ZA200405803B

ZA200405803B - Nicotinamide derivatives useful as PDE4 inhibitors

Info

Publication number: ZA200405803B
Application number: ZA200405803A
Authority: ZA
Inventors: Simon Bailey; Elisabeth C L Gautier; Alan J Henderson; Thomas V Magee; Anthony Marfat; John P Mathias; Dale G Mcleod; Sandra M Monaghan
Original assignee: Pfizer
Priority date: 2002-02-11
Filing date: 2004-07-21
Publication date: 2006-05-31
Also published as: GB0203196D0; GT200300035A

Description

NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 INHIBITORS

This invention relates to nicotinamide derivatives of general formula : i

R, AN NEA

H

R; N X rd eo’ in which Ry, R,, Ri, Ry, X, Y, and Z have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

The 3',5'-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another.

The enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene products is included within this class, and further diversity results from differential splicing and post- 4 translational processing of those gene products. The present invention is @® primarily concerned with the four gene products of the fourth family of PDEs, ie., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family.

The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic . monophosphate (CAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and . beneficial pharmacological effects resuiting from that inhibition have been shown in a variety of disease models (see, e.qg., Torphy et al., Environ. Heaith

Perspect. ,1894, 102 Suppl. 10, p. 79-84 ; Duplantier et al, J. Med. Chem., 1996, 39, p. 120-125 ; Schneider et al., Pharmacol. Biochem. Behav., 1995, 50,

p. 211-217 ; Banner and Page, Br. J. Pharmacol, 1995, 114, p. 93-98 ;

Barnette et al., J. Pharmacol. Exp. Ther., 1995, 273, p. 674-679 ; Wright et al.,

Can. J. Physiol. Pharmacol., 1997, 75, p. 1001-1008 ; Manabe ef al., Eur. J. ’

Pharmacol., 1997, 332, p. 97-107 and Ukita et al., J. Med. Chem., 1999, 42, p. 1088-1099). Accordingly, there continues to be considerable interest in the art with regard to the discovery of further selective inhibitors of PDE4s.

Successful 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 to the lungs of allergen-challenged _ animals while also reducing the bronchoconstriction and elevated bronchial ® responsiveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells (including CD4" T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iINANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4" T-lymphocytes, eosinophils and neutrophils.

PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and pa potentially interfere with the ability of airway epithelial cells to generate pro- ( inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema. Therefore, PDE4 inhibitors are particutarly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions and for wounds and some of them are in clinical development mainly for tretament of asthma, COPD, bronchitis and emphysema. "The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study.

These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFa) release in eosinophils, neutrophils and monocytes.

Some nicotinamide derivatives having a PDE4 inhibitory activity have

S already been synthetized. For example, the patent application N° WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of

PDE4D isozyme. These selective PDE4D inhibitors are represented by the following formula :

AY

: [i . : : A

RNA NE

R N E(CH,)R (O), wherein r may be equal to 0, (A), may be oxygen and (B)n may be NH, o may be equal to 0 or 1, R? and R® may be taken together with the carbon to which they are attached to form a (C3-Cy)cycloalkyl! ring, (D)e may be absent or may be —NH- or -N(C;-Ce)alkyl-, @ may be equal to 0 or 1, R* may be absent or : may represent a carboxy, R’ may be choosen from numerous substituents eo’ 15 among which a (Ci-Cs)alkyl, a (C;-C;)cycloalkyl, a (Ce-Cio)aryl or an {un)saturated (C;-C7)heterocyclic group, wherein each of said cycloalkyl, aryl or heterocycle may be optionally substituted by one to three substitutents.

The patent application N° WO 01/57036 also discloses nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various . 20 inflammatory allergic and respiratory diseases and conditions, of formula :

N

N Ww R2 m (9) es 4 Rb

RS

R6 wherein in particular :nis1or2, misOto 2,Y is =C(R%)- or —-[N=>(0)}-, Wis —-

O-, -S(=0)r or —=N(R3)-, Q represents various rings among which the monocyclic AN (Cs-Cr)cycloalkyl moieties, Z is —OR42, -C(=0)Rs2 or CN and Ry; is choosen ® from alkyl, alkenyl, cycloalkyl, phenyl, benzyl and monocyclic heterocyclic moieties.

However, there is still a huge need for additional PDE4 inhibitors showing improved therapeutic index with possibly less adverse effects such as for example emesis.

Thus, the present invention concerns new nicotinamide derivatives of general formula (1) : i ®

JH (1)

R; N X

Rl in which : < R, and R, are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C-Ca)alkyl and (C4-Cy)alkoxy, % Xis -O-, -S- or -NH-, : < Rj is a member selected from the groups consisting of : (a) phenyl, naphthyl, heteroaryl and (Cs-Cs)cycioalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, trifluoromethyl, trifiuoroethyl, trifluoromethoxy, trifluoroethyloxy, (Ci-Cas)alkyl, (C1-Ca)alkoxy, (Ci-Cs)thioalkyl, —C(=O)NH;, -

C(=O)NH((C1-Cy)alkyl), hydroxy, -O-C(=0)(C4-Cs)alkyl, -C(=0)-0-(Cy-Ca)alkyl, hydroxy(C4-Ca)alkyl, (C3-Cs)cycloalky! and (C3-Cs)cycloalkyloxy, or (b) the bicyclic groups conforming to one of the following structures (1.1) to (1.4): e 2, oy Q, oX 0) 0 (1.1) (1.2) (1.3) (1.4) where the symbol “+” indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1), + Y is a member selected from the group consisting of partial formulas (1.5) through (1.8) :

H Rs

SOIC ANSG ARSC

"YY (1.5) (1.6) (1.7) (1.8) where the symbol "+" indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions —NH- of formula (1) and “»«" indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1), and wherein Rs is a member selected from the groups consisting of (C4-Cs)alkyl . and phenyl(C4-Cs)alkyl, where said phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of : halo, cyano, (C4-Cylalkyl, (C;-Cy)alkoxy, hydroxy, hydroxy(C1-Cs)alkyi, carboxylic acid (-COOH), -C(=0)-O-(C;-C4)alkyl, (C;-Cs)haloalkyl and

C(=O)NH,

< Z is a member selected from the group consisting of partial formulas (1.9) through (1.15) :

O Pil 0, 0 0, ,0

AN ONT SN re (1.9) (1.10) (1.11) (1.12) 0 o 0 ¢ TH

MR " osC A AA ) 0 “o © HT fo — (1.13) (1.14) (1.15) ® where the symbol “" indicates the point of attachment of each partial formula (1.9) through (1.15) to the remaining portions Y of formula (1) and “++” indicates the point of attachment of each partial formula (1.9) through (1.15) to the remaining portions Ry of formula (1), + or alternatively Y-Z together represents a group of formula (1.16): 0)

NH jon (1.16) ® where the symbol “+” indicates the point of attachment of the partial formula (1.16) to the remaining portions —NH- of formula (1) and “++” indicates the point of attachment of the partial formula (1.16) to the remaining portions —R, of formula (1), ++ and Ry is a member selected from the groups consisting of : (a) phenyl, naphthyl heteroaryl and (C;-Cs)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOH), -C(=0)-0-(C4-Cs)alkyl, -(C1-Ca)alkyl- .

