Novel Tricyclic, Bicyclic, Monocyclic and Acyclic Amines as Potent Sodium Channel Blocking Agents
Cross Reference to Related Applications This application is entitled to priority pursuant to 35 U.S. C. § 119(e) to U.S. provisional patent application no. 60/602,819, filed August 19, 2004.
Background
Tricyclic antidepressants ("TCAs") have been clinically administered as mood stabilizing agents since their discovery in the early 1960s (Atkinson et al., Pain, 1998, 76:287). However, it was soon elucidated that these drugs also have highly effective analgesic properties. One potent member of the TCA class having efficacy for treating pain is amitriptyline (Fig. 1).
Amitriptyline has been therapeutically utilized in the treatment of migraines (Bowsher, European Journal of Pain, 2003, 7:1), diabetic neuropathy (Cerbo et al., Headache, 1998, 38:453), postherpetic neuralgia (Collins et al., Journal of Pain and Symptom Management, 2000, 20:449), and chronic lower back pain (McNeal et al., Journal of Medicinal Chemistry, 1985, 28:381). The mechanistic pathway by which amitriptyline functions in the treatment of pain has yet to be determined. However, amitriptyline's remarkable capabilities as a sodium channel blocker may correlate to its physiological functions. It has been shown that amitriptyline behaves as a potent sodium channel blocker (73.8 +/- 2.3 percent inhibition at 10 μM). This astonishingly high ability to block sodium channels is even much greater than the long-acting local anesthetic bupivacaine (63.6 +/- 2.4 percent inhibition at 10 μM) (Sudoh et al., Pain, 2003, 103:49).
Sodium ("Na") channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. Na channels play key roles in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and airway. As such, they play key roles in a variety of disease states such as epilepsy (See, Moulard et al., 2002, Expert Opin. Ther. Patents 12(1): 85-91)), pain (See, Waxman, et al., 1999, Proc. Natl. Acad. Sci. USA
96(14):7635-9 and Waxman, et al., 2000, J. Rehabil. Res. De.v 37(5):517-28), myotonia (See Meola et al., 2000, Neurol Sci 21(5):S953-61, and Mankodi et al., 2002, Curr. Opin. Neurol. 15(5):545-52), ataxia (See Meisle et al., 2002, Novartis Found Symp 241:72-81), multiple sclerosis (See Black et al., 2000, Proc. Natl. Acad. Sci. USA 97(21):11598-602, and Renganathan et al, 2003, Brain Res 959(2) 235-42), irritable bowel (See, Su et al, 1999, Am. J. Physiol. 277(6 Pt 1):G1180-8, and Laird et al., 2002, J. Neurosci. 22(19):8352-6), urinary incontinence and visceral pain (See Yoshimura et al, 2001, J. Neurosci. 21(21):8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See, Hurley et al., 2002, Ann. Pharmacother. 36(5):860- 73).
In general, voltage-gated sodium channels ("Navs") are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See Mao et al., 2000, Pain 87(1):7-17.), bupivacaine, phenytoin (See Jensen et al., 2002, Eur. J. Pain 6 (Suppl A: 61-8), lamotrigine (See Rozen,. 2001, Headache 41 Suppl 1 :S25-32, and Jensen, 2002, Eur. J. Pain 6 (Suppl A): 61-8), and carbamazepine (See Backonja, 2002, Neurology 59(5 Suppl 2):S14-7), have been shown to be useful attenuating pain in humans and animal models.
In general, pain is associated with a known tissue pathology (e.g., cancer pain, arthritic pain), inflammation, or injury to a body tissue (e.g., surgery). Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. Neuropathic pain can present as an acute pain but frequently occurs as a form of chronic pain.
The use of long-acting local anesthetics that elicit complete neural blockage for more than several hours is frequently desirable in the management of acute and chronic pain. Pain relief research during the last two decades has focused on the identification of new local anesthetics to produce analgesia of long duration with minimal impairment of autonomic function and low toxicity. One of the best known "long-acting" local
anesthetics developed to date, bupivacaine, reportedly blocks major nerve block for three to twelve hours. Unfortunately, bupivacaine is also highly cardiotoxic. The development of alternative "long-acting" local anesthetics met limited success.
Pain relief research also has focused on the identification of new neurolytic agents for the treatment of chronic pain and intractable cancer pain. Historically, spinal opiate administration, surgical intervention, or both, have been used to alleviate chronic and intractable cancer pain. When these methods fail to provide sufficient pain relief, phenol or absolute alcohol reportedly have been used as neurolytic agents to destroy the pathogenic nerve regions that are responsible for pain manifestation. However, these agents exert only weak local anesthetic effects and, accordingly, have been difficult to administer to alert patients without inducing additional pain. To date, a long-acting local anesthetic with no major side effects has not been available for the treatment of acute and chronic pain.
