[go: up one dir, main page]

MXPA04004711A - 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides. - Google Patents

1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides.

Info

Publication number
MXPA04004711A
MXPA04004711A MXPA04004711A MXPA04004711A MXPA04004711A MX PA04004711 A MXPA04004711 A MX PA04004711A MX PA04004711 A MXPA04004711 A MX PA04004711A MX PA04004711 A MXPA04004711 A MX PA04004711A MX PA04004711 A MXPA04004711 A MX PA04004711A
Authority
MX
Mexico
Prior art keywords
alkyl
alkoxy
pyrrolo
carboxylic acid
pyridin
Prior art date
Application number
MXPA04004711A
Other languages
Spanish (es)
Inventor
J O Donnell Christopher
Original Assignee
Neurogen Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurogen Corp filed Critical Neurogen Corp
Publication of MXPA04004711A publication Critical patent/MXPA04004711A/en

Links

Classifications

    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Disclosed are 1H-Pyrrolo[3,2-b]pyridine-3-carboxylic acid amides that bind to the benzodiazepine site of GABAA receptors. Such compounds can be used to modulate ligand binding to GABAA receptors in vivo and in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals, and livestock animals.

Description

AMIDAS OF THE ACID IH-PIRROLO [3, 2 b] PIRIDIN-3-CARBOXYLIC Field of the Invention This invention relates to 1H-pyrrolo [3, 2-b] pyridin-3-carboxylic acid amides that bind to the benzodiazepine site of the GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the composition of such compounds in the treatment of defl. central nervous system (CNS).
BACKGROUND OF THE INVENTION The pABAA receptor superfamily represents one of the classes of receptors through which the prothipal inhibitor neurotransmitter of y-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through d | B a protein complex called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization. In addition to being the site of neurotransmitter action, various drugs that include } in anxiolytic and sedative benzodiazepines bind to this receptor. The GABAA receptor comprises a chloride channel that generally, but not invariably [opens in response to ReI: 156117 GABA, allowing chloride to enter the cell. This, in turn, effects a decrease in neuronal activity through hyperpolarization of the cell membrane potential. The GABAA receptors are composed of 5 protein subunits.Diverse cDNAs for these subunits of the GABAA receptor have been cloned and their primary structures are determined.Although these subunits share a basic portion of helices spanning 4 membranes, there is a sufficient diversity of sequences To date, at least 5a, 3ß, 3 ?, 1e, 1d, and 2? subunits have been identified.The native GABAA receptors are typically composed of 2a, 2β, 1 ?. Several lines of evidence (such as such as message distribution, genome localization and study results suggest that the major receptor combinations that occur naturally are ^ 2y2, a2ß3? 2, a, 3? 3? 2 and a5? 3? 2 (Mohler et al., Neuroch. Res. : 20 (5): 631-36.) The binding sites of the GABAA receptor for GABA (2 per receptor complex) are formed by the amino acids from the subunits a and B. The amino acids of the subunits a and c together they form a benzodiaepine site per recipient. Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine enfLace sites associated with the GABAA receptor. | In addition to the benzodiazepine site (sometimes referred to as benzodiazepine or BDZ receptor), the GABAA receptor contains sites of interaction for several other types of drugs. These include a steroid binding site, a pychotoxin site, and a bajrbiturate site. The benzodiazepine site of the GABAA receptor is a different site in the receptor complex that does not overlap with the site of interaction for other types of drugs that bind to the receptor or to GABA (see for example, Cooper, et al., The Biochemical ^ Basis of Neuropharmacology, 6th ed. , 1991, pp. 145-148, Oxford University Press, New York). In a classical allosteric mechanism, the binding of a drug to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzod [iazepines and related drugs that enhance the ability of GABA to open GABAA receptor channels are regarded as agonists or partial agonists depending on the level of GABA improvement.
Other types of drugs, such as ß carboline derivatives that occupy the same site, negatively modulate the action of GABA are called inverse agonists. A third type of compound exists which occupies the same site as the inverse agonists and agonists and still has little or no effect of GABA activity. These, however, will block the action of inverse agonists or agonists and are referred to as GABAA Receptor antagonists.
Brief Description of the Invention This invention provides 1H-pyrrolo [3,2- b] pyridine-3-carboxylic acid amides that bind to the benzodiazepine site of GABAA receptors, including the human GABAA receptors. Preferred compounds of the invention bind with high selectivity and / or high affinity to GABAA receptors. The preferred compounds act as agonists, antagonists or reverse agonts of such receptors. As such, they are useful in the treatment of various CNS disorders. The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I The invention further provides methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient can be a human or another mammal. The treatment of humans, domestic animals (pets), livestock animals suffering from certain disorders with an effective amount of a cofunction of the invention, is encompassed by the invention. In a . separate aspect, invention provides methods to enhance the action of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention together in triples and wherein each carbon atom in R35 is substituted with one or more substituents selected independently from group c); J and L are independently selected each occurring in saturated, partially unsaturated and aromatic rings, having from 4 to 7 ring atoms, wherein 0, 1 or 2 of the ring atoms are oxygen or nitrogen, and the remaining atoms or carbon atoms, wherein the rings are unsubstituted or substituted with one or more substituents which are independently i) halogen, oxo, hydroxy, amir, cyano, C 1 -C 6 alkyl, Ci-C 3 alkoxy, C 1 alkoxy, Cg (alkyl: C: .- C6), haloalkyl C ^ -Ce, haloalkoxy C ^ Cs, or mono- or di- (Ci-C6) alkylamino; or ii) phenyl, pyridyl, pyrimidylch or pyrazinyl, each of which is unsubstituted or substituted with from 1 to 3 of halogen, hydroxy, amino] cyano, C1-C4 alkyl, C-d alkoxy, Ci-C2 haloalkyl, haloalkoxy Ci-C2, and mono or di (Ci-C4) alkylamino; or R4 is hydrogen, halogen or hydroxy. For Class I compounds, at least 1 of R1 (R2 and R3 is selected from b) and J is not phenyl or pyridyl. The variable wAr "is defined differently for each of Classes 1, 2, and 3. For compounds and salts of the Cias, e 1: Ar represents an aryl group, ar alkyl, heteroaryl or heteroaryl, each aryl or heteroaryl has 1 or 2 aromatic rings and 4 to 7 ring atoms in each aromatic ring, wherein, 0, 1 or 2 of the ring atoms selected are oxygen, nitrogeho or sulfur, and the remaining ring atoms are carbon atoms wherein each ring is optionally substituted with 1 or more of R40, wherein R0 is independently selected from hydroxy, halogen, cyano, nitro, amino, XR50, C1.C4-XR50 alkyl, and Y; X is independently selected each it is presented in the group consisting of a bond, -CH2-, -CHR60-, -O-, C (= 0) - (-C (= 0) 0-, -0C (= O) -, -S (0 ) n- -NH-, -NR60-, -C (= 0) NH-, -C (= O) NR60-, -S (0) nNH-, -S (0) nNRsc -NHC (= 0) - , -NRS0C (= O) -, NHS (0) n-, and -NR60S (O) n-; where n fes 0, 1, or 2 R50 R6o are independently selected Every one that occurs hydrogen, C-C8 alkyl, C3-C8 cycloalkyl, and (C3-CE) cycloalkyl (Ci-C6) alkyl, where n each alkyl and cycloalkyl contains zero, one, more triple double bonds, and wherein each carbon atom of the cycloalkyl alkyl cycloalkylalkyl is optionally substituted with one or more of oxo hydroxy, halogeno, cyano, amino, x-alkoxy, -NH (alkyl d-Cg), N (Ci-C6 alkyl) (alkyl Ci-C6), -NHC (= 0) (Ci-Cg alkyl), -N (Ci- C6 alkyl) C (= 0) (Ci-Ce alkyl), -NHS (0) n (Ci-C6 alkyl), - S (0) n (C6 alkyl), -S (O) "NH (Ci-C6 alkyl), -S (! 0) nN (Ci-C6 alkyl) (Ci-C6 alkyl), and 2, in where n is 0, 1, or; and Y, and Z are selected i dependently each presented with saturated rings, | partially saturated and aromatic, having from 4 to 7 ring atoms in each aromatic ring, wherein 0, 1 or 2 ring atoms are oxygen or nitrogen and the remaining ring atoms are carbon, and wherein Y, and Z are substituted or unsubstituted independently with one or more halogen, oxo, hydroxy, amino, cyano, Ci-C3 alkyl, Ci-C6 alkoxy, Ci-C6 alkoxy (CL-C6 alkyl), Ci-C3 haloalkyl < haloalko: ki Cx-Cg, or mono or di- (Ci-Cs) alkylamino. For the compounds and salts of Class 2: Ar represents heteroaryl or hydrocarbyl (Ci-C6) alkyl, wherein the heteroaryl is selected from quinolinyl, benzothienyl, indolyl, priidazinyl, piazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl. , phthalazinyl, imidazolyl, isoxazolyl, pyrazyl] yl, oxazolyl, thienyl, thiazolyl, indolizinyl, indézolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolidone, oxadiazolyl, thiadiazolyl, triazolyl, tetrazyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, sochromanyl, chromanonyl, chromanyl, tetrahydroisoquin, inyl, isoindolinyl, oxo, hydroxy, amino, cyano, Ci-C3 alkyl, Ci-C6 alkoxy / Ci-Ce alkoxy (CX alkyl- C6), Ci-C3 haloalkyl, Ci-C6 haloalkoxy, or mono- or di- (Ci-C3) alkylamino. For compounds and salts of (-lase 3: Ar represents phenyl, pyridyl or pyridinyl in each of which is substituted with 1 or more of R, wherein each R40 is independently hydroxy, halogen, cyano, nitro, amino, Ci-C3 alkyl, Ci-C6 alkoxy, Cx-Ce alkanoyl, Ci-C6 cycloalkyl, Ci-C6 cycloalkyl (Ci-C) alkyl, C3-C7-cycloalkyl-O-, C3 cycloalkyl- < † 7 (Ci- C4) alkoxy-, C2-C6 alkenyl, Ci-C6 alkylthio, halo (Ci-C6) alkyl, or halo (Ci-C6) alkoxy.
In addition, Ar in the compounds and salts of Class 3 must be replaced by at least one of -E-R50-G-RSo, -E-R5o-G-R6o, -E-Rso-GY, Ci-C-XRsof alkyl -NH-¾0-Y, - (NR50) R60-Y, or Y; wherein X is independently selected each that is presented from the group consisting of -O-, -C (= 0) -, - C (= 0) 0-, -0C (= 0) -, | S (O ): -N¾-, -NR60-, -C (= 0) NH-, C (= O) NR50-, - S (0) nNH-, -S (0) "NR60- -NHC (= 0) -, -NR60C (= O) - (NHS (0) n-, and -NR60S (O) n-, where n 0, 1, 6 2, R50 and Rso are independently selected from hydrogen, Cs alkyl, CX-C8 cycloalkyl, and (C3-C8) cycloalkyl (Ci-C3) alkyl, wherein each alkyl and cycloalkyl contains zero, one or more double or triple bonds, and wherein each carbon atom of the alkyl, cycloalkyl or cycloalkylalkyl is optionally substituted independently with one or more of oxo, hydroxy, halogen, cyano, amino, Ci-C6 alkoxy, -NH (Ci-C6 alkyl), -N (Ci C6 alkyl) (Ci-C6 alkyl), -NHC (= 0) (alkyl or Ci-C6), -N (CX alkyl- C6) C (= 0) (alkyl C ^ Cs), -NHS (¡D) "(Cx-C6 alkyl), S (O) n (Ci-Ce alkyl), -s (O) nNH (Ci-alkyl) C6), -S (0) nN (Ci-C6 alkyl) (Ci-C6 alkyl), and Z, wherein n is 0, 1 or 2, and Y, and Z are independently selected each that occur from saturated, partially saturated and aromatic rings that have from 4 to 7 ring atoms in each aromatic ring where 0, 1 or 2 atoms are oxygen, or nitrogen and the remaining ring atoms are carbon, wherein Y, and 2 are unsubstituted or substituted independently with one or more of halogen, oxo, hydroxy, amino, cyano, CX-C6 alkyl, Ci-C6 alkoxy, Ci-C6 alkoxy (Ci-C6 alkyl), Ci-C6 haloalkyl, haloalcosi Cx-Cg, or mono or di (Ci-C6) alkylamino.
Detailed Description of the Invention Specific embodiments of the invention include compounds and pharmaceutically acceptable salts, Classes 1, 2, and 3, wherein R 4 is hydrogen. Additionally, the invention relates to salts and compounds of class 1, of the formula I, wherein it represents an aryl, arylalkyl, heteroalkyl heteroarylalkyl, aryl or heteroaryl group which is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl , imidazolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl [1, 3, 4] thiadiazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl, benzddioxolyl, benzofuranyl, benzimizozolyl, benzoisoxolyl, and dihydro-benzodioxinyl and is optionally substituted by one or more of R 0 , and 40 is as defined above. Such compounds are referred to below as Class 1A compounds. The invention also includes compounds and pharmaceutically acceptable salts of the formula I, wherein Ri is selected from B). In this aspect, R2 R3 are independently selected from hydrogen, halogenic, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-Ce alkoxy, and mono- or di (Ci-C6) alkylamino; more preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, -OCF3, hydroxy, cyano, af] C1-C2 alkyl / Ci-C2 alkoxy and mono- or di- (Ci-C2) alkylamino, or R :: and R3 can be independently selected from hydrogen, halogen, methyl or ethyl. In this aspect, R 4 is preferably hydrogen; and Ar is as defined for compounds of Class 1A. Further included in the invention are compounds and pharmaceutically acceptable salts of the formula I, Class 1 A. The compounds and salts of the formula I, Class 1A are those wherein: Ri is selected from B); R2 and R3 is independently selected from hydrogen, halogen, methyl and ethyl; R4 is preferably hydrogene}; and R 0 is independently selected from each of C 1 -C 6 alkyl, C 1 -C 6 alkoxy; halogen or di (Ci-C6) alkylamino, mono or di (Ci-C6) alkoxymethylamino (d-C6) alkoxy, (Ci-C6) alkoxy (Ci-C3) alkyl, and (Ci-C6) alco < xi (0? -06) alkoxy The invention relates to an embodiment comprising compounds and pharmaceutically acceptable salts of Formula I, Class 1A, in which Ri is selected from B); and B) eg in this embodiment is -E-R35 / alkyl-Ci-C -O-R20, -E-R20-G-R30, -? - ?, -E-R20-L, J, or Ci-C6 alkyl -J; and E and G in this embodiment are independently NH, N-Ci- C6alkyl, or O. In this embodiment, R20, R30 and R35 of the invention are independently selected as they occur from: cyclic, branched and straight alkyl groups, and groups (cycloalkyl) alkyl, cyclic, branched and straight alkyl groups, and (cycloalkyl) alkyl groups consisting of 1 to 8 carbon atoms, containing zero or one or more double or triple bonds, wherein each R2o and R35 can further substituted with one or more substituents, independently selected from the group C) and at R35 to CF3, CHF2, -OCF3, hydroxy, cyano, Ci-C2 alkyl, Ci-C2 alkoxy, and mono- or di- (C1.-C2) ) alkylamino, or R2 and R3 can be independently selected from hydrogen, halogeno, methyl, and ethyl; R4 is preferably hydrogen; and R40 is independently selected each of Ci-C6 alkyl, Ci-C6 alkoxy; halogen, mono or di (Cj.-C6) alkylamino, mono or di (Ci-C6) alkylamino (Ci-C6) alkoxy, (Ci-C6) alkoxy (Ci-C6) alkyl, and (C; L-C6) alkoxy (Ci-C6) alkoxy. The invention further includes compounds and pharmaceutically acceptable salts of Formula I, Class 1 wherein Ar carries the defined definition for the compounds and salts of Class 1A and R40 is independently selected from hydroxy, halogen, cyano, amino, XR50, - (C1-C4) alkyl -XR50, and Y; X is independently selected from each group consisting of an enlice, -CH2-, -CHR60-, -0-, C (= 0) -, -S (0) n-, -NH-, and -NR60 -, where n is 0, 1, or 2; R50 and 60 is independently selected from hydrogen, cyclic, branched and straight alkyds, and (cycloalkyl) alkyl groups, cyclic, branched and straight alkyl groups and (cycloalkyl) alkyl groups consist of 1 to 8 carbons no, and contain zero or one or more double or triple bonds, one of which from 1 to 8 carbon atoms can be further substituted with one or more independently selected from hydrogen, halogen, methyl and ethyl. In the compounds of Formula I, Class 2A, R is preferably hydrogen. Another embodiment of the invention] relates to pharmaceutically acceptable compounds and salts of Formula I, Class 2A in which Ri is selected from hydrogen, halogen, Ci-C6 haloalkyl / Ci-C6 haloalkyl, hydroxy, cyano, amino, Ci alkyl -C6, Ci-C6 alkoxy, mono- or di- (Ci-C6) alkylamino and B), and B) is -E-R35, C-1 alkyl-C4-O-R20, -E-R2O-GR | 3 301 • EL, -E-R20-L, J or -alkyl, Ci-C6-J. E and G are independently ISfH, N-Ci-C6 alkyl, or 0; R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; and R4 is hydrogen. Another embodiment of the invention relates to pharmaceutically acceptable compounds and salts of Formula I, Class 2A, in which Ar, which is defined as for Class 2A compounds, is optionally substituted by one or more of R40. R40 for this embodiment is independently selected from Cj C6 alkyl, Ci-C6 alkoxy, - halogen, mono- or di- (Ci-C6) alkylamino, mono- or di- (C1-C6) alkylamino (Ci-C6) ) alkoxy, (Ci-C6) alkoxy (Ci-C3) alkyl, and (Ci-C6) alkoxy (Ci C6) alkoxy. this mode, ¾ is selected from hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 haloalkhoxy, hydroxy, cyano, amino, CX-C6 alkyl, Ci-C6 alkoxy / mono- or di- (Ci-Cs) alkylamino and B) . R2 and R3 in this embodiment are independently selected from hydrogen, halogen, Ci-C6 haloalkyl, CX-C6 haloalkoxy, hydroxy, cyano, aniño, Ci-C6 alkyl, Ci-C6 alkoxy, and mono- or di- (Ci-C6) alkylamino, or more preferably R2 and R3"are independently selected from hydrogen, halogen, CF3, CHF2, -OCF3, hydroxy, cyano, Ci-C2 alkyl, Ci-C2 alkoxy and mono- or di- (C1-C2) £. ] or R 2 and R 3 are independently selected from hydrogen, halogen, methyl and ethyl R 4 in this embodiment is hydrogen Another embodiment of the invention: includes compounds and pharmaceutically acceptable salts Formula I, Class 2A, in which Ar, is defined as Class 2A compounds that are optionally substituted by one or more of R40-R40 For this embodiment, each is independently selected from Ci-C6 alkyl, Cx-C6 alkoxy, halogen, mono- or di- (Cx) -C6) alkylamino, mono- or di- (Cx-fcC6) alkylamino (C-C6) alkoxy, (Ci-C6) alkoxy (Cx-Cg) alkyl, and (Ci-C: fes) alkoxy (Cx-C6) alkoxy. Rx is selected from hydrogen I, halogen, haloalkyl Cx-C6, haloalkoxy Cx-06, hydroxy, cyano, amino, CX-C6 alkyl / Cx-C6 alkoxy, mono- or di- (Cx-C6) alkylamino and B) substituted or substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, cyano, Ci-C6 alkyl, Ci-C6 alkoxy Ci-C6 alkoxy (Ci-C6 alkyl), Ci-C6 haloalkyl, Cx C6 haloalkoxy, and mono- or di- (Cx-C6) alkylamino; with the proviso that J is not phenyl or pyridyl; R2 and R3 in this embodiment are independently selected from hydrogen, halogen, Cx-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxy, cyano, anino, C6-C6alkyl, C6-C6alkoxy, and mono- or di- (Ci-). C6) alkylamino, or more preferably R and R3 are independently selected from hydrogen, halogen, CF3 CHF2, -0CF3, hydro: .i, cyano, Ci-C2 alkyl, Ci-C2 alkoxy, and mono- or di- (Ci -C2) alkylamino, or R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; R4 in this embodiment is preferably hydrogen. The invention also includes compounds and pharmaceutically acceptable salts of Formula I, wherein Ar is as defined for Class 2A compounds. R40 in this modality, is independently determined each one of hydroxy, hjalógeno, cyano, amino, XR50, C1-C4) alkyl-XR50, and Y. X in this modality is independently equenced each one of the group qiie consists of a bond, CH2-, -CHR60-, -O-, -C (= 0) -, -S (0 -NH-, and -R60- where n is O, 1, or 2; R50 and Reo in this modality is independently selected each hydrogen, cyclic alkyl groups, branched and straight, and groups (cycloalkyl) alkyl, cyclic, branched and straight alkyl groups, and (cycloalkyl) alkyl groups consisting of 1 to 8 carbon atoms, containing zero or one or more double or triple bonds, in each 1 to 8 carbon atoms can further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, cyano, amino, alkoxy Ci-C6, -NH (C-alkyl) -C6), N (Ci-Cg alkyl) (Ci-C6 alkyl) -NHC (= 0) (Ci-C6 alkyl), "(Ci-C6 alkyl) C (= 0) (CX-CJ alkyl)), -NHS (O) n (Ci-Ce alkyl), -S (0 ) n (Ci-C6 alkyl), -S (0) nNH (alkoxy Ci-C6), -S (O) nN (Ci-C6 alkyl) (C! -C6 alkyl), and Z, where n is 0, 1, or 2. Y, and Z in this embodiment, are independently selected from the following: saturated, partially saturated and aromatic rings, having from 4 to 7 ring atoms, 0, 1, or 2 ring atoms selected from oxygen and nitrogen, with remaining ring atoms that are carbon, where Y, and Z are substituted or unsubstituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, Ci-C6 alkyl / Cx-C5 alkoxy, Ci-C6 coxy (Ci-C6 alkyl), haloalkyl Ci -C6, haloalkoxy C: -C6, and mono- or di- (Ci- Cg) alkylamino. Such compounds! they will be referred to as Class 2B compounds. Other compounds and salts of Formula I, Class 2B included in the invention are those in which Ri is selected from hydrogen, halocene, haloalkyl i ~ C6, haloalkoxy Ci-C6, hydroxy, cyano, aniin, Ci-C6 alkyl, alkoxy • Ci-C6, mono or di- (Ci-Cg) alkylamino and B); R2 and R3 is independently selected from hydrogen, halogen, methyl and ethyl; and R is hydrogen. invention relates to pharmaceutically acceptable compounds and salts of Formula I, Class 3, in which Rx is selected from halogen hydrogen, Ci C6 haloalkyl, CX-C6 haloalkoxy, hydroxy, cyano, amino, Ci-C6 alkyl (Ci-alkoxy) -CSl and mono- or di (Ci-C6) alkylamino and B). In this embodiment, R2 and 3 are independently selected from hydrogen, halogen, haloalkyl Ci-C6, haloalkoxy Ci-C6, hydroxy, cyano, amino, CX alkyl C6, Ci-C3 alkoxy, and mono- or di (C! - C6) alkylamino or preferably R2 and R3 are independently selected from hydrogen, allogen, CF3, CHF2, -OCF3, hydroxy, cyano, Ci-C2 alkyl, Ci-C2 alejeoxy and mono- or di- (Ci-C2) alkylamino; and R4 is preferably hydrogen. Other compounds of Formula I, Class 3 are those in which Ar is phenyl, pyridyl D pyrimidinyl, each of which is optionally substituted by 1 or more of R40, wherein R40 is independently selected preferably each presented of hydroxy, halogen, cyano, araino, alkyl ???, Ci-C6 alkoxy, halo (Ci-C6) alk, and halo (Ci-C6) alkoxy Ar in this embodiment is also substituted by at least one of -E-R5o-G-R6o, - E-R50-G-, Ci-C4alkyl-XR5o, -NH-R60 Y, - (NR50) eo-Y / e Y; where X is selected independently for each one that is presented from the group consisting of, -C (= 0) -, -C (= 0) 0 0C (= 0) -, -S (0) n-, -NH -, -NR60-, 0) NH-, -C (= O) NRS0-NHC (= 0) and -NR60C (= O); R50 R60 are independently selected from hydrogen, cyclic, branched, and straight alkyl groups, and (cycloalkyl) alkyl groups, cyclic, branched and straight alkyl groups, and (cycloalkyl) alkyl groups consist of 1 carbon atoms can be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, cyano, amino, Ci-C6 alkoxy, -NH (Ci-C6 alkyl),: "J (Ci-C6 alkyl) ( C6-C6 alkyl), -NHC (= 0) (Cx-Cg alkyl), -N (C 1-6 -haloalkyl) C (= 0) (d-C6 alkyl), and Z. R2 and R3 in the preferred embodiments of the invention are independently selected [from hydrogen, halogen, Ci-C6 haloalkyl, haloalkoxy Ci_-fc6, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-C6 alkoxy, and mono- or di- (Ci-C6) alkylamino or preferably R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, -OCF3, hydroxy, cyano, Ci-C2 alkyl, Ci-C2 alkoxy, and mono- or di- (Ci-C2) alkylamino, or from hydrogen, halogen, methyl and ethyl In this embodiment, R4 is preferably hydrogen, Other compounds of the Formula I include those in which Ri is amino (Ci-C6) alkoxy, mono (C! -C3) alkylamino (Ci-C6) ) alkoxy, di (C 1 -C 3) alkylamino (C 1, -6) alkoxy, pyridyl (Ci-C 6) alkoxy, hydroxy (Ci-Cg) alkoxy, (C 1 -C 4) alkoxy (Ci-C 6) alkoxy, piperazinyl ( Ci-Cg) alkoxy wherein the piperazinyl group is optionally substituted with alkyl] lo (Ci-C6), morpholinyl (Ci-C6) alkoxy, or thiomorpholinyl (Ci-C6) alkoxy; R2 and R3 are inde- pendently selected from H, (Ci-Cg) alkyl, halogen or (Cx-C6) alkoxy. Within this preferred aspect, other preferred compounds of formula I are those wherein both R2 and R3 are both hydrogen. More preferred compounds of Formula I include those wherein Rx is amino (Cx-Ci) alkoxy, mono (C1-C4) alkylamino (Ci- C4) alkoxy, di (C1-C4) alkylamino (fc1-C4) alkoxy, pyridyl (Ca-C4) alkoxy, hydroxy (C1-C4) alkoxy, diperazinyl (C1-C4) alkoxy, wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl, or morpholinyl (Ci-C6) ajlcoxy Within this preferred aspect, other compounds of Formula I are those wherein both R 2 and R 3 are both hydrogen. The still more preferred compounds of Formula I include those wherein R2 and R3 are independently selected from H, (C1-C4) alkyl, halogen or (C1-C4) alkoxy, with the proviso that at least one of R2 and R3 is H. Other more preferred compounds of Formula I include those wherein Ri is (C1-C4) alkoxy, mono (C1-C4) alkylamino (Ci-C4) alkoxy, di (C1-C4) alkylamino ((I1) -C4) alkoxy, pyridyl (Ci-C4) alkoxy, hydroxy (C1-C4) alkoxy, p Lperazinyl (C! -C4) alkoxy, wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl,? Morpholinyl ( Ci-C6) alkoxy; R2 and R3 are independently selected from H, (C1-C4) alkyl or (C1-C4) alkoxy, the condition being that at least one of R2 and R3 is H. Within this preferred aspect, others Preferred compounds of Formula I are those wherein both R 2 and R 3 are both hydrogen, Still other preferred compounds of Formula I include those wherein Ri is amino ( C1-C4) alkoxy, | mono (C1-C4) alkylamino (Cx-C4) alkoxy, di (C1-C4) alkylamino (C-C4) alkoxy, pyridyl (Cx-C4) alkoxy, hydroxy (C! -C4) alkoxy, piperazinyl (C1-C4) ) alkoxy wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl, or morpholinyl (Ci-C4) coxy; R2 and R3 are independently selected from H, and alkyl (C1-C4), with the proviso that at the merits one of R2 and R3 is H. Within this preferred aspect, other compounds of the formula I are those wherein R2? R3 are both hydrogen, Still other preferred compounds of formula I include those wherein Ri is amino (C1-C4) alkoxy, mono (Ci-C4) alkylamino C4) alkoxy, di (C1-C4) alkylamino (<; fc2-C4) alkoxy, (C2-C4) alkoxy, hydroxy (C2-C4) alkoxy, piperazinyl (C2-C4) alkoxy wherein the piperazinyl group is optionally optionally (C1-C4) alkyl, or morpholinyl ( C2-C4) lcoxy R2 is H or methyl; and R3 is H. Within this preferred aspect, other preferred compounds of Formula I are those wherein both R2 and R3 are both hydrogen. Representative compounds of the present invention that are included by Formula I include, but are not limited to, the exposed compounds; in Elas 1, 2 and 3 and their addition salts, basic pharmaceutically acceptable acids. If the compound of the invention is obtained as a basic addition salt, the free b can be obtained by making basic a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in an organic solvent and treating the solution with an acid, in accordance with conventional processes for preparing addition salts from the base compounds. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed for example from non-toxic organic or organic acids. For example, such salts do not toxicis. conventional include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, sulfinic, phosphoric, nitric and the like; and salts prepared from organic acids such as alkanoic such as acetic, EOOC- (CH2)? - ????? where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic addition salts. The invention also includes hydrates of compounds of Formula I. The invention includes all crystalline forms of the compounds of Formula I. Certain crystalline forms may be preferred. The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that can be employed to prepare pharmaceutically acceptable addition salts and toxic acrylated prodrugs. the compounds encompassed by Formula I. The invention also encompasses the enantiomers and diastereomers of the described compounds. Those of ordinary experience in the field will readily recognize methods by which mixtures of enantiomers and diastereomers can be resolved. The definitions of Formula I as used herein include possible isomers, such as tautomers and rotamers. This invention relates to 1-rrolo [3,2-b] pyridin-3-carboxylic acid amides, preferred examples which bind with high affinity to the benzodiazepine site of GABAA receptors, including the human GABAA receptors. The amides of 1H-pyrrolo [3, 2-b] pyridin-3-carboxylic acid, which bind with high selectivity to the benzod | iazepine site of GABAA receptors, including human GABAA receptors, are also included in this invention. Without ceasing to adhere to a particular theory, it is believed that the interaction of the compounds of Formula I with the b < : nzodiazepine results in the pharmaceutical utility of these compounds The invention further comprises] methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of an S1I disorder. The compounds of the invention that act as agonists in the a2ß3? 2 receptor subtypes and < 3ß3? 2 are useful in the treatment of anxiety disorders such as panic disorders, obsessive-compulsive disorder and generalized anxiety disorder; IQ stress disorders include post-traumatic stress, and acute tension disorders. The compounds of the inventions that act as agonists in the a2ß3? 2 and a3ß3ß2 receptor subtypes are also useful in the treatment of depressive or bipolar disorders and in the treatment of sleep disorders. The compounds of the invention that act as inverse agonists in the subtype of the a5ß3? 2 receptor or in the receptive subtypes: r a-, .ß2? 2 and a5? 3? 2 are useful in the treatment of cognitive disorders including those resulting from Down syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and dementia related to stroke. The compounds of the invention which act as inverse agonists in a5β3 ?2 are particularly useful in the treatment of cognitive disorders through the improvement of memory, and particularly short-term memory, mental disorders, substance induced sleep disorder, Impairment of cognition, for example cognition, involvement of the mémorilla, impairment of short-term memory, Alzheimer's disease, Parkinson's disease, moderate cognitive impairment (MCI), cognitive decline related to age (ARCD), stroke. traumatic brain injury, dementia associated with AIDS and dementia associated with depression, anxiety or psychosis. Attention Deficit Disorder, for example attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD). Speech disorders, for example stuttering, including motor tic, clonic stuttering, dysfunction, speech blockage, dysarthria, Tourete's syndrome or] Jogospasm The invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with an excipient carrier pharmaceutically acceptable for the treatment of disorders responsive to modulation of the GABAA receptor, for example, treatment of anxiety depression, sleeping disorders or cognitive impairment by modulation of the GABAA receptor. The pharmaceutical compositions include pharmaceutical compositions that comprise a container that maintains a therapeutically effective amount of at least one modulator. of the GABAA receptor as described above and instructions (pd >eg, labeling) indicating that ligand GABAA receptor content is to be used for the treatment of a thyroid with response to modulation of the GABAA receptor in the patient. In a separate aspect, the invention provides a method for enhancing the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another active compound of the CNS. Such CNS active compounds include, but are not limited to, the following: for anxiety, serotonin receptor agonists and antagonists (for example 5-γ); for anxiety and depression, neurokinin receptor antagonists or corticotrophin-releasing factor receptor (CRFx) antagonists; for sleep disorders, melatonin receptor agonists and for neurodegenerative disorders, such as dementia Alzheimer's, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly, the invention provides a method for enhancing the antidepressant activity of the selective serotonin absorption inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI. Combination administration can be carried out in that it would be sufficient to inhibit the binding of benzodiazepine or GABA compounds to GABAA receptors in vi tro In one embodiment, such methods are useful in overdose treatments for benzodi) azepine drugs. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine GABAA receptor compound can be easily determined by means of a GABAA receptor binding assay, such as the assay described in Example 6. The GABAA receptors used to determining in vitro binding can be obtained from a variety of sources, for example, from rat cortex preparations or from cells expressing cloned human GABAA receptors. The present invention also. refers to methods for altering the signal transduction activity, particularly the conductance of the chloride ion of the GABAA receptors, the method comprising exposing the cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal transduction activity of the GABAA receptors in vivo, for example, in a patient giving an amount of a compound of Formula I that would be sufficient to alter the signal transducing activity of the GABAA receptors. vitro. The amount of a compound that would be sufficient to alter the signal transducing activity of GABAA receptors can be determined by means of a GABAA receptor signal transduction assay, such as the assay described in Example 7. Cells expressing GABA receptors in vivo, they can be, but are not limited to, neuronal cells or cells of the brain. Such cells can make contact with the compounds of the invention through contact with a body fluid containing the compound, for example through contact with cerebrospinal fluid. The alteration of the signal transducing activity of the GABAA receptors in ritro can be determined from a detectable change = n the electrophysiology of cells expressing the GABAA receptors, when such cells make contact with a co-moiety of the invention in the presence of of GABA. The intracellular record or the 1"patch-clamp" record can be used to quantify changes in the electrophysiology of the cell. A reproducible change in the behavior of an animal giving a compound of the invention can also be used to indicate that changes in the electrophysiology eg GABAA receptors that express the cells of the animal have occurred. The GABAA receptor ligands supplied by this invention and the labeled derivatives thereof are also useful as standards and reagents in the determination of the potential of a potential pharmacist. The experimental and control samples are then washed to remove the detectably labeled compound without link. The amount of the detectably labeled compound that binds remaining then is measured and the amount of the compound that is detectably labeled in the experimental and control samples is measured. A comparison that indicates the detection of a greater quantity of detectable label in the at least one washed experimental sample that is detected in any of the control samples, demonstrates the presence of the rec | GABAA tores in that experimental sample. The labeled compound dettactably used in this process can be labeled cpn a radioactive tag or a luminescent label directly or indirectly. When tissue sections are used in this procedure and the detectably labeled compound is radiolabelled, the compound labeled "link" can be detected autoradiographically to generate an autoradiogram. The amount of the detectable label in an experimental or control sample is pu < Measure by observing the autoradiograms and compare the pressure density of the autoradiograms.
Chemical Description and Terminology The compounds described herein may have one or more asymmetric planar centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in racemic or optically active forms. It is well known in the art to prepare optically active forms such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a column CLAR chiral. Many geometyric isomers of olefins, C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The geometric cis and trans isomers of the compounds of the present invention are described , and can be isolated as a mixture of isomers or as separate isomeric forms, All chiral forms (enantiomeric and diastereomeric and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless specific stereochemistry is indicated If a variable occurs more than once in any formula or constituent for a compound, its definition every time it is presented is independent of its definition every time it is presented again. shows that it is substituted with 0 to 3 R * (where R * indicates any variable group ta l as Ar, R1 # R2, 3", etc) then the group can be optionally substituted with up to three groups R *, and R * each presented is selected independently of the definition of R *. Also, combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. The script "-" that is not | between the two letters or symbols, it is used to indicate a placement plan for a substituent. For example "-NH-R6 |Y" is placed through the nitrogen atom. As used herein, "alkyl" is intended to include groups of hydrocarbons [straight or branched chain alkylates, having the specified number of carbon atoms. Alkyl groups of 2 or more carbon atoms may contain double or triple bonds. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl! Or, s-butyl, t-butyl, n-pentyl and s-pentyl. Preferred alkyl groups are Ci-C6 and C1-C4 alkyl groups. "Ci-C3 alkyl" denotes alkyl groups having from 1 to 6 carbon atoms. The most preferred alkyl groups are methyl, e: yl and propyl groups. As used herein, "ajlkoxy" represents an alkyl group as defined above, with an indicated number of carbon atoms placed through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoti, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy , neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy. "Ci-C6 alkoxy" denotes alkoxy groups having from 1 to 6 carbon atoms. Preferred alkoxy groups are methoxy, ethoxy, propoxy, and botoxy groups. "Alkenyl" is intended to include hydrocarbon chains of straight or branched configuration comprising one or more unsaturated carbon carbon bonds, which may occur at any stable point along the chain, such as nyl and propenyl. Alkenyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms and preferably 2-6 carbon atoms, "Alkynyl" is intended to include hydrocarbon chains of straight or branched configuration comprise one or more carbon-carbon triple bonds that may occur at any stable point along the chain, such as ethinyl and propinyl. Alkynyl groups typically have 2 to about 12 carbon atoms, more typically 2 to about 8 carbon atoms and preferably 2-6 carbon atoms.
"Aryl" refers to aromatic groups containing 1 or more rings, wherein the members of the ring or aromatic rings are carbon. When indicated, such groups can be substituted. Such groups include optionally substituted phenyl and optionally substituted naphthyl. The term "cycloalkyl" is intended to include saturated ring groups, which have a specific number of carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups will typically have 3 to about 8 members in the ring. In the terms "(cycloalkyl) alkyl" and "alkyl", defined above, the point of co [Location is through the carbon atom in the group alqvjilo. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl and cyclohexylmethyl. In the term "haloalkyl" the point of placement is through the carbon atom in the ring, as used herein, "haloalkyl" is intended to include straight and branched chain saturated aliphatic hydrocarbon groups, having the specific number of carbon atoms, substituted with 1 or more halogen atoms (for example -CVFW where v = 1 to 3 and w = 1 to (2 + 1) Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluormethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl). As used herein, "lialoalkoxy" denotes a haloalkyl group as defined above, with the indicated number of carbon atoms placed through an oxygen bridge. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy and tricloiromethoxy. As used herein, the term "heteroaryl" is intended to denote a 7- to 10-membered bicyclic or monocyclic or 5- to 7-membered bicyclic heterocyclic ring consisting of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S atoms and 0 in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, quinolinyl, benzothienyl, indolyl, pyridazinyl, pi trazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl, inda zolilo, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolilo, dihydro -benzodioxinyl, furanyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazyl, oxazolopyridinyl imidazopyridinyl, isothiazolyl, naphthyridinyl, cinolinyl carbazolyl, beta-carbol ynyl, i | socromanilo, chromanonyl, chromanyl, tetrahidroisoquino] ynyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazoli]] or pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, purinyl, benzodioxolyl, triazinyl, fencjxazinilo, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopiridini iraidazotiazolilo, dihidrobenzisoxázinilo, benzisoxazinilo, benzoxazinyl, dihidrobenzisotic.zinilo, benzopyranyl, benzothiopyranyl, coumarinyl, i socumarinilo, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihidroquinolinonilo, dihidroisoquinolinonilo, dihydrocoumarinyl, dihidroisocuma | rinilo, isoindolinonilo, benzodioxanyl, benzoxazolinonilp, pyrrolyl N-oxide, pyrimidinyl N- oxide, pyridazinyl oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N- xido, thiazolyl N-oxy indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide benzothiopyranil S-oxide, and benzothiopyranyl S, S-dioxide. Preferred heterocyclic groups include, but are not limited to, pyridinyl, pyrimicinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pirrcj > Lidinyl, morpholinyl, piperidinyl, piperazinyl, and limidazolyl. Also included are spiro and fused ring compounds containing, for example, the above heterocycles.
The term "oxo" indicates the oxygen atom that forms the carbonyl group. When an oxo group appears as a substituent, the pernitid valency of the substituted position is not exceeded. When an aryl or heteroaryl group is substituted with oxo, the aryl or heteroaryl group is converted to a partially saturated system. For example, pyridyl group substituted with oxo or pyridone. The phrase "pharmaceutically ab- ablable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or animals. without excessive toxicity, irritation, response to logic, or other problems or complications, in a proportion with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds wherein the parent compound is modified by making acid salts or base thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, acidic mineral or organic salts of basic waste such as amiñas; organic or alkali salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, yodhydric, sulfuric, sulfamic, sulfinic, phosphoric, nitric, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, pamoic ascorbic, malefic, hydroxymalonic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-aktoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, e: an disulfonic, oxalic, isethionic, HOOC- (CH2) n-ACOOH wherein n is 0-4, and the like, The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acid portion by conventional chemical methods. Generally, such salts can be prepared by reacting the acid or base forms of these compounds with an eskiquiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally , non-aqueous media, such as ether, ethyl acetate, ethanol, i.o.propanol, or acetonitrile are preferred. The lists of suitable products are found in Remington's Pharmaceuticals < † iences, 17th ed. , Mack Publishing Company, Easton, PA, p. JL418 (1985). The terms "trihaloalkyl" and "trihaloalkoxy" are exemplified, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules or syrups or elixirs, The compositions intended for oral use can be prepared from according to any method known in 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 preservatives in order to provide presentable preparations and preservatives. good pharmaceutically. The tablets contain the active ingredient? mixture with pharmaceutically acceptable non-toxic 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, sodium phosphate, disintegrating agents and granulators, 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 for a longer period. For example, a time-delayed 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 where the active ingredient is it is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. · Aqueous suspensions contain the active materials in admixture with suitable excipients for the manufacture of acupressure suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; Wetting or dispersing agents may be a naturally occurring phosphatide, for example, lecithin or condensation products of an alkylene oxide with fatty acids, for example pplioxyethylene stearate, or condensation products of ethylene oxide with chain aliphatic alcohols. long, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as the monoole of polyoxyethylene rbitol, or condensation products of ethylene oxide with partial esters sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, or, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic solution of sodium ruro. In addition, sterile oils are additionally employed as a solvent or suspending medium. For this purpose any soft fixed oil may be employed including synthetic mono or diglycerides. Also, 1 < Fatty acids such as oleic acid find use in the preparation of injectables. The compounds of general Formula I can also be administered in the form of adjuncts, for example, 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. Such materials are marketed from. cocoa and polyethylene glycols. The compounds of formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle.
By selling, adjuvants such as anesthetics can be dispersed in the vehicle | Local, preservatives and buffering agents For administration to non-human animals, the composition can also be added to the animal's diet or drinking water. It will be convenient to formulate these compositions of animal feed and water for drinking so that the animal takes an adequate amount of the composition together with its diet. It will also be convenient to present the composition as a premix for addition to water for drinking or food. Oxygen dose levels from 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of conditions above indicated (about 0.5 mg ha3a about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration.
The unit dosage forms will generally contain between about 1 mg around EjOO mg of an active ingredient. The dose frequency may also vary depending on the usadb compound and the particular disease treated. However, for the treatment of most disorders, a dose regimen of 4 times a day or less is preferred. For the treatment of anxiety, depression or cognitive impairment, a regimen of two: 1s or 2 times a day is particularly preferred. For the treatment of sleep disorders, a single dose that quickly reaches the effective concentrations is desired. It will be understood, however, that the specific level of dose for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time, d4 administration, route of administration and speed of excretion, combination of drugs and the severity of the particular disease that undergoes the therapy. The preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to, high solubility (preferably 500 ng / ml or s) in aqueous solutions, oral bioavailability, low toxicity, low whey protein binding, lack of clinically relevant EKG effects and desirable half-lives in vitro and in vivo. Penetration of the cerebro barrier to the blood for the compounds used to treat CNS disorders is necessary, although levels of the EXAMPLES are often preferred. Preparation of Compounds The synthetic routes for the preparation of the compounds of the invention are added in the following Schemes of Reaction. The reactions shown below show the specific methods for the synthesis of the compounds of the invention. However, someone of ordinary skill in the field will recognize that the reagents and reaction conditions may vary to obtain additional specific end products. In addition, it is quickly apparent that the additional compounds within the scope of the Formula! I, but not specifically described within the experimental sec, can be prepared analogously. When a protective group is used, the deprotection may be required. The appropriate protection groups and the method for protection and deprotection as described in Protecting Groups in Organic Syn: hesis by T. Greene are well known and appreciated in the art. The compounds and intermediates that are required for protection / deprotection will be readily apparent to those skilled in the art. (dimethylamino) methane to provide N, N-dimethylamine SAW . Hydrogenation of enamine VI in the presence of Raney nickel provides cleanly the 5-alkoxy-lH-pyrrolo [3, 2-b] iridin-3-carboxylic acid 7-ethyl ester, in step 5. Amination is conveniently carried out in Step 6 by reaction with an appropriate amine derivative in the presence of trimethylaluminum to produce the compound of Formula VIII. The following experimental examples illustrate, but do not limit, the present invention. In the examples, commercial reagents are used without purification. The purification by chromatography was carried out in Silica columns previously packed with Biotage (Dyax Corp, Biotage Division, Charlottesville, VA). The melting points (pf) are obtained using a Mettler Toledo melting point apparatus FP62 (Mettler-Toledo, Inc., Worthincjton, OH) with a temperature rise ratio of 10 ° C / min and are not correct The proton nuclear magnetic resonance spectra (1 H NMR) are recorded in solvents deuterated in a spectrometer They vary INOVA400 (400 MHz) (Varian | NMR Systems, Palo Alto, CA). Chemical changes are reported in parts per million (ppm, d) in relation to Me4Si (d 0.00). The proton NMR splitting patterns are designated as singl doublet (d), triplet (t), quartet (q), quintet), sextet (sex), septet (sep), multiplet (m), apparent (ap) and broad (br). Coupling qonstants are reported in hertz (Hz). Nuclear magnetic resonance spectra of carbon-13 (13 <1> NMR) are recorded in a Varian INOVA400 (100 MHz). Chemical changes are reported in parts per million ppm (d) with retraction to the central line of the 1: 1: 1 triplet of deuteroclorc [form (d 77.00), the central line of deuteromethanol (d 49.0) or deuterodimethylsulfoxide (d 39.7). The reported carbon resonance number 4e may not coincide with the number of carbon atoms in some molecules due to the chemically and chemically equivalent carbons, and may exceed the current carbon number due to the isomers with ormacionaj.es. The mass spectra (MS) are obtained using a Waters ZMD mass spectrometer using chemical pressure ionization. Atmospheric Injection Flow (APCI) (Waters Corporat ion, Milford, Mass). Mass detection with gas chromatography (CGE) is obtained using a Hewlett Packard HP 6890 GC series system with an HP 5973 mass selective detector and an HP-1 (crosslinked methyl siloxane) column (Agilent Technologies, Wilmington, DE). The CLAR spectra are recorded in | a? Hewlett Packard 1100 HPLC series system with a ZORBAX SB-C8 column, 5 μm, 4.6 x 150 mm (Agilent Technologies, ilmingtpn, DE) at 25 ° C using an elution gradient. Solvent A is water, Solvent B is acetonitrile, Solvent C is 1% trifluoroacetic acid in water. A linear gradient of four small pieces is used starting at 80% A, 10% B, 10% C and ending at 0% A, 90% B, 10% C. The remaining eluent at 0% A, 90% B, 10% C for three minutes. A linear gradient lasting one minute is used to return the eluent to 80% A, 10% B, 10% C and is maintained until the time of correction <jla equals to ten minutes, Ambient temperature (TA) tefiere to 20-25 ° C. The abbreviations "h" and "hrs" refer to "hours".
Example 1 Preparation of 6-methyl-lH-pyrrolo [3,2-b] iridin-3-carboxylic acid methyl ester A. Preparation of 2-chloro-5-methyl-3-nitro-pyridine 2-Chloro-5-methyl-3-nitro-p: ridine is prepared according to the method given in J. Mol Struct (1991) 248: 189-200 or can be purchased from EPECS and BioSPECS BV, Fleminglaan, The Netherlands .
B. Preparation of the diethyl ester < > of 2- (5-methyl-3-nitro-pyridin-2-yl) -malonic acid 2-yl) -acrylic as a visible oil which was used without further purification.
E. Preparation of the ethyl ester of} , l-hydroxy-6-methyl-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid A solution of the ethyl ester of 3-dimethylamino-2- (5-methyl-3-nitro-pyridin-2-yl) -acrylic acid (6.2 g, 0.022 mol) in ethanol (50 mL) was hydrogenated on Pd- C at 10% at 50 psi (3.51 Kg / cm2) for 48 h The catalyst was removed by filtration through a pad of celite, and the solvent was evaporated under vacuum E. residue was processed by chromatography on silica gel eluting with 7% MEOH-DCM containing a few drops of NH, OH to give the ethyl ester of l-hydroxy-6-methyl-lH-pyrrolo [3, 2 | b] pyridine-3-carboxylic acid 1H-RM (300 iHz, DMSO-d6) d 1.25 (t, J = 6.6 Hz, 3H), 4.21 (q, J = 6.6 Hz 2H), 7.59 (s, 1H), 8.15 (s, 1H), 8. 29 (s, 1H); RLE Caculate 220.2; found 221.12.F. Preparation of the ethyl ester of 6-methyl-lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid 50% (100 mL) and then with brine (100 mL). The organic layers were dried over Na 2 SO 4, filtered to remove solid and concentrated (in vacuo) to give the title compound as a 4.6: 1 regioisomer II / III mixture as a dark red oil: 1 H RM (400 MHz, CDC13 ) d 8.42 (d, 1H, J = 8.7 Hz, higher), 8.24 (d, J. = 8. | 3 Hz, lower), 7.69 (d, J = 8. 3 Hz, lower), 7.50 (d 1H , J = 8.7 Hz, higher), 5.44 (s, 1H, higher), 4.96 (s, 0.22H, lower), 4.32-4. 27 (m, 4H), 1.30-1.23 (m, 6H); MS (Cl) m / z 317.2 / 319 4 (M + 1).
B. Preparation of the ethyl ester of (6-chloro-3-nitro-pyridin-2-yl) -acetic acid A mixture of dietary ester LCO of 2- (6-chloro-3-nitro-pyridin-2-yl) -malonic acid (32. 5g, 103 mmol), LiCl (16.18g, 268 mmol), H20 (10 mL) , and dimethyl sulfoxide (50 mL) was stirred at 120 ° C for a period of 24 h. The mixture was cooled to room temperature and diluted with H20 (400 mL). 1N HCl (aqueous) ha3ta was added, all the solids were dissolved. The mixture was extracted with EtOAc (5 x 150 mL), and the combined organic extracts were washed with H20 (2 x 100 mL), then brine (100 mL), dried over Na2SO4. The mixture was filtered to remove solids, concentrated, and purified by instantaneous silica chromatography (eluting 5- (l-Methyl-piperidin-4-yloxy) -lH-pyrrolo [3,2- b] pyridine-3-carboxylic acid (60 mg, 0.20 mmol) The resulting mixture was heated to 100 ° C for a period of 3 h. The mixture was cooled to room temperature and Na2SO.10H2O (285 mg, 0.89 mmol) was added. The mixture was stirred for 30 minutes and the MeOH (5 mL) was added. The resulting mixture was filtered through a pad of celite and washed with MEOH (3 x 5 mL) and CHC13 (3 x 5 mL) The filtrate was concentrated and purified by chromatography on silica (gradient elution with 5% MeOH / CHCl 3 with 0.1 NH 4 OH to 8% MeOH / CHCl 3 with 0.1% NH 4 OH to 10% MeOH / CHC 3 with 0.1% NH 4 OH) to give the title compound as a light yellow solid (Cmp. # L) XH NMR (400 MHz, CD3OD) d 8.29-8.27 (m, 2H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.03 (dd, 1H, J = 7.1, 5.4 Hz), 6.63 (d, 1H, J = 8.7 Hz), 5.40-5.34 m, 1H), 2.86-2.80 (m, 2H), 2.57-2.52 (m, 2H), 2.35 (s, 3H),% .30-2.26 (m, 2H), 1.91-1.86 (m, 2H); 13 C NMR (100 MHz, CD 3 OD) d 163.9, 159.5, 152.4, 148.1, 139.1, 138.2, 131.6, 125.1, 124.1, 119.5, 114.2, 109.3, 107.2, 70.8, 53.6, 45.7, 30.8; MS (CD m / k 352.3 (M + 1).
Example 3 The compounds shown in Tables I, II and III are synthesized essentially in accordance with the procedures set forth in the Reaction Schemes and previous examples.
Com. Name Ri R2 Ar ¾ PMN Spec. of Mass (calc / obs. M + l or M-l) 27 (pyridin-2-CH3 H 282.3 / ilmethyl) -281.1 amind of 5- methoxy-pyrrol [3, 2-b] pyridine-3-carboxylic acid [6- (3-OEt H 411.51 / diethylamino-410.3-propoxy) -pyridin-3-yl] -amide NEt2 of 5- ethoxy-pyrrol [3,2-b] pyridine-3-carboxylic acid Com. Name Ri R2 Ar ¾ BMN Spec. of Mass (calc / obs. M + l or M-l) 5-Ethoxy-β-pyrrol [3, 2-b] pyridine-3-carboxylic acid (1-ethyl-lH-OEt H 299.33 / pyrazol-3-27.1. Yl) -amide / - 36 [4- (2- OEt H 325.37 / hydroxy-326.3 ethyl) -phenyl] -amide of 5-ethoxy-pyrrol [3,2-b] pyridine-3-carboxylic acid Com. Name Ri R2 Ar ¾ RM Spec. of Mass (calc / obs. M + l or M-l) 37 [4- (2-OEt H 380. 9-diethylamino-381.3 ethyl) -phenyl] -amide of 5-ethoxy-β-pyrrole [3, 2-b] pyridine-3-carboxylic acid 38 (3- OEt H 311.34 / hydroxymethyl 312.3-phenyl) -amido-5-ethoxy-1H-pyrrole [3,2-b] pyridine-3-carboxylic acid amide Com. Name Ri Ar XH RM Spec. of Mass (calc / obs. M + l or M-l) I (1-methyl-1H-XH RN (400 | 354.42 / pyrazole-3 MHz, CD30D) 355.4 il) -amide 11.22 (s, of 5-1H acid), 7.99 (s, (1-methyl-1H) 7.72 (d, piperidin-4-1H), 7.36 (d, iloxy) -lH-1H), 6.65 pyrrole [3, 2- (dd, 2H), b] pyridine-3- 5.31-5.26 (m, carboxylic 1H), 3.82 (s, 3H), 2.95- 2.87 (m, 2H), 2.72-2.65 (m, 2H), 2.42 (s, 3H), 2.30- 2.24 (m, 2H), 1.95-1.90 (m, 2H) Com. Name Ri R2 Ar ¾ NMR Spec. of Mass (calc / obs. M + l or -l) 93 (1-methyl-lH-H 368.20 / pyrazol-3- 369.3 il) -amido of 5- / [2- (l-Methyl- N pyrrolidin-2-yl) -ethoxy] -1H-pyrrolo [3, 2-b] pyridine-3-carboxylic acid 94 Pyridin-2-H 365.19 / 366.2-ylamide 5- [2- (1-Methyl-pyrrolidin-2) -yl) -ethoxy] -lH-pyrrolo [3,2-b] pyridine-3-carboxylic Cmp Name i R2 Ra H and / or 13C NMR E of M (calc / ob s M + lo Ml) 106 (3-methyl-c H 377.41 / isoxazole-5-H3 378.0 il) -amide of 5- (3-pyridin-2-yl-propoxy) -1H-pyrrole [3,2- b] pyridin-3- carboxylic 107 (1-ethyl-lH-CH 390.45 / pyrazole-3-H3 391.0 il) -amide of 5- (3-pyridin-2-yl-propoxy) -1H-pyrrole [3,2- b] pyridine- 3- carboxylic Name Ri R2 R3 ¾ and / or 13C NMR E of M (calc / ob s M + l or M-l) (1-methyl-1H-HH 1H (400MHz, CD30D) 383.46 / pyrazol-3-yl) - 8.04 (s, 1H), 7.80 384.1 amide (d, 1H, J = 8.7Hz), 7.49 (d, 1H , S- [2- (4- / J = 2.1Hz), 6.72 (d, Methyl-1H, J = 8.7Hz), piperazin-1- 6.65 (d, 1H, yl) -ethoxy] -lH- J = 2.1Hz), 4.65 (t, pyrrole [3.2-2H, J = 5.8Hz), 3.82b] pyridine-3- (S, 3H), 2.94 (t, carboxylic 2H, J = 5.8Hz), 2.90 -2.33 (m, 8H), 2.32 (s, 3H) Pyridin-2HH 13C (100MHz, 367.16 / ilamide of CDC13) 163.4, 368.1 acid 5- (2-16.1, 152.6, Morpholin-4-yl-148.4, 139.1, ethoxy) -lH-138.2, 131.4, pyrrole [3,2- 125.1, 123.9, b] pyridine 119.5, 114.4, -3- 110.3, 107.1, carboxylic 67.1, 63.6, 57.7, 54.1 Example 4 Preparation of compounds with sodium Radio Labeling of the Invention The compounds of the invention are prepared as radiolabelled probes upon synthesis using precursors comprising at least one atom which is a radioisotope. The radioisotope is preferably selected from at least one carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabelled probes are conveniently provided by a radioisotope supplier who specializes in conventional synthesis of radiolabelled probe compounds. Such providers include Amersham Corporation, Arlington Heights, Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochinery, Inc., Brea, CA. The labeled tritium probe compounds are also conveniently prepared catalytically by platinum-catalyzed exchange of tritiated acetic acid, exchange catalyzed with ep. tritiated trifluoroacetic acid or heterogeneous catalyzed exchange with tritium gas. Such preparations (also conveniently carried out as a custom radioetcheid by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate.) In addition, certain precursors may be subjected to the exchange of halogen with tritium with tritium gas. , reduction with tritium gas of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
Example 5 Receiver autoradiography The autoradiograph of the receptor (receptor mapping) is performed in vitro as described for Kuhar in sections 8.1.1 to 8.1.9 of Current Protocol < j > ls in Pharmacology (1998) John Wiley & Sons. New Ycjrk, using radioequipped compounds of the invention prepared as described in the preceding Example.
EXAMPLE 6 BINDING ASSAY The high affinity and high selectivity of the compounds of this invention for the benzodiazepine site of the GABAA receptor can be confirmed by using the binding assay described by Thomas and Tallman (J. Bijo. 1981; 156: 9838-9842, and J. Neurosci. 1983; 3: 433-440] Rapid cortical tissue is dissected and homogenized in 25 volumes (w / v) of buffer solution A (0.05 M Tris HC1 love solution equalizer, pH 7.4 a | 4 ° C.) The tissue homogenate is centrifuged cold (4 ° C &; at 20,000 x g for 20 minutes. The supernatant is decanted, the pelletizing is rehomogenized in the same volume of buffer solution, and centrifuged again at 20, 10,000 x g. The supernatant of this centrifugation step is decanted. The resulting pellet can be stored at 20 ° C overnight. The pelletizing is then thawed and resuspended in 25 volumes of Amortizing Solution A (original weight / volume), centrifuged at 20.00 0 x g and the supernatant is decanted. This washing step is repeated once. Finally, the pelletization is resumed in 50 volumes of Buffer Solution A. The incubations contain l | 00 μ? of tissue homogenate, 100 μ? of radioligand, (0.5 nM 3H-Rol5-1788 [3H-Flumazenil], specific activity 8 | 0 Ci / mmol), and the test or control compound (see below), and brought to a total volume of 500 μ? with Shock Absorbing Solution A. Incubations are carried out for 30 minutes s. 4 ° C and then quickly filtered through Wt.atman GFB filters to separate the free and bound ligand. Filters are washed twice with Fresh Buffer Solution A and counted in a liquid scintillation counter. The link: ~ IO specific (control) is determined by Rol5-1788 displacement with 10 μ? from Diazepan (Research Biochemicals International, Natick, MA) rat, access number to GENBAN. X15468; and? 2 of rat, access number to GENBA K L08497. For each subunit combination, sufficient message is injected for each constituent subunit to supply current amplitudes of > 10 nA when 1 μ is applied? GABA The compounds are evaluated against a GABA concentration that evokes < 10% of the evocable peak current GABA (for example, 1μ? -9μ?). Each ooc: .to is exposed to increasing concentrations of a compound that is evaluated (test compound) in order to evaluate a concentration / effect relationship. The efficiency of the test compound is calculated as a change in percentage in current amplitude: 100 * ((Ic / I) -1), where Ic is the current amplitude evoked by GABA. Observed in the presence of the test compound in I and the current amplitude evoked by GABA observed in the absence of the test compound. The specificity of a test compound for the benzodiazepine site is determined after the completion of the effect / concentration curve. After washing the oocytes sufficiently to separate the previously applied test compound, the oocyte is exposed to GABA + 1 μ? Rol5-1788, followed by exposure to GABA · + 1 μ? Rol5-1788 + test compound. The change in percentage due to the addition of compound is calculated as described above.
Any change in percentage observed in the presence of R015-1788 is subtracted from the changes in percentage in the current amplitude observed in the absence of 1 μ? R015-1788. These net values are used for the calculation of the average efficiency and the I! C50 values by standard methods. To evaluate the average efficiency and the ECS0 values, the concentration / e ect data are averaged across the cells and fit the logistic equation. It will be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (5)

NHC (= 0) -, -NHC (= 0) H, -NR30C (= O) -, - (NR30C (= 0) H, -NHS (0) n-, or -NR30S (0) "-; E and G are independently N, N (Ci-C6alkyl), S, and Glimpse R2o and R30 are independently a group (Ci.C8) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkjuyl (CY-CJ alkyl, wherein each alkyl and cycloalkyl group contains zero or one or more double or triple bonds, and wherein each carbon atom in the groups R2o and R30 are optionally substituted with one or more substituents selected irrespective of the group C), wherein C) consists of oxo, hydroxy, halogen, cyano, amino, Ci-Cealkoxy, -NH (Cx-Cgalquilo), -N (C: .- C6alkyl) (Ci C6alkyl), -NHC (= 0) (L-CS alkyl, -N (Ci-C3 alkyl) C (= 0) (Ci-Ce alkyl), - NHS (0) a (HC6 alkyl), -S (0 ) n (Ci-C6 alkyl), -S (0) nNH (Ci-C6 alkyl), -S (0) nN (Ci-C6 alkyl) (d-Cs alkyl), or L, where n is 0, 1, or 2, each R35 is independently a straight (Cx-Ce), (Cx-C8) branched, cyclic (C3-C8) alkyl or (C3-C8) cycloalkyl (Ci-C6) alkyl group, wherein each group alkyl and cycloalkyl contain zero or one or more double or triple bonds and wherein each carbon atom in R 35 is independently replaced with one or more substituents selected from group c); J and L are independently selected from saturated, partially unsaturated and aromatic rings, having from 4 to 7 ring atoms, in cyano, nitro, amino, XR5o, Cj1-C4-XR5o alkyl, or Y; X is independently selected from the group consisting of a bond, -CH2- / -CHR6o-, -0-, C (= 0) -, -C (= 0) 0-, -0C (= 0) -, -S (0) n-, -NH-, -NR60-, -C (= 0) NH-, | C (= 0) NRSO-, -S (0) nNH-, -S (O) nNR60 , -NHC (= 0) -, -NRS0C (= O) -, NHS (0) n-, and -NR60S (O) n-; ¾o ¾? are each independently selected from hydrogen, C L-C8 alkyl, C3-C8 cycloalkyl, and (C3-C8) cycloalkyl. { Ci-C6) alkyl, sn wherein each alkyl and cycloalkyl contains zero, one, or more double or triple bonds, and wherein each carbon atom of the alkyl, cycloalkyl cycloalkylalkyl is optionally independently substituted with one or more of oxo, hydroxy, halogen , cyano, amino, alkoxy Ci-C6, -NH (Ci-C6 alkyl), (Ci-C6 alkyl) (Ci-Ce alkyl)), -NHC (= 0) (Ci-C6 alkyl), -N (alkyl) Ci-C6) C (= 0) (Ci-C6 alkyl -NHS (O) n (alkylod-Ce), -S (0) n (Ci-C6 alkyl), -S (0) nNH (Ci-Ce alkyl) , -S (0) nN (Ci-C6 alkyl) (Ci-C6 alkyl), and Z, where n is 0, 1, or 2; and Y, and Z are independently selected from the following: saturated rings , partially unsaturated or aromatic, having from 4 hadta 7 ring atoms, 0, 1 or 2 ring atoms chosen from oxygen and nitrogen, with the remaining ring atoms being carbon, and wherein Y, and Z are substituted or not replaced »independently with one or more independently selectable substituents cited independently selected from i) halogen, oxo, hydroxy, amino, cyano, C1-6 alkyl; fc6, Ci-C6 alkoxy, alkoxyCx Cs (Ci- C6alkyl), haloalkylCi-C3, haloalkoxyCi-C6, and mono- or di- (Ci-C6) alkylamino and ii) phenylcj, pyridyl, pyrimidyl or pyrazinyl, each of which is unsubstituted or substituted with from 1 hast i 3 of substitute is independently chosen from laógeno, hydroxy, amino, cyano, Ci-C4 alkyl / alkoxy 3.-C4, Ci-C2 haloalkyl, Ci-C2 haloalkoxy, and mono- or di- (C1-C4)) alkylamino; R 4 is hydrogen, halogen or hydroxyl; Ar represents heteroaryl or heteroaryl (Ci-C6) alkyl, wherein the heteroaryl is selected from quinolinyl, benzothienyl, indolyl, pyridazinyl, piazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazyl, oxazolyl, thienyl, thiazolyl, indolizinyl, inqazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl, dihydro-benzodioxinyl, furanyl, birrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinolinyl, carbazolyl, Beta-carbolinyl, isochromanyl, chromanonyl, chromanyl, linilo tetrahidroisoquin, isoindolinyl, Ranilo isobenzotetrahidrof, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazole | yl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, puri benzodioxolyl, triazinyl, fenqxazinilo, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihidrobencisoxazinilo, bencisoxazinilo, benzoxazinyl, dihidrobencisoti zinilo, benzopyranyl, benzothiopyranyl, coumarinyl, .Jsocumarin it, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihidroquinolinonilo, dihidroisoquinolinonilo, dihydrocoumarinyl, dihidroisocumarinilo, isoindolinonilo, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide , N-oxide d <;; pyridazinyl, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, qiiinoxalinyl N-oxide, phthalazinyl N-oxide, Imidazole N-oxide Lo, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, lindazolyl N-oxide, benzothiazolyl N-oxide, behcimidazolyl N-oxide, N-oxide pyrrolyl, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and S, S-dioxide dje benzothiopyranyl, where Ar is optionally substituted by 1 or more of R40-R40 is independently selected from hydroxy, halogen, cyano, nitro, amino, X5o / Ci-C-XR50 alkyl, and Y; X is independently selected each time substituted or unsubstituted with one or more substituents independently selected from: i) halogen, oxo, hydroxy, amino, cyano, Ci-C6 alkoxy / alkoxyCi C6 (alquiloCi-C6) háloalquiloCi-C3-C6 haloalcoxiCi, mono- and di- (Ca-C6) alkylamino and ii) fenild pyridyl, pyrimidyl pyrazinyl, each cuajes is unsubstituted or substituted with from 1 high as 3 independently chosen substituents of iogeno, hydroxy, amino, cyano, Ci-C alkyl, Di-C alkoxy, Ci-C2 haloalkyl, Ci-C2 haloalkoxy, and mono- or di- (Ci-cJ) alkylamino; R 4 is hydrogen, halogen or hydroxyl; Ar represents phenyl, pyridyl or pyrimidinyl, wherein Ar is optionally substituted by 1 or more of R40; R40 is independently selected from hydroxy, halogen, cyano, nitro, amino, alkyl C! -C6, Ci-C6 alkoxy, Ci-C6 alkanoyl, C3-C7cycloalkyl, C3-C7 cycloalkyl (Ci-C4) alquilf, C3-C7-cycloalkyl-0-, C3-C7 (Ci-C) alkoxy -, C2-C6 alkenyl, alkylthio Ci-C6, halo (Ci-Cg) alkyl, or halo (C1, -C6) alkoxy, and Ar is substituted by at least one of -E-R5o-G-R60, -E R50-GY (alkyl CJ.-C4-XR50 -NH-R60 Y, - (NR50) R6O-Y, and Y, wherein X is independently selected each that is presented from the group consisting of -O-, - C (= 0) -, - C (= 0) 0-, -OC (= 0) -, -S (0) n-, -MH-, -NRS0-, -C (= 0) NH-, C (= O) NR60-, - S (0) nNH-, -S (O) nNR60, -NHC (= 0) -, -NR60C (= O) -, n is independently selected each that is presented as 0, 1 and 2. The compound or salt according to claim 1, characterized in that Ar represents an aryl, arylalkyl, heteroaryl or teteroarylalkyl group, the aryl or heteroaryl of which is selected. { Canvas phenyl, pyridyl, pyrimidinyl, pyrazinyl, pirroli or, imidazolyl, thienyl, thiazolyl, isothiazolyl, yl oxazo [1, 3, 4] thiadiazolyl, triazolyl, indolyl, cinchona ynyl, isoquinolinyl, benzodioxolyl, benzofurani | I, bencimiazolilo, benzoisoxolilo , and dihydro-benzod | oxinyl and optionally substituted by one or more of R (j) 5. The compound or salt according to claim 4, characterized in that R4 is hydrogen 6. The compound or salt according to claim 4, characterized jorque Ri is selected of B); R2 and R3 are independently selected from hydrogen, halogen, Ci-C6 haloalkyl, Ci-6 coxy halo, hydroxy, cyano, amino, Ci-C6 alkyl, -i-C3 alkoxy, and mono- or di (Ci-C6) alkylamino; and R4 is hydrogen. 7. The compound or salt according to claim 4, characterized in that Ri is selected from B); R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, -OCF3, hydroxy, cyano, Ci-C2 alkyl, Ci-C2 alkoxy and mono- or di- (Ci-C2) alkynylamino, and R4 is hydrogen. 8. The compound or salt according to claim 4, characterized p (j) wherein Ri is selected from B); R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; and R4 is hydrogen. 9. The compound or salt according to claim 4, characterized poique: R40 is independently selected from hydroxy, halogen, cyano, amino, XR50, (C1-C4) alkyl-XR50 / e and Y; X is independently selected from each group consisting of an enlkce, -CH2-, -CHR60-, -0-, C (= 0) -, -S (0) n-, -NH-, and -NR60 -; R50 Reo is independently selected from hydrogen, cyclic, branched and linear alkyl groups, and (cycloalkyl) cycloalkyl groups, cyclic, branched and linear alkyl groups and groups (cycloalkyl) alkyl consist of 1 to 8 carbon atoms, and contain zero or one or more double or triple bonds, each of which from 1 to 8 carbon atoms may be substituted, characterized in that Rx is selected from B); R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl; R4 is hydrogen; and R40 is independently selected from C-alquilo alkyl. - C6 l alkox :. Ci-C6; halogen, mono or di (Ci-C6) alkylamino, mono or di (Ci- 6) alkylamino (Ci-C6) alkoxy, (Ci-C6) alkoxy (Ci-Ce) alkyl, and (Ci-C < j coxi (C! -C6) alkoxy 12. The compound or salt according to claim 4, characterized park Rx is selected from B); B) is -E-R35, alkyl-CyrC-0- | -20r -E-R20 G-R30, R20-L, J, or Ci- C6-J alkyl; and E and G are independently ijlH, N-Ci- C6alkyl, or 0. /o / ¾o and R35 are independently selected from: cyclic, branched and linear alkyl groups, and (cycloalkyl) alkyl groups, the cyclic alkyl groups , branched and linear, and groupb (cycloalkyl) alkyl consisting of 1 to 8 carbon atoms, containing zero or one or more double or triple bonds; wherein in R2o and ¾s each of which 1 to 8 atoms of carbon may be further substituted with one or more substituents, independently selected from group C) and in R35 at least one of 1 to 8 carbon atoms is further substituted by one or more substituents independently selected from group C) wherein group C ) consists of: oxo, hydroxy, halogen, cyano, amino, Ci | Ce alkoxy, -NH (d-C6 alkyl), -N (Ci-C6 alkyl) (Ci-C6 alkyl), NHC (= 0) (alkyl) Ci-C6), - N (Ci-C6 alkyl) C (= 0) (Ci-C6 alkyl, -NHS (O) n (Ci-C6 alkyl), -S (0) n (Ci-C6 alkyl), -S (0) nMH (Ci-Cg alkyl), -S (0) nN (alkyl) Ci-C6) (Ci-C6 alkyl), and L; J and L are independently selected from each of heterocyclic saturated rings, having from 4 to 7 ring atoms, where 1 or 2 ring atoms are nitrogen, with remaining ring atoms which are carbon, in which ringings are substituted or unsubstituted with one or more substituents independently selected from halogen, bear, hydroxy, amino, cyano, Ci-C6 alkyl, iC6 alkoxy, Ci-C6 alkoxy (Ci-C6 alkyl), Ci-C6 haloalkyl, haloCi-C6 haloalkoxy |, and mono- or di- (Ci- C6) alkylamino; with the proviso that J is not a phenyl or pyridyl; R2 and R3 are independently selected from hydrogen, halogen, methyl, and ethyl; R4 is hydrogen; and R40 is independently selected from Ci-C6 alkyl, C6-C6 alkoxy; | halogen, mono od (Cx-C6) alkylamino, mono or di (Ci-C6) alkylamino (Ci-C6) alkoxy, (Ci-Cg) alkoxy (Ci-C6) alkyl, and (d-C6) alkoxy (Ci-) Ce) alkoxy 13. The compound or salt according to claim 2, characterized in that Ar represents an aryl, arylalkyl, heteroaryl, or heteroarylalkyl group, the aryl or heteroaryl of which is selected from piperazinyl, pyrrolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, or > : azolyl [1, 3, 4] thiadiazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl benzodioxolyl, benzofurani P-o, benzimiazolyl, benzoisoxolyl, and dihydro-benzodicjxinyl, and is optionally substituted by one or more of R40. 14. The compound or salt according to claim 13, characterized in that R4 is hydrogen. The compound or salt according to claim 13, characterized in that Ri is selected from hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 haloalkyl, hydroxy, cyano, amino, Cx-C6 alkyl, Ci-C6 alkoxy, mono- or di- (Ci-C6) alkylamino and B). R2 and R3 in this embodiment are independently selected from hydrogen, halogen, Cx-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-C6 alkoxy, and mono- or di-alkylamino (Cx- j, and R is hydrogen 16. The compound or sa] according to claim 13, characterized in that Ri is selected from hydrogen, halogen, haloCi-C6 haloalkoxy, Ci-C6 haloalkoxy, hydroxy, cyclo, amino, Ci- C6, Ci-C6 alkoxy, mono- or di- (Ci-C6) aldjlamino and B). R2 and R3 are independently selected from hydrogen, halogen, CF3, CHF2, -0CF3, hydro :: i, cyano, Ca-C2 alkyl, Ci-C2 alkoxy, and mono- or di- (C1-C2) alkylamino, and R4 It is hydrogen. 17. The compound or salt according to claim 13, characterized by Riir is selected from hydrogen, halogen, Ci- C6 haloalkyl, haloalkoxy i-C6, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-C6 alkoxy, mono- or di- (Ci-C6) alkylamino and B). B) is E-R35, C1-C4 alkyl-O-Rjo, -E-R20-G-R3o -É-L-, -E-R20-L, J, or C1-C4 alkyl-J; E and G are independently Nh, N-Ci-C6 alkyl, or O. R2 and R3 are independently selected from hydrogen, halogen, methyl and ethyl. 18. The compound or salt according to claim 13, characterized in that: R40 is independently selected from hydroxy, halogen, cyano, amin XR501 (C1-C4) alkyl-XR50, and Y; X is independently selected from the group consisting of a bond, -CH2-, -CHR6o- / -0-, C (= 0) -, -S (0) n-, -NH-, and -NR60 -; Yo and Reo is independently selected from hydrogen, alkylated or cyclic, branched and linear groups, and (cycloalkyl) alkyl groups, the cyclic, branched and linear alkyl groups and (cycloalkyl) alkyl groups consist of 1 to 8 carbon atoms. carbon, and contain zero or one or more Robles or triples, each of which from 1 to 8 arbon atoms can be further substituted with one or more selected substitutes of oxo, hydroxy, halogen, cyano, amino, alboxi Ci-Cg , - H (Ci-C6 alkyl), -N (C1-C6 alkyl) (Ci-C6 alkyl), -NHC (= 0) (Ci-C6 alkyl), - (Ci-C6 alkyl) C (= 0) (Ci-C6 alkyl, -NHS (O) n (Ci-Ce alkyl), -S (0) n (Ci-C6 alkyl), -S (0) nNH (Ci-Cg ailkyl), -S (0) nN (Ci-Cs alkyl) (Cx-C6 alkyl), and Z; Y, and Z are independently selected from: saturated, partially unsaturated or aromatic rings, having from 4 to 7 ring atoms, 0, 1 or 2 ring atoms selected from oxygen and nitrogen, with remaining ring atoms that are | carbon, wherein Y, and Z are substituted or unsubstituted with one or more substituents selected from halogen, oxo, hydroxy, amino, cyano, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 alkoxy (Ci-C6 alkyl) ), Ci-C6 haloalkyl, haloalkylCi-C6, and mono- or di- (Ci-C6) alkylamino; and n is independently selected each that is presented as 0, 1 and 2. B) is -E-R35, alkyl -Ci-C4-0-F | 20, -E-R2o-G-R3o, -E-L, -E R20-L, J, or Ci-C6-J alkyl; and E and G are independently N, N-C 1 -C 6 alkyl, or O R 20 R 30 and R 35 are independently selected from: cyclic, branched and linear alkyl groups, and (cycloalkyl) alkyl groups, the cyclic, branched alkyl groups and linear, and (cycloalkyl) alkyl groups consisting of 1 to 8 carbon atoms, which contain zero or one or more double or triple bonds wherein in R 2 and R 35 each of which 1 to 8 carbon atoms may also be substituted with one more substituents, independently selected from the group C) and at R35 at least one of 1 to 8 carbon atoms is further substituted by one or more substituents independently selected from group C) wherein the group C) consists of: oxo, hydroxy, halogen, cyano, amino, alkoxy C -Cs, -NH (d-C6 alkyl), -N (C ^-Cs alkyl) (Ci-C6 alkyl), NHC (= 0) (Ci-C6 alkyl), -N (Ci-C6 alkyl) C (= 0) (Cx-C alkyl), -NHS (O) n (d-C8 alkyl), -S (0) "(Ci-C6 alkyl), -S (O) nNH (Ci-Ce alkyl), -S (0) nN (d-C6 alkyl) (Cx-Cg alkyl), and L; J and L are each independently selected from: saturated heterocyclic rings, having from 4 to 7 ring atoms, wherein 1 or 2 ring atoms are nitrogen, with remaining ring atoms which are (cycloalkyl) alkyl groups , the cyclic, branched and linear alkyl groups, and (cycloalkyl) alkyl groups consist of 1 to 8 carbon atoms, and contain zero or one or more double or triple bonds, each of the 1 to 8 carbon atoms may be further substituted with one or more substituents selected independently from oxo, hydroxy, halogen, cyano, amino, a] coxy Ci-C6, -NH (Ci-Ce alkyl), -N (d-C5 alkyl) (Ci-C6 alkyl) ), - HC (= 0) (Ci-C6 alkyl), -N (C1-C6 alkyl) C (= 0) (d-C6i alkyl), yz. 26. The compound or salt in accordance with / indication 25, characterized in that Rx is selected from hydrogen, halogen, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-C6 alkoxy, mono- or di- (Ci-C6) 'alkylamino; Rs and R3 are independently selected from hydrogen, halogen, CF3, CHF2, -OCF3, hydroxy, cyano, C! -C2 alkyl, Ci-C2 alkoxy and mono- or di- (C: -C2) alkynylamino; and R4 is hydrogen. 27. The compound or salt according to claim 25, characterized in that: Ri is selected from hydrogen, halogen, CX-C6 haloalkyl, Ci-Ce haloalkoxy, hydroxy, cyano, amino, Ci-C6 alkyl, Ci-Ce alkoxy, mono- or di- (Ci-C6) allylamino and B). R2 and R3 are independently selected from hydrogen, halogen, halogen, methyl and ethyl and R4 is hydrogen. 28. The compound or salt according to claim 1, characterized in that it is selected from the group consisting of 5- (1-methyl-piperidin-4-yloxy) -lH-pyrrolo [3, 2-pyridin-2-ylamide. -b] pyridine-3-arboxylic; LH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid (2-fluoro-phenyl) -amide; pyridin-2-ylamide of Q.H-Pyrrolo [3, 2-b] pyridine-3-carboxylic acid; (2-fluoro-phenyl) -amide 7-chlorp-lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid; (4-methoxy-phenyl) -amide of the acid 6-methyl-lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid; (5-propoxy-pyridin-2-yl) -amide of 6-methyl-lH-pyrrolo [3,2- b] pyridine-3-carboxylic acid; pyridin-3-ylamide of the acid 6-methyl-lH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid; 5-Methoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid (2-fluoro-phenyl) -amide; pyridin-2-alamide of the acid 5-methoxy-lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid; 5-methoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid (4-methoxy-phenyl) -amide of 5-methylamino-lH-pyrroloic acid (4-methoxy-phenyl) -amide. [3, 2-b] pyridine-3-carboxylic acid; (2-fluoro-phenyl) -amide | 5-ethylamino-lH-pyrrolo [3, 2-b] pyridine-3-carboxyl iccg >; (2-fluoro-phenyl) -amide of the acid: 5-ethoxy-1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid; (4-methoxy-phenyl) -amide of 5-ethoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid; pyridin-2-ylamide of the acid < 3-5-ethoxy-lH-pyrrolo [3,2, b] pyridine-3-carboxylic acid; (5-chloro-pyridin-2-yl) -amide | of 5-ethoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid | 5-Ethoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid (6-bromo-pyridin-3-yl) -amide; 5-isopropoxy-lH-pyrrolo [3, 2-b] iridin-3-carboxylic acid (3-fluoro-phenyl) -amide; 3-isopropoxy-lH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid (3-fluoro-methoxy-phenyl) -amid.i; quinolin-8-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid ilamide; LH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid [4- (3-methanesulfonylamino-propoxy) -phenyl] -amide; (3-propyl- [1, 2, 4] thiadiazole-5-i :.) -amido of 1H-pyrrolo [3,2- b] pyridine-3-carboxylic acid (l-methyl-lH-pyrazole-3-) il) -amid. of 1H-pyrrolo [3, 2-b] pyridin-3-carboxylic acid pyrrolo [3, 2-b] iridin-3-carboxylic acid; 5-Ethoxy-lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid [4- (2-ethylamino-ethyl) -phenyl] -amide; 5-Ethoxy-lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid (3-hydroxymethyl-phenyl) -amide of 5-ethoxy-lH-pyrroloic acid (3-pyrrolidin-l-ylmethyl-phenyl) -amide of 5-ethoxy-lH- pyrrolo [3, 2-b] pyridin-3-carboxylic acid; 5-Ethoxy-lH-pyrrolo [3,2- b] pyridine-3-catrboxylic acid [4- (2-pyrrolidin-1-yl-ethyl) -phehyl] -amide; (3-methyl-isothiazol-5-yl) -amide] of 5-isopropoxy lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid LCO; 5-isopropoxy-lH pyrrolo [3, 2-b] iridin-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide of 5-isopropoxy-lH-pyrroloic acid (5-methyl-isoxazol-3-yl) -amide isopropoxy-lH pyrrolo [3, 2-b] pyridine-3-carboxylic acid (5-methyl-l-pyrazol-3-yl) -amide of 5-isopropoxy lH-pyrrolo [3,2-b] pyridin-3-amide carbox £ l | co; 5-isopropoxy lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid (l-ethyl-lH-pyrazol-3-yl) -amide; 5- (2-Methoxyethoxy) -lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide; 5- (2-Methoxyethoxy) -lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid (3-methyl-isoxazol-5-yl) -amide; 5- (2-Methoxyethoxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide; 5- (l-Met pyrrolidin-3-yloxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid pyridin-2-ylamide (5-methyl-isoxazol-3-yl) -amide. - (1-methyl-pyrrolidin-3-yloxy) -lH-pyrrolo [3, 2-b] pyridin-3-larboxylic acid; 5- (1-methyl pyrrolidin-3-yloxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid l-methyl-lH-pyrazol-3-yl) -amide; 5- (2-dimethylamino-ethoxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid (5-methyl-isoxazol-3-yl) -amide; pyridin-2-ylamide of Ej (2-dimethylamino-ethoxy) -1H-pyrrolo [3, 2-b] pyridine-3-carboxylic acid ilamide; (l-methyl-lH-pyrazol-3-yl) -amipa of 5- (2-dimethylamino-ethoxy) -lH-pyrrolo [, 2 • b] pyridin-3-carboxylic acid; 5- (1-Methyl azetidin-3-yloxy) -1H-pyrrolo [3, 2 -fc] pyridin-3-carboxylic acid (l-methyl-1H-pyrazol-3-yl) -amide; 5- (3-Dimethylamino-2,2-dimethyl-propoxy) -lH-pyrrolo [3,2-b] pyridine-3-carboxylic acid (l-methyl-lH-pyrazol-3-yl) -amide; pyridin-2-ylamide of the acid 5- (3-dimethylamino-2, 2- • dimethyl-propoxy) -lH-pyrrolo [3,2- b] pyridine-3-carboxylic acid; 5- (3-dimethylamino-propoxy) -lH-pyrrolo [(2, b) pyridin-3-carboxylic acid (6-methoxy-pyridin-3-yl) -amide; 5- (3-dimethylamino-propoxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid (3-fluoro-phenyl) -amide; 5- (3-dimethylamino-propoxy) -lH-pyrrolo [(i, 2-b) pyridin-3-carboxylic acid (3-methyl-isothiazol-5-yl) -amide; (L-methyl-lH-pyrazol-3-yl) -amide of ethylamino-propoxy) -lH-pyrrolo [3,2-pyridin-3-carboxylic acid; pyridin-2-ylamide of (3-diethylamino-propoxy) -pyrrolo [3, 2-b] pyridine-3-carboxylic acid | 5-Oxo-4,5-dihydro-lH-pyrrolo [3,2-b] pyridin-3 - (carboxylic acid pyridin-2-alamide (l-methyl-l-pyrazol-3-yl) -amide) 5- (4-dimethylamino-butoxy) lH-pyrrolo [3,2- b] pyridine-3-carboxylic acid (l-methyl-lH-pyrazol-3-yl) -amide of 5- (3 piperidin-1-yl-propoxy) -lH-pyrrolo [3, 2-b] pyridine-3-carboxylic acid pyridin-2-ylamide 5- (3-piperidin-1-yl-propoxy) -lH-pyrrolo [ 3, 2-b] pyridine-3-carboxylic acid (5- (3-azetidin) (l-methyl-1H-pyrazol-3-yl) -amidd)
1-yl-propoxy) -lH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid; 3-azetidin-1-yl-propoxy) -1H-pyrrolo [3, 2-b] pyridin-3-carboxylic acid in-2-amide; 5- [2- (1-Methyl pyrrolidin-2-yl) -ethoxy] -lH-pyrrolo [3 |, 2-b] pyridin-3-l- methyl-l-pyrazol-3-yl) -amide. -carboxylic acid, 5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -lH-pyrrolo [3, 2-b] pyridinecarboxylic acid pyridin-2-ylamide; pyridin-2-ylamide of (3-pyrro1-1-yl-propoxy) lH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid pyridin-2-ylamide; 5- (3-pyrrol-1-yl-propoxy) -lH-pyrrolo [3,2-b] pyridi-3-carboxylic acid (l-methyl-lH-pyrazol-3-yl) -amide; 5- (3-pyridin-2-yl-propoxy) -β-pyrrolo [3,2-b] pyridin-3-carboxylic acid (l-butyl-lH-pyrazol-3-yl) -amide; 5- (3-Pyridin-2-yl-propoxy) -lH-pyrrolo [3,2-b] pyrimid-3-carboxylic acid (l-propyl-lH-pyrazol-3-yl) -amide; 5- (3-pyridine) (l-methyl-lH-pyrazol-3-yl) -amide
2-yl-propoxy) -lH-pyrrolo [3, 2-b] iradin-3-carboxylic acid; 5- (3-pyridin-2-yl-propoxy) -lH-pyrrolo [3,2- b] pyridin-3-carboxylic acid pyridin-2-ylamide; 5- (-hydroxy-butoxy) -1H-pyrrolo [3, 2-b] pyridine-3-carboxylic acid pyridin-2-ylamide; 5- [3- (4-Methyl-piperazin-1-yl) -propoxy] -lH-pyrrolo [3, 2-b] pyridinyl] -pyridin-2-ylamide < jiin-3-carboxylic acid; 5- (3- (4-Methyl piperazin-1-yl) -propoxy] -lH-pyrrol [3,2-b] pyridine-3-carboxylic acid (l-methyl-1H-pyrazol-3-yl) -amide.; 3-morpholin-4-yl-propoxy) -lH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid pyridin-2-alamide; 5- (3-morpholin-4-yl-propoxy) -lH-pyrrolo [3,2-b] pyridin-3-carboxylic acid (l-methyl-lH-pyrazol-
3-yl) -amide; 5- [2- (4-Methyl-piperazin-1-yl) -ethoxy] -lH-pyrrolo [3, 2-b] pyridi-carboxylic acid pyridin-2-ylamide; 5- (2- (
4-methyl piperazin-1-yl) -ethoxy] -lH-pyrrolo 3, 2-b] pyridine-3-carboxylic acid (l-methyl-1H-pyrazol-3-yl) -amd;
5- (2-morpholin-4-yl-ethoxy) -IH-pyrrolo [3, 2-b] pyridin-3-carboxylic acid pyridin-2-ylamide; 5- (2-Morpholin-4-yl-ethoxy) -IH-pyrrolo [3,2-b] pyridi-3-carboxylic acid (l-methyl-lH-pyrazol-3-yl) -amide; and pharmaceutically acceptable salts thereof. A receptor that binds the compound exhibiting a K ii of 1 micromolar or less. 29. The compound or salt according to any of claims 1 to 3, characterized in that in a binding assay of the G- † BAA receptor, the compound shows a Ki of 100 nanomolar or less. 30. The compound or salt according to any of claims 1 to 3, characterized in that in a binding assay of the GABAA receptor, the compound shows a Ki of 10 nanomolar or less. 31. A pharmaceutical composition, characterized in that it comprises a compound or salt according to any of claims 1 to 3, together with a pharmaceutically acceptable carrier or excipient. 32. The pharmaceutical composition according to claim 31, characterized in that the pharmaceutical composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a | pill, capsule, syrup or transdermal patch 33 A method for treating anxiety, depression, a sleeping disorder, GABAA receptor deficiency disorder, and subsequently determining the presence or absence of a GABAA receptor in the sample. 37. The method of compliance with claim 36, characterized in that the presence or absence of a bound compound is detected using autoradiography. 38. A method for altering the signal transduction activity of a GABAA receptor, the method characterized in that it comprises contacting a cell that expresses the GABAA receptor with a solution comprising a compound or salt according to any of claims 1 at 3, at a sufficient concentration to produce a detectable alteration in the electropysiology of the cell, and thereby alter the signal transducing activity of the GABAA receptor. 39. A method for altering the signal transducing activity of the GABAA receptors / method characterized in that it comprises exposing the cells expressing the GABAA receptors to a compound or salt according to any of claims 1 to 3, at a sufficient concentration to inhibit the binding of R015-1788 in vitro, to cells expressing, the GABAA receptor. 40. The method according to claim 38, characterized in that the detectable alteration of the electrophysiology of the cell is a change in the conductance of the chloride ion in the cell. characterized in that Ri is amino (Ci-C6) alkoxy, mono (C1-C3) alkylamino (Ci-Cs) alkoxy, di (C1-C3) alkylamino (C-C6) alkoxy, pyridyl (Ci-C6) alkoxy, hydroxy ( Ci-C6) alkoxy, (C1-C4) alkoxy (C! -C6) alkoxy, piperazinyl (Ci-C6) alkoxy wherein the piperazinyl group is optionally substituted with alkyl or (Ci-C6), morpholinyl (Ci-C6) ) alkoxy, or thiomorpholinyl (Ci-C6) alc < pxi; R2 and R3 are independently selected from H, (Ci-C6) alkyl, halogen or (Ci-C6) alkoxy Ar is pyridyl, isoxazolyL oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrimidyl, or pyridazinyl, each of which is substitute or np is substituted with 1, 2 or 3 groups which are independently alkyl (Ci-C6), alkoxy (Cx-C6), halogen, OCF3, or CF3. 45. The compound of conformity with the claim 44, characterized in that Ri is amino (C1-C4) alkoxy, mono (C1-C4) alkylamino (Ci-C4) alkoxy, di (C1-C4) alkylamino (C y ji-C4) alkoxy, pyridyl (C x -C 4) alkoxy, hydroxy (C1-C4) alkoxy, piperazinyl (C1-C4) alkoxy, wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl, or morpholinyl (Ci-C6) lcoxy. 46. The conformation compound with the claim 45, characterized in that R2 and R3 are independently selected from H, (Ci-C4) alkyl, halogen or (C1-C4) alkoxy, with the proviso that at least one of R2 and R3 is H. Ar is pyridyl, isoxazolyl oxazolyl , pyrazolyl, pyrimidyl, or pyridazinyl, each of which is substituted or not substituted with 1, 2 or 3 groups which are independently alkyl, alkoxy, halogen, OCF3, or CF3. 47. The compound in accordance with the claim 46, characterized in that Rx is amino (0? -04) alkoxy, mono (Ca.-C4) alkylamino (Ci-C4) alkoxy, di (Ci-C4) alkylamino (C; J.-C4) alkoxy, pyridyl (Ci) -C4) alkoxy, hydroxy (C1-C4) alkoxy, pi-perazinyl (Ci-C4) alkoxy, wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl, or morpholinyl (Ci-C6) LYCOXY; R2 and R3 are independently selected from H, (C! -C4) alkyl, or (C1-C4) alkoxy, with the proviso that at least one of R2 and R3 is H. Ar is pyridyl, isoxazolyl, oxazole-5 -yl, pyrazolyl, pyrimidyl, or pyridazinyl, each) one of which is substituted or not substituted with 1, 2 or 3 groups which are independently (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halogen, OCF 3, or CF3. 48. The conforming compound with the claim 47, characterized in that Ri is amino (C1-C4) alkoxy, mono (C1-C4) alkylamino (Ci-C4) alkoxy, di (Ci-C4) alkylamino (Cj1-C4) alkoxy, pyridyl (Ci-C4) alkoxy, hydroxy (C1-C4) alkoxy, p-perazinyl (C1-C4) alkoxy, wherein the piperazinyl group is optionally SUBSTITUTED with (C1-C4) alkyl, or morpholinyl (C1-C4) a] lcoxy; R2 and R3 are independently selected from H and (C1-C4) alkyl, with the proviso that at least one of R2 and R3 is H. Ar is pyrid-2-yl, 1-oxato-1-5-yl, oxazole-5 -yl, pyrazol-3-yl, pyrimid-2-yl, or piifidazin-3-yl, each of which is substituted or not substituted with 1 or 2 groups which are independently alkyl (Ci-C), alkoxy ( Ci-C4), or halogen. 49. The compound according to claim 44, characterized in that Ri is amino (C2-C4) alkoxy, mono (Ci-C4) alkylamino (C2-C4) alkoxy, di (C1-C4) alkylamino (C | 2- C) alkoxy, (C2-C4) alkoxy, hydroxy (C2-C4) alkoxy, piperazinyl (C2-C4) alkoxy, wherein the piperazinyl group is optionally substituted with alkyl (Ci-C4), or morpholinyl (C2-C4) lcoxi; R2 is H or methyl; and R3 is H. 50. The compound according to claim 1, characterized in that Ri is amino (Ci-C6) alkoxy, mono (C1-C3) alkylamino (Ci-Cs) alkoxy, di (C1-C3) alkylamino (Ci-Cs) alkoxy, pyridyl (Ci-C6) alkoxy, hydroxy (Ci-C6) alkoxy, (Ci-C4) alkoxy (Ci-C6) alkoxy, piperazinyl (Ci-C6) alkoxy wherein the group piperazinyl is optionally substituted with alky (Ci-C6), morpholinyl C6) alkoxy, or thiomorpholinyl (Ci-C6) ale R2 and R3 are independently selected from H, C6) alkyl, halogen or (Ci-C6) alkoxy 51. The Composed in accordance with the claim 50, characterized in that Ri is amino (C1-C4) alkoxy, mono (C1-C4) alkylamino (Cx-C4) alkoxy, di (C! -C4) alkylamino (C.C4) alkoxy, pyridyl (Ci-). C4) alkoxy, hydroxy (C1-C4) alkoxy, piperazinyl (Ci-C4) alkoxy, wherein the piperazinyl group is optionally substituted with (C1-C4) alkyl, or morpholinyl (Ci-C6) alkoxy. 52. The compound according to claim 2, characterized in that Ri is amino (Ci-C6) alkoxy, mono (C1-C3) alkylamino (Ci-C6) alkoxy, di (C1-C3) alkylamino (C-C6) alkoxy , pyridyl (Ci-C6) alkoxy, hydroxy (Ci-C6) alkoxy, (C1-C4) alkoxy (Cx-C6) alkoxy, piperazinyl (C! -C6) alkoxy wherein | the piperazinyl group is optionally substituted with alky (Ci-C6), morpholinyl (Ci-C6) alkoxy, or thiomorpholinyl (Cx-Cg) alkoxy; R2 and R3 are independently selected from H, (Ci- C6) alkyl, halogen or (Ci-C6) al. Cooxox, 53. The compound according to claim 52, characterized in that Rx is amino (Cx-C4) alkoxy, mono (C1-C4) alkylamino (Cx-C4) alkoxy, di (C1-C4) alkylamino (CI-C4) alkoxy, pyridyl (Ci-C4) alkoxy, hydroxy (C1-C4) alkoxy, piperazinyl (Ci-Q) alkoxy, wherein the piperazinyl group is optionally substituted with alkyl (Cx-C, or morpholinyl (Ci-C5) alkoxy, 54. The compound according to claim 3, characterized in that Ri is amino (Ci-C6) alkoxy, | mono (Ci-C3) alkylamino (Ci-C6) alkoxy, di (C1-C3) alkylamino (< Íi-C6) alkoxy, pyridyl (Ci- C6) alkoxy, hydroxy (Ci-C6) alkoxy, (C1-C4) alkoxy (Ci-Cs) alkoxy, piperazinyl (Ci-C6) alkoxy wherein the piperazinyl group is optionally substituted with alkyl (Ci-Ce), morpholinyl (Ci-C6) alkoxy, or thiomorpholinyl (Ci-C6) alkoxy; R2 and R3 are independently selected from H, (Ci-C6) alkyl, halogen or (d-C6) alkoxy: 55. The compound according to claim 54, characterized in that Ri is amino (C1-C4) alkoxy, mono (Ci-C4) alkylamino (Ci-C4) alkoxy, di (C1-C4) alkylamino (IC1-C4) alkoxy, pyridyl (Ci-C4) alkoxy, hydroxy (C1-C4) alkoxy, p iperazinyl (C1-C4) ) alkoxy, wherein the piperazinyl group is optionally substituted with alkyl (Ci-C4), or morpholinyl (Ci-C6 alkoxy)
MXPA04004711A 2001-11-19 2002-11-19 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides. MXPA04004711A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33302701P 2001-11-19 2001-11-19
PCT/US2002/037157 WO2003044018A1 (en) 2001-11-19 2002-11-19 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides

Publications (1)

Publication Number Publication Date
MXPA04004711A true MXPA04004711A (en) 2005-08-16

Family

ID=23300941

Family Applications (1)

Application Number Title Priority Date Filing Date
MXPA04004711A MXPA04004711A (en) 2001-11-19 2002-11-19 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides.

Country Status (7)

Country Link
EP (1) EP1453831A1 (en)
JP (1) JP2005516901A (en)
AU (1) AU2002366092A1 (en)
BR (1) BR0214301A (en)
CA (1) CA2467542A1 (en)
MX (1) MXPA04004711A (en)
WO (1) WO2003044018A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2865208B1 (en) 2004-01-16 2009-01-16 Sanofi Synthelabo 1,4-DIAZABICYCLO [3.2.1] OCTANECARBOXMIQUE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF
FR2890072A1 (en) 2005-09-01 2007-03-02 Fournier S A Sa Lab New pyrrolopyridine derivatives are peroxisome proliferator activated receptor activators useful to treat e.g. hypertriglyceridimia, hyperlipidemia, hypercholesterolemia and diabetes
US20150374705A1 (en) 2012-02-14 2015-12-31 Shanghai Institues for Biological Sciences Substances for treatment or relief of pain
CA2914620C (en) 2013-06-05 2021-06-15 C&C Research Laboratories Heterocyclic derivatives and use thereof
GB201317363D0 (en) 2013-10-01 2013-11-13 Eisai Ltd Novel compounds
WO2023082044A1 (en) * 2021-11-09 2023-05-19 暨南大学 5-formyl heterocyclic amide compound and use thereof
CN116102549B (en) * 2021-11-09 2025-02-11 暨南大学 5-aldehyde heterocyclic amide compounds and their applications

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750702A (en) * 1993-10-27 1998-05-12 Neurogen Corporation Certain pyrrolo pyridine-3-carboxamides; a new class of GABA brain receptor ligands

Also Published As

Publication number Publication date
WO2003044018A1 (en) 2003-05-30
CA2467542A1 (en) 2003-05-30
AU2002366092A1 (en) 2003-06-10
BR0214301A (en) 2004-10-13
JP2005516901A (en) 2005-06-09
EP1453831A1 (en) 2004-09-08

Similar Documents

Publication Publication Date Title
US20040110778A1 (en) Heterocyclic compounds as ligands of the GABAA receptor
US20090069337A1 (en) 3&#39; substituted compounds having 5-ht6 receptor affinity
AU1481701A (en) Bicyclic and tricyclic heteroaromatic compounds
US20100022581A1 (en) Pyrrolidine-substituted azaindole compounds having 5-ht6 receptor affinity
JP2008525464A (en) Alpha-7 nicotinic receptor ligand and its production and use
EP1562945A1 (en) 1,4-diazabicyclo(3,2,2)nonane derivatives, preparation and therapeutical use thereof
CA2419966A1 (en) Aryl substituted tetrahydroindazoles and their use as ligands for the gaba-a receptor
US20100029629A1 (en) Acyclic compounds having 5-ht6 receptor affinity
JP2010519226A (en) 6&#39;-substituted indole and indazole derivatives having 5-HT6 receptor affinity
AU7092800A (en) Fused pyrrolecarboxamides: gaba brain receptor ligands
NZ528370A (en) Beta-carboline derivatives and its pharmaceutical use against depression and anxiety
US20100056491A1 (en) 4&#39;-amino cyclic compounds having 5-ht6 receptor affinity
MXPA04004711A (en) 1h-pyrrolo[3,2-b]pyridine-3-carboxylic acid amides.
MXPA04007606A (en) Substituted fused pyrazolecarboxylic acid arylamides and related compounds.
JP2009514980A (en) 1H-indazoles, benzothiazoles, 1,2-benzisoxazoles, 1,2-benzisothiazoles, and / chromones, and their production and use
US20100016297A1 (en) Alkyl-substituted 3&#39; compounds having 5-ht6 receptor affinity
US6861529B2 (en) Cycloalkypyrrole-3-carboxylic acid derivatives and heterocycloalkylpyrrole-3-carboxylic acid derivatives
US20100056531A1 (en) Alkyl-substituted 3&#39; compounds having 5-ht6 receptor affinity
US6673811B1 (en) 1H-pyrrolo [3,2-b] pyridine-3-carboxylic acid amines as GABAA receptor ligands
EP1506194B1 (en) SUBSTITUTED RING-FUSED IMIDAZOLE DERIVATES: GABA sb A /sb RECEPTOR LIGANDS
US20060166974A1 (en) Azabenzoxazoles for the treatment of CNS disorders
CA3008653A1 (en) Bruton&#39;s tyrosine kinase inhibitors

Legal Events

Date Code Title Description
FG Grant or registration