US20130005716A1 - Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors - Google Patents

Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors Download PDF

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US20130005716A1
US20130005716A1 US13/488,818 US201213488818A US2013005716A1 US 20130005716 A1 US20130005716 A1 US 20130005716A1 US 201213488818 A US201213488818 A US 201213488818A US 2013005716 A1 US2013005716 A1 US 2013005716A1
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Prior art keywords
oxide
ethyl
phenyl
carbonyloxy
difluoromethoxy
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Inventor
Elisabetta Armani
Gabriele Amari
Laura Carzaniga
Carmelida Capaldi
Oriana Esposito
Gino Villetti
Renato De Fanti
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMARI, GABRIELE, ARMANI, ELISABETTA, CAPALDI, Carmelida, CARZANIGA, LAURA, DE FANTI, RENATO, ESPOSITO, Oriana, VILLETTI, GINO
Publication of US20130005716A1 publication Critical patent/US20130005716A1/en
Priority to US14/048,651 priority Critical patent/US20140057882A1/en
Priority to US14/863,915 priority patent/US9931327B2/en
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the present invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them, and therapeutic uses of such compounds and compositions.
  • PDE4 phosphodiesterase 4
  • Airway obstruction characterizes a number of severe respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, increased mucous production and inflammation.
  • COPD chronic obstructive pulmonary disease
  • Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation.
  • One of the advantages of the inhalatory route over the systemic one is the possibility of delivering the drug directly at site of action, reducing systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
  • Inhaled corticosteroids are the current maintenance therapy of choice for asthma and together with bronchodilator beta 2 -agonists for acute symptom relief, they form the mainstay of current therapy for the disease.
  • the current management of COPD is largely symptomatic by means of bronchodilating therapy with inhaled anticholinergics and inhaled beta 2 -adrenoceptor agonists.
  • corticosteroids do not reduce the inflammatory response in COPD as they do in asthma.
  • PDEs phosphodiesterases
  • PDE4 inhibitors Various compounds acting as PDE4 inhibitors have been disclosed in the prior art. However, the usefulness of several PDE4 inhibitors of the first-generation such as rolipram and piclamilast has been limited due to their undesirable side effects. Said effects include nausea and emesis due to their action on PDE4 in the central nervous system and gastric acid secretion due to the action on PDE4 in parietal cells in the gut.
  • PDE4 exists in two distinct forms representing different conformations, that were designated as high affinity rolipram binding site or HPDE4, especially present in the central nervous system and in parietal cells, and low affinity rolipram binding site or LPDE4 (see Jacobitz, S et al., Mol. Pharmacol., 1996, 50, 891-899, which is incorporated herein by reference in its entirety), which is found in the immune and inflammatory cells. While both forms appear to exhibit catalytic activity, they differ with respect to their sensitivity to inhibitors. In particular compounds with higher affinity for LPDE4 appear less prone to induce side-effects such as nausea, emesis and increased gastric secretion.
  • roflumilast is under dosed in order to achieve an acceptable side effect profile.
  • EP 1 634 606 discloses, among others, ketone derivatives like benzofuran or 1,3-benzodioxole derivatives.
  • WO 94/02465 discloses, among others, ketone derivatives of general formula
  • R 1 is lower alkyl and R 2 may be alkyl, alkenyl, cycloalkyl, cycloalkyl, cycloalkenyl, cyclothioalkyl or cyclothioalkenyl.
  • WO 95/35281 in the name of Celltech Therapeutics relates to tri-substituted phenyl derivatives.
  • WO 2009/018909 discloses derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
  • PDE4 phosphodiesterase 4
  • WO 2009/077068 discloses further derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
  • PDE4 phosphodiesterase 4
  • WO 2010/089107 discloses further derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
  • PDE4 phosphodiesterase 4
  • Such reduction of side effects may be achieved, by way of example, through a low systemic exposure of the drug; an appropriate profile in terms of some pharmacokinetic characteristics, especially metabolic clearance, may be thus key to this goal.
  • the present invention is directed to compounds acting as inhibitors of the phosphodiesterase 4 (PDE4) enzyme, methods of preparing said compounds, compositions containing them and therapeutic use thereof.
  • PDE4 phosphodiesterase 4
  • the present invention is directed to derivatives of 1-phenyl-2-pyridinyl alkyl alcohols of general formula (I):
  • R 19 is hydrogen or, if different from hydrogen, it forms together with R 2 a group of formula (x) wherein bonds labeled with (1) and (2) indicate the points of attachment for group (x) to atoms bearing groups R 19 and R 2 respectively
  • R 3 is one or more substituents independently selected from the group consisting of H, CN, NO 2 , CF 3 and a halogen atom;
  • Z is a group —(CH 2 ) n — wherein n is 0 or 1;
  • A is a saturated and monocyclic (C 3 -C 7 )heterocycloalkylene group;
  • K is selected from the group consisting of:
  • the invention is directed to derivatives of 1-phenyl-2-pyridinyl alkyl alcohols of general formula (IG):
  • R 1 is selected from the group consisting of:
  • R 19 is hydrogen;
  • R 3 is one or more substituents independently selected from the group consisting of H, CN, NO 2 , CF 3 and a halogen atom;
  • Z is a group —(CH 2 ) n — wherein n is 0 or 1;
  • A is a saturated and monocyclic (C 3 -C 7 )heterocycloalkyl-ene group;
  • K is selected from the group consisting of:
  • invention is directed to derivatives of 1-phenyl-2-pyridinyl alkyl alcohols of general formula (IL):
  • R 1 and R 2 are different or the same and are independently selected from the group consisting of:
  • the present invention further provides the corresponding N-oxides on the pyridine ring of compounds of formula (I).
  • the present invention also provides the pharmaceutically acceptable salts and/or solvates thereof.
  • pharmaceutically acceptable salts refers to derivatives of compounds of formula (I) or of their corresponding N-oxides on the pyridine ring wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts within the invention comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.
  • Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • the present invention further provides a process for the preparation of compounds of the invention.
  • the present invention also provides pharmaceutical compositions of compounds of the invention either alone or in combination, in admixture with one or more pharmaceutically acceptable carriers.
  • the present invention provides the use of the compounds of the present invention as a medicament.
  • the present invention provides the use of the compounds of the present invention for the manufacture of a medicament.
  • the present invention provides the use of the compounds of the present invention for the prevention and/or treatment of any disease characterized by phosphodiesterase 4 (PDE4) overactivity and/or wherein an inhibition of PDE4 activity is desirable.