In view of the foregoing limitations of the existing local anesthetics to prolong the duration of anesthesia, a need still exists for useful long-acting local anesthetics for pain management. Preferably, such local long-acting anesthetics also will exhibit reversible effects. Such drugs would be useful and desirable, for example, in postoperative analgesia, and for treating acute and chronic pain. Preferably, such agents would have sufficient potency to permit administration of a single, relatively low dosage of the agent, thereby minimizing the likelihood of side effects that have been attributed to the existing local long-acting anesthetic agents.
Tricyclic antidepressants are frequently used as analgesics in pain management but only when administered systemically. Among them, amitriptyline has been used orally for the analgesic therapy of chronic pain. Arnitriptyline's sites of action are both central and peripheral. Despite the numerous reports on amitriptyline's analgesic effect on reducing pain when administered systemically, the exact mechanism of this effect remains unknown (see Wang et al., U.S. Patent No. 6,545,057 for a review).
There is a long felt need in the art for new compounds with sodium channel inhibiting activity and that have the ability to act as analgesics and anesthetics. The present invention satisfies these needs.
Summary of the Invention
Much is known about tricyclic antidepressants, but no bicyclic (two ring), monocyclic (one ring) or acyclic (no ring) analogues have been designed, synthesized, or evaluated for sodium channel activity (see U.S. Pat. No. 6,545,057). The present invention discloses a new class of amitriptyline analogues and derivatives which function as effective sodium channel activity inhibitors. In one aspect, the derivatives and analogues are acyclic derivatives and analogues of amitriptyline. In another aspect, the derivatives and analogues are monocyclic derivatives and analogues of amitriptyline. In yet another aspect, the derivatives and analogues are bicyclic derivatives and analogues of amitriptyline. In yet another aspect, the derivatives and analogues are tricyclic derivatives and analogues of amitriptyline. The medicinal chemistry progression is presented in Figure 2.
The present invention is directed to a series of compounds that have the ability to block sodium channels. In one aspect, the compounds of the invention are useful to treat diseases, disorders and conditions by modulating sodium channel activity. In another aspect of the invention, the compounds of the invention are useful for treating diseases, conditions, and disorders such as pain, arrhythmia, cancer, depression, and epilepsy.
In one embodiment, compounds of the invention have the general structure of Structures I and II.
In one embodiment, compounds of the invention have the general structure of
Structures III and IV.
III
IV
In one embodiment, compounds of the invention have the general structure of Structures V and VI. V VI
In one aspect of the invention, compounds of the invention are selected from the group of compounds comprising:
DPH-362 DPH-359 DPH-393
DPH-3109 DPH-394 DPH-361 , and DPH-398
In one embodiment, the compounds of the invention are selected from the group consisting of:
In one embodiment, compounds of the invention are useful for inducing anesthesia and analgesia. According to one aspect of the invention, a method for
inducing local anesthesia in a subject is provided. The method involves administering locally to a subject in need of such a treatment an effective amount of a compound of the invention an amount effective to block sensory and motor functions of a nerve(s) at the site of administration of the compound. As disclosed herein, the present invention provides compounds that are inhibitors of voltage-gated sodium ion channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to acute, chronic, neuropathic, or inflammatory pain, localized pain, cancer pain, intractable cancer pain, pain associated with trauma or injury, postoperative pain, visceral pain, radicular pain, sciatica, nociceptive pain, breakthrough pain, back pain, lower back pain, head and neck pain, leg pain, stroke, arthritis, migraine, cluster headaches, shingles, psoriasis, multiple sclerosis, trigeminal neuralgia, herpetic neuralgia, general neuralgias, diabetic neuropathy, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety, bipolar disorders, and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In one aspect, the additional agent is an anti- inflammatory agent.
It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
Brief Description of the Drawings
Figure 1 schematically illustrates the structures of examples of the TCA class of the drugs amitriptyline, doxepin, imipramine, and nortriptyline.
Figure 2 schematically illustrates medicinal chemistry transformations from tricyclic to bicyclic to monocyclic to acyclic.
Figure 3 schematically illustrates tricyclic, bicyclic, monocyclic, and acyclic analogues of amitriptyline.
