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WO1999010347A1 - 4-oxo-naphtyridine-3-carboxamides substitues comme ligands de recepteur de gaba du cerveau - Google Patents

4-oxo-naphtyridine-3-carboxamides substitues comme ligands de recepteur de gaba du cerveau Download PDF

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Publication number
WO1999010347A1
WO1999010347A1 PCT/US1998/017513 US9817513W WO9910347A1 WO 1999010347 A1 WO1999010347 A1 WO 1999010347A1 US 9817513 W US9817513 W US 9817513W WO 9910347 A1 WO9910347 A1 WO 9910347A1
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Prior art keywords
oxo
naphthyridine
carboxamide
tetrahydro
compound according
Prior art date
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PCT/US1998/017513
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English (en)
Inventor
Pamela Albaugh
Robert W. Desimone
Gang Liu
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Neurogen Corporation
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Publication date
Priority to BR9811362-3A priority Critical patent/BR9811362A/pt
Priority to CA002301599A priority patent/CA2301599C/fr
Priority to IL13429198A priority patent/IL134291A0/xx
Priority to JP2000507675A priority patent/JP2001514181A/ja
Priority to AU91173/98A priority patent/AU753800B2/en
Priority to KR1020007001948A priority patent/KR20010023313A/ko
Priority to SK216-2000A priority patent/SK2162000A3/sk
Priority to NZ502548A priority patent/NZ502548A/en
Priority to EP98943352A priority patent/EP1007526A1/fr
Application filed by Neurogen Corporation filed Critical Neurogen Corporation
Priority to SI9820055A priority patent/SI20270A/sl
Priority to HU0003258A priority patent/HUP0003258A3/hu
Priority to PL98338783A priority patent/PL338783A1/xx
Publication of WO1999010347A1 publication Critical patent/WO1999010347A1/fr
Priority to APAP/P/2000/001742A priority patent/AP2000001742A0/en
Priority to NO20000822A priority patent/NO20000822L/no
Priority to IS5382A priority patent/IS5382A/is
Priority to BG104192A priority patent/BG104192A/xx
Priority to LVP-00-29A priority patent/LV12539B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • This invention relates to substituted 4-oxo-napthyridine- 3-carboxamides and, in particular, such compounds which selectively bind to GABAa receptors.
  • This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine- type drugs, Down Syndrome, and sleep, seizure and cognitive disorders.
  • GABA ⁇ -Aminobutyric acid
  • GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA.
  • the 1, 4-Benzodiazepines such as diazepam, continue to be among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants .
  • a number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors.
  • agonists those compounds possessing activity similar to the benzodiazepines are called agonists.
  • Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists.
  • the GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al . , 1988; Duman et al . , 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and
  • Polish Patent No. 125299 discloses compounds of the formula :
  • N denotes a ring nitrogen in the 5- or 6- position
  • R is C0 2 H or C0 2 Et .
  • German Patent No. DD 279887 discloses a compound of the formula
  • Japanese Patent No . 72 -45118 discloses ampicillin derivatives of 1 , 4 -dihydro-4 -oxo- 3 -naphthyridines .
  • This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I.
  • the invention also provides compounds 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. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
  • X is hydrogen, halogen, -OR ⁇ ; alkyl optionally substituted with up to three groups selected independently from halogen and hydroxy, or -NR 2 R 3 ;
  • X is phenyl, naphthyl , 1- (5, 6, 7 , 8-tetrahydro) naphthyl or 4-
  • Y is lower alkyl having 1-8 carbon atoms optionally substituted with up to two groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, a heterocyclic group, -OR 4 ,-NR 5 R 6 , SR 7 , or aryl ; or
  • Y is a carbocyclic group ("the Y carbocyclic group") having from 3-7 members atoms, where up to three of which members are optionally hetero atoms selected from oxygen and nitrogen and where any member of the Y carbocyclic group is optionally substituted with halogen, -OR 4 ,-NR s R 6 , SR 7 , aryl or a heterocyclic group;
  • R- L is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where each alkyl may be optionally substituted with -0R 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 alkyl where each aryl is optionally substituted with up to three groups selected from halogen, hydroxy,
  • R 4 is as defined for R x ;
  • R 5 and R 6 carry the same definitions as R 2 and R 3 , respectively;
  • R 7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
  • R 8 is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3- 7 carbon atoms, or optionally substituted phenyl .
