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NZ619577B2 - Fluorinated arylalkylaminocarboxamide derivatives - Google Patents

Fluorinated arylalkylaminocarboxamide derivatives Download PDF

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Publication number
NZ619577B2
NZ619577B2 NZ619577A NZ61957712A NZ619577B2 NZ 619577 B2 NZ619577 B2 NZ 619577B2 NZ 619577 A NZ619577 A NZ 619577A NZ 61957712 A NZ61957712 A NZ 61957712A NZ 619577 B2 NZ619577 B2 NZ 619577B2
Authority
NZ
New Zealand
Prior art keywords
difluoro
ethylamino
butoxyphenyl
acetamide
phenyl
Prior art date
Application number
NZ619577A
Other versions
NZ619577A (en
Inventor
Paolo Pevarello
Original Assignee
Newron Pharmaceuticals Spa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Newron Pharmaceuticals Spa filed Critical Newron Pharmaceuticals Spa
Priority claimed from PCT/EP2012/060006 external-priority patent/WO2013000651A1/en
Publication of NZ619577A publication Critical patent/NZ619577A/en
Publication of NZ619577B2 publication Critical patent/NZ619577B2/en

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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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Abstract

Disclosed herein are fluorinated arylalkylaminocarboxamide derivatives of formula (I) wherein the substituents are as defined in the specification and pharmaceutically salts thereof. Also disclosed are pharmaceutical compositions containing the compounds as active ingredients and their use as sodium and/or calcium channel modulators intended for preventing, alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, inflammatory, ophtalmic, urolological, and gastrointestinal diseases, where the sodium and/or calcium channel have a pathological role. Examples of the compounds include 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, hydrochloride and 2-[2-fluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, hydrochloride. and/or calcium channel modulators intended for preventing, alleviating and curing a wide range of pathologies, including neurological, psychiatric, cardiovascular, inflammatory, ophtalmic, urolological, and gastrointestinal diseases, where the sodium and/or calcium channel have a pathological role. Examples of the compounds include 2-[2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, hydrochloride and 2-[2-fluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide, hydrochloride.

Description

FLUORINATED ARYLALKYLAMINOCARBOXAMIDE DERIVATIVES The present invention relates to ated arylalkylaminocarboxamide derivatives, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as sodium and/or calcium channel modulators.
The fluorinated arylalkylaminocarboxamide derivatives, object of the invention, are active as ion channel (in ular as sodium and/or calcium channel) modulators, and therefore useful in preventing, ating and curing a wide range of pathologies, including but not limited to neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urogenital and gastrointestinal diseases where the above mechanisms have been described as playing a pathological role.
Background of the invention Chemical Background l3ll describes, substituted 2—phenylethylamino derivatives as e—gated calcium and/or sodium channels modulators of general formula I R O W NVkN/RsI I 2 4 R R wherein: (a) J is a group A—[(CH2)n—O]r— in para position with respect to the ethylamino chain wherein: n is zero or 1; ris l; and A is methyl; cyclopentyl; or phenyl optionally substituted with a halo group; W is )alkoxy; R is hydrogen; R0 is hydrogen; or (C1—C2)alkyl; R1 is hydrogen; (C1—C4)alkyl ally substituted with a hydroxy group; cyclopropylmethyl; 2—propyn—l—yl; benzyl optionally substituted with one or two (C1—C2)alkoxy groups on the benzene ring; thiazolyl; a 5—6 membered saturated heterocyclyl ning a nitrogen atom, ally substituted with a (C1—C2)alkyl group; or heterocyclylmethyl wherein the heterocyclyl group is a 5—6 membered heterocylyl containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, optionally tuted with one or two groups selected from (C1—C2)alkyl, hydroxymethyl and )alkoxy; is hydrogen; (C1—C4)alkyl; or phenyl; is hydrogen; or (C1—C4)alkyl; and is hydrogen; (C1—C4)alkyl optionally substituted with a group selected from amino, (C1—C4)alkylamino, di—(Cl—C4)alkylamino, imidazolyl and pyrrolidinyl wherein the imidazolyl and the pyrrolidinyl group is optionally substituted with a (C1—C2)alkyl group; or benzyl; or R3 and R4, taken together with the adjacent nitrogen atom, form a idinyl, morpholinyl or piperazinyl ring ally substituted with a (C1—C2)alkyl group; is a group A—[(CH2)n—O]r— in para position with respect to the mino chain wherein: n is l; r is l; and A is phenyl; or phenyl substituted with a halo group; is hydrogen; is en; is (C1-C2)alkyl; is hydrogen; is (C1-C2)alkyl; is hydrogen; or (C1—C4) alkyl; and is hydrogen; or (C1—C4)alkyl; is hydrogen; is a group A—[(CH2)n—O] r— wherein: n is zero, 1 or 2; r is zero or 1; and A is (C1—C4)alkyl, trifluoromethyl; cyclopropyl; entyl; phenyl optionally substituted with a group selected from halo, methyl, methoxy, trifluoromethyl, amino, and dimethylaminomethyl; thienyl optionally substituted with a chloro group; l; isoxazolyl optionally substituted with one or two methyl groups; piperidinyl; morpholinyl; pyridinyl or pyrimidinyl, the pyridinyl and pyrimidinyl ring being optionally tuted with one or two methoxy groups; is hydrogen; or fluoro; is hydrogen; or (C1—C2)alkyl; is isopropyl; cyclopropylmethyl; furanylmethyl; tetrahydrofuranyl; or ydrofuranylmethyl; is hydrogen; or (C1—C4)alkyl; is hydrogen; or (C1—C4)alkyl; and is hydrogen; (C1—C4)alkyl optionally substituted with a group selected from (C1— oxy, amino, (C1—C4)alkylamino and di—(Cl—C4)alkylamino; or heterocyclyl wherein the heterocyclyl is selected from isoxazolyl, pyrazolyl, imidazolyl, thiazolyl and 1,3,4 thiadiazolyl and may be ally substituted with a (C1— C2)alkyl group; or R3 and R4 taken together with the adjacent nitrogen atom form a pyrrolidine ring; with the proviso that when A is (C1—C4)alkyl, trifluoromethyl, cyclopropyl or cyclopentyl, then r is 1; and with the further proviso that when R1 is isopropryl, then A is trifluoromethyl and n is 1; used for the manufacture of a medicament active as calcium and/or sodium channel modulators against disorders caused by dysfunctions of voltage gated calcium and/or sodium ls.
WC 2008/15 1702 describes substituted 2—[2—(phenyl)—ethylamino]alkaneamide derivatives as voltage—gated calcium and/or sodium channels modulators of general formula (I) wherein: X is —O—, —S— or —SOz—; Y is hydrogen, OH or O(C1—C4)alkyl; Z is =0 or :8; R is (C3—C10)alkyl; w—trifluoro(C3—C10)alkyl; R1 and R2 are, independently, hydrogen, y, (C1—C8)alkoxy, (C1—C3) alkylthio, halo, trifluoromethyl or 2,2,2—trifluoroethyl; or one of R1 and R2 is in ortho position to R—X— and, taken together with the same R—X—, represents a Ro—<O_ group where R0 is (C2-C9)alkyl; R3 and R,3 are, independently, hydrogen or (C1—C4)alkyl; R4 and R5 are, independently, hydrogen, (C1—C4)alkyl; or R4 is hydrogen and R5 is a group selected from —CH2—OH, —CH2—O—(C1—C6)alkyl, —CH(CH3)— 2—S—CH3, benzyl and 4—hydroxybenzyl; or R4 and R5, taken together with the adjacent carbon atom, form a (C3—C6)cycloalkyl residue; R6 and R7 are independently en or (C1—C6)alkyl; or taken together with the adjacent nitrogen atom form a 5—6 membered monocyclic saturated heterocycle, optionally containing one additional heteroatom chosen among —O—, —S— and -NR3- where R8 is hydrogen or ) alkyl; with the o that when X is —S—or —SOZ—, then Y is not OH or O(C1—C4) alkyl; if the case, either as single optical isomer in the isolated form or mixture thereof in any proportion and its pharmaceutically acceptable salts.
The ated compounds described in this application are not comprised by either WO 2007/07131 l or .
Biological Background Sodium channels play an important role in the neuronal network by transmitting electrical impulses rapidly throughout cells and cell networks, thereby coordinating higher processes ranging from locomotion to ion. These channels are large transmembrane proteins, which are able to switch between different sical states to enable selective permeability for sodium ions. For this process to occur an action potential is needed to depolarize the membrane, and hence these channels are said voltage—gated.
Voltage—gated sodium channels were originally classified based on their sensitivity to tetrodotoxin, from low nanomolar (Tetrodotoxin sensitive, TTXs) to high micromolar (Tetrodotoxin ant, TTXr). So far, 10 different sodium channel 06 ts have been identified and fied as Navl.l to Navl.9.
Navl.l to Navl.4, Navl.6 and Navl.7 are TTXs, whereas Navl.5, Navl.8 and 9 are TTXr, with ent degrees of ivity. Navl.l to Navl.3 and Navl.6, are primarily sed in the CNS, whereas Navl.4 and Navl.5 are mainly expressed in muscle (skeletal and heart, respectively) and Navl.8 and Navl.9 are predominantly expressed in small dorsal root ganglions (DRG).
Navl.3, a TTX—s sodium channel normally absent in adult neurons, is ulated following nerve injury as observed in the sensory s and spinal cord neurons of rodents following chronic nerve injuries (Waxman S.G., Kocsis J .D., Black J .A.: “Type III sodium channel mRNA is expressed in embryonic but not in adult spinal sensory neurons, and is reexpressed following axotomy”. J. Neurophysiol. 72, 466—470 (1994). Hains B.C., Klein J .P., Saab C.Y. et al.: “Upregulation of sodium channel Navl.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury”. J. Neurosci. 23, 8881—8892 (2003). Hains B.C., Saab C.Y., Klein JP. et al.: “Altered sodium channel expression in second—order spinal sensory neurons contributes to pain after peripheral nerve injury”. J. Neurosci. 24, 4832—4839 (2004)) and confirmed in human injured nerves after peripheral axotomy (Coward K., Aitken A., Powell A. et al.: “Plasticity of TTX—sensitive sodium channels PNI and brain III in injured human nerves”. Neuroreport 12, 495—500 (2001)) and in human painful neuromas (Black J .A., Nikolajsen L., Kroner K. et al.: ple sodium l isoforms and mitogen— activated protein kinases are t in painful human neuromas”. Ann. Neurol. 64(6), 644-653 (2008)). Navl.3 channels exhibit several ties that can contribute to neuronal xcitability. The rapid recovery from inactivation, and the ability to produce persistent current and ramp responses to small/slow depolarizations can support high— frequency firing. Interestingly, increased ry rates have been described after nerve injury that would contribute to increase neuronal excitability in pain conditions (Cummins T.R., Waxman S.G.: “Downregulation of Tetrodotoxin resistant sodium currents and lation of a rapidly repriming tetrodotoxin—sensitive sodium current in small spinal sensory neurons after nerve injury”. J. Neurosci. 17, 514 (1997). Cummins T.R., Aglieco F., Renganathan M. et al.: “Nav1.3 sodium ls: rapid repriming and slow closed—state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory s”. J. Neurosci. 21, 5952—5961 (2001). Lampert A., Hains B.C., Waxman S.G.: “Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury”. Exp. Brain 4, 660—666 (2006)).
Overall the specific expression and the biophysical properties of the Nav1.3 would implicate this channel in the tion of the TTX—sensitive ectopic discharges associated with chronic pain.
Nav1.7 channel is a TTX—s channel preferentially expressed in the primary DRG nociceptor neurons and in sympathetic ganglion neurons. It displays slow kinetics of tion to and from the inactivation state, that determine the possibility of generating currents in response to small subthreshold depolarizations and allow the channel to act as a threshold channel, thus amplifying generator potentials (Catterall W.A., Goldin A.L., Waxman S.G.: “International Union of Pharmacology. XLVII. Nomenclature and Structure—Function onships of Voltage—Gated Sodium Channels”. Pharmacol. Rev. 57, 397—409 (2005)). Over the past few years, Nav1.7 has gained a prominent role in pain research because human genetic studies have directly linked single point mutations of the SCN9A gene encoding for Nav1.7 to specific pain syndromes. Gain of function mutations, that lower the threshold for channel activation, are associated to a nt—inherited neuropathy, inherited erythromelalgia (IEM) whose hallmark symptom is severe g pain in the feet and hands in response to mild warmth and exercise (Dib—Hajj S.D., Rush A.M., Cummins T.R. et al.: “Gain—of—function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons”. Brain 128(8), 1847—1854 (2005).
Dib—Hajj S.D., Rush A.M., Cummins T.R., Waxman S.G.: “Mutations in the sodium l Nav1.7 underlie inherited erythromelalgia”. Drug ery Today: e isms 3(3), 343—350 (2006)).
One of the most compelling evidence that aged many companies to pursue research 2012/060006 programs towards Nav1.7 specific inhibitors, has been the discovery that loss of function ons of Nav1.7 gene determines a congenital insensitivity to pain (CIP) (Cox J .J Reimann F., Nicholas A.K. et al.: “An SCN9A channelopathy causes congenital inability to experience pain”. Nature 444, 894—8 (2006).
The TTX—r channel Nav1.8 is exclusively expressed in the peripheral sensory neurons.
Slow vation c, rapid repriming, rized threshold of tion and inactivation, make it ideal for maintaining action potential firing in depolarized fibers (Elliott A.A., Elliott J .R.: “Characterization of TTX—sensitive and TTX—resistant sodium currents in small cells from adult rat dorsal root ganglia”. J. Physiol. 463, 39—56 (1993).
Akopian A.N., Souslova V., England S. et al.: “The tetrodotoxin—resistant sodium channel SNS has a specialized function in pain pathways”. Nat. Neurosci. 2, 541—548 .
Renganathan M., Cummins T.R., Waxman S.G.: “Contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons”. J. Neurophysiol. 86, 629—640 (2001)).
However, the specific translocation and redistribution of Nav1.8 protein at the peripheral site of injury observed in immunohistochemical studies in animals and recently in humans (Novakovic S.D., Tzoumaka E., McGivem J .G. et al.: “Distribution of the tetrodotoxin— resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions”. J. Neurosci. 15, 18(6) 187 (1998). Black J.A., Nikolajsen L., Kroner K. et al.: “Multiple sodium l isoforms and mitogen—activated protein kinases are present in painful human neuromas”. Ann. Neurol. 64(6), 3 (2008)), or the redistribution and alterations of its activity in the ing uninjured neurons (Gold M., Weinreich D., Kim C.S. et al.: “Redistribution of Nav 1.8 in uninjured axons enables neuropathic pain”. J. Neurosci. 23, 158—166 (2003)), suggests a dynamic ement of this channel in the generation and maintenance of nociceptive impulses.
Another TTX—r channel, Nav1.9, is exclusively sed in small—diameter DRG neurons.
It is still one of the least understood s of the voltage gated sodium channels (VGSC) family, due to the difficulty to express the recombinant form in heterologous expression systems. terization of the biophysical properties of this channel was done in sensory neurons from Nav ll mice (Cummins T.R., Dib—Hajj S.D., Black J .A. et al.: “A novel persistent tetrodotoxin—resistant sodium current in SNS—null and wild—type small primary sensory neurons”. J. ci. 19 (24):RC43 (1999)). These neurons were shown to express a persistent (non—inactivating) TTX—r current, with substantial overlap between activation and steady—state inactivation centered close to resting potential (Roza C., Laird J.M.A., Souslova V. et al.: “The tetrodotoxin—resistant Na+ channel Navl.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice”. J.
Physiol. 550, 921—926 ). As a result of these properties, Navl.9 ls behave as strong regulators of excitability in cells in which they are present, playing a key role in setting the resting membrane potential as well as contributing to sub—threshold electrogenesis in small DRG neurons.
It has become clear that a number of drugs having a previously n mechanism of action actually act by modulating sodium l conductance, including local anaesthetics (LA), class I antiarrhythmics and anticonvulsants. Neuronal sodium channel blockers have found application with their use in the ent of epilepsy toin and carbamazepine), bipolar disorder (lamotrigine), preventing neurodegeneration, and in reducing neuropathic pain. Various anti—epileptic drugs that even through other mechanisms of action, stabilize neuronal excitability are approved for ent forms of neuropathic pain (gabapentin, pregabalin and carbamazepine).
In addition, an increase in sodium channel expression and/or activity has also been observed in several models of inflammatory pain, ting a role of sodium channels in inflammatory pain.
Calcium channels are membrane—spanning, multi—subunit proteins that allow controlled entry of calcium ions into cells from the extracellular fluid. Commonly, calcium channels are voltage dependent and are referred to as e—gated calcium channels (VGCC).
VGCCs are found throughout the mammalian nervous system, where they regulate the intracellular calcium ion levels that are important for cell viability and function.
Intracellular calcium ion concentrations are implicated in a number of vital processes in animals, such as neurotransmitter release, muscle contraction, pacemaker ty and secretion of hormones. All “excitable” cells in animals, such as neurons of the central nervous system (CNS), peripheral nerve cells, and muscle cells, including those of skeletal muscles, cardiac muscles and venous and al smooth muscles, have voltage ent calcium channels.
Calcium channels are a large family with many genetically, physiologically, and pharmacologically ct es. Based on the biophysical properties of calcium currents recorded from individual neurons, two super—families have been described: High Voltage Activated (HVA) and Low Voltage Activated (LVA) calcium channels. Calcium currents referred as L—type, P—type, Q—type, N—type, R—type are HVA and as T—type are LVA. In particular, the term e” was originally applied to channels with a large single channel conductance and long open time, and “T—type” was applied to channels with a tiny single channel conductance and a transient open time. Further exploration of functional calcium channel diversity identified the “N—type” channel expressed in neurons and the “P— type” channel, which is the dominant type expressed in cerebellar Purkinje s and is pharmacologically resistant to known blockers of L—type and N—type calcium channels.
From the lar identity, ten distinct calcium channel es have been identified, cloned and sed and grouped in three families: Cavl family (Cav 1.1, 1.2, 1.3, 1.4) is functionally related to the L—type Ca current; Cav2 family (Cav 2.1, 2.2, 2.3) is functionally related to the P/Q, N, R—type currents and Cav3 (Cav 3.1, 3.2, 3.3) family is onally related to the T—type current.
It is believed that calcium channels are relevant in certain disease states. A number of compounds useful in treating s cardiovascular es in mammals, ing humans, are thought to exert their beneficial effects by modulating functions of voltage dependant calcium channels t in cardiac and/or vascular smooth muscle. nds with activity against calcium channels have also been implicated for the treatment of pain.
In ular N—type calcium channels (Cav2.2), responsible for the tion of neurotransmitter e, are thought to play a significant role in nociceptive transmission, both due to their tissue distribution as well as from the results of several pharmacological studies. N—type calcium channels were found up—regulated in the ipsilateral dorsal horn in neuropathic pain models of injury (Cizkova D., Marsala J Lukacova N., Marsala M., Jergova S., Orendacova J ., Yaksh T. L. Exp. Brain Res. 147: 456—463 (2002)). Specific N— type calcium channel blockers were shown to be effective in reducing pain responses in neuropathic pain models (Mattews E. A., Dickenson A. H. Pain 92: 235—246 (2001)), in the phase II of the formalin test (Diaz A., Dickenson A. H. Pain 69: 93—100 (1997)) and the hyperalgesia ted by knee joint inflammation (Nebe J ., Vanegas H., Schaible H. G.
