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(12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger Et Al

(12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger Et Al

US 20130252924A1 (19) (12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger et al. (43) Pub. Date: Sep. 26, 2013

(54) COMPOUNDS AND METHODS FOR Publication Classification TREATING PAIN (51) Int. C. (75) Inventors: Josef Penninger, Vienna (AT); Graham A63/675 (2006.01) Gregory Neely, Sydney (AU); Shane A613 L/496 (2006.01) McManus, Vienna (AT); Henrik A613 L/50 (2006.01) Nilsson, Vienna (AT) A613 L/435 (2006.01) A613 L/506 (2006.01) (73) Assignee: AKRON MOLECULES GMBH, A 6LX3L/277 (2006.01) Vienna (AT) (52) U.S. C. CPC ...... A6 IK3I/675 (2013.01); A61 K3I/506 (21) Appl. No.: 13/884,920 (2013.01); A61 K3I/277 (2013.01); A61 K 3 1/50 (2013.01); A61K3I/435 (2013.01); (22) PCT Fled: Nov. 11, 2011 A6 IK3I/496 (2013.01) USPC ...... 514/81: 514/252.19; 514/521; 514/247; (86) PCT NO.: 514/352: 514/253.06 S371 (c)(1), (2), (4) Date: May 10, 2013 (57) ABSTRACT (30) Foreign Application Priority Data The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds Nov. 11, 2010 (EP) ...... 1O190922.4 for use in said therapies. Patent Application Publication Sep. 26, 2013 Sheet 1 of 25 US 2013/0252924 A1

Fig. 1

A : B Control painless Avoidance

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Fig. 2

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a sensia Patent Application Publication Sep. 26, 2013 Sheet 3 of 25 US 2013/0252924 A1

Fig. 3

Futch Sti-GalAZUAS-CD8:GFP Overlay

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Patent Application Publication Sep. 26, 2013 Sheet 4 of 25 US 2013/0252924 A1

Fig. 4

A. B Brain DRG 3. the are as Targeted o283 . - Endogenous c281

E. Actin so Hot plate D inflammatory pain

40 2O S 30 3. 15 20 5 s e 10

5. s 5 56 2 3 5 Temperature (C) Days after CFA Patent Application Publication Sep. 26, 2013 Sheet 5 of 25 US 2013/0252924 A1

Fig. 5

CACNA2D3 3p21.1 54.5 S. i Acute (wind up) Chronic

SSOSS S55 58518

Patent Application Publication Sep. 26, 2013 Sheet 6 of 25 US 2013/0252924 A1

Fig. 6

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Patent Application Publication Sep. 26, 2013 Sheet 7 of 25 US 2013/0252924 A1

Fig. 7

ES E. E. B Sensory cross-activation C Sensory cross-activation (heat) (tactile)

- 2.0 - 2.0 Š, 1.8 SS, 1.8 c 1.6 1.6 1.4 1.4 1.2 is 1.2 9 Oc1.0 9 1.00.8 2 0.6 2 0.6 30.4. 0.4. T. O.2 0.2 OT WIC AC O WC AC Patent Application Publication Sep. 26, 2013 Sheet 8 of 25 US 2013/0252924 A1

Fig. 8

Screening system Genome-wide screen etc.

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fighterest Terr's st is ret organelles sai is Nutfestirriterrodeting Secretary Functers is knocteries Patent Application Publication Sep. 26, 2013 Sheet 9 of 25 US 2013/0252924 A1

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C Nuclei stjgAL4>UAS-Lamin:GFP Projections sigAL4-UAS-CD8:GFP Patent Application Publication Sep. 26, 2013 Sheet 10 of 25 US 2013/0252924 A1

Fig. 1O

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Kerman score Patent Application Publication Sep. 26, 2013 Sheet 11 of 25 US 2013/0252924 A1

Fig. 11

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has us Patent Application Publication Sep. 26, 2013 Sheet 12 of 25 US 2013/0252924 A1

Fig. 12

A Left

3. Patent Application Publication Sep. 26, 2013 Sheet 13 of 25 US 2013/0252924 A1

Fig. 13

A 0.283 o283 left train right brain left brain right brain

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Patent Application Publication Sep. 26, 2013 Sheet 14 of 25 US 2013/0252924 A1

Fig. 14

Total Brain activity (Heat stimulation) A Peak height B Activation volume

C s SSC O C 55°C Temperature Temperature Total Brain activity (tactile stimulation) C Peak height D Activation volume

Patent Application Publication Sep. 26, 2013 Sheet 15 of 25 US 2013/0252924 A1

a Ceti Structure and Organees related

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Ca signating, 7 T-- \m pressings Brain's reward -s pathways; 4 is Al-kai, Adipocyte Biaticard Alzheirer ciferentiation; abitatistress;3 Apoptosis: disease A: 5 Patent Application Publication Sep. 26, 2013 Sheet 16 of 25 US 2013/0252924 A1

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Patent Application Publication Sep. 26, 2013 Sheet 17 of 25 US 2013/0252924 A1

Fig. 17

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Fig. 18

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NN SSBoy seei. ty 5 3.se t yrish y3: O 3. 3. 3. 33 3, 3.5 SO 3, 3.2 3.3 3.4 3.5 Temperature 1 (T + 1000 (K) C capsaicinuM (c.8, in O.O. O.1 0.5 1.O 5.0 is . . . s it- as - O. Nissary -- 0.8 E:s .. 5 /9A, . . s / / s -0.4 Pls -0.6 i E 0.8 KO x

-1.0'' WT . . . 2 o Logo capsaicin (M) Patent Application Publication Sep. 26, 2013 Sheet 19 of 25 US 2013/0252924 A1

Fig. 19

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s siggiant ortholoholog probability Patent Application Publication Sep. 26, 2013 Sheet 20 of 25 US 2013/0252924 A1

Fig 20

Patent Application Publication Sep. 26, 2013 Sheet 21 of 25 US 2013/0252924 A1

Fig. 21

A B C D Skilleds reachings Cage crosses Open( stance) Field (E.ecation)Open Field 4 E 5 & 3 54 $ 2 s 22 33 S. 2 9. O O Control KO Control KO Citro K

E F G H

Passive Water maze T-maze avoidance: 20 w 5 1OO 8. E 4 2e 3.SR 80 s 3 60 t s 40 g? 2O O. O Citro KO Control KO Control KO Control KO

Von Frey J Von Frey K Acetone 5 7 a 60 4 g 9. 3: 5 40 a 3 - 4 9 9 9. 9 2 E 3 S. ill- 2 - 20 c 8 1 O O O O Patent Application Publication Sep. 26, 2013 Sheet 22 of 25 US 2013/0252924 A1

Fig. 22

A Inflammatory pain OWT 40 WT CFA s KO ; 30 KO + CFA ana t a 20 9 10 O 540C Temperature B C Inflammatory pain 75 o O 3.5 50 3.0 s 25 2.5 OO 92.0 S 75 50 N 1.5 9. 25 1.0 O c. 0.5 VO 50 52 54 56 Temperature (C) Patent Application Publication Sep. 26, 2013 Sheet 23 of 25 US 2013/0252924 A1

Fig. 23 A CC model of chronic neuropathic pain

Pregabali CO3S Cas Aafia ele Ofrast 60 mg/kg 3 Ingkg 30 mg/kg 20 mg/kg 18 mg/kg

Compound

Fig. 23 B CCI model of chronic neuropathic pain

Pregabalin EOS tri BOSt. Adeo Adefy 60 mg/kg 60 mg/kg 200 g Kg 2 rigg 20 ring kg

Compound Patent Application Publication Sep. 26, 2013 Sheet 24 of 25 US 2013/0252924 A1

Fig. 23 C

CCI model of chronic neuropathic pain

Pregabalin a satilib a satirio effori Teofovir 60 mg kg 10 mg kg 30 mg kg 50 mg/kg 500 mg/kg

Cornpould

Fig. 24 A CFA model of chronic inflammatory pair

s is ele ". . . . . cS S. : * ...... E" i. I-S S. is." Af trail ... I as "it r it is 3. it 5. it is 50 kg

Corrixo and Patent Application Publication Sep. 26, 2013 Sheet 25 of 25 US 2013/0252924 A1

Fig. 24 B

CFA model of chronic inflammatory pain

Fig. 24 C CFA model of chronic inflammatory pair

Orig samur, 20 mg 2 kg a rigg US 2013/0252924 A1 Sep. 26, 2013

COMPOUNDS AND METHODS FOR 0004. It is a goal of the present invention to provide meth TREATING PAN ods of treating, ameliorating or Suppressing pain, in particular by the use of novel compounds for this purpose. 0001. The present invention relates to the field of method 0005. The present invention therefore provides the use of of treatment of pain and the provision of pharmaceutical new classes of compounds for the treatment, prevention or compounds Suitable for Such treatments. reduction of pain. These compounds are given in the claims, 0002 Acute and chronic pain affects millions of people and especially include Tenofovir (PMPA), , AMG after injury or Surgery and those Suffering from diseases like 706 (motesanib), BIRB 796 (Doramapimod), EKB-569 arthritis, cancer, and diabetes. Nociception (the detection of (Pelitinib), , , CI-1033 (), noxious or damaging stimuli) serves a crucial biological pur NSC161613, N6-Benzyladenosine-5'-, p-Ami pose: it alerts living organisms to environmental dangers, nobenzoly PAB-Jacid, NSC47091, , inducing the sensation of pain, reflex withdrawal and com (Nicotinamide), IBMX, , , , plex behavioural and emotional responses, which protect the V11294, CC-10004 (), LAS31025 (), CP80633 (), Catramilast/Atopik (Catramilast), organism from further damage. Noxious stimuli are detected BRL-61063 (Cimpyfylline), Daxalipram/mesopram (Dax by specialized high threshold primary sensory neurons (noci alipram), , , Efloxate, , ceptors), which transfer signals to the spinal cord and then , Etofylline, Hydrobromide (Broncholyt transmit them to the brain for higher level processing that ine), GRC3886 (oglemilast), oxtriphyllin (Choline theophyl results in the conscious awareness of the sensation called linate), Pumafentrine, Revamilast, Tofimilast, Tolafentrine, pain. The functional importance of pain perception is exem Seoanin (), GW 842470 (AWD 12-281), CDP-840, plified by individuals with defects in nociception; patients YM-976, CI-1018, D-4418, Lirimilast, SCH-351591, RPL with congenital insensitivity to pain do not survive past their 554, IPL-455903 (HT-0712), GSK256066, , twenties. , OPC-6535 (Tetomilast), IC485, L-826,141, 0003. Two basic types of pain can be distinguished—acute ONO-6126, CI-1044, MK-0873, T-2585, R1533 (MEM and chronic. Acute or nociceptive pain is generally self-lim 1414), Ronomilast (ELB-353), UK-500,001, AN2728, iting and serves a protective biological function by warning of DE-103, , (R)-Tofisopam (Dextofisopam), (S)- ongoing tissue damage caused by noxious chemical, thermal Tofisopam (Levotofisopam (USAN)), EKB-568, SU-14813, and mechanical stimuli. Examples of nociceptive pain LY-333531 (Ruboxistaurin), CGP-52421, SKI-606 (Bosu include: postoperative pain, pain associated with trauma, and tinib), Roscovitine, Tenofovir (PMPA), Methimazole, Ade the pain associated with arthritis. Chronic pain, on the other fovir dipivoxil (Bis-POM PMEA) (Adefovir), Acetazola hand, serves no protective biological function, and reflects mide, midostaurin (PKC-412), tozasertib (MK-0457, VX either poor resolution of the painful stimuli, or is itself a 680) or (CEP-701). A further compound is ima disease process. Chronic pain is unrelenting and not self tinib (STI-571), which is preferably used in the treatment on limiting and can persist for years and even decades after the non-inflammatory pain, especially in the treatment of neuro initial injury. Chronic pain is predominantly neuropathic in pathic pain. Alternative names or identification of the com nature and may involve damage either to the peripheral or pounds are given in brackets. Chemical structures of some of central nervous systems. these compounds are given as follows:

W11294 -(3-cyclopentyloxy-4- methoxyphenyl)methyl N-ethyl-8-propan-2- ylpurin-6-amine: Cys,

US 2013/0252924 A1 Sep. 26, 2013

-continued SU-14813 (SZ)-5-((5-fluoro-2- oxoindolin-3- ylidene)methyl)-N-(2- hydroxy-3- F morpholinopropyl)-2,4-dimethyl-1H-pyrrole-3- / carboxamide

CGP-524.21

NSC161613 2-[2-(2- H aminoacetyl)amino-3- (2,4- N dinitrophe- H phenyl)sulfanylpropanoyl aminopentanedioic acid

NSC47091 2-(3-carboxyprop-2- O enoylamino)-6-(Z)-3- carboxyprop-2- O N enoyl)aminobenzoic acid O O

0006. In preferred embodiments the inventive compound more preferred 100-fold, still preferred 150-fold higher than is an inhibitor (i.e. an antagonist) or modulator of any one of the affinity of the other targets selected from FRK, PDE4D, FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3. LPAR3, CAMK1D or FMO3. Inhibitors or ligands (i.e. binders) or modulators of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3 can be 0007 Surprisingly it has been shown that some of these used in the treatment of pain in a subject. In preferred embodi targets, such as FRK, FMO3, LPAR3 can be both activated, ments the FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or e.g. by an , or inhibited (e.g. by an inhibitor orantago FMO3 modulator is a selective FRK, PDE4D, LPAR3, nist) for an anti-pain effect in a patient. The group of CAMK1D, CSNK1G3 or FMO3 modulator. By “selective” it and antagonists is referred to herein as "modulators'. is meant that the affinity for one of FRK, PDE4D, LPAR3, Although in most cases an inhibitor is preferred for greater CAMK1D or FMO3 is at least 10-fold, preferably 25-fold, effect, it seems that modulation of activity of these targets in US 2013/0252924 A1 Sep. 26, 2013

any direction reduces the pain or sensation of pain. Preferably selected from a chloride and/or fluoride substituted aniline the modulator is a strong binder to these targets, especially group or a carbonyl substituted aniline. Preferably the aniline with a Kd of 1000 nM or less or an IC50 of 1000 nM or less. group is a carbonyl Substitution, Such as in dasatinib (dasat Preferred lower values for Kid and IC50 are 800 nM or less, inib), motesanib (AMG-706), doramapimod (BIRB 796), 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or pelitinib (EKB-569), Sorafenib (Sorafenib), canertinib (CI less, 200 nM or less, 100 nM or less, 50 nM or less or even 30 1033) and (STI-571), and can be used in the treat nM or less. ment of neuropathic pain. 0008. In particular preferred are FMO3 modulators or (0018. In preferred embodiments the FRK inhibitor is a inhibitors for use in the treatment of pain. Such compounds selective FRK inbibitor. By “selective” it is meant that the are e.g. Tenofovir and Methimazole. affinity for FRK is at least 10-fold, preferably 25-fold, more 0009. In particular preferred are FRK modulators or preferred 100-fold, still preferred 150-fold higher than the inhibitors for use in the treatment of pain. Such compounds affinity for other kinase receptors, especially one or are e.g. dasatinib, motesanib, Doramapimod, Pelitinib, Sor both of FLT3 or c-Kit. afenib, Vandetanib and Canertinib. (0019. In further embodiments there is provided an LPAR3 0010 Preferably the inhibitor is selected from compounds inhibitor or modulator for use in the treatment of pain. Such a with a Kd of lower than 3000 nM, preferably lower than 2000 compound is e.g. selected from NSC161613, NSC47091, nM, especially preferred lower than 1000 nM. In particular, N6-Benzyladenosine-5'-phosphate, p-Aminobenzoly PAB-J these compounds can be selected from dasatinib (Kd 0.31 nM), motesanib (Kd 99 nM), Doramapimod (Kd 360 nM), acid. Pelitinib (Kd 190 nM), sorafenib (Kd 440 nM) and Vandet 0020 Surprisingly it could be shown that in case of anib (Kd 480 nM). The Kd may also be up to 750 nM or up to LPAR3 both activators or agonists and inhibitors or antago 500 nM. nists can be effective in the treatment of pain. Thus any 0011 Kd, Kior IC50 values of course relate to the binding artificial change in the expression or activity of LPAR3 can or inhibiting capability of a given compound on a given target, ameliorate pain. Preferably the LPAR3 modulator is selected such as one of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 from compounds comprising N6-Benzyladenosine-5'-phos or FMO3, as associated herein. phate, p-Aminobenzoly PAB-J acid, NSC161613 and 0012. In preferred embodiments the FRK modulator is NSC47091. In particular preferred cases the LPAR3 modu selected from compounds comprising a Substituted pyridine, lator is an LPAR3 inhibitor. Such an inhibitor is e.g. p-Ami quinoline, isoquinoline or pyridine group. nobenzoly PAB-J acid, NSC161613 or NSC47091. 0013. In especially preferred embodiments the FRK (0021. In further embodiments there is provided a PDE4D modulator is an FRK inhibitor. An inhibitor orantagonist is a inhibitor or modulator for use in the treatment of pain. Such a compound that lowers or inhibits the activity of a given target compound may be selected from cilomilast, Roflumilast, Fil here FRK. This can be achieved by binding to the target, e.g. aminast, Piclamilast, V11294, , Apremilast, Arofyl but not necessarily to the catalytic center, and preventing the line, Atizoram, Catramilast, Cimpyfylline, Daxalipram, DOX catalytic activity of the target. ofylline, drotaverin, Efloxate, Etamiphylline, Etazolate, 0014 Preferably an inhibitor or modulator, in particular of Eto?ylline, Broncholytine, Irimilast, oglemilast, Choline FRK, is selected from compounds comprising a Substituted theophyllinate, Pumafentrine, Revamilast, Ronomilast, , quinoline, isoquinoline or pyridine group. Such Tofimilast, Tolafentrine, Trapidil, GW 842470 (AWD as from motesanib (AMG-706), Pelitinib (EKB-569), sor 12-281), CDP-840, YM-976, CI-1018, D-4418, Lirimilast, afenib (Sorafenib), Vandetanib (Vandetanib), canertinib (CI SCH-351591, RPL-554, IPL-455903 (HT-0712), 1033). GSK256066, Zardaverine, Vardenafil, Tetomilast, IC485, 00.15 Preferably an inhibitor or modulator, in particular of L-826,141, ONO-6126, CI-1044, MK-0873, T-2585, R1533 FRK, is selected from compounds comprising a Substituted (MEM-1414), UK-500,001, AN2728, DE-103, Tofisopam, aniline group with a Kd value less than 1000 nM, such as Dextofisopam, Levotofisopam (USAN). dasatinib (dasatinib), motesanib (AMG-706), Doramapimod (0022 Preferably the PDE4D inhibitor is selected from a (BIRB 796), Pelitinib (EKB-569), sorafenib (Sorafenib), Van compound comprising a 1,2-dioxy-aryl group with an ICso detanib Vandetanib). value of 1100 nM or less, preferably 1050 nM or less, pref 0016 Preferably an inhibitor or modulator, in particular of erably 1000 nM or less, preferably 950 nMorless, preferably FRK, is selected from compounds comprising a chlorine, 950 nM or less, preferably 900 nM or less. Such a PDE4D fluorine or chlorine and fluorine substituted aniline group. inhibitor is preferably selected from cilomilast (cilomilast, Such compounds are e.g. dasatinib, Pelitinib, Sorafenib, Van ICs of 11 nM), Roflumilast (Roflumilast, ICs of 0.68 nM), detanib and canertinib. Filaminast (Filaminast, ICs of 1000 nM), Piclamilast 0017. In preferred embodiments an FRKinhibitor selected (Piclamilast, ICs of 0.02 nM), (V11294, ICs of 200 nM), from compounds comprising an aniline group, selected from Apremilast (CC-10004), Atizoram CP80633), Catramilast dasatinib dasatinib), motesanib (AMG-706), doramapimod (Catramilast), Daxalipram (Daxalipram/mesopram, ICso of (BIRB 796), pelitinib (EKB-569), Sorafenib (sorafenib), van 1100 nM), drotaverin (Drotaverine), (Glaucine Hydrobro detanib vandetanib), canertinib (CI-1033) and imatinib (STI mide), oglemilast (GRC3886, ICs of 166 nM), Pumafentrine 571) is for use in the treatment of neuropathic pain, such as (Pumafentrine), Revamilast (Revamilast, ICs of 2.7 nM), trigeminal neuralgia, Such as post-herpetic neuralgia, such as Tolafentrine (Tolafentrine, ICs of 30 nM), CDP-840, ICs of painful diabetic neuropathy, such as painful diabetic periph 2.1 nM), (RPL-554), (IPL-455903 (HT-0712)), Zardaverine eral neuropathy, such as diabetic polyneuropathy, such as (Zardaverine, ICs of 390 nM), Tetomilast (OPC-6535, ICso sciatic pain, such as radiculopathy, Such as radicular pain or of 70 nM), (L-826,141, ICs of 2.4 nM), Ronomilast Such as non-inflammatory neuropathic pain. The aniline (ELB353, ICs of 3.5 nM), Tofisopam (Tofisopam, ICs of group is preferably a Substituted aniline group and is e.g. 900 nM). US 2013/0252924 A1 Sep. 26, 2013

