EP1140815A1 - Thioaminotetralin-derivate zur verwendung in der schmerzbehandlung - Google Patents

Thioaminotetralin-derivate zur verwendung in der schmerzbehandlung

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Publication number
EP1140815A1
EP1140815A1 EP99964898A EP99964898A EP1140815A1 EP 1140815 A1 EP1140815 A1 EP 1140815A1 EP 99964898 A EP99964898 A EP 99964898A EP 99964898 A EP99964898 A EP 99964898A EP 1140815 A1 EP1140815 A1 EP 1140815A1
Authority
EP
European Patent Office
Prior art keywords
compound
trans
amino
naphthalen
tetrahydro
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99964898A
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English (en)
French (fr)
Inventor
Dilip Dixit
Krzysztof Bednarski
Tiechao Li
Edward Roberts
Richard Storer
Wuyi Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire Canada Inc
Original Assignee
AstraZeneca AB
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Publication date
Priority claimed from SE9804493A external-priority patent/SE9804493D0/xx
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1140815A1 publication Critical patent/EP1140815A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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 to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/37—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention is related to compounds that exhibit analgesic activity and in particular compounds exhibiting analgesia due to their opioid receptor affinity.
  • the third, K exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin.
  • the ⁇ receptors seem to be more involved with analgesic effects.
  • the ⁇ receptors appear to deal with behavioral effects, although the ⁇ and the K receptors may also mediate analgesia.
  • Each opioid receptor when coupled with an opiate, causes a specific biological response unique to that type of receptor.
  • an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects.
  • Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd, In International Encyclopedia of Pharmacology and Therapeutics ; N.E. Williams and H. Wilkinson, Eds., Pergammon : (Oxford), 1 12, p.51 ( 1983). It is therefore an object of the present invention to provide compounds having analgesic effects but having as few side- effects as possible.
  • the present invention provides novel thio aminotetralin compounds represented by formula (I):
  • Z is S, SO or SO 2 ,
  • X is selected from anyone of (i) a bond
  • R 7 and R are independently selected from the group consisting of H , OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, C ⁇ -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- 6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COOR c wherein R e is C 2- 6alkenyl or
  • C 2- 6alkynyl; R and Rg can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
  • Ri is selected from the group consisting of H, C ⁇ . ⁇ alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ⁇ 2 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ⁇ 2 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6- i2 aryl> C 6 .i 2 aralkyl, C 6 -i 2 aryloxy, C M ? acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl;
  • R 2 and R 3 are independently selected from the group consisting of C ⁇ . 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C -6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6 -i 2 aryl, C 6- i 2 aralkyl, heteroaryl having from 6 to 12 atoms, and H; or
  • R 2 and R 3 may together form a saturated heterocycle of from 3 to 8 atoms
  • R and R 5 are independently selected from the group consisting of C ⁇ -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H;
  • R 4 and Rs can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
  • Re is hydrogen, OH, C ⁇ -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 . 6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, O- .
  • R 2 and R 3 are H or C ⁇ -6 alkyl.
  • the compounds of the present invention are useful in therapy, in particular as analgesics.
  • a method of treating pain in a mammal comprising administering to said mammal an analgesic amount of a compound or composition of the invention.
  • Still another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of pain.
  • compositions comprising compounds of the present invention and pharmaceutically acceptable carriers, diluents or adjuvants.
  • X is preferably -CR 7 R ⁇ - wherein R 7 and Rs are independently selected from the group consisting of OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, C ⁇ . 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, H, and COORc wherein R e is C ⁇ -6 alkyl; R and Rg can also be connected to form a C 3 . 8 cycloalkyl.
  • X is more preferably -CR Rs- wherein R 7 and Rg are independently selected from the group consisting of - ⁇ alkyl, and H. X is most preferably -CH 2 -.
  • Ri is preferably selected from the group consisting of H, Ci.i ⁇ alkyi, C 6 - ⁇ 2 aryl, and C 6- i2 aralkyl.
  • Ri is more preferably selected from the group consisting of C ⁇ . 6 alkyl, C 6- i 2 aryl, and C 6- i2 aralkyl. Ri is most preferably C ⁇ . 6 alkyl.
