WO2005030723A1 - Pyridylacetylenes for use as radiotracers and imaging agents - Google Patents

Pyridylacetylenes for use as radiotracers and imaging agents Download PDF

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WO2005030723A1
WO2005030723A1 PCT/EP2004/010743 EP2004010743W WO2005030723A1 WO 2005030723 A1 WO2005030723 A1 WO 2005030723A1 EP 2004010743 W EP2004010743 W EP 2004010743W WO 2005030723 A1 WO2005030723 A1 WO 2005030723A1
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formula
compound
methyl
free base
acid addition
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PCT/EP2004/010743
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Fabrizio Gasparini
Yves Auberson
Lea Kessler
Simon Mensah Ametamey
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Novartis Ag
Novartis Pharma Gmbh
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Priority to CA2539469A priority Critical patent/CA2539469C/en
Priority to AU2004275971A priority patent/AU2004275971B2/en
Priority to BRPI0414732-4A priority patent/BRPI0414732A/en
Priority to JP2006527359A priority patent/JP4965255B2/en
Priority to ES04765586T priority patent/ES2400713T3/en
Priority to EP04765586A priority patent/EP1670762B1/en
Priority to PL04765586T priority patent/PL1670762T3/en
Priority to US10/573,162 priority patent/US8674110B2/en
Priority to MXPA06003424A priority patent/MXPA06003424A/en
Publication of WO2005030723A1 publication Critical patent/WO2005030723A1/en
Priority to US14/162,885 priority patent/US20140142318A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel pyridylacetylene derivatives, their preparation, their use as radiotracers/markers and compositions containing them.
  • R is CH 3) (CH 2 ) n l, (CH 2 ) n Br or (CH 2 ) n F, n being 1 , 2, 3 or 4
  • R is 11 CH 3 , ( 3 H) 3 C, (CH 2 ) n 123 l (CH 2 ) n 76 Br or (CH 2 ) n 18 F, n being 1 ,2, 3 or 4
  • the compounds can exist as pure stereoisomers or mixtures thereof.
  • the invention provides a process for the production of the compounds of formula I and their salts, comprising the steps of
  • R a is respectively 11 CH 3 or ( 3 H) 3 C, reacting the compound of formula II
  • Rb is respectively (CH 2 ) n 18 F, (CH 2 ) n 123 l or (CH 2 ) n 76 Br, reacting a compound of formula III
  • n is as defined above and X is OTs or OMs, with respectively 18r F-c ⁇ >, 123
  • the reactions can be effected according to known methods, for example as described in the Examples.
  • Acid addition salts may be produced from the free bases in known manner, and vice-versa.
  • agents of the invention exhibit valuable properties as histopathological labeling agents, imaging agents and/or biomarkers, hereinafter "markers", for the selective labeling of the metabotropic glutamate receptor subtype 5 (mGlu ⁇ receptor).
  • agents of the invention are useful as markers for labeling the central and peripheral mGlu ⁇ receptors in vitro or in vivo (see Example 5-7).
  • the agents of the invention are therefore useful, for instance, for determining the levels of receptor occupancy of a drug acting at the mGlu5 receptor, or diagnostic purposes for diseases resulting from an imbalance or dysfunction of mGlu ⁇ receptors, and for monitoring the effectiveness of pharmacotherapies of such diseases.
  • the present invention provides an agent of the invention for use as a marker for neuroimaging.
  • the present invention provides a composition for labeling brain and peripheral nervous system structures involving mGlu ⁇ receptors in vivo and in vitro comprising an agent of the invention.
  • the present invention provides a method for labeling brain and peripheral nervous system structures involving mGlu ⁇ receptors in vitro or in vivo, which comprises contacting brain tissue with an agent of the invention.
  • the method of the invention may comprise a further step aimed at determining whether the agent of the invention labeled the target structure.
  • Said further step may be effected by observing the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any device allowing detection of radioactive radiations.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-[ 11 C-methyl]-oxime is synthesized by reacting [ 11 C]-Mel with the sodium salt of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (1mg) in dry DMF (400 ⁇ l). [ 11 C]-Mel is introduced via a slow stream of helium and when addition is completed the reaction mixture is heated to 120°C for 10 min.
  • Product purification is accomplished by reversed phase HPLC using a C-18 ⁇ -Bondapak column (7.8x300mm) and a mobile phase consisting of CH 3 CN/0.1% H 3 P0 4 (70/30) at a flow rate of 5 ml/min.
  • the retention time of the desired product is between 6 and 7 min.
  • 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-[ 11 C-methyl]-oxime is formulated in a solution containing polysorbatum (2%), ethanol (10%) and saline (0.9%).
  • LogD 2.5 (determined using the classical shake-flask method).
  • the title compound can be prepared by reacting 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2- enone oxime with [ 3 H]-Mel (0.5 equivalent) in the presence of K 2 C0 3 in DMF at 100°C for 180 min, followed by a purification by reversed phase chromatography.
  • the sodium salt of the 3-(6-methyl-pyridin-2-ylethynyl)-cycIohex-2-enone oxime (2mg) is reacted in dry DMF (400 ⁇ l) with [ 18 F]-2-fluoro-ethyltosylate (obtained from ethyleneditosylate and [ 18 F]-KF-Kryptofix complex) at 100°C for 10min.
  • the reaction mixture is purified through a tC-18 Sep-Pak cartridge, and the fractions containing the desired product are further purified by a semi-preparative reversed phase HPLC using a C18 Bondclone column (300x7.8 mm) and a mobile phase consisting of CH 3 CN/0.01 M H 3 P0 4 (70/30) at a flow rate of 4 ml/min.
  • the fraction containing the product (retention time between 12 and 13 min) is passed through a tC-18 Sep-Pak cartridge and eluted with 1 ml of ethanol. This ethanolic solution is buffered with 0.15M phosphate buffer to give after sterile filtration an isotonic and injectable solution.
  • the product is formulated in analogy to 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-(2- [18F-fluoro]-ethyl)-oxime (example 3).
  • the animals are sacrificed 30 min post-injection.
  • Organ or brain regions such as hippocampus, striatum, cortex and cerebellum are removed and measured in a gamma- counter.
  • the tissue distribution is expressed as percentage of injected dose per gram wet tissue (% ID/g organ).
  • Example 7 Results of the brain distribution study with 3-(6-methyl-pyridin-2- ylethvnyl)-cvclohex-2-enone O-f 11 C-methy ⁇ -oxime
  • K1, K2, K3 are individual values for control animals.
  • B1, B2, B3 are individual values for animals co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract

The present invention relates to novel pyridylacetylene derivatives of formula I, their Preparation, their use as radiotracers/markers and compositions containing them.

Description

PYRIDYLACETYLENES FOR USE AS RADIOTRACERS AND IMAGING AGENTS
The present invention relates to novel pyridylacetylene derivatives, their preparation, their use as radiotracers/markers and compositions containing them.
More particularly the invention provides a compound of formula I
Figure imgf000002_0001
wherein
R is CH3) (CH2)nl, (CH2)nBr or (CH2)nF, n being 1 , 2, 3 or 4
in free base or acid addition salt form.
Compounds of the formula I are preferred, wherein
R is 11CH3, (3H)3C, (CH2)n 123l (CH2)n 76Br or (CH2)n 18F, n being 1 ,2, 3 or 4
in free base or acid addition salt form.
In the case of possible stereoisomerism, e.g. cis/trans-isomerism of double bonds, the compounds can exist as pure stereoisomers or mixtures thereof.
In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, comprising the steps of
a) for the production of a compound of formula la
Figure imgf000003_0001
wherein Ra is respectively 11CH3 or (3H)3C, reacting the compound of formula II
Figure imgf000003_0002
with respectively 11CH3I or C(3H)3I, in the presence of a base, or
b) for the production of a compound of formula lb
Figure imgf000003_0003
wherein Rb is respectively (CH2)n 18F, (CH2)n 123l or (CH2)n 76Br, reacting a compound of formula III
Figure imgf000003_0004
wherein n is as defined above and X is OTs or OMs, with respectively 18r F-cΘ>, 123| lpΘ, or ^Br0, or reacting the compound of formula II with a compound of formula IV
X - Rb IV wherein X and Rb are as defined above,
and recovering the resulting compound of formula I in free base form or in form of an acid addition salt.
The reactions can be effected according to known methods, for example as described in the Examples.
Working up the reaction mixtures and purification of the compounds thus obtained may be carried out in accordance to known procedures.
Acid addition salts may be produced from the free bases in known manner, and vice-versa.
The starting materials of formulae II, III and IV are known or may be obtained in analogous manner to know procedures, e.g. as described in the Examples.
Compounds of formula I in free base or acid addition salt form, hereinafter referred to as agents of the invention, exhibit valuable properties as histopathological labeling agents, imaging agents and/or biomarkers, hereinafter "markers", for the selective labeling of the metabotropic glutamate receptor subtype 5 (mGluδ receptor).
More particularly the agents of the invention are useful as markers for labeling the central and peripheral mGluδ receptors in vitro or in vivo (see Example 5-7).
The agents of the invention are therefore useful, for instance, for determining the levels of receptor occupancy of a drug acting at the mGlu5 receptor, or diagnostic purposes for diseases resulting from an imbalance or dysfunction of mGluδ receptors, and for monitoring the effectiveness of pharmacotherapies of such diseases. ln accordance with the above, the present invention provides an agent of the invention for use as a marker for neuroimaging.
In a further aspect, the present invention provides a composition for labeling brain and peripheral nervous system structures involving mGluδ receptors in vivo and in vitro comprising an agent of the invention.
In still a further aspect, the present invention provides a method for labeling brain and peripheral nervous system structures involving mGluδ receptors in vitro or in vivo, which comprises contacting brain tissue with an agent of the invention.