COOH, -(C,-C4)alkyl-C(=0)-0-(C+-Cy)alkyl, halo, cyano, -C(=O)NH,, -(Ci- 200 Ca)alkyl, -(C4-C,)atkoxy, =(C4-Cq)haloalkyt, hydroxy and hydroxy(C4-Cs)alkyl, or

(b) (Cy-Ce)alkyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, carboxylic acid, -C(=0)-O-(C;-

Cs)alkyl, phenyl, naphthyl, heteroaryl or (C3-Cg)cycloalkyl group, where said phenyl, naphthyl, heteroaryl and (C;-Cg)cycloalkyl groups are each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOH), C(=0)0(C,-C,)alkyl, halo, cyano, -

C(=O)NHz, (C4-Cplalkyl, (Cq-Cslalkoxy, (C1-Cy)haloalkyl, hydroxy and hydroxy(C1-Cy4)alkyl, ~ or, if appropriate, their pharmaceutically acceptable salts and/or isomers,

Q 10 tautomers, solvates, polymorphs, isotopic variations and metabolites thereof, with the proviso that : 1) when : 2 Ry is selected from the group consisting of hydrogen atom, halo and methyl, “ Ris a hydrogen atom, «< Xis -O-, + Rj is a phenyl substituted by a (C,-Cs)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo, (C+-Cj)alkyi and (C,-C3)alkoxy,

CY “» Y is a partial formula (1.5) or (1.8):

H Re (1.5) (1.8) where the symbol “+” indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and "+" indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), . and wherein Rs is a member selected from the groups consisting of (C;-Ca)alkyl and phenyl(C4-Cq)alkyl, where said phenyl group is optionally substituted by halo, (C1-Ca)alkyl, (Ci-Ca)alkoxy of hydroxy, and » Z is a radical —-C(=0)-

then Rs cannot be : a) a (Cs-Cg)cycloalkyl optionally substituted by (C,-Cj)alkyl, b) a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and . heterocyclic ring are each optionally substituted by hydroxy, halo, (C:-Cs)alkyl or (Cy-Cs)alkoxy, or ¢) a (C1-Cg)alkyi optionally substituted with a hydroxy, or with a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C4-Cj)alkyl or (C4-C3)alkoxy, ® 2) and when : + Ry is selected from the group consisting of hydrogen atom, halo and meth, “» Ra is a hydrogen atom, % Xis -O-, + Rjis a phenyl substituted by a (C;4-Ca)thioalkyl in the -3 or ~4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo, (C-Cs)alkyl and (C,-C3)alkoxy, and < Y-Z represents a partial formula (1.16) :

O re (1.16) where the symbol “" indicates the point of attachment of the partial formula (1.16) to the remaining portions ~NH- of formula (1) and “=+" indicates the point of attachment of the partial formula (1.16) to the remaining portions —R4 of formula (1), then R4 cannot be : . 25 a)a(CsCs)cycloalkyl or b) a (Cs-Cg)alkyl optionally substituted by a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally ] substituted by hydroxy, halo, (C,-C3)alky! or (C,-C;)alkoxy, 3) and when : “ Ry is selected from the group consisting of hydrogen atom, halo and methyl,

S < R:is a hydrogen atom, % Xis -0-, <* Rj is a phenyl substituted by a (C4-Cs)thioalkyl in the -3 or —4 position of said phenyl and is also optionally substituted by 1 or 2 substituent(s) each - independently selected from the group consisting of halo, (C4-Ca)atkyl and (C,-

CY) 10 C;)alkoxy, and % Y is a partial formula (1.6) : (1.6) where the symbol “+” indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and “~" indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), and ( + Z is a radical -C(=0)-, then Rs cannot be a (C,-Ce)alkyl optionally substituted by a hydroxy, or by a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S.

It has been found that these nicotinamide derivatives are inhibitors of . PDE4 isoenzymes, particulary useful for the treatment of inflammatory, respiratory and allergic diseases and conditions or for wounds by showing } excellent therapeutic utility and therapeutic index.

In the here above general formula (1), halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro. (C4-Ca)alkyl or (C+-Cg)alkyl radicals denote a straight-chain or branched group containing respectively 1 to 4 and 1 to 6 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in (C1-Cy)alkoxy radicals, {Cq-Ca)thioalkyl radicals, (C4-Cs)haloalky! radicals, hydroxy(C+-Cs)alkyl radicals, C(=0)O(C4-C,)alkyl radicals etc... . Examples of suitable (C4-C.)alkyl and (C4-Cg)alkyl radicals are methyl, ethyl, n-propyl, iso- — propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl. Examples of ( suitable (C1-Cy)alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy. Examples of suitable (Cs-

Caq)thioalkyl radicals are thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, thio- n-butyl, thio-iso-butyl, thio-sec-butyl and thio-tert-butyl. (C+-Cs)haloalky! radicals are alkyl radicals substituted by halo. They can contain 1, 2, 3, 4, 5, 6 or 7 halogen atoms, if not stated otherwise. Said halo is preferably a fluoro, a chloro, a bromo or a iodo, in particular fluoro or chloro. For example in a fluoro- substituted alkyl radical, a methyl group can be present as a trifluoromethyl group. The same applies to hydroxy(C1-C4)alkyi radicals except that they are alkyl radicals substituted by a hydroxy group (-OH). According to a preferred (a embodiment of said invention, such radicals contain one hydroxy substituent. ®

Examples of suitable hydroxy(C,-C,)alkyl radicals are hydroxymethyl, 1- hydroxyethyl or 2-hydroxyethyl. (Cs-Cs)cycloalkyl radicals represent 3-membered to 8-membered saturated monocyclic rings. Examples of suitable (C;3-Cg)cycloalkyl radicals are in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and } cyclooctyl. These radical can be optionally substituted as indicated in the definition of Rs. Examples of substituted (Cs-Cg)cycloalkyl radicals are for : example 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 5- © 30 methylcyclohexyl, ~~ 6-methyicyclohexyl, 2-hydroxycyclohexyl, | 3- hydroxycyclohexyl, 4-hydroxycyciohexyl, 5-hydroxycyclohexyl, 6-

hydroxycyclohexyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 5- fluorocyclohexyl, 6-fluorocyclohexyl 2-methyl-3-hydroxycyclohexyl, 2-methyl-4- hydroxycyclohexyt, 2-hydroxy-4-methylcyclohexyl, etc...

In the hereabove general formula (1), heteroaryl is a radical of a 3 monocyclic or polycyclic aromatic system having 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatom(s) depending in number and quality of the total number of ring members. Examples of heteroatoms are nitrogen (N), oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be identical or different. Heteroaryl radicals can also be unsubstituted, eo) 10 monosubstituted or polysubstituted, as indicated in the definition of Rs and R; hereabove for general formula (1) according to the present invention. Preferably heteroaryl is a monocyclic or bicyclic aromatic radical which contains 1,2, 3or 4, in particular 1, 2 or 3, identical or different heteroatoms selected from the group consisting of N, O and S. Particularly preferably, heteroaryl is a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-membered to 6-membered monocyclic aromatic radical which contains (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen heteroatom or 1 sulphur heteroatom or (i) 1 or 2 oxygen or sulphur heteroatom(s). Examples of suitable heteroaryl radicals are the radicals derivated from pyrrole, furan, furazan, thiophene, imidazole,

CY pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazine, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole, purine, naphthyridine, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, and benzo-fused derivatives of these heteroaryls, such as for example benzofuran, benzothiophene, benzoxazole, and benzothiazole.

