[go: up one dir, main page]

NZ541999A - Substituted indoline and indole derivatives - Google Patents

Substituted indoline and indole derivatives

Info

Publication number
NZ541999A
NZ541999A NZ541999A NZ54199904A NZ541999A NZ 541999 A NZ541999 A NZ 541999A NZ 541999 A NZ541999 A NZ 541999A NZ 54199904 A NZ54199904 A NZ 54199904A NZ 541999 A NZ541999 A NZ 541999A
Authority
NZ
New Zealand
Prior art keywords
indol
dihydro
ylmethyl
alk
chlorothiophen
Prior art date
Application number
NZ541999A
Inventor
Nikolay Khanzhin
Mario Rottlander
William Patrick Watson
Original Assignee
Lundbeck & Co As H
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 Lundbeck & Co As H filed Critical Lundbeck & Co As H
Priority claimed from PCT/DK2004/000283 external-priority patent/WO2004096767A1/en
Publication of NZ541999A publication Critical patent/NZ541999A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic 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
    • C07D403/06—Heterocyclic 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 only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Disclosed are compounds of formula (I), wherein the substituents are as defined in the specification. The compounds are useful for the prevention, treatment and inhibition of disorders and diseases being responsive to opening of the KCNQ family of potassium ion channels, such as epilepsy.

