EP1651635A1 - Derives de nicotinamide agissant comme inhibiteurs de pde4 - Google Patents

Derives de nicotinamide agissant comme inhibiteurs de pde4

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Publication number
EP1651635A1
EP1651635A1 EP04744035A EP04744035A EP1651635A1 EP 1651635 A1 EP1651635 A1 EP 1651635A1 EP 04744035 A EP04744035 A EP 04744035A EP 04744035 A EP04744035 A EP 04744035A EP 1651635 A1 EP1651635 A1 EP 1651635A1
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EP
European Patent Office
Prior art keywords
nicotinamide
ylene
asthma
fluoro
methylsulfanyl
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Withdrawn
Application number
EP04744035A
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German (de)
English (en)
Inventor
S. c/o Pfizer Global Res.& Development BAILEY
C.G. c/o Pfizer Global Res. & Development BARBER
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Pfizer Ltd
Pfizer Products Inc
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Pfizer Ltd
Pfizer Products Inc
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Publication of EP1651635A1 publication Critical patent/EP1651635A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to nicotinamide derivatives of general formula :
  • 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.
  • 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
  • Some 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) :
  • X is hydrogen, methyl or halo
  • Y is attached to the 3- or 4-position on the phenyl ring, and is S(O) p R 1 , wherein R 1 is (C- ⁇ -C ) alkyl optionally substituted by (C 3 -C6)cycloalkyl and p is 0, 1 or 2,
  • n 1 or 2
  • Z is selected from hydrogen, (C ⁇ -C 3 )alkyl, halo and (C ⁇ -C 3 )alkoxy, each Z being independently selected when n is 2,
  • L is a 5- or 6-membered heterocyclic ring containing one or two nitrogen ring atoms, which ring is optionally substituted by OH, (C ⁇ -C 3 )alkyl (optionally substituted by OH or by (C ⁇ -C 3 )alkoxy), halo or by (C ⁇ -C 3 )alkoxy,
  • R is H, (C ⁇ -C 6 )alkyl (optionally substituted by OH or (C f Csialkoxy), SO 2 (C 1 -C 3 )alkyl), or COR"
  • R 3 and R 4 are each independently selected from H, (C ⁇ -C 3 )alkyl and C(O)(C ⁇ - C 3 )alkyl),
  • the nicotinamide derivative is not (i) 5-methyl-2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (ii) 5-methyl-2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (iii) 2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; or (iv) 2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide.
  • these nicotinamide derivatives are inhibitors of PDE4 isoenzymes, particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions or for wounds by showing excellent therapeutic utility and therapeutic index.
  • X is F and/or p is 0.
  • Y is attached to the 3-position on the phenyl ring, and/or Y is S(O) p CH 3 , S(O) p C 2 H 5 or S(O) p CH 2 (cyclopropyl). More preferably, Y is SCH 3 , SC 2 H 5 or SCH 2 (cyclopropyl). Still more preferably, Y is SCH . Yet more preferably Y is 3-SCH 3 .
  • (Z) n when (Z) n is not H or F, it is attached to the 3-, 4-, and/or 5-position on the phenyl ring.
  • (Z) n is H.
  • L is a piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, which ring is optionally substituted by OH, methoxy, hydroxymethyl, ethoxy, or methyl.
  • L is piperidin-1 ,3-ylene, piperidin- 1 ,4-ylene, pyrazin-5,1-ylene, 3-hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin- 2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 3-methoxypyridin-6,4-ylene, 2- methoxypyridin-5,3-ylene, 2-methoxypyridin-3,5-ylene, 3-ethoxypyridin-2,6-ylene, 3- hydroxymethylpyridin-2,6-ylene, 2-methylpyridin-3,6-ylene, 3-methylpyridin-4,6-ylene, 4-hydroxypirimidin-2,5-ylene or 4-hydroxypyrimidin-5,2-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.