  • PDE4 phosphodiesterase 4
  • the compounds of the present invention alone or combined with other active ingredients may be administered for the prevention and/or treatment of a disease the respiratory tract characterized by airway obstruction such as asthma and COPD.
  • the present invention provides the use of compounds of the present invention for the preparation of a medicament for the prevention and/or treatment of any disease characterized by phosphodiesterase 4 (PDE4) overactivity and/or wherein an inhibition of PDE4 activity is desirable.
  • PDE4 phosphodiesterase 4
  • the present invention provides methods for prevention and/or treatment of any disease wherein PDE4 inhibition is desiderable, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.
  • halogen atoms as used herein includes fluorine, chlorine, bromine, and iodine, preferably chlorine.
  • (C 1 -C x )alkyl where x is an integer greater than 1, refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x.
  • Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, and t-butyl.
  • (C 1 -C x )alkylene refers to a divalent (C 1 -C x )alkyl radical, wherein (C 1 -C x )alkyl is as above defined.
  • (C I -C x )alkoxyl where x is an integer greater than 1, refers to straight-chained and branched alkoxy groups wherein the number of constituent carbon atoms is in the range 1 to x.
  • Particular alkyl groups are methoxyl, ethoxyl, n-propoxyl, isopropoxyl, and t-butoxyl.
  • (C 1 -C x )haloalkyl refer to the above defined “(C 1 -C x )alkyl” groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different from each other.
  • Examples of said (C 1 -C 6 )haloalkyl groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl groups.
  • (C 3 -C y )cycloalkyl refers to saturated cyclic hydrocarbon groups containing from 3 to y ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • (C 3 -C y )heterocycloalkyl refers to monocyclic (C 3 -C y )cycloalkyl groups, in which at least one ring carbon atom is replaced by a heteroatom (e.g. N, NH, S or O).
  • a heteroatom e.g. N, NH, S or O.
  • Non-limiting examples of (C 3 -C y )heterocycloalkyl are represented by: pyrrolidinyl, thiazolidinyl, piperazinyl, piperidnyl, morpholinyl, thiomorpholinyl, and azetidinyl.
  • (C 3 -C y )heterocycloalkyl-ene refers to a divalent (C 3 -C y )heterocycloalkyl radical, wherein (C 3 -C y )heterocycloalkyl is as above defined.
  • (C 3 -C y )cycloalkylcarbonyl refers to (C 3 -C y )cycloalkylCO— groups wherein the group “(C 3 -C y )cycloalkyl” has the meaning above defined.
  • (C 2 -C 6 )alkenyl refers to straight or branched, conjugated or non-conjugated, carbon chains with one or more double bonds, in cis or trans configuration, wherein the number atoms is in the range 2 to 6.
  • (C 5 -C z )cycloalkenyl refers to cyclic hydrocarbon groups containing from 5 to z ring carbon atoms and one or more double bonds.
  • (C 2 -C 6 )alkynyl refers to straight or branched carbon chains with one or more triple bonds wherein the number of atoms is in the range 2 to 6.
  • (C 3 -C y )heterocycloalkyl(C 1 -C x )alkyl refers to the above “(C r C x )alkyl” group wherein one or more hydrogen atoms are replaced by one or more “(C 3 -C y )heterocycloalkyl” groups.
  • ring system refers to mono- or bicyclic ring systems which may be saturated, partially unsaturated or unsaturated, such as aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl or heteroaryl, having 5 to 11 ring atoms in which at least one ring atom is a heteroatom (e.g. N, S or O).
  • aryl refers to mono or bi-ring systems which have 6 to 10 ring atoms, wherein at least one ring is aromatic.
  • heteroaryl refers to mono or bi-ring systems with 5 to 11 ring atoms, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom (e.g. N, NH, S or O).
  • Suitable aryl or 5 or 6-membered heteroaryl monocyclic systems include, for instance, phenyl, thiophene (thiophenyl), benzene (phenyl), pyrrole (pyrrolyl), pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoxazolyl), oxazole (oxazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl), pyridine (pyridinyl), imidazolidine (imidazolidinyl), furan (furanyl) radicals and the like.
  • Suitable aryl or heteroaryl bicyclic systems include naphthalene (naphthyl), biphenylene (biphenylenyl), purine (purinyl), pteridine (pteridinyl), benzotriazole (benzotriazolyl), quinoline (quinolinyl), isoquinoline (isoquinolinyl), indole (indolyl), isoindole (isoindolyl), benzothiophene (benzothiophenyl), dihydrobenzo dioxin, dihydrobenzo dioxepin, benzo oxazin radicals and the like.
  • the present invention is directed to a class of compounds acting as inhibitors of the phosphodiesterase 4 (PDE4) enzyme.
  • Said class of compounds inhibits the conversion of cyclic nucleotides, in particular cyclic adenosine monophosphate (cAMP), into their inactive 5′-mononucleotide forms.
  • cAMP cyclic adenosine monophosphate
  • cyclic nucleotides in particular of cAMP, lead to the suppression of the activity of immune and pro-inflammatory cells such as mast cells, macrophages, T lymphocytes, eosinophils and neutrophils, resulting in a decrease of the release of inflammatory mediators which include cytokines such as IL-1, IL-3 and tumor necrosis factor-alpha (TNF- ⁇ ). It also leads to an airway smooth muscle relaxation and a decrease in oedema.
  • cytokines such as IL-1, IL-3 and tumor necrosis factor-alpha (TNF- ⁇ ).
  • the present invention relates to derivatives of 1-phenyl-2-pyridinyl alkyl alcohols of general formula (I), N-oxides on the pyridine ring and pharmaceutically acceptable salts or solvates thereof:
  • R 1 , R 2 , R 3 , R 19 , Z, A and K are as above defined.
  • the compounds according to the invention may accordingly exist as enantiomers.
  • they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • the present invention is directed to compounds of formula (I)′, which are compounds of formula (I) as above defined where the absolute configuration of carbon (1) is that shown below:
  • the absolute configuration for carbon (1) is assigned on the basis of Cahn-Ingold-Prelog nomenclature based on groups' priorities.
  • the absolute configuration at carbon (1) is (S).
  • the present invention is directed to compounds of formula (I)′′, which are compounds of formula (I)′ as above defined where the absolute configuration of carbon (2) is that shown below:
  • the present invention is directed to compounds of formula (I)′′′, which are compounds of formula (I)′ as above defined where the absolute configuration of carbon (2) is that shown below:
  • the invention provides compounds of formula (IH), which are N-oxides derivatives of the pyridine ring of compounds of formula (I), or pharmaceutically acceptable salts thereof:
  • 2-pyridinyl ring has two R 3 substituents which are halogen atom.