Description

New Zealand Paient Spedficaiion for Paient Number 541 999 *10056937231* 1 Substituted indoline and indole derivatives Field of the invention The present invention relates to novel substituted indole and indoline derivatives 5 being openers of the KCNQ family potassium ion channels. The compounds are useful for the prevention, treatment and inhibition of disorders and diseases being responsive to opening of the KCNQ family potassium ion channels, one such disease is epilepsy.
Background of the invention Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride and sodium into and out of cells. Such channels are present in all animal and human cells and affect a variety of processes including neuronal transmission, muscle contraction, and cellular secretion.
Humans have over 70 genes encoding potassium channel subtypes (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30) with a great diversity with regard to both stucture and function. Neuronal potassium channels, which are found in the brain, are primarily responsible for maintaining a negative resting membrane potential, as well 20 as controlling membrane repolarisation following an action potential.
One subset of potassium channel genes is the KCNQ family. Mutations in four out of five KCNQ genes have been shown to underlie diseases including cardiac arrhythmias, deafness and epilepsy (Jentsch Nature Reviews Neuroscience 2000, 1, 25 21-30).
The KCNQ4 gene is thought to encode the molecular correlate of a potassium channel found in outer hair cells of the cochlea and in Type I hair cells of the vestibular apparatus, in which, mutations can lead to a form of inherited deafness.
KCNQ1 (KvLQTl) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-lilce K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome WO 2004/096767 PCT/DK2004/000283 2 type 1 (LQT1), as well as being associated with a form of deafness (Robbins Pharmacol Titer 2001, 90, 1-19).
The genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to be mutated in 5 an inherited form of epilepsy known as benign familial neonatal convulsions (Rogawski Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localised in the pyramidal neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (Cooper et al. Proceedings National Academy of Science USA 2000, 97, 10 4914-4919).
KCNQ2 and KCNQ3 are two potassium channel subunits that form "M-currents" when expressed in vitro. The M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane 15 excitability by being the only sustained current in the range of action potential initiation (Marrion Annual Review Physiology 1997, 59, 483-504). Modulation of the M-current has dramatic effects on neuronal excitability, for example activation of the current will reduce neuronal excitability. Openers of these KCNQ channels, or activators of the M-current, will reduce excessive neuronal activity and may thus be 20 of use in the treatment, prevention or inhibition of seizures and other diseases and disorders characterised by excessive neuronal activity, such as neuronal hyperexcitability including convulsive disorders, epilepsy and neuropathic pain.
Retigabine (D-23129; N-(2-amino-4-(4-fluorobenzylamino)-plienyl) carbamic acid 25 ethyl ester) and analogues thereof are disclosed in EP554543. Retigabine is an anticonvulsive compound with a broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. It is active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests including: electrically induced seizures, seizures induced chemically by pentylenetetrazol, picrotoxin and N-methyl-30 D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse (Rostock et al. Epilepsy Research 1996, 23, 211-223). In addition, retigabine is active in the amygdala kindling model of complex partial seizures, further indicating that this compound has potential for anti-convulsive therapy. In clinical trials, retigabine has WO 2004/096767 PCT/DK2004/000283 3 recently shown effectiveness in reducing the incidence of seizures in epileptic patients (Bialer et al. Epilepsy Research 2002, 51, 31-71).
Retigabine has been shown to activate a K(+) current in neuronal cells and the 5 pharmacology of this induced current displays concordance with the published pharmacology of the M-channel, which recently was correlated to the KCNQ2/3 K(+) channel heteromultimer. This suggests that activation of KCNQ2/3 channels may be responsible for some of the anticonvulsant activity of this agent (Wickenden et al. Molecular Pharmacology 2000, 58, 591-600) - and that other agents working by the l o same mechanism may have similar uses.
KCNQ 2 and 3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden et al. Society for Neuroscience Abstracts 2002,454.7), and potassium channel modulators have been hypothesised to be active in both 15 neuropathic pain and epilepsy (Schroder et al. Neuropharmacology 2001, 40, 888-898).
Retigabine has also been shown to be beneficial in animal models of neuropathic pain (Blaclcburn-Munro and Jensen European Journal of Pharmacology 2003, 460, 109-20 116), and it is thus suggested that openers of KCNQ channels will be of use in treating pain disorders including neuropathic pain.
The localisation of KCNQ channel mRNA is reported in brain and other central nervous system areas associated with pain (Goldstein et al. Society for Neuroscience 25 Abstracts 2003, 53.8).
In addition to a role in neuropathic pain, the expression of mRNA for KCNQ 2-5 in the trigeminal and dorsal root ganglia and in the trigeminal nucleus caudalis implies that openers of these channels may also affect the sensory processing of migraine pain 30 (Goldstein et al. Society for Neuroscience Abstracts 2003, 53.8).
Recent reports demonstrate that mRNA for KCNQ 3 and 5, in addition to that for KCNQ2, are expressed in astrocytes and glial cells. Thus KCNQ 2, 3 and 5 channels 4 may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda et al., Society fen-Neuroscience Abstracts 2003, 53.9).
Retigabine and other KCNQ modulators may thus exhibit protection against the neurodegenerative aspects of epilepsy, as retigabine has been shown to prevent limbic neurodegeneration and the expression of markers of apoptosis following kainic acid-induced status epilepticus in the rat (Ebert et al. Epilepsia 2002, 43 Suppl 5, 86-95). This may have relevance for preventing the progression of epilepsy in patients, i.e. be anti-epileptogenic. Retigabine has also been shown to delay the progression of hippocampal kindling in the rat, a further model of epilepsy development (Tober et al. European Journal Of Pharmacology 1996, 303, 163-169).
It is thus suggested that these properties of retigabine and other KCNQ modulators may prevent neuronal damage induced by excessive neuronal activation, and may be of use in the treatment of neurodegenerative diseases, and be disease modifying (or antiepileptogenic) in patients with epilepsy.
Given that anticonvulsant compounds such as benzodiazepines and chlormethiazole are used clincially in the treatment of the ethanol withdrawal syndrome and that other anticonvulsant compounds e.g. gabapentin, are very effective in animal models of this syndrome (Watson et al. Neuropharmacology 1997, 36,1369-1375), other anticonvulsant compounds such as KCNQ openers are thus expected to be effective in this condition. mRNA for KCNQ 2 and 3 subunits are found in brain regions associated with anxiety and emotional behaviours such as bipolar disorder e.g. hippocampus and amygdala (Saganich et al. Journal of Neuroscience 2001, 21, 4609-4624), and retigabine is reportedly active in some animal models of anxiety-like behaviour (Hartz et al. Journal of Psychopharmacology 2003, 17 suppl 3, A28,B16), and other clinically used anticonvulsant compounds are used in the treatment of bipolar disorder.
WO 200196540 discloses the use of modulators of the M-current formed by expression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526 discloses that modulators of KCNQ5 can be utilized for the treatment of sleep disorders.
W001/022953 describes the use of retigabine for prophylaxis and treatment of neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy and neuropathic pain related to migraine.
W002/049628 describes the use of retigabine for the prevention, treatment, inhibition and amelioration of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific 15 phobias.
W097/15300 describes the use of retigabine for the treatment of neurodegenerative disorders such as Alzheimer's disease; Huntington's chorea; sclerosis such as multiple sclerosisand amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; Parkinson's 20 disease; encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens; trauma-induced neurodegenerations; neuronal hyperexcitation states such as in medicament withdrawal or intoxication; and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritides.
Hence, there is a great desire for novel compounds, which are potent openers of the KCNQ family potassium channels.
Also desired are novel compounds with improved properties relative to known 30 compounds, which are openers of the KCNQ family potassium channels, such as retigabine. Improvement of one or more of the following parameters is desired: half-life, clearance, selectivity, interactions with other medications, bioavailability, potency, formulability, chemical stability, metabolic stability, membrane permeability, solubility and therapeutic index. The improvement of such parameters may lead to improvements such as: • an improved dosing regime by reducing the number of required doses a day, • ease of administration to patients on multiple medications, • reduced side effects, • enlarged therapeutic index, • improved tolerability or • improved compliance.
Summary of the invention One object of the present invention is to provide novel compounds, which are potent openers of the KCNQ family potassium channels, or at least to provide the public with a useful choice.
The compounds of the invention are substituted indoline and indole derivatives of the general formula I or salts thereof wherein the dotted line, q, s, U, Y, X, Z, R1, R1, R2 and R3 are as defined below.
(U)s (I) INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 7 The invention further relates to a pharmaceutical composition comprising a compound of formula I, as defined below and one or more pharmaceutically acceptable carriers or diluents.
The invention also provides a use of a compound of the invention in the manufacture of a medicament for increasing ion flow in a potassium channel of a mammal such as In another aspect the invention provides a use of a compound of the invention in the 10 manufacture of a medicament for the prevention, treatment or inhibition of a disorder or condition that is responsive to an increased ion flow in a potassium channel.
In another embodiment the disorder or disease is selected from the group consisting of seizure disorders such as convulsions, epilepsy and status epilepticus.
In another embodiment said disorder or condition is selected from the group consisting of neuropathic and migraine pain disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy and neuropathic pain related to migraine.
In another embodiment said disorder or condition is selected from the group consisting of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, posttraumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal 25 disorders, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorder due to general medical condition and substance-induced anxiety disorder.
In another embodiment said disorder or condition is selected from the group consisting of neurodegenerative disorders such as Alzheimer's disease, Huntington's 30 chorea, a human. intellectual property OFFICE OF N 2 1 6 DEC 2008 7a multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other infection-related encephalopathies being caused by rubella viruses, herpes viruses, borrelia and by unknown pathogens, Creutzfeld-Jakob disease, Parkinson's disease, trauma-induced neurodegenerations.
In another embodiment said disorder or condition is selected from the group consisting of neuronal hyperexcitation states such as in medicament withdrawal or by intoxication.
The term "comprising" as used in this specification means "consisting at least in part of'. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
Description of the invention Accordingly, the present invention relates to substituted indole and indoline derivatives of the general formula I wherein H {7\ ^ X ^ R3 (I) INTELLECTUAL PROPERTY OFFICE OF N.2. 16 DEC 2008 received 7b the dotted line represents an optional bond; R1 and R1 are independently selected from the group consisting of hydrogen, Cj.6-5 alk(en/yn)yl, C3.g-cycloalk(en)yl, C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci.g-alk(en/yn)yl, hydroxy-C3„8-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-Ci_<;-alk(en/yn)yl, halo-Ci_6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-C i -6-alk(cn/yn)yl, cyano-C3_8-cycloalk(en)yl and cyano-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or 10 R1 and R1 together with the carbon atom to which they are attached form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms; s is 0 or 1; U is O, NR11, S, S02, S02NRn CO-O or CO-NR11; wherein R11 is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3.g-cycloalk(en)yl, C3-8- INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED WO 2004/096767 PCT/DK2004/000283 8 cydoalk(en)yl-Ci_6-alk(en/yn)yl; or R2 and R11 together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1,2 or 3 further heteroatoms; R2 is selected from the group consisting of hydrogen, Ci.6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1 -6-alk(en/yn)yl, Ar, Ar-Ci.6-alk(en/yn)yl, Ar-C3. g-cycloallc(en)yl, Ar-C3.g-cycloalk(en)yl-C 1 -6-alk(en/yn)yl, acyl, hydroxy-Ci.6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, halogen, halo-Ci_6-alk(en/yn)yl, halo-C3-g-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-C 1 ,<5-alk(en/yn)yl, cyano-Cj^-cycloalk(en)yl, cyano-C3.g-cycloalk(en)yl-Ci.6-aIk(en/yn)ylJ -N02, NR10R10-Ci_6-alk(en/yn)yl, NR10R10'-C3.8-cycloalk(en)yl and NR10R10,-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein R10 and R10' are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci.,s-alk(en/yn)yl3 halo-C3_8-cycloalk(en)yl5 halo-C3.s- / cycloalk(en)yl-Ci-6-aEc(en/yn)yl, cyano-Ci.6-alk(en/yn)yl, cyano-C3.g-cycloalk(en)yl and cyano-C3.s-cycloalk(en)yl-Ci.6-alk(en/yn)yl, or R10 and R10' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R2 is N02, halogen or cyano then s is 0; and with the proviso that when R2 is a hydrogen atom or acyl and s is 1 then U is NR11, O or S; wherein the group -(U)s-R2 is linked to position 4 or 6 of the indole or indoline; q is 0 or 1; Zis O or S; X is CO or SO2; with the proviso that q is 0 when X is S02; WO 2004/096767 PCT/DK2004/000283 9 R3 is selected from the group consisting of Ci_6-alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloallc(en)yl, C3-8-cycloalk(en)yl-Ci.c-aIb;(en/yn)yl, Ci-e-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar-Ci_6-aIk(en/yn)yl, Ar-C3-8-cycloallc(en)yl, Ar-het erocycloallc(en)yl, Ar-C3-8-cycloalk(en)yl-C 1-6-allc(en/yn)yl5 Ar-Ci.6-alk(en/yn)yl-C3.g-cycloalk(en)yl5 Ar-Ci-6-allc(en/yn)yl-heterocycloallc(en)yl, Ci.6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3.g-cycloallc(en)yloxy-Ci.6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-C3.g-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-C i -6-allc(e:n/yn)yl, Ar-Ci_6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci _6-alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-a-cycloalk(en)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-<5-alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-heterocycloallc(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-s-alk(en/yn)yl-C3-g-cycloalk(en)yl, hydroxy-C i -6-alk(en/yn)yl-heterocy cloalk(en)yl, h alo-C i alk(en/yn)yl , halo-C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci.6-alk(en/yn)yl, halo-Ci.6-aIk(en/yn)yl-c3.8-cycloalk(en)yl, halo-Ci. s-alk(en/yn)yl-heterocycloalk(en)yl5 halo-C i _6-alk(en/ yn)yl-Ar, halo-C3-8-. cycloalk(en)yl-Ar, halo-c3^-cycloalk(en)yl-Ci.6-alk(en/yn)yl-Ar, halo-Cue-alk.(en/yn)yl-c3 _s-cy cl oalk(en)yl-Ar, cyano-Ci-6-alk(en/yn)yl, cyano-C3_8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-Ci-6-allc(en/yn)yl-heterocycloallc(en)yl, acyl-C].6-alk(en/yn)yl, acyl-C3.s-cycloalk(en)yI, acyl-heterocycloalk(eii)yl, acyl-c3_8-cycloalk(en)yl-C 1 _6-alk(en/yn)yl, acyl-C 1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-Ci.6-alk(en/yn)yl-heterocycloaIk(en)yl and -NR12R12>, optionally substituted NR12R12'-C; .6-aUt(en/yn)yl, optionally substituted NR1 2Rj2'-c3-8-cycloallc(en)yl, optionally substituted NR12R12'-c3^-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein R12 and R12' are independently selected from the group consisting of hydrogen, Ci-s-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci^-alk(en/yn)yl3 Ar, Ar-Ci-e-alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl} Ar-C3.8-cycloallc(en)yl-Ci ^-allc(en/yn)yl, hydroxy-Ci -6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3^-cycloalk(en)yl-Ci_,s-alk(en/yn)yl, halo-Ci-<5-a1k(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-s-cycloall<(en)yl-Ci.6-allc(en/yn)yl, cyano-Ci.6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3.8-cycloallc(en)yl-Ci.6-allc(en/yn)yl, or R12 and R12 together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R is NR R then q is 0; and Y represents a group of formula II, III, V, XXX or XXXI: (R5): W II (R5)f (R5)j N XXX or (R5)* N' XXXI INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 11 wherein the line represents a bond attaching the group represented by Y to the carbon atom; 5 W is O or S; T is N, NH or O; L is N, C or CH; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; f is 0, 1, 2, 3, 4 or 5; j is 0,1, 2 or 3; with the proviso that when T is a nitrogen atom then j is 1, 2 or 3, and 20 one R5 group is attached to T; and when T is NH or an oxygen atom then j is 0, 1 or 2; k is 0, 1, 2, 3 or 4; and each R5 is independently selected from the group consisting of a Ci-6-alk(en/yn)yl, C3. 25 g-cycloalk(en)yl, C3.s-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ar, Ar-C 1 _6-alk(en/yn)yl, Ar- INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 DEC 2008 n r P C I \/ P D 12 thio, Ar-oxy, acyl, Ci-6-aUc(en/yn)yloxy, c3.8-cycloallc(en)yloxy, C3-8-cycloalk(en)yl-cm3-alk(en/yn)yloxy, halogen, halo-Ci-6-alk(en/yn)yl, halo-c3-8-cycloalk(en)yl, halo-c3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, -CO-NR6R6' , cyano, cyano-Ci.s-alk(en/yn)yl, cyano-c3-8-cycloalk(en)yl, cyano-c3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, -NR7R7', -S-R8and-S02R8,or two adjacent R5 together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms; R6 and R6' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl. C3_8-cycloaIk(en)yl, C3-8-cycloalk(en)yl-Ci.(S-aIk;(en/yn)yl and Ar; R7 and R7' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, c3-8-cycloa]k(en)yl-Ci^-alk(en/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C].6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C;,.8-cycloalIc(en)yl-C 1 _6-alIc(enyyn)yl3 Ar and—NR9R9'; wherein R9 and R9' are independently selected from the group consisting of hydrogen, Ci-g-allc(en/yn)yl, C3-8-cycloalk(en)yl and C3-s-cycloalk(eii)yl-Ci.6-alk(en/yn)yl; provided that when R8 is NR9R9' then Rs is not -S-R8; or salts thereof.
A particular embodiment of the invention relates to substituted indole and indoline derivatives of the general formula I 13 the dotted line represents an optional bond; R1 and R1' are independently selected from the group consisting of hydrogen, Ci-6-a1k(en/yn)yl, C3.s-cycloalk(en)yl, C3_8-cycloalk(en)yl-Ci-6-allc(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3.8-cycloalk(en)yl, hydroxy-C3_g-cycloalk(en)yl-C i _g-allc(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3„8-cycloalk(en)yl, halo-C3.8-cycloalk(en)yl-Ci -6-a]k(en/yn)yl, cyano-Ci-g-allc(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-g-cycloalk(en)yl-Ci_6-aUc:(en/yn)yl; or R1 and R1' form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 further heteroatoms; s is 0 or 1; U is O, NR11, S, S02, SOaNR'^CO-O or CO-NR11; wherein Ru is selected from the group consisting of hydrogen, Ci.6-alk(en/yn)yl, C3-s-cycl oalk(en)yl, C3-g-cycloallc(en)yl-Ci-6-alk(en/yn)yl; or R2 and R11 together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; R2 is selected from the group consisting of hydrogen, C1 _6-alk(en/yn)yl, C3.g-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci.6-aIk;(en/yn)yl5 Ar, Ar-C 1.6-alk(en/yn)yl, Ar-C3_ 8-cycloallc(en)yl, Ar-C3-8-cycloalk(en)yl-Ci.(S-alk(en/yn)yl, acyl, hydroxy-Ci_c- in c r c 1 \/ 1- 1 !! 14 alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3_8-cycloalk(en)yl-Ci_6-allc(en/yn)yl, halogen, halo-Ct-6-alk(en/yn)yl, halo-C3 .s-cyclo alk(en)yl, halo-C3-8-cycloaHc(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-C i-6-alk(en/yn)yl, cyan.0-C3.8-cycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, -N02, NR10Rll)-Ci.6-alk(en/yn)yl, NR10R10'-C3-8-cycloalk(en)yl and NR10R10'-C3.s-cycloalk(en)yl-Ci_6-allc(en/yn)yl; wherein R10 and R10' are independently selected from the group consisting of hydrogen, Ci_6-alk(en/yn)yl, C3.K-cycloalk(en)yl, C3.g-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci_6-alk(en/yn)yl, hydroxy-C3_8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C 1 -c,-alk(en7yn)yl, halo-Ci_6-alk(en/yn)yl, halo~C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C 1 ^-alk(en/'yn)yl, cyano-Ci.6-alk(en/yn)yl, cyano-C3_g-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, or R10 and R10' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1,2 or 3 further heteroatoms; with the proviso that when R2 is NO2, halogen or cyano then s is 0; and with the proviso that when R2 is a hydrogen atom or acyl and s is 1 then U is NR11, O or S; wherein the group -(U)s-R2 is linked to position 4 or 6 of the indole or indoline; q is 0 or 1; ZisOorS; X is CO or S02; with the proviso that q is 0 when X is S02; R3 is selected from the group consisting of C1 .e-allc(en/yn)yl, C3„8-cycloalk(en)yl, heterocycloallc(en)yl, C3-8-cycloahc(en)yl-Ci-6-alk(en/yn)yl, Ci.6-alk(en/yn)yl-C3_8-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar-Ci_6-aIk(en/yn)yl, Ar-C3-8-cycloallc(en)yl, Ar-heterocycloalk(en)yl, Ar-C3-8-cycloalk(en)yl-C 1.6-alk(en/yn)yl, Ar-C]_6-alk(en/yn)yl-C3_8-cycloalk(en)yl, Ar-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl; Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3_8-cycloalk(en)yloxy- Ci-6-alk(en/yn)yl? Ci_6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, Ci_6-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-Ci.6-alk(en/yn)yl, Ar-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci„6-alk(en/yn)yloxy-carbonyl-Ci_6-alk(en/yn)yl, C3_g-cycloalk(en)yloxy-carbonyl-Ci_6-alk(en/yn)yl, C3.g-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-carbonyl-Ci.6-5 alk(en/yn)yl, hydroxy-C i-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(cn)yl-C|_6-alk(cn/yn)yl, hydroxy-Ci.g-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy-Ci_6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3.g-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-C|-6-alk(cn/yn)yl-C3_g-cycloalk(en)yl. halo-CV 10 6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-Ar, halo-Cs.g-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-Ci.6-alk(en/yn)yl-Ar, halo-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl-Ar, cyano-Ci_6-alk(en/yn)yl, cyano-C3_8-cycloalk(en)yl, cyanq-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-Ci_6-alk(cn/yn)y 1-15 heterocycloalk(en)yl, acy 1-C i_6-alk(en/'yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yi, acyl-Ci-6-alk(en/yn)yl-C3-8-cyeIoalk(en)yl, acyl-Ci_6-alk(en/yn)yl-heterocycloalk(en)yl and -NRI2R12; wherein R12 and R12' are independently selected from the group consisting of hydrogen, Ci„g-20 alk(en/yn)yl, C3_g-cycloalk(en)yl, C3„g-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar-Ci-6-alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl, Ar-C3-8-cycloaik(en)yl-C i _6-alk(en/yn)yl, hydroxy-Ct-6-alk(en/yn)yl, hydroxy-C3-g-cycloalk(en)yl, hydroxy-C3.g-cycloalk(en)yl-Ci_6-alk(en/yn)yl, halo-Ci_6-alk(en/yn)yl, halo-C3.g-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, cyano-Ci_6-alk(en/yn)yl, cyano-C3-g-cycloalk(en)yl 25 and cyano-C3.g-cycloalk(en)yl-Ci_6-alk(en/yn)yl, or R12 and R12' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R3 is NR12R12 then q is 0; and Y represents a group of formula II, III, or V: intellectual property office of n.z. 16 DEC 2008 RECEIVED 16 (R5)a w II (Rs)f v wherein the line represents a bond attaching the group represented by Y to the carbon atom; W is O or S; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; INTELLECTUAL PROPERTY OFFICE OF N.2. 16 DEC 2008 RECEIVED! 17 f is 0, 1, 2, 3, 4 or 5; each R5 is independently selected from the group consisting of a Ci.6-alk(en/yn)yl, C3. 8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ar, Ar-Ci.6-alk(en/yn)yl, acyl, C1.6-alk(en/yn)yloxy, C3„s-cycloalk(en)yloxy, C3_g-cycloalk(en)yl-C j _6-alk(en/yn)yloxy, halogen, halo-Ci_6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3_g-cycloaIk(en)yl-Ci_6-alk(en/yn)yl, -CO-NR6R6 , cyano, cyano-C i_6-alk(en/yn)yl, cyano-C3.8-cycloalk(en)yl, cyano-C3_8-cycloalk(en)yl-Cj-6-alk(en/yn)yl, -NR7R7 , -S-R8 and -S02R8, or two adjacent Rs together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms; R6 and R6' are independently selected from the group consisting of hydrogen, Cj.6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3.s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; R7 and R7 are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3.)s-cycloalk(cn)yl-C|.6-alk(cn/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, Ar and-NR9R9 ; wherein R9 and R9' are independently selected from the group consisting of hydrogen, C1.6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; provided that when R8 is -NR9R9' then R5 is not -S-R8; or salts thereof.
INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED WO 2004/096767 PCT/DK2004/000283 18 One embodiment of the invention relates to compounds of formula I, wherein the dotted line represents a bond.
Another embodiment of the invention relates to compounds of formula I, wherein the 5 dotted line does not represent a bond.
One further embodiment of the invention relates to compounds of formula I, wherein R1 andR1' are independently selected from the group consisting of hydroxy-Ci-g-10 alk(en/yn)yl, hydroxy-C3.8-cycloalk(en)yl, hydroxy-C3.8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, halo-Ci.6-alk(en/yn)yl, halo-C3.g-cycloalk(en)yl, halo-C3_8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, cyano-Ci.(,-alk(en/yn)yl, cyano-C3-s-cycloalk(en)yl and c}^atio-C3-8-cycloalk(en)yl-Ci_6-allc(en/yn)yl.
Another embodiment of the invention relates to compounds of formula I, wherein R1 andR1' are independently selected from the group consisting of hydrogen, Ci.g-alk(en/yn)yl, C3.s-cycloalk(en)yl and C3^-cycloalk(en)yl-Ci-6-alk(en/yn)yl.
A further embodiment of the invention relates to compounds of formula I, wherein R1 20 and R1' form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms. In a further embodiment the 3-8 membered saturated or unsaturated ring is a saturated carbocyclic ring, typically cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Yet another embodiment of the invention relates to compounds of formula I, wherein R1 and R1' are independently selected from the group consisting of hydrogen and Ci_g-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein 30 at least one of R1 and R1' is Ci-6-alle(en/yn)yl5 typically Ci-3-alk(en/yn)yl.
In a preferred embodiment, the invention relates to compounds of formula I, wherein R1 or R1' is a hydrogen atom.
WO 2004/096767 PCT/DK2004/000283 19 In a preferred embodiment, the invention relates to compounds of formula I, wherein at least one of R1 and R1' is a hydrogen atom.
In a more preferred embodiment, the invention relates to compounds of formula I, 5 wherein both R1 and R1'are hydrogen atoms.
In a preferred embodiment, the invention relates to compounds of formula I, wherein s is 0.
In another preferred embodiment, the invention relates to compounds of formula I, wherein s is 1.
In one embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is O.
In another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is S.
In yet another embodiment, the invention relates to compounds of formula I, wherein 20 s is 1 and U is SO2.
In yet another embodiment, the invention relates to compounds of formula I, wherein sis 1 and U is S02NRn In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is CO-O.
In yet another embodiment, the invention relates to compounds of formula I, wherein sis 1 and U is CO-NR11.
In a preferred embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is NR11.
WO 2004/096767 PCT/DK2004/000283 In yet another embodiment, the invention relates to compounds of formula I, wherein s is 1 and U is SO2NR11, CO-NR11 or NR11 and Rn is a hydrogen atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein 5 s is 1 and U is NR11 and R11 is a hydrogen atom.
One embodiment of the invention relates to compounds of formula I, wherein R2 is selected from the group consisting of acyl, hydroxy-Ci-G-allc(en/yn)yl, hydroxy-C3_g-cycloalk(en)yl, hydroxy-C3.8-cycloalk(en)yl-Ci-s-alk(en/yn)yl, cyano-Ci-6-10 alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3_8-cycloallc(en)yl-Ci-6-alk(en/yn)yl3 NRioRio'_c16_aik(en/yn)yl, NR10R10'-C3_8-cycloa]k(en)yl and NR10R10-C3.8-cycloallc(en)yl-C].6-alk(en/yn)yl; with the proviso that when R2 is acyl and s is 1 then U is NR11, O or S.
Another embodiment of the invention relates to compounds of formula I, wherein R2 is selected from the group consisting of Ci.6-alk(en/yn)yl, C3.g-cycloalk(en)yl and C3. 8-cyclo alk(en)yl-C 1.6-alk(en/yn)yl.
Yet another embodiment of the invention relates to compounds of formula I, wherein 20 R2 is selected from the group consisting of Ar, Ar-Ci-6-alk(en/yn)yl, Ar-C3-g-cycloalk(en)yl and Ar-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl.
Yet another embodiment of the invention relates to compounds of formula I, wherein R2 is selected from the group consisting of halogen, halo-C]-r,-alk(en/yn)yl, halo-C3-8-25 cycloalk(en)yl, halo-C3-g-cycloalk(en)yl-Ci^-alk(en/yn)yl and cyano; with the proviso that when R2 is halogen or cyano then s is 0;.
In a preferred embodiment the invention relates to compounds of formula I, wherein R2 is NO2 or a hydrogen atom; with the proviso that when R2 is NO2 then s is 0; and with the proviso that when R2 is a hydrogen atom and s is 1 then U is NR11, O or S.