Particularly preferred are the heteroaryl radicals selected from pyrrolyl, ) pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazoly!, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1.3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Nitrogen 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 substituent(s) can be located at any desired position(s). Also, when a radical is polysubstituted, said substituents can be identical or different, uniess otherwise stated. ]

The nicotinamide derivatives of the formula (1) can be prepared using conventional procedures such as by the following illustrative methods in which

Ry, Rp, Ra, Ry, X,Y, and Z are as previously defined for the nicotinamide derivatives of the formula (1) unless otherwise stated.

Where Z in the general formula (1) represents a group of partial formula ® (1.9) through (1.15), the nicotinamide derivatives of the formula (1) may be prepared starting from a compound of formula (2.1) : 0

R, x N _-YH

H

P (2.1)

R; N 3

R; where Ri, Ry, X, Ra and Y are as previously described for the nicotinamide derivatives of formula (1). | ®

Where Z represents a group of partial formula (1.11), (1.12) or (1.14), the compounds of formula (2.1) may be reacted with the corresponding Rs- sulfonyl chloride derivative (RsSO.Cl or R4NHSO,Cl or R4C(=0O)NHSOCI) in a suitable solvent (e.g. dichloromethane) and in the presence of an organic base (e.g. triethylamine) at a temperature ranging from 0°C to room temperature (about 20°C).

Where Z represents a group of partial formula (1.9), (1.13) or (1.15), the compounds of formula (2.1) may be reacted with the corresponding Ru- oo ‘carboxylic acid derivative (R¢COOH or RgSO;NH-CH,-COOH or R:C(=O)NH-

CH,-COOH) using an activating agent in the presence of a suitable solvent (e.g.

dimethylformamide) and organic base (e.g. N-methylmorpholine) at room temperature. Activation of the acid may be achieved by using for example : a) 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethyicarbodiimide hydrochloride, or 5S b) carbonyldiimidazole, or c) oxalyl chloride and dimethylformamide (with dichloromethane as the solvent), or . d) o-(7-azabenzotriazol-1-yl)-N,N,N’N-tetramethyluronium hexafluorophos- phate (HATU reagent).

CY) 10 Where Z represents a group of partial formula (1.10), the compounds of formula (2.1) may be reacted with carbonyldiimidazole in a suitable solvent (such as dichloromethane) or with a phosgene equivalent (such as triphosgene) and the obtained intermediate is reacted with an amine bearing the substituent

Rs. it must be emphasized that when Ri and Rs in the nicotinamide derivatives of formula (1) represent alkoxy substituted phenyl rings, these structures can be converted to the hydroxy analogue using certain deprotection conditions well-known by the one skilled in the art. Similarly when R, contains an ester functionality, these structures can be easily converted to the carboxylic ® 20 acid by simple saponification using alkali metal hydroxides well-known by the one skilled in the art.

The compounds of general formula (2.1) may be prepared by removal of the protecting group “Prot” from the compounds of general formula (3.1):

Oo © ~ NT pron

H

» (3.1) } Rs N 0

R,

wherein Ry, Ry, X, R; and Y are as previously described for the nicotinamide derivatives of formula (1) and Prot is a suitable protecting group, which includes but is not limited to benzyl or a carbamate (e.g. butoxycarbonyl), by methods well known to those skilled in the art.

The compounds of formula (3.1) may be prepared according to two synthetic routes. The first synthetic route is shown in scheme 1 : 0 0)

R

! NX OR’ R, AS OR’

NT ®

Rs N Cl R XH R; N X (6) 7) 51 Ro 6] | o

R, _Y

XX N ~ or i _ Ri OH

Ry” "NT TX | >

JY Ry” “NT TX

R, H,N Prot an

Scheme 1 { wherein Ry, Rz2, X, Rs, Y and Prot are as previously described and R' represents a (C;-Cs)alkyl radical.

In a typical procedure the nicotinate ester of the formula (6) may be reacted with the appropriate alcohol, thiol or amine of formula R3XH (7) in the appropriate solvent (for example dimethylformamide or dioxan) containing a base, such as cesium carbonate, at temperatures ranging from room temperature to 100°C to give a compound of the formula (5.1). This can be } saponified with an alkali-hydroxide to give an acid of the formula (4.1) which is then converted to a compound of the formula (3) by reaction with a monoprotected diamine of the formula NH>-Y-Prot, using an activating agent such as those described in one of the activation methods outlined before (re. a) 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide } hydrochloride or b) carbonyldiimidazole or c) oxalyl chloride and

S dimethylformamide or d) HATU reagent with dichloromethane as the solvent).

According to another alternative, the compounds of formula (3.1) may be prepared as shown in scheme 2 :

O 0 . R — - ~

RY NCI Ry” NT TC (6) (5.2)

SY

HN Prot i 0

R, Yo

XX R Yo

N Pot NT N” Prot = -— P H

PS ) RN 0 R,XH Ry” NT Tcl (3.1) ) (4.2)

Scheme 2 wherein Ry, Rz, X, R3, Y, R’ and Prot are as previously described.

In a typical procedure the nicotinate ester of the formula (6) may be hydrolysed using an alkaline metal hydroxide to a nicotinic acid of the formula (5.2), which is reacted with a monoprotected diamine of the formula NH,-Y-

Prot, using one of the activation methods outlined before. The chloropyridine of the formula (4.2) obtained at the preceding step may then be reacted with the appropriate alcohol, thiol or amine of formula R;XH (7) in the appropriate solvent (for example dimethylformamide or dioxan) containing a base, such as cesium carbonate, at temperatures ranging from room temperature (about 20°C) to 100°C.

The compounds of formula (6) and (7), as well as the monoprotected diamine of the formula NH,-Y-Prot, are either commercial or they can be prepared by conventional procedures well known to the one skilled in the art.

Where Y-Z in the general formula (1) represents together a group of partial formula (1.16), the nicotinamide derivatives of the formula (1) may be prepared starting from a compound of formula (2.2) : ®

COOH

0 Ir

R, Xn N

H (2.2) ~

R; N 0

Ry where Ry, R2, X, and Rs are as previously described for the nicotinamide derivatives of formula (1), by reaction of an amine bearing a R; substituent and using one of the activation methods outlined before.

The compounds of formula (2.2) may be prepared starting from the ® corresponding ester of formula (3.2) :

COOR" (rT

R, XN N

H 2

P (32)

R; N X

Rs - "wherein Ry, Rs, X and Ry are as previously described for the nicotinamide derivatives of formula (1) and R” represents a (C4-C.) alkyl radical or a benzyl radical. If R” represents a (C;-C,) alkyl radical, the compounds of formula (2.2)

are obtained via saponification according to the standard procedures, else the compounds of formula (2.2) are obtained via hydrogenation according to the standard procedures well known by the one skilled in the art. ) The compounds of formula (3.2) may be prepared according to two synthetic routes. The first synthetic route is shown in scheme 3 : 0 lo)

R eet i.