0023. In a further preferred embodiment the PDE4D 0032. In preferred embodiments the CAMK1D modulator inhibitor or modulator comprises a 1,2-dioxy-aryl group Sub is a selective CAMK1D modulator. By “selective' it is meant stituted with an alkyl or flour-alkyl group, or 1,2-dioxy-aryl that the affinity for CAMK1D is at least 10-fold, preferably group condensed in a furan ring containing oxygen. Such a 25-fold, more preferred 100-fold, still preferred 150-fold compound is e.g. selected from cilomilast (cilomilast), Rof higher than the affinity for other receptors, lumilast (Roflumilast), Filaminast (Filaminast), Piclamilast especially one or both of FLT3 or c-Kit. (Piclamilast), (V11294), Apremilast (CC-10004), Daxalip 0033. In further embodiments there is provided a ram (Daxalipram/mesopram), drotaverin (Drotaverine), CSNK1G3 inhibitor or modulator for use in the treatment of broncholytine (Glaucine Hydrobromide), oglemilast pain. Such compound can be roscovitine. (GRC3886), Pumafentrine (Pumafentrine), Revamilast (Re 0034. The CSNK1G3 inhibitor or modulator preferably vamilast), Tolafentrine (Tolafentrine), (RPL-554), Zardaver comprises a ring. Such compound can be roscovitine. ine (Zardaverine), Tetomilast (OPC-6535), (L-826,141), Ronomilast (ELB353), Tofisopam (Tofisopam). 0035. In preferred embodiments the CSNK1G3 inhibitor is a selective CSNK1G3 inbibitor. By “selective” it is meant 0024. In another aspect of PDE4D inhibitors or modula that the affinity for CSNK1G3 is at least 10-fold, preferably tors there is provided a PDE4D inhibitor or modulator com 25-fold, more preferred 100-fold, still preferred 150-fold prising a 3.5-dichlor-pyridine group or a pyridine group that higher than the affinity for other tyrosine kinase receptors, is not condensed in a 2 ring structure. Such compounds may especially one or both of FLT3 or c-Kit. be selected from Roflumilast (Roflumilast), Piclamilast 0036. In preferred embodiments of the invention the com (Piclamilast), oglemilast (GRC3886), Revamilast (Revami pound for use in the treatment of pain comprises a quinoline last), GW 842470 (AWD 12-281), D-4418, SCH-351591. or isoquinoline group. Such compounds are e.g. , 0025. Also provided is a PDE4D inhibitor or modulator comprising a quinoline, isoquinoline or pyrimidine group. Pelitinib (EKB-569), drotaverin (Drotaverine), Pumafentrine (Pumafentrine), Tolafentrine (Tolafentrine), D-4418, SCH Such a compound can be selected from drotaverine (Dro 351591, RPL-554, (GSK256066), T-2585, Ronomilast taverine), Pumafentrine (Pumafentrine), Tolafentrine (To (ELB353), preferably the compound being an inhibitor of lafentrine), Trapidil (Seoanin), D-4418, SCH-351591, RPL FRK, PDE4D or CAMK1D. These compounds are preferably 554, SK256066, T-2585, Ronomilast (ELB353). for use in the treatment of neuropathic pain, preferably non 0026. In a further embodiment the PDE4D inhibitor or inflammatory neuropathic pain. modulator is selected from compounds comprising an aniline 0037. In preferred embodiments of the invention the com group, in particular preferred a carbonyl- or chlorine-substi pound for use in the treatment of pain comprises a chlorine tuted aniline. Such compounds are e.g. Apremilast (CC Substituted aniline group. Such compounds are e.g. selected 10004), Arofylline (LAS31025), CI-1044, T-2585 from dasatinib dasatinib), bosutinib (SKI-606), Sorafenib 0027. The PDE4D inhibitor or modulator for use accord (sorafenib), Canertinib (CI-1033), Arofylline (LAS31025), ing to the invention may comprise a purine ring. Such a T-2585, Pelitinib (EKB-569), preferably the compound being compound can be selected from (IBMX), (V11294), Arofyl an inhibitor of FRK, PDE4D or CAMK1D. These com line (LAS31025), Cimpyfylline (BRL-61063), Doxofylline pounds are preferably for use in the treatment of neuropathic (Doxofylline), Etamiphylline (Etamiphylline), Etofylline pain, preferably non-inflammatory neuropathic pain. (Etofylline), (oxtriphyllin), Theo phylline (). These compounds are preferably 0038. The inventive compound can be used in combina used for the treatment of neuropathic pain, especially non tion with other active /anti-pain compounds, prefer inflammatory neuropathic pain. ably only with those described herein or above or in the claims, or used as single active analgesic/anti-pain com 0028. In a further embodiment the PDE4D inhibitor or pound. modulator for use according to the invention is essentially the only active pharmaceutical ingredient of the composition or 0039. In preferred embodiments the compound for use medicament according to the invention, Such as the only according to the invention comprises a 1,2-Dioxyaryl group. active pharmaceutical ingredient, in particular the only anti Especially preferred the compound comprises a 1,2-Di pain compound, of the composition or medicament according oxyaryl group Substituted with a basic residue. Such as Van to the invention. Preferably the PDE4D inhibitor or modula detanib (Vandetanib), SKI-606 (Bosutinib). The compound tor for use according to the invention is not combined with or may comprise a 1,2-Dioxyaryl group Substituted with a used in combination with a phospholipase inhibitor. Espe cycloaliphatic residue. Such as cilomilast (cilomilast), Roflu cially preferred, CI-1018 is not combined with or used in milast (Roflumilast), Filaminast (Filaminast), Piclamilast combination with a phospholipase inhibitor when used (Piclamilast), V11294, CP80633 (Atizoram), Catramilast/ Atopik (Catramilast), CDP-840, IPL-455903 (HT-0712). The according to the invention. compound may comprise a 1,2-dioxy-aryl Substituted with an 0029. In further embodiments there is provided a alkyl residue, such as CC-10004 (Apremilast), Daxalipram/ CAMK1D inhibitor or modulator for use in the treatment of mesopram (Daxalipram), Drotaverine (drotaverin), Glaucine pain. Such a compound may be selected from Bosutinib, Hydrobromide (Broncholytine), Pumafentrine (Pumafen Pelitinib, EKB-568, SU-14813, Ruboxistaurin, CGP-52421. trine), Tolafentrine (Tolafentrine), RPL-554, Zardaverine 0030. The CAMK1D inhibitor or modulator preferably Zardaverine), OPC-6535 (Tetomilast), Tofisopam (Tofiso comprises a chlorine-substituted aniline group. Such com pam). The compound may comprise a 1,2-dioxy-aryl Substi pounds can be selected from Bosutinib (SKI-606) and Peli tuted with a fluor-alkyl group, such as GRC3886 (oglemilast), tinib (EKB-569). Revamilast (Revamilast), Zardaverine (Zardaverine), L-826, 0031 Preferably the CAMK1D inhibitor is selected from 141, ELB353 (Ronomilast). The compound may comprise a the group ofbosutinib (SKI-606), pelitinib (EKB-569), EKB 1.2-dioxy-aryl in a condensed furan ring with an oxygen, 568 and CGP-52421 for use in the treatment of pain. such as GRC3886 (oglemilast), Revamilast (Revamilast). US 2013/0252924 A1 Sep. 26, 2013

0040. In preferred embodiments the compound for use 0050. In preferred embodiments the compound for use according to the invention comprises an indole group, espe according to the invention comprises a aniline group, espe cially an indole group as part of a ringsystem, Such as CGP cially preferred a chloride and/or fluoride substituted aniline 52421, midostaurin (PKC-412). group. The compound may comprise a Chlor-fluor-aniline, 0041. In preferred embodiments the compound for use auch as EKB-569 (Pelitinib),CI-1033 (Canertinib). The com according to the invention comprises a Substituted indole, pound may comprise a Chloraniline or dichlor-aniline. Such such as GW 842470 (AWD 12-281), AMG-706 (motesanib), as dasatinib (dasatinib), Sorafenib (Sorafenib), LAS31025 SU-14813, LY-333531 (Ruboxistaurin), SKI-606 (Bosu (Arofylline), T-2585, SKI-606 (Bosutinib). The compound tinib). may comprise a Fluor-aniline, such as Vandetanib (Vandet 0042. In preferred embodiments the compound for use anib), SU-14813. according to the invention comprises a purine ring, such as 0051. In preferred embodiments the compound for use N6-Benzyladenosine-5'-phosphate, V11294, LAS31025 according to the invention comprises a carbonyl-substituted (Arofylline), BRL-61063 (Cimpyfylline), Doxofylline (Dox aniline, such as dasatinib (dasatinib), AMG-706 (motesanib), ofylline), Etamiphylline (Etamiphylline), Etofylline (Eto?yl BIRB 796 (Doramapimod), EKB-569 (Pelitinib), Sorafenib line), oxtriphyllin (Choline theophyllinate), Roscovitine (Sorafenib), CI-1033 (Canertinib), p-Aminobenzoly PAB-J (Roscovitine), Tenofovir (PMPA) (Tenofovir), Remofovir acid, CC-10004 (Apremilast), CI-1044, NSC47091. (Pradefovir), Adefovir dipivoxil (Bis-POM PMEA) (Ade 0052. In preferred embodiments the compound for use fovir). according to the invention comprises a diaryl-thioether 0043. In preferred embodiments the compound for use group, such as tozasertib (MK-0457, VX 680). according to the invention comprises a Sulfone or Sulfonic 0053. In preferred embodiments the compound for use acid or Sulfonamide group, especially a methyl-Suflone. Such according to the invention comprises a 1,3-Dioxyaryl group, as Lirimilast (Lirimilast). The compound may comprise a such as Efloxate (Efloxate). siaryl-sulfone, such as GSK256066, Vardenafil (Vardenafil). 0054. In preferred embodiments the compound for use The compound may comprise a sulfonic acid group. Such as according to the invention is selected from Methimazole, p-Aminobenzoly PAB-Jacid. The compound may comprise a AN2728, NSC161613, especially a compound without one or Sulfonamide group, such as Tolafentrine (Tolafentrine), more or all of the above mentioned groups. Acetazolamide (Acetazolamide). 0055. The present invention also provides a method of 0044. In preferred embodiments the compound for use treating pain in a subject comprising the administration of a according to the invention comprises a pyridine group. Pref therapeutic compound selected from the compounds of table erably the compound comprises an unsubstituted pyridine 1. In a related aspect the present invention provides the use of radical, such as Nicotinamide (Nicotinamide), or CI-1044. a compound of table 1 for the manufacture of an analgesic or The compound may comprise a 3.5-Dichlorpyridine group, a medicament for the treatment of pain in a subject. The such as Roflumilast (Roflumilast), Piclamilast (Piclamilast), invention is further defined by the subject matter of the GRC3886 (oglemilast), Revamilast (Revamilast), GW claims. 842470 (AWD 12-281), D-4418, SCH-351591. The com 0056. The inventive compounds have been identified by a pound may comprise a Substituted pyridine group, Such as thorough screening system based on genetic analysis, starting AMG-706 (motesanib), Sorafenib (Sorafenib), Etazolate from drosophila hits. Drosophila (fruit flies) respond to nox (Etazolate), Tofimilast (Tofimilast), GSK256066, MK-0873. ious stimuli, and have become a powerful model organism for 0045. In preferred embodiments the compound for use studying genetics, including the genetics of nociception. For according to the invention comprises a quinolone or isoquino instance, the TRP channel PAINLESS was previously iden line or condensed isoquinoline group. The compound may tified as a heat-responsive channel mediating thermal-based comprise a quinolone group such as EKB-569 (Pelitinib), nociception in fly larvae. Using genome-wide neuronal-spe D-4418, SCH-351591, GSK256066, MK-0873, SKI-606 cific RNAi knock-down, the present invention provides a (Bosutinib). The compound may comprise a isoquinoline or global screen for an innate behavior and identify hundreds of condensed isoquinoline group, Such as Drotaverine (dro novel genes implicated in nociception in the fly, including the taverin), Pumafentrine (Pumafentrine), Tolafentrine (To C.26-family channel Subunit straightjacket or the lafentrine), RPL-554, ELB353 (Ronomilast). phospholipid kinase PI3 Kgamma. The initial drosophila 0046. In preferred embodiments the compound for use screen yielded targets having homologous targets in various according to the invention comprises a pyrimidine group, organisms, including humans. For example, observation of such as Vandetanib (Vandetanib), CI-1033 (Canertinib), the mammalian straightjacket ortholog, C.263, and PI3 Seoanin (Trapidil), tozasertib (MK-0457, VX680). Kgamma in nociception was confirmed in knock-out mice 0047. In preferred embodiments the compound for use that exhibit significantly impaired basal pain sensitivity and according to the invention is a compound with 3 nitrogens in delayed thermal hyperalgesia after . In humans, a ring structures, such as YM-976. single polymorphisms (SNPs) in C.263 or PIK3CG 0048. In preferred embodiments the compound for use were found that are associated with reduced acute pain sen according to the invention comprises a carbonic or phospho sitivity in healthy Volunteers and chronic postSurgical back ric acid group. The compound may comprise a carbonic acid pain. Based on the validated genetic data various compounds group, such as OPC-6535 (Tetomilast). The compound may have been identified that are capable of treating or Suppress comprise a phosphoric acid group. Such as N6-Benzylad ing pain in various organisms, in particular in humans. In a enosine-5'-phosphate, Tenofovir (PMPA) (Tenofovir). further screening, several compounds have been identified 0049. In preferred embodiments the compound for use which modulate or antagonize or inhibit, that is lower the according to the invention comprises an esther group, such as targets activity in vivo or as can be determined in an in vitro Remofovir (Pradefovir) (Pradefovir), Adefovir dipivoxil assay as described herein or known in the art (e.g. (Bis-POM PMEA) (Adefovir). activity assay to determine ICso values), which are active in