WO 2004/096767 PCT/DK2004/000283 21 In one embodiment, the invention relates to compounds of formula I, wherein R2 is NO2 or a hydrogen atom or a halogen atom; with the proviso that when R2 is NO2 or a halogen atom then s is 0; and with the proviso that when R2 is a hydrogen atom and s is 1 then U is NR11, O or S.
In another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is NO2 or a halogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein R2 is a 10 hydrogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is selected from the group consisting of NO2, halogen and cyano.
In another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is a hydrogen atom.
In yet another embodiment, the invention relates to compounds of formula I, wherein R2 is Ci-6-alk(en/yn)yl, typically Ci-3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein Rz is C3-8-cycloalk(en)yl, typically C3-6-cycloalk(en)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein 25 R2 is Ax.
In yet another embodiment, the invention relates to compounds of formula I, wherein R2 is Ar-Ci.6-alk(en/yn)yl, typically Ar-Ci.3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein R2 is halo-Ci-6-alk(en/yn)yl, typically halo-Ci-3-alk(en/yn)yl.
WO 2004/096767 PCT/DK2004/000283 22 In yet another embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is a halogen atom.
In yet another embodiment, the invention relates to compounds of formula I, wherein 5 s is 0 and R2 is cyano.
In another preferred embodiment, the invention relates to compounds of formula I, wherein s is 0 and R2 is N02.
In a preferred embodiment, the invention relates to compounds of formula I, wherein R2 is a hydrogen atom; with the proviso that when s is 1 then U is NR11, O or S.
In one embodiment, the invention relates to compounds of formula I, wherein R2 is a hydrogen atom; with the proviso that when s is 1 then U is NR11.
In another embodiment, the invention relates to compounds of formula I, wherein R2 is a hydrogen atom, s is 1, U isNR11 and R11 is a hydrogen atom.
In one embodiment, the invention relates to compounds of formula I, wherein the 20 group -(U)s-R2 is linked to position 6 of the indole or indoline.
In a preferred embodiment, the invention relates to compounds of formula I, wherein the group -(U)s-R2 is linked to position 4 of the indole or indoline.
In a preferred embodiment, the invention relates to compounds of formula I, wherein X is CO.
In a preferred embodiment, the invention relates to compounds of formula I, wherein X is S02.
In a preferred embodiment, the invention relates to compounds of formula I, wherein q is 0.
WO 2004/096767 PCT/DK2004/000283 23 In a preferred embodiment, the invention relates to compounds of formula I, wherein qisl.
In one embodiment, the invention relates to compounds of formula I, wherein q is 1 and Z is a sulphur atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein q is 1 and Z is an oxygen atom.
In one embodiment, the invention relates to compounds of formula I, wherein X is SO2 and q is 0.
In one embodiment, the invention relates to compounds of formula I, wherein X is CO and q is 0.
In one embodiment, the invention relates to compounds of formula I, wherein X is CO, q is 1 and Z is an oxygen atom.
In one embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar-Ci_6-alk(en/yn)yl-heterocycloaIk(en)yl, C1-6-alk(en/yn)yloxy-heterocycloalk(en)yl, C1 _6-alk(en/yn)yloxy-carbonyl-Ci alk(en/yn)yl, C3_8-cycloalk(en)yloxy-carbonyl-Ci.6-alk(en/yn)yl, C3.g-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-carbonyl-Ci_6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloallt(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3.8-cycloalk(en)yl-C i_6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy-Ci-s-alk(en/yn)yl-heterocycloalk(en)yl, halo-heterocycloalk(en)yl, halo-Ci.6-aIk(en/yn)yl-heterocycloalk(en)yl, cyano-Ci.6-alk(en/yn)yl, cyano-C3_8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-s-cycloalk(en)yl-Ci.6-alk(en/yn)yl, cyano-Ci-6-allc(en/yn)yl-C3.8-cycloalk(en)yl, cyano-Ci-6-alk(en/yn)yl-heterocycloalk(eii)yl, acyl-Ci^-alk(en/yn)yl, acyl-C3.8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3.g- 24 cycIoalk(en)yl-Ci-6-alk(en/yn)yl> acyl-C1.6-alk(eri/yn)yl-C3-8-cycloaIk(en)yl and acyl-Ci.6-alk(en/yn)yl-heterocycloalk(en)yl.
In another embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of C[_6-a1k(en/yn)yl, C3-8-cyc1oalk(en)yl, heterocycloalk(en)yl, C3.8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ci.6-alk(en/yn)yl-C3-g-cycloalk(en)yl, Ar, Ar-C] _6-alk(en/yn)yl, Ar-C3.g-cycloalk(en)yl, Ar-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-C1.6-aLk(en/yn)yl-C3.g-cycloalk(en)yl, Cj.6-alk(en/yn)yloxy-Ci_6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C1.6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar-Ci-6-alk(en/yn)yloxy-Ci-6-allc(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3.g-cycloalk(en)yl, haIo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci.6-alk(enyyn)yl-C3-8-cycloalk(en)yl, halo-Ci-6-alk(en/yiL)yl-Ar, halo-C3-8-cycloalk(en)yl-Ar, lialo-C3_8-cycloalk(en)yl-C 1,6-allt(en/yn)yl-Ar, halo-Ci-6-alk(en/yn)yl-C3.8-cycloa]k(en)yl-Ar and -NRI2R12'; with the proviso that when R3 is NR12R12' then q is 0.
In yet another embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of Ci_6-alk(en/yn)yl, C3_g-cyclo alk(en)yl, heterocycloalk(en)yl, C3.8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3_8-cycloallc(en)yl, Ar, Ar-Ci-6-alk(en/yn)yl, Ar-Cj.8-cycloalk(en)yl, Ar-03-8-cycloaUt(en)yl-Ci.6-alk(en/yn)yl, Ai-Ci-6-alk(en/yn)yl-C3-g-cycloalk(en)yl, Ar-oxy-Ci. fi-alk(en/yn)yl, Ar-C1_<5-alk(en/yn)y1oxy-Ci^-alk(en/yn)yl, halo-Ci-s-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3.g-cycloalk(en)yl-Ci-6-alk(en/yn)yl5 halo-Ci-g-alk(en/yn)yl-C3-8-cyoloalk(en)yl and -NR12R12'; with the proviso that when R3 is NR12R12' then q is 0.
In yet another embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of Ci_6-allc(en/yn)yl, C3.8-cycloalk(en)yl, C3. 8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ci-6-ah<;(en/yn)yl-C3-8-cycloalk(en)yl, Ar, Ar-Ci-e-alk(en/yn)yl, Ar-C3^-cycloalk(en)yl, Ar-C3.8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-Ci_ 6-alk(en/yn)yl-C3.8-cycloallc(en)yl, Ar-oxy-C1.6-allc(en/yn)yl, Ar-Ci-6-alk(en/yn)yloxy-Ci_6-alk(en/yn)yl and -NR12R12'; with the proviso that when R3 is NR12R12' then q is 0.
In a preferred embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of Ci-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, heterocycloalk(en)yl, Ar, Ar-C i -6-alk(en/yn)yl, Ar-oxy-Ci_g-alk(eii/yn)yl, Ar-Ci^-alk(en/yii)yloxy-Ci-e-all<:(en/yn)yl, halo-Ci-6-alk(en/yn)yl and -NR12R12'; with the proviso that when R3 is NR12R12' then q is 0.
In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is selected from the group consisting of Ci^-alk(en/yn)yl, C3.8-cycloalk:(en)yl, Ar, Ar-Ci_6-alk(en/yn)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar-Ci-g-10 alk(en/yn)yloxy-C 1 -fi-alk(en7yn)yl and -NR12R12'; with the proviso that when R3 is NR12R12' then q is 0.
In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is Ci_6-alk(en/yn)yl, typically Ci_3-alk(en/yn)yl.
In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is C3.8-cycloalk(en)yl.
In yet another preferred embodiment, the invention relates to compounds of formula I, 20 wherein R3 is C3-s-cycloalk(en)yl-Ci-6-alk(eii/yn)yl.
In yetanother preferred embodiment, the invention relates to compounds of formula I, wherein R3 is heterocycloalk(en)yl.
In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is Ar.
In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is Ar-Ci.6-alk(en7yn)yl.
In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is Ci-6-allc(en/yn)yl-oxy-CK6-allc(en/yii)yl. 26 PC T/DK2004/000283 In yet another preferred embodiment, the invention relates to compoimds of formula I, wherein R3 is Ar-oxy-Ci_G-a]k(en/yn)yl.
In yet another preferred embodiment, the invention relates to compounds of formula I, 5 wherein R3 is Ar-Q _6-aUc(en/yn)yloxy~Ci ^-alk(en/yn)yl.
In yet another embodiment, the invention relates to compoimds of formula I, wherein R3 is Ci_6-aIk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)y].
In yet another embodiment, the invention relates to compounds of formula I, wherein R3 is halo-Ci.6-allc(en/yn)yl, such as halo-Ci_3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compoimds of formula I, wherein R3 is halo-Ci-6-aUc(en/'yn)yl-Ar, such as halo-Ci„3-alk(en/yn)yl-Ar.
In yet another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is -NR12R12', and q is 0.
In one embodiment, the invention relates to compounds of formula I, wherein X is 20 CO, q is 1, Z is an oxygen atom and R3 is selected from the group consisting of Ci-g-alk(en/yn)yl, Cj.g-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci.6-aUc(en/yn)yl-C3_g-cycloalk(en)yl, Ar-C i _6-alk(en/yn)yl, Ar-C3_8-cycIoalk(en)yl, Ar-C3. s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-Ci-6-alk(en/yn)yl-C3.8-cycloalk(en)yl, Ar-oxy-Ci-6-ant(en/yn)yl, Ar-Ci_6-alk(en/yn)yloxy-Ci.6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, 25 halo-C3.8-cycloalli(en)yl, halo-C3.s-cycloalk(en)yl-C] .6-alk(en/yn)yl and halo-Ci-6-alk(eny'yn)yl-C3.8-cycloalk(en)yl.
In another embodiment, the invention relates to compoimds of formula I, wherein X is CO, q is 1, Z is an oxygen atom and R3 is selected from the group consisting of Ci.6-30 allc(en/yn)yl, Ar-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl and halo-Ci-6-alk(en/yn)yl.
In one further embodiment, the invention relates to compounds of formula I, wherein X is CO, q is 0 and R3 is selected from the group consisting of Ci.6-alk(en/yn)yl, C3-8- 27 • cycloallc(en)yl, C3_8-cycloalk(en)yl-Cu6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3.s-cycloalk(en)yl, heterocycloallc(en)yl, Ax, Ajr-Ci-6-alk(en/yn)yl, Ar-C3.8-cycloalk(en)yl, Ar-C3.g-cycloaIk(en)yl-Ci.6-alk(en/ytL)yl5 Ar-Ci_6-alk(en/yn)yl-C3-8-cycloalk(en)yl3 Ar-oxy-Ci.6-aIk(en/yn)yl, Ar-Ci.6-alk(en/yn)yloxy-Ci.6-alk(en/yn)yl and -NR12R12'.
In yet another embodiment, the invention relates to compounds of formula I, wherein X is CO, q is 0 and R3 is selected from the group consisting of Ci-6-alk(en/yn)yl, C3.8-cycloalk(en)yl, heterocycloalk(en)yl, Ar, Ar-Ci.6-alk(en/yn)yI, Ar-oxy-Ci„6-allc(en/yn)yl and -NR12R12'.
In yet another embodiment, the invention relates to compounds of formula I, wherein X is SO2, q is 0 and R3 is selected from the group consisting of Ci-6-alk(en/yn)yl, C3. 8-cycloallc(en)yl, C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar-Ct-(;-alk(en/yn)yl, Ar-C3^-cycloalk(en)yl, Ar-C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar-Ci.<>-aIk(en/yii)yl-C3.8-cycloalk(en)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein X is S02, q is 0 and R3 is Ci-6-alk(en/yn)yl or Ax-Ci_6-a1k(en/yn)yl.
In one embodiment, the invention relates to compounds of formula I, wherein R3 is 4 A 4 trnf | A « A) NR R and q is 0 and wherein R and R are independently selected from the group consisting of hydrogen, Ci_6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3..8-cycIoalk(en)yl-Ci.6-alk(en/yn)yl, Ar, Ar-Ci.6-alk(en/yn)yl, Ar-C3.s-cycloalk(en)yl and Ar-C3-8-cycloalk(en)yI-C 1 _6-alk(en/yn)yl.
In another embodiment, the invention relates to compounds of formula I, wherein R3 is NR1ZR12' and q is 0 and wherein R12 and R12' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, Ar and Ar-C 1 _6-alk(en/yn)yl or wherein R12 and R12' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1,2 or 3 further heteroatoms.
WO 2004/096767 PCT/DK2004/000283 28 In a preferred embodiment, the invention relates to compounds of formula I, wherein R3 is NR12R12 and q is 0 and wherein R12 and R12' are independently selected from the group consisting of hydrogen, C]-6-alk(en/yn)yl, Ar and Ar-Ci^-alk(en/yn)yl, In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 is NR12R12 and q is 0 and wherein R12 and R12 together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms.
In one embodiment, the invention relates to compoimds of formula I, wherein R3 is NRizR12' and q is 0 and wherein at least one of R12 and R12' is a hydrogen atom.
In another embodiment, the invention relates to compounds of formula I, wherein R3 is NR12R12' and q is 0 and at least one of R12 and R12' is Cwalk(en/yn)yl, typically 15 Ci-3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein R3 is NR12R12' and q is 0 and one of R12 and R12' is Ar.
In yet another embodiment, the invention relates to compounds of formula I, wherein R3 is NR12R12' and q is 0 and one of R12 and R12' is Ar-Ci-6-alk(en/yn)yl, typically Ar-C i -3-alk(en/yn)yl.
In a preferred embodiment, the invention relates to compounds of formula I, wherein 25 Y is of formula II, III, V, XXX or XXXI.
In one embodiment, the invention relates to compoimds of formula I, wherein Y is of formula HI or IV.
In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula n or V.
WO 2004/096767 PCT/DK2004/000283 29 In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula V or XXXI.
In a preferred embodiment, the invention relates to compounds of formula I, wherein 5 Y is of formula II or III and W is a sulphur atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula H or HI and W is an oxygen atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula V.
In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXX and T is NH.
In a preferred embodiment, the invention relates to compoimds of formula I, wherein Y is of formula XXX and T is a nitrogen atom or an oxygen atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein 20 Y is of formula XXXI and L is a nitrogen atom.
In a preferred embodiment, the invention relates to compounds of formula I, wherein Y is of formula XXXI and L is C or CH.
In one embodiment, the invention relates to compounds of formula I, wherein each Rs is independently selected from the group consisting of Ar-Ci.6-alk(en/yn)yl, acyl, -CO-NR^R6', cyano, cyano-Ci-6-atk:(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3_ 8-cycloallc(en)yl-Ci-6-allc(en/yn)yl.
In another embodiment, the invention relates to compounds of formula I, wherein each R5 is independently selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3.g-cycloaJk(en)yl-Ci.6-allc(en/yn)yl5 Ar, C:.6-alk(en/yn)yloxy, C3.s-cycloallc(en)yloxy, C3-g-cycloalk(en)yl-Ci-s-allc(en/yn)yloxy, halogen, halo-Ci-6- alk(en/yn)yl, halo-Cs-ircycloalMenJyl, halo-C3-s-cycloalk(en)yl-Ci.6-aJk(en/yn)yl, -NR7R7', -S-R8 and -S02R8; or two adjacent Rs together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.
In yet another embodiment, the invention relates to compounds of formula I, wherein each R5 is independently selected from the group consisting of Ci.6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3-8-cycloahc(en)yl-Ci-6-allc(en/yn)yl, Ar, Ci_6-alk(en/yn)yloxy, C3-8-cycloallc(en)yloxy, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, -NR7R7', -S-R8 and -10 SC>2Rs; or two adjacent Rs together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.
In yet another embodiment, the invention relates to compounds of formula I, wherein 15 each R5 is independently selected from the group consisting of halogen, halo-Ci-s-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3.g-cycloalk(en)yl-Ci.6-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein each R5 is independently selected from the group consisting of Ci_s-allt(en/yn)yl, C3.8-20 cycloalk(en)yl, C3.g-cycloalk(en)yl-Ci.6-alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen, halo-Ci_6-allc(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3_8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, or two adjacent Rs together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.
In a preferred embodiment, the invention relates to compounds of formula I, wherein each Rs is independently selected from the group consisting of C1 _6-alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen, halo-Ci^-alk(en/yn)yl, or two adjacent R5 together with the aromatic group to which they are attached form a 4-30 8 membered ring which optionally contains one or two heteroatoms.
WO 2004/096767 PCTVDK2004/000283 31 In another preferred embodiment, the invention relates to compounds of formula I, wherein each R5 is independently selected from the group consisting of halogen aid halo-Ci-6-alk(en/yn)yl.
In an embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is a halogen atom.
In another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is halo-Ci-6-alk(en/yn)yl, typically halo-Ci-3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is Ci.s-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein 15 at least one substituent R5 is Ar.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is Ar-thio.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is Ar-oxy.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is Ci-6-alk(en/yn)yloxy.
In yet another embodiment, the invention relates to compoimds of formula I, wherein at least one substituent Rs is -NR7R7'.
In yet another embodiment, the invention relates to compounds of formula I, wherein 30 at least one substituent Rs is -S -R8.
In yet another embodiment, the invention relates to compoimds of formula I, wherein at least one substituent Rs is -SO2R8. 32 In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent Rs together with the aromatic group form a 4-8 membered ring, which optionally contains one or two heteroatoms.
! In a preferred embodiment, the invention relates to compounds of formula I, wherein two adjacent R5 together form -(CH2)n-CH2-, -CH=CH-(CH2)m-, -CH2-CH=CH-(CH2)p-,-CH=CH-CH=CH-, -(CH2)n'-0-, -0-(CH2)m.-0-, -CH2-0-(CH2)p.-0-, -CH2-0-CH2-0-CH2-, -(CH2V-S-, -S-(CH2)m-S-, -CH2-S-(CH2)p-S-, -CH2-S-CH2-S-CH2-5 10 -(CH2)n-NH-, -NH-(CH2)m—NH-, -CH2-NH-(CH2)p-NH-, - CH=CH-NH-, -0-(CH2)m~NH-, -CH2-0-(CH2)p.-NH- or-0-(CH2)rMI-CH2-, -S-(CH2)m-NH-, -N=CH-NH-, -N=CH-0- or -N=CH-S-, wherein m' is 1, 2 or 3, n' is 2, 3 or 4 and p' is 1 or 2.
In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R5 together form -CH2-0-CH2-.
In yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R5 together form -CH=CH-CH=CH-. ha yet another embodiment, the invention relates to compounds of formula I, wherein two adjacent R5 together form-0-CH2-0-.
In yet another embodiment, the invention relates to compounds of formula I, wherein 25 two adj acent R5 together form -0-CH2-0-CH2-.
In yet another embodiment, the invention relates to compounds of formula I, wherein m m |«) m mf at least one substituent R is -NR R ; and wherein R and R are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl 30 and C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yl.
WO 2004/096767 PCT/DK2004/000283 33 In yet another embodiment, the invention relates to compoimds of formula I, wherein at least one substituent R5 is -NR7R7; and wherein R7 and R7' are independently selected from the group consisting of hydrogen and Ci_6-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R is -NR R ; and wherein both R and R are Ci_g-alk(en/yn)yl, typically Ci-3-alk(en/yn)yl.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is -S-R8 or -S02R8; and wherein R8 is selected from the group consisting of hydrogen, Ci_6-alk(en/yn)yl, C3„8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(eii/yn)yl and Ar.
In yet another embodiment, the invention relates to compounds of formula I, wherein at least one substituent R5 is -S-R8 or -SO2R8; and wherein R8 is selected from the group consisting of Ci-6-alk(erj/yn)yl and Ar.
One embodiment of the invention relates to compounds of formula I, wherein s is 0 and q is 0.
Another embodiment of the invention relates to compounds of formula I, wherein R2 is a hydrogen atom and X is CO.
Yet another embodiment of the invention relates to compounds of formula I, wherein s is 0 and X is CO.
Yet another embodiment of the invention relates to compounds of formula I, wherein 30 R2 is a hydrogen atom and q is 0.
Yet another embodiment of the invention relates to compounds of formula I, wherein q is 0 and X is CO.
WO 2004/096767 PCT/DK2004/000283 34 One embodiment of the invention relates to compounds of formula I, wherein the total number of Ar-groups in the substituents R2, R3 and R5 equals to 0,1,2, or 3, typically 0 or L Another embodiment of the invention relates to compounds of formula I wherein neigther R2, R3 or R5 comprises an Ar-group.
Yet another embodiment of the invention relates to compounds of formula I, wherein the total number of Ar-groups in the substituents R2, R3 and R5 equals to 1.
Yet another embodiment of the invention relates to compounds of formula I, wherein the total number of Ar-groups in the substituents R2, R3 and R5 equals to 2.
One embodiment of the invention relates to compounds of formula I, wherein R3 is 15 not CH3 when X is SO2 and q is 0.
Another embodiment of the invention relates to compounds of formula I, wherein X-(Z)q-R3 is not SO2-CH3 when Y is of formula V.
Yet another embodiment of the invention relates to compounds of formula I, wherein R3 is NR12R12' and both R12 and R12'is different from Ar.
Yet another embodiment of the invention relates to compounds of formula I, wherein R3 is NR12R12' and one of R12 and R12'is Ar, with the proviso that Ar is different from 25 quinoline or phenyl.
Another embodiment of the invention relates to compounds of formula I, wherein Y is not of formula Y when X is CO and q is 0 and R3 is NR12R12' and one of R12 and R12' is Ar, typically quinoline or phenyl.
■ In another embodiment, the compound of formula I is not: N- [ 1 -(phenylmethyl)-lH-indol-5-yl] -Methanesulfonamide; N- [ 1 -[(4-fluorophenyl)methyl] -1 H-indol-5-yl] -Methanesulfonamide; N-[2,3-dihydro-1 -(phenylmethyl)-1 H-indol-5-yl]-Methanesulfonamide; N-[ 1 -(phenylmethyl)-1 H-indol-5-yl] -N'-4-quinolinyl-Urea; N-[l -(phenylmethyl)-1 H-indol-5-yl] -N'-4-quitiolinyl-Urea; or 1 -(1 -benzyl-5-indolinyl)-3-phenyl-Urea.
One aspect of the invention, relates to compoimds of general formula VII and salts thereof: R2 (R5)f (VII) wherein the dotted line, f, q, s, U, X, Z, R1, R1', R2, R3 and R5 are as defined under formula I. Any of the embodiments related to formula I are also embodiments of formula VII.
In one embodiment, the invention relates to compounds of the general formula VII, 15 wherein f is 0.
In another embodiment, the invention relates to compounds of the general formula VII being substituted by one substituent Rs, such as in the orto-, meta- or para-position.
In a preferred embodiment, the invention relates to compounds of the general formula VII, which are substituted by one substituent R5 in the para-position. 36 In one embodiment, the invention relates to compounds of the general formula VII being substituted by two independently selected R5 substituents, such as in the ortho-and para-position, in the meta- and para-position and in the orto- and meta-position.
In another embodiment, the invention relates to compounds of the general formula VII being substituted by three independently selected R5 substituents.
Also described herein are compounds of the general formula VIII or salts thereof: R2 H ™ X ^ R3 (VIII) wherein the dotted line, g, h, q, s, U, X, Z, R1, Rr, R2, R3 and R3 are as defined under formula I. Any of the embodiments related to formula I are also embodiments of formula VIII.
In one embodiment, described are compounds of the general formula VIII, wherein the nitrogen atom is attached to position 1 of the naphtyl group via the methylene group.
In another embodiment, described are compounds of the general formula VIII, 20 wherein the nitrogen atom is attached to position 2 of the naphtyl group via the methylene group.
INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 37 In yet another embodiment, described are compounds of the general formula VIII, wherein g is 0, 1, 2 or 3, typically 0, 1 or 2.
In yet another embodiment, described are compounds of the general formula VIII, 5 wherein h is 0, 1 or 2, typically 0 or 1.
In yet another embodiment, described are compounds of the general formula VIII, wherein g + h equals to 0, 1, 2 or 3.
In yet another embodiment, described are compounds of the general formula VIII, wherein both g and h are 0.
In yet another embodiment, described are compounds of the general formula VIII being substituted by one substituent R5.
In yet another embodiment, described are compounds of the general formula VIII being substituted by two independently selected R5 substituents.
In yet another embodiment, described are compounds of the general formula VIII 20 being substituted by three independently selected R5 substituents.
Yet another aspect of the invention relates to compounds of the general formula IX or salts thereof: INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 38 wherein the dotted line, a, q, s, U, X, Z, R1, R1', R2, R3 and R5 are as defined under formula I. Any of the embodiments related to formula I are also embodiments of 5 formula IX.
In an embodiment, the invention relates to compounds of the general formula IX, wherein the nitrogen atom is attached to position 2 of the heteroaromatic group via the methylene group.
In another embodiment, the invention relates to compounds of the general formula IX, wherein the nitrogen atom is attached to position 3 of the heteroaromatic group via the methylene group.
IS In yet another embodiment, the invention relates to compounds of the general formula IX, wherein W is an oxygen atom.
In a preferred embodiment, the invention relates to compounds of the general formula IX, wherein W is a sulphur atom.
In another embodiment, the invention relates to compounds of the general formula IX, wherein a is 0, 1 or 2. 39 In yet another embodiment, the invention relates to compounds of the general formula EX, wherein a is 0.
In yet another embodiment, the invention relates to compounds of the general formula 5 IX being substituted by one substituent R5, such as in position 5.
In yet another embodiment, the invention relates to compounds of the general formula IX being substituted by two independently selected R5 substituents.
In an embodiment, the invention relates to compounds of the general formula IX, wherein the nitrogen atom is attached to position 2 via the methylene group and wherein a substituent R5 is attached to position 5 of the heteroaromatic group.
Yet another aspect of the invention relates to compounds of the general formula X or salts thereof: (U)5 Ri (R5)b R1' W \ (R5)c (x) wherein the dotted line, b, c, q, s, U, X, Z, R1, R1', R2, R3 and Rs are as defined under formula I. Any of the embodiments related to formula I are also embodiments of formula X.
WO 2004/096767 PCT/DK2004/000283 40 In an embodiment, the invention relates to compounds of the general formula X, wherein the nitrogen atom is attached to position 2 of the heteroaromatic group via the methylene group.
In another embodiment, the invention relates to compounds of the general formula X, wherein the nitrogen atom is attached to position 3 of the heteroaromatic group via the methylene group.
In yet another embodiment, the invention relates to compoimds of the general formula 10 X, wherein W is an oxygen atom.
In yet another embodiment, the invention relates to compounds of the general formula X, wherein W is a sulphur atom.
In yet another embodiment, the invention relates to compounds of the general formula X, wherein b is 0,1,2 or 3, typically 0,1 or 2.
In yet another embodiment, the invention relates to compounds of the general formula X, wherein c is 0 or 1, typically 0.
In yet another embodiment, the invention relates to compounds of the general formula X, wherein b + c equals to 0, 1, 2, 3 or 4.
In yet another embodiment, the invention relates to compounds of the general formula 25 X, wherein both b and c are 0.
In yet another embodiment, the invention relates to compoimds of the general formula X, wherein b + c equals to 1. In one aspect thereof b is 1 and c is 0. In another aspect thereof b is 0 and c is 1.
In yet another embodiment, the invention relates to compounds of the general formula X being substituted by one substituent Rs. 41 In yet another embodiment, the invention relates to compounds of the general formula X being substituted by two independently selected R5 substituents.
In yet another embodiment, the invention relates to compounds of the general formula 5 X being substituted by three independently selected R5 substituents.
Also described herein are compounds of the general formula XI or salts thereof: H , N\ /-(ZW " X ^ R3 (XI) wherein the dotted line, d, e, q, s, U, X, Z, R1, R1, R2, R3 and R5 axe as defined under formula I. Any of the embodiments related to formula I are also embodiments of formula XI.
In an embodiment, described are compounds of the general formula XI, wherein the 15 nitrogen atom is attached to position 4 of the heteroaromatic group via the methylene group.
In another embodiment, described are compounds of the general formula XI, wherein the nitrogen atom is attached to position 5 of the heteroaromatic group via the 20 methylene group.
INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 42 In an embodiment, described are compoimds of the general formula XI, wherein the nitrogen atom is attached to position 6 of the heteroaromatic group via the methylene group.
In another embodiment, described are compounds of the general formula XI, wherein the nitrogen atom is attached to position 7 of the heteroaromatic group via the methylene group.
In yet another embodiment, described are compounds of the general formula XI, 10 wherein W is an oxygen atom.
In yet another embodiment, described are compounds of the general formula XI, wherein W is a sulphur atom.
In yet another embodiment, described are compounds of the general formula XI, wherein d is 0, 1 or 2, typically 0 or 1.
In yet another embodiment, described are compounds of the general formula XI, wherein e is 0, 1 or 2.
In yet another embodiment, described are compounds of the general formula XI, wherein d + e is 0, 1, 2, 3 or 4.
In yet another embodiment, described are compounds of the general formula XI, 25 wherein both d and e are 0.
In yet another embodiment, described are compounds of the general formula XI being substituted by one substituent R5.
In yet another embodiment, described are compounds of the general formula XI being substituted by two independently selected Rs substituents.
INTELLECTUAL PROPERTY OFFICE OF N.2. 1 6 DEC 2008 RECEIVED 43 In yet another embodiment, described are compounds of the general formula XI being substituted by three independently selected R5 substituents.
Yet another aspect of the invention relates to compounds of the general formula 5 XXXII or salts thereof: wherein the dotted line, j, q, s, T, U, X, Z, R1, R1, R2, R3 and R5 are as defined under formula I. Any of the embodiments related to formula I are also embodiments of 10 formula XXXII.
In an embodiment, the invention relates to compounds of the general formula XXXII, wherein the nitrogen atom is attached to the position indicated with 1 of the heteroaromatic group via the methylene group.
In another embodiment, the invention relates to compounds of the general formula XXXII, wherein the nitrogen atom is attached to the position indicated with 2 of the heteroaromatic group via the methylene group.
