Promoting cessation of smoking
阅读说明：本技术 促进吸烟停止 (Promoting cessation of smoking ) 是由 莫伊斯·A·可罕亚拉尔罕 盖瑞·比锐恩 史帝芬·E·巴茨 于 2014-07-11 设计创作，主要内容包括：本发明涉及使需要的对象停止或减少吸烟和/或咀嚼烟草或含烟碱产物的方法,所述方法包括给予所述对象有效量的某些氨基甲酸酯化合物。本发明还涉及防止需要的对象的吸烟和/或咀嚼烟草或含烟碱产物复发的方法,所述方法包括给予所述对象治疗有效量的某些氨基甲酸酯化合物。(The present invention relates to methods of stopping or reducing smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof, comprising administering to the subject an effective amount of certain carbamate compounds. The present invention also relates to methods of preventing relapse of smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds.)
1. Use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a composition for stopping or reducing smoking and/or chewing tobacco or a nicotine-containing product in a subject not addicted to, or dependent on, nicotine:
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3;
R1and R2Independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products is facilitated.
2. Use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a composition for preventing the relapse of smoking and/or chewing tobacco or a nicotine-containing product in a subject that is not addicted to, or dependent on, nicotine:
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3;
R1and R2Independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, substituted aryl, aralkyl, or substituted aralkyl,Cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein relapse of smoking and/or chewing tobacco or nicotine-containing products is prevented.
3. The use of claim 1, wherein x-0.
4. The use according to claim 1, wherein R is1And R2Is hydrogen and x is 0.
5. Use according to claim 1, wherein the compound of formula I is an enantiomer of formula I substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer of formula I predominates.
6. The use of claim 5, wherein the enantiomer of formula I predominates to the extent of about 90% or greater.
7. The use of claim 5, wherein the enantiomer of formula I predominates to the extent of about 98% or greater.
8. The use of claim 5, wherein the enantiomer of formula I is the enantiomer of formula Ia:
or a pharmaceutically acceptable salt or ester thereof.
9. The use as claimed in claim 8 wherein the enantiomer of formula Ia is the (R) or (D) enantiomer.
10. The use as claimed in claim 8 wherein the enantiomer of formula Ia is the (S) or (L) enantiomer.
11. The use as claimed in claim 8 wherein the enantiomer of formula Ia predominates to the extent of about 90% or greater.
12. The use as claimed in claim 8 wherein the enantiomer of formula Ia predominates to the extent of about 98% or greater.
13. Use according to claim 5, wherein the enantiomer of formula I substantially free of other enantiomers is a compound of formula Ib or a mixture of enantiomers in which the mixture of formula Ib predominates:
or a pharmaceutically acceptable salt or ester thereof.
14. The use of claim 13, wherein the compound of formula Ib predominates to the extent of about 90% or greater.
15. The use of claim 13, wherein the compound of formula Ib predominates to the extent of about 98% or greater.
16. The use of claim 1, wherein the effective amount of the compound of formula I is from about 0.01 mg/kg/dose to about 150 mg/kg/dose.
17. The use of claim 1, wherein the effective amount of the compound of formula I is from about 1 mg/day to about 7000 mg/day.
18. The use of claim 1, wherein the compound of formula I is administered orally.
19. The use of claim 1, wherein the compound of formula I is administered in the form of a capsule or tablet.
20. The use of claim 1, wherein the compound of formula I is administered in the form of a capsule at a dose of about 10 mg to about 1000mg without any excipients.
Technical Field
The present invention relates to methods of stopping or reducing smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof, comprising administering to the subject an effective amount of certain carbamate compounds. The present invention also relates to methods of preventing relapse of smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds.
Background
Smoking and chewing tobacco products are considered major health concerns. On average 435,000 people die prematurely from smoking-related diseases per day in the united states. A number of treatments are available to help people reduce or stop tobacco usage. One common treatment is the transdermal or chewing of chewing gum bases to administer nicotine. Other approved therapies include(Aminopenta ketone) and
Summary of The Invention
The present invention provides an effective and convenient method of helping people reduce and/or eliminate the use of tobacco and helping people who have discontinued the use of tobacco to prevent relapse. Accordingly, in one aspect, the present invention relates to a method of stopping or reducing smoking and/or chewing of tobacco or nicotine-containing products in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3; r1And R2Independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products is facilitated.
In another aspect, the present invention relates to a method of preventing relapse of smoking and/or chewing tobacco or a nicotine-containing product in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3;
R1and R2May be the same or different and is independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein relapse of smoking and/or chewing tobacco or nicotine-containing products is prevented.
In some embodiments of the invention, the method comprises the steps of: administering to the subject an effective amount of an enantiomer of formula I substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer of formula I predominates.
In some embodiments, the compound of formula I is a compound of formula Ia:
or a pharmaceutically acceptable salt or ester thereof.
In some embodiments, the compound of formula I is a compound of formula Ib:
or a pharmaceutically acceptable salt or ester thereof. The compounds are known as (R) - (β -amino-phenylpropyl) carbamate or O-carbamoyl- (D) -phenylaminopropanol and are alternatively known as ADX-N05, SKL-N05, SK-N05, YKP10A and R228060.
