Nicotinamide derivatives useful as PDE4 inhibitors Number:7,153,870 from the United States Patent and Trademark Office (PTO) owispatent This invention relates to nicotinamide derivatives of general formula (I): ##STR00001## in which R.sup.1, R.sup.2 and R.sup.3 have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.<H Nicotinamide, derivatives, Nicotinamide, de, 7153870.html, Patent, pto, 7153870

Title: Nicotinamide derivatives useful as PDE4 inhibitors

Abstract: This invention relates to nicotinamide derivatives of general formula (I): ##STR00001## in which R.sup.1, R.sup.2 and R.sup.3 have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

Patent Number: 7,153,870 Issued on 12/26/2006 to Mathias

Inventors: Mathias; John Paul (Sandwich, GB)
Assignee: Pfizer Inc. (New York, NY)

Appl. No.: 10/895,883

Filed: July 20, 2004

Foreign Application Priority Data


Jul 25, 2003 [GB]			0317509.8

Current U.S. Class: 514/336 ; 514/350; 546/268.1; 546/298

Current International Class: C07D 213/02 (20060101); A61K 31/44 (20060101)

Field of Search: 514/336,350 546/268.1,298

References Cited [Referenced By]

U.S. Patent Documents


6380218	April 2002	Marfat et al.
6559168	May 2003	Marfat et al.
6649633	November 2003	Chambers et al.
6740655	May 2004	Magee et al.
2002/0111495	August 2002	Magee et al.

Foreign Patent Documents


WO 9845268	Oct., 1998	WO
WO0157025	Aug., 2001	WO
WO0157036	Aug., 2001	WO
WO0260896	Aug., 2002	WO
WO 03/068232	Aug., 2003	WO
WO0368235	Aug., 2003	WO

Other References

Torphy et al., "Phosphodieterase IV Inhibitors as Therapy for Eosinophil-induced Lung Injury in Asthma", Environmental Health Perspectives, 1994, 102 Suppl. 10, p. 79-84. cited by other .
Duplantier et al., "Biarylcarboxylic Acids and -amides: Inhibition of Phospodiesterase Type IV verses [.sup.3H]Rolipram Binding Activity and Their Relationship to Emetic Behavior in the Ferret", J. Med. Chem., 1996, 39, p. 120-125. cited by other .
Schneider et al., "Discriminative Stimulus Properties of the Stereoisomers of the Phosphodiesterase Inhibitor Rolipram", Pharmacology Biochemistry Behavior, 1995, 50, p. 211-217. cited by other .
Banner and Page, "Acute versus chronic administration of phosphodiesterase inhibitors on allergen-induced pulmonary cell influx in sensitized guinea-pigs", British Journal of Pharmacology, 1995, 114, p. 93-98. cited by other .
Barnette et al., "The ability of phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity", J. Pharmacol. Exp. Ther., 1995, 273, p. 674-679. cited by other .
Wright et al., "Differential in vivo and in vitro bronchorelaxant activities of CP-80,633, a selective phosphodiesterase 4 inhibitor", Can. J. Physiol. Pharmacol., 1997, 75, p. 1001-1008. cited by other .
Manabe et al., "Anti-inflammantory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor", European Journal of Pharmacology, 1997, 332, p. 97-107. cited by other .
Ukita et al., "Novel Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives", J. of Med. Chem., 1999, 42, p. 1088-1099. cited by other .
PCT International Search Report, PCT/IB2004/002365. cited by other.

Primary Examiner: Davis; Zinna N.
Attorney, Agent or Firm: Ronau; Robert T. Goodman; Rosanne Ashbrook; Charles W.

Claims

The invention claimed is:

1. A compound of formula (I): ##STR00037## or a pharmaceutically acceptable salt or solvate thereof, wherein: R.sup.1 and R.sup.2 are each independently hydrogen, halo or (C.sub.1 C.sub.3)alkyl; and R.sup.3 is a 9- or 10-membered bicyclic heteroaryl containing from one to four nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted independently by one or two hydroxy, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy, hydroxy(C.sub.1 C.sub.4)alkyl or hydroxy(C.sub.2 C.sub.4)alkoxy.

2. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H, F, Cl or methyl.

3. A compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is F.

4. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is H or F.

