KR100501865B1 - Tri-Substituted Phenyl Derivatives Useful as PDE IV Inhibitors - Google Patents

Abstract

Compounds of formula (1) and salts, solvates, hydrates, prodrugs and N oxides thereof,

<Formula 1>

Wherein = W- is (1) = C (Y)-or (2) = N-, where Y is a halogen atom or an alkyl or -XR ^a group, where X is -O-, -S (O) _m- [wherein m is 0 or an integer of 1 or 2], or -N (R ^b )-[where R ^b is a hydrogen atom or an optionally substituted alkyl group] and R ^a is hydrogen An atom or an optionally substituted alkyl group; L is-XR wherein R is an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group, -C (R ¹¹ ) = C (R ¹ ) (R ² ) or [-CH (R ¹¹ )] _n CH (R ¹ ) (R ² ) group wherein R ¹¹ is hydrogen or fluorine atom or methyl group and R ¹ and R ² may be the same or different and each is hydrogen or fluorine atom or optionally substituted Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, -CO ₂ R ⁸ , wherein R ⁸ is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group, -CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ may be the same or different and as defined for R ⁸ ], -CSNR ⁹ R ¹⁰ , -CN or -NO ₂ group, or R ¹ and R ² are the same as the C atom to which they are attached Linked together to form an optionally substituted cycloalkyl or cycloalkenyl group, n is 0 or an integer of 1; Z is the group (A) Or (B) R ³ is a hydrogen or fluorine atom, an optionally substituted linear or branched alkyl group, or a hydroxyl group; R ⁴ is a hydrogen atom or a group-(CH ₂ ) _t Ar or-(CH ₂ ) _t -Ar- (L ¹ ) _n -Ar '; R ⁵ is — (CH ₂ ) _t Ar or — (CH ₂ ) _t —Ar— (L ¹ ) _n —Ar ′ group; R ⁶ is hydrogen or a fluorine atom, or an optionally substituted alkyl group; R ⁷ is hydrogen or fluorine atom, optionally substituted linear or branched alkyl group or OR ^c group, wherein R ^c is hydrogen atom or optionally substituted alkyl or alkenyl group, or alkoxyalkyl, alkanoyl, formyl, carbox Amido or thiocarboxamido groups. The compounds according to the invention are phosphodiesterase type IV inhibitors and are useful in the prevention and treatment of diseases such as asthma in the presence of unwanted inflammatory reactions or muscle spasms.

Description

Tri-Substituted Phenyl Derivatives Useful as PDE IV Inhibitors} Useful as Phosphodiesterase IV Inhibitors

The present invention relates to a novel series of trisubstituted phenyl derivatives, methods for their preparation, pharmaceutical compositions containing them, and their use in medicaments.

Many hormones and neurotransmitters modulate tissue function by enhancing intracellular levels of adenosine 3 ', 5'-cyclic monophosphate (cAMP). Cell levels of cAMP are regulated by mechanisms that control synthesis and degradation. Synthesis of cAMP is controlled by adenyl cyclase, which can be directly activated by a component such as forskolin or indirectly by binding of specific antagonists with cell surface receptors coupled with adenyl cyclase. . The degradation of cAMP is controlled by the routine of the phosphodiesterase (PDE) isoenzyme, which also controls the degradation of guanosine 3 ', 5'-cyclic monophosphate (cGMP). To date, the fruit group 7 (PDE I-VII) has been described and their distribution varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differentiation of cAMP differentiation in tissues. See for review of PDE distribution, structure, function and regulation: Beavo & Reifsnyder (1990) TIPS, 11 : 150-. 155 and Nicholson et al. (1991) TIPS, 12 : 19-27].

There is clear evidence that enhancement of cAMP in inflammatory leukocytes leads to inhibition of the leukemia activity. In addition, enhancement of cAMP in airway smooth muscle has an antifungal effect. In these tissues, PDE IV plays an important role in the hydrolysis of cAMP. Therefore, it can be expected that selective inhibitors of PDE IV will have therapeutic effects in inflammatory diseases such as asthma by achieving both anti-inflammatory and bronchodilating effects.

The design of PDE IV inhibitors has been limited to date, with limited potential to date, since many potential PDE IV inhibitors have been synthesized and have been capable of inhibiting one or more PDE isoenzyme types in a non-selective manner and do. The lack of selective action was a particular problem given that the broad role and requirement of cAMP in vivo is a potential selective PDE IV inhibitor with inhibitory action on PDE IV and little or no action on other PDE isoenzymes.

We have now identified a new class of trisubstituted phenyl derivatives, the components of which are potential inhibitors of PDE IV at concentrations with little or no inhibitory action on other PDE isoenzymes. These compounds inhibit human recombinant PDE IV enzymes and also enhance cAMP in isolated white blood cells. Accordingly, the compounds of the present invention are for use in medicaments, in particular in the prevention and treatment of asthma.

Thus, according to one aspect of the present invention, we provide a compound of Formula 1, and salts, solvates, hydrates, prodrugs and N oxides thereof:

Where

= W- is (1) = C (Y)-or (2) = N-, where Y is a halogen atom or an alkyl or -XR ^a group, where X is -O-, -S (O m- [where m is 0 or an integer of 1 or 2], or -N (R ^b )-[where R ^b is a hydrogen atom or an optionally substituted alkyl group], and R ^a is a hydrogen atom or An optionally substituted alkyl group;

L is -XR wherein R is an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group, -C (R ¹¹ ) = C (R ¹ ) (R ² ) or [-CH (R ¹¹ ) _n CH (R ¹ ) (R ² ) group wherein R ¹¹ is hydrogen or fluorine atom or methyl group, R ¹ and R ² may be the same or different and each is hydrogen or fluorine atom or optionally substituted alkyl , Alkenyl, alkynyl, alkoxy, alkylthio, -CO ₂ R ⁸ , wherein R ⁸ is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group, -CONR ⁹ R ¹⁰ [where R ⁹ and R ¹⁰ may be the same or different and as defined for R ⁸ ], -CSNR ⁹ R ¹⁰ , -CN or -NO ₂ group, or R ¹ and R ² together with the C atom to which they are attached Linked to form an optionally substituted cycloalkyl or cycloalkenyl group, n is 0 or an integer 1;

Z is the group (A) Or (B) , And here

R ³ is hydrogen or a fluorine atom, an optionally substituted linear or branched alkyl group, or a hydroxyl group;

R ⁴ is a hydrogen atom or a group-(CH ₂ ) _t Ar [where t is 0 or an integer of 1, 2 or 3, and Ar is a mono, optionally containing one or more hetero atoms selected from oxygen, sulfur or nitrogen atoms Cyclic or bicyclic aryl group or group-(CH ₂ ) _t -Ar- (L ¹ ) _n -Ar '[wherein L ¹ is a divalent linking group and Ar' is Ar, -COAr, -SO ₂ Ar, —SO ₂ NHAr, —SO ₂ N (Alk ¹ ) Ar [where Alk ¹ is 1, 2 or 3 —O— or —S— atoms or —S (O) _p − (where p is an integer of 1 or 2) or a C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene straight or branched chain optionally interrupted by a -N (R ^b )-group], -SO ₂ N [Ar] ₂ , -CONHAr, -CON (Alk ¹ ) Ar, -CON [Ar] ₂ , -NAlk ¹ SO ₂ Ar, -NHSO ₂ Ar, -N [SO ₂ Ar] ₂ , -NHSO ₂ NHAr , -NAlk ¹ SO ₂ NHAr, -NHSO ₂ N (Alk ¹ ) Ar, -NAlk ¹ SO ₂ NAlk ¹ Ar, -NHSO ₂ N [Ar] ₂ , -NAlk ¹ SO ₂ N [Ar] ₂ , -NHC ( O) Ar, -NAlk ¹ C (O) Ar, -N [C (O) Ar] ₂ , -NHC (O) NHAr, -NAlk ¹ C (O) NHAr, -NHC (O) N (Alk ¹ ) Ar, -NAlk ¹ C (O) N (Alk ¹ ) Ar, -NHC (O) OAr, -NAlk ¹ C (O) OAr, -C (S) NHAr, -C (S) NAlk ¹ Ar, -C (S ) Nlk ¹ Ar, -C (S) N [Ar] ₂ , -NHC (S) Ar, -NAlk ¹ C (S) Ar, -N [C (S) Ar] ₂ , -NHC (S) NHAr, -NAlk ¹ C (S) NHAr, -NHC (S) NAlk ¹ Ar, -NAlk ¹ C (S) NAlk ¹ Ar, -SO ₂ NHet [where -NHet is one or more other -O- or -S -An optionally substituted C _5-7 heterocyclic amino group optionally containing an atom or a -N (R ^b )-, -C (O)-or -C (S)-group], -CONHet, -CSNHet, -NHSO ₂ NHet, -NHC (O) NHet, -NHC (S) NHet, -SO ₂ NH (Het ') [where Het' is one or more -O- or -S- atoms or -N (R ^b ) -An optionally substituted C _5-7 monocyclic carbocyclic group optionally containing a group], -CONH (Het '), -CSNH (Het'), -NHSO ₂ NH (Het '), -NHC (O) NHHet 'or -NHC (S) NHHet';

R ⁵ is-(CH ₂ ) _t Ar or-(CH ₂ ) _t -Ar- (L ¹ ) _n -Ar 'group, provided that R ⁵ is-(CH ₂ ) _t Ar group and = W- is = C When (Y)-and L is -XR, R ⁴ is a group-(CH ₂ ) _t -Ar- (L ¹ ) _n Ar ';

R ⁶ is hydrogen or a fluorine atom, or an optionally substituted alkyl group;

R ⁷ is hydrogen or fluorine atom, optionally substituted linear or branched alkyl group or OR ^c group, wherein R ^c is hydrogen atom or optionally substituted alkyl or alkenyl group, or alkoxyalkyl, alkanoyl, formyl, carbox Amido or thiocarboxamido groups.

It will be appreciated that certain compounds of formula 1 may have one or more chiral centers, depending on the nature of the groups L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ . Where more than one chiral center is present, enantiomers or diastereomers may be present and the invention will be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates.

L is -C (R ¹¹ ) = C (R ¹ ) (R ² ) and / or Compounds of formula 1 wherein Z is a group (B) may exist as geometric isomers, depending on the nature of the groups R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ¹¹ , and the present invention relates to such isomers and their It will be understood to extend to the mixture.

In compounds of Formula 1 wherein = W- is = C (Y)-and Y is a halogen atom, Y can be, for example, a fluorine, chlorine, bromine or iodine atom.

When W is a group = C (Y)-and Y is -XR ^a in the compound of formula 1, R ^a is for example a hydrogen atom or an optionally substituted linear or branched alkyl group, for example methyl, ethyl, n Optionally substituted C _1-6 alkyl groups such as -propyl or i-propyl groups. Any substituent that may be present on the R ^a group includes one or more halogen atoms, such as fluorine or chlorine atoms. The R ^a group especially includes, for example, a -CH ₂ F, -CH ₂ Cl, -CHF ₂ , -CHCl ₂ , -CF ₃ or -CCl ₃ group.

In a compound of Formula 1, when = W- is a group = C (Y), where -Y is -N (R ^b ), = W- is = C (NH ₂ )-, = C (NHCH ₃ ) Or a = C (NHC ₂ H ₅ )-group.

In compounds of formula 1, X is an oxygen or sulfur atom or a group -S (O)-, -S (O) _2- , -NH- or C _1-6 alkylamino, for example C _1-3 alkylamino For example, methylamino [-N (CH ₃ )-] or ethylamino [-N (C ₂ H ₅ )-] group.

In the compound of formula 1, the alkyl group represented by Y, R, R ¹ , R ² or R ^b includes an optionally substituted linear or branched C _1-6 alkyl group optionally interrupted by one or more X atoms or groups. Examples include in particular C _1-3 alkyl groups such as methyl or ethyl groups. Optional substituents on these groups are halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or C _1-3 alkoxy such as hydroxyl or C _1-6 alkoxy, for example methoxy or ethoxy, or 1, 2 or 3 substituents selected from CO ₂ R ⁸ , -CONR ⁹ R ¹⁰ , -CSNR ⁹ R ¹⁰ or -CN group.

Alkenyl groups represented by R, R ¹ or R ² in the compound of Formula 1 include optionally substituted linear or branched C _2-6 alkenyl groups optionally interrupted by one or more X atoms or groups. Examples include, in particular, ethenyl, propen-1-yl and 2-methylpropen-1-yl groups. Optional substituents include those described above in connection with the alkyl group represented by the group R ¹ or R ² .

In the compound of formula 1, the alkynyl group represented by R ¹ or R ² includes an optionally substituted linear or branched C _2-6 alkynyl group optionally interrupted by one or more X atoms or groups. Examples include, in particular, ethynyl and propyn-1-yl groups. Optional substituents include those described above in connection with the alkyl group represented by the group R ¹ or R ² .

In the compound of formula 1, when R ¹ or R ² is an alkoxy or alkylthio group, it is for example optionally substituted linear or branched C _1-6 alkoxy or C _1- optionally interrupted by one or more X atoms or groups ₆ alkylthio group. Examples include in particular C _1-3 alkoxy, for example methoxy or ethoxy, or C _1-3 alkylthio, for example methylthio or ethylthio groups. Optional substituents include those described above in connection with the alkyl group represented by the group R ¹ or R ² .

When R ¹ and R ² in the compound of formula 1 are connected with the carbon atom to which they are attached to form a cycloalkyl or cycloalkenyl group, the group is, for example, a C _3-8 such as a cyclobutyl, cyclopentyl or cyclohexyl group Cycloalkyl groups or for example 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 2-cyclohexene- C ₃ containing 1 or 2 double bonds such as 1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl groups _-8 cycloalkenyl group, wherein each cycloalkyl or cycloalkenyl group is a halogen atom, for example fluorine, chlorine, bromine or iodine atom, linear or branched C _1-6 alkyl, for example methyl or ethyl C _1-3 alkyl, hydroxyl or C _1-6 alkoxy, such as for example from C _1-3 alkoxy such as methoxy or ethoxy groups Optionally substituted by one, two or three substituents taken.

When R in the compound of formula 1 is an optionally substituted cycloalkyl or cycloalkenyl group, it is for example a C _3-8 cycloalkyl group such as cyclobutyl, cyclopentyl or cyclohexyl group, or for example 2-cyclobutene- 1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1- C _3-8 cycloalkenyl groups containing one or two double bonds, such as one, 2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl, wherein each The cycloalkyl or cycloalkenyl group of a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom, linear or branched C _1-6 alkyl, for example C _1-3 alkyl, hydroxyl such as methyl or ethyl Or optionally substituted by 1,2 or 3 substituents selected from C _1-6 alkoxy, for example C _1-3 alkoxy such as methoxy or ethoxy groups Is substituted.