Exp. Brain Res. 120: 61—69 (1998)). Mutant mice, lacking the N—type calcium channels, were found to have a decreased response to persistent pain as seen by a decrease in pain response during phase II of the formalin test (Kim C., Jun K., Lee T., Kim S. S., Mcenery M. W., Chin H., Kim H. L, Park J. M., Kim D. K., Jung S. J., Kim J., Shin H. S. Mol. Cell Neurosci. 18: 235—245 (2001); Hatakeyama S., Wakamori M., Ino M., Miyamoto N., Takahashi E., Yoshinaga T., Sawada K., Imoto K., Tanaka 1., Yoshizawa T., Nishizawa Y., Mori Y., Nidome T., Shoji S. Neuroreport l2 : 2423—2427 (2001)) as well as to neuropathic pain, assessed by a se in mechanical nia and l hyperalgesia in the spinal nerve ligation model (Yamamoto T., Takahara A.: “Recent updates of N—type calcium channel blockers with therapeutic potential for neuropathic pain and stroke”. Curr. Top.
Med. Chem. 9, 377—395 (2009)). Interestingly, mice also showed lower levels of anxiety when compared to wild type (Saegusa H., Kurihara T., Zong S., Kazuno A., Matsuda Y.
Nonaka T., Han W., Toriyama H., Tanabe T., EMBO J. 20: 2349—2356 (2001)). The involvement of N—type m channels in pain has been further validated in the clinic by ziconotide, a peptide derived from the venom of the marine snail, Conus Magnus.
(Williams J .A., Day M., Heavner J .E.: “Ziconotide: an update and review”. Expert Opin.
Pharmacother. 9(9), 1575—1583 (2008)). A limitation in the eutic use of this peptide is that it has to be administered intrathecally in humans (Bowersox S. S. and Luther R. n, 36: 1651—1658 (1998); Vitale V., Battelli D., Gasperoni E., Monachese N.: “Intrathecal therapy with ziconotide: clinical experience and consideration on its use”.
Minerva Anestesiol. 74, 727—733 (2008)).
A comprehensive review on the role and usefulness of ion channel modulators in neuropathic pain treatment has recently been published. (E. Colombo et al.: “Ion channel modulators for the ent of athic pain”. Future Medicinal Chemistry, 2(5): 803— 842 (2010)).
All together these findings indicate that compounds able to block sodium and/or calcium channels have an important therapeutic potential in ting, alleviating and curing a wide range of pathologies, including neurological, psychiatric, vascular, urogenital intestinal and inflammatory diseases, where the above mechanisms have been described as playing a pathological role.
There are many papers and patents which describe sodium channel and/or calcium channel modulators or nists for the treatment or modulation of a plethora of disorders, such as their use as local anaesthetics, antiarrhythmics, antiemetics, antimanic anti—depressants, agents for the treatment of unipolar depression, anxiety, cardiovascular diseases, urinary incontinence, oea, inflammation, epilepsy, neurodegenerative conditions, nerve cell death, neuropathic pain, migraine, acute hyperalgesia and ation, renal disease, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, urinary tract disorders, gastrointestinal motility disorders, premature labour, obesity, immune and endocrinological system disorders, including le sclerosis.
A non—exhaustive list of patents/patent applications describing sodium and/or calcium channel blockers and uses thereof includes the references shown below.
US. Patent 5,051,403 relates to a method of ng neuronal damage associated with an ischemic condition, such as stroke, by administration of binding/inhibitory omega— conotoxin peptide wherein the peptide is characterized by specific inhibition of voltage— gated calcium channel ts selectively in neuronal s.
US. Patent 5,587,454 relates to compositions and methods of producing sia particularly in the treatment of pain and neuropathic pain.
US. Patent 5,863,952 relates to calcium channel antagonists for the treatment of ischaemic stroke.
US. Patent 6,011,035 relates to calcium channel blockers, useful in the treatment of conditions such as stroke and pain.
US. Patent 6,117,841 relates to calcium channel blockers and their use in the treatment of stroke, cerebral ischemia, pain, head trauma or epilepsy.
US. Patent 6,362,174 relates to N—type calcium channel blockers in the treatment of , cerebral ischemia, pain, epilepsy, and head trauma.
US. Patent 6,380,198 concerns the use of the m channel blocker flunarizine for the topical treatment of glaucoma.
US. Patent 6,420,383 and US. Patent 6,472,530 relate to novel m channel blockers, useful for treating and preventing a number of disorders such as hypersensitivity, y, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tract disorders, gastrointestinal motility disorders and cardiovascular disorders.
US. Patent 6,458,781 relates to compounds that act to block calcium channels and their use to treat stroke, cerebral ischemia, pain, head trauma or epilepsy.
US. Patent 6,521,647 s to the use of calcium channel rs in the treatment of renal disease in animals, ally chronic renal failure.
W0 97/10210 relates to lic heterocyclic derivatives, and their use in therapy, in particular as calcium channel nists, e. g. for the treatment of ischaemia, in particular ischaemic stroke.
WO 03/018561 relates to quinoline compounds as N—type calcium l antagonists and s of using such compounds for the treatment or prevention of pain or nociception.
WO 03/057219 relates to sodium channel blockers useful as agents for treating or modulating a central nervous system disorder, such as neuropathic pain, inflammatory pain, inflammation—related pain or epilepsy.
W0 99/14199 discloses substituted 1,2,3,4,5,6—hexahydro—2,6—methano—3—benzazocines— —oles as potent sodium channel blockers useful for the ent of several diseases, such as stroke, neurodegenerative disorders, Alzheimer’s Disease, Parkinson’s Disease and cardiovascular disorders.
WO 01/74779 discloses new aminopyridine sodium channel blockers and their use as anticonvulsants, local etics, as antiarrythmics, for the ent or prevention of neurodegenerative conditions, such as amyotrophic lateral sclerosis (ALS), for the treatment or prevention of both, acute or chronic pain, and for the treatment or prevention of diabetic neuropathy.
WO 04/087125 discloses amino acid derivatives as inhibitors of mammalian sodium channels, useful in the treatment of chronic and acute pain, tinnitus, bowel disorders, bladder dysfunction and demyelinating diseases.
WO 904 relates to quinazolines useful as modulators of ion channels, and their preparation, pharmaceutical compositions, and use as inhibitors of e—gated sodium ls, which is useful in treatment of various diseases.
WO 06/024160 ses the preparation of piperazine—l—carboxamide derivatives as calcium channel blockers.
WO 06/110917 describes spiro—oxindole compounds and their preparation, ceutical compositions and use as sodium channel blockers.
WO 06/027052 describes the use of selected (R)—2—[(halobenzyloxy)benzylamino]— propanamides and the pharmaceutically acceptable salts thereof for the manufacture of medicaments that are selectively active as sodium and/or calcium l modulators and therefore useful in preventing, alleviating and curing a wide range of pathologies, including pain, migraine, peripheral diseases, cardiovascular diseases, inflammatory processes affecting all body systems, disorders ing skin and related tissues, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, urogenital, metabolic and seizure disorders, where the above mechanisms have been described as g a ogical role.
W0 922 discloses the preparation of benzazepinone amino acids as sodium channel blockers.
WO 07/021941 relates to the ation of N—thiazolyl benzenesulfonamides as tors of voltage—gated sodium channels.
WO 08/141446 discloses amino acid derivatives as calcium channel blockers.
W0 09/005460 describes the preparation and applications of Navl.7 sodium channel tors for treatment of pain disorders.
WO 09/039328 discloses pyridyl—sulfonamides as modulators of sodium channels, their preparation, pharmaceutical compositions, and use in treating various diseases.
WO 09/045381 relates to N—substituted oxindoline derivatives as m channel blockers.
WO 073 discloses the preparation of piperazine derivatives as Cav2.2 calcium channel modulators.
WO 10/014257 describes the preparation of tetrahydropyridine and dihydropyrrole compounds as calcium channel rs for treatment of pain and other disorders.
The cytochrome P450 superfamily (abbreviated as CYP) is a large and diverse group of enzymes and the function of most CYP enzymes is to catalyze the oxidation of organic substances. The ates of CYP enzymes include xenobiotic substances such as drugs and other toxic chemicals. CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for at least 75% of the total metabolism. Human CYPs are primarily membrane—associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells (Smith G., ns M.J.
Xenobiotica 28 (12): 1129—65 (1998)). Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the CYP (enzyme inhibition). This is a major source of e drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP—mediated metabolism of another drug, the second drug may late within the body to toxic levels. Hence, avoiding drug ctions may necessitate dosage adjustments or the choice of drugs that do not interact with the CYP system.
Cytochrome P450 2D6 (CYP2D6), a member of the cytochrome P450 mixed—function e system, is one of the most ant enzymes involved in the metabolism of xenobiotics in the body (Wolf C.R., Smith G. IARC Sci. Publ.; 148: 209—29 (1999)).
Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable ility in its expression in the liver. The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1. Alternatively d ript variants encoding different isoforms have been found for this gene.
CYP2D6 shows the largest ypical variability among the CYPs, largely due to 2012/060006 genetic polymorphism. The genotype accounts for normal, reduced, and non—existent CYP2D6 function in subjects.
The CYP2D6 function in any particular subject may be bed as one of the following: 0 poor metabolizers — these ts have little or no CYP2D6 function 0 intermediate metabolizers — these subjects metabolize drugs at a rate somewhere between the poor and extensive metabolizers 0 extensive metabolizers — these subjects have normal CYP2D6 function 0 ultrarapid metabolizers — these subjects have multiple copies of the CYP2D6 gene expressed, and therefore greater—than—normal CYP2D6 function.
Therefore, patients undergoing any therapeutical treatment may be classified according to the above subject definitions.
Many ychotic drugs used for schizophrenia treatment are CYP2D6 substrates: examples of these drugs include haloperidol, risperidone, perphenazine, thioridazine, aripiprazole and sertindole. If a drug is able to potently inhibit CYP2D6 the subject taking said drug may become a poor metabolizer, i.e. may ence an increase in plasma levels of a CYP2D6 metabolized drug taken concomitantly. Quinidine, tine, bupropion and ine are powerful CYP2D6 inhibitors and the use of potent inhibitors can render a patient that is a CYP2D6 extensive metabolizer into a phenotypic poor lizer (De Leon J., Armstrong S.C., Cozza K.L. Psychosomatics; 47(1): 75—85 (2006)). A CYP2D6 poor metabolizer phenotype may have a major role in personalizing risperidone doses (De Leon J., Susce M.T., Pan R.M., Wedlun P.J., Orrego M.L., Diaz F.J. Pharmacopsychiatry; 40(3), 93—102 (2007)). As a further example, sertindole undergoes extensive hepatic metabolism by CYP2D6 and 3A4 to two principal metabolites. CYP2D6 poor lizers may have sertindole clearance reduced by 50—67%. The concomitant administration of sertindole and CYP2D6 inhibitors should be used with extreme caution (Murdoch D., Keating G.M. CNS Drugs; 20(3): 233—255 (2006)).
It is therefore highly desirable, in view of avoiding undue drug—drug interactions, to have nds which are unable to inhibit the major human CYPs, in particular CYP2D6, for example in a psychosis and schizophrenia setting, but also in any pathology treated with a drug that is also a CYP2D6 substrate (Foster A. Mobley B, Wang Z. Pain Practice; 7(4): 352—356 (2007)).
Description of the invention The object of this ion is a new class of fluorinated kylamino carboxamide derivatives which are highly potent as sodium and/or m channel modulators and therefore useful in preventing, alleviating and curing a wide range of ogies, including, but not limited to psychiatric, neurological, cardiovascular, inflammatory, ophthalmic, urogenital, gastrointestinal diseases where the above mechanisms have been described as playing a pathological role. Said compounds are also characterized in that they are substantially free from any CYP2D6 inhibitory effect or exhibit a significantly reduced CYP2D6 inhibitory effect.
In this description and claims, the expression “sodium and/or m channel modulator(s)” means compounds able to block sodium and/or calcium currents in a voltage and/or use—dependent manner.
In this description and claims the expression “substantially free from any CYP2D6 inhibitory effect” means that the nd exhibits a IC50[uM] Value in the in vitro cytochrome inhibition test according to Example 10 which is higher than 40 while the expression “reduced CYP2D6 inhibitory effect” means that the nds exhibits a IC50[uM] value which is higher than 20.
In particular, the object of the present invention is a compound of general formula I 56R1 wherein: W is a group A—[(CH2)m—O] — wherein: m is zero, 1, 2, or 3; A is (C1—C4)alkyl optionally tuted with one to three fluorine atoms; (C3—C6)cycloalkyl; phenyl optionally ituted with a group selected from halo, methyl, methoxy, trifluoromethyl, acetylamino, and dimethylaminomethyl; thienyl optionally substituted with a chloro group; furanyl; isoxazolyl, thiazolyl; piperidinyl; morpholinyl; pyridinyl or pyrimidinyl, the nyl and pyrimidinyl ring being optionally substituted with one or two methoxy groups; J independently is hydrogen, (C1—C4)alkyl ; (C1—C4)alkoxy; or an halo group; n is l or 2; R1 is hydrogen; (C1—C4)alkyl optionally substituted with a hydroxy group or a (C1— C4)alkoxy group; or (C3—Cg)cycloalkyl; R2 and R2, are independently hydrogen; (C1—C4)alkyl optionally substituted with a (C1— C4)alkoxy group; phenyl ally substituted with a (C1—C4)alkyl, a (C1— C4)alkoxy or an halo group; benzyl optionally substituted with a (C1—C4)alkyl, a (C1—C4)alkoxy or an halo group on the benzene ring; or R2 and R2, taken together with the adjacent carbon atom form a (C3—C6)cycloalkylidene group.
R3 is hydrogen; or (C1—C4)alkyl; R4 is hydrogen; (C1—C4)alkyl; phenyl; cyclohexyl; or benzyl; or R3 and R4, taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl ring, the piperidinyl ring being optionally substituted with one or two (C1—C2)alkyl group(s), and the piperazinyl ring being optionally substituted on the other N—atom with a (C1—C4)alkyl, benzyl, or phenylsulfonyl group; or a idinyl, piperidinyl, morpholinyl or piperazinyl ring fused with a benzene ring; R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically able salt.
The term “(C1—C4)alkyl” or the “(C1—C4) alkyl” moiety in the other utents (e. g. in the terms alkoxy) as used in this description and , when no otherwise specified, identifies a straight or branched alkyl radical or moiety; es of said radicals or moieties include, tively: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert— butyl or methoxy, ethoxy, propoxy, isopropoxy, butoxy oxy and tert—butoxy.
The term “(C1—C4)alkyl” when substituted with “one to three fluorine atoms” identifies a straight or branched alkyl radical of l to 4 carbon atoms wherein one to three hydrogen atoms attached to the same or different carbon atoms are independently substituted by fluorine. Preferred entative examples of this term are romethyl, 2,2,2— trifluoroethyl, 3,3,3—trifluoropropyl and 4,4,4—trifluorobutyl.
The terms “(C3—C6)cycloalkyl” and "(C3—C6)cycloalkylidene” as used in this description and claims, when not otherwise specified, fies a cycle—forming alkyl or alkylidene radical or moiety; es of said radicals or moieties include, tively cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or cyclopropylidene, cyclobutylidene, cyclopentylidene and cyclohexylidene.
The term “halo”, when not otherwise specified herein, means an halogen atom radical such as fluor‘o, chloro, bromo and iodo.
Where the compounds of this invention contain at least one asymmetric carbon atom they can exist as single enantiomers or diastereoisomers or a mixture thereof, the invention includes within its scope all the possible single optical isomers in the ed form of said compounds and the es thereof in any proportion, e.g., the racemic mixtures.
Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with organic and inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, oric, acetic, propionic, tartaric, fumaric, citric, benzoic, succinic, cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, , malonic, fumaric, tartaric, p- toluenesulfonic, methanesulfonic, glutaric acid and the like.
The compounds of a I are active as calcium and/or sodium channel modulators and therefore useful in preventing alleviating and curing a wide range of ogies, including but not limited to psychiatric, neurological, cardiovascular, inflammatory, ophthalmic, urogenital and gastrointestinal es where the above mechanisms have been described as playing a pathological role, said nds being characterized in that they are substantially free from any CYP2D6 inhibitory effect or exhibit a significantly reduced CYP2D6 inhibitory effect.
A preferred group of compounds of formula I of this invention comprises a compound wherein: W is a group A-[(CH2)m-O]- wherein: m is zero, 1, 2 or 3; A is (C1-C4)alkyl optionally substituted with one to three fluorine atoms; (C3-C6)cycloalkyl; phenyl optionally substituted with a halo group; or thiazolyl J independently is hydrogen; C1-C4 alkyl; chloro; or fluoro; n is 1 or 2; R1 is hydrogen; (C1-C4)alkyl optionally substituted with a hydroxy group; or a (C1- C4)alkoxy group; or )cycloalkyl; R2 is hydrogen; or (C1-C4)alkyl; R2. is hydrogen; (C1—C4)alkyl optionally tuted with a (C1-C4)alkoxy,; or a phenyl group, the phenyl group being optionally substituted with a (C1-C4)alkoxy group; R3 is hydrogen; or (C1-C4)alkyl; R4 is hydrogen; (C1-C4)alkyl; phenyl; or cyclohexyl; or R3 and R4, taken er with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, linyl, piperidinyl or piperazinyl, the piperydinyl ring being optionally substituted with one or two (C1—C2)alkyl group(s) and the piperazinyl ring being optionally substituted on the other N—atom with a (C1—C4)alkyl, benzyl, or phenylsulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl or piperazinyl ring fused with a benzene ring; R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt.
A more preferred group of compounds of formula I ses a compound wherein; W is a group 2)m—O]— wherein: m is l or 2; A is (C1—C4)alkyl optionally substituted with one to three fluorine atoms; phenyl optionally substituted with a chloro or fluoro group; or thiazolyl; J ndently is hydrogen; methyl; or fluoro; n is lor 2 R1 is hydrogen; (C1—C4)alkyl optionally substituted with a hydroxy group or a (C1— C4)alkoxy group; R2 is en; or methyl; R2, is hydrogen; (C1—C4)alkyl optionally substituted with a methoxy; or a phenyl; group, the phenyl group being optionally substituted with a methoxy group; R3 is hydrogen; or (C1—C4)alkyl; R4 is hydrogen; (C1—C4)alkyl; phenyl; or cyclohexyl; or R3 and R4, taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, linyl, piperidinyl, or zinyl ring, the piperidinyl ring being optionally substituted with one or two methyl group(s) and the piperazinyl ring being optionally substituted on the other N—atom with a methyl, benzyl or sulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring fused with a benzene ring; R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt.
