SK2162000A3 - Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands - Google Patents

Abstract

The present invention encompasses structures of Formula (I) or the pharmaceutically acceptable non-toxic salts thereof wherein: X is hydrogen, halogen, (un)substituted alkyl, (un)substituted alkoxy or amino; and Y is (un)substituted alkyl, aryl, or heteroaryl, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.

Description

Substituted 4-oxonaphthyridine-3-carboxamides as brain GABA receptor ligands

Technical field

The present invention relates to substituted 4-oxonaphthyridine-3-carboxamides and in particular to such compounds which selectively bind to GABA receptors. The present invention also relates to pharmaceutical compositions containing such compounds and the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down's syndrome, sleep disorders, seizure and cognitive disorders.

BACKGROUND OF THE INVENTION

Γ-Aminobutyric acid (GABA) is considered to be one of the major inhibitor of amino acid transmitters in mammalian brain. Over 40 years have passed since its presence in the brain has been demonstrated (Roberts & Frankel, J. Biol. Chem. 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950). Since then, enormous efforts have been made to include GABA in the etiology of seizure disorders, sleep disorders, anxiety and cognitive disorders (Tallman and Gallager, Ann. Rev. Neuroscience 21-44, 1985). It has been reported that broadly, albeit unevenly, mammalian brain distributed GABA is a transmitter at approximately 30% of brain synapses. GABA mediates many of its actions through a complex of proteins located on cell bodies and nerve endings; these are called GABA receptors. Postsynaptic responses to GABA are mediated by changes in chloride electrical conductivity, which generally, although not invariable, lead to hyperpolarization of the cell. Drugs that interact with the GABA receptor may have

the spectrum of pharmacological activity dependent on their ability to modify the action of GABA.

1,4-Benzodiazepines, such as diazepam, are among the most widely used drugs in the world such as anxiolytics, sedative hypnotics, muscle relaxants and anticonvulsants. Many of these compounds are extremely potent drugs; such efficacy shows a site of action with high affinity and specificity for individual receptors. Initial electrophysiological studies have shown that the main effect of benzodiazepines was an increase in GABA-ergic inhibition. Currently, compounds with similar activity to benzodiazepines are called agonists. Compounds with opposite activity to benzodiazepines are called inverse (inverted) agonists and compounds blocking both types of activity are called antagonists.

GABA-receptor subunits were cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). Many distinct cDNAs were identified by cloning and expression as a subunit of the GABA receptor complex. These are categorized into α, β, γ, δ, ε and provide a molecular basis for GABA-receptor heterogeneity and typical regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The γ subunit has been shown to allow drugs such as benzodiazepines to modify GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in ligand binding to the GABA receptor indicates unique profiles of subtype specific pharmacological effect.

The discovery of the "benzodiazepine receptor" and the following definition of the nature of the interaction between GABA and benzodiazepines reveals that, in terms of behavior, important interactions of benzodiazepines with different neurotransmitter systems are mostly adequate for the increased ability of GABA itself to modify these systems. Each modified system may be sequentially associated with expression of behavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activity (either sedative, anxiolytic and anticonvulsant, or alertness, seizures and anxiety).

Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylic acids and esters have appeared. See, for example, Eur. J. Med. Chim. Ther. (1977), 12 (6), 549-55.

Polish patent no. 125299 discloses compounds of the formula:

wherein N is a ring nitrogen at the 5 or 6 position and R is CO ₂ H or CO ₂ Et.

Several 1,4-dihydro-4-oxo-1,5-naphthyridine-3 carboxamide penicillin derivatives have been disclosed which are said to have antibacterial activity. For example, German patent no. DD 279887 discloses a compound of formula

Japanese patent no. 72-45118 discloses ampicillin derivatives of 1,4-dihydro-4-oxo-3-naphthyridines.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula I that interact with the GABA binding site, the benzodiazepine receptor.

The invention also provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, Down's syndrome, sleep disorders, seizure and cognitive disorders, and overdose of benzodiazepine drugs and for enhancing alertness. Therefore, a comprehensive embodiment of the invention is directed to compounds of formula I:

where

X is hydrogen, halogen, -OR ¹ , C 1 -C 6 -alkyl optionally substituted with up to three groups independently selected from halogen and hydroxy, or -NR ² R ³ ;

X is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, pyridyl, pyrimidinyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, benzofuranyl, benzothienyl each of which is optionally substituted with up to three groups selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₄ -alkoxy, C 1 -C 6 -alkylthio, hydroxy, amino, mono- or di (C 1 -C 6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; or

X represents a carbocyclic group ("carbocyclic group

X) containing 3 to 7 members, up to 2 of which members are optionally heteroatoms selected from the group consisting of:

Λ.

U.

oxygen and nitrogen, wherein the carbocyclic group X is optionally substituted with one or more groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio or heterocyclic;

Y is lower alkyl of 1 to 8 carbon atoms optionally substituted by up to two groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, heterocyclic, -OR ⁴ , -NR ⁵ R ⁶ , SR ⁷ or aryl; or

Y represents a carbocyclic group ("carbocyclic group X) containing 3 to 7 members, up to 3 of which members are optionally heteroatoms selected from oxygen and nitrogen and wherein each member of carbocyclic group Y is optionally substituted with halogen, -OR ⁴ , - NR ⁵ R ^6, SR ^7, aryl or heterocyclic group;

R ¹ is hydrogen, lower alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein each alkyl may be optionally substituted with -OR ⁴ or -NR ⁵ R ⁶ ;

R ² and R ³ are the same or different and represent hydrogen, lower alkyl optionally mono- or disubstituted by alkoxy, aryl, halogen or mono- or di-lower alkyl;

aryl or aryl (C 1 -C 6) alkyl, wherein each aryl is optionally substituted with up to three groups selected from halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C ₆ -alkoxy or mono- or di (C 1 -C 6) alkylamino;

C 3 -C 7 cycloalkyl optionally mono- or disubstituted with halogen, alkoxy or mono or di-lower alkyl; or

-SO ₂ R ^b ;

R ⁴ has the same meaning as R ¹ ;

R ⁵ and R ⁶ have the same meanings as R ² and R ³ ;

R ⁷ is hydrogen, lower alkyl of 1 to 6 carbon atoms or Cycloalkyl of 3 to 7 carbon atoms; and

R ⁸ is lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to carbon atoms or optionally substituted phenyl.

These compounds are highly selective agonists, antagonists or inverse agonists of the brain GABA receptors or precursors of agonists, antagonists or inverse agonists of the brain GABA receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down's syndrome, sleep disorders, cognitive and seizure disorders, and overdose of benzodiazepine drugs and to increase alertness.

A detailed description of the invention follows

The novel compounds of the invention can be described by the general formula I above.

In formula I above, -NR ² R ^{3 may} also represent a heterocyclic group, such as piperidine, in the case where R ² and R ³ together form a C ₅ -alkylene group. Furthermore, R ² and R ³ together may represent an alkylene or alkenylene group optionally containing up to two heteroatoms selected from nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

Similarly, the -NR ⁵ R ^{6 group} in formula I above may also represent a heterocyclic group such as piperidine, in which case R ⁵ and R ⁶ together form a C 5 -alkylene group. Furthermore, R ⁵ and R ⁶ together may represent an alkylene or alkenylene group optionally containing up to two

heteroatoms selected from the group consisting of nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

Preferred compounds of formula I are those wherein X is (Όχ-ϋβ) alkoxy, more preferably (C 1 -C 3) alkoxy. Particularly preferred compounds of formula I include those wherein X is methoxy or ethoxy.

Still other preferred compounds of formula I include those wherein Y is lower alkyl, for example methyl or ethyl, substituted with phenyl, pyridyl or pyrimidinyl. More preferably, Y is benzyl optionally substituted with halogen, (C 1 -C ₆ ) alkyl, (Οχ-Οβ) alkoxy, amino, or mono or di (Οχ-Οβ) alkyl.

Where R ² and R ³ in formula I represent optionally substituted aryl or aryl (Οχ-β) alkyl, the aryl group is more preferably phenyl, pyridyl or pyrimidinyl and the alkyl groups are more preferably methyl and ethyl. More preferred are benzyl and phenyl. Benzyl is particularly preferred.

Where X is optionally substituted C 1 -C ₆ -alkyl, the alkyl group is more preferably optionally substituted methyl, ethyl or propyl. More preferred are perhalomethyl and trihalomethyl. The preferred halogen is fluorine. Particularly preferred is 2,2,2-trifluoroethyl.

X in formula I may be optionally substituted phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl, 4- (1,2-dihydro) indenyl, pyridyl, pyrimidinyl, isoquinolyl, benzofuranyl or benzothienyl, or more preferably 1 , 2,3,4-tetrahydroisoquinolinyl.