In another embodiment, the invention relates to compounds of the general formula XXXII, wherein the nitrogen atom is attached to the position indicated with 3 of the heteroaromatic group via the methylene group.
(U)s (XXXII) INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 DEC 2008 RECEIVED WO 2004/096767 PCT/DK2004/000283 •A 44 In yet another embodiment, the invention relates to compoimds of the general formula XXXII. wherein T is an oxygen atom.
In yet another embodiment, the invention relates to compounds of the general formula 5 XXXH, wherein T is a nitrogen atom.
In yet another embodiment, the invention relates to compounds of the general formula XXXH, wherein T represents NH.
In another embodiment, the invention relates to compounds of the general formula XXXH, wherein j is 0, 1,2 or 3.
In yet another embodiment, the invention relates to compounds of the general formula XXXH, wherein j is 0.
In yet another embodiment, the invention relates to compounds of the general formula XXXII being substituted by at least one substituent R5. In one aspect thereof, the compound of the general formula XXXII is substituted in the position indicated with 1. In another aspect thereof, the compound of the general formula XXXII is 20 substituted in the position indicated with 2. In yet another aspect thereof, the compound of the general formula XXXH is substituted in the position indicated with 3. In yet another aspect thereof, T represents a nitrogen atom at which the compound of the general formula XXXII is substituted.
In yet another embodiment, the invention relates to compounds of the general formula XXXII being substituted by two independently selected R5 substituents.
In yet another embodiment, the invention relates to compounds of the general formula XXXII being substituted by two or three independently selected Rs substituents.
In yet another embodiment, the invention relates to compounds of the general formula XXXH being substituted by three independently selected Rs substituents. 45 One aspect of the invention, relates to compoimds of general formula XXXHL and salts thereof: wherein the dotted line, k, q, s, L, U, X, Z, R1, R1', R2, R3 and R5 are as defined . under formula I. Any of the embodiments related to formula I are also embodiments of formula XXXIII.
In one embodiment, the invention relates to compoimds of the general formula 10 XXXHI, wherein k is 0.
In another embodiment, the invention relates to compounds of the general formula XXXIII being substituted by one substituent R5, such as in the position being orto, meta or para to the nitrogen atom.
In a preferred embodiment, the invention relates to compounds of the general formula XXX1IJL, which are substituted by one substituent R5 in the position being para to the nitrogen atom.
In one embodiment, the invention relates to compounds of the general formula XXXm being substituted by two independently selected R5 substituents, such as in the in the positions being ortho and para to the nitrogen atom, of in the positions being meta and para to the nitrogen atom, or in the positions being orto and meta to the nitrogen atom.
(U)s (XXXIII) WO 2004/096767 PCT/DK2004/000283 46 hi another embodiment, the invention relates to compounds of the general formula XXXIII being substituted by three independently selected R5 substituents.
In one embodiment of the invention, the compounds of the following list and salts thereof are preferred: N-[4-Chloro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3r3-dimethylbutyramide, N-[4-Chloro-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide, [l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester, N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide, 4-Fluoro-N-[l-(4-fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-benzamide, N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide, N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-ihiophen-2-ylacetamidef N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide, 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-l,l-diisopropylurea, Morpholine-4-carboxylic acid [1 -(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH- indol-5-yl]-amide, Pyrrolidine-1 -carboxylic acid [1 -(5-chlorothiophen-2-ylmethyl) -2,3-dihydro-lH-indol-5-yl]-amide, [l-(5-Chlorothiophen-2-yhnethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid 2-benzyloxyethyl ester, 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-l-methyl-l -propylurea, [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid tert-butyl ester, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide, Butane-1 -sulfonic acid [J-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-4-fluorobenzamide, 47 N-[l-(5-Chlofothiophen-2-ylinethyl)-2,3-dihydro-lH~indol-5-yl]-2,2-dimethylpropionamide, N-[l-(5-Chlorothiophen-2-ylrnethyl)-2,3-dihydro-lII-indol-5-yl]-2-phenoxyacetamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide, Cyclopentanecarboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide, N- [ 1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-thiophen-2-ylacetamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-isonicotinamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-4- dimethylaminobenzamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-2> 3 -dihydro-lH-indol-5-yl]-6-trifluoromethylnicotinamide, l-tert-Buty!-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea, 1-[1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-3-ethylurea, l-Benzyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea, l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-phenethylurea, l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-2-ylurea, 1-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-3-ylurea, 2,2-Dimethyl-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro~lH-indol-5-ylJ-propionamide, N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropionamide, 2-(4-Fluorophenyl)-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5• yl]-acetamide, N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide, 48 N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropionamide, N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropioTiam ide, N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide, or N-[l-(5-Chlorothiophen-2-ylmethyl)-lH-indol-5-ylJ-3,3-dimethylbutyramide.
Ih another embodiment of the invention, the compounds of the following list and salts thereof are preferred: N-[4-Chloro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-ylJ-3,3-dimethylbutyramide; N-[4-Chloro-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; fl-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester; N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide; 4-Fluoro-N-[l-(4-fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-benzamide; N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(4-Fluorobeiizyl) -2,3-dihydro-lH-indol-5-yl]-2-thiophen-2-ylacetamide; N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 3-[l~(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-l,l-diisopropylurea; Morpholine-4-carboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5 -yl]-am ide; Pyrrolidine-1 -carboxylic acid [1 -(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-am ide; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid 2-benzyloxyethyl ester; 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3~dihydro~lH-indol-5-yl]-l-methyl-l-propylurea; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid tert-butyl ester; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide; 49 Butane-1-sulfonic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]~ amide; N-[l-(5-Chloi-othiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-4-fluorobenzamide; N-[l-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-2,2-dimethylpropionamide; N-[l-(5-CMorothiophen-2-ylmethyl)-2,3-dihydro-l~FI-indol-5-yl]-2-phenoxyacetamide; N~[l-(5~Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(5-Chlorothiophen-2~ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; Cyclopentanecarboxylic acid [l-(5-chlorothiophen-2-ylmethyI)-2,3-dihydro-lH-indol-5-yl]-amide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-thiophen-2-ylacetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-isonicotinamide; N-[l-(5-Chlorothiophen-2~ylmethyl)-2,3-dihydro-lH-indol-5-yl]-4-dimethylaminobenzamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N'[l-(5-Chlorothiophen-2-ylmethylJ-2,3-dihydro-lH-indol-5-yl]-6-trifluoromethylnicotinamide; l-tert-Butyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea; l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-ethylurea; l-Benzyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea; l-[l-(5-Chlorothiophen-2-yhnethyl)-2,3-dihydro-lH-indol-5-yl]-3-phenetkylurea; l-[l-(5-Chlorothiophen-2-yhnethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-2-ylurea; l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-3-ylurea; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester, 2,2-Dimethyl-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-propionamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropionamide; 50 2-(4-Fluorophenyl)-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl) - 6-nitro~2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH~indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amiiio-l-(4-trifluoromeihylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2,2-10 dimethylpropionamide; N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropionamide; N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[6-Amino-l-(4-trifluorometlTylbenzyl)-2,3-dihydro-l H-indol-5-ylJ-3,3-dimethylbutyramide; N-[6-Amino-l-(4-fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide-, N-[6-Amino-l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3- dimethylbutyramide; N-[l-(5-Chlorothiophen-2-ylmethyl)-lH-indol-5-yl]-3,3-dimeihylbutyramide\ N-[6-Bromo-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dim&thylbutyramide; N-[6-Bromo-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; 25 N-[l-(4-Chlorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; N-[l-(4-Isopropylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(3-Fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(6-Chlorobenzo[l, 3]dioxol-5-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; 51 N-[l-(2-Chloro-5-trifluoromethylberizyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-{l-[5-(4-Chlorophenoxy)-l,3-dimethyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(6-p-tolyloxy-pyridin-3-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-butyramide; N-{l-[6-(4-Chlorophenylsulfanyl)~pyridin-3-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide; N-{l-[6-(4- Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Ditnethyl-N-fl-(6-trifluoromethylpyridin-3-ylmethyl)-2,3-dihydro-lH-indol-5-yl]~ butyramide; 3,3-Dzmethyl-N-[l-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; N-[l-(6-Fluoro-4H-benzo[l,3]dioxin-8-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(6-phenoxypyridin-3-yhnethyl)-2,3-dihydro-lH-indol-5-ylJ-butyramide; 3,3-Dimethyl-N-[1 -(3-methyl~5-phenyl-isoxazol-4-yl?nethyl)-2,3-dihydro-lH-indol-5-ylj-butyramide; N-(l-Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-lH-indol-5-yl)-3,3-dimethylbutyramide; N-{l-[l-(4-Fluorophenyl)-5-methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; 3J3-Dimethyl-N-[l-(4-pyrrol-l-yl-benzyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; N-[l-(4-Chlorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]~ acetamide; 2-(4-Fluorophenyl)-N-[1 -(4-isopropylbenzyl)-2,3-dihydro-lH-indol-5-yl]-acetamide; 2-(4-Fluorophenyl)-N-[l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihyd?-o-lH-indol-5-ylJ-acetam ide; WO 2004/096767 PCT/DK2004/000283 52 N-[l-(6-Chlorobenzofl, 3]dioxol-5-ylm ethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl) -acetamide; N-[l-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-yhnethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[l-(2-Chloro-5-trifluoromethylbeixzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-{l-[5-(4-Chlorophenoxy)-l,3-dimeihyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-2-(4-fluoropheriyl)-acetamide; N-{l-[6-(4-Cyanophenoxy) -pyridin-3-ylmethyl/ -2,3-dihydro-l H-indol-5 -yl}-2-(4-fluorophenyl)-acetamide; 2~(4-Fluorophenyl) -N-[l-(3 -methyl-b enzo[b] th iophen -2-ylmethyl) -2,3-dihydro-l H-indol-5-yl]-acetamide; N-[l-(6-Fluoro-4H-benzo[l,3]dioxin-8-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2~(4-Fluorophenyl)-N-[l-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-lH-indol-5-yl]- acetamide; N-(l-Benzo[b]thiopheii-2-ylmethyl-2,3-dihydro-lH-indol-5-yl)-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-{l-[l-(4-fluorophenyI)-5-methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-acetamide; 2-(4-Fluorophenyl)-N-[l-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-acetamide; and 2-(4-Fluorophenyl)-N-[l-(4-pyrrol-l-yl-benzyl)-2,3-dihydro-lH-indol-5-ylJ-acetamide.
Accoiding to one embodiment, the invention relates to a pharmaceutical composition comprising one or more phaimaceutically acceptable carriers or diluents and a compound of formula I wherein the dotted line, s, q, U, X, Z, Y, R1, R1', R2 and R3are as defined above, accordingly any of the dotted line, a, b, c, d, e, f, g, h, j, k, s, q, L, T, U, X, Z, Y, W, R1, R1', R2, R3, R5, R6, R6', R7, R7', R8, R9, R9', R10, R10', R11, R12 and R12' are as defined under formula I, or salts thereof. Pharmaceutical compositions of the invention may thus comprise one or more compoimds of formula WO 2004/096767 PCT/DK2004/000283 53 I or salts thereof, such as one compound of formula I or a salt thereof; or two compounds of formula I or salts thereof; or three compounds of formula I or salts thereof.
The invention thus provides a pharmaceutical composition for oral or parenteral administration, said pharmaceutical composition comprising at least one compound of formula I or a salt thereof in a therapeutically effective amount together with one or more pharmaceutical^ acceptable carriers or diluents.
In one aspect, the compounds of the invention may be administered as the only therapeutically effective compound.
In another aspect the compounds of the invention may be administered as a part of a combination therapy, i.e. the compounds of the invention may be administered in 15 combination with other therapeutically effective compounds having e.g. anticonvulsive properties. The effects of such other compounds having anti-convulsive properties may include but not be limited to activities on: • ion channels such as sodium, potassium, or calcium channels • the excitatory amino acid systems e.g. blockade or modulation of NMDA 20 receptors • the inhibitory neurotransmitter systems e.g. enhancement of GAB A release, or blockade of GABA-uptake or • membrane stabilisation effects.
Current anti-convulsive medications include, but are not limited to, tiagabine, 25 carbamazepine, sodium valproate, lamotrigine, gabapentin, prcgabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide as well as members of the benzodiazepine and barbiturate class.
In one aspect, the compounds of the invention have been found to have effect on 30 potassium channels of the KCNQ family, in particular the KCNQ2 subunit.
In one embodiment, the invention relates to the use of one or more compounds according to the invention in a method of treatment. The disorder or condition to be WO 2004/096767 PCT/DK2004/000283 54 prevented, treated or inhibited is responsive to an increased ion flow in a potassium channel such as the KCNQ family potassium ion channels. Such disorder or condition is preferably a disorder or condition of the central nervous system.
The compounds of the invention are considered useful for increasing ion flow in a voltage-dependent potassium channel in a mammal such as a human.
The compoimds of the invention are considered useful for the prevention, treatment or inhibition of a disorder or condition being responsive to an increased ion flow in a 10 potassium channel such as the KCNQ family potassium ion channels. Such disorder or condition is preferably a disorder or condition of the central nervous system.
The compounds of the invention are thus considered useful for preventing, treating or inhibiting disorders or diseases such as seizure disorders, neuropathic and migraine 15 pain disorders, anxiety disorders and neurodegenerative disorders.
Accordingly, the compounds of the invention are considered useful for the prevention, treatment or inhibition of disorders or conditions such as convulsions, epilepsy, anxiety disorders, neuropathic pain and neurodegenerative disorders.
According to one particular embodiment, the compounds of the invention are thus considered to be usefiil for preventing, treating or inhibiting seizure disorders such as convulsions, epilepsy and status epilepticus.
In one embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of convulsions.
In another embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of epilepsy, epileptic syndromes and epileptic 30 seizures.
In yet another embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of anxiety disorders such as anxiety and 55 conditions and diseases related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorders, generalized 5 anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorders, performance anxiety, hypochondriacal disorders, anxiety disorder due to general medical condition and substance-induced anxiety disorder and anxiety disorder not otherwise specified.
In yet another embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, 15 agoraphobia, specific phobias, anxiety disorder due to general medical condition and substance-induced anxiety disorder.
In yet another embodiment, the compounds of the invention are also considered useful in the prevention, treatment and inhibition of neuropathic pain and migraine pain 20 disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy and neupathic pain related to migraine.
In yet another embodiment,, the compounds of the invention are considered useful in the prevention, treatment and inhibition of neurodegenerative disorders such as 25 Alzheimer's disease; Huntington's chorea; multiple sclerosis; amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies induced by ADDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens; trauma-induced neurodegenerations; neuronal hyperexcitation states such as in medicament withdrawal or intoxication; and neurodegenerative diseases of the 30 peripheral nervous system such as polyneuropathies and polyneuritides.
In yet another embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of neurodegenerative disorders such as WO 2004/096767 PCT/DK2004/000283 56 Alzheimer's disease; Huntington's chorea; multiple sclerosis; amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia and unknown pathogens; and trauma-induced neurodegenerations.
In yet another embodiment, the compounds of the invention are considered useful in the prevention, treatment and inhibition of neuronal hyperexcitation states such as in medicament withdrawal or intoxication.
The invention provides compounds showing effect in one or more of the following tests: • "Relative efflux through the KCNQ2 channel" Which is a measure of the potency of the compound at the target channel • "Maximum electroshock" Which is a measure of seizures induced by non-specific CNS stimulation by electrical means • "Pilocarpine induced seizures" Seizures induced by pilocarpine are often difficult to treat with many existing antiseizure medications and so reflect a model of "drug resistant seizures" 20 • "Electrical seizure-threshold tests" and "Chemical seizure-threshold tests" These models measure the threshold at which seizures are initiated, thus being models that detect whether compounds could delay seizure initiation.
• "Amygdala kindling" Which is used as a measure of disease progression, as in normal animals the 25 seizures in this model get more severe as the animal receives further stimulations.
According to one particular aspect of the invention, the compounds are KCNQ2 active with an EC50 of less than 15000nM such as less than lOOOOnM as measured by the 30 test "Relative efflux through the KCNQ2 channel" which is described below. According to another particular aspect of the invention, the compounds are KCNQ2 active with an EC50 of less than 2000nM such as less than 1500nM as measured by the test "Relative efflux through the KCNQ2 channel" which is described below. 57 According to yet another particular aspect of the invention, the compounds are KCNQ2 active with an EC50 of less than 200nM such as less than 150nM as measured by the test "Relative efflux through the KCNQ2 channel" which is described below.
According to one particular aspect of the invention, the compounds have an ED50 of less than 15 mg/lcg in the test "Maximum electroshock" which is described below. According to another particular aspect of the invention, the compoimds have an ED50 of less than 5 rag/kg in the test "Maximum electroshock" which is described below.
According to one particular aspect of the invention, the compounds have an ED50 of less than 5 mg/kg in the "Electrical seizure -threshold test" and "Chemical seizure -threshold test" which is described below.
Some compounds have few or clinically insignificant side effects. Some of the 15 compounds are thus tested in models of the unwanted sedative, hypothermic and ataxic actions of the compounds.
Some of the compounds have a large therapeutic index between anticonvulsant efficacy and side-effects such as impairment of locomotor activity or ataxic effects as 20 measured by performance on a rotating rod. This means that the compounds will expectedly be well tolerated in patients permitting high doses to be used before side effects are seen. Thereby compliance with the therapy will expectedly be good and administration of high doses may be permitted making the treatment more efficacious in patients who would otherwise have side effects with other medications.
Definitions The term heteroatom refers to a nitrogen, oxygen or sulphur atom.
Halogen means fluoro, chloro, bromo or iodo.
The expressions Ci.5-alk(en/yn)yl and Ci.6-alk(an/en/yn)yl mean a Ci„5-alkyl, C2-6-allcenyl or a C2.6-aUcyn.yl group. The term Ci-6-alkyl refers to a branched or un- 58 branched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-l-propyl. Similarly, C2-6-alkenyl and C2-6-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one' triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The expression Ci_3-alk(en/yn)yl means a Ci-3-alkyl, C2-3-alkenyl or a C2-3~alkynyl group. The term Ci.3-alkyl refers to a branched or un-branched alkyl group having from one to three carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl and 2-propyl. Similarly, C2-3-alkenyl and C2.3-alkynyl, respectively, designate such groups having from two to three carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 3-propenyl, ethynyl, 1-propynyl and 3-propynyl.
The expressions C3_8-cycloa]1c(en)yl and C3.g-cycloalk(an/en)yl mean a C3_8-cycloallcyl- or cycloalkenyl group. The term C3.g-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term C3.g-cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond.
The expressions C3_6-cycloalk(en)yl and C3.6-cycloalk(an/en)yl mean a C3-6-cycloalkyl- or cycloalkenyl group. The term Cj^-cycloalkyl designates a monocychc or bicyclic carbocycle having three to six C-atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The term heterocycloalk(en)yl designates a monocyclic or bicyclic ring system wherein the ring is formed by 4 to 8 atoms selected from 2-7 carbonatoms and 1 or 2 heteroatoms selected from N, S, or O. 59 When two substituents together with a carbon atom to which they are attached form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms, then a monocycEc ring system is formed by 3 to 8 atoms selected from 1-8 carbonatoms and 0-2 heteroatoms selected from N, S, or O. Examples of such ring systems are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term halo-Ci_6-alk(en/yn)yl designates Ci-6-alk(en/yn)yl being substituted with one or more halogen atoms, including but not limited to trifluoromethyl. Similarly, halo-C3-8-cycloalk(en)yl designates C3-s-cycloalk(en)yl being substituted with one or more halogen atoms and halo-heterocycloalk(en)yl designates heterocycloalk(en)yl being substituted with one or more halogen atoms.
The termNR12R12'-Ci-6-alk(en/yn)yl designates Ci-6-alk(en/yn)yl being substituted withNRnR12'. The term NR12R12>-C3-g-cycloallc(en)yl designates C3-8-cycloalk(en)yl being substituted with NR12R12'. The termNR12R12'-C3.8-cycloalk(en)yl-Ci-<5-alk(en/yn)yl designates C3.g-cycloalk(en)yl-Ci.6-alk(en/yn)yl being substituted with NR12R12'. When any of NR12R12'-Ci.6-alk(en/yn)yl, NR12R12'-C3-8-cycloalk(en)yl and NR12R12'-C3-8-cyCloalk(en)yl-Ci_6-alk(en/yn)yl is optionally substituted, then any of Ci.6-alk(en/yn)yl, C3.8-cycloalk(en)yl, C3-S-cycloalk(en)yl-Ci-6-alk(en/yn)yi is optionally substituted with one or more substituents independently being Ci_c-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-anc(en/ya)yl or Ar.
As used herein, the term acyl refers to formyl, Ci-6-alk(en/yn)ylcarbonyl, C3.8-cycloalk(en)ylcarbonyl, Ar-carbonyl, Ar-Ci-s-alk(en/yn)ylcarbonyl or a C3.8-cycloalk(en)yl-Ci_6-alk(en/yn)yl-carbonyl group, wherein Ci_6-alk(en/yn)yl, C3_8-cycloall<(en)yl and Ar are as defined above.
When two substituents together with a nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms, then a monocyclic ring system is formed by 4 to 8 atoms selected from the nitrogen atom, 1-7 carbonatoms and 0-3 further heteroatoms selected from N, S, or O. Examples of such ring systems are azetidine, beta-lactame, pyrrolidine, 60 piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine, ixnidazolidine, azetidine, beta-lactame, tetrazole andpyrazole.
When two adjacent substituents together with the aromatic group to which they are 5 attached form a 4-8 membered ring, which optionally contains one or two heteroatoms, then a ring system is formed by 4-8 atoms selected from 3-8 carbonatoms and 0-2 heteroatoms selected from N, S, or O. Such two adjacent substituents may together form: -(CH2)n"-CH2-, -CH=CH-(CH2)m»-, -CH2-CH=CH-(CH2)p..-, -CH=CH-CH=CH-, 10 -(CH2)n"-0-, -0-(CH2)m>--0-, -CH2-0-(CH2)p.-0-, -CH2-0-CH2-0-CH2-, -(CH2)n"-S-, -S-(CH2)m"--S-, -CH2-S-(CH2)p»-S-) -CH2-S-CH2-S-CH2-, -(CH2)n"-NIi-, -NH-(CH2)m>—NH-, -CH2-NH-(CH2)P»-NH-, - CH=CH-NH-, -0-(CH2)m'—NH-, -CH2-0-(CH2)P"-NH- or-0-(CH2)P"-NH-CH2-, -S-(CH2)m»-NH-, -N=CH-NH-, -N=CH-0- or -N=CH-S-, wherein m" is 1,2 or 3, n" is 2, 3 or 4 and p" 15 is 1 or 2.
The term Ar refers to optionally substituted aromatic systems of 5-10 carbon atoms, wherein 0,1,2,3 or 4 carbon atoms may be replaced by heteroatoms independently selected from N, S, or O. Examples of such Ar groups are optionally substituted 20 phenyl, optionally substituted naphtyl, optionally substituted pyridine, optionally substituted pyrrole, optionally substituted pyrimidine, optionally substituted quinoline, optionally substituted indole, optionally substituted thiophene, optionally substituted foran, optionally substituted thiazole and optionally substituted oxazole. Ar may be substituted or unsubstituted. When substituted, Ar is substituted with 25 one or more substituents independently selected from the group consisting of hydroxyl, halogen, Ci-6-alk(en/yn)yl, C3„8-cycloalk(en)yl, C3-g-cycloalk(en.)yl-C1^-alk(en/yn)ylJ halo-Ci_6-ali:(en/yn)yl, Ci.6-alk(en/yn)yIoxy, C3-8-alk(en/yn)yloxy, acyl, nitro or cyano, -CO-NH-Ci.6-alk(en/yn)yl, -CO-N(Ci^-alk(en/yn)yl)2, -NH2, -NH-Ci-r 3Q alk(en/yn)yl, -N(C t _s-alk(en/yn)yl)2, -S- Cms-alk(en/yn)yl, -S02-C i -a-alk(en/yn)yl, -S02N(Ci-6-alk(en/yn)yl)2 and -S02NH-Cu-alk(enyyn)yl; or two adjacent substituents may together with the aromatic group to which they are attached form a 4-8 membered ring, which optionally contains one or two heteroatoms and which may be saturated or unsaturated. 61 The terms C3.g-cycloallc(en)yl-Ci-alk(en/yn)yl, Ci.6-alk(en/yn)yl-C3-8-cycloaIk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar~Ci-6-alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl, Ar-heterocycloaIk(en)yl, Ar-C3.8-cycloalk(en)yl-Ci-c-alk(eii/yn)yl, Ar-Ci.6-aHi(en/yn)yl-C3-8-cycloali;(en)yl, Ar-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ci-6-alk(en/yn)yloxy, C2^-alkenyloxy. C2-6-alkynyloxy, C3.g-cycIoaIk(en)yloxy5 Ci_6-alk(eii/yn)yloxy-Ci.s-allc(en/yn)yl5 C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, Ci_g-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-Ci-6-aLl£(en/yn)yl) Ar-Ci.6-alk(en/yn)yloxy-Ci-6-alk(en/ya)yl, Ci-g- alk(en/yn)ylcarbonyl, C3_8-alk(ea/yn)ylcarbonyl, Ar-carbonyl, Ar-Ci-e-aUc(en/yn)ylcarbonyl. C3.g-cycloalk(en)yl-Ci-6-alk(eii/yn)ylcarbonyl, -CO-Ci-g-alk(en/yn)yl, -S-Ci-6-alk(en/yn)yl, -S02-Ci-6-alk(en/yn)yl and -S020-Ci-6-alk(en/yn)yl, Ci _6-allc(en/yn)yloxy-carbonyl-C i-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C] _c-alk(en/yn)yl, C3_8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-carbonyl-Ci.6-alk(en/yn)yl, acyl, acyl-Ci-6-alk(en/yn)yl, acyl-C3.8-cycloaIk:(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, acyl-Ci_c-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-Ci_6-alk(en/yn)yl-heterocycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3.3-cycloalk(en)yl3 hydroxy- heterocycloallc(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, hydroxy-Q-g-alk(en/yn)yl-C3-8-cycloallc(en)yl, hydroxy-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3_8-cycloalk(en)yl, halo-heterocycloallc(en)yl, halo-C3-s-cycloalk(en)yl-C].6-alk(en/yn)yl, halo-Ci^-alk(en/yn)yl-C3^-cycloalk(en)yl, halo-Ci. 6-aIli(eii/yn)yl-heterocycloalk(en)yl, halo-C i .6-alk(en/yn)yl-Ar, halo-C3.8-cycloalk(en)yl-Ar, halo-C3.g-cycloaUc(en)yl-Ci^-alk(eii/yn)yl-Ar, halo-Ci^-alk(en/yn)yl-C3-8-cycloalk(en)yl-Ar, halo-heterocycloalk(en)yl-Ar, cyano-C 1-6-allc(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3„8-cycloalk(en)yl-Ci -6-alk(en/yn)yl, cyano-C] .6-alk(en/yn)yl-C3_8-cycloalk(en)yl, cyano-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl etc. designate such groups in which the Ci-e-allt(en/yn)yl, C2-e-alkenyl, C2-6-alkynyl, C3.8-cycloallc(en)yl, heterocycloalk(en)yl, Ar, cyano, halo-C L_ The pharmaceutically acceptable salts of the invention are preferably acid addition salts. The acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed with non-toxic acids. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, 10 hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, ethanesulfonic, tartaric, ascorbic, pamoic, gluconic, citraconic, aspartic, stearic, 15 palmitic, EDTA, glycolic, p-anoinobenzoic, glutamic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, itaconic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutical acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts 20 listed in J. Pharm. Sci. 1977,66,2, which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates, 30 which the present compounds are able to form.