The method of the invention may comprise a further step aimed at determining whether the agent of the invention labeled the target structure. Said further step may be effected by observing the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any device allowing detection of radioactive radiations.
The following examples illustrate the invention.
Example 1: 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-[11Cmethyl]-oxime
3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-[11C-methyl]-oxime is synthesized by reacting [11C]-Mel with the sodium salt of 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (1mg) in dry DMF (400 μl). [11C]-Mel is introduced via a slow stream of helium and when addition is completed the reaction mixture is heated to 120°C for 10 min. Product purification is accomplished by reversed phase HPLC using a C-18 μ-Bondapak column (7.8x300mm) and a mobile phase consisting of CH3CN/0.1% H3P04 (70/30) at a flow rate of 5 ml/min. The retention time of the desired product is between 6 and 7 min. 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-[11C-methyl]-oxime is formulated in a solution containing polysorbatum (2%), ethanol (10%) and saline (0.9%). LogD = 2.5 (determined using the classical shake-flask method).
The starting materials are prepared as described hereafter: a) 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone
A solution of 2-ethynyl-6-methyl-pyridine (702 mg, 6 mmol), 3-bromo-cyclohex-2-enone (1.26 g, 7.2 mmol), bis-(triphenylphosphine)-palladium-dichloride (168 mg, 0.24 mmol), copper(l) iodide (93 mg, 0.48 mmol), triethylamine (4.8 ml, 34.4 mmol) in 12ml DMF is heated to 55°C for 1 h. After that time the solution is diluted with ethyl acetate (500 ml) and washed with sat aq. NaHC03 (1 X 150 ml). The water phase is extracted with ethyl acetate (1 X 150 ml) and the combined organic phases are dried over Na2S04, filtered and concentrated in vacuo. The residue (1.88 g) is purified on column chromatography (silica gel, eluent hexane/ethyl acetate 3:1 v/v) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 1.05 g (yield = 82 %) of the title compound as a light yellow oil.
b) 3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime
A solution of 3-(6-methyl-pyridin-2-ylethynyl)-cycIohex-2-enone (422 mg, 2 mmol) and hydroxylamine hydrochloride (278 mg, 4 mmol) in pyridine (20 ml) is stirred for 17 h at RT. After that time the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate (300 ml) and washed with sat NaHC03 (1 X 50 ml). The water phase is extracted with ethyl acetate (1 X 50 ml). The combined organic phases are dried over Na2S04, filtered and concentrated in vacuo. The residue (0.45 g) is purified on column chromatography (Silica gel, eluent hexane/ethyl acetate 2:1 v/v) and the fractions containing the desired compound are collected and concentrated in vacuo to yield 0.192 g (yield = 42 %) of the title compound as light yellow crystals, m.p. 166-168°C.
Example 2: 3-(6-Methyl-pyridin-2-ylet vnyl)-cyclohex-2-enone 0-rtri(3H)-methyll-oxime
The title compound can be prepared by reacting 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2- enone oxime with [3H]-Mel (0.5 equivalent) in the presence of K2C03 in DMF at 100°C for 180 min, followed by a purification by reversed phase chromatography.
Example 3: 3-(6-Methyl-pyridin-2-ylethvnyl)-cvclohex-2-enone 0-(2-r18F-fluoro1-ethvD- oxime