5. A compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.2 is H.

6. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is a 9- or 10-membered bicyclic heteroaryl containing from one to three nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted independently by one or two hydroxy, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy or hydroxy(C.sub.1 C.sub.4)alkyl.

7. A, compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is a C-linked 9- or 10-membered bicyclic heteroaryl containing from one to three nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted independently by one or two hydroxy, F, Cl, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy or hydroxy(C.sub.1 C.sub.4)alkyl.

8. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is a C-linked 9- or 10-membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted independently by one or two groups selected from OH, (C.sub.1 C.sub.3)alkyl, (C.sub.1 C.sub.3)alkoxy and hydroxy(C.sub.1 C.sub.3)alkyl.

9. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is indolyl, isoindolyl, indolizinyl, indazolyl, benzoimidazolyl, imidazopyridyl, pyrrolopyridazinyl, pyrrolopyridyl, benzotriazolyl, pyrazolopyridyl, imidazopyridyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, quinazolinyl, phthalazinyl or naphthyridinyl, said R.sup.3 being optionally substituted independently by one or two hydroxy, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy, hydroxy(C.sub.1 C.sub.4)alkyl or hydroxy(C.sub.2 C.sub.4)alkoxy.

10. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is indazolyl, benzoimidazolyl, benzotriazolyl, imidazo[1,2-a]pyridyl, pyrrolo[1,2-b]pyridazinyl or quinolyl hydroxy, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy, hydroxy(C.sub.1 C.sub.4)alkyl or hydroxy(C.sub.2 C.sub.4)alkoxy.

11. A compound of claim 9 or 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.3 is optionally substituted by one or two hydroxy, methyl, ethyl, propyl, hydroxymethyl or hydroxyethyl.

12. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H, F, Cl or methyl; R.sup.2 is H or F; and R.sup.3 is a C-linked 9- or 10-membered bicyclic heteroaryl containing from one to three nitrogen atoms wherein the bicyclic heteroaryl is optionally substituted by one or two hydroxy, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy or hydroxy(C.sub.1 C.sub.4)alkyl.

13. A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is F; R.sup.2 is F; and R.sup.3 is indazolyl, benzoimidazolyl, benzotriazolyl, imidazo[1,2-a]pyridyl, pyrrolo[1,2-b]pyridazinyl or quinolyl, said R.sup.3 being optionally substituted independently by one or two hydroxy, methyl, ethyl, propyl, hydroxymethyl or hydroxyethyl.

14. Syn-Pyrazolo[1,5-a]pyridine-2-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-1-Isopropyl-1H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-2-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; Syn-1H-Indazole-3-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-2-Methyl-3H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-3H-Benzotriazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; Syn-Quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; Syn-3-Hydroxy-quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; or Syn-1-(2-Hydroxy-ethyl)-1H-indazole-3-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; or a pharmaceutically acceptable salt or solvate thereof.

15. Syn-2-Methyl-3H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfonyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-Quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; or Syn-3-Hydroxy-quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine -3-carbonyl]-amino}-cyclohexyl)-amide; or a pharmaceutically acceptable salt or solvate thereof.

16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient, diluent or carrier.

17. A method of treating a disease, disorder or condition in a mammal, which condition comprises administering to said mammal in need of such treatment a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient, wherein the disease, disorder or condition is selected from: 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, 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 aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, challcosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis', 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, cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis, and seasonal allergic rhinitis, perennial allergic rhinitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or sphenoid sinusitis.

18. A method of claim 17 wherein the disease, disorder or condition is chronic obstructive pulmonary disease, asthma or chronic bronchitis.

Description

This invention relates to nicotinamide derivatives of general formula (I):

##STR00002## in which R.sup.1, R.sup.2 and R.sup.3 have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

The 3',5'-cyclic nucleotide phosphodiesterases (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-translational processing of those gene products. The present invention is primarily concerned with the four gene products of the fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family.

The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models (see, e.g., Torphy et al., Environ. Health Perspect., 1994, 102 Suppl. 10, p. 79 84; Duplantier et al., J. Med. Chem., 1996, 39, p. 120 125; Schneider et al., Pharmacol. Biochem. 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 et 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.sup.+ T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4.sup.+ T-lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and potentially interfere with the ability of airway epithelial cells to generate pro-inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema. Therefore, PDE4 inhibitors are particularly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions and for wounds and some of them are in clinical development mainly for treatment of asthma, COPD, bronchitis and emphysema.

