WO2011091050A1 - Conjugués oligomères-tricycliques - Google Patents
Conjugués oligomères-tricycliques Download PDFInfo
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- WO2011091050A1 WO2011091050A1 PCT/US2011/021733 US2011021733W WO2011091050A1 WO 2011091050 A1 WO2011091050 A1 WO 2011091050A1 US 2011021733 W US2011021733 W US 2011021733W WO 2011091050 A1 WO2011091050 A1 WO 2011091050A1
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- 0 C*(CCO*(C)CCN(C)CCCNC=CC)OC Chemical compound C*(CCO*(C)CCN(C)CCCNC=CC)OC 0.000 description 6
- ATQVTMLYIBDVJL-VUTZLFHMSA-N C[C@H]1C(CC2C3)C2C3CC1 Chemical compound C[C@H]1C(CC2C3)C2C3CC1 ATQVTMLYIBDVJL-VUTZLFHMSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- This invention comprises (among other things) chemically modified tricyclics that possess certain advantages over tricyclics lacking the chemical modification.
- the chemically modified tricyclics described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.
- Clinical depression also called major-depressive disorder or unipolar depression
- major-depressive disorder is a common psychiatric disorder, characterized by a persistent lowering of mood, loss of interest in usual activities and diminished ability to experience pleasure.
- depression is commonly used to describe a temporary decreased mood
- clinical depression is a serious illness that involves the body, mood, and thoughts and cannot simply be willed or wished away. It is often a disabling disease that affects a person's work, family and school life, sleeping and eating habits, general health and ability to enjoy life.
- the course of clinical depression varies widely: depression can be a once in a life-time event or have multiple recurrences, it can appear either gradually or suddenly, and either last for few months or be a life-long disorder. Having depression is a major risk factor for suicide; in addition, people with depression suffer from higher mortality from other causes.
- Clinical depression is usually treated by psychotherapy, antidepressants, or a combination of the two.
- Neuropathy is a disease of the peripheral nerve or nerves.
- the four major forms of nerve damage are polyneuropathy, autonomic neuropathy, mononeuropathy, and mononeuritis multiplex.
- a more common form is peripheral polyneuropathy, which mainly affects the feet and legs.
- neuropathy Aside from diabetes (i.e., diabetic neuropathy), the common causes of neuropathy are herpes zoster infection, HIV-AIDS, toxins, alcoholism, chronic trauma (such as repetitive motion disorders) or acute trauma (including surgery), neurotoxicity and autoimmune conditions such as celiac disease.
- Neuropathic pain is common in cancer as a direct result of the cancer on peripheral nerves (e.g., compression by a tumor), as a side effect of many chemotherapy drugs, and as a result of electrical injury. In many cases the neuropathy is "idiopathic," meaning no cause is found.
- Neuropathic pain is usually perceived as a steady burning and/or "pins and needles” and/or “electric shock” sensations and/or tickling. The difference is due to the fact that "ordinary” pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool) sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive.
- Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, neuropathic pain, nocturnal enuresis, and ADHD, but they have also been used successfully for headache (including migraine headache), anxiety, insomnia, smoking cessation, bulimia nervosa, irritable bowel syndrome, narcolepsy, pathological crying or laughing, persistent hiccups, interstitial cystitis, and ciguatera poisoning, and as an adjunct in schizophrenia.
- Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, neuropathic pain, nocturnal enuresis, and ADHD, but they have also been used successfully for headache (including migraine headache), anxiety, insomnia, smoking cessation, bulimia nervosa, irritable bowel syndrome, narcolepsy, pathological crying or laughing, persistent hiccups, interstitial cystitis, and ciguatera poisoning, and as an adjunct in schizophrenia.
- Tricyclics may also possess affinity for muscarinic and histamine HI through H4 receptors to varying degrees. Although norepinephrine and dopamine are generally considered stimulatory neurotransmitters, tricyclic antidepressants also increase the effects on HI histamine, and thus most have sedative effects and may also be useful as anti-histaminic compounds.
- Oxcarbazepine is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics. Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon-carbon double bond on the dibenzazepine ring. This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia or agranulocytosis occasionally associated with carbamazepine.
- Eslicarbazepine acetate is an antiepileptic drug. It is a prodrug which is activated to
- eslicarbazepine S-licarbazepine
- an active metabolite of oxcarbazepine S-licarbazepine
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer.
- Exemplary compounds of the invention include those having the following structure:
- D is C or N
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 each are independently selected from the group consisting of nil, hydrogen, halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, dioxo, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, unsubstituted or optionally substituted;
- R is selected from hydrogen, alkyl, and acyl;
- X is a spacer moiety
- POLY is a water-soluble, non-peptidic oligomer.
- Exemplary compounds of the invention include those having the following structure:
- D is C or N
- R 1 is selected from alkyl, amino, acylamino, acyl, amido, aryloxy, alkylamino,
- dialkylamino wherein each alkyl group independently has from 1 to 6 carbon atoms
- piperidino pyrrolidino, N-(lower alkyl)-2-piperidyl, morpholino, 1 -piperizinyl, 4-(lower alkyl)- 1 -piperizinyl, 4-(hydroxyl-lower alkyl)- 1 -piperizinyl, and 4-(methoxy-lower alkyl)- 1- piperizinyl, each of which is independently optionally substituted;
- each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, dioxo, aryl, heteroaryl, cycloalkyl, and
- heterocycloalkyl each of which is independently optionally substituted;
- R 10 is selected from hydrogen, alkyl, and acyl
- X is a spacer moiety
- POLY is a water-soluble, non-peptidic oligomer.
- tricyclic residue is a compound having a structure of a tricyclic compound that is altered by the presence of one or more bonds, which bonds serve to attach (either directly or indirectly) one or more water-soluble, non-peptidic oligomers.
- Exemplary tricyclics structure encompassed by at least one of the structures defined herein as Formula I:
- R 1 is selected from the group alkyl, amino, acylamino, acyl, amido, aryloxy, alkylamino, dialkylamino having about 2 to 4 inclusive carbon atoms, piperidino, pyrrolidino, N-(lower alkyl)-2- piperidyl, morpholino, 1 -piperizinyl, 4-(lower alkyl)- 1 -piperizinyl, 4-(hydroxyl-lower alkyl)- 1- piperizinyl, and 4-(methoxy-lower alkyl)- 1 -piperizinyl, unsubstituted or optionally substituted;
- each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, alkoxy, dioxo, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each of which is independently optionally substituted; and
- R 10 is selected from hydrogen, alkyl, and acyl.
- composition comprising a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble and non-peptidic oligomer, and optionally, a pharmaceutically acceptable excipient.
- a dosage form comprising a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form.
- a method is provided, the method comprising covalently attaching a water-soluble, non-peptidic oligomer to a tricyclic.
- a method comprising administering a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer.
- Figure 1 shows blocking effects of carbamazepine and its conjugates on sodium current at 0.1 Hz (A) vs. 3 Hz (B) in isolated human atria! myocytes. Data are mean ⁇ SEM.
- Figure 2 shows blocking effects of carbamazepine and its conjugates on sodium cuirent at 0.1 Hz (A) vs. 3 Hz (B) in isolated rat dorsal root ganglion cells. Data are mean ⁇ SEM.
- Figure 3 shows mean ( ⁇ SEM) percent sodium current block at 100 ⁇ at 0.1 Hz
- Figure 4 shows mean ( ⁇ SEM) percent specific binding of desipramine and its conjugates to noradrenalin transporters in rat forebrain membranes.
- Figure 5 shows the analgesia activity of the tested compound against the standard analgesic, morphine.
- Figure 6 shows the mean (+ SEM) number of paw withdrawals when the tested compound is tested with mechanical allodynia as described in Example 11.
- Figure 7 shows the mean (+ SEM) number of paw withdrawals when the tested compound is tested with mechanical hyperalgesia as described in Example 1 1.
- Figure 8 shows the mean (+ SEM) paw withdrawal latency when the tested compound is tested with thermal hyperalgesia as described in Example 11.
- an unfiltered aqueous preparation of a "water-soluble" oligomer transmits at least 75%, in certain embodiments at least 95%, of the amount of light transmitted by the same solution after filtering.
- the water-soluble oligomer is at least 95% (by weight) soluble in water or completely soluble in water.
- an oligomer is non- peptidic when it has less than 35% (by weight) of amino acid residues.
- oligomers used in connection with present the invention are homo-oligomers.
- the water-soluble, non-peptidic oligomer typically comprises one or more monomers serially attached to form a chain of monomers.
- the oligomer can be formed from a single monomer type (i.e., is homo-oligomeric) or two or three monomer types (i.e., is co-oligomeric).
- oligomer is a molecule possessing from about 1 to about 30 monomers.
- oligomers for use in the invention include those having a variety of geometries such as linear, branched, or forked, to be described in greater detail below.
- PEG polyethylene glycol
- polyethylene glycol is meant to encompass any water-soluble poly( ethylene oxide).
- a "PEG oligomer” an oligoethylene glycol is one in which substantially all (in certain embodiments all) monomeric subunits are ethylene oxide subunits, though the oligomer may contain distinct end capping moieties or functional groups, e.g., for conjugation, PEG oligomers for use in the present invention will comprise one of the two following structures: "-(CH 2 CH 2 0) n - M or
- variable "n" ranges from about 1 to 30, in certain embodiments from about 2 to about 30, and the terminal groups and architecture of the overall PEG can vary.
- PEG further comprises a functional group, A, for linking to, e.g., a small molecule drug
- the functional group v/hen covalently attached to a PEG oligomer does not result in formation of (i) an oxygen-oxygen bond (-0-0-, a peroxide linkage), or (ii) a nitrogen-oxygen bond (N-O, O-N).
- end-capped and “terminally capped” are interchangeably used herein to refer to a terminal or endpoint of a polymer having an end-capping moiety.
- the end-capping moiety comprises a hydroxy or Ci -20 alkoxy group, in certain embodiments a C O alkoxy group, and in certain embodiments a C 1-5 alkoxy group.
- examples of end-capping moieties include alkoxy (e.g., methoxy, ethoxy and benzyloxy), as well as aryl, heteroaryl, cyclo, heterocyclo, and the like.
- the end-capping moiety may include one or more atoms of the terminal monomer in the polymer [e.g., the end-capping moiety "methoxy" in CH 3 0(CH 2 CH 2 0) n - and CH 3 (OCH 2 CH 2 ) N -].
- the end-capping group can also be a silane.
- the end-capping group can also comprise a detectable label.
- the amount or location of the polymer and/or the moiety (e.g., active agent) to which the polymer is coupled can be determined by using a suitable detector.
- suitable detectors include photometers, films, spectrometers, and the like.
- the end-capping group can also comprise a phospholipid. When the polymer has an end-capping group comprising a phospholipid, unique properties are imparted to the polymer and the resulting conjugate.
- Exemplary phospholipids include, without limitation, those selected from the class of phospholipids called
- phosphatidylcholines include, without limitation, those selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine,
- dipalmitoylphosphatidylcholine dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine, and lecithin,
- targeting moiety is used herein to refer to a molecular structure that helps the conjugates of the invention to localize to a targeting area, e.g. , help enter, permeate, or penetrate a cell, or bind a receptor.
- the targeting moiety comprises of vitamin, cofactor, antibody, antigen, receptor, DNA, R A, sialyl Lewis X antigen, hyaluronic acid, sugars, cell specific lectins, steroid or steroid derivative, RGD peptide, cell penetrating or cell targeting moiety, ligand for a cell surface receptor, serum component, or combinatorial molecule directed against various intra- or extracellular receptors.