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified 63 optical isomers or racemic mixtures thereof are included within the scope of the invention.
Furthermore, when a double bond or a fully or partially saturated ring system is 5 present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
The compounds of this invention may exist in unsolvated as well as in solvated forms with solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention. Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates or camphorsulphonate) salts. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S.
Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). 64 Optically active compounds can also be prepared from optically active starting materials.
The invention also encompasses prodrugs of the present compounds, which on 5 administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general formula I, VII, VIII, IX, X, XI, XXXH or XXXHI which are readily convertible in vivo into the required compound of the formula I, VII, VIII, IX, X, XI, XXXH or XXXIII. Conventional procedures for the 10 selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
Whenever mentioned in relation to the compounds of the formulas I, VII, VUI, IX, X, XI, XXXH or xxxm, the terms epilepsy and epilepsies embrace any of the epilepsies, epileptic syndromes and epileptic seizures referred to in International League Against Epilepsy: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Commission on Classification and Terminology of 20 the International League Against Epilepsy. Epilepsia 1981 22: 489-501 and in International League Against Epilepsy: Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989 30(4): 389-399.
Whenever mentioned in relation to the compounds of the formulas I, VII, VUI, IX, X; XI, XXXII or XXXIII, the term anxiety disorders embraces conditions and diseases related to panic attack, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, 30 acute stress disorders, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorders and anxiety disorder not otherwise specified as defined by 65 American Psychiatric Association Diagnostic and statistical manual of mental disorders, 4ed 1994: 110-113, 393-444 and 623-627.
Pharmaceutical compositions The compounds of this invention are generally utilized as the free base or as a pharmaceutically acceptable salt thereof. Representative examples are mentioned above.
If desired, the pharmaceutical composition of the invention may comprise the 10 compound of formula I in combination with further pharmacologically active substances such as those described in the foregoing.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. 15 The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and 25 intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such 30 as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
WO 2004/096767 PCT/DK2004/000283 66 Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
The pharmaceutical compositions of this invention or those which are manufactured 15 in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will 25 depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to he treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from WO 2004/096767 about 0.5 mg to about 200 mg. 67 For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for 5 oral administration.
The compoimds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is a base addition salt of a compound having the utility of a free acid. When a compound of the invention 10 contains a free acid such salts may be prepared in a conventional manner by treating a solution or suspension of a free acid of the compound of the invention with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
For parenteral administration, solutions of the novel compounds of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, 20 intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Solutions for injections may be prepared by dissolving the active ingredient and 25 possible additives in a part of the solvent for inj ection, preferably sterile water, adjusting the solution to a desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
WO 2004/096767 PCT/DK2004/000283 68 Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkyl ethers of cellulose corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like.
Any other adjuvants or additives usually used for such purposes such as colourings, flavouiiags, preservatives etc. may be used provided that they axe compatible with the active ingredients.
Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, 10 fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical compositions formed by combining the novel compounds of the 15 invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include one or more suitable excipients. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous 25 liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tablette, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. 69 If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
If desired, the pharmaceutical composition may comprise the compound of the formula I, VII, VIII, IX, X or XI in combination with further pharmacologically active substances such as those described in the foregoing.
Typical examples of recipes for the formulation of the invention are as follows: 1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base: Compound of formula I, VII, VIII, IX, X or XI .0 mg Lactose Maize starch Hydroxypropylcellulose Microcrystalline cellulose Croscarmellose Sodium Type A Magnesium stearate 60 mg 30 mg 2.4 mg 19.2 mg 2.4 mg 0.84 mg 2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base: Compound of formula I, I, VII, VIII, IX, X or XI 0.5 mg Lactose Maize starch Povidone Microcrystalline cellulose Croscarmellose Sodium Type A Magnesium stearate 46.9 mg 23.5 mg 1.8 mg 14.4 mg 1.8 mg 0.63 mg 3) Syrup containing per miililitre: Compound of formula I, VII, VIII, IX, X or XI mg Sorbitol 500 mg INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 70 Hydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 mL Flavour 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL 4) Solution for injection containing per millilitre: Compound of formula I, VII, VIII, IX, X or XI 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharin sodium 0.5 mg 15 Water 71 Preparation of the compounds of the invention Scheme 1 N / PG1 (U)s XIV Ft2 NO, N / R2 Scheme 2 NO, NO, N / PG1 XXII R3 XXVI (UL R2 R3 I VX' R3 "(A NX' R3 I '(z>c N / PG1 '(U), XXV R2 s=0, R2=CI, Br, I, N02 72 The compounds of the invention of the general formula I, wherein the the dotted line, q, s, U, Y, X, Z, R1, R1', R2 and R3 are as defined above, accordingly any of dotted line, a, b, c, d, e, f, g, h, s, q, U, X, Z, Y, W, R1, R1', R2, R3, Rs, R6, R6', R7, R7, R8, R9, R9, R10, R10 , R11, R12 and R12 are defined under formula I are prepared by the 5 methods as described below and as represented in-the Schemes 1 and 2.
Indoles and indolines of the general formula XII and XIH substituted at position 4 or 6 with R2-(U)S- are commercially available, described in the literature or prepared according to methods known to chemists skilled in the art [R. J. Sundberg 'Tyiroles 10 and their Benzo Derivatives: (iii) Synthesis and Applications" in Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C.W. Rees (Editors), vol. TV, pp 313-376, Pergamon Press, 1984]. Indoles of the general formula XII can be converted into indolines of the general formula XHI by methods known to chemists skilled in the art such as catalytic hydrogenation or reduction with NaBH^CN in appropriate solvents 15 such as acetic acid [S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth, I. T. Forbes et al. J. Med. Chem. 41, 1998,1598-1612]. Compounds of the general formula XH or Xm with s being 0 and R2 being in particular but not limited to substituted aryl or substituted heteroaryl as defined above can be prepared from corresponding compounds with R2 being I or Br by means of C-C coupling reactions known to 20 chemists skilled in the art, such as Suzuki coupling, Stille coupling, or other transition metal catalysed cross-coupling reactions [D.W. Knight "Coupling Reactions Between sp2 Carbon Centers" in Comprehensive Organic Synthesis, v. 3, pp. 481-520, Pergamon Press 1991 ].
Compounds of the general formula XIV are prepared by protection of the indoline nitrogen of the compounds of the general formula XIII with an appropriate protecting group (PG1) [Protective Groups in Organic Synthesis, 3rd Edition T. W. Greene, P. G. M. Wuts, Wiley Interscience 1999], such as a trifluoroacetyl group known to chemists skilled in the art as TFA group, by reaction with the reagent forming the protective 30 group such as trifluoroacetic acid anhydride in a suitable solvent, such as 1,2-dichloroethane at appropriate temperatures.
WO 2004/096767 PCT/DK2004/000283 "73 The obtained compoimds of the general formula XIV are converted into compounds of the general formula XV by regioselective nitration at position 5 of the indoline moiety by methods known to chemists skilled in the art [R. Behnisch " Aromatische Nitro-Verbindungen" in. Methoden der Organische Chemie/(Houben-Weyl) p. 255, v.
E16d, Thieme: 1992] such as reaction with concentrated nitric acid in appropriate solvent such as acetic anhydride, acetic acid, concentrated sulphuric acid or mixtures thereof at appropriate temperatures. The nitro compounds of the general formula XV where R2 is halogen, in particular fluorine, and s is 0 can be converted into compounds of the general formula XV, where U is O, NR11 or S and R2 is as defined 10 above, by nucleophilic aromatic substitution reactions known to chemists skilled in the art such as reaction with the appropriate nucleophiles forming the -(U)s-R2 group such as thiophenols, alkylsulfides, alcohols, phenols, amines, and anilines in their neutral or deprotonated form. The compoimds of the general formula XV where U is S02 can be obtained from the compounds of the general formula XV, where U is S, 15 by oxidation according to methods known to the chemist skilled "in the art, for example by oxidation with NaIC>4 in the presence of RuC13 as a catalyst or with 3-chloroperoxybenzoic acid.
The nitro group in compounds of the general formula XV can be reduced with 20 suitable reducing agents such as zinc or iron powder in the presence of acid such as acetic acid or aqueous hydrochloric acid, or hydrogen gas or ammonium formiate in the presence of a suitable hydrogenation catalyst such as palladium on activated carbon in suitable solvents such as methanol, ethanol, or tetrahydrofuran, at suitable temperatures or under ultrasonic irradiation, to obtain anilines of the general formula 25 XVI. Alternatively, tin (II) chloride or sodium dithionite can be used as reducing agents under conditions well known to the chemist skilled in the art.
Compounds of the general formula XVII are prepared from compounds of the general formula XVI by the reaction with suitable electrophilic reagents forming an R3-(Z)q-30 X group, such as alkyl, aryl or heteroaryl chloroformiates or carbamyl chlorides, acid chlorides, acid bromides, acid iodides, sulfonyl chlorides, isocyanates, carbonic acid anhydrides, activated carbonic acids with activating reagents such as carbodiimides or others as known to chemists skilled in the art in suitable solvents, such as acetonitrile, 74 tetrahydrofuran, 1,2-dichloroethane, or methylene chloride, at suitable temperature, such as room temperature or reflux, with or without addition of bases, such as magnesium oxide, potassium carbonate, sodium hydride, trialkylamines, sodium- or potassium alcoholates, or pyridine, reactions well known to the chemist skilled in the 5 art. Then the protective group PG1 is removed according to methods known to chemists skilled in the art [Protective Groups in Organic Synthesis, 3rd Edition T. W. Greene, P. G. M. Wuts, Wiley Interscience 1999], furnishing compounds of the general formula XVIII. For example, when PG1 is TFA, it can be removed by hydrolysis with aqueous potassium carbonate in an appropriate solvent, such as 10 methanol, at a suitable temperature.
Finally, the obtained anilines of the general formula XVTO are subjected to reductive alkylation reactions, known to chemists skilled in the art, with aldehydes of the general formula YCHO where Y is defined as above in the presence of suitable 15 reducing agent such as NaBH3CN in suitable solvents such as methanol, ethanol, tetrahydrofuran, acetonitrile or mixtures thereof, with or without addition of catalytic amounts of acid, such as acetic acid, at suitable temperatures forming compounds of the invention of the general formula I, where R1 and R1' are hydrogens. Alternatively, a (YXR'XR^C- group can be introduced by nucleophilic substitution reactions with 20 the appropriate electrophiles of the general formula (Y)(R1)(R1')C-LG, where LG is a suitable leaving group such as iodide, bromide, or sulphonate, under conditions known to the chemist skilled in the art, furnishing the compounds of the invention of the general formula I.
Alternatively, compounds of the general formula XIX are commercially available, described in the literature or can be prepared from compounds of the general formula XV by deprotection as described above. Then they are subjected to reductive alkylation with aldehydes of the general formula YCHO or to nucleophilic substitution reactions with electrophiles of the general formula (Y)(R1)(R1')C-LG as 30 described above, furnishing compounds of the general formula XX. Then the nitro group is reduced as described above forming compounds of the general formula XXI. Finally, the compounds of the invention of the general formula I with indoline moiety WO 2004/096767 PCT/DK2004/000283 75 are obtained by the method described above for the conversion of compounds of the general formula XVI into compounds of the general formula XVII.
Optionally, compounds of the invention of the general formula I with indole moiety 5 can be obtained from indolines of the general formula I by means of dehydrogenation known to chemists skilled in the art such as oxidation with appropriate reagents such as 2,3.5,6-tetrachloro-[ 1,4]benzoquinone, Mn02, or catalytic dehydxogenation in the presence of a catalyst such as Pd on charcoal or RuCl2(PPh3)3 in appropriate solvents such as toluene or xylene at appropriate temperatures.
Alternatively, compounds of the general formula I where -(U)s-R2 is attached to the position 6 of the indoline moiety, can be prepared by a route shown in Scheme 2 as follows: 5-Nitroindoline is protected with an appropriate protecting group, such as TFA group, as described above for compounds of the general formula XIV, furnishing compounds of the general formula XXII. Then the nitro group is reduced as described above for preparation of compounds of the general formula XVI, furnishing compounds of the general formula XXm, They are converted into compounds of the general formula 20 XXIV with appropriate electrophiles forming R3-(Z)q~X as described above for compounds of the general formula XVH. Compounds of the general formula XXV where s is 0 and R2 is N02 or halogen such as CI, Br or I, are obtained by means of regioselective electrophilic aromatic substitution, well known to chemists skilled in the art, with appropriate electrophiles such as N-chlorosuccinimide, bromine, iodine, 25 iodochloride in the appropriate solvent , such as acetic acid or by nitration under conditions as described for compounds of the general formula XV.
Compounds of the general formula XXV where s is 0 and R2 is substituted aryl or substituted heteroaryl as defined above can be prepared from corresponding 30 compounds of the same general formula where R2 is I or Br by means of C-C coupling reactions known to chemists skilled in the art as described above. Then the protective group is removed as described above, furnishing the compounds of the general formula XXVI.
WO 2004/096767 PCT/DK2004/000283 76 Finally, the compounds of the invention of the general formula I with indoline moiety are prepared from the compounds of the general formula XXVI by reductive alkylation or by nucleophilic substitution reactions as described above. Also, the compounds of the invention of the general formula I with indole moiety can be 5 obtained from indolines of the general formula I by means of dehydrogenation as described above.
Examples Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped 10 with an APPI (atmospheric pressure photo ionisation) ion source and Shimadzu LC-8A/SLC-10A LC system. Column: 30 X 4.6 mm Waters Symmetry C18 column with 3.5 (im particle size; Solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 minutes and with a flow rate of 2 mL/minute. Purity was 15 determined by integration of the UV (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes.
Preparative LC-MS-purification was performed on the same instrument. Column: 50 X 20 mm YMC ODS-A with 5 pm particle size; Method: Linear gradient elution with 20 80% A to 100% B in 7 minutes and with a flow rate of 22.7 mL/minute. Fraction collection was performed by split-flow MS detection.
NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.8%D) were 25 used as solvents. TMS was used as internal reference standard. Chemical shift values axe expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet and br. = broad.
Preparation of intermediates Preparation of intermediates of the general formula XXII and XIV 77 1 -Trifluoroacetyl-5-nitroindoline.
To a suspension of 5-nitroindoIine (5.51 g, 33.56 mmol) in 1,2-dichloroethane (15 ml) trifluoroacetic anhydride (20 ml) was added. After 60 min the obtained solution was 5 quenched with heptane (200 ml) and the title compound was separated by filtration in two crops. Yield 7.12 g, 81.5%. 'H NMR (DMSO-d6): 3.34 (t, 2H), 4.38 (t, 2H), 8.19 (m, 3H). l-Trifluoroacetyl-4-chloroindoline was prepared analogously from 4-chloroindoline 10 [S. M. Bromidge, S. Dabbs, D. T. Davies, D. M. Duckworth, I. T. Forbes et al. J. Med. Chem. 41, 1998, 1598-1612]. NMR (DMSO-d6): 3.26 (t, 2H), 4.34 (t, 2H), 7.27 (d: 1H), 7.34 (t, 1H), 8.01 (d, 1H).
Preparation of intermediates of the general formula XV l-Trifluoroacetyl-4-chloro-5-nitroindoline.
To a solution of l-trifluoroacetyl-4-chloromdoline (197 mg, 0.838 mmol) in acetic anhydride (3 ml) and acetic acid (0.3 ml) a solution of fuming HNO3 (0.4 ml) was added by small portions during 5 hours. The resulting reaction mixture was poured 20 into ice, neutralised with saturated aqueous NaHCOa, and extracted with ethyl acetate. The organic solution was filtered via plug of Si02 (10 g), evaporated in vacuo and purified by flash chromatography on SiCh with gradient heptane - 1:4 ethyl acetate/heptane to give 70 mg of the title compound as yellow solid, yield 31%. NMR (DMSO-d6): 3.33 (t, 2H), 4.42 (t, 2H), 8.10 (s, 2H).
Preparation of intermediates of the general formula XX l-(5-Clilorothiophen~2-ylmethyl)-5-nitroindoline.
To a solution of 5-nitroindoline (3.23 g, 19.67 mmol) and 5-chlorothiophene-2-carboxaldehyde (4.2 g, 28.6 mmol) in methanol (45 ml) and acetic acid (8 ml) a solution of NaBHjCN (0.9 g) in methanol (8 ml) was added dropwise during 10 min. The obtained reaction mixture was stirred overnight. The title compound was WO 2004/096767 PCT/DK2004/000283 78 separated by filtration, washed with methanol and water and dried in vacuo to furnish 4.6 g of red crystalline solid. Yield 79.3%. LC/MS (m/z) 293.9 ([M]+); RT = 3.59, (UV, ELSD) 98%, 99.8%. lB. NMR (DMSO-ds): 3.04 (t, 2H), 3.62 (t, 2H), 4.68 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.01 (d, 1H), 7.85 (unresolved m, 1H), 8.00 (dd, 1H).
The following compound was prepared analogously using appropriate aldehydes: 1 -(4-Fluorobenzyl)-5-nitroindoline.
Yellow needles, yield 3.66 g, 72.2%. LC/MS (m/z) 272.0 ([M]+); RT = 3.35, (UV, 10 ELSD) 99%, 100%. XH NMR (DMSO-d6): 3.06 (t, 2H), 3.61 (t, 2H), 4.52 (s, 2H), 6.63 (d, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.83 (unresolved m, 1H), 7.97 (dd, 1H).
Preparation of intermediates of the general formula XXI, XXH, and XVI l-(5- Chlorothiophen-2-ylmethyl)-5-aminoindoline.
To a cold (ice/water bath) vigorously stirred solution of l-(5-Chlorothiophen-2-yhnethyl)-5-nitroindoline (4.013 g, 13.62 mmol) in THE (100 ml) and acetic acid (15 ml) zinc powder (25 g) was added by small portions maintaining the temperature below 40°C. The cold bath removed and the stirring continued at room temperate until 20 reaction completion (1 hour). The obtained suspension was filtered via a plug of Si02 (25 g) with ethyl acetate as an eluent and obtained solution was evaporated in vacuo. The obtained residue was treated with saturated aqueous NaHCC>3, extracted with ethyl acetate, dried over NaaSCU and evaporated in vacuo to give the title compound as a dark green oil. Yield 3.30 g, 91.5%. LC/MS (m/z) 265.9 ([M+lf); RT = 1.85, 25 (UV, ELSD) 93%, 100%. JH NMR (DMSO-ds): 2.73 (t, 2H), 3.08 (t, 2H), 4.25 (s, 2H), 4.40 (br. s, 2H, NH2), 6.30 (dd, 1H), 6.41 (d, 1H), 6.43 (unresolved m, 1H), 6.89 (d, 1H), 6.95 (d, 1H).
The following compounds were prepared analogously: l-(4-Fluorobenzyl)-5-aminoindoline.
The obtained crude product after filtation via Si02 was dissolved in a small amount of methanol, quenched with saturated aqueous NallCOs, and the title compound was 79 separated by filtration, washed with water, and dried in vacuo. Yield 2.40 g, 93.2%, darlc violet solid. LC/MS (m/z) 265.9 ([M+lf); RT = 1.74, (UV, ELSD) 87%, 98%. 'H NMR (DMSO-d6): 2.72 (t, 2H), 3.01 (t, 2H), 4.04 (s, 2H), 4.36 (br. s, 2H, NH2), 6.28 (d, 1H), 6.34 (d, 1H), 6.44 (s, 1H), 7.14 (t, 2H), 7.38 (t, 2H). l-Trifluoroacetyl-5-aminoindoline.
The title compound was prepared from l-trifluoroacetyl-5-nitroindolme (6.67 g, 25.65 mmol). The crude product after filtration via Si02 was used in the next step without purification. Yield 6.11 g, 100%. LC/MS (m/z) 230.1 ([M]+); RT = 1.29, (UV, ELSD) 10 97%, 98%. lH NMR (DMSO-d6): 3.10 (t, 2H), 4.18 (t, 2H), 5.18 (br. s, 2H, NH2), 6.43 (dd, 1H), 6.53 (s, 1H), 7.75 (d, 1H). l-Trifluoroacetyl-4-chloro-5-aminoindolim. lR NMR (CDC13): 3.23 (t, 2H), 4.28 (t, 2H), 6.67 (d, 1H), 7.93 (d, 1H).
Preparation of intermediates of the general formula XXIV and XVII 3,3-Dimethyl-N-[l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-indol-5-yl]-butyramide. To a cold (ice/water bath) solution of l-trifluoroacetyl-5-aminoindoline (2.69 g, 11.7 20 mmol) in CH2CI2 Zer/-buty1 acetyl chloride (1.88 g, 14 mmol) was added followed by addition of Et3N (4 ml). After 5 min the reaction mixture was quenched with saturated aqueous NaHC03 and stirred for 30 min. The organic layer was filtered via plug of Si02 (20 g) with ethyl acetate as an eluent and evaporated to a small volume. It was quenched with heptane and the title compound was separated by filtration. Yield 3.10 25 g, 81%, white solid. LC/MS (m/z) 329.2 ([M+lf); RT = 3.04, (UV, ELSD) 97%, 100%. 'HNMR (DMSO-d6): 1.02 (s, 9H), 2.18 (s, 2H), 3.22 (t, 2H), 4.26 (t, 2H), 7.38 (dd, 1H), 7.72 (s, 1H), 7.96 (d, 1H), 9.86 (s, 1H, NHCO).
The following compounds were prepared analogously from l-trifluoroacetyl-5-30 aminoindoline and appropriate acid chloride or chloroformiate: N-[4-Chloro-l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide was prepared from l-trifluoroacetyl-4-chloro-5-aminoindoline. 80 The reaction mixture was evaporated and used in the next step without characterisation. 2.2-Dimethyl~N-[l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-indol-5-yl]-propionamide. rH NMR (DMSO-de): 1.22 (s, 9H), 3.23 (t, 2H), 4.28 (t, 2H), 7.47 (dd, 1H), 7.71 (s, 1H), 7.96 (d, 1H), 9.26 (s, 1H, NHCO). 2-(4-Fluorophenyl)-N-[l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lB-indol-5-yl]-acetamide.
LC/MS (m/z) 367.0 ([M+l]+); RT = 3.00, (UV, ELSD) 92%, 99%. *H NMR (DMSO-de): 3.22 (t, 2H), 3.63 (s, 2H), 4.27 (t, 2H), 7.15 (t, 2H), 7.36 (dd, 2H), 7.39 (dd, 1H), 7.69 (s, 1H), 7.97 (d, 1H), 10.24 (s, 1H, NHCO). [1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-l H-indol-5-ylj^carbamic acid ethyl ester. 15 The title compound was prepared using 1,2-dichloroethane as a solvent and pyridine as a base. LC/MS (m/z) 302.1 ([M]+); RT = 2.85 (UV, ELSD) 79%, 100%. *H NMR (DMSO-ds): 1.24 (t, 3H), 3.22 (t, 2H), 4.12 (q, 2H), 4.26 (t, 2H), 7.31 (br. d (unresolved dd), 1H), 7.49 (s, 1H), 7.94 (d, 1H), 9.70 (s, 1H, NHCO). [l-(2,2,2-Trifluoroacetyl)-2t3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester.
The title compound was prepared using 1,2-dichloroethane as a solvent and pyridine as a base. LC/MS (m/z) 315.9 ([Mf); RT = 3.11 (UV, ELSD) 89%, 99%. *H NMR (DMSO-dg): 0.93 (t, 3H), 1.64 (m, 2H), 3.22 (t, 2H), 4.03 (t, 2H), 4.26 (t, 2H), 7.32 (br. d (unresolved dd), 1H), 7.50 (s, 1H), 7.94 (d, 1H), 9.71 (s, 1H, NHCO).
Preparation of intermediates of the general formula XXV and XXVI 3.3-Dimethyl-N~(6-nitro-2,3-dihydro-lH-indol~5-yl)-butyramide.
To a cold (ice/water bath) stirred solution of 3,3-dimethyl-N-[l-(2,2,2-30 trifluoroacetyl)-2,3-dihydro-lH-indol-5-yl]-butyramide (1.96 g, 5.98 mmol) in acetic anhydride (30 ml) and acetic acid (5 ml) a solution of fuming HN03 (650 mg, 10.3 mmol) in acetic acid (5 ml) was added dropwise during 5 min. After 5 min the reaction mixture was poured into ice and neutralised with solid NaHCOs which was 81 added by small portions with stirring until gas formation ceased. The yellow solid of 3,3-dimethyl-N-[6-nitro-l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-indol-5-yI]-butyramide was filtered, washed with water and dried in vacuo. LC/MS (m/z) 374.0 ■([M+lf); RT = 3.45 (UV, ELSD) 94%, 99%. 'H NMR (DMSO-d6): 1.03 (s, 9H), 5 2.23 (s, 2H), 3.35 (t, 2H), 4.36 (t, 2H), 7.66 (s, IH), 7.51 (s, IH), 10.17 (s, IH, ' NHCO).
The solid was redissolved in methanol (30 ml) followed by addition of K2CO3 " (2.0 g) in water (7 ml). The colour changed immediately from yellow to dark red. After stirring for 15 min the reaction mixture was poured into ice/water and the title 10 compound was isolated by filtration to give 1.52 g of purple solid, yield 91.8%. LC/MS (m/z) 277.0 ([Mf); RT = 2.30 (UV, ELSD) 91%, 99%. lH NMR (CDC13): 1.10 (s, 9H), 2.29 (s, 2H), 3.10 (t, 2H), 3.63 (t, 2H), 4.80 (very br. s, NH), 7.30 (s, IH), 8.46 (s, IH), 10.14 (s, IH, NHCO).
The following compounds were prepared analogously: 2,2-Dimethyl-N-(6-nitro-2,3-dihydro-l H-indol-5-yl)-propionamide.
LC/MS (m/z) 264.1 ([M+lf); RT = 2.19 (UV, ELSD) 96%, 95%. 'H NMR (DMSO-ds): 1.19 (s, 9H), 3.00 (t, 2H), 3.51 (dt, 2H), 5.98 (br. s, NH), 6.97 (s, IH), 7.44 (s, 20 IH), 9.57 (s, IH, NHCO). 2-(4-Fluorophenyl)-N-(6-nitro-2,3-dihydro-lH-indol-5-yl)-acetamide.
LC/MS (m/z) 315.0 ([Mf); RT = 2.33 (UV, ELSD) 87%, 99%. ]H NMR (DMSO-d6): 2.99 (t, 2H), 3.49 (dt, 2H), 3.62 (s, 2H), 6.00 (br. s, NH), 6.91 (s, IH), 7.15 (t, 2H), 25 7.28 (s, IH), 7.33 (dd, 2H), 9.95 (s, IH, NHCO). [6-Nitro-2,3-dihydro-lH-indol-5-yl]-carbamic acid ethyl ester.
LC/MS (m/z) 250.9 ([M]+); RT = 1.92 (UV, ELSD) 93%, 98%. *H NMR (DMSO-d5): 1.19 (t, 3H), 2.99 (t, 2H), 3.50 (dt, 2H), 4.06 (q, 2H), 5.96 (br. s, NH), 6.92 (s, IH), 30 7.24 (s, IH), 9.22 (s, IH, NHCO). [6-Nitro-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester.
WO 2004/096767 PCT/DK2004/000283 82 LC/MS (m/z) 264.9 ([M]+); RT = 2.36 (UV, ELSD) 93%, 99%. ]H NMR (DMSO-d6): 0.89 (t, 3H), 1.59 (m, 2H), 2.99 (t, 2H), 3.50 (t, 2H), 3.97 (t, 2H), 5.96 (br. s, NH), 6,92 (s, IH), 7.24 (s, IH), 9.22 (s, IH, NHCO). 3,3-Dimethyl-N-(6-bromo-2,3-dihydro-l H-indol-5-yl)-butyramide.
To a stirred solution of 3,3-dimethyl-N-[l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-iiidol-5-yl]-butyramide (0.624 g, 1.90 mmol) in acetic acid (20 ml) bromine (0.195 • ml, 1 eq.) was added. After 45 min more bromine (0.195 ml) was added. The reaction mixture was poured into soution of Na2S03 (5 g) in water (100 ml). The product N-[6-10 bromo-l-(2,2,2-trifluoro-acetyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide was separated by filtration, washed with saturated aqueous NaHC03 and water to furnish 0.555 g of colorless solid. Yield 71%. LC/MS (m/z) 409.0 ([M+l]+); RT = 3.38 (UV, ELSD) 97.5%, 85.5%. 'H NMR (DMSO-d6): 1.05 (s, 9H), 2.25 (s, 2H), 3.22 (t, 2H), 4.30 (t, 2H), 7.55 (s, IH), 8.25 (s, IB), 9.37 (s, IH, NHCO). 15 The solid (100 mg) was redissolved in methanol (10 ml) followed by addition of K2CO3 (0.52 g) in water (5 ml). After stirring at 50°C for 5 min, the reaction mixture was poured into ice/water mixture and the title compound was isolated by filtration to give 0.057 g of colorless solid. Yield 75%. LC/MS (m/z) 313.0 ([M+l]+); RT = 1.71, (UV, ELSD) 97.5%, 98.9%.
Preparation of intermediates of the general formula XVIII N-(4-Chloro-2,3-dihydro-lH-indol-5-yl)-3,3-dijnethylbutyramide.
To a solution of crude N-[4-Chloro-l-(2,2,2-tnfluoroacetyl)-2,3-dihydro-lII-indol-5-25 yl]-3,3-dimethylbutyramide (ca. 100 mg) in MeOH (10 ml) a solution of K2CO3 (0.5 g) in water (2 ml) was added. The obtained mixture was heated at 50°C for 5 min and quenched with ethyl acetate and water. The organic solution was filtered via Si02 (5 g) and evaporated in vacuo to furnish 20 mg of the title compound. The crude product was used in the next step without purification. LC/MS (m/z) 267.1 ([M+l]~); RT = 30 1.61 (UV, ELSD) 45%, 78%.
WO 2004/096767 . PCT/DK2004/000283 83 N-(2,3-Dihydro-lH-indol-5-yl)-2-(4-fluoro-phenyl)-acetamide.
To a solution of 2-(4-Fluorophenyl)-N-[l-(2,2,2-trifluoroacetyl)-2,3-di"hydro-lH-indol-5-yl]-acetamide (1.3 g, 3.55 mmol) in methanol (50 ml) K2CO3 (7.6 g) in water (20 ml) was added. The reaction mixture was kept at 50°C for 5 min, poured into 5 water and the title compound was separated by filtration. Yield 0.742 g, 77.4%. LC/MS (m/z) 271.0 ([M+lf); RT = 1.42, (UV, ELSD) 94.5%, 98.7%. lll NMR (DMSO-d6): 2.85 (t, 2H), 3.36 (t, 2H), 3.55 (s, 2H); 5.28 (br, IH, NH); 6.41 (d, IH); 7.06 (dd, IH); 7.12 (t, 2H); 7.28 (d, IH); 7.35 (dd, 2H); 9.75 (s, 1H,NHC0).
The following compound was prepared analogously from 3,3-dimethyl-N-[l-(2,2,2-trifluoroacetyl)-2,3-dihydro-lH-indol-5-yl]-butyramide: N-(2,3-Dihydro-lH-indo!-5-yl)-3,3-dimethyl-butyramide.
LC/MS (m/z) 232.9 ([M+l]+); RT = 1.43, (UV, ELSD) 94.4%, 88.1%. !H NMR 15 (DMSO-ds): 1.00 (s, 9H); 2.09 (s, 2H); 2.84 (t, 2H); 3.37 (t, 2H); 5.25 (br, IH, NH); 6.41 (d, IH); 7.02 (dd, IH); 7.29 (d, IH); 9.34 (s, IH, NHCO).
Compounds of the invention Example 1 la N-[4-Chloro-l-(4-ti'ifluoromethylbenzyl) -2,3-dihydro-l H-ifidol-5-yl]-3,3- dimethylbutyj-amide.