  • These 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.
  • novel compounds encompassed by the invention can be described by the general Formula I set forth above.
  • -NR 2 R 3 can also represent a heterocyclic group such as, for example, piperidine in the case where R 2 and R 3 together form a C 5 -alkylene group. Further, 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 .
  • the -NR 5 R 6 group in Formula I above can also represent a heterocyclic group such as, for example, piperidine in the case where R 5 and R 6 together form a C 5 - alkylene group.
  • R 5 and R 6 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.
  • Preferred compounds of Formula I are those where X represents alkoxy. Particularly preferred compounds of Formula I include methoxy or ethoxy as the X group.
  • Still other preferred compounds of Formula I include those where the Y is lower alkyl, e.g., methyl or ethyl, substituted with phenyl , pyridyl, or pyrimidinyl .
  • a more preferred Y group is benzyl optionally substituted with halogen, (Cj-Cg) alkyl , (C x -C ⁇ ) alkoxy, amino, or mono- or di (C x - C 6 ) alkyl.
  • R 2 and R 3 in Formula I represent optionally substituted aryl or aryl (Ci-Cg) alkyl
  • the aryl group is preferably phenyl, pyridyl, or pyrimidinyl and the alkyl groups are preferably methyl and ethyl . More preferred are benzyl and phenyl. Particularly preferred is benzyl.
  • the alkyl group is preferably optionally substituted methyl, ethyl, or propyl . More preferred are perhalomethyl and trihaloethyl .
  • halogens are fluorine. Particularly preferred is
  • X in Formula I may be an optionally substituted phenyl, naphthyl, 1- (5 , 6, 7 , 8-tetrahydro) naphthyl , 4- (1,2- dihydro) indenyl, pyridinyl , pyrimidyl, isoquinolinyl , benzofuranyl , or benzothienyl group, or preferably a 1,2,3,4- tetrahydroisoquinolinyl group.
  • n 0, 1, or 2
  • m is an integer of from 1 to 5, with the proviso that the sum of n + m is not less than 1 or greater than 5;
  • R x is hydrogen, lower alkyl, or (C 3 -C 7 ) cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di alkylamino; (iii) a group of the formula:
  • R 2 and R 3 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -S0 2 R 8 where R 8 is 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 the formula:
  • R 2 is as defined above for iii;
  • R 4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C ⁇ C g ) alkoxy or mono- or di (C x -C 6 ) alkylamino groups; and G is as defined above for ii; (v) a group of the formula:
  • R 2 and G are as defined above for iv and ii, respectively, and R 5 and R 6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -S0 2 R 8 where R 8 is (Ci-Cg) 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;
  • K is lower alkylene having 1-6 carbon atoms optionally substituted with alkyl or alkylene, or a cyclic group of the formula K'
  • K' independently represents hydrogen or (C x -
  • n 0, 1, or 2
  • m is an integer of from 1 to 5, with the proviso 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 , where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or dialkylamino; (x) a group of the formula:
  • K is as defined above for ix
  • R 13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more alkoxy or mono- or di (C -
  • K is as defined above for ix
  • R 7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; and (xiii) a group of the formula:
  • K is as defined above for ix; and R 14 and R 15 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -S0 2 R 8 where 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 ;
  • K and R 15 are as defined above in ix and xii, respectively;
  • K is as defined above for ix;
  • R 10 and R 10 ' are the same or different and are selected from hydrogen, alkyl, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
  • R n , R X1 ' , and R 12 are the same or different and are selected from hydrogen, C ⁇ C g alkyl, halogen, hydroxy, -OR 4 , -CR 7 (R 9 )NR 5 R 6 , -CR 9 (R 16 ) OR 4 , or R xl and R 12 taken together with the atoms to which they are attached form a (hetero) cyclic ring;
  • R 16 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
  • R 17 is hydrogen, lower alkyl, or (C 3 -C 7 ) cycloalkyl , where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di alkylamino; (xviii) a group of the formula:
  • R 18 represents hydrogen, amino, mono-, or di (C 1 - C 6 ) alkylamino, or alkyl optionally substituted with a R 19 where R 18 represents:
  • V and V are independently CH or nitrogen
  • A' ' is alkylene; and R 20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted independently with halogen, hydroxy, alkoxy, amino, or mono- or di (C 1 - C 6 ) alkylamino .
