Classifications

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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
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  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

• This invention relates to a combination of nicotinamide derivatives of general formula :
• R R 2 , R3, 4, X, Y, n and m have the meanings indicated below, and a tiotropium salt, namely tiotropium bromide and to the uses of such combinations.
• the 3',5'-cyclic nucleotide phosphodiesterases comprise a large 10 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- 15 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 20 degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram.
• cAMP adenosine 3',5'-cyclic monophosphate
• a number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models (see, e.g., Torphy et al., Environ. Health Perspect. ,1994, 102 Suppl. 10, p. 79-84 ; Duplantier et al., J. Med. Chem., 1996, 39, p. 120-125 ; Schneider et al., Pharmacol. Biochem.
• PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bronchial responsiveness occurring after allergen challenge.
• PDE4 inhibitors also suppress the activity of immune cells (including CD4 + T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation.
• immune cells including CD4 + T-lymphocytes, monocytes, mast cells, and basophils
• eNANC excitatory nonadrenergic noncholinergic neurotransmission
• iNANC potentiate inhibitory nonadrenergic noncholinergic neurotransmission
• PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4 + T-lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and potentially interfere with the ability of airway epithelial cells to generate pro- inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema.
• PDE4 inhibitors are particularly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions, and for wounds and some of them are in clinical development mainly for treatment of asthma, COPD, bronchitis and emphysema.
• the effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study.
• TNF ⁇ tumor necrosis factor alpha
• nicotinamide derivatives having a PDE4 inhibitory activity have already been synthetized.
• 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 :
• A may be oxygen
• B may be NH
• r may be equal to 0
• E may be O
• R 5 may be a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group containing 1 to 4 heteroatoms and R 1 may be an aryl optionally substituted by various substituents.
• N° WO 01/57036 also discloses nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory allergic and respiratory diseases and conditions, of formula :
• n 1 or 2
• m 0 to 2
• Y C(R )- or -[N->(0)]-
• W is - 0-
• -S( 0)t- or -N(R 3 )-
• Q represents various rings among which phenyl
• Muscarinic receptor antagonists prevent the effects resulting from passage of impulses through the parasympathetic nerves. This action results from their ability to inhibit the action of the neurotransmitter acetylcholine by blocking its binding to muscarinic cholinergic receptors.
• muscarinic receptor subtypes There are at least three types of muscarinic receptor subtypes. Mi receptors are found primarily in brain and other tissue of the central nervous system, M 2 receptors are found in heart and other cardiovascular tissue, and M 3 receptors are found in smooth muscle and glandular tissues. The muscarinic receptors are located at neuroeffector sites on, e.g., smooth muscle, and in particular M 3 -muscarinic receptors are located in airway smooth muscle. Consequently, anti-cholinergic agents may also be referred to as muscarinic receptor antagonists.
• the parasympathetic nervous system plays a major role in regulating bronchomotor tone, and bronchoconstriction is largely the result of reflex increases in parasympathetic activity caused in turn by a diverse set of stimuli.
• Anti-cholinergic agents have a long history of use in the treatment of chronic airway diseases characterised by partially reversible airway narrowing such as COPD and asthma and were used as bronchodilators before the advent of epinephrine. They were thereafter supplanted by ⁇ 2-adrenergic agents and methylxanthines.
• ipratropium bromide has led to a revival in the use of anti-cholinergic therapy in the treatment of respiratory diseases.
• muscarinic receptors on peripheral organ systems such as salivary glands and gut and therefore systemically active muscarinic receptor antagonists are limited by dry mouth and constipation.
• muscarinic receptor antagonists are ideally produced by an inhaled agent which has a high therapeutic index for activity in the lung compared with the peripheral compartment.
• Anti-cholinergic agents also partially antagonize bronchoconstriction induced by histamine, bradykinin, or prostaglandin F 2 ⁇ , which is deemed to reflect the participation of parasympathetic efferents in the bronchial reflexes elicited by these agents.
• the anti-cholinergic tiotropium is a quaternary ammonium compound in structure, and central effects from this agent are generally lacking because such agents do not readily cross the blood-brain barrier.
• agents with these characteristics are inhaled, their actions are confined almost entirely to the mouth and airways. Even when inhaled at several times the recommended dose, these agents produced little or no change in heart rate, blood pressure, bladder function, intraocular pressure, or pupillary diameter. This selectivity results from the very inefficient absorption of these agents from the lung or gastrointestinal tract.
