Cebranopadol

CAS: 863513-91-1

(1r,4r)-6′-Fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine

• C₂₄H₂₇FN₂O
• Average mass: 378.482391 Da

Grünenthal GmbH  innovator

Cebranopadol(GRT-6005) is a novel first in class compounds with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor.

 Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several experimental model models of acute and chronic pain (tail–flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5–5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side–effect profile.

GRT-6005 is a centrally active analgesic in phase II clinical development for the oral treatment of neuropathic pain in patients with painful diabetic polyneuropathy and for the treatment of pain due to osteoarthritis of the knee. It is being developed by Grüenenthal and Forest. No recent development has been reported for research into the treatment of moderate to severe pain following bunionectomy. In 2010, GRT-6005 was licensed to Forest and Grünenthal in Canada and the U.S. for the treatment of moderate to severe chronic pain.

Description: IC50 Value: N/A Cebranopadol and GRT 6006 are novel first-in-class compounds with unique pharmacological and pharmacokinetic profiles that may enhance their effect in certain pain conditions. The unique mode of action of these compounds builds on the ORL-1 receptor and, supported by the established mu opioid receptor, is particularly suitable for the treatment of moderate to severe chronic pain [1]. in vitro: N/A in vivo: N/A Clinical trial: Cebranopadol has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with further Phase II studies planned prior to initiation of Phase III studies.

Neuropathic pain

Neuropathic pain is caused when peripheral nerves are damaged by mechanical, metabolic or inflammatory way. The pain occurring images are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli) in. As a result, the lesions to increased expression of Na + channels and thus to spontaneous activity in the damaged axons and their Nachbaraxonen (England et al., Neurology, 1996, 47, 272-276).The excitability of the neurons is increased and they react to incoming stimuli with an increased discharge frequency. This results in an increased sensitivity to pain, which contributes to the development of hyperalgesia and spontaneous pain (Baron, Clin J Pain 2000;. 16 (2 Suppl), 12-20). The causes and manifestations, and therefore the treatment needs of neuropathischerm pain are varied. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves.Causes may be operations, such as phantom pain after amputation, stroke, multiple sclerosis, spinal cord injury, alcohol or drug abuse or other toxins, cancers but also

Metabolic diseases such as diabetes, gout, kidney failure or liver cirrhosis, or infectious diseases such as mononucleosis, ehrlichiosis, typhoid, diphtheria, HIV, syphilis or Lyme disease. The pain experience is very different signs and symptoms that can change over time in number and intensity. Paradoxically, patients with neuropathic pain outline a slowdown or failure of acute pain perception and the simultaneous increase of neuropathic pain. The typical symptoms of neuropathic pain as tingling, burning, shooting or described, or radiating electrifying. Pharmacological basis for treatment of neuropathic pain include tricyclic antidepressants and anticonvulsants, which are used as monotherapy or in combination with opioids. These drugs usually provide only a certain pain relief during a pain-free but is often not achieved. The often-adjusting side effects are dose increases while the drug to achieve adequate pain relief often in the way. In fact, a higher dosage of a μ-opioid is often required as the treatment of acute pain, thereby reducing the side effects get even more important for satisfactory treatment of neuropathic pain. By the occurrence of typical μ-opioid tolerance development and the concomitant need for dose escalation of this problem is exacerbated. In summary it can be stated that neuropathic pain is difficult to treat and today is alleviated by high doses of μ-opioids only partially (Saudi Pharm J. 2002, 10 (3), 73-85). There is therefore an urgent need for medicines for the treatment of chronic pain, the dose should not be increased until the occurrence of intolerable side effects to ensure a satisfactory pain treatment.

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http://www.google.com/patents/US7547707

 

Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).

Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).

 

24		hemicitrate	more non-polar diastereomer
25		hemicitrate	more polar diastereomer

 

 

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WO 2013113690

(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

http://www.google.com/patents/WO2013113690A1?cl=en

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see A4

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One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).

 

 

The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms

A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.

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ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500117c

synthesis…………http://pubs.acs.org/doi/suppl/10.1021/ml500117c/suppl_file/ml500117c_si_001.pdf

6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)

hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).

13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);

112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+

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US20120034297 *	Aug 4, 2011	Feb 9, 2012	Gruenenthal Gmbh	Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

WO2004043967A1	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2008040481A1	Sep 26, 2007	Apr 10, 2008	Gruenenthal Gmbh	MIXED ORL 1/μ AGONISTS FOR TREATING PAIN

• CORAL – Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer

  Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.Average amount of daily rescue medication at the end of the maintenance period.

  UK Clinical Trials Gateway, 07 October 2013

• +

  CORAL XT – Open-label Extension Trial of the CORAL Trial

  An Open-label, Multi-site Trial to Describe the Safety and Tolerability of Oral Cebranopadol Administered for 26 Weeks in Subjects With Cancer-related Pain Who Have Completed Treatment in the KF6005/07 Trial.Absolute…

  UK Clinical Trials Gateway, 12 December 2013

WO2004043967A1 *	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2005066183A1 *	Dec 21, 2004	Jul 21, 2005	Gruenenthal Gmbh	Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor
US20050153998 *	Aug 19, 2004	Jul 14, 2005	Fumitaka Ito	Tetrahydroisoquinoline or isochroman compounds

 

 

Citing Patent	Filing date	Publication date	Applicant	Title
US7799931 *	Feb 17, 2009	Sep 21, 2010	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7951948 *	Apr 19, 2010	May 31, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7960404	Aug 21, 2009	Jun 14, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8034936	Nov 4, 2010	Oct 11, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds useful to treat substance dependency
US8053576	Feb 17, 2009	Nov 8, 2011	Gruenenthal Gmbh	Treating conditions associated with the nociceptin/ORL1 receptor system, e.g. pain, drug withdrawal, anxiety, muscle relaxants, anxiolytic agents; e.g. 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluorene
US8288406	Sep 22, 2010	Oct 16, 2012	Gruenenthal Gmbh	Hydroxymethylcyclohexylamines
US8288430	Mar 25, 2009	Oct 16, 2012	Grunenthal Gmbh	Spiro(5.5)undecane derivatives
US8293758 *	Mar 25, 2009	Oct 23, 2012	Grunenthal Gmbh	Substituted spirocyclic cyclohexane derivatives
US8357705	Mar 25, 2009	Jan 22, 2013	Gruenenthal Gmbh	Substituted cyclohexyldiamines
US8404740	Aug 21, 2009	Mar 26, 2013	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8614245 *	Jan 8, 2013	Dec 24, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US8618156 *	Jul 6, 2012	Dec 31, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

 

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com