MXPA04007736A - Nicotinamide derivatives useful as pde4 inhibitors. - Google Patents

Nicotinamide derivatives useful as pde4 inhibitors.

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Publication number
MXPA04007736A
MXPA04007736A MXPA04007736A MXPA04007736A MXPA04007736A MX PA04007736 A MXPA04007736 A MX PA04007736A MX PA04007736 A MXPA04007736 A MX PA04007736A MX PA04007736 A MXPA04007736 A MX PA04007736A MX PA04007736 A MXPA04007736 A MX PA04007736A
Authority
MX
Mexico
Prior art keywords
alkyl
group
hydroxy
formula
asthma
Prior art date
Application number
MXPA04007736A
Other languages
Spanish (es)
Inventor
Thomas Victor Magee
Original Assignee
Pfizer
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer filed Critical Pfizer
Publication of MXPA04007736A publication Critical patent/MXPA04007736A/en

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    • 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
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

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Abstract

The invention relates to nicotinamide derivatives of formula (1) and to processes for the preparation of, compositions containing and the uses of, such derivatives. The nicotinamide derivatives according to the present invention are phosphodiesterase-4 inhibitors and are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions as well as for wounds healing.

Description

NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 INHIBITORS DESCRIPTIVE MEMORY This invention relates to nicotinamide derivatives of the general formula: wherein Ri, l¾, R 3, R 4, X, Y, n and m have the meanings indicated below, and processes for the preparation of said derivatives, the interates used in the preparation of said derivatives, the compositions containing said derivatives and to the uses of said derivatives. Phosphodiesterases (PDEs) that act on 3 ', 5'-cyclic nucleotides comprise a large class of enzymes divided into at least eleven different families that differ from each other structurally, biochemically and pharmacologically. Enzymes encompassed within each family are called vulgar isoenzymes or isozymes. Within this class a total of more than fifteen gene products are included and the differential splicing and post-translational processing techniques of these gene products generate even more diversity. The present invention relates mainly to the four gene products of the fourth PDE family, ie, PDE4A, PDE4B, PDE4C and PDE4D. These enzymes are collectively known as isoforms or subtypes of the family of PDE4 isozymes. PDE4 are characterized by the high-affinity, selective hydrolytic degradation of the second messenger cyclic nucleotide, 3 ', 5'-cyclic adenosine monophosphate (cAMP), and by their sensitivity to inhibition by rolipram. In recent years, several selective PDE4 inhibitors have been discovered and beneficial pharmacological effects have been observed as a result of that inhibition in various disease models (see, eg, Torphy er a /. Environ, Health Perspect, 1994, 102 Suppl. 10, pp. 79-84; Duplantier et al, J. Chem., 1996m 39, p.120-125; Schneider et al., Pharmacol. Biochem. Behav., 1995, 50, p. 21-1-217; Banner and Page, Br. J. Pharmacol., 1995, 114, pp. 93-98, Barnette ef al., J. Pharmacol. Exp. Ther., 1995, 273, p 674-679; Wright et al., Can. J. Physiol Pharmacol., 1997, 75, p.1001 -1008, Manabe et al., Eur. J. Pharmacol., 1997, 332, P. 97-107 and Ukita ef al., J. Chem. 1999 , 42, p.1088-1099). Accordingly, there is still considerable interest in the art in relation to the discovery of more selective PDE4 inhibitors. Satisfactory results have already been obtained in the art with the discovery and development of selective PDE4 inhibitors. In vivo, PDE4 inhibitors reduce the influx of eosinophils into the lungs of animals provoked by allergens while also reducing bronchoconstriction and elevated bronchial response after allergen challenge. PDE4 inhibitors also suppress the activity of immune system cells (including CD4 + T lymphocytes, monocytes, mast cells and basophils), reduce pulmonary edema, inhibit excitatory non-cholinergic-non-adrenergic neurotransmission (eNANC), potentiate neurotransmission not cholinergic-non-adrenergic inhibitory (iNANC), reduce the mitogenesis in the smooth muscles of the respiratory tract and induce bronchodilation. PDE4 inhibitors also suppress the activity of several inflammatory cells associated with the pathophysiology of COPD, including monocytes / macrophages, CD4 + T lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce mitogenesis in vascular smooth muscles and potentially interfere with the ability of airway epithelial cells to generate proinflammatory ators. Through the release of acidic neutral proteases and hydrolase from their granules, and through the generation of species with reactive oxygen, neutrophils contribute to the tissue destruction associated with chronic inflammation and, moreover, are involved in the pathology of such conditions. like emphysema. Therefore, PDE4 inhibitors are particularly useful for the treatment of a high number of inflammatory, respiratory and allergic diseases, disorders or conditions, as well as for wounds and some of them are in clinical development mainly for the treatment of asthma, COPD , bronchitis and emphysema.
The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis to profile and select inhibitors for further studies. These effects include the elevation of cA P and the inhibition of superoxide production, degranulation, chemotaxis and tumor necrosis factor (TNFa) release in eosinophil, neutrophils and monocytes. As stated above, the present invention relates to PDE4 inhibitors of the family of nicotinamide derivatives. Nicotinamide derivatives having PDE4 inhibitory activity have already been synthesized. For example, Patent Application No. WO 98/45268 describes nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme. These selective PDE4D inhibitors are represented by the following formula: in which in particular myn can be equal to 1 and p can be equal to 0. A can be oxygen, can be NH, r can be equal to O, E can be O, NH or S, R5 can be a heterocyclic group ( C3-C7) cyclic or bicyclic, saturated or unsaturated, containing 1 to 4 hetero-archanes and R1 can be an aryl optionally substituted with various substituents. Also patent application No. WO 01/57036 also describes nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory, allergic and respiratory diseases and conditions, of the formula: where, in particular: n is 1 or 2, m is 0 to 2, Y is = C (RE) - or [N? (0)] -, W is -O-, S (= 0) t- or -N (R3) -, Q represents various rings, among them phenyl, Z is -OR-I2, -C (= 0) Ri2 or CN and R12 is chosen from alkyl, alkenyl, cycloalkyl, phenyl, benzyl and heterocyclic moieties monocyclic However, there is still a pressing need for additional PDE4 inhibitors that lend an improved therapeutic index, with possibly less adverse effects, such as, for example, emesis. Thus, the present invention relates to new nicotinamide derivatives of general formula (1): wherein: m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, each of Ri and R2 is a member independently selected from the group consisting of a hydrogen atom, halo, cyano, alkyl ( C C4) and alkoxy (Ci-C-4), X is -O-, -S- or -NH-, R3 is a member selected from the groups consisting of: (a) phenyl, naphthyl, heteroaryl and cycloalkyl ( C3-C8), each optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, cyano, (C1-C4) alkyl, alkoxy (CrC4), tialkyl (C4), -C (= 0) NH2, -C (= 0) NH ((C4) alkyl), hydroxy, -OC (= 0) alkyl (CrC4), -C (= 0) -0-alkyl (C4) and hydroxy-alkyl (Ci-C4), or (b) bicyclic groups that respond to one of the following structures (1.1) a (1.2) (1.3) (1.4) in which the symbol "*" indicates the point of attachment of each partial formula (1.1) to (1.4) to the remaining portion of formula (1), and is a selected member of the group formed by the partial formulas (1 .5) to (1.11): HH (1 .6) (1.7) (1.8)} (1.9) (1.10) (1.1 1) in which the symbol "*" indicates the point of union of each partial formula (1 .5) a (1.1 1) to the remaining portions -NH- of formula (1) and "**" indicates the point of union of each partial formula (1 .5) to (1 .1 1) to the remaining portions -R4 of Formula 1 ), and R4 is a member selected from the groups that consist in: (a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3 substituents, each one selected from the group formed by carboxylic acid, -C (= 0) -0- (C1-C4) alkyl, halo, cyano, -C (= 0) NH2, alkyl (CrC4), alkoxy (CVC4), haloalkyl (CrC4), hydroxy and hydroxy (C1-C4) alkyl, or (b) (C 1 -C 4) alkyl optionally substituted with a hydroxy group, carboxylic acid, C (= 0) -0-C 1 -C 4 alkyl, phenyl, naphthyl or heteroaryl, wherein said phenyl, naphthyl and heteroaryl are optionally substituted each one with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) 0 -alkyl (C4), halo, cyano, -C (= 0) NH2, (C1-C4) alkyl or alkoxy (CrC4), haloalkoxy (C C4), hydroxy and hydroxy-alkyl (C C4). or, if appropriate, its salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or pharmaceutically acceptable metabolites. It has been found that these nicotinamide derivatives are inhibitors of PDE4 isoenzymes, particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions and for the treatment of wounds, by demonstrating excellent therapeutic utility and therapeutic index. In the general formula (1) given above, halo represents a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine. The alkyl radicals (Ci-C) represent a straight or branched chain group having 1, 2, 3, or 4 carbon atoms. This also applies if they carry substituents or if they are found as substituents of other radicals, for example on alkoxy radicals (C4), thioalkyl radicals (CrC), haloalkyl radicals (CrC), hydroxy-alkyl radicals (CrC4), C-radicals. (= 0) -alkyl (Ci-C4), etc. Examples of suitable (C C4) alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl and tere-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. Examples of suitable thioalkyl radicals (CrC4) are thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, thio-n-butyl, thio-iso-butyl, thio-sec-butyl and thio-tert-butyl. Halo (C 1 -C 4) alkyl radicals are alkyl radicals substituted with halo. They may contain 1, 2,3,4,5, 6 or 7 halogen atoms, unless otherwise indicated. Said halo is preferably fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. For example, in an alkyl radical substituted with fluorine, a methyl group in the form of a trifluoromethyl group may be present. The same applies to the hydroxy-alkyl radicals (CrC4), except that they are alkyl radicals substituted with a hydroxy group (-OH). According to a preferred embodiment of said invention, such radicals contain a hydroxy substituent. Examples of suitable hydroxy (C 1 -C 4) alkyl radicals are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl. The cycloalkyl radicals (C3-C8) represent saturated monocyclic rings of 3 to 8 members. Examples of suitable (C3-C3) cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. These radicals may be optionally substituted as indicated in the definition R3. Examples of substituted (C3-C8) cycloalkyl radicals are 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 5-methylcyclohexyl, 6-methylcyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 5-hydroxycyclohexyl, 6-hydroxycyclohexyl , 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 5-fluorocyclohexyl, 6-fluorocyclohexyl, 2-methyl-3-hydroxycyclohexyl, 2-methyl-4-hydroxycyclohexyl, 2-hydroxy-4-methylcyclohexyl, etc.
