (69mg, 0.40mmol) were dissolved in dichloromethane (10mL) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with 10% citric acid solution and the layers separated by filtration through a phase separation tube.
  • the PDE4 inhibitory activity of the nicotinamide derivatives of the formula (1 ) is determined by the ability of compounds to inhibit the hydrolysis of cAMP to AMP by PDE4 (see also reference 1 ).
  • Tritium labelled cAMP is incubated with PDE4.
  • the radiolabelled AMP produced is able to bind yttrium silicate SPA beads. These SPA beads subsequently produce light that can be quantified by scintillation counting.
  • the addition of a PDE4 inhibitor prevents the formation of AMP from cAMP and counts are diminished.
  • the IC50 of a PDE4 inhibitor can be defined as the concentration of a compound that leads to a 50% reduction in counts compared to the PDE4 only (no inhibitor) control wells.
  • the anti-inflammatory properties of the nicotinamide derivatives of the formula (1) are demonstrated by their ability to inhibit TNF ⁇ release from human peripheral blood mononuclear cells (see also reference 2).
  • Venous blood is collected from healthy volunteers and the mononuclear cells purified by centrifugation through Histopaque (Ficoll) cushions. TNF ⁇ production from these cells is stimulated by addition of lipopolysaccharide. After 18 hours incubation in the presence of LPS, the cell supernatant is removed and the concentration of TNF ⁇ in the supernatant determined by ELISA. Addition of PDE4 inhibitors reduces the amount of TNF ⁇ produced.
  • IC 50 is determined which is equal to the concentration of compound that gives 50% inhibition of TNF ⁇ production as compared to the LPS stimulated control wells. All the examples were tested in the assay described above and found to have an IC 50 (TNF ⁇ screen) of less than 10 nM. And for most of the tested compounds, they were found to have an IC 50 (TNF ⁇ screen) of even less than 1 nM.

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Abstract

L'invention concerne des dérivés de nicotinamide de formule générale (I) dans laquelle R1, R2, et R3 ont les significations définies dans le présent fascicule, ainsi que des compositions les contenant et les utilisations de ces dérivés en tant qu'inhibiteurs de PDE4.
EP04744024A 2003-07-25 2004-07-13 Derives de nicotinamide utiles en tant qu'inhibiteurs de pde4 Withdrawn EP1651647A1 (fr)

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PCT/IB2004/002365 WO2005010001A1 (fr) 2003-07-25 2004-07-13 Derives de nicotinamide utiles en tant qu'inhibiteurs de pde4

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