PY) Ry NC Ry” NT ct ). ©) (5.2) alkyl-4-amino- cyclohexyl! carboxylate

Y 1]

COOR'

COOR" @] wel Ie ! XX

R,XH “

R; NT x 3 R; N Ci (7)

Scheme 3 where Ry, Ra, X, Rs, R'and R” are as previously described.

In a typical procedure, the nicotinic acid of formula (5.2), which is obtained from a compound of formula (6) as previously described, may be reacted with an alkyl-4-aminocyclohexylcarboxylate using one of the activation method outlined before. The chloropyridine of formula (4.3) is then reacted with the appropriate alcohol, thiol or amine of formula R3XH (7) in the appropriate solvent (for example dimethylformamide or dioxan) containing a base, such as cesium carbonate, at temperatures ranging from room temperature (about 20°C) to 100°C.

According to another alternative, the compounds of formula (3.2) may also be prepared directly from compounds of formula (4.1) as previously ) described :

Oo

R

! | N OH

R NT X

2 | (4.1) ®

Rs by reaction with an alkyl-4-aminocyclohexylcarboxylate using one of the activation method outlined before. Said compound of formula (4.1) may be prepared as already described here above.

According to a final alternative, the nicotinamide derivatives of formula (1) may also be prepared by reaction of the acid of formula (4.1) as previously described:

Oo \

R, | IAN OH } ®

Z

ReONR ey

R; with an amine derivative of formula (8) : NHz-Y-Z-Ry, using one one of the activation method outlined before. Said compound of formula (4.1) may be prepared as already described here above.

The amine derivative of formula (8) may be prepared according to the ~ following scheme 4 © SIE --

z - N ——= HN

PLAN ~ Z FANG

HO R, Prot” “Y7 TR ZYTTTR } oY 4 4 (10) Prot—N (9) (8)

Scheme 4 wherein Rs, Z and Y are as previously described for the nicotinamide derivatives of formula (1) and Prot is a suitable protecting group, which includes

S buts not limited to benzyl or a carbamate (e.g. butoxycarbonyl). ® In a typical procedure, the protected amine Prot-NH-Y may be reacted with the acid of formula (10), using one of the activation methods outlined previously. Deprotection of the resulting compound of formula (9) by methods well known to those skilled in the art, affords the amine of formula (8).

The compounds of formula (10) as well as the monoprotected amine of the formula Y-Prot-NH-Y, are either commercial or they can be prepared by conventional procedures well known to the one skilled in the art.

All of the above reactions and the preparations of novel starting materials using in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as ® procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

For some of the steps of the here above described process of preparation of the nicotinamide derivatives of formula (1), it can be necessary to protect the potential reactive functions that are not wished to react. In such a case, any compatible protecting radical can be used. In particular methods such as those described by T.W. GREENE (Protective Groups in Organic

Synthesis, A. Wiley-Interscience Publication, 1981) or by McOMIE (Protective

Groups in Organic Chemistry, Plenum Press, 1973), can be used.

Also, the nicotinamide derivatives of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

According to a first aspect, particularly preferred are nicotinamide derivatives of the formula (1) in which: 4 R; and R, are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C4-Cas)alkyl and (C4-Cs)alkoxy, < Xis -O-, < Rj is a member selected from the groups consisting of : — (a) phenyl optionally substituted with 1 to 3 substituents each independently ( selected from the group consisting of halo, cyano, trifluoromethyl, trifiuoromethoxy, (Ci-Cs)alkyl or (C4-Ca)alkoxy, (Cs-Calthioalkyl, —C(=O)NHz, -

C(=O)NH ((C4-Cs)alkyl), hydroxy, -0-C(=0)(C4-Cy)alkyl, -C(=0)-0O-(C4-Ca)alkyl, hydroxy (C4-Ca)alkyl, (C3-Cs)cycloalky! and (C3-Cs)cycloalkyloxy, or (b) the bicyclic groups conforming to one of the following structures (1.1) to (1.4): ~ 7%

O 0 o—/ fo ® (1.1) (1.2) (1.3) (1.4) where the symbol +" indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1), + Y is a member selected from the group consisting of partial formulas (1.5) through (1.8):

H >" LA] Rs ot OE OT (1.5) (1.6) (1.7) (1.8)

where the symbol "+" indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions -NH- of formula (1) and “s+” indicates the point of attachment of each partial formula (1.5) through (1.8) to ] the remaining portions Z of formula (1), and wherein Rs is a member selected from the groups consisting of (C,-C,)alkyl and phenyl(C4-Cs)alkyl, where said phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, (Ci-Cs)alkyl, (Ci-Cg)alkoxy, hydroxy, hydroxy(C4-C)alkyl, carboxylic acid, -C(=0)-O-(C4-C4)alkyl, (C4-Cs)haloalkyt and ~C(=0)NH,,

Y), 10 < Z is a member selected from the group consisting of partial formulas (1.9) . through (1.11) and (1.15) : 0 i Oo. 0 0 H

EN . A BEEPS AA . xe H . .w . (1.9) (1.10) (1.11) (1.15) © where the symbol “+” indicates the points of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and "+" indicates the point of attachment of each partial formula (1 .9) through (1.11) and (1.135) to the remaining portions R, of formula (1), * or alternatively Y-Z together represents a group of formula (1.16): ) i

NH jon: (1.16) where the symbol “+” indicates the point of attachment of the partial formula . 20 (1.16) to the remaining portions —-NH- of formula (1) and “+” indicates the point of attachment of the partial formula (1.16) to the remaining portions —-R, of : formula (1), < and R4 is a member selected from the groups consisting of : (a) phenyl, naphthyl, heteroaryl and (C;-Cg)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group

Claims

1. A compound of the formula (1) : O i DE: Rj N X Rl in which : « R; and R; are each a member independently selected from the group @ consisting of hydrogen atom, halo, cyano, (C+-Cs)alkyl and (C4-Cs)alkoxy, Xis -O-, -S- or -NH-, 2 Rs is a member selected from the groups consisting of : (a) phenyl, naphthyl, heteroaryl and (C3-Cs)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethyloxy, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, (Ci-Cslthioaikyl, ~C(=O)NHj, —- C(=O)NH((C1-Cs)alkyl), hydroxy, -0-C(=0)(C4-Cy)alkyl, -C(=0)-0-(C+-Cs)alkyl, hydroxy(C1-Ca)alkyl, (C3-Cg)cycloatkyl and (C3-Cg)cycloalkyloxy, or (b) the bicyclic groups conforming to one of the following structures (1.1) to

(1.4): @® o—/ o)

(1.1) (1.2) (1.3) (1.4) where the symbol “+” indicates the point of attachment of each partial formula

(1.1) through (1.4) to the remaining portion of formula (1), : 20 VY is a member selected from the group consisting of partial formulas (1.5) : through (1.8) :

] } 3 Oo mT ot ; (1.5) (1.6) (1.7) (1.8) where the symbol “+” indicates the point of attachment of each partial formula

(1.5) through (1.8) to the remaining portions —NH- of formula (1) and “»»" indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1), ® and wherein Rs is a member selected from the groups consisting of (C-C,)alkyl 7 and phenyl(C4-Cy)alkyl, where said phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, (Ci-Cyalkyl, (C4-Cy)alkoxy, hydroxy, hydroxy(C1-C,)alkyl, carboxylic acid (-COOH), -C(=0)-0-(C1-Cy)alkyt, (C1-Ca)haloalkyl and - C(=O)NH,, < Z is a member selected from the group consisting of partial formuias (1.9) through (1.15) : 0 i 0, 0 o, 0