In the general formula (I) given above, heteroaryl is a radical of a monocyclic or polycyclic aromatic system having 5 to 14 members in the rings, which contains 1, 2, 3, 4 or 5 heteroatom (s) depending on their number and quality of the total number of members in the rings. Examples of heteroatoms are nitrogen (N), oxygen (O) and sulfur (S) if several heteroatoms are present, these may be the same or different. The heteroaryl radicals may also be substituted, monosubstituted or polysubstituted, as indicated in the definition of R3 and R4 herein above for the general formula (1) according to the present invention, preferably, heteroaryl is a monocyclic or bicyclic aromatic radical containing 1, 2, 3 or 4 in particular 1, 2 or 3, same or different heteroatoms selected from the group consisting of N, O and S. With particular preference, heteroaryl is a monocyclic or bicyclic aromatic radical with 5 to 10 members in the rings, in particular a 5 to 6 membered monocyclic aromatic radical, containing (i) from 1 to 4 nitrogen heteroatom (s) or (i) 1 or 2 nitrogen heteroatom (s) and 1 oxygen heteroatom or 1 heteroatom of sulfur or (iü) 1 or 2 heteroatom (s) of oxygen or sulfur. Examples of suitable heteroaryl radicals are the radicals derived from pyrrole, furan, furazane, thiophene, imidazole, pyrazole, oxazole, soxazole, thiazole, isothiazole, tetrazole, triazine, pyridine, pyrrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole. , purine, naphthyridine, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline and benzene concentration derivatives with these heteroaryls, such as, for example, enzofuran, benzothiophene, benzoxazole and benzothiazole. Particularly preferred are heteroaryl radicals selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,4-triazolyl, tetrazolyl, oxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,4-oxadiazolyl, 1,3,4 -oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. The nitrogen-containing heteroaryl radicals can also be present as N-oxides or as quaternary salts. In the general formula (1) according to the present invention, when a radical is mono- or poly-substituted, said or said substituents may be located in any desired positions. Also, when a radical is polysubstituted, said substituents may be identical or different. The nicotinamide derivatives of formula (1) can be prepared using conventional procedures, such as by the following illustrative methods, wherein Ri, R2, G¾, R 4, X, Y, n and m are as defined above for the derivatives of nicotinamide of formula (1), unless otherwise indicated. The nicotinamide derivatives of formula (1) can be prepared starting from a compound of formula (2): wherein Ri, R2, X, R3, n and m are as described above for the nicotinamide derivatives of formula (1). When Y represents a group of partial formula (1.7), (1.8) or (1 .10), the compounds of formula (2) are reacted with the corresponding R4-sulfonyl chloride derivative (R4S02CI or R4NHS02CI or R4C (= 0) NHS02CI) in a suitable solvent (for example dichloromethane) and the presence of an organic base (for example triethylamine) at a temperature in the range of 0 ° C to room temperature (approximately 20 ° C). When Y represents a group of partial formula (1.5), (1.9) or (1.1 1), the compounds of formula (2) are reacted with the corresponding R4-carboxylic acid derivative (R4COOH or R4S02-NH-CH2COOH or R4C (0) NH-CH2-COOH) using an activating agent in the presence of a suitable solvent (for example dimethylformamide) and an organic base (for example N-methylmorpholine) at room temperature. Activation of the acid can be produced for example using: a) 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, b) carbonyldiimidazole, or c) oxalyl chloride and dimethylformamide (with dichloromethane as the solvent). When Y represents a group of partial formula (1.6), the compounds of formula (2) are reacted with carbonyldiimidazole in a suitable solvent (such as dichloromethane) and the obtained intermediate is reacted with an amine bearing the substituent R4.
It should be noted that when R3 and R4 in the nicotinamide derivatives of formula (1) represent phenyl rings substituted with alkoxy, these structures can be converted to the analogous hydroxy using certain deprotection conditions well known to one skilled in the art. The compounds of general formula (2) can be prepared by separating the protective group "Prot" from the compounds of general formula (3): wherein Ri, R2, X, R3 n and m are as described above for the nicotinamide derivatives of formula (1) and Prot is a suitable protecting group, including, but not limited to, a benzyl group, carbamate ( for example, tert-butyloxycarbonyl), amido (for example trifluoroacetamide) or myido (for example phthalimide, using deprotection conditions well known to those skilled in the art.) Compounds of formula (3) can be prepared as indicated in Scheme 1: wherein R1 f R2, X, R3 n, m and Prot are as previously described and R 'represents an alkyl radical (CrC4). In a typical procedure, the nicotinate ester of formula (6) can be reacted with the appropriate alcohol, thiol or amine of formula R3XH (7) in the appropriate solvent (eg, dimethylformamide or dioxane) containing a base, such as cesium carbonate, at temperatures in the range of room temperature to 100 ° C to give a compound of formula (5.1). This can be saponified with an alkali metal hydroxide to give an acid of formula (4.1) which is then converted to a compound of formula (3) by reaction with a monoprotected diamine of formula (8): using an activating agent such as any of those described in one of the aforementioned activation methods (i.e., a) 1-hydroxybenzotriazole and 1- (3-dithymethylpropyl) -3-ethylcarbodiimide hydrochloride, or b) carbonyldiimidazole or c) oxalyl chloride and dimethylformamide, with dichloromethane as the solvent). According to another alternative, the compounds of formula (3) can be prepared as indicated in Scheme 2: SCHEME 2 wherein R- ?, R2, X, R3 n, m and R 'and Prot are as defined above. In a typical procedure, the nicotinate ester of formula (6) can be hydrolyzed using an alkali metal hydroxide to give a nicotinic acid of formula (5.2), which is reacted with a monoprotected diamin of formula (8) using one of the activation methods mentioned above. The chloropyridine of formula (4.2) obtained in the preceding step can be reacted with the appropriate alcohol, thiol or amine of formula R3XH (7) in the appropriate solvent (for example dimethylformamide or dioxane) containing a base, such as carbonate of cesium at temperatures in the range of room temperature to 100 ° C. The compounds of formula (6) and (7) are either of commercial origin or can be prepared by conventional procedures well known to those skilled in the art. The monoprotected diamine of formula (8) can be prepared by reacting a large excess of a diamine of formula (9): wherein m and n are as defined above, with a suitable derivatizing agent such as di-tert-butyl dicarboxylate (to give the tert-butyloxycarbonyl derivative) at room temperature in a suitable solvent (such as dichloromethane). The compounds of formula (9) are commercially available or can be easily prepared by conventional methods well known to those skilled in the art. All the above reactions and the preparations of new starting materials that are used in the preceding methods are conventional, the reactants and reaction conditions suitable for their realization or preparation as well as the methods for isolating the desired products will be well known to those skilled in the art. technique, with reference to bibliographic precedents and to the examples and preparations included here. For some of the steps of the preparation process described above for nicotinamide derivatives of formula (1), it may be necessary to protect the potential reactive functions that you do not want them to react to. In such a case, any compatible protective radical can be used. In particular, methods such as those described by T. W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by McO IE (Protective Groups in Organic Chemistry, Plenum Press, 1973) can be used. Also, the nicotinamide derivatives of formula (1) as well as the intermediates for their preparation can be purified according to various well-known methods, such as, for example, crystallization or chromatography. According to a general aspect of the present invention, the nicotinamide derivatives of formula (1) are preferred as previously described, except for compounds for which: 1) m is different from 0 simultaneously when Y represents the partial formula ( 1.5) and R4 representing an unsubstituted (C1-C4) alkyl, 2) m equals 0 simultaneously when Y represents the partial formula (1.5) and R4 represents a phenyl, a naphthyl or heteroaryl, each of they optionally substituted with 1 to 3 substituents, independently selected from the group consisting of carboxylic acid, halo, cyano, alkyl (Ci- C4), alkoxy (Ci-C4), haloalkyl (CrC4), hydroxy and hydroxy- (Ci -C4), or R4 represents an alkyl (CrC4) optionally substituted with 1 to 3 substituents independently selected from the group consisting of carboxylic acid, halo, cyano, alkyl (Ci-C4), alkoxy (CrC4), hydroxy and hydroxy-alkyl ( C C4), and 3) m equals 0 simultaneously when Y rep represents the partial formula (1.6) and R4 represents a phenyl or a naphthyl, each of them optionally substituted with 1 to 3 substituents, independently selected from the group consisting of carboxylic acid, halo, cyano, alkyl (CrC4), alkoxy (C4) ), halo (C 4) alkyl, hydroxy and hydroxy (C 1 -C 4) alkyl. Particular preference is given to the nicotiamide derivatives of formula (1), in which:? m and n are equal to 1,? each Ri and R2 is a member independently selected from the group consisting of a hydrogen atom, halo, cyano, alkyl (C-i-C4) and alkoxy (C4),? X is -O-,? R3 is a member selected from the groups consisting of: a) phenyl, naphthyl, heteroaryl and (C3-C8) cycloalkyl, each optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, cyano , alkyl (CrC4), alkoxy (C4), thioalkyl (C4), -C (= 0) NH2, - C (= 0) NH (alkyl (CrC4)), hydroxy, -0-C (= 0) alkyl (d-C4), - C (= 0) -0-alkyl (C4) and hydroxy-alkyl (Ci-C4), or b) bicyclic groups correspond to one of the following structures (1.1) a ( 1.4): (1.2) (1.3) (1.4) where the "*" indicates the point of attachment of each partial formula (1.1) to (1 .4) to the remaining portion of formula (1),? And is a group -C (= 0) - partial formula (1.5)? and R4 is a member selected from the groups consisting of: a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) - 0-alkyl (C4), halo, cyano, -C (= 0) NH2, (C4) alkyl, alkoxy (CrC4), haloalkyl (Ci-C4), hydroxy and hydroxy (Ci-C4), ob ) (Ci-C4) alkyl substituted with a hydroxy group, carboxylic acid * C (= 0) -0-alkyl (CrC4), phenyl, naphthyl or heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) -0-alkyl (CrC4), halo, cyano, -C (= 0) NH2, alkyl (CrC4), alkoxy (C C4), haloalkyl (CrC4), hydroxy and hydroxy- (Ci-C4) alkyl, or, if appropriate, their salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or pharmaceutically acceptable metabolites thereof. More particularly preferred are the nicotinamide derivatives of formula (1), wherein: m and n are equal to 1,? each of Ri and R2 is a member independently selected from the group consisting of a hydrogen atom, halo and methyl,? X is -O-,? R3 is a phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, cyano, alkyl (C4), alkoxy (Ci-C4), thioalkyl (C1-C4), -C (= 0 ) NH2, -C (= 0) NH ((C4) alkyl), hydroxy, -0-C (= 0) - (alkyl (CrC4)) and hydroxy-alkyl (CrC4),? And is a group -C (= 0) - partial formula (1.5)? and R4 is a member selected from the groups consisting of: a) phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) -0-alkyl (CrC4), halo, cyano, -C (= 0) NH2, (C4) alkyl, alkoxy (Ci-C4), haloalkyl (CrC4), hydroxy and hydroxy-alkyl (CrC4), or b) (C1-C4) alkyl substituted with a hydroxy or a phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, halo, cyano, -C (= 0) NH2, alkyl (C4), alkoxy ( C C4), haloalkyl (Ci-C), hydroxy and hydroxy-alkyl (Ci-C4), or, if appropriate, their salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or pharmaceutically acceptable metabolites thereof . Still more particularly preferred are the nicotinamide derivatives of formula (1), wherein:? m and n are equal to 1,? R1 is a hydrogen atom or a fluoro radical and R2 is a hydrogen atom,? X is -O-,? R3 is a phenyl optionally substituted with a substituent selected from the group consisting of halo and -C (= 0) -0-alkyl (CrC4),? And it is a group -C (= 0) - of partial formula (1.5); ? and R4 is a member selected from the groups consisting of: a) phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, (Ci-C4) alkyl and hydroxy, or b) alkyl (Ci-C4) ) substituted with a hydroxy or a phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, (C 4) alkyl and hydroxy, or, if appropriate, its salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or pharmaceutically acceptable metabolites thereof. Particularly preferred nicotinamide derivatives of formula (I) are those described in the Examples section hereinafter, ie: 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-3-methylbenzoylamino) methyl] benzyl} -nicotinamide, 3- (3 { 4 - [(3-hydroxybenzoylamino) methyl] benzyl} -nicotinamide, 2- (4-fluorophenoxy) -N-. {4 - [(6) ethyl ester) -fluoro-2-hydroxybenzoylamino) methyl] benzyl.} - nicotinamide, 2- (4-fluorophenoxy) -N- { 4 - [(5-fluoro-2-hydroxybenzoylamino) methyl] benzyl.} - nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(3-hydroxy-4-methylbenzoylamino) methyl] benzyl} -n¡cotinamida, 2- (4-fluorophenoxy) -N-. { 4 - [(3-hydroxy-benzoylamino) meth] benzyl} nicotinamide 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxybenzoylamino) methyl] benzyl} nitrocarrier, 2- (4-fluorophenoxy) -N-. { 4 - [(4-hydroxybenzoylamino) meth] benzyl} n¡cotnamnam, 2- (4-fluorophenoxy) -N-. { 4 - [(2-Hydroxy-4-methyl-benzolamyl) methyl] benzyl} -nicotnamide, 2- (4-fluorophenoxy) -N-. { 4 - [(3-Hydroxy-2-methylbenzoylamino) methy1] benzyl} -nicotinamida, 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-5-methyl-benzoylamino) meth] benzyl} -n¡cotinamida, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(2-Hydroxybenzoylamino) methyl] benzyl} -n¡cotinamida, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-acetylamino) methyl] benzyl} -n¡cotinamide, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(4-Hydroxybenzolamino) methyl] benzyl} -nicotnamnam, 3- (3. {4 - [(3-hydroxybenzoylamino) methyl] benzylcarbamoyl}. - pindin-2-yloxy) benzoic acid ethyl ester, 3- (3-ethyl) ethyl ester - { 4 - [(2-hydroxyphenylacetylamino) methyl] benzylcarbamoyl.