In addition to the compounds of Formula I, the invention includes compounds of Formula IA

-J ki -

where

X is (i) hydrogen, halogen, mono- or dialkylamino, alkoxy, (ii) a group of the formula ^R ' _-g - ^O where G is lower alkylene of 1 to 6 carbon atoms or a cyclic group of formula (CH3) n

(CH ₂ ) m wherein n is 0, 1 or 2 and m is an integer from 1 to 5, with the proviso that the sum of n + m is not less than 1 or greater than 5; and

R ¹ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen, lower alkyl or a mono- or di (C ₁ -C ₈ ) alkylamino;

(iii) a group of formula fAr’n ^ o ^

wherein G is as defined in ii above; and

R ² and R ³ independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ₂ R ⁸ , where R ⁸ is (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl or optionally substituted phenyl, or

R ² and R ³ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl;

(iv) a group of formula

R * where

R ² is as defined in iii above;

R ⁴ is hydrogen, lower alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, and may optionally be substituted with one or more (C 1 -C ₆ ) alkoxy or mono- or di (C 1 -C 6) alkylamino; and

G is as defined above in ii;

(v) a group of the formula:

Where R ^and R ^C R ^{S are}

R ² and G are as defined above for iv and ii, and

R ⁵ and R ⁶ independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ₂ R 6 wherein R ⁸ is (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl or optionally substituted phenyl, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl, (vi) a group of the formula wherein G is as defined in ii above; or

(vii) a group of formula

wherein each G is as defined in ii above; and

Y is (viii) lower alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, each of which may be optionally substituted with one or more groups selected from hydroxy, halogen, (C 1 -C 8) alkoxy, alkoxyalkoxy, wherein each alkoxy is (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) alkylthio, (C 3 -C 7) cycloalkylthio, aryl, heteroaryl or mono- or di (C 1 -C ₆ ) alkylamino;

(ix) a group of formula

.I

ΛΛί.

wherein K is lower C 1 -C 6 alkylene optionally substituted with (C 1 -C 6) alkyl or alkylene, or a cyclic group of formula k '

or (C 1 -C 8) alkyl m is an integer from + m not less wherein K 1 independently represents hydrogen or alkylene, n is 0, 1 or 2, and 1 to 5, provided that the sum of n is 1 or greater than 5; and

R ⁹ is hydrogen, lower alkyl or (C 3 -C 7) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy or mono- or dialkylamino;

group of formulas

wherein K is as defined in ix above;

(xi) a group of the formula wherein

K has the meaning given above in ix, a

R ¹³ is hydrogen, cycloalkyl are optionally alkoxy or mono- or di (C 1 -C ₆ ) alkylamino; and lower alkyl of 1 to 6 carbon atoms or up to 7 carbon atoms, wherein alkyl and cycloalkyl substituted with one or more (C 1 -C 8) ^- (xii) group of the formula

where

K has the meaning given above in ix, a

R ⁷ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; and (xiii) a group of the formula '' ^K 'NR'_; R ' ⁵ where

K has the meaning given above in ix ;, a

R ¹⁴ and R ¹⁵ independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,

-SO ² R ⁸ , wherein R ⁸ is as defined above, or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl;

(xiv) a group of formula

wherein K and R ¹⁵ are as defined in ix and xii above;

(xv) a group of formula

3R

wherein K is as defined in ix above;

R ¹⁰ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, halogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms or cycloalkoxy of 3 to 7 carbon atoms;

R ¹¹ , R ¹¹ and R ¹² are the same or different and are selected from the group consisting of hydrogen, (C 1 -C 8) alkyl, halogen, hydroxy, -OR ⁴ , -CR ⁷ (R ⁹ ) NR ⁵ R ⁶ , -CR ⁹ (R ¹⁶ ) OR ⁴ , or

R ¹¹ and R ¹² together with the atoms to which they are attached form a heterocyclic ring; and

R ¹⁶ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms;

(xvi) a group of formula

wherein K is as defined in ix above; and W is heteroaryl;

(xvii) a group of formula

where

K is as defined in ix above; R ¹⁰ and R ¹¹ are as defined in xv above, and

R ¹⁷ is hydrogen, lower alkyl or (C 3 -C 7) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy or mono- or di (C 1 -C 6) alkylamino;

.-. , »·, * 4’, · .., p;, J i- '· -Ι' * Λ9Αύΐ & <Μ »

y. ·. ·> Ί · · · · ί-„ ^, ι ^ Λ4Γ ·. ·. (xviii) a group of the formula

where

A, R ¹⁰ _of R ¹² and R ¹⁷ are as defined above;

(xix) a group of formula w R I * X ' ATA

wherein each K is independently as defined in ix above and R ¹⁰ is as defined above;

(xx) a group of the formula wherein K, R ¹⁰ , R ¹¹ ,

R ¹⁴ and R ¹⁵ are as defined above;

(xxi) a group of formula

wherein A, R ^10, R ^12, R ¹⁴ and R ¹⁵ are as defined above;

(xxii) pyrimidinyl (C 1 -C ₆ ) alkyl or pyridyl (C 1 -C ₆ ) alkyl; or

- _Λ ', * / “./-/i« / T ^ ¹ “·. « _i * V

about. .--> w? »T * ijaSiZ» iJA * Í ·; A &quot; 4.4 &quot; (xxiii) group of the formula

wherein R ¹⁸ is hydrogen, amino, mono- or di (C 1 -C 6) alkylamino or C 1 -C 8 -alkyl optionally substituted with R ¹⁹ , wherein R ¹⁸ is

wherein V and V 'are independently CH or nitrogen;

A 1 'is C 1 -C 6 -alkylene; and

R ²⁰ is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono-, di- or trisubstituted independently by halogen, hydroxy, C 1 -C ₆ -alkoxy, amino, or mono- or di (C 1 -C 6) alkylamino.

Preferred pyrimidinyl (C 1 -C ₆ ) alkyl groups Y are 2- and 4-pyrimidinylmethyl. Preferred pyridyl (C 1 -C ₆ ) alkyl groups Y are 2- and 4-pyridylmethyl.

Preferred benzyl groups Y are those wherein R ¹⁸ is amino or substituted methyl or ethyl. More preferred R ¹⁸ substituents are piperazin-1-yl or piperidin-1-yl substituted at the 4-position with a halogenated benzyl group. Particularly preferred benzyl groups Y are 4- [1- [4- (4-fluorobenzyl) piperazinyl] methyl] benzyl and 4- [1- [4- (4-fluorobenzyl) piperidinyl] methyl] benzyl.

Preferred groups "X" in formula IA are various quinolyl, isoquinolyl, tetrahydroquinolyl or tetrahydroisoquinolyl groups, for example groups of formulas:

The following formulas are preferred embodiments of the invention:

wherein Y is as defined above, wherein

Z is halogen and Y is as defined above,

wherein R ¹ and Y are as defined above; ^, '. <;j'íí-rtK'rf. · '-' · ***? & where R ² ,

IN

R ³ and Y are as defined above,

wherein R ² , R ⁸ and Y are as defined above,

VII wherein R ¹ , G and Y are as defined above.

VIII

wherein R ² , R ³ , G and Y are as defined above;

IX wherein R ² , R ⁴ , G and Y are as defined above;

wherein R ² , R ⁵ , R ⁶ , G and Y are as defined above;

XI wherein G and Y are as defined above;

XII wherein R ² , G and Y are as defined above;

wherein X is as defined above and U is (C 1 -C ₆ ) cycloalkyl;

(C 1 -C ₆ ) lower alkyl;

fefe. h> LS-, 3.a.aSai> Ž * ^ - aAaa · A <fc .¾¼¾.¾. αγΙ & χϊΉ .jXi. Mttfc.fe, ...

wherein X, K and R ¹ are as defined above;

wherein X and K are as defined above;

wherein X, K and R ⁴ are as defined above;

0 0 x. . 7 r Ϊ cj N SR H X / H XVII wherein X, K and R ⁷ are defined higher;

wherein X, K and R ¹⁵ are as defined above;

where

R ¹⁰ and R ¹⁰ 'are the same or different and can be selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, halogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms or cycloalkoxy of 3 to 7 carbon atoms;

R ¹¹ and R ¹¹ 'and R ¹² are the same or different and can be selected from hydrogen, (C 1 -C 6) alkyl, halogen, hydroxy, -OR ⁴ , -CR ⁷ (R ⁹ ) Nr ⁵ R ⁶ , -CR ⁷ (R ⁹ ) OR ⁴ ; or

R ¹¹ and R ¹² together with the atoms to which they are attached form a (hetero) cyclic ring; and

R ⁹ is as defined above;

wherein X and K are as defined above; and

W is heteroaryl;

N H

XXII where X,

K, R ¹ , R ¹⁰ and R ¹¹ are as defined above,

wherein X, K, R ¹ , R ¹⁰ and R ¹² are as defined above;

Wherein X, A and R ¹⁰ are as defined above;

wherein X, A, R ^14, R ^15,

R ¹⁰ and R ¹¹ are as defined above;

Preferred compounds of the invention are included in the following formulas.

Formula XXVII

where

A is C 1 -C ₆ -alkylene;

R ^a is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C 6 -alkylamino or mono- or di-C 1 -C 8 -alkylamino-lower alkyl; and R ^b is lower alkyl or lower cycloalkyl.

More preferred compounds of formula XXVII are those wherein

A is methylene, R ^a is phenyl optionally substituted with methyl or ethyl, and R ^b is lower alkyl. Particularly preferred compounds n of formula XXVII are those wherein A is methylene, R ^a is fale and R ^b is C 1 -C 6 alkyl.

Formula XXVIII

where

A is C 1 -C ₆ -alkylene;

R ^a and R ^a are independently phenyl groups optionally mono-, di-or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di (C 1 -C ₆ ) alkylamino;

full or mono- or di (C 1 -C ₆ ) alkylamino-lower alkyl; and

R ^c is hydrogen or lower alkyl.