If the group R ⁷ in the compound of formula 1 is an OR ^c group, it is for example a hydroxyl group; Or a group -OR ^C , wherein R ^c is an optionally substituted linear or branched C _1-6 alkyl group such as C _1-3 , such as a methyl or ethyl group C _1-3 alkoxy C _1-3 alkyl groups, C _1-6 such as C _2-6 alkenyl groups, methoxymethyl, ethoxymethyl or ethoxyethyl groups, such as alkyl groups, ethenyl or 2-propen-1-yl groups Alkanoyl, for example C _1-3 alkanoyl groups such as acetyl groups, or formyl [HC (O)-], carboxamide (CONR ¹² R ^12a ) or thiocarboxamido (CSNR ¹² R ^12a ) groups Wherein R ¹² and R ^12a in each case may be the same or different and each is a hydrogen atom or an optionally substituted linear or branched C _1-6 alkyl such as C _1- such as methyl or ethyl groups ₃ alkyl group. Any substituents that may be present on such R ^c , R ¹² or R ^12a groups include those described below in connection with alkyl groups R ⁶ or R ⁷ .

The alkyl group represented by R ³ , R ⁶ or R ⁷ in the compound of formula 1 is an optionally substituted linear or branched C _1-6 alkyl group such as C _1- such as methyl, ethyl, n-propyl or i-propyl group. _It includes ₃ alkyl groups. Any substituent that may be present on these groups is one or more halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C _1-6 alkoxy, for example C such as methoxy or ethoxy groups. _1-3 alkoxy.

When the group R ⁶ in the compound of formula 1 is a halogen atom, it may be for example a fluorine, chlorine, bromine or iodine atom.

If R ¹ or R ² is a -CO ₂ R ⁸ , -CONR ⁹ R ¹⁰ or CSNR ⁹ R ¹⁰ group, it can be for example a -CO ₂ H, -CONH ₂ or -CSNH ₂ group, or R ¹ or R ^{The divalent} groups -CO ₂ R ⁸ , -CONR ⁹ R ¹⁰ , -CSNR ⁹ R ¹⁰ , -CONHR ¹⁰ , or -CSNHR ¹⁰ (wherein R ⁸ , R ⁹ and R ^10, if present, are methyl or ethyl groups If the same C _1-3 alkyl groups}, which C _6-12 aryl group, for example C _6-12 optionally substituted, such as phenyl, or 1- or 2-naphthyl group, or an optionally substituted benzyl or phenethyl group It may be an aryl C _1-3 alkyl group. Optional substituents that may be present on these aryl groups include the R ¹³ substituents discussed below in connection with the group Ar.

In the compound of Formula 1, the groups-(CH ₂ ) _t Ar and-(CH ₂ ) _t Ar (L ¹ ) _n Ar 'when present are -Ar, -CH ₂ Ar,-(CH ₂ ) ₂ Ar, -(CH ₂ ) ₃ Ar-, -Ar-Ar ', -Ar-L ¹ -Ar', -CH ₂ ArAr ', -CH ₂ ArL ¹ Ar',-(CH ₂ ) ₂ ArAr '. ^{_{- (CH 2) 2 ArL 1}} Ar ', - (CH 2) 3 ArAr' or - (CH _{2) 3} ArL ¹ Ar may be 'date.

Monocyclic or bicyclic aryl groups represented by the groups Ar or Ar 'in the compound of formula 1 are for example optionally substituted C _6-12 Aryl groups such as optionally substituted phenyl, 1- or 2-naphthyl, indenyl or isoindenyl groups.

When the monocyclic or bicyclic aryl group Ar or Ar 'contains one or more hetero atoms, Ar or Ar' may be, for example, 1, 2, 3 or 4 hetero atoms selected from oxygen, sulfur or nitrogen atoms. It may be an optionally substituted C _1-9 heteroaryl group containing. Typically, the Ar or Ar 'heteroaryl group may be, for example, a monocyclic or bicyclic heteroaryl group. Monocyclic heteroaryl groups include, for example, 5 or 6 membered heteroaryl groups containing 1, 2, 3 or 4 hetero atoms selected from oxygen, sulfur or nitrogen atoms. Bicyclic heteroaryl groups include 9 or 10 membered heteroaryl groups containing 1 or 2 or more hetero atoms selected from, for example, oxygen, sulfur or nitrogen atoms.

Examples of heteroaryl groups represented by Ar or Ar 'include pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, iso Thiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- Oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2, 3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindoleyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyri Degree [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6 , 7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. Examples of bicyclic heteroaryl groups include quinolinyl or isoquinolinyl groups.

The heteroaryl groups represented by Ar or Ar 'may be attached to the residue of the molecule of formula 1 via any ring carbon or hetero atom as appropriate. Thus, for example, when the group Ar or Ar 'is a pyridyl group it may be a 2-pyridyl, 3-pyridyl or 4-pyridyl group. If it is a thienyl group, it may be a 2-thienyl or 3-thienyl group, and similarly if it is a furyl group it may be a 2-furyl or 3-furyl group. In another example, when the group Ar or Ar 'is a quinolinyl group it may be 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and when it is isoquinolinyl It may be a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl group.

If the Ar or Ar 'group in the compound of formula 1 is a nitrogen containing heterocycle, it may form quaternary salts, for example N-alkyl quaternary salts, and the present invention will be understood to extend to such salts. Thus, for example, when the groups Ar or Ar 'are pyridyl groups, the pyridinium salts can form N-alkylpyridinium salts such as, for example, N-methylpyridinium.

The aryl or heteroaryl group represented by Ar or Ar 'in the compound of Formula 1 may be optionally substituted by one, two or three or more substituents [R ¹³ ], respectively. Substituent R ¹³ may be selected from one atom or group R ¹⁴ or —Alk ² (R ¹⁴ ) _m , wherein R ¹⁴ is a halogen atom or amino (—NH ₂ ), substituted amino, nitro, cyano , Hydroxyl (-OH), substituted hydroxyl, cycloalkoxy, formyl [HC (O)-], carboxyl (-CO ₂ H), esterified carboxyl, thiol (-SH), substituted thiol , -C (O) Alk ² , -SO ₃ H, -SO ₂ Alk ² , -SO ₂ NH ₂ , -SO ₂ NHAlk ² , -SO ₂ N [Alk ² ] ₂ , -CONH ₂ , -CONHAlk ² , CON [Alk ² ] ₂ , -NHSO ₂ H, -NAlk ² SO ₂ H, -NHSO ₂ Alk ² , -NAlk ² SO ₂ Alk ² , -N [SO ₂ Alk ² ] ₂ , -NHSO ₂ NH ₂ ,- NAlk ² SO ₂ NH ₂ , -NHSO ₂ NHAlk ² , -NAlk ² SO ₂ NHAlk ² , -NHSO ₂ N [Alk ² ] ₂ , -NAlk ² SO ₂ N [Alk ² ] ₂ , -NHC (O) H, -NHC (O) Alk ² , -NAlk ² C (O) H, -NAlk ² C (O) Alk ² , -N [C (O) Alk ² ] ₂ , -NHC (O) OH, -NHC (O ) OAlk ² , -NAlk ² C (O) OH, -NAlk ² C (O) OAlk ² , -NHCONH ₂ , -NHCONHAlk ² , -NHCON [Alk ² ] ₂ , -NAlk ² CON [Alk ² ] ₂ ,- NAlk ² CONH [Alk ² ], -NAlk ² CONH ₂ , -C (S) H, -C (S) Alk ² , -CSNH ₂ , -CSNHAlk ² , -CSN [Alk ² ] ₂ , -NHC (S) H, -NHCSAlk ² , -NAlk ² C (S) H, -NAlk ² C (S) Alk ² , -N [C (S) Alk ² ] ₂ , -N [C (O) Alk ² ] SO ₂ H, -NHCSNH ₂ , -NHCSNHAlk ² , -NHCSN [Alk ² ] ₂ , -NAlk ² CSN [Alk ² ] ₂ , -NAlk ² CSNHAlk ² , -NAlk ² CSNH ₂ or -N [C (O) Alk ² ] SO _{2 When} Alk ^{2 is the} group, Alk ² is 1, 2 or 3 -O- or -S- atoms or -S (O) _p- [ Wherein p is an integer 1 or 2] or a linear or branched C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene chain optionally interrupted by a —N (R ⁸ )-group ; m is 0 or an integer 1, 2 or 3.

When _m in the group -Alk ² (R ¹⁴ ) _m is an integer 1, 2 or 3, it will be understood that a substituent or substituents R ¹⁴ may be present on any suitable carbon atom in -Alk ² . Where more than one R ¹⁴ substituents are present they may be the same or different and may be present on the same or different carbon atoms in Alk ² . Obviously, if m is 0 and R ¹⁴ substituent is not present or Alk ² is -SO ₂ 1 group alkylene, alkenylene or alkynylene chain represented by Alk ² when forming part of the same and Alk ² is an alkyl , Alkenyl or alkynyl group.

When R ¹⁴ is a substituted amino group it is a group-NH [Alk ² (R ^14a ) _m ] [wherein Alk ² and m are as defined above and R ^14a is as defined above for R ¹⁴ but is substituted amino, Not a substituted hydroxyl or substituted thiol group] or a group -N [Alk ² (R ^14a ) _m ] ₂ , wherein the -Alk ² (R ^14a ) _m groups are the same or different, respectively.

When R ¹⁴ is a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.

When R ¹⁴ is a cycloalkoxy group it is for example C _5-7 such as a cyclopentyloxy or cyclohexyloxy group It may be a cycloalkoxy group.

When R ¹⁴ is a substituted hydroxyl or substituted thiol group it can be the group -OAlk ² (R ^14a ) _m or -SAlk ² (R ^14a ) _m , where Alk ² , R ^14a and m are as defined above. same.

The esterified carboxyl group represented by group R ¹⁴ comprises a group of formula —CO ₂ Alk ³ , wherein Alk ³ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl Or an optionally substituted linear or branched C _1-8 alkyl group such as t-butyl group; C _6-12 aryl C _1-8 alkyl groups such as optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl groups; C _6-12 aryl groups such as optionally substituted phenyl, 1-naphthyl or 2-naphthyl groups; C _6-12 aryloxy C _1-8 alkyl groups such as optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; Optionally substituted C _1-8 alkanoyloxy C _1-8 alkyl groups such as pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl groups; Or a C _6-12 aroyloxy C _1-8 alkyl group, such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk ³ group include the R ¹³ substituents described above.

It will be appreciated that the group Ar or Ar 'may be attached to the residue of the molecule of formula 1 via one ring carbon atom or hetero atom.

Particular examples of chain Alk ² , if present, are one, two or three -O- or -S- atoms, or -S (O)-, -S (O) ₂ -or -N (R ⁶ ) -groups. Methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, optionally blocked by , 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chains.

Particularly useful atoms or groups represented by R ¹³ are fluorine, chlorine, bromine or iodine atoms, or C _1-6 alkyl such as methyl or ethyl, C _1-6 alkylamino such as methylamino or ethylamino, C _1-6 hydroxyalkyl, for example hydroxymethyl or hydroxyethyl, C _1-6 alkylthiol, for example methylthiol or ethylthiol, C _1-6 alkoxy, for example methoxy or ethoxy, C _5-7 cycloalkoxy, for example cyclopentyloxy, halo C _1-6 alkyl, for example trifluoromethyl, C _1-6 alkylamido, for example methylamino or ethylamino, amino (-NH ₂ ), Amino C _1-6 alkyl, for example aminomethyl or aminoethyl, C _1-6 dialkylamino, for example dimethylamino or diethylamino, nitro, cyano, hydroxyl (-OH), formyl [HC (O)-], carboxyl (-CO ₂ H), -CO ₂ Alk ³ wherein Alk ³ is as defined above, C _{1 -6} alkanoyls such as acetyl, thiol (-SH), thio C _1-6 alkyl such as thiomethyl or thioethyl, sulfonyl (-SO ₃ H), C _1-6 alkylsulfonyl, eg For example methylsulfonyl, aminosulfonyl (-SO ₂ NH ₂ ), C _1-6 alkylaminosulfonyl, for example methylaminosulfonyl or ethylaminosulfonyl, C _1-6 dialkylaminosulfonyl, eg For example dimethylaminosulfonyl or diethylaminosulfonyl, carboxamido (-CONH ₂ ), C _1-6 alkylaminocarbonyl, for example methylaminocarbonyl or ethylaminocarbonyl, C _1-6 di Alkylaminocarbonyl, for example dimethylaminocarbonyl or diethylaminocarbonyl, sulfonylamino (-NHSO ₂ H), C _1-6 alkylsulfonylamino, for example methylsulfonylamino or ethylsulfonylamino , C _1-6 dialkylsulfonylamino, for example dimethylsulfonylamino or diethylsulfonylamino, aminosulfonylamino (-NHS O ₂ NH ₂ ), C _1-6 alkylaminosulfonylamino, for example methylaminosulfonylamino or ethylaminosulfonylamino, C _1-6 dialkylaminosulfonylamino, for example dimethylaminosulfonylamino Or diethylaminosulfonylamino, C _1-6 alkanoylamino, for example acetylamino, C _1-6 alkanoylamino, C _1-6 alkyl, for example acetylaminomethyl or C _1-6 alkoxycarbonyl Amino, for example methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino thiocarboxamido (-CSNH ₂ ), C _1-6 alkylaminothiocarbonyl, for example methylamino Thiocarbonyl or ethylaminothiocarbonyl, C _1-6 dialkylaminothiocarbonyl, for example dimethylaminothiocarbonyl or diethylaminothiocarbonyl, aminocarbonylamino, C _1-6 alkylaminocarbonyl Amino, for example methyla Noka Viterbo carbonyl-amino or amino-ethyl-aminocarbonyl, C _1-6 dia skill aminocarbonylamino, for example, dimethylamino-carbonyl-amino or diethylamino-carbonyl-amino, amino-thiocarbonyl, amino, C _1-6 alkylamino Thiocarbonylamino, for example methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C _1-6 dialkylaminothiocarbonylamino, for example dimethylaminothiocarbonylamino, or diethylaminothiocarbon Carbonylamino, aminocarbonyl C _1-6 alkylamino, for example aminocarbonylmethylamino or aminocarbonylethylamino, aminothiocarbonyl C _1-6 alkylamino, for example aminothiocarbonylmethylamino or amino Thiocarbonylethylamino, formylamino C _1-6 alkylsulfonylamino, for example formylaminomethylsulfonylamino or Formylaminoethylsulfonylamino, thioformylamino C _1-6 alkylsulfonylamino, for example thioformylaminomethylsulfonylamino, or thioformylethylsulfonylamino, C _1-6 acylaminosulfonyl Amino, such as acetylaminosulfonylamino, C _1-6 thioacylaminosulfonylamino, such as thioacetylaminosulfonylamino group.