  • Ri can also be , wherein n is an integer between 1 to 5, Rx and Rxi are independently H, C ⁇ -6 alkyl, C 2-6 alkenyl or C 2 . 6 alkynyl. More preferably, n is 1 or 2 and Rx and Rxi are C ⁇ -6 alkyl. Most preferably, Rx and R i are methyl or ethyl. In an alternative embodiment, Ri is selected from the group consisting of
  • n is an integer selected between 1 and 5.
  • Ri is C 6-12 aryl or heteroaryl having from 6 to 12 atoms.
  • Ri is selected from the group consisting of
  • A is selected from the group consisting of C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-C ⁇ -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-C 1-6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N- .6 alkyl, N-C 2 .
  • Ri is C 6 - ⁇ 2 aralkyl or heteroaryl having from 6 to 12 atoms. More preferably, Ri is selected from the group consisting of
  • A is selected from the group consisting of C ⁇ -6 alkyl, Q ⁇ alkyl, C 2- 6alkenyl, C 2-6 alkynyl, O-C, -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, , S-C ⁇ -6 alkyl, S-C 2-6 alkenyl, S-C 2-6 alkynyl, N-C 1-6 alkyl, N-C 2-6 alkenyl, N-C 2-6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is C ⁇ -6 alkyl, C 2- 6alkenyl or C 2- 6alkynyl and Y is -(CH 2 ) m - wherein m is an integer selected between 1 and 5.
  • Ri is
  • A is preferably selected from the group consisting of C ⁇ -6 alkyl, O-C ⁇ -6 alkyl,
  • R a is C ⁇ -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.
  • A is more preferably selected from the group consisting of C ⁇ -6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, and
  • COOH is most preferably selected from the group consisting of amidino, guanido, and
  • R 2 and R 3 are preferably H.
  • R 4 and R 5 are preferably C ⁇ alkyl substituted by a hydroxyl.
  • R» and Rs are preferably C )- alkyl.
  • R 4 and R 5 are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl.
  • R 4 and R 5 are preferably ethyl.
  • R 4 and R 5 are preferably methyl.
  • R_ can be substituted at any position on the aromatic ring. More preferably Re is adjacent to the carbon bearing the OH.
  • the present invention provides compounds of the formula (II) or (D )
  • R is preferably, H, methyl, halogen or OR b wherein R b is C ⁇ -6 alkyl, C ⁇ . 6 alkenyl or
  • Re is most preferably H.
  • the compounds of the present invention contains at least 2 chiral centers which are marked by an asterik (*) on the general formula (I).
  • the compounds of formula (I) thus exist in the form of different geometric( i.e. trans and cis) and optical isomers (i.e. (+) or (-) enantiomers).
  • the compounds may therefore be in the form of cis isomers or trans isomers.
  • Each cis or trans isomers also exists as a (+) and (-) enantiomer. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the compounds of the present invention are in the form of the trans isomers.
  • the compounds of the present invention are present in the form of trans (+) and trans (-) enantiomers.
  • Preferred compounds of the invention include:Trans-7-Amino-8,8-dimethyl-6- methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol
  • (+)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #33);Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydronaphthalen-2-ol (Compound #34); Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2- ol (Compound #35);Trans7-Amino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8- tetrahydro-naphthalen-2-ol (Compound #36);Trans-7-amino-6-(4-amino-phenylsulfanyl)- 8,8-dimethyl-5
  • the compound of the present invention is selected from the group consisting of compound#l, compound#3, compound#4, compound#5, compound#9, compound#ll, compound#15, compound#31, compound#32, compound#33, compound#36, compound#37, compound#39 compound#41, compound#43, compound #44 and compound #45.
  • the compound of the present invention is selected from the group consisting of compound#l, compound#3, compound#5, compound#32, compound#33, compound#36, compound #44 and compound #45.
  • pain represents "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
  • the term “pain” also includes “acute pain” and chronic pain. Acute pain is usually immediate and of a short duration. Acute pain can be present further to an injury, short-term illness, or surgical/medical procedure.
  • Examples of acute pain include a burn, a fracture, an overused muscle, or pain after surgery. Cancer pain may be long-lasting but acute due to ongoing tissue damage.
  • Some chronic pain is due to damage or injury to nerve fibers themselves (neuropathic pain).
  • Chronic pain can result from diseases, such as shingles and diabetes, or from trauma, surgery or amputation (phantom pain). It can also occur without a known injury or disease.
  • the present invention s directed to the treatment of all type of pain, including acute and chronic pain.
  • alkyl represents an unsubstituted or substituted (by a halogen, nitro, aminoamidino, amidino, guanido, CONH 2 , COOH, O-C ⁇ -6 alkyl, O-C -6 alkenyl, O-C 2 . 6 alkynyl, amino, hydroxyl or COOQ, wherein Q is Ci- ⁇ alkyl, C -6 alkenyl, a C -6 alkynyl) straight chain, branched chain, or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, flurohexyl or cyclopropyl).
  • alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g., CF 3 -, or CF 3 CH 2 -).
  • saturated heterocycle represents a carbocyclic ring in which one or more of the from 3 to 8 atoms of the ring are elements other than carbon, such as N, S and O;
  • aryl represents an aromatic ring having from 6 to 12 carbon atoms, which may be substituted by a C ⁇ -6 alkyl, C 2 . 6 alkenyl, a C 2-6 alkynyl, halogen, nitro, aminoamidino, amidino, guanido, CONH 2 , COOH, O-C ⁇ -6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, amino, hydroxyl or COOQ, wherein Q is C ⁇ -6 alkyl, C 2-6 alkenyl, a C 2-6 alkynyl, such as phenyl and naphthyl.
  • aralkyl represents an aryl group attached to the adjacent atom by a Ci- ⁇ alkyl, Ci- ⁇ alkenyl, or C ⁇ . 6 alkynyl(e.g., benzyl).
  • aryloxy represents an aryl or aralkyl moiety covalently bonded through an oxygen atom (e.g., phenoxy).
  • heteroaryl represents an aromatic ring in which one or more of the from
  • 6 to 12 atoms in the ring are elements other than carbon, such as O, N, and S (e.g pyridine, isoquinoline, or benzothiophene).
  • acyl refers to a radical derived from a carboxylic acid, substituted (by halogen(F, Cl, Br, I), C 6-2 o aryl or C ⁇ -6 alkyl) or unsubstituted, by replacement of the OH group.
  • an acyl radical may be aliphatic or aromatic, substituted (by halogen, .
  • phosphoryl represents a radical derived from a phosphono moeity in which the hydrogen atom of at least one of the -OH can be replaced by C ⁇ -6 alkyl, C 2 - 6 alkenyl, C 2- 6alkynyl, C ⁇ .6heteroalkyl, C 6 -i2 aryl, C 6- i2 aralkyl, and C 6 - ⁇ 2 heteroaryl(e.g., diethoxyphosphorylmethyl).
  • halogen encompasses chloro, fluoro, bromo and iodo
  • the sulfur atom can be at different oxydation level, S, SO, or SO 2 . All such oxydation level are within the scope of the present invention.
  • the starting ketone AA was dissolved in a suitable solvent such as DMF, acetonitrile, THF, DME and was treated with sodium hydride or any other base such as potassium t- butoxide, sodium bis(trimethylsilyl)amide.
  • a suitable solvent such as DMF, acetonitrile, THF, DME
  • sodium hydride or any other base such as potassium t- butoxide, sodium bis(trimethylsilyl)amide.
  • the resulting mixture was then treated with ethyl iodide or any other alkyl halide such as methyl iodide, allyl bromide, diiodobutane to produce the compound A.
  • the compound A was dissolved in a suitable solvent such as pyridine, DMF, ethanol and was treated with hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide to produce the compound B.
  • a suitable solvent such as pyridine, DMF, ethanol
  • hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide
  • the compound B was dissolved in a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine. The mixture was then heated to 50°C or at any higher temperature to produce the compound C.
  • a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine.
  • the compound C in was dissolved in a suitable solvent as dichloromethane (CH 2 C1 2 ) or in any other solvent such as dichloroethane, and was treated with BBr 3 or any other demethylating agent such as BC1 3 , HBr, to produce the compound D.
  • a suitable solvent as dichloromethane (CH 2 C1 2 ) or in any other solvent such as dichloroethane
  • BBr 3 any other demethylating agent such as BC1 3 , HBr
  • the compound E was dissolved in a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HC1, BF 3 .OEt 2 , PTSA, to produce the compound F.
  • a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HC1, BF 3 .OEt 2 , PTSA, to produce the compound F.
  • PPTS pyridinium p-toluenesulfonate
  • HC1, BF 3 .OEt 2 , PTSA pyridinium p-toluenesulfonate
  • a non alcoholic solvent can be used in combination with
  • the protecting groups of the compound F were removed under appropriate conditions e.g. with TFA or with any other acid such as HC1, PTSA, to produce the compound la.
  • a method of agonizing or activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing or activating amount of a compound or composition of the invention.
  • compositions comprising compounds of the present invention and derivatives thereof, in combination with pharmaceutically acceptable carriers diluents or adjuvants.
  • pharmaceutically acceptable derivatives is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compounds of formula (I) or (II) or any other compound such as a prodrug which, upon administration to the recipient, is capable of providing (directly or indirectly) compounds of formula (I) or (U) or an active metabolite or residue thereof.
  • compositions which comprise a pharmaceutically effective amount of a compound of the invention, or pharmaceutically acceptable salts thereof, and preferably, a pharmaceutically acceptable carrier, diluent or adjuvant.
  • pharmaceutically effective amount is the amount of compound required upon administration to a mammal in order to induce analgesia.
  • opioid receptor agonizing amount refers to the amount of compound administered to a mammal necessary to bind and/or activate opioid receptors in vivo.
  • Therapeutic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions.
  • Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • a composition of the invention is in the form of a unit dose.
  • the unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients.
  • binding agents such as acacia, gelatin, sorbitol, or polyvinylpyrolidone
  • fillers such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants such as magnesium stearate
  • disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose
  • pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • the compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
  • the compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents.
  • the compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Liquid oral preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may or may not contain conventional additives.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats
  • emulsifying agents such as sorbitan monooleate or acaci
  • non-aqueous vehicles which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol
  • preservatives for instance methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, n- propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid
  • the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
  • the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic.
  • fluid unit dosage forms may be prepared by utilizing the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle.
  • the compound Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package.
  • Adjuvants such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use.
  • Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition).
  • Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration.
  • the compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle.
  • a surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound.
  • compositions of this invention comprise a pharmaceutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Typically, they contain from about 0.01% to about 99% by weight, preferably from about 10% to about 60% by weight, of a compound of this invention, depending on which method of administration is employed.
  • the compounds of the present invention can be administered in combination with one or more further therapeutic agents.
  • the one or more further therapeutic agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, narcotics, antidepressants, anticonvulsants, corticosteroid, tramadol, sumatriptan, and capsaicin.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs include aspirin (Anacin, Bayer, Bufferin), ibuprofen (Motrin, Advil, Nuprin), naproxen sodium (Aleve) and ketoprofen (Orudis KT)
  • narcotics include drugs derived from opium (opiates), such as morphine and codeine, and synthetic narcotics (opioids), such as oxycodone, methadone and meperidine (Demerol).
  • antidepressants include amitriptyline (Elavil), trazodone (Desyrel) and imipramine (Tofranil) may be used with other analgesics. These drugs are especially useful for neuropathic, head and cancer pain.
  • anticonvulsants include drugs developed for epilepsy, these drugs, such as phonation (Dilantin) and carbamazepine (Tegretol), can also help control chronic nerve pain.
  • Tramadol (Ultram) is a synthetic analgesic used primarily for chronic pain, but is also prescribed for acute pain.
  • Sumatriptan may reduce pain from migraine headache by constricting blood vessels.
  • Capsaicin (Zostrix), a topical cream made from an extract of red peppers, can help relieve skin sensitivity resulting from shingles. Capsaicin can also be used to treat pain from arthritis, cluster headaches, diabetic neuropathy and pain after mastectomy.
  • compounds may be used to identify opioid receptors from non-opioid receptors.
  • compounds of the invention are radiolabeled e.g. by incorporating 3H or 14C within its structure or by conjugation to 1251.
  • Such radiolabeled forms can be used directly to identify the presence of opioid receptors and in particular ⁇ opioid receptors in a receptor population. This can be achieved by incubating membrane preparations with a radiolabeled compound of the invention. The presence and or amount of opioid receptors in the preparation is determined from the difference in membrane-bound radioactivity against a control preparation devoid of opioid receptors.
  • radiolabeled forms of the present compounds can be exploited to screen for more potent opioid ligands, by determining the ability of the test ligand to displace the radiolabeled compound of the present invention.
  • Step 1 7-Methoxy-l,l-dimethyl-3,4-dihydro-lH-naphthalen-2-one (A)
  • Step 2 7-Methoxy-l,l-dimethyl-3-methylsulfanyI-3,4-dihydro-lH-naphthalen-2- one(B)
  • Step 3 7-Methoxy-l,l-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen-2-one oxime (C)
  • Step 4 7-Methoxy-l,l-dimethyl-3-methylsulfanyl-3,4-dihydro-lH-naphthalen-2- ylamine (mixture of cis and trans) (D)
  • Step 6 ( ⁇ )-Cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen- 2-ol, hydrochloride (compound #2)
  • Step 1 l,l-Diethyl-7-methoxy-3,4-dihydro-lJ 1 7-naphthalen-2-one (A)
  • the resulting purpule solution was stirred for lh at 0°C then stirred for over night at r.t.
  • the mixtutre was quenched with water, then diluted with Et 2 0.
  • the organic layer was then washed with H 2 O, brine, dried over MgSO , filtered then evaporated.
  • the residu was purified by a flash chromatography (5%AcOEt/ Hex) (4.40g, 78%).
  • Step 2 l,l-Diethyl-7-methoxy-3,4-dihydro-l//-naphthalen-2-one oxi e (B)
  • Step 3 7,7-Diethyl-5-methoxy-la,2,7,7a-tetrahydro-l/7-l-aza- cyclopropa [b] naphthalene (C)
  • Step 4 7,7-Diethyl-la ⁇ ,7,7a-tetrahydro-l /-l-aza-cyclopropa[6]naphthalen-5-oI (D)
  • Step 5 5-terf-Butoxycarbonyloxy-7,7-diethyI-la,2,7,7a-tetrahydro-l-aza- cyclopropa[6]naphthalene-l-carboxylic acid tert-butyl ester (D)
  • the residu was purified by a flash chromatography ( 5% to 25% AcOEt/Hex) (2.44g, 84%).
  • Step 6 Thioacetic acid S-(trans-3-tert-butoxycarbonylamino-6-tert- butoxycarbonyloxy-4,4-diethyl-l,2,3,4-tetrahydro-naphthalen-2-yl) ester (E)
  • Step 7 Carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyI-trans-6-mercapto- 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (F)
  • Step 8 Carbonic acid 7-tert-butoxycarbonylamino-8,8-diethyl-trans-6- methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (G)
  • Step 9 ( ⁇ )-Trans-l,l-diethyl-7-hydroxy-3-methylsulfanyl-l,2,3,4-tetrahydro- naphthalen-trans-2-yl-ammonium; chloride (compound #3)
  • Step 1 7-Methoxy-l,l-dimethyi-3,4-dihydro-lH-naphthalen-2-one oxime (A)
  • Step 2 5-Methoxy-7,7-dimethylmethyl-la,2,7,7a-tetrahydro-l -l-aza- cy clopropa [b] naphthalene(B)
  • LiAlH (IM in THF ,1.431, 1.43 mol) was added dropwise to a solution of diethylamine (108 ml, 1.05 mol) and 7-Methoxy-lJ-dimethyl-3 ,4-dihydro- lH-naphthalen-2-one oxime ( 112.6g, 0.51 mol) in THF (700ml) at 0-8°C.
  • the reaction mixture was brought to reflux and refluxed for lh.
  • An excess of LiAlH 4 was quenched with water solids were filtered off and washed with 25% MeOH in acetone followed by 5% aq ammonia in MeOH .
  • the mother liquid was purified by flash chromatography using hexane/ethyl acetate (1/1) followed by ethyl acetate to give lOg (10%) of the target compound.
