WO2002102387A1 - Treatment of neuropathic pain - Google Patents

Treatment of neuropathic pain Download PDF

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Publication number
WO2002102387A1
WO2002102387A1 PCT/DK2002/000407 DK0200407W WO02102387A1 WO 2002102387 A1 WO2002102387 A1 WO 2002102387A1 DK 0200407 W DK0200407 W DK 0200407W WO 02102387 A1 WO02102387 A1 WO 02102387A1
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Prior art keywords
alkyl
compound
bond
spiro
piperidine
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PCT/DK2002/000407
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French (fr)
Inventor
Connie Sanchez
Ejner Knud Moltzen
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H. Lundbeck A/S
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Publication of WO2002102387A1 publication Critical patent/WO2002102387A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/547—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame spiro-condensed or forming part of bridged ring systems

Definitions

  • R 4 to R 7 are independently selected from hydrogen, halogen, C ⁇ -C 6 alkyl, C ⁇ -C alkoxy, hydroxy, C ⁇ -C 6 alkylthio, C ⁇ -C 6 alkyl- or di(C ⁇ -C 6 )alkylamino, cyano, trifluoromethyl, or trifluoromethylthio; and
  • the present invention relates to the use as above of a compound wherein Z 3 is a bond, and Z 2 is "O" or "S" and Z 1 is CH 2 .
  • the present invention relates the use of such compounds wherein X is O, S or NR 10 wherein R 10 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, adamantyl or C 3 -C 8 cycloalkyl(C ⁇ -C 6 )alkyl, C 3 -C 8 cycloalkenyl or C 3 -C 8 cycloalkenyl(C ⁇ -C 6 )alkyl, C ⁇ -C 6 alkylcarbonyl, phenylcarbonyl, amino(C ⁇ -C 6 )alkyl, mono- or di(C ⁇ -C 6 )alkylamino(C ⁇ - C 6 )alkyl, C ⁇ -C 6 alkylsulfonyl,
  • C -8 -cycloalkyl designates a carbocyclic ring having 3-8 carbon, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Halogen means fluoro, chloro, bromo or iodo.
  • each of the dotted lines may or may not represent a bond, i.e. that the ring and the side chain respectively may or may not have a double bond in the positions of the dotted lines, provided that only two at a time indicate a bond and that adjacent dotted lines do not both indicate a bond.
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromo-theophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • the compound is used as the base or the fumarate.
  • the acid addition salts according to the invention may be obtained by treatment of -[4-[l-(4-fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan-l(3 ),4'- piperidine] with the acid in an inert solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and if desired micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process.
  • Precipitation of the salt is preferably carried out in an inert solvent, e.g. an inert polar solvent such as an alcohol (e.g. ethanol, 2-propanol and n-propanol).
  • WO 9924436 describes the hydrochloride of l'-[4-[l-(4-Fluoro ⁇ henyl)-3-indolyl]-l-butyl]- spiro [isobenzofuran- l(3H),4'-piperidine] which is a preferred compound according to the present invention.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
  • the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
  • Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine.
  • adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
  • the compound of the invention is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 ⁇ g/kg to lOmg/kg body weight, preferably 25 ⁇ g/day/kg to 1.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body weight.
  • the formalin pain model is a well-established animal model of persistent somatic pain (Dubuisson, D. and Dennis, S.G. Pain 4, 1977, 161-174 ). It has been described as a model of clinical inflammatory pain (Tj ⁇ lsen, A. and Hole, K., In: Dickenson, A.H. and Besson, J-
  • phase 1 This is follow by inflammatory processes and nerve sensitisation (phase 2).
  • phase 2 The latter phase models the neuropathic pain condition.
  • drugs are active in the model, e.g. morphine and in particular antiepileptic drugs
  • NSAIDs non-steroid antiinflammatory drugs

Abstract

The present invention relates the use of a spiro-piperidine compounds for the preparation of a medicament useful for the treatment of neuropathic pain.