Embodiments of the invention include the use of a compound of formula I to promote cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products in a subject in need thereof. Other embodiments of the invention include the use of a compound of formula I to prevent relapse smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof.
Embodiments of the invention include the use of a compound of formula I for the manufacture of a medicament for promoting cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products in a subject in need thereof. Other embodiments of the invention include the use of a compound of formula I for the manufacture of a medicament for preventing relapse of smoking and/or chewing tobacco or nicotine-containing products in a subject in need thereof.
Detailed description of the invention
The present invention will be described herein with reference to examples, which are given as exemplary embodiments of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Unless otherwise specified, it is specifically stated that the various features of the invention described herein can be used in any combination. Furthermore, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted. For example, if the specification states that a composition includes components A, B and C, it is specifically stated that either one or a combination of A, B or C can be omitted and excluded individually or in any combination.
Definition of
The terms "a", "an", "the" and "the" as used herein mean one or more. For example, "a" cell means a single cell or a plurality of cells.
As used herein, "and/or" is meant to encompass any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative.
As used herein, the term "about," when referring to a numerical value such as a dosage (e.g., amount of a compound), is meant to encompass variations of 20%, ± 10%, ± 5%, ± 1%, ± 0.5% or even ± 0.1% of that particular amount.
The terms "comprises," "comprising," "including," and "containing," when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
As described herein, the transition phrase "consisting essentially of …" is intended to interpret the scope of the claims to include particular materials or steps therein, as well as those that do not materially affect the basic and novel characteristics of the claimed invention. See Inre Herz,537F.2d 549,551-52,190U.S.P.Q.461,463(CCPA 1976) (highlighted initially); see also MPEP § 2111.03. Therefore, the term "consisting essentially of …" as used in the claims or specification of the present invention is not intended to be interpreted as equivalent to "comprising".
The term "effective amount" as used herein means an amount of a compound, composition and/or formulation of the present invention sufficient to produce a desired effect, which may be a therapeutic effect and/or a beneficial effect. The effective amount will vary with the following factors known to those skilled in the art within the knowledge and experience: the age, general condition of the subject, the severity of the condition to be treated, the particular agent administered, the duration of the treatment, the nature of any concurrent therapy, the pharmaceutically acceptable carrier employed and the like. An "effective amount" in any individual, if appropriate, can be determined by one of skill in the art with reference to relevant books and literature and/or by using routine experimentation.
The "subject" of the invention is typically a mammalian subject and preferably a human. Subjects include males and/or females of any age, including juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is not addicted to nicotine, i.e., experiences little or no symptoms of craving when nicotine intake is stopped. In some embodiments, the subject relies on nicotine but is not addicted. In some embodiments, the subject does not ingest nicotine at a rate sufficient to maintain a state of stable nicotine levels. In some embodiments, the subject is a "light and intermittent smoker", i.e., who smokes no more than 5 cigarettes per day. In other embodiments, the subject ingests nicotine at a rate less than daily.
The term "nicotine addiction" refers to subjects experiencing withdrawal symptoms without maintaining a steady level of nicotine (e.g., cessation of nicotine intake). Withdrawal symptoms include, but are not limited to, irritability, depressed mood, dysphoria, anxiety, lack of concentration, dizziness, insomnia, tremor, increased hunger and weight gain.
As used herein, the term "nicotine dependence" encompasses physical dependence and behavioral dependence, meaning that a subject does not experience symptoms of craving without maintaining a stable level of nicotine (e.g., stopping nicotine intake), but has difficulty in quitting nicotine intake.
The "object in need thereof" according to the present invention is an object currently smoking and/or chewing tobacco or a product containing nicotine or an object having a possibility of relapse smoking and/or chewing tobacco or a product containing nicotine.
The term "smoking and/or chewing tobacco or nicotine-containing product" as used in reference to a subject means the use of any product that provides nicotine. The term as used herein includes the use of smoking products (e.g., cigarettes, cigars, pipes) or chewing products (e.g., chewing tobacco, impregnated tobacco, snuff), as well as the use of non-tobacco nicotine delivery products (e.g., gums, transdermal patches, nasal sprays, inhalers, vaporizers, pellets, tablets, lozenges, strips, sticks).
The term "cessation" refers to complete cessation of activity, such as smoking and/or chewing of tobacco or nicotine-containing products.
As used herein, the terms "reduce," "reducing," "decline," and similar terms mean a reduction of at least about 5%, 10%, 15%, 20%, 25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more, such as a reduction in smoking and/or chewing tobacco or nicotine-containing products or a reduction in nicotine intake. In particular embodiments, the decrease results in no or substantially no (i.e., minimal, e.g., less than about 10% or even 5%) detectable activity or amount.
As used herein, the term "promoting" in conjunction with the cessation or reduction of smoking and/or chewing tobacco or nicotine-containing products means increasing the ability of a subject to reduce or stop the intake of nicotine. In some embodiments, facilitating encompasses reducing craving for nicotine and/or reducing physical and/or behavioral dependence on nicotine.