} Pindin-2-yloxy) benzoic acid, 3- (3. {4 - [(3-hydroxyphenylacetylamino) methyl) ethyl ester l] benzylcarbamoyl, pyridin-2-yloxy) benzoic acid, 3- (3. {4 - [(4-hydroxy-phenylacetylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) benzoic acid ethyl ester The nicotinamide derivatives of formula (1) can also be optionally transformed into pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the nicotinamide derivatives of formula (1) include their acid addition salts and their base salts. Suitable salts of acid addition are formed from non-toxic, mineral or organic acids, which form non-toxic salts. Suitable examples of these acid addition salts are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. Suitable base salts are formed from bases, which form non-toxic salts, such as alkali metal salts, earth metal salts or addition salts with ammonia and physiologically tolerable organic amines. Suitable examples of base salts are sodium, potassium, aluminum, calcium, magnesium, zinc or ammonium salts, as well as addition salts with triethylamine, ethanolamine, diethanolamine, benzylamine, dicyclohexylamine, N-benzyl-p-phenethylamine. , N, N'-dibenzylethylenediamine, diphenylenediamine, quinine, choline, arginine, lysine, leucine, dibenzylamine, tris (2-hydroxyethyl) amine or, a, a-tris (hydroxymethyl) methylamine. The compounds containing both acid groups and basic groups can be presented as internal salts or betaines, which are also included in the present invention. For an in-depth look at suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, p.1-19. Generally salts can be obtained from the nicotinamide derivatives of formula (1) according to conventional procedures well known to those skilled in the art, for example, by combining them with an organic or inorganic acid or basic solvent or dispersant, or alternatively from other salts by anion exchange or cation exchange. The salt can precipitate in the solution and be collected by filtration or can be recovered by evaporation of the solvent. The nicotinamide derivatives of formula (1) can also be present as stereoisomeric forms. If the nicotinamide derivatives of formula (1) contain one or more centers of asymmetry, these, independently of one another, may have configuration (S) or configuration (R). The invention includes all possible stereoisomers of the nicotinamide derivatives of formula (1), for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example, mixtures of enantiomers and / or diastereomers, in all proportions. Thus, the invention relates to enantiomerically pure enantiomers, both levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in any proportion. Also, the invention relates to diastereomers in diastereomerically pure form and in the form of mixtures in all proportions. In the presence of cis / trans isomerism, the invention relates both to the cis form and to the trans form and to the mixtures of these forms in any proportion. If desired, individual stereoisomers can be prepared by making use of stereochemically homogeneous starting materials in the synthesis, by stereoselective synthesis or by separation of a mixture according to conventional methods, for example by chromatography, crystallization or chromatography on chiral phases. If appropriate, derivation can be carried out before the separation of stereoisomers. A mixture of stereoisomers can be separated in the phase of nicotinamide derivatives of formula (1) or in the phase of a starting substance or of an intermediate in the course of the synthesis. The compounds of formula (1) according to the invention can also contain mobile hydrogen atoms, ie they are present in various tautomeric forms. The present invention also relates to all tautomers of the compounds of formula (1). The present invention further includes other types of derivatives of the nicotinamide derivatives of formula (1), for example, solvates such as hydrates and polymorphs, ie, the various crystalline structures different from the nicotinamide derivatives according to the present invention. The present invention also includes all suitable isotopic variations of the nicotinamide derivatives of formula (1) or a pharmaceutically acceptable salt thereof. An isotopic variation of the nicotinamide derivatives of formula (1) or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number for an atomic mass different from the mass Atomic found habitually in nature. Examples of isotopes that can be incorporated into the nicotinamide derivatives of formula (1) and their pharmaceutically acceptable salts include the isotopes of hydrogen, carbon, nitrogen, oxygen, nitrogen, oxygen, sulfur, fluorine and chlorine such as 2H, 3H, 13C. , 14C, 15N, 170, 180, 35S, 18F and 36CI, respectively. Certain isotopic variations of the nicotinamide derivatives of formula (I) and their pharmaceutically acceptable salts, for example those in which a radioactive group such as 3H or 14C are incorporated, are useful in studies of drug distribution and / or tissue substrates. tritium, that is, 3H, and carbon 14, that is, 14C, are isotopes particularly preferred for their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium, i.e., 2H, can give certain therapeutic advantages resulting from their greater metabolic stability, for example, an increase in in vivo half-life or a duration in dosing needs, so it may be preferred give some circumstances. The isotopic variations of the nicotinamide derivatives of formula (1) and their pharmaceutically acceptable salts of this invention can be prepared generally by conventional methods such as the illustrative methods or preparations described in the examples and preparation sections hereinafter, using the appropriate isotopic variations of suitable reagents. If appropriate, the present invention also relates to the active metabolites derived from nicotinamide of formula (1), i.e., which are formed during cellular metabolism and which are active in the organism. For example, such metabolites may be glucuronide derivatives, N-oxide derivatives of sulfonate derivatives of the compounds of formula (1). According to an additional aspect, the present invention relates to mixtures of nicotinamide derivatives of formula (1), as well as mixtures with or of their salts, solvates, polymorphs, isomeric forms, metabolites and / or pharmaceutically acceptable isotopic forms. According to the present invention, all the forms mentioned hereinabove of the nicotinamide derivatives of formula (1), except pharmaceutically acceptable salts (ie, said solvates, polymorphs, isomeric forms, tautomers, metabolites and isotopic forms) are defined in the following (including the claims) as "derivative forms" of the nicotinamide derivatives of formula (1). The nicotinamide derivatives of formula (1), their salts and / or pharmaceutically acceptable derivative forms are valuable pharmaceutical active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which PDE4 enzymes are implicated, in particular the disorders inflammatory, allergic disorders, respiratory diseases and injuries. The nicotinamide derivatives of formula (1) and their pharmaceutically acceptable derivative forms, 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 may be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral (gastric) or parenteral (non-gastric) administration and which contain as an active constituent an effective dose of at least one nicotinamide derivative of the formula (1), its salts and / or pharmaceutically acceptable derivative forms, in addition to conventional excipients and / or pharmaceutically innocuous additives. Thus, the present invention also relates to compositions containing a nicotinamide derivative of formula (1), and / or its pharmaceutically acceptable salts and / or forms, together with conventional and pharmaceutically innocuous excipients and / or additives. Such compositions are prepared according to well-known methods and compatible with classical pharmaceutical practice. In general, said compositions contain from 0.5% to 60% by weight of the active compound and from 40% to 99.5% by weight of excipients and / or additives. In accordance with the present invention, said excipients and / or additives are agents well known to those skilled in the art to impart favorable properties to the final pharmaceutical composition. Typical excipients and / or additives include, but are not limited to, acidifying and alkalizing agents, aerosol propellants, antimicrobial agents (including antibacterial, antifungal and antiprotozoal agents), antioxidants, pH regulating agents, agents chelators, dermatologically active agents, dispersing agents, suspending agents, emollients, emulsifying agents, penetration enhancers, preservatives, sequestering agents, solvents, stabilizers, reinforcing agents, sugars, surfactants and flavorings. Moreover, said compositions are prepared in a compatible manner for the proposed route of administration, which is used for any given patient, as well as appropriate for the disease, disorder or condition of which a particular patient is being treated. Suitable routes of administration that may be considered are parenteral and parenteral routes of administration, such as, for example, topical, oral, intranasal, pulmonary, rectal, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intratraumatic, intrasternal routes, intramuscular, subcutaneous or ocular. When administration by oral route is proposed, the nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and / or derivative forms can be administered in the form of tablets, capsules, multiparticles, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for applications of immediate, delayed, modified, continuous, pulsed or controlled release. The nicotinamide derivatives of formula (1), their salts and / or pharmaceutically acceptable derivative forms can also be administered as rapidly dispersing or dissolving dosage forms, or in the form of a high energy dispersion or as coated particles. Suitable formulations of the nicotinamide derivatives of formula (1), their salts and / or pharmaceutically acceptable derivative forms may be in coated or uncoated form, as desired. Such solid pharmaceutical compositions, e.g., tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, phosphate, calcium dibasic, calcium phosphate dibasic, glycine and starch (preferably corn starch, potato or tapioca), disintegrants such as sodium salt of croscarmellose sodium starch glycolate and certain complex silicates and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and gum arabic. Additionally, lubricating agents may be included such as magnesium stearate, stearic acid, glyceride behenate and talc. As a general example, a formulation of the tablet could typically contain between about 0.01 mg and 500 mg of active compound while the weights of excipients in the tablet can range from 50 mg to 1,000 mg. The tablets can be manufactured by a conventional method, for example by direct pressing or by a dry or wet granulation process. The cores of the tablets can be coated with appropriate coatings. Solid compositions of a similar type can also be employed as gelatin capsule fillers or HPMC. Preferred excipients in connection therewith include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable derivative forms can be combined with various sweetening or flavoring agents, coloring matters or dyes, with emulsifying agents and / or suspensors and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. The nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable derivative forms can also be administered by injection, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly. or subcutaneous, or can be administered by infusion or needleless injection techniques. For such administration, it is best to use them in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose in sufficient quantity to make the solution isotonic with the blood. The aqueous solutions should be suitably buffered (preferably at a pH of 3 to 9) if necessary. The preparation of such formulations under sterile conditions is easily carried out by classical pharmaceutical techniques well known to those skilled in the art. Both for oral administration and for injection to human patients, the daily dosage level of the nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable derivative forms, will usually be from 0.001 mg / kg to 100 mg / kg. (in individual or fractional doses). The nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and / or their derivative forms can also be administered intranasally or by inhalation and conveniently delivered in a dry powder inhaler or aerosol presentation form in a pressurized container, pump, sprayer, atomizer or nebulizer, with or without the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1-tetrafluoroethane (HFA 134A [trademark] or 1, 1, 2,3,3) , 3-heptafluoropropane (HFA 227EA [trademark], carbon dioxide or other suitable gas.) In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to discharge a measured quantity. Sprayer, atomizer or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol and propellant as solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. example, made of gelatin), for use in an inhaler or inhaler containing a powder mixture of a nicotinamide derivative of formula (1) and a suitable powder base such as lacto sa or starch. The aerosol or dry powder formulations are preferably arranged so that each measured dose or "aspirated amount" contains from 1 μg to 4000 μg of a nicotinamide derivative of formula (1) for delivery to the patient. The total daily dose with an aerosol will be in the range of 1 μg to 20 mg, which can be delivered in a single dose, or more usually, in divided doses throughout the day. The nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable derivative forms can also be administered topically or transdermally, in the form of creams, gels, suspensions, lotions, ointments, dusting powders, sprays, foams, creams, apposites with the incorporated drug, solutions, sponges, microemulsifying fibers, films, patches, cutaneous, ointments such as vaseline or soft paraffin-based ointments or by means of a skin patch or other device. Penetration enhancers can be used and the compound can be used in combination with cyclodextrins. In addition, the compound can be released using iontophoresis, electroporation, phonophoresis or sonophoresis, they could be administered directly at the site of a wound. They could be incorporated in a coated suture. For example, they can be incorporated into a lotion or cream consisting of an aqueous or oily emulsion of mineral oils, sorbitan monostearate, polysorbate 60, cetyl esters, cereille alcohol, 2-octyldodecanol, benzyl alcohol, water, polyethylene glycols and / or liquid paraffin, or can be incorporated into a suitable ointment consisting of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compound, emulsifying wax and water, or in the form of a hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers, or as a dry powder or liquid spray or aerosol with butane / propane, HFA, CFC, C02 or other suitable propellant, which optionally also includes a lubricant such as sorbitan trioleate, or in the form of a drug dressing incorporated, that is, as a tulle dressing, with water dressings impregnated with white soft paraffin or polyethylene licoles or with hydrogel, hydrocolloid, alginate or film dressings. For topical administration to human patients with acute / surgical or scarred wounds, the daily dosage level of the compounds, in suspension or other formulation, could be from 0.01 to 50 mg / ml, preferably from 0.3 to 30 mg / ml. The dosage will vary with the size of the wound, regardless of whether it is an open wound, closed or partially closed, and whether the skin is intact or not. Alternatively, the nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable forms can be administered rectally, for example, in the form of a suppository of a gel, other forms can be considered. They can also be administered by the ocular route, in particular for ocular healing. For ophthalmic use, the compounds can be formulated as micronized suspensions in sterile, buffered and isotonic saline, or preferably as solutions in sterile, buffered and isotonic saline, optionally in combination with a preservative such as benzylalkonium chloride. Alternatively, they can be formulated into an ointment such as petrolatum. The various pharmaceutical formulations described hereinbefore are also detailed in "Pharmacie galenique" by A. Lehir (ed. Mason, 1992, 2nd edition). In any case, the doctor will determine the actual dosage that will be most suitable for any individual patient and will vary with the patient's age, weight, health status and sex, as well as the severity of the disease, disorder or condition. in question, the optional combination with other treatment (s), the response of the particular patient and, in general, any peculiar factor of the disease, disorder or condition in question and the patient. Thus, in a daily dose for men it may normally contain from 50 mg to 5 g of active compound for administration one or two or more times in a period, whichever is appropriate. Of course, there may be individual cases where higher or lower dosage ranges are needed, and they are also within the scope of the invention.