More preferred compounds of formula XXVIII are those wherein A is methylene, R ^a and R ^a are independently phenyl optionally substituted with methyl or ethyl and R ^c is lower alkyl. Particularly preferred compounds of formula XXVII are those wherein A is methylene, R ^a is phenyl substituted in the para position by lower alkyl, R ^a 'is phenyl and R ^c is C 1 -C 3 -alkyl.

Formula XXIX

where

A is C 1 -C 6 -alkylene;

R ^d and R ^e are independently lower alkyl groups.

More preferred compounds of formula XXIX are those wherein A is C 2 -C 4 -alkylene. Particularly preferred compounds of formula XXIX are those wherein A is C 2 -C ₄ -alkylene, R ^d is C 1 -C 3 -alkyl, and R ^e is C 2 -C ₄ -alkyl.

Formula XXX

where

A is C 1 -C ₆ -alkylene;

R ^d is lower alkyl; and

R ^f is a group of formula

wherein E is oxygen or nitrogen; and M is C 1 -C 3 -alkylene or nitrogen.

More preferred compounds of Formula XXX are those wherein A is C 1 -C 3 -alkylene. Even more preferred compounds of Formula XXX are those wherein A is C 2 -C ₄ -alkylene, R ^d is C 1 -C 3 -alkyl, and R ^e is C 2 -C 4 -alkyl. Particularly preferred compounds of formula XXX are those wherein A is C 2 -C 4 -alkylene, R ^d is C 1 -C 3 -alkyl, R ^e is C 2 -C 4 -alkyl and E is nitrogen and M is methylene, E is oxygen and M is methylene or ethylene, or both E and M are nitrogen.

Other preferred compounds of formula XXX are those wherein R ^f is furanyl, tetrahydrofuranyl or imidazolyl.

Formula XXXI

where

A is C 1 -C ₆ -alkylene;

R ^d is lower alkyl optionally substituted with amino or mono- or di (C 1 -C ₆ ) alkylamino; and

R ^a is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C ₆ -alkylamino or mono- or di-C 1 -C ₆ -alkylamino-lower alkyl.

More preferred compounds of formula XXXI are those wherein A is C 1 -C ₃ -alkylene, R ^a 'is phenyl optionally substituted with methyl or ethyl and R ^d is C 1 -C ₃ -alkyl. Even more preferred compounds of Formula XXXI are those wherein A is methylene, R ^a 'is phenyl optionally substituted with methyl or ethyl and R ^d is C 3 -C 6 alkyl. Even more preferred compounds of Formula XXXI are the sodium, potassium or ammonium salts of the parent compound.

Other preferred compounds of formula XXXI are those wherein R ^a 'is phenyl substituted with mono- or di- (C 1 -C ₆ ) alkylamino-lower alkyl.

Formula XXXIa where

A is C 1 -C 6 -alkylene;

R ^d is lower alkyl; and

R ^a is phenyl, pyridyl, imidazolyl, pyrimidinyl or pyrrolyl, each optionally substituted with up to two groups selected from halogen, lower alkyl, lower alkoxy, mono- or di- (C 1 -C 6) alkylamino, or mono- or di -C 1 -C 8 -alkylamino lower alkyl.

More preferred compounds of formula XXXIa are those wherein R ^a is imidazolyl and R ^d is C 1 -C 3 -alkyl. Even more preferred compounds of Formula XXXI are those wherein A is methylene, R ^a '' is imidazolyl and R ^d is C 3 -C ₆ -alkyl.

Formula XXXII

ABOUT

ABOUT

N H where

A is C 1 -C 6 -alkylene; and

R ^d and R ^e are independently lower alkyl groups.

More preferred compounds of formula XXXII are those wherein

A is C 1 -C 3 -alkylene. Particularly preferred compounds of formula XXXII are those wherein A is C 1 -C ₃ -alkylene, R ^d is C 1 -C 3 -alkyl and R ^e is C 1 -C 3 -alkyl.

Formula XXXIII where

D is nitrogen or CH;

D 'is nitrogen or oxygen;

A is C 1 -C 6 -alkylene; and

R ^a is phenyl, pyridyl or thiazolyl, each optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C 6 -alkylamino, or mono- or di-C 1 -C 6 alkylamino- lower alkyl.

More preferred compounds of formula XXXIII are those wherein

A is C 1 -C ₃ -alkylene, R ^a 'is phenyl optionally substituted with lower alkyl or halogen and D is nitrogen. Even more preferred compounds of Formula XXXIII are those wherein A is methylene, R ^a 'is phenyl

optionally substituted with lower alkyl or halogen,

D is nitrogen and D 'is oxygen.

Formula XXXIV where

A is C 1 -C 6 -alkylene; and

R ^a is hydrogen;

R ^a is thienyl or phenyl, each optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C ₆ alkylamino, or mono- or di-C 1 -C ₆ -alkylamino lower alkyl .

More preferred compounds of formula XXXIV are those wherein A is C 1 -C 3 -alkylene and R ^a 'is phenyl optionally substituted with lower alkyl or halogen. Even more preferred compounds of formula XXXIV are those wherein A is methylene, R ^a 'is phenyl optionally substituted with lower alkyl, lower alkoxy or halogen.

Formula XXXV

where

A is C 1 -C 8 -alkylene; and R ^d is lower alkyl;

A represents oxygen or methylene; and r is an integer from 1 to 3.

More preferred compounds of formula XXXV are those wherein A is C 1 -C 3 -alkylene. Particularly preferred compounds of formula XXXV are those wherein A is C 1 -C 3 -alkylene and R ^d is C 1 -C 3 -alkyl.

Formula XXXVa

where

A is C 1 -C 8 -alkylene; and

R ^h and R ^h are independently hydrogen or lower alkyl, wherein each alkyl is optionally substituted with lower alkoxy;

A 1 represents oxygen or methylene; and r is an integer from 1 to 3.

More preferred compounds of formula XXXVa are those wherein

A is C 1 -C 3 -alkylene. Particularly preferred compounds of formula XXXV are those wherein A is C 1 -C 3 -alkylene and R ^h is C 1 -C ₃ -alkyl.

Formula XXXVI

where

A is C 1 -C 6 -alkylene;

R ⁹ is lower alkoxy-lower alkyl; and

R ^a is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C ₆ -alkylamino, or mono- or di-C 1 -C 6 -alkylamino-lower alkyl.

Formula XXXVII ο ο

where

R ³ is halogen or lower alkyl; and

R ^k is lower alkyl or cycloalkyl, each of which is optionally substituted with hydroxy, lower alkyl or lower alkoxy; or

R ^k is phenyl (C 1 -C 6) alkyl, wherein the phenyl group is optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C 6 alkylamino, or mono- or di-C 1 -C 6 -alkylamino lower alkyl.

Formula XXXVIII

where

A is C 1 -C 6 -alkylene;

R ¹ is lower alkoxy, benzyloxy, lower alkoxy-lower alkoxy, amino or mono or di-C 1 -C 6 -alkylamino; and

R ^r is pyranyl, dihydropyranyl, tetrahydropyranyl or hexahydropyranyl, pyridine, dihydropyridine, tetrahydropyridine, or piperidine.

Preferred compounds of formula XXXVIII are those wherein R ¹ is lower alkoxy and R ^m is tetrahydropyranyl.

where

Formula XXXIX

O O

A is C 1 -C 6 -alkylene;

R ^N is lower alkoxy, lower alkoxy-lower alkoxy, benzyl or a group of formula

About where

D is nitrogen or CH; and

D 'is nitrogen or oxygen; and

R c is pyranyl, 2- or 3-thienyl; or

R 0 is 2-, 4- or 5-thiazolyl or 2-, 4- or 5-imidazolyl, each of which may be optionally substituted with lower alkyl.

Preferred compounds of formula XXXIX are those wherein

Formula XXXX

where

A is C 1 -C 6 -alkylene;

R ^h and R ^h are independently hydrogen or lower alkyl, wherein each lower alkyl is optionally substituted by lower alkoxy; a * \

R ^a is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C 6 -alkylamino or mono- or di-C 1 -C ₆ -alkylamino-lower alkyl; or

R ^a is thienyl optionally substituted with lower alkyl.

Formula XXXXI

where

A is C 1 -C 6 -alkylene;

D is nitrogen or CH;

D 'is nitrogen or oxygen; and

R ^p is lower alkyl or lower alkyl optionally substituted with lower alkoxy.

Formula XXXXII

where

A is C 1 -C 6 -alkylene;

X is as defined in formula I; and

R ^{18 is} (i) amino or mono- or di (C 1 -C 8) alkylamino; or (ii) lower alkyl optionally substituted

where

V and V 'are independently CH or nitrogen;

A 1 'is C 1 -C 6 -alkylene; and

R ²⁰ is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono-, di- or trisubstituted independently by halogen, hydroxy, C 1 -C ₆ -alkoxy, amino, or mono- or di (C 1 -C 6) alkylamino.

More preferred compounds of formula XXXXII are those wherein

V is nitrogen and X is C 1 -C 8 -alkoxy or C 1 -C 6 -alkyl optionally substituted with up to three halogen atoms. Particularly preferred compounds of formula XXXXII are those wherein V and V 'are nitrogen; X is C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl optionally substituted with up to three halogen atoms; A '' is methylene or ethylene; and R ²⁰ is halogenated phenyl. A preferred group R ²⁰ is

4-fluorophenyl. Very preferred compounds of formula XXXXII are those wherein X is 2,2,2-trifluoroethyl; V and V 'are nitrogen, R ²⁰ is halogenated phenyl; and A and A 'are methylene or ethylene.