As used herein, the term "preventing relapse" in conjunction with smoking and/or chewing tobacco or nicotine-containing products means preventing the subject from taking nicotine after the subject has stopped taking nicotine. In some embodiments, the term encompasses permanent cessation of nicotine intake. In other embodiments, the term encompasses a delay in the recovery of nicotine uptake as compared to the recovery time of a subject not administered a compound of the invention. The recovery delay can be, for example, hours (e.g., 1, 6, 12, 24 hours), days (e.g., 1, 2, 3, 4,5, 6, 7 days), weeks, months, or longer. In other embodiments, the term encompasses reducing the risk of recovery from nicotine intake, e.g., reducing the risk by at least about 10%, 20%, 30%, 40%, 50% or more.
The term "pharmaceutically acceptable salt or ester" shall mean a non-toxic salt or ester of a compound employed in the present invention, typically prepared by the translation of the free acid with a suitable organic or inorganic base or vice versa. Examples of such salts include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, edetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, propionate laureate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate (glycopyrrolate), hexylresorcinate (hexylresorcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, monobromide, methylnitrate, methanesulfonate, napsylate, nitrate, oleate, oxalate, pamoate, Palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, 8-chlorotheolate (teoclate), methanesulfonate, triethyliodide, and valerate.
As used herein, a compound, therapeutic agent, or known agent is "administered concurrently" or "administered in combination" with a compound of the invention, meaning that the known agent and one or more compounds of the invention are administered concurrently and in addition to the known agent and one or more compounds of the invention at a time when both the known agent and one or more compounds of the invention have a therapeutic effect. In some cases, the therapeutic or beneficial effect will be a synergistic effect. Such concurrent administration may include administration of a known agent simultaneously (i.e., at the same time), before, after, relative to the administration of a compound of the invention. One skilled in the art would have no difficulty in determining the appropriate rhythm, sequence and dosage of administration of the particular agent and the compound of the invention.
Furthermore, in some embodiments, the compounds of the present invention, or salts or esters thereof, are used alone or in combination with each other or with one or more other therapeutic or beneficial agents for the preparation of a medicament intended to promote cessation or reduction of tobacco/nicotine use or to prevent relapse use in a subject in need thereof.
The present invention is based in part on the following findings: the phenylalkylcarbamates of formula I have novel and unique pharmacological properties. While the exact mechanism of action is not fully understood, it is believed that these compounds do not act through the large majority of other known mechanisms that stimulate the production of their effects by drugs. Nicotine withdrawal is mediated in part by a decrease in dopamine levels (De Biasi et al, annu. rev. neurosci.34:105 (2011)). Aminonon-tacones can assist in cessation of smoking by normalizing dopamine levels (De Biasi et al, Annu. Rev. Neurosci.34:105 (2011); Roddy, BMJ 328:509 (2004)). Like amitotanone, the compounds of formula I increase dopamine and norepinephrine levels. Furthermore, the compounds of formula I share other properties with amitotanone, such as psychostimulant activity and antidepressant activity, without sexual side effects, which teach similar effects on actions (e.g. cessation of smoking). For these reasons, the compounds of formula I are particularly suitable for use as statins in tobacco and nicotine use.
One aspect of the present invention relates to a method of stopping or reducing smoking and/or chewing of tobacco or nicotine-containing products in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3; r1 and R2 are independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products is facilitated.
Another aspect of the invention relates to a method of preventing relapse of smoking and/or chewing tobacco or a nicotine-containing product in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3; r1 and R2 are independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein relapse of smoking and/or chewing tobacco or nicotine-containing products is prevented.
In some embodiments of the above method, R is a group selected from the group consisting of: alkyl of 1 to 3 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluoromethyl. In some embodiments of the above method, R is a group selected from the group consisting of: alkyl of 1-3 carbon atoms, halogen, alkoxy of 1-3 carbon atoms.
In some embodiments of the above methods, R1And R2May be the same or different and is independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, and cycloalkyl of 3 to 7 carbon atoms. In some embodiments of the above methods, R1And R2Independently selected from: hydrogen and alkyl of 1 to 8 carbon atoms. In some embodiments of the above methods, R1And R2Independently selected from: hydrogen and alkyl of 1 to 3 carbon atoms.
It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized using techniques known in the art and methods described herein.
In one embodiment, the compound of formula (I) is a compound of formula Ia:
or a pharmaceutically acceptable salt or ester thereof.
In one embodiment, the formula I is a derivative ofThe compound is the (D) enantiomer, wherein R1And R2Is hydrogen and x is 0 (compound Ib).
Or a pharmaceutically acceptable salt or ester thereof. The compound is the (R) enantiomer; if named for structure, is (R) - (beta-amino-phenylpropyl) carbamate. This compound is the dextro enantiomer and is therefore also referred to as O-carbamoyl- (D) -phenylaminopropanol. These designations may be used interchangeably throughout this specification.
The invention encompasses the use of isolated enantiomers of compounds of formula I (e.g., compounds of formula Ia or Ib). In one embodiment, a pharmaceutical composition comprising the isolated S-enantiomer of formula I is used to provide treatment to a subject. In another embodiment, a pharmaceutical composition comprising the isolated R-enantiomer of formula I is used to provide treatment to a subject.