The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFa) release in eosinophils, neutrophils and monocytes.

Some nicotinamide derivatives having a PDE4 inhibitory activity have already been synthetized. For example, the patent application WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme.

The patent applications WO 01/57036 and WO 03/068235 also disclose nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory allergic and respiratory diseases and conditions.

However, there is still a huge need for additional PDE4 inhibitors that are good drug candidates. In particular, preferred compounds should bind potently to the PDE4 enzyme whilst showing little affinity for other receptors and enzymes. They should also possess favourable pharmacokinetic and metabolic activities, be non-toxic and demonstrate few side effects. Furthermore, it is also desirable that the ideal drug candidate will exist in a physical form that is stable and easily formulated.

The present invention therefore provides new nicotinamide derivatives of formula (I):

##STR00003## and pharmaceutically acceptable salts, pro-drugs, solvates and polymorphs thereof wherein: R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, halo and (C.sub.1 C.sub.3)alkyl; and wherein R.sup.3 is a 9- or 10-membered bicyclic heteroaryl containing from 1 to 4 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy, hydroxy(C.sub.1 C.sub.4)alkyl and hydroxy(C.sub.2 C.sub.4)alkoxy.

Preferably R.sup.1 is H, F, Cl or methyl, more preferably R.sup.1 is F.

Preferably R.sup.2 is H or F, more preferably R.sup.2 is H.

Preferably R.sup.3 is a 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heterocyclic ring system is optionally substituted by one or two groups selected from OH, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy and hydroxy(C.sub.1 C.sub.4)alkyl.

More preferably R.sup.3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, F, Cl, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy and hydroxy(C.sub.1 C.sub.4)alkyl.

Yet more preferably R.sup.3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or two groups selected from OH, (C.sub.1 C.sub.3)alkyl, (C.sub.1 C.sub.3)alkoxy and hydroxy(C.sub.1 C.sub.3)alkyl.

Particularly preferred R.sup.3 groups are selected from the group consisting of: indole, isoindole, indolizine, indazole, benzoimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, and naphthyridine.

Highly preferred R.sup.3 groups are selected from the group consisting of: indazole, benzoimidazole, benzotriazole, imidazo[1,2-a]pyridine, pyrrolo[1,2-b]pyridazine and quinoline.

Preferred optional substitutent groups for the bicyclic ring system of R.sup.3 are selected from OH, methyl, ethyl, propyl, hydroxymethyl and hydroxyethyl.

According to a further aspect the present invention provides compounds of formula (I) wherein R.sup.1 is H, F, Cl or methyl; R.sup.2 is H or F; and R.sup.3 is a C-linked 9 or 10 membered bicyclic heteroaryl containing from 1 to 3 nitrogen atoms wherein said bicyclic heteroaryl is optionally substituted by one or more groups selected from OH, halo, (C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)alkoxy and hydroxy(C.sub.1 C.sub.4)alkyl.

According to a preferred aspect the present invention provides compounds of formula (I) wherein R.sup.1 is F; R.sup.2 is F; and wherein the ring system of R.sup.3 is an optionally substituted bicyclic heteroaryl selected from the group consisting of: indazole, benzoimidazole, benzotriazole, imidazo[1,2-a]pyridine, pyrrolo-[1,2-b]pyridazine and quinoline.

Preferred compounds according to the present invention are selected from the group consisting of: Syn-Pyrazolo[1,5-a]pyridine-2-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-1-Isopropyl-1H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-2-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-1H-Indazole-3-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-2-Methyl-3H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridin-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-3H-Benzotriazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-Quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-3-Hydroxy-quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; and Syn-1-(2-Hydroxy-ethyl)-1H-indazole-3-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide and pharmaceutically acceptable salts, pro-drugs, solvates and polymorphs thereof.

More preferred compounds are selected from the group consisting of: Syn-2-Methyl-3H-benzoimidazole-4-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino- }-cyclohexyl)-amide; Syn-Imidazo[1,2-a]pyridine-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridin-3-carbonyl]-amino}-cyclohexyl)-amide; Syn-Quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl]-amino}-cyclohexyl)-amide; and Syn-3-Hydroxy-quinoline-8-carboxylic acid(4-{[5-fluoro-2-(3-methylsulfanyl -phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-amide and pharmaceutically acceptable salts, pro-drugs, solvates and polymorphs thereof.