To a solution of N-(4-chloro-2,3-dihydro-lH-in.dol-5-yl)-3,3-dimethylbutyramide (10 mg), 4-trifluomethylbenzaldehyde (0.06 ml) and acetic acid (0.03 ml) in methanol (0.3 ml) NaBH3CN (100 mg) was added. After 60 min the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHC03 solution. The organic layer was filtered via plug of Si02 (2 g), evaporated and purified by preparative LC/MS to give 11 mg of the title compound as colourless solid. LC/MS (m/z) 425.2 ([M+l]4); RT = 4.01, (UV, ELSD) 95%, 99%. *H NMR (DMSO-d5): 1.03 (s, 9H), 2.16 (s, 2H), 2.97 (t, 2H), 3.40 (t, 2H), 4.41 (s, 2H), 6.48 (d, IH), 7.03 (d, IH), 7.56 (d, 2H), 7.72 (d, 2H), 9.12 (s, IH, NECO).
WO 2004/096767 PCT/DK2004/000283 84 The following compound was prepared analogously using 5-chloro-2-thiophenecarboxaldehyde: lb N-[4-Chloro-l-(5-chlorothiophen-2-ylmethyl)~2,3-dihydro-lH-indol-5-yl]-3,3-5 dimethylbutyramide, LC/MS (m/z) 397.0 ([M+lf); RT = 3.91, (UV, ELSD) 97%, 99%. JH NMR (DMSO-d6): 1.03 (s, 9H), 2.17 (s, 2H), 2.92 (t, 2H), 3.37 (t, 2H), 4.46 (s, 2H), 6.60 (d, IB), 6.95 (d, 1H), 6.99 (d, IH), 7.07 (d, IH), 9.12 (s, IH, NHCO).
Example 2 2a [l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester. To a cold (ice/water bath) solution of l-(4-fluorobenzyl)-5-aminoindoline in acetonitrile (0.2 M, 0.15 ml) propyl chloroformiate (0.02 ml or ca. 20 mg) was added 15 followed by pyridine (0.03 ml). The reaction mixture was allowed to stand at room temperature for 60 min and evaporated in vacuo. The title compound was separated by preparative LC/MS, yield 5.8 mg, 59%. LC/MS (m/z) 329.1 ([M+lf); RT = 2.68, (UV, ELSD) 94%, 99%.
The following compounds were obtained analogously from corresponding 5-aminoindolines and commercially available appropriate chloroformiates, carbamyl chlorides, sulphonyl chlorides, acid chlorides, di-tert-butyl dicarbonate (B0C2O) or isocyanates, which are listed in the Table 1 below. Pyridine was used as a base in case of chloroformiates, carbamyl chlorides, and sulphonyl chlorides. Triethylamine was 25 used as a base in case of acid chlorides. No base was used in case of isocyanates and Boc20: 2\>N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonarnide. LC/MS (m/z) 395.3 ([M-lf); RT = 3.17, (UV, ELSD) 80%, 100%. 2c 4-Fluoro-N-[l-(4-fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-benzamide. LC/MS (m/z) 365.4 ([M+lf); RT = 2.90, (UV, ELSD) 96%, 100%. 85 2&N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimelhylbutyramide. LG/MS (m/z) 341.1 ([M+lf); RT - 2.79, (UV, ELSD) 94%, 100%. 2e N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-thiophen-2-ylacetamide. LC/MS (m/z) 367.1 ([M+lf); RT = 2.72, (UV, ELSD) 93%, 100%. 2f N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide. LC/MS (m/z) 379.3 ([M+lf); RT = 2.82, (UV, ELSD)'95%, 100%. 2g 3-[l-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-l, 1 -diisopropylurea.
LC/MS (m/z) 392.3 ([M+lf); RT = 3.14, (UV, ELSD) 75%, 89%. 2h Morpholine-4-carboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide.
■ LC/MS (m/z) 378.2 ([M+lf); RT = 2.33, (UV, ELSD) 97%, 100%. / ' 2i Pyrrolidine-l-carboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide.
LC/MS (m/z) 362.0 ([M+lf); RT = 2.48, (UV, ELSD) 83%, 99%. 2j [l-(5~Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH~indol-5-yl]-carbamic acid 2-benzyloxyethyl ester.
LC/MS (m/z) 442.1 ([Mf); RT = 3.52, (UV, ELSD) 62%, 86%. 2k 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-ylJ-l-methyl-l-propylurea.
LC/MS (m/z) 364.3 ([M+lf); RT = 2.73, (UV, ELSD) 94%, 100%. 21 [1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid tert-butyl ester.
LC/MS (m/z) 364.3 ([Mf); RT = 3.50, (UV, ELSD) 97%, 100%.
WO 2004/096767 PCT/DK2004/000283 86 2mN-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide.
LC/MS (m/z) 418.2 ([Mf); RT = 3.44, (UV, ELSD) 98%, 100%. 2n Butane-1-sulfonic acid [l-(5-chlorothiophen~2-ylmeihyl)-2,3-dihydro-lH-indol-5-yl]-amide.
LC/MS (m/z) 384.1 ([M]+); RT = 3.43, (UV, ELSD) 98%, 100%. 2oN-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-4-fluorobenzamide.
LC/MS (m/z) 386.0 ([M]+); RT = 3.35, (UV, ELSD) 91%, 100%. 2p N-[l-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2,2-dimethylpropionamide.
LC/MS (m/z) 349.0 ([M+l]+); RT = 3.21, (UV, ELSD) 94%, 100%. 2q N-fl-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-ylJ-2- phenoxyacetamide.
LC/MS (m/z) 398.0 ([M]+); RT = 3.46, (UV, ELSD) 80%, 100%. 2r N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
LC/MS (m/z) 362.1 ([M]+); RT = 3.34, (UV, ELSD) 84%, 99%. 2s N-[1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-butyramide. LC/MS (m/z) 335.0 ([M+l]4); RT = 2.95, (UV, ELSD) 78%, 99%. 2t Cyclopentanecarboxylic acid[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide.
LC/MS (m/z) 361.1 ([M+l]4); RT = 3.22, (UV, ELSD) 84%, 99%. 2u N-fl-(5-Chlorothiopken-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2-thiophen-2-ylacetamide.
WO 2004/096767 PCT/DK2004/000283 87 LC/MS (m/z) 388.1 ([Mf); RT = 3.22, (UV, ELSD) 76%, 98%. 2v N-[l-(5-Chlorothiophen-2-ybnethyl)-2,3-dihydro-lH-indol-5-yl]-isomcotinamide. LC/MS (m/z) 370.0 ([M+lf); RT = 2.22, (UV, ELSD) 96%, 100%. 2w N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5~yl]-4-dimethylaminobenzamide.
LC/MS (m/z) 412.0 ([M+lf); RT = 3.09, (UV, ELSD) 87%, 100%. 2x N-[1 ~(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluoroph enyl) -a cetamide.
LC/MS (m/z) 401.0 ([M+lf); RT = 3.31, (UV, ELSD) 84%, 100%. 2y N-[1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-6-trifluoromethylnicotinamide.
LC/MS (m/z) 437.1 ([M]4); RT - 3.46, (UV, ELSD) 90%, 99%. 2z l-tert-Butyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea. LC/MS (m/z) 364.3 ([M+l]4); RT = 2.80, (UV, ELSD) 97%, 100%. 2aa 1 -fl-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ-3-ethylurea. LC/MS (m/z) 335.1 ([M]"1); RT = 2.34, (UV, ELSD) 96%, 100%. 2ab l-Benzyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-urea. LC/MS (m/z) 398.2 ([M+l]4); RT = 2.85, (UV, ELSD) 84%, 100%. 2ac l-[l-(5-Chloroth iophen -2-ylmethyl) -2,3-dihydro-1 H-indol-5-ylJ-3-phenethylurea. LC/MS (m/z) 411.9 ([M+l]4); RT = 3.00, (UV, ELSD) 87%, 97%. 2ad l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-2-ylurea.
LC/MS (m/z) 390.0 ([M+lf); RT = 3.01, (UV, ELSD) 94%, 92%.
WO 2(104/096767 PCT/DK2004/000283 88 2ae l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thiophen-3-ylurea.
LC/MS (m/z) 390.2 ([M+l]4); RT = 2.98, (UV, ELSD) 96%, 100%. 2af [l-(5-Chlorothiophen-2-yhnethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester.
LC/MS (m/z) 351.2 ([Mf); RT = 3.48, (UV, ELSD) 94.0%, 98.0%. 'H NMR (DMSO-de): 0.92 (t, 3H); 1.62 (sextet, 2H); 2.84 (t, 2H); 3.22 (t, 2H), 3.89 (t, 2H), 4.38 (s, 2H), 6.59 (d, IH); 6.92 (d, IH); 6.98 (d, IH); 7.07 (br. d (dd), IH); 7.18 (br. s, IH); 9.20 (br s5 IH, NH). 89 Table 1. Chloroformiates, sulphonyl chlorides, carbamyl chlorides, acid chlorides, and isocyanates used in the preparation of compounds of the invention 2a - 2af Compound of the Reagent invention MW Supplier Catalog number 2a n-PROPYL CHLOROFORMATE 122.55 Aldrich 24,946-7 2b ALPHA-TOLUENESULFONYL 190.649 CHLORIDE Aldrich ,971-9 2c 4-FLUOROBENZOYL CHLORIDE 158.559 Aldrich 11,994-6 2d TERT-BUTYLACETYL CHLORIDE 134.605 Aldrich B 8,880-2 2e THIOPHENE-2-ACETYL CHLORIDE 160.624 Aldrich 19,599-5 2f 4-FLUOROPHENYLACETYL CHLORIDE 172.585 Aldrich 46,695-6 2g DnSOPROPYLCARBAMYL CHLORIDE 163.647 Aldrich S31,027-1 2h MORPHOLESTE-4-C ARB ONYL 149.576 CHLORIDE Aldrich 34,829-5 2i 1-PYRROLIDINECARBONYLCHLORIDE133.577 Aldrich ,635-0 2j 2-BENZYLOXYETHYL 214.647 CHLOROFORMATE Aldrich 52,514-6 2k N-IS OPROPYL-N-METHYL-C ARB AMYL 135.59 Lundbeck C0005221 CHLORIDE 21 DI-TERT-BUTYL DICARBONATE 218.247 Fluka 34660 2m ALPHA-TOLUENESULFONYL 190.649 CHLORIDE Aldrich ,971-9 2n 1 -BUTANESULFONYL CHLORIDE 156.632 Aldrich 26,360-5 2o 4-FLUOROBENZOYL CHLORIDE 158.559 Aldrich 11,994-6 2P PIVALOYL CHLORIDE 120.578 Aldrich T7,260-5 2q PHENOXYACETYL CHLORIDE 170.594 Aldrich ,862-3 2r TERT-BUTYLACETYL CHLORIDE 134.605 Aldrich B8,880-2 2s BUTYRYL CHLORIDE 106.551 Aldrich ,961-4 2t CYCLOPENTANECARBONYL 132.589 CHLORIDE Aldrich 32,831-6 2u THIOPHENE-2-ACETYL CHLORIDE 160.624 Aldrich 19,599-5 2v IS ONICOTINOYL CHLORIDE 178.018 Aldrich 22,875-3 HYDROCHLORIDE 2w 4-DIMETHYLAMINOBENZOYL 183.637 CHLORIDE Aldrich 52,611-8 2x 4-FLUOROPHENYLACETYL CHLORIDE 172.585 Aldrich 46,695-6 2y 6-(TRIFLUOROMETHYL)NICOTIN OYL 209.554 Fluoroche 9368 CHLORIDE m 2z TERT-BUTYLISOCYANATE 99.132 Aldrich 14,445-2 2aa ETHYL ISOCYANATE 71.08 Aldrich E3,330-0 2ab BENZYL ISOCYANATE 133.149 Aldrich 22,726-9 2ac PHENETHYL ISOCYANATE 147.176 Aldrich 45,617-9 2ad 2-THIENYL ISOCYANATE 125.151 Maybridge CC 13006 2ae 3-THIENYL ISOCYANATE 125.151 Maybridge CC 13106 2af n-PROPYL CHLOROFORMATE 122.55 Aldrich 24,946-7 90 Example 3 3a 2,2-DimetIiyl-N-[6-nitro-l-(4-t)-ifluoromethylbenzyl)-2,3-diiiydro-lH-indol-5-yl]-propionamide.
To a stirred solution of 2,2-Dimethyl-N-(6-nitro-2,3-dihydro-lH-indol-5-yl)-propionamide (0.379 g, 1.44 mmol) in methanol (25 ml) 4-triflaorometbylbenzaldehyde (0.8 ml), acetic acid (0.8 ml) and a solution of NaBHjCN (0.8 g) in methanol (10 ml) were added in 4 portions during 3 hours until reaction completion. The obtained reaction mixture was concentrated in vacuo to a small volume, quenched with saturated aqueous NaHCCh solution, and sonicated for several minutes. The title compound was separated by filtration to give 0.574g of red solid, yield 95%. LC/MS (m/z) 422.1 ([M+l]4); RT = 4.11, (UV, ELSD) 96%, 99%.
NMR (DMSO-de): 1.20 (s, 9H), 3.04 (t, 2H), 3.42 (t, 2H), 4.49 (s, 2H), 7.09 (s, IH), 7.48 (s, IH), 7.57 (d, 2H), 7.73 (d, 2H), 9.62 (s, IH, NHCO).
The following compounds were prepared analogously: 3b N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-lH-indol-5-yl]-2J2-dimethylpropionamide.
LC/MS (m/z) 394.0 ([M+l]"); RT = 4.07, (UV, ELSD) 97%, 98%. *H NMR (DMSO-d6): 1.20 (s, 9H), 3.00 (t, 2H), 3.41 (t, 2H), 4.55 (s, 2H), 6.97 (d, IH), 7.01 (d, IH), 7.22 (s, IH), 7.47 (s, IH), 9.62 (s, IH, NHCO). 3c 2-(4-Fluorophenyl)-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-acetamide.
LC/MS (m/z) 474.2 ([M+lf); RT = 3.89, (UV, ELSD) 80%, 97%. 3d N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 445.1 ([Mf); RT = 3.88, (UV, ELSD) 79.8%, 98.9%. 'H NMR (DMSO-de): 2.98 (t, 2H); 3.41 (t, 2E), 3.63 (s, 2H), 4.54 (s, 2H), 6.96 (d, IH); 7.0 (d, IH); 7.16 (t, 2H); 7.17 (s, IH); 7.31 (s, IH); 7.34 (dd, 2H); 10.03 (s, IH, NH). 91 PC T/DK2004/000283 3e N-[l-(5-Chlorothiophen-2-ybnethyl)-6-iiitro-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
LC/MS (m/z) 407.1 ([Mf); RT = 4.07, (UV, ELSD) 72.4%, 98.7%. 'H NMR (DMSO-dfi): 1.01 (s, 9H); 2.16 (s, 2H); 2.99 (t, 2H); 3.41 (t 2H), 4.54 (s, 2H), 6.98 (d, 5 IH); 7.01 (d, IH); 7.14 (s, IH); 7.23 (s, IH); 9.76 (s, IH, NH).
Example 4 4a N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-10 dimethylbutyramide.
To a solution of 3.3-dimethyl-N-(6-mtro-2,3-dihydro- lH-indol-5 -yl)-butyramide (15 mg), 5-ahloro-2-thiophenecarboxaldehyde (50 mg), and acetic acid (0.1 ml) in methanol (5 ml) NaBtLCN (200 mg) was added. After 30 min the reaction mixture was concentrated in vacuo to a small volume and partitioned between ethyl acetate 15 and water. The organic solution was washed with aqueous HC1 (1 M) and saturated aqueous NaHCCh and evaporated in vacuo.
The obtained residue was dissolved in tetrahydrofuran (10 ml) and acetic acid (2 ml) followed by addition of Zn powder (1 g). The obtained suspension was sonicated for 5 min, more Zn powder was added (0.5 g) and sonication continued for 20 2 min. The obtained suspension was filtered via a plug of SiC>2 (2 g), evaporated, and the title compound was separated by preparative LC/MS to give 6.5 mg of colourless solid, yield 32%. LC/MS (m/z) 378.0 ([M+l]4); RT = 2.36, (UV, ELSD) 93%, 98%. %. }H NMR (DMSO-ds): 1.03 (s, 9H), 2.17 (s, 2H), 2.82 (t, 2H), 3.30 (t, 2H), 3.55 (very br. s, NH2 and'H20), 4.38 (s, 2H), 6.27 (s, IH), 6.81 (s, IH), 6.93 (d, IH), 7.00 25 (d, IH), 9.27 (br. s, IH, NHCO). 4b N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2,2-dimethylpropionamide.
The title compound was prepared from the above 2,2-dimethyl-N-[6-nitro-l-(4-30 trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-propionamide (see example 3) by reduction with Zn powder as described above for l-(5-Chlorothiophen-2-ylmethyl)-5-aminoindoline (see preparation of intermediates of the general formula XXI). The crude solid residue after filtration via SiOa was treated with ethyl acetate and heptane 92 and the title compound was separated by filtration. Yield 0.375 g, 71%, colourless solid. LC/MS (m/z) 392.3 ([M+l]4); RT = 2.38, (UV, ELSD) 97%, 99%. lH NMR (DMSO-d6): 1.20 (s, 9H), 2.77 (t, 2H), 3.25 (t, 2H), 4.28 (s, 2H), 4.34 (s, 2H, NH2), 5.96 (s, IH), 6.64 (s, IH), 7.56 (d, 2H), 7.71 (d, 2H), 8.47 (s, 1H, NHCO).
The following compounds were prepared analogously from corresponding 6-nitroindolines of the general formula XXV in two steps via reductive alkylation with appropriate aldehyde as described in the example 3 followed by reduction with Zn powder as described above. 4c N-[6-Ammo-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2,2-dimethylpropionamide.
LC/MS (m/z) 364.2 ([M+l]4); RT = 2.19, (UV, ELSD) 98%: 99%. NMR (DMSO-d6): 1.20 (s, 9H), 2.72 (t, 2H), 3.21 (t, 2H), 4.33 (s, 2H), 4.39 (br. s, 2H, NH2), 6.07 (s, IH), 6.64 (s, IH), 6.91 (d, IH), 6.98 (d, IH), 8.48 (s, IH, NHCO). 4d N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-IH-indol-5-yl]-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 444.0 ([M+l]4); RT = 2.65, (UV, ELSD) 95%, 99%. 'HNMR (DMSO-d6): 2.76 (t, 2H), 3.24 (t, 2H), 3.57 (s, 2H), 4.26 (s, 2H), 4.51 (br. s, 2H, NH2), 5.92 (s, IH), 6.73 (s, 1H), 7.14 (t, 2H), 7.36 (dd, 2H), 7.55 (d, 2H), 7.71 (dd, 2H), 9.08 (s, IH, NHCO). 4e N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-iiidol-5-yl]-3,3- dimethylbutyramide.
LC/MS (m/z) 406.0 ([M+lf); RT = 2.58, (UV, ELSD) 97.4%, 99.0%. 'H NMR (DMSO-ds): 1.02 (s, 9H); 2.12 (s, 2H); 2.78 (t, 2H); 3.24 (t, 2H); 4.28 (s, 2H), 4.48 (s, 2H, NH2); 5.93 (s, IH); 6.74 (s, IH); 7.56 (d, 2H); 7.71 (d, 2H); 8.81 (s, 1H,NH). 4f N-[6-Amino-l-(4-fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3- dimethylbutyramide.
WO 2004/096767 PCT/DK2004/000283 93 LC/MS (m/z) 356.0 ([M+lf); RT = 2.26, (UV, ELSD) 96.7%, 98.9%. NMR (DMSO-de): 1.02 (s, 9H); 2.13 (s, 2H); 2.73 (t, 2H); 3.18 (t, 2H); 4.16 (s, 2H), 4.48 (s, 2H, NH2); 5.98 (s, IH); 6.71 (s, IH); 7.17 (t, 2H); 7.36 (dd, 2H); 8.80 (s, IH, NH). 4g N-[6-Amino-l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
LC/MS (m/z) 424.0 ([M+lf); RT = 2.58, (UV, ELSD) 92.0%, 98.8%. 'H NMR (DMSO-ds): 1.01 (s, 9H); 2.12 (s, 2H); 2.79 (t, 2H); 3.28 (t, 2H); 4.27 (s, 2H), 4.48 (s, 2H,NH2); 5.90 (s, IH); 6.75 (s, IH); 7.39 (d, IH); 7.45 (d, IH); 7.78 (t, IH); 8.80 (s, 1H,NH).
Example 5 'AN-[l-(5-Chlorothiophen-2-ylmethyl)-lH-indol-5-yl]-3,3-dimethylbutyramide. To a solution of N- [ 1 ~(5-Chlorotliiophen-2-yknetkyl)-2,3-dihydro-1 H-indol-5~yl]-3,3-dimethylbutyramide (20 mg) in dimethylsulfoxide-d^ (0.6 ml) 2,3,5,6-tetrachloro-[l,4]benzoquinone (65 mg) was added. The obtained mixture was heated at 70°C for 5 min, allowed to cool and poured into aqueous NaHS03 solution (1 g in 5 ml) followed by addition of 25% aqueous NH3 (5 ml) and 10% aqueous NaOH (5 ml). The mixture was extracted with CH2CI2 (3x10 ml), the combined organic solution was washed with water and 1M HC1, filtered via plug of Si02 (10 g) and eluted with ethyl acetate/heptane (1:1). The crude product after evaporation was purified by preparative LC/MS to give 5 mg of the title compound as colourless solid. LC/MS (m/z) 361.1 ([M+lf); RT = 3.43, (UV, ELSD) 96%, 99%. *H NMR (DMSO-d6): 1.03 (s, 9H), 2.16 (s, 2H), 5.51 (s, 2H), 6.41 (d, IH), 6.95 (d, IH), 6.98 (d, IH), 7.21 (dd, IH), 7.41 (d, IH), 7.44 (d, IH), 7.87 (d, IH), 9.60 (s, IK, NHCO).
Example 6 6a N-[6-Bromo-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-y!]-3,3- dimethylbutyramide.
The title compound was prepared from 3,3-dimethyl-N-(6-bromo-2,3-dihydro-lH-indol-5-yl)-butyraniide (25 mg) and 4-trifluoromethylbenzaldehyde (64 mg) as WO 2004/096767 PCT/DK2004/000283 94 described in example 1. Yield 16.7 mg. LC/MS (m/z) 469.1 ([M+l]4); RT. = 3.99, (UV, ELSD) 97.4%, 95.1%.
' The following compound was prepared analogously using appropriate aldehyde: 6b N-[6-Bromo-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
Yield 16.8 mg. LC/MS (m/z) 443.1 ([M+l]4); RT = 3.92, (UV, ELSD) 96.3%, 94.9%. Example 7 General procedure: To a mixture of aldehyde (25 mg or 0.025 ml) and appropriate indoline (7 mg) in methanol (0.5 ml) NaBH/jCN (20 mg) in methanol (0.2 ml) was added followed by acetic acid (0.05 ml). The obtained solution or suspension was sonicated for 5 min and then kept at 50°C for 60 min followed by evaporation in vacuo. The residue was dissolved in DMSO (2.5 ml) and water (100 ml). The product was isolated by preparative LC/MS.
The following compounds were prepared accordingly from either N-(2,3-Dihydro-lH-indol-5-yl)-3,3-dimethyl-butyramide (compounds 7a-7z) or from N-(2,3-Dihydro-lH-indol-5-yl)-2-(4-fluoro-phenyl)-acetamide (compounds 7aa-7aw) and the appropriate aldehyde (see Table 2 below): 7a N-[l-(4-Chlorobenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide. LC/MS (m/z) 357.2 ([M+l]4); RT = 3.17, (UV, ELSD) 77.1%, 97.2%. 7b 3,3-Dimethyl-N-[l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-butyramide.
LC/MS (m/z) 391.4 ([M+lf); RT = 3.44, (UV, ELSD) 91.8%, 99.6%. 7c N-[l-(4-Isopropylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimetliylbutyramide. LC/MS (m/z) 365.4 ([M+l]4); RT = 3.13, (UV, ELSD) 89.4%, 99.2%.
WO 2004/096767 PCT/DK2004/000283 95 7d N-[l-(3-Fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3- dimethylbutyramide.
LC/MS (m/z) 409.2 ([M+l]"); RT = 3.60, (UV, ELSD) 69.6%, 98.2%. 7e N-[l-(6- Chlorobenzo[l, 3]dioxol-5'ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyrarnide.
LC/MS (m/z) 401.0 ([M+lf); RT = 3.22, (UV, ELSD) 94.6%, 99.5%. 7iN-[l-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
LC/MS (m/z) 417.2 ([M+lf); RT = 2.23, (UV, ELSD) 93.3%, 98.9%. 7gN-[l-(2-Chloro-5-trifluoromethylbe?izyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide.
LC/MS (m/z) 425.2 ([M+l]"); RT = 3.79, (UV, ELSD) 75.4%, 98.4%. 7h N-{l-[5-(4-Chlorophenoxy)-l,3-dimethyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide.
LC/MS (m/z) 467.3 ([M+lf); RT = 2.71, (UV, ELSD) 95.2%, 99.8%. 7j 3,3-Dimethyl-N-fi-(6-p-tolylox)>-pyridin-3-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide.
LC/MS (m/z) 430.2 ([M+lf); RT = 3.15, (UV, ELSD) 76.6%, 97.9%. 7k N-{l-[6-(4-Chlorophenylsulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide.
LC/MS (m/z) 466.0 ([M+lf); RT = 3.45, (UV, ELSD) 69.3%, 97.1%. l\N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]'2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide.
LC/MS (m/z) 441.4 ([M+l]"4); RT = 2.98, (UV, ELSD) 79.8%, 98.9%.
WO 2004/096767 PCT/DK2004/000283 96 7m 3,3-Dimethyl-N-f1 -(6-trifluoromethylpyridin-3-ylmethyl) -2,3-dihydro-l H-indol-5-yl]-butyramide.
LC/MS (m/z) 392.4 ([M+lf); RT = 3.10, (UV, ELSD) 82.5%, 99.5%. 7p 3,3-Dimethyl-N-[l-(3-methyl-benzo[b]thiophen-2-y2methyl)-2,3-dihydro-lH-indol-5-yl]-butyramide.
LC/MS (m/z) 393.3 ([M+lf); RT = 3.56, (UV, ELSD) 72.8%, 97.9%. 7q N-[l-(6-Fluoro-4H-bsnzo[l, 3] dioxin-8-ylmethyl)-2,3-dihydro-lH-mdol-5-ylJ-3,3-dimetkylbutyramide.
LC/MS (m/z) 399.2 ([M+lf); RT = 2.75, (UV, ELSD) 84.9%, 99.3%. 7s 3,3-Dimethyl-N-[1 -(6-phenoxypyridin-3-ylmethyl)-213-dihydro-lH-indol-5-yl]-butyramide.
LC/MS (m/z) 416.2 ([M+lf); RT = 2.98, (UV, ELSD) 67.5%, 96.5%. 7u 3,3-Dimethyl-N-[l-(3-methyl-5-phenyl-isoxazol-4-ylwiethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide.
LC/MS (m/z) 404.4 ([M+l]1); RT = 3.24, (UV, ELSD) 97.6%, 99.9%. 7v N-(l-Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-lH--indol-5-yl)-3,3-dimethylbutyramide.
LC/MS (m/z) 379.3 ([M+lf); RT = 3.44, (UV, ELSD) 71.8%, 97.6%. 7w N-{l-[l-(4-Fluorophenyl)-5~methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-3,3-dimethylbutyramide.
LC/MS (m/z) 421.4 ([M+l]4); RT = 2.24, (UV, ELSD) 79.5%, 98.9%. 7y 3,3-Dimethyl-N-[!-(5-methylthiophen-2-ylmethyl) -2,3-dihydro-l H-indol-5-yl]-butyramide.
LC/MS (m/z) 343.1 ([M+l]1); RT = 2.84, (UV, ELSD) 59.9%, 89.1%. lx3,3-Dimethyl-N-[l'(4-pyrrol-l-yl'benzyl)-2,3-dihydro-lH-indol-5-yl]-butyramide. 97 LC/MS (m/z) 388.3 ([M+l]1); RT = 3.03, (UV, ELSD) 81.1%, 99.5%. 7aa N-[l-(4-Chlorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide. LC/MS (m/z) 395.1 ([M+l]1); RT = 2.99, (UV, ELSD) 93.4%, 93.1%. 7ab 2-(4-Fluorophe}iyl)-N-[l-(4-trifluoromethylbenzyI)-2,3-dihydro-lH-indol-5-yl]-acetamide.
LC/MS (m/z) 429.1 ([M+lf); RT= 3.24, (UV, ELSD) 76.6%, 87.4%. 7ac 2-(4-Fluorophenyl)-N~[l-(4-isopropylbenzyl)-2,3-dihydro-lH-indol-5-yl]-acetamide.
LC/MS (m/z) 403.1 ([M+lf); RT = 2.96, (UV, ELSD) 91.5%, 83.7%. 7ad 2-(4-Fluorophenyl)-N~[l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl/-acetamide.
LC/MS (m/z) 447.2 ([M+l]1); RT = 3.36, (UV, ELSD) 79.3%, 90.4%. 7ae N-[l-(6~Chlorobenzo[l ,3]dioxol-5-yImethyl)-213-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 439.0 ([M+l]1); RT = 3.02, (UV, ELSD) 94.0%, 92.2%. 7af N-[1 -(3,5-Dimethyl-l -phenyl~lH-pyrazol-4-ylmethyl)-2,3-dihydro-l H-indol-5-ylJ-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 455.0 ([M+l]1); RT = 2.14, (UV, ELSD) 97.1%, 91.4%. la%N-[l-(2-ChlorO'5-ti-ifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 463.1 ([M+l]1); RT = 3,53, (UV, ELSD) 98.3%, 95.3%. 7ah N-{l-[5-(4-Chlorophenoxy)-l,3-dimethyl'lH-pyrazol-4-ylmethylJ-2,3-dihydro- lH-indol-5-yl}-2-(4'fluorophenyl)-acetamide.
LC/MS (m/z) 503.3 ([M-lf); RT = 2.55, (UV, ELSD) 92.3%, 90.5%.
WO 2004/096767 PCT/DK2004/000283 98 7ai N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 479.1 ([M+lf); RT = 2.81, (UV, ELSD) 84.1%, 87.1%. 7al 2-(4-Flu,orophenyl)-N-[l-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1 H-indol-5-y I]-acetamide.
LC/MS (m/z) 431.2 ([M+l]4); RT = 3.34, (UV, ELSD) 60.2%, 88.8%. 7am N-[l-(6-Fluoro-4H-benzo[l, 3]dioxin-8-ylmethyl)-2,3-dihydro-lH-indol-5-ylJ -2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 437.0 ([M+l]"1); RT = 2.62, (UV, ELSD) 79.7%, 83.6%. 7ao 2-(4-Fluorophenyl)-N-[l-(6-phetioxypyridin-3-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-acetamide.
LC/MS (m/z) 454.3 ([M+lf); RT = 2.81, (UV, ELSD) 77.9%, 83.1%. 7a.rN-(l-Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-lH-indol-5-yl)-2-(4-fluorophenyl)-acetamide.
LC/MS (m/z) 417.2 ([M+lf); RT = 3.22, (UV, ELSD) 80.2%, 89.4%. 7as 2-(4-Fluorophenyl)-N-{l-[l-(4-fluorophenyl)-5-methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-acetamide.
LC/MS (m/z) 459.3 ([M+lft; RT = 2.15, (UV, ELSD) 91.5%, 88.7%. 7au 2-(4-Fluorophenyl)-N-[l-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-acetamide.
LC/MS (m/z) 381.1 ([M+l]4); RT =2.71, (UV, ELSD) 76.6%, 82.9%. 7av 2-(4-Fliioropkenyl)-N'-[l-(4-py?rol-l-yl-benzyl)~2,3-dihydro-l H-ijidol-5-yl]-acetamide, LC/MS (m/z) 426.1 ([M+lf); RT = 2.87, (UV, ELSD) 92.2%, 88.2%.
WO 2004/096767 PCT/DK2004/000283 99 Table 2. Aldehydes used in the preparation of compounds of the invention 7a — 7av Compound of the Aldehyde invention MW Supplier Catalog number 7a 4-CHLOROBENZALDEHYDE 140.568 Aldrich 7b 4-(TRIFLUOROMETHYL)- 174.12 Aldrich BENZALDEHYDE 7c 4-ISOPROPYLBENZALDEHYDE 148.204 Aldrich 7d 3-FLUORO-4-(TRIFLUOROMETHYL)- 192.111 ABCR AV20008 BENZALDEHYDE 7e 6-CHLOROPIPERONAL 184.577 ABCR AVI 3607 7f 3,5-DIMETHYL-1 -PHENYLPYRAZOLE- 200.24 Acros 40852-0050 4-C ARB OXALDEHYDE Organics 7g 2-CHLORO-5-(TRIFLUOROMETHYL)- 208.566 Aldrich 37,682-5 BENZALDEHYDE 7h -(4-CHLOROPHENOXY)-l,3- 250.684 Bionet 11F-431S DIMETHYL-1H-PYRAZOLE-4- Research CARBALDEHYDE 7j 6-(4-METHYLPHENOXY)- 213.235 Bionet 5L-355S NICOTINALDEHYDE Research 7k 6-[(4-CHLOROPHENYL)SULFANYL]- 249.72 Bionet 5L-356S NICOTINALDEHYDE Research 71 4-[(5-FORMYL-2-PYRIDINYL)OXY]~ 224.218 Bionet 6L-309S B ENZENE C ARB ONITRILE Research 7m 6-(TRIFLUOROMETHYL)P YRIDINE-3 - 175.109 Fluoroche 9397 CARBOXALDEHYDE m 7p 3-METHYLBENZO[B]THIOPHENE-2- 176.238 ABCR AVI 1375 CARBOXALDEHYDE 7q -FLU ORO-4H-1,3 -BENZODIOXINE-5- 182.149 Maybridge CC 01904 CARB ALDEHYDE 7s 6-PHENOXYNICOTINALDEHYDE 199.208 Maybridge CC 19604 7u 3-METHYL-5-PHENYL-4- 187.197 Maybridge CC 20304 ISOXAZOLECARB ALDEHYDE 7v 1 -BENZOTHIOPHENE-2- 162.211 Specs 942/2503463 CARB ALDEHYDE 9 7w l-(4-FLUOROPHENYL)-5-METHYL-lH- 204.203 Maybridge MO 00310 PYRAZOLE-4-CARB ALDEHYDE 7y -METHYL-2- 126.178 Aldrich M8,441-0 THIOPHENEC ARB OXALDEHYDE 7z 4-( 1H-P YRROL-1 -YL)BENZ ALDEHYDE 171.198 Maybridge N/A 7aa 4-CHLOROBENZALDEHYDE 140.568 Aldrich 7ab 4-(TRIFLUOROMETHYL)- 174.12 Aldrich BENZALDEHYDE 7ac 4-ISOPROPYLBENZALDEHYDE 148.204 Aldrich 7ad 3-FLUORO-4-(TRIFLUOROMETHYL)- 192.111 ABCR AV20008 BENZALDEHYDE 100 7ae 6-CHLOROPIPERONAL 184.577 7af 3,5-DIMETHYL-1-PHENYLPYRAZOLE- 200.24 4-CARBOXALDEHYDE 7ag 2-CHLORO-5- 208.566 (TRIFLUOROMETHYL)BENZALDEHYD E 7ah 5-(4-CHLOROPHENOXY)-l,3- 250.684 DIMETHYL-1H-PYRAZOLE-4-CARBALDEHYDE 7ai 4-[(5-FORMYL-2- 224.218 PYRIDINYL)OXY]BENZENECARB ON1T RILE 7al 3-METHYLBENZO[B]THIOPHENE-2- CARBOXALDEHYDE 7am 5-FLUORO-4H-1,3-BENZODIOXINE-5- CARBALDEHYDE 7ao 6-PHENOXYNICOTINALDEHYDE 7ar l-BENZOTHIOPHENE-2- CARBALDEHYDE 7as 1 -(4-FLUOROPHENYL)-5-METHYL-1H- 204.203 PYRAZOLE-4-CARB ALDEHYDE 7au 5-METHYL-2- 126.178 TfflOPHENECARBOXALDEHYDE 7av 4-( 1H-PYRROL-1 -YL)BENZALDEHYDE 171.198 199.208 162.211 ABCR AVI3607 Acros 40852-0050 Organics Aldrich 37,682-5 Bionet 11F-431S Research Bionet 6L-309S Research 176.238 ABCR AVI 1375 182.149 Maybridge CC 01904 Maybridge CC 19604 Specs 942/2503463 9 Maybridge MO 00310 Aldrich M8,441-0 Maybridge N/A 101 PCT/DK2 This exemplifies a KCNQ2 screening protocol for evaluating compounds of the present invention. The assay measures the relative efflux through the KCNQ2 channel, and was carried out according to a method described by Tang et al. (Tang, 10 W. et. al., J. Biomol. Screen. 2001, 6, 325-331) for hERG potassium channels with the modifications described below.
An adequate number of CHO cells stably expressing voltage-gated KCNQ2 channels were plated at a density sufficient to yield a mono-confluent layer on the day of the 15 experiment. Cells were seeded on the day before the experiment and loaded with 1 [j.Ci/ml [86Rb] over night. On the day of the experiment cells were washed with a HBSS-containing buffer. Cells were pre-incubated with drug for 30 minutes and the 86 "4" Rb efflux was stimulated by a submaximal concentration of 15 mM KC1 in the continued presence of drug for additional 30 minutes. After a suitable incubation 20 period, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). Cells were lysed with 2 mM NaOH and the amount of 86Rb+ was counted. The relative efflux was calculated ((CPMSUper/(CPMSUper+ CPMceii))cnipd/ (CPMsuper/(CPMsl,per+ CPMceii))^^ KCl)* 100-100.
The compounds of the invention have an EC50 of less than 20000nM, in most cases less than 2000 nM and in many cases less than 200 nM. Accordingly, the compounds of the invention are considered to be useful in the treatment of diseases associated with the KCNQ family potassium channels.
Electrophysiological patch-clamp recordings.
Voltage-activated KCNQ2 currents were recorded from mammalian CHO cells by use of conventional patch-clamp recordings techniques in the whole-cell patch-clamp configuration (Hamill OP et.al. PfliigersArch 1981; 391: 85-100). CHO cells with 102 stable expression of voltage-activated KCNQ2 channels were grown raider normal cell culture conditions in C02 incubators and used for electrophysiological recordings 1-7 days after plating. KCNQ2 potassium channels were activated by voltage steps up to + 80 mV in increments of 5-20 mV (or with a ramp protocol) from a membrane 5 holding potential between - 100 mV and - 40 mV (Tatulian L et al. J Neuroscience 2001; 21 (15): 5535-5545). The electrophysiological effects induced by the compounds were evaluated on various parameters of the voltage-activated KCNQ2 current. Especially effects on the activatiorfthreshold for the current and on the maximum induced current were studied.
Some of the compounds of the invention have been tested in this test. A left-ward shift of the activation threshold or an. increase in the maximum induced, potassium current is expected to decrease the activity in neuronal networks and thus make the compounds useful in diseases with increased neuronal activity - like epilepsia.
Maximum electroshock The test was conducted in groups of male mice using corneal electrodes and administering a square wave current of 26mA for 0.4 seconds in order to induce a convulsion characterised by a tonic hind limb extension (Wlaz et al. Epilepsy 20 Research 1998, 30,219-229).
Pilocarpine induced seizures Pilocarpine induced seizures are induced by intraperitoneal injection of pilocarpine 250mg/kg to groups of male mice and observing for seizure activity resulting in loss 25 of posture within a period of 30 minutes (Starr et al. Pharmacology Biochemistry and Behavior 1993,45,321-325).
Electrical seizure -threshold test A modification of the up-and-down method (Kimball et al.. Radiation Research 1957, 30 1-12) was used to determine the median threshold to induce tonic hind-limb extension in response to corneal electroshock in groups of male mice. The first mouse of each group received an electroshock at 14 mA, (0.4 s, 50 Hz) and was observed for seizure activity. If a seizure was observed the current was reduced by 1 mA for the next PCT7DK2004/000283 103 mouse, however, if no seizure was observed then the current was increased by 1 mA. This procedure was repeated for all 15 mice in the treatment group.
Chemical seizure -threshold test The threshold dose of pentylenetetrazole required to induce a clonic convulsion was measured by timed infusion of pentylenetetrazols (5mg / mL at 0.5 mL/minute) into a lateral tail vein of groups of male mice (Nutt et al. J Pharmacy and Pharmacology 1986,38,697-698), Amygdala kindling Rats underwent surgery to implantation of tri-polar electrodes into the dorsolateral amygdala. After surgery the animals were allowed to recover before the groups of rats received either varying doses of test compound or the drug's vehicle. The animals were stimulated with their initial after discharge threshold + 25 |_iA daily for 3-5 weeks and on each occasion seizure severity, seizure duration, and duration of electrical after discharge were noted. (Racine. Electroencephalography and Clinical Neurophysiology 1972,32, 281-294). _ Side effects Central nervous system side-effects were measured by measuring the time mice would remain on rotarod apparatus (Capacio et al. Drug and Chemical Toxicology 1992, 15, 177-201); or by measuring their locomotor activity by counting the number of infrared beams crossed in a test cage (Watson et al. Neuropharmacology 1997,36, 1369-1375). Hypothermic actions on the animals core body temperature of the compound were measured by either rectal probe or implanted radiotelemetry transmitters capable of measuring temperature (Keeney et al. Physiology and Behaviour 2001, 74, 177- = 184).
Pharmacokinetics The pharmacokinetic properties of the compounds were determined via. i.v. and p.o. dosing to Spraque Dawley rats, and, thereafter, drawing blood samples over 20 hours. Plasma concentrations were determined with LC/MS/MS. 104