According to the present invention, the nicotinamide derivatives of formula (1), their salts and / or their pharmaceutically acceptable derivative forms can also be used in combination with a cyclodextrin. It is known that cyclodextrins form inclusion and non-inclusion complexes with drug molecules. The formation of a drug-cyclodextrin complex can modify the properties of solubility, dissolution rate, bioavailability and / or stability of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizer. The α-, β-, and β-cyclodextrins are those most commonly used and suitable examples can be found in WO-A-91/11172, WO-A-94/02518 and WO-A-98/551 8. According to another embodiment of the present invention, the nicotinamide derivatives of formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, can also be used as a combination with one or more additional therapeutic agents that must be coadministered to a patient to obtain some particularly desired therapeutic end result. The second and subsequent additional therapeutic agents can also be nicotinamide derivatives of formula (1), or their salts, formed derivatives or pharmaceutically acceptable compositions thereof, or one or more PDE4 inhibitors known in the art. More particularly, the second and subsequent therapeutic agents will be chosen from a different class of therapeutic agents. In the sense in which they are used herein, the terms "co-administration" and "in combination with", when referring to the nicotinamide derivatives of formula (1) and one or more other therapeutic agents, are intended to mean and refer to they include the following: • simultaneous administration of such nicotinamide derivative (s) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases said components essentially at same time to said patient, • essentially 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 one another in separate dosage forms that are administered to the patient substantially at the same time, whereby said components are released essentially at the same time in 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 in separate dosage forms that are administered to the patient at consecutive times with an appreciable time interval between each administration, whereby said components are released at essentially different times in said patient; and • 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 together in a single dosage form that releases said components in a manner controlled, with which they are administered simultaneously, consecutively and / or underhand at the same time and / or at different times to said patient. Suitable examples of other therapeutic agents that can be used in combination with the nicotinamide derivatives of formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, include, but are not limited to: (a) 5-lipoxygenase inhibitors (5-LO) or protein antagonists that activate 5-lipoxygenase (FLAP), (b) leukotriene antagonists (LTRA), including LTB4, LTC4, LTD4 and LTE4 antagonists. (c) histamine receptor antagonists, including H1 and H3 antagonists, (d) vasoconstrictor sympathomimetic agents such as a2 and a2 adrenergic receptor agonists for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents, ( f) β2 adrenergic receptor agonists, (g) theophylline, (h) sodium cromoglycate, (i) COX-1 inhibitors (NSAIDs) and selective inhibitors of COX-2, (j) oral or ihnalated glucocorticosteroids, (k) monoclonal antibodies active against endogenous inflammatory entities, (I) anti-tumor necrosis factor agents (anti-TNF-a), (m) inhibitors of the molecules of adhesion, including VLA-4 antagonists, (n) Kinetic Bi and B2 receptor antagonists, (or) immunosuppressive agents, (p) matrix metalloprotease inhibitors (MMPs), (q) receptor antagonists? ?? , NK2 and NK3, (r) elastase inhibitors, A2a adenosine receptor agonists, and (t) urokinase inhibitors, (u) compounds that act as dopamine receptors, p. Eg, D2 agonists, and (v) modulators of the NF route «P, p. eg, IKK inhibitors. According to the present invention, the combination of the nicotinamide derivatives of formula (1) with: muscarinic M3 receptor agonists or anticholinergic agents, including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, parenzepine and telenzepine - β2 adrenergic receptor agonists including albutarol, salbutamol, formoterol and salmeterol, glucocorticosteroids, in particular glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone-acetonide , beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate - or A2a adenosine receptor agonists. It will be appreciated that all references to treatment made here include curative, polylative and prophylactic treatments. The description now refers to the therapeutic applications that the nicotinamide derivatives of formula (1) may have. The nicotinamide derivatives of formula (1) inhibit the PDE4 isozyme, so they have a wide range of therapeutic applications, as described hereinafter, due to the essential role played by the PDE4 family of isozymes in the physiology of all animals. mammals The enzymatic role performed by the PDE4 isozymes is the intracellular hydrolysis of 3'-5'-adenosine monophosphate (cAMP) within the pro-inflammatory leukocytes. In turn, cAMP is responsible for measuring the effects of numerous hormones in the body and, as a consequence, the inhibition of PDE4 plays a significant role in a wide range of physiological processes. There is a lot of literature in the state of the art that describes the effects of PDE inhibitors on the various responses of inflammatory cells that, in addition to the increase in cAMP, include the inhibition of superoxide production, degranulation, chemotaxis and factor release. of tumor necrosis (TNF) in eosinophils, neutrophils and monocytes. Therefore, a further aspect of the present invention relates to the nicotinamide derivatives of formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for use in the treatment of diseases, disorders and conditions in which they are involved the isozymes of PDE4. More specifically, the present invention also relates to the nicotinamide derivatives of formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for use in the treatment of diseases, disorders and conditions selected from the group consisting of: Asthma of any type, etiology or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, bronchial asthma atopia mediated by IgE, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused due to pathophysiological alterations, extrinsic caused by environmental factors, essential asthma unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial infection, fungal, protozoic or viral, nonallergic asthma, incipient asthma and infantile dyspnoea syndrome, water or chronic bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema. obstructive or inflammatory diseases of the respiratory tract, whichever member is selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated with it, COPD characterized due to progressive and irreversible obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS) and exacerbation of airway hyperreactivity as a result of other pharmacotherapy, pneumoconiosis of any type, ethylogy or pathogenesis, in particular pneumoconiosis which is a selected member of the group formed by aluminosis or illness of the workers of bauxite, anthracosis or asthma of the miners, asbestosis or asthma of water vapor adjuster workers, calicosis or disease caused by flint dust, ptilosis caused by inhalation of dust from the feathers of ostrich, sinderosis caused by inhalation n of iron particles, silicosis or disease of milling workers, byssinosis or iron asthma, silicosis or disease of milling workers, byssinosis or asthma by cotton dust and talcum 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, pseudomembranous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus and streptococcus and gallbladder bronchitis, bronchiectasis of any kind, allergy or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindrical bronchiectasis, bronchiectasis sacculate, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis, seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of any type, ethylogy or pathogenesis, in particular sinusitis which is a member selected from the group consisting of purulent or non-purulent sinusitis, acute or chronic sinusitis and ethmoid sinusitis front to the maxillary or sphenoid, rheumatoid arthritis of any kind, ethyogy or pathogenesis, in particular rheumatoid arthritis which is a member selected from the group consisting of acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, arthritis proliferative, psoriatic arthritis and vertebral arthritis, gout and fever and pain associated with inflammation, a disorder related to eosinophils of any type, ethylogy or pathogenesis, in particular an eosinophil-related disorder which is a member selected from the group consisting of eosinophilia, eosinophilia pulmonary infiltration, Loffler's syndrome, eosinophilic pneumonia chronic, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, granulomas containing eosinophils that, allergic granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotizing vasculitis, dermatitis aTOP ica, allergic dermatitis, contact dermatitis or allergic or atopic eczema, urticaria of any kind, etiology or pathogenesis, in particular urticaria which is a member selected from the group formed by immune urticaria, complement-mediated urticaria, urticaria by urticariogenic material, urticaria induced by physical agents, stress-induced urticaria, idiopathic urticaria, water urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal or acquired form, contact urticaria, giant urticaria and popular urticaria, conjunctivitis of any type 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 otherw ier 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, iritis, 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 autoimmune disease / inflammatory 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, granulomatosis Wegner, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, malabsorption syndrome, autoimmune inflammatory bowel diseases, ulcerative colitis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, pneumonitis with chronic hypersensitivity, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type I, dry keratoconjunctivitis, epidermal keratoconjunctivitis, pulmonary fibrosis diffuse interstitial or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idophatic nephrotic syndrome, nephropathy with minimal change, inflammatory / hyperproliferative skin diseases, benign familial pemphigus, pemphigus erythematosus, pemphigus foliaceus and pemphigus vulgarity, prevention of the rejection of halogic grafts after organ transplantation, inflammatory bowel disease (IBD) of any kind, etiology or pathogenesis, in particular inflammatory bowel disease that is a sele of the group consisting of collagenous colitis, politis colitis, transmural colitis, polypost colitis, transmural colitis, ulcerative colitis and Crohn's disease (CD), septic shock of any kind, etiology or pathogenesis, in particular septic shock which is a selected member of the group formed by renal failure, acute renal failure, cachexia, malarial cachexia, hypophysical cachexia, uraemic cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancer cachexia and cachexia as consequences of infection by the human immunodeficiency virus (HIV), disease hepatic, pulmonary hypertension of any kind, ethylogy 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 hypertension pulmonary hypoxia, diseases of bone loss, primary osteoporosis and secondary osteoporosis, diseases of the central nervous system of any kind, etiology or pathogenesis, in particular a disorder of the central nervous system that is a member selected from the group consisting of depression, Alzheimer's disease, Parkinson's disease, impaired learning and memory capacity, tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany Huntingston's chorea, Wilson's disease, agitans paralysis and thalamic atrophies, infection, especially virus infection wherein such viruses increase the production of TNF-a in their host, or where such viruses are sensitive to upregulation of TNF-a in their host so that their replication or other vital activities are influenced adversely, including a virus that is a selected member of the trained group or for HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and Herpes-viruses including Herpes zoster and Herpes simplex, yeast and yeast infections where said fungi and yeasts are sensitive to regulation in promotion by TNF-a or incite the production of TNF-a in its host, for example fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic infections by fungi and yeasts, including but not limited to, polymyxins, eg, polymycin B, imidazoles, eg, clotrimazole, econazole, miconazole and ketoconazole, triazoles, eg, fluconazole and itranazole as well as amphotericins, eg, amphotericin B and amphotericin B liposomal , ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infections, lupus erythematosus, kidney and ureter disease, urogenital disorders and gastroin testicles and prosthetic diseases, reduction of scar formation in the human or animal body, such as the formation of scars when healing acute wounds, and psoriasis, other dermatological and cosmetic uses, including antiphlogistic activities, skin softeners and to increase the moisture and elasticity of the skin. Yet another aspect of the present invention also relates to the use of the nicotinamide derivatives of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, for the manufacture of a drug with a PDE4 inhibitory activity. In particular, the present invention relates to the use of the nicotinamide derivatives of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, for the manufacture of a drug derived forms or compositions thereof, for the manufacture of a drug for the treatment of inflammatory, respiratory, allergic and scarring diseases, disorders and conditions, and more precisely for the treatment of the diseases, disorders and conditions that have been listed above. Accordingly, the present invention provides a particularly insting method for the treatment of a mammal, including a human, which includes treating said mammal with an effective amount of a nicotinamide derivative of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof. More specifically, the present invention provides a particularly insting method of treating a mammal, including a human, to treat an inflammatory, respiratory, allergic and scarring disease, disorder or condition, including treatment of said mammal with a effective amount of a nicotinamide derivative of formula (1), its salts and / or pharmaceutically acceptable derivative forms. The following examples illustrate the preparation of the nicotinamide derivatives of formula (1).