US 2013/0252924 A1 Sep. 26, 2013

7,8-dihydroneopterin, 7'-Isothiocyanato-11-hydroxy-1'1'- Buthionine Sulfoximine, Butyrate, butyrolactone I, C 1027, dimethylheptylhexahydrocannabinol, 7C3MT, 7H-Pyrrolo C 76, CACP, Calcijex, Calcimycin, calphostin C, Calyculin, (2,3-d)pyrimidine, 8-((4-bromo-2,3-dioxobutyl)thio)-ad Camptothecin, Canef, , Cannabinoids, Cannabis, enosine 3',5'-cyclic monophosphate, 8-(2,6-dichlorophenyl)- Cantharidin, CAPE. Capsaicin, capsaicinoids, capsaZepine, 10-methyl-3-((4-morpholin-4-ylphenyl)amino)-2,4,10 Carbachol, , carbapenem, Carbapenems, car triazabicyclo(4.4.0)deca-1,3,5,7-tetraen-9-one, 8-(3- bobenzoxy-leucyl-leucyl-norvalinal, Carbolines, Carboxy chlorostyryl), 8-anilinonaphthalene-1-sulfonic acid, ethyl-phenethylamino-ethylcarboxamidoadenosine, Cardio 8-Hydroxy-2-(di-n-propylamino)tetralin, 8-Isoprostane, lipins, carebastine, CARNOSOL, carrageenans, carvacrol, 8,10-bis((2,2-dimethyl-1-oxopropyl)oxy)-11-methyl-1234 , Casodex, caspofungin, casticin, , CB tetrahydro-6H-benzo(beta)quinolizin-6-one, 9-(4-ami 3717, Cbdica, CCPA, CD 437, CDP840, Cefoxitin, , nophenyl)-9H-pyrido(3,4-b)indole, 9-anthroic acid, 9-CRA, cephalomannine, cephalosporins, cepharanthine, cerebrol 9-hydroxy-, 9,10-anthraquinone, 9H-xanthene. A ysin, cerivastatin, Cetomacrogol, cetrorelix, , CGP 71915, A-300-I, a-ADP, A73025, Abbott, , Absele, 12177, CGS 15943A, CGS 21680, CH-THF, CH2CHO, ABT-737, acetamide 45, Aceton, acetonitrile, acetyl-11-ke Chalcone, CHAPS, Chinine, Chitosan, Chloramphenicol, toboswellic acid, , acetyl-Valerenolic acid, chlorophenyl-ethane, chlorophyllin, chlorophyllypt, chlor Aclarubicin, Acolen, ACON, ACT D, actinium, Actosin, , Chlorpropham, ChlorZoxazone, Cholestanol, adalimumab, Adalin, Adanon, Adfeed, adinazolam, Adofeed, CHOLINE, Chonsurid, chromophore, , chymostatin, Adrenor, Adrin, AEBSF, Aeromax, afloqualone, AGMA CI1033, cicaprost, cifostodine, , Cilazapril, Cilo TINE, AIDSVAX, ajoene, ajulemic acid, alachlor, Aladerm, milast, , , cinacalcet, cinitapride, cin alaninate, Alat, Alcolo, Alcuronium, Aldara, ALDO, Aldrich, namic aldehyde, cionin, Cipol N. , Ciprol, cis alemtuzumab, Alfarol, , ALIMTA, alliskiren, Alli, 9, trans-11-conjugated , Cisapride, Citalopram, ALLN, alloxazine, , almokalant, aloesin, Citox, CITRULLINE, , clevidipine, clobazam, Alprenolol, Alvesco, AM 1387, AM 251, Am 80, AMD 070, Clodronic Acid, clofarabine, Clofibric Acid, Clomipramine, Amiloride, Aminacrine, Amine BB, amino-polyethyleneox Clonazepam, Clonidine, , clotiazepam, CloZap ide-sulfonate, aminoflavone, , , ine, N-oxide, CNI 1493, Co 2-1970, Coagulin, Amphotericin B, amprenavir, , amsonic acid, , compactin, CONT, , Cotrim, , Amygdalin, AN 207, Anaboleen, anacardic acid, Ananda CRA 024781, CRA 026440, Crestor, Crodacid, Crypt-2.2.2, mide, Anco, Andrographis, Androtine, Aneol, Ang II, Aniso cryptdin 3, cryptotanshinone, cryptoxanthin, CUBE, CVT mycin, Anon, Anthocyanins, anthra(1.9-cd)pyrazol-6(2H)- 3146, cyanidin 3-rutinoside, cyanidin-3-, cyanogi one, anthracene, anthralin, Anthricin, anthrone, antibiotic G nosin-LA, Cyclandelate, cyclohexyl carbamic acid 3'-car 418, antibiotic H107, Antimycin A, Any vim, APAP, APDC, bamoylbiphenyl-3-yl ester, cyclo-hexyl-methyl, cyclopam Aphidicolin, Aphloiol, apicidin, , apocynin, Apo ine, Cyclopentenone, cyclopiaZonic acid, , transferrin, aprepitant, APRL, AQ4N, arabinogalactan, Arac, Acetate, cyStathionine, cysteamine, cysteinyl Aralen, Arasine, Areca, , Areether, , arip , Cytarabine, cytochalasin B, Cytochalasin D, iprazole, Aron, Artein, Artra, arvanil, asiatic acid, asiatico cytochalasin E, D 22888, D23129, DA 8159, Dacarbazine, side, ASmax, ASmol, ASTA, astatine, Astemizole, Astragalo DADSO, , danaproid, Dapsone, Daral, Darifenacin, side A, atazanavir, ATL 146e, Atorel, , darunavir, dasatinib, Daunorubicin, Dayfen, DBPC, DDB, Atovaquone, ATRA, Atropine, Auranofin, AuTM, auxin, ava DDE, Debrisoquin, decursin, Deethylamiodarone, defer simibe, AVE 0118, , Avid, Axert, AXsain, Aza-dC, iprone, Deferoxamine, deguelin, dehydroaripiprazole, Dehy AZa-deoxycytidine, azacyclonol, AZadc, azamulin, azaspir droepiandrosterone Sulfate, dehydroxymethylepoxyquino ane, , azelastine, azelnidipine, azido ruthenium, micin, , delta8-THC, Denagard, denbinobin, AZine, Azithromycin, AZobisisobutyramidinium dichloride, denileukin diftitox, , Depas, deramciclane, des Azole, AZoles, Azolidine, AZophen, Azor, BA (VAN), Ba ethylchloroquine, , desisobutyrylciclesonide, des 0108E, bacitracin, Baclofen, bacterial lysate, bafilomycin methylazelastine, Desmethyldeprenyl, Devazepide, Dexfen A1, Bagren, , , Barnidipine, BAY fluramine, dexloxiglumide, , dFdC. 11-7085, BB-K8, BCNU, Beflavin, Belt, benazepril, benda DEMO, DHEA, DHLA, di-(1-isoquinolinyl)-di-(pyridyl-2') mustine, , benzamidine, benzimidazolide, Benzo , Diaben, Diacomit, diadenosine tetraphosphate, Dial, diazepines, Benzodioxoles, , Diamide, DIAN, diarsenic trioxide, Dibenzanthracene, N-oxide, benzylamine, benzyloxycarbonyleucyl-leucyl-leu Dicid, , Dicyclohexylcarbodiimide, diethyl male cine aldehyde, benzyloxycarbonylvalyl-alanyl-aspartyl fluo ate, Diethyl-benzoquinone-imine, Digicor, Digitin, , romethyl ketone, beractant, berberine, bergamottin, bergap Dihydroqinghaosu, Dihydroxycholecalciferols, diisopropyl tol, beta-glycerophosphoric acid, beta-lapachone, beta fluorophosphate, dilapiol, , Dimethadione, dim Naphthoflavone, beta-propiolactone, Bethanechol, betulinic ethyl fumarate, , dimethyl-hydrazide, acid, bexarotene, Bezafibrate, BG 9928, BGC945, biapige dimethylamino-purine, dimuonium, dinitrophenol, Dinopro nin, BIBX 1382BS, biphenyl-4-ol, BIRB 796, bisindolylma stone, dioxirane, Dipalmitoyl, diphenylalanine, Dipheny leimide I, bisindolylmaleimide III, Bisoprolol, bisperoxova lamine, diphenyleneiodonium, , Dipyrone, dis nadium, -Glycidyl Methacrylate, bizelesin, codermolide, Diterpenes, Dithionite, , Diuron, BL 1521, Bla-S. Blow, BM 41.440, BML 241, BMS 310705, divinyl , d1-pr, DMGG, DMPX, DMSO, Dob BMS204352, BMS453, Bo-Xan, Boltin, Bonopen, boron, utamine, Doca, Doconexent, dodecyl-phosphocholine, dode Borrelia-burgdorferi, bortezomib, , bosutinib, cyloctaethyleneglycol monoether, , DOTA, botrocetin, BPDE, BR-II, Brake, bredinin, Brefeldin A, Bro Doxazosin, Doxorubicin, Doxycycline, DPC 681, DPCPX, mazepam, bromocis-Stilbene, brucine, bryostatin 1, Budes Droxia, DTMC, dulcin, Durapatite, DX 9065a, Dxms, onide, bufalin, bufuralol, , BuOH, Bupivacaine, Dynatra, E 10, E 3330, E-MIX 80, E.O., EACA, ebastine, , , , Busulfan, ebrotidine, Echinomycin, Econ, econazole, ecteinascidin US 2013/0252924 A1 Sep. 26, 2013

743, Edetic Acid, Edex, , EGCg, EGTA, eletriptan, 3213, KMTB, Kojic acid, KR-31543, KRM 1648, L365260, Elicide, Empecid, Enalapril, Endocannabinoids, endomor L 740,093, L-454,560, L-696,474, L-T3, LAAM, lacidipine, phin 1, Enediynes, , enone, , entaca lactacystin, lactisole, lamotrigine, Lanol, , lapa pone, Entex, enzastaurin, EOS, EPC-K(1), EPEG, EPIB, epi tinib, lacquinimod, latrunculin A, latrunculin B, lavendustin A, batidine, Epicar, Epoprostenol, epoxybergamottin, epsilon LBH589, leflunomide, lenalidomide, Lendorm, Lentinan, viniferin, erastin, ergosterol-5.8-peroxide, Eril, , leptomycin B. Leucovorin, Leukotriene C4, Leukotriene D4. erucin, Eryc, erythritol anhydride, esterbut-3, , ET18 , Leupeptin, Levamisole, Levitra, levobupiv Ome, Etfc cpd, Ethacrynic Acid, Ethan, Ethinyl-oestradiol, acaine, , leVugen, liarozole, Lidocaine, lilo , Ethynodiol Diacetate, Eticol, Etidronic Acid, pristone, Lipoate, Lipofectamine, lipoteichoic acid, , Etoposide, , etravirine, Eufor, Eugenol, Lipoxins, lissamine rhodamine B, lithocholic acid, LMWH, eupatilin, everolimus, Evex, Evodin, eXenatide, ExoSurf. LNAC, lonafarnib, , lopinavir, , Expectorants, Extina, Ezerin, ezetimib, Facet, Facid, facile, Lorazepam, Lorex, lorglumide, , Lovan, loxiglu Factor IIa, FAMP. Fanchinine, Farnesyl-PP, farnesylthiosali mide, LUF 5831, lupeol, luteolin, LY 1 17018, LY 29311 1, cylic acid, , , , , LY231514, LYCOPENE, lysophosphatidic acid, Lysophos fenitrothion, fenofibric acid, Fenretinide, , ferulic phatidylcholines, Lysophosphatidylglycerol, lysyl-arginyl acid, Filipin, fingolimod, fipronil, , Flanin F. Flavon, alanyl-lysyl-alanyl-lysyl-threonyl-threonyl-lysyl-lysyl-argi , flavopiridol, Flavyl. FLCZ. Flecamide, Floxacillin, nine, M&B22948, Malix, , manumycin, , Flunitrazepam, fluorexon, Fluorouracil, flu maraviroc, , MCYST-LR, Me-nle-asp-phe-NH2, voxamine, FOLATE-ANALOG, , Fonofos, mead ethanolamide, MeAsO(OH)2. Mebumal, Mechlore Format, Formyl-Tetrahydrofolate. Forskolin, fosamprenavir, thamine, 17-Acetate, Mefenamic Foscarnet, FR 120480, FR 235222, fraxin, FTY 720P, Acid, Megalomicin, Melarsoprol, Melatol, meletin, melitten, fucoidan, , fumagillin, Fura-2, . Fura , Melphalan, , menadiol, Menhaden mon, Furylfuramide, Gabexate, gadolinium, Gadolinium oil, menthofuran, Meperidine, Mephenyloin, mesalamine, DTPA, galactocerebroside, galactomannan, , galatu Mesaton, Meth, methanandamide, methanethiosulfonate ronate, gallic acid, Gallogen, gambierol, Gambogic acid, ethylammonium, Methimazole, methionyl-leucyl-phenylala gamma-butyric-acid, Ganciclovir, gastrin 17, gatifloxacin, nine, , Methox-salen, Methoxy-psoralen, meth , Geldanamycin, Gemfibrozil, gemtuzumab, Gen oxyamine, , methoxy-morphinan, methyl chlo tamicins, gepirone, geraniol, geranylcoumarin, , roformate, Methyl , Methyl paraben, methyl GF 120918, GGTI 298, GI 129471, gingerol, ginsenoside Rd, salicylate, methyl , methyl-dopa, methyl-phos ginsenoside Rf, ginsenoside Rg1, ginsenoside Rh2, Ginseno phorothioate, methyl-Pyridinium, , Methy sides, GLCa, Gliclazide, Glumin, Glyoxal, Gnidimacrin, lamylnitrosamine, Methylene-tetrahydrofolate, methylene GnRH, Go 6976, gossypol, GR 79236X, gramicidin S. Gra tetrahydrofolates, methylglyoxal, methylmaltrexone, nisetron, Gravistat, Grofo, , GW 4064, GW methyloxidanyl, methylparaben, methylphosphate, Methyl 501516, H 89, Halan, halofuginone, harmine, Harzol, has , methylxanthines, , sium, HDMTX, Hecogenin, Hectorol, Heet,helenalin, Hemi Metopiron, , mevalonic acid, micafungin, cholinium3, herbimycin, hesperadin, HESPERETIN, Hexa , Mictonorm, Midazolam, , MIII, dimethrine, hexarelin, Hgln, himbacine, Hk, Hocus, HOE , Mimosine, , Mit-C, mithramycin, 33342, honokiol, Horner, HS1200, HU 211, HyateC, MitoTracker-Red, Mitoxantrone, mizolastine, MLN8054, Hydroxin, hydride, , Hydroxychloroquine, mofarotene, Monensin, mono-N-demethyladinazolam, hydroxycotinine, hydroxylamine, Hydroxytryptophol, mono(2-ethylhexyl), monoethylglycineXylidide, Hyhorin, Hypaque, , hypericin, Hypericum-perfo monomethylarsonic acid, monoterpenes, monuron, , ratum, hypochlorous acid, iberin, IBMX, , ibudi morpholine, morusin, motexafin gadolinium, Motuporin, last, IC 831423, , icaritin, icilin, ICRF 193, IDS 23, moxifloxacin, MPEG, Muraglitazar, mutalipocin II, myco Ifosfamide, Ikarugamycin, ilimaquinone, , Imadyl, phenolic acid, Mycose, Myocol, , myxothiazol. imatinib, imidafenacin, imidazo-pyridine, imidazolidin-2- N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide, one, imidazolidin-one, imidazolidine, Imidazoline, imida N-(2-hydroxypropyl)methacrylamide, N-(3-(4-chlorophe Zolyl-disulfide, Imipenem, Imizin, Immulina, Immunoferon, nyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5- Impulsin, Imrecoxib, Imutex, , indiplon, indirubin, (trifluoromethyl)pyridin-2-yl)oxy)propanamide, N-(3-meth indole-3-acetic acid, indole-3-methanol, indolin-2-one, indo oxyphenyl)-4-chlorocinnamanilide, N-(3-oxododecanoyl) lin-one, infliximab, inhibin B, INOmax, -1,3,4,5-tet homoserine lactone, N-(4-(6-(4-(1-(4-fluorophenyl)ethyl) rakisphosphate, inulin, Iodoacetamide, iodomethane, iodor piperazin-1-yl)pyrimidin-4-yloxy)benzo(d)thiazol-2-yl) esiniferatoxin, Ionomycin, ionophore, Iopanoic Acid, acetamide, N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4- Iophendylate, IPADE, IPOMEANOL, Iressa, irinotecan, yloxy)benzothiazol-2-yl)acetamide, N-(4-cyano-benzo(b) irisolidone, Isatin, isaxonine, isoamylol, isobutyl-methyl thiophene-2-carbonyl)guanidine, N-(5-(((5-(1,1- , Isodonol, isoflavone, , Isol, Isoliquiriti dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4- genin, isometronidazole, isoprenoids, Isopropyl Thiogalac piperidinecarboxamide, N-acetylcysteine lysinate, toside, Isoprostanes, , isosilybin A, Isosorbide n-acetylmuramyl-l-alanyl-d-isoglutamine, N-acetyl Dinitrate, isothiocyanates, Isotretinoin, Isradipine, istrade neuraminic acid, N-desmethylclobazam, N-ethylmaleimide, fylline, , ivabradine, , ixabepilone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-methyl jadomycin B, Jexin, JHW 015, JTE 013, K 252, K-PAM, Sulfonyl-6-(2-propargyloxyphenyl)hexanamide, N-oleoyl K-SR, , kaempferol-3-O-(2,3,4-tri-O-acetyl-al , N-phenyl-1-naphthylamine, N.N.N',N'-tetram pha-1-rhamnopyranoside), KAFA, Kaken, Kamalin, Kaolin, ethylethylenediamine, N(6)-cyclohexyl-2-O- Kathon 886, KB 141, Kemi, kenpaullone, , Keto methyladenosine, N(6)-cyclopentyladenosine, N3-IQ, , Keto-pgflalpha, ketoglutarate, Kipca, KMD Nadroparin, naftifine, nal-NH2, NALS. nanchangmycin, US 2013/0252924 A1 Sep. 26, 2013

Naproxen, naratriptan, narbonolide, NARIGENIN, Narkotil, succinate, quinupristin-dalfopristin, R-138727, R-99224, Nasol, natalizumab, nateglinide, Naxy, nebivolol, Nefaz , raltitrexed, Ramipril, ramiprilat, RAMP Raniti odone, nefiracetam, Nelfinavir, , Neopterin, Neo dine, RAPA, , rebamipide, reboxetine, remifenta stigmine, Neut, , NFBA, Nialk, , nil, renzapride, repaglinide, Resiniferotoxin, residuimod, , , niobium, nitecapone, nitroanil Retardex, Riacon, Ribavirin, Riboflavin, Rifabutin, rifamy ide, nitroaspirin, Nitrofurans, NITROPYRENE, nitro cins, Rifocin, , risedronic acid, risperidone, Ris samines, NitroSoanabasine, Nitrosocysteine, nitrosulindac, tocetin, , rituximab, Ro 13-8996, Ro 23-7553, Ro Nizatidine, NK 104, NK314, NMDA, NN 703, Noan, Nobi 23-7637, Ro 24-7429, Ro 31-6233, Ro 31-7549, Ro 31-8220, letin, NOC 18, Nocodazole, nodularin, Nodularin V, nolatr R04383596, Robitet, , roflumilast, rokitamycin, exed, Nonoxynol, noralfentanil, , Nor , romidepsin, rooperol, ropivacaine, roscovitine, clozapine, Nordihydroguaiaretic Acid, Norethindrone, rosiglitaZone, , rosuvastatin, Roxithromycin, noreximide, norfluoxetine, , norharman, norketo Rozevin, RPR 121056, RU 58668, ruboxistaurin, rugosin E, bemidone, norlaudanosoline, normeperidine, , rutecarpine, , S-(beta-p-methoxypropiophenone)thia norverapamil, novobiocin, NS-187, NSC 23766, NSC mine, S-Nitroso-N-Acetylpenicillamine, S-Nitrosothiols, 366140, NSC 663284, NSC-134754, NU2058, number-one, S-phenyl-N-acetylcysteine, sabarubicin, sabcomeline, Safin nutlin3, NVP-AEW541, Nylon, O-(chloroacetylcarbamoyl) gol, Safrole, SAGA, SAHA, Saikosaponin, , Salvin, fumagillol, O-desethylreboxetine, O-Due, o-quinone, obova Samarium, SAMe, sanguinarine, Sapogenins, Saquinavir, tol, OCDD, octanediol, Octoxynol, , Okadaic Sarasar, Sarna, sauchinone, saxatilin, SB 218078, SB Acid, , olefins, oleoylethanolamide, olimelin, olm 225002, SB 415286, SB-705498, scandium, SCH 66712, esartan, olomoucine, olomoucine II, Oltipraz, , schizandrer A, scoparone, Scopoletin, Score, SDX 308, Sel omega-agatoxin, omega-Conotoxin GVIA, omega-N-Me egiline, Seocalcitol, Sep-Pak, Serad, , , thylarginine, , omeprazole Sulfone, , SEW2871, shikonin, siderophore, , silvestrol, sily ONCB, Ondansetron, ONO4819, Optef, OR 1246, oroxylin bin, Sincalide, Sizofuran, SK-7041, SK&F 106528, SM A, , Osten, osteum, OSU 03012, Ouabain, 7368, Sodium pentosan polysulfate, , sor OVEX. Ovex, oxaliplatin, Oxarol, oxaspirodion, , afenib, sorbinil, Sorbo, Sorbose, spiroglumide, Spironolac Oxazepam, oXcarbazepine, Oxotremorine, oxotremorine M. tone, squamocin, SR 144528, SR 27897, SR 48692, SR , Oxyntomodulin, Oxytrol, p-ABA, p-XSC, 80327A, SR 90107A-ORG 31540, ST 638, stallimycin, p-Xylol, , paeonol, palladium, palmitoleate, , staurosporine, Stearin, Stereoisomerism, Steviol, PALMITOYL, Palmitoylcarnitine, pamidronate, panaxadiol, Stevioside, STIL, stilbene-disulphonate, Stilbenes, Stim, panepoxydone, pantoprazole, , Papite, PAPP, Streptomycin, Styrene, styrene-methylmethacrylate copoly , Paroxetine, Parsal, Parthenolide, PC 314, PCA mer, SU 5416, SU 6668, SU 95.16, Suberate, suberosin, suc 4230, PCSO, PD 134308, PD 144795, PD 180988, PD 98059, cinic semialdehyde, , Suldox, Sulfadoxine-py pectin, , Penicillins, Penite, Pentagastrin, Pen rimethamine, Sulfamethazine, sulfamethoxazole toxifylline, Peplomycin, peppermint oil, Pepstatin A, Pera hydroxylamine, Sulfaphenazole, Sulfasalazine, sulfate cel zine, , Perillol, Perilymph, periodate, , lufine, Sulfate-sulfate, Sulfidonitrogen.(...), , perovskite, PFPA, Phebestin, phen, phenolate, Phenols, phe Sulfo-N-Succinimidyl oleate, Sulfo-Succinimidyl-oleate, Sul noXodiol, , , phenylpropiona fogalactosylglycerolipid, Sulfones, Sulfonic acid, Sulfonyl mide, phenyl-Pyridinium, Phenyloin, pheophorbide a, phlo phenyl-ethyl, Sulforafan, , sulindac sulfone, sulto retin, PHOB, phorate, phorbol, phorbol 12-phenylacetate pride, , Synthos, T 0070907, T 0901317, Tacrine, 13-acetate 20-homoVanillate, phosphatidylethanolamines, , . Tamogel, , tandospirone, Phosphatidylinositol 4,5-Diphosphate, phosphatidylinositol Tangeretin, tanshinone, taurocholic acid, Taurodeoxycholic phosphate, PtdIns(4,5)P2, phytanic acid, Picibanil, picric Acid, taurourSodeoxycholic acid, tautomycetin, TAXO acid, pifithrin, Pilot, pimecrolimus, pioglitaZone, pipecoloxy TERE, TBDZ, TBHQ, TCAT, technetium, Tegafur, Teleoci lidide, , , Pira, pirinixic acid, , din, tellithromycin, Temazepam, temozolomide, temsiroli PKC412, plumbagin, Pluronic p85, PMDT, PMPA, PMSF, mus, terbinafine, terephthalic acid, Terfenadine, PNPP, Podophyllotoxin, polidocanol, poly-gamma teriflunomide, terrein, territrem A, territrem B, territrem C, glutamate, ponicidin, poractant alfa, , potas tertiapin, tetra-mu3-sulfido-tetrairon, tetrachloroethene, tet sium tellurate(IV), PQQ Cofactor, , Pravastatin, radecanoyl-phorbol-acetate, , tetram Prazosin, PRDL, Precursor mrna, , pregnane, ethylrhodamine, tetramethylsilane, tetraphene, Tetraprenol, Pregnanes, , 16alpha-carboni tetrasulfanide, , Thapsigargin, thiamine disul trile, Pregnyl, preussin, Primidone, , Proanthocya fide, thiazole, Thiazolidinediones, thioacetamide, Thioaceta nidins, , Probucol, Procasil, Procetofen, procya Zone, thiobenzamide, thiocoraline. Thiole. Thiopental, nidin B2, Prodix, prolactin, polymeric, Propafenone, thioredoxin dithiol, . Thiostrepton, Propanesulfonate, Propofol, propyl pyrazole triol, propyne, peptide SFLLRNP, thrombin Tokushima, Throm prostratin, protopanaxadiol, protopanaxatriol, PS15, Pseudo boxane A2, B2, Thyminose, thymol, thymo hypericin, Pseudomonas-exotoxin, Psoralens, psychosine-3'- quinone, Thyrotropin, , , tipranavir, tir sulfate ester, PTBP. pteridine, Pterostilbene, PURAC, Puro ilazad, titanium alloy (TiA16V4), TMC-95A, Tmndga, TMSI, mycin, , Pyocyanine, Pyra, pyranones, pyrazole, Tobrex, tocotrienols, tofisopam, tolrestat, Tolterodine, tolu Pyrethrins, pyridazine, Pyrimethamine, pyrimidin-2-one ene, -DITHIOL, , Topotecan, beta-ribofuranoside, Pyro, pyrogallol sulfonphthalein, pyr , Tosylarginine Methyl Ester, Tosyllysine Chlo role-2-carboxylic acid, dithiocarbamic acid, pyr romethyl Ketone, Tosylphenylalanyl Chloromethyl Ketone, roloazepinone, Qingkailing, , , Quicifal. TPN+, Tracer, , trans-, , Tra quinazoline, Quinolinium, , quinuclidin-3-yl-1- Zodone, Tremode, Tremorine, Tretinoin, Triad, Triamcino phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate mono lone, triazolam, triazoles, tributylstannane, trichostatins, Tri

US 2013/0252924 A1 Sep. 26, 2013 15

CG8203, CG8233, CG8288, CG8325, CG8326, CG8394, 0059. According to the present invention pain and condi CG8432, CG8436, CG8440, CG8487, CG8520, CG8625, tions associated with pain, e.g. itching or depression, can be CG8631, CG8651, CG8663, CG8732, CG8764, CG8771, treated or prevented, in particular in the meaning of a prophy CG8849, CG8912, CG8914, CG9022, CG9022, CG9032, lactic administration. “Preventing or “prevention herein CG9067, CG.9102, CG9160, CG9172, CG9231, CG9280, does not require absolute Success in the sense of an absolute CG9288, CG9305, CG9311, CG9323, CG9343, CG9350, prevention of pain but indicates a reduced risk of developing CG9388, CG9447, CG.9453, CG9460, CG9519, CG.9548, a disease or painful condition, or developing pain with CG9588, CG9603, CG9633, CG9636, CG9636, CG9650, reduced severity. Likewise, “treatment” shall not be con CG9678, CG9696, CG9696, CG9720, CG9742, CG9753, Strued as an absolute cure, but may also relate to amelioration CG9753, CG9825, CG9825, CG9901, CG9901, CG9948, or Suppression of pain or pain associated conditions. CG9948, CG9983, as well as their orthologues, in particular 0060 Pain and pain associated conditions and diseases to human orthologues (such as described in Neely et al., 2010, be treated according to the present invention can include incorporated herein by reference). These genes are referred acute pain, chronic pain, Somatogenic pain, neuropathic pain, psychogenic pain, heat induced pain, physical pain and noci herein as “pain genes”. Preferred genes are selected from ception in general, or hyperalgesia. In particular embodi CG10095, CG10096, CG100.98, CG10158, CG10481, ments the pain is selected from neuropathic pain, inflamma CG11033, CG11456, CG11577, CG11586, CG11590, tory pain, nociceptive pain, rheumatic pain, , low CG11592, CG11820, CG11967, CG12004, CG12334, , pelvic pain, myofascial pain, vascular pain, CG12785, CG12797, CG13096, CG13162, CG13623, migraine, wound associated pain, inflammatory pain, CG 1371, CG14351, CG14442, CG14514, CG14980, arthritic pain, diabetic pain, pain from cancer or Somatic CG16725, CG16854, CG1804, CG18088, CG18130, visceral pain, all in both acute and chronic forms. The pain CG18213, CG18249, CG18480, CG 1968, CG2052, can also be related to phantom pain, pain from a part of the CG2747, CG30005, CG31103, CG31267, CG31955, body that has been lost or from which the brain no longer CG3213, CG32150, CG3224, CG32792, CG33346, receives physical signals. CG3996, CG4110, CG4351, CG4477, CG4946, CG5516, 0061 Pain can be generally classified to two broad catego CG5565, CG5819, CG5969, CG5986, CG6136, CG6294, ries, acute and chronic. The treatment of any acute or chronic CG6340, CG6553, CG6583, CG6637, CG6724, CG6852, pain is Subject matter of the present invention. Acute pain is CG6901, CG7006, CG7042, CG7175, CG7358, CG7376, usually associated with a specific cause Such as a specific CG7556, CG7728, CG7800, CG8233, CG8325, CG8436, injury and is often sharp and severe. Acute pain begins Sud CG8771, CG9067, CG9288, CG9636, CG9650. These genes, denly and is not persistent. Chronic pain is long-term pain, as well as their orthologue counterparts, in particular human with a typical duration of more than three months leading to orthologs (Neely et al., 2010), or their respective gene prod significant psychological and emotional problems. Chronic ucts are preferred targets for therapy according to the present pain is generally associated with clinical conditions charac invention. According to the present invention function of at terised by chronic and/or degenerative lesions. Common least one of these genes is modified by the inventive com examples of chronic pain are neuropathic pain (e.g. painful pounds, in particular the Small molecules given in table 1. In diabetic neuropathy, post-herpetic neuralgia), rheumatoid preferred embodiments the compound modulates at least two, arthritis, osteoarthritis, fibromyalgia, back pain, headache, three, four, five or six or more of these genes (or orthologues). carpal tunnel syndrome, cancer pain, and chronic post-Surgi Further compounds Suitable to modulate gene function cal pain. Pain can also be divided into a number of different include the administration of therapeutic proteins or nucleic Subtypes according to differing pathophysiology, including acids, such as transgenes or inhibitory nucleic acids (RNAi nociceptive, inflammatory and neuropathic pain. Also some molecules, siRNA, antisense RNA or DNA). Such interfering types of pain can be classified in multiple categories, for nucleic acids bind messages of the genes leading to degrada example pain associated with cancer can have a nociceptive tion and reduced gene expression. Preferred therapeutic pro and neuropathic component. Nociceptive pain consists of teins include the gene products of these genes (as agonists) or Somatic pain (musculo-skeletal pain) and visceral pain (pain antibodies which specifically bind these proteins (as antago associated with the viscera, which encompass the organs of nists, but also as agonists if protein activity is increased— the abdominal cavity). Common causes of Somatic pain Such as by binding and blocking an inhibitor binding site). include cancer metastasis Such as to the bone and postSurgical The inventive compounds can act as either agonist by increas pain from a Surgical incision in addition to musculo-skeletal ing the gene function (via mRNA regulation or interaction disorders such as dystrophinopathy, and polymyosi with the protein) of a protein in the enzymatic pathway of any tis. Nociceptive pain also includes tissue injury-induced pain one of the above listed genes or an antagonist in said path and inflammatory pain Such as that associated with arthritis. ways. The antagonizing or activating (agonist) activity of the Another type of inflammatory pain is visceral pain which compounds acts preferably on the identified pain genes (in includes pain associated with gastrointestinal disorders (GI) cluding their gene product) themselves or on a binding part such as functional bowel disorder (FBD) and inflammatory ner thereof. With the inventive methods it is possible to sup bowel disease (IBD). Further examples of visceral pain press pain or, alternatively to increase pain, e.g. to treat include the pain associated with dysmenorrhea, cystitis and hyposensitivities. Depending on the goal an antagonist or pancreatis and pelvic pain. Additional pain types include agonist of the gene targets may be used. In preferred embodi dysfunctional pain such as fibromyalgia, Temporomandibu ments antagonists of the pain genes are used. lar Joint Disorder (TMJ), Irritable bowel syndrome (IBS) and 0058. The subject to be treated according to the present musculo-skeletal pain). Neuropathic pain is caused by dam invention can be any non-human animal or a human. Prefer age to the peripheral or central nervous system. Examples of ably the Subject is a mammal, in particular preferred embodi central neuropathic pain include pain from spinal cord injury, ments a human. , and fibromyalgia. Diabetes and US 2013/0252924 A1 Sep. 26, 2013

related metabolic disorders are a common cause of peripheral respectively. An example thereof is a phosphate buffer. Tonic neuropathic pain (diabetic neuropathy). Some of the human Substances serve for adjusting the osmolarity and may com conditions and pathologies characterised by the presence of prise ionic Substances. Such as, e.g., inorganic salts, such as neuropathic pain include, but are not limited to, cancer (can NaCl, or also non-ionic Substances. Such as, e.g. glycerol or cer neuropathy), HIV neuropathy, Parkinson's disease, epi carbohydrates. lepsy, immunodeficiency, post-herpetic syndromes, trauma, 0066. The inventive compound or medicament can be ischaemia, Sciatica, multiple Sclerosis, peripheral neuropa administered topical, enteral or parenteral, in particular pre thy, trigeminal neuralgia, back pain, phantom limb pain, car ferred oral or rectal, intravenous, intraarterial, intramuscular, pal tunnel syndrome, central poststroke pain and pain asso Subcutaneous, intradermal or intraperitoneal, transdermal, ciated with chronic alcoholism, hypothyroidism, uraemia, transmucosal or inhalational. Preferred routes of administra spinal cord injury, and vitamin deficiency. Preferably the pain tion of the inventive agent according to the present invention is neuropathic pain, Such as trigeminal neuralgia, such as are parenteral routes, preferably intraperitoneal or intrave post-herpetic neuralgia, such as painful diabetic neuropathy, nous administration, intravenous administration being spe Such as painful diabetic peripheral neuropathy, such as dia cifically preferred. Intravenous administration can be per betic polyneuropathy, such as Sciatic pain, Such as radicul formed e.g. via bolus injection or by continuous intravenous opathy, such as radicular pain or Such as non-inflammatory delivery over a longer time period (e.g. 30 minto 6 h, espe neuropathic pain. Pain may be selected from fibromyalgia, cially 1 to 3 h). Further routes include oral or transdermal or postoperative pain, trigeminal neuralgia, post-herpetic neu Subcutaneous routes. In particular preferred is oral adminis ralgia, painful diabetic neuropathy, painful diabetic periph tration. For digestible agents, such as active proteins, peptides eral neuropathy, diabetic polyneuropathy, sciatic pain, or siRNA, parenteral routes are preferred. radiculopathy, radicular pain, lumbar pain. Preferably the 0067. The medicament or the compound to be used pain is caused by the conditions as mentioned above related to according to the invention can be prepared to be suitable for the given pain type. In particular the paintype can be the only oral or intranasal administration. These administration forms pain type in a subject. E.g. preferably a neuropathic pain is of the medicament of the present invention allow for a rapid caused by affected nerves but not caused by inflammation, i.e. an uncomplicated uptake of the active Substances via the neuropathic pain is the only pain in the Subject and is non mucous membranes. For a nasal intake, nose drops or nose inflammatory. sprays are Suitable. For an oral administration, Solid or liquid 0062. About is used to refer to certain dosages that can medicaments may, e.g., be taken directly or in a dissolved or vary from a given value, nevertheless with the same effects as diluted state, respectively. the indicated dose. In some embodiments “about may refer 0068. The medicament or compound to be used according to +/-20% or 10% of a given value. to the invention can be prepared for an intravenous, intra 0063 Preferably the compound is administered in a dos arterial, intramuscular, intravascular, Systemic, intraperito age sufficient to treat or prevent pain or associated conditions neal or Subcutaneous administration. For this purpose, e.g., and diseases. Administration can e.g. be a singe dose admin injections or transfusions are Suitable. Administrations istration or a successive or repeated administration, e.g. twice directly into the bloodstream have the advantage that the a day, daily or in an interval of at least 1 day, at least 2 days, active substances of the medicament will be distributed in the at least 3 days, at least 1 week, preferably at least 2 weeks, at entire body and will quickly reach the target tissue or cells, in least 4 weeks, at least 8 weeks or even more preferred at least particular the peripheral nerves, spinal cord cells or brain 12 weeks. Preventive administrations are usually a short time cells. before expected pain, if controllable or foreseeable—such as 0069. The compound may be administered in a effective in scheduled Surgery—e.g. up to 1 hour (h), 2 h, 3 h, 4h, 5h, therapeutic dose. Effective doses are in the range of dosages 6 h, 8 h, 10h, 12 hor up to 24h or even up to 48 h beforehand, known for the compounds for other, non-pain related admin as well as any interval in between. istrations. In particular, for a specific use a dosage can be 0064. According to a further preferred embodiment of the determined by a simple test using drosophila or mouse test present invention, the compound is provided in a pharmaceu systems. Further possible therapeutic doses of the com tical composition or a medicament, in particular an analge pounds for the inventive treatment can be the same dosage sics. The composition or medicament may comprise a phar disclosed or approved for other therapeutic uses for each of maceutical carrier. Pharmaceutical carrier Substances serve these compounds. Example dosages are at least 0.01 mg/kg, for a better tolerance of the medicament and allow for a better at least 0.1 mg/kg, at least 1 mg/kg, at least 10 mg/kg and/or solubility as well as a better of the active up to 1 mg/kg, up to 10 mg/kg, up to 100 mg/kg, up to 1 g/kg, Substances contained in the medicament. Examples of this are and any dosages in between. Preferred dosage ranges are emulsifiers, thickening agents, redox components, starch, between 0.01 mg/kg and 1 g/kg, preferably between 0.1 Solutions, polyethylene glycolor lipids. The choice of mg/kg and 100 mg/kg. a Suitable pharmaceutical carrier is highly dependent on the 0070 The examples show that the inventive pain tests manner of administration. For oral administrations, liquid or revealed pharmaceutical compounds that are well known to Solid carriers may be used, for injections, liquid final compo be therapeutically applicable for the treatment of human con sitions are required. For cellular targeting, such as for inhibi ditions and diseases. The compounds may now also be used tory nucleic acids, Suitable vehicles can be included Such as for the treatment of pain and pain associated secondary dis liposomes or microsomes. eases. Of course the full list of compounds according to table 0065 Preferably, the medicament or the compound to be 1 provides new therapeutic concepts. used according to the invention comprises buffer Substances 0071. The present invention also relates to a method of or tonic substances. By means of a buffer, the pH of the modulating the gene expression or gene function in a cell, medicament can be adjusted to physiological conditions, and wherein the gene is selected from one or more of the genes moreover, pH fluctuations can be attenuated, or buffered, listed in table 1, in particular selected from the genes above, US 2013/0252924 A1 Sep. 26, 2013 17 oran ortholog counterpart thereof, comprising administering activity of any one of the genes listed above or given in table a compound of table 1 to said cell. The cell can be a nerve cell, 1. The test may comprise recombinantly expressing the gene including pain or thermosensitive nerve cells, and/or prefer product in a Suitable host cell or cell lines, such as mammal ably selected from spinal cord cells, brain cells or peripheral cell lines, in particular CHO cells, contacting said cell or cell nerve cells. The cell can be of the “pain matrix' such as the line with a candidate compound and detecting a deviation in thalamus, the S1 and S2 Somatosensory cortex, the cingulum, gene function when compared to normal levels without con amygdala, hypothalamus, or the motor cortex. The inventive tacting with the compound. Further tests compromising bind administration be be for treatment, alleviation or prevention ing of the compound to the gene product (the expressed of pain or hyperalgesia in a Subject. protein) and detecting binding events. Other tests include the 0072. In a further aspect the present invention relates to use of animal models and testing the compounds for behav method of screening active compounds Suitable for the treat ioural changes when exposed to pain, Such tests are disclosed ment of pain comprising testing for modulation, including in the examples. Additional, information on optimal dosages Suppression or activation, preferably suppression, of gene can be obtained with these tests. TABLE 1 List of therapeutic compounds: Small Molecule: name of compound (see list of synonyms below), Interacting Gene Symbol: human gene name of therapeutic target, Interacting GeneID: uman gene ID. Drosophila ID: ortholog Drosophila gene ID: Interacting Gene Interacting Small Molecule Symbol GeneD Drosophila Id (1S,2S)-2-(2-(N-((3- CYP3A4, 1576, CG2060, benzimidazol-2-yl)propyl)-N- methylamino)ethyl)-6-fluoro 1,2,3,4-tetrahydro-1-isopropyl 2-naphtyl cyclopropanecarboxylate dihydrochloride (5-(2-methoxy-5-chloro-5- CYP3A4, 1576, CG2060, phenyl)furan-2- ylcarbonyl)guanidine (6S)-5,6,7,8-tetrahydrofolic TYMS, 7298, CG3181, acid (TG)-A-L FOXP3, 50943, CG16899, alpha-hydroxyergocalciferol CYP3A4, 1576, CG2060, -(1-cyclohexylethylamino)-4- CYP3A4, 1576, CG2060, henylphthalazine -(2-methyl-4- CYP3A4, 1576, CG2060, methoxyphenyl)-4-((2- hydroxyethyl)amino)-6- trifluoromethoxy-2,3- dihydropyrrolo(3.2-c)(quinoline -(2,3-dichlorobenzoyl)-5- CNR2, 1269, CG12796, methoxy-2-methyl-(2- (mopholin-4-yl)ethyl)-1H indole -(2,3-dihydro-1,4- HDAC3, 8841, CG2128, benzodioxin-5-yl)-4-((5-(4- fluorophenyl)-3- pyridinyl)methyl) -(6-((3-methoxyestra- NFKB1, S1PR1, ADORA1, 4790, 1901, 134, CG11992, CG12796, CG9753, 3.5 (10)-trien-17 yl)amino)hexyl)-1H-pyrrole 2,5-dione -adamantyl propargyl ether NFKB1, 4790, CG11992, -aminobenzotriazole CYP4F3, CYP4A11, CYP3A5, 4051, 1579, 1577, CG2060, CG2060, CG2060, -aminooxy-3-aminopropane SLC25A21, 89874, CG5254, -hydrazino-4-(3,5-dimethyl)- PDE4A, 5141, CG14940, -pyrazolyl-5H-pyridazino (4,5- b)indole -hydroxymethylmidazolam CYP3A4, 1576, CG2060, -hydroxypyrene GSTT1, 2952, CG30005, -Methyl-4-phenylpyridinium NFKB1, 4790, CG11992, -Nitropyren-8-ol CYP3A5, CYP4F3, 1577,4051, CG2060, CG2060, -phosphatidyl-1D-myo- KHDRBS1, NCF4, 10657, 4689, CG3613, CG5821, CG7129, inositol 3- -stearoyl-2-oleoyl-sn-glycero- NCF4, 4689, CG7129, 3-phosphocholine 1-bis(3'-indolyl)-1-(4-t- PSMD9, 5715, CG9588, butylphenyl)methane ,1-dimethylbutyl-1-deoxy- CNR2, 1269, CG12796, Delta(9)-THC

US 2013/0252924 A1 Sep. 26, 2013

0847 felbamate, 2-phenyl-1,3-propanediol dicarbamate, 0870 fluvoxamine, (1E)-5-methoxy-1-4-(trifluorom ADD-03055, Essex brand offelbamate; ethyl)phenylpentan-1-one O-(2-aminoethyl)oxime, flu 0848. Felodipine, 1A Brand of Felodipine, AbZ Brand of Voxamine; Felodipine, Agon; 0871 FOLATE-ANALOG, FOLATE-ANALOG; 0849 Fenfluramine, Fenfluramine, Fenfluramine Hydro 0872 fondaparinux, Arixtra, fondaparinux, fondaparinux chloride, Fenfluramine Hydrochloride, (+-)-Isomer; Sodium; 0850 fenitrothion, fenitrothion, MEP, O,0-dimethyl O-(3- 0873 Fonofos, Dyfonate, Dyphonate, Fonofos; methyl-4-nitrophenyl)thiophosphate; 0874 Format, 2-Pyridine carboxylic acid, 3,6-dichloro-, 0851 fenofibric acid, 2-(4-(4-chlorophenoxy)phenoxy) 2-Pyridinecarboxylic acid, 3,6-dichloro-, 3,6-Dichloro-2- propionic acid, fenofibric acid, fenofibric acid potassium pyridinecarboxylic acid; salt; 0875. Formyl-Tetrahydrofolate, Formyl-Tetrahydro 0852. Fenretinide, 13-cis-Isomer Fenretinide, 4 Hydrox folate; yphenyl-retinamide, 4-HPR: 0876 Forskolin, Coleonol, Forskolin; 0853. Fentanyl, Cephalon Brand of Fentanyl Buccal 0877 fosamprenavir, (3-(((4-aminophenyl)sulfonyl)(2- OraVescent, Fentanest, Fentanyl: methylpropyl)amino)-(phenylmethyl)-2-(phosphonooxy) 0854 ferulic acid, 4-hydroxy-3-methoxycinnamic acid, propyl)carbamic acid C-(tetrahydro-3-furanyl) ester, fos 8,8-diferulic acid, ferulic acid; amprenavir, fosamprenavir, 0855 Filipin, Desoxylagosin, Filimarisin, Filipin; 0878 Foscarnet, Foscarnet, Foscarnet Barium (2:3) Salt, 0856 fingolimod, 2-amino-2-(2-(4-octylphenyl)ethyl)-1, Foscarnet Calcium (2:3) Salt; 3-propanediol hydrochloride, fingolimod, fingolimod 0879 FR 120480, FR 120480; hydrochloride; 0880 FR 235222, FR 235222, FR-235222, FR235222; 0857 fipronil, 5-amino-1-2,6-dichloro-4-(trifluorom 0881 fraxin, fraxin: ethyl)phenyl)-4-(trifluoromethyl)sulfinyl)-1H-pyrazole 0882 FTY720P, FTY720P, FTY-720P, FTY720P; 3-carbonitrile, fipronil; 0883 fucoidan, fucan sulfate, fucan sulfate Hor-1, 0858 fisetin, 2-(3,4-Dihydroxyphenyl)-3,7-dihydroxy fucoidan: 4H-1-benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3,7-di 0884 fulvestrant, 7-(9-(4.4.5.5.5-pentafluoropentylsulfi hydroxy-4H-chromen-4-one, 3,3',4',7-Tetrahydroxyfla nyl)nonyl)estra-1,3,5(10)-triene-3,17-diol, AstraZeneca brand of fulvestrant, Faslodex; VOne: (0885 fumagillin, (2E,4E,6E.8E)-10-((3R,4S,5S,6R)-5- 0859 Flanin F, 1H-Purin-6-amine, flavin dinucleotide, methoxy-4-(2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl) 1H-Purin-6-amine, flavine dinucleotide, -flavin oxiran-2-yl)-1-Oxaspiro[2.5oct-6-yloxy)-10-oxodeca-2, dinucleotide; 4,6,8-tetraenoic acid, 2.4.6.8-decatetraenedioic acid, 4-(1, 0860 Flavon, 2-Phenyl-gamma.-benzopyrone, 2-Phenyl 2-epoxy-1,5-dimethyl-4-hexenyl)-5-methoxy-1-Oxaspiro 4-benzopyron, 2-phenyl-4-chromenone; (2.5)oct-6-yl ester, Fugillin; 0861 flavonols, a flavonol, flavonols: 0886. Fura-2. Fura 2, Fura-2: 0862 flavopiridol, (-)cis-5,7-dihydroxy-2-(2-chlorophe 0887 furafylline, furafylline: nyl)-8-(4-(3-hydroxy-1-methyl)piperidinyl)-4H-1-ben 0888. Furamon, (2-Furylmethyl)trimethylammonium Zopyran-4-one, flavopiridol, HMR 1275; iodide, 2-Furanmethanaminium, N.N.N-trimethyl-, 0863 Flavyl. 1-Propanamine, 3-(10,11-dihydro-5H iodide, 2-Furanmethanaminium, N.N.N-trimethyl-, iodide dibenzo(a,d)cyclohepten-5-ylidene)-N,N-dimethyl-, (9CI): 1-Propanamine, 3-(10,11-dihydro-5H-dibenzoa.dcyclo 0889 Furylfuramide, AF2, AF-2, AF2: hepten-5-ylidene)-N,N-dimethyl-, 10,11-Dihydro-5- 0890 Gabexate, Foy, Gabexate, Gabexate Mesilate: (gamma-dimethylaminopropylidene)-5H-dibenzo(a,d) 0891 gadolinium, 64Gd, gadolinio, gadolinium; cycloheptene; (0892. Gadolinium DTPA, Berlex Brand of Gadopentetate 0864 FLCZ, alpha.-(2,4-Difluorophenyl)-alpha.-(1H-1, Dimeglumine, Gadolinium Diethylenetriaminepenta ace 2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-, tic Acid, Gadolinium Diethyl-lenetriaminepenta-acetic 1H-1,2,4-Triazole-1-ethanol, ..alpha.-(2,4-difluorophe Acid; nyl)-alpha.-(1H-1,2,4-triazol-1-ylmethyl)-, 1H-1,2,4- 0893 galactocerebroside, galactocerebroside; Triazole-1-ethanol, alpha-(2,4-difluorophenyl)-alpha 0894 galactomannan, galactomannan; (1H-1,2,4-triazol-1-ylmethyl)-; 0895 galangin, 3,5,7-trihydroxy-2-phenyl-4H-benzopy 0865 Flecamide, 3M Brand of Flecamide Acetate, ran-4-one, 3.5.7-trihydroxy-2-phenyl-4H-chromen-4-one, Alphapharm Brand of Flecamide Acetate, Alpharma Brand 3.5.7-Trihydroxyflavone; of Flecamide Acetate; 0896 galaturonate, (2R.3S4S.5R)-3,4,5,6-tetrahydroxy 0866 Floxacillin, Floxacillin, , Fluoro oxane-2-carboxylic acid, (2R,3S,4S,5S,6R)-3,4,5,6-tet chloroxacillin; rahydroxyoxane-2-carboxylic acid, (2S,3R,4S.5R.6R)-3, 0867 flufenamic acid, 2-3-(trifluoromethyl)anilinoben 4.5,6-tetrahydroxyoxane-2-carboxylic acid; zoic acid, 2-3-(TRIFLUOROMETHYL)PHENYL 0897 gallic acid, 3,4,5-trihydroxybenzoic acid, gallic AMINOBENZOIC ACID, 3'-trifluoromethyldipheny acid, Pyrogallol-5-carboxylic acid; lamine-2-carboxylic acid; 0898 Gallogen, (1)Benzopyrano (5.4.3-cde) (1)benzopy 0868 Flunitrazepam, 1A Brand of Flunitrazepam, betap ran-5,10-dione, 2,3,7,8-tetrahydroxy-, 2,3,7,8-Tetrahy harm Brand of Flunitrazepam, ct Arzneimittel Brand of droxy(1)benzopyrano (5.4.3-cde) (1)benzopyran-5,10-di Flunitrazepam; fluorexon, fluorexon; one, 2,3,7,8-Tetrahydroxy(1)benzopyrano (5.4.3-cde)-(1) 0869 Fluorouracil, 5 Fluorouracil, 5 Fluorouracil biosyn, benzopyran-5,10-dione: 5 FU Lederle: 0899 gambierol, gambierol;