Figure 4 schematically illustrates a series of representative pathways for preparing tricyclic, bicyclic, monocyclic, and acyclic compounds of the invention. Figure 5 schematically illustrates seven analogues of the present invention, as well as the chemical structure of amitriptylene.
Detailed Description of the Invention Abbreviations Batrachotoxin- BTX
Hydrogen- H Sodium - Na
Tricyclic antidepressants- TCAs Voltage-gated sodium channel- NaV Definitions
In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below.
As used herein, the articles "a" and "an" refer to one or to more than one, i.e., to at least one, of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
A disease or disorder is "alleviated" if the severity of a symptom of the disease, condition, or disorder, or the frequency with which such a symptom is experienced by a subject, or both, are reduced.
"Analgesia" is defined as a condition in which nociceptive stimuli are sensed but are not interpreted as pain. "Anesthesia" is a state characterized by total loss of sensation, the result of pharmacologic depression of nerve function. Thus, analgesia
does not produce anesthesia whereas anesthesia produces analgesia.
As used herein, an "analog" of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5- fluorouracil is an analog of thymine). The term "cancer," as used herein, is defined as proliferation of cells whose unique trait- loss of normal controls- results new characteristics such as unregulated growth, lack of differentiation, local tissue invasion, and metastasis. Examples include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, pancreatic cancer, colorectal cancer, renal cancer, leukemia, non small cell carcinoma, and lung cancer.
As used herein, a "derivative" of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
As used herein, an "effective amount" means an amount sufficient to produce a selected effect.
The terms "formula" and "structure" are used interchangeably herein.
As used herein, "homology" is used synonymously with "identity."
The term "inhibit," as used herein, refers to the ability of a compound of the invention to reduce or impede a described function, such as having inhibitory sodium channel activity. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%. The terms "inhibit" and "block" are used interchangeably herein.
As used herein, an "instructional material" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the peptide of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal. The instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound.
Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
As used herein, the term "neurological disease" or "neurological condition" includes neurological related maladies such as spasticity, seizures, depression or mood disorders, neuropathic pain, Alzheimer's Disease, Parkinson's Disease, HIV Dementia and neurological disorders that involve excessive activation of the N-methyl-D- aspartate (NMDA) receptor.
As used herein, the term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents. The term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans. As used herein, the term "purified" and like terms relate to an enrichment of a molecule or compound relative to other components normally associated with the molecule or compound in a native environment. The term "purified" does not necessarily indicate that complete purity of the particular molecule has been achieved during the process. A "highly purified" compound as used herein refers to a compound that is greater than 90% pure.
The term "sodium channel activity," as used herein, refers to activities of sodium channels and the results of activities of sodium channel, which can be measured or monitored using in vitro and in vivo assays. For example, voltage-gated sodium channels are responsible for the rising phase of the action potential in excitable membranes and certain known anesthetics and anticonvulsants target specific sites in sodium channels to block Na+ currents, thus reducing excitability in neuronal, muscle, or central nervous system. Thus, nerve transmission is regulated. Sodium channel activity, or the results of sodium channel activity, can be measured, analyzed, or monitored using various assays such as binding, gating, ion permeation, current, and various methods which measure parameters indicative of pain or reaction, such as motor function, proprioception, nocifensive reaction.
A "subject" of diagnosis or treatment is a mammal, including a human.
As used herein, the term "treating" includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms. A "prophylactic" treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs. A "therapeutically effective amount" of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
As used herein, the term "treating" includes prophylaxis of the specific disease, disorder, or condition, or alleviation of the symptoms associated with a specific disease, disorder, or condition and/or preventing or eliminating said symptoms.
Chemical Definitions
As used herein, the term "halogen" or "halo" includes bromo, chloro, fluoro, and iodo. The term "haloalkyl" as used herein refers to an alkyl radical bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
The term "C1-Cn alkyl" wherein n is an integer, as used herein, represents a branched or linear alkyl group having from one to the specified number of carbon atoms. Typically, C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like.
The term "C2-Cn alkenyl" wherein n is an integer, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
The term "C2-Cn alkynyl" wherein n is an integer refers to an unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like. The term "C3-Cn cycloalkyl" wherein n = 8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
As used herein, the term "optionally substituted" refers to from zero to four substituents, wherein the substituents are each independently selected. Each of the independently selected substituents may be the same or different than other substituents. As used herein the term "aryl" refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. "Optionally substituted aryl" includes aryl compounds having from zero to four substituents, and "substituted aryl" includes aryl compounds having one or more substituents. The term (C5-C8 alkyl)aryl refers to any aryl group which is attached to the parent moiety via the alkyl group.