The present invention additionally provides compounds of formula (I) wherein R.sup.1, R.sup.2, and R.sup.3 are as previously defined and wherein the optional substituent groups of R.sup.3 additionally comprise hydroxymethoxy.

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 or for wounds.

In the here above general formula (I), halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.

(C.sub.1 C.sub.3)alkyl or (C.sub.1 C.sub.4)alkyl radicals denote a straight-chain or branched group containing respectively 1 to 3 and 1 to 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in (C.sub.1 C.sub.4)alkoxy radicals and hydroxy(C.sub.1 C.sub.4)alkyl radicals. Examples of suitable (C.sub.1 C.sub.3)alkyl and (C.sub.1 C.sub.4)alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Examples of suitable (C.sub.1 C.sub.4)alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy. Hydroxy(C.sub.1 C.sub.4)alkyl and hydroxy(C.sub.2 C.sub.4)alkoxy radicals may contain more than one hydroxy group (--OH). According to a preferred embodiment of said invention, such radicals contain one hydroxy substituent. Examples of suitable hydroxy(C.sub.1 C.sub.4)alkyl radicals are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl.

In the hereabove general formula (I), "9- or 10-membered bicyclic heteroaryl" means a radical of a bicyclic aromatic system having 9 or 10 ring members, which contains 1, 2, 3 or 4 nitrogen (N) atom(s) depending in number and quality of the total number of ring members. Examples of additional, optional heteroatoms are oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be identical or different. Heteroaryl radicals can also be unsubstituted, monosubstituted or polysubstituted, as indicated in the definition of R.sup.3 hereabove for general formula (I) according to the present invention. Preferably bicyclic heteroaryl is a bicyclic aromatic radical which contains 1, 2 or 3 nitrogen (N). Examples of suitable bicyclic heteroaryl radicals are the radicals derivated from indole, isoindole, indolizine, indazole, purine, napthyridine, phthalazine, quinoline, quinazoline, quinoxaline, cinnoline, isoquinoline, benzoimidazole, imidazo[1,2-a]pyridine, benzotriazole, pyrazolo[1,5-a]pyridine and pyrazolopyrimidine. Particularly preferred are the bicyclic heterocyclic radicals selected from indole, isoindole, indolizine, indazole, benzoimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, and naphthyridine. Nitrogen bicyclic heteroaryl radicals can also be present as N-oxides or as quaternary salts.

In the general formula (I) 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, unless otherwise stated.

The nicotinamide derivatives of the formula (I) can be prepared using conventional procedures such as by the following illustrative methods in which R.sup.1, R.sup.2 and R.sup.3 are as previously defined for the nicotinamide derivatives of the formula (I) unless otherwise stated.

The compounds of formula (I) may be prepared by the methods disclosed hereunder, and exemplified in the Examples and Preparations. Other methods may be used in accordance with the skilled person's knowledge.

Unless otherwise provided herein: PyBOP.RTM. means Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate; PyBrOP.RTM. means bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; CDI means N,N'-carbonyldiimidazole; WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Mukaiyama's reagent means 2-chloro-1-methylpyridinium iodide; HATU means O-(7-Azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate; HBTU means O-Benzotriazol-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate; DCC means N,N'-dicyclohexylcarbodiimide; CDI means N,N'-carbonyldiimidazole; HOAT means 1-hydroxy-7-azabenzotriazole; HOBT means 1-hydroxybenzotriazole hydrate; Hunig's base means N-ethyldiisopropylamine; Et.sub.3N means triethylamine; NMM means N-methylmorpholine; NMP means 1-methyl-2-pyrrolidinone; DMAP means 4-dimethylaminopyridine; NMO means 4-methylmorpholine N-oxide; KHMDS means potassium bis(trimethylsilyl)amide; NaHMDS means sodium bis(trimethylsilyl)amide; DIAD means diisopropyl azodicarboxylate; DEAD means diethyl azodicarboxylate; DIBAL means diisobutylammonium hydride; Dess-Martin periodinane means 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; TBDMS-Cl means tert-butyldimethylchlorosilane; TMS-Cl means chlorotrimethylsilane; Boc means tert-butoxycarbonyl; CBz means benzyloxycarbonyl; MeOH means methanol, EtOH means ethanol, and EtOAc means ethyl acetate; THF means tetrahydrofuran; DMSO means dimethyl sulphoxide; DCM means dichloromethane; DMF means N,N-dimethylformamide; ACOH means acetic acid; TFA means trifluoroacetic acid; RT means room temperature; 3.degree. means tertiary; eq means equivalents; Me means methyl; Et means ethyl; Bn means benzyl; other abbreviations are used in accordance with standard synthetic chemistry practice.