EXAMPLE 1 2- (4-fluorophenoxy) -N- (4 (2-hydroxy-3-methylbenzylamino) methylbenzyl-nicotinamide A solution of 2-hydroxy-3-methylbenzoic acid (18 mg, 0.773 mmol), 1-hydroxybenzotriazole (157 mg, 1.16 mmol), 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmole), N- (4-aminomethyl-benzyl) -5-fluoro-2- (4-fluorogenoxy) nicotinamide hydrochloride (300 mg, 0.773 mmol) (see preparation 3) and N-methylmorpholine (0.17 ml, 1.55 moles) in N, N-dimethylformamide (6 ml) was stirred under nitrogen at room temperature for 18 hours. The mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulfate. Then the solvent was removed in vacuo and the residue was triturated with diethyl ether (3 times, 10 ml) to give 2- (4-dlfuorphenoxy) -N-. { 4-. { (2-hydroxy-3-methylbenzolamine) methyl] -benzyl} nitricamide (80 mg) as a whitish foam. H NMR (300 MHz, DMSO-d6): d 13.1 1 (1 H, s), 8.32-8.42 (1 H, m), 8.15-8.21 (1 H, m), 8.08-8.14 (1 H, d) , 7.66-7.75 (1 H, m), 7.10-7.60 (10H, m), 6.73-6.81 (1 H, t), 4.37-4.56 (4H, m), 2.16 (3H, s) ppm. LRMS (thermospray): m / z [M + H] + 486, [M + NH 4] + 503.
EXAMPLES 2-13 The compounds of the following tabulated examples (Table 1) of the general formula: were separated by a method similar to that of Example 1 using the appropriate amine and carboxylic acid as starting materials.
TABLE 1 1 The organic phase was washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate in the operating procedure. 2 The compound was purified by flash column chromatography on silica gel eluting with a solvent gradient of pentane: ethyl acetate (95: 5 changing to 70:30 by volume).
EXAMPLE 2 1 H NMR (300 MHz, DMSO-d 6): d = 11.28 (1 H, s), 8.73-8.85 (1 H, m), 8.10-8.22 (2 H, m), 7.16-7.36 (10 H, m), 6.63 -6.76 (2H, m), 4.47-4.56 (2H, d), 4.40-4.46 (2H, d), ppm. LRMS (thermospray): m / z [M + H] + 490, [M + NH 4] + 507.
EXAMPLE 3 1 H NMR (300 MHz, DMSO-d 6): d = 12.20 (1 H, s), 9.23-9.11 (1 H, m), 8.83-8.92 (1 H, m), 8.17-8.21 (1 H, m) , 8.10-8.15 (2H, m), 7.67-7.75 (1H, m), 7.18-7.33 (10H, m), 6.86-6.96 (2H, m), 4.42-4-51 (4H, m) ppm. LRMS (thermospray): m / z [M + H] + 490, [M + NH 4] + 507.
EXAMPLE 4 1 H NMR (300 MHz, DMSO-d 6): d = 9.46 (1 H, s), 8.83-8.92 (1 H, t), 8.75-8.82 (1 H, t), 8.16-8.20 (1 H, d) , 8.09-8.14 (1H, d), 7.15-7.32 (11H, m), 7.06-7.14 (1H, d), 4.43-4.51 (2H, d), 4.34-4.42 (2H, d) , 2.13 (3H, s) ppm. LRMS (thermopulverization): m / z [M + H] + 486, [M + NH 4f 503.
EXAMPLE 5 1 H NMR (300 MHz, CDCl 3): d = 8.54-8.61 (1 H, d), 8.23-8.32 (1 H, m), 8.17-8.23 (1 H, m), 7.61-7.80 (1 H, m) , 7.35-7.40 (2H, m), 7.02-7.30 (9H, d), 6.90-7.00 (1H, m), 6.70-6.78 (1H, m), 4.60-4.70 (2H, d), 4.48- 4.59 (2H, d) ppm. LRMS (thermopulverization): m / z [M + H] + 472, [M + NH 4] + 489.
EXAMPLE 6 H NMR (300 MHz, CDCl 3): d = 12.02-12.50 (1 H, broad s), 8.53-8.70 (1 H, broad s), 8.10-8.26 (2 H, broad s), 6.92-7.50 (12H, m ), 6.63-6.88 (2H, m), 4.56-4.77 (4H, 2 xm) ppm. LRMS (thermopulverization): m / z [M + H] + 472, [M + NH 4] + 489.
EXAMPLE 7 H NMR (300 MHz, DMSO-d6): d = 9.93 (1H, s), 8.84-8.91 (1H, t), 8.68-8.76 (1H, t), 8.17-8.21 (1H, m), 8.10-8.15 (1H, d), 7.69-7.76 (2H, d), 7.18-7.33 (9H, m), 6.74-6.81 (2H, d), 4.44-4.52 (2H, d), 7.37-4.43 (2H, d) ppm. LRMS (thermospray): m / z [M + H] + 472, [M + NH 4] +489.
EXAMPLE 8 H NMR (300 MHz, DMSO-d6): d = 12.45.-12.60 (1H, broad s), 9. 17-9.25 (1H, t), 8.84-8.92 (1H, t), 8.16-8.20 (1H, d), 8.09-8.14 (1H, d), 7.72-7.78 (1H, d), 7.16-7.34 (9H , m), 6.67-6.73 (2H, m), 4.40-4.58 (4H, 2xd) .2.25 (3H, s) ppm. LRMS (thermospray): m / z [M + H] + 486, [M + NH 4] + 503.
EXAMPLE 9 H NMR (300 MHz, DMSO-d6): d = 9.43 (1H, s), 8.87-8.96 (1H, t), 8.60-8.67 (1H, t), 8.16-8.21 (1H, d), 8.10-8.15 (1H, d), 7.28-7.34 (1H, d), 7.20-7.28 (8H, m), 6.96-7.03 (H, t), 6.80-6.86 (1H, d), 6.73-6.77 (1H, d) .4.47-4.54 (2H, d), 4.34-4.40 (2H, d), 2.07 (3H, s) ppm. LRMS (thermospray): m / z [M + H] + 486, [M + NH 4] + 503.
EXAMPLE 10 1 H NMR (300 MHz, DMSO-d 6): d = 12.23 (1 H, s), 9.18-9.26 (1 H, t), 8.82-8.92 (1 H, t), 8.15-8.20 (1 H, d) , 8.10-8.15 (1 H, d), 7.69 (1 H, s), 7.15-7.34 (10H, m), 6.77-6.81 (1 H, d), 4.42-4.54 (4H, 2xd), 2.20 (3H , s) ppm. LRMS (thermospray): m / z [M + H] + 486, [M + NH 4] + 503.
EXAMPLE 11 1 H NMR (400 MHz, DMSO-d 6): d = 9.24-9.31 (1 H, m), 8.92-9.00 (1 H, m), 8.18-8.20 (1 H, d), 8.02-8.07 (1 H, dd), 7.83-7.87 (1 H, d), 7.35-7.40 (1 H, t), 7.18-7.35 (8H, m), 6.83-6.92 (2H, t), 4.42-4.56 (4H, m) ppm. LRMS (electrospray): m / z [M + Naf 512, [M-N] + 488.
EXAMPLE 12 1 H NMR (400 MHz, DMSO-d 6): d = 8.93-9.00 (1 H, m), 8.13-8.22 (2H, m), 8.02-8.08 (1 H, m), 7.14-7.27 (8H, m) , 5.38-5.43 (1 H, t), 4.43-4.51 (2H, d), 4.21-4.27 (2H, d), 3.79-3.84 (2H, d) ppm. LRMS (electrospray): m / z [M-H] + 426.
EXAMPLE 13 1 H NMR (400 MHz, DMSO-d 6): d = 9.89 (1 H, s), 8.90-8.98 (1 H, t), 8.64-8.73 (1 H, t), 8.19-8.21 (1 H, d) , 8.02-8.06 (1H, dd), 7.70-7.77 (2H, d), 7.24-7.30 (2H, d), 7.17-7.23 (6H, d), 6.73-6.79 (2H, d), 4.42-4.48 (2H, d), 4.36-4.40 (2H, d) ppm. LRMS (electrospray): m / z [M + Na] + 512, [M-H] + 488.
EXAMPLE 14 Ethyl 3- (3-4-f- (3-hydroxybenzoylamino) methylenebenzylcarbamoyl) pyridin-2-yloxy) benzoic acid ethyl ester 3-Hydroxybenzoic acid (27 mg, 0.19 mmol), 1-hydroxy-benzotriazole (31 mg, 0.23 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (45 mg, 0.23 mmol) were added. ) to a solution of 3- [3- (4-aminomethylbenzylcarbamoyl (pyridin-2-yloxy) benzoic acid ethyl ester hydrochloride (100 mg, 0.19 mmol) (see preparation 9) and N-methylmorpholine ( 0.11 ml, 0.97 mmol) in N, N-dimethylformamide (15 ml) The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and Water (20 ml) The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, then the residue was purified by flash column on silica gel eluting with a solvent gradient of dichloromethane: methanol (99: 1 changing to 98: 1 in volume) giving ethyl ester of 3- (3-. { 4 - [(3-hydroxybenzoylamino) methyl] benzylcarbamoyl} pyridin-2-yloxy) -benzoic acid (45 mg) as a whitish foam. HNR (400 MHz, CDCl 3): d = 8.54-8.60 (1 H, d), 8.21-8.38 (2 H, broad t + s), 8.17-8.20 (1 H, d), 7.86-7.92 (1 H, d ), 7.78 (1 H, s), 7.41-7.48 (1 H, t), 7.28-7.37 (2H, m), 7.08-7.26 (6H, m), 6.86-6.95 (2H, m), 4.61 -4.67 (2H, d), 4.45-4.53 (2H, d), 4.30-4.37 (2H, quartet), 1.31-1.38 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 526, [M + Na] + 548, [M-H] + 524.
EXAMPLES 15-18 The compounds of the following tabulated examples (table 2) of the general formula: were prepared by a method similar to that of Example 14 using the appropriate carboxylic acid as the starting material TABLE 2 EXAMPLE 15 1 H NMR (400 MHz, CDCl 3): d = 8.90-9.10 (1 H, broad s), 8.49-8.53 (1 H, d), 8.28-8.34 (1 H, m), 8.13-8.16 (1 H, d ), 7.87-7.92 (1 H, d), 7.77 (1 H, s), 7.53-7.59 (2 H, d), 7.40-7.47 (1 H, t), 7.28-7.33 (1 H, m), 7.14 -7.26 (5H, m, partially masked by the solvent), 7.08-7.13 (1H, t), 6.75-6.81 (1H, t), 6.66-6.73 (2H, d), 4.58-4.66 (2H, d ), 4.46-4.52 (2H, d), 4.28-4.34 (2H, quartet), 1 .31-1.38 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 526, [M + Na] + 548, [M-Hf 524.