If desired, two R ¹³ substituents may be linked together to form a cyclic group such as a cyclic ether, for example a C _2-6 alkylenedioxy group such as ethylenedioxy.

It will be understood that when two or more R ¹³ substituents are present, they are not necessarily required to be the same atom and / or group. The R ¹³ substituent may be present at any ring carbon atom away from being attached with the rest of the molecule of formula (1). Thus, for example, any substituent in the phenyl group represented by Ar or Ar 'may be present in the 2-, 3-, 4-, 5- or 6-position relative to the residue of the molecule and the ring carbon atom attached.

In the compound of formula 1, when the group — (CH ₂ ) _t Ar (L ¹ ) _n Ar ′ is present at R ⁴ and / or R ⁵ , the linker group L ¹ may be any divalent linking group. Particular examples of L ¹ groups which may be present in the compounds of the present invention include groups of the formula-(Alk ⁴ ) _r (X ^a ) _s (Alk ⁵ ) _t- , wherein Alk ⁴ and Alk ⁵ are each one or more Optionally substituted linear or branched C _1-6 , optionally interrupted by, for example, 1, 2 or 3 heteroatoms or carbocyclic or heteroatom containing groups Alkylene, C _2-6 Alkenylene or C _2-6 alkynylene chain, X ^a is —O— or —S— atom or —S (O) —, —S (O) ₂ — or —N (R ^b ) — group, r Is 0 or integer 1, t is 0 or integer 1, s is 0 or integer 1, provided that at least one of r, s or t is 0 and at least one of the others is integer 1.

Heteroatoms capable of blocking Alk ⁴ or Alk ⁵ chains include, for example, carbocyclic groups comprising -O- or -S- atoms, for example cycloalkyl, for example cyclopentyl or cyclohexyl, or cycloalkenyl For example, cyclopentenyl or cyclohexenyl groups. Specific hetero atom-containing groups capable of blocking Alk ⁴ or Alk ⁵ are -S (O)-, -S (O) _2- , -N (R ^b )-, -C (O)-, -C (S)- , -C (NR ^b )-, CON (R ^b )-, -CSN (R ^b )-, -N (R ^b ) CO-, -N (R ^b ) CS-, -SON (R ^b )-, -SO ₂ N (R ^b )-, -N (R ^b ) SO-, -N (R ^b ) SO _2- , -N (R ^b ) SO ₂ N (R ^b )-, -N (R ^b ) Oxygen, sulfur or nitrogen containing groups such as SON (R ^b )-or -N (R ^b ) CON (R ^b )-groups. When the chain Alk ⁴ or Alk ⁵ is interrupted by two or more hetero atoms, carbocyclic or hetero atom containing groups, those atoms or groups are adjacent to each other, for example the group -N (R ^b ) -C (NR ^b It will be appreciated that it may form) -N (R ^b )-or -O-CONH-.

Any substituents that may be present on the Alk ⁴ or Alk ⁵ chain include those described above in connection with R ¹ when the group R ¹ is an alkyl group.

The group-(L ¹ ) _n Ar 'may be attached to the group Ar via any useful carbon or hetero atom present in the two groups. Thus, for example, when Ar is a phenyl group,-(L ¹ ) _n Ar 'is the carbon in Ar at the 2-, 3-, 4-, 5- or 6- position relative to the rest of the molecule and the attached Ar carbon atom And may be attached via a carbon or hetero atom in-(L ¹ ) _n Ar '.

Particular examples of Alk ⁴ or Alk ^{5 in} the group (L ¹ ) _n Ar ′ are optionally substituted methylene, optionally interrupted by 1, 2 or 3 hetero atoms, carbocyclic or hetero atom containing groups as described above, Ethylene, propylene, butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chains.

Particular examples of the group-(L ¹ ) _n Ar 'are the groups -Alk ⁴ Ar', -XAr ', -Alk ⁴ XAr' and -XAlk ⁵ Ar ', in particular for example -CH ₂ Ar',-(CH ₂ ) ₂ Ar ',-(CH ₂ ) ₃ Ar', -CH ₂ OCH ₂ Ar ', -CH ₂ SCH ₂ Ar', -CH ₂ N (R ^b ) CH ₂ Ar ', -CH = CHAr',- CH ₂ CH = CHAr ', -OAr', -SAr ', -N (R ^b ) Ar', -CH ₂ OAr ', -CH ₂ SAr', -CH ₂ N (R ^b ) Ar ', -CH ₂ OCH ₂ OAr ', -OCH ₂ Ar', -O (CH ₂ ) ₂ Ar ', -SCH ₂ Ar', -S (CH ₂ ) ₂ Ar ', -N (R ^b ) CH ₂ Ar' and -N (R ^b ) (CH ₂ ) ₂ Ar ′.

In these particular groups, Ar 'may be as described in the supra, in particular an optionally substituted C _6-12 aryl or C _1-9 heteroaryl group, in particular an optionally substituted phenyl or pyridyl group or -COPh (wherein Ph is an optionally substituted phenyl group), -SO ₂ Ph, -SONHPh, -SO ₂ N (Alk ¹ ) Ph, -SO ₂ N [Ph] ₂ , -CONHPh, -CON (Alk ¹ ) Ph, -CON [ Ph] ₂ , -NAlk ¹ SO ₂ Ph, -NHSO ₂ N (Alk ¹ ) Ph, -NAlk ¹ SO ₂ Alk ¹ Ph, -NHSO ₂ N [Ph] ₂ , -NAlk ¹ SO ₂ N [Ph] ₂ , -NHC (O) Ph, -NAlk ¹ COPh, -NC (O) N [Ph] ₂ , -NHC (O) NHPh, -NAlk ¹ C (O) NHPh, -NHC (O) N (Alk ¹ ) Ph , -NAlk ¹ C (O) N (Alk ¹ ) Ph, -NHC (O) OPh, -NAlk ¹ C (O) OPh, -C (S) NHPh, -C (S) NAlk ¹ Ph, -N ( S) N [Ph] ₂ , -NHC (S) Ph, -NAlk ¹ C (S) Ph, -N [C (S) Ph] ₂ , -NHC (S) NHPh, -NAlk ¹ C (S) NHPh , -NHC (S) NAlk ¹ Ph or NAlk ¹ C (S) NAlk ¹ Ph group. In these groups, the group Alk ¹ may in particular be a methyl or ethyl group.

If a -NHet group is present at R ⁴ and / or R ⁵ , this may be for example a pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group. Any substituent that may be present on such groups includes the R ¹³ substituents described above for the Ar or Ar 'groups.

If a Het 'group is present at R ⁴ and / or R ⁵ it is for example a pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or cyclohexyl group Can be. Any substituent that may be present on such groups includes the R ¹³ substituents described above.

In the compound of formula 1, when an ester group is present, for example the group CO ₂ R ⁸ or —CO ₂ Alk ^3, this may advantageously be a metabolically sensitive ester.

The presence of certain substituents in the compound of Formula 1 may allow salts of the compound to be formed. Suitable salts include pharmaceutically acceptable salts such as acid addition salts derived from inorganic or organic acids, and salts derived from inorganic or organic bases.

Acid addition salts may be hydrochloride, hydrobromide, hydroiodide, alkylsulfonates such as methanesulfonate, ethanesulfonate, or isethionates, arylsulfonates such as p-toluenesulfonate, besylate or Includes naphsylate, phosphate, sulfate, hydrogen sulfate, acetate, trifluoroacetate, propionate, citrate, maleate, fumarate, malonate, succinate, lactate, oxalate, tartrate and benzoate do.

Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts. Include.

Prodrugs of compounds of formula (I) include those compounds, for example esters, alcohols or aminos, which may be of in vivo metabolism by means of metabolism, for example by hydrolysis, reduction, oxidation or transesterification. Convertible to a compound.

Particularly useful salts of the compounds according to the invention include pharmaceutically acceptable salts, in particular pharmaceutically acceptable acid addition salts.

The group = W- in the compound of formula 1 is preferably a = C (Y)-group. In this type of compound Y is preferably ^a -XR ^a group wherein X is -O- and R ^a is an optionally substituted ethyl group or, in particular, an optionally substituted methyl group. Particularly useful substituents that may be present on the R ^a group include 1,2 or 3 fluorine or chlorine atoms.

Particularly useful group 1 of the compounds of the present invention have Formula 1, wherein L is group-XR. X in this type of compound is preferably -O-. In these compounds the group R is preferably an optionally substituted cycloalkyl group, in particular an optionally substituted cyclopentyl group, in particular a cyclopentyl group.

In another group of the compound of formula 1, L is preferably a —CH═C (R ¹ ) (R ² ) group. R ¹ and R ² in this type of compound are preferably linked together with the C atom to which they are attached to an optionally substituted cycloalkyl or cycloalkenyl group, in particular substituted cyclopentyl or cyclohexyl or in particular cyclopentyl or cyclohexyl Form a practical skill.

The groups R ⁴ and R ⁵ in the compound of formula 1 are each independently, preferably (CH ₂ ) _t Ar or — (CH ₂ ) _t Ar— (L ¹ ) _n —Ar ′ groups, in particular CH ₂ Ar or — CH ₂ Ar (L ¹ ) _n Ar 'group or in particular -Ar, Ar-Ar' or ArL ¹ Ar 'group. Particularly useful R ⁴ or R ⁵ groups of this type are those in which Ar or Ar 'optionally contain one or more heteroatoms selected from oxygen, sulfur or in particular nitrogen atoms, and are optionally substituted by one, two or three or more R ¹³ substituents. Group which is a monocyclic aryl group. In these compounds, when the group represented by Ar or Ar 'is a heteroaryl group, it is preferably a nitrogen-containing monocyclic heteroaryl group, in particular a 6-membered nitrogen-containing heteroaryl group. Thus, in a preferred example, the groups R ⁴ and R ⁵ may each contain a 6 membered nitrogen containing heteroaryl Ar or Ar 'group. In another preferred embodiment R ⁴ may contain a monocyclic aryl group or a monocyclic or bicyclic heteroaryl group Ar or Ar 'containing one or more oxygen, sulfur or nitrogen atoms, and R ⁵ is 6 The original nitrogen-containing heteroaryl group Ar or Ar 'may be contained. In these examples, the six-membered nitrogen containing heteroaryl group can be an optionally substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or imidazolyl group. Specific examples are optionally substituted 2-pyridyl, 3-pyridyl, 5-imidazolyl, or especially 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl or 3-pyrazinyl. Monocyclic aryl groups can be phenyl groups or substituted phenyl groups, and monocyclic or bicyclic heteroaryl groups containing one or more oxygen, sulfur or nitrogen atoms are optionally substituted 2-furyl, 3-furyl, 2-thienyl , 3-thienyl, 2-thiazolyl, 2-benzo (b) thiophenyl, 2-benzo (b) furyl or 4-isoquinolinyl group.

In another preferred one for the particular type of R ⁴ group just mentioned, in particular when L ¹ is a —CH ₂ — group, Ar ′ is —NHC (O) NHPh (herein Ph is as just described), -NHCH ₃ C (O) NHPh, -NHC (O) NCH ₃ Ph, -NCH ₃ C (O) NCH ₃ Ph, -COPh, -NHSO ₂ NHPh, -NCH ₃ SO ₂ NHPh, -NCH ₃ SO ₂ NCH ₃ Ph, -NHCOPh, -NCH ₃ COPh or -NHSO ₂ Ph group.

Usually, when R ⁴ and / or R ⁵ in a compound of Formula 1 contain a substituted phenyl group it is, for example, one, two or trisubstituted phenyl groups where the substituent is one atom or group R ¹³ as defined above. Can be. When the R ⁴ and / or R ⁵ group contains a monosubstituted phenyl group, the substituents may be present at 2-, or preferably 3-, or especially 4-positions relative to the ring carbon atoms attached to the rest of the molecule. If the R ⁴ and / or R ⁵ group contains a disubstituted phenyl group, the substituent may be present at the 2,6 position with respect to the ring carbon atom attached to the rest of the molecule.

Particularly useful substituents R ¹³ which may be present on the Ar group, in particular on the phenyl group, in R ⁴ and R ⁵ are halogen atoms or alkyl, haloalkyl, amino, substituted amino, nitro, —NHSO ₂ NH ₂ , —NHSO ₂ NHCH ₃ , -NHSO ₂ N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHC (O) NH ₂ , -NCH ₃ C (O) NH ₂ , -NHC (O) NHCH ₃ , -NHC (O) NHCH ₂ CH ₃ or —NHC (O) N (CH ₃ ) ₂ group, wherein said atom or group is optionally separated from the rest of the Ar group by the group Alk ² as defined above, respectively.

When R ⁴ and / or R ⁵ in the compound of formula 1 contain a substituted pyridyl group it is for example 1 or 2 atoms or groups R ¹³ as defined above, in particular 1 or 2 such as fluorine or chlorine atoms One or disubstituted pyridyl groups, such as one or disubstituted 2-pyridyl, 3-pyridyl or especially 4-pyridyl groups, substituted by two halogen atoms, or methyl, methoxy, hydroxyl or nitro groups. Particularly useful pyridyl groups of these types are 3-monosubstituted 4-pyridyl or 3,5-disubstituted 4-pyridyl, or 2- or 4-monosubstituted 3-pyridyl or 2,4-disubstituted 3 It is a pyridyl group.

Particularly useful groups of the compounds of formula (1) and their salts, solvent compounds, hydrates, prodrugs and N oxides have formula (2):

Wherein -L is OR, where R is an optionally substituted cycloalkyl group, -CH = C (R ¹ ) (R ² ) or -CH ₂ CH (R ¹ ) (R ² ) group, wherein R ¹ and R ² are joined together with the carbon atom to which they are attached to form a cycloalkyl group; Z is as defined for Formula (1).

When Z is a group (A) in the compound of formula (1) or (2), the preferred group of compounds is that the group R ³ is a hydrogen atom; The group R ⁶ is a methyl group or in particular a hydrogen atom; The group R ⁷ is a methyl group or in particular a hydrogen atom; R ⁴ and R ⁵ are as defined for Formula (1). In this type of compound R ⁶ and R ⁷ are each in particular a hydrogen atom.