Description

TREATMENT OF NEUROPATHIC PAIN
Field of invention
The present invention relates to the use of certain spiro-piperidine compounds for the preparation of medicaments useful for the treatment of neuropathic pain.
Background of the Invention
Neuropathic pain refers clinically to a group of cronic pain syndromes. They share the common feature that they are caused by an initial nerve damage which subsequently results in an abnormal sensoric processing in the central and peripheral nervous system. Neuropathic pain conditions are the consequence of a number of diseases, e.g. diabetes, AIDS, multiple sclerosis, amputees and cancer. The available analgetic drug do often produce insufficient pain relief. Tricyclic antidepressants and some antiepileptic drugs, e.g. gabapentin, lamotrigine and carbamazepine are efficient in some patients. However, there is still a large unmet need for efficient drugs for the treatment of these conditions.
It has now, surprisingly, been found that certain spiro-piperidines disclosed in WO 92/22554 show a beneficial effect in the treatment of neuropathic pain.
The compounds disclosed in WO 92/22554 are described therein as sigma receptor ligands and are considered useful for the treatment of a range of psychiatric and neurological disorders, including psychosis, movement disorders, such as dystonia and tardive dyskinesia, motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's, ischemia, epilepsy, convulsion, amnesia, senile dementia of the Alzheimer type and anxiety.
No references seem to imply that compounds with effect at sigma receptors would be useful for the treatment of neuropathic pain. Description of the Invention
According to the present invention a medicament for the treatment of neuropathic pain is provided.
More specifically, the present invention relates to the use of a a spiro-piperidine compound having the general formula (I)
Figure imgf000003_0001
(I)
wherein X is CHR10, O, S, SO, SO2 or NR10, R10 being hydrogen, Cι-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, adamantyl or C3-C8 cycloalkyl(Cι-C6)alkyl, C -C8 cycloalkenyl or C3-C8 cycloalkenyl(Cι-C6)alkyl, Cι-C6 alkylcarbonyl, phenylcarbonyl, amino(Cι- C6)alkyl, mono- or di(Cι-C6)alkylamino(Cι-C6)alkyl, Cι-C6 sulfonyl , phenylsulfonyl, or phenyl(Cι-C6)alkyl or phenyl optionally substituted with one or more substituents independently selected from the following: halogen, Cι-C6 alkyl, C]-C6 alkoxy, hydroxy, trifluoromethyl, and cyano, or R10 is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2- oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
one or two of the dotted lines may be a bond; when the dotted line emanating from Y indicates a bond, Y is N or CH; or when said dotted line indicates no bond, Y is CH2, NH, C=O or C=S;
Ra - Rd are independently selected from hydrogen, halogen, Cι-C6 alkyl, Cι-C6 alkoxy, hydroxy, Cι-C6 alkylthio, Cι-C6 alkylsulphonyl, Cι-C6 alkyl- or di(Cι-C6)alkylamino, cyano, trifluoromethyl, or trifiuoromethylthio; U is CH2, O or S; or when, one of the dotted lines emanating from U indicates a bond, U is
CH; the bond between Q1 or Q2, respectively, and U may also be a triple bond and in such case U is "C";
Q1 is selected from a bond, alkylene or alkenylene and Q2 is alkylene having at least two C- atoms, alkenylene or a group Q3D wherein Q3 is alkylene having at least two C-atoms, or alkenylene and D is CR8R9 where R8 and R9 are independently selected from the substituents defined below for R4 - R7, Q1 and Q2 having together from 2 to 20 carbon atoms and being optionally substituted with one or more hydroxy groups, any such hydroxy group being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive; and
9
R and R are independently hydrogen, C]-C6 alkyl or they may be linked together thereby forming an ethylene or propylene bridge;
R4 to R7 are independently selected from hydrogen, halogen, Cι-C6 alkyl, Cι-C alkoxy, hydroxy, Cι-C6 alkylthio, Cι-C6 alkyl- or di(Cι-C6)alkylamino, cyano, trifluoromethyl, or trifluoromethylthio; and
Z1 is CH2, O or S;
9 ι
Z and Z are independently a bond, CH2, O or S, with the proviso that Z may not be S or O when Z is S or O, and that Z and Z may not both be a bond; or Z1 and Z2 may together represent a group -CH=CH-;
•] 1 9 or when Z is a bond, Z and Z may together represent a 3-membered divalent group containing one O- or S-heteroatom; or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of neuropathic pain.