- the targeting moiety may also comprise a lipid or a phospholipid.
- exemplary phospholipids include, without limitation, phosphatidylcholines, phospatidylserine, phospatidylinositol, phospatidylglycerol, and phospatidylethanolamine. These lipids may be in the form of micelles or liposomes and the like.
- the targeting moiety may further comprise a detectable label or alternately a detectable label may serve as a targeting moiety.
- the amount and/or distribution/location of the polymer and/or the moiety (e.g., active agent) to which the polymer is coupled can be determined by using a suitable detector.
- suitable detector include, without limitation, fluorescers, chemiluminescers, moieties used in enzyme labeling, colorimetric (e.g., dyes), metal ions, radioactive moieties, gold particles, quantum dots, and the like.
- Branched in reference to the geometry or overall structure of an oligomer, refers to an oligomer having two or more polymer "aims" from a branch point.
- Formked in reference to the geometry or overall structure of an oligomer, refers to an oligomer having two or more functional groups (typically through one or more atoms) extending from a branch point.
- a "branch point” refers to a bifurcation point comprising one or more atoms at which an oligomer branches or forks from a linear structure into one or more additional aims.
- reactive refers to a functional group that reacts readily or at a practical rate under conventional conditions of organic synthesis. This is in contrast to those groups that either do not react or require strong catalysts or impractical reaction conditions in order to react (i.e., a "nonreactive” or "inert” group).
- a "protecting group” is a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions.
- the protecting group may vary depending upon the type of chemically reactive group being protected as well as the reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule.
- Functional groups which may be protected include, by way of example, carboxylic acid groups, amino groups, hydroxyl groups, thiol groups, carbonyl groups and the like.
- protecting groups for carboxylic acids include esters (such as a -methoxybenzyl ester), amides and hydrazides; for amino groups, carbamates (such as tert-butoxycarbonyl) and amides; for hydroxyl groups, ethers and esters; for thiol groups, thioethers and thioesters; for carbonyl groups, acetals and ketals; and the like.
- Such protecting groups are well-known to those skilled in the art and are described, for example, in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1 99, and references cited therein.
- a functional group in “protected form” refers to a functional group bearing a protecting group.
- the term “functional group” or any synonym thereof encompasses protected forms thereof.
- a "physiologically cleavable” or “hydrolyzable” or “degradable” bond is a relatively labile bond that reacts with water (i.e., is hydrolyzed) under physiological conditions.
- the tendency of a bond to hydrolyze in water may depend not only on the general type of linkage connecting two central atoms but also on the substituents attached to these central atoms.
- Appropriate hydrolytically unstable or weak linkages include but are not limited to carboxylate ester, phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, orthoesters, peptides, oligonucleotides, thioesters, thiolesters, and carbonates.
- An "enzymatically degradable linkage” means a linkage that is subject to degradation by one or more enzymes.
- a “stable” linkage or bond refers to a bond, typically a covalent bond, that is substantially stable in water, that is to say, does not undergo hydrolysis under physiological conditions to any appreciable extent over an extended period of time.
- hydrolytically stable linkages include but are not limited to the following: carbon-carbon bonds (e.g., in aliphatic chains), ethers, amides, urethanes, amines, and the like. Generally, a stable linkage is one that exhibits a rate of hydrolysis of less than about 1-2% per day under physiological conditions. Hydrolysis rates of representative chemical bonds can be found in most standard chemistry textbooks.
- “Monodisperse” refers to an oligomer composition wherein substantially all of the oligomers in the composition have a well-defined, single molecular weight and defined number of monomers, as determined by chromatography or mass spectrometry. Monodisperse oligomer compositions are in one sense pure, that is, substantially having a single and definable number (as a whole number) of monomers rather than a large distribution.
- a monodisperse oligomer composition possesses a MW/Mn value of 1.0005 or less, and in certain embodiments, a MW/Mn value of 1.0000.
- a composition comprised of monodisperse conjugates means that substantially all oligomers of all conjugates in the composition have a single and definable number (as a whole number) of monomers rather than a large distribution and would possess a MW/Mn value of 1.0005, and in certain embodiments, a MW/Mn value of 1.0000, if the oligomer were not attached to the moiety derived from a small molecule drug.
- composition comprised of monodisperse conjugates may however, include one or more nonconjugate substances such as solvents, reagents, excipients, and so forth.
- Bimodal in reference to an oligomer composition, refers to an oligomer composition wherein substantially all oligomers in the composition have one of two definable and different numbers (as whole numbers) of monomers rather than a large distribution, and whose distribution of molecular weights, when plotted as a number fraction versus molecular weight, appears as two separate identifiable peaks.
- each peak is generally symmetric about its mean, although the size of the two peaks may differ.
- the polydispersity index of each peak in the bimodal distribution, Mw/Mn is 1.01 or less, in certain embodiments 1.001 or less, and in certain embodiments 1.0005 or less, and in certain embodiments a MW/Mn value of 1.0000.
- a composition comprised of bimodal conjugates means that substantially all oligomers of all conjugates in the composition have one of two definable and different numbers (as whole numbers) of monomers rather than a large distribution and would possess a MW/Mn value of 1.01 or less, in certain embodiments 1.001 or less and even in certain embodiments 1.0005 or less, and in certain embodiments a MW/Mn value of 1.0000 if the oligomer were not attached to the moiety derived from a small molecule drug.
- a composition comprised of bimodal conjugates can include, however, one or more nonconjugate substances such as solvents, reagents, excipients, and so forth
- a "tricyclic” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000 Daltons and having some degree of activity as tricyclic therapeutic as described herein.
- a “biological membrane” is any membrane made of cells or tissues that serves as a barrier to at least some foreign entities or otherwise undesirable materials.
- a “biological membrane” includes those membranes that are associated with physiological protective barriers including, for example: the blood-brain barrier (BBB); the
- the term "biological membrane” does not include those membranes associated with the middle gastro-intestinal tract (e.g., stomach and small intestines).
- a "biological membrane crossing rate,” provides a measure of a compound's ability to cross a biological membrane (such as the blood-brain barrier (BBB)).
- BBB blood-brain barrier
- a variety of methods may be used to assess transport of a molecule across any given biological membrane. Methods to assess the biological membrane crossing rate associated with any given biological barrier (e.g., the blood-cerebrospinal fluid barrier, the blood-placental barrier, the blood-milk barrier, the intestinal barrier, and so forth), are described herein and/or in the relevant literature, and/or may be determined by one of ordinary skill in the art.
- a “reduced rate of metabolism” in reference to the present invention refers to a measurable reduction in the rate of metabolism of a water-soluble oligomer-small molecule dmg conjugate as compared to the rate of metabolism of the small molecule drug not attached to the water-soluble oligomer (i.e., the small molecule drug itself) or a reference standard material.
- the same “reduced rate of metabolism” is required except that the small molecule drug (or reference standard material) and the corresponding conjugate are administered orally.
- Orally administered drugs are absorbed from the gastro-intestinal tract into the portal circulation and may pass through the liver prior to reaching the systemic circulation.
- the degree of first pass metabolism may be measured by a number of different approaches. For instance, animal blood samples may be collected at timed intervals and the plasma or serum analyzed by liquid chromatography/mass spectrometry for metabolite levels. Other techniques for measuring a "reduced rate of metabolism" associated with the first pass metabolism and other metabolic processes are known, described herein and/or in the relevant literature, and/or may be determined by one of ordinary skill in the art.
- a conjugate of the invention may provide a reduced rate of metabolism reduction satisfying at least one of the following values: at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; and at least about 90%.
- a compound (such as a small molecule drug or conjugate thereof) that is "orally bioavailable" is one that in certain embodiments possesses a bioavailability when administered orally of greater than 25%, and in certain embodiments greater than 70%, where a compound's bioavailability is the fraction of administered drug that reaches the systemic circulation in unmetabolized form.
- Alkyl refers to a hydrocarbon chain ranging from about 1 to 20 atoms in length.
- alkyl groups include methyl, ethyl, propyl, butyl, pentyl, 2-methylbutyl, 2-ethylpropyl, 3-methylpentyl, and the like.
- alkyl includes cycloalkyl when three or more carbon atoms are referenced.
- “Lower alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms, and may be straight chain or branched, as exemplified by methyl, ethyl, n-butyl, i-butyl, t-butyl.
- Non-interfering substituents are those groups that, when present in a molecule, are typically non-reactive with other functional groups contained within the molecule.
- Alkoxy refers to an -O-R group, wherein R is alkyl or substituted alkyl, in certain embodiments Ci-C 2 o alkyl (e.g., methoxy, ethoxy, propyloxy, etc.), in certain
- “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to component that may be included in the compositions of the invention causes no significant adverse toxicological effects to a patient.
- aryl means an aromatic group having up to 14 carbon atoms.
- Aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthalenyl, and the like.
- Substituted phenyl and “substituted aryl” denote a phenyl group and aryl group, respectively, substituted with one, two, three, four or five (e.g. 1-2,1-3 or 1-4 substituents) chosen from halo (F, CI, Br, I), hydroxy, cyano, nitro, alkyl (e.g., Ci -6 alkyl), alkoxy (e.g., Ci_6 alkoxy), benzyloxy, carboxy, aryl, and so forth.
- Chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
- an "alkyl” moiety generally refers to a monovalent radical (e.g., CH 3 -CH 2 -)
- a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH 2 -), which is equivalent to the term “alkyl ene.”
- alkyl ene e.g., -CH2-CH 2 -
- aryl refers to the corresponding multivalent moiety, arylene. All atoms are understood to have their normal number of valences for bond formation (i.e., 1 for H, 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
- terapéuticaally effective amount are used interchangeably herein to mean the amount of a water-soluble oligomer-small molecule drug conjugate present in a composition that is needed to provide a desired level of active agent and/or conjugate in the bloodstream or in the target tissue.
- the precise amount may depend upon numerous factors, e.g., the particular active agent, the components and physical characteristics of the composition, intended patient population, patient considerations and may readily be determined by one skilled in the art, based upon the information provided herein and available in the relevant literature.
- a "difunctional" oligomer is an oligomer having two functional groups contained therein, typically at its termini. When the functional groups are the same, the oligomer is said to be homodifunctional. When the functional groups are different, the oligomer is said to be
- a basic reactant or an acidic reactant described herein include neutral, charged, and any corresponding salt forms thereof.
- patient refers to a living organism suffering from or prone to a condition that can be prevented or treated by administration of a conjugate as described herein, and includes both humans and animals.
- conjugate as described herein, and includes both humans and animals.
- “Optional” or “optionally” means that the subsequently described circumstance may but need not necessarily occur, so that the description includes instances where the
- Nil refers to the absence of a substituent group.
- the substituent may be represented in the structure as a chemical bond or hydrogen in the resulting structure.
- the present invention is directed to (among other things) a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic residue is a residue of a
- R 1 is selected from the group alkyl, amino, acylamino, acyl, amido, aryloxy, alkylamino, dialkylamino having about 2 to 4 inclusive carbon atoms, piperidino, pyrrolidino, N-(lower alkyl)-2- piperidyl, morpholino, 1 -piperizinyl, 4-(lower alkyl)- 1 -piperizinyl, 4-(hydroxyl-lower alkyl)- 1- piperizinyl, and 4-(methoxy- lower alkyl)- 1 -piperizinyl, each of which is independently optionally substituted;
- R 10 is selected from hydrogen, alkyl, and acyl.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic residue is a residue of a compound having a structure encompassed by the following formula:
- R 1 is amido
- Y is selected from -C(0)-CH 2 - and -C(-OR 10 )-CH 2 -;
- each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are hydrogen;
- R 10 is selected from hydrogen, alkyl, and acyl.