  • L is piperidin-1 ,4-ylene, pyrazin-5,1-ylene, 3-hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 2-methoxypyridin-3,5-ylene, 3- hydroxymethylpyridin-2,6-ylene or 3-methylpyridin-4,6-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety. Yet more preferably, L is piperidin-1 ,4-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.
  • R is H, CH 3 , C 2 H 5 , COCH 3 , SO 2 CH 3 , COC 2 H 4 (pyridyl), COC 2 H 5 , CO(cyclopropyl), COCH 2 OH, CO(2-hydroxy-4-methylphenyl), CO(2-hydroxy-4- methoxyphenyl) or CO(2-hydroxyphenyl).
  • R is H, COCH 3 or SO 2 CH 3 . Most preferably R is H or COCH 3 .
  • halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
  • Examples of suitable (C ⁇ -C 3 )alkyl, (C ⁇ -C 4 )alkyl and (C- ⁇ -C 6 )alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • Examples of suitable (CrC 4 )alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso- butyloxy, sec-butyloxy and tert-butyloxy.
  • Examples of suitable (C ⁇ -C )thioalkyl radicals are thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, thio-n-butyl, thio-iso-butyl, thio- sec-butyl and thio-tert-butyl.
  • (C 3 -C 6 )cycloaIkyl radicals represent 3-membered to 6-membered saturated monocyclic rings.
  • suitable (C 3 -C 6 )cycloalkyl radicals are in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. These radicals can be optionally substituted.
  • a heterocyclic ring is a radical of a monocyclic or polycyclic aromatic system having 5 to 14 ring members, which contains 1, 2 or 3 heteroatom(s) depending in number and quality of the total number of ring members, selected from nitrogen (N), oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be identical or different. Heterocyclic rings can also be unsubstituted, monosubstituted or polysubstituted, as indicated in the definition of R2 hereabove for general formula (1) according to the present invention.
  • heterocyclic radicals are the radicals derivated from piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, pyrrole, furan, furazan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazine, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole, purine, naphthyridine, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, and benzo-fused derivatives of these heteroaryls, such as for example benzofuran, benzothiophene, benzoxazole, and benzothiazole.
  • heteroaryl radicals selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1 ,2,4- triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrinnidinyl, and pyrazinyl.
  • the nicotinamide derivatives of the formula (1) can be prepared using conventional procedures such as by the following illustrative methods in which X, L, Y, Z and R are as previously defined for the nicotinamide derivatives of the formula (1) unless otherwise stated.
  • the compounds of formula (I) may be made by reaction of the corresponding nicotinic acid (II) with a compound of formula NH 2 -L-R
  • reaction suitably in the presence of an acid/amine, or peptide, coupling agent.
  • the reaction may suitably be carried by reaction of the acid with carbonyldiimidazole in a suitable inert solvent such as dichloromethane, followed by addition of the compound NH 2 -L-R, suitably in the presence of a base such as 4-dimethylaminopyridine, as exemplified in Examples 1-4 below.
  • acids (II) An alternative method starting from acids (II) is to use a suitable diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide in conjunction with an agent such as 1- hydroxybenzotriazole.
  • the acid (II) may be added to the mixture in an inert solvent such as dichloromethane, followed by addition of the amine NH 2 -L-R .
  • This reaction type, reagents, conditions, solvents and variations thereof are exemplified in Examples 57-69 below.
  • the acids of formula (II) and amines of formula NH 2 -L-R may be commercially available, or can be made using the methods described herein, including in the Preparations below, the art mentioned herein, or routine adaptation thereof.
  • Compounds of formula (I) may be made by a coupling reaction of a chloro-compound of formula (III) with a phenol of formula (IV).
  • the phenol (IV) and chloro-compound (III) are mixed with caesium carbonate in an inert solvent such as toluene:N-methylpyrrolidine at ambient temperature, followed by addition of copper (I) iodide and then heating to a suitable temperature such as 110°C.
  • an inert solvent such as toluene:N-methylpyrrolidine
  • copper (I) iodide iodide
  • chloro-compounds (III) and the phenols (IV) may be commercially available, or can be made using the methods described herein, including in the Preparations below, the art mentioned herein, or routine adaptation thereof.