In certain situations, the compounds of formula I may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds may be, for example, racemates or optically active forms. In these cases, the individual enantiomers, i. optically active forms, obtained by asymmetric synthesis or by resolution of racemates. Racemate decomposition can be achieved, for example, by conventional methods such as crystallization in the presence of a decomposition reagent or by chromatography using, for example, a chiral HPLC column.

Representative compounds of the present invention that include Formula I include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable acid and base addition salts. In addition, when the compound of the invention is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the salt formed with the acid. Conversely, if the product is a free base, then an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the acid solution according to conventional procedures to prepare acid addition salts from basic compounds.

Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic, such as acetic, HOOC- (CH2) -ACOOH wherein n is 0 to 4 and the like. Non-toxic pharmaceutical salts with bases include salts of bases such as sodium, potassium, calcium, ammonium and the like. A person skilled in the art will recognize the wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

The term lower alkyl as used herein refers to branched or unbranched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.

The term cycloalkyl as used herein refers to cycloalkyl groups of 3 to 7 carbon atoms, such as

for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term aryl in the present invention refers to an aromatic carbocyclic group with one ring (e.g. phenyl), multiple rings (e.g. biphenyl) or multiple condensed rings, of which at least one is aromatic, (e.g. 1,2,3,4-tetrahydronaphthyl, naphthyl) (anthryl or phenanthryl), which is optionally mono-, di- or trisubstituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy.

The term lower alkoxy in the present invention refers to branched or unbranched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, tert-butoxy, p-butoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

As used herein, cycloalkoxy means cycloalkylalkoxy of 3 to 7 carbon atoms, wherein cycloalkyl is as defined above.

The term halogen in the present invention means fluorine, bromine, chlorine and iodine.

The term heteroaryl (aromatic heterocycle) in the present invention means systems with one or more five-, six- or seven-membered aromatic rings containing at least one to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Also heteroaryl

jY (á áž áž áž ž ž fe fe fe ad ad ad ad))))), e: -à 3¾¾¾.¾ -.λ _.

groups include, for example, thienyl, furyl, thiazolyl, imidazolyl, (iso) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.

Specific examples of heteroaryl groups are as follows:

where

Q is nitrogen or -CR ⁹ ;

T is -NR ⁷ , oxygen or sulfur; and

R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ , R ¹¹ ', R ¹² are as defined above.

Where Y represents a carbocyclic group, it is attached to the amide nitrogen by a single bond. The result is an amide of formula

wherein X is as defined above and

represents a carbocyclic group Y.

Where X is a carbocyclic group, such a moiety or group includes aromatic heterocycles (heteroaryl), unsaturated heterocyclic ring systems and saturated heterocyclic ring systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl. Preferred carbocyclic groups are attached to the parent naphthyridine moiety by a nitrogen atom in the carbocyclic group X. Thus, for example, if the pyrrolidinyl is a carbocyclic group X, it is preferably a 1-pyrrolidinyl group of the formula:

Where Y is a carbocyclic group, such a component or group includes aromatic heterocycles (heteroaryl groups), unsaturated heterocyclic ring systems and saturated heterocyclic ring systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl. Preferred carbocyclic groups Y are attached to the parent naphthyridine carboxamide group by a nitrogen atom in the carbocyclic group Y. Thus, for example, if piperidinyl is a carbocyclic group X, it is preferably a 1piperidinyl group of the formula:

The term "optionally substituted phenyl" as used herein refers to phenyl groups which are unsubstituted or substituted by up to 3 groups selected independently from halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, and mono- or di-lower alkylamino.

Representative compounds of the invention are shown in Table 1 below.

Table 1

Compound 1

Compound 2

compound 3

Compound 4

compound 5

Compound 7

Compound 8

Compound 9

H

Compound 10

The pharmaceutical utility of the compounds of this invention is demonstrated by the following GABA receptor activity assays.

Assays are performed as described in Thomas and Tallman (J. Bio. Chem. 156: 9838-9842, J. Neurosci. 3: 433440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w / v) of 0.05 Tris HCl buffer (pH 7.4 at 4 ° C). The tissue homogenate is centrifuged cold (4 ° C) at 20,000 x g for 20 minutes. The supernatant was decanted and the pellet rehomogenized in an equal volume of buffer and centrifuged again at 20,000 x g. The supernatant was decanted and the pellet was frozen overnight at -20 ° C. The pellet is then thawed and rehomogenised in 25 volumes (original weight / volume) of buffer and the procedure is performed twice. The pellet is finally resuspended in 50 volumes (w / v 0.05 M Tris HCl buffer (pH 7.4 at 40 ° C)).

Incubations consist of 100 ml tissue homogenate, 100 ml radioligand 0.5 nM ( ³ H-Rol5-1788 [ ³ H-Flumazenil], specific activity 80 Ci / mmol), drug or blocker and buffer to a total volume of 500 ml. Incubations are allowed to stand at 4 ° C for 30 minutes and then filtered through GFB filters to separate free ligands from bound ligands. The filters are washed twice with fresh buffer of 0.05 M Tris HC1 (pH 7.4 at 4 ^e C) and counted in a liquid scintillation counter. To

In some tubes, 1.0 mM diazepam is added to determine non-specific binding. Data are collected in triplicate, average is determined and% inhibition of total specific binding is calculated. Total specific binding = total - non-specific. In some cases, the amount of unlabeled drugs varies and overall dislocation of the binding curves is performed. Data is converted to Ki values. When tested according to the assay described above, the compounds of the invention have a K i of less than 1 μΜ.

In addition, the following assay may be used to determine whether the compounds of the invention are agonists, antagonists or inverse agonists and thus their specific pharmaceutical utility. The following assay can be used to determine specific GABA receptor activity.

The assays are performed as described in White and Gurley (NeuroReport (>: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 15, 1995) with modifications. Laevis are enzymatically isolated and filled with a non-polyadenylated cRNA mixed in a 4: 1: 4 ratio for human derived α, β, γ subunits, and a message sufficient to achieve current amplitudes greater than 10 nA is used when 1 μΜ GABA is used.

Electrophysiological recordings are made using a voltage clamp technique of two electrodes at a membrane maintaining a potential of -70 mV.

Compounds are evaluated against a concentration of GABA that elicits less than 10% of the maximum current elicited by GABA. Each oocyte is exposed to increase compound concentration to evaluate the concentration / effect relationship. Compound potency is expressed as a percentage change in current amplitude: 100 * ((Ic / I) -1), where Ic is the GABA-induced current amplitude monitored in the presence of compound and I is the GABA-induced current amplitude monitored in the absence of compound.

The compound specificity for the Rol5-1788 position is determined by subsequent termination of the concentration / activity curve. After washing the oocytes sufficient to remove the previously used compound, the oocyte is exposed to GABA + 1 μΜ RO15-1788, then exposed to GABA + 1 μΜ Rol5-1788 + compound. The percentage change appropriate to the addition of the compound is calculated as described above. Any percent change observed in the presence of Rol5-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μΜ Rol5-1788. These net values are used to calculate the average efficiency and EC50 values.

To evaluate the mean efficacy and EC ₅₀ values, the mean concentration / effect data across the cells is generated and adjusted to a logarithmic equation. Mean values are reported as mean ± standard deviation.

The substituted 4-oxo-naphthyridine-3-carboxamides of the formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down's syndrome, sleep disorders, cognitive and seizure disorders and overdose with benzodiazepine drugs and to increase the alertness of human and non-human animals. dogs, cats and breeding animals such as sheep, pigs and cattle.

The compounds of formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants

and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of Formula I and a pharmaceutically acceptable carrier. One or more compounds of Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and, if desired, other active ingredients. Pharmaceutical compositions containing compounds of formula I may be in a form suitable for oral use, for example, as tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may comprise one or more agents selected from the group consisting of sweetening, flavoring, coloring, and preservative agents to provide pharmaceutical formulated and acceptable compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over time. For example, a time delay material such as glycerol monostearate or glycerol distearate may be used.

Oral formulations may also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily a medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; the dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate, or products of condensation of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycethanol, or condensation products of ethylene oxide acids and hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, for example those mentioned above, and flavoring agents may be added to provide palatable preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the above examples. In addition, excipients such as sweetening, coloring and flavoring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums such as acacia or tragacanth, naturally occurring phosphatides such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcent, colorants, preservatives and flavoring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using the appropriate dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending agent. For this purpose any bland fixed oil may be employed including synthetic mono- or diacylglycerols. In addition, fatty acids such as oleic acid are used in the injectable preparation.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

The compounds of formula I may be administered parenterally in a sterile medium. The drug may, depending on the vehicle and concentration used, be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffers may be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful at

treatment of the conditions indicated above (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the species of host animal to be treated, the particular mode of administration and the body weight of the host. Dosage unit forms will generally contain about 1 mg to about 500 mg of the active ingredient.

However, it will be appreciated that the specific dosage level for any patient will depend on various factors including the efficacy of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and elimination rate, drug combination and severity of treatment of the individual disease. .

For administration to non-human animals, the composition may also be added to animal feed or drinking water. It will be desirable to formulate these compositions in animal feed and drinking water with a milled dose of drug to provide the animal with an appropriate amount of the composition with its nutrition. It will also be appreciated that the composition is provided as a premix for addition to food or drinking water.

Scheme I provides an illustration of the preparation of the compounds of the present invention.