- R 1 is amido
- Y is selected from -,-C(0)-CH;>- , -C(-
- R 10 is selected from hydrogen, alkyl, and acyl. In certain embodiments R 10 is selected from lower alkyl and lower acyl. In certain embodiments, R 10 is acetyl.
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each hydrogen.
- Examples of specific tricyclic compounds include those selected from the group consisting of amineptine, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomiprimine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, lofepramine, melitracen, metapramine, mirtazapine, nortriptyline, opipramol, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, carbamazepine, oxcarbazepine, eslicarbazepine acetate, chlorpromazine, promethazine, clozapine, loxapine, and eslicarbazepine.
- the tricyclic residue is a residue of a compound selected from oxcarbazepine, eslicarbazepine acetate, and eslicarbazepine.
- the tricyclic residue is a residue of oxcarbazepine.
- an advantage of the compounds of the present invention is their ability to retain some degree of tricyclic activity while also exhibiting a decrease in metabolism.
- the tricyclic residue- and oligomer-containing compounds described herein ⁇ in contrast to the oligomer-free "original" tricyclic structure -- are not metabolized as readily because the oligomer serves to reduce the overall affinity of the compound to substrates that may metabolize tricyclics.
- the extra size introduced by the oligomer - in contrast to the oligomer-free "original" tricyclic structure ⁇ reduces the ability of the compound to cross the blood-brain barrier. Even should the linkage between the residue of the tricyclic and the oligomer be degradable, the compound still offers advantages (such as avoiding first-pass metabolism upon initial absoiption).
- a compound of the invention when administered by any of a number of suitable administration routes, such as parenteral, oral, transdermal, buccal, pulmonary, or nasal, exhibits reduced penetration across the blood-brain barrier.
- the compounds of the invention exhibit slowed, minimal or effectively no crossing of the blood-brain barrier, while still crossing the gastro-intestinal (GI) walls and into the systemic circulation if oral delivery is intended.
- the compounds of the invention maintain a degree of bioactivity as well as bioavailability in comparison to the bioactivity and bioavailability of the compound free of all oligomers.
- this barrier restricts the transport of drugs from the blood to the brain.
- This barrier consists of a continuous layer of unique endothelial cells joined by tight junctions.
- the cerebral capillaries which comprise more than 95% of the total surface area of the BBB, represent the principal route for the entry of most solutes and drugs into the central nervous system.
- RBP in situ rat brain perfusion
- a physiologic buffer containing the analyte (typically but not necessarily at a 5 micromolar concentration level) is perfused at a flow rate of about 10 mL/minute in a single pass perfusion experiment. After 30 seconds, the perfusion is stopped and the brain vascular contents are washed out with compound- free buffer for an additional 30 seconds. The brain tissue is then removed and analyzed for compound
- blood-brain barrier permeability can be estimated based upon a calculation of the compound's molecular polar surface area ("PSA"), which is defined as the sum of surface contributions of polar atoms (usually oxygens, nitrogens and attached hydrogens) in a molecule.
- PSA molecular polar surface area
- the PSA has been shown to correlate with compound transport properties such as blood-brain barrier transport.
- Methods for determining a compound's PSA can be found, e.g., in, Ertl, P., et al., J. Med. Chem. 2000, 43, 3714-3717; and Kelder, J., et al, Pharm. Res. 1999, 16, 1514- 1519.
- the water-soluble, non-peptidic oligomer-small molecule drug conjugate exhibits a blood-brain barrier crossing rate that is reduced as compared to the crossing rate of the small molecule drug not attached to the water-soluble, non-peptidic oligomer.
- Exemplary reductions in blood-brain barrier crossing rates for the compounds described herein include reductions of: at least about 5%; at least about 10%; at least about 25%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; or at least about 90%, when compared to the blood-brain barrier crossing rate of the small molecule drug not attached to the water-soluble oligomer.
- a reduction in the blood-brain barrier crossing rate for a conjugate of the invention is at least about 20%.
- the compounds of the invention include a tricyclic residue.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- n is an integer of from 1 to 3 inclusive;
- X and Y are selected from the group consisting of hydrogen and halo selected from fluoro, chloro and bromo;
- R and R' are selected from the group consisting of hydrogen and lower alkyl having from one to five carbon atoms inclusive;
- n is an integer of from 1 to 12 inclusive.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: (3' - dimethylaminopropylidene) - dibenzo(a,d) - cycIohepta-l,4-diene N-oxide, and or the hydrochloric acid addition salt thereof.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: a formula selected from the group consisting of 2-chloro-l 1 -(1- piperizinyl)dibenz(b,f)[l,4]ox-azepine, 2-chloro-l l-(l-piperizinyl)dibenz(b,f)[l,4]ox-azepine hydrochloride, 2-chloro- l l-(l-piperizinyl)dibenz(b,f)[l,4]ox-azepine fumarate, 2-chloro-l 1-(1- piperizinyl)dibenz(b,f)[l,4]ox-azepine sulfate,
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: 5-(3'-dimethylamino-2' - methylpropyl)dibenzo[a,d][l,4]- cycloheptadiene.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a stmcture encompassed by the following formula: a formula selected from the group consisting of 3-chloro-5-(y- dimethylamino-propyl)-iminodibenzyl, a pharmaceutically acceptable acid addition salt of 3- chloro-5-(y-dimethylamino-propyl)-iminodibenzyl, and 3-chloro-5-(y-dimethylamino-propyl)- iminodibenzyl hydrochloride.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: a formula selected from the group consisting of
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: a formula selected from the group consisting of 5-(y-methylamino- propyl)-iminodibenzyl and nontoxic addition salts thereof, N-(3-methylaminopropyl)- iminodibenzyl, and N-(3-methylaminopropyl)-iminodibenzyl hydrochloride.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic is a compound selected from the group consisting of a 10-(basic substituted)-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepine of the formula:
- X represents alkylene having between 2 and 3 inclusive carbon atoms
- Y is a member of the class consisting of dialkylamino having between 2 and 4 inclusive carbon atoms, pyrrolidino, piperidino, and morpholino
- Ri and R 2 represent, interchangeably, a member of the class consisting of hydrogen, methyl, and ethyl
- R and R4 represent, interchangeably, a member of the class consisting of hydrogen, chloro, methyl, ethyl, methoxy, and ethoxy.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic residue is selected from the group consisting of a compound of the formula:
- alkylene has 2 to 4 carbons inclusive, and at least two carbons separate X from the heterocyclic nucleus;
- X is selected from the group consisting of dialkylamino of 2 to 4 carbons, pyrrilidino, piperidino, and morpholino; and each Y is independently selected from the group consisting of hydrogen, chloro, methyl, methoxy, and ethoxy,
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic is a compound selected from the group consisting of: the substituted 5H-dibenzo[b,e][l,4]diazepine derivatives of the formula:
- Ri is selected from the class consisting of hydrogen, methyl, and ethyl
- -X-Y is a basic radical wherein X is a hydrocarbon chain containing between 2 and 3 inclusive carbon atoms, and Y is selected from the class consisting of dialkylamino having between 2 and 4 inclusive carbon atoms, piperidino, pyrrolidino, N-(lower alkyl)-2-piperidyl, morpholino, l-piperizinyl, 4- (lower alkyl)-l-piperizinyl, 4-(hydroxyl-lower alkyl)-l-piperizinyl, and 4-(methoxy-lower alky])- l-piperizinyl and R 2 and R 3 are selected from the class consisting of hydrogen, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylmercapto, and ethylmercapto.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- R is a member selected from the group consisting of CH 3 and C2H5
- Ri is a member selected from the group consisting of CI, CH 3 , CF 3 , and C 2 H 5 .
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- R is a member selected from the group consisting of CH 3 and C2H5
- Ri is a member selected from the group consisting of H, CI, CH 3 , CF 3 , and C 2 H 5 .
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula: 1 l-(3-dimethylaminopropylidene) - 6,11 - dihydro-dibenz-(b,e)thiepin.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- R ⁇ is a member of the group consisting of hydrogen and halo and A is 4- ( ⁇ -hydroxyethyl-piperidino).
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- n is a whole number from 0 to 1 and i is alkyl having from 1 to 4 carbon atoms.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- X and Y are each selected from the group consisting of hydrogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, thioalkoxy having from 1 to 4 carbon atoms, chloro, fluoro, trifluoromethyl, acyl having from 1 to 4 carbon atoms, and
- dialkylsulfonamido having from 1 to 8 carbon atoms.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- R 2 and R 3 are each a member of the group consisting of hydrogen, fluoro, chloro, lower alkyl, lower aloxy, lower alkylthio, and trifluromethyl and Z is di-lower-alkylamino.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic compound is selected from the group consisting of a free base and its water soluble acid addition salts, said free base having the formula: Alk lene-Am
- alkylene represents an alkylene chain of 2-3 carbon atoms and Am represents a member selected from the group consisting of a low molecular dialkylamino radical, the N-piperidino-, N-morpholino-, and N-pyrrolidino radicals.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- R 1 is selected from the group consisting of H and CH 3 ;
- R 2 represents an alkyl group having a maximum of 4 carbon atoms
- n is selected from the group consisting of 1 , 2, and 3;
- R 3 is selected from the group consisting of phenyl and phenyl substituted with a maximum of three substituents selected from the group consisting of F, CI, OH, CF 3 , as well as alkyl and alkoxy containing a maximum of 4 carbon atoms; and a phenyl group having at the 3,4-positions a substituent selected from the group consisting of alkylidenedioxy (having a maximum of 6 carbon atoms), cycloalkylidenedioxy (having a maximum of 6 carbon atoms), and
- R is selected from the group consisting of H, F, CI, OCH 3 , CF 3 , and S0 2 N(CH3) 2 .
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- each of R 1 and R 2 is a lower-alkyl group;
- X is selected from the group consisting of hydrogen, halo, lower-alkyl and lower-alkyloxy;
- Y is selected from the group consisting of hydrogen and halo;
- heterocyclic amine radicals is selected from the group consisting of pyrrolidine, piperidine, morpholine, thiamorpholine, N'-lower-alkylpiperizine, and C-lower alkyl derivatives of the foregoing.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic has a structure encompassed by the following formula:
- each of R and R is a lower-alkyl group;
- X is selected from the group consisting of hydrogen, halo, lower-alkyl and lower- alkyloxy;
- Y is selected from the group consisting of hydrogen and halo;
- heterocyclic amine is selected from the group consisting of di-lower-alkylamino, benzyl-lower-alkylamino, the radical of a heterocyclic amine, having a saturated five-membered ring, and the radical of a heterocyclic amine having a saturated six-membered ring, said heterocyclic amines being selected from the group consisting of pyn-olidine, piperidine, morpholine, thiamoipholine, N 1 - loweralkylpiperizine, and C-lower alkyl derivatives of the foregoing.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic compound has the formula:
- R and R' are the same or different and each represent hydrogen or alkyl of one to five carbon atoms
- Rj is hydrogen, alkyl, of one to five carbon atoms, or benzyl.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer wherein the tricyclic compound has the formula:
- R is selected from the group consisting of hydrogen, lower alkyl, phenyl, and benzyl.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-pe tidic oligomer, wherein the tricyclic compound has the formula:
- each of X and Y represents a member selected from the group consisting of hydrogen and halo.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic compound is 10,1 l-dihydro-10- oxo-5H-dibenz(b,f)azepine-5-carboxamide.