In particular the present invention relates to the use as above of a compound wherein at least one of Z1, Z2 and Z3 designates O or S.
In one embodiment the present invention relates to the use as above of a compound wherein Z3 is a bond, and Z2 is "O" or "S" and Z1 is CH2. In particular, the present invention relates the use of such compounds wherein X is O, S or NR10 wherein R10 is Cι-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, adamantyl or C3-C8 cycloalkyl(Cι-C6)alkyl, C3-C8 cycloalkenyl or C3-C8 cycloalkenyl(Cι-C6)alkyl, Cι-C6 alkylcarbonyl, phenylcarbonyl, amino(Cι-C6)alkyl, mono- or di(Cι-C6)alkylamino(Cι- C6)alkyl, Cι-C6 alkylsulfonyl, phenylsulfonyl, or phenyl(Cι-C6)alkyl or optionally substituted phenyl.
In particular, the present invention relates to the use of such compounds wherein Y is CH and the dotted line emanating from Y indicates a bond.
In another embodiment, the present invention relates to the use as above of a compound wherein X is O.
In a further embodiment, the present invention relates to the use as above of a compound wherein X is NR10 wherein R10 is optionally substituted phenyl.
In a specific embodiment, the present invention relates to the use of a compound selected from the following: 1 '-[2-(5-Fluorobenzofuran-3-ylmethyloxy)-l -ethyl]spiro[isobenzofuran-l(3H),4'- piperidine], and -[4-[l-(4-Fluorophenyl)-3-indolyl]-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], or or a pharmaceutically acceptable salt thereof .
The terms Cι-6-alkyl, Cι-6-alkoxy, Cι-6-alkylthio, etc. designate such branched or unbranched groups having from one to six carbon atoms. Exemplary of such groups are methyl, ethyl, 1- propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l-propyl, methoxy, ethoxy,l- propoxy, 2-propoxy, methylthio, ethylthio, 1-propylthio, 2-propylthio, methylsulphonyl, ethylsulphonyl, or the like.
The term C -8-cycloalkyl designates a carbocyclic ring having 3-8 carbon, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Halogen means fluoro, chloro, bromo or iodo.
The term "one or two of the dotted lines may be a bond" is intended to mean that each of the dotted lines may or may not represent a bond, i.e. that the ring and the side chain respectively may or may not have a double bond in the positions of the dotted lines, provided that only two at a time indicate a bond and that adjacent dotted lines do not both indicate a bond.
The compounds which may be used according to the present invention may be prepared as described in WO 92/22554.