The sodium salt of the 3-(6-methyl-pyridin-2-ylethynyl)-cycIohex-2-enone oxime (2mg) is reacted in dry DMF (400 μl) with [18F]-2-fluoro-ethyltosylate (obtained from ethyleneditosylate and [18F]-KF-Kryptofix complex) at 100°C for 10min. The reaction mixture is purified through a tC-18 Sep-Pak cartridge, and the fractions containing the desired product are further purified by a semi-preparative reversed phase HPLC using a C18 Bondclone column (300x7.8 mm) and a mobile phase consisting of CH3CN/0.01 M H3P04 (70/30) at a flow rate of 4 ml/min. The fraction containing the product (retention time between 12 and 13 min) is passed through a tC-18 Sep-Pak cartridge and eluted with 1 ml of ethanol. This ethanolic solution is buffered with 0.15M phosphate buffer to give after sterile filtration an isotonic and injectable solution.
Example 4: 3-(6-Methyl-pyridin-2-ylethvnyl)-cvclohex-2-enone Q-r18F-fluoro1-metrιvD- oxime
The sodium salt of the 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone oxime (2mg) is reacted in dry DMF (400 μl) with [18F]CH2OTf at 100°C for 30min. After an initial purification by passing the reaction mixture through a tC-18 Sep-Pak cartridge, 3-(6-methyl-pyridin-2- ylethynyl)-cyclohex-2-enone 0-[18F-fluoro]-methyl-oxime was finally purified by a semi- preparative reversed phase HPLC using a C18 Bondclone column (300x7.8 mm) and a mobile phase consisting of CH3CN/0.01 M H3P04 (70/30) at a flow rate of 4 ml/min. The product is formulated in analogy to 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone 0-(2- [18F-fluoro]-ethyl)-oxime (example 3).
Example 5: Kt/ICsn determination (binding assay)
In vitro, the affinity for the mGluδ receptor is determined using a radioligand displacement technique as described by Gasparini et al, Biorg. Med. Chem. Lett. 2002, 12, 407-409. 3-(6- methyl-pyridin-2-ylethynyl)-cyclohex-2-enone O-methyl-oxime shows an IC50 of 8 nM (Hill coefficient 1.08; 95 % confidence intervals: 6.0-10.0 nM) for the displacement of [3H]-2- methyl-6-((3-methoxyphenyl)ethynyl)-pyridine from membrane of L-tk cells stably expressing the human mGluδ receptor (Daggett et al, Neuropharm. 199δ, 34:871-886). Using the Cheng-Prusoff equation, a Kj of 4 nM is calculated (radioligand concentration used for the assay: 2 nM).
Example 6: Organ and brain structure distribution Two groups of male adult Sprague-Dawley rats weighing 2δ0-300 g are used for the biodistribution studies. The first group (n= 3) serves as the control group and the second group (n = 3) serves as the blockade group. Each animal received 2δ0-300 pmol (0.6-40 MBq) of 3-(6-methyl-pyridin-2-ylethynyl)-cyc!ohex-2-enone 0-[11C-methyl]-oxime via a lateral tail vein. The blockade group is co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)- pyridine (1 mg/kg) whereas the control group (n=3) receives a corresponding volume of 0.9% NaCI. The animals are sacrificed 30 min post-injection. Organ or brain regions such as hippocampus, striatum, cortex and cerebellum are removed and measured in a gamma- counter. The tissue distribution is expressed as percentage of injected dose per gram wet tissue (% ID/g organ).
Example 7: Results of the brain distribution study with 3-(6-methyl-pyridin-2- ylethvnyl)-cvclohex-2-enone O-f11C-methyπ-oxime
The table below displays the percentage of the injected dose normalized per gram of tissue. K1, K2, K3 are individual values for control animals. B1, B2, B3 are individual values for animals co-injected with 2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine.
Organ K1 K2 K3 B1 B2 B3 Hippocampus 0.16154 0.25440 0.21264 0.05184 0.06195 0.05972 Striatum 0.22564 0.30685 0.28164 0.06495 0.07158 0.06487 Cortex 0.14849 0.18316 0.16909 0.04964 0.05582 0.05431 Cerebellum 0.03322 0.03925 0.03699 0.04052 0.03608 0.03421 Midbrain 0.07703 0.10559 0.09091 0.03876 0.04700 0.04422 Restbrain 0.05519 0.06520 0.06070 0.03832 0.04762 0.04383
Whole brain 0.11123 0.13659 0.12999 0.04580 0.05118 0.04951