Most preferably, a nd of formula I according to this ion is selected from the group consisting of: 2— [2,2—Difluor0—2— oxyphenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 1— l) 2— [2,2—Difluor0—2— (3 —pentyloxyphenyl)—ethylamin0] —N,N—dimethyl—acetamide (Example 1— 2— [2,2—Difluor0—2— oxyphenyl)—ethylamin0] —N,N—dipr0pyl—acetamide (Example 1—3) 2— [2,2—Difluor0—2— oxy—4—methylphenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 1—4) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —N,N—dibutyl—acetamide; (Example 1—5) 2— [2,2—Difluor0—2— (3—hexyloxyphenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 1— 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } —N,N—dimethyl— acetamide; (Example 1—7) 2— [2,2—Difluor0—2— (3 —pentyloxyphenyl)—ethylamin0] —N,N—dipr0pyl—acetamide; (Example 1— 8) 2— { 2,2—Difluoro—2—[3—(3—(3—fluor0phenyl)—pr0poxy)—phenyl] —ethylamin0 } —N,N—dimethyl— acetamide; (Example 1—9) 2— { 2,2—Difluor0—2— [3— (3— (3—chlor0phenyl)—pr0poxy)—phenyl] —ethylamin0 } —N,N—dimethyl— acetamide; (Example 1—10) 2— [2,2—Difluor0—2— (3—but0xy—2—fluor0phenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 1—1 1) 2— { 2,2—Difluor0—2— [3— (3—phenylpr0p0xy)—phenyl] amin0 } —N,N—dimethyl—acetamide; (Example 1— 12) 2— { 2,2—Difluor0—2— [3— (3—thiazol—2—yl—pr0poxy)—phenyl] —ethylamin0 } —N,N—dimethyl— acetamide; (Example 1—13) 2— [2,2—Difluor0—2— (3—benzyloxyphenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 1-14) 2— [2,2—Difluor0—2— oxyphenyl)—ethylamin0] — l—(pyrrolidin— l —yl)—ethan0ne; le 1- 15) 2— ifluor0—2— (3—butoxyphenyl)—ethylamin0] —N—methyl—N—phenyl—acetamide; (Example 1-16) 2— { 2,2—Difluoro—2—[3—(3—phenylpr0poxy)—phenyl] amin0 } — l—(pyrrolidin— l —yl)— ethanone; (Example 1—17) 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } — l—(pyrrolidin— l —yl)— ethanone; (Example l— l 8) 2— [2,2—Difluor0—2— (3—benzyloxyphenyl)—ethylamin0] — l—(morpholin—4—yl)—ethan0ne; (Example l— 19) 2— { 2,2—Difluor0—2— [3— (3—phenylpr0p0xy)—phenyl] amin0 } — l— (morpholin—4—yl)— ethanone; (Example l—20) 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } — l—(morpholin—4—yl)— ethanone; (Example l—2 l) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(2H—benz0[b] [ l ,4] oxazin—4(3H)—yl)— ethanone; (Example l—22) 2— [2,2—Difluor0—2— (3—benzyloxyphenyl)—ethylamin0] — l—(pyrrolidin— l —yl)—ethan0ne; le l—23) 2— { 2,2—Difluor0—2— [3— (3—phenylpr0p0xy)—phenyl] amin0 } —N—methyl—N—phenyl— acetamide; le l—24) 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } —N—methyl—N—phenyl— acetamide; (Example l—25) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(4—methylpiperazin— l —yl)—ethan0ne; (Example l—26) 2— { 2,2—Difluor0—2— [3— nylpr0p0xy)—phenyl] —ethylamin0 } — l— (4—methylpiperazin— l—yl)— ethanone; (Example l—27) 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } — l—(4—methylpiperazin— l — yl)—ethan0ne; (Example l—28) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(piperidin— l—yl)—ethan0ne; (Example 1— 2— { 2,2—Difluor0—2— [3— (3—phenylpr0p0xy)—phenyl] —ethylamin0 } — l— (piperidin— l—yl)—ethan0ne; (Example l-30) 2— { 2,2—Difluor0—2— [3— (4,4,4—triflu0robutoxy)—phenyl] —ethylamin0 } — l—(piperidin— l —yl)— ethanone; le l—3 l) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —N,N—diethyl—acetamide; le l—32); 2— { 2,2—Difluor0—2— [3—(2—flu0robenzyloxy)—phenyl] —ethylamin0 } —N,N—dimethyl—acetamide; (Example l-33) 2— [2,2—Difluor0—2— oxyphenyl)—ethylamin0] — —3,S—dimethylpiperidin— l —yl)— ethanone; (Example l—34) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(3,4—dihydroisoquinolin—2( lH)—yl)— ethanone; (Example 1—35) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —N,N—diisopropyl—acetamide; le 1— 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] lohexyl—N—methyl—acetamide; (Example 1—37) 2— [2,2—Difluor0—2— (3—benzyloxyphenyl)—ethylamin0] — l—(piperidin— l—yl)—ethan0ne; (Example 1-38) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—[4— (phenylsulfonyl)—piperazin— l —yl] — ethanone; (Example 1—39) 2— [2,2—Difluor0—2— oxyphenyl)—ethylamin0] — l—(indolin— l —yl)—ethan0ne; (Example 1— 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(4—benzylpiperazin— l —yl)—ethan0ne; (Example 1—4 1) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] — l—(azetidin— l—yl)—ethan0ne; (Example 1— 2—[2,2—Difluor0—2— (3—but0xyphenyl)—ethylamin0]—N,N—dimethyl—propanamide; (Example 2— 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —3—meth0xy—N,N—dimethyl—propanamide; (Example. 2—2) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —3—(4—methoxyphenyl)—N,N—dimethyl— propanamide; (Example 2—3) 2— [2,2—Difluor0—2— (3—butoxyphenyl)—ethylamin0] —2—N,N—trimethyl—propanamide; (Example 2-4) 2— ifluor0—2— oxyphenyl)—ethylamin0] —4—N,N—trimethyl—pentanamide; (Example 2-5) 2—{ [2,2—Difluor0—2— (3 —butoxyphenyl)—ethyl] —methylamin0 } —N,N—dimethyl—acetamide; (Example. 3— l) 2—{ [2,2—Difluor0—2— (3 —butoxyphenyl)—ethyl] —(3—meth0xypropyl)—amino } —N,N—dimethyl— acetamide; (Example 3—2) 2—{ [2,2—Difluor0—2— (3 —butoxyphenyl)—ethyl] —(2—meth0xyethyl)—amino } —N,N—dimethyl— acetamide; (Example 3—3) 2— or0—2— (3—but0xyphenyl)—ethylamin0] —N,N—dimethyl—acetamide; (Example 4— l) 2— { 2—Fluor0—2— chlorobenzyloxy)—phenyl] —ethylamin0 } —N,N—dimethyl—acetamide; WO 00651 (Example 4—2) 2— { 2—Fluoro—2— [3—(3—fluorobenzyloxy)—phenyl] —ethylamino } —N,N—dimethyl—acetamide; (Example 4—3) if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt..
The compounds of formula I, object of the present invention, are prepared according to a tic s which comprises: a) the reaction of a compound of formula II wherein J, W, and n have the same meanings d in formula I above, with a suitable fluorinating agent, such as obenzenesulfonimide, to give a compound of formula R5 R6 %N "I wherein J, W, n, R5 and R6 have the same meanings as defined in formula I above b) reaction of a compound of formula III with a suitable reducing agent, such as lithium aluminium hydride, to give a compound of formula IV R5 R6 N H 2 I IV The nd of formula I wherein J, W, n, R2, R2’, R3, R4, R5, and R6 have the same represent a (C3-C8) lic ketone. common knowledge of the skilled person.
The removal of the optional protective groups is carried out according to conventional techniques.
For a general reference to the use of protective groups in orgamic chemistry, see Theodora W. Greene and Peter G.M. Wuts “Protective groups in organic synthesis”, John Wiley & Sons, Inc., 11 Ed., 1991.
The preparation of the salts of the compounds of formula I is d out according to known methods.
For the preparation of a single enantiomers or diastereoisomers, if the case, of a compound of formula I, said compound may be obtained through a sterically controlled synthesis or by using reagents having the appropriate chirality or separating the desired isomer from the omeric or diastereoisomeric mixture thereof according to conventional procedures. For instance, single optically active enantiomers may be obtained from their tes by chiral chromatography or by converting them into a mixture of diastereoisomeric derivatives, separating the diastereoisomeric derivatives and restoring the respective omers. reoisomers can be separated from their mixtures by means of conventional techniques based on their different physico—chemical properties, such as chromatography, distillation, or fractional crystallization.
Pharmacology The compounds of the invention may be used for the manufacture of a medicament active as sodium and/or calcium channel modulators against disorders caused by dysfunctions of voltage gated calcium and/or sodium channels being characterized in that they are substantially free from any CYP2D6 inhibitory effect or exhibit a icantly reduced CYP2D6 tory effect.
The sodium channel modulating ty of the fluorinated phenylalkylamino derivatives was measured through a fluorescence—based sodium influx assay (Table 1), h patch clamp techniques in tutive and/or Nav 1.3 transfected cell lines (Table 2) and in al neurons.
The CYP2D6 tion was assessed by performing in vitro inhibition studies using Supersomes, microsomes derived from baculovirus infected insect cells; the baculoviruses have been engineered to express one or more drug metabolizing enzyme cDNAs (Table WO 00651 The in viva analgesic activity of the above compounds was assessed in the “rat complete Freund’s adjuvant model” and in the “Bennett model of neuropathic pain in rats” .
The in vivo sodium channel blocking and anticonvulsant activity were measured using the “Maximal electroshock test” in mice (Table 4).
The anti mania activity was measured using the “Amphetamine and iazepoxide— induced hyperlocomotion in mice” model.
The anti—schizophrenia and anti—addiction ties were ed using the “Test of cognitive impairment in schizophrenia” and the “Cocaine—induced behavioural sensitization test“ in rats.
“Acute bladder irritation by acetic acid in rats” and “Intermediate bladder tion by cyclophosphamide in rats” tests were used as models for ical diseases.
The anti migraine activity was measured using the “migraine test” in rats.
Such substances exhibit also “use and frequency—dependency”, i.e. an enhancement of the block during a high frequency stimulation when there is a large accumulation of channels in the inactivated state, such as in neuronal pathological conditions. Functionally, the use— ent block s in depression of neuronal ty at high frequency firing and with lower blocking capacity at normal firing rate suggesting that the compounds of this invention may selectively s abnormal activity of the calcium and/or sodium channels, leaving unaffected the physiological activity, thus decreasing CNS depressant effects (Catterall W. A., Trends Pharmacol. Sci. 8: 57-65 (1987)).
The compounds of the ion are active in vivo when orally or intraperitoneally administered in the range of 0.1 to 100 mg/kg in different animal models hereafter described.
In view of the above described mechanisms of action, the compounds of the present invention are useful in the prevention or treatment of neuropathic pain. Neuropathic pain syndromes include, and are not limited to: diabetic neuropathy; sciatica; non—specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV—related neuropathy; neuralgia, such as post—herpetic neuralgia and trigeminal neuralgia, Morton’s neuralgia, causalgia; and pain resulting from physical , amputation, phantom limb, cancer, toxins or chronic inflammatory conditions; central pain such as the one observed in thalamic syndromes, mixed central and peripheral forms of pain such as x regional pain syndromes (CRPS) also called reflex sympathetic dystrophies.
The compounds of the invention are also useful for the ent of chronic pain. Chronic pain includes, and is not limited to, chronic pain caused by inflammation or an inflammatory—related condition, ostheoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (resulting from systematic, al or primary spine disease such as radiculopathy), bone pain (due to osteoarthritis, osteoporosis, bone metastasis or unknown reasons), pelvic pain, spinal cord injury—associated pain, cardiac chest pain, non—cardiac chest pain, central post—stroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry’s disease, AIDS pain, ric pain or pain caused by headache, temporomandibular joint syndrome, gout, fibrosis or thoracic outlet syndromes, in ular rheumatoid arthritis and osteoarthritis.
The nds of the invention are also useful in the treatment of acute pain caused by acute injury, illness, sport—medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and strains, musculotendinous strain, cervicobrachial pain syndromes, dyspepsis, gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis or surgery (such as open heart or bypass surgery), post operative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain or dental pain.
The compounds of the invention are also useful in the treatment of headaches such as migraine, n type headache, transformed migraine or evolutive headache, r headache, as well as secondary headache disorders, such as the ones derived from infections, lic disorders or other systemic ses and other acute headaches, smal hemicrania and the like, resulting from a worsening of the above mentioned primary and secondary headaches.
The compounds of the invention are also useful for the treatment of neurological conditions such as epilepsy including simple partial seizure, complex partial seizure, secondary generalized seizure, further including e seizure, myoclonic seizure, clonic seizure, tonic seizure, tonic clonic seizure and atonic seizure. The nds of the invention are also useful for the treatment of neurodegenerative ers of various origins such as Alzheimer’s Disease and other dementia conditions such as Lewys body, fronto—temporal ia and taupathies; amyotrophic lateral sclerosis, Parkinson’s Disease and other parkinsonian syndromes; essential tremors; other spino cerebellar degeneration and Charcot—Marie—Toot neuropathy.
The compounds of the invention are also useful for the ent of cognitive disorders and of psychiatric disorders. atric disorders include, and are not limited to major depression, mia, mania, bipolar disorder (such as bipolar disorder type I, bipolar 2012/060006 disorder type II), cyclothymic disorder, rapid cycling, ultradian cycling, mania, hypomania, schizophrenia, schizophreniform disorders, schizoaffective disorders, personality disorders, attention disorders with or without hyperactive behaviour, onal disorders, brief psychotic disorders, shared psychotic disorders, psychotic er due to a general medical condition, nce—induced tic disorders or a psychotic disorder not otherwise ied, anxiety disorders such as lised y disorder, panic disorders, post—traumatic stress disorder, e control disorders, phobic disorders, dissociative states and moreover in smoke, drug addiction and alcoholism. In particular bipolar disorders, psychosis, anxiety and addiction.
Compounds of the ion are also useful in the treatment of diseases such as vertigo, tinnitus, muscle spasm, and other disorders including and not limited to cardiovascular diseases (such as cardiac arrhythmia, c infarction or angina pectoris, hypertension, cardiac ischemia, al ischemia) endocrine disorders (such as acromegaly or diabetes insipidus) diseases in which the pathophysiology of the disorder involves excessive or ecretory or ise inappropriate cellular secretion of an endogenous substance (such as catecholamine, a hormone or a growth factor).
The compounds of the invention are also useful in the selective treatment of liver disease, such as inflammatory liver es, for example chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, non— alcoholic steatohepatitis and liver transplant rejection.
The compounds of the invention inhibit inflammatory processes affecting all body systems.
Therefore are useful in the treatment of inflammatory processes of the muscular—skeletal system of which the following is a list of examples but it is not comprehensive of all target ers: arthritic ions such as alkylosing spondylitis, al arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, rheumatic disease; disorders affecting skin and related tissues: eczema, psoriasis, dermatitis and inflammatory conditions such as sunburn; disorders of the respiratory system: asthma, allergic rhinitis and respiratory distress syndrome, lung disorders in which inflammation is involved such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and inological systems: periarthritis nodosa, thyroiditis, aplastic anaemia, scleroderma, myasthenia gravis, le sclerosis and other demyelinizating disorders, encephalomyelitis, sarcoidosis, nephritic syndrome, Bechet’s syndrome, polymyositis, prostatic hyperplasia, annexitis, pelvic mation, bartholinitis and vaginitis. In It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include a serotonin receptor modulator including a SHTlB/lD agonist, such as a triptan (e. g. sumatriptan or iptan); an adenosine Al agonist; an adenosine A2 antagonist; a purinergic P2X antagonist, an EP ; an NMDA tor, such as a glycine nist; an AMPA modulator; a substance P antagonist (e.g. an NKl antagonist); a cannabinoid; a nicotinic receptor agonist; an alpha—l or 2 adrenergic agonist; acetaminophen or phenacetin; a 5—lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e. g. methotrexate); gabapentin, pregabalin and related compounds; L—dopa and/or dopamine agonists; a catechol—O—methyltransferase inhibitor; a lic antidepressant (e.g. amitryptiline); a e stabilising antiepileptic drug; a monoaminergic uptake inhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; a free radical scavenger; an alpha—synuclein aggregation inhibitor; a cholinesterase inhibitor, a cholesterol lowering agent; an alpha—secretase modulator; a beta—secretase modulator; a beta—amyloid aggregation inhibitor; an tor of the release, or action, of tumor necrosis factor alpha; an antibody therapy, such as monoclonal antibody therapy; an ral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune system modulator (e.g. interferon); an opioid analgesic, such as morphine; a vanilloid receptor antagonist; an analgesic, such as a cyclooxygenase—l and/or cyclooxygenase—2 inhibitor ; a local anaesthetic such as ine and derivatives; a stimulant, including caffeine; an H2— antagonist (e.g. ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminium or ium hydroxide; an antiflatulent (e.g. simethicone); a decongestant (e. g. phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or esoxyephedrine, naphazoline, xylometazoline, propylhexedrine, or levo—desoxyephedrine); antitussive (e.g. codeine, odone, hen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non—sedating antihistamine; an antipsychotic agent, including typical and al antipsychotics (e.g. haloperidol, risperidone, clozapine); an anti—depressant, such as a selective serotonin re—uptake inhibitors, serotonin and noradrenaline re—uptake tors, MAO tors and tryciclics antidepressant drugs; a mood stabilizer (e.g. lithium, igine, valproate); an anxyolitic agent (e.g. benzodiazepines, buspirone), beta— adrenergic receptors antagonists, morphine or morphine derivatives, other calcium or sodium l blocker. It is to be understood that the present invention covers also the use of a compound of formula (I) or a pharmaceutically acceptable salt f in conjunction with one or more other therapeutic agents. For said use, the compounds of formula (I) and the other therapeutic agent(s) may be administered either jointly or sequentially.
The compounds of the present invention are useful in human and nary medicaments.
It is to be understood that as used herein the terms “treatment” or “treating” whenever not specifically defined otherwise, include prevention, alleviation and cure of pathological affection, in particular, they include both treatment of ished symptoms and prophylactic treatment. The compounds of the present invention for their therapeutic or preventive use in the above mentioned pathologies will be preferably used as active ingredients in a pharmaceutical ition.
Therefore, a further object of the present invention are pharmaceutical compositions containing a therapeutically ive amount of a compound of the invention or a salt thereof in admixture with a pharmaceutically acceptable r.
Accordingly, the expression “therapeutically effective” when referred to an “amount”, a “dose” or “dosage” of the compounds of this ion is intended as an “amount”, a “dose” or “dosage” of any said compounds sufficient for use in both treatment of the established symptoms and the prophylactic treatment of the above said pathological ions.
The pharmaceutical compositions object of the present invention may be administered in a variety of ate and modified release dosage forms, e. g. orally, in the form of tablets, troches, capsules, sugar or film coated tablets, liquid solutions, emulsions or suspensions; rectally, in the form of suppositories; parenterally, e.g. by intramuscular and/ or depot formulations; intravenous injection or infusion; locally and transdermally in form of patch and gel and cream.
Suitable pharmaceutically acceptable, therapeutically inert organic and/or nic carrier materials useful in the preparation of such composition include, for e, water, gelatin, arabic gum, lactose, starch, cellulose, ium stearate, talc, ble oils, cyclodextrins, polyalkyleneglycols and the like.
The composition comprising the fluorinated arylalkylaminocarboxamide derivatives of formula I as above defined can be sterilized and may contain further well known components, such as, for example, preservatives, stabilizers, g or emulsifying agents, WO 00651 e. g. paraffin oil, mannite monooleate, salts to adjust osmotic pressure, buffers and the like.
For example, the solid oral forms may contain, together with the active ingredient, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e. g. silica, talc, c acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disgregating agents, e. g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non—toxic and cologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known , for example, by means of mixing, granulating, ting, sugar—coating, or film—coating processes.
The preparation of the pharmaceutical compositions object of the invention can be carried out according to common techniques.
The oral formulations comprise ned release formulations that can be prepared in conventional manner, for instance by applying an enteric coating to tablets and granules.