Typically, the group Z in the compound of formula 1 or 2 is preferably group 1 of type (A). In this type of compound R ³ , R ⁶ and R ⁷ are each in particular a hydrogen atom, R ⁵ is in particular an optionally substituted pyridyl group, in particular a 4-pyridyl group and R ⁴ is especially-(CH ₂ ) _t -Ar- ( L ¹ ) _n -Ar 'group, in particular -Ar- (L ¹ ) _n -Ar' group. Specific examples of the -Ar- (L ¹ ) _n -Ar 'group are -Ar-Ar, -Ar-O-Ar, -Ar-CH ₂ -Ar, -Ar- (CH ₂ ) ₂ Ar, -Ar-NHC (O) NHAr, -Ar-CH ₂ NHC (O) NHAr, -Ar-COAr, -Ar-CH ₂ COAr, -Ar-NHSO ₂ NHAr, -Ar-CH ₂ NHSO ₂ NHAr, -Ar-NHSO ₂ Ar , -Ar-CH ₂ NHSO ₂ Ar, -Ar-NCH ₃ C (O) NHAr, -Ar-CH ₂ NCH ₃ C (O) NHAr, -Ar-NCH ₃ SO ₂ NHAr or -Ar-CH ₂ NCH ₃ SO ₂ NHAr groups. Ar in these groups may in particular be an optionally substituted phenyl group. Optional substituents are for example halogen atoms such as chlorine or fluorine atoms, alkyl such as methyl, haloalkyl such as trifluoromethynyl, amino, substituted amino such as methylamino, ethyl Amino, dimethylamino, nitro, -NHSO ₂ NH ₂ , -NHSO ₂ NHCH ₃ , -NHSO ₂ N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHC (O) NH ₂ , -NCH ₃ C (O) NH ₂ , -NHC (O) NHCH ₃ , -NHC (O) NHCH ₂ CH ₃ or -NHC (O) N (CH ₃ ) ₂ group, wherein said atom or group is optionally selected from the rest of the phenyl group by a -CH ₂ -group Are separated.

In this example, when Ar is a phenyl group, the — (L ¹ ) _n Ar group or any other substituent may be attached with any useful ring carbon atom away from being attached with the rest of the compound of formula (1).

Particularly useful compounds according to the invention are:

(±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-trifluoromethylphenyl) phenylethyl]} pyridine;

(±) -4- [2- (4-benzyloxyphenyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] pyridine;

(±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-nitrophenyloxy) phenyl] ethyl} pyridine;

Isomers of (E) and (Z) of 4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethenyl] -3- (phenylethyl) pyridine);

(±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] -3- (phenylethyl) pyridine;

(±) -4- {2- [4- (4-aminophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine;

(±) -4- {2- [4- (4-acetamidophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine;

(±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-N ', N'-dimethylaminosulfonylaminophenyl) phenyloxy] ethyl} pyridine ;

(±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-methylsulfonylaminophenyl) phenyloxy] ethyl} pyridine;

(±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4'-methyl-4-biphenyl) ethyl] pyridine;

(±) -N- {3- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylmethyl} -N 'phenylurea;

Or their respective isomers or degraded enantiomers and salts, solvates, hydrates, prodrugs and N oxides.

The compounds according to the invention are selective and potential inhibitors of PDE IV. The ability of a compound to act in this way can simply be determined by the tests described herein below in the Examples.

Special applications in which the compounds of the present invention can be used include the prevention and treatment of asthma, especially asthma associated with inflamed lungs, cystic fibrosis, or inflammatory airway disease, chronic bronchitis, eosinophil granulomas, psoriasis and other benign and malignant proliferative Skin diseases, endotoxin shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic nephritis, atopic dermatitis, gall margin, adult respiratory pain symptoms, tastelessness of diabetes, In the treatment of allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, arterial restenosis and atherosclerosis.

The compounds of the present invention can also inhibit neuronal inflammation through enhancement of cAMP in sensory neurons. Thus, they are analgesic, anti-tissue and anti-pain hypersensitivity in inflammatory diseases associated with hypersensitivity and pain.

The compounds according to the invention can also enhance cAMP in leukocytes and thereby inhibit unwanted leukocyte activation in immune based diseases such as rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease.

The compounds according to the invention can also be used to lower gastric acid secretion and thus treat conditions associated with hypersecretion.

The compounds of the invention can inhibit cytokine synthesis by inflammatory cells in response to immunity or infectious stimuli. Thus, they are useful in the treatment of bacterial, fungal or viral induced sepsis and septic shock, where cytokines such as tumor necrosis factor (TNF) are important media. The compounds of the present invention can also inhibit inflammation and fever caused by cytokines and are therefore useful in the treatment of inflammation and cytokine mediated chronic tissue degradation resulting from diseases such as rheumatoid or deformable arthritis.

Excessive production of cytokines such as TNF in bacterial, fungal or viral infections or in diseases such as cancer leads to cachexia and muscle weakness. The compounds of the present invention may ameliorate these symptoms with the enhancement of the prognosis of quality of life.

The compounds of the present invention can also enhance cAMP in certain regions of the brain, thereby interfering with depression and memory impairment.

The compounds of the present invention can inhibit cell proliferation in certain tumor cells and thus can be used to prevent tumor growth and invasion of normal tissues.

The compounds according to the invention can be administered as pharmaceutical compositions for the prevention and treatment of diseases, and according to a further aspect of the invention the inventors have combined the compounds of formula 1 with one or more pharmaceutically acceptable carriers, excipients or diluents It provides a pharmaceutical composition containing.

Pharmaceutical compositions according to the invention may be selected for oral, buccal parenteral, costly, topical or rectal administration, or for formulation by inhalation or aeration.

For oral administration, pharmaceutical compositions may be formulated, for example, in the form of tablets, sugar tablets or capsules, prepared by conventional means, such as a binder (e.g., alphaated corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose). ); Fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); Lubricants (eg magnesium stearate, talc or silica); Disintegrants (eg potato starch or sodium glycolate); Or pharmaceutically acceptable excipients such as wetting agents (eg sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid formulations for oral administration may, for example, be selected for the formulation of solutions, syrups or suspensions, or they may be present as constituent wet products with water or other suitable vehicle before use. Such liquid formulations may be prepared by conventional means together with pharmaceutically acceptable additives such as suspensions, emulsifiers, non-aqueous vehicles and preservatives. The formulations may also contain buffer salts, flavors, colorants and sweeteners as appropriate.

Formulations for oral administration may be suitably formulated to provide controlled release of the active compound.

For buccal administration, the composition may select a formulation of tablets or sugar tablets formulated in a conventional manner.

The compounds of formulas (1) and (2) may be formulated for parenteral administration by infusion, for example by injection or injection into the buccal side. Injectable formulations may be present in unit dose formulations, eg, in glass ampoules or in multiple dose containers, eg, glass vials. Injectable compositions may be selected from oily or aqueous vehicles, such as suspensions, solutions or emulsions, and may contain formulations such as suspending agents, stabilizers, preservatives and / or dispersants. Alternatively, the active ingredient may be a constituent powder with a suitable vehicle, eg, sterile pyrogen free water, before use.

In addition to the formulations described above, the compounds of Formulas 1 and 2 may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.

For administration by non-administration or inhalation, the compounds for use according to the invention are suitable promoters, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas With the use of the mixture, it is conveniently delivered in the formulation of a pressurized pack or aerosol spray display for a nebulizer.

If desired, the composition may be present in a pack or preparation device that may contain one or more unit dose formulations containing the active ingredient. The pack or preparation device may be accompanied by instructions for administration.

The amount of a compound of the invention required for the prophylaxis or treatment of a particular inflammatory condition will vary depending on the compound selected and the condition of the patient to be treated. Typically, however, the daily dose will be about 100 ng-100 mg / kg body weight, eg about 0.01-40 mg / kg body weight, about 10 ng-50 mg / body weight for parenteral administration for oral or buccal administration. kg, and about 0.05-about 1,000 mg, for example about 0.5-about 1,000 mg, for nonadministration or administration by inhalation or aeration.

The compounds according to the invention can be prepared by the following methods. The symbols W, L, Z, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹¹ are described above for Formula 1 unless otherwise specified when used in the following formulae. It will be understood to represent one group. If reactive functional groups such as hydroxy, amino, thio or carboxyl groups are desired in the final product in the reaction to be described later, it will not be necessary to protect them so as to exclude their unwanted participation in the reaction. Conventional protecting groups can be used according to standard practice (see, eg, Green, TW, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981).

Accordingly, according to a further aspect of the invention, L is a -C (R ¹¹ ) = C (R ¹ ) (R ² ) group, R ¹¹ is a hydrogen atom or a methyl group, and R ³ is a hydrogen atom when present The compound of 1 can be prepared by coupling a compound of formula 3 wherein R ¹¹ is as described above with an olefinating agent.

Particular examples of olefining agents are compounds (R ¹ ) (R ² ) CHP (D) ₃ Hal {where Hal is a halogen atom, such as a bromine atom, D is an optionally substituted alkyl such as methyl, or aryl, In particular phenyl groups}; Phosphoran (R ¹ ) (R ² ) C═P (D) ₃ ; Phosphonate (DO) ₂ P (O) CH (R ¹ ) (R ² ); Or silane derivatives such as compounds of formula (D) ₃ SiC (R ¹ ) (R ² ), for example trialkylsilanes such as (CH ₃ ) ₃ SiC (R ¹ ) (R ² ).

Bases for use in the reaction are organometallic bases, for example alkyllithium, for example organolithium compounds such as n-butyllithium, halides such as sodium halide or potassium, or sodium alkoxides, for example sodium methoxide. Alkoxides such as seeds.

The reaction can be carried out with a suitable solvent such as an alkyl sulfoxide, for example a polar nonprotic solvent such as methyl sulfoxide, an amide such as N, N-dimethylformamide or hexamethylphosphorus triamide; Ethers such as non-polar solvents such as tetrahydrofuran or diethyl ether, or aromatic solvents such as benzene, toluene or xylene; Or in a polar protic solvent such as alcohol, for example ethanol. Preferably, the reaction is carried out at low temperature, for example at about −78 ° C. to about room temperature.

The olefinating agent used in this reaction may be a known compound or may be prepared from known starting materials using reagents and conditions similar to those used to prepare the known compounds, or either. For example, phosphorane can be prepared in situ by reacting a phosphonium salt with a base of the type described above. In another example, phosphonates can be prepared by reacting halides (R ¹ ) (R ² ) CHHal with phosphite (DO) ₃ P, as described in the Arbuzov reaction. The silane derivatives react halosilane (D) ₃ SiHal with a base such as lithium diisopropylamide at low temperature, for example about -10 ° C., in a solvent such as ether, for example cyclic ether, for example tetrahydrofuran. Can be prepared by

According to a further aspect of the invention the compounds of formula ( ¹ ) wherein L is group-C (R ¹¹ ) = CH (R ¹ ) and R ¹ is an optionally substituted alkyl, alkenyl or alkynyl group, also represent intermediates of formula (3) It can be prepared by reacting with an organometallic reagent and then dehydrating the corresponding alcohol.

Examples of organometallic reagents include organolithium R ¹ Li or organo magnesium R ¹ MgHal reagents. The reaction with the organometallic reagent may be carried out at low temperature, for example −10 ° C.-room temperature, in an ether such as diethyl ether or a solvent such as cyclic ether such as for example tetrahydrofuran. Dehydration can be carried out in the presence of a base such as an amine, for example triethylamine, using an acid such as an organic acid such as p-toluene sulfonic acid or trifluoroacetic acid.

The intermediate of formula 3 wherein R ¹¹ is a methyl group is reacted with an intermediate of formula 3 wherein R ¹¹ is a hydrogen atom with an organometallic reagent such as methyllithium or CH ₃ MgHal using the conditions just described, and then the resulting alcohol is oxidized, For example, it may be prepared by oxidizing with manganese dioxide.

Intermediates of formula (3), wherein R ¹¹ is a hydrogen atom, may be prepared by acid hydrolysis of a protected aldehyde of formula (4), wherein P is a protected aldehyde group, for example a dioxanyl group, for example trifluoroacetic acid or By reaction with, deprotection in the presence of a solvent such as acetone, or a solvent mixture such as chloroform, and water.

Intermediates of formula 4, wherein Z is a group (A), wherein R ³ is a hydroxyl group, the intermediate of formula (4) uses a ketone of formula (5) using an organometallic base, such as an organolithium reagent, for example a base such as n-butyllithium By reacting with reagent R ⁵ CHR ⁶ R ⁷ at about −70 ° C.-room temperature in a solvent such as ether, for example tetrahydrofuran.

Intermediates of formula (5) can be prepared by oxidizing the alcohol of formula (6) at room temperature in a solvent such as dichloromethane using an oxidizing agent such as manganese (IV).

Intermediates of formula (6) may be prepared by reacting a halide of formula (8) to be described below with aldehyde R ⁴ CHO at about −70 ° C.-room temperature in a solvent such as tetrahydrofuran in the presence of a base such as n-butyllithium. have.

An intermediate of formula (4) wherein Z is a group (A), wherein R ³ is a hydrogen atom, and an intermediate of formula (4) wherein Z is a group (B), L is -C (R ¹¹ ) = C (R ¹ ) (R ² Prepared by hydrogenation using reagents and conditions to be described later herein for the hydrogenation of compounds of formula ( ^I ), which is a) group, to obtain a compound of formula ( ^I ) wherein L is -CH (R ¹¹ ) -CH (R ¹ ) (R ² ) groups Can be.

An intermediate of formula (4) wherein Z is a group (B) is an intermediate of formula (4) wherein Z is a group (A) and R ³ is a hydroxyl group using an acid, for example trifluoroacetic acid, with an amine such as triethyl It may be prepared by dehydration at low temperature, for example about −10 ° C., in a solvent such as dichloromethane in the presence of a base such as an amine.

Intermediate of formula 4, wherein Z is a group (B)

(a) an intermediate of Formula 7 wherein R ⁵ CH ₂ R ⁶ and W ^a are a -C (0) R ⁴ group;

(b) an intermediate of formula 7 with an aldehyde or ketone R ⁵ COR ⁶ and W ^a being a -CH ₂ R ⁴ group; or

(c) Intermediate of formula (7) in which Alk ^a is an alkyl group (Alk ^a ) ₃ SiCH (R5) (R6) and W ^a is -C (0) R ⁴ , in each case being suitable in the presence of a base or an acid; It can be prepared by condensation in a solvent.