Unless otherwise specified, the term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the "heterocycle", "heterocyclyl", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members.
The term "heteroatom" means for example oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring. The term "heterocyclic group" refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing from one to three heteroatoms wherein the
heteroatoms are selected from the group comprising of oxygen, sulfur, and nitrogen.
As used herein the term "heteroaryl" refers to an optionally substituted mono- or bicyclic carbocyclic ring system having one or two aromatic rings containing from one to three heteroatoms and includes, but is not limited to, furyl, thienyl, pyridyl and the like.
The term "bicyclic" represents either an unsaturated or saturated stable 7- to 12- membered bridged or fused bicyclic carbon ring. The bicyclic ring may be attached at any carbon atom which affords a stable structure. The term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like. The compounds of the present invention contain one or more asymmetric centers in the molecule. In accordance with the present invention a structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
The compounds of the present invention may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. For example the following structure:
N ' NH is understood to represent a mixture of the structures:
The term "pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of the compounds of the present invention and which are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Compounds of the present invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, or optically pure diastereomers, as
well as mixtures of enantiomers, mixtures of diastereomers, and racemic mixtures of such stereoisomers. The present invention includes within its scope all such isomers and mixtures thereof.
The present invention is directed to a series of monocyclic, bicyclic, tricyclic, and acyclic amine compounds that have activity as sodium channel blockers, hi one aspect, the compounds of the invention have analgesic activity. In another aspect, the compounds of the invention have anesthetic activity.
The present invention provides acyclic, monocyclic, bicyclic, and tricyclic derivatives, modifications and analogues of tricyclic antidepressants such as amitriptyline. In one aspect, the compounds of the invention have sodium channel inhibiting activity. In another aspect, the compounds of the invention have analgesic activity. In yet another aspect, the compounds of the invention have anesthetic activity.
In accordance with one embodiment, the compounds of the invention have the general structure:
wherein R
1, R
2, R
3, and R
4 are independently selected from the group consisting of H, Ci-C
12 alkyl, C
2-C
12 alkenyl, C
2-C
12 alkynyl, halo, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, R
5 is independently selected from the group consisting of H, halo, hydroxy and amino, and n is an integer selected from the range of 0-9
In one embodiment, a compound of Formula I or II is provided wherein R1 and R2 are independently selected from the group consisting Of C1-C12 alkyl, C1-C12 alkenyl, C1-Ci2 alkynyl, optionally substituted C5-C8 cycloalkyl, optionally substituted C5-C8 heterocyclic, optionally substituted Cs-C8 aryl and optionally substituted C5-C8 heteroaryl, wherein the substituents of the optionally substituted carbocyclic rings are selected from the group consisting Of C1-C4 alkyl, halo, amino and hydroxy, R3, and R4
are independently selected from the group consisting of H and C1-C4 alkyl, R5 is independently selected from the group consisting of H, halo, hydroxy and amino, and n is an integer selected from the range of 0-3.
In another embodiment, a compound of Formula I or II is provided wherein R1 is optionally substituted C5-C6 aryl, R2 is selected from the group consisting Of C1-C12 alkyl, C1-Cj2 alkenyl, C1-C12 alkynyl, optionally substituted C5-C8 cycloalkyl, optionally substituted C5-C8 heterocyclic, optionally substituted C5-C8 aryl and optionally substituted C5-C8 heteroaryl, wherein the substituents of the optionally substituted carbocyclic rings are selected from the group consisting Of C1-C4 alkyl, halo, amino and hydroxy, R3, and R4 are independently selected from the group consisting of H and C1-C4 alkyl, R5 is independently selected from the group consisting of H, halo, hydroxy and amino, and n is an integer selected from the range of 0-3.