Scheme I

R ⁴ OH. KOH aJtho

HNR ?, 1-PrOH. Δ

IN NaOH. EtOH Δ

0 X. .N. .CO, H Y í I C M I H

1) Et3N.CICO2Et.DMF

2) HjNY

3) HjNY (XS) α / αβ H ₂ NCH ₂ CH ₂ NMe ₂ eJkbO 1 N NaOH, EtOH. Δ

In Scheme I, X and Y have the meanings given above for Formula I.

One skilled in the art will recognize that starting materials can be varied and additional steps can be used to produce the compounds of the present invention as illustrated by the following examples. In some cases, protection of certain reactive groups may be necessary to achieve some of the above transformations. In general, the need for such protecting groups and the conditions of attachment and removal of such groups by those skilled in the art of organic synthesis will be clear.

The invention is further illustrated by the following examples, which are not to be construed as limiting the invention to the scope and spirit of the specific procedures described herein.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of starting materials and intermediates

Starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.

Representative examples of the processes for preparing the intermediates of the invention are given below.

1. 2-Benzylamino-5-nitropyridine

A solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) and benzylamine (2.3 mL, 21 mmol) in ethanol (10 mL) was heated at reflux for 2 hours. The reaction mixture was left at ambient temperature and 1.2 N HCl was added, the precipitate was collected, washed with water and dried to give 2.02 g of 2-benzylamine-5-nitropyridine as a yellow solid.

2. 2-Benzylamino-5-aminopyridine

A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and 10% Pd / C (202 mg) in ethanol (20 mL) was charged to a Paar flask.

and shaken under hydrogen (3 mmHg) for 3 hours. The mixture was filtered through celite using dichloromethane and concentrated in vacuo to give 1.76 g of 2-benzylamino-5-aminopyridine as a burgundy oil.

3. Diethyl (2-benzylamino-5-pyridylaminomethylene) malonate

A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethylethoxymethylene malonate (1.78 mL, 8.82 mmol) was heated at 130 ° C for 2 hours. The mixture was aspirated during heating. After cooling, the product was triturated with hexanes / ether (2: 1) and collected to give 2.74 g of diethyl (2-benzylamino-5-pyridylaminomethylene) malonate as a golden solid.

4. Ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Diethyl (2-benzylamino-5-pyridylaminomethylene) malonate (2.23

g) was added to diphenyl ether (10 mL) preheated to 230 ° C. Heating was continued for 0.5 hours, the reaction flask was removed from the oil bath, and the mixture was allowed to cool to ambient temperature. The product was triturated with ether / hexanes (1: 1), collected, washed with ether and dried to give 1.47 g of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as brown solids.

5. 6-Benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid

A mixture of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (60 mg), 1 N NaOH (2 mL) and ethanol (0.5 mL) was heated to reflux for 2 hours . The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride solution was added. The resulting precipitate was collected, washed with water

and ether, then dried to give 35 mg of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a brown solid.

6. 2-Ethoxy-5-nitropyridine

At room temperature, 2-chloro-5-nitropyridine was added to a homogeneous solution of potassium hydroxide (3.93 g, 70 mmol) in ethanol (35 mL). The reaction mixture was stirred for 1 hour, then diluted with saturated aqueous ammonium chloride solution and cooled in an ice bath. The precipitate was collected, washed with water and dried to give 3.60 g of 2-ethoxy-5-nitropyridine as a beige solid.

7. 2-Ethoxy-5-aminopyridine

A mixture of 2-ethoxy-5-nitropyridine (3.60 g) and 10% Pd / C (360 mg) in ethanol (40 mL) was placed in a Paar flask and shaken under hydrogen (344,740 Pa) for 16 hours. The mixture was filtered through celite using dichloromethane and concentrated to give 2.892 g of 2-ethoxy-5-aminopyridine as a golden solid.

. Diethyl (2-ethoxy-5-pyridylaminomethylene) malonate

A mixture of 2-ethoxy-5-aminopyridine (2.89 g, 20.9 mmol) and diethylethoxymethylene malonate (4.23 mL, 20.9 mmol) was heated at 130 ° C for 4.5 hours. The mixture was aspirated during heating. After cooling, the product was triturated with hexanes / ether (2: 1) and collected to give 6.04 g of diethyl (2-ethoxy-5-pyridylaminomethylene) malonate as a beige solid.

9. Ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

• i

Diethyl (2-ethoxy-5-pyridylaminomethylene) malonate (6.04 g) was added to diphenyl ether (20 mL) preheated to 230 ° C. Heating was continued for 0.5 h, the reaction flask was removed from the oil bath and allowed to cool to ambient temperature. The product was triturated with ether / hexanes (1: 1), collected, washed with ether and dried to give 2.98 g of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as a yellow-brown solid.

10. 6-Ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid

A mixture of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (2.98 g), 1 N NaOH (50 mL) and ethanol (10 mL) was heated to reflux. 2 hours. The reaction mixture was cooled in an ice bath, acidified and the resulting precipitate was collected, washed with water and dried to give 2.42 g of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a beige solid substances.

11. [(n-tert-butoxycarbonyl) methylaminomethyl) benzylminine hydrochloride

a) A solution of α-bromo-p-toluonitrile (4.90 g, 25 mmol) in acetonitrile (50 mL) was added dropwise to a stirred solution of a 40% aqueous solution of methylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL). ml) at 0 ° C. The reaction mixture was stirred for 0.5 h, then concentrated in vacuo. Water was added to the residue and extraction was performed twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.41 g of 4- (methylaminomethyl) benzonitrile as a yellow oil containing about 30% Ν, Ν-bis (4-benzonitrile) methylamine. The aqueous layer was adjusted to pH greater than 8 and extracted twice with dichloromethane

and methanol (9: 1). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 1.13 g of pure 4- (methylamino) benzonitrile as a colorless oil.

b) D-tert-Butyl dicarbonate (1.77 g, 8.1 mmol) was added to a stirred mixture of 4- (methylaminomethyl) benzonitrile (1.13 g, 7.7 mmol) and 1 N NaOH (15 mL) in 1, 4-dioxane (15 mL) at ambient temperature. The reaction mixture was stirred for 2 hours, poured into saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.81 g of crude 4- {N- (tert-butoxycarbonyl) methylaminomethyl] benzonitrile. The crude material was filtered through celite and a layer of silica gel (2.54 cm), eluting first with hexane and then with diethyl ether. The diethyl ether filtrate was concentrated to give pure 4- (N - (tert-butoxycarbonyl) methylaminomethyl] benzonitrile as a colorless oil. To it was added 10% Pd / C (170 mg) and ethanol in a Paar flask. The mixture was shaken under hydrogen (4 mmHg) for 4.5 hours, then filtered through celite and concentrated in vacuo. The residue was taken up in ethanol, cooled in an ice bath, and 1.0 M HCl (10 mL) in diethyl ether was added dropwise. The resulting precipitate was filtered and dried in a vacuum oven to give 1.346 g of [(n-tert-butoxycarbonyl) methylaminomethyl) benzylamine hydrochloride as a pale gray solid.

Example 2

N-n-Butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (59 mg, 90.2 mmol) and triethylamine (59 mL, 0.42 mmol) in Ν, Ν-dimethylformamide (1 mL) at 0 ° C was added ethyl chloroformate (39 mL, 0.41 mmol). After one hour

n-butylamine (99 mL, 1.0 mmol) was added by shaking at 0 ° C. The reaction mixture was further stirred at 0 ° C for 2 hours, then poured into saturated aqueous sodium chloride solution. The mixture was cooled in an ice bath, the precipitate was collected, washed with water and diethyl ether, then dried to give 49 mg of N-n-butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide as a brown solid compound (compound 1). An alternative name for this compound is N-butyl- (4-oxo-6- (benzylamino) - (3hydro-5-azoquinolyl) formamide).

2. N- [2- (Ethylthio) ethyl] -6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of 6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (55 mg, 0.25 mmol) and triethylamine (73 mL, 0.53 mmol) in N, N-dimethylformamide (2 mL) at 0 ° C was added ethyl chloroformate (49 mL, 0.52 mmol). After stirring at 0 ° C for 0.5 h, 2- (ethylthio) ethylamine hydrochloride (172 mg, 1 mmol) and triethylamine (139 mL, 1 mmo) were added. The reaction mixture was stirred at 0 ° C for 0.5 h, then poured into 1.2 N HCl, cooled in an ice bath, and the resulting precipitate was collected, washed with water and dried to give 57 mg of N- [2- (ethylthio) ethyl] - 6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide as a beige solid; mp 257-259 ° C (d) (compound 5).

3. N- [4- (methylaminomethyl) benzyl] -6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide hydrochloride

To a solution of 6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (106 mg, 0.4 mmol) and triethylamine (117 mL, 0.84 mmol) in a mixture tetrahydrofuran and N, N-dimethylformamide (4: 1, 2 mL) at 0 ° C were added ethyl chloroformate (66 mL, 0.82 mmol). After stirring at 0 ° C for 1.25

..Jur '•' -, ^1, .. '***''' h, added 4 - [(N-tert-butoxycarbonyl) aminomethyl] benzylamintí (120 mg, 0.42 mmol) and triethylamine (59 mL , 0.42 mmol). The reaction mixture was stirred at 0 ° C for 0.75 hours, then left at ambient temperature and stirred for 20 hours. N, N-dimethylethylenediamine (132 mL, 1.2 mmol) was added, the reaction mixture was stirred for 1 hour, then concentrated in vacuo. The residue was cooled in an ice bath, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give 177 mg of 4 - [(N-tert-butoxycarbonyl) methylaminomethylbenzyl] -6- (2-methoxyethoxy) -4-oxo-1,4-oxo dihydro-5naftyridín-3-carboxamide.