Bases for use in these reactions include inorganic bases such as alkali and alkaline earth metal bases such as hydroxides such as sodium hydroxide or potassium; Alkoxides such as sodium, ethoxide; Organic bases such as amines such as piperidine; And organolithium bases such as alkyllithium, for example n-butyllithium base. Suitable solvents include alcohols such as ethanol, or ethers such as tetrahydrofuran. Acids for use in the reaction include organic acids, for example carboxylic acids such as acetic acid.

The reaction can be carried out at any suitable temperature, for example around -78 ° C.- or at reflux, depending on the nature of the starting material.

In general, the base, acid, solvent and reaction conditions can be selected from the known alternative ranges for this type of reaction, depending on the nature of the starting material.

In the silane derivative of the formula (Alk ^a ) ₃ SiCH (R ⁵ ) (R ⁶ ), Alk ^a may be a C _1-6 alkyl group such as, for example, a methyl group. Derivatives of this type are for example compounds R ⁵ -CH ₂ -R ⁶ at low temperature, for example at about -10 ° C, in a solvent such as tetrahydrofuran in the presence of a base such as lithium diisopropylamide. It can be prepared by reacting with a silane derivative such as chlorotrialkylsilane, for example chlorotrimethylsilane.

Starting materials R ⁵ COR ⁶ and R ⁵ CH ₂ R ⁶ are known compounds or may be prepared from known starting materials in a manner similar to those used for the preparation of known compounds.

Intermediates of formula (7), wherein -W ^a is a -C (0) R ⁴ group}, the aldehyde of formula (7) in which -W ^a is a -CHO group is reacted at low temperature, for example, in a solvent such as tetrahydrofuran. After reacting with an organometallic reagent at about 10 ° C., the resulting alcohol can be prepared by oxidizing with an oxidizing agent such as manganese dioxide in a solvent such as dichloromethane.

Intermediates of formula (7), wherein -W ^a is -CHO, are compounds of formula (8) wherein Hal is a halogen atom, e.g. bromine atom), or a compound of formula (8) in a solvent such as amide, for example dimethylformamide, It can be prepared by reacting with an organometallic reagent such as n-butyllithium at -60 ° C or lower.

The intermediate of formula (8) may be an acid catalyst, for example an aldehyde or ketone of formula (9) wherein Hal is a halogen atom such as bromine atom, for example using a suitable diol such as 1,3-propanediol For example, it may be prepared by protecting with an aldehyde or ketone protecting group at an elevated temperature such as reflux temperature in an aromatic solvent such as toluene in the presence of 4-toluenesulfonic acid.

Typically, this reaction can optionally be used to protect the aldehyde in any of the intermediates described herein.

Intermediates of formula 9 are known compounds or may be prepared by methods analogous to known compounds or one of the two.

In another process according to the invention, the compound of formula (1), wherein Z is a group (B), comprises a compound of formula (10) in phosphate ester (R'O) (OR ") P (O) CH ( R ⁵ ) (R ⁶ ), wherein R ′ and R ″ may be the same or different and are an alkyl or aralkyl group.

Suitable bases include organolithium, for example organometallic bases such as n-butyllithium, alkoxides, for example alkali metal alkoxides such as sodium ethoxide or sodium methoxide, and hydrates such as potassium or sodium hydrate. do. Solvents include ethers such as tetrahydrofuran, for example diethyl ether or cyclic ethers, and alcohols such as methanol or ethanol.

The phosphonate derivatives used in this reaction are known compounds or the phosphite P (OR ') ₂ (OR ") is reacted with a compound R ⁵ CHR ⁶ Hal, wherein Hal is a halogen atom, for example a bromine atom, using conventional methods. It can be prepared by or by one of the two.

In which R ⁴ is the reaction of a corresponding compound of R ⁴ is a hydrogen atom is an intermediate of the formula 10 is not a hydrogen atom the same as those described for compounds of formula (I) with an organometallic reagent, W is ^a -C (O) R ⁴ group It can be prepared by oxidizing as already described for the preparation of the intermediate of formula (7).

The intermediate of formula 10 wherein R ⁴ is a hydrogen atom is a halide of formula 11 wherein Hal is a halogen atom, for example bromine or a chlorine atom, from the intermediate of formula 8 wherein W ^a is -CHO. It can be prepared by reacting with an organometallic reagent using the same reagents and conditions as described above for the preparation.

Intermediates of formula 11, wherein L is a -C (R ¹¹ ) = C (R ¹ ) (R ² ) group, the phosphonium salts as described above for the preparation of compounds of formula 1 from the intermediate of formula 3 It can be prepared by coupling with (R ¹ ) (R ² ) CHP (D) ₃ Hal.

Intermediate of formula 11, wherein L is an -XR group, corresponds to a compound RHal in which Hal is a halogen atom at ambient or above, e.g., about 40-50 ° C., in a solvent such as dimethylformamide in the presence of a base. Can be prepared by alkylation. Intermediates of formula (11), wherein L is -XH, can be prepared by known compounds or from known starting materials using conventional methods, for example as corresponding aldehyde roll starting materials by oxidation when X is -O- or either .

In yet another method according to the invention, the compound of formula 1 wherein one or both of R ⁴ and R ⁵ is a-(CH ₂ ) _t Ar (L ¹ ) _n Ar 'group is represented by Formula 12 {where Z' is As defined for Z in Formula 1, wherein one or both of R ⁴ and R ⁵ are a group-(CH ₂ ) _t ArE, wherein E is boronic acid -B (OH) ₂ or tin reagent Sn (R ¹⁵ ) ₃ , wherein R ¹⁵ is an alkyl group, for example a methyl group}, can be prepared by coupling a compound of the formula Ar ′ (L ¹ ) _n L ² , in which L ² is a leaving group, in the presence of a complex salt metal catalyst. have.

Special leaving groups L ² include, for example, halogen atoms such as bromine, iodine or chlorine atoms, and alkyl sulfonates such as trifluoromethanesulfonate. Special tin reagents include, for example, compounds in which R ¹⁵ in formula S _n (R ¹⁵ ) ₃ is a methyl group.

Suitable catalysts include heavy metal catalysts, for example palladium catalysts such as tetrakis (triphenylphosphine) palladium. The reaction is heated in an inert solvent, for example an aromatic hydrocarbon such as toluene or benzene, or an ether such as dimethoxyethane or dioxane, optionally in the presence of a base, for example an alkali carbonate such as sodium carbonate, for example refluxing. Can be carried out at a temperature. Typically, the metal catalyst and reaction conditions may be selected from a range of known alternatives for this type of reaction depending on the nature of the compound of formula 12 and / or of the compound of Ar ′ (L ¹ ) _n L ² [Example See, eg, Miyaura, N et al. (Synth. Comm. (1981), 11 , 513; Thompson, WJ and Gaudino, J., J. Org. Chem, (1984), 49 , 5237 and Sharp, MJ Et al., Tetrahedron Lett. (1987), 28 , 5093).

Intermediate Ar ′ (L ¹ ) _n L ² may be a known compound or may be prepared from known starting materials in a manner similar to that used for the preparation of known compounds, or either. Thus, for example, when L ² is intended to obtain a halogen atom compound _{^{Ar '(L 1) n L}} 2 , such as a bromine or chlorine atom, and are not available to the compound is easy, such a compound is the corresponding amine It can be prepared, for example, by diazotizing with nitrite, such as sodium nitrite, at low temperature in aqueous acid and then reacting with the appropriate copper halide (I) in aqueous acid.

The intermediate of formula 12 may be halogen-metal exchanged with a base such as n-butyl or t-butyllithium followed by a borate salt such as triisopropylborate, or a tin reagent wherein R is as described above and Hal is a halogen atom such as a chlorine atom. It may be prepared by reacting (R ¹⁵ ) ₃ SnHal in a solvent such as tetrahydrofuran, optionally at low temperature, for example at about −70 ° C.

In another example of the method according to the invention, one or both of R ⁴ and R ⁵ are a group — (CH ₂ ) _t ArL ¹ Ar ′ wherein L ¹ is —X ^a (Alk ⁵ ) _t -chain Compounds of Formula 1 are as defined above for Z 'as defined for Z in Formula 1, wherein one or both of R ⁴ and R ⁵ are groups-(CH ₂ ) _t ArX ^a H Thus, there are L ² can be prepared by a leaving group reagent _{^{Ar '(Alk 5) t L}} 2 and reaction.

The reaction can be carried out in a solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine or potassium tert-butoxide at a suitable temperature, for example room temperature.

According to a further aspect of the invention, the compound of formula 1 wherein L is a group -CH (R ¹ ) (R ² ) wherein R ² is -CO ₂ R ⁸ or -CONR ⁹ R ¹⁰ is a compound of formula 13 {here Hal is a halogen atom such as chlorine or bromine atom} and reacted with diazoalkane CH (R ¹ ) N ₂ and then in the presence of silver oxide or silver salt, optionally in the presence of a base R ⁸ OH or R ⁹ R It can be prepared by reacting with ¹⁰ NH.

The intermediate of formula 13 is oxidized to an intermediate of formula 3 wherein R ¹¹ is a hydrogen atom using an oxidizing agent such as permanganate or chromic acid to give the corresponding carboxylic acid which is then halogenated, such as thionyl chloride, phosphorus pentachloride or phosphorus oromide It can be prepared by reacting with a cargo reagent.

According to another aspect of the invention, the compound of formula 1 wherein L is a group -XR, R ³ is a hydroxyl group, R ⁷ is a hydrogen atom is an organometallic reagent R ^{5 wherein} the intermediate of formula 10 is an intermediate It can be prepared by reacting with R ⁶ CHM.

The metal atom represented by M contains a lithium atom, for example.

The reaction can be carried out at low temperature, for example about -70 ° C- ambient temperature in a solvent such as cyclic ether such as tetrahydrofuran. This reaction is particularly suitable for the preparation of compounds of formula 1 wherein R ⁵ is an electron deficient group such as a 2- or 4- pyridyl group.

In another method according to the present invention, the compound of formula 1, wherein W is = N- and R ⁷ is a hydroxyl group, the compound of formula 1 is prepared using the compound of formula 14 or N oxide thereof as a starting material Can be prepared by reacting with reagent R ⁵ C (O) R ⁶ using the conditions described herein.

N oxides of compounds of formula 14 may be prepared by converting compounds of formula 14 to hydrogen peroxide or peroxy acids, for example, in carboxylic acid solutions such as acetic acid, halogenated solvents such as dichloromethane, or ethers such as tetrahydrofuran. It can be prepared by reacting with peracetic acid, peroxymonophthalic acid, trifluoroacetic acid or metachloroperbenzoic acid. It will be appreciated that in this case the compound of formula 1 can be obtained as its N oxide.

Reagent R ⁵ C (O) R ⁶ is a known compound or can be prepared by a method analogous to the preparation of known compounds.

Intermediate of formula 14 is a halide of formula 15 wherein Hal is a halogen atom such as bromine, chlorine or iodine atom, wherein X is -O-, -S- or -NH- in the presence of a base It can be prepared by reacting with compound RXH.

Bases used in this reaction include hydrates such as sodium hydride, or organometallic bases such as butyllithium at temperatures above room temperature, for example at 80 ° C., in a solvent such as amide, for example dimethylformamide.

Intermediates of formula 15 may be prepared by reacting a commercially available amine of formula 16 with nitric acid (prepared in situ by reacting sodium nitrate with an acid such as sulfuric acid or hydrobromic acid) to produce a diazonium salt .

This is in turn optionally reacted with halo acids, for example hydrobromic acid, hydrochloric acid or hydroiodic acid, in the presence of the corresponding copper halide (I) (CuBr or CuI) or halogen, for example Br ₂ , Cl ₂ or I ₂ . Can be.

Compounds of formula 1 may be prepared by internal conversion of another compound of formula 1. For example, a compound of Formula 1 wherein L is a -CH ₂ -CH (R ¹ ) (R ² ) group can be prepared by hydrogenation of a compound of Formula 1 wherein L is a -CH = C (R ¹ ) (R ² ) group. Can be. Hydrogenation can be carried out using, for example, hydrogen in the presence of a catalyst. Suitable catalysts include platinum or palladium optionally supported on an inert carrier such as carbon or calcium carbonate; Nickel, such as Raney nickel, or metals such as rhodium. The reaction is carried out in a suitable solvent, for example an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, or an ester such as ethyl acetate, optionally in the presence of a base, for example a tertiary organic base such as triethylamine. Under, for example, ambient temperature.

Alternatively, the reaction can be carried out by transition hydrogenation using an organic hydrogen donor and a transition agent. Suitable hydrogen donors include, for example, acids such as formic acid, alcohols such as formate, for example ammonium formate, benzyl alcohol or ethylene glycol, hydrazine, and cycloalkenes such as cyclohexane or cyclohexadiene. The transfer agent is for example a transition metal optionally supported on an inert carrier as discussed above, such as palladium or platinum, nickel such as Raney nickel, ruthenium, for example tris (triphenylphosphine) ruthenium chloride or copper Can be. The reaction can usually be carried out at ambient or elevated temperature, optionally in the presence of a solvent, for example an alcohol such as ethanol, or an acid such as acetic acid.

Identical hydrogenation or transition hydrogenation reagents and conditions include (a) a compound of Formula 1 wherein L is an -XR group and X is a group (B), wherein L is an -XR group and Z is a group (A), wherein R ³ and R ⁷ is a compound of Formula 1, each being a hydrogen atom; And (b) a compound of Formula 1 wherein the NO ₂ group is present as a substituent on an Ar or Ar 'group to an internal conversion into a compound of Formula 1 wherein the NH ₂ group is present as a substituent on an Ar or Ar' group.

In another example of an internal conversion process, compound 1 wherein Z is a group (A), wherein R ⁷ is an OR ^c group, where R ^c is an alkyl or alkenyl group, wherein Z is a group (A), wherein R ⁷ may be prepared by reacting a compound of Formula 1 which is a —OH group with reagent R ^c —OH in the presence of an acid such as sulfuric acid.

In yet another example of an internal conversion process, the compound of Formula 1 wherein Z is a group (A) wherein R ⁷ is an OR ^c group, wherein R ^c is a carboxamido or thiocarboxamido group is Z the group (a) and, where R ⁷ is an isocyanate in a solvent such as tetrahydrofuran in the presence of a base such as sodium hydrate a compound of formula 1 -OH group R ^c N = ^c = O or an isothiocyanate R ^c It can be prepared by reacting with N = C = S. Compounds R ^c N═C═O and R ^C N═C═S are known compounds or may be prepared using the reagents and conditions used for the preparation of the known compounds. When R ^C N = C = S is not useful, the compound of formula (1) wherein R ^C is a thiocarboxamido group is a compound of formula (1) in which R ^C is a carboxamido group Using a thiation reagent such as Lawessson's reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiodiphosphane-2,4-disulfide] It can be prepared by internal conversion.