The liquid dispersion for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or ol and/or sorbitol.
Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or ons for intramuscular injections may n, together with the active compound, a pharmaceutically acceptable carrier, e. g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. The solutions for enous injections or infusion may contain as carrier, for example, sterile water or ably they may be in the form of sterile, s, isotonic saline solutions.
The suppositories may contain, together with the active ingredient, a pharmaceutically acceptable carrier, e. g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or in.
The pharmaceutical compositions comprising the fluorinated arylalkylaminocarboxamide derivatives of a I as above d will contain, per dosage unit, e. g., capsule, , powder ion, teaspoonful, suppository and the like from about 0.1 to about 500 mg of 3333 one or more active ients most preferably from I to 10 mg.
Optimal therapeutically effective doses to be stered may be readily determined by those skilled in the art and will vary, basically, with the strength of the preparation, with the mode of administration and with the advancement of the condition or er treated.
In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutically effective level.
MENTAL PART The lI-I-NMR spectra are stored in solution of CDC]; or DMSO-d6 with a Varian Gemini 200 MHz spectrometer. The chemical shifts are defined as d with CDCI3 or DMSO-dg’, and D20 as internal standards.
The S analyses are performed with a Gilson instrument by utilizing a X-Terra RP18 column (5 um, 4.6x50 mm) coupled to a UV detector (220 nm) and a Finnigan Aqa mass spectrometer (electron spray, positive ionization mode). General conditions utilized for the analyses: flow: 1.2 ml/min; column temperature: 50°C; A/B elution gradient (eluent A: 0.1% formic acid in water; eluent B: 0.1% formic acid in acetonitrile): 5-95% of B from 0 to 8.0 minutes, 95% of B from 8.0 to 9.5 minutes.
Abbreviations which are used in the description of the Schemes and the Examples that follow are: DCM: romethane EtAc: ethyl acetate THF: tetrahydrofuran PE: petroleum ether DMF: dimethylformamide DMSO: dimcthylsulfoxide DIPEA: diisopropylethylamine NaH: sodium hydride LiAlI-h: m aluminum hydride LC/MS: Liquid Chromatography/Mass ometry TLC: Thin Layer Chromatography 2012/060006 RT: room temperature BoczO: di—tert—butyl—dicarbonate EXAMPLES For better illustrating the invention the following examples are given.
Example 1-1: 2— [2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] —N,N—dimethyl—acetamide, hydrochloride; F F HNQL W0 N/ Formula: C16H24F2N202 MW: 314.36 Mass/charge ratio: 315.36 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.58 (bs, 2H), 7.47 (t, 1H), 6.98—7.29 (m, 3H), 4.08 (s, 2H), 4.04 (t, 2H), 3.86 (t, 2H), 2.93 (s, 3H), 2.91 (s, 3H), 1.62-1.82 (m, 2H), 1.34-1.54 (m, 2H), 0.95 (t, 3H).
The above nd is synthesized according to Scheme 1 Scheme 1 F F F F 0 W0 NH2 C W \ —> \N —> F F N O W F E W0 ———> O F F F H H / O N/ G W0 \ HCI \ Step A To a solution of 2—(3—methoxyphenyl)acetonitrile (2 g; 13.59 mmol) in 13 mL of dry DCM) cooled at 0°C under nitrogen atmosphere, a 1M solution of BBr3 in DCM (28.54 mmol; 28.54 mL) is slowly added dropwise. The mixture is stirred at room temperature for hours. The reaction mixture is then poured into ice, water is added and the organic phase is extracted three times with DCM, washed with brine and dried over anhydrous NaZSO4. After evaporation, the crude mixture is chromatographed on silica gel using PE/EtAc ) as an eluant, ng 1.28 g (71%) of 2—(3—hydroxyphenyl)acetonitrile.
Step B To a solution of 2—(3—hydroxyphenyl)acetonitrile (2.29 g; 17.11 mmol) in dry DMF (25 mL), K2C03 (7.08 g; 51.33 mmol), KI (0.61 g; 3.70 mmol) and 1—bromobutane (4.69 g; 3.69 mL; 34.22 mmol) are added and the mixture is stirred at 60°C for 5 hours and then at room temperature overnight. The reaction mixture is extracted with EtAc (150 mL) and washed with brine (150 mL): the acqueous phase is acidified with 0.1N HCl and extracted again with ethyl e. The combined organic phases are dried over anhydrous NaZSO4, filtered and evaporated. The crude mixture is purified by flash—chromatography (eluant: PE/EtAc 99/1) yielding, after evaporation, 3.07 g (95%) of utoxyphenyl)acetonitrile.
Step C A solution of 2—(3—butoxyphenyl)acetonitrile (903 mg; 4.80 mmol) in dry THF (75 mL) is cooled at —78°C and tert—butyllithium (1.6M in pentane; 6.6 mL; 10.56 mmol) is added dropwise while maintaining the al temperature n —75°C and —78°C. The solution is stirred for 10 s at —78°C then a solution of N—fluorobenzensulfonimide (N—FSI; 3.78 g; 12.00 mmol) in dry THF (12 mL) is added within 15 minutes. The reaction mixture is stirred at —78°C for 2 hours then quenched with 0.01 N HCl at —78°C and t to room temperature. Ethyl acetate (50 mL) is then added and the mixture evaporated. 1.79 g of benzenesulfonimide side—product precipitate (white solid) is filtered off. The solution is washed with brine and dried over anhydrous NagSO4. After evaporation, the crude residue is flash—chromatographed (eluant; petroleum ethyl acetate, 99.5/0.5 then eum PE/EtAc, 99/1) to give 559 mg (52%) of pure 2,2— difluoro—[2—(—3—methoxphenyl)]acetonitrile and further 355 mg of the same product to be further purified.
Step D A solution of AlCl3 (400 mg; 3.00 mmol) in dry ethyl ether (6 mL) is stirred at 0°C for 30 three times with EtAc, dried over anhydrous , filtered and evaporated, 2,2-Difluoro- dimethyl—acetamide, hydrochloride (Example 1—1).
Examples 1-2 to 1-42. These compounds are prepared according to the same procedure described in Scheme 1 using the suitable reagents.
Example 1-2: 2— [2,2—Difluoro—2— (3 loxyphenyl)—ethylamino] —N,N—dimethyl— ide, hydrochloride; /\/\/ N/ Formula: C17H26F2N202 MW: 328.41 Mass/charge ratio: 329.25 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.37 (bs, 2H), 7.47 (t, 1H), 7.02-7.24 (m, 3H), 4.06 (s, 2H), 4.03 (t, 2H), 3.83 (t, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 1.74 (q, 2H), 1.28-1.50 (m, 2H), 0.91 (t, 3H).
Example 1-3: —Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dipropyl—acetamide, hydrochloride; F O F NQL a: C20H32F2N202 MW: 370.49 Mass/charge ratio: 371.10 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 8.84 (bs, 2H), 7.48 (t, 1H), 7.02-7.26 (m, 3H), 4.03 (s, 2H), 3.94 (s, 2H), 3.78 (t, 2H), 3.21-3.29 (m, 2H), 3.06-3.19 (m, 2H), 1.64—1.79 (m, 2H), 1.37-1.61 (m, 2H), 0.95 (t, 3H), 0.86 (t, 3H), 0.64 (t, 3H).
Example 1-4: 2—[2,2—Difluoro—2—(3—butoxy—4—methylphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride; WO 00651 Formula: F2N202 MW: 328.41 Mass/charge ratio: 329.08 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.44 (bs, 2H), 7.15-7.17 (tdd, 3H), 4.03 (s, 2H), 4.03 (t, 2H), 3.81 (s, 2H), 3.09 (s, 2H), 2.80 (s, 3H), 2.78 (s, 3H), 2.13 (s, 3H), 1.77 (tt, 2H), 1.40 (tq, 2H), 0.88 (t, 3H).
Example 1-5: 2— [2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino] —N,N—dibutyl—acetamide, hydrochloride; F O \/\/O NdLNM Formula: C22H36F2N202 MW: 398.54 Mass/charge ratio: 399.33 (MH+, ESI pos, 3.2KV, 25V, 350°C) Example 1-6: 2—[2,2—Difluoro—2—(3—hexyloxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride; W\/ N/ Formula: F2N202 MW: 342.43 Mass/charge ratio: 343.31 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.47 (bs, 2H), 7.47 (t, 1H), 7.03-7.24 (m, 3H), 4.03 (s, 2H), 3.84 (t, 2H), 3.83 (s, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 1.64—1.81 (m, 2H), 1.36—1.54 (m, 2H), 1.22-1.37 (m, 4H); 0.89 (t, 3H).
Example 1-7: 2—{2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—phenyl]—ethylamino}—N,N— dimethyl—acetamide, hydrochloride; F F O F “fl F>l\/\/O F \©)K/ [11/ Formula: C16H21F5N202 MW: 368.35 Mass/charge ratio: 369.20 (MH+, ESI pos, 3.2KV, 25V, 400°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.41 (bs, 2H), 7.43-7.58 (m, 1H), 6.99—7.29 (m, 3H), 4.11 (t, 2H), 4.06 (t, 2H), 3.84 (t, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 2.31-2.48 (m, 2H), 1.86-2.09 (m, 2H), .37 (m, 4H); 0.89 (t, 3H).
Example 1-8: 2—[2,2—Difluoro—2—(3—pentyloxyphenyl)—ethylamino]—N,N—dipropyl— acetamide, hydrochloride; F O /\/\/O /\/ a: C21H34F2N202 MW: 384.51 Mass/charge ratio: 385.22 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 8.82 (bs, 1H), 7.48 (t, 1H), 7.03-7.29 (m, 3H), 4.04 (s, 2H), 3.91 (s, 2H), 3.80 (t, 2H), 3.21-3.28 (m, 2H), 3.06-3.19 (m, 2H), 1.64—1.79 (m, 2H), 1.37-1.61 (m, 4H), 0.92 (t, 3H), 0.87 (t, 3H), 0.63 (t, 3H).
Example 1-9; 2—{2,2—Difluoro—2—[3—(3—(3—fluorophenyl)—propoxy)—phenyl]—ethylamino}— N,N—dimethyl—acetamide, hydrochloride; mo FF 0 WMT/ Formula: C21H25F3N202 MW: 394.44 Mass/charge ratio: 395.19 (MH+, ESI pos, 3.2KV, 25V, 400°C). 2012/060006 e 1-10; 2— { 2,2—Difluoro—2— (3—chlorophenyl)—propoxy) —phenyl] —ethylamino } — N,N—dimethyl—acetamide, hydrochloride; (Ewe F 0 \©)K/ T/ Formula: C21H25ClF2N202 MW: 410.90 Mass/charge ratio: 411.75 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-11; 2—[2,2—Difluoro—2—(3—butoxy—2—fluorophenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride; \/\/O HdLN/ Formula: C16H23F3N202 MW: 332.37 Mass/charge ratio: 33.15 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-12; 2— { 2,2—Difluoro—2— [3— (3 —phenylpropoxy)—phenyl] —ethylamino } —N,N— dimethyl—acetamide, hydrochloride; ©W©5Udoklw Formula: C21H26F2N202 MW: 376.45 Mass/charge ratio: 377.28 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-13; 2—{2,2—Difluoro—2—[3—(3—thiazol—2—yl—propoxy)—phenyl]—ethylamino}—N,N— dimethyl—acetamide, hydrochloride; {MOWHQKT// N F O Formula: C13H23F2N3Ozs MW: 383.46 Mass/charge ratio: 384.22 (MH+, ESI pos, 3.2KV, 25V, 350°C). e 1- 14; 2— ifluoro—2— (3—benzyloxypheny1)—ethy1amino] —N,N—dimethy1— acetamide, hloride; QVOQSUJLT/ Formula: C19H22F2N202 MW: 348.40 Mass/charge ratio: 349.22 (MH+, ESI pos, 3.2KV, 15V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.40 (bs, 1H), 7.29-7.60 (m, 6H), 7.09—7.29 (m, 3H), 5.18 (s, 2H), 4.04 (s, 2H), 3.83 (t, 2H), 2.93 (s, 3H), 2.90 (s, 3H).
Example 1- 15; 2— [2,2—Difluoro—2—(3—butoxypheny1)—ethy1amino] — 1 — (pyrrolidin— 1 —y1)— ethanone, hloride; \/\/O HQL Formula: C18H26F2N202 MW: 340.42 Mass/charge ratio: 341.02 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.34 (bs, 1H), 7.47 (t, 1H), 7.07-7.21 (m, 3H), 4.03 (t, 2H), 3.94 (s, 2H), 3.84 (t, 2H), 3.36 (t, 4H), 1.85-2.01 (m, 2H), 1.76-1.85 (m, 2H), 1.64- 1.76 (m, 2H), 1.45 (m, 2H), 0.95 (t, 3H).
Example 1-16; 2—[2,2—Difluoro—2—(3—butoxypheny1)—ethy1amino]—N—methy1—N—pheny1— acetamide, hydrochloride; F O F NQL W0 N Formula: C21H26F2N202 MW: 376.45 Mass/charge ratio: 347.23 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-17; 2—{2,2—Difluoro—2—[3—(3—pheny1propoxy)—pheny1]—ethy1amino}—1—(pyrrolidin— l—yl)—ethanone, hydrochloride; mofinib Formula: C23H28F2N202 MW: 402.49 Mass/charge ratio: 403.26 (MH+, ESI pos, 3.2KV, 15V, 400°C).
Example 1-18; 2— { 2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—phenyl] —ethylamino } — l— (pyrrolidin— l —yl)—ethanone; Fij/VOOBFVHJD a: C13H23F5N202 MW: 394.39 Mass/charge ratio: 395.23 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.48 (bs, 2H), .61 (m, 1H), 7.01-7.26 (m, 3H), 4.11 (t, 2H), 3.96 (s, 2H), 3.86 (t, 2H), 3.28-3.40 (m, 4H), 2.33—2.48 (m, 2H), 1.68— 2.04 (m, 6H).
Example 1-19; 2—[2,2—Difluoro—2—(3—benzyloxy—phenyl)—ethylamino]—l—(morpholin—4—yl)— ethanone, hydrochloride; (EV. F O HVLNd \\/° Formula: C21H24F5N203 MW: 390.43 Mass/charge ratio: 39l.22 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-20; 2— { 2,2—Difluoro—2— [3—(3—phenylpropoxy)—phenyl] amino } — l — (morpholin—4—yl)—ethanone, hydrochloride; mowndjxoO O Formula: C23H23F2N203 MW: 418.49 Mass/charge ratio: 419.18 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-21; 2— { fluoro—2— [3— (4,4,4—trifluorobutoxy)—phenyl] amino } — 1— (morpholin—4—yl)—ethanone, hloride; Formula: C18H23F5N203 MW: 410.39 Mass/charge ratio: 411.22 (MH+, ESI pos, 3.2KV, 15V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.70 (bs, 2H), 7.50 (t, 1H), 6.88-7.37 (m, 3H), 4.15 (s, 2H), 4.12 (t, 2H), 3.87 (t, 2H), 3.54-3.67 (m, 4H), 3.44-3.54 (m, 2H), 3.32-3.44 (m, 2H), 2.32-2.47 (m, 2H), 1.86-2.06 (m, 2H).
Example 1-22; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino) 1—(2H— benzo[b] [1,4]oxazin—4(3H)—yl)— ethanone, hydrochloride; F 0 \\/° Formula: C22H26F2N203 MW: 404.46 Mass/charge ratio: 405.29 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-23; 2—[2,2—Difluoro—2—(3—benzyloxyphenyl)—ethylamino]—1—(pyrrolidin—1—yl)— ethanone, hydrochloride; ©Vo©5CHiNQ WO 00651 Formula: C21H24F2N202 MW: 374.43 Mass/charge ratio: 375.27 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-24; 2—{2,2—Difluoro—2—[3—(3—phenylpropoxy)—phenyl]—ethylamino}—N—methyl— N—phenyl—acetamide, hydrochloride; ©Wo©SUJLTQ Formula: C26H23F2N202 MW: 438.52 Mass/charge ratio: 439.38 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-25; 2— { 2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—phenyl] —ethylamino } —N— —N—phenyl—acetamide, hydrochloride; Formula: C21H23F5N202 MW: 430.42 Mass/charge ratio: 431. 29 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-26; 2— [2,2—Difluoro—2— oxyphenyl)—ethylamino] — l —(4—methylpiperazin— l— yl)—ethanone, hydrochloride; F O \/\/O Hde/fi \\/N\ Formula: C19H29F2N302 MW: 369.46 Mass/charge ratio: 370.07 (MH+, ESI pos, 3.2KV, 15V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 7.28-7.49 (m, 1H), 6.92-7.18 (m, 3H), 4.04 (t, 2H), 3.62—3.85 (m, 1H), 3.52 (s, 2H), 3.32 (t, 2H), .19 (m, 8H), 2.69 (s, 3H), 1.61-1.84 (m, 2H), 1.48 (dq, 2H), 0.96 (t, 3H).
Example 1-27; 2— { 2,2—Difluoro—2— [3—(3—phenylpropoxy)—phenyl)—ethylamino } — l— (4— methylpiperazin— 1—yl)—ethanone, hydrochloride; ©WO F F HiN/fi \\/N\ Formula: C24H31F2N302 MW: 431.53 Mass/charge ratio: 431.37 (MH+, ESI pos, 3.2KV, 15V, 400°C).
Example 1-28; 2— { 2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—phenyl)—ethylamino } — 1—(4— piperazin— 1—yl)—ethanone, hydrochloride; F F o F HdL F/;\/\/O N/\\ F \\/N\ Formula: C19H26F5N302 MW: 423.43 Mass/charge ratio: 424.28 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.56 (bs, 1H), 9.57 (bs, 1H), 7.37-7.60 (m, 1H), .28 (m, 3H), 4.29—4.59 (m, 1H), 4.16-4.30 (m, 1H), 4.11 (t, 2H), 3.80 (t, 2H), 2.87- 3.94 (m, 8H), 2.77 (s, 3H), 2.33-2.47 (m, 2H), 1.85-2.06 (m, 2H).
Example 1-29; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]— 1—(piperidin—1—yl)— ethanone, hydrochloride; \/\/O HQLNQ Formula: C19H28F2N202 MW: 354.44 Mass/charge ratio: 355.03 (MH+, ESI pos, 3.2KV, 15V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.37 (bs, 2H), 7.47 (t, 1H), .21 (m, 3H), 4.07 (s, 2H), 3.84 (t, 2H), 3.45-3.54 (m, 2H), 3.21-3.32 (m, 2H), 1.66—1.81 (m, 2H), 1.33—1.66 (m, 8H), 0.95 (t, 3H).
Example 1-30; 2— { 2,2—Difluoro—2—[3—(3—pheny1propoxy)—pheny1] —ethy1amino } — 1 — idin— 1—y1)—ethanone, hydrochloride; QWOerFULD Formula: C24H30F2N202 MW: 416.52 Mass/charge ratio: 417.34 (MH+, ESI pos, 3.2KV, 15V, 350°C).
Example 1-31; 2— { 2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—pheny1] — ethy1amino } — 1 — (piperidin— 1—y1)—ethanone, hydrochloride; FEWREDBFVHQCLNQ Formula: F5N202 MW: 408.41 Mass/charge ratio: 408.07 (MH+, ESI pos, 3.2KV, 15V, 350°C).
Example 1-32; 2—[2,2—Difluoro—2—(3—butoxypheny1)—ethy1amino]—N,N—diethy1—acetamide, hydrochloride; F F HJNJ \/\/O Formula: C13H23F2N202 MW: 342.43 Mass/charge ratio: 343.05 (MH+, ESI pos, 3.2KV, 15V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 7.47 (t, 1H), 7.07-7.20 (m, 3H), 4.03 (t, 2H), 4.02 (s, 2H), 3.84 (t, 2H), 3.34 (q, 2H), 3.24 (q, 2H), 1.64-1.82 (m, 2H), 1.36-1.55 (m, 2H), 1.12 (t, 3H), 1.07 (t, 3H), 0.95 (t, 3H). e 1-33; 2—{2,2—Difluoro—2—[3—(2—fluorobenzyloxy)—pheny1]—ethy1amino}—N,N— dimethy1—acetamide, hydrochloride; CLOEjUJLT/F a: C19H21F3N202 MW: 366.39 Mass/charge ratio: 367.18 (MH+, ESI pos, 3.2KV, 15V, 400°C).
Example 1-34; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] — 1—(cis—3,5— dimethylpiperidin— ethanone, hydrochloride; F O \/\/O defiv Formula: C21H32F2N202 MW: 382.50 Mass/charge ratio: 383.34 (MH+, ESI pos, 3.2KV, 15V, 350°C).
Example 1-35; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] — 1—(3,4— dihydroisoquinolin—2(1H)—yl)—ethanone, hydrochloride; F]: O W Woo Formula: C23H23F2N202 MW: 402.49 Mass/charge ratio: 403.22 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-36; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—diisopropyl— acetamide, hydrochloride; F F \/\/O HQOLNk Formula: F2N202 MW: 370.49 Mass/charge ratio: 371.19 (MH+, ESI pos, 3.2KV, 25V, 350°C). e 1-37; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N—cyclohexyl—N—methyl— acetamide, hydrochloride; F O O F NQL W0 N Formula: C21H32F2N202 MW: 382.50 Mass/charge ratio: 383.31 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-38; 2—[2,2—Difluoro—2—(3—benzyloxyphenyl)—ethylamino]—l—(piperidin—l—yl)— ethanone, hydrochloride; C“comic a: C21H32F2N202 MW: 388.46 Mass/charge ratio: 389.21 (MH+, ESI pos, 3.2KV, 25V, 400°C). e 1-39; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—l—[4—(phenylsulfonyl)— piperazin— l—yl] —ethanone, hydrochloride; F O W0 NQLN/\\ \\/N\S/’O O©|| Formula: C24H31F2N3O4S MW: 495.59 Mass/charge ratio: 496.24 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-40; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] — l —(indolin— l—yl)— ethanone, hydrochloride; \/\/O HQLN WO 00651 Formula: C22H26F2N202 MW: 388.46 harge ratio: 389.25 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 1-41; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—1—(4—benzylpiperazin—l— yl)—ethanone, dihydrochloride; \/\/O HQkN/fi \\/N Formula: C25H33F2N302 MW: 445.56 Mass/charge ratio: 446.34 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 1-42; 2— [2,2—Difluoro—2— (3 —butoxyphenyl)—ethylamino)— 1—(azetidin— 1—yl)— ethanone, hydrochloride; F O F Ndk W0 N§ Formula: C17H24F2N202 MW: 326.39 Mass/charge ratio: 327.13 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H—NMR (300 MHz, DMSO—d6) 5 ppm 7.31—7.46 (m, 1H), 6.95—7.13 (m, 3H), 4.01 (t, 4H), 3.84 (t, 2H), 3.14—3.24 (m, 2H), 3.104 (dq, 2H), 2.18 (dt, 2H), 1.63—1.79 (m, 2H), 1.45 (dq, 2H), 0.94 (t, 3H).
Example 2-1: 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] —N,N—dimethyl— propanamide, hloride; \/\/O NfikT/ Formula: C17H26F2N202 MW: 328.41 Mass/charge ratio: 329.02 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.48 (bs, 1H), 7.47 (t, 1H), 7.04-7.24 (m, 3H), 4.24-4.51 (m, 1H), 4.03 (t, 2H), 3.71-3.95 (m, 1H), 3.51—3.71 (m, 1H), 2.98 (s, 3H), 2.89 (s, 3H), 1.62-1.82 (m, 2H), 1.42 (d, 3H), 1.34-1.54 (m, 2H), 0.95 (t, 3H).
The above nd was sized according to Scheme 2 Scheme 2 Step A 75 mg (0.23 mmol) of N—tert—butoxycarbonyl—2,2—difluoro—2—(3—butoxyphenyl)—ethylamine are dissolved in dry DMF (5 mL). The solution is cooled to 0°C and NaH (6.7 mg; 1.2 eq) is added. The solution is stirred at at RT for 10 min, then cooled again to 0°C and 2—chloro— N,N—dimethylpropanamide (31 mg; 0.23 mmol) are added. After 4 hours a further 1.2 eq of NaH (6.7 mg) are added. The reaction e is stirred overnight at RT, then quenched with water, evaporated, the residue taken up with water and EtAc. The organic layer is ted and the water layer extracted three times with EtAc. The combined organic phases are dried over anhydrous Na2S04, filtered and evaporated. The resulting crude residue is flash—chromatographed (eluant: petroleum ether/EtAc, 9/1 to 8/2). 2—[N—tert— butoxycarbonyl—2,2—difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethylpropanamide (84 mg; 81%) is obtained as pale yellow oil.
Step B 84 mg (0.196 mmol) of 2—[N—tert—butoxycarbonyl—2,2—difluoro—2—(3—butoxyphenyl)— ethylamino]—N,N—dimethylpropanamide are dissolved in 3 mL of DCM and 0.49 mL (1.96 mmmol; 10 eq) of a 4M HCl solution in dioxane are added. After 8 hours, further 10 eq (0.49 mL) of 4M HCl 1 dioxane are added and the mixture is stirred overnight. Further 5 eq (0.245 mL) of 4M HCl in dioxane are the added and the mixture stirred for further 24 hours. The solution is evaporated, the white residue suspended in diethyl ether and then evaporated twice. The residue is hromatographed on silica gel (DCM/MeOH l/l as an eluant ed by MeOH/conc. NH3 95/5). and the free base 2—[2,2—difluoro—2—(3— butoxyphenyl)—ethylamino]—N,N—dimethylpropanamide is isolated as a pale yellow fluid.
The compound is ved in DCM (3 mL) and 4M HCl in dioxane is added to bring the solution to pH 2. The mixture is stirred for 10 minutes and then evaporated. The white residue is taken up with ether and evaporated twice. 45 mg (49%) of 2—[2,2—difluoro—2—(3— butoxyphenyl)—ethylamino]—N,N—dimethylpropanamide, hydrochloride (Example 2—l) are Examples 2-2 to 2-5. These compounds are prepared according to the procedure described in Scheme 2.
Example 2-2; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—3—methoxy—N,N—dimethyl— propanamide; F O WOWNJAN/|OF H Formula: C13H23F2N203 MW: 358.43 Mass/charge ratio: 359.40 (MH+, ESI pos, 3.2KV, 15V, 400°C). 1H—NMR (300 MHz, 6) 8 ppm 7.39—7.59 (m, 1H), 7.06—7.21 (m, 3H), 4.64 (t, 1H), 4.03 (t, 2H), .87 (m, 4H), 3.30 (s, 3H), 3.02 (s, 3H), 2.91 (s, 3H), 1.59—1.81 (m, 2H), 1.36-1.57 (m, 2H), 0.94 (t, 3H).
Example 2-3; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—3—(4—methoxyphenyl)— N,N—dimethyl—propanamide, hydrochloride; F O W0 N N/ Formula: C24H32F2N203 MW: 434.53 Mass/charge ratio: 435.36 (MH+, ESI pos, 3.2KV, 25V, 400°C).
Example 2-4; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—2—N,N—trimethyl— propanamide, hloride; F O T/F H Formula: C18H28F2N202 MW: 342.43 harge ratio: 342.31 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 2-5; 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—4—N,N—trimethyl— pentanamide, hydrochloride; F O \/\/OWIN N/ Formula: C20H32F2N202 MW: 370.49 Mass/charge ratio: 371.33 (MH+, ESI pos, 3.2KV, 25V, 350°C).
Example 3-1; 2—{ [2,2—Difluoro—2— (3 —butoxyphenyl)—ethyl] —methylamino } —N,N—dimethyl— acetamide, hydrochloride; F F NdLN/I \/\/O a: C17H26F2N202 MW: 328.41 Mass/charge ratio: 329.17 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H-NMR (300 MHz, DMSO-d6) 8 ppm 7.45 (t, 1H), 7.04-7.18 (m, 3H), 4.03 (t, 2H), 3.73— 3.91 (m, 2H), 3.70-4.13 (m, 2H), 2.86 (s, 3H), 2.84 (s, 3H), 2.80 (s, 3H), 1.62-1.82 (m, 2H), 1.37-1.57 (m, 2H), 0.94 (t, 3H).
The above compound is synthesized according to Scheme 3 Scheme 3 O O F F We Mr .brjwb/ F F \ B W0 / Examples 3-2 to 3-3. These compounds are prepared according to the procedure described in Scheme 3.
Step A 107.5 mg (0.34 mmol) of the free base of 2—[2,2—difluoro—2—(3—butoxyphenyl)—ethylamino]— N,N—dimethyl—acetamide (see Example 1—1) are dissolved in dry THF (10 mL). To this solution, formaldehyde (36.5% water on, 52.1 ML; 0.69 mmol), acetic acid (2.5 mL), and MP—CNBH3 (2.3 mmol/g; 325 mg; 0.75 mmol) are added sequentially. After ng 1 hour the reaction is completed. After further stirring for 1.5 hours, the reaction mixture is evaporated. The crude residue is flah—chromatographed on silica gel using OH (99.5/0.5) as an eluant. 73.1 mg (65%) of pale yellow fluid 2—{[2,2—difluoro—2—(3— butoxyphenyl)—ethyl]—methylamino}—N,N—dimethyl—acetamide are obtained.
Step B A solution of 73.1 mg of 2—{[2,2—difluoro—2—(3—butoxyphenyl)—ethyl]—methylamino}—N,N— dimethyl—acetamide in DCM (3 mL) is stirred and few drops of 4M HCl in dioxane are added until reaching pH 2. The reaction mixture is stirred for 5 minutes and then evaporated. The white solid residue is suspended in EtZO and evaporated twice to yield 77.4 mg (96%) of white solid 2—{[2,2—difluoro—2—(3—butoxyphenyl)—ethyl]—methylamino}— N,N—dimethyl—acetamide, hydrochloride (Example 3—1). e 3-2: 2—{[2,2—Difluoro—2—(3—butoxyphenyl)—ethyl]—(3—methoxypropyl)—amino}— N,N—dimethyl—acetamide, hydrochloride; W0 / Formula: C20H32F2N203 MW: 386.49 Mass/charge ratio: 387.28 (MH+, ESI pos, 3.2KV, 25V, . 1H-NMR (300 MHz, DMSO-d6+TFA) 8 ppm 7.38-7.50 (m, 1H), 7.08—7.17 (m, 3H), 3.98— 4.11 (m, 4H), 3.85 (t, 2H), 3.33 (t, 2H), 3.21 (s, 3H), 3.12—3.20 (m, 2H), 2.88 (s, 3H), 2.86 (s, 3H), 1.78-1.91 (m, 2H), 1.65-1.78 (m, 2H), 1.36-1.54 (m, 2H), 0.94 (t, 3H).
Example 3-3; 2—{ [2,2—Difluoro—2—(3—butoxyphenyl)—ethyl]—(2—methoxyethyl)—amino}—N,N— dimethyl—acetamide, hydrochloride; F O Formula: C19H30F2N203 MW: 372.46 Mass/charge ratio: 373.30 (MH+, ESI pos, 3.2KV, 25V, 400°C). 1H-NMR (300 MHz, DMSO-d6+TFA) 8 ppm 7.38 (t, 1H), 6.95-7.11 (m, 3H), 4.01 (t, 2H), 3.50 (s, 2H), 3.42 (t, 2H), 3.28 (t, 2H), 2.85 (s, 3H), 2.79 (s, 3H), 2.76 (s, 3H), 1.63-1.79 (m, 2H), 1.35-1.52 (m, 2H), 0.94 (t, 3H).
Example 4-1: 2— [2—Fluoro—2— (3—butoxyphenyl)—ethylamino] —N,N—dimethyl—acetamide, hloride; \/\/O HQkN/ Formula: C16H25FN202 MW: 296.39 Mass/charge ratio: 297.04 (MH+, ESI pos, 3.2KV, 25V, 350°C) 1H—NMR (300 MHz, DMSO—d6) 5 ppm 9.35 (bs, 2H), 7.22—7.487 (m, 1H), 6.83—7.07 (m, 3H), 5.97 (ddd, 1H), 4.10 (s, 2H), 4.004 (t, 2H), 3.55 (td, 1H), 3.33—3.47 (m, 1H), 2.95 (s, 3H), 2.91 (s, 3H), 1.56—1.78 (m, 2H), 1.29—1.54 (m, 2H), 0.94 (t, 3H).
The above compound is synthesized according to Scheme 4 Scheme 4 /O HO \\ W0 C \ N \N DWO 2 E\/\/0 NY FOYO o o F \/\/O N\)L[\\j/i>\/\/O\©)\/N\|fikl\\lF Step A To a solution of ethoxyphenyl)acetonitrile (2 g; 13.59 mmol) in 13 mL of dry dichloromethane (DCM) cooled at 0°C under an inert atmosphere, a 1M on of BBr3 in DCM (28.54 mmol; 28.54 mL) is slowly added se. The mixture is stirred at room temperature for 20 hours. The reaction mixture is then poured into ice, water is added and the organic phase is extracted three times with dichloromethane, washed with brine and dried over anhydrous NaZSO4. After evaporation, the crude mixture is purified by flash— chromatography on silica gel using petroleum ether/EtAc (80/20) as an eluant, affording 1.28 g (71%) of 2—(3—hydroxyphenyl)acetonitrile.
Step B 2012/060006 To a solution of ydroxyphenyl)acetonitrile (2.29 g; 17.11 mmol) in dry DMF (25 mL), K2CO3 (7.08 g; 51.33 mmol), KI (0.61 g; 3.70 mmol) and 1—bromobutane (4.69 g; 3.69 mL; 34.22 mmol) are added and the mixture is stirred at 60°C for 5 hours and then at room temperature overnight. A TLC (DCM/EtAc 95/5) shows no presence of starting al. After evaporation, the on mixture is extracted with ethyl acetate (150 mL) and washed with brine (150 mL twice): the acqueous phase is acidified with 0.1N HCl and extracted again with ethyl acetate. The combined organic layers are dried over anhydrous NaZSO4, filtered and evaporated. The crude mixture is purified by hromatography (eluant: petroleum ether/ethyl acetate 99/1) yielding, after evaporation, 3.07 g (95%) of 2— (3—butoxyphenyl)acetonitrile as a pale yellow oil.
Step C Tert—buthyllithium ( 1268 uL; 2.16 mmol) is added dropwise to a solution of 2—(3— butoxyphenyl)acetonitrile (371 mg; 1.96 mmol) in THF (16 mL) at —78°C, under nitrogen here. The light yellow solution turned into orange and stirring is continued for 1 hour. A solution of N—fluorobenzenesulfonimide (618 mg; 1.96 mmol) in THF (2 mL) is added dropwise and the reaction is stirred at —78°C for 2 hours. TLC (petroleum ether/EtAc 9:1) reveals no presence of starting material and two more apolar spots. The reaction is then quenched by adding 0.01N HCl, then more water is added and extracted with DCM (three times). The combined organic layers are dried over NagSO4, filtered and evaporated.
The crude residue is purified by flash tography (petroleum ether/EtAc, 99/1) affording 217 mg (53%) of 2—(3—butoxyphenyl)—2—fluoroacetonitrile as a colorless oil.
Step D To a on of 2—(3—butoxyphenyl)—2—fluoroacetonitrile (109 mg: 0.53 mmol) in dry THF (5 mL), borane tetrahydrofurane complex (2.10 mL; 2.10 mmol) is added and the reaction is stirred at 0°C for 2 hours and then at RT for 6 hours. An LC/MS shows almost complete conversion. The reaction is ed adding slowly few drops of EtOH and few drops of conc. HCl/EtOH (1:5) and stirring is continued for 5 min. DCM was then added, followed by 5% aqueous NaHCO3. The two phases are separated and the s phase is extracted twice with DCM. The combined organic layers are dried over NaZSO4, filtered and evaporated. The crude residue is purified using a SCX cartridge (eluant: DCM/MeOH 1/1 to MeOH/conc. aq. NH3 95/5)affording 2—(3—butoxyphenyl)—2—fluoroethanamine (92 mg; 0.43 mmol; 83%) as a pale yellow oil.
Step E DIPEA (0.106 mL; 0.61 mmol) is added to a solution of 2—(3—butoxyphenyl)—2— fluoroethaneamine (92 mg; 0.43 mmol) and BoczO (0.121 mL; 0.52 mmol) in dry THF (6 mL) and the reaction is d at RT for 2 hours. An LC/MS shows complete conversion.
DCM is added and the solution is washed with 5% aq. NaHCO3 and 1N HCl, dried over anhydrous NagSO4, filtered and evaporated to give tert—butyl 2—(3—butoxyphenyl)—2— fluoroethylcarbamate (136 mg; 0.437 mmol; 100%) as a pale yellow oil.
Step F A solution of tert—butyl 2—(3—butoxyphenyl)—2—fluoroethylcarbamate (136 mg; 0.44 mmol) in dry DMF (4 mL) under nitrogen atmosphere is cooled to 0°C and sodium hydride (22.7 mg; 0.57 mmol) is added. The mixture is stirred at RT for 10 min, then is cooled again to 0°C and 2—chloro—N,N—dimethyl—acetamide (0.054 mL; 0.524 mmol) is added. The reaction mixture is stirred at RT for 4 hours. An LC/MS shows very low conversion. Additional sodium hydride (38 mg; 0.96 mmol) is added followed after 10 min by 2—chloro—N,N— dimethyl—acetamide (0.09 mL; 0.87 mmol). ng is continued for 12 hours. An LC/MS shows almost complete sion. The t is evaporated, EtAc is added and the solution is washed with brine, then dried over anhydrous NaZSO4, filtered and evaporated.
The crude residue is purified by flash—chromatography (DCM/EtAc from 96/4 to 95/5) yielding tert—butyl N— butoxyphenyl)—2—fluoroethyl]—N— [(2—dimethylamino)—2— oxoethyl)]—carbamate (100 mg; 0.25 mmol; 58%) as a colourless oil.
Step G A mixture of tert—butyl N— [2—(3—butoxyphenyl)—2—fluoroethyl]—N— [(2—dimethylamino)—2— oxoethyl)]—carbamate (96 mg; 0.24 mmol) and 4M HCl in dioxane (363 uL; 1.45 mmol) in dry DCM (6 mL) is stirred at RT for 4 hours. An LC/MS show complete conversion. The solvent is evaporated affording 2—[2—(3—butoxyphenyl)—2—fluoroethylamino)]—N,N— dimethyl—acetamide (50 mg; 0.17 mmol; 70%) as a pale yellow amorphous solid which is ated with EtAc, filtered and dried to give 22.2 mg (0.067 mmol; 44%) of white solid 2—[2—(3—butoxyphenyl)—2—fluoroethylamino]—N,N—dimethyl—acetamide, hydrochloride. le 4-1).