The above application specifically describes the preparation of the following compounds which may be useful according to the present invention: -[4-(3-Indolyl)-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], r-[4-(3-Indolyl)-l-butyl]-spiro[lH-2-benzopyran-4(3H),4'-piperidine], 1 '-[5-(3-Indolyl)- 1 -pentyl]-spiro[ lH-2-benzopyran-4(3H),4'-piperidine],
1 '-[6-(3-Indolyl)- 1 -hexyl]-spiro[ lH-2-benzopyran-4(3H),4'-piperidine], l'-[4-(5,6-Dichloro-3-indolyl)-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], 1 '-[4-(5 -Fluoro-3 -indolyl)- 1 -butyl] -spiro[isobenzofuran- 1 (3H),4'-piperidine] , 1 '-[4-( 1 -Methyl-3 -indolyl)- 1 -butyl]-spiro [isobenzofuran- 1 (3H),4'-piperidine] , 6-Fluoro-l'-(4-(3 -indolyl)- l-butyl)spiro[isobenzofuran-l(3H),4'-piperidine], -[4-[l-(4-Fluorophenyl)-3-indolyl]-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], 1 ,4-Dihydro- 1 '-[4-[ 1 -(4-Fluorophenyl)-3 -indolyl] - 1 -butyl] spiro [3H-2-benzopyran-3 ,4'- piperidine],
1 '- [4- [ 1 -(3 -Thienyl)-3 -indolyl] - 1 -butyl] spiro [isobenzofuran- 1 (3H),4'-piperidine] , l'-[4- [ 1 -(2-Thienyl)-3 -indolyl] - 1 -butyl] spiro[isobenzofuran- 1 (3H),4'-piperidine] , -[4-[l-(3-Furanyl)-3-indolyl]-l-butyl]spiro[isobenzofuran-l(3H),4,-piperidine], -[4-[l-(4-Pyridyl)-3-indolyl]-l-butyl]spiro[isobenzofuran-l(3H),4'-piperidine], -(4-(l-Methanesulfonyl-3-indolyl)-l-butyl)spiro[isobenzofuran-l(3H),4'-piperidine], -(4-(l-p-Toluenesulfonyl-3-indolyl)-l-butyl)spiro[isobenzofuran-l(3H),4'-piperidine], 6-Fluoro-l '-(4-(l-(2-thienyl)sulfonyl-3-indolyl)-l-butyl)spiro[isobenzofuran-l(3H),4'- piperidine],
1 ' -(4-( 1 - Acetyl-3 -indolyl)- 1 -butyl)spiro[isobenzofuran- 1 (3H),4 ' -piperidine] , r-[3-[l-(4-Fluorophenyl)-3-indolyloxy]-l-propyl]spiro[isobenzofuran-l(3H),4'-piperidine], -[3-[6-Chloro-l-(4-fluorophenyl)-3-indolyloxy]-l-propyl]spiro[isobenzofuran-l(3H),4'- piperidine], r-[3-[5-Chloro-l-(4-fluorophenyl)-3-indolyloxy]-l-propyl]spiro[isobenzofuran-l(3H),4'- piperidine],
1 '-[4- [ 1 -(4-Fluorophenyl)-3 -indolyl] - 1 -butyl] spiro [ lH-2-benzopyran-4(3H)>4'-piρeridine] } l'-[4-[5-Fluoro-l-(4-fluorophenyl)-3-indolyl]-l-butyl]spiro[isobenzofuran-l(3H),4'- piperidine],
1 '-[4-[ 1 -(4-Fluorophenyl)-3-indolyl]- 1 -butyl]spiro[benzo[c]thiophene-l (3H),4'-piperidine],
8'-[4-[l-(4-Fluorophenyl)-3-indolyl]-l-butylspiro[isobenzofuran-l(3H),3'-8- azabicyclo[3,2,l]octane], 6-Fluoro- 1 '-[4-[ 1 -(4-fluorophenyl)-3-indolyl]- 1 -butyl]spiro[isobenzofuran- 1 (3H),4'- piperidine], l'-[4-[l-(4-Fluorophenyl)-3-indolyl]-l-butyl]-6-isopropylspiro[isobenzofuran-l(3H),4'- piperidine],
7-Fluoro- 1 '-[4-[ 1 -(4-fluorophenyl)-3-indolyl]- 1 -butyl]spiro[isobenzofuran- 1 (3H),4'- piperidine],
1 '-[4-[ 1 -(4-Fluorophenyl)-3 -indolyl] - 1 -butyl] -5 -methylspiro [isobenzofuran- 1 (3H),4'- piperidine],