  • such R 3 substituents are two chlorine atoms at positions 3 and 5 of the pyridine ring.
  • R 1 is (C 1 -C 6 )haloalkyl or (C 1 -C 6 )alkyl.
  • R 2 is (C 1 -C 6 )alkyl which optionally is substituted by (C 3 -C 7 )cycloalkyl or is a (C 3 -C 7 )cycloalkyl.
  • R 1 and R 2 together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (q) fused to the phenyl moiety which bears groups OR 1 and —OR 2 , wherein asterisks indicate carbon atoms shared with such phenyl ring:
  • R 1 is (C 1 -C 6 )haloalkyl and R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl.
  • R 1 is (C 1 -C 6 )alkyl and R 2 is (C 1 -C 6 )alkyl.
  • R 19 is hydrogen
  • R 19 is hydrogen
  • R 1 is (C 1 -C 6 )haloalkyl
  • R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl.
  • R 19 if different from hydrogen, forms together with R 2 a group of formula (x) wherein bonds labeled with (1) and (2) indicate the points of attachment for group (x) to atoms bearing groups R 19 and R 2 respectively
  • a preferred group of compounds of general formula (I) is that wherein the 2-pyridinyl ring is substituted in positions 3 and 5 with two atoms of chlorine, according to the general formula (IA):
  • R 1 , R 2 , R 19 , K, z, and A are as defined above for compounds of formula (I); and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • R 3 , K, Z and A are as defined above for compounds of formula (I); and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • K, Z and A are as defined above for compounds of formula (I); and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • A is a (C 3 -C 7 )heterocycloalkyl-ene group comprising a nitrogen atom which represents the connecting point to group K as below represented:
  • A is selected in the list of di-radicals below reported:
  • A is selected in the list of di-radicals below reported:
  • A is a group
  • Z is a group —(CH 2 ) n — in which n is zero.
  • R 1 , R 2 , R 3 and K are as defined above for compounds of formula (I), R 19 is hydrogen, Z is a bond (i.e., n is zero), and A is a thiazolidine divalent radical group as above represented; and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • R 1 , R 2 , R 3 and K are as defined above for compounds of formula (I), R 19 is hydrogen, Z is a bond (i.e. n is zero), A is a thiazolidine divalent radical group and stereogenic center have absolute configuration as above represented; and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • R 1 is (C 1 -C 6 ) haloalkyl
  • R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl
  • 2-pyridinyl ring is substituted in positions 3 and 5 with two chlorine R 3 groups
  • K is a group
  • R 1 , R 2 , R 3 and K are as defined above for compounds of formula (I), Z is a bond (i.e. n is zero), R 19 is hydrogen and A is a pyrrolidine divalent radical group as above represented; and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • R 1 , R 2 , R 3 and K are as defined above for compounds of formula (I), Z is a bond (i.e. n is zero), R19 is hydrogen, A is a pyrrolidine divalent radical group, and the stereogenic centers have the absolute configuration as above represented; and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • R 1 is (C 1 -C 6 )haloalkyl
  • R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl
  • 2-pyridinyl ring is substituted in 3 and 5 with two chlorine R 3 groups
  • K is a group
  • K is selected in the list of groups below reported:
  • K is selected in the list of groups below reported:
  • K is selected in the list of groups below reported:
  • K is a group
  • R 4 is selected in the group consisting of: a group phenyl, a 5 or 6-membered heteroaryl group, a monocyclic (C 3 -C 7 )heterocycloalkyl and a bicyclic ring system; and each of which is optionally substituted by one or more groups R 5 .
  • R 4 is a group phenyl or a 5 or 6-membered heteroaryl group, each of which is optionally substituted by one or more groups R 5 .
  • R 4 is a group phenyl which is optionally substituted by one or more groups R 5 .
  • R 4 is a 5 or 6-membered heteroaryl group which is optionally substituted by one or more groups R 5 .
  • R 4 is a monocyclic (C 3 -C 7 )heterocycloalkyl optionally substituted by one or more groups R 5 .
  • R 4 is a bicyclic ring system optionally substituted by one or more groups R 5 .
  • the number of substituents R 5 is zero, 1, or 2. In a further preferred embodiment, such number is 1.
  • R 5 is independently selected in the group consisting of:
  • R 5 is independently selected in the group consisting of:
  • R 5 is independently selected in the group consisting of:
  • R 5 is selected in the group consisting of:
  • Z is a bond
  • R19 is hydrogen
  • A is a (C 3 -C 7 )heterocycloalkyl-ene group comprising a nitrogen atom which represents the connecting point to group K
  • K is selected in the list of groups consisting of:
  • R 4 is a group phenyl or a 5 or 6-membered heteroaryl group, each of which is optionally substituted by one or more groups R 5 : and the corresponding N-oxide on the pyridine ring, or pharmaceutically acceptable salts thereof.
  • the present invention provides the compounds reported below:
  • the compounds of the invention are selected in the group consisting of:
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (III) in a suitable dipolar solvent, such as THF, methanol, ethanol or DCM, in the presence of an appropriate reducing agent, such as sodium triacetoxy borohydride, sodium cyano borohydride or sodium borohydride, and of an appropriate acid, such as acetic acid, HCl in methanol or ammonium acetate. It could be useful to preform the imine before adding the reducing agent.
  • a suitable dipolar solvent such as THF, methanol, ethanol or DCM
  • an appropriate reducing agent such as sodium triacetoxy borohydride, sodium cyano borohydride or sodium borohydride
  • an appropriate acid such as acetic acid, HCl in methanol or ammonium acetate. It could be useful to preform the imine before adding the reducing agent.
  • the reaction proceeds smoothly at room temperature (RT) over 1 to 12 hours.
  • Typical reaction conditions comprise reacting a compound of formula (XVI), where X is a leaving group such as Cl or Br, with a compound of formula (II) in a suitable polar aprotic solvent, such as acetonitrile or DMF, in the presence of an appropriate base such as K 2 CO 3 , alkaline bicarbonate, TEA or DIPEA, at a temperature ranging from RT to 70° C.
  • a suitable polar aprotic solvent such as acetonitrile or DMF
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (IV) in a suitable dipolar aprotic solvent, such as DMF, chloroform or DCM, in the presence of an appropriate condensing agent such as EDC, DCC, HOBT, HOAT, or CDI, and, if necessary, of an appropriate agent, such as DMAP, HOBT, 4-pyrrolidinopyridine (4-PPY) or other 4-alkylamino pyridine, at room temperature.