- a compound comprising a tricyclic residue covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the tricyclic compound is (S)-10-Acetoxy- 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.
- the tricyclic compound residue is a residue of a tricyclic compound having the formula:
- R 10 is selected from hydrogen, alkyl, and acyl when— represents a single bond
- R 10 is absent when— represents a double bond.
- the tricyclic compound residue is a residue of a tricyclic compound having the formula:
- the tricyclic compound residue is a residue of a tricyclic compound having the formula:
- R is selected from lower alkyl and lower acyl.
- R is acetyl.
- tricyclics can be obtained from commercial sources.
- tricyclics can be obtained through chemical synthesis. Examples of tricyclics as well as synthetic approaches for preparing tricyclics are described in the literature and in, for example, DE2030492A1, DE2030492A, DE2030492B2, DE2030492C3, GB1191800A, US2554736, US2948718, US3177209, US3205264, US3244748, US3271451, US3299139, US3312689, US3409640, US3419547, US3438981, US3442949, US3454554, US3467650, US3527766, US3574852, US3622565, US3637660, US3663696, US3758528, US3963778, and US3642775.
- Each of these (and other) tricyclics can be covalently attached (either directly or through one or more atoms) to a water-soluble and non-peptidic oligomer.
- Exemplary molecular weights of small molecule drugs include molecular weights of: less than about 950; less than about 900; less than about 850; less than about 800; less than about 750; less than about 700; less than about 650; less than about 600; less than about 550; less than about 500; less than about 450; less than about 400; less than about 350; and less than about 300.
- the small molecule drug used in the invention may be in a racemic mixture, or an optically active form, for example, a single optically active enantiomer, or any combination or ratio of enantiomers (i.e., scalemic mixture).
- the small molecule drug may possess one or more geometric isomers.
- a composition can comprise a single geometric isomer or a mixture of two or more geometric isomers.
- a small molecule dmg for use in the present invention can be in its customary active form, or may possess some degree of modification.
- a small molecule drug may have a targeting agent, tag, or transporter attached thereto, prior to or after covalent attachment of an oligomer.
- the small molecule drug may possess a lipophilic moiety attached thereto, such as a phospholipid (e.g., distearoylphosphatidylethanolamine or "DSPE,” dipalmitoylphosphatidylethanolamine or "DPPE,” and so forth) or a small fatty acid.
- DSPE distearoylphosphatidylethanolamine
- DPPE dipalmitoylphosphatidylethanolamine
- the tricyclic for coupling to a water-soluble, non-peptidic oligomer possesses a free hydroxyl, carboxyl, thio, amino group, or the like (i.e., "handle") suitable for covalent attachment to the oligomer.
- the tricyclic may be modified by introduction of a reactive group, in certain embodiments by conversion of one of its existing functional groups to a functional group suitable for formation of a stable covalent linkage between the oligomer and the drug. Both approaches are illustrated in the Experimental section.
- each oligomer is composed of up to three different monomer types selected from the group consisting of: alkylene oxide, such as ethylene oxide or propylene oxide; olefinic alcohol, such as vinyl alcohol, 1-propenol or 2-propenol; vinyl pyrrolidone;
- each oligomer is, independently, a co-oligomer of two monomer types selected from this group, or, in certain embodiments, is a homo-oligomer of one monomer type selected from this group.
- the two monomer types in a co-oligomer may be of the same monomer type, for example, two alkylene oxides, such as ethylene oxide and propylene oxide.
- the oligomer is a homo-oligomer of ethylene oxide.
- the terminus (or termini) of the oligomer that is not covalently attached to a small molecule is capped to render it unreactive.
- the terminus may include a reactive group. When the terminus is a reactive group, the reactive group is either selected such that it is unreactive under the conditions of formation of the final oligomer or during covalent attachment of the oligomer to a small molecule drug, or it is protected as necessary.
- the water-soluble, non-peptidic oligomer can have any of a number of different geometries.
- the water-soluble, non-peptidic oligomer can be linear, branched, or forked.
- the water-soluble, non-peptidic oligomer is linear or is branched, for example, having one branch point.
- the molecular weight of the water-soluble, non-peptidic oligomer, excluding the linker portion, is generally relatively low.
- Exemplary values of the molecular weight of the water-soluble polymer include: below about 1500; below about 1450; below about 1400; below about 1350; below about 1300: below about 1250; below about 1200; below about 1 150; below about 1 100; below about 1050; below about 1000; below about 950; below about 900; below about 850; below about 800; below about 750; below about 700; below about 650; below about 600; below about 550; below about 500; below about 450; below about 400; below about 350; below about 300; below about 250; below about 200; and below about 100 Daltons.
- Exemplary ranges of molecular weights of the water-soluble, non-peptidic oligomer include: from about 100 to about 1400 Daltons; from about 100 to about 1200 Daltons; from about 100 to about 800 Daltons; from about 100 to about 500 Daltons; from about 100 to about 400 Daltons; from about 200 to about 500 Daltons; from about 200 to about 400 Daltons; from about 75 to 1000 Daltons; and from about 75 to about 750 Daltons.
- the number of monomers in the water-soluble, non-peptidic oligomer falls within one or more of the following ranges: between about 1 and about 30 (inclusive); between about 1 and about 25; between about 1 and about 20; between about 1 and about 15; between about 1 and about 12; between about 1 and about 10.
- the number of monomers in series in the oligomer (and the corresponding conjugate) is one of 1 , 2, 3, 4, 5, 6, 7, or 8.
- the oligomer (and the corresponding conjugate) contains 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 monomers.
- the oligomer (and the corresponding conjugate) possesses 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 monomers in series.
- n is an integer that can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, and can fall within one or more of the following ranges: between about 1 and about 25; between about 1 and about 20; between about 1 and about 15; between about 1 and about 12; between about 1 and about 10.
- the water-soluble, non-peptidic oligomer has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 monomers, these values correspond to a methoxy end-capped oligo(ethylene oxide) having a molecular weights of about 75, 119, 163, 207, 251, 295, 339, 383, 427, and 471 Daltons, respectively.
- the oligomer has 11, 12, 13, 14, or 15 monomers, these values correspond to methoxy end-capped oligo(ethylene oxide) having molecular weights corresponding to about 515, 559, 603, 647, and 691 Daltons, respectively.
- the composition containing an activated form of the water-soluble, non-peptidic oligomer may be monodisperse. In those instances, however, where a bimodal composition is employed, the composition will possess a bimodal distribution centering around any two of the above numbers of monomers.
- a bimodal oligomer may have any one of the following exemplary combinations of monomer subunits: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, and so forth; 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, and so forth; 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, and so forth; 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, and so forth; 5-6, 5-7, 5-8, 5-9, 5-10, and so forth; 6-7, 6-8, 6-9, 6-10, and so forth; 7-8, 7-9, 7- 10, and so forth; and 8-9, 8-10, and so forth.
- the composition containing an activated form of the water-soluble, non-peptidic oligomer will be trimodal or even tetramodal, possessing a range of monomers units as previously described.
- Oligomer compositions possessing a well-defined mixture of oligomers i.e., being bimodal, trimodal, tetramodal, and so forth
- can be prepared by mixing purified monodisperse oligomers to obtain a desired profile of oligomers a mixture of two oligomers differing only in the number of monomers is bimodal; a mixture of three oligomers differing only in the number of monomers is trimodal; a mixture of four oligomers differing only in the number of monomers is tetramodal
- a desired profile of oligomers a mixture of two oligomers differing only in the number of monomers is bimodal; a mixture of three oligomers differing only in the number of monomers is trimodal; a mixture of four oligomers differing only in the
- the water-soluble, non-peptidic oligomer is obtained from a composition that is unimolecular or monodisperse. That is, the oligomers in the composition possess the same discrete molecular weight value rather than a distribution of molecular weights.
- Some monodisperse oligomers can be purchased from commercial sources such as those available from Sigma- Aldrich, or alternatively, can be prepared directly from commercially available starting materials such as Sigma-Aldrich.
- Water-soluble, non-peptidic oligomers can be prepared as described in Chen Y., Baker, G.L., J. Org. Chem., 6870-6873 (1999),
- the spacer moiety (through which the water-soluble, non-peptidic polymer is attached to the tricyclic) may be a single bond, a single atom, such as an oxygen atom or a sulfur atom, two atoms, or a number of atoms.
- a spacer moiety is typically but is not necessarily linear in nature.
- the spacer moiety, "X,” is hydrolytically stable, and in certain embodiments is also enzymatically stable.
- the spacer moiety "X" is one having a chain length of less than about 12 atoms, and in certain embodiments less than about 10 atoms, and in certain embodiments less than about 8 atoms and in certain embodiments less than about 5 atoms, whereby length is meant the number of atoms in a single chain, not counting substituents.
- the linkage does not comprise further spacer groups.
- the spacer moiety "X" comprises an ether, amide, urethane, amine, thioether, urea, or a carbon-carbon bond. Functional groups such as those discussed below, and illustrated in the examples, are typically used for forming the linkages.
- the spacer moiety may also comprise (or be adjacent to or flanked by) other atoms, as described further below.
- a spacer moiety of the invention, X may be any of the following: "-" (i.e., a covalent bond, that may be stable or degradable, between the tricyclic residue and the water-soluble, non-peptidic oligomer), -0-, -NH-, -S-, -C(O)-, -C(0)0-, -OC(O)-, -CH 2 -C(0)0-, -CH 2 -OC(0)-, -C(0)0-CH 2 -, -OC(0)-CH 2 -, C(0)-NH, NH- C(0)-NH, 0-C(0)-NH, -C(S)-, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -O-CH2-, -CH 2 -0-, -0-CH 2 -
- R 6 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl.
- Additional spacer moieties include, acylamino, acyl, aryloxy, alkylene bridge containing between 1 and 5 inclusive carbon atoms, alkylamino, dialkylamino having about 2 to 4 inclusive carbon atoms, piperidino, pyrrolidino, N-(lower alkyl)-2-piperidyl, morpholino, 1-piperizinyl, 4-(lower alkyl)- 1-piperizinyl, 4-(hydroxyl-lower alkyl)- 1-piperizinyl, and 4-(methoxy- lower alkyl)- 1-piperizinyl.
- a group of atoms is not considered a linkage when it is immediately adjacent to an oligomer segment, and the group of atoms is the same as a monomer of the oligomer such that the group would represent a. mere extension of the oligomer chain.
- the linkage "X" between the water-soluble, non-peptidic oligomer and the small molecule is typically formed by reaction of a functional group on a terminus of the oligomer (or nascent oligomer when it is desired to "grow” the oligomer onto the tricyclic) with a
- an amino group on an oligomer ma ⁇ ' be reacted with a carboxylic acid or an activated carboxylic acid derivative on the small molecule, or vice versa, to produce an amide linkage.
- reaction of an amine on an oligomer with an activated carbonate (e.g. succinimidyl or benzotriazyl carbonate) on the drug, or vice versa forms a carbamate linkage.
- reaction of an alcohol (alkoxide) group on an oligomer with an alkyl halide, or halide group within a drug, or vice versa forms an ether linkage.
- a small molecule having an aldehyde function is coupled to an oligomer amino group by reductive amination, resulting in formation of a secondary amine linkage between the oligomer and the small molecule.
- the water-soluble, non-peptidic oligomer is an oligomer bearing an aldehyde functional group.
- the oligomer will have the following structure: CH 3 0-(CH 2 -C3 ⁇ 4-0) n -(CH 2 ) p -C(0)H, wherein (n) is one of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and (p) is one of 1. 2, 3, 4, 5, 6 and 7.