1 '. [4-[ l -(4-Methylphenyl)-3 -indolyl] - 1 -butyl] spiro [ 1 H-2-benzoρyran-4(3H),4'-piperidine] , -[4-[5-Fluoro-l-(3-thienyl)-3-indolyl]-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], 1 '- [4- [ 1 -(3 -Pyridinyl)-3 -indolyl] - 1 -butyl] spiro [ lH-2-benzopyran-4(3H),4'-piperidine] ,
1 '-[4-( 1 -(2-Thiazolyl)-3-indolyl)- 1 -butyl] spiro [isobenzofuran- 1 (3H),4'-piperidine] ,
6-Trifluoromethyl- -[4-[l-(4-fluorophenyl)-3-indolyl]-l-butyl]spiro[isobenzofuran- l(3H),4'-piperidine],
4-Fluoro-l'-[4-[l-(4-fluorophenyl)-3-indolyl]-l-butyl]spiro[isobenzofuran-l(3H),4'- piperidine],
2,3 -Dihydro- 1 ' -[4-[ 1 -(4-fluorophenyl)-3 -indolyl]- 1 -butyl] spiro [4H- 1 -benzopyran-4,4 ' - piperidine], 6-Fluoro- -[4-[5-fluoro-l-(4-fluorophenyl)-3-indolyl]-l-butyl]spiro[isobenzofuran-l(H),4'- piperidine],
1 ' -(4-(Benzo[b] thiophen-3 -yl)- 1 -butyl)spiro[isobenzofuran- 1 (3H),4 ' -piperidine] ,. l,4-Dihydro-r-(4-(benzo[b]thiophen-3-yl)-l-butyl)spiro[3H-2-benzopyran-3,4'-piperidine], r-(4-(5-Methylbenzo[b]thiophen-3-yl)-l-butyl)spiro[isobenzofuran-l(3H),4'-piperidine], -[3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-l-propyl]spiro[isobenzofuran-l(3H),4'- piperidine], -[4-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-l-butyl]-spiro[isobenzofuran-l(3H),4'- piperidine], -[4-(2,3-Dihydro-3-indolyl)-l-butyl]spiro[l,3-benzodioxole-2,4'-piperidine], -[4-(2,3-Dihydro-3-indolyl)-l-butyl]spiro[isobenzofuran-l(3H),4'-piperidine], -[4-(2,3-Dihydro-3-indolyl)-l-butyl]spiro[lH-2-benzopyran-4(3H),4'-piperidine], -[2-[5-Chloro-l-(4-fluorophenyl)-3-indolyloxy]-l-ethyl]spiro[isobenzofuran-l(3H),4'- piperidine], r-[3-(5-Fluorobenzofuran-3-yl)-l-propyl]spiro[isobenzofuran-l(3H),4'-piperidine], -[4-(5-Fluorobenzofuran-3-yl)-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine], l'-[4-[l-(4-Fluorophenyl)-5-trifluoromethylindazol-3-yl]-l-butyl]spiro[isobenzofuran- l(3H),4'-piperidine],
1 '- [4-(5 -Trifluoromethylindazol-3-yl)- 1 -butyl]-spiro [isobenzofuran- 1 (3H),4'-piperidine] , 1 ' -(4-( 1 ,2-Benzisoxazol-3 -yl)- 1 -butyl)spiro[isobenzofuran- 1 (3H),4' -piperidine] , l-(4-(l,2-Benzisoxazol-3-yl)-l-butyl)spiro[3H-2-benzopyran-3,4'-piperidine],
1 ' -(3 -( 1 ,2-Benzisoxazol-3 -yl)- 1 -propyl)spiro[isobenzofuran- 1 (3H),4 ' -piperidine] , -(4-(l,2-Benzisothiazol-3-yl)-l-butyl)spiro[isobenzofuran-l(3H),4'-piperidine], l'-[4-(3-Indolyl)-l-butyl]-spiro[l,3-benzodioxole-2,4'-piperidine], -(4-(lH-Inden-3-yl)-l-butyl)-spiro[isobenzofuran-l(3H),4'-piperidine],
1 '-[4-(Indan- 1 -yl)- 1 -butyl] -spiro [isobenzofuran- 1 (3H),4'-piperidine] ,