Claims

1. A compound of formula I
Figure imgf000009_0001
wherein
R is CH3, (CH2)nl, (CH2)nBr or (CH2)nF, n being 1 , 2, 3 or 4 in free base or acid addition salt form.
2. A compound according to claim 1 , wherein
R is 11CH3, (3H)3C, (CH2)n 123l, (CH2)n 76Br or (CH2)n 18F, n being 1 ,2, 3 or 4 in free base or acid addition salt form.
3. A process for the production of a compounds of formula I as defined in claim 1 , or a salt thereof, comprising the step of a) for the production of a compound of formula la
Figure imgf000009_0002
wherein Ra is respectively 1 CH3 or (3H)3C, reacting the compound of formula II
Figure imgf000010_0001
with respectively 11CH3I or C(3H)3I, in the presence of a base, or
b) for the production of a compound of formula lb
Figure imgf000010_0002
wherein Rb is respectively (CH2)n 18F, (CH2)n 1 3l or (CH2)n 76Br, reacting a compound of formula III
Figure imgf000010_0003
wherein n is as defined in claim 1 and X is OTs or OMs, with respectively Iδ Fr-ΩΘ, 123| lpΘ, or
76 Br®, or reacting the compound of formula II with a compound of formula IV
X - Rb IV wherein X and Rb are as defined above, and recovering the resulting compound of formula I in free base form or in form of an acid addition salt.
4. A compound of formula I as defined in claim 1 , in free base or acid addition salt form, for use as a marker for neuroimaging.
δ. A composition for labeling brain and peripheral nervous system structures involving mGluδ receptors in vivo and in vitro comprising a compound of formula I as defined in claim 1 , in free base or acid addition salt form.
6. A method for labeling brain and peripheral nervous system structures involving mGluδ receptors in vitro or in vivo, which comprises contacting brain tissue with a compound of formula I as defined in claim 1 , in free base or acid salt form.
PCT/EP2004/010743 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents WO2005030723A1 (en)

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AU2004275971A AU2004275971B2 (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents
BRPI0414732-4A BRPI0414732A (en) 2003-09-26 2004-09-24 pyridylacetylenes for use as radiotracers and imaging agents
JP2006527359A JP4965255B2 (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radioactive tracers and contrast agents
ES04765586T ES2400713T3 (en) 2003-09-26 2004-09-24 Pyridyl-acetylenes for use as radio-trackers and imaging agents
EP04765586A EP1670762B1 (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents
PL04765586T PL1670762T3 (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents
US10/573,162 US8674110B2 (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents
MXPA06003424A MXPA06003424A (en) 2003-09-26 2004-09-24 Pyridylacetylenes for use as radiotracers and imaging agents.
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WO2010084050A2 (en) 2009-01-13 2010-07-29 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
EP2305652A2 (en) 2005-12-08 2011-04-06 Novartis AG Trisubstituted quinazolinone derivatives as vanilloid antagonists
WO2011092290A1 (en) 2010-02-01 2011-08-04 Novartis Ag Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists
WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2011095450A1 (en) 2010-02-02 2011-08-11 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2012004400A1 (en) * 2010-07-09 2012-01-12 Recordati Ireland Limited Novel spiroheterocyclic compounds as mglu5 antagonists
WO2012164473A1 (en) 2011-05-27 2012-12-06 Novartis Ag 3-spirocyclic piperidine derivatives as ghrelin receptor agonists
WO2013164790A1 (en) 2012-05-03 2013-11-07 Novartis Ag L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists

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