  • a suitable dipolar aprotic solvent such as DMF, chloroform or DCM
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (XVII) in a suitable solvent such as pyridine or DCM, and in the presence, if necessary, of an appropriate base such as TEA, DIPEA, DBU, or another organic base at a temperature ranging from 0° C. to room temperature.
  • a suitable solvent such as pyridine or DCM
  • an appropriate base such as TEA, DIPEA, DBU, or another organic base at a temperature ranging from 0° C. to room temperature.
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (V) in a suitable polar aprotic solvent, such as DMF or acetonitrile, in the presence of an appropriate base such as K 2 CO 3 , alkaline bicarbonate, TEA or DIPEA, at a temperature ranging from RT to 50° C.
  • a suitable polar aprotic solvent such as DMF or acetonitrile
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (VI) in a suitable polar aprotic solvent such as DMF or acetonitrile, in the presence of an appropriate base such as K 2 CO 3 , alkaline bicarbonate, TEA, or DIPEA, at a temperature ranging from RT to 50° C.
  • a suitable polar aprotic solvent such as DMF or acetonitrile
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (XVIII) in a suitable polar aprotic solvent, such as DMF or acetonitrile, in the presence of an appropriate base such as K 2 CO 3 , alkaline bicarbonate, TEA, or DIPEA, at a temperature ranging from RT to 50° C.
  • Compound (XIX) thus obtained is successively reacted with a suitable oxidizing agent, such as MCPBA or hydrogen peroxide, in a suitable polar solvent, such as DCM, chloroform, EtOH or MeOH, at a temperature ranging from room temperature to 60° C.
  • a suitable oxidizing agent such as MCPBA or hydrogen peroxide
  • a suitable polar solvent such as DCM, chloroform, EtOH or MeOH
  • Typical reaction conditions comprise reacting a compound of formula (II) with a compound of formula (VII) in a suitable solvent such as pyridine or DCM, and in the presence, if necessary, of an appropriate base such as TEA, DIPEA, DBU, or another organic base at a temperature ranging from 0° C. to room temperature.
  • a suitable solvent such as pyridine or DCM
  • an appropriate base such as TEA, DIPEA, DBU, or another organic base at a temperature ranging from 0° C. to room temperature.
  • compounds of formula (I) may be prepared according to Scheme 7 below by reaction of a compound of formula (VIII), with an appropriate compound of formula (IX).
  • Typical reaction conditions comprise reacting a compound of formula (VIII) with a compound of formula (IX) in a suitable polar aprotic solvent, such as DMF, THF, chloroform, or DCM, in the presence of an appropriate condensing agent such as EDC, DCC, or CDI and of an appropriate agent, such as DMAP, HOBT, 4-pyrrolidinopyridine (4-PPY) or other 4-alkylamino pyridine at room temperature; removal of possibly present protecting group is performed under conditions known to the person skilled in the art or as described in ‘Protection Groups in Organic Synthesis’ by T. W. Green and P. Wutz, (Wiley-Interscience publication, 1999, which is incorporated herein by reference in its entirety).
  • a suitable polar aprotic solvent such as DMF, THF, chloroform, or DCM
  • Typical coupling reaction conditions comprise reacting a compound of formula (VIII) with a compound of formula (X) in a suitable polar aprotic solvent, such as DMF, THF, chloroform, or DCM, in the presence of an appropriate (coupling) condensing agent such as EDC, DCC, or CDI and of an appropriate agent such as DMAP, HOBT, 4-pyrrolidinopyridine (4-PPY) or other 4-alkylamino pyridine at room temperature; removal of protecting group is performed under conditions known to the person skilled in the art or as described in ‘Protection Groups in Organic Synthesis’ by T. W. Green and P.
  • a suitable polar aprotic solvent such as DMF, THF, chloroform, or DCM
  • deprotection may be conveniently performed under acidic conditions (such as HCl in dioxane or in AcOEt or TFA in CH 2 Cl 2 ).
  • acyl chloride can be preformed, by reacting compound (X) with oxalyl chloride or thionyl chloride or other reagents well known to those skilled in the art, in a suitable aprotic solvent such as DCM at 0 degrees, in presence, if necessary, of a catalytic amount of DMF, and successively adding compound (VIII) and an appropriate base such as TEA or DIPEA.
  • a suitable aprotic solvent such as DCM at 0 degrees
  • Typical reaction conditions comprise reacting a compound of formula (Ie) as above defined with a suitable acid, such as TFA or BBr 3 or BCl 3 , at a temperature ranging from room temperature to 40 degrees.
  • a suitable acid such as TFA or BBr 3 or BCl 3
  • the N-oxides on the 2-pyridinyl ring of the compounds of general formula (I) and embodiments thereof may be prepared according to methods available in the literature and well known to the skilled person. For instance, they may be prepared by dissolving the compound of general formula (I) or embodiments thereof in CH 2 Cl 2 or CHCl 3 , then adding an oxidizing agent such as m-chloro perbenzoic acid (mCPBA) to the resulting solution.
  • mCPBA m-chloro perbenzoic acid
  • Other oxidizing agents which may be used are hydrogen peroxide, perbenzoic acid, and peracetic acid.
  • the corresponding N-oxides are prepared by carrying out the oxidation step before further functional groups are introduced, for example on compounds of formula (II) or (VIII).
  • the process for preparation of compounds of formula (I) or embodiments thereof is performed starting from N-oxide on the pyridine ring of compound of formula (VIII), thus allowing the preparation of compound of formula (I) or embodiments thereof in the form of N-oxides on the pyridine ring.
  • Compounds of general formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (XVI), (XVII), (XVIII), (XIX), and (X) may be commercially available, their preparation may be specifically described in the literature or they may be prepared according to methods available in the literature and known to the person skilled in the art.
  • Typical reaction conditions for the process described in Scheme 43 comprise: a) adding a solution of a compound of formula (VII) in pyridine (3-30 vol. preferably 8 vol.) to a refrigerated solution of a compound of formula (XI), in pyridine (3-30 vol.
  • compounds of formula (IDa) obtained as above reported according to Scheme 43 are crystallized by a process comprising: dissolving the compounds in EtOH (8 vol); g) vigorously stirring overnight at room temperature; h) filtering the solid formed; and, optionally, i) washing the solid obtained from step h) with EtOH (2 vol) and 1) drying the solid under vacuum.
  • step 1) of Scheme 43 is conducted by drying first the solid under vacuum at room temperature, followed by drying under vacuum at 60° C.