• Tiotropium and derivatives thereof disclosed in EP 0 418 716 B1 constitutes quaternary nitrogen compounds having the structure of Formula (I): wherein X- is a physiologically acceptable anion, especially bromide, and pharmaceutically acceptable solvates thereof.
• the present invention relates to novel PDE4 inhibitors of the nicotinamide family in combination with tiotropium or a derivative thereof, namely tiotropium bromide.
• novel PDE4 inhibitors of the present invention are nicotinamide derivatives of general formula (1 ) :
• ⁇ m 0, 1 , 2 or 3
• ⁇ n 0, 1 , 2 or 3,
• ⁇ Ri and R 2 are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C ⁇ -C 4 )alkyl and (C ⁇ -C 4 )alkoxy, ⁇ X is -0-, -S- or -NH-,
• ⁇ R 3 is a member selected from the groups consisting of :
• ⁇ Y is a member selected from the group consisting of partial formulas (1.5) through (1.11) :
• these nicotinamide derivatives are inhibitors of PDE4 isoenzymes, particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions and for the treatment of wounds by showing excellent therapeutic utility and therapeutic index.
• halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
• Examples of suitable (C ⁇ -C )alkyl radicals are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, /so-butyl, sec-butyl and etf-butyl.
• Examples of suitable (CrC 4 alkoxy radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, n-butyloxy, /so-butyloxy, sec-butyloxy and fetf-butyloxy.
• Examples of suitable (C ⁇ -C- 4 )thioalkyl radicals are thiomethyl, thioethyl, thio-n-propyl, thio- /so-propyl, t io-n-butyl, thio-/so-butyl, thio-sec-butyl and thio-tert-butyl.
• (C C )haloalkyl 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.
• a fluoro-substituted alkyl radical a methyl group can be present as a trifluoromethyl group.
• hydroxy(C ⁇ -C 4 )alkyl radicals except that they are alkyl radicals substituted by a hydroxy group (-OH). According to a preferred embodiment of said invention, such radicals contain one hydroxy substituent.
• suitable hydroxy(C ⁇ -C 4 )alkyl radicals are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl.
• (C 3 -C 8 )cycloalkyl radicals represent 3-membered to 8-membered saturated monocyclic rings.
• suitable (C 3 -C 8 )cycloalkyl radicals are in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. These radicasl can be optionally substituted as indicated in the definition of R 3 .
• substituted (C 3 -C 8 )cycloalkyl radicals are 2- methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 5-methylcyclohexyl, 6-methylcyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4- hydroxycyclohexyl, 5-hydroxycyclohexyl, 6-hydroxycyclohexyl, 2- fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 5-fluorocyclohexyl, 6- fluorocyclohexyl 2-methyl-3-hydroxycyclohexyl, 2-methyl-4-hydroxycyclohexyl, 2-hydroxy-4-methylcyclohexyl, etc... .
• heteroaryl is a radical of a 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.
• 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, monosubstituted or polysubstituted, as indicated in the definition of R 3 and R 4 hereabove for general formula (1 ) according to the present invention.
• the heteroaryl is a monocyclic or bicyclic aromatic radical which contains 1 , 2, 3 or 4, in particular 1 , 2 or 3, identical or different heteroatoms selected from the group consisting of N, O and S.
• the 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 (iii) 1 or 2 oxygen or sulphur heteroatom(s).
• heteroaryl radicals are the radicals derivated from pyrrole, furan, furazan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazine, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole, purine, naphtyridine, phthalazine, quinoline;- isoquinoline, quinoxaline, quinazoline, cinnoline, and benzo-fused derivatives of these heteroaryls, such as for example benzofuran, benzothiophene, benzoxazole, and benzothiazole.
• heteroaryl radicals selected from pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
• Nitrogen heteroaryl radicals can also be present as N-oxides or as quaternary salts.
• the nicotinamide derivatives of the formula (1 ) can be prepared using conventional procedures such as by the following illustrative methods in which R-i, R2, R3, R4, X, Y, n and m are as previously defined for the nicotinamide derivatives of the formula (1 ) unless otherwise stated.
• the nicotinamide derivatives of the formula (1) may be prepared starting from a compound of formula (2) :
• a suitable solvent e.g. dichloromethane
• an organic base e.g. triethylamine
• the compounds of formula (2) may be reacted with the corresponding R 4 -carboxylic acid derivative (R 4 COOH or R 4 S0 2 NH-CH 2 -COOH or R 4 C(0)NH-CH 2 -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.