EXAMPLE 16 1 H NMR (400 MHz, CDCl 3): d = 9.61 (1H, s), 8.54-8.60 (1H, d), 8.14-8.21 (2H, m), 7.91-7.96 (1H, d), 7.72-7.74 (1H m), 7.43-7.49 (1H, t), 7.29-7.33 (1H, d), 7.19-7.24 (2H, m), 7.08-7.18 (4H, m), 6.90-7.00 (2H, m), 6.73 -6.80 (2H, m), 4.58-4.63 (2H, d), 4.29-4.39 (4H, m), 3.56 (2H, s), 1.35-1.41 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 540, [M + Na] + 562, [- H] + 538.
EXAMPLE 17 1 H NMR (400 MHz, CDCl 3): d = 8.52-8.59 (1H, d), 8.19-8.25 (1H, m), 8.16-8.19 (1H, d), 7.90-7.94 (1H, d), 7.78 (1H , s), 7.44-7.49 (1H, t), 7.28-7.32 (1H, d), 7.18-7.23 (2H, d), 7.04-7.18 (4H, m), 6.64-6.73 (3H, m), 6.28 -6.35 (1H, m), 4.58-4.66 (2H, d), 4.26-4.38 (4H, m), 3.42 (2H, s), 1.33-1.38 (3H, t) ppm. LRMS (electrospray): m / z [M-H] + 538.
EXAMPLE018 H NMR (400 MHz, CDCl 3): d = 8.55-8.61 (1H, d), 8.18-8.23 (1H, m), 8.15-8.18 (1H, d), 7.90-7.94 (1H, d), 7.78 (1H , s), 7.43-7.49 (1H, t), 7.26-7.30 (1H, d), 7.18-7.25 (2H, m), 7.04-7.17 (3H, m), 6.95-7.01 (2H, d), 6.64-6.75 (3H, m), 6.17-6.24 (1 H, m), 4.58-4.68 (2H, d), 4.30-4.40 (4H, m), 3.46 (2H, s), 1.32-1.40 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 540, [M + Na] + 562, [M-H] + 538. The following preparations describe the preparation of certain intermediates used in the preceding examples.
PREPARATION 1 (4-aminomethylbenzyl) carbamic acid tert-butyl ester A solution of di-tert-butyl dicarboxylate (4.62 g, 21.2 mmol) dissolved in dichloromethane (50 ml) was added to a solution of 4-aminomethylbenzylamine (14.4 g, 106 mmol) in dichloromethane (50 ml) at 0 ° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Then the reaction mixture was washed sequentially with water (100 ml) and a 10% aqueous solution of citric acid (200 ml) and the organic phase was discarded. The pH of the aqueous phase was then adjusted to pH greater than 8 by the addition of 0.88 ammonia and extracted with dichloromethane (3 times, 200 ml). Then the combined organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give (4-aminomethylbenzyl) carbamic acid tert-butyl ester (4.29 g) as a white solid. 1 H NMR (400 Hz, CDCl 3): d = 7.22-7.26 (4H, d), 4.80-4.90 (1 H, broad s), 4.23-4.30 (2H, m), 3.82 (2H, s), 1 .43 (2H, s), 1.38 (2H, s) ppm. LRMS (electrospray): m / z [M-H] + 237.
PREPARATION 2 tert-Butyl Ester of r4 - ((f2- (4-fluorophenoxy) pyridine-3-carbonyl-amino) methyl) carbamic benzamide In N, N-dimethylformamide (50 ml) at room temperature, 2- (4-fluorophenoxy) nicotinic acid was dissolved (see reference patent application WO 98/45268) (6.20 g, 26 mmol), 1-hydroxybenzotriazole ( 5.39 g, 40 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.62 g, 34 mmol) and (4-aminomethylbenzyl) carbamic acid tert-butyl ester (6.28 g, 26 mmol) was added ( see Preparation 1) followed by the addition of N-methylmorpholine (4.4 mL, 40 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hours and then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer was separated. Then the organic phase was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with diethyl ether (15 mL) to give [4- (. {[2- (4-fluorophenoxy)) pyridine-3-carbonyl] amino] methyl] benzyl] carbamic acid tert-butyl ester (9.52). g) as a whitish solid. 1 H NMR (300 MHz, CDCl 3): d = 8.56-8.76 (1 H, m), 8.06-8.14 (2 H, m), 6.96-7.40 (9 H, m, partially masked by the solvent), 4.58-4.95 (3 H , m), 4.20-4.40 (2H, broad s), 1.56 (9H, s) ppm. LRMS (thermospray): m / z [+ NH4] + 469.
PREPARATION 3 N- (4-aminomethylbenzyl) -2- (4-fluorophenoxy) -nicotinamide hydrochloride [4- ( { [2- (4-fluorophenoxy) pyridine-3-carbonyl] amino] methyl] benzyl] carbamic acid tert-butyl ester (9.51 g, 21 mmol) was dissolved (see Preparation 2). ) in dichloromethane (60 ml) and hydrogen chloride gas was bubbled into the solution at 0 ° C until it became saturated (30 minutes). Then the reaction mixture was stirred under nitrogen atmosphere at room temperature for a further 1 hour before removing the solvent in vacuo. The resulting white precipitate was triturated with ethyl ether (3 times, 10 ml) to give N- (4-aminomethylbenzyl) -5-fluoro-2- (4-fluorophenoxy) -nicotinamide hydrochloride (7.92 g) as a white solid. . 1 H NMR (300 MHz, DMSO-d 6): d = 8.96-9.07 (1 H, m), 8.40-8.60 (2 H, m), 8.17-8.22 (1 H, d), 8.1 1 -8.16 (1 H, m), 7.36-7.44 (4H, m), 7.18-7.33 (5H, m), 4.43-4.58 (2H, m, partially masked by the solvent), 3.86-3.99 (2H, m) ppm. LRMS (thermospray): m / z [M + H] + 352.
PREPARATION 4 Tertiary butyl ester of acid r4-. { r 2 -chloro-5-fluoropyridin-3-carbonyl) aminolmethyl) benzcarbamic In N, N-dimethylformamide (50 ml) at room temperature, 2-chloro-5-fluoronicotinic acid (see preparation 10) (2.0 g, 11.4 mmol), 1-hydroxybenzotriazole (1.85 g, 13.7 mmol) and hydrochloride were stirred. of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (2.62 g, 13.7 mmol) and (4-aminomethylbenzyl) carbamic acid tert-butyl ester (2.69 g, 11.4 mmol) was added (see Preparation 1) followed of the addition of N-methylmorpholine (2.5 ml, 22.8 mmol). Then the reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hours, partitioned between dichloromethane (100 ml) and water (100 ml) and the organic layer was separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give tert-butyl acid ester [4-. { [2-chloro-5-fluoropyridine-3-carbonyl) amino] methyl) benzyl) carbamic acid (4.08 g) as a white solid. 1 H NMR (400 Hz, DMSO-d 6): d = 9.10-9.17 (1 H, t), 8.52-8.54 (1 H, d), 7.99-8.04 (1 H, dd), 7.26-7.35 (3H, m), 7.18-7.22 (2H, d), 4.39-4.44 (2H, d), 4.06-4.11 (2H, d), 1.38 (9H, s) ppm. LRMS (electrospray): m / z [M + Na] + 416, [M-H] + 392.
PREPARATION 5 Tert-butyl ester of r4- (ff5-fluoro-2- (4-fluorophenoxy) -pyridine-3-carbonyl-amino) methyl) benzylcarbamic acid ester Tertiary butyl ester of acid [4-. { [2-chloro-5-fluoropyridine-3-carbonyl) amino] methyl) benzyl) carbamic (100 mg, 0.29 mmol) (see preparation 4), 4-fluoro-phenol (28 mg, 0.29 mmol) and cesium carbonate (800 mg, 2.5 mmol) in N, N-dimethyl formamide (10 ml) at 60 ° C under nitrogen atmosphere for 18 hours. Then the reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic layer was separated. Then the organic layer was washed with a saturated aqueous solution of sodium chloride (3 times, 10 ml), the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of 50 ml. ethyl acetate: 5:95 pentane which changes to 30:70 by volume, to give [4- ( { [5-fluoro-2- (4-fluorophenoxy) pyridine-3-carbonyl] tert-butyl ester] amino.} methyl) benzyl] carbamic (57 mg) as a white foam. 1 H NMR (400 MHz, DMSO-d 6): d = 8.97-9.02 (1 Hm t), 8.79-8.21 (1 H, d), 8.03-8.08 (1 H, dd), 7.30-7.36 (1 H, m ), 7.19-7.30 (6H, m), 7.1 1 -7.16 (2H, d), 4.44-4.50 (2H, d), 4.03-4.08 (2H, d), 1.36 (9H, s) ppm. LRMS (electrospray): m / z [M-H] + 468.
PREPARATION 6 N- (4-aminomethylbenzyl) -5-fluoro-2- (4-fluorophenoxy) nicotinamide hydrochloride [4- (. {[[5-Fluoro-2- (4-fluorophenoxy)) pyridine-3-carbonyl] amino] methyl] benzyl] carbamic acid tert-butyl ester (1.62 g, 3.44 mmol) (see Preparation 5) in a 2.25 M solution of hydrochloric acid in methanol (100 mL) and the mixture was stirred at room temperature under nitrogen atmosphere for 4 hours before removing the solvent in vacuo. The residue was dissolved in water (50 ml), the pH was adjusted to a pH higher than 8 by the addition of sodium hydrogencarbonate and extracted with dichloromethane (3 times, 50 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give N- (4-aminomethylbenzyl) -5-fluoro-2- (4-fluorophenoxy) nicotinamide hydrochloride (1.25 mg) as a gum.
PREPARATION 7 (4- ({r (2-Chloropyridine-3-carbonyl) amino-methyl} -benzyl) carbamic acid tert-butyl ester In N, N-methylformamide (50 ml) at room temperature, 2-clornicotinic acid (2.86 g, 18.2 mmol), 1-hydroxybenzotriazole (3.0 g, 21.8 mmol) and 1- (3- hydrochloride were dissolved. dimethylaminopropyl) -3-ethylcarbodiimide (4.18 g, 21.8 mmol) and (4-aminomethylbenzyl) carbamic acid tert-butyl ester (4.29 g, 18.2 mmol) (see Preparation 1) was added followed by the addition of N- methylmorpholine (4 mL, 36.3 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hours, then it was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer was separated. Then the organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was then triturated with diethyl ether (2 times, 10 ml) to give (4- {[[(2-chloropyridine-3-carbonyl) amino] methyl} -benzylcarbamic acid tert-butyl ester ( 6.71 g) as a white solid. 1 H NMR (400 MHz, DMSO-d 6): d = 9.01-9.08 (1 H, t), 8.43-8.47 (1 H, m), 7.89-7.93 (1 H, d), 7.45-7.50 (1 H, m), 7.30-7.37 (1 H, m), 7.26-7.31 (2H, d), 7.17-7.21 (2H, d), 4.39-4.43 (2H, d), 4.03-4.10 (2H, d), 1.37 (9H, s) ppm. LRMS (electrospray): m / z [m-H] + 374.