J . JN os AS

* .s H ‘x * HN [ 15 (1.9) (1.10) (1.11) (1.12) 0 o 0 9 7H ARN tr Cs . AA ) oo DE 0

(1.13) (1.14) (1.15) where the symbol “+” indicates the point of attachment of each partial formula : (1.9) through (1.15) to the remaining portions Y of formula (1) and “++” indicates the point of attachment of each partial formula (1.9) through (1.15) to the remaining portions R, of formula (1), “ or alternatively Y-Z together represents a group of formula (1.16):

0)

NH . jon:

(1.16) where the symbol “+” indicates the point of attachment of the partial formula

(1.16) to the remaining portions —NH- of formula (1) and “+” indicates the point of attachment of the partial formula (1.16) to the remaining portions —Rg of formula (1), 2 and Ru is a member selected from the groups consisting of : C3 (a) phenyl, naphthyl heteroaryl and (Cs-Cg)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOCH), -C(=0)-0-(C1-C4)alkyl, -(C4-C,)alkyl- COOH, -(Ci-Ca)alkyl-C(=0)-O-(C+-Ca)alkyl, halo, cyano, -C(=O)NHz, -(Ci- Ca)alkyl, -(C1-Cs)alkoxy, -(C4-Cy)haloalkyl, hydroxy and hydroxy(C,-Ca)alkyl, or (b) (C1+-Ce)alkyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, carboxylic acid, -C(=0)-O-(Cs- Ca)alkyl, phenyl, naphthyl, heteroaryl or (Cs-Cs)cycloalky! group, where said phenyl, naphthyl, heteroaryl and (Ca-Cs)cycloalkyl groups are each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOH), C(=0)0(C,-Ca)alkyl, halo, cyano, - @ C(=O)NHz, (C+-Ca)alkyl, (C+-Ca)alkoxy, (C1-Cs)haloalkyl, hydroxy and hydroxy(C1-Ca)alky!, or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates, polymorphs, isotopic variations and metabolites thereof, with the proviso that : 1) when: + Ry is selected from the group consisting of hydrogen atom, halo and methyl, #R,isa hydrogen atom, TD EE * Xis -O-,

< Rj is a phenyl substituted by a (C,-Calthioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo, (C4-C3)alkyl and (C1-Cj)alkoxy, > Y is a partial formula (1.5) or (1.8) : H Rs

(1.5) (1.8) where the symbol “+” indicates the point of attachment of each partial formula to ( the remaining portions —~NH- of formula (1) and “+” indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), and wherein Rs is a member selected from the groups consisting of (C4-C,)alky! and phenyl(C4-C4)alkyl, where said phenyl group is optionally substituted by halo, (C+-Cs)alkyl, (C4-Ca)alkoxy or hydroxy, and + Z is a radical -C(=0)- then R4 cannot be : a) a (C3-Cs)cycloalkyl optionally substituted by (Ci-Cj)alkyl, b) a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and ® heterocyclic ring are each optionally substituted by hydroxy, halo, (C;-Cj)alkyl 7 or (C1-Cj)alkoxy, or c) a (C4-Ce)alky! optionally substituted with a hydroxy, or with a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C1-Cs)alkyl or (C4-Cj)alkoxy, : 2) and when : “ R, is selected from the group consisting of hydrogen atom, halo and methyl, + Rjis a hydrogen atom, * Xis -O-,

< Rj is a phenyl substituted by a (C+-Ca)thioalkyl in the ~3 or —4 positicn of said phenyl and is aiso optionally substituted by 1 substituent selected from the group consisting of halo, (C4-Ca)alky! and (C;-Cs)alkoxy, and < Y-Z represents a partial formula (1.16): 0 NH jon:

(1.16) where the symbol “+ indicates the point of attachment of the partial formula ®

(1.16) to the remaining portions —NH- of formula (1) and “++” indicates the point of attachment of the partial formula (1.16) to the remaining portions —Rs of formula (1), then R4 cannot be : a) a (C3-Cg)cycloalky! or b) a (C+-Ce)alkyl optionally substituted by a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C4-Cs)alky! or (C4-Ca)alkoxy, 3) and when : ® « R, is selected from the group consisting of hydrogen atom, halo and methyl, + R, is a hydrogen atom, » Xis -O-, + Rj is a phenyl substituted by a (C-Ca)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 or 2 substituent(s) each independently selected from the group consisting of halo, (C4-Cs)alkyl and (Cs- C,)alkoxy, and % Y is a partial formula (1.6) :

(1.6) where the symbol “” indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and “=” indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), 9 and < Zis a radical -C(=Q)-, ® then Ry cannot be a (C4-Ce)alky! optionally substituted by a hydroxy, or by a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S.

2. A compound according to claim 1 wherein : < Ri and R; are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C1-Ca)alkyl and (C,-Cy)alkoxy, + Xis -O-, “* Rj is a member selected from the groups consisting of : (a) phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, trifluoromethyl, g ) trifluoromethoxy, (C4-Cs)alkyl or (C1-Cs)alkoxy, (C1-Cy)thioalkyl, ~C(=O)NH,, - B C(=O)NH((C-Ca)alkyl), hydroxy, -0-C(=0)(C4-Cs)alkyl, -C(=0)-0-(C+-Cy)alkyl, hydroxy(C,-Cg)alkyl, (C3-Cs)cycloalkyl and (C3-Csg)cycloalkyloxy, or (b) the bicyclic groups conforming to one of the following structures (1.1) to

(1.4): QQ o—/ 0

(1.1) (1.2) (1.3) (1.4)

where the symbol “+” indicates the point of attachment of each partial formula

(1.1) through (1.4) to the remaining portion of formula (1), < Y is a member selected from the group consisting of partial formulas (1.5) through (1.8) : H Rs ot or mT Ot

(1.5) (1.6) (1.7) (1.8) where the symbol “+” indicates the point of attachment of each partial formula CB

(1.5) through (1.8) to the remaining portions —NH- of formula (1) and “s+” indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1), and wherein Rs is a member selected from the groups consisting of (C4-Cy)alkyl and phenyl(C1-Ca)alkyl, where said phenyl group is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, cyano, {(Ci-Calalkyl, (Cs-Ca)alkoxy, hydroxy, hydroxy(C,-Cs)alkyl, carboxylic acid, -C(=0)-O-(C+-Ca)alkyt, (C1-Cs)haloalkyl and —C(=0)NH_, & 7 is a member selected from the group consisting of partial formulas (1.9) through (1.11) and (1.15) : i Pil 0, ,0 2 o" A A AN 0

(1.9) (1.10) (1.11) (1.15) where the symbol “+” indicates the points of attachment of each partial formula

(1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and “++” indicates the point of attachment of each partial formula (1.9) through (1.11) and (1.15) to the remaining portions R, of formula (1), < or alternatively Y-Z together represents a group of formula (1.16):

0 AA : NH A

(1.16) where the symbol "+" indicates the point of attachment of the partial formula