Route A

##STR00004##

Nicotinic acids or acid derivatives of formula (II) are either available commercially or may be obtained by analogy with the methods of Haylor et. al. (EP 0634413 examples 9 and 10, pages 12 13), or Marzi et. al. (European Journal of Org. Chem. 2001 (7), 1371 1376). The protected amines of formula (III) are either available commercially or may be prepared by analogy with the method of Oku et al (WO 99/54284, for example, at page 80, preparation 77(1)).

In the scheme above, R.sup.1, R.sup.2 and R.sup.3 are as previously defined, PG is a suitable amine protecting group, typically Boc, CBz or Bn, and preferably Boc, and LG is a suitable leaving group, typically halo, and preferably Cl.

Step (a)--Acid-Amine Coupling.

This acid/amine coupling may be undertaken by using either: (i) an acyl chloride derivative of acid or acid derivative (II)+amine (III), with an excess of acid acceptor in a suitable solvent; or (ii) the acid or acid derivative (II) with a conventional coupling agent+amine (III), optionally in the presence of a catalyst, with an excess of acid acceptor in a suitable solvent.

Typically the conditions are as follows: (i) acid chloride of acid (II) (generated in-situ), an excess of amine (III), optionally with an excess of 3.degree. amine such as Et.sub.3N, Hunig's base or NMM, in DCM or THF, without heating for 1 to 24 hrs; or (ii) acid (II), WSCDI/DCC/CDI optionally in the presences of HOBT or HOAT, an excess of amine (III), with an excess of NMM, Et.sub.3N, Hunig's base in THF, DCM or EtOAc, at RT for 4 to 48 hrs; or, acid (II), PYBOP.RTM./PyBrOP.RTM./Mukaiyama's reagent, an excess of amine (III), with an excess of NMM, Et.sub.3N, Hunig's base in THF, DCM or EtOAc, at RT for 4 to 24 hrs.

The preferred conditions are: either treatment of (II) with oxalyl chloride and catalytic DMF in DCM at RT for 3 hours followed by the addition of Hunig's base or Et.sub.3N and the amine and stirring at RT for 18 hours; treatment of (II) with CDI in DMF at RT for 1 hour followed by the addition of the amine and stirring at RT for 72 hours.

Step (b)--Ether Formation

Substitution of the leaving group, LG, wherein said leaving group is for example a halogen and is preferably chlorine, of the compound (IV) with a substituted phenol to give compounds of formula (V).

Compounds of general formula (V) can be prepared from compounds of general formula (IV) via treatment with an optionally substituted, 3-methylsulphanyl-phenol in the presence of a suitable base, in a suitable solvent. Alkali metal salts are used as the base (e.g. Cs.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH) and MeCN, dioxan, toluene or NMP are suitable solvents for use. The reaction is carried out at elevated temperature.

Preferred conditions are: reaction of compound (IV), wherein the LG is chlorine, with an excess of optionally substituted, 3-methylsulphanyl-phenol in the presence of caesium carbonate in dioxan or MeCN at about 100.degree. C., optionally at reflux temperatures, for from about 24 to about 72 hours.

Step (c)--Removal of Protecting Group

Deprotection of the N protecting group (PG), from compounds of general formula (V) to provide compounds of general formula (VI) is undertaken using standard methodology, as described in "Protective Groups in Organic Synthesis" by T. W. Greene and P. Wutz.

For example when PG is Boc, the preferred conditions are: treatment of compound (V) with a strong acid (e.g. TFA, HCl), in a suitable solvent such as for example dioxan or DCM at room temperature. Preferred conditions herein for removal of a Boc group are treatment with hydrochloric acid (preferably 4M HCl) in dioxan at RT for about 5 hrs. Exemplified herein as preparation 18.