PREPARATION 8 Ethyl ester of acid 3-. { 3-t4-tert-butoxycarbonylaminomethyl) -benzylcarbamoyl-pyridin-2-yloxy) benzoic acid (4- {[[(2-Chloropyridine-3-carbonyl) amino] methyl} -benzylcarbamic acid tert-butyl ester (12.0 g, 32.2 mmol) was stirred (see Preparation 7). ), 3-hydroxybenzoic acid ethyl ester (6.42 g, 38.6 mmol) and cesium carbonate (15.7 g, 48.3 mmol) in dioxane (180 mL) at 70 ° C under nitrogen atmosphere for 18 hours. There was still starting material, so another aliquot of 3-hydroxybenzoic acid ethyl ester (6.42 g, 38.6 mmol) and cesium carbonate (15.7 g, 48.3 mmol) was added along with dioxane (420 ml) and N, Nd Methylformamide (40 ml) and the reaction was stirred at 70 ° C for a further 22 hours. Then the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml) and the organic layer was separated. Then the organic layer was washed with a saturated aqueous solution of sodium chloride (3 times, 100 ml), the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of 50 ml. ethyl acetate: hexane 0: 100 which changes to 50:50 by volume to give ethyl ester of 3- acid. { 3- [4-tert-butoxycarbonylaminomethyl) benzylcarbamoyl] pyridin-2-yloxybenzoic acid (7.42 mg) as a whitish foam. H NMR (400 MHz, DMSO-d6): d = 8.92-8.98 (1 H, t), 8.18-8.21 (1 H, d), 8.14-8.18 (1 H, d), 7.81-7.85 (1 H, d), 7.77 (1 H, s), 7.54-7.610 (1 H, t), 7.46-7.50 (1 H, m), 7.27-7.31 (2H, d), 7.22-7.26 (1 H, m), 7.14-7.18 (3H, d), 4.47-4.51 (2H, d), 4.29-4.35 (2H, quartet), 4.04-4.08 (2H, d), 1 .37 (9H, s), 1.28-1.35 (3H , t) ppm. LRMS (electrospray): m / z [M + Na] + 528, [M-H] + 504.
PREPARATION 9 rN- (4-aminomethylbenzyl) -2- (4-fluorophenoxy) 1-nicotinamide hydrochloride Ethyl ester of 3- acid was dissolved. { 3- [4-tert-butoxycarbonylaminomethyl) benzylcarbamoyl] pyrldin-2-yloxy} benzoic acid (7.42 g, 14.7 mmol) (see Preparation 8) in dichloromethasone (100 ml) and hydrogen chloride gas was bubbled through the solution at 0 ° C until it became saturated (30 minutes). The solvent was removed in vacuo yielding [N- (4-aminomethylbenzyl) -2- (4-fluorophenoxy)] nicotinamide hydrochloride (7.16 mg) as a white solid. 1 H NMR (400 Hz, DMSO-d 6): d = 9.48-9.54 (1 H, m), 8.83-9.03 (3 H, broad s), 8.62-8.66 (1 H, m), 8.57-8.63 (1 H, d), 8.35-8.42 (1 H, d), 8.22 (1 H, s), 8.01-8.08 (1 H, t), 7.93-7.98 (1 H, d), 7.81-7.91 (4H, m), 7.68-7.74 (1 H, d), 4.94-5.01 (2H, d), 4.76-4.81 (2H, quatrain), 4.36-4.42 (2H, m), 1.75-1.80 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 406.
PREPARATION 10 2-chloro-5-fluoronicotinic acid Ethyl 2-chloro-5-fluoronicotinate (50.4 g, 0.247 mmol) (see reference J. Med. Chem., 1993, 36 (18), 2676-88) was dissolved in tetrahydrofuran (350 ml) and an 2M aqueous solution of lithium hydroxide (247 ml, 0.495 mol). The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to pH equal to 1 by addition of 6N hydrochloric acid and then extracted with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give a solid which was triturated with diethyl ether and then dried under vacuum to give 2-chloro-5-cluoronicotinic acid (40.56 g) as a solid. White. 1 H NMR (400 MHz, DMSO-d 6): d = 8.20 (1 H, s), 8.62 (1 H, s) ppm. LRMS (electrospray): m / z [M + H] + 174.
In vitro activity of the nicotinamide derivatives The PDE4 inhibitory activity of the nicotinamide derivatives of formula (1) is determined by the ability of the compounds to inhibit the hydrolysis of cAMP to AMP by PDE4 (see also reference 1). labeled cAMP is incubated with tritium with PDE4. After incubation, the radiolabeled AMP produced is able to bind to yttrium silicate SPA beads. These SPA beads then produce light that can be quantified by scintillation counting.MU.
The addition of a PDE4 inhibitor prevents the formation of AMP from cAMP and decreases the counts. The IC50 of a PDE4 inhibitor can be defined as the concentration of a compound that leads to a 50% decrease in counts compared to the control wells containing only PDE4 (without inhibitor). The anti-inflammatory properties of the nicotinamide derivatives of formula (1) are demonstrated by their ability to inhibit the release of TNFα from human peripheral blood mononuclear cells (see also reference 2). Venous blood is collected from healthy volunteers and the mononuclear cells are purified by centrifugation through Histopaque pads (Ficoll). The production of TNFa from these cells is stimulated by the addition of lipopolysaccharide. After 18 hours of incubation in the presence of LPS, the supernatant is separated from the cells and the concentration of TNFa in the supernatant is determined by ELISA. The addition of PDE4 inhibitors reduces the amount of TNFa produced. An IC50 is determined which is equal to the concentration of compound that produces 50% inhibition of TNFa production compared to the control wells stimulated with LPS. All examples were tested in the assays described above and found to have a Cl50 (TNFa screen) less than 500 nM. And for most of the compounds tested, they were found to have a Cl50 (TNFa count) even less than 200 nM.
References: 1. Thompson JW, Teraski WL, Epstein PM, Strada SJ., "Assay of nucleotide phosphodiesterase and resolution of multiple molecular forms of the soenzyme", Advances in cyclic nucleotides research, edited by Brooker G, Greengard P, Robinson GA, Raven Press, New York 1979, 10, p. 69-92. 2. Yoshimura T, Kurita C, Nagao T, Usami E, Nakao T, Watanabe S, Kobayashi J, Yamazaki F, Tanaka H, Nagai H., "Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysacchande-stimulated human blood mononuclear cells ", Gen. harmacol., 1997 29 (4), p. 63

Claims (4)

NOVELTY OF THE INVENTION CLAIMS
1. - A compound of formula (1): in which; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; each of Ri and R2 is a member independently selected from the group consisting of a hydrogen atom, halo, cyano, alkyl (CrC4) and (C4) alkoxy; X is -O-, -S- or -NH-; R3 is a member selected from the groups consisting of: (a) phenyl, naphthyl, heteroaryl, and (C3-C8) cycloalkyl, each optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, cyano, (C4) alkyl, (C4) alkoxy, thioalkyl (CrC4), -C (= 0) NH2, -C (= 0) NH ((C4) alkyl), hydroxy, -0-C (= 0) alkyl (C4), -C (= 0) -0-alkyl (C4) and hydroxy-alkyl (Ci-C4), or (b) the bicyclic groups which respond to one of the following structures ( 1.1) to (1 .4): (1.2) (1.3) (1.4) in which the symbol "*" indicates the point of attachment of each partial formula (1.1) a (1 .4) to the remaining portion of formula (1); And he is a selected member of group formed by the partial formulas (1.5) to (1.1 1): H H (1.5) (1.6) (1.7) (1.8) (1.9) (1.10) (1.11.) in which the symbol "*" indicates the point of attachment of each partial formula (1.5) to (1 .11) to the remaining portions -NH- of formula (1) and "**" indicates the point of union of each partial formula (1.5) to (1 .1 1) to the remaining portions -R4 of Formula 1 ); and R4 is a member selected from the groups consisting of: (a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, -C (= 0) -0-alkyl (C4), halo, cyano, -C - (= 0) NH2, alkyl (Ci-C4), (C1-C4) alkoxy, haloalkyl (C4), hydroxy and hydroxy (C1-C4) alkyl, or (b) alkyl (CrC4) optionally substituted with a hydroxy group, carboxylic acid, C ( = 0) -0-alkyl (C4), phenyl, naphthyl or heteroaryl, wherein said phenyl, naphthyl and heteroaryl are each optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) -0-alkyl (Ci-C4), halo, cyano, -C (= 0) NH2, alkyl (C4) or alkoxy (CrC4), haloalkoxy (C4), hydroxy and hydroxy (C1-C4) alkyl; or their salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or pharmaceutically acceptable metabolites.
2. The compound according to claim 1, except the compounds for which: 1) m is different from 0 simultaneously when Y represents the partial formula (1.5) and R4 represents an unsubstituted alkyl (CrC), 2) m is equal to 0 simultaneously when Y represents the partial formula (1.5) and R4 represents a phenyl, a naphthyl or a heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of carboxylic acid, halo, cyano, (C4) alkyl, alkoxy (CrC4), haloalkyl (C4), hydroxy and hydroxy (C1-C4) alkyl, or R4 represents a (C1-C4) alkyl optionally substituted with a hydroxy, carboxylic acid or a heteroaryl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of carboxylic acid, halo, cyano, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, hydroxy and hydroxy-alkyl (Ci-C), and 3) m is equal to 0 simultaneously when Y represents the partial formula (1.6) and R4 represents a phenyl or a naphthyl, each of them optionally substituted with 1 to 3 substituents, independently selected from the group consisting of carboxylic acid, halo, cyano, (C1-C4) alkyl, (C1-6) alkoxy C4), halo- (C1-C4) alkyl, hydroxy and hydroxy-alkyl (d-c4).