The invention also includes the use of mixtures of enantiomers of formula I. In one aspect of the invention, one enantiomer predominates. The predominant enantiomer in the mixture is present in the mixture in an amount greater than any other enantiomer present in the mixture, e.g., in an amount greater than 50%. In one aspect, one enantiomer predominates to the extent of 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater. In one embodiment, the predominant enantiomer in a composition comprising a compound of formula I is the S-enantiomer of formula I.
The present invention provides methods of using enantiomers and mixtures of enantiomers of compounds represented by formula I. The carbamate enantiomer of formula I contains an asymmetric chiral carbon at the benzyl position (i.e., the second aliphatic carbon adjacent to the phenyl ring).
An isolated enantiomer is an enantiomer substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is isolated by separation techniques or prepared without the corresponding enantiomer.
The term "substantially free" as used herein means that the compound is made up of a significantly larger proportion of one enantiomer. In a preferred embodiment, the compound comprises at least about 90% by weight of one enantiomer. In other embodiments of the invention, the compounds comprise at least about 99% by weight of one enantiomer.
The compounds of formula I can be synthesized by methods known to those skilled in the art. Salts and esters of compounds of formula I may be prepared by treating the compounds with a suitable mineral or organic acid (HX) in a suitable solvent or by other methods well known to those skilled in the art.
Details of reaction schemes for synthesizing compounds of formula I and representative examples for the preparation of specific compounds have been described in U.S. patent 5,705,640, U.S. patent 5,756,817, U.S. patent 5,955,499, U.S. patent No. 6,140,532, all of which are incorporated herein by reference in their entirety.
As can be seen from formula I, some of the compounds of the present invention have at least one and possibly more asymmetric carbon atoms. It is understood that stereochemically pure isomeric forms of the compounds and racemates thereof are included within the scope of the present invention. Stereochemically pure isomeric forms may be obtained by applying the principles known in the art. Diastereomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from one another by selective crystallization of diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers can also be prepared from suitable stereochemically pure starting materials, or by synthesis using stereoselective reactions.
During the preparation process of any of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by means of conventional protecting Groups, see for example protecting Groups in Organic Chemistry (Protective Groups in Organic Chemistry), ed.f.w.mcomie, Plenum Press, 1973; and t.w.greene & p.g.m.wuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), third edition, John Wiley & Sons, 1999. The protecting group may be removed in a convenient subsequent stage using methods known in the art.
The compounds may be administered to a subject by any conventional route of administration, including, but not limited to: oral, buccal, topical, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, transdermal, or intravenous injection). Compounds for direct administration to the nervous system can include intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal, or paraspinal routes of administration, for example, using intracranial or intraspinal needle or catheter delivery, with or without the use of pump devices. Depending on the route of administration, the compounds of formula I may be formulated in any form. For example, forms suitable for oral administration include solid forms such as pills, gel capsules, tablets, caplets, capsules, granules and powders (including immediate release, timed release and sustained release formulations). Forms suitable for oral administration also include liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. In addition, forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.
In certain embodiments, the pharmaceutical compositions of the present invention comprise one or more compounds of formula I or salts or esters thereof without any pharmaceutically acceptable carriers or excipients. In other embodiments, the pharmaceutical compositions of the present invention comprise one or more compounds of formula I or salts or esters thereof, in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier is an inert pharmaceutically acceptable excipient including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. In preparing the compositions for oral administration, any conventional pharmaceutical carrier may be employed. For example, for liquid oral formulations, suitable carriers and additives include: water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like; for solid oral preparations, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
The composition may take the form of: tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols or any other suitable composition; and comprises at least one compound of the invention, optionally in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those of ordinary skill in the art, and excipients and methods of formulating compositions can be found in standard references such as: remington's Pharmaceutical Sciences (Remington Pharmaceutical Sciences), 17 th edition, Mark Publishing Co., Mack Publishing Co., Italyton, Pa, 1985, the entire contents of which are incorporated herein by reference for all purposes. Suitable liquid carriers (particularly for injectable solutions) include water, aqueous saline solutions, aqueous dextrose solutions, and glycols.
The carbamate compound may be provided as an aqueous suspension. The aqueous suspensions of the present invention may contain a carbamate compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Suitable excipients may include, for example: suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example, phospholipids of natural origin (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyoxyethylene sorbitan monooleate).
The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. The formulation may be osmotically regulated.
The oily suspensions used in the method of the present invention may be formulated by suspending the carbamate compound in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid paraffin) or a mixture thereof. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. See Minto, J.Pharmacol. exp.Ther.281:93-102,1997 for an example of an injectable oily vehicle. The pharmaceutical formulations of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil, as described above, or a mixture thereof.
Suitable emulsifiers include: gums of natural origin, such as gum acacia and gum tragacanth, phospholipids of natural origin, such as soya lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents, as in syrups and elixirs. Such formulations may also contain a demulcent, a preservative, or a coloring agent.
In some embodiments, the compound may be provided in the form of a personal nebulizer (e.g., an electronic cigarette) that vaporizes a liquid solution containing the compound into an aerosol mist for inhalation or insufflation.
The selected compound (alone or in combination with other suitable ingredients) may be formulated as an aerosol formulation (i.e., it may be in "aerosolized" form) for administration by inhalation. The aerosol formulation may be placed in a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations of the invention suitable for parenteral administration, e.g., by the intra-articular (intra-articular), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Acceptable carriers and solvents that may be employed are water and ringer's solution, isotonic sodium chloride, and sterile, fixed oils are generally employed as a solvent or suspending medium. For this purpose, any non-volatile oil that is less irritating, including synthetic mono-or diglycerides, may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. These solutions are sterile and generally free of undesirable substances.
If the compounds have sufficient solubility, they may be dissolved directly in physiological saline, with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds are prepared in aqueous starch or sodium carboxymethylcellulose solution, or in a suitable oil, for example arachis oil. These preparations may be sterilized by a conventionally known sterilization technique. The formulations may contain pharmaceutically acceptable auxiliary substances as required to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.
The concentration of the carbamate compound in these formulations can vary widely, and will be selected primarily based on fluid volume, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For intravenous administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. The recommended formulations may be presented in unit-dose or multi-dose sealed containers (e.g., ampoules and vials). Injectable solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Carbamate compounds suitable for use in the practice of the present invention may be administered orally. Compositions the amount of a compound of the invention may vary widely, depending on the type of composition, unit dose size, type of excipient, and other factors well known to those skilled in the art. In general, the final composition may comprise, for example, 0.000001% to 100% by weight (% w) of the carbamate compound, for example, 0.00001% to 50% by weight, with the remainder being excipients.
Pharmaceutical formulations for oral administration may be formulated using pharmaceutically acceptable carriers well known in the art, in appropriate dosages for oral administration. Such carriers enable the pharmaceutical preparations to be formulated as tablets, pills, powders, coatings, capsules, liquids, lozenges, gels, syrups, slurries, suspensions and the like, in unit dosage forms suitable for ingestion by a subject. In other embodiments, the pharmaceutical formulation may be formulated for oral administration without any pharmaceutically acceptable carrier.
Formulations suitable for oral administration may consist of: (a) a liquid solution, such as an effective amount of a pharmaceutical formulation dissolved in a diluent (e.g., water, saline, or PEG 400); (b) capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as a liquid, solid, granules or gelatin; (c) suspensions in suitable liquids; and (d) a suitable emulsion.
Pharmaceutical preparations for oral use can be obtained by: the compounds according to the invention are mixed with solid excipients, the mixture obtained is optionally ground, and after addition of suitable complementary compounds the mixture is processed to granules, if desired to obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein fillers including, but not limited to: sugars, including lactose, sucrose, mannitol, or sorbitan; starch from corn, wheat, rice, potato, or other crops; cellulose, such as methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose; gums including acacia and tragacanth; and proteins such as gelatin and collagen. .
If desired, disintegrating or solubilizing agents may be added, for example, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Tablet forms may contain one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrants, and pharmaceutically compatible carriers. Lozenge forms may comprise the active ingredient in a flavor, such as sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and similar forms containing, in addition to the active ingredient, carriers known in the art.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration. Such formulations may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of the invention may also be administered by intranasal, intraocular, intravaginal and intrarectal routes (including suppositories, insufflation, powder and aerosol formulations) (e.g. steroid inhalants, see Rohatagi, J.Clin. Pharmacol.35:1,187 (1995); Tjwa, Ann. allergy Asthma immunol.75:107 (1995)).
The compounds of the invention may be delivered transdermally, by a topical route, formulated in the form of sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, patches and aerosols.
The compounds of the present invention may also employ an encapsulating material and the term "composition" may include the active agent and encapsulating material in the form of a formulation, with or without other carriers. For example, the compounds of the present invention may also be delivered in the form of microspheres for sustained release in vivo. In one embodiment, the microspheres may be administered by intradermal injection of microspheres containing the drug (e.g., mifepristone), with slow release subcutaneously (see Rao, J.Biomater.Sci.Polym. Ed.7:623 (1995)), as biodegradable and injectable gel formulations (see, e.g., Gao, pharm.Res.12: 857(1995)), or as microspheres for oral administration (see, e.g., Eyles, J.pharm.Pharmacol.49: 669(1997)), both transdermal and intradermal routes achieving sustained delivery for weeks or months.
In another embodiment, the compounds of the invention may be delivered by using liposomes that are fused to the cell membrane or are endocytosed, i.e. by binding the surface membrane protein receptor of the cell using a ligand attached to the liposome resulting in endocytosis. The active agent may also be administered in the form of a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearamide, or phosphatidylcholine.
Delivery of carbamate compounds can be focused to target cells in vivo by using liposomes, particularly where the liposomes are surface-loaded with ligands specific for the target cells, or otherwise preferentially directed to a particular organ (see, e.g., Al-Muhammed, J.Microencapsu.13: 293 (1996); Chonn, Curr. Opin. Biotechnol.6:698 (1995); Ostro, am.J.Hosp. Pharm.46:1576 (1989)).
The active drug may also be delivered by coupling the compound molecule using the monoclonal antibody as a separate carrier. The active drug may also be coupled to soluble polymers as targetable drug carriers. Such polymers include: polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyoxyethylene-polylysine substituted with palmitoyl residues. In addition, the active drug may be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.