In still further examples of the internal conversion process, the compound of formula 1 wherein Z is a group (A), wherein R ³ is a fluorine atom is a compound of formula 1 wherein Z is a group (A), wherein R ³ is a hydroxyl group Can be prepared by reacting with a fluorinating agent such as diethylaminosulfur trifluoride (DAST) at low temperature, for example about 0 ° C., in a solvent such as a chlorinated solvent such as dichloromethane.

In still further examples of the internal conversion process, the compound of formula 1 wherein Z is a group (A), wherein R ³ is an alkyl group is a compound of formula 1 wherein Z is a group (A), where R ³ is a hydrogen atom Can be prepared by alkylation with reagent R ³ L ¹ using a base such as n-butyllithium or lithium diisopropylamide. In this method, R ⁴ of the starting material is preferably an electron recessing group.

Compounds of formula ( ¹ ) wherein L is a group -CH (R ¹ ) (R ² ) can also be prepared by internal conversion of compounds of formula ( ¹ ) wherein L is a -CH (R ¹ ) CO ₂ H group. For example, a compound of Formula 1 wherein L is a group -CH (R ¹ ) CONR ⁹ R ¹⁰ is a compound of Formula 1 wherein L is a group -CH (R ¹ ) CO ₂ H (or -CH (R ¹ ) C (O) Hal Active derivatives thereof) can be prepared by reacting with an amine R ⁹ R ¹⁰ NH using standard conditions.

In another example of an internal conversion process, a compound of Formula 1 wherein L is a group -CH (R ¹ ) (R ² ), where R ² is a nitrile group, wherein (a) L is a group -CH (R ¹ ) CH ₂ The corresponding compound of formula 1, which is NH ₂ , is dehydrogenated with, for example, nickel peroxide; Or (b) the corresponding aldehyde [obtained by reduction of a compound of formula ( ¹ ) wherein L is a group -CH (R ¹ ) CO ₂ H] using (i) Li in MeNH ₂ or NH ₃ followed by pyridinium chlorochromate Use; Or (ii) reaction with hydroxylamine hydrogen chloride in a solvent such as borane-Me ₂ S and then pyridinium chlorochromate in an amine such as an aromatic amine such as pyridine, followed by formic acid or hydrochloric acid. It can be prepared by treating with acid.

According to a further internal conversion method, the compound of formula (1) wherein Z is a group (B) is a acid or base catalyst for the corresponding compound of formula (1) wherein Z is a group (A), wherein R ³ or R ⁷ is a hydroxyl group It can be prepared by dehydration using the removed removal.

Suitable acids include, for example, phosphoric acid or sulfonic acids, for example 4-toluenesulfonic acid. The reaction can be carried out at elevated temperature, for example at reflux, in an inert organic solvent, for example a hydrocarbon such as toluene. Base catalyzed removal can be carried out using trifluoroacetic anhydride in a solvent such as dichloromethane or tetrahydrofuran at low temperature, for example at about 0 ° C.-ambient temperature in the presence of an organic base such as triethylamine. Can be.

In yet another example of an internal conversion process, the compound of formula 1 wherein Ar or Ar 'is substituted by amido, such as acetamido, or alkyl aminosulfonylamino, eg, dimethylaminosulfonylamino group, is Or a compound of formula 1 wherein Ar 'is substituted by an amino group using anhydrides such as acetic anhydride, or sulfamoyl halides such as dimethylsulfamoyl chloride at room temperature in a solvent such as an amine such as pyridine It can be prepared by reacting.

In still further examples of the internal conversion process, the compound of formula 1 wherein Ar or Ar 'is substituted by alkylsulfonylamino, for example methylsulfonylamino group, is a compound of formula 1 wherein Ar or Ar' is substituted by amino group. In the presence of a base, for example triethylamine or a tertiary amine such as N-methylmorpholine, with an alkylsulfonyl halide such as methanesulfonyl chloride in a halogenated solvent such as dichloromethane. It can be prepared by reacting.

N oxides of the compounds of formula (1) can be prepared by oxidizing the corresponding nitrogen base, for example in the presence of an acid such as acetic acid, using an oxidizing agent such as hydrogen peroxide at elevated temperature, for example at about 70-80 ° C., or alternatively a solvent, for example For example in dichloromethane by reaction with peracids such as peracetic acid at ambient temperature.

Salts of the compounds of formula (1) may be prepared by applying the compounds of formula (1) to a suitable acid or a suitable solvent or solvent mixture, for example an organic solvent such as ether, for example diethyl ether, It can be prepared by reacting with a base.

If it is desired to obtain a special enantiomer of the compound of formula (1) it can be prepared using any suitable conventional method for decomposing enantiomers using the corresponding mixture of ethanethiomers as starting material.

Thus, for example, diastereomeric derivatives, such as salts, can be prepared by reacting a mixture of enantiomers of formula (1), such as racemates, and appropriate chiral compounds such as chiral acids or bases. Suitable chiral acids are, for example, tartaric acid and other tartrates such as dibenzoyl tartrate and dytoluoyl tartrate, sulfonates such as camphor sulfonate, mandelic acid and other mandelate, and 1,1'-binaphthalene- 2,2'-diyl hydrogen phosphate. The diastereomer can then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered by treatment with an acid or a base, for example when the diastereomer is a salt.

In another decomposition method, the racemates of Formula 1 can be separated using chiral high performance liquid chromatography. Alternatively, special enantiomers may optionally be obtained by using the appropriate chiral intermediate in one of the methods described above.

The following examples illustrate the invention. In the examples the following abbreviations are used: DME-ethylene glycol dimethyl ether; THF-tetrahydrofuran; CH ₂ Cl ₂ -dichloromethane; Et ₂ O-diethyl ether; EtOH-ethanol; RT-room temperature; DMF-N, N-dimethylformamide; EtOAc-ethyl acetate; DMPU-1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone; BuLi-butyllithium.

<Intermediate 1>

5-bromo-2-methoxyphenol

The title compound was prepared as described in International Patent Specification WO 93/10118.

<Intermediate 2>

4-bromo-2-cyclopentyloxyanisole

The title compound was prepared as described in International Patent Specification WO 94/10118.

<Intermediate 3>

(4-bromophenyl) (3-cyclopentyloxy-4-methoxyphenyl) ketone

The title compound was prepared as described in International Patent Specification WO 94/14742.

<Intermediate 4>

4- [2- (4-bromophenyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) -2-hydroxyethyl] pyridine

The title compound was prepared as described in International Patent Specification WO 94/14742.

<Intermediate 5>

(E) and (Z) isomers of 4- [2- (4-bromophenyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) ethenyl] pyridine

The title compound was prepared as described in International Patent Specification WO 94/14742.

<Intermediate 6>

Acyl Sultam (1)

Sultams were synthesized as described in International Patent Application No. PCT / GB 94/02799.

<Intermediate 7>

(1R, 5S) -N-[(3R) -3- (4-benzyloxyphenyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) propano Japanese] -10-10-dimethyl-3-thia-4-azatrisilo [5.2.1.0 ^1.5 ] decane-3,3 dioxide

A solution of 4-bromobenzyloxybenzene (22.3 g, 84.9 mmol, 2.2 equiv) in THF (100 mL) was turned into magnesium turnings in THF (10 mL) containing 1,2-dibromoethane (2 drops). 2.44 g, 101.9 mmol, 2.6 equiv) and the mixture was heated to reflux for 0.5 h. The cooled solution was added dropwise to a solution of intermediate 6 (20.68 g, 38.6 mmol) in THF-Et ₂ O (1: 5; 600 mL) at -40 ° C and the mixture was warmed to -10 ° C over 4 hours. Ammonium chloride solution (10%; 150 mL) and EtOA _C (300 mL) were added and the organic layer was separated and mixed with additional EtOA _C portion (3 × 100 mL). The extract was dried (MgSO ₄ ) and concentrated in vacuo and the yellow residue was recrystallized from EtOH to give the title compound (17.93 g) as a pale yellow solid. δ H (CDCl ₃ ) 0.69 (3H, s, M eCMe), 0.87 (3H, s, MeC M e), 1.15-1.35 (2H, br m), 1.4-1.5 (1H, br m), 1.5-2.0 ( 12H, br m), 3.31 (1H, d, J 13.8 Hz, C H SO ₂ ), 3.44 (1H, d, J 13.8 Hz, C H SO ₂ ), 3.65-3.75 (1H, m, NC H ), 4.51 (1H, d, J 11.5HZ, C H CHO), 4.58 (1H, br m, OC H ), 4.95-5.1 (3H, m, OC H ₂ + CHC H CO), 6.55-6.65 (3H, m , C ₆ H ₃ ), 6.86 (2H, about d, J 8.7 Hz, ortho for 2xAr H benzyloxy), 7.25-7.45 (9H, m, C ₆ H ₅ + pyridine H ₃ , H ₅ + 2xAr H benzyl Meta for oxy), and 8.37 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₂ , H ₆ ).

<Intermediate 8>

(R) -4- [2- [3-cyclopentyloxy-4-methoxyphenyl) -2- (4-hydroxyphenyl) ethyl] pyridine

The mixture of Example 3 (9.35 g, 19.5 mmol, cyclohexadiene (25 mL, 195 mmol), and 10% Pd / C (1.0 g) in EtOH (300 mL) was heated to reflux for 2 hours. The reaction mixture was filtered through Celite ^R (Celite) and the filtrate and washes were concentrated in vacuo to give the title compound (7.6 g) as a white foam: δ H (CDCl ₃ ) 1.4-1.9 (1H, br m, ( CH ₂ ) ₄ ), 3.2-3.35 (2H, m, CHC H ₂ ), 3.79 (3H, s, O M e), 4.05 (1H, about t, J about 7.8 Hz C H CH ₂ ), 4.65 (1H , br m, OC H ), 6.6-6.8 (5H, m, ortho for C ₆ H ₃ + 2xAr H OH), 6.9-7.0 (4H, m, pyridine H ₃ , H ₅ + 2xAr H OH ) And 8.36 (2H, about d, J about 4.5 Hz pyridine H ₂ , H ₆ ).

Intermediate 9

4-methyl-3-pyridinecarboxaldehyde

n-BuLi (1.6 M in hexane) (2.2 mmol, 1.37 mL) was added dropwise at −78 ° C. to a stirred solution of N, N, N′-trimethylethylenediamine (2.4 mmol, 0.245 g) in THF. A 3-pyridinecarboxaldehyde solution (2 mmol, 0.214 g) in THF was added and the mixture was stirred for 15 minutes followed by an additional portion of n-BuLi (1.6 M in hexane) (4 mmol, 2.5 mL). After stirring at −70 ° C. for 2 hours, iodomethane was added, the mixture was stirred at room temperature for 30 minutes, then poured into aqueous NaCl solution, extracted twice with Et ₂ O, dried (MgSO ₄ ), Filtration and concentration in vacuo. The residue was chromatographed (SiO ₂ ; Et ₂ O) to afford the title compound as an oil.

<Intermediate 10>

(4-methyl-3-phenylethenyl) pyridine

Benzyltriphenylphosphonium bromide (mixture with sodium amide) (99 mmol, 4.96 g) was stirred in THF for 30 minutes at room temperature. A red solution was obtained. A solution of intermediate 9 in THF (8.3 mmol, 1 g) was added and the reaction mixture was stirred for 16 h and poured into aqueous NaHCO ₃ solution, extracted twice with CH ₂ Cl ₂ , dried (MgSO ₄ ), filtered and Concentrated in vacuo. The residue was chromatographed (SiO ₂ ; Et ₂ O) to give the title compound (1.5 g) as an oily compound.

<Intermediate 11>

(4-methyl-3-phenylethyl) pyridine

A stirred solution of intermediate 10 (1.8 g) in EtOH was hydrogenated with H ₂ -Pd / C for 16 hours. The title compound was obtained as an oil.

<Intermediate 12>

3-cyclopentyloxy-4-methoxybenzaldehyde

The title compound was prepared as described in International Patent Specification WO 94/20455.

Intermediate 13

2-bromo-4-methylpyridine

To a 48% aqueous solution of HBr (56.55 mL, 520.64 mmol) 2-amino-4-methylpyridine (10 g, 92.47 mmol) was added slowly below -5 ° C. Bromine (14 mL, 274 mmol) was then added dropwise while maintaining 0 ° C., then a solution of sodium nitrate (17.5 g, 254 mmol) in water (20 mL) was carefully added to maintain 5 ° C. or lower. After stirring for 1 hour, a solution of NaOH (37 g, 940 mmol) in H ₂ O (50 mL) was added at 25 ° C. or below. The reaction mixture was extracted with Et ₂ O (3 × 75 mL) and the mixed layers were washed (brine), dried (MgSO ₄ ) and then evaporated to dryness to afford a crude oil. Flash chromatography (SiO ₂ ; hexanes / Et ₂ O, 50:50) gave the title compound (10.2 g) as a yellow oil. δ H (CDCl ₃ ) 2.45 (3H, s, ArC H ₃ ), 7.00 (1H, d, pyridine H ₅ ), 7.25 (1H, s, pyridine H ₃ ), and 8.15 (1H, d, pyridine H ₆ ). m / z 172 M + 1), 174 (M + 1).

<Intermediate 14>

2-cyclopentyloxy-4-methylpyridine

To a cold (0 ° C.) suspension of sodium hydride (2 g, 50 mmol) in DMF (20 mL) was added cyclopentanol (4.99 mL, 55 mmol) dropwise and the solution was allowed to warm to room temperature and stirred for 1 hour. Intermediate 13 (8.6 g, 49.67 mmol) was added dropwise and the reaction mixture was heated at 80 ° C for 2 h. After cooling, H ₂ O (100 ml) was added and the mixture was extracted with Et ₂ O (3 × 100 ml), washed (brine), dried (MgSO ₄ ) and then evaporated to dryness to give an orange oil. Chromatography (SiO ₂ ; hexanes / Et ₂ O, 50:50) gave the title compound (7.5 g) as an orange oil. m / z 179 (M + l). δ H (CDCl ₃ ) 1.5-2.0 (8H, m, (CH ₂ ) ₄ ), 2.25 (3H, s, C H ₃ ), 5.35 (1H, m, OC H ), 6.45 (1H, s, pyridine H ₂ ), 6.65 (1H, d, pyridine H ₅ ) and 7.96 (1H, d, pyridine H ₆ ).