In another embodiment, a compound of Formula I or II is provided wherein R1 is optionally substituted phenyl, R2 is selected from the group consisting Of C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl, optionally substituted C5-C8 cycloalkyl and optionally substituted C5-Cg aryl, wherein the substituents of the optionally substituted rings are selected from the group consisting Of C1-C4 alkyl, R3, and R4 are independently selected from the group consisting of H and C1-C4 alkyl, R5 is hydroxy, and n is an integer selected from the range of 0-3. In another embodiment, compounds are provided having the general structure of structures III or IV:
111 IV
wherein R
2 is selected from the group consisting Of Ci-C
12 alkyl, C
1-C
12 alkenyl, C
1-Ci
2 alkynyl, C
1-C
12 haloalkyl, Ci-Ci
2 hydroxyalkyl, optionally substituted C
5-C
8 cycloalkyl, optionally substituted C
5-C
8 heterocyclic, optionally substituted C
5-C
8 aryl and optionally substituted C
5-C
8 heteroaryl, wherein the substituents of the optionally substituted carbocyclic rings are selected from the group consisting Of C
1-C
4 alkyl, halo, amino and hydroxyl, R
6 is selected from the group consisting of H and C
1-C
4 alkyl, and R
5 is independently selected from the group consisting of H, halo, hydroxy and amino. In one embodiment R
2 is Ci-C
12 alkyl, C
5-C
8 cycloalkyl, Cs-C
8 heterocyclic, C
5-C
8 aryl and C5-C
8 heteroaryl, R
6 is H, and R
5 is independently selected from the group consisting of H, halo, hydroxy and amino. In another embodiment R
2 is selected from the group consisting Of C
1-C
12 alkyl, C
1-C
12 alkenyl, C
1-C
12 alkynyl, C
1-C
12 haloalkyl, C
1-C
12 hydroxyalkyl, optionally substituted C
6 cycloalkyl, optionally substituted C
6 heterocyclic, optionally substituted C
6 aryl and optionally substituted C
6 heteroaryl, wherein the substituents of the optionally substituted carbocyclic rings are selected from the group consisting Of C
1-C
4 alkyl, R
6 is selected from the group consisting of H and C
1-C
4 alkyl, and R
5 is independently selected from the group consisting of H, halo, hydroxy and amino.
In another embodiment, compounds of the invention are provided having the general structure of structures of V and VI:
V VI
wherein R2 is selected from the group consisting Of C1-C12 alkyl, Ci-C12 alkenyl, C1-C12 alkynyl, C1-C12 haloalkyl, C1-Ci2 hydroxyalkyl, optionally substituted C5-C8 cycloalkyl,
optionally substituted C5-C8 heterocyclic, optionally substituted C5-C8 aryl and optionally substituted C5-C8 heteroaryl, wherein the substituents of the optionally substituted carbocyclic rings are selected from the group consisting Of C1-C4 alkyl, halo, amino and hydroxyl, and R5 is independently selected from the group consisting of H, halo, hydroxy and amino.
In one embodiment, the compounds of the invention are selected from the group consisting of novel tricyclic, bicyclic, monocyclic, and acyclic derivatives of amirriptyline with sodium channel inhibiting activity, analgesic activity, and anesthetic activity. In one aspect, the compounds of the invention are selected from the group comprising:
wherein Rl, R2, R3, R4, and R5 are independently H, alkyl, halogen, aromatic, alkynyl, and heteroatom, and n= 0-9.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each
other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, (Cahn et al. Angew. Chem. Inter. Edit., 5, 385; (1966) errata 511; Cahn et al. Angew. Chem., 78, 413; (1966) Cahn and Ingold J. Chem. Soc. (London), 612; (1951) Cahn et al. Experientia, 12, 81; (1956), Cahn, J. Chem. Educ, 41, 116, (1964)) or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture."
Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine,
trimethyl amine, diethyl amine, txi(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
The amitriptyline analogs of the present invention can be formulated with known solubilizing agents, excipients, and pharmaceutically acceptable carriers to prepare pharmaceuticals compositions. Compositions comprising the sodium channel inhibitors of the present invention can be administered to treat diseases and conditions associated with inappropriate or excessive ion channel activity. Examples of diseases or conditions where sodium channel modification may provide an effective therapy include epilepsy, cancer, arrhythmia, depression and pain, including neuropathic pain. Figure 3 represents various amitriptyline analogs that may be used in accordance with the present invention to block sodium channel activity. In one embodiment, a method of treating a disease, condition, or disorder by blocking sodium channel activity comprises the step of administering to a patient a composition comprising a compound of the general structure of Formula I or II, wherein R1 is optionally substituted C5-C6 aryl, R2 is! selected from the group consisting Of C1- C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl, optionally substituted C5-C8 cycloalkyl, optionally substituted C5-C8 heterocyclic, optionally substituted C5-C8 aryl and optionally substituted C5-C8 heteroaryl, wherein the substituents of the optionally
substituted carbocyclic rings are selected from the group consisting Of C1-C4 alkyl, halo, amino and hydroxy, R3, and R4 are independently selected from the group consisting of H and C1-C4 alkyl, R5 is independently selected from the group consisting of H, halo, hydroxy and amino, and n is an integer selected from the range of 0-3. In accordance with one embodiment of the present invention, a method of blocking sodium channel activity in a population of cells is provided. The method comprises the steps of contacting the cells with a compound of Formulas I, II, III, IV, V or VI. In one aspect, the sodium channel activity is blocked to alleviate the symptoms of a disease, disorder, or condition, or pain associated with a disease, disorder, or condition.