  • Typical reaction conditions for the process described in Scheme 44 comprise: a) adding under stirring a solution of conc. HCl (about 5M; large excess) in dry AcOEt (9 vol.) to a solution of a compound of formula (XII) in AcOEt (6 vol.) at room temperature; b) stirring; c) filtering the precipitated solid; optionally d) washing the obtained solid with AcOEt; and optionally e) drying the solid obtained under vacuum at room temperature.
  • Typical reaction conditions for the process described in Scheme 45 comprise: a) adding a compound of formula (XIV), DMAP, and EDC to a solution of a compound of formula (XV) in DMF; b) stirring the mixture, preferably overnight; c) pouring the mixture into cold water; d) filtering the precipitate; optionally e) dissolving the precipitate in DCM, washing the solution with water, drying and evaporating the solvent; and optionally f) dissolving the solid obtained from step d) or e) in boiling MTBE (3.5 vol.) adding petroleum ether (4 vol.) under stirring, stirring at room temperature, filtering the solid obtained and drying it at room temperature under vacuum.
  • a process is provided for the preparation of compounds of formula (IDaa), i.e. a compound of formula (IDa) wherein R 1 is (C 1 -C 6 ) haloalkyl, R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl, 2-pyridinyl ring is substituted in 3 and 5 with two chlorine R 3 groups, K is a group
  • R 4 is a phenyl group which is optionally substituted by one or more groups R 5 ; which process comprises sequentially performing reactions as provided in Schemes 43, 44, and 45 above described.
  • A′ is (C 3 -C 7 )heterocycloalkyl-ene group comprising a group —NH—.
  • compounds of formula (XI) as above defined are provided as intermediates in the process of preparation of compounds of formula (IDa).
  • R 1 is (C 1 -C 6 )haloalkyl and R 2 is (C 1 -C 6 )alkyl which is substituted by (C 3 -C 7 )cycloalkyl, and the pyridine ring is substituted by two groups R 3 placed at position 3 and 5.
  • compounds of formula (II) as above defined are provided which act as inhibitors of the phosphodiesterase 4 (PDE4) enzyme, thus solving the above mentioned need of identifying further PDE4 inhibitors endowed with a high affinity for PDE4 enzyme, and possibly showing an appropriate developability profile as an inhalation treatment for example in terms of reduced side effects.
  • PDE4 phosphodiesterase 4
  • compositions containing compounds of formula (II) and therapeutic uses thereof are also provided by the present invention.
  • any of the described groups may be present as such or in any properly protected form.
  • functional groups present in the compounds of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX) and which could generate unwanted side reaction and by-products, need to be properly protected before the alkylation, acylation, coupling, oxidation, or sulfonylation takes place. Likewise, subsequent deprotection of those same protected groups may follow upon completion of the said reactions.
  • protecting group designates a protective group adapted to preserve the function of the group it is bound to.
  • protective groups are used to preserve amino, hydroxyl, or carboxyl functions.
  • Appropriate protecting groups may thus include, for example, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl, or benzyl esters or the like, which are well known to those skilled in the art (see, for a general reference, T. W. Green; Protective Groups in Organic Synthesis (Wiley, N.Y. 1999) which is incorporated herein by reference in its entirety).
  • selective protection and deprotection of any of the said groups for instance including carbonyl, hydroxyl, or amino groups, may be accomplished according to very well known methods commonly employed in organic synthetic chemistry.
  • Optional salification of the compounds of formula (I) or N-oxides on the pyridine ring thereof may be carried out by properly converting any of the free acidic or amino groups into the corresponding pharmaceutically acceptable salts.
  • the operative conditions being employed for the optional salification of the compounds of the invention are all within the ordinary knowledge of the skilled person.
  • the present invention also provides pharmaceutical compositions of compounds of the invention or of compounds of formula (II) in admixture with one or more pharmaceutically acceptable carriers, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A., which is incorporated herein by reference in its entirety.
  • Administration of the compounds of the present invention or of compounds of formula (II) may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally, and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
  • Various solid oral dosage forms may be used for administering compounds of the present invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders.
  • the compounds of the present invention or compounds of formula (II) may be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants, and the like.
  • diluents such as sucrose, mannitol, lactose, starches
  • excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants, and the like.
  • Time release capsules, tablets, and gels are also advantageous in administering the compounds of the present invention or compounds of formula (II).
  • liquid oral dosage forms may also be used for administering compounds of the present invention or compounds of formula (II), including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention or compounds of formula (II).
  • the compounds of the present invention or compounds of formula (II) may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the present invention or of compounds of formula (II) may be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates, and polyethylene glycols.
  • a suitable excipient such as cocoa butter, salicylates, and polyethylene glycols.
  • Formulations for vaginal administration may be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
  • the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear, or nose.
  • Topical administration may also involve transdermal administration via means such as transdermal patches.
  • the compounds according to the present invention or compounds of formula (II) are preferably administered by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols, and propellant-free inhalable formulations.
  • the powder may be filled in gelatine, plastic, or other capsules, cartridges, or blister packs or in a reservoir.
  • a diluent or carrier generally non-toxic and chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention or compounds of formula (II).
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention or compounds of formula (II) either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers, and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the present invention or compounds of formula (II) may be in form of solutions or suspensions in an aqueous, alcoholic, or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat®.
  • the compounds of the present invention or compounds of formula (II) may be administered as the sole active agent or in combination with other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders, e.g. beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (FINE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs), and mucus regulators.
  • beta2-agonists e.g. beta2-agonists, antimuscarinic agents, corticosteroids, mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophil elastase (
  • the present invention also provides combinations of a compound of the present invention or of compounds of formula (II), with a ⁇ 2-agonist selected from the group consisting of carmoterol, GSK-642444, indacaterol, milveterol, arformoterol, formoterol, salbutamol, levalbuterol, terbutaline, AZD-3199, BI-1744-CL, LAS-100977, bambuterol, isoproterenol, procaterol, clenbuterol, reproterol, fenoterol and ASF-1020, and salts thereof.
  • a ⁇ 2-agonist selected from the group consisting of carmoterol, GSK-642444, indacaterol, milveterol, arformoterol, formoterol, salbutamol, levalbuterol, terbutaline, AZD-3199, BI-1744-CL, LAS-100977, bambuterol, isoprotereno
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a corticosteroid selected from the group consisting of fluticasone propionate, fluticasone furoate, mometasone furoate, beclometasone dipropionate, ciclesonide, budesonide, GSK 685698, and GSK 870086.