Step (d)--Reaction of De-Protected Amino Group with R.sup.3COOH

Compounds of the general formula (I) may be prepared by reaction of amines of general formula (VI) via treatment with a suitable acid of formula R.sup.3COOH according to the general methods described previously for step (a).

The preferred conditions are: treatment of a solution of amine (VI) and acid R.sup.3COOH in NMP or DMF, with WSCDI, HOBT and NMM or Hunig's base, at RT for from about 18 to about 72 hours.

The transformation (VI) to (I) is exemplified by Examples 1 to 9.

Route B

Compounds of general formula (I) may alternatively be prepared by the following route.

##STR00005##

The compound of formula (VII) may be prepared from the amine (III) by reaction with R.sup.3COOH according to the methods described previously in step (d), Route A. Preferred conditions provide stirring a solution of amine (III) in DCM with Hunig's base, HOBT, WSCDI and acid R.sup.3COOH at RT for about 48 hours.

The de-protected amine compound of general formula (VIII) may be prepared from the protected amine compound of general formula (VII) via removal of the protecting group PG, preferably a Boc group, by analogy to the methods described previously in step (c), Route A. Preferred conditions provide compounds of general formula (VIII) via treatment of a solution of (VII) in DCM at 0.degree. C. with bubbled hydrogen chloride gas for about 2 hours followed by stirring for about 90 minutes at RT.

The amide compounds of general formula (IX) may be prepared by reaction of the amine of general formula (VIII) with the acid (II) according to the methods described previously in steps (a) and (d), Route A. Preferred conditions provide amide (IX) via treatment of a solution of amine (VIII) and the appropriate nicotinic acid (II) in DCM with Hunig's base, HOBT and WSCDI with stirring for about 18 hours at RT.

Compounds of formula (I) may be prepared by substitution of the leaving group, LG, of the compounds of formula (IX) by an optionally substituted, 3-methylsulphanyl-phenol group as described previously in step (b), Route A. Preferred conditions provide compounds of general formula (I) via treatment of compounds of general formula (IX) and optionally substituted, 3-methylsulphanyl-phenol in MeCN and DMF in the presence of caesium carbonate at reflux temperatures from about 18 to about 36 hours.

The compounds of formula (I) may also be prepared by the process outlined in Route C.

Route C

##STR00006## wherein R.sup.alk represents a C.sub.1 C.sub.4 alkyl group or Bn, preferably a C.sub.1 C.sub.3 alkyl group and more preferably Et.

Compounds of formula (X) are either available commercially or may be obtained from the compounds of formula (II), using standard esterification conditions. The protected amines of formula (III) are either available commercially or may be prepared by analogy with the method of Oku et. al. (WO 99/54284) as described herein before.

Compounds of formula (XI) may be prepared by reaction of the ester (X) with optionally substituted, 3-methylsulphanyl-phenol, as described previously in step (b), Route A. Suitable optional catalysts for use in this reaction include CuI.

Preferred conditions for use herein are treatment with caesium carbonate in dioxan at about 100.degree. C. for about 48 hours. Exemplified herein by preparation 15.

Step (e)--Ester Hydrolysis

Hydrolysis of the ester (XI) may be achieved in the presence of acid or base, in a suitable solvent, optionally at elevated temperature to afford the acid (XII). Typically, the ester (XI) is treated with a suitable base such as an alkali metal hydroxide (eg LiOH, NaOH) or a carbonate base (eg K.sub.2CO.sub.3, Cs.sub.2CO.sub.3) in aqueous solvent (MeOH, EtOH, dioxan, THF) at RT, to give the acid (XII). Preferred conditions herein provide for treatment of ester (XI) in THF with a 1M aqueous solution of LiOH at RT for about 2 hours. Exemplified herein by preparation 16.

Alternatively compounds of formula (XII) may be prepared from compounds of formula (II) by reaction with optionally substituted 3-methylsulphanyl-phenol, as described previously in step (b), Route A.

Reaction of the acid of formula (XII) with the amine of formula (VIII) as described previously in Route A, step (a) and Route B, step (a) provides the compounds of formula (I). Preferred conditions herein for formation of compounds of formula (I) from the corresponding acid of formula (XII) are treatment of acid (XII) in DCM and DMF with oxalyl chloride for about 2 hours at RT (to form the acid chloride), followed by treatment with a solution of the amine (VIII) and Et.sub.3N in DCM at RT for about 48 hours.