  • Certain compounds of formula (I) may be transformed into other compounds of formula (I) by suitable functional group interconversion (FGI) of a type well-known to those skilled in the art.
  • FGI functional group interconversion
  • the compound of formula (I) contains an ester or acid moiety, these can be interconverted readily by known hydrolysis or esterification methods respectively.
  • 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.
  • the nicotinamide derivatives of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • Y is preferably attached to the 3-position on the phenyl ring, and represents in particular S(O) p CH 3 , S(O) p C 2 H 5 or S(O) p CH 2 (cyclopropyl), preferably SCH 3 , SC 2 H 5 or SCH 2 (cyclopropyl), more preferably SCH 3 , most preferably 3-SCH 3 .
  • (Z) n is not H or F, it is preferably attached to the 3-, 4-, and/or 5-position on the phenyl ring.
  • (Z) n is preferably H.
  • L is preferably a piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, which ring is optionally substituted by OH, methoxy, hydroxymethyl, ethoxy, or methyl, in particular piperidin-1 ,3-ylene, piperidin-1 ,4-ylene, pyrazin-5,1 -ylene, 3- hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 3-methoxypyridin-6,4-ylene, 2-methoxypyridin-5,3-ylene, 2- methoxypyridin-3,5-ylene, 3-ethoxypyridin-2,6-ylene, 3-hydroxymethylpyridin-2,6- ylene, 2-methylpyridin-3,6-ylene, 3-methylpyridin-4,6-ylene, 4-hydroxypirimidin-2,
  • L is piperidin-1 , 4-ylene, pyrazin-5,1 -ylene, 3-hydroxypyridin-6,4- ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 2- methoxypyridin-3,5-ylene, 3-hydroxymethylpyridin-2,6-ylene or 3-methylpyridin-4,6- ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety, most preferably L is piperidin-1 ,4-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.
  • R is H, CH 3 , C 2 H 5 , COCH 3 , SO 2 CH 3 , COC 2 H 4 (pyridyl), COC 2 H 5 , CO(cyclopropyl), COCH 2 OH, CO(2-hydroxy-4-methylphenyl), CO(2-hydroxy-4- methoxyphenyl) or CO(2-hydroxyphenyl), in particular H, COCH 3 or SO CH 3 .
  • R is H or COCH 3 .
  • the nicotinamide derivatives of formula (1 ) may also be optionally transformed in pharmaceutically acceptable salts.
  • these pharmaceutically acceptable salts of the nicotinamide derivatives of the formula (1) 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 (1) may be readily prepared by mixing together solutions of the nicotinamide derivative of formula (1 ) 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, d 6 -acetone, d 6 -DMSO.
  • references to nicotinamide derivatives of formula (1) include references to salts thereof and to solvates and clathrates of compounds of formula (1) and salts thereof.
  • the invention includes all polymorphs of the nicotinamide derivatives of formula (1). Also within the scope of the invention are so-called “prodrugs" of the nicotinamide derivatives of formula (1). Thus certain derivatives of nicotinamide derivatives of formula (1) 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 (1) 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 (1) may themselves act as prodrugs of other nicotinamide derivatives of formula (1 ).
  • Nicotinamide derivatives of formula (1) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a nicotinamide derivative of formula (1) 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 (1 ), 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 (1 ).
  • 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.
  • 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 (1 ), as well as mixtures with or of their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms and/or isotope forms.
  • the nicotinamide derivatives of formula (1) 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 (1 ) 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 (1 ), 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 (1 ), 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.
  • the nicotinamide derivatives of formula (1) 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 (1 ), 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
  • 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.
  • 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 (1) 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, electroporation, 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 (1 ) 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 (1) 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 monohydrate,
  • 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 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.
  • 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 (1) per actuation and the actuation volume may vary from 1 /I to 1OO /I.
  • a typical formulation may comprise a nicotinamide derivative of formula (1 ), 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 (1), 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 (1 ).