Claims (33)

1.WHAT WE CLAIM IS: 1 A substituted indoline or indole derivative of the general formula I
2.H ^
3.^ Xr ^ R3
4.(I) wherein the dotted line represents an optional bond; 1 1*;10 R andR are independently selected from the group consisting of hydrogen, Cj.;6-alk(en/yn)yl, C3_8-cycloalk(en)yl, C3_8-cycloalk(en)yl-Ci_6-alk(en/yn)yl, hydroxy-Ci.6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci.6-alk(en/yn)yl, hal o-C,-6-alk(cn/yn)yl, halo-C3-g-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-C i_6-alk(en/'yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-15 cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or;R1 and R1 together with the carbon atom to which they are attached form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms;;20;s is 0 or 1;;25;U is O, NR11, S, S02, S02NRn COO or CO-NR11; wherein R11 is selected from the group consisting of hydrogen, Cj-6-alk(en/yn)yl, C3_g-cycloalk(en)yl, C3.8-cycloalk(en)yl-Ci_6-alk(en/yn)yl; or R2 and R11 together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms;;INTELLECTUAL PROPERTY OFFICE OF N.2.;16 DEC 2008;RECEIVED;105;R2 is selected from the group consisting of hydrogen, Ci_ | <1 1 ' 1 30 16. A compound according to Claim 15, wherein R is NR R , q is 0 and R and R12' are independently selected from the group consisting of hydrogen, C1 .6-alk(en/yn)yl, Ar and Ar-Ci_6-alk(en/yn)yl, or R12 and R12> together with the
5.E
6.O lu
7.CT>
8.LU crZ > _j O
9.CD < t- 0
10.LU U.
11.UJ oq; lu u.
12.CT3 0
13.JO uj
14.LU t~ 2
15.CC
16.Ill nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms.
17. A compound according to any one of Claims 1-16, wherein Y is of formula II or 5 III and W is a sulphur atom.
18. A compound according to any one of Claims 1-16, wherein Y is of formula XXX and T is a nitrogen atom or an oxygen atom. 10
19. A compound according to any one of Claims 1-16, wherein Y is of formula XXXI and L is C or CH.
20. A compound according to any of Claims 1-19, wherein each R5 is independently selected from the group consisting of C].6-alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, 15 halogen and halo-C i _6-alk(en/yn)yl or or two adjacent R5 together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.
21. A compound according to any one of Claims 1-20, said compounds being 20 selected from the group consisting of: N-[4-Chloro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; N-[4-Chloro-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5 -yl]-3,3-dimethylbutyramide; 25 [1 -(4-Fluorobenzyl)-2,3-dihydro-l H-indol-5-ylJ-carbamic acid propyl ester; N-[1 -(4-Fluorobenzyl)-2,3-dihydro-l H-indol-5-ylJ-C-phenyl-methanesulfonamide; 4-Fluoro-N-[l-(4-fluorobenzyl)-2,3-dihydro-l H-indol-5-yl]-benzamide; N-[l-(4-Fluorobenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; 30 N-[l-(4-Fluorobenzyl)-2,3-dihydro-l H-indol-5-yl]-2-thiophen-2-ylacetamide; N-[I-(4-Fluorobenzyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-l, 1 -diisopropylurea; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 DEC 2008 RECEIVFn 112 Morpholine-4-carboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide; Pyrrolidine-l-carboxylic acid [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid 2-benzyloxyeihyl ester; 3-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-1-methyl-l-propylurea; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid tert-butyl ester; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl-methanesulfonamide; Butane-1-sulfonic acid [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-ylj-amide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-4-fluorobenzamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol~5~yl]-2,2-dimethylpropionam ide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2-phenoxyacetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1 H-indol-5-yl]-butyramide; Cyclopentanecarboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-amide; N-fl-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2-thiophen-2-ylacetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-isonicotinamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-4-dimethylaminobenzamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; INTELLECTUAL PROPERTY I OFFICE OF N.2. 16 DEC RECEIVEDl 113 N-[l-(5-Chlorothiophen-2-ylmethyl)-2>3-dihydro-lH-indol-5-yl]-6-trifluoromethylnicotinamide; 1 -tert-Butyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl] -urea; l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3-ethylurea; l-Benzyl-3-[1 -(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-urea; 1-[1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3-phenethylurea; 1-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3-thiophen-2-ylurea; 1 -[1 -(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3-thiophen-3-ylurea; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1 H-indol-5-yl]-carbamic acid propyl ester, 2,2-Dimethyl-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-propionamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-l H-indol-5-yl]-2,2-dimethylpropionamide; 2-(4-Fluorophenyl)-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-S-yl] -acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3 -dihydro-1 H-indol-5 -yl]-2-(4-fluorophenyl)-acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyr amide; N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-2,2-dimethylpropionamide; N-[6-Amino-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2,2-dimethylpropionamide; N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RECEIVED 114 N-[6-Amino-l-(4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l-(4-fluorobenzyl)-2,3-dihydro-1 H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3 -dimethylbutyramide-, N-[l-(5-Chlorothiophen-2-ylmethyl)-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Bromo-l-(4-trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5~yl]-3,3- dimethylbutyramide; N-[6-Bromo-l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-fl-(4-Chlorobenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(4-trifl.uoromethylbenzyl)-2,3-dihydro-1 H-indol-5-yl]-butyramide; N-[l-(4-Isopropylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbulyramide; N-[l-(3-Fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyr amide; N-[l-(6-Chlorobenzo[l,3]dioxol-5-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimelhylbutyramide; N-[l-(3,5-Dimethyl-l -phenyl-lH-pyrazol-4-ylmethyl)-2,3-dihydro-l H-indol-S-yl] -3,3-dimethylbutyramide; N-[l~(2-Chloro-5-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-3,3-dimethylbutyramide; N-{l-[5-(4-Chlorophenoxy)-l,3-dimethyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro~ 1 H-indol-5-yl}-3,3-dimethylbutyramide; 3,3 -Dimethyl-N-[1 - (6-p-tolyloxy-pyridin-3 -ylmethyl)-2,3-dihydro-l H-indol-5-yl/-butyramide; N-{l-[6-(4-Chlorophenylsulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-l H-indol-S-yl}-3,3-dimethylbutyramide; N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-l H-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(6-trifluoromethylpyridin-3-ylmethyl)-2,3-dihydro-l H-indol-S-yl]-butyramide; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 DEC 2008 r f r. p i \/ p n 115 3,3-Dimethyl-N-[l-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-butyramide; N-[l-(6-Fluoro-4H-benzo[l, 3Jdioxin-8-ylmethy!)-2,3-dihydro-l H-indol-5-yl]-3,3 -dimethylbutyramide; 3,3 -Dimethyl-N-[l-(6-phenoxypyridin-3 -ylmethyl) -2,3 -dihydro-1 H-indol-5-yl] -butyramide; 3,3 -Dimethyl-N-[l-(3-methyl-5-phenyl-isoxazol-4 -ylmethyl)-2,3-dihydro -1H-indol-5-yl]-butyramide; N-(l -Benzo[bJthiophen-2-ylmethyl-2,3-dihydro-l H-indol-5-yl)-3,3-dimethylbuiyr amide; N-{1-[1 -(4-Fluorophenyl)-5-methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(5-methylthiophen-2-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-butyramide; 3,3 -Dimethyl-N-[1 - (4-pyrrol-1 -yl-benzyl) -2,3 -dihydro-1 H-indol- 5-yl]-butyramide; N-[l-(4~Chlorobenzyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[l-(4-trifluoromethylbenzyl)-2! 3-dihydro-l H-indol-5 -yl] -acetamide; 2-(4-Fluorophenyl)-N-[l-(4-isopropylbenzyl)-2,3-dihydro-l H-indol-5-yl]-acetamide; 2-(4-Fluorophenyl)-N-[l-(3-fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5 -ylJ-acetam ide; N-[l-(6-Chlorobenzo[ 1,3] dioxol-5-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-2-{4-fluorophenyl)-acetamide; N-[l-(3,5-Dimethyl-l -phenyl-lH-pyrazol-4-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[l-(2-Chloro-5-trifluoromethylbenzyl)-2,3-dihydro-l H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-{l-[5-(4-Chlorophenoxy)-l,3-dimethyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-2-(4-jluorophenyl)-acetamide; INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 ocr.PivF'n 1L6 N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-l H-indol-5-yl}-2-(4-jl uorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[l-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1 H-indol-5-yl]-acetamide; 5 N-f1 -(6-Fluoro-4H-benzo[l, 3]dioxin-8-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-2- (4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[1 -(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-l H-indol-5-yl]-acetamide; N-(l -Benzofb]thiophen-2-ylmethyl-2,3-dihydro-l H-indol-5 -yl)-2- (4-10 fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-{l-[l-(4-f!uorophenyl)-5-methyl-lH-pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-acetamide; 2-(4-Fluorophenyl)-N-[ 1 -(5-methylthiophen-2-ylmethyl)-2,3-dihydro-l H-indol-S-yl]-acetamide; and 15 2-(4-Fluorophenyl)-N-[l-(4-pyrrol-l-yl-benzyl)-2,3-dihydro-l H-indol-5-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising one or more pharmaceutically 20 acceptable carriers or diluents and a compound according to any one of claims 1- 21.
23. A use of a compound of any one of claims 1-21 in the manufacture of a medicament for increasing ion flow in a potassium channel of a mammal such as 25 a human.
24. A use of a compound of any one of claims 1-21 in the manufacture of a medicament for the prevention, treatment or inhibition of a disorder or condition that is responsive to an increased ion flow in a potassium channel. 30
25. A use according to claim 24, wherein said disorder or condition is a disorder or condition of the central nervous system. INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 DEC 2008 RECEIVED 117
26. Use according to Claim 24, wherein said disorder or disease is selected from the group consisting of seizure disorders such as convulsions, epilepsy and status epilepticus.
27. Use according to Claim 24, wherein said disorder or condition is selected from the group consisting of neuropathic and migraine pain disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy and neuropathic pain related to migraine
28. Use according to Claim 24, wherein said disorder or condition is selected from the group consisting of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorder due to general medical condition and substance-induced anxiety disorder.
29. Use according to Claim 24, wherein said disorder or condition is selected from the group consisting of neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other infection-related encephalopathies being caused by rubella viruses, herpes viruses, borrelia and by unknown pathogens, Creutzfeld-Jakob disease, Parkinson's disease, trauma-induced neurodegenerations.
30. Use according to Claim 24, wherein said disorder or condition is selected from the group consisting of neuronal hyperexcitation states such as in medicament withdrawal or by intoxication.
31. A compound according to claim 1, substantially as herein described with reference to any example thereof. INTELLECTUAL PROPERTY OFFICE OF N.Z. 16 DEC 2008 RFrpivpn 118
32. A pharmaceutical composition according to claim 22, substantially as herein described with reference to any example thereof.
33. A use according to claim 23 or claim 24, substantially as herein described with reference to any example thereof.
NZ541999A 2003-04-25 2004-04-23 Substituted indoline and indole derivatives NZ541999A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200300631 2003-04-25
PCT/DK2004/000283 WO2004096767A1 (en) 2003-04-25 2004-04-23 Sustituted indoline and indole derivatives