To the crude 4 - [(N-tert-butoxycarbonyl) methylaminomethylbenzyl] -6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide in dichloromethane (1 mL) was added dropwise at room temperature a mixture of trifluoroacetic acid and dichloromethane (1: 1, 2 mL). The reaction mixture was stirred for 1 hour, concentrated in vacuo, the residue was dissolved in ethanol, and 1.0 M HCl in diethyl ether (0.8 mL) was added. The precipitate was collected to give 68 mg of N - [(4-methylaminomethyl) benzyl] -6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide hydrochloride (compound 10).

4. N- (4-Methoxybenzyl) -6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of 6- (pyrrolidino) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (80 mg, 0.3 mmol) and triethylamine (0.11 mL, 0.8 mmol) in a mixture tetrahydrofuran and N, N-dimethylformamide (5: 1, 6 mL) at 0 ° C were added ethyl chloroformate (0.09 mL, 0.9 mmol). After stirring at 0 ° C for 0.5 h, 4-methoxybenzylamine (0.1 mL, 0.8 mmol) was added. The reaction mixture was stirred

ώ ...

, A

The mixture was left at ambient temperature and stirred for 0.5 hours. Water was added and the resulting precipitate was collected, washed with water and diethyl ether, and dried. The solid was combined with 1N NaOH (5 mL) and ethanol (2 mL) and heated at reflux for 0.25 hours. The reaction mixture was cooled in an ice bath, 3N HCl was added to pH 8 and the precipitate was collected, washed with water and diethyl ether, and dried to give 69 mg of N- (4-methoxybenzyl) -6-pyrrolidino-4-oxo-1 4-dihydro-1,5-naphthyridine-3-carboxamide, m.p. Mp 270-272 ° C (compound 8).

5a. N-benzyl-6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridin

3-carboxamide, sodium salt

N- (Benzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (914 mg, 2.83 mmol) was suspended in ethyl alcohol (9 mL) and 10N NaOH ( 0.27 ml). The mixture is heated until homogeneous, then cooled and concentrated. The resulting solid was treated with ethyl acetate (5 mL) and ethyl alcohol (250 mL) and the resulting mixture was stirred for 22 hours. The precipitate was collected, washed with ethyl acetate, and dried to give N-benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide sodium salt (compound 12) (960 mg) as a light brown solid.

5.b N-Benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine 3-carboxamide, potassium salt, (compound 13), m.p. Mp 286-288 ° C.

Example 3

The following compounds were prepared essentially according to the procedures described in Examples 1 and 2:

(a) N-n-butyl-6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 14), m.p. 330 ° C (d), (b) N-propan-3-ol-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 15), m.p. 271-272 ° C; (c) N-n-butyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 16), m.p. 274-276 ° C; (d) N- (2-ethylthio) ethyl-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 17), m.p. 257-259 ° C; (e) N-n-butyl-6- (N-benzylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 18), (f) N-n-pentyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 19), m.p. 265-265 ° C; (g) N- (3-isopropoxy) propyl-6-ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 20), (h) N-Benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 21), m.p. 275-278 ° C; (i) N-2-pentyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 22), (j) N- (2-tetrahydrofuranyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; mp 235-237 ° C, (compound 4), (k) N- (3-methoxy) propan-2-ol-6-ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide (compound 23),

(1) N- (3-methoxy) propyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 24); (m) N- (2-methoxy) ethyl- 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (compound 25), (n) N-isoamyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5 -naftyridín3-carboxamide; (compound 26), m.p. 279-281 ° C; (o) N- (2-furanyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 27), m.p. 245 (d) C, (p) N- (3-methoxybenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; mp 250-253 ° C, (compound 11), (q) N- (3-ethoxy) propyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 28), m.p. 224-225 ° C, (r) N-2- (2-methyl) butyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 29), m.p. 282-283 ° C; (s) N-2-pentan-1-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 30), m.p. 232-234 ° C; (t) N-5-pentanol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 31), m.p. 223-224 ° C; (u) N-1-cyclohexan-2-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 32), m.p. 268-270 ° C; (v) N-benzyl-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 33), m.p. 273-274 ° C, r

Λ ..Λ, .Μ., Ιί, Λ.

(w) N- (2-fluorobenzyl) -6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 34), m.p. 266-271 ° C; (x) N- (3-fluorobenzyl) -6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 35), m.p. 281 ° C; (y) N- (4-fluorobenzyl) -6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 36), m.p. 283-286 ° C; (z) N- (imidazol-4-ylmethyl) -6-ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 6), [Alternative name: 6-ethoxy-4-oxo (3-hydro-5-azoquinolyl)) - N (imidazol-4-ylmethyl) formamide] (aa) N-4-tetrahydropyranyl-6-ethoxy- 4-oxo-l, 4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 37), m.p. 303 DEG -305 DEG C. (bb) N- (3-thienyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 38), m.p. 324-325 ° C, (cc) N-2- (6-methyl) heptan-6-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 39), m.p. 281 ° C, (dd) N- (2-tetrahydropyranyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 40), m.p. 204 DEG -206 DEG C. (ee) N- (2-fluorobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 41), m.p. 157-162 ° C, (f) N- (3-fluorobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 42), m.p. 297-302 ° C,

(gg) N- (4-fluorobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 43), (hh) N- (4-methoxybenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 44), m.p. 186 ° C; (ii) N- (3-fluorobenzyl) -6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 45), m.p. 301 ° C; (j) N- (4-benzyl) -6- (N-methyl, N-toluenesulfonylamino) -4-oxo-

1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 2), [alternative name: (6-methyl ((4-methylphenyl) sulfonyl) amino) -4-oxo- (3-hydro-5-azoquinolyl)) - N-benzylformamide] (kk) N-benzyl-6- (methylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 46), (11) N-piperonyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; mp 190 ° C, (compound 9), (mm) N-piperonyl-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 47, mp 186 ° C, (nn) N-2- (imidazol-4-ylethyl) -6-ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 48), m.p. 268 ° C, (oo) N- (4-methylbenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 49), m.p. 270-271 ° C, (pp) N-benzyl-6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 50), m.p. &Gt; 300 ° C

(qq) N-benzyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 51), m.p. 246-249 ° C; (rr) N-Isoamyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 52), m.p. 295-298 ° C, (ss) N-benzyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 53), m.p. 88-90 ° C; (tt) N- (2-fluorobenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 7), 1.1. 137-139 ° C; (uu) N- (3-ethoxy) propyl-6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (Compound 54), 1.1. 150 DEG-152 DEG C. (vv) N-n-butyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 55), m.p. 275-277 ° C; (ww) N- (2-pyridyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (Compound 56), 1.1. 125-127 ° C, (xx) N- (2-thienyl) methyl-6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 57), m.p. 235-236 ° C, (γ) N-isoamyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 58), m.p. 254-256 ° C, (zz) N- (2-thienyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 59), 1.1. 277-279 ° C,

(aaa) N- (2-thienyl) methyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 60), m.p. 240 ° C, (bbb) N- (2-thiazolyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 61), m.p. 270-272 ° C; (ccc) N- (4-methylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 62), (ddd) N- [4- (1-methylamino) ethyl] benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 63), m.p. 259 DEG-262 DEG C., (eee) N- (2-tetrahydrofuranyl) methyl-6-dimethylamino-4-oxo-

1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 64),

mp 285 DEG-288 DEG C. (fff) N-n-Pentyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxainide; (compound 65), 1.1. 278-280 ° C; (ggg) N- (3-methoxybenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 66), m.p. 204-205 ° C, (hhh) N- (3-fluorobenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (Compound 67), m.p. 263 DEG-265 DEG C. (iii) N- (4-methylaminomethyl) benzyl-6- (2-methoxyethoxy) -4-oxo-

1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 68),

mp 275 DEG-277 DEG C. (j) N-n-butyl-6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 69), m.p. 57-58 ° C, (kkk) N- (4-methoxybenzyl) -6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 70), m.p. 270-272 ° C, (111) N- (2-thienyl) methyl-6-pyrrolidino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 71), m.p. 265 DEG-267 DEG C., (mmm) N- [4- (1-methylamino) ethyl] benzyl-6-dimethylamino-4-oxo-

1,4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (compound 72), (nnn) N- (4-methylaminomethyl) benzyl-6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride;

(compound 73), m.p. 270-271 ° C, (ooo) N- [4- (1-methylamino) ethyl] benzyl-6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 74), m.p. 260 DEG-263 DEG C., (ppp) N- [4- (1-methylamino) ethyl] benzyl-6-pyrrolidino-4-oxo-

1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 75),

mp 298-302 ° C, (qqq) N- (4-ethoxybenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 76), m.p. 278-281 ° C, (rrr) N- (4-ethoxybenzyl) -6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 77), m.p. 265-267 ° C, ·, 3 *, '-^' ^ · '. · ~

ÄβΧΛίΑ .äújďtefe &. ^ Ť

(sss) N- (4-Chlorobenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide, (compound 78), m.p. 295-297 C C;

(ttt) N- (4-Chlorobenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 79), m.p. 276-278 ° C, (uuu) N-piperonyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (compound 80), m.p. 246-247 ° C; (vvv) N-benzyl-6- (2-methylamino) ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 81), (www) N-benzyl-6- (2-dimethylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 82), m.p.