1 '-[4-(l -Indanyl)-but-3-en- 1 -yl]-spiro[isobenzofuran- 1 (3H),4'-piperidine] , l '-(4-(2,3-Dihydro-l-(4-fluorophenyl)-3-indolyl)-l-butyl)spiro[isobenzofuran-l(3H),4'- piperidine], r-[3-(Benzo[b]thiophen-3-ylthio)-l-propyl]spiro[isobenzofuran-l(3H),4'-piperidine], -[3-(Benzo[b]thiophen-3-ylthio)-l-propyl]spiro[3H-2-benzopyran-3,4'-piperidine], 1 ' - [4-(2,3 -Dihydro-benzo [b] thiophen-3-yliden)- 1 -butyl] spiro [isobenzofuran- 1 (5H),4 ' - piperidine] -S.S-dioxide, -[4-(2,3-Dihydro-benzo[b]thiophen-3-yl)-l-butyl]spiro[isobenzofuran-l(-?H),4'- piperidine]-1S',5'-dioxide, 1 ' - [3 -(Benzo[b]thiophen-3 -yloxy)- 1 -propyl] spiro[isobenzofuran- 1 (3H), ' -piperidine] , r-[2-(Benzo[b]thiophen-3-ylmethyloxy)-l-ethyl]spiro[isobenzofuran-l(5H),4'-piperidine], 1 '- [2-(5 -Fluorobenzofuran-3 -ylmethyloxy)- 1 -ethyl] spiro[isobenzofuran- 1 (3H),4 ' - piperidine],
1 '- [2-(Benzofuran-3 -ylmethyloxy)- 1 -ethyl] -4-fluorospiro[isobenzofuran- 1 (3H),4 ' - piperidine] and
1 '-[4-(l -(2-Dimethylamino- l-ethyl)-3 -indolyl)- 1 -butyl] spiro [isobenzofuran- 1 (3H),4'- piperidine].
According to the invention the compounds of formula (I) may be used as the base of the compound or as a pharmaceutically acceptable acid addition salt thereof or as an anhydrate or hydrate of such salt. The salts of the compound used in the invention are salts formed with non-toxic organic or inorganic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Preferably the compound is used as the base or the fumarate.
The acid addition salts according to the invention may be obtained by treatment of -[4-[l-(4-fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzo-furan-l(3 ),4'- piperidine] with the acid in an inert solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and if desired micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process. Precipitation of the salt is preferably carried out in an inert solvent, e.g. an inert polar solvent such as an alcohol (e.g. ethanol, 2-propanol and n-propanol).
WO 9924436 describes the hydrochloride of l'-[4-[l-(4-Fluoroρhenyl)-3-indolyl]-l-butyl]- spiro [isobenzofuran- l(3H),4'-piperidine] which is a preferred compound according to the present invention.
According to the invention, the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be administered in any suitable way e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule or in the form of a suspension, solution or dispersion for injection.
Methods for the preparation of solid pharmaceutical preparations are well known in the art. Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive such as colourings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
The compound of the invention is most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 μg/kg to lOmg/kg body weight, preferably 25 μg/day/kg to 1.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body weight.