3. The compound according to claim 1, further characterized in that: m and n are equal to 1; each of Ri and R2 is a member independently selected from the group consisting of a hydrogen atom, halo, cyano, (C1-C4) alkyl and (C1-C4) alkoxy; X is -O-; R3 is a member selected from the groups consisting of: (a) phenyl, naphthyl, heteroaryl and (C3-C8) cycloalkyl, each selected from the group consisting of halo, cyano, alkyl (C4), alkoxy (C4) ), thioalkyl (C1-C4), -C (= 0) NH2, -C (= 0) NH (alkyl (CrC4)), hydroxy, -0-C (= 0) alkyl (C4), - C (= 0) -0- (C1-C4) alkyl and hydroxy (C4) alkyl, or (b) the bicyclic groups correspond to one of the following structure (1.1) to (1.4): (1.2) (1.3) (1.4) where the symbol "*" indicates the point of attachment of each partial formula (1.1) to (1.4) to the remaining portion of formula (1); And it is a group -C (= 0) - of partial formula (1.5); and R4 is a member selected from the groups consisting of: (a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) -0-alkyl (C4), halo, cyano, -C (= 0) NH2, alkyl (C4), alkoxy (C4), haloalkyl (C1-C4), hydroxy and hydroxy-alkyl (C4), or (b) (C1-C4) alkyl substituted with a hydroxy group, carboxylic acid, C (= 0) -0-alkyl (d-C4), phenyl, naphthyl or heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with 1 to 3 substituents each selected from the group consisting of carboxylic acid, C (= 0) -0-C 1 -C 4 alkyl, halo, cyano, -C (= 0) NH 2, alkyl ( C C4), (C4) alkoxy, (C4) haloalkyl, hydroxy and hydroxy-alkyl (CrC4), or their pharmaceutically acceptable salts and / or isomers, tautomers, polymorph solvates, isotopic variations or metabolites thereof. 4 - The compound according to claim 1, further characterized in that: m and n are equal to 1; each of R1 and R2 is a member independently selected from the group consisting of a hydrogen, halo and methyl atom; X is -O-; R3 is a phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, cyano, alkyl (CC), alkoxy (Ci-C4), thioalkyl (C4), - (C = 0) N H2, -C (= 0) NH (alkyl (d-C4)), hydroxy, -0-C (= 0) - (alkyl (CrC4)), -C (= 0) -0- (alkyl) (C1-C4)) and hydroxy-alkyl (C4); And it is a group -C (= 0) - of partial formula (1.5); and R4 is a member selected from the groups consisting of: (a) phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid C (= 0) -0-alkyl (CrC4), halo, cyano, -C (= ONH2, alkyl (Ci-C4), alkoxy (C-1-C4), haloalkyl (C-1-C4), hydroxy and hydroxy-alkyl (C4), or (b) alkyl (C1 -C4) substituted with a hydroxy or a phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents, each selected from the group consisting of carboxylic acid, C (= 0) -0-alkyl (C1-C4) , halo, cyano, -C (= 0) NH 2, (C 4) alkyl, alkoxy (CrC 4), haloalkyl (C 1 -C 4), hydroxy and hydroxy (C 1 -C 4) alkyl, or their pharmaceutically acceptable salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or metabolites thereof 5. The compound according to claim 1, further characterized in that: m and n are equal to 1, Ri is a hydrogen atom or a fluoro radical and R2 is a hydrogen atom; X is -O-; R3 is phenyl optionally substituted with a substituent selected from the group consisting of halo and -C (= 0) -0-alkyl (CrC4); And it is a group -C (= 0) - of partial formula (1.5); and R4 is a member selected from the groups consisting of: (a) phenyl optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, alkyl (CrC4) and hydroxy, or selected from the group consisting of halo, (C4) alkyl and hydroxy, or (b) (CrC4) alkyl substituted with a hydroxy or a phenyl, wherein said phenyl is optionally substituted with 1 to 3 substituents, each selected from the group consisting of halo, alkyl ( C C4) and hydroxy, or their pharmaceutically acceptable salts and / or isomers, tautomers, solvates, polymorphs, isotopic variations or metabolites thereof. 6. The compound according to claim 1, further characterized in that it is selected from the group consisting of: 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-3-methylbenzoylamino) methy1] benzyl} - N-tacinamide, 3- (3. {4 - [(3-hydroxybenzoylamino) methyl] benzylcarbamoyl} -pihdin-2-yloxybenzoic acid ethyl ester, 2- (4-fluorophenoxy) -N-. { 4 - [(6-fluoro-2-hydroxybenzolamino) methyl] benzyl] -nicotinamide, 2- (4-fluorophenoxy) -N-. {4 - [(5-fluoro-2-hydroxybenzoylamine) methyl) ] benzyl.}. -nicotinamide. , 2- (4-fluorophenoxy) -N-. { 4 - [(3-hydroxy-4-methylbenzoylamino) methyl] benzyl} -nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(3-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(2-Hydroxybenzolamine) methyl] benzyl} nitric acid, 2- (4-fluorophenoxy) -N-. { 4 - [(4-hydroxybenzoylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-4-methylbenzoylamino) methyl] benzyl} -nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(3-hydroxy-2-methylbenzoylamino) methyl] benzyl} -nicotinamide, 2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxy-5-methyl-benzoylamino) methyl] benzyl} -nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxybenzoylamino) methyl] benzyl} -nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(2-hydroxyacetylamino) methyl] benzyl} -nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N-. { 4 - [(4-hydroxybenzoylamino) methyl] benzyl} -nicotinamide, ethyl ester of acid 3- (3- { 4 - [(3-hydroxybenzoylamino) methyl] benzylcarbamoyl.} - pyridin-2-yloxy) benzoic acid ethyl ester 3- (3-. {4 - [(2)] -hydroxyphenylacetylammon) methyl] benzylcarbamoyl.] - pyridin-2-yloxy) benzoic acid, 3- (3. {4 - [(3-hydroxy-vinylacetylamino) methyl] benzyl-carbamoyl, ethyl ester} -pyridin-2-yloxy) benzoic acid 3- (3. {4 - [(4-hydroxy-phenylacetylamino) methyl] benzylcarbamoyl} -pyridin-2-yloxy acid ethyl ester ) benzoic acid 7.- A process for the preparation of a compound of formula (1) according to claim 1, or a pharmaceutically acceptable salt or form thereof, characterized in that it comprises the step of reacting a compound of formula: wherein R t, R 2, X, R 3, n and m are as defined in claim 1, with the corresponding R 4 -sulfonyl chloride derivative when Y represents a group of partial formula (1.7), (1.8) or (1 .10) , or with the corresponding R4-carboxylic acid derivative when X represents a group of partial formula (1.5), (1.9) or (1.1 1), or a carbonyldiimidazole when Y represents a group of partial formula (1.6). 8. A pharmaceutical composition that includes a compound of formula (1) according to claim 1, or a pharmaceutically acceptable salt or form thereof, together with conventional pharmaceutically acceptable excipients and / or additives. 9. A compound of the formula (1) according to claim 1, or a pharmaceutically acceptable salt, derivative form or composition thereof, for use as a medicament. 10. A compound of the formula (1) according to claim 1, or a pharmaceutically acceptable salt, derivative form or composition thereof, for use in the treatment of diseases, disorders and conditions in which the PDE4 isozymes are involved. 1. The use of a compound of formula (1) according to claim 1, or of a salt, pharmaceutically acceptable derivative form or composition thereof, for the manufacture of a drug having PDE4 inhibitory activity. 12. The use of a compound of formula (1) according to claim 1, or of a pharmaceutically acceptable salt or derivative thereof, for the manufacture of a drug for the treatment of inflammatory, respiratory and respiratory diseases, disorders and conditions. allergic and for the treatment of wounds. 13. The use of a compound of formula (1) according to claim 1, or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders and conditions selected from the group formed by: asthma of any type, etiology or pathogenesis, in particular asthma which is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial asthma mediated by IgE, bronchial asthma, essential asthma, true asthma, asthma intrinsic caused by pathophysiological alterations, 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-induced asthma, asthma occupational, infectious asthma caused by bacterial, fungal, protozoal or viral infection, nonallergic asthma, incipient asthma and dyspnoea syndrome of the infant; acute or chronic bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema; obstructive or inflammatory diseases of the respiratory tract, whatever their type, etiology or pathogenesis, in particular an obstructive or inflammatory disease of the respiratory tract 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 with it, COPD that is characterized by progressive and irreversible obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS) and exacerbation of airway hyperresponsiveness as a result of another pharmacotherapy; pneumoconisis of any type, etiology or pathogenesis, in particular pneumoconiosis that is a member selected from the group formed by aluminosis or bauxite workers disease, anthracosis or asthma of the miners, asbestosis or asthma of water vapor adjusters, calicosis or disease caused by flint dust, ptilosis caused by inhalation of dust from ostrich feathers, siderosis caused by inhalation of iron particles, silicosis or from disease of milling workers, byssinosis or asthma from cotton dust and pneumoconiosis talcum powder; bronchitis of any kind, etiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, pseudomembranous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal bronchitis and streptococci and gallbladder bronchitis, bronchiectasis of any kind, etiology or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindrical bronchiectasis, bronchiectasis sacculate, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis, seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of any type, etiology or pathogenesis, in particular sinusitis which is a member selected from the group consisting of purulent or non-purulent sinusitis, acute or chronic sinusitis and cold ethmoid sinusitis maxillary or sphenoid nerve; rheumatoid arthritis of any kind, etiology or pathogenesis, in particular rheumatoid arthritis which 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; gout and fever and pain associated with inflammation; a disorder related to eosinophils of any type, etiology or pathogenesis, in particular an eosinophil-related disorder which is a member selected from the group consisting of eosinophilia, eosinophilia with pulmonary filtration, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis , aspergilloma, granulomas containing eosinophils, allergic granulomatous vasculitis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotizing vasculitis; atopic dermatitis, allergic dermatitis, contact dermatitis or allergic or atopic eczema; urticaria of any type, etiology or pathogenesis, in particular urticaria which is a member selected from the group formed by immune urticaria, urticaria mediated by the complement, urticaria induced by urticariogenic material, urticaria induced by physical agents, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal or acquired form, contact urticaria, giant urticaria and popular urticaria; conjunctivitis of any type, etiology or pathogenesis, in particular conjunctivitis which 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 any type, etiology or pathogenesis, in particular uveitis which is a member selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, non-granulomatous uveitis, phacoantigenic uveitis, uveitis posterior, choroiditis and chorioretinitis; psoriasis; multiple sclerosis of any type, etiology or pathogenesis, in particular multiple sclerosis which is a member selected from the group consisting of primary progressive multiple sclerosis and relapsing remitting multiple sclerosis; autoimmune / inflammatory diseases of any kind, etiology or pathogenesis, in particular autoimmune / inflammatory disease which is a member selected from the group consisting of autoimmune hematological disorders, hemolytic anemia, aplastic anemia, anemia of pure red blood cells, idiopathic thrombocytopenic purpura, systemic lupus erythematosus , polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, malabsorption syndrome, inflammatory autoimmune intestinal diseases, ulcerative colitis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, pneumonitis with chronic hypersensitivity, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type I, dry keratoconjunctivitis, epidermal keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, pulmonary fibrosis, diopathic, cystic fibrosis, glomerulonephritis itis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, nephropathy with minimal change, cutaneous inflammatory / hyperproliferative diseases, benign familial pemphigus, pemphigus erythematosus, pemphigus foliaceus and pemphigus vulgaris; prevention of rejection of allogeneic grafts after organ transplantation; inflammatory bowel disease (IBD) of any type, etiology or pathogenesis, in particular inflammatory bowel disease which is a member selected from the group consisting of collagenous colitis, polypost colitis, transmural colitis, ulcerative colitis and Crohn's disease (CD); septic shock of any type, etiology or pathogenesis, in particular septic shock which is a selected member of the group consisting of renal insufficiency, acute renal failure, cachexia, malarial cachexia, pituitary cachexia, uraemic cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancerous cachexia and cachexia as a consequence of infection by the human immunodeficiency virus (HIV); liver disease; pulmonary hypertension of any 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; diseases due to loss of bone mass, primary osteoporosis and secondary osteoporosis; diseases of the central nervous system of any kind, etiology or pathogenesis, in particular a disorder of the central nervous system which is a member selected from the group consisting of depression, Alzheimer's disease, Parkinson's disease, impairment of learning and memory capacity , tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany the chorea of Huntington, Wilson's disease, agitans paralysis and thalamic atrophies; infection, especially virus infection where such viruses increase the production of TNF-a in their host, or where such viruses are sensitive to upregulation of TNF-a in their host so that their replication or other vital activities are are adversely influenced, including viruses that are a member selected from the group consisting of HIV-1, HIV-2 and HIV-3, cytomegalovirus (CV), influenza, adenovirus and Herpes-viruses including Herpes zoster and Herpes simplex; fungal and yeast infections wherein said fungi and yeasts are sensitive to upregulation by TNF-a or incite the production of TNF-a in their host, for example fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic infections by fungi and yeasts, including but not limited to, polymyxins, eg, polymycin B, imidazoles, eg, clotrimazole, econazole, miconazole and ketoconazole, triazoles, e.g., fluconazole and itranazol as well as amphotericins, eg, 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 prosthetic diseases; reduction of scar formation in the human or animal body, such as the formation of scars when healing acute wounds; and psoriasis, other dermatological and cosmetic uses, including antiphlogistic activities, skin softeners and to increase the moisture and elasticity of the skin.
MXPA04007736A 2002-02-11 2003-02-03 Nicotinamide derivatives useful as pde4 inhibitors. MXPA04007736A (en)

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PCT/IB2003/000377 WO2003068232A1 (en) 2002-02-11 2003-02-03 Nicotinamide derivatives useful as pde4 inhibitors

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BR0307574A (en) 2004-12-21
UY27657A1 (en) 2003-09-30
CA2475708A1 (en) 2003-08-21
EP1476157A1 (en) 2004-11-17
JP2005522449A (en) 2005-07-28
AU2003202116A1 (en) 2003-09-04
TW200304824A (en) 2003-10-16
AR038404A1 (en) 2005-01-12
AU2003245812A1 (en) 2003-09-04
PE20030921A1 (en) 2003-11-05
GT200300034A (en) 2003-09-11
PA8566501A1 (en) 2003-11-12
PA8566601A1 (en) 2003-11-12
HN2003000062A (en) 2003-09-24
WO2003068232A1 (en) 2003-08-21
SV2004001481A (en) 2004-05-07
PE20030860A1 (en) 2003-10-25
UY27658A1 (en) 2003-09-30
GT200300033A (en) 2003-10-11
WO2003068234A1 (en) 2003-08-21
GB0203193D0 (en) 2002-03-27

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