- the (n) values include 3, 5 and 7 and the (p) values include 2, 3 and 4.
- the termini of the water-soluble, non-peptidic oligomer not bearing a functional group is capped to render it unreactive.
- that group is either selected such that it is unreactive under the conditions of formation of the linkage "X,” or it is protected during the formation of the linkage "X.”
- the water-soluble, non-peptidic oligomer includes at least one functional group prior to conjugation.
- the functional group typically comprises an electrophilic or nucleophilic group for covalent attachment to a small molecule, depending upon the reactive group contained within or introduced into the small molecule.
- nucleophilic groups that may be present in either the oligomer or the small molecule include hydroxyl, amine, hydrazine (-NHNH 2 ), hydrazide (-C(0)NH H 2 ), and thiol.
- nucleophiles include amine, hydrazine, hydrazide, and thiol, particularly amine.
- Most small molecule drugs for covalent attachment to an oligomer will possess a free hydroxyl, amino, thio, aldehyde, ketone, or carboxyl group.
- electrophilic functional groups that may be present in either the oligomer or the small molecule include carboxylic acid, carboxylic ester, particularly imide esters, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, silane, alkoxysilane, and halosilane.
- succinimidyl ester or carbonate imidazoyl ester or carbonate, benzotriazole ester or carbonate
- vinyl sulfone chloroethylsulfone
- vinylpyridine pyridyl disulfide
- iodoacetamide glyoxal
- dione mesylate, tosylate, and tresylate (2,2,2-trifluoroethanesulfonate.
- sulfur analogs of several of these groups such as thione, thione hydrate, thioketal, is 2-thiazolidine thione, etc., as well as hydrates or protected derivatives of any of the above moieties (e.g. aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, ketal, thioketal, thioacetal).
- an "activated derivative" of a carboxylic acid refers to a carboxylic acid derivative that reacts readily with nucleophiles, generally much more readily than the underivatized carboxylic acid.
- Activated carboxylic acids include, for example, acid ha!ides (such as acid chlorides), anhydrides, carbonates, and esters.
- esters include imide esters, of the general form -(CO)0-N[(CO)-] 2 ; for example, N-hydroxysuccinimidyl (NHS) esters or N-hydroxyphthalimidy] esters.
- imidazolyl esters and benzotriazole esters and propionic acid or butanoic acid esters as described in co-owned U.S. Patent No.
- electrophilic groups include succinimidyl carbonate, maleimide, benzotriazole carbonate, glycidyl ether, imidazoyl carbonate, p-nitrophenyl carbonate, acrylate, tresylate, aldehyde, and orthopyridyl disulfide.
- electrophilic groups are subject to reaction with nucleophiles, e.g., hydroxy, thio, or amino groups, to produce various bond types.
- the reactions favor formation of a hydrolytically stable linkage.
- carboxylic acids and activated derivatives thereof which include orthoesters, succinimidyl esters, imidazolyl esters, and benzotriazole esters, react with the above types of nucleophiles to form esters, thioesters, and amides, respectively, of which amides are the most hydrolytically stable.
- Aldehydes, ketones, glyoxals, diones and their hydrates or alcohol adducts i.e., aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, and ketal
- Aldehydes, ketones, glyoxals, diones and their hydrates or alcohol adducts i.e., aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, and ketal
- amine linkage reductive amination
- electrophilic functional groups include electrophilic double bonds to which nucleophilic groups, such as thiols, can be added, to form, for example, thioether bonds.
- nucleophilic groups such as thiols
- These groups include maleimides, vinyl sulfones, vinyl pyridine, acrylates, methacrylates, and acrylamides.
- Other groups comprise leaving groups that can be displaced by a nucleophile; these include chloroethyl sulfone, pyridyl disulfides (which include a cleavable S-S bond), iodoacetamide, mesylate, tosylate, thiosulfonate, and tresylate.
- Epoxides react by ring opening by a nucleophile, to form, for example, an ether or amine bond. Reactions involving
- the tricyclic may not have a functional group suited for conjugation.
- the tricyclic has an amide group, but an amine group is desired, it is possible to modify the amide group to an amine group by way of a Hofmann rearrangement, Curtius rearrangement (once the amide is converted to an azide) or Lossen rearrangement (once amide is concerted to hydroxamide followed by treatment with tolyene-2-sulfonyl chloride/base).
- DCC dicyclohexylcarbodiimidc
- a conjugate of a small molecule tricyclic bearing a hydroxyl group wherein the hydroxyl group-bearing small molecule tricyclic is coupled to an oligomeric ethylene glycol halide to result in an ether (-0-) linked small molecule conjugate.
- This can be performed, for example, by using sodium hydride to deprotonate the hydroxyl group followed by reaction with a halide-terminated oligomeric ethylene glycol.
- a conjugate of a small molecule tricyclic moiety bearing a hydroxyl group (such as, for example, the tricyclic moieties having structures encompassed within Formula I) wherein the hydroxyl group-bearing small molecule tricyclic moiety is coupled to an oligomeric ethylene glycol bearing an haloformate group [e.g.,
- [-0-C(0)-0-] linked small molecule conjugate This can be performed, for example, by combining a tricyclic moiety and an oligomeric ethylene glycol bearing a haloformate group in the presence of a nucleophilic catalyst (such as 4-dimethylaminopyridine or "DMAP") to thereby result in the corresponding carbonate-linked conjugate.
- a nucleophilic catalyst such as 4-dimethylaminopyridine or "DMAP”
- a conjugate of a small molecule tricyclic bearing an amine group it is possible to prepare a conjugate of a small molecule tricyclic bearing an amine group.
- the amine group-bearing small molecule tricyclic and an aldehyde-bearing oligomer are dissolved in a suitable buffer after which a suitable reducing agent (e.g., NaCNBH 3 ) is added.
- a suitable reducing agent e.g., NaCNBH 3
- a carboxylic acid-bearing oligomer and the amine group-bearing small molecule tricyclic are combined, typically in the presence of a coupling reagent (e.g., DCC).
- a coupling reagent e.g., DCC
- the result is an amide linkage formed between the amine group of the amine group-containing small molecule tricyclic and the carbonyl of the carboxylic acid-bearing oligomer.
- the conjugates of the invention can exhibit a reduced blood-brain barrier crossing rate. Moreover, the conjugates maintain at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%,
- an oligomer obtained from a monodisperse or bimodal water soluble oligomer is conjugated to the small molecule drug.
- the drug is orally bioavailable, and on its own, exhibits a non-negligible blood-brain barrier crossing rate.
- the ability of the conjugate to cross the blood-brain barrier is determined using an appropriate model and compared to that of the unmodified parent drug. If the results are favorable, that is to say, if, for example, the rate of crossing is significantly reduced, then the bioactivity of conjugate is further evaluated.
- the compounds according to the invention maintain a significant degree of bioactivity relative to the parent drug, i.e., greater than about 30% of the bioactivity of the parent drag, or in certain embodiments, greater than about 50% of the bioactivity of the parent drug.
- oligomer size By making small, incremental changes in oligomer size and utilizing an experimental design approach, one can effectively identify a conjugate having a favorable balance of reduction in biological membrane crossing rate, bioactivity, and oral bioavailability. In some instances, attachment of an oligomer as described herein is effective to actually increase oral bioavailability of the drug.
- one of ordinary skill in the art using routine experimentation, can determine a best suited molecular size and linkage for improving oral bioavailability by first preparing a series of oligomers with different weights and functional groups and then obtaining the necessary clearance profiles by administering the conjugates to a patient and taking periodic blood and/or urine sampling. Once a series of clearance profiles have been obtained for each tested conjugate, a suitable conjugate can be identified.
- Animal models (rodents and dogs) can also be used to study oral drug transport.
- non- n vivo methods include rodent everted gut excised tissue and Caco-2 cell , monolayer tissue-culture models. These models are useful in predicting oral drug bioavailability.
- the tricyclic compounds have sedative, hypnotic, anti-anxiety, tranquilizing, anticonvulsant, and muscle relaxant effects in mammals and birds. They also exhibit antidepressant and analgesic actions in mammals.
- Dish test Mice in Petri dishes (10 cm diameter, 5 cm high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicate tranquilization. ED50 equals the dose of test compound at which 50% of the mice remain in the dish.
- Pedestal test The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute.
- the ED50 intraperitoneal administration is determined by identifying the amount of compound that causes 50% of the mice to stay on the pedestal.
- Nicotine antagonism test Mice in a group of 6 are injected with the test compound. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg/kg). The control mice show over-stimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death. The ED50 (intraperitoneal administration) is determined by identifying the amount of compound that causes 50% of the mice to not show over-stimulation.
- Antagonism to strychnine (as sulfate): The test consists of orally administering into mice the test compound, and 30 minutes later 3 mg/kg strychnine sulfate intraperitoneally. The survivors after 4 hours reflect the activity of the compound as a muscle relaxant and antispasmodic.
- an anti-depressant The main function of an anti-depressant is to return the depressed individual to normal functioning. This should be carefully differentiated from psychic stimulants such as the amphetamines which produce over-stimulation in the normal individual.
- Many different methods have been and are used to evaluate antidepressant activity. In general these methods involve antagonism to a depressant such as reserpine or tetrabenazine or a synergistic increase of the toxicity of certain compounds (i.e. yohimbine or 3,4-dihydroxyphenylalanine) and comparison of the drug action of the new compound with other known antidepressants. No single test alone can determine whether or not a new compound is an antidepressant or not, but the profile evidenced by various tests will establish the anti-depressant action if present. A number of such tests are described below.
- hypothermic tests with oxotermorine [l-(4-pyrrolidino-2-butynyl)-2- pyrrolidinone], Oxotremorine (as well as apomorphine and tetrabenazine) produces hypothermic responses in mice. This response is blocked by anticholinergics and anti-depressants such as atropine and imipramine respectively.
- Mice are injected intraperitoneally with 1 mg of oxotremorine. The lowering of the body temperature is measured rectally with an electronic thermometer, before and 30 minutes after drug administration. About four degree centigrade difference between the control mice (oxotremorine alone) and the treated mice (oxotremorine and test compound) is used to indicate the antagonistic action of the test compound.
- mice are administered the test compound intraperitoneally one hour prior to the subcutaneous injection of apomorphine hydrochloride 10 mg/kg. The mice are then placed in a plastic box (6"xl 1 "x5") lined at the bottom with a cellophane-backed, absorbent paper. The degree of damage to the paper at the end of 30 min is scored from zero to 4. The scores of 3 and 4 indicate that the compound is a potentiator of apomorphine in this test.
- the tricyclic derivative itself or the conjugate of tricyclic or a derivative thereof has activity (such as analgesic activity)
- activity such as analgesic activity
- the compound of interest can be administered to a mouse topically and analgesia assessed as described in olesnikov et al. (1999) J, Pharmacol. Exp. Ther. 290:
- the distal portion of the tail (2-3 cm) is immersed in a DMSO solution containing the compound of interest for the stated time, typically two minutes. Testing is performed on the portion of the tail immersed in the treatment solution, because the analgesic actions of agents administered in this manner are restricted to the exposed portions of the tail.
- Antinociception, or analgesia is defined as a tail-flick latency for an individual animal that is twice its baseline latency or greater. Baseline latencies typically range from 2.5 to 3.0 seconds, with a maximum cutoff latency of 10 seconds to minimize tissue damage in analgesic animals. ED 50 values can be determined.
- the present invention also includes pharmaceutical preparations comprising a conjugate as provided herein in combination with a pharmaceutical excipient.
- the conjugate itself will be in a solid form (e.g., a precipitate), which can be combined with a suitable pharmaceutical excipient that can be in either solid or liquid form.