Various techniques are known in the art for testing the activity of compounds of the invention. For example, the rat sciatic nerve blockade technique and whole-cell voltage clamp experiments and cell culture can be used. Neurobehavioral examination can be used to evaluate of motor function, proprioception, and nocifensive reaction. Motor function can be evaluated by measuring the "extensor postural thrust" of the hind limbs. Proprioception can be evaluated based on resting posture and postural reactions ("tactile placing" and "hopping"). These and other techniques are known to those of ordinary skill in the art (see for example, Tikhonov et al., 2005, FEBS Letters, 20:4207- 4212; Nau et al., 2004, J. Membr. Biol. 201:1-8; Fitch et al., 2005, Anal. Biochem., 342:2:260-270; Chevalier et al., 2004, Life ScL, 76:319-329; Kong et al., J. Comb. Chem., 2004, 6:6:928-933; Wartenburg et al., 2004, J. Anesth. 18:2:100-106).
In one embodiment, one or more compounds of the invention can be administered in a therapeutically effective amount sufficient to induce anesthesia in a subject at the site of administration for at least 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, or 96 hours. In another embodiment, the compound induces analgesia.
The compounds of the invention are useful when administered locally in treating all categories of pain, whether acute or chronic, local or general. A subject to whom one or more compounds of the invention are administered can be experiencing or at risk of experiencing any of the forgoing categories of pain.
The compositions of the invention are useful for alleviating pain in a subject.
As used herein, "alleviating pain" refers to treating a subject so as to remove existing pain or to suppress or inhibit pain which would otherwise ensue from a pain-causing event. The treatment may be either therapeutic (while the patient is experiencing pain) or prophylactic (i.e., as preemptive anesthesia or analgesia). The treatment may be for acute or chronic pain. Examples of acute pain include pain that can occur following trauma to body tissues, e.g., surgery, injury, and so forth. Examples of chronic pain included, but are not limited to, intractable cancer pain, rheumatoid arthritis, shingles, painful diabetic neuropathy and so forth. The method of the invention can also be applied to the treatment of pain that is associated with a skin condition such as psoriasis, eczema, and shingles. In one embodiment of the invention, the pain is lower back or leg pain caused by a pathology relating to the sciatic nerve. In one aspect, the pain is related to sciatica.
Both non-biodegradable and biodegradable polymeric matrices can be used to deliver the compositions of the invention to the subject. Biodegradable matrices are preferred. Such polymers may be natural or synthetic polymers. Synthetic polymers are preferred. The polymer is selected based on the period of time over which release is desired, generally in the order of a few hours to a year or longer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable. The polymer optionally is in the form of a hydrogel that can absorb up to about 90% of its weight in water and further, optionally is cross-linked with multi¬ valent ions or other polymers. In general, the compositions of the invention are delivered using the bioerodible implant by way of diffusion, or more preferably, by degradation of the polymeric matrix.
Exemplary synthetic polymers which can be used to form the biodegradable delivery system include: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, poly-vinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy- propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose
propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl alcohols), polyvinyl acetate, poly vinyl chloride, polystyrene and polyvinylpyrrolidone. Examples of non-biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof.
Examples of biodegradable polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid), and poly(lactide-cocaprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion.
Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules, 1993, 26, 581-587, the teachings of which are incorporated herein, polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). Thus, the invention provides a composition of the above-described therapeutic agents for use as a medicament, methods for preparing the medicament and methods for the sustained release of the medicament in vivo.
When the compositions of the invention are to be used to alleviate epidural or intrathecal pain, injection or administration of the compositions through a catheter is the most simple mode of administration. The compounds of the invention can be administered, for example, in an aqueous medium, such as an isotonic solution, or in a non-aqueous medium, such as glycerol or an oil. Alternatively, the compounds of the invention can be administered as an injectable suspension to achieve a more prolonged effect. The preferred medium for intrathecal injection is isotonic dextrose. Other exemplary pharmaceutically acceptable intrathecal carriers include hypobaric (e.g., 50% normal saline) and hyperbaric (e.g., 5-8% glucose) solutions (See, e.g., Neural Blockade, ed., Cousins & Bridenbaugh, pp. 213-251 (1988). In general, the compounds of the invention are present in an intrathecal formulation in an amount ranging from about 0.1% to about 10% by weight, based upon the total weight of the composition. Preferably, the compounds of the invention are present in an amount ranging from about 0.25% to about 2.5% by weight and, most preferably, the compounds are present in an amount ranging from about 0.5% to about 1% by weight. In some embodiments, it is preferred that the compounds of the invention be formulated in a pharmaceutically acceptable intrathecal or topical carrier that is not suitable for oral administration.