Examples 4-2 to 4-3. These compounds were prepared according to the procedure described in Scheme 4.
Example 4-2; 2— { ro—2— [3—(3—chlorobenzyloxy)—phenyl] —ethylamino } —N,N—dimethyl— acetamide, hydrochloride; Example 4-3; 2— { 2—Fluoro—2— [3—(3—fluorobenzyloxy)—phenyl] —ethylamino } —N,N—dimethyl— acetamide, hydrochloride; Example 5: N—Type calcium l influx assay llVIR32 human neuroblastoma cells constitutively s both L— and N—type channels.
Under differentiating conditions, llVIR32 cells preferentially express on the membrane surface N—type calcium channels. The remaining L—type calcium channels are blocked using the selective L—type blocker nifedipine. In these experimental conditions only N—type channels can be detected.
IMR32 cells are differentiated using 1 mM dibutyryl—cAMP and 2.5 uM bromodeoxyuridine for 8 days (4 times) in 225 cm2 flask, then detached, seeded at 200,000 cells/well on 96 poly—L—lysine—coated plates and further incubated for 18—24h in the presence of differentiating buffer before use.
The Ca2+ Kit Assay (Molecular Devices, CA — USA), based on a fluorescent calcium indicator and able to detect the calcium influx determined by depolarizing conditions, is used for the assay.
Differentiated cells are incubated with dye loading for 30 minutes at 37°C then, nifedipine alone (1 uM) or in the presence of otoxin (as reference standard) or test compounds are added for further 15 minutes.
The fluorescence (excitation: 485 nm, emission: 535 nm wavelength) is ed before and after (30—40s) the ted injection of 100 mM KCl depolarizing on using a Victor plate reader (Perkin Elmer, MA — USA).
The inhibition curves are calculated from 5 concentrations, each in triplicate, and the IC50 determined using a linear regression analysis.
The compounds of the present invention inhibit N—type calcium channels with pharmacologically significant IC50 values.
Example 6: TTXs—sodium channel influx assay ND7/23 rat dorsal root ganglion—derived cell line endogenously expresses a mixed population of TTXs sodium ls (such as Navl.3, Navl.2, Navl.l, Navl.6). These cells lack of TTXr sodium channels as shown by the e of their tive ripts.
ND7/23 cells are grown in Dulbecco’s ed Eagle Medium (DMEM, Invitrogen, CA — USA) supplemented with10% Foetal Bovine Serum (FBS, Invitrogen, CA — USA) and lmM sodium piruvate. The cells are seeded at 50,000 cells/well on 96 poly—L—lysine— coated plates and further incubated for 18—24h before use.
The ne Potential Kit Assay (Molecular Devices, CA — USA), based on a negatively charged fluorescent dye able to monitor changes in membrane potential caused by the sodium influx due to the channel opening, is used for the assay.
Cells are ted with the dye loading for 30 minutes at 25°C. Then, lOOnM of the toxin Anemonia sulcata (used as enhancer of the channel opener response) alone or in the presence of TTX (as reference standard) or test compound are added for further 15 minutes.
The fluorescence (excitation: 530 nm, emission: 565 nm ngth) is measured before and after (40—45s) the automated injection of the sodium channel opener veratridine (100 MM ) using a Victor plate reader (Perkin Elmer, MA — USA).
The tion curves are calculated from 5 concentrations, each in triplicate, and the IC50 ined using a linear regression analysis.
The compounds of the present invention inhibit TTXs sodium channels with cologically significant IC50 values.
The results, obtained with some compounds which are representative of the entire class of compounds of the invention are reported in Table 1.
Table 1 COMPOUND 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example l—l) 2—[2,2—Difluoro—2—(3—pentyloxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example 1—2) 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dipropyl— acetamide, hydrochloride le l—3) 2—[2,2—Difluoro—2—(3—hexyloxyphenyl)—ethylamino]—N,N—dimethyl— acetamide , hydrochloride (Example l—6) 2—{2,2—Difluoro—2—[3—(4,4,4—trifluorobutoxy)—phenyl]—ethylamino}— N,N—dimethyl—acetamide, hydrochloride (Example l—7) 2—[2,2—Difluoro—2— (3—benzyloxyphenyl)—ethylamino] —N,N—dimethyl— acetamide, hydrochloride (Example 1— l4) 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] — l olidin— l— hanone, hydrochloride (Example 1— 15) 2— { 2,2—Difluoro—2— 4,4—trifluorobutoxy)—phenyl]—ethylamino } — l—(pyrrolidin— l —yl)—ethanone (Example 1— 18) WO 00651 2— { 2,2—Difluoro—2— [3—(4,4,4—trifluorobutoxy)—phenyl]—ethylamino } — l—(morpholin—4—yl)—ethanone, hydrochloride (Example 1—2 1) 2—[2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino] — 1—(4— methylpiperazin—l—yl)—ethanone, hydrochloride (Example 1—26) 2— { 2,2—Difluoro—2— [3—(4,4,4—trifluorobutoxy)—phenyl]—ethylamino } — 1—(4—methylpiperazin—1—yl)—ethanone, hydrochloride (Example 1—28) 2— ifluoro—2— (3—butoxyphenyl)—ethylamino] — 1—(piperidin— 1—yl)— ethanone, hydrochloride (Example 1—29) 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—diethyl— acetamide, hydrochloride (Example 1—32) 2— [2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino] — 1 — (azetidin— 1 —yl)— ethanone, hydrochloride (Example 1—42) 2—[2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino]—N,N—dimethyl— propanamide, hloride (Example 2—1) 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—3—methoxy—N,N— dimethyl—propanamide (Example 2—2) 2—{ [2,2—Difluoro—2— oxyphenyl)—ethyl]—methylamino}—N,N— dimethyl—acetamide, hydrochloride (Example 3— 1) 2—{ [2,2—Difluoro—2—(3—butoxyphenyl)—ethyl]—(3—methoxypropyl)— —N,N—dimethyl—acetamide, hydrochloride (Example 3—2) 2—{ [2,2—Difluoro—2— (3 —butoxyphenyl)—ethyl]—(2—methoxyethyl)— amino}—N,N—dimethyl—acetamide, hydrochloride (Example 3—3) 2—[2—Fluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example 4—1) Example 7: Patch clamp studies of calcium currents inhibition Cells and methods: onal tion of the N—type Ca ts is studied using whole cell patch clamp methods (Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Pflugers Arch. 391: 85—100 (1981)) on HEK293 cells expressing recombinant human N—type channels, obtained after transient transfection of h 061B (hCaV2.2) + Blb + 0625—1 subunits.
Membrane currents are recorded and filtered at 5 kHz with an Axon Axopatch 200B ier and digitized with an Axon Digidata 1322A (Axon Instruments, CA, USA).
Voltage clamping of membrane potentials and data acquisition are controlled online with Axon pClamp8 software. Measuring and reference electrodes are AgCl—Ag electrodes.
Cells have initial seal resistances of >1 G9 and access resistances of 4.2 i 0.2 MQ. Cells are continuously used with ellular ons using a Biologic RSC—200 (Biologic SAS, France).
For calcium currents recording the control bath solution contained (mM): choline chloride (70), MgClg (l), BaClz (20), TEA'Cl (50), Hepes (10), glucose (10). al pipette solution ts of (mM): CsCl (140), EGTA (10), MgClg (2), Hepes (10), MgATP (l), GTP Tris (0.3).
Compounds are dissolved as 20 mM stock solutions in DMSO and then diluted to the final concentration in the external solutions. e protocols and data analyses: A ep protocol is used to determine the voltage dependence of the block: N—type current is ted by a 600 ms step pulse to +10 mV (test pulse) from a 5000 ms preconditioning ial of —110 mV (resting ion) or —50/—55 mV (half maximal steady—state inactivated condition), respectively.
The amplitude of calcium current peaks evoked by the respective test pulses at a frequency of 0.06 Hz are measured before and after exposure to the test substance. Tonic block of currents is calculated as the difference between the peak m current ed at the end of a stabilization period in the control external bath solution and peak currents measured at the end of test substance perfusion period (when steady state is reached) divided by control peaks. Drug concentration—inhibition curves are obtained by plotting tonic blocks versus drug concentrations. Dose—response curves are fitted to the tonic block data, according to the logistic equation: y = A2+ (A1—A2)/[l+ (x/IC50)p]. Al and A2 are fixed values of 0 and 1 corresponding to 0 and 100% t inhibition, x is the drug concentration, IC50 is the drug concentration resulting in 50% current inhibition and p is the corresponding slope factor.
The compounds of the present invention inhibit N—type calcium channels with pharmacologically significant IC50 values.
Example 8: Patch clamp studies of sodium currents inhibition Cells and methods: Functional inhibition of the sodium currents is studied using whole cell patch clamp methods (Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J Pflugers Arch. 391 (2): 85—100 (1981)) on the hybrid cell line ND7/23 (Wood JN, Bevan SJ, Coote PR, Dunn PM, Harmar A, Hogan P, Latchman DS, Morrison C, Rougon G, Theveniau M.: “Novel cell lines display properties of nociceptive sensory neurons”. Proc.
Biol. Sci. Sep 22;241(1302):187—94 (1990)), that express a mixed population of voltage gated sodium channels. ne currents are recorded as decribed in the example above.
For sodium current recording control bath solution contained (mM): NaCl (80), choline chloride (38), CaClz (1.3), MgClz (2), KCl (2), CdClz (0.4), NiClz (0.3), TEA'Cl (20), Hepes (10), glucose (10). Internal pipette solution consists of (mM): CsF (65), CsCl (65), NaCl (10), CfiClz (1.3), MgClz (2), Hepes (10), EGTA (10), MgATP (1).
Compounds are dissolved as 20 mM stock solutions in DMSO and then diluted to the final concentration in the external solutions.
Voltage protocols and data analyses: A two—step protocol is used to ine the voltage dependence of the block: sodium current is activated by a 30 ms step pulse to 0 mV (test pulse) from a 2000 ms preconditioning potential of —100 mV (resting condition) or —70 mV (half maximal steady— state inactivated condition), respectively.
Drug concentration—inhibition curves are obtained by plotting tonic blocks in the resting and depolarized condition, versus drug trations. Dose—response curves are fitted to the tonic block data, according to the ic equation: y = A2+(A1—A2)/[1+(x/IC50)p]. A1 and A2 are fixed values of 0 and 1 corresponding to 0 and 100% current inhibition, x is the drug tration, IC50 is the drug concentration resulting in 50% current inhibition and p is the corresponding slope factor.
Besides the voltage dependent block calculated as IC50s from the resting and the depolarized membrane potential, respectively, a better evaluation of the apparent affinity of drug for the inactivated state is done by calculating the Ki ing to the on 1/Kdep=h/Kr + (1—h)/Ki where Kr is the affinity of drug for the resting/closed state; Kdep is the IC50 in the depolarized condition, h and (1—h) are the fractions of ls present at the rest and dep potentials, tively (De Luca et al. “Optimal ements for high affinity and use—dependent block of skeletal muscle sodium channel by N—benzyl analogs of tocainidelike compounds”. Mol Pharmacol 64:932—945.(2003)). In fact although the IC50 value at resting tion of maximal availability current 2 Imax) can be considered as the affinity constant for closed/resting (Kr) channels, the IC50 from depolarized ial (the specific Vhalf was used as preconditioning depolarized ial) is influenced by the 2012/060006 relative proportion of resting ls in equilibrium with inactivated ones and by the ability of the drug to influence such an equilibrium based on its affinity for inactivated state.
Ki represents a better estimation of the inactivated—state block, cleaned from the closed/resting state block.
The s, obtained with compounds which are representative of the entire class of compounds of the ion are reported in Table 2.
Table 2 COMPOUND Ki [HM] 2—[2,2—Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example 1— l) 2—[2,2—Difluoro—2— (3—hexyloxyphenyl)—ethylamino] —N,N—dimethyl— acetamide , hydrochloride (Example 1—6) 2— { 2,2—Difluoro—2— [3— (4,4,4—trifluorobutoxy)—phenyl] —ethylamino } — N,N—dimethyl—acetamide, hydrochloride (Example l—7) 2—[2,2—Difluoro—2— (3—benzyloxyphenyl)—ethylamino] —N,N— dimethyl—acetamide, hloride (Example 1— 14) 0.5 2—[2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino] — l—(pyrrolidin— l — yl)—ethanone, hydrochloride le 1— 15) 2— { fluoro—2— [3— (4,4,4—trifluorobutoxy)—phenyl] —ethylamino } — l—(pyrrolidin— l—yl)—ethanone (Example 1—18) 2—[2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino] — l—(piperidin— l— yl)—ethanone, hydrochloride (Example 1—29) 2—[2,2—Difluoro—2— (3—butoxyphenyl)—ethylamino] —N,N—diethyl— 0.3 acetamide, hydrochloride (Example 1—32) 2—{ [2,2—Difluoro—2— (3 —butoxyphenyl)—ethyl] —(2—methoxyethyl)— amino } —N,N—dimethyl—acetamide, hydrochloride (Example 3—3) 1 .7 2—[2—Fluoro—2—(3—butoxyphenyl)—ethylamino] imethyl— l.l acetamide, hydrochloride (Example 4— l) Data expressed as K values at MM concentration demonstrate that the compounds of the invention are potent as inhibitors of sodium ls.
Example 9: Inhibition of sodium currents in cortical neurons Cell Preparation and culturing: cortical neurons are prepared from nic Wistar rats (E17—E19). Brains of E17 / E19 rats are removed and placed in ice—cold Hank’s solution (Hank’s solution rogen, CA — USA) + e 30% + Pen—Strep 100x (Invitrogen, CA — USA) 100U—100ug/ml and Hepes—NaOH SmM).
Cortex are isolated, cut in small parts and washed twice with Hank’s solution. The solution is removed except 1—2 ml and the tissue is mechanically dissociated. After the mechanical dissociation, 5 ml of complete DMEM (Dulbecco’s modified Eagle medium) (Invitrogen, CA — USA) + FBS (Invitrogen, CA — USA) 10% + Glutamine (Invitrogen, CA — USA) 2mM + Pen—Strep 100U—100ug/ml are added, and cell suspension is centrifuged for 5 min at 1000 rpm. Supernatant is removed and 5 ml of complete Neurobasal (Invitrogen, CA — USA) medium is added + B27 supplement (code 17504044, Invitrogen, CA — USA) 2% + Glutamine 2mM + Pen—Strep 100U—100ug/ml).
Cells are counted and diluted in Neurobasal medium to a tration of 400000 cells per poly—D—lysine Sug/ml treated Petri dish.
Cortical neurons are used from day 6th till day 11th after plating, and once a week asal medium is changed.
Whole Cell Patch Clamp ings: Experiments on cortical neurons are carried out using rd whole cell patch clamp methods (Hamill O. P., Marty A., Neher E., n B., Sigworth F. J., Pflugers Arch. 391 (2): 85—100 (1981)). Membrane currents are recorded and filtered at 5 kHz with an Axon Axopatch 200B ier and data digitized with an Axon Digidata 1322A (Axon Instruments, CA, USA). Protocol playing and data acquisition are controlled online with Axon pClamp8 software. Measuring and reference electrodes are AgCl—Ag electrodes. A Sutter Instrument (Sutter Instrument, CA, USA) P—87 Puller is used for pulling patch clamp pipettes with a resistance of 2—3 MQ from Harward licate glass tubes. Cells are continuously superfused with extracellular solutions, using a solution changer Biologic 0 (Bio—Logic Sas, France).
Solutions: Sodium current recording control bath solution contains (mM): NaCl (60), cholineCl (60), CaClz (1.3), MgClz (2), KCl (2), CdClz (0.4), NiClz (0.3), TEACl (20), Hepes (10), glucose (10). Internal pipette solution consists of (mM): CsF (65), CsCl (65), NaCl (10), CaC12(1.3), MgClz (2), Hepes (10), EGTA (10), MgATP (l). 2012/060006 Voltage protocols and data analyses: cells are clamped at —90 mV, then a two step protocol is used to determine the e dependence of the block. Sodium currents are activated by a 30ms step pulse to —10mV (test pulse) from a 2000ms preconditioning potential of — 110mV (resting ion) and a potential of ~ —50mV (half maximal steady—state ion).
Drug concentration—inhibition curves are obtained by plotting tonic blocks in the resting and depolarized condition, versus drug trations. Dose—response curves are fitted to the tonic block data, ing to the logistic equation: y = A2+(A1—A2)/[1+(x/IC50)p]. A1 and A2 are fixed values of 0 and 1 corresponding to 0 and 100% current inhibition, x is the drug tration, IC50 is the drug concentration resulting in 50% current inhibition and p is the corresponding slope factor.
The compounds of the present invention inhibit sodium ts of cortical neurons with pharmacologically significant IC50 values.
Example 10: Inhibition of Cytochrome P4502D6 (CYP2D6) The inhibition of Cytochrome 6 (CYP2D6) is assessed by performing in vitro inhibition studies using Supersomes, microsomes derived from baculovirus infected insect cells; the baculoviruses are engineered to express one or more drug metabolizing enzyme cDNAs. omes catalyze the same enzymatic reactions as human liver microsome enzymes, but they contain much higher enzyme activity than other ome sources (Crespi CL. and Penman B.W., Advances Pharmacology, 43, 171—188 (1997); Crespi CL. and Miller V.P., Analytical Biochemistry, 248, 188—190 (1997)).
Kits wih Supersomes are supplied by GENTEST (MA, USA).
Serial dilution of test compound and positive control in a 96—well plate Test compound is dissolved in DMSO 500 X the highest final concentration desired in the IC50 assay. 30 ml of deionized water is pre—warmed to 37°C and all kit components are placed on ice. For each well of column 1, 149.4 uL of NADPH—Cofactor Mix, (187.5 ul of Cofactors, 150 pl of G6PDH, 100 pl of Control Protein and 14.56 ml of 37°C water) are added.
In each well from Column 2 to 12, 100 pl of Cofactor/DMSO mix (40 uL DMSO in 9.96 ml of NADPH—Cofactor Mix) are added. To each well of column 1, 0.6 ul of test compound or positive control are added. 50 ul from each well of column 1 are serially diluted to column 8. The extra 50 ul from column 8 are discarded. The plate is covered and pre—incubated at 37°C for 10 minutes.
Preparation of enzyme/substrate mix: 7.92 ml of pre—warmed zed water, 75 ul of , 3 ul of 10 mM AMMC and 2 ml of pre—warmed buffer are mixed. on initiation and termination After the pre—incubation time (10’), 100 pl of enzyme/substrate mix to each well from column 1 to 10 are added. The plate is incubated at 37°C for 30 minutes. After this time, 75 ul of Stop Reagent to each well are added. For blank controls, 100 pl of enzyme/substrate mix are added to columns ll and 12. g the results Plates are read at the Victor plate reader (Perkin Elmer, MA — USA) at 390 nm excitation and 460 nm emission wavelenghts.
The results, obtained with some compounds which are representative of the entire class of compounds of the invention are reported in Table 3, compared with the corresponding de— fluorinated reference standards of the closest prior art.
Table 3 Corresponding de-fluorinated IC50 Fluorinated derivative derlvatlve. . [uM] 2—[2,2—Difluoro—2—(3—butoxyphenyl)— 2—[2—(3—Butoxyphenyl)— 5.8 ethylamino]—N,N—dimethyl— ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example acetamide, hydrochloride l—l) 2— [2,2—Difluoro—2— (3 yphenyl)— 2—[2—(3—Butoxyphenyl)— 3.0 ethylamino] — l — (pyrrolidin— l —yl)— ethylamino] — l—(pyrrolidin— l—yl)— ethanone, hydrochloride ethanone, hloride le l—l5) 2—[2—Fluoro—2—(3—butoxyphenyl)— 2—[2—(3—Butoxyphenyl)— 5.8 ethylamino]—N,N—dimethyl— ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example acetamide, hloride 4—1) 2— [2,2—Difluoro—2— (3 —butoxyphenyl)— 2—[2—(3—Butoxyphenyl)— 2.5 ethylamino]—N,N—diethyl—acetamide, ethylamino]—N,N—diethyl— hydrochloride (Example l—32) acetamide, hydrochloride 2— [2,2—Difluoro—2— (3 —butoxyphenyl)— O \] 2—[2—(3—Butoxyphenyl)— ethylamino]—N,N—dipropyl— ethylamino]—N,N—dipropyl— acetamide, hydrochloride (Example acetamide, hydrochloride 1-3) 2— [2,2—Difluoro—2— (3 —butoxyphenyl)— . 2—[2—(3—Butoxyphenyl)— l—‘ l—‘ ethylamino] — l — (piperidin— l—yl)— mino] — l—(piperidin— l —yl)— ethanone, hydrochloride ethanone, hydrochloride (Example 1—29) 2-{ [2,2-Difluoro(3- 2-{ [2-(3-Butoxyphenyl)-ethyl]-(3- \] b.) phenyl)—ethyl] — (3— methoxypropyl)—amino } —N,N— methoxypropyl)—amino } —N,N— dimethyl—acetamide, hydrochloride yl—acetamide, hydrochloride (Example 3—2) 2—[2,2—Difluoro—2— (3—butoxyphenyl)— 2—[2—(3—Butoxyphenyl)— 00 ethylamino] —N,N—dimethyl— ethylamino] —N,N—dimethyl— propanamide, hloride propanamide, hydrochloride (Example 2— l) 2—[2,2—Difluoro—2— (3— 2—[2— tyloxyphenyl)— b.) M pentyloxyphenyl)—ethylamino]—N,N— ethylamino]—N,N—dimethyl— dimethyl—acetamide, hydrochloride acetamide, hydrochloride (Example 1—2) 2—[2,2—Difluoro—2—(3— . 2—[2—(3—Hexyloxyphenyl)— hexyloxyphenyl)—ethylamino]—N,N— ethylamino]—N,N—dimethyl— dimethyl—acetamide , hydrochloride acetamide, hloride (Example 1—6) 2-{2,2-Difluoro[3-(4,4,4- 2-{2-[3-(4,4,4-trifluorobutoxy)- U] 0 trifluorobutoxy)—phenyl] — phenyl] —ethylamino } — l — (pyrrolidin— ethylamino } — l olidin— l—yl)— l—yl)—ethanone, hydrochloride ethanone (Example 1— 18) 2-{2,2-Difluoro[3-(4,4,4- 2—{2-[3-(4,4,4_ >—* 00 trifluorobutoxy)—phenyl] — trifluorobutoxy)phenyl] — ethylamino } — l —(morpholin—4—yl)— ethylamino } — l— (morpholin—4—yl)— ethanone, hydrochloride le ethanone, hydrochloride 1-21) 2—[2,2—Difluoro—2— (3— 2—[2—(3—Benzyloxyphenyl)— benzyloxyphenyl)—ethylamino]—N,N— mino]—N,N—dimethyl— dimethyl—acetamide, hydrochloride ide, hydrochloride (Example 1— l4) 2-{ [2,2-Difluoro(3- 2-{ [2-(3-Butoxyphenyl)-ethyl]-(2- phenyl)—ethyl] — (2— methoxyethyl)—amino } —N,N— methoxyethyl)] —amino } —N,N— dimethyl—acetamide, hydrochloride dimethyl—acetamide, hydrochloride (Example 3-3) From the data presented in Table 3 it is apparent the difluoro—substituted derivatives always display inhibitory activity on CYP2D6 with IC50 values above 20pm and, in most cases, near or above 40 MM, whilst the corresponding unsubstituted analogs from the prior art are endowed with tory activities, most often in the single digit micromolar range.
Example 11: Complete Freund’s adjuvant model of c inflammatory pain Monoarthritis is induced in rats (200 g weight) by an intra—plantar injection into the left hind paw of 100 ul of complete Freund’s adjuvant (CFA) containing heat—killed and dried Mycobacterium tubercolasis in a mixture of paraffin oil and an emulsifying agent, mannite monooleate. The CFA injection produces an area of localized edema and inflammation starting from few hours after injection, with a progressive reduction in the mechanical withdrawal threshold.
Each animal is allowed to develop the arthritis over a period of 8—9 days before testing.
Mechanical nia Mechanical allodynia thresholds is determined according to the method of Chaplan et al.
(Chaplan S. R., Bach F. W., Pogrel J. W., Chung J. M., Yaksh T. L. J. Neurosci. Methods 53: 55—63 (1994)). Rats are placed in individual c boxes of 24 x 10 x15 cm on a mesh metal floor and allowed to acclimate for about 30 minutes before testing. A series of calibrated von Frey hairs ting, Wood Dale, IL, USA) with thmically incremental stiffness ranging from 2.83 to 5.88 expressed Logo of [10 x force in (mg)] are applied to the paw with a modified up—down method (Dixon W. J. Am. Stat. Assoc. 60: 967—978 (1965)). In the absence of a paw awal response to the initially selected hair, WO 00651 a thicker hair corresponding to a er stimulus is presented until a sharp withdrawal is recorded. The procedure is repeated twice. Each hair is presented perpendicularly against the paw, with sufficient force to cause slight bending, and held 2—3 s. The stimulation of the same intensity is applied five/six times to the hind paw at intervals of few seconds. The mechanical threshold is expressed as Logo of [10 x force in (mg)] indicating the force of the von Frey hair to which the animal react (paw withdrawn, licking or shaking).
The mechanical allodynia thresholds are measured before (pre—drug) and at 30, 60, 90,120, 240 and 360 minutes after the ent. A 24 h threshold is also measured.
The compounds of the invention are administered in a range of doses of 0,1 — 100 mg/kg. e 12: Bennett model of neuropathic pain in rats Effects on athic pain are tested in the chronic constriction injury model in the rat (Bennett,G.J. and K., “A peripheral mononeuropathy in rat that es disorders of pain sensation like those seen in man”. Pain, 33, 87—107 (1988)). Under pentobarbital anesthesia (Nembutal, 50mg/kg, i.p.), unilateral multiple ons are performed on male Sprague—Dawley rats (l40—l60g) at the right common sciatic nerve. The sciatic nerve is exposed by blunt dissection at the level of mid—thigh and four loose res (5—0 chromic catgut) are placed around the nerve taking care not to interrupt the epineural circulation.
After operation, animals are allowed to recover for one week. Animals develop a cold allodynia which is stable for at least five weeks. Cold allodynia is tested on a metal plate cooled by a water bath to a constant ature of 4°C. The animals, randomly assigned to groups of 10 for each test dose and vehicle, are observed for periods of 2 minutes before and after application of test compound and the number of brisk awal reactions is counted. Several time points after application are tested. Percent maximal possible effect (%MPE) and standard error of the mean (SEM) of each time point is determined with the pre—test value used as 100%MPE. The area under the data (AUD) is calculated for the observation period and expressed as t inhibition of vehicle control. Significance is calculated by paired t—test on the percent AUD values.
Example 13: Maximal electroshock test (MES) in mice The maximal electroshock test (MES) is used commonly in the screening of anti—epileptic drugs in rodent models.
Animals and Apparatus: Male CDl mice weighing 25 g are used. The procedure described by White et al. (White H. S., ad J. H., in M. R., Swinyard E. A., and Wolf H. H. Antiepileptic Drugs 4th ed: 99—110 (1995), Raven Press, Ltd., New York) is followed. An Ugo Basile electroconvulsive generator Model ECT UNIT 7801 (Ugo Basile, Italy) is used to deliver an electrical stimulus sufficient to produce a hindlimb tonic extensor response in at least 97% of l animals. The stimulus is delivered intra—aurally through clip electrodes in mice (0.7 s of a 40 mA shock, with a pulse train of 80 Hz having a pulse duration of 0.4 ms). The acute effect of compounds administered intraperitoneally or orally 15—60 minutes before MES ion are examined and compared with a vehicle control group. Ten mice are studied per group. Complete suppression of the hindlimb tonic extensor component of seizures is taken as evidence of anticonvulsant activity.
The compounds of the invention are administered enously (iv), orally (os) or intraperitoneally (ip) at the doses of 0.1 — 100 mg/kg.
The results, obtained with a compound representative of the entire chemical class of the invention, administered iv and/or po, 15 minutes before testing, and reported in Table 4, demonstrate that these compounds are active as anticonvulsant drugs.
Table 4 COMPOUND 50 % Protection —Difluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethyl— acetamide, hydrochloride (Example 1—1) (9.8 mg/kg, po) 2—[2—Fluoro—2—(3—butoxyphenyl)—ethylamino]—N,N—dimethyl— (4.0 mg/kg, iv) ide, hydrochloride (Example 4— 1) Example 14: Amphetamine and chlordiazepoxide—induced hyperlocomotion in mice In this model, mice are treated with a mixture of d—amphetamine plus an anxiolytic dose of the benzodiazepine, chlordiazepoxide (Rushton R., Steinberg H. “Combined effects of chlordiazepoxide and d—amphetamine on activity of rats in an unfamiliar environment”.
Nature 12—3 (1966); Arban R., Maraia G., nborough K., Winyard L., Wilson A., Gerrard P., Large C. “Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania”. oural Brain Research, 158: 123—132 (2005)). The model has been claimed to mimic some aspects of mania in r disorder.
Importantly, the ctivity induced by the mixture of d—amphetamine and chlordiazepoxide could be prevented by prior administration of the established mood stabilizer, lithium, as well as other mood stabilizers drugs (e. g. magnesium valproate and carbamazepine). Therefore, this model has face and predictive validity as a model of bipolar disorder and ents a valuable tool to determine, if a test nd could be a potential mood stabilizer drug candidate.
Amphetamine (AMP) (2.5 mg/kg) plus chlordiazepoxide hloride (CDZ) (3 mg/kg/ip) are stered to male Albino Swiss mice (25—32 g) in a volume of 10 ml/kg.
The locomotor activity is recorded using Opto—M3 System (Columbus Instruments, OH — USA) which is multi—channel activity monitor. Opto—M3 system has 10 infrared emitters and respective amount of receivers (0.5” beam spacing), attached to the PC computer and calculating both ambulatory activity and total counts. Thus the system differentiates forward locomotion (ambulation) from stereotyped like nt (total counts). Mice are pretreated with the test compound (5 mg/kg) and 10 min later, with AMP (2.5 mg/kg) or AMP jointly with CD2 (3 mg/kg). After successive 30 min. the mice are treated again with the same dose of the test compound and are placed individually in the motor activity cages.
The locomotor activity (ambulation and total activity count) is evaluated for 30 min. Each group ts of 8—10 mice.
Statistical analysis: the data are evaluated by an analysis of variance ), followed, when appropriate, by individual comparison with the control using Dunnett’s test.
Amphetamine—chlordiazepoxide administration induces a significant se in locomotor activity.
Example 15: Model of Cognitive impairment in schizophrenia Cognitive impairment is often associated with schizophrenia and it has come to be recognized as a core element of the er, bearing on patient’s recovery and re— integration into society.
Particular st has recently attracted a pharmacological model of cognitive dysfunctions in schizophrenia, which is based on the effects of glutamate NMDA receptor antagonists such as phencyclidine (PCP) and ketamine (Javitt DC, Zukin SR. Am. J. Psychiatry. 148:1301—1308. (1991)) which impair attention and increase sivity” and “compulsive” perseveration in mice performing a complex task (Greco B, Invernizzi RW, Carli M. Psychopharmacology (Berl) l79(l):68—76 ).
Materials and s Animals: Male DBA/2N mice (Charles River, Italy) are used. The mice weigh 25—30 g at the start of the experiments, and are housed under temperature—controlled conditions (21°C) with a 12 hours light 12 hours dark cycle (light on 7:00 am—7:00 pm). Food (Rieper, Italy) is available ad libitum. The animals have two hours of access to water at the end of each day's testing.
The five-choice serial reaction time task apparatus: The test apparatus consists of four 21.6 x 17.8 x 12.7 cm chambers (Med Associates Inc. GA — USA), as previously described (Greco B, Invemizzi RW, Carli M. Psychopharmacology (Berl) 179(1):68—76 (2005)).
Stimuli and recording of responses, are managed by a SmartCtrlTM Package 8 In/ 16 Out (Med Associates Inc. GA — USA) with additional interfacing by MED—PC for Windows (Med Associates Inc. GA — USA). The running program for the 5—Choice Serial Reaction Time (5—CSRT) task is custom—written.
Behavioural procedures: habituation to liquid reinforcer and nose-poking in the holes.
Mice are d for one week and their body weight recorded. They are then water— ed by allowing them 2—hours access to water in the early evening until their body weight has stabilised (8 days). Then, over the next two days the mice are habituated in their home cages to the reinforcer (10% e solution) used afterwards in the operant procedures. On the following two days mice are habituated to the operant boxes. During this stage, 10% sucrose solution is available in a small bowl placed below the receptacle hole of the box. First, mice have to learn that every 5 seconds the liquid reward is available in a small cup in the receptacle hole. During this period head entries are recorded.
During the next period, mice are d to poke their noses into the illuminated holes.
Immediately after a poke in the water receptacle a LED at the rear of one of the holes is turned on. A oke in the lighted hole extinguishes the light stimulus and the liquid dipper provides a 0.01 mL liquid reward in the receptacle hole. Any se in one of the other four holes have no consequence and is not recorded. The light us is ted in all five holes in random order. A mouse is switched to the 5—CSRT task after it has completed at least 50 rewarded nose—poke trials in one 30—min session.
The five-choice serial reaction time task. The start of the session is signalled by illumination of the house—light and the delivery of a 0.01 mL liquid reward. Nose poking in the receptacle hole begins the first trial. After a fixed delay (the trial interval, ITI), the LED at the rear of one of the holes comes on for a short period. The LED stimulus is presented the same number of times in each hole during a complete session, with the order of tation randomised by the computer. While the light is on, and for a short period afterwards (the limited hold), responses in the hole that is illuminated (correct response) result in the liquid reward. Responses in the holes that have not been illuminated (incorrect responses) or e to respond within the limited hold (omissions) cause the house—lights to be turned off for a short period (time out). Responses in the holes while the house—light is off restart the time out. After the delivery of the liquid reward, or at the end of time out, the mouse starts the next trial by poking its nose into the receptacle hole.
Responses made in the holes after a correct response (perseverative responses), or after the end of time out before nose—poking into the receptacle hole, result in a period of time out. ses in the holes during the ITI (anticipatory responses) also result in a period of time out. After anticipatory responses a nose—poke into the receptacle hole restart the current trial. Each daily session consists of 100 trials or 30 min of g, whichever is completed sooner, after which all lights are turned off and further responses have no effect.
In the first session of the test schedule, the stimulus and limited hold each last 1 minute and, depending on individual performance, they are progressively reduced to 1 . The stimulus duration is d in the following sequence: 60, 30, 10, 5, 2.5, 2, 1.5 and 1 second (baseline). The lTl and time out both lasts 2 seconds during the first session and the ITI is raised to 5 seconds in uent sessions; time out is not changed. Throughout the whole period of training and experiments each mouse has one session per day on a 5— CSRT task.
Drugs and treatment les. The test compound is dissolved in water and is administered intraperitoneally (IP) at the dose of 10 mg/kg. Five minutes after the treatment mice are injected with vehicle (saline) or PCP (1.5 mg/kg) and 10 minutes later they start the test session. In each experiment the various combination of the test nd with vehicle or PCP are administered according to a Latin—square . At least 48 hours are left n the drug testing days. During these intervening days the mice are tested on the 5—CSRT task to re—establish baseline performance and to check for any residual effects of drugs. tical is: The main dependent variables selected for analysis are: (a) the percentage of correct responses (total correct responses/total correct + total incorrect responses X 100); (b) percentage of omissions (total omissions/ total correct responses + total incorrect responses + total ons X 100); (c) the number of anticipatory responses in the holes during the ITI; (d) the number of perseverative responses in the holes after a correct response. Correct responses and omissions, as percentages, are transformed according to the formula 2 arcsin (SQRT (%X/ 100)), to normalize the distributions in accordance with the ANOVA model.
The effects of the test compound (n=12) on PCP induced deficits in the 5—CSRT task are analysed independently by a within subjects 2 X 2 ANOVA with factors Drug (test compound) and PCP. Subsequently the treatment group means are compared using a post- hoc Tukey—Kramer test. Statistical software (SAS Institute Inc., NC — USA) is run on Micro VAX 3500 computer (Digital, MA — USA).
Example 16: e—induced behavioural sensitization test Drug addiction is a pathological behaviour characterized by sive drug seeking and intake. One animal model of these behavioral changes is the long—lasting increase in locomotor activity induced by repeated administration of psychostimulant drugs in rodents (Robinson T. E. and Berridge K.C. Brain Res. Brain Res. Rev. 18, 247—91 (1993)) known as drug—induced behavioural sensitization. The effect of test compounds are evaluated in a model of cocaine—induced behavioral sensitization in rat.
Locomotor activity apparatus: Male Wistar rats weighing 200—250 g upon arrival are used.
Locomotor activity is measured in sixteen identical metal wire hanging cages each measuring 36 cm (L) X 25 cm (W) X 20 cm (H). Each cage contains two sets of infrared emitter—detector ells positioned along the long aXis 1 cm above the grid floor and 8 cm from the front and back of the cage. Background noise is provided by a white noise generator. Movement within the cages produces photocell interruptions, which are automatically ed by an IBM—compatible computer.
Sensitization ure and treatment: Animals are habituated to the locomotor activity chambers for 2—3 utive days before the eXperiment. Rats e 5 daily i.p. injections of cocaine (15 mg/kg) or saline and either the test compound (0.1—100 mg/kg) or its vehicle and locomotor activity is recorded for 3 h. Ten days after the last ion of cocaine or saline (day 15), the animals are challenged with 15 mg/kg of cocaine in absence of the test compound and locomotor activity is again monitored for 3 hours.
By the fifth day of ent with e, animals ated i.p. with vehicle show an increased locomotor response (20% higher then the first day, p < 0.05). Ten days after the last injection of e or saline, the animals are challenged with 15 mg/kg of cocaine in absence of the test compound and locomotor activity is again monitored for 3 h. The rats previously d with cocaine and that have not received the test nd are ed to show an increased locomotor activity response to cocaine (30% higher then first day, p <0.05). If the rats that have been pretreated with the test compound during the 5 day— cocaine treatment do not show an increase in locomotor activity the test compound is considered to have an effect in preventing psychostimulant drugs addiction. (Koob G. F., Sanna P. P., Bloom F. E. Neuron 21: 467—476 (1998); Robinson T. E., Berridge K. C.
Brain Res. Brain Res. Rev. 18: 247—291 (1993)) tical is: Data (total number of beam breaks in 3 hours) are analyzed using a two way ANOVA with repeated measures on one factor including the four experimental groups (i.e., saline/vehicle, saline/test compound, cocaine/vehicle and cocaine/test compound) and two time points (day 1 and day 5) followed by a simple effects analysis. A second two way ANOVA with repeated measures on one factor is used to compare day 1 and the challenge day followed by a Newman—Keuls post hoc test.