  • Preferred pyrimidinyl alkyl Y groups are 2- and 4- pyrimidinylmethyl .
  • Preferred pyridyl (Ci-Cg) alkyl Y groups are 2- and 4-pyridylmethyl .
  • Preferred benzyl Y groups are those where R 18 is amino or a substituted methyl or ethyl group. 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 Y groups are 4-[l-[4-(4- Fluorobenzyl) piperazinyl] methyl] benzyl and 4-[l-[4-(4- Fluorobenzyl ) piperidinyl] methyl] benzyl .
  • Preferred "X" groups in Formula IA are various quinolinyl, isoquinolinyl , tetrahydroquinolinyl or tetrahydroisoquinolinyl groups, e.g., groups of the formulas:
  • R 2 , R s , R 6 , G, and Y are defined above
  • R 10 , R 10 ' are the same or different and may be selected from hydrogen, alkyl , halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;
  • R n R n an R i2 are the same or different and may be selected from hydrogen, alkyl , halogen, hydroxy, -OR 4 ,- CR 7 (R 9 )N R 5R 6 , -CR 7 (R 9 )OR 4 ; or
  • R lx and R 12 taken together with the atoms to which they are attached form a (hetero) cyclic ring;
  • R 9 is as defined above. wherein X and K are defined above; and 5 W is heteroaryl .
  • A is C ⁇ -C 6 alkylene
  • R a is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-
  • R b is lower alkyl or lower cycloalkyl.
  • More preferred compounds of Formula XXVII are those where A is methylene, R a is phenyl optionally substituted with methyl or ethyl, and R b is lower alkyl. Particularly preferred compounds of Formula XXVII are those where A is methylene, R a is phenyl and R b is C ⁇ C, alkyl.
  • A is 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 ⁇ C g alkylamino, or mono- or di-C x -Cg alkylamino lower alkyl; and
  • R c is hydrogen or lower alkyl.
  • More preferred compounds of Formula XXVIII are those where 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 where A is methylene, R a is phenyl substituted in the para position with lower alkyl, R a ' is phenyl, and R c is C 1 -C 3 alkyl .
  • A is C x -C 6 alkylene
  • R d and R e are independently lower alkyl groups.
  • More preferred compounds of Formula XXIX are those where A is r. - Ci alkylene. Particularly preferred compounds of Formula XXIX are those where A is C 2 -C 4 alkylene, R d is C 1 -C 3 alkyl, and R e is C 2 -C 4 alkyl.
  • A is C 1 -C 6 alkylene
  • R d is lower alkyl
  • R f is a group of the formula:
  • E oxygen or nitrogen
  • M is C x -C 3 alkylene or nitrogen
  • A is C ⁇ -C 6 alkylene
  • R d is lower alkyl optionally substituted with amino or mono- or di (C- L -Cg) alkylamino; and R a ' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C x -C 6 alkylamino, or mono- or alkylamino lower alkyl . More preferred compounds of Formula XXXI are those where A is C x -C 3 alkylene, R a ' is phenyl optionally substituted with methyl or ethyl, and R d is C 1 -C 3 alkyl.
  • Still more preferred compounds of Formula XXXI are where A is methylene, R a ' is phenyl optionally substituted with methyl or ethyl, and R d is C 3 -C 6 alkyl.
  • Particularly preferred compounds of Formula XXXI are sodium, potassium, or ammonium salts of the corresponding parent compound.
  • A is Ci-Cg alkylene
  • R d is lower alkyl
  • R a " is phenyl, pyridyl, imidazolyl, pyrimidinyl, or pyrrolyl, each of which is 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 ⁇ C g alkylamino lower alkyl .