Compounds of formula (V) as described in Route A, may alternatively be prepared by reaction of acid (XII) with the protected amine (III), according to the methods described for step (a), of Route A. This is exemplified herein by preparation 17.

Further Routes

Certain R.sup.3 groups may undergo further functional group interconversions (FGIs) and transformations, such as alkylation of a hydroxy substituent group, using a suitable alkylbromide, in the presence of a suitable alkali metal base (such as K.sub.2CO.sub.3), optionally in the presence of a catalyst (eg KI) in a suitable solvent such as acetonitrile and/or N,N-dimethylformamide at elevated temperature, or demethylation of a methoxy group by treatment with lithium iodide in pyridine or collidine, or by treatment with BBr.sub.3 in dichloromethane.

As detailed hereinbefore for certain compounds of the description, a suitable protecting group strategy may be employed. For example, a hydroxyl group may be protected using a tetrahydropyran group, and deprotection may be achieved by treatment with a solution of acetic acid:water:tetrahydrofuran (4:1:2 by volume) at RT for up to 18 hrs. Further, a benzyloxy group may be used and deprotected to give the corresponding hydroxyl compound, for example by using a reduction (e.g. with palladium black in acid).

For example, reaction of amine (VI) with a carboxylic acid of the formula, QR.sup.3COOH, wherein Q is an alcohol protecting group (eg THP or phenyl, preferably THP), to provide a protected amide can be carried out as described in step (c) of Scheme A. Preferred conditions for such reaction are: treatment of a solution of amine (VI) in NMP with the carboxylic acid, QR.sup.3COOH, HOBT, WSCDI and Hunig's base at RT for about 72 hours.

Removal of protecting group, Q, from the protected amide can be achieved by a standard method specific for that protecting group, as described in "Protective Groups in Organic Synthesis" by T. W. Greene and P. Wutz. Preferred conditions for such deprotection herein, when Q=THP, are: treatment of (VII) with a AcOH:water (4:1 by volume) mixture at about 60.degree. C. for about 17 hours. Protection/deprotection strategies are exemplified in Preparation 19 and in Example 10 herein.

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 (I), 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 (I) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

Thus according to a further embodiment the present invention provides a process for the preparation of a nicotinamide derivative of the formula (I) as described in claim 1 comprising: (i) reaction of amines of general formula (VI) via treatment with a suitable acid of formula R.sup.3COOH; or (ii) substitution of the leaving group, LG, of the compounds of formula (IX) by an optionally substituted, 3-methylsulphanyl-phenol group; or (iii) reaction of the acid of formula (XII) with the amine of formula (VIII) wherein formulae (VI), (IX) and (XII) are as defined hereinbefore.

The present invention additionally provides compounds of the general formulae (VI), (IX) and (XII) as defined hereinbefore.

According to a yet further embodiment the present invention provides processes for the preparation of compounds of general formulae (VI), (IX) and (XII) wherein said processes are as illustrated by steps (a), (b) and (c) Route A, steps (c) and (a) Route B and steps (b) and (e) Route C herein.

The nicotinamide derivatives of formula (I) may also be optionally transformed in pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the nicotinamide derivatives of the formula (I) include the acid addition and the base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodie, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L-tartrate, 1-hydroxy-2-naphtoate, 3-hydroxy-2-naphthoate and tosylate saltes.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002).

A pharmaceutically acceptable salt of a nicotinamide derivative of the formula (I) may be readily prepared by mixing together solutions of the nicotinamide derivative of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d.sub.6-acetone, d.sub.6-DMSO.

Also within the scope of the invention are clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are are present in non-stoichiometric amounts. For a review of such complexes, see J Pharm Sci, 64 (8), 1269 1288 by Haleblian (August 1975).

Hereinafter all references to nicotinamide derivatives of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.

The invention includes all polymorphs of the nicotinamide derivatives of formula (I).

Also within the scope of the invention are so-called "prodrugs" of the nicotinamide derivatives of formula (I). Thus certain derivatives of nicotinamide derivatives of formula (I) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to nicotinamide derivatives of formula (I) having the desired activity. Such derivatives are referred to as "prodrugs".

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the nicotinamide derivatives of formula (I) with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Finally, certain nicotinamide derivatives of formula (I) may themselves act as prodrugs of other nicotinamide derivatives of formula (I).