When the compositions of the invention are to be used to alleviate a topical pain, the compounds can be administered as a pure dry chemical (e.g., by inhalation of a fine powder via an insufflator) or as a pharmaceutical composition further including a pharmaceutically acceptable topical carrier. Thus, the pharmaceutical compositions of the invention include those suitable for administration by inhalation or insufflation or for nasal, intraocular, or other topical (including buccal and sub-lingual) administration. For administration to the upper (nasal) or lower respiratory tract by inhalation, the compounds of the invention can be delivered from an insufflator, nebulizer, or a pressurized pack or other convenient means of delivering an aerosol spray. Alternatively, the compounds of the invention can be delivered as a dry powder composition containing, for example, the pure compound together with a suitable powder base (e.g., lactose, starch). For intra-nasal administration, the compounds of the invention can be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or
metered-dose inhaler. Exemplary atomizers are known to those of ordinary skill in the art. Drops, such as eye drops or nose drops, can be formulated with an aqueous or non¬ aqueous base which optionally further includes one or more dispersing agents, solubilizing agents or suspending agents. Apparatus and methods for delivering liquid sprays and/or drops are well known to those of ordinary skill in the art.
For topical administration to the eye, nasal membranes or to the skin, the compounds according to the invention may be formulated as ointments, creams, or lotions, or as a transdermal patch or intraocular insert or iontophoresis. For example, ointments and creams can be formulated with an aqueous or oily base alone or together with suitable thickening and/or gelling agents. Lotions can be formulated with an aqueous or oily base and, typically, further include one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. (See, e.g., U.S. Pat. No. 5,563,153, entitled "Sterile Topical Anesthetic Gel", issued to Mueller, D., et al., for a description of a pharmaceutically acceptable gel-based topical carrier).
In general, a therapeutically effective amount of the compounds of the invention will vary with the subject's age, condition, and sex, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. The dosage may be adjusted by the individual physician or veterinarian, particularly in the event of any complication. A therapeutically effective amount typically varies from 0.01 mg/kg to about 1000 mg/kg, preferably from about 0.1 mg/kg to about 200 mg/kg and most preferably from about 0.2 mg/kg to about 20 mg/kg, in one or more dose administrations daily, for one or more days.
As used herein, the term "physiologically acceptable" ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if
necessary or desirable, shaping or packaging the product into a desired single- or multi- dose unit.
Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to a human, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs, birds including commercially relevant birds such as chickens, ducks, geese, and turkeys. Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intrathecal or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage.
The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By
way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.
In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents. Particularly contemplated additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers.
Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.
As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate. Known surface active agents include, but are not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen
phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patents numbers 4,256,108; 4,160,452; and 4,265,874 to form osmotically- controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation. Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid
suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n- propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
Powdered and granular formulations of a pharmaceutical preparation of the
invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in- water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.
Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e. about 200C) and which is liquid at the rectal temperature of the subject (i.e. about 37°C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives. Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid
carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives. A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for vaginal administration. Such a composition may be in the form of, for example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon, a douche preparation, or gel or cream or a solution for vaginal irrigation. Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, douche preparations may be administered using, and may be packaged within, a delivery device adapted to the vaginal anatomy of the subject. Douche preparations may further comprise various additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.
As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition throμgh a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3 -butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in- water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-
administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute
alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w)
solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in macrocrystalline form or in a liposomal preparation.
As used herein, "additional ingredients" include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other "additional ingredients" which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, which is incorporated herein by reference.
Typically, dosages of the compound of the invention which may be administered to an animal, preferably a human, range in amount from 1 μg to about 100 g per kilogram of body weight of the animal. While the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration. Preferably, the dosage of the compound will vary from about 1 mg to about 1O g per kilogram of body weight of the animal. More preferably, the dosage will vary from about 10 mg to about 1 g per kilogram of body weight of the animal.