  • 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 poly(D,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 (1) 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 (1 ) 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 (1 ) 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 91/11 172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the nicotinamide derivatives of formula (1 ) 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 (1 ), 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 (1), 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 (1) 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 by said
  • Suitable examples of other therapeutic agents which may be used in combination with the nicotinamide derivatives of the formula (1), their pharmaceutically acceptable salts and/or their derived forms include, but are by no mean limited to : (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4,
  • Histaminic receptor antagonists including H1, H3 and H4 antagonists
  • Adhesion molecule inhibitors including VLA-4 antagonists
  • ⁇ muscarinic M3 receptor agonists or antichoHnergic 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
  • the nicotinamide derivatives of formula (1 ) 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 (1), their pharmaceutically acceptable salts and/or derived forms, in the treatment of diseases, disorders, and conditions in which the PDE4 isozymes are involved. More specifically, the present invention also concerns the use of the nicotinamide derivatives of formula (1), 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 IgEDmediated 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, ⁇ chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, ⁇ obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory
  • 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,
  • 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 ves
  • 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 bronchiectasis and follicular bronchiectasis,
  • 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
  • ⁇ 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,
  • 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), ⁇ liver injury,
  • 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,
  • ⁇ bone loss diseases, primary osteoporosis and secondary osteoporosis ⁇ 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
  • ⁇ infection especially infection by 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, ⁇ yeast and
  • 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, chronic sinusitis and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis asthma
  • emphysema bronchiectasis
  • chronic sinusitis chronic sinusitis and 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 (1 ), 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 (1 ), 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 (1 ), 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 (1 ), its pharmaceutically acceptable salts and/or derived forms.
  • Flash chromatography refers to column chromatography on silica gel (Kieselgel 60, 230-400 mesh, from E. Merck, Darmstadt. Kieselgel 60 F 254 plates from E. Merck were used for TLC, and compounds were visualised using UV light, 5% aqueous potassium permanganate or Dragendorff's reagent (oversprayed with aqueous sodium nitrite).
  • Thermal analyses by Differential Scanning Calorimetry (DSC) and ThermoGravimetric Analysis (TGA) were obtained using Perkin Elmer DSC7 and TGA7. Moisture sorption characteristics were recorded using Surface Measurement Systems Ltd. Automated Water Sorption Analyser DVS 1.
  • Powder X-ray diffraction (PXRD) pattern was determined using a Siemens D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. Other measurements were taken using standard equipment.
  • Hexane refers to a mixture of hexanes (hplc grade) b.p. 65-70°C.
  • "Ether” and “Et 2 O” refers to diethyl ether.
  • Acetic acid refers to glacial acetic acid.
  • HOAt 1-Hydroxy-7-aza-1 H-1,2,3-benzotriazole
  • HAt 1-Hydroxy-7-aza-1 H-1,2,3-benzotriazole
  • HOAt 1-Hydroxy-7-aza-1 H-1,2,3-benzotriazole
  • “HOBt” is 1- hydroxy-1H-1 ,2,3-benzotriazole.
  • N-[(dimethylamino)-1 H-1 ,2,3-triazolo[4,5-b]pyridin-1- ylmethylene]-N-methylmethaninium hexafluorophosphate N-oxide (HATU) and 7- azabenzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) were purchased from PerSeptive Biosystems U.K. Ltd.
  • DIPE refers to diisopropyl ether.
  • Reverse-phase silica gel for flash chromatography was obtained from Fluka (Fluka 100, C ⁇ 8 , 40-63 ⁇ ).
  • DCM dichloromethane
  • THF tetrahydrofuran
  • WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • EtOAc is ethyl acetate.
  • MeOH is methanol.
  • DMSO dimethylsulphoxide.
  • ACE-CI is 1- chloroethyl chloroformate.
  • NMM is N-methylmorpholine.
  • Pentane refers to High Performance Liquid Chromatography (HPLC) grade n-pentane (b.pt.35-37°C). Nomenclature has been allocated using the commercially available ACD program. Standard abbreviations are used throughout, e.g. "Me” is methyl, “Et” is ethyl, “Pr” is propyl, “Ph” is phenyl, etc.