  • a corticosteroid selected from the group consisting of fluticasone propionate, fluticasone furoate, mometasone furoate, beclometasone dipropionate, ciclesonide, budesonide, GSK 685698, and GSK 870086.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with an antimuscarinic agent selected from the group consisting of aclidinium, tiotropium, ipratropium, trospium, glycopyrronium, and oxitropium salts.
  • an antimuscarinic agent selected from the group consisting of aclidinium, tiotropium, ipratropium, trospium, glycopyrronium, and oxitropium salts.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a PDE4 inhibitor selected from the group consisting of AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779, IBFB-211913, AWD-12-281, cipamfylline, cilomilast, roflumilast, BAY19-8004 and SCH-351591, AN-6415, indus-82010, TP1-PD3, ELB-353, CC-11050, GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414, and RPL-554.
  • a PDE4 inhibitor selected from the group consisting of AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-377
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a P38 MAP kinase inhibitor selected from the group consisting of semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minokine, and losmapimod and salts thereof.
  • a P38 MAP kinase inhibitor selected from the group consisting of semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, minokine, and losmapimod and salts thereof.
  • the present invention provides combinations of a compound of the present invention or of a compound of formula (II) with an IKK2 inhibitor.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a HNE inhibitor selected from the group consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C, and prolastin inhaled.
  • a HNE inhibitor selected from the group consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin, SPHD-400, prolastin C, and prolastin inhaled.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a leukotriene modulator selected from the group consisting of montelukast, zafirlukast, and pranlukast.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a NSAID selected from the group consisting of ibuprofen and ketoprofen.
  • the present invention also provides combinations of a compound of the present invention or of a compound of formula (II), with a mucus regulator selected from the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, and gefitinib.
  • a mucus regulator selected from the group consisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, and gefitinib.
  • the dosages of the compounds of the present invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.
  • the compounds of the present invention or compounds of formula (II) may be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.
  • the dosage of the compounds of the present invention or of compounds of formula (II) is advantageously comprised between 0.01 and 20 mg/day, preferably between 0.1 and 10 mg/day.
  • the compounds of the present invention or compounds of formula (II) alone or combined with other active ingredients may be administered for the prevention and/or treatment of any obstructive respiratory disease such as asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD).
  • any obstructive respiratory disease such as asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • any disease wherein PDE4 inhibition is required include: allergic disease states such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic
  • Such diseases also include neurological and psychiatric disorders such as Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, depression, stroke, and spinal cord injury.
  • neurological and psychiatric disorders such as Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, depression, stroke, and spinal cord injury.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride;
  • DMAP 4-dimethylaminopyridine;
  • DMF dimethylformamide;
  • EtOAc or AcOEt Ethyl acetate;
  • RT room temperature;
  • THF tetrahydrofurane;
  • DCM dichloromethane;
  • (Ipr) 2 O diisopropylether;
  • MIK methyl isobutyl ketone;
  • MEK methyl ethyl ketone;
  • MTBE methyl tert-butyl ether;
  • AcOH acetic acid;
  • vv volumes;
  • v/w ratio volume/weight;
  • the enantiomeric purity was determined on Hewlett Packard 1050 HPLC system using Chiracel OD column (5 ⁇ 4.6 ⁇ 250 mm), eluting using isocratic mixture of hexane and isopropanol in different ratios as indicated in each specific example.
  • Trifluoroacetate Salts when stated in the Salt Name column, compounds containing one or more basic centres and purified by reverse-phase HPLC (Method 2 or 3) were obtained as 2,2,2-trifluoroacetic acid salts, once clean fractions collected from chromatography were evaporated under reduced pressure without any further basic treatment.
  • Hydrochloride Salts when stated in the Salt Name column, Compounds containing one or more basic centres which underwent Boc deprotection under acidic condition without any further basic work-up, were obtained as hydrochloride salts.
  • the salt stoichiometry was determined, if required, by NMR.
  • Diastereoisomeric ratio by LC/UV/MS when indicated, is estimated to be affected by an experimental error of ⁇ 1%.
  • diastereoisomeric ratio is determined by 1 H NMRand it is estimated to be >95:5 when a single diastereoisomer was detected using NMR analysis.
  • Step 1 4-((S)-2-((S)-2-acetoxy-2-phenylacetoxy)-2-(3-(cyclopropyl-methoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (161)
  • Step 2 4-((S)-2-((S)-2-acetoxy-2-phenylacetoxy)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)ethyl)-3,5-dichloropyridine 1-oxide (162)
  • Step 3 4-((S)-2-((S)-2-acetoxy-2-phenylacetoxy)-2-(4-(difluoromethoxy)-3-methoxyphenyl)ethyl)-3,5-dichloropyridine 1-oxide (163)
  • Step 4 (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (164)
  • 3,5-dichloro-4-methylpyridine (160) 54 g, 331 mmol was dissolved in dry THF (480 mL) under anargon atmosphere and it was cooled at ⁇ 78° C. in dry-ice/acetone bath.
  • LHMDS 1N THF solution (331 ml, 331 mmol) was added drop-wise by keeping the temperature at ⁇ 78°. The mixture was stirred at ⁇ 78° for 1 hour. After that, a solution of 3,4-dimethoxybenzaldehyde (50 g, 301 mmol) in dry THF (120 ml) was added drop-wise by keeping the temperature at ⁇ 78° C. When the addition was completed, the mixture was allowed to warm at RT.
  • the reaction was poured in ice and water (1 L), and the mixture was stirred until a copious precipitate formed.
  • the solid was filtered, and dissolved in ethyl acetate (500 ml), dried over Na 2 SO 4 and the solvent evaporated under vacuum.
  • the crude was crystallized in CHCl 3 /hexane.
  • the precipitate was filtered, washed with hexane and dried under vacuum at 40° C. for 8 hours to give 55 g (yield 45%).
  • the mother liquor solution was evaporated under vacuum at 40° C., dissolved in ethyl acetate (200 ml) and extracted with 200 ml of water.
  • the organic solution was dried over Na 2 SO 4 and the solvent evaporated under vacuum at 40° C.
  • the crude was crystallized in CHCl 3 /hexane, and additional 15 g of the desired product (166) were obtained (overall yield 70%).
  • Step 2 Synthesis of ((R)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (167)
  • Step 3 Synthesis of (R)-((S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (168)
  • Step 1 Synthesis of 2-(3,5-dichloropyridin-4-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethanol (171)
  • 3,5-dichloro-4-methylpyridine (166) (4.37 g, 0.016 mol) was dissolved in dry THF (40 mL) under an argon atmosphere and it was cooled at ⁇ 78° C. in dry-ice/acetone bath.