  • More preferred compounds of Formula XXXIa are those where R a " is imidazolyl and R d is C x -C 3 alkyl. Still more preferred compounds of Formula XXXI are where A is methylene, R a " is imidazolyl, and R d is C 3 -C 6 alkyl.
  • A is C 1 -C 6 alkylene
  • R d and R e are independently lower alkyl groups
  • More preferred compounds of Formula XXXII are those where A is C x -C 3 alkylene.
  • Particularly preferred compounds of Formula XXXII are those where A is C 1 -C 3 alkylene, R d is C x -C 3 alkyl, and R e is C x -C 3 alkyl.
  • D is nitrogen or CH
  • D' is nitrogen or oxygen;
  • A is C x -C 6 alkylene;
  • R a ' is phenyl, pyridyl, or thiazolyl, each of which is optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-
  • More preferred compounds of Formula XXXIII are those where A is C x -C 3 alkylene, R a ' is phenyl optionally substituted with lower alkyl or halogen, and D is nitrogen. Still more preferred compounds of Formula XXXIII are where A is methylene, R a ' is phenyl optionally substituted with lower alkyl or halogen, D is nitrogen, and D' is oxygen.
  • A is C x -C 6 alkylene; and R a ' is hydrogen;
  • R a ' is thienyl or phenyl, each of which is optionally
  • A is C x -C 3 alkylene, and R a ' is phenyl optionally substituted with lower alkyl or halogen. Still more preferred compounds of Formula XXXIV are where A is methylene, R a ' is phenyl optionally substituted with lower alkyl, lower alkoxy or halogen.
  • A is C x -C 6 alkylene
  • R d is lower alkyl
  • A' represents oxygen or methylene; and r is an integer of from 1-3. More preferred compounds of Formula XXXV are those where A is C x -C 3 alkylene. Particularly preferred compounds of Formula XXXV are those where A is C x -C 3 alkylene, and R d is C x -C 3 alkyl.
  • A is C x -C 6 alkylene
  • R h and R h ' are independently hydrogen or lower alkyl, where each alkyl is optionally substituted with lower alkoxy;
  • A' represents oxygen or methylene; and r is an integer of from 1-3.
  • More preferred compounds of Formula XXXVa are those where A is C x -C 3 alkylene. Particularly preferred compounds of Formula XXXV are those where A is C x -C 3 alkylene, and R h is C x -C 3 alkyl .
  • A is C x -C 6 alkylene ;
  • R g is lower alkoxy lower alkyl;
  • R a ' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C x -C 6 alkylamino, or mono- or di-C x -C 6 alkylamino lower alkyl .
  • R. is halogen or lower alkoxy; 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 X _C 6 ) alkyl where the phenyl group is optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-
  • A is C x -C 6 alkylene
  • R x is lower alkoxy, benzyloxy, lower alkoxy lower alkoxy, amino , or mono- or di - (C x -C 6 ) alkylamino ; and R_, is pyranyl , dihydropyranyl , tetrahydropyranyl , or hexahydropyranyl , pyridine , dihydropyridine , tetrahydropyridine , or piperidine .
  • Preferred compounds of Formula XXXVIII are those where R x was alkoxy and R_, is tetrahydropyranyl .
  • A is C x -C 6 alkylene;
  • R n is lower alkoxy, lower alkoxy lower alkoxy, benzyl, or a group of the formula :
  • D is nitrogen or CH; and D' is nitrogen or oxygen; and
  • R 0 is pyranyl, 2- or 3 -thienyl
  • 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 where Formula XXXX
  • A is C x -C 6 alkylene
  • R h and R h ' are independently hydrogen or lower alkyl, where each lower alkyl is optinally substituted with lower alkoxy; and R a ' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C x -C 6 alkylamino, or mono- or di-C x -C 6 alkylamino lower alkyl; or R a ' is thienyl optionally substituted with lower alkyl.
  • A is C x -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.
  • A is C x -C 6 alkylene
  • X is defined as above for Formula I;
  • V and V are independently CH or nitrogen;
  • A'' is C x -C 6 alkylene;
  • R 20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted independently with halogen, hydroxy, C x -C 6 alkoxy, amino, or mono- or di (C x -C 6 ) alkylamino .
  • More preferred compounds of Formula XXXXII are those where V is nitrogen and X is C x -C 6 alkoxy or C x -C 6 alkyl optionally substituted with up to three halogen atoms.
  • Particularly preferred compounds of XXXXII are those where V and V are nitrogen; X is C x -C 3 alkoxy or C x -C 3 alkyl optionally substituted with up to three halogen atoms;
  • A'' is methylene or ethylene; and R 20 is halogenated phenyl.
  • a preferred R 20 group is 4-fluorophenyl .
  • XXXXII are those where X is 2 , 2 , 2-trifluoroethyl ; V and V are nitrogen; R 20 is halogenated phenyl; and A and A' are methylene or ethylene.
  • compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Representative compounds of the present invention include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid and base addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n-ACOOH where n is 0-4, and the like.
  • Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
  • acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I .
  • lower alkyl in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl , isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl , 2-pentyl, isopentyl, neopentyl , hexyl , 2-hexyl, 3-hexyl, and 3-methylpentyl .
  • cycloalkyl in the present invention is meant cycloalkyl groups having 3-7 atoms such as, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , and cycloheptyl .
  • aryl an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl) , or multiple condensed rings in 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, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
  • aromatic e.g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl, anthryl , or phenanthryl
  • lower alkoxy in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2- pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy .
  • cycloalkoxy in the present invention is meant cycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl is defined above.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • heteroaryl aromatic heterocycle in the present invention is meant one or more aromatic ring systems of 5-, 6- , or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups include, for example, thienyl, furanyl , thiazolyl, imidazolyl, (is) oxazolyl , pyridyl , pyrimidinyl , (iso) quinolinyl, naphthyridinyl , benzimidazolyl, and benzoxazolyl .
  • heteroaryl groups are the following:
  • Q is nitrogen or -CR 9 ;
  • T is -NR 7 , oxygen, or sulfur; and R 9 , R x0 , R xo ' , R X1 , R xx ' , R X2 are as defined above.
  • X is a carbocyclic group
  • such moiety or group includes both aromatic heterocycles (heteroaryl) , unsaturated heterocylic ring systems, and saturated heterocyclic ring systems.
  • examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl.
  • Preferred X carbocyclic groups are linked to the parent naphthyridine moiety by a nitrogen atom in the X carbocyclic group.
  • pyrrolidinyl is the X carbocyclic group, it is preferably a 1 -pyrrolidinyl group of the formula :
  • Y is a carbocyclic group
  • such moiety or group includes both aromatic heterocycles (heteroaryl groups) , unsaturated heterocylic ring systems, and saturated heterocyclic ring systems.
  • examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl.
  • Preferred Y carbocyclic groups are linked to the parent naphthyridine carboxamide group by a nitrogen atom in the Y carbocyclic group.
  • piperidinyl is the Y carbocyclic group, it is preferably a 1- piperidinyl group of the formula:
  • phenyl groups that are unsubstituted or substituted with up to 3 groups selected independently from halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, and mono- or di- lower alkylamino.
  • Compound 10 The pharmaceutical utility of compounds of this invention is indicated by the following assays for GABAa receptor activity.
  • Rat cortical tissue is dissected and homogenized in 25 volumes
  • homogenate is centrifuged in the cold (4°) at 20,000 x g for
  • the supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and
  • the pellet is frozen at -20°C overnight.
  • the pellet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice.
  • the pellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HCl
  • Incubations contain 100 ml of tissue homogenate, 100 ml
  • radioligand 0.5 nM 3 H-Rol5-1788 [ 3 H-Flumazenil] specific activity 80 Ci/mmol
  • drug or blocker 3 H-Rol5-1788 [ 3 H-Flumazenil] specific activity 80 Ci/mmol
  • the following assay may be used to determine if the compounds of the invention are agonists, antagonists, or inverse agonists, and, therefore, their specific pharmaceutical utility.
  • the following assay can be employed to determine specific GABAa receptor activity.
  • Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of -70 mV.
  • Compounds are evaluated against a GABA concentration that evokes ⁇ 10% of the maximal evokable GABA current.
  • Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship.
  • Compound efficacy is expressed as a percent-change in current amplitude: 100* ( (Ic/I) -1) , where Ic is the GABA evoked current amplitude observed in the presence of compound and I is the GABA evoked current amplitude observed in the absence of compound .
  • Specificity of a compound for the Rol5-1788 site is determined following completion of the concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA + 1 ⁇ M Rol5-1788, followed by exposure to GABA + 1 ⁇ M Rol5-1788 + compound. Percent change due to addition of 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 ⁇ M Rol5-1788. These net values are used for the calculation of average efficacy and EC 50 values.
  • Formula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.
  • the compounds of general 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.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general 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.
  • compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • 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; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the 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.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • 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 such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant 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 those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • 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 of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the 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 a demulcent, a preservative and flavoring and coloring 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 those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general 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 temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can 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 in the treatment of the above- indicated conditions (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 the host animal to be treated, the particular mode of administration, and the body weight of the host. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions with a mullet-dose of the drug so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water .
  • the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.

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Abstract

La présente invention concerne des structures de la formule (I) ou leurs sels non toxiques et acceptables du point de vue pharmaceutique; dans la formule (I): X est hydrogène, halogène, alkyle (non) substitué, alcoxy ou amine (non) substitué; et Y est alkyle (non) substitué, aryle ou hétéroaryle; ces composés sont des agonistes, antagonistes ou agonistes inverses de récepteurs de GABAa du cerveau ou des promédicaments d'agonistes, d'antagonistes ou d'agonistes inverses de récepteurs de GABAa du cerveau. Ces composés s'utilisent dans le diagnostic et le traitement de l'anxiété, du syndrome de Down, du sommeil, de troubles cognitifs et épileptiques et de l'overdose de médicaments au benzodiazépine et pour l'activation de la vigilance.
PCT/US1998/017513 1997-08-25 1998-08-24 4-oxo-naphtyridine-3-carboxamides substitues comme ligands de recepteur de gaba du cerveau WO1999010347A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
EP98943352A EP1007526A1 (fr) 1997-08-25 1998-08-24 4-oxo-naphtyridine-3-carboxamides substitues comme ligands de recepteur de gaba du cerveau
IL13429198A IL134291A0 (en) 1997-08-25 1998-08-24 Substituted 4-oxo-napthyridine-3- carboxamides as gaba brain receptor ligands
SI9820055A SI20270A (sl) 1997-08-25 1998-08-24 Substituirani 4-okso-naftiridin-3-karboksamidi kot ligandi možganskih GABA receptorjev
AU91173/98A AU753800B2 (en) 1997-08-25 1998-08-24 Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands
KR1020007001948A KR20010023313A (ko) 1997-08-25 1998-08-24 Ｇａｂａ 뇌 수용체 리간드로서의 치환된4-옥소-나프티리딘-3-카르복스아미드
SK216-2000A SK2162000A3 (en) 1997-08-25 1998-08-24 Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands
NZ502548A NZ502548A (en) 1997-08-25 1998-08-24 Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands
BR9811362-3A BR9811362A (pt) 1997-08-25 1998-08-24 Composto
JP2000507675A JP2001514181A (ja) 1997-08-25 1998-08-24 Ｇａｂａ脳レセプタリガンドとしての置換４−オキソ−ナフチリジン−３−カルボキサミド
CA002301599A CA2301599C (fr) 1997-08-25 1998-08-24 4-oxo-naphtyridine-3-carboxamides substitues comme ligands de recepteur de gaba du cerveau
HU0003258A HUP0003258A3 (en) 1997-08-25 1998-08-24 Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands
PL98338783A PL338783A1 (en) 1997-08-25 1998-08-24 Substituted 4-oxo-naphtyridin-3-carboxamides as ligands of cerebral gaba receptors
APAP/P/2000/001742A AP2000001742A0 (en) 1997-08-25 2000-02-01 Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands.
NO20000822A NO20000822L (no) 1997-08-25 2000-02-18 Substituerte 4-okso-3-karboksamider som GABA- hjernereseptorligander
IS5382A IS5382A (is) 1997-08-25 2000-02-22 Setin 4-oxo-napthyridine-3-karboxamíð sem tengistGABA viðtökum í heila
BG104192A BG104192A (en) 1997-08-25 2000-02-25 Substituted 4-oxo-naphthyridine-3-carboxamides as gaba brain receptor ligands
LVP-00-29A LV12539B (en) 1997-08-25 2000-03-16 EDIBLE 4-OXY-NAFTIRIDINE-3-CARBOXAMES AS A GAS HEAD-BAND RECEPTOR

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US91818097A 1997-08-25 1997-08-25
US08/918,180 1997-08-25

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AU (1) AU753800B2 (fr)
BG (1) BG104192A (fr)
BR (1) BR9811362A (fr)
CA (1) CA2301599C (fr)
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IL (1) IL134291A0 (fr)
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NO (1) NO20000822L (fr)
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OA (1) OA11293A (fr)
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WO2000068202A1 (fr) * 1999-05-06 2000-11-16 Neurogen Corporation 4-oxo-quinoline-3-carboxamides substitues: ligands des recepteurs cerebraux gaba
WO2000071528A1 (fr) * 1999-05-25 2000-11-30 Neurogen Corporation 4h-1,4-benzothiazine-2-carboxamides et leur utilisation en tant que ligands des recepteurs cerebraux gaba
WO2002069948A1 (fr) * 2001-03-01 2002-09-12 Pfizer Products Inc. Utilisation d'agonistes inverses de gabaa combines avec des agonistes partiels de recepteurs nicotiniques, un oestrogene, des modulateurs selectifs des recepteurs des oestrogenes ou la vitamine e pour le traitement de troubles cognitifs
WO2002032412A3 (fr) * 2000-10-17 2003-03-20 Pfizer Prod Inc Utilisation combinee d'inhibiteurs de l'acetylcholinesterase et des agonistes inverses gabaa dans le traitement de troubles cognitifs
US6559145B2 (en) 2000-07-12 2003-05-06 Pharmacia & Upjohn Company Heterocycle carboxamides as antiviral agents
US6562822B2 (en) 2000-07-12 2003-05-13 Pharmacia & Upjohn Company Heterocyle carboxamides as antiviral agents
US6730682B2 (en) 2000-07-12 2004-05-04 Pharmacia & Upjohn Company Heterocycle carboxamides as antiviral agents
WO2004106336A1 (fr) * 2003-05-27 2004-12-09 Pfizer Products Inc. Procede de preparation et de purification de 1,5-naphtyridine-3-carboxyamides
US6841558B2 (en) 2000-10-12 2005-01-11 Merck & Co., Inc. Aza-and polyaza-naphthalenyl carboxamides useful as HIV intergrase inhibitors
WO2004106334A3 (fr) * 2003-05-28 2005-01-20 Pfizer Prod Inc Procede de preparation de 1,5-naphtyridine-3-carboxyamides par amidation directe d'esters
US6919351B2 (en) 2000-10-12 2005-07-19 Merck & Co., Inc. Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors
US6921759B2 (en) 2000-10-12 2005-07-26 Merck & Co., Inc. Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors
US6924282B2 (en) 2001-08-17 2005-08-02 Merck & Co., Inc. Sodium salt of an HIV integrase inhibitor
US7279487B2 (en) 2002-01-17 2007-10-09 Merck & Co., Inc. Hydroxynaphthyridinone carboxamides useful as HIV integrase inhibitors
US7323460B2 (en) 2002-03-15 2008-01-29 Merck & Co., Inc. N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors

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EP2540722B1 (fr) * 2006-10-16 2016-06-08 Bionomics Limited Nouveaux composés anxiolytiques
RS55585B1 (sr) * 2006-11-22 2017-06-30 Clinical Research Associates LLC Postupci za lečenje daunovog sindroma, krhkog x sindroma i autizma

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DE2407744A1 (de) * 1973-02-26 1974-08-29 Allen & Hanburys Ltd Chinolin-3-carboxamidotetrazolderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende mittel
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DD279875A1 (de) * 1987-07-03 1990-06-20 Inst Pharmakologische Forschun Verfahren zur herstellung von aktivierten carbonsaeureestern
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068202A1 (fr) * 1999-05-06 2000-11-16 Neurogen Corporation 4-oxo-quinoline-3-carboxamides substitues: ligands des recepteurs cerebraux gaba
WO2000071528A1 (fr) * 1999-05-25 2000-11-30 Neurogen Corporation 4h-1,4-benzothiazine-2-carboxamides et leur utilisation en tant que ligands des recepteurs cerebraux gaba
US6448246B1 (en) 1999-05-25 2002-09-10 Neurogen Corporation Substituted 4H-1,4-benzothiazine-2-carboxamide: GABA brain receptor ligands
US6903097B2 (en) 2000-07-12 2005-06-07 Pharmacia & Upjohn Company Heterocycle carboxamides as antiviral agents
US6559145B2 (en) 2000-07-12 2003-05-06 Pharmacia & Upjohn Company Heterocycle carboxamides as antiviral agents
US6562822B2 (en) 2000-07-12 2003-05-13 Pharmacia & Upjohn Company Heterocyle carboxamides as antiviral agents
US6730682B2 (en) 2000-07-12 2004-05-04 Pharmacia & Upjohn Company Heterocycle carboxamides as antiviral agents
US6921759B2 (en) 2000-10-12 2005-07-26 Merck & Co., Inc. Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors
US6919351B2 (en) 2000-10-12 2005-07-19 Merck & Co., Inc. Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors
US6841558B2 (en) 2000-10-12 2005-01-11 Merck & Co., Inc. Aza-and polyaza-naphthalenyl carboxamides useful as HIV intergrase inhibitors
WO2002032412A3 (fr) * 2000-10-17 2003-03-20 Pfizer Prod Inc Utilisation combinee d'inhibiteurs de l'acetylcholinesterase et des agonistes inverses gabaa dans le traitement de troubles cognitifs
WO2002069948A1 (fr) * 2001-03-01 2002-09-12 Pfizer Products Inc. Utilisation d'agonistes inverses de gabaa combines avec des agonistes partiels de recepteurs nicotiniques, un oestrogene, des modulateurs selectifs des recepteurs des oestrogenes ou la vitamine e pour le traitement de troubles cognitifs
US6924282B2 (en) 2001-08-17 2005-08-02 Merck & Co., Inc. Sodium salt of an HIV integrase inhibitor
US7279487B2 (en) 2002-01-17 2007-10-09 Merck & Co., Inc. Hydroxynaphthyridinone carboxamides useful as HIV integrase inhibitors
US7323460B2 (en) 2002-03-15 2008-01-29 Merck & Co., Inc. N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors
WO2004106336A1 (fr) * 2003-05-27 2004-12-09 Pfizer Products Inc. Procede de preparation et de purification de 1,5-naphtyridine-3-carboxyamides
WO2004106334A3 (fr) * 2003-05-28 2005-01-20 Pfizer Prod Inc Procede de preparation de 1,5-naphtyridine-3-carboxyamides par amidation directe d'esters

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IL134291A0 (en) 2001-04-30
LV12539A (en) 2000-10-20
JP2001514181A (ja) 2001-09-11
EG21717A (en) 2002-02-27
NZ502548A (en) 2002-06-28
PL338783A1 (en) 2000-11-20
AU753800B2 (en) 2002-10-31
CN1268136A (zh) 2000-09-27
NO20000822L (no) 2000-04-13
YU10500A (sh) 2002-10-18
CA2301599A1 (fr) 1999-03-04
KR20010023313A (ko) 2001-03-26
HUP0003258A3 (en) 2001-05-28
TW574221B (en) 2004-02-01
SI20270A (sl) 2000-12-31
BG104192A (en) 2001-05-31
NO20000822D0 (no) 2000-02-18
CA2301599C (fr) 2003-03-25
AP2000001742A0 (en) 2000-02-24
HUP0003258A2 (en) 2001-03-28
BR9811362A (pt) 2000-08-22
OA11293A (en) 2002-11-19
PE130999A1 (es) 1999-12-16
EP1007526A1 (fr) 2000-06-14
IS5382A (is) 2000-02-22
AU9117398A (en) 1999-03-16
SK2162000A3 (en) 2001-03-12
LV12539B (en) 2001-01-20

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