Publications (1)

Publication Number Publication Date
NZ541999A true NZ541999A (en) 2009-03-31

Family

ID=58707218

Family Applications (1)

Application Number Title Priority Date Filing Date
NZ541999A NZ541999A (en) 2003-04-25 2004-04-23 Substituted indoline and indole derivatives

Country Status (10)

Country Link
KR (1) KR20060004957A (en)
CN (1) CN1777582A (en)
AR (1) AR044517A1 (en)
BR (1) BRPI0409317A (en)
CA (1) CA2523102A1 (en)
EA (1) EA200501669A1 (en)
IS (1) IS8002A (en)
NZ (1) NZ541999A (en)
UA (1) UA80190C2 (en)
ZA (1) ZA200507186B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103508960B (en) * 2012-06-29 2017-12-12 江苏先声药业有限公司 Benzheterocyclic derivatives
CN108863893A (en) * 2018-07-09 2018-11-23 湖南博隽生物医药有限公司 Indolinyl derivative and its application in drug
CN112010808B (en) * 2019-05-31 2021-11-30 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof

Also Published As

Publication number Publication date
CA2523102A1 (en) 2004-11-11
IS8002A (en) 2005-08-29
KR20060004957A (en) 2006-01-16
ZA200507186B (en) 2006-11-29
BRPI0409317A (en) 2006-04-25
EA200501669A1 (en) 2006-04-28
CN1777582A (en) 2006-05-24
UA80190C2 (en) 2007-08-27
AR044517A1 (en) 2005-09-14

Similar Documents

Publication Publication Date Title
US20060264496A1 (en) Substituted indoline and indole derivatives
CN102516204B (en) The morpholine replaced and thiomorpholine derivatives
JP5237643B2 (en) Substituted pyridine derivatives
US7683058B2 (en) Substituted pyrimidine derivatives
WO2006029623A1 (en) Substituted aniline derivatives
BRPI0615631A2 (en) compound, pharmaceutical composition, and use of a pharmaceutical composition
NZ541999A (en) Substituted indoline and indole derivatives
MXPA06010329A (en) Substituted morpholine and thiomorpholine derivatives

Legal Events

Date Code Title Description
PSEA Patent sealed
RENW Renewal (renewal fees accepted)