Pharmacological Tests
The formalin pain model is a well-established animal model of persistent somatic pain (Dubuisson, D. and Dennis, S.G. Pain 4, 1977, 161-174 ). It has been described as a model of clinical inflammatory pain (Tjølsen, A. and Hole, K., In: Dickenson, A.H. and Besson, J-
M.R., Editors, 1997. The Pharmacology of Pain, Springer-Verlag, Berlin, 1-20). Formalin injected subcutaneously in a hind paw produces initially a local stimulation of the nociceptors, this is referred to as phase 1. This is follow by inflammatory processes and nerve sensitisation (phase 2). The latter phase models the neuropathic pain condition. A number of drugs are active in the model, e.g. morphine and in particular antiepileptic drugs
(e.g. gabapentine, lamotrigine, carbamazepine) that have shown beneficial effects in clinical neuropatic states. However, these treatments are accompanied by troublesome side effects.
The non-steroid antiinflammatory drugs (NSAIDs) that are used for treatment of inflammatory processes in tissue and have relatively weak effects on neuropathic pain conditions have weak activity in the formalin model.
Experimental Procedure
Fifty microlitres of 2.5% formalin were administered s.c. into the plantar region of the right hind-paw. Following the injection, the animal was placed into an observation chamber, and its subsequent nociceptive behaviour observed. A mirror behind the observation chamber allowed the experimenter an unobstructed view of the injected paw. Observation of the animal's behaviour was made from 0-5 min (phase 1) and 20-30 min (phase 2) following formalin injection. The total time the animal spent licking, biting or shaking the injected paw was recorded. All animals (n=6-10) received a formalin injection and a s.c. injection of either vehicle or test drug 30 min or 2 h before the formalin test.
Results
In Table 1 below percent inhibition of the pain response in phase 2 is given for various doses of 1 '-[4-[ 1 -(4-Fluorophenyl)-3 -indolyl] -1 -butyl]-spiro[isobenzofuran- 1 (3H),4'-pipe- ridine] :
Figure imgf000011_0001
Figure imgf000012_0001
Table l: *:p< 0.001
The testing of -[4-[l-(4-Fluorophenyl)-3-indolyl]-l-butyl]-spiro[isobenzofuran-l(3H),4'- piperidine] in the formalin pain model showed that the compound potently inhibited the pain response in phase 2, in a dose dependent manner.
The compound, 1 '-[2-(5-Fluorobenzofuran-3-ylmethyloxy)-l-ethyl]spiro[isobenzofuran- 1(-?H),4' -piperidine] also showed potent and dose dependent inhibition of the pain response in phase 2.

Claims

Claims
1. The use of a spiro-piperidine compound having the general formula I
Figure imgf000013_0001
(i)
wherein X is CHR10, O, S, SO, SO2 or NR10, R10 being hydrogen, Cι-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, adamantyl or C3-C8 cycloalkyl(Cι-C6)alkyl, C3-C8 cycloalkenyl or C -C8 cycloalkenyl(Cι-C6)alkyl, Cι-C6 alkylcarbonyl, phenylcarbonyl, amino(Cι- C6)alkyl, mono- or di(Cι-C6)alkylamino(C]-C6)alkyl, Cι-C6 alkylsulfonyl, phenylsulfonyl, or phenyl(Cι-C6)alkyl or phenyl optionally substituted with one or more substituents independently selected from the following: halogen, Cι-C6 alkyl, Cι-C6 alkoxy, hydroxy, trifluoromethyl, and cyano, or R10 is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2- oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
one or two of the dotted lines may be a bond; when the dotted line emanating from Y indicates a bond, Y is N or CH; or when said dotted line indicates no bond, Y is CH2, NH, C=O or C=S;
Ra - Rd are independently selected from hydrogen, halogen, C]-C6 alkyl, Cι-C6 alkoxy, hydroxy, Cι-C6 alkylthio, Cι-C6 alkylsulphonyl, Cι-C6 alkyl- or di(C]-C6)alkylamino, cyano, trifluoromethyl, or trifluoromethylthio;