  • LHMDS IN THF solution (28 ml, 28 mmol) was added drop-wise by keeping the temperature at ⁇ 78°. The mixture was stirred at ⁇ 78° for 1 hour. After that, a solution of 2,3-difluoro-3,4-benzodioxolocarboxaldheyde (5 g, 0.026 mol) in dry THF (10 ml) was added drop-wise by keeping the temperature at ⁇ 78° C.
  • Step 1 3,5-dichloro-4-(2-(4-methoxyspiro[benzo[d][1,3]dioxole-2,1′-cyclopentane]-'7-yl)-2-oxoethyl)pyridine 1-oxide (173)
  • Step 2 3,5-dichloro-4-(2-hydroxy-2-(4-methoxyspiro[benzo[d][1,3]dioxole-2,1′-cyclopentane]-7-yl)ethyl)pyridine 1-oxide (174)
  • Step 1 4-((S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2)
  • Step 2 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-pyrrolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (3) 4-((S)-2-((S)-1-(tert-butoxycarbonyppyrrolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2) (300 mg, 0.486 mmol) was dissolved in Dioxane/HCl (4M, 2 ml) and stirred at RT for 8 hours. After that time, the solvent was removed on a rotavapour under reduced pressure and dried in a vacuum oven overnight to yield the wanted product as an hydrochloride salt (200 mg; yield 80%).
  • Compound 6, 7, 181, and 183 were obtained by reacting its appropriate Boc-protected precursor with AcOEt/HCl (5M), followed by filtration at room temperature of the hydrochloride salt, which spontaneously precipitates from the reaction mixture.
  • Compounds 177, 178, and 179 were obtained by performing Step 2 with HCl in EtOAc and removing the solvent without heating.
  • Step 1 4-((S)-2-((S)-1-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)benzoyl)pyrrolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (18)
  • Step 2 3,5-dichloro-4-((S)-2-((S)-1-(4-(cyclopropylmethoxy)-3-(methylsulfonamido)benzoyl)pyrrolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide (19)
  • Step 3 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-nitrobenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (25)
  • Step 4 4-((2S)-2-(3-(4-aminobenzoyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (26)
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoro methoxy)phenyl)-2-((S)-1-(4-methoxy-3-(methylsulfonyloxy)benzoyl)pyrrolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (30)
  • Step 1 3-((1,3-dioxolan-2-yl)methyl)-N,N-dimethylbenzamide (196) 3-((1,3-dioxolan-2-yl)methyl)benzoic acid (250 mg, 1.201 mmol), dimethylamine hydrochloride (147 mg, 1.801 mmol), EDC (345 mg, 1.801 mmol), and DMAP (513 mg, 4.20 mmol) were dissolved in DCM (30 ml) and the solution was stirred at RT for 1 hour. The reaction mixture was washed twice with 1N HCl, and the organic layer was dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give the desired product (244 mg, 1.037 mmol, 86% yield) MS/ESI + 236.18 [MH] +
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoro-methoxy)phenyl)-2-((S)-3-(2-(3-(dimethylcarbamoyl)phenyl)acetyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (198)
  • Methyl 3-(cyclopropylmethoxy)-5-nitrobenzoate (44) (4.9 g, 19.5 mmol) was dissolved in MeOH (200 ml), and Pd/C 5 % (1.5 g, 0.7 mmol) was added. The solution was shaken under hydrogen atmosphere on a Parr apparatus at 40 psi for 1 hour. The catalyst was filtered on a Diatomaceus earth pad, and the solvent was evaporated under vacuum to give 3.67 g of the desired product (yield 85%).
  • Step 4 methyl 3-(cyclopropylmethoxy)-5-(N-(2-morpholinoethyl)methylsulfonamido)benzoate (47)
  • Step 5 3-(cyclopropylmethoxy)-5-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid (48)
  • Step 6 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-5-(N-(2-morpholinoethyl)methylsulfonamido)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide formate (49)
  • Step 1 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(5-formylthiophene-2-carbonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (50) 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (5) (200 mg, 0.374 mmol), 5-formylthiophene-2-carboxylic acid (233 mg, 1.494 mmol), DMAP (100 mg, 0.822 mmol), and EDC (358 mg, 1.868 mmol) were dissolved in DMF (2 ml).
  • Step 2 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(5-((dimethylamino)methyl)thiophene-2-carbonyl)thiazolidine-2-carbonyl oxy)ethyl)pyridine 1-oxide (51)
  • Step 1 4-((2S)-2-(3-(3-carboxy-4-methoxyphenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide, (122)
  • Step 2 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(dimethylcarbamoyl)-4-methoxyphenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (123)
  • Step 1 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-nitrophenyl sulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (134)
  • Step 2 4-((2S)-2-(3-(4-aminophenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (135)
  • Step 1 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(methylsulfonamido)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (142)
  • Step 2 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(4-(N-(2-morpholinoethyl)methylsulfonamido)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide formate (143)
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoro-methoxy)phenyl)-2-((S)-3-(2-(3-(dimethylcarbamoyl)phenyl)-2-oxoethyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (261)
  • Methyl thiazolidine-2-carboxylate hydrochloride (145) (20 g; 109 mmol) was dissolved in pyridine (100 ml), then 4-nitrobenzene-1-sulfonyl chloride (27 g, 124 mmol) was added at 0° C., and the mixture was stirred for 3 hours. After that time, the reaction was quenched with HCl 1N to precipitate a solid that was filtered on a fit and washed with water several times. The orange solid was triturated in acetone, washed with acetone ( ⁇ 2) and dried under vacuum to yield 27 g (76%).