- Exemplary excipients include, without limitation, those selected from the group consisting of carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof.
- a carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer may be present as an excipient.
- Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffmose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, maltitol, lactitol, xylitol, sorbitol, myoinositol, and the like.
- the excipient can also include an inorganic salt or buffer such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
- the preparation may also include an antimicrobial agent for preventing or deterring microbial growth.
- antimicrobial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.
- An antioxidant can be present in the preparation as well. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the conjugate or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.
- a surfactant may be present as an excipient.
- exemplary surfactants include: polysorbates, such as “T een 20" and “Tween 80,” and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, NJ); sorbitan esters; lipids, such as phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters; steroids, such as cholesterol; and chelating agents, such as EDTA, zinc and other such suitable cations.
- acids or bases may be present as an excipient in the preparation.
- acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.
- Suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumerate, and combinations thereof.
- the amount of the conjugate in the composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is stored in a unit dose container. A therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the conjugate in order to determine which amount produces a clinically desired endpoint.
- the amount of any individual excipient in the composition will vary depending on the activity of the excipient and particular needs of the composition. Typically, the optima] amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects.
- excipients will be present in the composition in an amount of about 1% to about 99% by weight, in certain embodiments from about 5%-98% by weight, in certain embodiments from about 15-95% by weight of the excipient, and in certain embodiments less than 30% by weight.
- compositions can take any number of forms and the invention is not limited in this regard.
- Exemplary preparations are most preferably in a form suitable for oral administration such as a tablet, caplet, capsule, gel cap, troche, dispersion, suspension, solution, elixir, syrup, lozenge, transdermal patch, spray, suppository, and powder.
- Oral dosage forms are preferred for those conjugates that are orally active, and include tablets, caplets, capsules, gel caps, suspensions, solutions, elixirs, and syrups, and can also comprise a plurality of granules, beads, powders or pellets that are optionally encapsulated.
- Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts.
- Tablets and caplets can be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferable when preparing tablets or caplets containing the conjugates described herein.
- the tablets and caplets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, flow agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact.
- Suitable binder materials include, but are not limited to, starch (including com starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethylcellulose, and the like), and Veegum.
- Lubricants are used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e., particle breakage) when pressure is relieved.
- Useful lubricants are magnesium stearate, calcium stearate, and stearic acid.
- Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums, or crosslinked polymers.
- Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.
- Stabilizers as well known in the art, are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.
- Capsules are also preferred oral dosage forms, in which case the
- conjugate-containing composition can be encapsulated in the form of a liquid or gel (e.g., in the case of a gel cap) or solid (including particulates such as granules, beads, powders or pellets).
- Suitable capsules include hard and soft capsules, and are generally made of gelatin, starch, or a cellulosic material. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like.
- parenteral formulations in the substantially dry form typically as a lyophilizate or precipitate, v/hich can be in the form of a powder or cake
- parenteral formulations in the substantially dry form typically as a lyophilizate or precipitate, v/hich can be in the form of a powder or cake
- formulations prepared for injection which are typically liquid and requires the step of reconstituting the dry form of parenteral formulation.
- suitable diluents for reconstituting solid compositions prior to injection include bacteriostatic water for injection, dextrose 5% in water, phosphate-buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.
- compositions intended for parenteral administration can take the form of nonaqueous solutions, suspensions, or emulsions, each typically being sterile.
- nonaqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
- parenteral formulations described herein can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
- adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
- the formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat.
- the conjugate can also be administered through the skin using conventional transdermal patch or other transdermal delivery system, wherein the conjugate is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
- the conjugate is contained in a layer, or "reservoir,” underlying an upper backing layer.
- the laminated structure can contain a single reservoir, or it can contain multiple reservoirs.
- the conjugate can also be formulated into a suppository for rectal administration.
- the conjugate is mixed with a suppository base material which is (e.g., an excipient that remains solid at room temperature but softens, melts or dissolves at body temperature) such as coca butter (theobroma oil), polyethylene glycols, glycerinated gelatin, fatty acids, and combinations thereof.
- a suppository base material which is (e.g., an excipient that remains solid at room temperature but softens, melts or dissolves at body temperature) such as coca butter (theobroma oil), polyethylene glycols, glycerinated gelatin, fatty acids, and combinations thereof.
- Suppositories can be prepared by, for example, performing the following steps (not necessarily in the order presented): melting the suppository base material to form a melt; incorporating the conjugate (either before or after melting of the suppository ba se material); pouring the melt into a mold; cooling the melt (e.g., placing the melt-containing mold in a room temperature environment) to thereby form suppositories; and removing the suppositories from the mold.
- the invention also provides a method for administering a conjugate as provided herein to a patient suffering from a condition that is responsive to treatment with the conjugate.
- the method comprises administering, generally orally, a therapeutically effective amount of the conjugate (preferably provided as part of a pharmaceutical preparation).
- Other modes of administration are also contemplated, such as pulmonary, nasal, buccal, rectal, sublingual, transdermal, and parenteral.
- parenteral includes subcutaneous, intravenous, intra-arterial, intraperitoneal, intracardiac, intrathecal, and intramuscular injection, as well as infusion injections.
- oligomers In instances where parenteral administration is utilized, it may be necessary to employ somewhat bigger oligomers than those described previously, with molecular weights ranging from about 500 to 30K Daltons (e.g., having molecular weights of about 500, 1000, 2000, 2500, 3000, 5000, 7500, 10000, 15000, 20000, 25000, 30000 or even more).
- the method of administering may be used to treat any condition that can be ' remedied or prevented by administration of the particular conjugate.
- Those of ordinary skill in the art appreciate which conditions a specific conjugate can effectively treat.
- the actual dose to be administered will vary depend upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, the judgment of the health care professional, and conjugate being administered.
- Therapeutically effective amounts are known to those skilled in the art and/or are described in the pertinent reference texts and literature. Generally, a therapeutically effective amount will range from about 0.001 mg to 1000 mg, preferably in doses from 0.01 mg/day to 750 mg/day, and in certain embodiments in doses from 0.10 mg/day to 500 mg/day.
- the unit dosage of any given conjugate (again, preferably provided as part of a pharmaceutical preparation) can be administered in a variety of dosing schedules depending on the judgment of the clinician, needs of the patient, and so forth.
- the specific dosing schedule will be known by those of ordinary skill in the art or can be determined experimentally using routine methods.
- Exemplary dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, three times weekly, twice weekly, once weekly, twice monthly, once monthly, and any combination thereof. Once the clinical endpoint has been achieved, dosing of the composition is halted.
- One advantage of administering the conjugates of the present invention is that a reduction in first pass metabolism may be achieved relative to the parent drug. Such a result is advantageous for many orally administered drugs that are substantially metabolized by passage through the gut. In this way, clearance of the conjugate can be modulated by selecting the oligomer molecular size, linkage, and position of covalent attachment providing the desired clearance properties.
- One of ordinary skill in the art can determine the ideal molecular size of the oligomer based upon the teachings herein.
- reductions in first pass metabolism for a conjugate as compared to the corresponding nonconjugated small drug molecule include: at least about 10%, at least about 20%, at least about 30; at least about 40; at least about 50%; at least about 60%, at least about 70%, at least about 80% and at least about 90%.
- the invention provides a method for reducing the metabolism of an active agent.
- the method comprises the steps of: providing monodisperse or bimodal conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to, a water-soluble oligomer, wherein said conjugate exhibits a reduced rate of metabolism as compared to the rate of metabolism of the small molecule drug not attached to the water-soluble oligomer; and administering the conjugate to a patient.
- administration is carried out via one type of administration selected from the group consisting of oral administration, transdermal administration, buccal administration, transmucosa! administration, vaginal administration, rectal administration, parenteral administration, and pulmonary administration.
- the conjugates are particularly useful when the small molecule drug is metabolized by a hepatic enzyme (e.g., one or more of the cytochrome P450 isoforms) and/or by one or more intestinal enzymes.
- a hepatic enzyme e.g., one or more of the cytochrome P450 isoforms
- intestinal enzymes e.g., one or more of the cytochrome P450 isoforms
- Desipramine, iminodibenzyl, sodium hydride (NaH), l-bromo-3-chloropropane, lithium amide (LiNH 2 ) were purchased from Sigma-Aldrich (St Louis, MO). DCM was dislilled from Ca3 ⁇ 4. DMF (anhydrous), toluene (anhydrous), and other organic solvents were used as they purchased.
- Desipramine (2.00 g, 6,60 mmol) was dissolved in methanol (40 mL) and saturated NaHC0 3 (80 mL). The reaction was kept at room temperature for 30 min and the solution pH was >10. After the methanol was removed under reduced pressure, the aqueous solution was extracted with DCM (50 mL + 25 mL x 2). The combined organic layers were dried over Na 2 S0 4 , filtered, and the solvent removed under reduced pressure. The resulting residue was solidified overnight by vacuum drying and a yellowish sample (1.79 g, >100% yield) was obtained.
- mPEG 5 -Br and mPEG 8 -Br were used for the other desipramine derivative syntheses using a similar procedure.
- the product quality was characterized with NMR, analytical-HPLC and identified by LC-MS/MALDI.
- mPEG 7 -desipramine The above iminodibenzyl alleviation product mixture (325 mg, 1.2 mmol) was added to a microwave reaction tube together with mPEG7-NH 2 (340 ⁇ , 1.0 mmol), K2CO3 (207 mg, 1.5 mmol) was added with H 2 0 (1 mL). The starting material was suspended at the top layer f the water phase - stirring was difficult before heating occurred. The microwave reaction was carried oat at 120°C over 2 hrs, The reaction was monitored by TLC for the disappearance of mPEG-NI3 ⁇ 4. The reaction was then diluted with an aqueous NalTCO? solution and extracted with CM (10 mL x 3).
- the product mixture contained a nearly 1 : 1 ratio of mono- to di-alkylation products which were inseparable by TLC.
- N-mPEG 3 -3-(10,ll-dihydro-dibenzo[b,f]azepin-5-yl)-propylamine (34a): R f
- N-mPEG 7 -3-(10,ll-dihydro-dibenzo[b,f]azepin-5-yI)-propyIamine (34b): R f
- IC50 values were obtained from non-linear regression analysis of dose-response curves and were calculated only for those compounds that showed >50% inhibition of binding at the highest concentration tested. 3 ⁇ 4 was obtained using the Cheng Prusoff correction using experimental 3 ⁇ 4 values that were previously determined under the same assay conditions.
- Binding affinity at the H2 receptor was nearly 3 orders of magnitude lower than that at the HI receptors for all the molecules tested. mPEG conjugation also resulted in a reduction in binding affinity at the H2 receptors, and this effect was also PEG size dependent.
- Kj values could not be determined for the mPEG-6 and mPEG-7 amitriptyline at the H2 receptors, since >50% inhibition could not be observed at the highest concentration tested.
- the loss in binding affinity at the H2 receptor was greater than the loss in binding affinity at the HI receptor ( ⁇ 23 -fold versus parent) suggesting that mPEG conjugation increased the HI :H2 receptor selectivity, making the mPEG-amitriptyline conjugates more selective for HI receptors.
- No measurable binding to the H3 and H4 receptors was detected at the highest concentrations tested.
- Kj values at the H3 and H4 receptors could not be determined since ⁇ 50% inhibition of radioligand binding was obtained at the highest concentration tested.
- Receptor source Human recombinant CHO or CHO Kl cells expressing individual histamine H 1, H2, H3, or H4 receptors.