In certain embodiments, the composition may be in unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, patch, autoinjector device or suppository for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
Alternatively, the composition may be presented as a form suitable for once weekly or once monthly administration; for example, an insoluble salt of the active compound, such as a decanoate salt, can be adapted as a depot formulation for intramuscular injection.
The pharmaceutical compositions contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository, and the like, the amount required to deliver an effective dose of the active ingredient as described above. For example, the pharmaceutical compositions described herein may contain from about 10 to 1000mg of active ingredient per dosage unit, such as from about 25 to 600mg of active ingredient, for example from about 75 to 400mg of active ingredient, such as from about 25,50,75,100,125,150,175,200,225,250,275,300, 325,350,375,400,425,450,475,500,525,550,575,600mg or more, or any range therein.
In some embodiments of the invention, carbamate compounds suitable for use in the practice of the invention can be administered alone or in parallel with at least one or more other compounds or therapeutic agents, e.g., in parallel with other agents that promote cessation or reduction of smoking or prevention of relapse. Examples include, but are not limited to
The method comprises the following steps: administration of an effective amount of one of the carbamate compounds described herein to a patient in need of treatment, as well as an effective amount of one or more other compounds or therapeutic agents that provide a beneficial combined therapeutic effect, for example, can enhance the effect of the compounds of the present invention.
Pharmaceutically acceptable salts and esters refer to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. These salts include salts formed by the reaction of an acidic proton present in the compound with an inorganic or organic base. Suitable inorganic salts include those formed with alkali metals (e.g., sodium and potassium), magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as amines (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like). Pharmaceutically acceptable salts can also include acid addition salts formed by the reaction of the amine group of the parent compound with inorganic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, malic acid, alkylsulfonic acids, and arylsulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compound. If two acidic groups are present, the pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly if more than two acidic groups are present, some or all of these groups may form salts or esters.
The compounds of the present invention may exist in the unsalified or unsalified form, or in the salt-forming and/or ester-forming form of such compounds, and the nomenclature of such compounds is intended to include the original (unsalified and unsalified) compounds and their pharmaceutically acceptable salts and esters. The invention includes pharmaceutically acceptable salt and ester forms of formula (la). More than one crystalline form of the enantiomer of formula I may be present and these are also included within the scope of the present invention.
The pharmaceutical compositions of the present invention may optionally include, in addition to the carbamate compound, at least one other therapeutic or beneficial agent for promoting smoking cessation or reduction or preventing relapse. For example, the carbamate compounds of formula I can be physically mixed with other compounds in a fixed dose combination to simplify their administration.
Methods of formulating pharmaceutical compositions have been described in a number of published documents, such as pharmaceutical dosage forms: tablets (Pharmaceutical Dosage Forms: tables), second edition, revised and expanded, volumes 1-3, compiled by Lieberman et al; dosage form of the drug: parenteral drugs (Pharmaceutical Dosage Forms: Parenteral medicines), Vol.1-2, eds. Avis et al; and "pharmaceutical dosage form: dispersions (Pharmaceutical Dosage Forms: Dispersesystems), volumes 1-2, eds. Lieberman et al; published by massalder (Marcel Dekker, Inc), all of which are incorporated herein by reference in their entirety and for all purposes.
The pharmaceutical compositions are generally formulated to be sterile, substantially isotonic and in full compliance with the Good Manufacturing Practice (GMP) regulations of the U.S. food and drug administration.
The treatment provided by the methods provided herein uses a carbamate compound to promote cessation or reduction of tobacco/nicotine use or prevention of relapse in a mammal. The amount of carbamate compound required to provide a benefit is defined as the effective dose. The dosage regimen and the amount effective for the application, i.e., the amount administered or the dosage regimen, will depend on a variety of factors including the disease state, the physical state of the patient, age, and the like. The mode of administration should also be considered when calculating the dosage regimen for the patient.
Based on conventional techniques and The disclosure of The present invention, one skilled in The Art can determine without undue experimentation an effective amount of a particular substituted carbamate compound for use in The practice of The present invention (see, e.g., Lieberman, Pharmaceutical Dosage Forms (volumes 1-3, 1992); Lloyd,1999, Science and Technology of Pharmaceutical Compounding (The Art, Science and Technology of Pharmaceutical Compounding); and Pickar,1999, dose calculation (Dosage Calculations)). An effective amount is also one in which the beneficial effects of the active agent outweigh any toxic or detrimental side effects in the clinical context. It is also understood that for each specific subject, specific dosage regimens should be evaluated and adjusted over time based on the individual need and the professional judgment of the person administering or supervising the administration of the compounds.
For therapeutic purposes, the compositions or compounds described herein can be administered to a subject as a single bolus, via continuous delivery over an extended time period, or in a repeated dosing regimen (e.g., an hourly, daily, or weekly repeated dosing regimen). The pharmaceutical formulations of the present invention may be administered, for example, one or more times per day, 3 times per week, or once per week. In one embodiment of the invention, the pharmaceutical formulation of the invention is administered orally once or twice daily.