  • Step 3 7-Methoxy-l,l-dimethyl-3-phenylsulfanyl-l,2,3 » 4-tetrahydro-naphthalen- trans-2-yl-amine(C)
  • Step 1 (-)-Trans-[Carbonic acid 2-(S)-isopropyl-5-(R)-methyl-cyclohex-(R)-yl ester 7- (R)-(2-(S)-isopropyl-5-(R)-methyl-cycIohex-(R)-yloxycarbonyl-(R)-amino)-8,8- dimethyl-6-methylsulfanyI-5,6,7,8-tetrahydronaphthalen-2-yl ester].
  • Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (0J50g, 0.6 mmoles), was dissolved in 30 ml of dichloromethane at 0°C.
  • pyridine (0.240ml, 3mmoles)
  • (L)-(-)-menthyl chloroformate (0.320ml, 1.5 mmoles) were added.
  • the mixture was allowed to reach room temperature and it was further stirred for 2 hours.Aqueous sodium bicarbonate was added and stirred for 20 minutes. Organic phase was separated and aqueous layer was extracted with three portions of dichloromethane.
  • Step 2 (-)-Trans-7-Hydroxy-l,l-dimethyl-3-methylsulfanyl-l ⁇ ,3 » 4-tetrahydro- naphthalen-2-yl)-carbamic acid 2-isopropyl-5-methylcyclohexyl ester.
  • Step 3 (-)-Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro- naphthalen-2-ol hydrochloride.
  • Affinity for ⁇ opioid receptor was assessed in vitro using radioligand binding assay employing rat brain membrane preparations as described in Schiller et al., Biophys. Res. Commun., 85, pJ322 (1975) incorporated herein by reference.
  • Male Sprague-Dawley rats weighing between 350-450g were sacrificed by inhalation of CO2.
  • the rats were decapitated and the brains minus cerebellum were removed and place in ice-cold saline solution and then homogenized in ice-cold 50 mM Tris buffer pH 7.4 (lOml/brain).
  • the membranes were centrifuged at 14000 rpm for 30 min. at 4°C.
  • the pellets were re- suspended in approximately 6ml/brain of ice-cold Tris buffer 50mM pH 7.4 and stored at - 78°C until ready for use. Protein quantification of the brain homogenate was conducted according to protein assay kit purchased (Bio-Rad).
  • Radioligand 50 ⁇ l, membranes 100 ⁇ l and serially diluted test compound were incubated for 1 hr at room temperature or 22°C. Non specific binding was determined using 500 fold in the presence of tracer and membranes. Free ligand was separated from bound by filtration through Whatman GF/B paper (presoaked in polyethylenimine 1 % aqueous solution) and rinsing with ice-cold 50mM Tris pH 7.4 using a Brandel cell harvester. The filters were dried and radioactivity was counted in a 24 well microplate in the presence of 500 ⁇ l scintillant per well.
  • PBQ phenyl-p-benzoquinone
  • ED50 values dose of compound which induced a 50% reduction in the number of writhes observed compared to the control
  • the PBQ was injected at time intervals of 5, 20 or 30 minutes after intravenous, subcutaneous or oral administration respectively of the compound (or medium, or standard).
  • Aqueous solution of 0.02% PBQ was prepared by dissolving PBQ in 5% ethanol/saline 0.9% solution.
  • mice CD-I Male mice CD-I were weighed and marked on their tail. Tail is placed between two light beams at specific intensity using a Tail Flick Analgesia Meter, Columbus Instrument. Each mouse was tested at specific time points after compound or saline injection and latency period was noted. Cut off latency was settled at 10 seconds. ED 50 value was calculated from results obtained for different doses at 5 minutes for intravenous injection and at 30 minutes for oral and subcutaneous injection using non linear regression analysis of the dose response curve.

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EP99964898A 1998-12-22 1999-12-17 Thioaminotetralin-derivate zur verwendung in der schmerzbehandlung Withdrawn EP1140815A1 (de)

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SE9804493A SE9804493D0 (sv) 1998-12-22 1998-12-22 Novel compounds
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PCT/SE1999/002401 WO2000037438A1 (en) 1998-12-22 1999-12-17 Novel thio-aminotetralin compounds useful in pain management

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US5545755A (en) * 1989-05-31 1996-08-13 The Upjohn Company Therapeutically useful 2-aminotetralin derivatives
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