The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even lees frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type, and age of the
animal, etc.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In accordance with one embodiment, a kit is provided for treating a subject in need of immuno-modulation. Preferably, the subject is a human. In one embodiment, the kit comprises one or more of the compounds of the present invention and may also include one or more known immuno-suppressants. These pharmaceuticals can be packaged in a variety of containers, e.g., vials, tubes, microtiter well plates, bottles, and the like. Other reagents can be included in separate containers and provided with the kit; e.g., positive control samples, negative control samples, buffers, cell culture media, etc. Preferably, the kits will also include instructions for use.
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein.
One of ordinary skill in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.
Examples
The invention is now described with reference to the following examples. These examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.
Novel tricyclic, bicyclic, monocyclic, and acyclic compounds of the invention can be prepared according to Scheme 1 using amitriptyline as a reference compound (see also Figure 3). Methods for preparing tricyclic antidepressants such as
amitriptyline are known to those of ordinary skill in the art (see for example, see U.S. Pat. No. 6,545,057). Scheme 1-
R1, R2, R3, R4, R5 HH, alkyl, halogen, aromatic, alkynyl, hetereoatom n = 0-9
The sodium channel is a transmembrane protein with three subunits: α, βl, and β2. However, it has been found that the α unit alone contains the key pharmacological and physiological elements, with all known drug interactions occurring there (West et al, Neuron, 1992, 8:59).
Representative compounds of the invention were synthesized from the synthetic
schemes presented in Scheme 2 and Figure 4. Scheme 2-
![Figure imgf000038_0003](https://patentimages.storage.googleapis.com/b6/cc/37/fcdc7de58ea178/imgf000038_0003.png)
![Figure imgf000038_0004](https://patentimages.storage.googleapis.com/11/d2/19/d45f6b4faa9177/imgf000038_0004.png)
Batrachotoxin (BTX), isolated from the Columbian poison dart frog, is a known neurotoxin which preferentially binds to site 2 of the sodium channel in its open state. Voltage-gated Na+ channels are dynamic transmembrane proteins responsible for the rising phase of the action potential in excitable membranes. Local anesthetics (LAs) and structurally related antiarrhythmic and anticonvulsant compounds target specific sites in voltage-gated Na+ channels to block Na+ currents, thus reducing excitability in neuronal, cardiac, or central nervous tissue. A high-affinity LA block is produced by binding to open and inactivated states of Na+ channels rather than to resting states and suggests a binding site that converts from a low- to a high-affinity conformation during gating. Methods for studying sodium channels and methods of regulating sodium channels are well known in the art (Tikhonov et al., 2005, FEBS Letters, 579:4207- 4212; Nau et al., 2004, J. Membr. Biol. 201:1:1-8; Bosnians et al., 2004, FEBS Letters, 577:245-248; U.S. Pat. Pub. No. 2005/0137190).
The degree of [ H]-BTX binding, i.e., inhibition, is known to be lowered by the presence of local anesthetics, anticonvulsants, and antiarrhythmic drugs. Evaluation of the ability of compounds of the invention to displace [3 H] -BTX from the sodium channel protein were carried out in order to determine their potency as sodium channel inhibitors. The novel bicyclic analogue structures of some compounds of the invention and data demonstrating the ability of these compounds of the invention (DPH-3109, DPH-361, DPH-398, DPH-393, DPH-394, DPH-362, and DPH-359) to displace [3H]- BTX, relative to amitriptylene, are presented in Figure 5 and Table 1.
Table 1.
The structures of the compounds tested and compared to amitriptyline in Table 1 are as follows:
DPH-3109 DPH-394 DPH-361 DPH-398
The results demonstrate that the derivative compounds of the invention bind potently to the sodium channel and are as potent as amitriptyline as inhibitors of 3H-
BTX. These data establish that bicyclic derivatives are equally as potent as amitriptyline (tricyclic derivatives) at inhibiting sodium channels, and thus are likely to be useful in treating diseases (pain, epilepsy, cancer, arrhythmia, depression) in which ion channel modulation is important. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated by reference herein in their entirety. One of skill in the art will appreciate that the superiority of the compositions and methods of the invention relative to the compositions and methods of the prior art are unrelated to the physiological accuracy of the theory explaining the superior results. Headings are included herein for reference and to aid in locating certain sections. These headings are not intended to limit the scope of the concepts described therein under, and these concepts may have applicability in other sections throughout the entire specification.
Other methods which were used but not described herein are well known and within the competence of one of ordinary skill in the art of clinical, chemical, cellular, histochemical, biochemical, molecular biology, microbiology and recombinant DNA techniques.
The description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. Accordingly, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.