  • Methyl iodide 14.67ml, 0.235mol was added dropwise to a solution of 3-methoxy- benzenethiol (30g, 0.214mol) and potassium carbonate (29.6g, 0.214mol) in acetone (400ml) under nitrogen at 3°C.
  • the reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure.
  • the residue was diluted with water (300ml) and the aqueous layer was extracted with diethylether (3x200ml).
  • the combined organic extracts were dried over MgSO 4 and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87g) as a pale yellow liquid.
  • Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M.Winn et. al.) (5.02g, 24Jmmol), 3-methylsulfanylphenol (3.5g, 25mmol) and caesium carbonate (8.13g, 25mmol) were suspended in dioxan (50ml) and the reaction was heated to 100°C and stirred at this temperature under nitrogen for 8h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50ml).
  • the title compound was prepared using the method of te/t-butyl 1-acetyl-3- pyrrolidinylcarbamate using propionyl chloride. Trituration with diethyl ether afforded a white solid (22.25g, 86%).
  • the title compound was prepared using the method of tert-butyl 1-acetyl-3- pyrrolidinylcarbamate using isobutyryl chloride. Trituration with diethyl ether afforded a white solid (24.05g, 88%).
  • the title compound was prepared using the method of tert-butyl 1-acetyl-3- pyrrolidinylcarbamate using isovaleryl chloride. Trituration with diethyl ether afforded a white solid (24.62g, 85%).
  • the title compound was prepared following the method of 1-acetyl-3-pyrrolidinamine as a colourless oil (9.0g, 69%).
  • the title compound was prepared following the method of 1-acetyl-3-pyrrolidinamine as a brown oil (12.44g, 84%).
  • Carbonyldiimidazole 64mg, 0.393mmol was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-ethanone (51 mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat.
  • Carbonyldiimidazole 64mg, 0.393mmol was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane
  • Carbonyldiimidazole 64mg, 0.393mmol was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-2-methyl-propan-1-one (62mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat.
  • Carbonyldiimidazole 64mg, 0.393mmol was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-3-methyl-butan-1-one (67mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat.
  • Trifluoroacetic acid 25ml was added to a solution of 4- ⁇ [5-fluoro-2-(3-methylsulfanyl- phenoxy)-pyridin-3-carbonyl]-amino ⁇ -piperidine-1-carboxylic acid tert-butyl ester (2.3g, 4.99mmol) and in dichloromethane (25ml) and the reaction was stirred under nitrogen at room temperature for 2h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100ml) and sat. sodium bicarbonate solution (100ml).
  • Acetaldehyde (25 ⁇ l, 0.404mmol) was added to a solution of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) in dichloromethane (4ml) under nitrogen at room temperature and the reaction was stirred for 1 h.
  • Sodium triacatoxyborohydride (125mg, 0.538mmol) was then added and the reaction was stirred at room temperature for 3h.
  • the reaction was diluted with dichloromethane (5ml), quenched with sat. sodium bicarbonate solution (1 ml) and further diluted with water (3ml).
  • Glyceraldehyde dimer (27mg, 0.202mmol) was added to a solution of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) in dichloromethane (4ml) under nitrogen at room temperature and the reaction was stirred for 1 h.
  • Sodium triacatoxyborohydride (125mg, 0.538mmol) was then added and the reaction was stirred at room temperature for 3h.
  • the reaction was diluted with dichloromethane (5ml), quenched with sat. sodium bicarbonate solution (1 ml) and further diluted with water (3ml).
  • reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120DI, 0753mmol).
  • the reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube.