• a suitable solvent e.g. dimethylformamide
• organic base e.g. N-methylmorpholine
• Activation of the acid may be achieved by using for example : a) 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, b) carbonyldiimidazole, or c) oxalyl chloride and dimethylformamide (with dichloromethane as the solvent).
• the compounds of formula (2) may be reacted with carbonyldiimidazole in a suitable solvent (such as dichloromethane) and the obtained intermediate is reacted with an amine bearing the substituent R 4 .
• a suitable solvent such as dichloromethane
• R3 and R 4 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 to the one skilled in the art.
• the compounds of general formula (2) may be prepared by removal of the protecting group "Prof from the compounds of general formula (3) :
• Ri, R2, X, R3, n and m 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 a benzyl group, a carbamate (e.g. te/f-butyloxycarbonyl), an amide (e.g. trifluoroacetamide) or an imide (e.g. phtalimide), using deprotection conditions well-known to the one skilled in the art.
• a suitable protecting group which includes but is not limited to a benzyl group, a carbamate (e.g. te/f-butyloxycarbonyl), an amide (e.g. trifluoroacetamide) or an imide (e.g. phtalimide), using deprotection conditions well-known to the one skilled in the art.
• Ri, R 2 , X, R 3 , n, m and Prot are as previously described and R' represents a (C- ⁇ -C 4 )alkyl radical.
• the nicotinate ester of the formula (6) may be reacted with the appropriate alcohol, thiol or amine of formula R 3 XH (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).
• the appropriate solvent for example dimethylformamide or dioxan
• a base such as cesium carbonate
• an activating agent such as those described in one of the activation methods outlined before (i.e. a) 1-hydroxybenzotriazole and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or b) carbonyldiimidazole or c) .
• oxalyl chloride and dimethylformamide, with dichloromethane as the solvent i.e. a) 1-hydroxybenzotriazole and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or b) carbonyldiimidazole or c) .
• oxalyl chloride and dimethylformamide, with dichloromethane as the solvent
• the compounds of formula (3) may be prepared as shown in scheme 2 :
• 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 (8) using one of the activation methods outlined before.
• the chloropyridine of the formula (4.2) obtained at the preceding step may be reacted with the appropriate alcohol, thiol or amine of formula R 3 XH (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.
• the monoprotected diamine of the formula (8) may be prepared by reaction of a large excess of a diamine of formula (9) :
• m and n are as defined above, with a suitable derivatizing agent such as di-fe/t-butyldicarboxylate (to give the ferf-butyloxycarbonyl derivative) at room temperature in a suitable solvent (such as dichloromethane).
• a suitable derivatizing agent such as di-fe/t-butyldicarboxylate (to give the ferf-butyloxycarbonyl derivative) at room temperature in a suitable solvent (such as dichloromethane).
• the compounds of formula (9) are commercial or they can be easily prepared by conventional procedures well known to the one skilled in the art.
• any compatible protecting radical can be used.
• methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by McOMIE (Protective Groups in Organic Chemistry, Plenum Press, 1973), can be used.
• nicotinamide derivatives of formula (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.
• m is different from 0 simultaneously with Y representing the partial formula (1.5) and R4 representing a non-substituted (C ⁇ -C 4 )alkyl,
• R 4 representing a phenyl, a naphtyl or a heteroaryl each optionally substituted with 1 to 3 substituents independently selected from the group consisting of carboxylic acid, halo, cyano, (C ⁇ -C 4 )alkyl,
• R 4 representing a phenyl or a naphtyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of carboxylic acid, halo, cyano, (C ⁇ -C 4 )alkyl, (Cr
• ⁇ m and n are equal to 1 ,
• ⁇ Ri and R 2 are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C ⁇ -C )alkyl and (C ⁇ -C )alkoxy,
• ⁇ X is -0-
• ⁇ R 3 is a member selected from the groups consisting of :
• ⁇ m and n are equal to 1 ,
• ⁇ Ri and R 2 are each a member independently selected from the group consisting of hydrogen atom, halo and methyl, ⁇ X is -O-,
• ⁇ and R 4 is a member selected from the groups consisting of :
• ⁇ Ri is a hydrogen atom or a fluoro and R 2 is a hydrogen atom, ⁇ X is -0-,
• nicotinamide derivatives of the formula (1) are as described in the Examples section hereafter, i.e. : 2-(4-Fluoro-phenoxy)-N- ⁇ 4-[(2-hydroxy-3-methyl-benzoyl amino)-methyl]-benzyl ⁇
• the nicotinamide derivatives of formula (1) may also be optionally transformed in pharmaceutically acceptable salts.