Example 17: Acute bladder irritation by acetic acid in rats ments are performed using adult etized female Sprague Dawley rats (170—200 g). A catheter (PE—50) is inserted via a midline abdominal incision into the bladder through the bladder dome, and then intravescical pressure is measured to monitor bladder activity during continuous on of 0.15% of acetic acid. Continuous intravesical infusion of acetic acid irritates the bladder and s the ontraction intervals (ICI) in anesthetized rats. ICIs, maximal contraction pressure, and pressure thresholds inducing reflex bladder contraction are measured before and after intravesical infusion of acetic acid in rats treated with nds of the invention.
Example 18: Intermediate bladder irritation by cyclophosphamide (CYP) in rats Experiments are performed using both adult awake and anesthetized female Sprague Dawley rats (170—200 g). Chemical cystitis is induced by CYP, which is lized to acrolein, an irritant ated in the urine. CYP (150 mg/kg/i.p.) is stered one day before the experiment. Pre—treatment with CYP causes bladder irritation and very frequent voidings with an ICI of about 150—200 seconds between voids.
Active nds increase the ICI in both awake and anesthetized rats used in this experimental model.
Example 19: Migraine test in rats Animals and surgery: Male Wistar rats (250—350 g) are anesthetized with sodium pentobarbital (50 mg/kg i.p.) dissolved in .
The trachea and left femoral artery are cannulated for artificial ventilation (55 strokes/minute) and for measurement of mean blood pressure (MBP) respectively. The femoral vein is cannulated for the intravenous administration of test agents.
Body temperature is maintained at 37—38 °C by automatic control of a heating pad.
Animals are placed in a stereotaxic frame and a longitudinal incision is made in the scalp.
A burr hole is drilled in the skull and a stainless steel bipolar electrode Plastics One MS 306 (Plastics One Inc. VA — USA) is lowered into left ophthalmic branch of the trigeminal ganglion (3.8 mm dorsal to bregma, 2.5 mm lateral from the midline and 9.5 mm below the dural surface) and secured with dental cement. Correct ent of the ode is confirmed by a brief electrical stimulation, which cause movement of the jaw due to activation of the trigeminal fiber. Following removal of the brain, the correct position of the electrode into the fiber, is visually checked at the end of each ment.
A second hole is drilled ipsilateral of the electrode (1.5 mm rostral to bregma, and 1.5 mm lateral from the sagittal suture) and a needle probe (tip diameter 0.8 mm) of a laser doppler flowmeter is fixed pointing with its tip onto a branch of the middle cerebral artery (MCA) and Cerebral Blood Flow (CBF) change recorded on—line by the ux 4001 Laser Doppler system (Perimed, Italy).
Artefacts of the laser Doppler reading during electrical stimulation of the trigeminal ganglion due to muscular movements are prevented by a bolus of iv injection of the uscular blocker pancuronium bromide (0.6 mg/kg iv). esia and neuromuscular blockade are maintained all over the experiment with an on of sodium pentobarbital and onium (12.5 mg/kg/h + 2.4 mg/kg/h, respectively).
Experimental protocol: At the end of the surgery, a pause of thirty minutes is taken in order to stabilize the measured ters.
Rest CBF is increased by electrical stimulation with rectangular pulse of 0.5 ms length, 1— 10 Hz, 0.5—1 mA for periods of 30s. After two averaged pre—drug stimulations, vehicle or drugs are administered.
Active compounds reduce the increase in blood flow induced by inal stimulation.

Claims (35)

1. A compound of l formula I R5 R6 R1 O W N R3 N I R2 R2' R4 5 (J)n wherein: W is a group A-[(CH2)m-O] - n: m is zero, 1, 2, or 3; A is (C 1-C4)alkyl optionally substituted with one to three fluorine atoms; )cycloalkyl; phenyl optionally susbstituted with a group selected from halo, methyl, methoxy, trifluoromethyl, 10 acetylamino, and dimethylaminomethyl; thienyl optionally substituted with a chloro group; furanyl; isoxazolyl, thiazolyl; piperidinyl; morpholinyl; pyridinyl or pyrimidinyl, the pyridinyl and pyrimidinyl ring being optionally substituted with one or two methoxy groups; J independently is hydrogen, (C1-C4)alkyl; (C1-C4)alkoxy; or an halo group; 15 n is 1 or 2; R1 is hydrogen; (C1-C4)alkyl optionally substituted with a hydroxy group or a (C1- oxy group; or (C3-C8)cycloalkyl; R2 and R2’ are ndently hydrogen; (C1-C4)alkyl optionally substituted with a (C1- C4)alkoxy group; phenyl optionally substituted with a (C1-C4)alkyl, a (C1- 20 C4)alkoxy or an halo group; benzyl optionally substituted with a (C1-C4)alkyl, a (C1-C4)alkoxy or an halo group on the e ring; or R2 and R2’ taken together with the adjacent carbon atom form a (C3-C6)cycloalkylidene group. R3 is hydrogen; or (C1-C4)alkyl; R4 is hydrogen; (C1-C4)alkyl; phenyl; cyclohexyl; or benzyl; or 25 R3 and R4, taken together with the adjacent nitrogen atom, form an inyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl ring, the piperidinyl ring being optionally substituted with one or two (C1-C2)alkyl s), and the piperazinyl ring being optionally substituted on the other N-atom with a (C1-C4)alkyl, benzyl, or sulfonyl group; or a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl 30 ring fused with a benzene ring; R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single optical isomer in the isolated form or as a mixture f in any proportion and its pharmaceutically acceptable salt.
2. A nd of claim 1, n: W is a group A-[(CH2)m-O]- wherein: m is zero, 1, 2 or 3; A is )alkyl optionally substituted by one to three fluorine atoms; (C3-C6)cycloalkyl; phenyl optionally substituted with a halo group; or thiazolyl J independently is en; C1-C4 alkyl; chloro; or fluoro; 10 n is l or 2; RI is hydrogen; (C1-C4)alkyl optionally substituted with a hydroxy group or a (C1- C4)alkoxy group; or (C3-C6)cycloalkyl; R2 is hydrogen; or (Cl-C4)alkyl; R2, is en; (Cl-C4)alkyl optionally substituted with a (Cl-C4)alkoxy; or a 15 phenyl group, the phenyl group being optionally substituted with a (C1-C4)alkoxy group; R3 is hydrogen; or (C1-C4)alkyl; R4 is hydrogen; (C1-C4)alkyl; phenyl; or exyl; or R3 and R4, taken together with the adjacent nitrogen atom, form an azetidinyl, pyrrolidinyl, 20 morpholinyl, piperidinyl or piperazinyl, the piperydinyl ring being optionally substituted with one or two (C1-C2)alkyl group(s) and the piperazinyl ring being optionally substituted on the other N-atom with a (C1-C4)alkyl, benzyl, or phenylsulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl or piperazinyl ring fused with a benzene ring; 25 R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single optical isomer in the isolated form or as a mixture thereof in any proportion and its pharrnaceutically acceptable salt.
3. A nd of any one of claims 1 and 2. wherein: 30 W is a group A—[(CH2)m-O]— wherein: m is l or 2; A is (C1-C4)alkyl optionally substituted by one to three fluorine atoms; phenyl optionally substituted with a chloro or fluoro group; or thiazolyl; J independently is hydrogen; methyl; or fluoro; nis 1-2 R1 is hydrogen; (C1—C4)alkyl optionally substituted with a hydroxy group or a (C1- C4)alkoxy group; R2 is hydrogen; or ; R2, is hydrogen; )alkyl optionally substituted with a y; or a phenyl group, the phenyl group being optionally substituted with a methoxy group; R3 is hydrogen; or (C1-C4)alkyl; R4 is hydrogen; (Cl-C4)alkyl; phenyl; or cyclohexyl; or R3 and R4, taken together with the adjacent nitrogen atom, form an azetidinyl, 10 pyrrolidinyl, morpholinyl, piperidinyl, or zinyl ring, the piperidinyl ring being optionally substituted with one or two methyl group(s) and the piperazinyl ring being optionally substituted on the other N-atom with a methyl, benzyl or phenylsulfonyl group; or a pirrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring fused with a benzene ring; 15 R5 is hydrogen or fluoro; and R6 is fluoro; if the case, either as single l isomer in the isolated form or as a mixture thereof in any proportion and its pharmaceutically acceptable salt.
4. A compound of any one of claims 1 to 3, selected from: 20 2-[2,2—Difluoro—2—(3—butoxyphenyl)-ethylamin0]-N,N-dimethyl-aoetamide; 2-[2,2—Difluoro(3-pentyloxyphenyl)—ethylamino]-N,N—dimethyl-acetamide 2-[2,2—Difluoro—2—(3-butoxyphenyl)-ethylamin0]—N,N-dipropyl-acetamide 2-[2,2—Difluoro(3-butoxy-4—methylphenyl)—ethylamino]-N,N-dimethyl-acetamide; 2-[2,2—Difluoro—2—(3-butoxyphenyl)-ethylamin0]—N,N-dibutyl-acetamide; 25 2-[2,2—Difluoro(3-hexyloxyphenyl)-ethylamino]-N,N-dimethyl-acetamide; 2-{ 2,2—Difluoro—2—[3-(4,4,4—trifluorobutoxy)—phenyl]-ethylamino }-N,N—dimethyl- acetamide; 2-[2,2—Difluoro—2—(3—pentyloxyphenyl)—ethylamino]-N,N—dipropyl-acetamide; 2-{ 2,2-Difluoro—2-[3-(3-(3-fluorophenyl)-propoxy)-phenyl]-ethylamino }-N,N—dimethyl- 30 acetamide; 2-{ 2,2-Difluoro—2-[3-(3-(3-chlorophenyl)-propoxy)-phenyl]-ethylamino }-N,N-dimethyl- acetamide; —Difluoro(3-butoxy-Z-fluorophenyl)-ethylamino]-N,N-dimethyl-acetamide; 2-{ fluoro—2—[3-(3-phenylpropoxy)—phenyl]—ethylamino }-N,N—dimethyl-acetamide; 2-{2,2-Difluoro[3-(3-thiazolyl-propoxy)-phenyl]-ethylamino}-N,N-dimethylacetamide 2-[2,2-Difluoro(3-benzyloxyphenyl)-ethylamino]-N,N-dimethyl-acetamide; 5 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](pyrrolidinyl)-ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]-N-methyl-N-phenyl-acetamide; 2-{2,2-Difluoro[3-(3-phenylpropoxy)-phenyl]-ethylamino}(pyrrolidinyl)- ethanone; 2-{2,2-Difluoro[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}(pyrrolidinyl)- 10 ethanone; 2-[2,2-Difluoro(3-benzyloxyphenyl)-ethylamino](morpholinyl)-ethanone; 2-{2,2-Difluoro[3-(3-phenylpropoxy)-phenyl]-ethylamino}(morpholinyl)- ethanone; 2-{2,2-Difluoro[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}(morpholinyl)- 15 ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](2H-benzo[b][1,4]oxazin-4(3H)-yl)- ethanone; 2-[2,2-Difluoro(3-benzyloxyphenyl)-ethylamino](pyrrolidinyl)-ethanone; 2-{2,2-Difluoro[3-(3-phenylpropoxy)-phenyl]-ethylamino}-N-methyl-N-phenyl- 20 acetamide; 2-{2,2-Difluoro[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}-N-methyl-N-phenylacetamide -Difluoro(3-butoxyphenyl)-ethylamino](4-methylpiperazinyl)-ethanone; 2-{2,2-Difluoro[3-(3-phenylpropoxy)-phenyl]-ethylamino}(4-methylpiperazinyl)- 25 ethanone; 2-{2,2-Difluoro[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}(4-methylpiperazin hanone; -Difluoro(3-butoxyphenyl)-ethylamino](piperidinyl)-ethanone; 2-{2,2-Difluoro[3-(3-phenylpropoxy)-phenyl]-ethylamino}(piperidinyl)-ethanone; 30 2-{2,2-Difluoro[3-(4,4,4-trifluorobutoxy)-phenyl]-ethylamino}(piperidinyl)- ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]-N,N-diethyl-acetamide; 2-{2,2-Difluoro[3-(2-fluorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](cis-3,5-dimethylpiperidinyl)- ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](3,4-dihydroisoquinolin-2(1H)-yl)- ethanone; 5 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]-N,N-diisopropyl-acetamide; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]-N-cyclohexyl-N-methyl-acetamide; 2-[2,2-Difluoro(3-benzyloxyphenyl)-ethylamino](piperidinyl)-ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino][4-(phenylsulfonyl)-piperazinyl]- ethanone; 10 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](indolinyl)-ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](4-benzylpiperazinyl)-ethanone; -Difluoro(3-butoxyphenyl)-ethylamino](azetidinyl)-ethanone; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-propanamide; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]methoxy-N,N-dimethyl-propanamide; 15 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino](4-methoxyphenyl)-N,N-dimethylpropanamide 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]N,N-trimethyl-propanamide; 2-[2,2-Difluoro(3-butoxyphenyl)-ethylamino]N,N-trimethyl-pentanamide; 2-{[2,2-Difluoro(3-butoxyphenyl)-ethyl]-methylamino}-N,N-dimethyl-acetamide; 20 2-{[2,2-Difluoro(3-butoxyphenyl)-ethyl]-(3-methoxypropyl)-amino}-N,N-dimethylacetamide 2-{[2,2-Difluoro(3-butoxyphenyl)-ethyl]-(2-methoxyethyl)-amino}-N,N-dimethylacetamide 2-[2-Fluoro(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide; 25 2-{2-Fluoro[3-(3-chlorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide; 2-{2-Fluoro[3-(3-fluorobenzyloxy)-phenyl]-ethylamino}-N,N-dimethyl-acetamide; if the case, either as single optical isomer in the isolated form or a mixture thereof in any proportion, and its ceutically acceptable salt.
5. A compound of claim 4 which is selected from 2-[2,2-difluoro(3-butoxyphenyl)- 30 mino]-N,N-dimethyl-acetamide, luoro(3-butoxyphenyl)-etylamino]-N,N- dimethyl-acetamide, its single optical isomer in the isolated form or a mixture thereof in any proportion, and the pharmaceutically acceptable salts thereof.
6. A compound of claim 5 which is 2-[2,2-difluoro(3-butoxyphenyl)-ethylamino]-N,N- dimethyl-acetamide or a pharmaceutically acceptable salt thereof.
7. A compound as in any one of claims 1 to 6 wherein the ceutically able salt is the hydrochloride.
8. A compound of any one of claims 1 to 7 for use as a medicament. 5
9. A compound of any one of claims of 1 to 8 for use as a medicament active as sodium and/or calcium channel modulator against disorders caused by dysfunctions of e gated sodium and/or calcium channels.
10. A compound of claim 9 wherein the disorder caused by dysfunctions of voltage gated sodium and/or calcium channels is selected from neuropathic pain, chronic pain, acute 10 pain, headaches, neurological conditions, neurogenerative disorders, cognitive disorders, psychiatric disorders, vertigo, tinnitus, muscle spasm, cardiovascular diseases, endocrine disorders involving excessive or hypersecretory or otherwise inappropriate cellular secretion of an endogenous substance, liver diseases, inflammatory processes affecting all body systems, disorders of the gastrointestinal (GI) tract, disorders of the genito-urinary 15 tract, ophthalmic diseases and eating ers.
11. A compound of any one of claims 1 to 10 for use as a medicament for the treatment of neuropathic pain, chronic pain and/or acute pain.
12. A nd of any one of claims 1 to 10 for use as a medicament for the treatment of hes. 20
13. A compound of any one of claims 1 to 10 for use as a medicament for the ent of neurological conditions.
14. A nd of claim 13, wherein the neurological condition is epilepsy.
15. A compound of any one of claims 1 to 10 for use as a medicament for the treatment of cognitive and/or psychiatric disorders. 25
16. A compound as in any one claims 1 to 10 for use as a medicament for the treatment of inflammatory processes affecting all body systems, the ers of gastrointestinal tract, the disorders of genito-urinary tract, the ophthalmic diseases, the liver diseases, the cardiovascular and/or egenerative disorders caused by dysfunctions of voltage gated sodium and/or calcium channels. 30
17. A compound of any one of claims 1 to 7 for use as a medicament for the treatment of a disorder caused by dysfunction of e gated sodium and/or calcium channels as in any one of claims 9 to 16 in patients that are poor metabolizers, i.e., have little or no CYP2D6 function, or are assuming drugs that are CYP2D6 inhibitors.
18. A compound of any one of claim 1 to 17 for use as a medicament in conjunction with one or more other therapeutic agents.
19. A pharmaceutical composition containing a compound of the any one of claims 1 to 7 as active ingredient er with a pharmaceutically acceptable excipient.
20. A pharmaceutical ition of claim 19 containing a further therapeutical agent.
21. Use of a compound of any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a disorder caused by dysfunctions of e gated sodium and/or calcium channels in a patient.
22. A use as in claim 21, n the disorder caused by dysfunctions of voltage gated sodium and/or calcium channels is selected from neuropathic pain, chronic pain, acute pain, headaches, neurological conditions, neurogenerative disorders, cognitive disorders, psychiatric disorders, vertigo, us, muscle spasm, cardiovascular diseases, endocrine disorders involving excessive or ecretory or otherwise inappropriate cellular secretion of an endogenous substance, liver diseases, inflammatory processes affecting all body systems, disorders of the gastrointestinal (GI) tract, disorders of the genito-urinary tract, ophthalmic diseases and eating disorders.
23. A use as in any one of claims 21 and 22, wherein the disorder is a neuropathic pain, chronic pain and/or acute pain.
24. A use as in any one of claims 21 and 22, wherein the disorder is headache.
25. A use as in any one of claims 21 and 22, n the er is a cognitive and/or psychiatric er.
26. A use as in any one of claims 21 and 22, wherein the disorder is a neurological condition.
27. A use as in claim 26, wherein the neurological condition is epilepsy.
28. A use as in any one of claims 21 and 22, wherein the er is an inflammatory process affecting all body systems, a disorder of the gastrointestinal tract, a er of the genito-urinary tract, an ophthalmic disease, a liver disease, a cardiovascular, and/or neurodegenerative disorder caused by dysfunctions of voltage gated sodium and/or calcium channels.
29. A use as in any one of claims 21 to 28 wherein the patient is a poor metabolizer having very little or no CYP2D6 function, or is assuming drug(s) that is(are) CYP2D6 inhibitor(s).
30. A compound of claim 7 which is the hydrochloride salt of 2-[2,2-difluoro(3- butoxyphenyl)ethylamino]-N,N-dimethyl-acetamide.
31. A pharmaceutical ition of any of claims 19 and 20, wherein the compound is the hydrochloride salt of 2-[2,2-difluoro(3-butoxyphenyl)ethylamino]-N,N-dimethyl-acetamide.
32. A use as in any one of claims 21 and 22, n the compound is the hydrochloride salt of 2-[2,2-difluoro(3-butoxyphenyl)ethylamino]-N,N-dimethylacetamide.
33. A compound according to claim 1 substantially as herein bed or exemplified.
34. A pharmaceutical composition according to claim 19 substantially as herein described or ified.
35. A use according to claim 21 substantially as herein described or exemplified.
NZ619577A 2011-06-27 2012-05-29 Fluorinated arylalkylaminocarboxamide derivatives NZ619577B2 (en)

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