Nicotinamide derivatives of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a nicotinamide derivative of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the nicotinamide derivative contains, for example, a keto or oxime group, tautomeric isomerism (`tautomerism`) may occur. It follows that a single nicotinamide derivative may exhibit more than one type of isomerism.

Included within the scope of the present invention are all optical isomers, geometric isomers and tautomeric forms of the nicotinamide derivatives of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.

Conventional techniques for the preparation/isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.

The present invention also includes all pharmaceutically acceptable isotopic variations of a nicotinamide derivative of formula (I). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.

Examples of isotopes suitable for inclusion in the nicotinamide derivatives of the invention include isotopes of hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.13C and .sup.14C, nitrogen, such as .sup.15N, oxygen, such as .sup.17O and .sup.18O, phosphorus, such as .sup.32P, sulphur, such as .sup.35S, fluorine, such as .sup.18F, and chlorine, such as .sup.36Cl.

Substitution of the nicotinamide derivative of formula (I) isotopes such as deuterium, i.e. .sup.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Certain isotopic variations of the nicotinamide derivatives of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Isotopic variations of the nicotinamide derivatives of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.

According to a further aspect, the present invention concerns mixtures of nicotinamide derivatives of the formula (I), as well as mixtures with or of their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms and/or isotope forms.

According to the present invention, all the here above mentioned forms of the nicotinamide derivatives of formula (I) except the pharmaceutically acceptable salts (i.e. said solvates, polymorphs, isomeric forms and isotope forms), are defined as "derived forms" of the nicotinamide derivatives of formula (I) in what follows.

The nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutical active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the PDE4 enzymes are involved, in particular the inflammatory disorders, allergic disorders, respiratory diseases and wounds.

The nicotinamide derivatives of formula (I) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy or prophylaxis. They can be administered per se, in mixtures with one another or in combination with other drugs, or in the form of pharmaceutical preparations which permit enteral (gastric) or parenteral (non-gastric) administration and which as active constituent contain an efficacious dose of at least one nicotinamide derivative of the formula (I), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives. The term "excipient" is used herein to describe any ingredient other than the compound of the invention.

The choice of excipient will to a large extent depend on the particular mode of administration.

The nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.

Oral Administration

The nicotinamide derivatives of formula (I) their pharmaceutically acceptable salts and/or derived forms of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981 986 by Liang and Chen (2001).

The composition of a typical tablet in accordance with the invention may comprise:

TABLE-US-00001 Ingredient % w/w Nicotinamide derivative of formula (1) 10.00* Microcrystalline cellulose 64.12 Lactose 21.38 Croscarmellose sodium 3.00 Magnesium stearate 1.50 *Quantity adjusted in accordance with drug activity.

A typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion. The tablet formulation may comprise one or more layers and may be coated or uncoated.

Examples of excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti-oxidants, flavours and colourants.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 14 (2001). Other modified release formulations are described in U.S. Pat. No. 6,106,864.

Parenteral Administration

The nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and/or derived forms of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of nicotinamide derivatives of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.

Topical Administration

The nicotinamide derivatives of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated--see, for example, J Pharm Sci, 88 (10), 955 958 by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Thus nicotinamide derivatives of formula (I) may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.

Inhaled/Intranasal Administration

The nicotinamide derivatives of formula (I) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose in anhydrous or monohydrate form, preferably monohydrate, mannitol, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose or trehalose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as dichlorofluoromethane.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 .mu.g to 20 mg of the nicotinamide derivative of formula (I) per actuation and the actuation volume may vary from 1 .mu.l to 100 .mu.l. A typical formulation may comprise a nicotinamide derivative of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of the nicotinamide derivative of formula (I), a suitable powder base such as lactose or starch and a performance modifier such as 1-leucine, mannitol, or magnesium stearate.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 .mu.g to 4000 .mu.g of the nicotinamide derivative of formula (I). The overall daily dose will typically be in the range 1 .mu.g to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Sustained or controlled release can be obtained by using for example poly(D,L-lactic-co-glycolic acid).

Flavouring agents, such as methol and levomethol and/or sweeteners such as saccharing or saccharin sodium can be added to the formulation.

Rectal/Intravaginal Administration

The nicotinamide derivatives of formula (I) may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations