JP2006522742A - A group of calcium channel inhibitors consisting of benzhydryl groups spaced from piperazine - Google Patents

Abstract

Provided are certain piperazine substituted compounds useful for altering calcium channel activity.
A compound comprising a heterocyclic 6-membered ring containing at least one nitrogen bonded to a benzhydryl moiety via a linker.

Description

Related applications

  This application is US continuation application No. 10 / 409,868, filed April 8, 2003; and it is US continuation application No. 10/060900, filed January 29, 2002. And that is the US continuation-in-part 09/476927 filed December 30, 1999 (currently US Pat. No. 6,387,897); and it is the United States application filed September 23, 1999. No. 09/401699 (currently US Pat. No. 6,294,533); and US Ser. No. continuation No. 09/107037 (currently US Pat. No. 09/107037) filed Jun. 30, 1998. No. 6,011,035). The contents of these applications are incorporated herein by reference.

  The present invention relates to compounds useful in treating conditions associated with abnormal calcium channel function. More particularly, the present invention relates to compounds comprising substituted or unsubstituted derivatives of heterocyclic structures having 6-membered rings that are useful in the treatment of several conditions (eg, stroke and pain).

  In WO 01/45709 published on June 28, 2001, piperidine or calcium having a structure in which a piperazine ring links one benzhydryl structure to another aromatic structure or benzhydryl structure. A channel blocker is disclosed. This announcement (which is based on the above-mentioned parent application No. 09/476927) is hereby incorporated by reference and considered herein. As explained in these applications, natural calcium channels have been classified as T, L, N, P and Q types by their electrophysiological and pharmacological properties. T-type (or low voltage activated) channels are used to describe a broad class of molecules that are transiently activated by a negative potential and are very sensitive to various changes in resting potential. It has been. L, N, P and Q-type channels are activated at higher potentials (high voltage activated type) and exhibit various kinetic characteristics and voltage dependent characteristics. The biophysical properties of these high-voltage activated channels alone are somewhat overlapping and cannot be completely distinguished, so pharmacological properties are effective in further distinguishing them . There is debate about whether the Q-type channel and the P-type channel have different entities as molecules. Some types of calcium permeability do not fall properly in any of the above categories. Furthermore, even within one category, there is a variability in properties that suggests that other subtypes of calcium channels remain unclassified.

  Biochemical analysis indicates that the high-potential activated calcium channel of nerve cells is a hetero-oligomeric complex composed of at least three different subunits (α1, α2δ and β). This α1 subunit is a major subunit that forms a pore, and there is a binding site between a potential sensor and a calcium channel antagonist. The α2 subunit, in which most of the molecule is located outside the cell, is connected to the transmembrane δ subunit by a disulfide bond. Both are originally a single polypeptide made from one gene, but are cleaved into two molecules by proteolytic action in vivo. The β subunit is a hydrophilic protein that is not modified by a sugar chain, and has a high binding affinity in a region exposed to the cytoplasm of the α1 subunit. The fourth subunit, the γ subunit, is specific for the L-type calcium channel expressed in T-tubules of skeletal muscle.

  Recently, each of these α1 subtypes has been cloned, and it has become possible to prepare recombinant proteins from the resulting genes, enabling more thorough pharmacological studies. These channels were designated α1A-α1I and α1S and were associated with the subtypes described above. α1A channel belongs to P / Q type; α1B represents N; α1C, α′1D, α1F and α1S represent L; α1E represents a new type of calcium permeability and α1G-α1I represents T type Represents a family member.

  Further details regarding the function of N-type channels (which are primarily localized to neurons) are disclosed, for example, in US Pat. No. 5,623,051. The disclosure of which is hereby incorporated by reference. As stated, the N-type channel has a site that binds to syntaxin, one of the proteins anchored to the presynaptic membrane. Blocking this interaction also blocks the presynaptic response to calcium influx. Thus, compounds that block the interaction between syntaxin and its binding site may be useful for neuroprotection and analgesia. Such compounds have the added benefit of enhanced specificity due to effects on presynaptic calcium channels.

  US Pat. No. 5,646,149 describes a group of calcium channel antagonists that can be described as AYB, with one piperazine directly binding to Y or B containing a piperidine ring. is doing. The most important component of these molecules is represented by A and it must be an antioxidant; therefore, piperazine or piperidine itself is said to be important. The compounds exemplified here contain benzhydryl substituents, which are based on known calcium channel blockers (see below). In some cases, the antioxidant may be a methoxy substituent and / or a phenyl group containing a hydroxyl substituent. However, in most of the illustrative compounds, one benzhydryl moiety is simply attached to the heterocycle via one CH or C = group. In a small number of compounds where the alkylene chain is between CH and a heterocycle with two phenyl groups attached, the antioxidant must be attached to the heterocycle via one unsubstituted alkylene. In most of these cases, the antioxidant is a bicyclic system. In the case where the antioxidant can simply be one phenyl structure moiety attached through one alkynylene, the linker from the heterocycle to the phenyl structure moiety contains at least 6 atoms in the chain. US Pat. No. 5,703,071 discloses compounds that are said to be useful in treating ischemic diseases. An essential part of this molecule is one tropolone residue; piperazine derivatives, including their benzhydryl derivatives, are one of the permissible substituents. US Pat. No. 5,428,038 discloses compounds that are said to have neuroprotective and anti-allergic effects. These compounds are coumarin derivatives that may include piperazine and other 6-membered ring derivatives. One possible substituent on the heterocycle is diphenylhydroxymethyl. Thus, approaches in the art for various indications that may include calcium channel blocking activity include piperidine or piperazine structural moieties incidentally substituted with benzhydryl, but additional substituents. Has used compounds that require functionality to be maintained.

  Certain compounds containing both a benzhydryl moiety and piperidine or piperazine are known to be calcium channel antagonists and neuroleptics. For example, Gould, RJ, et al. Describe antischizophrenic neuroleptics such as ridofuradine, fluspirylene, pimozide, clopimozide, penfluridol in the American Academy of Sciences (80, 5122-5125) in 1983. . Flupirylene not only blocks N-type calcium flow (reported by Grantham, CJ et al .: Brit. J. Pharmacol. (1944) 111: 483-488) but also binds to L-type calcium channels (King, VK Reported by J. Biol. Chem. (1989) 264: 5633-5641)). Furthermore, lomelidine developed by Kanebo is a known calcium channel blocker, but it does not work only for N-type channels. A review of various publications on lomerizine is written by Dooley, D., page 116 to page 125, Volume 1 of the Current Opinion in CPNS Investigational Drugs (1999).

  Further, benzhydryl derivatives of piperidine and piperazine are described in WO 00/01375 published on January 13, 2000, which is hereby incorporated by reference. This International Publication is consistent with Grandfather Application No. 09/401699 mentioned above. As is known in the prior art, references to compounds of this type can be found in WO 00/18402 published April 6, 2000 and in Bioorganic and Medicinal Chemistry by Chiarini, A. et al. In the 1996 description (Volume 4, pages 1629 to 1635).

  Various other piperidine or piperazine derivatives containing aryl substituents attached via a non-aromatic linker are known as calcium channel blockers, US Pat. No. 5,292,726, WO 99/43658, Breitenbucher, JG et al., 1998 Tat Lett (Vol. 39, pages 1295 to 1298).

  The present invention is based on the recognition that combining a heterocyclic 6-membered ring containing at least one nitrogen linked to a benzhydryl moiety via a linker enables effective calcium channel blocking activity. . In some cases, increased specificity for N-type and / or T-type channels or reduced specificity for L-type channels has been shown. These compounds are useful for the treatment of stroke, pain and other calcium channel related disorders, as described further below. By focusing on these structural parts, compounds are prepared that are useful when dealing with several indications related to the activity of calcium channels.

ここで、Ａｒはフェニル、複素環式芳香族である６員環若しくは５員環、又は、融合芳香族若しくは複素環式芳香族系あって、それぞれが、１つ又はそれ以上の非干渉置換基で任意に置換されていてもよく；
Ｘ^１は、１員〜５員を含むリンカーであり；
ｎは０又は１であり；
Ｒ^１からＲ^３のそれぞれは、独立に１つの非干渉非水素置換基を表し；
それぞれのｌは、独立に０〜５であり；
ｍは０〜４であり；
Ｘ^２は少なくとも５員からなる１つの鎖を含むリンカーであり；
Ａは、Ｈ、ＯＲ、ＳＲ、ＮＲ_２、又はハロ、このときＲはＨ又は低級アルキル（１−６Ｃ）であり；
但し
（ａ）Ａｒは５員環若しくは６員環複素環式置換基、又は置換されていてもよい融合芳香族、若しくは複素環式芳香族置換基であり；及び／又は
（ｂ）ｎは０であり；及び／又は
（ｃ）ｍは１〜４であり；及び／又は
（ｄ）Ｘ^２は＝Ｏ、ＯＲ、ＳＲ、ＮＲ_２、及び／又はハロに置換されるアルキレン基であり；及び／又は
（ｅ）Ｘ^２は少なくとも６員からなる１つの鎖であり；及び／又は
（ｆ）Ｘ^２はＮ、Ｓ、Ｏから選ばれる少なくとも１つのへテロ原子を含み；及び／又は
（ｇ）Ａは、ＯＲ、ＳＲ、ＮＲ_２、又はハロ、このときＲはＨ又は低級（１−６Ｃ）アルキル基であり；及び／又は
（ｈ）Ａｒは少なくとも１つのｔ−ブチル成分、若しくは少なくとも１つの置換アルコキシ基で置換され；及び／又は
（ｉ）Ｘ^１は、Ｏ、Ｎ、及びＳから選ばれる少なくとも１つのへテロ原子を含む。 This invention relates to stroke, anxiety, bladder hypersensitivity, inflammatory bowel disease, head trauma, migraine, chronic neuropathic acute pain, epilepsy, with calcium metabolism including functions mediated by synaptic calcium channels It relates to compounds useful in treating conditions such as hypertension, cardiac arrhythmia and other symptoms. The compounds in this invention are some benzhydryl derivatives of piperazine having substituents that enhance the calcium channel blocking activity of the compounds. Thus, as one aspect, the present invention is directed to a compound represented by the formula (1).

Where Ar is phenyl, a heterocyclic aromatic 6-membered ring or 5-membered ring, or a fused aromatic or heterocyclic aromatic system, each having one or more non-interfering substituents Optionally substituted with
X ¹ is a linker containing 1 to 5 members;
n is 0 or 1;
Each of R ¹ to R ³ independently represents one non-interfering non-hydrogen substituent;
Each l is independently 0-5;
m is 0-4;
X ² is a linker comprising one chain of at least 5 members;
A is, H, OR, SR, NR _2, or halo, where R is H or lower alkyl (l6C);
Where (a) Ar is a 5-membered or 6-membered heterocyclic substituent, or an optionally substituted fused aromatic or heterocyclic aromatic substituent; and / or (b) n is 0 And / or (c) m is 1-4; and / or (d) X ² is an alkylene group substituted with ═O, OR, SR, NR ₂ , and / or halo; and And / or (e) X ² is a chain of at least 6 members; and / or (f) X ² contains at least one heteroatom selected from N, S, O; and / or (g ) A is OR, SR, NR ₂ , or halo, where R is H or a lower (1-6C) alkyl group; and / or (h) Ar is at least one t-butyl moiety, or at least 1 One of substituted with a substituted alkoxy group; and / or (i) ^{X 1} is, O, N And at least one hetero atom selected from S.

ここで、Ａｒ、Ｒ^１〜Ｒ^３、ｌ、ｍ、Ｘ^２、Ａは上で述べた通りであり、ｈｅｔはＯ、Ｓ、及びＮから選ばれるヘテロ原子であり、並びにＸ^１’は１員鎖を欠いたＸ^１である。 In a group of preferred embodiments, these compounds are represented by formula (2) as follows:

Here, Ar, R ^{1 to} R ³ , l, m, X ² , A are as described above, het is a heteroatom selected from O, S, and N, and X ^{1 ′} is 1 X ¹ lacking a member chain.

ここで、Ａｒ、Ｘ^１、Ｒ^１−Ｒ^３、ｌ、ｍ、ｎ、Ａ、及びＡｒは上で述べた通りであり、Ｘ^２'は１員鎖を欠いたＸ^２である。 In another embodiment, the compound of the present invention is represented by the following formula (3):

Here, Ar, X ¹ , R ¹ -R ³ , 1, m, n, A, and Ar are as described above, and X ^{2 ′} is X ² lacking a one-membered chain.

ここで、Ｒ^４はカルボン酸基、又は、そのエステル、若しくはアミドであり、Ａｒ、Ｒ^２-Ｒ^３、Ｘ^１、ｌ、ｎ、Ｘ^２、Ａは上で述べた通りである。 In still another embodiment, the present invention is designated as a compound represented by the following formula (4).

Here, R ⁴ is a carboxylic acid group, or an ester or amide thereof, and Ar, R ² -R ³ , X ¹ , 1, n, X ² , and A are as described above.

The substituents R ^{1 to} R ³ , the substituent of Ar, and the substituent of the substituted alkoxy in (h) are each independently optionally substituted alkyl (1-10C), alkenyl (2 -10C), alkynyl (2-10C), aryl (6-10C), arylalkyl (7-16C), or arylalkenyl (7-16C), each optionally further from 1 to 4 It may contain a terror atom (N, O, or S). Further, herein, alkyl, alkenyl, and other optional substituents may contain one or more ═O. This includes embodiments in which each of these substituents may independently form one acyl, amide, or ester bond with the atom to which it is attached. Substituents R ¹ to R ³ , Ar substituents, or substituted alkoxy group substituents are each independently one or more halo, CF ₃ , OCF, NO ₂ , NR ₂ , OR, SR, COOR, and / or CONR ₂ are included. Here, R is H or an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, or arylalkenyl as described above. Furthermore, S may be oxidized. In addition, two substituents at adjacent positions in the same ring are fused to the above-described substituent ring or the above-mentioned optionally substituted fused ring, and optionally to one or more. It may form a 3 to 7 membered saturated or unsaturated ring containing a telo atom (N, S, O). In addition, the fused rings described herein may further be fused to additional aromatic substructures, such as those shown in the structure of the P35 compound.

In addition, a combination of R ² and R ³ may form one bond or a bridge between the phenyl groups to which they belong. For example, R ² and R ³ together can be one bond, or one or more CR ₂ groups, one NR group, one O, or S. Here, S is optionally oxidized or a combination thereof.

  The present invention also uses the compound of formula (1) to modulate the activity of calcium channels, preferably the activity of N-type and T-type calcium channels, for treating certain unfavorable physiological conditions. Also directed to several ways for. The symptoms dealt with here are related to abnormal calcium channel activity. From another aspect, the present invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds for the preparation of a medicament for the treatment of conditions requiring modulation of calcium channel activity. Is.

  The compounds of formula (1) useful in the methods of the present invention exert their desired effect by virtue of their ability to modulate the activity of N-type and / or T-type calcium channels. This makes them useful in the treatment of certain symptoms. Among the symptoms for which antagonist activity is desired are stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, bladder hypersensitivity, and chronic neuropathic acute pain. Calcium flux is also associated with other neurological diseases such as schizophrenia, anxiety, depression, other psychoses, neurodegenerative diseases, drug / alcohol addiction and withdrawal symptoms. Other symptoms that can be treated include cardiovascular symptoms such as hypertension and cardiac arrhythmia. In addition, T-type calcium channels are associated with certain types of cancer, diabetic infertility and sexual dysfunction.

  Although anti-taxes of formula (1) generally have this activity, once this class of calcium channel modulators is obtained, a subtle selection of compounds for a particular disorder is possible. The availability of this class of compounds not only provides a class of general utility for symptoms affected by calcium channel activity, but also delves into specific interactions with specific types of calcium channels. Provides a large number of compounds that can be investigated and manipulated. If a calcium channel produced by the aforementioned recombinant DNA technology of α1A-α1I type or α1S type is obtained, this selection process is facilitated. References; Dubel, SJ, 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, TP, et al., Neuron (1991) 7: 45-57; Soong, TW, et al., Science (1993) 260: 1133-1136; Tomlinson, WJ, et al., Neuropharmacology (1993) 32: 1117-1126; Williams, ME, et al., Neuron ( 1992) 8: 71-84; Williams, ME, et al., Science (1992) 257: 389-395; Perez-Reyes, et al., Nature (1998) 391: 896-900; Cribbs, LL, et al ., Circulation Research (1998) 83: 103-109; Lee, JH, et al., Journal of Neuroscience (1999) 19: 1912-1921; McRory, JE, et al., Journal of Biological Chemistry (2001) 276: 3999-4011.

It is known that calcium channel activity is associated with a number of diseases and that certain types of channels are associated with specific symptoms. The association of N-type and T-type channels in conditions associated with neurotransmission would indicate that the compounds of the invention that target N-type receptors are most useful in these conditions. For N-type channels, these symptoms are as follows:
Chronic pain neuropathic pain
Diabetic peripheral neuropathy
Postherpetic neuralgia
Trigeminal neuralgia
AIDS-related neuropathy Cancer pain Inflammatory pain
Osteoarthritis pain
Rheumatoid arthritis pain
Fibromyalgia Acute pain Nociceptive pain Postoperative pain Mood disorder Anxiety disorder
Generalized anxiety disorder
Social anxiety disorder
Panic disorder
Obsessive-compulsive disorder
Post-traumatic stress disorder depression addiction
Cocaine dependence and withdrawal
Opioid dependence and withdrawal
Alcohol dependence and withdrawal
Nicotine dependence and withdrawal gastrointestinal disorders inflammatory bowel disease irritable bowel syndrome urogenital disorders urinary incontinence interstitial colitis sexual dysfunction

For T-type channels, these symptoms are as follows:
Cardiovascular disease Hypertension Arrhythmia
Atrial fibrillation congestive heart failure angina pectoris partial attack
Temporal lobe epilepsy generalized seizure tonic clonic seizure diabetes cancer chronic pain neuropathic pain
Diabetic peripheral neuropathy
Postherpetic neuralgia
Trigeminal neuralgia
Cancer pain
AIDS-related neuropathy Inflammatory pain
Osteoarthritis pain
Rheumatoid arthritis pain
Fibromyalgia Acute pain Nociceptive pain Postoperative pain

Many of those belonging to the genus of the compound of formula (1) exhibit high affinity for N-type channels and / or T-type channels. That is, as described below, they are sorted by their ability to interact with N-type and / or T-type channels as an initial indicator of desired function. It is desirable for the compound to exhibit an IC ₅₀ at a concentration of 1 μM. The IC ₅₀ is a concentration that inhibits the flow of calcium, barium, or other osmotic divalent cations to some practical extent.

  There are three distinct types of calcium channel inhibition. The first, referred to as “open channel block”, is the calcium channel exhibited at an artificial quiescent negative potential of about −100 mV (distinguishable from a typical intrinsic resting potential of about −70 mV). Is conveniently indicated when is maintained. Under these conditions, when the presented channel is rapidly depolarized, calcium ions will flow through the channel, transiently exhibiting a peak current, and then the current decays. An open channel blocker inhibitor can reduce the current shown by this peak flow and further accelerate its decay rate.

  This type of inhibition is referred to herein as “inactivation inhibition”. A distinction is made from the second type of blocking. When maintained at a lower quiescent potential, such as a physiologically important potential of -70 mV, a sudden depolarization causes some percentage of these channels to change structure and become active, That is, it cannot become an open state. Thus, the peak current due to calcium ion flow is not reduced because the open channels are blocked, but not because some of those channels cannot be opened (inactivated). Become. “Inactivated” type inhibitors increase the proportion of receptors in an inactivated state.

  The third type of inhibition is called “resting channel block”. Resting channel blockade is a channel blockage that occurs in the absence of membrane depolarization, usually leading to opening or inactivation. For example, quiescent channel blockers reduce the amplitude of the peak current very early after depolarization after drug administration without additional suppression during the depolarization.

  It is also useful to evaluate side effects that may occur for maximum effective use in therapy. For example, in addition to being able to modulate a particular calcium channel, it is desirable for the compound to have very low activity against HERG potassium channels expressed in the heart. Compounds that block this channel with strong potency will cause a lethal reaction. Therefore, for compounds that modulate this calcium channel, it is necessary to further show that there is no functional inhibition of this HERG potassium channel. Similarly, it is undesirable for a compound to inhibit the function of cytochrome p450. Because this enzyme is necessary for detoxification of drugs. Ultimately, compounds are evaluated for their specificity for the type of calcium ion channel by comparing their activity among the various types of calcium channels. And specificity for one particular channel type is preferred. Compounds that successfully pass these tests are then tested in experimental animal models as actual candidate drugs.

  The compounds of the present invention modulate the activity of calcium channels; in general, such modulation is the inhibition of the activity of channels that transport calcium. As described below, the effect of a particular compound on the activity of a calcium channel can be readily ascertained by routine analytical evaluation. In that case, the conditions are set so that the channel is activated and the effect of the compound on this activation (whether proactive or inhibitory) is assayed. A typical analytical evaluation is described below.

Compounds of the invention The substituents in the basic structures of formulas (1) to (4) are as described above. These include alkyl, alkenyl, alkynyl, and other substituents.

  The terms “alkyl”, “alkenyl”, and “alkynyl” mean straight chain, branched chain, and monovalent cyclic substituents, when they are unsubstituted or otherwise specified, Only C and H are included. Specific examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and similar molecules. Typically, alkyl, alkenyl, and alkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl). Desirably they contain 1-6C (lower alkyl) or 2-6C (lower alkenyl or lower alkynyl).

  Heteroalkyl, heteroalkenyl, and heteroalkynyl are similarly defined, but contain one or more O, S, or N heteroatoms, or combinations thereof in the backbone residues. But you can.

  As used herein, “acyl” includes the definition of alkylalkenyl, alkynyl, attached to an additional residue via a carbonyl group, and heteroacyl includes the related heterotype.

  "Aromatic" moiety or "aryl" moiety refers to a monocyclic or fused bicyclic moiety such as phenyl or naphthyl; "heteroaromatic" also refers to O, S, And a monocyclic or fused bicyclic ring system containing one or more heteroatoms selected from N. The inclusion of one heteroatom allows the inclusion of a 5-membered ring as well as a 6-membered ring. Thus, typical aromatic / heteroaromatic compounds include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, etc. including. Since tautomers are theoretically possible, phthalimides are also considered aromatic compounds. Any monocyclic or fused bicyclic system having aromatic character with respect to electron distribution through the ring system is included in this definition. Typically, the ring system contains 5-12 ring member atoms.

  Similarly, the terms “arylalkyl” and “heteroarylalkyl” are typically substituted or unsubstituted, saturated, or composed of 1-8C or its hetero form. Aromatic compounds that contain an unsaturated carbon chain and are attached to another residue via one carbon chain, and a heterocyclic aromatic compound system. These carbon chains may further contain a carbonyl group. Thus, they allow them to donate substituents as acyl or heteroacyl moieties.

  In general, any alkyl, alkenyl, alkynyl, acyl, and aryl group contained in a substituent may itself optionally be substituted with additional substituents. The properties of these substituents are similar to those listed for the main substituents themselves. Thus, when a specific example of a substituent is alkyl, the alkyl is optionally substituted so that it has chemical implications and further does not erode the size limitations of the alkyl itself. It may be substituted by the remaining substituents listed as groups; for example, alkyl or alkyl substituted by alkenyl will simply extend the upper limit of carbon atoms for those embodiments. However, alkyl substituted by aryl, amino, alkoxy, etc. is included.

Non-interfering substituents generally include, but are not limited to: alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, ═O, halo, OR, NR ₂ , SR, —SOR, — SO ₂ R, —OCOR, —NRCOR, —NRCONR ₂ , —NRCOOR, —OCONR ₂ , —RCO, —COOR, SO ₂ R, NRSOR, NRSO ₂ R, —SO ₃ R, —CONR ₂ , SO ₂ NR ₂ . Here, each R is independently a substituent such as H or alkyl (1-8C), —CN, —CF ₃ , NO ₂ , etc.

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. More desirably, Ar is phenyl, pyridyl or pyrimidyl. Most preferably Ar is phenyl. Each of these embodiments is optionally alkyl, alkenyl, alkynyl, aryl, O-aryl, O-alkylaryl, O-aroyl, NR-aryl, N-alkylaryl, NR-aroyl, halo, OR, NR ₂ , SR, —OOCR, —NROCR, RCO, —COOR, —CONR ₂ , and / or SO ₂ NR ₂ as defined above (wherein each R is independently H, or , alkyl (l-8C)), and / or, -CN, -CF _3, and / or may be substituted with NO _2. These alkyl, alkenyl, alkynyl and aryl moieties may be further substituted with similar substituents.

Preferred substituents for Ar include tertiary butyl, methoxy, substituted alkoxy, hydroxyl group, and halo. Preferred examples of R ¹ include ═O and carboxy. Preferred embodiments of R ² and R ³ include alkoxy, halo, and alkyl.

The linker X ¹ may or may not be present. When present, it typically has 1 to 5 members in the chain linking the piperazine ring to Ar. A preferred form is alkylene, optionally containing one or more, preferably one heteroatom selected from O, S or N. Preferably, but not necessarily, the heteroatom is adjacent to the aromatic group as shown in formula (2). In many embodiments, X ¹ includes ═O, preferably it is adjacent to the piperazine ring.

The linker X ² is essential and contains at least 5 members in its chain. In many embodiments, X ² includes ═O substituted adjacent to the piperazine ring. X ² may further contain one or more heteroatoms. It is preferably one heteroatom selected from O, S or N and may further comprise a substituent such as OR, SR, NR ₂ and / or halo.

  The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts containing inorganic or organic acids, or may be prepared from inorganic or organic bases in the acid form of the compounds of the present invention. Suitable pharmaceutically acceptable acids and bases are well known in the art and include hydrochloric acid, sulfuric acid, citric acid, acetic acid, or tartaric acid and potassium hydroxide, sodium hydroxide, hydroxide. Ammonium, caffeine, various amines, and the like. Methods for preparing such suitable salts have been established in the prior art.

  In addition, in some cases, the compounds of the present invention contain one or more enantiomeric centers. The present invention includes isolated stereoisomers as well as mixtures of stereoisomers with varying degrees of stereoisomer content purity.

Synthesis of the Compounds of the Invention The compounds of the invention may be synthesized using conventional methods. An example of such a method is schematic 1-5:

Reaction Scheme 1 is used in preparing the compounds of the present invention having keto substituents at X ¹ and X ² . Modifications of the indicated product P44 and product P46 can be made by modifying the substituents on the phenyl ring contained in formula (1) above.

  Reaction Scheme 2 is used to prepare the compounds of the present invention within the scope of the embodiment of formula (2). Variation of R and substitution of the fluoro substituent in compound 6 results in a variant having the corresponding variation in the compound previously shown as 8. In particular, the compounds P1, P2, P3, P4, P5, P6, P7, P8, P39, P9, P10, P11, P12, P13, P14 and P15 may be synthesized in this manner.

  Reaction scheme (3) shows the synthesis of a compound of the invention containing a tertiary butyl substituent at Ar.

  Reaction scheme (4) shows, for example, the synthesis of the compounds of the present invention which contain one keto substituent on the piperazine ring in compounds P48-P57.

  Reaction scheme (5) shows, for example, the synthesis of compounds of the present invention in compounds P36-P47 containing one various substituents on the piperazine ring.

  By using the above method, all the compounds shown in FIG. 1 are synthesized.

Libraries and Screening The compounds of the present invention can be synthesized individually using the prior art per se, or contained within a single combinatorial (a new method for synthesizing multiple compounds at once) library. it can.

  The synthesis of combinatorial libraries is now technically common. A suitable description for such synthesis can be found, for example, in the following literature; Wentworth, Jr., P., et al., Current Opinion in Biol. (1993) 9: 109-115; Salemme, FR, et al., Structure (1997) 5: 319-324. These libraries contain compounds with various substituents and degrees of unsaturation as well as different chain lengths. This library contains at least ten, but typically hundreds to thousands, and therefore specifically for specific subtypes of calcium channels, namely N-type channels. It may be screened for compounds that are effective. In addition, by using standard screening procedures, such libraries may be used to screen for compounds that block additional channels and receptors such as sodium and potassium channels.

  Methods for performing these screening functions are well known in the art. Such methods can also be used to ascertain the ability of one compound individually to activate or inhibit a channel. Typically, the channel to be examined is expressed on the surface of a recombinant host cell such as a human embryonic kidney cell. The ability of a library component to bind to the channel to be tested is, for example, a compound such as a ligand that normally binds to that channel or one antibody to that channel. Measured by ability to displace one labeled binding ligand. More typically, the ability to antagonize the channel is measured in the presence of calcium, barium, or other osmotic divalent cations. Also, the ability of a compound to interfere with the generated signal is measured by standard techniques. More specifically, one method includes the binding of a radioisotope-labeled reagent that interacts with a target calcium channel, followed by a binding rate constant, a dissociation rate constant, a dissociation constant, and others. Analysis of equilibrium binding measurements including, but not limited to, competitive binding by other molecules.

  Another method involves screening for the effect of the compound by electrophysiological analytical evaluation. At this time, individual cells are pierced with microelectrodes and currents through calcium channels are recorded before and after administration of the compound of interest.

  In another method, a high-throughput spectrophotometric assay, a fluorescent dye sensitive to intracellular calcium concentration is added to the cell line, followed by changing the potassium chloride or intracellular calcium concentration. Includes consideration of the effects of compounds on the ability of depolarization by other methods.

  As stated earlier, more reliable analytical evaluations can act as blockers for open channels, or against those that function by promoting channel inactivation or stop the function of channel blockers. Can be used to distinguish between inhibitors of calcium flux. Methods for distinguishing between these types of inhibitors are described in more detail in the examples below. In general, open channel blockers are analyzed by measuring the level of peak current when depolarization is imposed on a background resting potential of about −100 mV in the presence and absence of the candidate compound. Be evaluated. In the case of open channel blockers that function well, this observed peak current may be reduced, further accelerating the decay of this current. Compounds that are inactive channel blockers are usually determined by their ability to shift the voltage dependence of inactivation towards more negative potentials. This is also reflected in the ability to suppress peak currents at more depolarized holding potentials (eg -70 mV) and at stimuli of higher frequencies (eg 0.2 Hz vs. 0.03 Hz). Eventually, quiescent channel blockers will reduce peak current amplitude during the very early depolarization after drug administration, without additional inhibition during the depolarization.

Utility and Administration For use as therapeutics in humans and animals, the compounds of the invention can be formulated as pharmaceutical or veterinary compositions. The manner of administration and the type of treatment desired (eg, prevention, prevention, treatment) will depend on the subject being treated; the compound will be formulated to meet these parameters. An overview of such technology can be found below. This is incorporated herein by reference: Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa.

  In general, for use in therapy, the compound of formula (1) may be used alone or as a mixture of two or more compounds of formula (1) or in combination with other pharmaceutical agents. Good. Depending on the mode of administration, the compound will be formulated into a suitable composition so that it will be easily delivered.

  The formulations may be formulated in a manner suitable for systemic administration or partial administration. Systemic administration includes that designed for injection (eg, intramuscular, intravenous, or subcutaneous injection) or is prepared for transdermal, transmucosal, or oral administration Also good. The formulations will usually include diluents as well as immunostimulants, buffers, preservatives, etc. in certain cases. The compounds can also be administered during the composition of the liposomes or as a fine grain emulsion.

  For injection, the formulations are prepared in conventional forms, either as liquid solutions or as suspensions, or as solid forms for making solutions or suspensions prior to injection, or as emulsions. Can. Suitable suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions further include substantial amounts of non-toxic adjuvants such as humectants or emulsifiers or pH adjusters such as sodium acetate, sorbitan monolaurate, and the like. May be included.

  Various sustained-release systems for drugs have also been devised. See, for example, US Pat. No. 5,624,677.

  Systemic administration may also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the invention. Preferred dosage forms include syrups, capsules, tablets as understood in the prior art.

  For administration to humans and animals, the dose of the compound of the present invention is typically 0.1 to 15 mg / kg, desirably 0.1 to 1 mg / kg. However, dosage levels are highly dependent on the condition, efficacy, patient condition, practitioner's judgment, and frequency and method of administration.

  The following examples are intended to illustrate but not limit the present invention.

Example 1
6,6-Bis- (4-fluoro-phenyl) -1- [4- (3,4,5, -trimethoxy-benzoyl) -piperazin-1-yl] -hex-5-en-1-one (P58 ) Synthesis

  Anhydrous 6,6-bis- (4-fluoro-phenyl) -hex-5-enoic acid (2.64 g, 8.75 mmol) and iodine cyclodextrin inclusion body (CDI) (1.42 g, 8.75 mmol) The mixture was stirred in tetrahydrofuran (30 ml) at room temperature for 1 hour under a nitrogen environment. Piperazin-1-yl- (3,4,5, -trimethoxy-phenyl) -methanone (2.45 g, 8.75 mmol) in anhydrous tetrahydrofuran (30 ml) was added to the above solution and the resulting mixture was Stir overnight at room temperature. The resulting mixture is diluted with ethyl acetate (30 ml), washed with water (2 x 30 ml) and dried over magnesium sulfate. After evaporation of the solvent, column chromatography with dichloromethane: methanol (15: 1) gave the desired product in 49% yield.

Example 2
6,6-Bis- (4-fluoro-phenyl) -5-hydroxy-1- [4- (3,4,5, -trimethoxy-benzoyl) -piperazin-1-yl] -hexane-1-one (P44 ) Synthesis

  6,6-Bis- (4-fluoro-phenyl) -1- [4- (3,4,5, -trimethoxy-benzoyl) -piperazin-1-yl] -hex-5-en-1-one (1 Sodium borohydride (22 mg, 0.58 mmol) is added to an anhydrous tetrahydrofuran solution (20 ml) of .3 g, 2.3 mmol), and then boron trifluoride ether (0.2 ml, 1.43 mmol) is added dropwise. . After the resulting mixture was stirred at room temperature for 3 hours, excess sodium borohydride was decomposed by adding water (0.1 ml). The mixture was then oxidized by adding 3M sodium hydroxide (0.3ml) followed by hydrogen peroxide (0.5ml, 3mmol). After stirring for 1 hour and a half at 30 ° C. to 40 ° C., the mixture was washed with brine (30 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography using ethyl acetate: hexane (3: 1) to obtain the desired product in 64% yield.

Example 3
6,6-bis- (4-fluoro-phenyl) -6-hydroxy-1- [4- (3,4,5, -trimethoxy-benzoyl) -piperazin-1-yl] -hexane-1-one (P46 ) Synthesis

  6,6-Bis- (4-fluoro-phenyl) -1- [4- (3,4,5, -trimethoxy-benzoyl) -piperazin-1-yl] -hex-5-en-1-one (1 A solution of mercury acetate (0.9 g, 2.87 mmol) in water: tetrahydrofuran (1: 1, 6 ml) was added to an anhydrous tetrahydrofuran solution (20 ml) of .62 g, 2.87 mmol). The resulting mixture was refluxed overnight. To this was added sodium hydroxide (3M, 3 ml) followed by sodium borohydride (54 mg, 1.43 mmol). After the mixture was stirred for 4 hours, the separated organic layer was saturated with sodium chloride.