• these pharmaceutically acceptable salts of the nicotinamide derivatives of the formula (1 ) include the acid addition and the base salts thereof.
• Suitable acid addition salts are formed from mineral or organic non-toxic acids which form non-toxic salts. Suitable examples of these acid addition salts are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
• Suitable base salts are formed from bases, which form non-toxic salts, such as alkali metal salts, earth metal salts or addition salts with ammonia and physiologically tolerable organic amines.
• Suitable examples of these base salts are the sodium, potassium, aluminium, calcium, magnesium, zinc or ammonium salts as well as addition salts with triethylamine, ethanolamine, diethanolamine, trimethylamine, methylamine, propylamine, diisopropylamine, N,N- dimethylethanolamine, benzylamine, dicylohexylamine, N-benzyl- ⁇ - phenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, quinine, choline, arginine, lysine, leucine, dibenzylamine, tris(2-hydroxyethyl)amine, or ⁇ , ⁇ , ⁇ -tris(hydroxymethyl)methylamine.
• Salts can generally be obtained from the nicotinamide derivatives of the formula (1) according to customary procedures known to the person skilled in the art, for example by combining with an organic or inorganic acid or base solvent or dispersant, or alternatively from other salts by anion exchange or cation exchange.
• the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
• the nicotinamide derivatives of the formula (1 ) can also be present in stereoisomeric forms. If the nicotinamide derivatives of the formula (1 ) contain one or more centers of asymmetry, these can independently of one another have the (S) configuration or the (R) configuration.
• the invention includes all possible stereoisomers of the nicotinamide derivatives of the formula (1), for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios.
• the invention thus relates to enantiomers in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
• the invention likewise relates to diastereomers in diastereomerically pure form and in the form of mixtures in all ratios.
• the invention In the presence of cis/trans isomerism, the invention relates to both the cis form and the trans form and mixtures of these forms in all ratios.
• stereoisomers can be prepared, if desired, by use of stereochemically homogeneous starting substances in the synthesis, by stereoselective synthesis or by separation of a mixture according to customary methods, for example by chromatography, crystallization or by chromatography on chiral phases. If appropriate, derivatization can be carried out before separation of stereoisomers.
• a stereoisomer mixture can be separated at the stage of the nicotinamide derivatives of the formula (1) or at the stage of a starting substance or of an intermediate in the course of the synthesis.
• the compounds of the formula (1) according to the invention can moreover contain mobile hydrogen atoms, i.e. be present in various tautomeric forms.
• the present invention also relates to all tautomers of the compounds of the formula (1).
• the present invention furthermore includes other types of derivatives of nicotinamide derivatives of the formula (1 ), for example, solvates s ⁇ ch as hydrates and polymorphs, i.e. the various different crystalline structures of the nicotinamide derivatives according to the present invention.
• the present invention also includes all suitable isotopic variations of the nicotinamide derivatives of the formula (1) or a pharmaceutically acceptable salt thereof.
• An isotopic variation of the nicotinamide derivatives of the formula (1 ) or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
• Certain isotopic variations of the nicotinamide derivatives of the formula (1 ) and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e. 3 H, and carbon-14, i.e.
• isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e. 2 H, 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.
• isotopic variations of the nicotinamide derivatives of the formula (1) and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations sections hereafter using appropriate isotopic variations of suitable reagents.
• the present invention also concerns the active metabolites of the nicotinamide derivatives of the formula (1), i.e. the derivatives which are formed during the cellular metabolism and that are active on organism.
• active metabolites can be glucuronide derivatives, N-oxide derivatives or sulfonate derivatives of the compounds of the formula (1 ).
• the present invention concerns mixtures of nicotinamide derivatives of the formula (1), as well as mixtures with or of their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms, metabolites and/or isotope forms.
• the combinations of the present invention may be prepared using methodology, which is well understood by the artisan of ordinary skill.
• the various components of the overall composition are brought together in any practical order, which will be dictated largely by considerations of convenience. Those components having reduced water solubility, but sufficient solubility in the same co-solvent with water, may all be dissolved in said co-solvent, after which the co-solvent solution will be added to the water portion of the carrier whereupon the solutes therein will become dissolved in the water.