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol)
  • 4- methylsulfanyl-phenol ( ⁇ lmg, 0.37mmol)
  • caesium carbonate (163mg, O. ⁇ mmol) ⁇
  • the reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol)
  • 4- methylsulfanyl-3-methyl-phenol (57mg, 0.37mmol)
  • caesium carbonate (163mg, O. ⁇ mmol)
  • dimethylformamide (l . ⁇ ml)
  • the reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, 9 ⁇ washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro- ⁇ -fluoro-nicotinamide (100mg, 0.33mmol)
  • 3- methyIsulfanyl-4-chloro-phenol (US4005148)
  • caesium carbonate (163mg, O. ⁇ mmol) were suspended in dimethylformamide (1.5ml) and the reaction was heated to 5 ⁇ °C and stirred at this temperature under nitrogen for 18h.
  • the reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol)
  • 3- methylsulfanyl-4-chloro-phenol 64mg, 0.37mmol
  • caesium carbonate (163mg, O. ⁇ mmol)
  • the reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro- ⁇ -fluoro-nicotinamide (100mg, 0.33mmol)
  • 4- methylsulfanyl-3, ⁇ -dimethyl-phenol 62mg, 0.37mmol
  • caesium carbonate (163mg, O. ⁇ mmol)
  • dimethylformamide 1.6ml
  • the reaction was quenched with sat. ammonium chloride solution (1ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro- ⁇ -fluoro-nicotinamide (100mg, 0.33mmol), 2,3- dihydrobenzo[b]thiophen- ⁇ -ol (56mg, 0.37mmol) and caesium carbonate (163mg, O. ⁇ mmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5 ⁇ °C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol)
  • 4- methylsulfanyl-2-fluoro-phenol (58mg, 0.37mmol)
  • caesium carbonate (163mg, O. ⁇ mmol)
  • the reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol)
  • 3- methylsulfanyl-4-methyl-phenol (67mg, 0.37mmol)
  • caesium carbonate (163mg, O. ⁇ mmol)
  • the reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml).
  • the residue5 was purified by flash column chromatography on silica gel eluting with ethyl acetate : cyclohexane (40 : 60 changing to 90 : 10, by volume) to give 5-fluoro-N-(1 - methanesulfonyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (99mg) as a white foam.
  • 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75mg, 0.394mmol) and 1 -hydroxybenzotriazole (60mg, 0.394mmol) were added to a suspension of 5- fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (2ml). This was stirred under nitrogen at room temperature for 15min, and a solution of 2-ethyl-2H-pyrazol-3-ylamine (44mg, 0.394mmol) in dichloromethane (2ml) was added.
  • 2-Amino-3-hydroxypyridine (83mg, 0752mmol) and triethylamine (300DI, 2.14mmol) were dissolved in dimethylformamide (800DI) under nitrogen at room temperature and a solution of ⁇ -fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150mg, 0.637mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113mg, 0.690mmol) and 1-hydroxybenzotriazole (80mg, 0.690mmol) in dimethylformamide ( ⁇ ml) and the reaction was stirred at room temperature for 24h.
  • reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% sodium bicarbonate solution (20ml), brine (20ml), dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • 2-Aminopyridine (120mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 6-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (35 ⁇ mg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41 mmol) in dimethylformamide (7.5ml) and the reaction was stirred at room temperature for 24h.
  • reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% sodium bicarbonate solution (20ml), brine (20ml), dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • 3-Aminopyridine (120mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (3 ⁇ 5mg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41 mmol) in dimethylformamide (7. ⁇ ml) and the reaction was stirred at room temperature for 24h.
  • reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% aqueous ammonia solution (20ml), brine (20ml), dried over Na 2 SO 4 and the solvent was removed under reduced pressure.
  • 2-Amino-4-hydroxypyrimidine (142mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1ml) under nitrogen at room temperature and a solution of ⁇ -fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (35 ⁇ mg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41mmol) in dimethylformamide (7.5ml) and the reaction was stirred at room temperature for 24h.
  • 5-Amino-2-methoxypyridine (89mg, 0716mmol) and triethylamine (200DI, 2.14mmol) were dissolved in dimethylformamide (1ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg, 0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide ( ⁇ ml) and the reaction was stirred at room temperature for 18h.
  • reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (100 : 0 : 0 changing to 98 : 2 : 0 then 97.5 : 2.5 : 0.25, by volume) and the product was crystallised from DIISOPROPYLETHER ( ⁇ ml) to give 5-Fluoro-N-(6-methoxy-pyridin-3-yl)-2-(3- methylsulfanyl-phenoxy)-nicotinamide (139mg) as an off-white solid.
  • 3-Amino-2-methoxypyridine (89mg, 0716mmol) and triethylamine (200DI, 2.14mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg, 0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide ( ⁇ ml) and the reaction was stirred at room temperature for 3h.
  • reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.26, by volume) and the product was crystallised from DIISOPROPYLETHER ( ⁇ ml) to give 5- fluoro-N-(2-methoxy-pyridin-3-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (92mg) as an off-white solid.
  • reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (97.6 : 2.6 : 0.25 changing to 95 : ⁇ : O. ⁇ , by volume) and the product was crystallised from diisopropyl ether ( ⁇ ml) to give 5-Fluoro-N-(3-hydroxymethyl-pyridin-2-yl)-2-(3-methylsulfanyl- phenoxy)-nicotinamide (127mg) as an off-white solid.
  • 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 IC 50 of a PDE4 inhibitor can be defined as the concentration of a compound that leads to a 60% 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 5 o 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 IC50 (TNF ⁇ screen) of less than 300 nM. And for most of the tested compounds, they were found to have an IC 50 (TNF ⁇ screen) of even less than 100 nM.

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Abstract

L'invention se rapporte à des dérivés de nicotinamide de la formule générale (I), dans laquelle X, Y, n, Z, L et R ont les définitions données, ainsi qu'à des procédés de préparation de ces dérivés, à des intermédiaires utilisés pour leur préparation, à des compositions les contenant et à leurs utilisations.
EP04744035A 2003-07-25 2004-07-13 Derives de nicotinamide agissant comme inhibiteurs de pde4 Withdrawn EP1651635A1 (fr)

Applications Claiming Priority (2)

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GBGB0317472.9A GB0317472D0 (en) 2003-07-25 2003-07-25 Nicotinamide derivatives useful as PDE4 inhibitors
PCT/IB2004/002376 WO2005009989A1 (fr) 2003-07-25 2004-07-13 Derives de nicotinamide agissant comme inhibiteurs de pde4

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PE20060272A1 (es) 2004-05-24 2006-05-22 Glaxo Group Ltd (2r,3r,4s,5r,2'r,3'r,4's,5's)-2,2'-{trans-1,4-ciclohexanodiilbis-[imino(2-{[2-(1-metil-1h-imidazol-4-il)etil]amino}-9h-purin-6,9-diil)]}bis[5-(2-etil-2h-tetrazol-5-il)tetrahidro-3,4-furanodiol] como agonista a2a
GB0514809D0 (en) 2005-07-19 2005-08-24 Glaxo Group Ltd Compounds
US8420647B2 (en) * 2010-01-21 2013-04-16 Hoffmann-La Roche Inc. 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds
US20160214967A1 (en) * 2013-09-30 2016-07-28 The University Of Tokyo Activator of adiponectin receptor

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US4861891A (en) * 1988-08-31 1989-08-29 Pfizer Inc. Antidepressant N-substituted nicotinamide compounds
TW429148B (en) * 1995-10-27 2001-04-11 Pfizer Pharmaceutical agents for the treatment of acute and chronic inflammatory diseases
ID22781A (id) * 1997-04-04 1999-12-09 Pfizer Prod Inc Turunan-turunan nikotinamida
GB9715584D0 (en) * 1997-07-23 1997-10-01 Eisai Co Ltd Compounds
DE19854081A1 (de) * 1998-11-24 2000-05-25 Bayer Ag Substituierte N-Pyrazolyl-phenoxynicotinsäure-(thio)amide
AU2003245711A1 (en) * 2002-02-11 2003-09-04 Pfizer Inc. Nicotinamide derivatives useful as pde4 inhibitors

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JP2006528659A (ja) 2006-12-21
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