US 2013/0252924 A1 Sep. 26, 2013

0954 Hexadimethrine, 1,5-Dimethyl-1,5-Diazaundeca 0982 , 3-isobutyryl-2-isopropylpyrazolo(1.5-a) methylene Polymethobromide, Hexadimethrine, Hexa pyridine, ibudilast, KC 404: dimethrine Bromide: 0983 IC831423, IC 831423; 0955 hexarelin, hexarelin; 0984 icariin, icariin; 0956 Hgln, (+-)-Glutamine, (2R)-2,5-diamino-5-oxo 0985 icaritin, icaritin: pentanoic acid, gamma.-Glutamine; 0986) icilin, AG-3-5 compound, icilin; 0957 himbacine, himbacine, NSC-23969, NSC23969; 0987 ICRF 193, ICRF 193; 0958 Hk, Hk: 0988 IDS 23, IDS 23, IDS-23, Rheuma-Hek: 0959 Hocus, (-) (5.alpha., 6.alpha.)-7,8-Didehydro-4,5- 0989 Ifosfamide, Asta Z. 4942, Holoxan, Ifosfamide: epoxy-17-methylmorphinan-3,6-diol, (-)- hydro 0990 Ikarugamycin, Ikarugamycin; chloride, (-)-; 0991) ilimaquinone, ilimaquinone; 0960| HOE 33342, H33342, HOE 33342, HOE-33342; 0992 Iloprost, Ciloprost, CoTherix Brand of Iloprost, Ilo 0961 honokiol, honokiol; prost; 0962 Horner, (+)-(5Z,7E)-26.26.26.27.27.27 0993 Imadyl, (+-)-6-Chloro-alpha-methylcarbazole-2- Hexafluoro-9,10-secocholesta-5, 7,10(19)-triene-1alpha, acetic acid, (..+-)-6-Chloro-alpha.-methylcarbazole-2- 3beta,25-triol, (1R,3S.5Z)-5-[(2E)-2-[(R.3aS,7aR)-7a acetic acid, 2-(6-Chloro-9H-carbazol-2-yl)propanoic acid; methyl-1-((R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5- 0994) imatinib, CGP 57148, CGP-57148, CGP57148B; (trifluoromethyl)hexyl)-2,3.3a,5,6,7-hexahydro-1H 0995 imidafenacin, imidafenacin, KRP 197, KRP-197: inden-4-ylidenelethylidene-4-methylene-cyclohexane-1, 0996 imidazo-pyridine, imidazo-pyridine: 3-diol, (1R,3S.5Z)-5-[(2E)-2-[(1R,3aS,7aR)-7a-methyl 0997 imidazolidin-2-one, 1,3-ethyleneurea, 2-imidazoli 1-(11R)-6,6,6-trifluoro-5-hydroxy-1-methyl-5- dinone, 2-imidazolidone; (trifluoromethyl)hexyl)-2,3.3a,5,6,7-hexahydro-1H 0998 imidazolidin-one, imidazolidin-one; inden-4-ylidenelethylidene-4-methylenecyclohexane-1, 0999 imidazolidine, C1CNCN1, imidazolidine: 3-diol; 1000 Imidazoline. Imidazoline; 0963 HS1200, HS1200, HS-1200, HS1200; 1001 imidazolyl-disulfide, imidazolyl-disulfide: 0964 HU 211, 1,1-dimethylheptyl-11-hydroxytetrahy 1002 Imipenem, Anhydrous Imipenem, Imipemide, Imi drocannabinol, 1,1-dimethylheptyl-7-hydroxy-delta(6)- penem; tetrahydrocannabinol, 11-hydroxy-delta(8)-tetrahydro 1003. Imizin, 10,11-Dihydro-N,N-dimethyl-5H-dibenz cannabinol-dimethylheptyl: b.fazepine-5-propanamine hydrochloride, 3-(5,6-dihy 0965) HyateC, antihemophilic factor, blood coagulation drobenzob1benzazepin-11-yl)-N,N-dimethyl-propan factor viii, coagulation factor viii; 1-amine hydrochloride, 3-(5,6-dihydrobenzob.1 0966 Hydroxin, 2-methyl-3-hydroxy-4,5-bis(hydroxy benzazepin-11-yl)-N,N-dimethylpropan-1-amine methyl)pyridine, 2-Methyl-3-hydroxy-4,5-bis(hydroxym hydrochloride: ethyl)pyridine, 2-Methyl-3-hydroxy-4,5-di(hydroxym 1004 Immulina, Immulina; ethyl)pyridine: 1005 Immunoferon, Immunoferon, Immunoferon; 0967 hydride, hydride, hydrogen anion; 1006 Impulsin, Anandamide (16:0), Hexadecanamide, 0968 Hydromorphone, Dihydromorphinone, Dilaudid, N-(2-hydroxyethyl)-, Hydroxyethylpalmitamide: Hydromorphon; 1007 Imrecoxib, Imrecoxib: 0969) Hydroxychloroquine, Hydroxychlorochin, 1008 Imutex, 1,3-Diaza-2,4-cyclopentadiene, 1,3-Diaza Hydroxychloroquine, Hydroxychloroquine Sulfate; 2.4-cyclopentadiene-, 1.3-Diazole; 0970 hydroxycotinine, 1-methyl-3-hydroxy-5-(3-py 1009 Indinavir, Crixivan, Indinavir, Indinavir Sulfate; ridyl)-2-pyrrolidinone, 3'-hydroxycotinine, hydroxycoti 1010 indiplon, indiplon, NBI 34060; n1ne. 1011 indirubin, indigo red, indirubin; 0971 hydroxylamine, dihydridohydroxidonitrogen, 1012 indole-3-acetic acid, 1H-indol-3-ylacetic acid, H2NHO, HYDROXYAMINE; 2-(indol-3-yl)ethanoic acid, 3-Indolylessigsaeure; 0972 Hydroxytryptophol, Hydroxytryptophol; 1013 indole-3-methanol, 1H-indol-3-ylmethanol, 3-hy 0973 Hyhorin, Conestoral, Conjugated , Con droxymethylindole, 3-indolylcarbinol: jugated estrogens: 1014 indolin-2-one, 3Z-3-((1H-pyrrol-2-yl)-meth 0974 sodium sulfate: ylidene)-1-(1-piperidinylmethyl)-1, 3-2H-indol-2-one, 0975) Hypaque, 3,5-diacetamido-2,4,6-triiodo-benzoic indolin-2-one, tetrahydroindolinone; acid; sodium, 3,5-diacetamido-2,4,6-triiodobenzoic acid; 1015 indolin-one, indolin-one: Sodium, Diatrizoate; hyperforin, hyperforin, octahydrohy 1016 infliximab, Centocor brand of infliximab, Essex perforin, tetrahydrohyperforin; brand of infliximab, infliximab; 0976 hypericin, hypericin, mono-(123I) iodohypericin; 1017 inhibin B, inhibin B; 0977. Hypericum-perforatum, Hypericum-perforatum, 1018) INOmax, Amidogen, oxo-, INOmax, Mononitrogen 0978 hypochlorous acid, Chlor(I)-saeure, chloranol, monoxide; HCIO: 1019 inositol-1,3,4,5-tetrakisphosphate, inositol-1,3,4,5- 0979 iberin, iberin; tetrakisphosphate; 0980 IBMX, 1-methyl-3-(2-methylpropyl)-3,7-dihydro 1020 inulin, (1,2-beta-D-fructosyl)n, (2,1-beta-D-Fruc 1H-purine-2,6-dione, 1-methyl-3-(2-methylpropyl)-3,9- tosyl)n, (2->1)-beta-D-fructofuranan; dihydro-1H-purine-2,6-dione, 1-methyl-3-(2-methylpro 1021. Iodoacetamide, Iodoacetamide: pyl)-7H-purine-2,6-dione: 1022 iodomethane, CH3I. Iodimethan, iodomethane: 0981 ibopamine, Escandine, ibopamine, ibopamine 1023) iodoresiniferatoxin, I-RTX cpd, iodo-resinifera hydrochloride; toxin, iodoresiniferatoxin;

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