U is CH2, O or S; or when, one of the dotted lines emanating from U indicates a bond, U is CH; the bond between Q1 or Q2, respectively, and U may also be a triple bond and in such case U is "C"; I • 9
Q is selected from a bond, alkylene or alkenylene and Q is alkylene having at least two C- atoms, alkenylene, or a group Q3 D wherein Q3 is alkylene having at least two C-atoms, or alkenylene and D is CR R9 where R8 and R9 are independently selected from the substituents defined below for R4 - R7 , Q1 and Q2 having together from 2 to 20 carbon atoms and being optionally substituted with one or more hydroxy groups, any such hydroxy group being optionally esterified with an aliphatic carboxylic acid having from two to twentyfour carbon atoms inclusive; and
R2 and R3 are independently hydrogen, -C6 alkyl or they may be linked together thereby forming an ethylene or propylene bridge;
R4 to R7 are independently selected from hydrogen, halogen, Cι-C6 alkyl, Cι-C6 alkoxy, hydroxy, Cι-C6 alkylthio, Cι-C6 alkyl- or di(Cι-C6)alkylamino, cyano, trifluoromethyl, or trifluoromethylthio; and
Z1 is CH2, O or S;
Z2 and Z3 are independently a bond, CH2, O or S, with the proviso that Z1 may not be S or O when Z2 is S or O, and that Z2 and Z3 may not both be a bond; or Z1 and Z2 may together represent a group -CH=CH-; or when Z3 is a bond, Z1 and Z2 may together represent a 3-membered divalent group containing one O- or S-heteroatom, or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of neuropathic pain.
2. The use according to Claim 1, characterized in, that the compound of the general
1 9 " Formula I used is a compound wherein at least one of Z , Z and Z designates O or S.
3. The use according to Claim 2, characterized in, that the compound of the general Formula I used is a compound wherein Z is a bond, and Z is O or S and Z is CH2.
4. The use according to Claim 3, characterized in, that the compound of general Formula I used is a compound wherein X is O, S or NR10 wherein R10 is Cι-C6 alkyl, C2-C6 alkenyl,
C3-C8 cycloalkyl, adamantyl or C3-C8 cycloalkyl(Cι-C6)alkyl, C3-C8 cycloalkenyl or C3-C8 cycloalkenyl(Cι-C6)alkyl, C]-C6 alkylcarbonyl, phenylcarbonyl, amino(Cι-C6)alkyl, mono- or di(Cι-C6)alkylamino(Cι-C6)alkyl, Cι-C6 alkylsulfonyl, phenylsulfonyl, or phenyl(Cι- C6)alkyl or optionally substituted phenyl.
5. The use according to Claim 4, characterized in, that the compound of general Formula I used is a compound wherein Y is CH and the dotted line emanating from Y indicates a bond.
6. The use according to Claims 3-4, characterized in, that the compound of general Formula I used is a compound wherein X is O.
7. The use according to Claims 3-4, characterized in, that the compound of general Formula I wherein or NR10 wherein R10 is optionally substituted phenyl.
8. The use according to Claim 1, characterized in, that the compound of the general Formula I used is selected from the following: -[2-(5-Fluorobenzofuran-3-ylmethyloxy)-l-ethyl]spiro[isobenzofuran-l(-?H),4'- piperidine], and
1 '-[4-[ 1 -(4-Fluorophenyl)-3-indolyl]- 1 -butyl]-spiro[isobenzofuran- 1 (3H),4'-piperidine], or or a pharmaceutically acceptable salt thereof .
9. The use according to Claim 8, characterised in, that the compound used is l'-[4-[l-(4 Fluorophenyl)-3-indolyl]-l-butyl]-spiro[isobenzofuran-l(3H),4'-piperidine] hydrochloride.
10. A method for the treatment of neuropathic pain comprising administering to an individual in need thereof a pharmaceutically acceptable amount of a compound of formula I or a pharmaceutically acceptable salt thereof
PCT/DK2002/000407 2001-06-18 2002-06-18 Treatment of neuropathic pain WO2002102387A1 (en)

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