- Aminopotentidine (3 ⁇ ) phosphate (pH 7.4) at 10, 30, 100 nM, 3, (0.1 nM) 25°C for 2 h. 30 ⁇
- Methyl-histamine Methyl- HC1 (pH 7.4), 5 mM 10, 30, 100 nM, 3,
- Carbamazepine and three its conjugates' effects on sodium channels were evaluated in vitro to determine their blocking properties using the whole-cell patch clamp method in isolated cardiac (human atrial myocytes) and neuronal (rat dorsal root ganglion) cells, [0224] Human myocytes were obtained from specimens of human right atrial appendage obtained during surgery from hearts of patients undergoing cardiopulmonary bypass. The procedure produced rod-shaped, ion tolerant cells which were used within 24 hours after isolation (Dumb el aL 1995, Am J Physiol 263:Hi335-H1342).
- Dorsal root ganglion neurons were prepared from rats, post-natal day 14-13 (Blair aud-Bean, 2002, JNeurosci 22: 10277- 10290). Animals were anesthetized with iscflurane, decapitated, and ganglia were removed. Pieces of ganglia were treated to produce individual cells that were used within 43 hours after isolation.
- the cell was in a bathing "external" solution (consisting of (nyM): 115 TMA chloride, 10 NaCl, 5 CsCl, 1.8 Ca'3 ⁇ 4 1.2 MgCl 2 , 10 HEPES, 1 1 dextrose, pH adjusted to 7.4 with TMA-OH).
- Pipette tip resistance was approximately 1.0 to 2.0 ⁇ when filled with the internal solution.
- Suction was then applied to the pipette interior to seal ⁇ ) tie cell membrane onto the tip. Another suction pulse then broke the membrane, establishing electrical access into the interior of the. cell.
- the cellular interior .tb ⁇ n became dialyzed by the solution the patch pipette was filled .with.
- IC50 values were obtained from non-linear regression analysis of dose-response curves ( Figure 4) and were calculated for those compounds that showed >50% inhibition of binding at the highest concentration tested.
- Kj was obtained using the Cheng Prusoff correction using experimental 3 ⁇ 4 values that were previously determined under these assay conditions.
- Incubations were carried out for 2 hours at 25°C in buffer containing 50 raM Tris HC1, 10 mM MgCl2 and 1 mM EDTA. Following incubations, the membranes were washed the bound radioactivity was measured. Non-specific binding was measured in the presence of excess Atropine as the cold ligand and subtraction of this value from the total binding yielded the specific binding at each test compound concentration.
- IC 50 values were obtained from non-linear regression analysis of dose-response curves and were calculated only for those compounds that showed >50% inhibition of binding at the highest concentration tested. Ki was obtained using the Cheng Prusoff correction using Kd values that were experimental determined previously under these assay conditions.
- An analgesic assay was used to determine whether a given compound can reduce and/or prevent visceral pain in mice.
- the assay utilized CD- 1 male mice (5-8 mice per group), each mouse being approximately 0.015-0.030 kg on the study day. Mice were treated according to standard protocols.
- mice were given a single "pretreatment" dose of a compound lacking covalent attachment of a water-soluble, non-peptidic oligomer, a corresponding version comprising the compound covalently attached to a water-soluble, non-peptidic oligomer, or control solution (IV, SC, IP or orally) thirty minutes prior to the administration of the acetic acid solution.
- the animal was given an IP injection of an irritant (acetic acid) that induces "writhing" which may include: contractions of the abdomen, twisting and turning of the trunk, arching of the back and the extension of the hindlimbs.
- Mice were given a single IP injection (0.1 mL/10 g bodyweight) of a 0.5% acetic acid solution.
- Figure 5 shows the analgesia activity of the tested compound against the standard analgesic, morphine.
- Oxcarbazepine (e.g., 118 mg, 0.5 mmol) is dissolved in 5 ml THF, and NaH
- the weight of the animals at the time of surgery averaged 200-250 grams. Animals were maintained in a temperature-controlled environment with a constant natural 12 hours light/12 hours dark cycle and adequate food and water at all times.
- Anesthesia method General anesthesia for L5 spinal nerve transection was induced and maintained with isoflurane (3% for induction, 2% for maintenance).
- L5 spinal nerve transection A clean, aseptic technique was used for the entire procedure. To expose the L5 spinal nerve, a 3-cm incision was made to the skin overlying L5- Sl. The muscle tissue was separated and retracted from the left superior articular processes and the transverse process. The L6 transverse process was then partially removed. The L5 spinal nerve was transected after being gently separated from the L4 spinal nerve. The wound was then irrigated with sterile saline and closed in two layers using 5-0 silk suture (fascial plane) and surgical skin staples.
- Test article (Oxcarbazepine, m-PEG-3 oxcarbazapine, m-PEG-5 oxcarbazapine, and m-PEG-7 oxcarbazapine, as prepared in Example 10) was administered in blinded fashion at 50 mg/kg on day 7 post-L5 spinal nerve transection via oral gauvage.
- Mechanical allodynia and hyperalgesia Animals were acclimated to the environment and the experimenter prior to the start of the study.
- the 2 g, 6 g and 10 g von Frey filaments were used to assess allodynia since these stimuli are normally innocuous to na ' ive animals and elicit few responses prior to nerve transection. Following nerve transection and prior to oral administration of test articles the animals respond robustly to the 2 g, 6 g, and 10 g von Frey filaments.
- the 15 g, 26 g and 60 g filaments are used to assess hyperalgesia (response to noxious stimulus) since these stimuli elicit paw withdrawals in na ' ive animals and an increased number of paw withdrawals followed nerve transection. In the absence of treatment, the mechanical allodynia and hyperalgesia remains stable for at least 3 weeks.
- Evaluation of mechanical allodynia or hyperalgesia was determined by counting the number of paw withdrawals in response to 5 applications of each of the von Frey filaments to the hindpaw on the same side as the nerve transection. Results are expressed either as the total number of paw withdrawals for the allodynic filaments (2 g, 6 g and 10 g for a total of 15 possible paw withdrawals) or the hyperalgesic filaments (15 g, 26 g and 60 g for a total of 15 possible paw withdrawals).
- Thermal hyperalgesia was evaluated using the Hargreaves test. For these studies, individual rats were tested in a plexiglass boxes placed on a room temperature glass surface above a radiant heat source focused on the medial plantar surface of the affected hindpaw. When the heat source is turned on, the animals hindpaw is heated from below. The time until the animal lifts its hindpaw (paw withdrawal latency, measured in seconds) is an indicator of thermal hyperalgesia. Under the conditions used in this study, paw withdrawal latency decreases from 10-12 seconds prior to nerve injury to 6-8 seconds after L5 nerve transection, indicating the development of thermal hyperalgesia. In the absence of further treatment, the thermal hyperalgesia remained stable for at least three weeks.
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Abstract
L'invention concerne des conjugués comprenant des résidus de médicaments antidépresseurs et anticonvulsivants tricycliques, notamment de l'acétate d'eslicarbazépine et de l'oxcarbazépine, liés de façon covalente par l'intermédiaire d'une liaison stable ou dégradable à un oligomère hydrosoluble, de préférence un oligomère de poly(éthylène glycol) (PEG). Un conjugué selon l'invention, lorsqu'il est administré par une quelconque voie sélectionnée parmi un certain nombre de voies d'administration, présente des caractéristiques qui sont différentes des caractéristiques du médicament à petites molécules non lié à l'oligomère hydrosoluble.
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US29627210P | 2010-01-19 | 2010-01-19 | |
US61/296,272 | 2010-01-19 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105085465A (zh) * | 2015-08-17 | 2015-11-25 | 苏州黄河制药有限公司 | 一种以邻卤甲基苯甲酸甲酯为原料合成盐酸多塞平的方法 |
CN105367538A (zh) * | 2015-11-26 | 2016-03-02 | 苏州黄河制药有限公司 | 一种以邻卤甲基苯甲酸甲酯为原料制备盐酸多塞平的方法 |
CN110698451A (zh) * | 2019-10-29 | 2020-01-17 | 山东诚汇双达药业有限公司 | 取代二苯并[ b,e ]硫(氧)杂七环-11(6H)-酮类化合物及其制备方法 |
US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
Citations (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2554736A (en) | 1951-05-29 | Tertiary aminoalkyl-iminodibenzyls | ||
US2948718A (en) | 1960-08-09 | New n-heterocyclic compounds | ||
GB905692A (en) * | 1958-09-10 | 1962-09-12 | Geigy Ag J R | Phenothiazine derivatives, and their preparation |
US3177209A (en) | 1960-09-16 | 1965-04-06 | Kefalas As | Dihydroanthracene compounds |
US3205264A (en) | 1962-06-15 | 1965-09-07 | Merck & Co Inc | Process for the preparation of 10, 11-dihydro-5-(gamma-methyl-and dimethyl-amino propylidene)-5h-dibenzo[a, d] cycloheptene |
US3244748A (en) | 1962-07-03 | 1966-04-05 | Merck & Co Inc | 5h-dibenzo [a, d] cycloheptenes |
US3271451A (en) | 1962-07-03 | 1966-09-06 | Merck & Co Inc | Process for preparing 5-(3-methylaminopropyl)-5h-dibenzo [a, d] cycloheptenes |
US3299139A (en) | 1963-02-20 | 1967-01-17 | Dumex Ltd As | 5-(3'-dimethylaminopropylidene)-dibenzo [a, d]-cyclohepta-[1, 4]-diene nu-oxide and hydrochloride thereof |
US3312689A (en) | 1959-09-22 | 1967-04-04 | Wander Ag Dr A | 10-(basic substituted)-dibenzodiazepines |
US3409640A (en) | 1959-07-22 | 1968-11-05 | Schering Corp | 5-(3'-dimethylamino-2'-methyl-propyl)dibenzocycloheptenes |
US3438981A (en) | 1963-07-09 | 1969-04-15 | Boehringer & Soehne Gmbh | Dibenzooxepine and dibenzothiepine derivatives |