• a surfactant may be employed.
• the combination of the nicotinamide derivatives of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, with tiotropium or a derivative thereof are suitable for the therapy and prophylaxis of numerous disorders in which the PDE4 enzymes and the muscarinic receptors are involved, in particular the inflammatory disorders, allergic disorders and respiratory diseases.
• the nicotinamide derivatives of formula (1 ) and their pharmaceutically acceptable salts and derived forms as mentioned above with tiotropium or a derivative thereof 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, or in the form of pharmaceutical preparations, which permit administration thereof to the mammal to be treated and which contain in addition customary pharmaceutically innocuous excipients and/or additives.
• the present invention also relates to compositions containing an efficacious dose of a combination of at least one nicotinamide derivative of formula (1 ) and/or their pharmaceutically acceptable salts and/or derived forms, and tiotropium or a derivative thereof as defined above in addition to customary pharmaceutically innocuous excipients and/or additives.
• Such compositions are prepared according to well-known methods compatible with the standard pharmaceutical practice.
• Said compositions generally contain from 0.5 % to 60 % in weight of the active compound and from 40 % to 99.5 % in weight of excipients and/or additives.
• said excipients and/or additives are agents well known to the artisan for providing favourable properties in the final pharmaceutical composition.
• Typical excipients and/or additives include, but are by no mean limited to, acidifying and alkalizing agents, aerosol propellants, anti-microbial agents (including anti-bacterial, anti- fungal and anti-protozoal agents), antioxidants, buffering agents, chelating agents, dermatologically active agents, dispersing agents, suspending agents, emollients, emulsifying agents, penetration enhancers, preservatives, sequestering agents, solvents, stabilizers, stiffening agents, sugars, surfactants and flavouring agents.
• said compositions are prepared in a form compatible for the intended route of administration, which is used for any given patient, as well as appropriate to the disease, disorder or condition for which any given patient is being treated. Suitable routes of administration that can be envisaged include intranasal and pulmonary routes.
• nicotinamide derivatives of the formula (1 ), their pharmaceutically acceptable salts and/or their derived forms with tiotropium or a derivative thereof are preferably administered intra-nasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g.
• Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a nicotinamide derivative of the formula (1) and a suitable powder base such as lactose or starch. Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains from 1 ⁇ g to 4000 ⁇ g of a nicotinamide derivative of the formula (1) for delivery to the patient.
• the overall daily dose with an aerosol will be in the range of from 1 ⁇ g to 20 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.
• the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight, health state and sex of the patient as well as the severity of the disease, disorder or condition to treat, the optional combination with other treatment(s), the response of the particular patient and in general any factor peculiar to the concerned disease, disorder or condition and to the patient.
• the daily dose among men may usually contain from 50 mg to 5 g of active compounds for administration singly or two or more at a time, as appropriate. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
• compositions of the invention may also be used in combination with a cyclodextrin.
• Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
• the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
• ⁇ -, ⁇ - and ⁇ -cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
• the terms "in combination with” is intended to mean, and does refer to and include the following :
• nicotinamide derivatives of formula (1 ) inhibit the PDE4 isozyme and thereby have a wide range of therapeutic applications, as described further below, because of the essential role, which the PDE4 family of isozymes plays in the physiology of all mammals.
• the enzymatic role performed by the PDE4 isozymes is the intracellular hydrolysis of adenosine 3',5'-monophosphate (cAMP) within pro-inflammatory leukocytes.
• cAMP adenosine 3',5'-monophosphate
• PDE4 inhibition plays a significant role in a variety of physiological processes.
• a further aspect of the present invention relates to the use of the combinations of the instant invention in the treatment of diseases, disorders, and conditions in which the PDE4 isozymes and the muscarinic receptors are involved. More specifically, the present invention also concerns the combination of the invention, 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 whez infant syndrome, • chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema,
• obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) and exacerbation of airways hyper-reactivity consequent to other drug therapy,
• COPD chronic osinophilic pneumonia
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• COPD 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
• pneumoconiosis of whatever type, etiology, or pathogenesis in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis,
• bronchitis of whatever type, etiology, or pathogenesis in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,
• branch iectasis of whatever type, etiology, or pathogenesis in particular branch iectasis 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 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,
• an eosinophil-related disorder of whatever type, etiology, or pathogenesis in particular an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia, pulmonary infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, granulomas containing eosinophils, allergic granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotizing vasculitis,
• PAN polyarteritis nodosa
• 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, and
• 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.