  • Step 4 4-((2S)-2-(3-(4-aminophenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (149)
  • Step 5 4-((S)-2-((S)-3-(4-aminophenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (150)
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-1-(1-methyl-1H-imidazol-2-ylsulfonyl)pyrrolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (155)
  • Step 2 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(hydroxymethyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (271)
  • Step 3 4-((2S)-2-(2-(3-benzoylthiazolidin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (274)
  • Step 1 ethyl 2-(3-(phenylsulfonyl)thiazolidin-2-yl)acetate (276)
  • Step 3 3,5-dichloro-4-((2S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(phenylsulfonyl)thiazolidin-2-yl)acetoxy)ethyl)pyridine 1-oxide (278)
  • Step 1 1-(3-(dimethylcarbamoyl)phenylsulfonyl)azetidine-3-carboxylic acid (280)
  • Step 2 (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(1-(3-(dimethylcarbamoyl)phenylsulfonyl)azetidine-3-carbonyloxy)ethyl)pyridine 1-oxide (281)
  • Step 1 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(vinylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (286)
  • Step 2 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(2-morpholinoethylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (287)
  • Step 2 (S)-1-(2-(phenylsulfonyl)ethyl)pyrrolidine-2-carboxylic acid (290)
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoro-methoxy)phenyl)-2-((S)-1-(2-(phenylsulfonyl)ethyl)pyrrolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (291)
  • Step 3 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoro-methoxy)phenyl)-2-((S)-3-(3-(dimethylcarbamoyl)benzylsulfonyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (295)
  • Step 1 4-((S)-2-((S)-3-(tert-butoxycarbonyl)thiazolidine-2-carbonyloxy)-2-(4-(difluoromethoxy)-3-methoxyphenyl)ethyl)-3,5-dichloropyridine 1-oxide (297)
  • Step 2 3,5-dichloro-4-((S)-2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (298)
  • Step 3 3,5-dichloro-4-((S)-2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-((S)-3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (299)
  • Step 2 3,5-dichloro-4-((S)-2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-((S)-1-(phenylsulfonyl)pyrrolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (305)
  • Step 1 (S)-ethyl 3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carboxylate (318)
  • Step 2 (S)-3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carboxylic acid (319)
  • Step 3 3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-2-((S)-3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (320)
  • U937 human monocytic supernatants cells lysate were cultured, harvested and supernatant fraction prepared essentially as described in Torphy T J, et al., 1 J. Pharmacol. Exp. Ther., 1992; 263:1195-1205, which is incorporated herein by reference in its entirety.
  • U937 cells Cell Bank, Interlab Cell Line Collection, ICLC HTL94002 were grown at 37° C., 5% CO 2 in RPMI 1640 with GlutaMAXTM-I medium supplemented with 10% fetal bovine serum and 100 ⁇ g/ml Pen-strep (Gibco).
  • PDE4 activity was determined in cells supernatants by assaying cAMP disappearance from the incubation mixtures.
  • concentration of the test compounds ranged between 10 ⁇ 12 M and 10 ⁇ 6 M. Reactions were stopped by enzyme heat inactivation (2.5 minutes at 100° C.), and residual cAMP content was determined using the ‘LANCE cAMP Assay’ from PerkinElmer following the providers instructions.
  • the results of the tested compounds, representatives of the invention, expressed as mean ⁇ standard deviation of the nM concentration of the test compound producing 50% inhibition of cAMP disappearance (IC 50 ) are shown in the following Table:
  • PDE4 binding potencies are indicated as follows: >10 nM “+”; 10-1 nM “++”; 1-0.1 nM “+++”; ⁇ 0.1 nM “++++”.
  • Percentage of inhibition of PDE4 activity was calculated, assuming cAMP disappearance in the absence of inhibitors as 100% and cAMP disappearance in heat inactivated samples as 0%.
  • PDE4 binding potencies are indicated as follows: >10 nM “+”; 10-1 nM “++”; 1-0.1 nM “+++”; ⁇ 0.1 nM “++++”.
  • the assay which is based on the known inhibitory activity exerted by PDE4 inhibitors on the lipopolyshaccarides (LPS)-induced tumour necrosis factor-alpha (TNF- ⁇ release in peripheral blood mononuclear cells (PBMCs), was performed according to a method previously described (Hatzelmann A et al., J. Pharmacol. Exp. Ther., 2001; 297:267-279; and Draheim R et al., J. Pharmacol. Exp. Ther., 2004; 308:555-563, which are incorporated herein by reference in their entireties).
  • LPS lipopolyshaccarides
  • Cryopreserved human PBMCs (100 ⁇ l/well) were incubated in 96-well plates (10 5 cells/well), for 30 minutes, in the presence or absence (50 microl) of the test compounds whose concentrations ranged from 10 ⁇ 12 M to 10 ⁇ 6 M or from 10 ⁇ 13 M to 10 ⁇ 7 M. Subsequently, LPS (3 ng/ml) was added.
  • PDE4 Compound No. inhibition 239, 240, 241, 242, 206, 271, 210, 310, 250, 251, 252, ++++ 269, 287, 299, 35, 37, 38, 52, 54, 56, 59, 64, 66, 73, 74, 82, 83, 84, 85, 88, 90, 91, 92, 93, 94, 95, 96, 97, 101, 106, 107, 109, 113, 115, 116, 118, 119, 123, 124, 128, 129, 130, 131, 132, 133, 139, 140, 150, 155 238, 201, 203, 228, 207, 198, 209, 295, 243, 186, 187, +++ 185, 281, 253, 288, 200, 16, 17, 20, 22, 26, 31, 32, 34, 36, 39, 40, 41, 49, 51, 53, 55, 57, 58, 60, 61, 62, 63, 65
  • PDE4 binding potencies are indicated as follows: >10 nM “+”; 10-1 nM “++”; 1-0.1 nM “+++”; ⁇ 0.1 nM “++++”.
  • the effects of the tested compounds were calculated as percentage of inhibition of TNF- ⁇ release, assuming LPS-induced TNF- ⁇ production in the absence of inhibitor compound as 100% and basal TNF- ⁇ production of PBMCs in the absence of LPS as 0%.
  • results of tested compounds for compounds of formula (II) expressed as mean ⁇ 95% confidence limits of the molar concentration of the test compound producing 50% inhibition of LPS-induced TNF- ⁇ release (IC 50 ) are shown in the following Table:
  • PDE4 binding potencies are indicated as follows: >10 nM “+”; 10-1 nM “++”; 1-0.1 nM “+++”; ⁇ 0.1 nM “++++”.

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US9440954B2 (en) 2012-06-04 2016-09-13 Chiesi Farmaceutici S.P.A. Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors
US9169245B2 (en) 2012-12-05 2015-10-27 Chiesi Farmaceutici S.P.A. Inhibitors of PDE4 enzyme and antagonists of muscarinic M3 receptor
US9199980B2 (en) 2012-12-05 2015-12-01 Chiesi Farmaceutici S.P.A. Compounds
US9090606B2 (en) 2012-12-05 2015-07-28 Chiesi Farmaceutici S.P.A. Compounds
US9944612B2 (en) 2012-12-05 2018-04-17 Chiesi Farmaceutici S.P.A. 1-phenyl-2-pyridinyl alkyl alcohol derivatives as phosphodiesterase inhibitors
US9326976B2 (en) * 2014-06-05 2016-05-03 Chiesi Farmaceutici S.P.A. Carbamate derivatives
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