Example 4
1- {4- [2- (3,4-dimethoxy-phenoxy) ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one (P59) Composition

A. Synthesis of 2- (3,4-dimethoxy-phenoxy) -ethanol

  Potassium carbonate (1.07 g, 7.78 mmol) was added to a solution of 3,4, dimethoxyphenol (1.0 g, 6.48 mmol) in anhydrous N, N-dimethylformamide (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added and the mixture was heated to 120 degrees overnight. The mixture was cooled, dissolved in ethyl acetate, extracted with water (20 ml), saturated with sodium chloride (4 times with 20 ml), dried over magnesium sulfate and dried under reduced pressure. The obtained product was purified by column chromatography using silicon dioxide (hexane: ethyl acetate 3: 1) to obtain the desired product in a yield of 60%.

B. Synthesis of 4- (2-bromo-ethoxy) -1,2-dimethoxybenzene

  Triphenylphosphine (1.3 g (5 mmol)) was added to a cooled solution of 2- (3,4-dimethoxy-phenoxy) -ethanol (0.55 g, 2.77 mmol.) In dichloromethane (15 ml). A solution of carbon tetrabromide (1.65 g, 5 mmol) in dichloromethane (3 ml) was added dropwise to the above solution under a nitrogen environment. The solution was stirred for 30 minutes. After adding ethyl acetate, the solvent was evaporated under reduced pressure. The obtained product was purified by column chromatography using silicon dioxide (hexane: ethyl acetate 1: 1) to obtain the desired product in a yield of 85%.

C. 1- {4- [2- (3,4-dimethoxy-phenoxy) ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one (P59) Composition

  4- (2-Bromo-ethoxy) -1,2-dimethoxy benzene (1.41 g, 4.86 mmol) and 6,6-bis- (4-fluorophenyl) -1-piperazin-1-yl-hexane-1 To a solution of -one (1.81 g, 4.86 mmol.) In anhydrous N, N-dimethylformamide (40 ml) was added potassium carbonate (0.8 g, 5.83 mmol.) And the mixture was stirred at 120 ° C. overnight. Stir. Ethyl acetate was added, washed with water (2 x 30 ml) and brine (3 x 10 ml), dried over magnesium sulfate and evaporated under reduced pressure. The product was purified by column chromatography using silicon dioxide (hexane: ethyl acetate 1: 1) and then using ethyl acetate to obtain the desired product in 57% yield.

Example 5
Synthesis of 1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (3,4-dimethoxy-phenoxy) -ethyl] -piperazine (P60)

  1- {4- [2- (3,4-Dimethoxy-phenoxy) ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one (0.7 g , 1.2 mmol) in tetrahydrofuran (15 ml) was added lithium aluminum hydride (100 mg, 2.4 mmol). The mixture was stirred overnight at room temperature under a nitrogen environment. After adding ethyl acetate, it was washed with water (2 x 10 ml) and saturated brine (3 x 5 ml), dried over magnesium sulphate and evaporated under reduced pressure. The obtained product was purified by column chromatography using silicon dioxide (dichloromethane: methanol 10: 1) to obtain the desired product in a yield of 73%.

Example 6
1- [4- (3,5-Di-tert-butyl-4-methoxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one Synthesis of (P18)

A. Synthesis of 3,5-di-tert-butyl-4-methoxy-benzoic acid methyl ester

  3,5-Di-tert-butyl-4-hydroxy-benzoic acid (0.7 g, 2.79 mmol) was added to a solution of potassium hydroxide (313 mg, 5.59 mmol) in anhydrous acetone (8 ml) to obtain The mixture is stirred overnight at room temperature until all the potassium hydroxide is dissolved. After adding methyl iodide (0.41 ml, 6.69 mmol), the resulting mixture was refluxed for 24 hours. Water (8 ml) was added and the aqueous phase was extracted with ether (2 times). The organic phase was washed with 10% sodium hydroxide (once), water (once) and saturated ammonium chloride and then dried over magnesium sulfate. Purification using hexane: ethyl acetate (30: 1) gave 0.6 g of pure product.

B. Synthesis of 3,5-di-tert-butyl-4-methoxy-benzoic acid

  A mixture of 3,5-di-tert-butyl-4-methoxy-benzoic acid methyl ester (0.56 g, 2.01 mmol) and lithium hydroxide (253 mg, 6.03 mmol) was added to tetrahydrofuran: methanol: water (3: 1: 1, 50 ml) at room temperature for 2 days. Thereafter, the solvent was removed, the remaining one was dissolved in water, and acidified to pH 3 with 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. Upon drying, 0.51 g of pure product was isolated.

C. Synthesis of 4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazine-1-carboxylic acid tertiary butyl ester

  To a solution of 6,6-bis- (4-fluoro-phenyl) -hexanoic acid, (2.94 g, 9.66 mmol) in anhydrous dichloromethane (80 ml), monoboc piperidine (1.98 g, 10.63 mmol) was added to nitrogen. Added in the environment. Ethylene dichloride (4.07 g, 21.26 mmol) and dimethylaminopyridine (catalyst) were added to the reaction product, and the reaction mixture was stirred overnight at room temperature in a nitrogen environment. The reaction product was then concentrated under reduced pressure. The resulting product was dissolved in ethyl acetate: water (10: 1) (250 ml). The organics were washed with water (2 x 50 ml) and 10% sodium hydroxide (50 ml), dried over magnesium sulfate and dried to dryness. The product thus obtained was purified using hexane: ethyl acetate (1: 1) to obtain the desired product in a yield of 78%.

D. Synthesis of 6,6-bis- (4-fluoro-phenyl) -1-piperazin-1-yl-hexane-1-one

  To a solution of 4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazine-1-carboxylic acid tert-butyl ester (4.25 g, 8.99 mmol) in anhydrous dichloromethane (100 ml) Fluoroacetic acid (32 ml) was added and the resulting mixture was stirred at room temperature for 3 hours. After evaporation of the solvent and excess trifluoroacetic acid, the residue was dissolved in dichloromethane (150 ml), washed with saturated sodium bicarbonate (twice) and dried over magnesium sulfate. By evaporating the solvent, 3.9 g of pure product was obtained.

E. 1- [4- (3,5-Di-tert-butyl-4-methoxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one Synthesis of (P18)

  To a solution of 6,6-bis- (4-fluoro-phenyl) -1-piperazin-1-yl-hexane-1-one (1.41 g, 3.78 mmol) in anhydrous dichloromethane (60 ml) was added 3,5-di- -Tertiary butyl-4-methoxy-benzoic acid (0.91 g, 3.44 mmol) was added under a nitrogen environment. Ethylene dichloride (1.45 g, 7.57 mmol) and dimethylaminopyridine (catalyst) were added to the reaction, and the reaction mixture was stirred overnight at room temperature under a nitrogen environment. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10: 1) (100 ml). The organic phase was washed with water (30 ml, twice) and 10% sodium hydroxide (30 ml), then dried over magnesium sulfate and dried to dryness. The resulting residue was purified using hexane: ethyl acetate (1: 2) to obtain the desired product in 76% yield.

Example 7
Synthesis of 4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- (3,4,5-trimethoxy-benzyl) -piperazin-2-one (P48)

A. Synthesis of 2-ketopiperazine

  A solution of ethyl bromoacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml) at room temperature. After performing this operation slowly over 3 hours, the resulting mixture is allowed to stand for a further 2 hours. Sodium ethoxide (21% wt, 22 ml, 59.8 mmol) is added dropwise thereto. The mixture is stirred at room temperature overnight and then the solvent is evaporated. N, N-dimethylformamide (40 ml) is added to the residue and stirred at a temperature of 60 ° C. to 70 ° C. for 24 hours. The salt was filtered and the solvent was evaporated. The residue was purified by column chromatography using dichloromethane: methanol: aqueous ammonia (90: 10: 0.1) to give a yellow solid in 45% yield.

B. Synthesis of 4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-2-one

  To a solution of 2-ketopiperazine (400 mg, 3.94 mmol) in anhydrous dichloromethane (30 ml) was added 4,4′-difluorodiphenylhexanoic acid, (1.0 g, 3.28 mmol) under a nitrogen environment. Ethylene dichloride (0.8 g, 4.26 mmol) and dimethylaminopyridine (catalyst) were added to the reaction, and the reaction mixture was stirred at room temperature overnight under a nitrogen environment. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10: 1) (80 ml). The organic phase was washed with water (20 ml, twice) and 10% sodium hydroxide (20 ml), then dried over magnesium sulfate and dried to dryness. The resulting residue was purified using dichloromethane: methanol (20: 1) to give the desired product in 62% yield.

C. Synthesis of 4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- (3,4,5, -trimethoxy-benzyl) -piperazin-2-one (P48)

  4- [6,6-Bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-2-one (0.5 g, 1.29 mmol) and trimethoxybenzyl bromide (337 mg, 1.29 mmol) in anhydrous N , N-dimethylformamide (10 ml) was added with sodium hydride (60%, 60 mg, 1.48 mmol) under nitrogen. After the mixture was stirred at room temperature overnight, water (10 ml) was added and the suspension was extracted with ethyl acetate (40 ml) and dried over magnesium sulfate. This was dried and purified using dichloromethane: methanol (20: 1) to give the desired product in 63% yield.

Example 8
Synthesis of 1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5, -trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester (P36)

A. Synthesis of 1,4-dibenzyl-piperazine-2-carboxylic acid ethyl ester

  To a stirred solution of N, N′-dibenzyl-ethane-1,2-diamine (1 eq) in anhydrous benzene was added triethylamine (2 eq) and the mixture was heated to 40 ° C. under a nitrogen environment. When a solution of 2,3-dibromo-propionic acid ethyl ester (1 equivalent) in anhydrous benzene was added slowly, a dense white precipitate immediately formed. The mixture was heated to 80 ° C. for 3 hours and then cooled and filtered, and the filtrate was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting oil was purified by column chromatography using silicon dioxide gel (hexane: ether 4: 1) to give a yield of 82%.

B. Synthesis of piperazine 2-carboxylic acid ethyl ester

  Dissolve 1,4-dibenzyl-piperazine-2-carboxylic acid ethyl ester (1 equivalent) in ethanol while warming, using hydrogen with 10% or more palladium carbon catalyst at room temperature and normal pressure until hydrogen uptake is complete. Turned into. The obtained mixture was filtered through celite, and the solvent was evaporated to obtain an oil distilled under reduced pressure.

C. Synthesis of 4- (3,4,5-trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester

  Piperazine 2-carboxylic acid ethyl ester (2.25 g, 14.25 mmol) was dissolved in anhydrous benzene (30 ml), and then triethylamine (2.2 ml, 15.67 mmol) was added. A solution of trimethoxybenzyl bromide (3.72 g, 14.25 mmol) in anhydrous benzene (30 ml) was added dropwise thereto. The resulting mixture was stirred at room temperature overnight under a nitrogen environment. The resulting salt was removed by filtration and the solvent was dried. The crude product was purified using dichloromethane: methanol (15: 1) to give the desired product in 62% yield.

D. Synthesis of 1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5, -trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester (P36)

  4- (3,4,5-Trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester (2.0 g, 5.91 mmol) was dissolved in anhydrous benzene (30 ml), and then triethylamine (0.65 g, 6. 5 mmol) was added and the resulting solution was stirred for 1 hour. A solution of 1- [6,6-bis- (4-fluoro-phenyl) -hexyl bromide (2.08 g, 5.91 mmol) in anhydrous benzene (30 ml) was added dropwise thereto. The resulting mixture was stirred overnight at room temperature under a nitrogen environment. The mixture was washed twice with water (30 ml), dried over magnesium sulfate and evaporated to dryness. The crude product was purified using hexane: ethyl acetate (3: 1) to give the desired product in 56% yield.

Example 9
Synthesis of 1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5, -trimethoxy-benzyl-piperazine-2-carboxylic acid

  1- [6,6-Bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5, -trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester (0.64 g, 1. 04 mmol) and lithium hydroxide (132 mg, 3.14 mmol) in tetrahydrofuran: methanol: water (3: 1: 3, 35 ml) as solvent were stirred at room temperature overnight. The solvent was then evaporated and the residue was dissolved in water (10 ml) and acidified to pH 3 with 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. Purification by column chromatography using dichloromethane: methanol (15: 1) gave the desired product in 51% yield.

Example 10
Evaluation of calcium channel blocking activity

  The activity of the antagonist is constant or transiently or transiently expressed on human fetal kidney cells expressing rat-derived N-type channels (α1B + α2b + β1b subunits) using 5 mM barium as a charge carrier. It was measured by cell patch recording. Instead, a L-type channel (α1C + α2δ + β1b cDNA subunit) and a P / Q-type channel (α1A + α2δ + β1b cDNA subunit) derived from rat may be used.

  For transient expression, host cells were cultured in DMEM medium supplemented with 2 mM glutamine and 10% fetal calf serum, for example, human fetal kidney cells HEK293 (ATCC # CRL 1573). HEK293 cells were transformed by α1B + β1b + α2δ N-type calcium channel subunit genes from rats with vertebrate expression vectors by standard calcium phosphate DNA coprecipitation (eg, Current Protocols in Molecular Biology). reference).

After culturing for 24 to 72 hours, the culture medium was removed and replaced with an external recording solution (see below). The Axopatch 200B amplifier (Axon Instruments, Burlingame, Calif.) Connected to an IBM compatible personal computer with pCLAMP software installed was used for the whole cell patch clamp experiment. A patch pipette made of borosilicate glass (Sutter Instrument Co., Novato, Calif.) Is a cesium methane sulfonate solution (MM composition: 109 methyl cesium sulfate (CsCH ₃ SO ₄ ), magnesium tetrachloride, 9 ethylene glycol bis. 2 aminoethyl ether tetraacetic acid (EGTA), 9HEPES, pH 7.2) and polished to a resistance of about 4 MΩ (Microforge, Narishige, Japan). The cells were soaked in 5 mM Ba ⁺⁺ (mM ratios as follows: barium pentachloride, magnesium chloride, 10HEPES, 40 tetraethylammonium chloride, 10 glucose, 87.5 cesium chloride, pH 7.2). The current data shown is from 100-100 mV and / or -80 mV to various potentials (minimum -20 mV, maximum +30 mV) with a 0.066 Hz frequency test pulse continuously for 100 milliseconds. Induced by adding. The drug was perfused directly into the vicinity of the cells using a microperfusion system.

Normalized dose response curves were fitted using the Hill equation to determine IC50 values (Sigmaplot 4.0, SPSS Inc., Chicago, Ill.). The steady-state inactivation curve was plotted as the normalized test pulse amplitude following a 5 second pre-inactivation pulse at a potential increase of +10 mV. The inactivation curve was fitted using the following Boltzmann equation (Sigmaplot 4.0); I _peak (normalized) = 1 / (1 + exp ((V−V _h ) z / 25.6)) V, and V _h, respectively, acclimatization (for acclimatize to their conditions) potential, and a semi-inactivation potentials, z is the slope factor.

Example 11
Other methods

  The method of Example 10 was modified slightly as described in the description below.

A. Transformation of HEK cells

N-type calcium channel blocking activity was evaluated using HEK293, a human embryonic kidney cell stably transfected with rat brain-derived N-type calcium channel subunit (α1B + α2δ + β1b cDNA subunit). Alternatively, N-type calcium channel (α1B + α2δ + β1b cDNA subunit), L-type calcium channel (α1C + α2δ + β1b cDNA subunit), and P / Q-type calcium channel (α1A + α2δ + β1b cDNA subunit) are transiently expressed in HEK293 cells. It was. Briefly, the cells were in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal calf serum, 200 U / ml penicillin, and 0.2 mg / ml streptomycin. And cultured under conditions of 37 ° C. and 5% CO ₂ . Cells having a confluence of 85% were detached from each other with 0.25% trypsin / 1 mM ethylenediaminetetraacetic acid, and then spread on a glass cover glass to a concentration of 10%. After 12 hours, the culture medium was removed and the appropriate calcium channel cDNA was transiently transferred to these cells by standard calcium phosphate methods. After adding fresh DMEM, the cells were transferred to a 28 ° C./5% CO ₂ environment. These cells were cultured for 1 or 2 days until total cell recording.

B. Inhibition measurement

For the whole cell patch clamp experiment, an Axopatch 200B amplifier (Axon Instruments, Burlingame, Calif.) Connected to a personal computer installed with pCLAMP software was used. The external and internal recording solutions were 5 mM barium chloride, 1 mM magnesium chloride, 10 mM HEPES, 40 mM tetraethylammonium chloride (TEACl), 10 mM glucose, 87.5 mM cesium chloride (pH 7.2), and 108 mM methylcesium sulfate ( CsCH ₃ SO ₄ ), 4 mM magnesium chloride, 9 mM ethylene glycol bis 2 aminoethyl ether tetraacetic acid (EGTA), 9 mM HEPES (pH 7.2). Current was typically induced from a maintenance potential of -80 mV to +10 mV using Clampex software (Axon Instruments). Typically, the current was initially induced by a low frequency stimulus (0.03 Hz) and stabilized before applying the compounds. The compound was then administered during the addition of a low frequency pulse sequence of 2 to 3 minutes to assess tonic blockade. And then the pulse frequency was raised to 0.2 Hz in order to evaluate the frequency dependent blockage. Data were analyzed using Clampfit (Axon Instruments) and SigmaPlot 4.0 (Jandel Scientific).

  Some results for N-type, P / Q-type, and L-type calcium channels of the compounds of the present invention are shown in Table 1:

[Table 1]

Example 12
Channel blocking activity of various inventive compounds

Using the procedures described in Examples 10 and 11, the activity of various compounds of the invention to block N-type calcium channels was tested and the results are shown in Table 2. These results show IC ₅₀ values in the range of 0.05 μM to 1 μM. In addition, FIGS. 2, 3, and 4 show the specificity of compounds P18, P36, and P104 that selectively block N-type calcium channels relative to L-type calcium channels and P / Q-type calcium channels. Is shown.

[Table 2]

Example 13
α _1G   Blocking the T channel

Standard patch clamp techniques were used to identify T-type current blockers. Briefly, the aforementioned HEK cell line stably expressing the human α1G subunit was used for all recordings (passage number 4-20, 37 ° C., 5% CO ₂ environment). In order to obtain a T-type current, the culture solution was exchanged with an external solution (see below), and then a plastic dish with semi-confluent cells was placed on the stage of a ZEISS AXIOVERT S100 microscope. The whole cell patch has a resistance value of about 5 MΩ (see below for the internal solution), and a pipette (outer diameter: 1.5 mm, inner diameter: 0. 0 mm) made using a SUTTER P-97 glass electrode preparation device. 86 mm, length: 10 cm borosilicate glass with filaments).

[Table 3]

Ｔ型電流は、ふたつの電圧プロトコルを用いることで確実に得る事ができる：「非不活性化」、及び、「不活性化」 [Table 4]

A T-type current can be reliably obtained by using two voltage protocols: “deactivation” and “deactivation”.

  In the non-inactivation protocol, the sustain potential is set to -110 mV, with 40 mV, -100 mV before the 50 millisecond test current, with a 1 second pre-pulse. In the inactivation protocol, the pre-pulse is about -85 mV for 1 second, which inactivates about 15% of the T-type channel, as shown below.

The test compound was dissolved in an external solution containing 0.1% to 0.01% dimethyl sulfoxide. After standing for about 10 minutes, they were administered by gravity drop near the cells using WPI microtubules. A “non-inactivated” pre-pulse was used to examine the resting block of one compound. An “inactivation” protocol was used to study voltage-dependent blockade. However, the initial data was obtained using a non-inactivation protocol. The IC ₅₀ value for P18 was found to be 0.022 μM under this protocol.

  The results for some of the compounds of the present invention are shown in Table 5.

[Table 5]

Example 14
Activity of inventive compounds in formalin-induced pain models

  The effect of the compounds of the present invention delivered into the submembrane space in the rat formalin model was measured. The compound was prepared as a stock solution at a concentration of about 10 mg / ml using propylene glycol as a solvent. Eight male Holzmann rats from 275g to 375g were randomly selected to test one compound.

  The following study groups were used with test compounds administered intraperitoneally (IP), vehicle control (propylene glycol), and saline.

[Table 6]

  Before starting drug administration, baseline behavioral data and test data are taken. These data are taken again at selected times after injection of the test compound or control.

  On the morning of the test day, a small metallic band (0.5 g) was loosely placed around the animal's right hind paw. Rats were placed in a cylindrical Plexiglas container for a minimum of 30 minutes to acclimate. The test compound or vehicle control was administered 10 minutes before formalin (50 μl of 5% formalin) was injected into the dorsal surface of the rat right hind leg. The animal is then placed in the room of an automated formalin lab where the movement of the leg infused with formalin is monitored and the number of leg atrophys in increments of 60 minutes thereafter is recorded. It was done. (See Malmberg, A.M., and Yaksh, T.L., Anesthesiology (1993) 79: 270-281.)

  The results are expressed as the maximum expected effect ± standard error of the mean, with a saline control of 100%.

[Table 7]

FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 1 shows an illustrative compound of the invention. FIG. 2 is a graph showing the selectivity of compound P18 of the present invention for N, PQ, T, and L-type channels. FIG. 3 is a graph showing the selectivity of compound P36 of the present invention for N, PQ, T and L-type channels. FIG. 4 is a graph showing the selectivity of compound P104 of the present invention for N, PQ, T, and L-type channels.

Claims (18)

A compound represented by the following formula (1):

Where Ar is phenyl, a heterocyclic aromatic 6-membered or 5-membered ring, or a fused aromatic or heterocyclic aromatic system, each of which is one or more non-interfering substituents Optionally substituted;
X ¹ is a linker containing 1 to 5 members;
n is 0 or 1;
Each of R ¹ to R ³ independently represents a non-interfering non-hydrogen substituent;
Each l is independently 0-5;
m is 0-4;
X ² is a linker comprising a chain of at least 5 members;
A is, H, OR, SR, NR _2, or halo, where R is H or lower alkyl (l6C);
Where (a) Ar is a 5-membered or 6-membered heteroaryl substituent, or an optionally substituted fused aromatic or heterocyclic aromatic substituent; and / or (b) n is 0 And / or (c) m is 1-4; and / or (d) X ² is an alkylene group substituted with ═O, OR, SR, NR ₂ , and / or halo; and / Or (e) X ² is a chain of at least 6 members; and / or (f) X ² contains at least one heteroatom selected from N, S, O; and / or (g) A is OR, SR, NR ₂ , or halo, where R is H or a lower (1-6C) alkyl group; and / or (h) Ar is at least one t-butyl moiety, or at least one Substituted with a substituted alkoxy group; and / or (i) X ¹ includes at least one heteroatom selected from O, N, and S. The compound of claim 1 represented by formula (2):

Here, Ar, R ^{1 to} R ³ , l, m, X ² , A are as described above, het is a heteroatom selected from O, S, and N, and X ^{1 ′} is 1 X ¹ lacking a member chain. The compound of claim 1 represented by formula (3):

Here, Ar, X ¹ , R ¹ -R ³ , 1, m, n, A, and Ar are as described above, and X ^{2 ′} is X ² lacking a one-membered chain. The compound of claim 1 represented by formula (4):

Here, R ⁴ is ═O, or a carboxylic acid group, or an ester or amide thereof, and Ar, R ^{2 to} R ³ , X ¹ , 1, n, X ² , and A are as described above. Each non-interfering substituent is independently alkyl (1-10C), alkenyl (2-10C), alkynyl (2-10C), aryl (6-10C), arylalkyl (7-16C), or arylalkenyl (7-16C), each optionally further comprising 1 to 4 heteroatoms (N, O, or S), each of which is optionally further substituted, or each incoherent The substituent is independently ═O, halo, CF ₃ , OCF, NO ₂ , NH ₂ , OH, or SH, where S may be oxidized. . The phenyl groups represented by A and B are linked via one bond or one or more CR ₂ components, wherein each R is H or a lower alkyl group (1-6C); one or more of the CR ₂ is, NR, O, or any of the compounds of may claims 1 to 5 be replaced by S.   Each l is independently 0 or 1, The compound in any one of Claims 1-6. The compound of any of claims 1 to 7, X ² is replaced by = O in close proximity to the piperazine ring. The compound of any of claims 1-8 in which X ¹ is replaced by = O at the next position of the piperazine ring. The compound according to any one of claims 1 to 9, wherein each R ² and R ³ is independently alkoxy, halo, or alkyl. The compound according to any one of claims 1 to 10, wherein m is 1, and R ¹ is = O, a carboxylic acid group, or an ester or amide thereof.   12. A compound according to any of claims 1 to 11, wherein Ar is optionally substituted phenyl.   13. The compound of claim 12, wherein the phenyl is unsubstituted or substituted with one or more tertiary butyl, methoxy, substituted alkoxy, hydroxy, and / or halo.   14. The compound of claim 13, wherein the substituted alkoxy is substituted with an amino group.   The compound according to any one of claims 1 to 11, wherein Ar is an optionally substituted pyrimidyl, pyridyl, benzothiazole, benzimidazole, or indole. 6,6-bis- (4-fluoro-phenyl) -1- [4- (2-phenylsulfanyl-ethyl) -piperazin-1-yl] -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (4-fluoro-phenoxy) -ethyl] -piperazine;
1- {4- [2- (Benzo [1,3] dioxol-5-yloxy) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1- on;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (2-phenylsulfanyl-ethyl) -piperazine;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (4-methoxy-phenoxy) -ethyl] -piperazine;
1- {4- [2- (2,4-difluoro-phenoxy) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- [4- (2-phenoxy-ethyl) -piperazin-1-yl] -hexane-1-one;
1- {4- [2- (2,4-dichloro-phenoxy) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- {4- [2- (4-methoxy-phenoxy) -ethyl] -piperazin-1-yl} -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (2-phenoxy-ethyl) -piperazine;
6,6-bis- (4-fluoro-phenyl) -1- {4- [2- (3,4,5-trimethoxy-phenoxy) -ethyl] -piperazin-1-yl} -hexane-1-one;
1- {4- [2- (benzothiazol-2-ylsulfanyl) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
[4- (2- {4- [6,6-Bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -ethoxy) -2,3,6-trimethyl-phenyl] -carbamic acid Tertiary butyl ester;
4- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -ethoxy) -2,3,6-trimethyl-phenylamine;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (2,4-dichloro-phenoxy) -ethyl] -piperazine;
[2- (4- {4- [6,6-Bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-ylmethyl} -2,6-di-tert-butyl-phenoxy) -ethyl] -Dimethyl-amine;
4- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-ylmethyl} -2,6-di-tert-butyl-phenol;
1- [4- (3,5-Di-tert-butyl-4-methoxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one ;
1- [4- (3,5-Di-tert-butyl-4-methoxy-benzyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one ;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,5-di-tert-butyl-4-methoxy-benzyl) -piperazine;
{4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl}-(3,5-di-tert-butyl-4-methoxy-phenyl) -methanone;
1- {4- [3,5-Di-tert-butyl-4- (2-dimethylamino-ethoxy) -benzoyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) ) -Hexane-1-one;
1-benzo [1,3] dioxol-5-ylmethyl-4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazine;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,5-di-tert-butyl-benzyl) -piperazine;
{4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl}-(3,5-di-tert-butyl-4-hydroxy-phenyl) -methanone;
1- [4- (3,5-Di-tert-butyl-4-hydroxy-benzyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one ;
1- [4- (3,5-dibromo-4-hydroxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [4- (3,5-Di-tert-butyl-4-hydroxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one ;
1- [4- (3,5-di-tert-butyl-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (4-tert-butyl-benzyl) -piperazine;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (9H-thioxanthen-9-yl) -piperazine;
2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -benzothiazole;
6,6-bis- (4-fluoro-phenyl) -1- (4-pyrimidin-2-yl-piperazin-1-yl) -hexane-1-one;
2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -pyrimidine;
6,6-bis- (4-fluoro-phenyl) -1- [4- (9H-thioxanthen-9-yl) -piperazin-1-yl] -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5-trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester;
6,6-Bis- (4-fluoro-phenyl) -1- {4- [2- (3,4,5-trimethoxy-benzylamino) -ethyl] -piperazin-1-yl} -hexane-1-one ;
9,9-bis- (4-fluoro-phenyl) -1- [4- (3,4,5-trimethoxy-benzyl) -piperazin-1-yl] -nonan-1-one;
(2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -ethyl) -phenyl-amine;
1- [9,9-bis- (4-fluoro-phenyl) -nonyl] -4- (3,4,5-trimethoxy-benzyl) -piperazine;
(4- {4- [Bis- (4-fluoro-phenyl) -methoxy] -butyl} -piperazin-1-yl)-(3,4,5-trimethoxy-phenyl) -methanone;
6,6-bis- (4-fluoro-phenyl) -1- [4- (4-trifluoromethoxy-benzoyl) -piperazin-1-yl] -hexane-2-one;
1- [4- (4-Bromo-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -5-hydroxy-1- [4- (3,4,5-trimethoxy-benzoyl) -piperazin-1-yl] -hexane-1-one;
1- {4- [bis- (4-fluoro-phenyl) -methoxy] -butyl} -4- (3,4,5-trimethoxy-benzyl) -piperazine;
6,6-bis- (4-fluoro-phenyl) -6-hydroxy-1- [4- (3,4,5-trimethoxy-benzoyl) -piperazin-1-yl] -hexane-1-one;
4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -1- (3,4,5-trimethoxy-benzyl) -piperazine-2-carboxylic acid;
4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- (3,4,5-trimethoxy-benzyl) -piperazin-2-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -4- (3,5-di-tert-butyl-4-methoxy-benzoyl) -piperazin-2-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,4,5-trimethoxy-benzoyl) -piperazin-2-one;
4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -1- (3,4,5-trimethoxy-benzyl) -piperazin-2-one;
4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- (3,5-di-tert-butyl-4-methoxy-benzyl) -piperazin-2-one;
4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- [2- (4-fluoro-phenoxy) -ethyl] -piperazin-2-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,5-di-tert-butyl-4-methoxy-benzoyl) -piperazin-2-one;
4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -1- (3,5-di-tert-butyl-4-methoxy-benzoyl) -piperazin-2-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,5-di-tert-butyl-4-methoxy-benzyl) -piperazin-2-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -4- (3,5-di-tert-butyl-4-hydroxy-benzoyl) -piperazin-2-one;
6,6-bis- (4-fluoro-phenyl) -1- [4- (3,4,5-trimethoxy-benzoyl) -piperazin-1-yl] -hex-5-en-1-one;
1- {4- [2- (3,4-dimethoxy-phenoxy) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (3,4-dimethoxy-phenoxy) -ethyl] -piperazine;
1- [6,6-bis- (4-fluoro-phenyl-)-hexyl] -4- (3,4,5-trimethoxy-benzyl) -piperazine-2-carboxylic acid;
4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -1- (3,4,5-trimethoxy-benzyl) -piperazine-2-carboxylic acid ethyl ester;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3, -4-dimethoxy-benzyl) -piperazine;
1- [4- (3,4-dimethoxy-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [2- (benzo [1,3] dioxol-5-yloxy) -ethyl] -4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazine;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (3,4,5-trimethoxy-phenoxy) -ethyl-]-piperazine;
1- (4-Amino-2,3,5-trimethyl-phenoxy) -3- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -propane- 2-ol;
1- {4- [3- (4-Amino-2,3,5-trimethyl-phenoxy) -2-hydroxy-propyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) ) -Hexane-1-one;
1- (4-benzothiazol-2-yl-piperazin-1-yl) -6,6-bis- (4-fluoro-phenyl-)-hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (3,5-bis-trifluoromethyl-benzyl) -piperazine;
1- [4- (3,5-bis-trifluoromethyl-benzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [4- (4-tert-butylbenzoyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (4-bromo-benzyl) -piperazine;
2- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -ethylsulfanyl) -benzothiazole;
6,6-bis- (4-fluoro-phenyl) -1- [4- (4-hydroxy-3,5-dimethoxy-benzoyl) -piperazin-1-yl] -hexane-1-one;
4- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-ylmethyl} -2,6-dibromo-phenol;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- (4-trifluoromethoxy-benzyl) -piperazine;
(2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -ethyl)-(3,4,5-trimethoxy-benzyl) -amine;
1- {4- [2- (4-Fluoro-phenoxy) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- [4- (2-phenylamino-ethyl) -piperazin-1-yl] -hexane-1-one;
1- [6,6-bis- (4-fluoro-phenyl) -hexyl] -4- [2- (2,4-difluoro-phenoxy) -ethyl] -piperazine;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -2-oxo-ethyl) -benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl-)-hexyl] -piperazin-1-yl} -2-oxo-ethyl) -4-chloro-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -2-oxo-ethyl) -4-methyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl-}-2-oxo-ethyl) -4-isopropyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -2-oxo-ethyl) -4-tert-butyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-yl} -2-oxo-ethyl) -4-fluoro-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -4-chloro-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -4-methyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -4-isopropyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -4-tert-butyl-benzamide;
N- (2- {4- [6,6-bis- (4-fluoro-phenyl) -hexanoyl] -piperazin-1-yl} -2-oxo-ethyl) -4-fluoro-benzamide;
1- [4- (2-benzylamino-ethyl) -piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- {4- [2- (4-chloro-benzylamino) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- {4- [2- (4-methyl-benzylamino) -ethyl] -piperazin-1-yl} -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- {4- [2- (4-isopropyl-benzylamino) -ethyl] -piperazin-1-yl} -hexane-1-one;
1- {4- [2- (4-tert-butyl-benzylamino) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
1- {4- [2- (4-Fluoro-benzylamino) -ethyl] -piperazin-1-yl} -6,6-bis- (4-fluoro-phenyl) -hexane-1-one;
6,6-bis- (4-fluoro-phenyl) -1- [4- (1-hydroxy-pyridin-4-carbonyl) -piperazin-1-yl] -hexane-1-one;
4- {4- [6,6-bis- (4-fluoro-phenyl) -hexyl] -piperazin-1-ylmethyl} -2,6-dimethoxy-phenol;
9,9-diphenyl-1- [4- (3,4,5-trimethoxy-benzyl) -piperazin-1-yl] -nonan-1-one;
1- [4- (3,5-Di-tert-butyl-4-methoxy-benzoyl) -2-methyl-piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane -1-on;
1- [4- (3,5-Di-tert-butyl-4-methoxy-benzoyl) -3-methyl-piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane -1-on;
1- [4- (3,5-Di-tert-butyl-benzoyl) -2-methyl-piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one Or 1- [4- (4-tert-butyl-benzoyl) -2-methyl-piperazin-1-yl] -6,6-bis- (4-fluoro-phenyl) -hexane-1-one The compound of claim 1.   A pharmaceutical composition for treating a condition characterized by the activity of calcium channels, wherein the composition is a mixture with pharmaceutically acceptable excipients, at least A pharmaceutical composition comprising a unit dosage of one compound. 17. A method for treating a symptom associated with calcium channel activity in a patient, wherein the method requires a patient in need of such treatment, at least one compound of any of claims 1-16, or their A method comprising administering a pharmaceutical composition.

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