194-198 ° C; (xxx) N- (4-ethylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 83), m.p. 194 ° C (d), (yyl) N -benzyl-6- (2-methoxy) ethylamino-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (compound 84), m.p. 254-257 ´C, (zzz) N- (3-methylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride;

(compound 85), m.p. 187 ° C

(aaaa) N- (4-dimethylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (compound 86), m.p. 200 ° C (d), (bbbb) N- (3-methylaminomethyl) benzyl-6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride;

(compound 87), m.p. 184 ° C (d), (cccc) N- [4- (1-Imidazolylmethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 88), m.p. 143-145 ° C; (dddd) N- [4- (1-morpholinomethyl) benzyl] -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 89), m.p. 215 DEG-218 DEG C. (eeee) N- [3- (1-morpholinomethyl) benzyl] -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 90), m.p. 195-198 ° C, (ffff) N- {4- [1- (4-methylpiperazinomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 91), ( gggg) N- [4- (1,2,3,4-triazol-1-yl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (compound 92) .

mp 195-200 ° C, (hhhh) N-benzyl-6-benzylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (compound 93), (iiii) N-cyclohexyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (compound 94), (jjj) N-cyclohexylmethyl-6-ethoxy-4 -oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (compound 95), (kkkk) N- (4-aminobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine- 3-carboxamide (compound 96);

(1111) N- (4-pyridylmethyl) -6-ethoxy-4-oxo-1,4-tetrahydro-

1,5-naphthyridine-3-carboxamide (compound 97);

(mmmm) N-benzyl-6-tetrahydroisoquinolyl-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 98);

(nnnn) N- {4- [1- [4- (4-Fluorobenzyl) piperazinyl] methyl] benzyl} -6- (2,2,2-trifluoroethyl) -4-oxo-1,4-tetrahydro-1,4- 5naftyridin-3-carboxamide; (compound 99), m.p. Mp 234-235 ° C;

(oooo) N- (3-isopropoxypropyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (compound 3), [alternative name: (6-ethoxy-4-oxohydropyridino [ 3,2-b] pyridin-3-yl) -N- [3- (methylethoxy) propyl] carboxamide].

The invention and the method and procedure for carrying out and using it are now described in clear, complete, concise and precise terms to enable any person skilled in the art to practice and use it. It will be understood that the foregoing preferred embodiments of the present invention and modifications thereof may be made without departing from the spirit and scope of the present invention as defined in the claims. The following claims conclude this specification, in particular to show and clearly claim the subject matter of the invention.

Claims (105)