In the present invention, an effective dose of a bioactive agent can include repeated doses within an extended treatment regimen that produces clinically significant results. Determination of an effective dose herein is generally based on animal model experiments and subsequent human clinical experiments, and is guided by determining an effective dose and dosing regimen that significantly reduces the occurrence or severity of the targeted exposure symptom or condition in the subject. Suitable models in this regard include, for example, murine, rat, porcine, feline, primate other than human, and other acceptable animal model subjects known in the art. Alternatively, an effective dose can be determined using in vitro models (e.g., immunological and histopathological analysis).
Using these models, appropriate concentrations and dosages can generally be determined with only ordinary calculation and adjustment to administer an effective amount of the biologically active agent (e.g., an orally, intranasally, transdermally, intravenously, or intramuscularly effective amount to elicit the desired response). However, effective amounts can also vary based on the particular compound employed, the mode of administration, the strength of preparation, the mode of administration, the level of nicotine dependence. In addition, factors associated with the particular patient being treated, including patient age, weight, diet, time of administration, may result in the need to adjust the dosage.
In exemplary embodiments of the invention, unit dosage forms of the compounds may be prepared for standard dosing regimens. In this way, the composition can be easily subdivided into smaller doses according to the physician's instructions. For example, a unit dose may be formulated as a packaged powder, vial or ampoule, preferably in capsule or tablet form.
Effective administration of the carbamate compounds of the invention can be, for example, an oral or parenteral dosage of about 0.01 mg/kg/dose to 150 mg/kg/dose. For example, administration can be from about 0.1 mg/kg/dose to about 25 mg/kg/dose, such as from about 0.2 to 18 mg/kg/dose, such as from about 0.5 to about 10 mg/kg/dose. Thus, for a subject with an average body weight of 70 kg, a therapeutically effective amount of the active ingredient may be, for example, about 1 mg/day to 7000 mg/day, such as about 10 to 2000 mg/day, such as about 50 to 600 mg/day, such as about 10, 25,50,75,100,125,150,175,200,225,250,275,300, 325,350,375,400,425,450,475,500,525,550,575, or 600 mg/day or more, or any range therein. In one embodiment, the compound of formula I is administered in the form of a capsule in a dosage of about 10 mg to about 1000mg without any excipients.
The methods of the invention also provide kits for promoting cessation or reduction of tobacco/nicotine use or prevention of relapse. After formulating a pharmaceutical composition comprising one or more of the carbamate compounds of the invention and possibly one or more additional compounds of benefit in a suitable carrier, it is placed in a suitable container and labeled for promoting cessation or reduction of tobacco/nicotine use or prevention of relapse. In addition, another medicament containing at least one other therapeutic or beneficial agent may also be placed in the container and labeled for treatment of a designated disease. Such labels may include, for example, instructions regarding the dosage, frequency of administration, and method of administration of each drug.
All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety for the purpose of disclosing the contents relating to the sentences and/or paragraphs of the cited references, and for any other purpose that might be used.
The present invention will be described herein with reference to examples, which are given as exemplary embodiments of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Unless otherwise specified, it is specifically stated that the various features of the invention described herein can be used in any combination. Furthermore, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted. For example, if the specification states that a composition includes components A, B and C, it is specifically stated that either one or a combination of A, B or C can be omitted and excluded individually or in any combination.
Definition of
The terms "a", "an", "the" and "the" as used herein mean one or more. For example, "a" cell means a single cell or a plurality of cells.
As used herein, "and/or" is meant to encompass any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative.
As used herein, the term "about," when referring to a numerical value such as a dosage (e.g., amount of a compound), is meant to encompass variations of 20%, ± 10%, ± 5%, ± 1%, ± 0.5% or even ± 0.1% of that particular amount.
The terms "comprises," "comprising," "including," and "containing," when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
As described herein, the transition phrase "consisting essentially of …" is intended to interpret the scope of the claims to include particular materials or steps therein, as well as those that do not materially affect the basic and novel characteristics of the claimed invention. See Inre Herz,537F.2d 549,551-52,190U.S.P.Q.461,463(CCPA 1976) (highlighted initially); see also MPEP § 2111.03. Therefore, the term "consisting essentially of …" as used in the claims or specification of the present invention is not intended to be interpreted as equivalent to "comprising".
The term "effective amount" as used herein means an amount of a compound, composition and/or formulation of the present invention sufficient to produce a desired effect, which may be a therapeutic effect and/or a beneficial effect. The effective amount will vary with the following factors known to those skilled in the art within the knowledge and experience: the age, general condition of the subject, the severity of the condition to be treated, the particular agent administered, the duration of the treatment, the nature of any concurrent therapy, the pharmaceutically acceptable carrier employed and the like. An "effective amount" in any individual, if appropriate, can be determined by one of skill in the art with reference to relevant books and literature and/or by using routine experimentation.
The "subject" of the invention is typically a mammalian subject and preferably a human. Subjects include males and/or females of any age, including juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is not addicted to nicotine, i.e., experiences little or no symptoms of craving when nicotine intake is stopped. In some embodiments, the subject relies on nicotine but is not addicted. In some embodiments, the subject does not ingest nicotine at a rate sufficient to maintain a state of stable nicotine levels. In some embodiments, the subject is a "light and intermittent smoker", i.e., who smokes no more than 5 cigarettes per day. In other embodiments, the subject ingests nicotine at a rate less than daily.