<Example 1>

a) (E) and (Z) isomers of 4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-trifluoromethylphenyl) phenyl] ethenyl} pyridine

A mixture of intermediate 5 (500 mg, 1.1 mmol) and detrakis (triphenylphosphine) palladium in DME (20 ml) was stirred at rt for 0.5 h. Sodium carbonate solution (2M; 1.5 ml 3.0 mmol) and 4-trifluoromethylphenyl boric acid (190 mg, 1.0 mmol) were added and the reaction mixture was heated to reflux for 18 hours. The mixture was cooled, partitioned between water (10 ml) and EtOAc (20 ml), the organic layer was separated and mixed with additional EtOAc portion (2 × 10 ml). The extract was washed with brine (15 ml), dried (MgSO ₄ ) and concentrated in vacuo to give a pale brown oil. The residue was chromatographed (SiO ₂ ; EtOAc-hexanes, 1: 1) to give the title compound (410 mg) as a colorless oil. δ H (CDCl ₃ ) 1.5-2.0 (8H, br m, (C H ₂ ) ₄ ), 3.86 and 3.89 (3H, s, O M e), 4.57 and 4.70 (1H, br m, OC H ), 6.6- 7.8 (14H, m, 2 × C ₆ H ₄ + C ₆ H ₃ + pyridine H ₃ , H ₅ + C = C H ), and 8.3-8.45 (2H, m, pyridine H ₂ , H ₆ ).

The following compounds were prepared in a similar manner to the compounds of Example 1 a).

b) (E) and (Z) isomers of 4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4'-methyl-4-biphenyl) ethenyl] pyridine

Intermediate 5 (0.40 g, 0.80 mmol), tetrakis (triphenylphosphine) palladium (0.051 g, 0.045 mmol) in DME (20 ml), sodium carbonate solution (2M, 1.49 ml, 2.7 mmol) and 4-methylbenzeneboric acid (0.1151 g, 0.846 mmol) was used as starting material. Chromatography (SiO ₂ ; EtOAc-hexanes, 1: 1) afforded the title compound (0.311 g). δH (CDCl ₃ ) 1.25 (1H, t), 1.5-1.75 (6H, m), 1.85 (2H, s), 2.4 (3H, s), 3.95 (3H, s), 6.4-6.9 (5H, m) , 7.2-7.3 (3H, m), 7.5 (1H, m), 7.55-7.6 (3H, m), and 8.4 (2H, m).

<Example 2>

a) (±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-trifluoromethylphenyl) phenylethyl]} pyridinium formate

A mixture of Example 1 compound (380 mg) and 10% Pd / C (50 mg) in formic acid (5 ml) and EtOH (35 ml) was heated to reflux for 3 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give a yellow oil which was chromatographed (SiO ₂ ; EtOAc-hexane, 1: 1) to give the title compound (190 mg) as a pale yellow solid. δ H (CDCl ₃ ) 1.5-1.95 (8H, br m, (C H ₂ ) ₄ ), 3.57 (2H, d, J 7.9 Hz, CHC H ₂ ), 3.80 (3H, s, O M e), 4.24 ( 1H, t, J 7.9 Hz, C H CH ₂ ), 4.68 (1H, br m, OC H ), 6.65-6.75 (2H, m, meta for 2xAr H OMe), 6.78 (1H, d, J 8.1 Hz , Ortho for Ar H OMe), 7.29 (2H, d, J 8.2 Hz, meta for 2xAr H CF ₃ ), 7.41 (2H, d, J 5.6 Hz, pyridine H ₃ , H ₅ ), 7.53 (2H, d, ortho to 2xAr H CF ₃ ), 7.63 (2H, d, J 8.8 Hz, 2xArH of C ₆ H ₄ CF ₃ ), 7.67 (2H, d, J 8.8 Hz, 2xAr H of C ₆ H ₄ CF ₃ ), And 8.62 (2H, broad doublet, J about 5 Hz, pyridine H ₂ , H ₆ ); m / z (EI) 517 ( M ⁺ , 8%), 426 (15), 425 (48), 358 (20), 357 (100), 296 (22), and 69 (28).

The following compounds were prepared in a similar manner to the compounds of Example 2a).

b) (±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4'-methyl-4-biphenyl) ethyl] pyridine

Compound (0.311 g, 0.673 mmol) of Example 1b in EtOH (35 ml) and 10% formic acid in 10% Pd / C was used as starting material. Purification by HPLC (60-80% acetonitrile-water) gave the title compound (0.23 g). δH (MeOH) 1.5-1.75 (9H, m), 2.3 (3H, s), 3.3 (2H, dd), 3.5 (2H, d), 3.65 (3H, s), 4.3 (1H, t), 6.8 ( 3H, d), 7.2 (2H, d), 7.3 (2H, d), 7.35 (2H, d), 7.45 (2H, d), and 8.5 (2H, m), m / z (ES ⁺ ) 464.2 ( M + H ⁺ ).

<Example 3>

(R) -4- [2- (4-benzyloxyphenyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] pyridine

n-BuLi (1.6 M solution in hexane) (27 ml, 43.0 mmol, 1.5 equiv) was added dropwise to a solution of ethanethiol (10.6 ml, 14.3 mmol, 5 equiv) in THF (300 ml) at about −10 ° C. After 0.5 h, a solution of intermediate 7 (20.6 g, 28.7 mmol) in THF (200 ml) was added dropwise and the reaction mixture was stirred at rt for 12.5 h. Water (10 ml) was added and the solvent removed in vacuo. The residual foam was dissolved in EtOH (100 ml) and aqueous sodium hydroxide (2M; 200 ml) and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to about 50 ° C. and treated with concentrated hydrochloric acid (37 ml) to pH 5 and then heated to reflux for 0.75 h. The organic solvent was removed in vacuo and the residue was partitioned between aqueous NaOH solution (1.0 M; 400 ml) and Et ₂ O (400 ml). The organic layer was separated and mixed with an additional Et ₂ O capacity (3 × 100 ml) and the extract was washed with aqueous NaOH solution (1.0 M; 2 × 100 ml) and then dried (MgSO ₄ ) and concentrated in vacuo. Chromatography of the remaining pale yellow gum (SiO ₂ ; hexane-Et ₂ O, 7: 3-100% Et ₂ O) afforded the title compound (9.35 g) as a white solid (I found C, 79.76; H, 6.98; N , 2.62.C ₃₂ H ₃₃ NO ₃ .calc'd: C, 79.63; H, 7.11; N, 3.00%); δ H (CDCl ₃ ) 1.5.2.1 (8H, br m, (CH ₂ ) ₄ ), 3.27 (2H, d, J 7.8 Hz, CHC H ₂ ), 3.79 (3H, s, O M e), 4.09 (1H , t, J 7.8 Hz, C H CH ₂ ), 4.63 (1H, br m, OC H ), 5.02 (2H, s, OC H ₂ ), 6.64 (1H, d, J 2.0 Hz, Ar H cyclopentyloxy For ortho), 6.67 (1H, dd, J 8.2, 2.0 Hz, para for Ar H cyclopentyloxy), 6.74 (1H, d, J 8.2 Hz, ortho for Ar H OMe), 6.87 (2H, approximately d, J about 8.6 Hz, ortho for 2xAr H benzyloxy), 6.91 (2H, about d, J about 4.5 Hz, pyridine H ₃ , H ₅ ), 7.08 (2H, about d, J about 8.6 Hz, 2xAr H Meta) for benzyloxy, 7.3-7.5 (5H, m, C ₆ H ₅ ), and 8.38 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₂ , H ₆ ).

<Example 4>

(R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-nitrophenyloxy) phenyl] ethyl] pyridine

Potassium tert-butoxide (258 mg, 2.19 mmol) was added to a solution of intermediate 8 (710 mg, 1.83 mmol) in DMF (25 ml) and DMPU (10 ml) and the mixture was stirred at room temperature. After 0.5 h, 4-bromonitrobenzene (553 mg, 2.74 mmol) was added and the solution was stirred at rt overnight. Water (100 ml) and aqueous sodium hydroxide solution (2 M; 20 ml) were added and the mixture was extracted with Et ₂ O (3 × 150 ml). The extract was washed with aqueous sodium hydroxide solution (1M; 2 × 30 ml), water (2 × 100 ml) and brine (100 ml), then dried (MgSO ₄ ) and concentrated in vacuo. The yellow residue was chromatographed (SiO ₂ ; Et ₂ O) to give the title compound (729 mg) as a pale yellow solid. δ H (CDCl ₃ ) 1.5-1.9 (8H, br m, (C H ₂ ) ₄ ), 3.32 (2H, d, J 7.9 Hz, CHC H ₂ ), 3.81 (3H, s, O M e), 4.18 ( 1H, t, J 7.9 Hz, C H CH ₂ ), 4.67 (1H, br m, OC H ), 6.66 (1H, d, J 2.0 Hz, Ortho for Ar H cyclopentyloxy), 6.71 (1H, dd , J 8.2, 2.0 Hz, Para for Ar H cyclopentyloxy), 6.77 (1H, d, J 8.2 Hz, Ortho for Ar H OMe), 6.9-7.05 (6H, m, CHC ₆ H ₄ + pyridine H ₃ , H ₅ ), 7.2-7.3 (2H, m, meta for Ar H NO ₂ ), 8.15-8.25 (2H, m, ortho for Ar H NO ₂ ), and 8.42 (2H, dd, J 4.5, 1.6 Hz, pyridine H ₂ , H ₆ ).

<Example 5>

Isomers of (E) and (Z) of 4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethenyl] -3- (phenylethyl) pyridine

A catalytic amount of tosic acid was added to a solution of the compound of Example 10 a) (1.8 g, 4.32 mmol) in toluene (150 ml) and the mixture was heated to reflux for 8 hours in a Dean StArk apparatus. The solution was cooled, poured into aqueous NaHCO ₃ and extracted twice with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed to give the title compound (1.3 g) as a yellow solid. Melting point 78-80 ° C. (Found: C, 81.44; H, 7.35; N, 3.62. Calcd for C ₂₇ H ₂₉ NO ₂ : C, 81.17; H, 7.32; N, 3.51%). δ H (CDCl ₃ ) 1.6-2.0 (8H, br m, (C H ₂ ) ₄ ), 2.9-3.1 (4H, m, Ar (C H ₂ ) ₂ ), 3.81 (3H, s, OC H ₃ ), 4.85 (1H, s, OC H ), 6.9-7.4 (9H, m, ArH and C H = C H ), 7.37 (1H, d, J 8 Hz, ArH), 8.37 (1H, s, H ₂ pyridine) and 8.42 (1H, doublet, J 5 Hz, H ₆ pyridine).

<Example 6>

4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] -3- (phenylethyl) pyridine

The compound of Example 5 (800 mg, 2 mmol) was hydrogenated using the reagents and conditions described to yield Intermediate 11 with Intermediate 10 as the starting material. Purification by chromatography (Si ₂ O; Et ₂ O) gave the title compound (605 mg) as a colorless gum (found: C, 80.82; H, 7.77; N, 3.54. C ₂₇ H ₃₁ NO ₂ Calculated: C, 80.76; H, 7.78; N, 3.49%). δ H (CDCl ₃ ) 1.5-1.9 (8H, m, (C H ₂ ) ₄ ), 3.27-3.29 (8H, m, alkyl H), 3.81 (3H, s, OC H ₃ ), 4.67 (1H, m, OC H ), 6.59 (1H, br s, ArH), 6.65 (1H, d, J 7 Hz, ArH), 6.78 (1H, d, J 7 Hz, ArH), 7.03 (1H, d, J 5 Hz, H ₅ pyridine ), 7.1-7.4 (5H, m, C ₆ H ₅ ), and 8.3-8.4 (2H, m, H ₂ , H ₆ pyridine).

<Example 7>

4- {2- (S)-[4- (4-aminophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine dihydrochloride

A stirred solution of the compound of Example 4 (800 mg, 1.46 mmol) in EtOH (100 ml) was hydrogenated to 10% Pd / C (100 mg) under hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through Celite ^R and the filtrate was concentrated in vacuo to give a pale brown glass which was partitioned between aqueous 1M NaOH and EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and then concentrated in vacuo to give an oily solid. Chromatography (SiO ₂ ; EtOAc-Et ₂ O, 1: 1) gave the title compound free base (384.9 mg) as an almost white solid. δ H (CDCl ₃ ) 1.50-1.90 (8H, br m), 3.27 (2H, d, J 7.9 Hz), 3.79 (3H, s), 4.10 (1H, t, J 7.9 Hz), 4.65 (1H, br m ), 6.63-6.69 (4M, m), 6.75 (1H, d, J 8.2 Hz), 6.80-6.85 (4H, m), 6.93 (2H, dd, J 4.5, 1.5 Hz), 7.09 (2H, dd, J 6.5, 2.0 Hz), and 8.38 (2H, doublet of doublets, J 7.4, 1.5 Hz).

Free base (384.9 mg, 0.801 mmol) in Et ₂ O (50 ml) was treated with 1.0 M HCl in Et ₂ O (1.76 ml) at room temperature. The resulting oily precipitate was dissolved by the addition of EtOH and the solvent was removed in vacuo. The residue was suspended in Et ₂ O and the solvent was removed in vacuo to yield a fairly light buff solid. Recrystallization (THF-EtOH) gave the title compound a high gloss, fairly pale buff solid. δ H (CD ₃ OD) 1.5-1.9 (8H, m), 3.72 (2H, m (redundant)), 3.76 (3H, s), 4.46 (1H, t, J 8.2 Hz), 4.75 (1H, m), 6.81 (1H, s), 6.84 (1H, s), 6.85 (1H, s), 6.97 (2H, dd, J 6.6, 2.0 Hz), 7.06 (2H, dd, J 6.75, 2.3 Hz), 7.30-7.40 (4H, m), 7.87 (2H, d, J 6.6 Hz) and 8.634 (2H, d, J 6.45 Hz). m / z (El ⁺ ) 480 (M ⁺ ).

<Example 8>

a) 4- {2- (S)-[4- (4-acetamidophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine hydrochloride

A free base solution of the compound of Example 7 (322 mg, 0.67 mmol) in pyridine (10 ml) was heated with acetic anhydride (126 μl) and the mixture was stirred at rt for 24 h. The solvent was removed in vacuo and the residue was azeotroduced twice with toluene and partitioned between aqueous NaOH (pH 13) and EtOAc. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried (Na ₂ SO ₄ ) and then concentrated in vacuo to yield an off-white glass. Chromatography (SiO ₂ ; EtOAc) gave the title compound organic base (303.6 mg) as off-white glass.