(1.16) to the remaining portions ~NH- of formula (1) and “++” indicates the point of attachment of the partial formula (1.16) to the remaining portions -R, of formula (1), [ * and Rs is a member selected from the groups consisting of : (a) phenyl, naphthyl, heteroaryl and (Cs-Cs)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOH), -C(=0)-0-(C4-Cq)alkyl, (C4-Cy)alkyl- COOH, (C4-Cy)alkyl-C(=0)-0-(C-Cy)alkyl, halo, cyano, -C(=O)NH,, (Ci- Cs)alkyl, (C4-Cs)alkoxy, (C4-Cs)haloalkyl, hydroxy and hydroxy(C4-C.)alkyl, or (b) (C+-Celalkyi optionally substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, carboxylic acid, -C(=0)-0-(C;- Cs)alkyl, phenyl, naphthyl, heteroaryl or (Cs-Cg)cycloalkyl group, where said phenyl, naphthyl, heteroaryl and (C3-Ce)cycloalkyl groups are each optionally ® substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid, C(=0)O(C,-Cs)alkyl, halo, cyano, —C(=O)NH,, (C;- Ca)alkyl or (C4-Cy)alkoxy, (Cy-Cy)haloalkyl, hydroxy and hydroxy(C,-C)alkyl, or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates, polymorphs, isotopic variations and metabolites thereof, with the proviso that : 1) when : * Ry is selected from the group consisting of hydrogen atom, halo and methyl, < Rz is a hydrogen atom, < Xis-O-,

< Rj is a phenyl substituted by a (C4-Cs)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo, (C4-Ca)alkyl and (C,-Ca)alkoxy, < Y is a partial formula (1.5) or (1.8) : H Rs

(1.5) (1.8) where the symbol “+” indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and "++" indicates the point of CB attachment of each partial formula to the remaining portions Z of formula (1), and wherein Rs is a member selected from the groups consisting of (C4-C.)alkyl and phenyl(C4-Cs)alkyl, where said phenyl group is optionally substituted by halo, (C1-Cs)alkyl, (C+-Cs)alkoxy or hydroxy, and < Z is a radical ~C(=0)- then R; cannot be : a) a (Cs-Cs)cycloalkyl optionally substituted by (C+-Cs)alkyl, b) a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C-Cs)alkyl @ or (C,4-Cs)alkoxy, or c) a (C1-Cg)alkyl optionally substituted with a hydroxy, or with a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C+-Cs)alky! or (Ci-Cs)alkoxy, 2) and when : : % R, is selected from the group consisting cf hydregen atom, halo and methyl. + Rjis a hydrogen atom, ) + Xis -O-,

* Rj is a phenyl substituted by a (C1-Ca)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo, (C+-Cj)alky! and (C-C3)alkoxy, and ] <* Y-Z represents a partial formula (1.16): 0 Co

(1.16) . where the symbol “+” indicates the point of attachment of the partial formula : (1.16) to the remaining portions ~NH- of formula (1) and “++” indicates the point of attachment of the partial formula (1.16) to the remaining portions —-R, of formula (1), then R, cannot be : a) a (C3-Cs)cycloalkyl or b) a (C4-Ce)alkyl optionally substituted by a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C4-C3)alkyl or (C1-Cj)alkoxy, ® 3) and when : “» Ri is selected from the group consisting of hydrogen atom, halo and methyl, “+ Rz is a hydrogen atom, < Xis -O-, + Ris a phenyl substituted by a (C1-Cs)thioalkyl in the ~3 or —4 position of said phenyl and is also optionally substituted by 1 or 2 substituent(s) each - independently selected from the group consisting of halo, (C+-Cj)alkyl and (C;- Cj;)alkoxy, and ’ Y is a partial formula (1.6) :

(1.6) where the symbol “+” indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and “=” indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), and % Z is a radical -C(=0O)-, then Rs cannot be a (C1-Ce)alkyl optionally substituted by a hydroxy, or by a 5- @ or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) : independently selected from N, O and S. 3A compound according to claim 1 wherein: & Ry and R, are each a member independently selected from the group consisting of hydrogen atom and halo, % Xis -O-, < Rj is a member selected from the groups consisting of : (a) phenyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, (Cq-Ca)alkyi, (C4-Cy4)altkoxy, trifluoromethyl, trifluoromethoxy, (Cs-Cg)cycloalkyl, (C»-Cs)cycloalkyloxy and CJ - (C1-Cajthioalkyl, or (b) the bicyclic groups conforming to one of the following structures (1.1), (1.3) or(1.4): Q, 2 Q o—/ I (iy (1.3). (1.4)

(1.1), (1.3) or (1.4) to the remaining portion of formula (1), < Y is a member selected from the group consisting of partial formulas (1.5) ) through (1.8) : H Re

(1.5) (1.6) (1.7) (1.8) [ where the symbol "+" indicates the point of attachment of each partial formula oo (1.5) through (1.8) to the remaining portions ~NH- of formula (1) and “s+” indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1), and wherein Rs is a phenyl(Cs-Cslalkyl where said phenyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of hydroxy, carboxylic acid, C(=0)O(C,-Cs)alkyl and hydroxy(C;- Ca)alkyl, «+ Z is a member selected from the group consisting of partial formulas (1.9) through (1.11) and (1.15) : bg RE SP al Oo

(1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and "++" indicates the point of attachment of each partial formula (1.9) through (1.11) and (1.195) to the remaining portions R of formula (1), +» or alternatively Y-Z together represents a group of formula (1.16):

Oo

NH . Jon:

(1.16) where the symbol “+" indicates the point of attachment of the partial formula

(1.16) to the remaining portions —NH- of formula (1) and “«+" indicates the point of attachment of the partial formula (1.16) to the remaining portions -R,4 of formula (1), < and R; is a member selected from the groups consisting of : ¢o (a) phenyl, naphthyl, heteroaryl and (Cs-Cg)cycloalkyl, each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (-COOH), -C(=0)-O-(Cy-Cs)alkyl, (C4-Cs)atkyl- COOH, (Ci-C,4)alkyl-C(=0)-0-(C1-Cy)alkyt, halo, (Ci-Cslalkyl, (C4-Cs)alkoxy, hydroxy(C,-Cs)alkyl and hydroxy, or (b) (Cs-Ce)alkyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, carboxylic acid, -C(=0)-O-(C;- Cs)alkyl, phenyl, naphthyl, heteroaryl or (C3-Cs)cycloaikyl group, where said phenyl, naphthyl, heteroaryl and (Cs-Cg)cycloalkyl groups are each optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid (COOH), C(=0)O(C,-Cys)alkyl, halo, (C4-Cs)alkyi, @ (C1-Cs)alkoxy, hydroxy(C4-C,s)alkyl and hydroxy, or, if appropriate, their pharmaceutically acceptable salts and/or iscmers, tautomers, solvates, polymorphs, isotopic variations and metabolites thereof, with the proviso that :

. 1) when : < R; is selected from the group consisting of hydrogen atom and halo, +“ Rzis a hydrogen atom, ¢Xis-0-, Ce

* Rj is a phenyl substituted by a (C,-Cy)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo and (C4-Cs)alky), ] ** Y is a partial formula (1.5) or (1.8): H Rs

