KR20070044803A - Diarylamine derivatives as calcium channel blockers - Google Patents

Abstract

N-diarylaminoalkyl-substituted piperazine / 4-aminopiperidine compounds of formula (1) are disclosed. Wherein each A and B is independently a six-membered aromatic or nonaromatic, carbocyclic or heterocyclic moiety or aminoalkyl, or only one of A and B will be H or alkyl (1-8C) Or A and B form an optionally substituted 6-membered aromatic or non-aromatic, carbocyclic or heterocyclic moiety; R ¹ is H or alkyl (1-8C); Z is N or CHNR ² , wherein R ² is H or alkyl (1-8C); X is straight-chain alkylene (1-4C), wherein any at least one carbon adjacent to nitrogen is in the form of C═O; Each R ³ is an independent substituent; n = 0-2 and Ar is a 6-membered aromatic or heteroaromatic ring; The cyclic moieties included in each A or B and each Ar moiety in formula (1) may be substituted with one or more substituents. This compound and its salts or conjugates can block N-type and T-type calcium channels and are useful for treating diseases mediated by calcium ion channel activity such as chronic pain.

Diarylamine Derivatives, Blocking Calcium Channels.

Description

Diarylamine derivatives as calcium channel blockers {DIARYLAMINE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS}

Related Applications

This application is an application claiming priority over US Patent Application No. 10 / 821,584, filed April 9, 2004, and which claims priority to US Patent Application No. 10 / 928,564, filed August 27, 2004, The contents of the foregoing patent applications are all incorporated by reference in the present invention.

Technical field

The present invention relates to compounds useful for treating diseases associated with calcium channel function. More specifically, the present invention relates to compounds containing substituted or unsubstituted diarylamine derivatives of six-membered heterocyclic moieties useful for treating diseases such as stroke and pain.

Calcium influx into cells through voltage-gated calcium channels mediates a variety of cellular and physiological responses, including excitatory contraction, hormone secretion and gene expression (Miller, 1987; Augustine et al., 1987). In neurons, calcium channels directly affect the membrane potential and contribute to electrical properties such as excitability, repeat ignition patterns, and pacemaker activity. Furthermore, calcium influx affects the function of neurons by directly regulating calcium-dependent ion channels and by regulating the activity of calcium-dependent enzymes such as protein kinase C and calmodulin-dependent protein kinase II. Increasing the calcium concentration at the presynaptic nerve ends triggers the release of neurotransmitters and calcium channels, which also affects neurogenesis and growth cone migration in growing neurons.

Calcium channels mediate various normal physiological functions and are also associated with several disorders in humans. Non-limiting examples of calcium-mediated human disorders include congenital migraine, cerebellar ataxia, angina pectoris, epilepsy, high blood pressure, ischemia and some arrhythmias. The clinical treatment of some of these disorders has been aided by the development of therapeutic calcium channel antagonists (eg, dihydropyridine, phenylalkylamine and benzothiazepine all target L-type calcium channels) (Janis & Triggle, 1991). ).

Congenital calcium channels are classified into T-, L-, N-, P / Q and R-types according to their electrophysiological and pharmacological properties (see Catterall, 2000; Huguenard 1996). T-type (or low voltage activated) channels describe a wide range of molecules that are temporarily activated at negative potentials and are very sensitive to changes in rest potentials.

L, N and P / Q-type channels are more positively active (high voltage active) and exhibit various kinetics and voltage-dependent characteristics (Catterall, 2000; Huguenard 1996). L-type channels can be distinguished by their sensitivity to several small organic molecules, including dihydropyridine (DHPs), phenylalkylamines and benzothiazepines, which are used for therapeutic purposes. In contrast, N-type and P / Q-type channels are high affinity targets for certain peptide toxins produced by venous spiders and sea snails: N-type channels are Conus geographus ( Conus). ω-conopeptide isolated from geographus ) and ω-conotoxin MVIIA isolated from Conus magus (ω-CTx-MVIIA) and ω-conopexin GVIA (ω-CTx-GVIA) and Conus magus Blocked by P / Q-type channels, while resistant to ω-CTx-MVIIA, while sensitive to ω-agatoxin IVA (ω-Aga-IVA), a triangular pyramidal net spider peptide Do. R-type calcium channels are sensitive and are blocked by tarantula toxin SNX-482.

High voltage-activated calcium channels of neurons bind tightly to large (> 200 kDa) pore-forming subunits, α ₁ subunits, which are the targets of the identified pharmacological agents to regulate channel biophysical properties and are located in the cytoplasm. And -70 kDa β subunit and ˜170 kDa α ₂ δ subunit (Stea et al., 1994; see Catterall, 2000). At the molecular level, nine α ₁ subunit genes have been identified that are expressed in the nervous system, which have been shown to encode all major classes of innate calcium currents (Table 1).

Classification of Neuronal Calcium Channels Congenital class cDNA Gene name ω-Aga-IVA ω-CTx-GVIA ω-CTx-MVIIA Dihydropyridine P / Q-type α _1A Ca _γ 2.1 √ - - - N-type α _1B Ca _γ 2.2 - √ √ - L-type α _1C Ca _γ 1.2 - - - √ L-type α _1D Ca _γ 1.3 - - - √ R-type α _1E Ca _γ 2.3 - - - - L-type α _1F Ca _γ 1.4 - - - √ T-type α _1G Ca _γ 3.1 - - - - T-type α _1H Ca _γ 3.2 - - - - T-type α _1I Ca _γ 3.3 - - - -

Calcium channels have been known to mediate the development and maintenance of neuronal sensitization processes associated with neuropathic pain and provide an attractive target for the development of analgesics (reviewed in Vanegas & Schaible, 2000). All high threshold Ca channel types are expressed in the spinal cord and the contribution of L-, N and P / Q-types in sensitive invasion is currently being studied. In contrast, studies of the functional role of these channels in more chronic pain anomalies strongly suggest pathophysiological roles for N-type channels (reviewed in Vanegas & Schaible, 2000).

Mutations in the calcium channel α ₁ subunit gene of an animal may provide important clues of potential therapeutic targets for pain treatment. Genetically altered mice in which the α _1B N-type calcium channel gene has been invalidated have been reported in several independent groups (Ino et al., 2001; Kim et al., 2001; Saegusa et al., 2001; Hatakeyama et al., 2001). α _1B N-type null mice showed viable, gestational, and normal cooperative movement. In one study, ambient temperature, blood pressure and heart rate were all normal in mice knocked out of the N-type gene (Saegusa et al., 2001). In another study, pressure reflection mediated by the sympathetic nervous system decreased after bilateral carotid artery occlusion (Ino et al., 2001). In another study, studies of mice for other behavioral changes revealed that they were normal except for significantly lower anxiety-related behaviors (Saegusa et al., 2001). It may be a target. Mice without functional N-type channels in all studies show a marked decrease in chronic and inflammatory pain responses. In contrast, mice without N-type channels generally showed normal acute nociceptive responses.

Two examples of FDA-approved or therapeutic drugs acting on N-type channels are gabapentin and ziconotide. Gabapentin, 1- (aminomethyl) cyclohexaneacetic acid (Neurontin ^® ), is an anticonvulsant originally found to be active in many animal seizure models (Taylor et al., 1998). Subsequent studies have shown that gabapentin also has hyperalgesia in a number of other animal pain models, including chronic constriction damage (CCI), thermal hyperalgesia, inflammation, diabetic neuropathy, and static and dynamic mechanical pain associated with postoperative pain. Successful prevention (Taylor et al., 1998; Cesena & Calcutt, 1999; Field et al., 1999; Cheng, JK. Et al., 2000; Nicholson, 2000).

Although the mechanism of its activity is incompletely understood, current evidence suggests that gabapentin does not directly interact with GABA receptors in many neurons, but rather mediates the activity of high threshold calcium channels. Although this interaction remains unknown as the reason for the therapeutic effect in neuropathic pain, it has been shown that gabapentin binds to the calcium channel α ₂ δ auxiliary subunit.

In humans, gabapentin exhibits clinically induced anti-hyperalgesic activity over a wide range of neuropathic pain disorders. Numerous open label case studies and three large double blind trials suggest that gabapentin may be useful in the treatment of pain. Treatment of Diabetic Neuropathy (Backonja et al., 1998), Post shingles neuralgia (Rowbotham et al., 1998), Trigeminal neuralgia, Migraine and pain associated with cancer and multiple sclerosis (Di Trapini et al., 2000; Caraceni et al., 1999; Houtchens et al., 1997 (See also Magnus, 1999; Laird & Gidal, 2000; Nicholson, 2000) at doses ranging from 300-2400 mg / day.

Kono not suited (Prialt ^®; SNX-111) is a bluish-purple snail (cone snail) peptide RC Magus (Conus known to reversibly block the N- type calcium channel magus ) is a synthetic analgesic extracted from MVIIA. In various animal models, selective blockade of N-type channels through intramedural administration of ziconotide significantly reduces formalin stage 2 responses, thermal hyperalgesia, mechanical pain and postoperative pain (Malmberg & Yaksh, 1994). Bowersox et al., 1996; Sluka, 1998; Wang et al., 1998).

Ziconotide has been evaluated in several therapeutic trials through intramedullary administration for the treatment of a variety of conditions including post shingles neuralgia, annular syndrome, HIV-associated neuropathic pain, and refractory cancer pain (reviewed in Mathur, 2000). Bar). In clinical trials phases II and III of patients unresponsive to intramenoral opiates, ziconotids had markedly reduced pain scores and, in many special cases, were stable after years of sustained pain. Ziconotide has also been tested in the management of severe postoperative pain as well as brain damage after stroke and severe head trauma (Heading, 1999). In two case studies, ziconotide was further found to be useful for the treatment of refractory stiffness after spinal cord injury in patients who are unresponsive to baclofen and morphine (Ridgeway et al., 2000). In one case, Ziconotide reduced stiffness from mild to mild with little side effects. Although significant side effects including memory loss, confusion and sedation at the required dose in another patient prevented the continuation of treatment, Ziconotide also reduced stiffness to mild.

T-type calcium channels are involved in a variety of medical conditions. In mice without genes expressing the α _1G subunit, resistance to small seizures was observed (Kim et al., 2001). Other studies also implicate the α _1H subunit in the development of epilepsy (Su et al., 2002). There is strong evidence that some existing anticonvulsant drugs, such as etosuccimid, function through blocking of T-type channels (Gomora et al., 2001).

Low voltage activated calcium channels are frequently expressed in tissues of the cardiovascular system. Mibefradile, a calcium channel blocker 10-30 times more selective for T-type channels than L-type channels, has been found to be useful for hypertension and angina. It was recovered immediately on the market due to interaction with other drugs (Heady et al., 2001).

Increasing evidence suggests that T-type calcium channels may also be involved in pain. Miberadyl and ethosuccimid both exhibited anti-hyperalgesic activity in a spinal cord neuronal connection model of neuropathic pain in Lett (Dogrul et al., 2003).

U.S. Patent 6,011,035; 6,294,533; 6,310,059; And 6,492,375; PCT publications WO 01375 and WO01 / 45709; PCT publications based on PCT CA 99/00612, PCT CA 00/01586; PCT CA 00/01558; PCT CA 00/01557; PCT CA 2004/000535; And PCT CA 2004/000539, and US Patent Application 10 / 746,932, Dec. 23, 2003; 10 / 746,933 dated December 23, 2003; 10 / 409,793 dated April 8, 2003; 10 / 409,868, April 8, 2003; 10 / 655,393 dated September 3, 2003; 10 / 821,584 dated April 9, 2004; And 10 / 821,389 dated April 9, 2004, disclose calcium channel blockers wherein the piperidine or piperazine ring is substituted with various aromatic moieties. These applications and publications are incorporated herein by reference.

US Pat. No. 5,644,149 discloses calcium antagonists having the formula A-Y-B, wherein B contains a piperazine or piperidine ring directly linked to Y. Essential components of these molecules are represented by A, which must be an antioxidant; Piperazine or piperidine itself is believed to be important. Exemplary compounds contain benzhydryl substituents based on known calcium channel blockers (see below). U.S. Patent 5,703,071 discloses compounds known to be useful for treating ischemic diseases. An essential part of this molecule is a tropolone moiety, piperazine derivatives among the permissible substituents, and their benzhydryl derivatives. U. S. Patent No. 5,428, 038 discloses compounds known to exert neuroprotective and anti-allergic effects. These compounds are coumarin derivatives that may include derivatives of piperazine and other six-membered heterocycles. Permissible substituents for heterocycles are diphenylhydroxymethyl. Thus, attempts in the art for a variety of indications that may be associated with calcium channel blocking activity include compounds with piperidine or piperazine groups, even substituted with benzhydryl, but with additional substituents to maintain functionality. Was used.

Certain compounds having both benzhydryl groups and piperidine or piperazine groups are known as calcium channel antagonists and neuroleptic drugs. For example, Gould, RJ et al. Proc Natl Acad Sci USA (1983) 80: 5122-5125 discloses antischizophrenic neuroleptic drugs such as lidofrazine, flupyriene, pimozide, clopimozide and fenfluridol. In addition, flupyriene not only blocks N-type calcium currents (Brittham, CJ et al., Brit J Pharmacol (1944) 111: 483-488) but also binds to sites on L-type calcium channels (King, VK et al., J Biol Chem (1989) 264: 5633-5641). In addition, lomerizin as marketed by Kenebo KK is a known calcium channel blocker. However, lomerizin is not specific for the N-type channel. Public literature related to Romerizine can be found in Dooley, D., Current. Opinion in CPNS Investigational Drugs (1999) 1: 116-125.

The foregoing documents are listed in the references section for convenience, but should not be regarded as prior art.

[Initiation of invention]

The present invention includes conditions related to calcium metabolism, including synaptic calcium channel-mediated functions such as stroke, anxiety, irritable cystitis, inflammatory bowel disease, irritable bowel syndrome, interstitial colitis, head trauma, migraine, chronic, neuropathic and To treat acute pain, drug and alcoholism, neuropathic disorders, psychosis, sleep disorders, depression, epilepsy, diabetes, cancer, male infertility, high blood pressure, pulmonary arterial hypertension, cardiac arrhythmia, congestive heart failure, angina pectoris and other signs It relates to useful compounds. Compounds of the present invention are diarylamino derivatives of piperazine or amino piperidine with substituents that enhance the calcium channel blocking activity of the compound.

Accordingly, one aspect of the present invention relates to a compound of the formula and a salt or a conjugate thereof,

Wherein each A and B is independently a six-membered aromatic or nonaromatic, carbocyclic or heterocyclic moiety or aminoalkyl, or only one of A and B will be H or alkyl (1-8C) Or A and B form an optionally substituted 6-membered aromatic or non-aromatic, carbocyclic or heterocyclic moiety;

R ¹ is H or alkyl (1-8C);

Z is N or CHNR ² , wherein R ² is H or alkyl (1-8C);

X is straight-chain alkylene (1-4C), wherein any at least one carbon adjacent to nitrogen is in the form of C═O;

Each R ³ is independently ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , CN, N0 _A substituent selected from the group consisting of ₂ , NR ₂ , OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR, SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR, or NRS0 ₂ R Wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl and alkylaryl, and the two substituents on adjacent carbons are optionally substituted 5-7 members May form a ring;

n = 0-2,

Ar is a 6-membered aromatic or heteroaromatic ring;

Wherein the cyclic moieties included in each A or B and each Ar moiety in formula (1) are = 0 (in the non-aromatic cyclic moiety), alkyl (1-6C), halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , N0 ₂ , NR ₂ , OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR, SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR and NRS0 ₂ R May be substituted with one or more substituents selected from the group, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl or alkylaryl, and two adjacent substituents Can form a 5-7 membered ring,

Wherein any alkyl, cyclic, or aryl group described above is ═O, halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , N0 ₂ , NR ₂ OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR , SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR, or NRS0 ₂ R, wherein R can be H or alkyl (1-8C), alkenyl (2-8C) , Alkynyl (2-8C), aryl or alkylaryl.

The invention also relates to a method of modulating calcium channel activity, preferably N-type and T-type channel activity using a compound of formula (1), and thus to a method of treating certain undesirable physiological diseases. Will; These diseases are associated with calcium channel activity. In another aspect, the invention provides pharmaceutical compositions containing such compounds and strokes, anxiety, irritable cystitis, inflammatory bowel disease, irritable bowel syndrome, interstitial colitis, head trauma, migraine, chronic, neuropathic and acute pain, Drugs and alcohol, including neurotoxic disorders, psychosis, sleep disorders, depression, epilepsy, diabetes, cancer, male infertility, hypertension, pulmonary arterial hypertension, cardiac arrhythmias, congestive heart failure and angina It relates to the use of such compounds for the manufacture of drugs for the treatment of diseases.

[Embodiment aspect of the invention]

Compounds of formula (1) useful in the methods of the invention exert a desired effect through their ability to modulate the activity of N-type and / or T-type calcium channels. The compounds are therefore useful for the treatment of certain diseases. Such diseases that require antagonist activity include stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, irritable bladder irritable bowel syndrome, interstitial colitis and chronic, neuropathic and acute pain. Calcium flux is also associated with schizophrenia, anxiety, depression, other psychosis, neurodegenerative disorders, other neurological disorders such as drug and alcoholism and withdrawal. Other treatable diseases include cardiovascular diseases such as hypertension, pulmonary arterial hypertension, congestive heart failure, angina pectoris, cardiac arrhythmias such as atrial fibrillation and ventricular fibrillation. In addition, T-type calcium channels have also been associated with certain types of cancer, diabetes, male infertility, sleep disorders and sexual dysfunction.

Chronic pain may include cancer pain and osteoarthritis, inflammatory pain associated with rheumatoid arthritis and myofascial pain, and neuropathic pain. Neuropathic pain includes, but is not limited to, diabetic neuropathy, shingles neuralgia, trigeminal neuralgia, cancer pain and neuropathy related diseases such as AIDS. Acute pain disorders include nociceptive pain and postoperative pain.

Anxiety includes, but is not limited to, the following diseases: generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, and post-traumatic stress syndrome.

Neuropathic disorders include Parkinson's disease, Alzheimer's disease, multiple sclerosis, neuropathy, Huntington's disease and amyotrophic lateral sclerosis (ALS).

Compounds of formula (1) generally have this activity, while the use of this class of calcium channel modulators allows the selection of compounds according to subtle differences in certain diseases. The availability of this class of compounds not only provides a universal compound species for symptoms affected by calcium channel activity, but also allows compounds that can be studied and manipulated to specifically interact with specific types of calcium channels. It may also provide a large number. This selection process is made easier by the use of recombinantly prepared calcium channels of the α _1A -α _1I and α _1S types described above. Dubel, S. J. et al . , Proc . Natl . Acad . Sci . USA (1992) 89: 5058-5062; Fujita, Y. et al., Neuron (1993) 10: 585-598; Mikami, A. et al., Nature (1989) 340: 230-233; Mori, Y. et al., Nature (1991) 350: 398-402; Snutch, T. P. et al., Neuron (1991) 7: 45-57; Soong, T. W. et al., Science (1993) 260: 1133-1136; Tomlinson, W. J. et al., Neuropharmacology (1993) 32: 1117-1126; Williams, M. E. et al., Neuron (1992) 8: 71-84; Williams, M. E. et al., Science (1992) 257: 389-395; Perez-Reyes et al., Nature (1998) 391: 896-900; Cribbs, L. L. et al., Circulation Research (1998) 83: 103-109; Lee, J. H. et al., Journal of Neuroscience (1999) 19: 1912-1921; McRory, J. E. et al., Journal of Biological Chemistry (2001) 276: 3999-4011.

It is known that calcium channel activity is involved in various disorders, and that certain types of channels are associated with certain diseases. Association of N-type and T-type channels in diseases related to neurotransmission indicates that compounds of the invention aimed at N-type channels are most useful in these diseases. Many members of the compound of formula (1) exhibit high affinity for N-type channels and / or T-type channels. Therefore, screening for the ability to interact with N-type and / or T-type channels as an initial indicator as to whether they have the desired function as follows. It is preferred that the compound exhibit an IC ₅₀ value of <1 μM. IC ₅₀ is a concentration that inhibits calcium, barium or other permeable divalent cation flow by 50% at a specific applied potential.

Calcium channel inhibition is divided into three types. First, what is referred to as "open channel blockage" is easily achieved when the displayed calcium channel is artificially maintained at a negative resting potential of about -100 mV (distinguishable from the general endogenous resting potential maintained at about -70 mV). It is explained. If the dished channel suddenly depolarizes in this condition, calcium ions will flow through the channel and disappear after showing peak current flow. Open channel blocking inhibitors attenuate the current present in the peak flow and may also accelerate the rate of current attenuation.

This type of inhibition is distinguished from the second type of blocking, referred to herein as "inactivation inhibition". When maintained at a potential lower than the negative resting potential, such as -70 mV, which is a physiologically important potential, certain proportions of the channels can cause structural changes that prevent them from being activated, i.e., opened, by sudden depolarization. Thus, the peak current due to the calcium ion flow is attenuated not because the open channel is blocked, but because some channels are not open (inactive). Inactive type inhibitors increase the proportion of receptors that are in an inactive state.

The third type of inhibition is called "pause channel block". Idle channel blockage is the inhibition of channels that occur in the absence of membrane depolarization, leading primarily to openness or inertness. For example, the resting channel blocker reduces the peak current magnitude during the first depolarization immediately after drug application without further inhibition during depolarization.

To be most effective in treatment, it is also helpful to assess any possible side reactions. Thus, in addition, in order to be able to modulate certain calcium channels, it is desirable for the compounds to have very low activity compared to HERG K + channels expressed in the heart. Compounds that block this channel with high efficiency can cause fatal reactions. Therefore, for compounds that modulate calcium channels, it should also be shown that HERG K ⁺ channels are not inhibited. Similarly, it would be undesirable for a compound to inhibit cytochrome p450 because this enzyme is required for drug detoxification. Finally, compounds for calcium ion channel type specificity are evaluated by comparing their activity among various types of calcium channels, and specificity for one particular channel type is preferred. Compounds are tested as actual drug candidates in animal models after successful completion of these experiments.

Compounds of the invention modulate the activity of calcium channels; In general, the regulation is to inhibit the channel's ability to carry calcium. As mentioned above, the effect of certain compounds on calcium channel activity can be readily ascertained by conventional assays conditioned to activate the channel and assess the effect of the compound on this activation (positive or negative). The general analysis is described below.

[Compound of the present invention]

Substituents of the basic structure of the formula (1) have been described above. The substituents include alkyl, alkenyl, alkynyl, and the like substituents.

As used in this application, the terms "alkyl," "alkenyl" and "alkynyl" are straight, branched and cyclic monovalent containing only C and H when unsubstituted or otherwise mentioned. ) Substituents. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl and the like. Generally, alkyl, alkenyl and alkynyl substituents contain 1-10C or 1-8C (alkyl) or 2-10C or 2-8C (alkenyl or alkynyl). Preferably they comprise 1-6C or 1-4C (lower alkyl) or 2-6C or 2-4C (lower alkenyl or lower alkynyl).

Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined but may contain one or more 0, S or N heteroatoms or combinations thereof in the backbone residue. These are the "heteroforms" of the carbonaceous moieties involved.

Cyclic forms such as alkyl, heteroalkyl, etc., including unsaturated forms, are included in the definition as described above. This is also explicitly referred to as cycloalkyl or cycloheteroalkyl. Thus, cycloalkyl may include cyclopentyl, cyclohexyl, cyclobutyl, and the like; Cycloalkenyls include cyclohexenyl, cyclohexadienyl, cyclopentenyl, cyclopentadienyl, and the like. Their heteroforms include substituents including morpholine, piperazine, piperidine, thiazolidine, pyrrolidine and the like. In certain embodiments substituents A and B combine with the carbon to which they are attached to form a six membered ring comprising piperazine, piperidine, morpholine, benzene, pyridine, and the like.

As used herein, "acyl" includes the definitions of alkyl, alkenyl, alkynyl, each of which is coupled to additional residues via a carbonyl group. Heteroacyl includes associated heteroforms.

"Aromatic" moiety or "aryl" moiety refers to a monocyclic or mixed bicyclic moiety such as phenyl or naphthyl; "Heteroaromatic" also refers to monocyclic or mixed bicyclic ring systems containing one or more heteroatoms selected from 0, S and N. The inclusion of heteroatoms allows the contents of 5-membered rings to be regarded as aromatic rings as well as 6-membered rings. Thus, common aromatic / heteroaromatic systems include pixydil, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, Thiazolyl, oxazolyl, imidazolyl and the like. Since tautomers are theoretically possible, phthalimides are also considered aromatic. Any monocyclic or mixed ring bicyclic having aromatic character in terms of electron distribution is included in this definition. In general, ring systems contain 5-12 membered atoms.

Similarly, "arylalkyl" and "heteroarylalkyl" are further residues throughout the carbon chain, including carbon chains that are substituted or unsubstituted, saturated or unsaturated, generally 1-8C, or a hetero form thereof. Aromatic and heteroaromatic systems coupled to water. These carbon chains also include carbonyl groups to provide substituents such as acyl or heteroacyl moieties.

In general, any alkyl, alkenyl, alkynyl, acyl or aryl (including heterotype) contained in a substituent may be optionally substituted by additional substituents. The properties of these substituents are similar to those mentioned for the main substituents themselves. Thus, in embodiments where the substituent is alkyl, this alkyl may be optionally substituted by residual substituents listed as substituents that are chemically understandable and do not impair the size limit of the alkyl itself; That is, alkyl substituted by alkyl or alkenyl simply extends the upper limit of carbon atoms for these embodiments. However, alkyl substituted by aryl, amino, alkoxy and the like are included.

In general, non-limiting examples of non-interfering substituents include alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, = 0, halo, OR, NR ₂ , SR, -SOR, -SO ₂ R, SO ₂ R, -OC OR, -NRCOR, -NRCONR ₂ , -NRCOOR, -OCONR ₂ , -RCO, -COOR, NRSOR, NRS0 ₂ R, -CONR ₂ , SONR ₂ , and / or S02NR ₂ (where each R is independently H Or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl or arylalkyl), -CN, -CF ₃ , NO ₂ And like substituents.

In the compounds of the present invention, Ar is preferably optionally substituted phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, pyridazinyl, benzotriazolyl or benzimidazolyl This is good. More preferably Ar is preferably phenyl, pyridyl or pyrimidyl. Most preferably Ar is phenyl. Each of these embodiments is alkyl, alkenyl, alkynyl, aryl, O-aryl, O-alkylaryl, O-aroyl, NR-aryl, N-acylaryl, NR-aroyl, halo, OR, NR ₂ , SR, -OOCR, -NROCR, RCO, -COOR, -CONR ₂ , and / or S0 ₂ NR ₂ may be optionally substituted with each R independently H or alkyl (1-8C). ), Alkenyl (2-8C), alkynyl (2-8C), aryl or alkylaryl, and / or by-CN, -CF ₃ , and / or NO ₂ . Their alkyl, alkenyl, alkynyl, cyclic and aryl moieties may be further substituted with similar substituents.

Among the preferred substituents for Ar are alkyl, CF ₃ , CHF ₂ , OR, SR, N ₂ (RR is as described above) and halo. Preferred embodiments of R ¹ are methyl and H. Preferred embodiments of R ³ include OH and carboxy, including COOH itself as well as esters and amides.

The compounds of the present invention have ionizable groups and can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts associated with inorganic or organic acids, or may be prepared from inorganic or organic bases in the acidic form of the compounds of the invention. Hydrochloric acid, sulfuric acid, citric acid, acidic or tartaric acid, and pharmaceutically acceptable suitable acids and bases such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like are well known to those skilled in the art. Methods of preparing suitable salts are well established in the art.

In certain cases, the compounds of the present invention contain one or more chiral centers. The present invention includes stereoisomeric mixtures of varying degrees of chiral purity, as well as isolated stereoisomeric forms.

In addition, the compounds of the present invention can be substances designed to alter pharmacokinetics by coupling via a pair for a target or for other reasons. Thus, the present invention further encompasses conjugated compounds of these compounds. For example, polyethylene glycol is often coupled to a substance that enhances half life; Compounds are coupled to liposomes or other particulate carriers either covalently or noncovalently. They are also coupled via a linker moiety to a target agent such as an antibody or peptidomimetic. Accordingly, the present invention also directly deals with the compound of formula (1) when modified to be included in this type of conjugate compound.

Synthesis of Compound of the Invention

The compounds of the present invention can be synthesized by conventional methods.

Scheme 1 is illustrative and can be used to prepare compounds with piperazine rings adjacent to C═O. The piperidine homologue can be substituted and the reaction of nitrogen of CHNH ₂ is substituted with the nitrogen of piperazine. Also shown is the pathway where the alkylene component (ie CH ₂ ) is adjacent to N of the CHNH of piperazine or piperidine.

Figure 1 illustrates the synthesis of R ¹ is H, a and b are both optionally substituted phenyl, Z is N, X is CH ₂ CO, and two Ar are unsubstituted phenyl. . It is clear that the same scheme can be applied to the remaining embodiments allowing for such named substituents. In the first step, compounds 1 and 2 are coupled via a Grignard reaction to form diphenyl methanol, which is then converted to diphenyl methyl chloride. The resulting compound 4 is then treated with piperazine (or alternatively 4-amino piperidine) to give compound 5. Compound 5 is then reacted with diphenylamino acetic acid by forming an amide with an unsubstituted piperazine ring nitrogen or 4-amino group of piperidine. Or a compound of formula (5) with the α-brominated form of amide 7 to give the desired compound as indicated above. If Z is CHNR ² , the 4-amino group is replaced by the nitrogen of piperazine in this reaction.

[Library and Screening]

The compounds of the present invention can be synthesized either individually using methods known in the art or as members of a combinatorial library.

Synthesis of combinatorial libraries is well known in the art. Suitable substrates for such synthesis are described, for example, in Wentworth, Jr., P. et al., Current Opinion in Biol . (1993) 9: 109-115; Salemme, FR et al., Structure (1997) 5: 319-324. Libraries contain compounds of varying degrees of substituent and unsaturation as well as different chain lengths. These libraries, which contain as little as 10, but generally hundreds to thousands of components, can then be screened for compounds that are particularly effective for specific subtypes of calcium channels, ie N-type channels. In addition, using standard screening protocols, this library can be screened for compounds that block additional channels or receptors such as sodium channels, potassium channels and the like.

Methods of performing such screening functions are well known in the art. Such methods are also useful for individually identifying the ability of a compound to promote or antagonize a channel. In general, targeted channels are expressed on the surface of recombinant host cells, such as human embryonic renal cells. The performance of the components of the library to bind the channel to be tested is measured by the ability of the compound in this library to transfer a label binding ligand, such as a ligand normally associated with the channel or antibody to the channel, for example. More generally, the ability to antagonize channels is measured in the presence of calcium, barium or other penetrating divalent cations, and the ability of compounds to interfere with the generated signal is measured using standard techniques. More specifically, one method involves equilibrium, including binding of radiolabeled agents that interact with calcium channels and competitive binding by on rate, off rate, K _d values, and other molecules. Follow-up analysis of binding measurements is involved.

Another method involves screening the effect of the compound by electrophysiological analysis by plugging the microelectrode into individual cells and recording the current through the calcium channel before and after application of the subject compound.

Another method, high-throughput spectroscopic analysis, utilizes the loading of the cell line with fluorescent dyes sensitive to intracellular calcium concentrations and determines the performance of the compounds for the performance of depolarization or by other means of altering potassium chloride or intracellular calcium levels. Use follow-up of effects.

As mentioned above, more critical assays are used to distinguish inhibitors of calcium flow that act as channel blockers or as resting channel blockers against those that act by promoting channel inactivation. Methods of distinguishing this type of inhibition are described in more detail in the Examples below. In general, open-channel blockers are estimated by measuring the level of current when depolarization is applied with a background resting potential of about −100 mV, with and without a candidate compound. Successful open-channel blockers will attenuate the observed peak currents and promote their disappearance. Compounds that are generally inactivated channel blockers are determined by their ability to alter the voltage dependence of the inactivation for larger negative potentials. This is also reflected in the ability to attenuate the peak current at more depolarized holding potentials (ie -70 mV) and at high frequency stimuli, ie 0.2 Hz vs. 0.03 Hz. Finally, the resting channel blocker reduces the magnitude of the peak current during the first depolarization after drug application without further inhibition during depolarization.

[ Usage and Administration]

When used as a therapy for human and animal subjects, the compounds of the present invention may be formulated pharmaceutically or as a veterinary composition. Depending on the subject to be treated, the type of administration, and the type of treatment desired, such as prevention, prevention, treatment, and the like, the compounds of the present invention are formulated in a manner consistent with these factors. The gist of this technologyReminton's Pharmaceutical Sciences, latest edition, Mack Pulishing Co., EASTon, PA., incorporated herein by this reference.

In general, for therapeutic use, the compound of formula (1) may be used alone, as a mixture of two or more compounds of formula (1), or as a combination with other pharmaceuticals. Depending on the type of administration, the compounds of the present invention will be formulated in a suitable composition that can facilitate delivery.

Formulations may be prepared in a manner suitable for systemic administration or for local or topical administration. Systemic formulations include those designed for injection purposes (eg, intramuscular, intravenous or subcutaneous), or may be prepared for transdermal administration, transmucosal administration, or oral administration. This formulation will generally include a diluent and, if appropriate, excipients, buffers, preservatives, and the like. The compounds of the present invention may also be administered in liposome compositions or as microemulsions.

Injectable formulations may be prepared in conventional forms as liquid solutions or suspensions, or as solids suitable for liquid solutions or suspensions immediately before injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions also include amounts of nontoxic auxiliary substances such as, for example, wetting or emulsifying agents, pH buffers, and the like, such as sodium acetate, sorbitan monolaurate, and the like.

Various delayed release systems for drugs are also designed. See, for example, US Pat. No. 5,624,677.

Systemic administration also includes relatively noninvasive methods such as the use of suppositories, transdermal patches, mucosal delivery agents and intranasal administration. Oral administration is also suitable for the compounds of the present invention. Suitable forms include syrups, capsules, tablets, as known in the art.

When administered to an animal or human subject, the dosage of the compound of the present invention is generally 0.1-15 mg / kg, preferably 0.1-1 mg / kg. However, dosage levels are highly dependent on the nature of the disease, the symptoms of the patient, the efficacy of the drug, the judgment of the attending physician and the frequency and type of administration.

The following examples are intended to illustrate the invention and not to limit it.

Example  One

1- (4-[(4- Chloro - Phenyl )- Phenyl - methyl ] -Piperazin-1-yl) -2-

Of diphenylaminoethanone  synthesis

A. Synthesis of (4 -chloro - phenyl ) -phenyl -methanol

A solution of 4-chlorobenzaldehyde (1.03 g, 7.34 mmol) in dry ether (10 ml) was added slowly to a solution of phenylmagnesium bromide (2.3 ml in ether, 6.98 mmol, 3.0 M) under nitrogen. The mixture was heated to reflux for 1 hour, then cooled to 0 ° C. and hydrolyzed with 1 N HCI (40 ml). The aqueous phase was extracted with ether (3X) and combined with an organic layer dried over MgS0 ₄ . The crude product was purified using hexane: ethyl acetate (5: 1) as eluent to yield 1.5 g of pure product.

B. Synthesis of 1 -chloro- 4- ( chloro - phenyl - methyl ) -benzene

To a solution of (4-chloro-phenyl) -phenyl-methanol (2.41 g, 11.06 mmol) in dry benzene (20 ml) was added SOC1 ₂ (8.25 ml, 110 mmol) and anhydrous CaCl ₂ (2 g). The mixture was heated to reflux for 2 hours, then cooled and stirred overnight at room temperature. The mixture was then filtered and the solvent removed in vacuo yielding a pale yellow oil which was used in the next step without further purification.

C. Synthesis of 1-[(4 -chloro - phenyl ) -phenyl - methyl ] -piperazine

1-chloro-4- (chloro-phenyl-methyl) -benzene (4.12 g, 17.4 mmol) in butanone (20 ml), piperazine anhydrous (5.98 g, 69.6 mmol), anhydrous K ₂ C0 ₃ (2.40 g, 17.4 mmol) and KI (2.88 g, 17.4 mmol) were refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered to remove solvent in vacuo. The residue was dissolved in CH ₂ C1 ₂ (100 ml) and washed with water (30 ml). Chromatography (CH ₂ Cl ₂ : CH ₃ 0H: NH ₄ 0H 90: 10: 0.5) was followed by drying and removal of solvent to yield the desired product in 57% yield.

D. Synthesis of Final Product

To a solution of 1-[(4-chloro-phenyl) -phenyl-methyl] -piperazine (0.59 g, 2.08 mmol) in dry CH ₂ Cl ₂ (40 ml) was added nitrogen to diphenylaminoacetic acid (0.472 g, 2.08 mmol). Added under. EDC (0.797 g, 4.16 mmol) and DMAP (cat) were added to the reaction and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction was then concentrated at low pressure. The residue was dissolved in ethyl acetate: water (10: 1) (150 ml). The organics were washed with water (30 ml, 2x) and 10% NaOH (30 ml), dried over MgSO ₄ and evaporated to dryness. The resulting residue was purified by column chromatography using hexanes: ethyl acetate (3: 1) to afford the desired product in 76% yield.

Example  2

2- Diphenylamino -1- [4- ( Phenyl -Pyridin-4-yl- methyl ) -Piperazin-1-yl]- Ethanon

Synthesis of

To a solution of 1- (phenyl-pyridin-4-yl-methyl] -piperazine (0.58 g, 2.29 mmol) in dry CH ₂ Cl ₂ (40 ml) was added diphenylaminoacetic acid (0.51 g, 2.29 mmol) under nitrogen. To this reaction was added EDC (0.878 g, 4.58 mmol) and DMAP (cat) and the reaction mixture was stirred overnight at room temperature under nitrogen and then the reaction was concentrated at low pressure. 10: 1) (150 ml) The organics were washed with water (30 ml, 2 ×) and 10% NaOH (30 ml), dried over MgSO ₄ and evaporated to dryness The resulting residue was dried over hexanes: ethyl acetate ( Purification by circular chromatography using 1: 1) yielded the desired product in 79% yield.

Example  3

2- (4- Benzhydryl Piperazin-1-yl) -N, N- Diphenyl - Acetamide  synthesis

To a solution of diphenylmethyl piperazine (0.6 g, 2.37 mmol) in dry CH ₃ CN (20 ml) was 2-bromo-N, N-diphenyl acetamide (0.68 g, 2.37 mmol) and NaHCO ₃ (0.4 g, 4.74 mmol) was added under nitrogen. The reaction mixture was refluxed overnight. After cooling, the solvent was evaporated and the residue was taken up in water (15 ml) and extracted with CHC1 ₃ (3 × 50 ml). The organics were dried over MgSO ₄ and evaporated to dryness. The resulting residue was purified by column chromatography using hexanes: ethyl acetate (2: 1) to afford the desired product in 84% yield.

Example  4

2- [4- (1- methyl Piperidine-4- Methyl ) -Piperazin-1-yl] -N, N- Diphenyl - Acetamide  synthesis

2-bromo-N, N-diphenyl acetamide (0.61) in 1- (1-methyl-piperidin-4ylmethyl) -piperazine (0.5 g, 2.7 mmol) in dry CH ₃ CN (20 ml) g, 2.7 mmol) and NaHCO ₃ (0.45 g, 5.4 mmol) were added under nitrogen. The reaction mixture was refluxed overnight. After cooling, the solvent was evaporated and the residue was taken up in water (15 ml) and extracted with CHC1 ₃ (3 × 50 ml). The organics were dried over MgSO ₄ and evaporated to dryness. The resulting residue was purified by column chromatography using CH ₂ Cl ₂ : CH ₃ OH (10: 1) to afford the desired product in 80% yield.

Example  5

Summary of Preparation Compounds

The following compounds were prepared according to the general procedure described above:

Also prepared were compounds 1-34 and 39-47 described above, wherein the nitrogen of piperazine coupled to diphenyl amine via Z was substituted with CHNH, and compounds 35-38 wherein Z was N.

Example  6

N-type channel blocking activity of various compounds of the invention

A. Transformation of HEK Cells:

N-type calcium channel blocking activity in HEK 293, human embryonic renal cells stably transfected with rat brain N-type calcium channel subunits (α _1B + α ₂ δ + β _1b cDNA subunits) Was measured. Or N-type calcium channel (α _1B + α ₂ δ + β _1b cDNA subunit), L-type channel (α _1C + α ₂ δ + β _1b cDNA subunit) and P / Q-type channel (α _1A + α ₂ δ + β _1b CDNA subunit) was transiently expressed in HEK 293 cells. Briefly, cells were cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 200 U / ml penicillin and 0.2 mg / ml streptomycin at 37 ° C. in 5% CO ₂ . . When reaching 85% confluency, cells were aliquoted with 0.25% trypsin / 1 mM EDTA and plated with 10% confluency on glass cover. After 12 hours the medium was replaced and cells were transiently transfected using standard calcium phosphate protocol and appropriate calcium channel cDNA's. Fresh DMEM was fed and cells were transferred to 28 ° C./5% CO ₂ . Cells were incubated for 1-2 days prior to cell recording.

B. Measurement of Inhibition Rate

Whole cell patch clamp experiments were performed using an Axopatch 200B amplifier (Axon Instruments, Burlingame, Calif.) connected to a personal computer with pCLAMP software. External and internal recording solutions were 5 mM BaCl ₂ , 10 mM MgCl ₂ , 10 mM HEPES, 40 mM TEACl, 10 mM glucose, 87.5 mM CsCl, pH 7.2 and 108 mM CsMS, 4 mM MgCl ₂ , 9 mM EGTA, 9 mM HEPES, pH 7.2. Clampex software (Axon Instruments) was used to derive the current from the holding potential of -80 mV to +10 mV. In general, currents were first induced with low frequency stimulation (0.067 Hz) and stabilized before application to the compound. The stiffness cutoff was then calculated by applying to the compound for 2-3 minutes during the low frequency pulse train, then increasing the pulse frequency to 0.2 Hz to measure the frequency dependent cutoff. Data was analyzed using Clampfit (Axon Instruments) and SigmaPlot 4.0 (Jandel Scientific).

Specific data for N-type channels is shown in Table 1A below. See Example 5 for structure.

Example  7

T-type channel inhibitory activity of various inventive compounds

Standard patch clamp techniques were used to identify blockers of T-type current. Briefly, the above-described HEK cell line stably expressing human α _1G T-type channels was used for all recordings (passage #: 4-20, 37 ° C., 5% CO ₂ ). To obtain a T-type current, the plastic container containing the semi-confluent cells was placed on the stage of the ZEISS AXIOVERT S100 microscope after removing the culture medium with extracellular fluid (see below). Whole-cell patches were obtained using a pipette (borosilicate glass with filament, OD: 1.5 mm, ID: 0.86 mm, 10 cm length), with a SUTTER P-97 puller with a resistance of ˜5 MΩ. (Intracellular fluid see below).

Extracellular fluid 500 ml  - pH  7.4, 265.5 mOsm salt final mM stock  M final ml CsCl 132 One 66 CaCl2 2 One One MgCl2 One One 0.5 HEPES 10 0.5 10 Glucose 10 ------------- 0.9 g

Intracellular Fluid 50 ml  - CsOH  contain pH  7.3, 270 mOsm salt final mM stock  M final ml Cs-methanesulfonate 108 ------------- 1.231 gr / 50 ml MgCl2 2 One 0.1 HEPES 10 0.5 One EGTA-Cs 11 0.25 2.2 ATP 2 0.2 0.025 (1 aliquot / 2.5 ml)

T-type currents were reliably obtained using the following two voltage protocols:

(1) "non-inert", and

(2) "inert"

In the non-inactivating protocol, the holding potential is set to -110 mV, with a pre-pulse for 1 second at -100 mV before the test pulse is applied at -40 mV for 50 ms. In the inert protocol, the pre-pulse is applied at about -85 mV for 1 second, inactivating about 15% of the T-type channel.

Test compounds were dissolved in extracellular fluid 0.1-0.01% DMSO. After ˜10 min of rest, the test compound was applied close to the cell by gravity using a WPI microfill tube. The dormant blocking of compounds was investigated using "non-inactivated" pre-pulses. Voltage-dependent blocking was studied using the "inactive" protocol. However, the initial data presented below were mainly obtained using only non-inactive protocols. IC ₅₀ values for various compounds of the invention are shown in Table 4.

Example  8

Activity of Compounds of the Invention in Formalin-Induced Pain Models

The effects of the compounds of the invention carried into the jugular vein in the rat formalin model were measured. The compound was dissolved in about 10 mg / ml propylene glycol stock solution. Eight Holtzman male rats, 275-375 g in size, were randomly selected for each test item.

The following study groups of saline delivered to the test group, carrier control (propylene glycol) and intraperitoneal (IP) were used:

Formalin Model Dosing Group Test group / Control Dosage root Per group Rat compound 30mg / kg IP 6 Propylene glycol N / A IP 4 Saline N / A IP 7

N / A = not applicable

Basic behavioral data and test data were measured before drug delivery began. This data was collected again at the selected time after injection of the test or control group.

On the morning of the test day, a small metal band (0.5 g) was loosely wound around the right hind paw. The rats were placed in a cylindrical Plexiglas room for at least 30 minutes. Rats were dosed with test or vehicle control for 10 minutes on the right rear instep surface, followed by injection of formalin (50 μl of 5% formalin). The animals were then placed in an automatic formalin instrument to monitor the movement of the formalin-injected foot and to measure the number of feet flinching every minute for at least 60 minutes thereafter (Malmberg, AB et al., Anesthesiology (1993) 79: 270-281).

When saline control group = 100%, the result was shown as the maximum possible effect ± SEM.

compound Step I step II  all step IIA step IIB 7 60 ± 7 63 ± 10 63 ± 13 64 ± 11

Example  9

Neuropathic  Spinal Cord Neural Connection Model of Pain

Spinal Nerve Ligation (SNL) injury was induced using a Kim and Chung process (Kim and Chung 1992) in rats weighing 200-300 grams (Harlan, Indianapolis, Indiana). Anesthesia was induced using 2% halotan in 0 ₂ at 2 L / min and maintained at 0.5% halotan at 0 ₂ . Rats were treated surgically and after exposure of the dorsal spine from L4 to S2, the L ₅ and L ₆ spinal cord nerves were firmly connected using 4-0 silk sutures at the dorsal root ganglion ends. The incision was closed and the animals were allowed to recover for 5 days. Rats that failed to exhibit motor deficiency (eg, foot-drawing) or subsequent tactile dysfunction were excluded from later testing. Sham control rats performed the same surgery and treatment as the experimental animals, but without SNL.

Hargreave and colleagues' methods (Hargreaves et al., 1988) were used to measure foot-withdrawal latency for heat invasive stimuli. Rats were acclimated in a plexiglass fence of clear glass plates maintained at 30 ° C. A radiant heat source (ie, high intensity projector lamp) was activated with a timer and directed to the sole surface of the rat with nerve damage or carrageenin injection. The paw withdrawal latency was determined with a photovoltaic cell that stopped the lamp and the timer when the foot was crouched. Latency withdrawing feet from the radiant heat source was measured before carrageenan or L5 / L5 SNL, 3 hours after carrageenan, 7 hours after L5 / L6 SNL but before and after drug administration. The maximum cut-off was 40 seconds to prevent tissue damage. Therefore, the foot withdrawal latency was determined to be near 0.1 second. The reversal of heat hyperalgesia was manifested by the return of the paw withdrawal incubation to the pre-treatment basal incubation (ie 21 seconds). On this basis, a significant increase in paw withdrawal latency (p <0.05) resulted in anti-invasiveness. The data was converted to% antihyperalgesia with the formula: (100qx (test incubation-basal incubation) / (cutoff-basal incubation)) to determine antihyperalgesia.

Compound 7 of propylene glycol solution was orally administered at a dose of 30 mg / kg. Percent activity was calculated for heat hyperalgesia.

Neuropathic  Painful SNL  % Active in model Minutes Heat Hyperalgesia (% activation) 30 38.45 ± 18.52 60 78.54 ± 10.74 90 40.21 ± 17.08 120 20.98 ± 10.36

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Claims (19)

Compounds and salts or conjugates thereof of the formula:

Wherein each A and B is independently a 6-membered aromatic or non-aromatic, carbocyclic or heterocyclic moiety or aminoalkyl, or only one of A and B will be H or alkyl (1-8C) Or A and B form an optionally substituted 6-membered aromatic or non-aromatic, carbocyclic or heterocyclic moiety; R ¹ is H or alkyl (1-8C); Z is N or CHNR ² , wherein R ² is H or alkyl (1-8C); X is straight-chain alkylene (1-4C), wherein any at least one carbon adjacent to nitrogen is in the form of C═O; Each R ³ is independently ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , CN, N0 _A substituent selected from the group consisting of ₂ , NR ₂ , OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR, SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR, or NRS0 ₂ R Wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl and alkylaryl, and the two substituents on adjacent carbons are optionally substituted 5-7 members May form a ring; n = 0-2, Ar is a 6-membered aromatic or heteroaromatic ring; Wherein the cyclic moieties included in each A or B and each Ar moiety in formula (1) are = 0 (in the non-aromatic cyclic moiety), alkyl (1-6C), halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , N0 ₂ , NR ₂ , OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR, SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR and NRS0 ₂ R May be substituted with one or more substituents selected from the group, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl or alkylaryl, and two adjacent substituents Can form a 5-7 membered ring, Wherein any alkyl, cyclic, or aryl group described above is ═O, halo, CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , N0 ₂ , NR ₂ OR, SR, COR, COOR, CONR ₂ , NROCR, OOCR , SOR, S0 ₂ R, S0 ₃ R, SONR ₂ , S0 ₂ NR ₂ , NRSOR, or NRS0 ₂ R, wherein R can be H or alkyl (1-8C), alkenyl (2-8C) , Alkynyl (2-8C), aryl or alkylaryl. The compound of claim 1, wherein Z is N. 7. The compound of claim 1, wherein Ar is independently phenyl or pyridinyl. The compound of claim 1, wherein R ¹ is H. 7. The compound of claim 1, wherein each A and B is independently substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl. The compound of claim 1, wherein the substituents on Ar, A and / or B are selected from the group consisting of CF ₃ , alkyl, halo, hydroxy and alkoxy. The compound of claim 1, wherein n is 0 or each R ³ is independently = 0 or COOH. The compound of claim 1, wherein X comprises one C═O group. The compound of claim 8, wherein the C═O group is adjacent to the nitrogen to which Ar is bonded. The compound of claim 8, wherein the C═O group is adjacent to Z. 10. The compound of claim 1, wherein A and B together form an optionally substituted 6 membered aromatic or non-aromatic, carbocyclic or heterocyclic moiety. The compound of claim 9, wherein the cyclic moiety is piperidine. The compound of claim 1 selected from the group consisting of: 1- (4-benzhydryl-piperazin-1-yl) -2-diphenylamino-ethanone; 1- {4-[(2,4-Dimethyl-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- {4-[(2,4-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- {4-[(4-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- {4-[(3-chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- {4-[(2-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- {4-[(2,3-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- [4- (benzo [1,3] dioxol-5-yl-phenyl-methyl) -piperazin-1-yl] -2-diphenylamino-ethanone; 2-diphenylamino-1- (4-[(4-methoxy-phenyl)-(4-trifluoromethyl-phenyl) -methyl] -piperazin-1-yl} -ethanone; 2-diphenylamino-1- [4- (1-methyl-piperidin-3-ylmethyl) -piperazin-1-yl] -ethanone; 2-diphenylamino-1- (4-pyridin-3-ylmethyl-piperazin-1-yl) -ethanone; 2-diphenylamino-1- (4-pyridin-2-ylmethyl-piperazin-1-yl) -ethanone; 2-diphenylamino-1-4- (phenyl-pyridin-3-yl-methyl) -piperazin-1-yl] -ethanone; 2-diphenylamino-1- [4- (phenyl-pyridin-2-yl-methyl) -piperazin-1-yl] -ethanone; 1- {4-[(4-tert-butyl-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 2- (4-benzhydryl-piperazin-1-yl) -N, N-diphenyl-acetamide; 2- {4-[(2,4-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2,4-Dimethyl-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(4-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(3-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2,3-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- [4- (benzo [1,3] dioxol-5-yl-phenyl-methyl) -piperazin-1-yl] -N, N-diphenyl-acet amide; 2- {4-[(4-methoxy-phenyl)-(4-trifluoromethyl-phenyl) -methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- [4- (1-Methyl-piperidin-4-ylmethyl) -piperazin-1-yl] -N, N-diphenyl-acetamide; 2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -N, N-diphenyl-acetamide; 2- [4- (1-methyl-piperidin-3-ylmethyl) -piperazin-1-yl] -N, N-diphenyl-acetamide; N, N-diphenyl-2- [4- (phenyl-pyridin-3-yl-methyl) -piperazin-1-yl] -acetamide; N, N-diphenyl-2- [4- (phenyl-pyridin-2-yl-methyl) -piperazin-1-yl] -acetamide; 2- (4-[(4-tert-butyl-phenyl) -phenyl-methyl] -piperazin-1-yl) -N, N-diphenyl-acetamide; 2- {4-[(4-methoxy-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- (4-benzhydryl-2,3-dioxo-piperazin-1-yl) -N, N-diphenyl-acetamide; 2- (4-benzhydryl-2,5-dioxo-piperazin-1-yl) -N, N-diphenyl-acetamide; 1-benzhydryl-4- (2-diphenylamino-acetyl) -piperazine-2,5-dione; 2-[(1-benzhydryl-piperidin-4-yl) -methyl-amino] -N, N-diphenyl-acetamide; N- (1-benzhydryl-piperidin-4-yl) -N-methyl-N ', N'-diphenyl-ethane-1,2-diamine; N- (1-benzhydryl-piperidin-4-yl) -2-diphenylamino-N-methyl-acetamide; N- (1-benzhydryl-piperidin-4-yl) -N-methyl-N ', N'-diphenyl-malonamide; 4-benzhydryl-1- (2-diphenylamino-acetyl) -piperazine-2-carboxylic acid; 4-benzhydryl-1-[(diphenylcarbamoyl) -methyl] -piperazine-2-carboxylic acid ethyl ester; 4-benzhydryl-1-[(diphenylcarbamoyl) -methyl] -piperazine-2-carboxylic acid; 2-diphenylamino-1- [4- (1-methyl-piperidin-4-ylmethyl) -piperazin-1-yl] -ethanone; 2- [4- (1-Methyl-piperidin-4-ylmethyl) -piperazin-1-yl] -2-oxo-N, N-diphenyl-acetamide; 2-diphenylamino-1- [4- (1-phenyl-piperidin-4-ylmethyl) -piperazin-1-yl] -ethanone; 2-oxo-N, N-diphenyl-2- [4- (1-phenyl-piperidin-4-ylmethyl) -piperazin-1-yl] -acetamide; 2- {4-[(4-Chloro-phenyl)-(1-methyl-piperidin-4-yl) -methyl] -piperazin-1-yl-2-oxo-N, N-diphenyl-acet amides; And 4-benzhydryl-1- (2-diphenylamino-acetyl) -piperazine-2-carboxylic acid. The compound of claim 13 selected from the group consisting of: 1- (4-benzhydryl-piperazin-1-yl) -2-diphenylamino-ethanone; 1- {4-[(2,4-Dimethyl-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- (4-[(2,4-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl) -2-diphenylamino-ethanone; 1- {4-[(4-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 1- (4-[(3-chloro-phenyl) -phenyl-methyl] -piperazin-1-yl) -2-diphenylamino-ethanone; 1- (4-[(2-chloro-phenyl) -phenyl-methyl] -piperazin-1-yl) -2-diphenylamino-ethanone; 1- {4-[(2,3-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone; 2-diphenylamino-1- [4- (1-methyl-piperidin-3-ylmethyl) -piperazin-1-yl] -ethanone; 2- (4-benzhydryl-piperazin-1-yl) -N, N-diphenyl-acetamide; 2- {4-[(2,4-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2,4-Dimethyl-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(4-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(3-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2-Chloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- {4-[(2,3-Dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -N, N-diphenyl-acetamide; 2- [4- (1-Methyl-piperidin-4-ylmethyl) -piperazin-1-yl] -N, N-diphenyl-acetamide; And 2- [4- (3-dimethylamino-propyl) -piperazin-1-yl] -N, N-diphenyl-acetamide. The compound according to claim 14, which is 1- {4-[(2,3-dichloro-phenyl) -phenyl-methyl] -piperazin-1-yl} -2-diphenylamino-ethanone. A composition comprising a mixture of the compound of claim 1 and a pharmaceutically acceptable additive. A method for treating a disease mediated by calcium channel activity, comprising administering to a subject in need thereof a sufficient amount of the compound of claim 1 to treat the disease. 18. The method of claim 17, wherein the disease is stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, irritable cystitis, irritable bowel syndrome, interstitial colitis and chronic pain, inflammatory pain, neuropathic pain, acute pain, mental Schizophrenia, anxiety, depression, neurodegenerative disorders, drug and alcoholism and withdrawal; Cardiovascular diseases; Sleep disorder, cancer, diabetes, male infertility and sexual dysfunction. Stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, irritable bladder irritable bowel syndrome, interstitial colitis and chronic pain, inflammatory pain, neuropathic pain, acute pain, schizophrenia, anxiety, depression, neurodegenerative disorders, Drug and alcoholism and withdrawal; Cardiovascular diseases; A method of treating a disease selected from the group consisting of sleep disorders, cancer, diabetes, male infertility and sexual dysfunction, comprising administering to a subject in need thereof a sufficient amount of the compound of claim 1 to treat the disease. Including method.