The free base (303.6 mg) in EtOH-Et ₂ O (30 ml; 1: 2) was treated with 1.0 M HCl in Et ₂ O (0.62 ml) and then recrystallized as described for the compound of Example 7. (THF-Et ₂ O) The title compound was obtained as an off-white amorphous solid (high gloss). δH (CD ₃ OD) 1.50-1.90 (8H, br m), 2.11 (3H, s), 3.67 (2H, d, J 8.3 Hz), 3.76 (3H, s), 4.40 (1H, t, J 8.3 Hz ), 4.73 (1H, br m), 6.79 (1H, s), 6.83 (1H, s), 6.84 (1H, s), 6.85-6.95 (4H, m), 7.28 (2H, d, (fine split) , J 8.5 Hz), 7.50 (2H, dd, J 6.9, 2.3 Hz), 7.80 (2H, d, J 6.4 Hz), and 8.60 (2H, d, J 5.9 Hz).

The following compounds were prepared in a similar manner to the compounds of Example 8a).

b) 4- {2- (S)-(3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-N ', N'-dimethylaminosulfonylaminophenyl) phenyloxy] ethyl } Pyridyl Hydrochloride

The compound of Example 7 (250 mg, 0.52 mmol) in pyridine (15 ml) and dimethylsulfamoyl chloride (112 μl, 1.04 mmol) was used as starting material. Chromatography (SiO ₂ ; EtOAc-Et ₂ O, 1: 2) gave the title compound free base (188.1 mg) as off-white glass. δ H (CDCl ₃ ) 1.50-1.90 (8H, br m), 2.84 (6H, s), 3.29 (2H, t, J 7.9 Hz), 3.80 (3H, s), 4.13 (1H, t, J 7.9 Hz) , 4.66 (1H, br m), 6.68 (1H, dd, J 8.2, 2.0 Hz), 6.76 (1H, d, J 8.2 Hz), 6.80-6.95 (6H, m), 7.14 (2H, d, J 8.6 Hz), 7.16 (2H, d, J 8.9 Hz), and 8.40 (2H, d, J 6.0 Hz).

Free base (259.1 mg, 0.44 mmol) in EtOH-Et ₂ O (40 ml, 1: 1) was treated with aqueous 1.0 M HCl in Et ₂ O (0.5 ml) and then recrystallized (THF-Et ₂ O) The title compound was obtained as a high gloss off-white solid. m / z (ES ⁺ ) M ⁺ + H 558.δ H (CD ₃ OD) 1.50-1.90 (8H, br m), 2.77 (6H, s), 3.38 (2H, d, J 8.1 Hz), 3.76 (3H , s), 4.26 (1H, t, J 8.1 Hz), 4.70 (1H, m), 6.74 (1H, d, J 1.9 Hz), 6.75-6.89 (6H, m), 7.10-7.30 (6H, m) And 8.29 (2H, doublet of doublets, J 6, 1.5 Hz).

Example 9

4- {2- (S)-(3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-methylsulfonylaminophenyl) phenyloxy] ethyl} pyridine hydrochloride

A solution of free base (0.3667 g, 0.6 mmol) and N-methylmorpholine (264 μl, 0.24 mmol) of the compound of Example 7 in anhydrous CH ₂ Cl ₂ (15 ml) was added to methanesulfonyl chloride (93 μl, 1.2 Mmol) and the mixture was stirred at rt for 24 h. The crude mixture was partitioned between water and EtOAc and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with aqueous 0.5 M NaOH and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a pale brown glass. Chromatography (SiO ₂ ; EtOAc-Et ₂ O, 2: 1) gave the title compound free base (230 mg) as an off-white glassy solid. δ H (CDCl ₃ ) 1.50-1.90 (8H, br m), 2.98 (3H, s), 3.29 (2H, d, J 7.9 Hz), 3.80 (3H, s), 4.14 (1H, t, J 7.9 Hz) , 4.68 (1H, m), 6.65 (1H, d, J 2.0 Hz), 6.68 (1H, dd, J 8.2, 2.0 Hz), 6.77 (1H, d, J 8.2 Hz), 6.8-7.0 (6H, m ), 7.15 (2H, d, J 8.6Hz), 7.20 (2H, d, J 8.9Hz), and 8.40 (2H, d, J 4.5 , 1.5Hz).

Salts were obtained using the method described for the compound of Example 7. A colorless glass was obtained using a solution of free base (224.8 mg, 0.4024 mmol) in Et ₂ O-EtOH (40 ml, 3: 1) and aqueous 1.0 M HCl in Et ₂ O (0.44 ml) as starting material, which was recrystallized. (THF-Et ₂ O) afforded the title compound as an off-white solid of considerable shine. m / z (El ⁺ ) 550 (M ⁺ ).

<Example 10>

a) (±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2-hydroxyethyl] -3-phenylethylpyridine

n-BuLi (1.6 M in hexane) (8.03 mmol, 5.02 ml) was added dropwise to a solution of intermediate 11 (1.45 g, 7.3 mmol) in THF and the mixture was stirred for 30 minutes before intermediate 12 (1.77 g, 8.03 mmol) in THF ) Solution was added. The mixture was stirred at −78 ° C. for 30 minutes, then warmed to room temperature, poured into aqueous NaHCO ₃ solution, extracted twice with CH ₂ Cl ₂ , dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound (2.3 g) as an off-white solid.

The following compounds were prepared in a similar manner to the compounds of Example 10a).

b) [2- (3-cyclopentyloxy-pyrid-4-yl) -1-pyrid-4-yl] ethanol

Intermediate 14 (1 g, 5.61 mmol), n-BuLi (1.6M) (3.5 ml) pyridine-4-carboxaldehyde (534 μl, 5.61 mmol) in THF (10 ml) under N ₂ was used as starting material. Chromatography (SiO ₂ ; Et ₂ O) gave the title compound (550 mg) as a yellow oil. δ H (CDCl ₃ ) 1.5-2.0 (8H, m, (CH ₂ ) ₄ ), 2.9 (2H, m, C H ₂ -CHOH), 4.93 (1H, t, C H OH), 5.37 (1H, m, OC H ), 6.51 (1H, s, pyridine H ' ₃ ), 6.65 (1H, d, pyridine H ' ₅ ), 7.24 (2H, d, pyridine H ₃ , H ₅ ), 8.2 (1H, d, pyridine H ' ₅ ), and 8.51 (2H, d, pyridine H ₂ , H ₆ ).

The activity and selectivity of the compounds according to the invention are shown in the following tests. In these tests the abbreviation FMLP stands for peptide N-formyl-met-leu-phe.

1. Isolated Enzymes

The potential and selectivity of the compounds of the present invention was determined using the apparent PDE isozyme as follows:

i. PDE I, rabbit heart

ii. PDE II, rabbit heart

iii. PDE III, Rabbit Heart, Jurkat Cells

iv. PDE IV, HL 60 cells, rabbit brain, rabbit kidney and human recombinant PDE IV

v. PDE V, rabbit lung, guinea pig lung

Genetically encoded human PDE IV has been cloned from human mononuclear leukocytes (Livi et al., 1990, MoleculAr and CellulAr Biology, 10 , 2678). Using a similar method, we cloned the human PDE IV gene from a number of sources, including eosinophils, neutrophils, white blood cells, mononuclear leukocytes, brain and neural tissue. These genes were transfected into yeast using induction vectors and various recombinant proteins have been expressed, which have the biochemical properties of PDE IV (Beavo and Reifsnyder, 1990, TIPS, 11 , 150). These recombinant enzymes, in particular human eosinophil recombinant PDE IV, have been used as the basis for screens for potential selective PDE IV inhibitors.

The enzyme was purified to isoenzyme homogeneity using standard chromatographic techniques.

Phosphodiesterase activity was analyzed as follows. The reaction was carried out in 150 μl (final concentration) of a standard mixture containing: 50 mM 2-[[tris (hydroxymethyl) methyl] amino] -1-ethanesulfonic acid (TES) -NaOH buffer (pH 7.5), 10 mM MgCl ₂ , 0.1 μM [ ³ H] -cAMP and vehicle or test compound at various concentrations. The reaction was initiated by the addition of enzyme and carried out at 30 ° C. for 5-30 minutes. The reaction was terminated by addition of [ ¹⁴ C] -5'AMP containing 50 μl 2% trifluoroacetic acid to determine recovery of the product. One portion of the sample was then applied to a column of neutral alumina and [ ³ H] -cAMP was eluted with 10 ml 0.1 TES-NaOH buffer (pH 8). [ ³ H] -5'AMP product was eluted with 2 ml 2M NaOH into a scintillation vial containing 10 ml scintillation cocktail. Recovery of [ ³ H] -5'AMP was determined using [ ¹⁴ C] -5'AMP and all analyzes were performed in the linear range of the reaction.

Compounds according to the invention, such as the compounds of the Examples herein, induce concentration dependent inhibition of recombinant PDE IV at 0.1-1,000 nM with little or no activity on PDE I, II, III or V at concentrations of up to 100 μM.

2. Enhancement of cAMP in White Blood Cells

The effect of the compounds of the present invention on intracellular cAMP was studied using human neutrophils or guinea pig eosinophils. Human neutrophils were then incubated with dihydrocytocalacin B and test compounds for 10 minutes and then isolated from peripheral blood stimulated by FMLP. Guinea pig eosinophils were obtained by intraperitoneal irrigation of animals pretreated with intraperitoneal injection of human plasma. Eosinophils were isolated from intraperitoneal leachate and incubated with isoprenin and test compounds. With both cell types, the suspension was centrifuged at the end of the culture, the cell pellet was resuspended in buffer and boiled for 10 minutes before cAMP was measured by specific radioimmunoassay (DuPont).

The most potential compounds according to the examples induced concentration dependent enhancement of cAMP in neutrophils and / or eosinophils at concentrations of 0.1 nM-1 μM.

3. Inhibition of leukocyte function

The compounds of the present invention have been studied for their effects on the peroxide formation, chemotaxis and adhesion of neutrophils and eosinophils. Isolated leukocytes were incubated with dihydrocytocalin B and test compounds for peroxide formation alone prior to stimulation with FMLP. The most potential compounds of the examples induced concentration dependent inhibition of peroxide formation, chemotaxis and adhesion at concentrations of 0.1 nM-1 μM.

Lipopolysaccharide (LPS) induced synthesis of tumor necrosis factor (TNF) by human peripheral blood mononuclear leukocytes (PBM) is inhibited by the compounds of the Examples at concentrations of 0.01 nM-10 μM.

4. adverse effect

Typically, in our tests, no toxic effects were observed when the compounds of the present invention were administered to animals at pharmacologically effective doses.

Claims (6)

A compound of Formula 1, or a salt, solvate, hydrate, or N-oxide thereof: <Formula 1> Where R is a C _1-6 alkyl or C _3-8 cycloalkyl group optionally having up to 3 substituents selected from halogen atoms, hydroxy groups and C _1-6 alkoxy groups; R ^a is a hydrogen atom, a C _1-6 alkyl group or a C _1-6 haloalkyl group; Z is the group (A) Or (B) , And here One of R ⁴ and R ⁵ is -Ar (Alk ⁴ ) _r (O) _s (Alk ⁵ ) _t Ar 'and the other is -Ar or a hydrogen atom (only R ⁴ is possible), where Ar and Ar' are each A phenyl group and a 5 or 6 membered heteroaryl group containing up to 4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the phenyl and heteroaryl groups are halogen atoms, C _1-6 alkyl, C _1-6 halo Alkyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, nitro, -NHSO ₂ NH ₂ , -NHSO ₂ NHCH ₃ , -NHSO ₂ N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHC ( Up to ₃ selected from O) NH ₂ , -NCH ₃ C (O) NH ₂ , -NHC (O) NHCH ₃ , -NHC (O) NHCH ₂ CH ₃ and -NHC (O) N (CH ₃ ) ₂ groups Optionally has a substituent of; Alk ⁴ and Alk ₅ each represent a C _1-6 alkylene group optionally having up to 3 substituents selected from halogen atoms, hydroxy groups and C _1-6 alkoxy groups; r, s and t each independently represent 0 or 1; The compound of claim 1, wherein Z is a group (A), R ⁴ is a group —Ar (Alk ⁴ ) _r (O) _s (Alk ⁵ ) _t Ar ′, wherein Ar and Ar ′ are an optionally substituted phenyl group , R ⁵ is an optionally substituted pyridyl group compound. The 4-pyridyl group compound according to claim 2, wherein R ⁵ is optionally substituted. A compound according to claim 1, wherein Z is group (B) and R ⁴ is a hydrogen atom. The method of claim 1, (±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-trifluoromethylphenyl) phenylethyl]} pyridine; (±) -4- [2- (4-benzyloxyphenyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] pyridine; (±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-nitrophenyloxy) phenyl] ethyl} pyridine; (E) and (Z) isomers of 4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethenyl] -3- (phenylethyl) pyridine); (±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl] -3- (phenylethyl) pyridine; (±) -4- {2- [4- (4-aminophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine; (±) -4- {2- [4- (4-acetamidophenyloxy) phenyl] -2- (3-cyclopentyloxy-4-methoxyphenyl) ethyl} pyridine; (±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-N ', N'-dimethylaminosulfonylaminophenyl) phenyloxy] ethyl} pyridine ; (±) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-methylsulfonylaminophenyl) phenyloxy] ethyl} pyridine; (±) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4'-methyl-4-biphenyl) ethyl] pyridine; Or their respective isomers, isolated enantiomers, salts, solvates, hydrates, or N-oxides thereof. Asthma, cystic fibrosis, inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis or the like, comprising a compound of formula 1 according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, excipient or diluent Other benign or malignant proliferative skin disease, endotoxin shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of myocardium and brain, inflammatory arthritis, chronic nephritis, atopic dermatitis, gall margin, adult respiratory pain symptoms, diabetes Tasteless, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, atherosclerosis, atherosclerosis, neurological inflammation, rheumatoid arthritis, ankylosing spondylitis, transplant rejection, graft-versus-host disease, gastric acid secretion, bacterial-, fungal- Or virally induced sepsis, deformed arthritis, cachexia, muscle weakness, depression, memory impairment and cell proliferation of tumor cells. Emitter selected PDE IV- pharmaceutical composition for the treatment or prevention of related diseases.