US3442949A (en) | 1965-05-03 | 1969-05-06 | Merck & Co Inc | Method for preparing 5-(3-aminopropylidene)-5h-dibenzo - (a,d) - 10,11 - dihydrocycloheptenes |
US3454554A (en) | 1960-10-14 | 1969-07-08 | Colgate Palmolive Co | Aminoalkyliminodibenzyl compounds |
US3467650A (en) | 1958-12-06 | 1969-09-16 | Geigy Chem Corp | 3 - chloro - 5 - (alpha - dimethylaminopropyl)-iminodibenzyl and its acid addition salts |
GB1191800A (en) | 1968-12-10 | 1970-05-13 | Nii Farmakologii I Khim | 00-(beta-Diethylaminopropionyl)-2-Trifluoromethylphenothiazine Hydrochloride |
US3527766A (en) | 1961-06-08 | 1970-09-08 | Spofa Vereinigte Pharma Werke | Derivative of 6,11-dihydrodibenz-(b,e)thiepin |
DE2030492A1 (de) | 1969-06-20 | 1971-02-11 | Societe Generale de Recherches et dApphcations Scientifiques L SOGERAS", Paris | Neue Derivate des Dibenzo eckige Klammer auf b f eckige Klammer zu azepins |
US3574852A (en) | 1962-03-27 | 1971-04-13 | Dumex Ltd As | Treating depression with the n-oxide of n-(3' - dimethylamino propyl)-iminodibenzyl |
US3622565A (en) | 1967-01-18 | 1971-11-23 | Rhone Poulenc Sa | Dibenzazepine derivatives and their preparation |
US3637660A (en) | 1967-04-13 | 1972-01-25 | Leo Ab | Dibenzazepine derivatives |
US3642775A (en) | 1969-03-10 | 1972-02-15 | Ciba Geigy Corp | 10-oxo-10 11-dihydro-dibenzazepine derivative |
US3663696A (en) | 1966-05-20 | 1972-05-16 | American Cyanamid Co | Treatment of depression with 2-chloro-11 - (piperazinyl)dibenz - (b,f)(1,4)oxazepines and acid addition salts thereof |
US3758528A (en) | 1970-03-13 | 1973-09-11 | Science Union & Cie | Tricyclic compounds |
US3963778A (en) | 1965-11-10 | 1976-06-15 | Bayer Aktiengesellschaft | Basic oximes and their preparation |
US4609664A (en) * | 1980-09-02 | 1986-09-02 | Sandoz Ltd. | Antiasthmatic piperidylidene derivatives |
WO1996016541A1 (fr) * | 1994-11-18 | 1996-06-06 | Supratek Pharma, Inc. | Agents biologiques lies a des polymeres |
US5672662A (en) | 1995-07-07 | 1997-09-30 | Shearwater Polymers, Inc. | Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications |
US6214820B1 (en) * | 1998-10-21 | 2001-04-10 | Novo Nordisk A/S | Compounds, their preparation and use |
WO2002098949A1 (fr) | 2001-06-04 | 2002-12-12 | Nobex Corporation | Procedes de synthese de melanges sensiblement monodisperses de polymeres contenant des fractions de polyethylene glycol |
WO2005020913A2 (fr) * | 2003-08-25 | 2005-03-10 | Combinatorx, Incorporated | Preparations, conjugues, et combinaisons de medicaments dans le traitement de neoplasmes |
US20050136031A1 (en) | 2003-12-16 | 2005-06-23 | Bentley Michael D. | Chemically modified small molecules |
WO2006088786A2 (fr) * | 2005-02-14 | 2006-08-24 | Combinatorx, Incorporated | Composes et utilisations de ceux-ci |
WO2009073154A1 (fr) * | 2007-11-28 | 2009-06-11 | Nektar Therapeutics Al, Corporation | Composés tricycliques conjugués à un oligomère |
WO2009151590A2 (fr) * | 2008-06-09 | 2009-12-17 | Nektar Therapeutics | Procédés de traitement de métaboliseurs alternatifs de cyp2d6 |
WO2010088340A1 (fr) * | 2009-01-28 | 2010-08-05 | Nektar Therapeutics | Conjugués oligomère-phénothiazine |
-
2011
- 2011-01-19 WO PCT/US2011/021733 patent/WO2011091050A1/fr active Application Filing
Patent Citations (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2948718A (en) | 1960-08-09 | New n-heterocyclic compounds | ||
US2554736A (en) | 1951-05-29 | Tertiary aminoalkyl-iminodibenzyls | ||
GB905692A (en) * | 1958-09-10 | 1962-09-12 | Geigy Ag J R | Phenothiazine derivatives, and their preparation |
US3467650A (en) | 1958-12-06 | 1969-09-16 | Geigy Chem Corp | 3 - chloro - 5 - (alpha - dimethylaminopropyl)-iminodibenzyl and its acid addition salts |
US3409640A (en) | 1959-07-22 | 1968-11-05 | Schering Corp | 5-(3'-dimethylamino-2'-methyl-propyl)dibenzocycloheptenes |
US3419547A (en) | 1959-09-22 | 1968-12-31 | Wander Ag Dr A | Certain 10-basically substituted-5h-dibenzo[b,e,][1,4]diazepine compounds |
US3312689A (en) | 1959-09-22 | 1967-04-04 | Wander Ag Dr A | 10-(basic substituted)-dibenzodiazepines |
US3177209A (en) | 1960-09-16 | 1965-04-06 | Kefalas As | Dihydroanthracene compounds |
US3454554A (en) | 1960-10-14 | 1969-07-08 | Colgate Palmolive Co | Aminoalkyliminodibenzyl compounds |
US3527766A (en) | 1961-06-08 | 1970-09-08 | Spofa Vereinigte Pharma Werke | Derivative of 6,11-dihydrodibenz-(b,e)thiepin |
US3574852A (en) | 1962-03-27 | 1971-04-13 | Dumex Ltd As | Treating depression with the n-oxide of n-(3' - dimethylamino propyl)-iminodibenzyl |
US3205264A (en) | 1962-06-15 | 1965-09-07 | Merck & Co Inc | Process for the preparation of 10, 11-dihydro-5-(gamma-methyl-and dimethyl-amino propylidene)-5h-dibenzo[a, d] cycloheptene |
US3271451A (en) | 1962-07-03 | 1966-09-06 | Merck & Co Inc | Process for preparing 5-(3-methylaminopropyl)-5h-dibenzo [a, d] cycloheptenes |
US3244748A (en) | 1962-07-03 | 1966-04-05 | Merck & Co Inc | 5h-dibenzo [a, d] cycloheptenes |
US3299139A (en) | 1963-02-20 | 1967-01-17 | Dumex Ltd As | 5-(3'-dimethylaminopropylidene)-dibenzo [a, d]-cyclohepta-[1, 4]-diene nu-oxide and hydrochloride thereof |
US3438981A (en) | 1963-07-09 | 1969-04-15 | Boehringer & Soehne Gmbh | Dibenzooxepine and dibenzothiepine derivatives |
US3442949A (en) | 1965-05-03 | 1969-05-06 | Merck & Co Inc | Method for preparing 5-(3-aminopropylidene)-5h-dibenzo - (a,d) - 10,11 - dihydrocycloheptenes |
US3963778A (en) | 1965-11-10 | 1976-06-15 | Bayer Aktiengesellschaft | Basic oximes and their preparation |
US3663696A (en) | 1966-05-20 | 1972-05-16 | American Cyanamid Co | Treatment of depression with 2-chloro-11 - (piperazinyl)dibenz - (b,f)(1,4)oxazepines and acid addition salts thereof |
US3622565A (en) | 1967-01-18 | 1971-11-23 | Rhone Poulenc Sa | Dibenzazepine derivatives and their preparation |
US3637660A (en) | 1967-04-13 | 1972-01-25 | Leo Ab | Dibenzazepine derivatives |
GB1191800A (en) | 1968-12-10 | 1970-05-13 | Nii Farmakologii I Khim | 00-(beta-Diethylaminopropionyl)-2-Trifluoromethylphenothiazine Hydrochloride |
US3642775A (en) | 1969-03-10 | 1972-02-15 | Ciba Geigy Corp | 10-oxo-10 11-dihydro-dibenzazepine derivative |
DE2030492A1 (de) | 1969-06-20 | 1971-02-11 | Societe Generale de Recherches et dApphcations Scientifiques L SOGERAS", Paris | Neue Derivate des Dibenzo eckige Klammer auf b f eckige Klammer zu azepins |
DE2030492B2 (de) | 1969-06-20 | 1974-10-24 | Societe Generale De Recherches Et D'applications Scientifiques Sogeras, Paris | Neue, durch den Chinuclidinylrest substituierte Dibenzo eckige Klammer auf b/eckige Klammer zu azepine |
US3758528A (en) | 1970-03-13 | 1973-09-11 | Science Union & Cie | Tricyclic compounds |
US4609664A (en) * | 1980-09-02 | 1986-09-02 | Sandoz Ltd. | Antiasthmatic piperidylidene derivatives |
WO1996016541A1 (fr) * | 1994-11-18 | 1996-06-06 | Supratek Pharma, Inc. | Agents biologiques lies a des polymeres |
US5672662A (en) | 1995-07-07 | 1997-09-30 | Shearwater Polymers, Inc. | Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications |
US6214820B1 (en) * | 1998-10-21 | 2001-04-10 | Novo Nordisk A/S | Compounds, their preparation and use |
WO2002098949A1 (fr) | 2001-06-04 | 2002-12-12 | Nobex Corporation | Procedes de synthese de melanges sensiblement monodisperses de polymeres contenant des fractions de polyethylene glycol |
WO2005020913A2 (fr) * | 2003-08-25 | 2005-03-10 | Combinatorx, Incorporated | Preparations, conjugues, et combinaisons de medicaments dans le traitement de neoplasmes |
US20050136031A1 (en) | 2003-12-16 | 2005-06-23 | Bentley Michael D. | Chemically modified small molecules |
WO2006088786A2 (fr) * | 2005-02-14 | 2006-08-24 | Combinatorx, Incorporated | Composes et utilisations de ceux-ci |
WO2009073154A1 (fr) * | 2007-11-28 | 2009-06-11 | Nektar Therapeutics Al, Corporation | Composés tricycliques conjugués à un oligomère |
WO2009151590A2 (fr) * | 2008-06-09 | 2009-12-17 | Nektar Therapeutics | Procédés de traitement de métaboliseurs alternatifs de cyp2d6 |
WO2010088340A1 (fr) * | 2009-01-28 | 2010-08-05 | Nektar Therapeutics | Conjugués oligomère-phénothiazine |
Non-Patent Citations (12)
Title |
---|
"Medical Economics", 1998, MONTVALE, article "Physician's Desk Reference" |
"Remington: The Science & Practice of Phaimacy", 1995, WILLIAMS & WILLIAMS |
BLAIR; BEAN, J NEUROSCI, vol. 22, 2002, pages 10277 - 10290 |
C. DULSAT ET AL: "Eslicarbazepine acetate", DRUGS OF THE FUTURE, vol. 34, no. 3, 1 January 2009 (2009-01-01), pages 189, XP055001396, ISSN: 0377-8282, DOI: 10.1358/dof.2009.034.03.1352675 * |
CHEN Y.; BAKER, G.L., J. ORG. CHEM., 1999, pages 6870 - 6873 |
CRUMB ET AL., AM J PHYSIOL, vol. 263, 1995, pages H1335 - H1342 |
ERTL, P. ET AL., J. MED. CHEM., vol. 43, 2000, pages 3714 - 3717 |
HAASZ FERENC ET AL: "Dibenz(b,f)azepines, part 7: Synthesis of new, potentially CNS active dibenz (b,f)azepine derivatives", ARCHIV DER PHARMAZIE, WILEY - VCH VERLAG GMBH & CO. KGAA, DE, vol. 329, no. 12, 1 January 1996 (1996-01-01), pages 551 - 553, XP002524412, ISSN: 0365-6233, DOI: 10.1002/ARDP.19963291207 * |
HOLDER, J. ET AL., PHARM. RES., vol. 16, 1999, pages 1514 - 1519 |
KIBBE, A.H.: "Handbook of Pharmaceutical Excipients", 2000, AMERICAN PHARMACEUTICAL ASSOCIATION |
KOLESNIKOV ET AL., J PHARMACOL. EXP. THER., vol. 290, 1999, pages 247 - 252 |
T.W. GREENE; G.M. WUTS: "Protecting Groups in Organic Synthesis", 1999, WILEY |
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US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
CN105085465A (zh) * | 2015-08-17 | 2015-11-25 | 苏州黄河制药有限公司 | 一种以邻卤甲基苯甲酸甲酯为原料合成盐酸多塞平的方法 |
CN105367538A (zh) * | 2015-11-26 | 2016-03-02 | 苏州黄河制药有限公司 | 一种以邻卤甲基苯甲酸甲酯为原料制备盐酸多塞平的方法 |
CN110698451A (zh) * | 2019-10-29 | 2020-01-17 | 山东诚汇双达药业有限公司 | 取代二苯并[ b,e ]硫(氧)杂七环-11(6H)-酮类化合物及其制备方法 |
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