(1.5) (1.8) where the symbol "+" indicates the point of attachment of each partial formula to ® the remaining portions —NH- of formula (1) and “s+” indicates the point of : attachment of each partial formula to the remaining portions Z of formula (1), and wherein Rs is a phenyl(C1-C,)alkyl, where said phenyl group is optionally substituted by hydroxy, and © Zis a radical -C(=0)- then Rs cannot be : a) a (Cs-Cs)cycloalkyl optionally substituted by (C1-Cs)alkyl, b) a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C4-Cj)alkyl © or (C4-Cj)alkoxy, or 4 c) a (C+-Ce)alky! optionally substituted with a hydroxy, or with a phenyt or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C1-Cs)alkyl or (C,-Cs)alkoxy, 2) and when : . <* Ry is selected from the group consisting of hydrogen atom and halo, » Rz is a hydrogen atom, % Xis -O-, * R3 is a phenyl substituted by a (C1-Co)thioalkyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of halo and (C+-Cj)alkyl, and

2 Y-Z represents a partial formula (1.16) : 0 NH :

(1.16) to the remaining portions —NH- of formula (1) and “==” indicates the point of attachment of the partial formula (1.16) to the remaining portions -R4 of formula (1), o then Rs cannot be : a) a (C3-Cs)cycloalkyl or b) a (C4-Ce)alkyl optionally substituted by a phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl and heterocyclic ring are each optionally substituted by hydroxy, halo, (C,-Cj)alkyl or (C4+-Ca)alkoxy, 3) and when : + R, is selected from the group consisting of hydrogen atom and halo, + Ris a hydrogen atom, < Xis -O-, @® + Rj is a phenyl substituted by a (C1-Cs)thioalkyt in the -3 or —4 position of said phenyl and is also optionally substituted by 1 substituent(s) selected from the group consisting of halo and (C+-Cj)alkyl, + VY is a partial formula (1.6) : Lr

(1.8) "where the symbol "+" indicates the point of attachment of each partial formula to the remaining portions —NH- of formula (1) and “«" indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), and % Z is a radical -C(=0)., then R; cannot be a (C1-Ce)alkyl optionally substituted by a hydroxy, or by a 5- 5S or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S. AA compound according to claim 1 wherein : ** Ry is a hydrogen atom or fluoro and R2 is a hydrogen atom, 9 * Xis -O-, 10% Rj is a member selected from the groups consisting of : (a) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyloxy, and methyithio, or (b) the bicyclic groups conforming to one of the following structures (1.1), (1.3) or (1.4): Q, ® o—/ D

(1.1) (1.3) (1.4) where the symbol "+" indicates the point of attachment of each partial formula

(1.1), (1.3) or (1.4) to the remaining portion of formula (1), » Y is a member selected from the group consisting of partial formulas (1.5) through (1.8): H Rs

(1.5) (1.6) (1.7) (1.8)

where the symbol “+" indicates the point of attachment of each partial formula

(1.5) through (1.8) to the remaining portions —NH- of formula (1) and “++” indicates the point of attachment of each partial formula (1.5) through (1.8) to the remaining portions Z of formula (1), and wherein Rs is a benzyl group substituted by a hydroxy substitutent on the ring, < 7 is a member selected from the group consisting of partial formulas (1.9) through (1.11) and (1.15) : i Bil 0, .0 TY A I CL

(1.9) through (1.11) and (1.15) to the remaining portions Y of formula (1) and

“.«" indicates the point of attachment of each partial formula (1 .9) through (1.11) and (1.15) to the remaining portions Rg of formula (1). < or alternatively Y-Z together represents a group of formula (1.16): O NH jog: . Qo

(1.16) to the remaining portions ~NH- of formula (1) and "+" indicates the point of attachment of the partial formula (1.16) to the remaining portions —Rs of formuta (1), + and Ry is a member selected from the groups consisting of : (a) phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of carboxylic acid, -C(=0)-O-methyi, fluoro, chloro, methyl, iso-propyl, methoxy and hydroxy, or (b) naphthyl! optionally substituted by a hydroxy, (c) pyridyl optionally substituted by a hydroxy or a ~C(=0)Omethyi group,

(d) a (Cs-Cs)cycloalkyl optionally substituted with a substituent selected from the group consisting of hydroxy, -C(=0)-0-(C;-C;)alky! and (C4-Cy)alkyl-C(=0)- O-(C4-Cy)alkyl, . (e) (Cy-Celalkyl optionally substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, carboxylic acid, -C(=0)Omethyl, —C(=0)O0ethyl, (C;-Cs)cycloalkyl and phenyl, where said phenyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of fluoro, chloro, methyl, methoxy and hydroxy, or, if appropriate, their pharmaceutically acceptable salts and/or isomers, @ 10 tautomers, solvates, polymorphs, isotopic variations and metabolites thereof, with the proviso that : 1) when : * Ry is selected from the group consisting of hydrogen atom and fluoro, <* R2 is a hydrogen atom, % Xis -O-, “ Rs is a phenyl substituted by a —S-methyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent selected from the group consisting of fluoro, chloro, methyl and ethyl, ® <Y is a partial formula (1.5) or (1.8) : 7 H Rs

(1.5) (1.8) where the symbol “+” indicates the point of attachment of each partial formula to the remaining portions -NH- of formula (1) and “++” indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), . and wherein Rs is a benzyl optionally substituted by hydroxy, and + Zis a radical -C(=0)- then R4 cannot be : a) an unsubstituted (C3-Cg)cycloalkyl,

b) a phenyl optionally substituted by hydroxy, fluoro, chloro, methyl, iso-propyl or methoxy or (C;-C3)alkoxy, c) a pyridyl optionally substituted by a hydroxy, or d) a (Cy-Ce)alkyl optionally substituted with a hydroxy, or with a phenyl . optionally substituted by hydroxy, fluoro, chloro, methyl or methoxy, 2) and when : + R; is selected from the group consisting of hydrogen atom and fluoro, “ R; is a hydrogen atom, 2 Xis -O-, + Rj; is a phenyl substituted by ~S-methyl in the —3 or —4 position of said o phenyl and is also optionally substituted by 1 substituent selected from the group consisting of fluoro, chloro, methyl and ethyl, and + Y-Z represents a partial formula (1.16) : 0 NH jon

(1.16) to the remaining portions ~NH- of formula (1) and “++” indicates the point ® of attachment of the partial formula (1.16) to the remaining portions —Ra of formula (1), then Ry cannot be : a) a (C3-Cg)cycloalkyl or b) a (Cy-Ce)alky! optionally substituted by a phenyl optionally substituted by hydroxy, fluoro, chloro, methyl and methoxy, 3) and when : : < R; is selected from the group consisting of hydrogen atom and fluoro, < Ris a hydrogen atom, EE Xis -O-,

< Rj is a phenyl substituted by ~-S-methyl in the —3 or —4 position of said phenyl and is also optionally substituted by 1 substituent(s) selected from the group consisting of fluoro, chloro, methyl and ethyl, . “* Y is a partial formula (1.6) : ie

(1.6) where the symbol “«” indicates the point of attachment of each partial formula to @ the remaining portions —NH- of formula (1) and “+” indicates the point of attachment of each partial formula to the remaining portions Z of formula (1), and «+ Zis a radical -C(=0)-, then R4 cannot be a (C1-Cs)alkyl optionally substituted by a hydroxy.

5. A compound according to claim 1 of formula : — CH, H N OF 5 ® ALT TT H ~ NT To gy

F

6. A compound according to claim 1 of formula

OH 0) T N 0 OH . NTO ot

F

7. A process for the preparation of a compound of the formula (1) as described CB “claim 1 wherein Z represent a group of partial formula (1.9) to (1.15), or a pharmaceutically acceptable salt or derived form thereof, characterized in that it comprises the step of reacting a compound of formula : 0 H (2.1) R; N 0 Rs, wherein R1, Rs, X, Rs and Y are as defined in claim 1, with the corresponding Rs-sulfonyl chloride derivative where Z represents a CB group of partial formula (1.11), (1.12) or (1.14), or with the corresponding Rs-carboxylic acid derivative where Z represents a group of partial formula (1.9), (1 13) or (1.15), or with carbonyldiimidazole where Z represents a group of partial formula

(1.10).

8. A process for the preparation of a compound of the formula (1) as described in claim 1 wherein Y-Z represents together a group of partial formuia (1.16) or a pharmaceutically acceptable salt or derived form thereof, characterized in that it Co comprises the step of reacting:a compound of formula:

COOH el . R, XN N

H 2.2 P (2:2) : R; N X R, wherein Ry, R,, X, and Rj; are as defined in claim 1, with an amine bearing a R, substituent.

® 9. A pharmaceutical composition including a compound of the formula (1) as 3 S defined in claim 1 or a pharmaceutically acceptable salt or derived form thereof, together with customary pharmaceutically innocuous excipients and/or additives.

10. A compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament.

11. A compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions in which the PDE4 isozymes are involved.

12. A compound of the formula (1) as defined in claim 1 or a pharmaceutically pot ® acceptable salt, derived form or composition thereof, for use in the treatment of inflammatory, respiratory and allergic diseases, disorders, and conditions and in the treatment of wounds.

13. A compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : ~~ » asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced . asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma and wheezy infant syndrome, « chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, eo « obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) and exacerbation of airways hyper-reactivity consequent to other drug therapy, « pneumoconiosis of whatever type, etiology, or pathogenesis, in particular CM pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers’ disease, anthracosis or miners’ asthma, asbestosis or steam-fitters’ asthma, chalicosis or flint disease, ptilesis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders’ disease, byssinosis or cotton-dust asthma and talc pneumoconiosis; e bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute : : bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, » bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis, ¢ seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of EJ whatever type, etiology, or pathogenesis, in particular sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or sphenoid sinusitis, » rheumatoid arthritis of whatever type, etiology, or pathogenesis, in particular rheumatoid arthritis that is a member selected from the group consisting of acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and vertebral arthritis, ® e gout, and fever and pain associated with inflammation, * an eosinophil-related disorder of whatever type, etiology, or pathogenesis, in particular an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia, pulmonary infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic ) aspergillosis, aspergilloma, granulomas containing eosinophils, allergic granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa : (PAN) and systemic necrotizing vasculitis, » atopic dermatitis, allergic dermatitis, contact dermatitis, or allergic or atopic eczema,

WO #3/068235 - PCT/IB03/00439 o urticaria of whatever type, etiology, or pathogenesis, in particular urticaria that is a member selected from the group consisting of immune- mediated urticaria, complement-mediated urticaria, urticariogenic material-induced urticaria, physical agent-induced urticaria, stress- induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal dominant form or in the acquired form, contact urticaria, giant urticaria and papular urticaria, « conjunctivitis of whatever type, etiology, or pathogenesis, in particular conjunctivitis that is a member selected from the group consisting of o" actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis and vernal conjunctivitis, + uveitis of whatever type, etiology, or pathogenesis, in particular uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis, e psoriasis, eo « 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, e autoimmunef/inflammatory diseases of whatever type, etiology, or pathogenesis, in particular an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis,

dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases, ulcerative colitis, endocrin opthamopathy, Grave's disease, ) sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type |, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, ® 10 minimal change nephropathy, inflammatory/hyperproliferative skin Cn? diseases, benign familial pemphigus, pemphigus erythematosus, pemphigus foliaceus, and pemphigus vulgaris, * prevention of allogeneic graft rejection following organ transplantation, » inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis, in particular inflammatory bowel disease that is a member selected from the group consisting of collagenous colitis, colitis polyposa, transmural colitis, ulcerative colitis and Crohn's disease (CD), ¢ septic shock of whatever type, etiology, or pathogenesis, in particular ® septic shock that is a member selected from the group consisting of > 20 renal failure, acute renal failure, cachexia, malarial cachexia, hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia suprarenalis or Addison's disease, cancerous cachexia and cachexia as a consequence of infection by the human immunodeficiency virus (HIV), e liver injury, » pulmonary hypertension of whatever type, etiology or pathogenesis . including primary pulmonary hypertension / essential hypertension, pulmonary hypertension secondary to congestive heart failure, pulmonary hypertension secondary to chronic obstructive pulmonary disease, pulmonary venous hypertension, pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension, + bone loss diseases, primary osteoporosis and secondary osteoporosis, e central nervous system disorders of whatever type, etiology, or pathogenesis, in particular a central nervous system disorder that is a member selected from the group consisting of depression, Alzheimers disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany Huntington's chorea, Wilson's disease, paralysis Qo agitans, and thalamic atrophies, o infection, especially infection by viruses wherein such viruses increase the production of TNF-a in their host, or wherein such viruses are sensitive to upregulation of TNF-a in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1, HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and Herpes viruses including Herpes zoster and Herpes simplex, + yeast and fungus infections wherein said yeast and fungi are sensitive to - upregulation by TNF-a or elicit TNF-a production in their host, e.g. ® fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but are not limited to, polymixins, e.g.

Polymycin B, imidazoles, e.g. clotrimazole, econazole, miconazole, and ketoconazole, triazoles, e.g. fluconazole and itranazole as well as amphotericins, e.g.

Amphotericin B and liposomal Amphotericin B, + ischemia-reperfusion injury, ischemic heart disease, autoimmune ’ diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV oo infections, lupus erythematosus, kidney and ureter disease, urogenital and gastrointestinal disorders and prostate diseases,

e reduction of scar formation in the human or animal body, such as scar formation in the healing of acute wounds, and e psoriasis, other dermatological and cosmetic uses, including antiphlogistic, skin-softening, skin elasticity and moisture-increasing activities.

14. The use of a compound of the formula (1) as defined in claim 1 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having a PDE4 inhibitory activity.

15. The use of a compound of the formula (1) as defined in claim 1 or of a pharmaceutically acceptable sait, derived form or composition thereof, for the manufacture of a drug useful in the treatment of inflammatory, respiratory and allergic diseases, disorders and conditions and in the treatment of wounds.

16. The use of a compound of the formula (1) as defined in 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 described in claim 13.

17. A compound according to claim 1, substantially as herein described and exemplified.

18. A process according to claim 7 or 8, substantially as herein described and exemplified.

19. A pharmaceutical composition according to claim 9, substantially as herein described and exemplified. The use of a compound according to claim 14, 15 or 16, substantially as herein AMENDED SHEET

261A described and exemplified.

AMENDED SHEET