PATENT A compound of the formula or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, halogen, -OR ¹ , C 1 -C 8 -alkyl optionally substituted with up to three groups independently selected from halogen and hydroxy, or -NR ² R ³ ; X is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, pyridyl, pyrimidinyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, benzofuranyl or benzothienyl, each optionally substituted with up to three groups selected from halogen, C 1 -C 8 - alkyl, C 1 -C ₄ -alkoxy, C 1 -C 6 -alkylthio, hydroxy, amino, mono- or di (C 1 -C 8) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; or X is a 3 to 7 membered carbocyclic group, of which up to 2 are optionally heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group X is optionally substituted with one or more halo, C 1 -C 6 -alkoxy, mono- or di (C 1 -C 8) alkylamino, sulfonamide, aza (C 3 -C 7) cycloalkyl, C 3 -C ₇ -cycloalkylthio, C 1 -C 8 -alkylthio, phenylthio or heterocyclic; Y is lower alkyl of 1 to 8 carbon atoms optionally substituted by up to two groups selected from halogen, C 3 -C 7 -cycloalkyl, C 1 -C 8 -alkoxy, mono- or di (C 1 -C ₆ ) alkylamino, sulfonamide, aza (C 3 -C 7) cycloalkyl, (C 3 -C 7) cycloalkylthio, C 1 -C 6 -alkylthio, phenylthio, heterocyclic, -OR ⁴ , -NR ⁵ R ⁶ , SR ^7, or optionally substituted aryl; or Y represents a carbocyclic group of 3 to 7 members, up to 3 of which members are, optionally, heteroatoms selected from oxygen and nitrogen and wherein each member of the carbocyclic group Y is optionally substituted with halogen, -OR ⁴ , -NR ⁵ R ⁶ , SR ⁷ , aryl or heterocyclic; R ¹ is hydrogen, lower alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein each alkyl may be optionally substituted with -OR ⁴ or -NR ⁵ R ⁶ ; R ² and R ³ are the same or different and represent hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy, aryl, halogen or mono or di-lower alkyl; aryl or aryl (C 1 -C ₆ ) alkyl, wherein each aryl is optionally substituted with up to three groups selected from halogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or mono- or di (C 1 -C 6) alkylamino ; cycloalkyl of 3 to 7 carbon atoms optionally mono or disubstituted by halogen, alkoxy or mono- or di-lower alkyl; or -SO ₂ R ⁸ ; R ⁴ has the same meaning as R ¹ ; R ⁵ and R ⁶ have the same meanings as R ² and R ³ ; R ⁷ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; and R ⁸ is lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or optionally substituted phenyl. 2. A compound of formula N H or a pharmaceutically acceptable salt thereof, wherein X is (i) hydrogen, halogen, mono- or dialkylamino, alkoxy, (ii) a group of formula wherein G is lower alkylene of 1 to 6 carbon atoms or a cyclic group of formula (CH 1) n (CH ₂ ) m where n is 0 , 1 or 2 and m is an integer from 1 to 5, provided that the sum of n + m is not less than 1 or greater than 5; and R ¹ is hydrogen, lower alkyl or C 3 -C 7 -cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen, lower alkyl or a mono- or di (C 1 -C 8) alkylamino; (iii) a group of formula ^{R, with} R _g, and wherein G is as defined above for ii; and R ² and R ³ are independently hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3-7 carbon atoms, -SO 2 R ^8, wherein R ⁸ is _(C-C6) alkyl, (C 3 ml · C7) cycloalkyl or optionally substituted phenyl, or R ² and R ³ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl; (iv) a group of formula R ² 4 'R O. _G , tK where R ² is as defined in iii above; R ⁴ is hydrogen, lower alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms and may optionally be substituted with one or more (C 1 -C 6) alkoxy groups or mono- or di (C 1 -C 6) alkylamino groups; and G is as defined above in ii; (v) a group of the formula: R ⁶ R ⁿ - _g A where R ² and G are as defined above for iv and ii, and R ⁵ and R ⁶ independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ² R ⁸ , wherein R ⁸ is (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl or optionally substituted phenyl, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterocyclic moiety; (Vii) s ~ g where G is as defined in ii above; or a group of the formula wherein each G is as defined in ii above; and Y is (viii) lower alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, each of which may be optionally substituted with one or more groups selected from halogen, (C 1 -C ₆ ) alkoxy, alkoxyalkoxy, wherein each alkoxy is (C 1 -C 8) alkoxy; (C 1 -C 6) alkylthio, (C 3 -C 7) cycloalkylthio, aryl, hetroaryl or mono- or di (C 1 -C ₆ ) alkylamino; (ix) a group of formula OR where K is lower alkylene of 1 to 6 carbon atoms optionally substituted by (Οχ-Οβ) alkyl or alkylene, or a cyclic group of the formula The I (CH) _m - (- where K 'independently represents hydrogen or (C 1 -C ₆ ) alkyl or alkylene, n is 0, 1 or 2 and m is an integer from 1 to 5, provided that the sum of n + m is not less than 1 or greater than 5; R ⁹ is hydrogen, lower alkyl or (C 3 -C 7) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halo, lower alkoxy or mono- or dialkylamino; (x) a group of formula wherein K is as defined in ix above; (xi) a group of the formula wherein K has the meaning given above in ix, a R ¹³ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, wherein alkyl and cycloalkyl are optionally substituted with one or more (C 1-6 alkyl); Cq) alkoxy or mono- or di (C ₁ -C ₆ ) alkylamino; and (xii) a group of the formula wherein K has the meaning given above in ix, a R ⁷ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; and (xiii) a group of the formula 1b NR R where K has the meanings given above in ix; a. <.. λ .. .'.- Ú /, -,. R ¹⁴ and R ¹⁵ independently represent hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ₂ R ⁸ , wherein R ⁸ is as defined above, or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a heterocyclic moiety; (xiv) a group of the formula wherein K and R ¹⁵ are as defined in ix and xii above; (xv) a group of the formula wherein K is as defined in ix above; R ¹⁰ and R ¹⁰ are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxy, lower alkoxy of 1 to 6 carbon atoms or cycloalkoxy of 3 to 7 carbon atoms; R ¹¹ , R ¹¹ and R ¹² are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxy, -OR ⁴ , -CR ⁷ (R ⁹ ) NR ⁵ R ⁶ , -CR ⁹ (R ¹⁶ ) OR ⁴ , or R ¹¹ -R ¹² together with the atoms to which they are attached form a heterocyclic ring; and R ¹⁶ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; wherein K is as defined in ix above; and W is heteroaryl; (xvi) a group of formula (xvii) a group of formula wherein K is as defined in ix above; R ¹⁰ and R ¹¹ are as defined in xv above, and R ¹⁷ is hydrogen, lower alkyl or C ₃ -C ₇ -cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy or mono- or di (C 1 -C 6) alkylamino; (xviii) a group of the formula wherein A, R ^10, R ¹² and R ¹⁷ are as defined above; wherein each K is independently as defined in ix above and R ¹⁰ is as defined above; (xx) a group of the formula wherein K, R ¹⁰ , R ¹¹ , R ¹⁴ and R ¹⁵ are as defined above; (xxi) a group of the formula wherein K, R ¹⁰ , R ¹² , R ¹⁴ and R ¹⁵ are as defined above. A compound according to claim 1 which is wherein A is C 1 -C ₆ -alkylene; R ^a is phenyl optionally mono-, di- or -trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di (C 1 -C 6) alkylamino or mono- or di (C 1 -C 6) alkylamino-lower alkyl; and R ^b is lower alkyl or lower cycloalkyl. A compound according to claim 1 which is wherein A is C 1 -C 8 -alkylene; R ^a and R ^a are independently phenyl groups optionally mono-, di-or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di (C 1 -C 8) alkylamino or mono- or di (C 1 -C 8) alkylamino-lower alkyl; and R ^c is hydrogen or lower alkyl. The compound of claim 1 which is wherein A is C 1 -C 6 alkylene; R ^d and R ^e are independently lower alkyl groups. The compound of claim 1 which is wherein A is C 1 -C 6 -alkylene; R ^d is lower alkyl; and R ^f is a group of the formula wherein E is oxygen or nitrogen; and M is C 1 -C 3 -alkylene or nitrogen. 7th The compound of claim 1 which is wherein A is C 1 -C ₆ -alkylene; R ^d is lower alkyl; and R ^a is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono- or di-C 1 -C 8 -alkylamino or mono- or di-C 1 -C 6 -alkylamino-lower alkyl. A compound according to claim 1 which is 0 0 pd-O. .N. A H Aaa and N 5 1] H where And it is Ci-C6 alkylene; and R ^d a R ^e are independently below alkyl groups. The compound of claim 1 which is wherein D is nitrogen or CH; D 'is nitrogen or oxygen; A is C 1 -C 8 -alkylene; and R ^a 'is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono or di-C 1 -C 6 -alkylamino or mono- or di-C 1 -C 6 -alkylamino-lower alkyl. The compound of claim 1 which is ; .ι- · where Π A is C 1 -C 6 -alkylene; and R ^a 'is phenyl optionally mono-, di- or trisubstituted with halogen, lower alkyl, lower alkoxy or mono or di-C 1 -C 6 -alkylamino or mono- or di-C 1 -C 6 -alkylamino-lower alkyl. The compound of claim 1 which is wherein A is C 1 -C 6 -alkylene; and R ^d is lower alkyl; A 1 represents oxygen or methylene; and R is an integer from 1 to 3. A compound according to claim 1 which is wherein A is C 1 -C 6 -alkylene; and ^Rg is lower alkyloxy lower alkyl; and R '' is phenyl optionally mono-, di- or trisubstituted by halogen, lower alkyl, lower alkoxy or mono-X. or di-C 1 -C 6 -alkylamino or mono- or di-C 1 -C 6 -alkylamino-lower alkyl. 13. A compound according to claim 1 which is N-n-butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- [2- (ethylthio) ethyl] -6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. 15. A compound according to claim 1 which is N- [4- (methylaminomethyl) benzyl] -6- (2-methoxyethoxy) -4-oxo-1,4-dihydro- 1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-methoxybenzyl) -6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. 17. A compound according to claim 1 which is N-n-butyl-6-chloro- 4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-propan-3-ol-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 19. A compound according to claim 1 which is N-n-butyl-6-ethoxy- 4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-ethylthio) ethyl- 6-methoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-butyl-6- (N-benzylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-n-pentyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-isopropoxy) propyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-benzyl-6-ethoxy- 4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 25. A compound according to claim 1 which is N-2-pentyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-tetrahydrofuranyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-methoxy) propan-2-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-methoxy) propyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 29. A compound according to claim 1 which is N- (2-methoxy) ethyl- 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-isoamyl-6-ethoxy- 4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-furanyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. * · »* '·' Í 'i', 'A' A compound according to claim 1 which is N- (3-methoxybenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-ethoxy) propyl- 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-2- (2-methyl) butyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 35. The compound of claim 1 which is N-2-pentan-1-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 36. The compound of claim 1 which is N-5-pentanol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 37. The compound of claim 1 which is N-1-cyclohexane-2ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 38. The compound of claim 1 which is N-benzyl-6-methoxy- 4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 39. A compound according to claim 1 which is N- (2-fluorobenzyl) - 6-methoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 40. The compound of claim 1 which is N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (4-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4/5-imidazolylmethyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is Ν-4-tetrahydropyranyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 44. The compound of claim 1 which is N- (3-thienyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 45. The compound of claim 1 which is N-2- (6-methyl) heptan-6-ol-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 46. A compound according to claim 1 which is N- (2-tetrahydropyranyl) methyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (3-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 49. The compound of claim 1 which is N- (4-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (4-methoxybenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 52. A compound according to claim 1 which is N-benzyl-6- (N-methyl, N-toluenesulfonylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-benzyl-6 (methylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-piperonyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-piperonyl-6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-2- (4/5-imidazolyl) ethyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (4-methylbenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide C. A compound according to claim 1 which is N-benzyl-6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-benzyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-isoamyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-benzyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 62. A compound according to claim 1 which is N- (2-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. • ι * ·· * 63. A compound according to claim 1 which is N- (3-ethoxy) propyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-butyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-pyridyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-thienyl) methyl-6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-isoamyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-thienyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-thienyl) methyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 69. A compound according to claim 1 which is N- (2-thiazolyl) methyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-methylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- [4- (1-methylamino) ethyl] benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. _b ^J. '* ·' * · · J * -> * '-i ·' ·· I. - Μ,. «. Ι, ηΜΛ tofcMk-taiHt» ·. f-. - ^k Tľ * --- ffŤ-. ^^ Li ^ .i-II 72. A compound according to claim 1 which is N- (2-tetrahydrofuranyl) methyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide, 73. A compound according to claim 1 which is N-n-pentyl-6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 74. A compound according to claim 1 which is N- (3-methoxybenzyl) -6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-methylaminomethyl) benzyl-6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-n-butyl-6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 78. A compound according to claim 1 which is N- (4-methoxybenzyl) -6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-thienyl) methyl-6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- [4- (1-methylamino) ethyl] benzyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 81. A compound according to claim 1 which is N- (4-methylamino) -benzyl-6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. A compound according to claim 1 which is N- [4- (1-methylamino) ethyl] benzyl-6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide, 83. A compound according to claim 1 which is N- [4- (1-methylamino) ethyl] benzyl-6-pyrrolidino-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide. 84. A compound according to claim 1 which is N- (4-ethoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 85. A compound according to claim 1 which is N- (4-ethoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 87. A compound according to claim 1 which is N- (3-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-piperonyl-6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 89. A compound according to claim 1 which is N-benzyl-6- (2-methylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-benzyl-6- (2-dimethylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 91. A compound according to claim 1 which is N- (4-ethylaminomethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 92. A compound according to claim 1 which is N-benzyl-6- (2-methoxy) ethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 93. A compound according to claim 1 which is N- (3-methylamino-methyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 94. The compound of claim 1 which is hydrochloride N- (4-dimethylamino-methyl) benzyl-6-ethoxy-4-oxo-l, 4-tetrahydro- 1,5-naphthyridine-3-carboxamide. 95. A compound according to claim 1 which is N- (3-methylaminomethyl) benzyl-6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 96. A compound according to claim 1 which is N- [4- (1-imidazolylmethyl) benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, wherein Y is pyrimidinylmethyl, pyridylmethyl or a group of the formula wherein R ¹⁸ is hydrogen, amino, mono- or di (C 1-7). C 6) alkylamino or C 1 -C 8 -alkyl optionally substituted with R ¹⁹ , wherein R ¹⁸ is wherein V and V 'are independently CH or nitrogen; A 1 'is C 1 -C 6 -alkylene; and R ²⁰ is phenyl, pyridyl or pyrimidinyl, each of which is optionally independently mono-, di- or trisubstituted with halogen, hydroxy, C 1 -C ₆ -alkoxy, amino, or mono- or di (C 1 -C 6 alkylamino). 98. A compound according to claim 1 which is wherein A is C 1 -C ₆ -alkylene; X is as defined above for Formula I; and R ¹⁸ is (i) amino or mono- or di (C 1-7) -C) alkylamino; or (ii) lower alkyl optionally substituted with wherein V and V 'are independently CH or nitrogen; A 1 'is C 1 -C ₆ -alkylene; and R ²⁰ is phenyl, pyridyl or pyrimidinyl, each of which is optionally independently mono-, di- or trisubstituted with halogen, hydroxy, C 1 -C 6 -alkoxy, amino, or mono- or di (C 1 -C 6) alkylamino. A compound according to claim 1 which is N-benzyl-6-benzylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-cyclohexyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-cyclohexylmethyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 102. The compound of claim 1 which is N- (4-aminobenzyl) -6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 103. The compound of claim 1 which is N- (4-pyridylmethyl) -6-ethoxy-4-oxo-l, 4-tetrahydro-5naftyridín-3-carboxamide. 104. A compound according to claim 1 which is N-benzyl-6-tetrahydroisoquinolyl-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 105. The compound of claim 1 which is {- {4- [1- [4- (4-Fluorobenzyl) piperazinyl] methyl] benzyl} -6- (2,2,2-trifluoroethyl) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide .