AR127730A1 - AMPK ACTIVATORS - Google Patents

AMPK ACTIVATORS

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Publication number
AR127730A1
AR127730A1 ARP220103197A ARP220103197A AR127730A1 AR 127730 A1 AR127730 A1 AR 127730A1 AR P220103197 A ARP220103197 A AR P220103197A AR P220103197 A ARP220103197 A AR P220103197A AR 127730 A1 AR127730 A1 AR 127730A1
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Argentina
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alkyl
independently selected
halogen
hydrogen
optionally substituted
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ARP220103197A
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Spanish (es)
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Iyassu Sebhat
Shuwen He
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Kallyope Inc
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Publication of AR127730A1 publication Critical patent/AR127730A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12Antidiarrhoeals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Esta divulgación está dirigida, al menos en parte, a los activadores de AMPK útiles para el tratamiento de afecciones o trastornos relacionados con AMPK. En algunas realizaciones, la afección o el trastorno están relacionados con el eje intestino-cerebro. En algunas realizaciones, la afección o el trastorno están relacionados con infección sistémica e inflamación a causa de una barrera intestinal permeable. En algunas realizaciones, los activadores de AMPK son compuestos restringidos al intestino. En algunas realizaciones, los activadores de AMPK son agonistas, súper agonistas, agonistas completos o agonistas parciales. Reivindicación 1: Un compuesto de fórmula (1), o una sal farmacéuticamente aceptable de este, caracterizado porque: X es -O- o -S-; Y es -N- o -CR⁶-; R¹, R², R³ y R⁴ se seleccionan cada uno independientemente, en cada aparición, de halógeno, hidroxilo, alquilo C₁₋₄, -CN y haloalquilo C₁₋₄; n se selecciona de 0, 1, 2, 3 y 4; o se selecciona de 0, 1, 2, 3 y 4; p se selecciona de 0, 1 y 2; q se selecciona de 0, 1, 2, 3 y 4; R⁵ se selecciona de hidrógeno y alquilo C₁₋₄; R⁶ se selecciona de hidrógeno, halógeno, alquilo C₁₋₄ y haloalquilo C₁₋₄; D se selecciona de -P(O)(OR¹¹)₂, -P(O)R¹¹(OR¹¹), -S(O)₂OH y -L-K; L se selecciona de ˡ-(C(R¹³)₂)ʳ-, ˡ-O(C(R¹³)₂)ʳ-, ˡ-N(R¹²)(C(R¹³)₂)ₛ-, ˡ-C(O)O-, ˡ-OC(O)-, ˡ-C(O)N(R¹²)-, ˡ-N(R¹²)C(O)-, ˡ-N(R¹²)S(O)₂-, ˡ-S(O)₂N(R¹²)-, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros, donde ˡ denota la conexión con K; r se selecciona de 1, 2 y 3; s se selecciona de 0, 1, 2 y 3; K se selecciona de (I) y (II): (I) alquilo C₁₋₁₀ o heteroalquilo C₁₋₁₀, cada uno de los cuales está sustituido opcionalmente con uno a seis sustituyentes independientemente seleccionados de: halógeno, -OR¹⁴, -SR¹⁴, -N(R¹⁴)₂, -N⁺(R¹⁵)₃, -C(O)R¹⁴, -C(O)OR¹⁴, -OC(O)R¹⁴, -OC(O)N(R¹⁴)₂, -C(O)N(R¹⁴)₂, -N(R¹⁴)C(O)R¹⁴, -N(R¹⁴)C(O)OR¹⁴, -N(R¹⁴)C(O)N(R¹⁴)₂, -N(R¹⁴)S(O)₂(R¹⁴), -S(O)R¹⁴, -S(O)₂R¹⁴, -S(O)₂N(R¹⁴)₂, =O, -CN, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, carbociclo C₃₋₁₀ y heterociclo de 3 a 10 miembros, donde cada carbociclo C₃₋₁₀ y heterociclo de 3 a 10 miembros está sustituido opcionalmente con uno a seis sustituyentes seleccionados independientemente de halógeno, alquilo C₁₋₆, -OR¹⁴, =O y -S(O)₂OH; y (II) carbociclo C₃₋₁₀ y heterociclo de 3 a 10 miembros, cada uno de los cuales está opcionalmente sustituido con uno a seis sustituyentes independientemente seleccionados de halógeno, -OR¹⁴, -SR¹⁴, -N(R¹⁴)₂, -N⁺(R¹⁵)₃, -C(O)R¹⁴, -C(O)OR¹⁴, -OC(O)R¹⁴, -OC(O)N(R¹⁴)₂, -C(O)N(R¹⁴)₂, -N(R¹⁴)C(O)R¹⁴, -N(R¹⁴)C(O)OR¹⁴, -N(R¹⁴)C(O)N(R¹⁴)₂, -N(R¹⁴)S(O)₂(R¹⁴), -S(O)R¹⁴, -S(O)₂R¹⁴, -S(O)₂N(R¹⁴)₂, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, =O, -CN, alquilo C₁₋₁₀ y heteroalquilo C₁₋₁₀, donde cada alquilo C₁₋₁₀ y heteroalquilo C₁₋₁₀ está sustituido opcionalmente con uno a seis sustituyentes seleccionados independientemente de halógeno, -OR¹⁴, -SR¹⁴, -N(R¹⁴)₂, -N⁺(R¹⁵)₃, -C(O)OR¹⁴, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂R¹⁶, -S(O)₂OH y =O; R¹¹ se selecciona independientemente, en cada aparición, de hidrógeno, alquilo C₁₋₄ y haloalquilo C₁₋₄; R¹² se selecciona independientemente, en cada aparición, de hidrógeno y alquilo C₁₋₄ opcionalmente sustituido con halógeno, -OH, -NH₂ y -C(O)N(H)₂; R¹³ se selecciona independientemente, en cada aparición, de hidrógeno, alquilo C₁₋₄, haloalquilo C₁₋₄ e hidroxialquilo C₁₋₄; R¹⁴ se selecciona independientemente, en cada aparición, de: hidrógeno; y alquilo C₁₋₁₀ y heteroalquilo C₁₋₁₀ opcionalmente sustituido con uno a seis sustituyentes independientemente seleccionado de halógeno, -OR²¹, -SR²¹, -N(R²¹)₂, -N⁺(R¹⁵)₃, -C(O)R²¹, -C(O)OR²¹, -OC(O)R²¹, -OC(O)N(R²¹)₂, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²¹, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, =O y -CN; y carbociclo C₃₋₁₀ y heterociclo de 3 a 10 miembros, donde cada carbociclo C₃₋₁₀ y heterociclo de 3 a 10 miembros está sustituido opcionalmente con uno a seis sustituyentes seleccionados independientemente de halógeno, alquilo C₁₋₆, -OR²¹, -N⁺(R¹⁵)₃, -S(O)R²¹, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, -S(O)₂N(R²¹)₂, =O y -CN; R¹⁵ se seleccionan cada uno de alquilo C₁₋₄; R¹⁶ se selecciona independientemente, en cada aparición, de hidrógeno y alquilo C₁₋₆; R²¹ se selecciona independientemente, en cada aparición, de hidrógeno, alquilo C₁₋₆, haloalquilo C₁₋₆, hidroxialquilo C₁₋₆ y carbociclo C₃₋₆, donde el carbociclo C₃₋₆ está opcionalmente sustituido con uno a seis sustituyentes independientemente seleccionados de -OH, alquilo C₁₋₆, haloalquilo C₁₋₆, hidroxialquilo C₁₋₆ y =O.This disclosure is directed, at least in part, to AMPK activators useful for the treatment of AMPK-related conditions or disorders. In some embodiments, the condition or disorder is related to the gut-brain axis. In some embodiments, the condition or disorder is related to systemic infection and inflammation due to a leaky intestinal barrier. In some embodiments, AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists, super agonists, full agonists, or partial agonists. Claim 1: A compound of formula (1), or a pharmaceutically acceptable salt thereof, characterized in that: X is -O- or -S-; Y is -N- or -CR⁶-; R¹, R², R³ and R⁴ are each independently selected, at each occurrence, from halogen, hydroxyl, C₁₋₄ alkyl, -CN and C₁₋₄ haloalkyl; n is selected from 0, 1, 2, 3 and 4; or is selected from 0, 1, 2, 3 and 4; p is selected from 0, 1 and 2; q is selected from 0, 1, 2, 3 and 4; R⁵ is selected from hydrogen and C₁₋₄ alkyl; R⁶ is selected from hydrogen, halogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl; D is selected from -P(O)(OR¹¹)₂, -P(O)R¹¹(OR¹¹), -S(O)₂OH and -L-K; L is selected from ˡ-(C(R¹³)₂)ʳ-, ˡ-O(C(R¹³)₂)ʳ-, ˡ-N(R¹²)(C(R¹³)₂)ₛ-, ˡ-C(O )O-, ˡ-OC(O)-, ˡ-C(O)N(R¹²)-, ˡ-N(R¹²)C(O)-, ˡ-N(R¹²)S(O)₂-, ˡ -S(O)₂N(R¹²)-, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl, where ˡ denotes the connection with K; r is selected from 1, 2 and 3; s is selected from 0, 1, 2 and 3; K is selected from (I) and (II): (I) C₁₋₁₀ alkyl or C₁₋₁₀ heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR¹⁴, -SR¹⁴, -N(R¹⁴)₂, -N⁺(R¹⁵)₃, -C(O)R¹⁴, -C(O)OR¹⁴, -OC(O)R¹⁴, -OC(O)N(R¹⁴)₂, -C( O)N(R¹⁴)₂, -N(R¹⁴)C(O)R¹⁴, -N(R¹⁴)C(O)OR¹⁴, -N(R¹⁴)C(O)N(R¹⁴)₂, -N(R¹⁴) S(O)₂(R¹⁴), -S(O)R¹⁴, -S(O)₂R¹⁴, -S(O)₂N(R¹⁴)₂, =O, -CN, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle, where each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C₁₋₆ alkyl, -OR¹⁴, =O and -S(O)₂OH; and (II) C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR¹⁴, -SR¹⁴, -N(R¹⁴)₂, -N⁺ (R¹⁵)₃, -C(O)R¹⁴, -C(O)OR¹⁴, -OC(O)R¹⁴, -OC(O)N(R¹⁴)₂, -C(O)N(R¹⁴)₂, -N (R¹⁴)C(O)R¹⁴, -N(R¹⁴)C(O)OR¹⁴, -N(R¹⁴)C(O)N(R¹⁴)₂, -N(R¹⁴)S(O)₂(R¹⁴), - S(O)R¹⁴, -S(O)₂R¹⁴, -S(O)₂N(R¹⁴)₂, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH , =O, -CN, C₁₋₁₀ alkyl and C₁₋₁₀ heteroalkyl, where each C₁₋₁₀ alkyl and C₁₋₁₀ heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR¹⁴, -SR¹⁴, -N( R¹⁴)₂, -N⁺(R¹⁵)₃, -C(O)OR¹⁴, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂R¹⁶, -S(O )₂OH and =O; R¹¹ is independently selected, at each occurrence, from hydrogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl; R¹² is independently selected, at each occurrence, from hydrogen and C₁₋₄ alkyl optionally substituted with halogen, -OH, -NH₂ and -C(O)N(H)₂; R¹³ is independently selected, at each occurrence, from hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ hydroxyalkyl; R¹⁴ is independently selected, at each occurrence, from: hydrogen; and C₁₋₁₀ alkyl and C₁₋₁₀ heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR²¹, -SR²¹, -N(R²¹)₂, -N⁺(R¹⁵)₃, -C(O)R²¹, -C(O)OR²¹, -OC(O)R²¹, -OC(O)N(R²¹)₂, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²¹, -P( O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, =O and -CN; and C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle, wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C₁₋₆ alkyl, -OR²¹, -N⁺ (R¹⁵)₃, -S(O)R²¹, -P(O)(OR¹⁶)₂, -P(O)R¹⁶(OR¹⁶), -S(O)₂OH, -S(O)₂N(R²¹)₂, =O and -CN; R¹⁵ are each selected from C₁₋₄ alkyl; R¹⁶ is independently selected, at each occurrence, from hydrogen and C₁₋₆ alkyl; R²¹ is independently selected, at each occurrence, from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl and C₃₋₆ carbocycle, where the C₃₋₆ carbocycle is optionally substituted with one to six substituents independently selected from - OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl and =O.

ARP220103197A 2021-11-23 2022-11-22 AMPK ACTIVATORS AR127730A1 (en)

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