• 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.
• a still further aspect of the present invention also relates to the use of the combinations of the invention, for the manufacture of a drug having a PDE4 inhibitory activity and an anti-muscarinic activity.
• the present inventions concerns the use of the combinations of the invention, for the manufacture of a drug for the treatment of inflammatory, respiratory and allergic diseases, disorders, and conditions and more precisely for the treatment of diseases, disorders, and conditions that are listed above.
• the present invention provides a particularly interesting method of treatment of a mammal, including a human being, with a combination of a PDE4 inhibitor and tiotropium including treating said mammal with an effective amount of a combination of the invention. More precisely, the present invention provides a particularly interesting method of treatment of a mammal, including a human being, to treat an inflammatory, respiratory and allergic disease, disorder or condition, including treating said mammal with an effective amount of a combination of a nicotinamide derivative of formula (1 ), its pharmaceutically acceptable salts and/or derived forms with tiotropium or a derivative thereof.
• reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure.
• Example 14 were prepared by a similar method to that of Example 14 using the appropriate carboxylic acid starting material.
• Example 18 1 H NMR (400MHz, CDCI 3 ): ⁇ 8.55-8.61 (1 H, d), 8.18-8.23 (1 H, m), 8.15-8.18 (1 H, d), 7.90-7.94 (1 H, d), 7.78 (1 H, s), 7.43-7.49 (1 H, t), 7.26-7.30 (1 H, d), 7.18-7.25 (2H, m), 7.04-7.17 (3H, m), 6.95-7.01 (2H, d), 6.64-6.75 (3H, m), 6.17-6.24 (1 H, m), 4.58-4.68 (2H, d), 4.30-4.40 (4H, m), 3.46 (2H, s), 1.32-1.40 (3H, t) ppm.
• LRMS electrospray
• the pH of the aqueous phase was then adjusted to pH higher than 8 by addition of 0.88 ammonia and extracted with dichloromethane (3-fold 200 ml).
• the combined organic extracts were then dried over anhydrous magnesium sulphate and the solvent removed in vacuo giving (4-aminomethyl-benzyl)-carbamic acid ferf-butyl ester (4.29 g) as a white solid.
• reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was then triturated with diethylether (2-fold 10 ml) to give (4- ⁇ [(2-chloro-pyridine-3-carbonyl)-amino]- methyl ⁇ -benzyl)-carbamic acid ferf-butyl ester (6.71 g) as a white solid.
• PREPARATION 8 3-(3-r4-tert-Butoxycarbonylamino-methyl)-benzylcarba- mov ⁇ -pyridin-2-yloxy>-benzoic acid ethyl ester
• Ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (see reference J. Med. Chem., 1993, 36(18), 2676-88) was dissolved in tetrahydrofuran (350 ml) and a 2 M aqueous solution of lithium hydroxide (247 ml, 0.495 mol) added. The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to pH equal to 1 by addition of 6N hydrochloric acid and then extracted with dichloromethane.
• the PDE4 inhibitory activity of the nicotinamide derivatives of the formula (1) is determined by the ability of compounds to inhibit the hydrolysis of cAMP to AMP by PDE4 (see also reference 1). Tritium labelled cAMP is incubated with PDE4. Following incubation, the radiolabelled AMP produced is able to bind ytrium silicate SPA beads. These SPA beads subsequently produce light that can be quantified by scintillation counting. The addition of a PDE4 inhibitor prevents the formation of AMP from cAMP and counts are diminished.
• the IC 50 of a PDE4 inhibitor can be defined as the concentration of a compound that leads to a 50% reduction in counts compared to the PDE4 only (no inhibitor) control wells.
• the anti-inflammatory properties of the nicotinamide derivatives of the formula (1 ) are demonstrated by their ability to inhibit TNF ⁇ release from human peripheral blood mononuclear cells (see also reference 2).
• Venous blood is collected from healthy volunteers and the mononuclear cells purified by centrifugation through Histopaque (Ficoll) cushions. TNF ⁇ production from these cells is stimulated by addition of lipopolysaccharide. After 18 hours incubation in the presence of LPS, the cell supernatant is removed and the concentration of TNF ⁇ in the supernatant determined by ELISA. Addition of PDE4 inhibitors reduces the amount of TNF ⁇ produced. An IC 50 is determined which is equal to the concentration of compound that gives 50% inhibition of TNF ⁇ production as compared to the LPS stimulated control wells.

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