The term "nicotine addiction" refers to subjects experiencing withdrawal symptoms without maintaining a steady level of nicotine (e.g., cessation of nicotine intake). Withdrawal symptoms include, but are not limited to, irritability, depressed mood, dysphoria, anxiety, lack of concentration, dizziness, insomnia, tremor, increased hunger and weight gain.
As used herein, the term "nicotine dependence" encompasses physical dependence and behavioral dependence, meaning that a subject does not experience symptoms of craving without maintaining a stable level of nicotine (e.g., stopping nicotine intake), but has difficulty in quitting nicotine intake.
The "object in need thereof" according to the present invention is an object currently smoking and/or chewing tobacco or a product containing nicotine or an object having a possibility of relapse smoking and/or chewing tobacco or a product containing nicotine.
The term "smoking and/or chewing tobacco or nicotine-containing product" as used in reference to a subject means the use of any product that provides nicotine. The term as used herein includes the use of smoking products (e.g., cigarettes, cigars, pipes) or chewing products (e.g., chewing tobacco, impregnated tobacco, snuff), as well as the use of non-tobacco nicotine delivery products (e.g., gums, transdermal patches, nasal sprays, inhalers, vaporizers, pellets, tablets, lozenges, strips, sticks).
The term "cessation" refers to complete cessation of activity, such as smoking and/or chewing of tobacco or nicotine-containing products.
As used herein, the terms "reduce," "reducing," "decline," and similar terms mean a reduction of at least about 5%, 10%, 15%, 20%, 25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more, such as a reduction in smoking and/or chewing tobacco or nicotine-containing products or a reduction in nicotine intake. In particular embodiments, the decrease results in no or substantially no (i.e., minimal, e.g., less than about 10% or even 5%) detectable activity or amount.
As used herein, the term "promoting" in conjunction with the cessation or reduction of smoking and/or chewing tobacco or nicotine-containing products means increasing the ability of a subject to reduce or stop the intake of nicotine. In some embodiments, facilitating encompasses reducing craving for nicotine and/or reducing physical and/or behavioral dependence on nicotine.
As used herein, the term "preventing relapse" in conjunction with smoking and/or chewing tobacco or nicotine-containing products means preventing the subject from taking nicotine after the subject has stopped taking nicotine. In some embodiments, the term encompasses permanent cessation of nicotine intake. In other embodiments, the term encompasses a delay in the recovery of nicotine uptake as compared to the recovery time of a subject not administered a compound of the invention. The recovery delay can be, for example, hours (e.g., 1, 6, 12, 24 hours), days (e.g., 1, 2, 3, 4,5, 6, 7 days), weeks, months, or longer. In other embodiments, the term encompasses reducing the risk of recovery from nicotine intake, e.g., reducing the risk by at least about 10%, 20%, 30%, 40%, 50% or more.
The term "pharmaceutically acceptable salt or ester" shall mean a non-toxic salt or ester of a compound employed in the present invention, typically prepared by the translation of the free acid with a suitable organic or inorganic base or vice versa. Examples of such salts include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, edetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, propionate laureate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate (glycopyrrolate), hexylresorcinate (hexylresorcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, monobromide, methylnitrate, methanesulfonate, napsylate, nitrate, oleate, oxalate, pamoate, Palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, 8-chlorotheolate (teoclate), methanesulfonate, triethyliodide, and valerate.
As used herein, a compound, therapeutic agent, or known agent is "administered concurrently" or "administered in combination" with a compound of the invention, meaning that the known agent and one or more compounds of the invention are administered concurrently and in addition to the known agent and one or more compounds of the invention at a time when both the known agent and one or more compounds of the invention have a therapeutic effect. In some cases, the therapeutic or beneficial effect will be a synergistic effect. Such concurrent administration may include administration of a known agent simultaneously (i.e., at the same time), before, after, relative to the administration of a compound of the invention. One skilled in the art would have no difficulty in determining the appropriate rhythm, sequence and dosage of administration of the particular agent and the compound of the invention.
Furthermore, in some embodiments, the compounds of the present invention, or salts or esters thereof, are used alone or in combination with each other or with one or more other therapeutic or beneficial agents for the preparation of a medicament intended to promote cessation or reduction of tobacco/nicotine use or to prevent relapse use in a subject in need thereof.
The present invention is based in part on the following findings: the phenylalkylcarbamates of formula I have novel and unique pharmacological properties. While the exact mechanism of action is not fully understood, it is believed that these compounds do not act through the large majority of other known mechanisms that stimulate the production of their effects by drugs. Nicotine withdrawal is mediated in part by a decrease in dopamine levels (De Biasi et al, annu. rev. neurosci.34:105 (2011)). Aminonon-tacones can assist in cessation of smoking by normalizing dopamine levels (De Biasi et al, Annu. Rev. Neurosci.34:105 (2011); Roddy, BMJ 328:509 (2004)). Like amitotanone, the compounds of formula I increase dopamine and norepinephrine levels. Furthermore, the compounds of formula I share other properties with amitotanone, such as psychostimulant activity and antidepressant activity, without sexual side effects, which teach similar effects on actions (e.g. cessation of smoking). For these reasons, the compounds of formula I are particularly suitable for use as statins in tobacco and nicotine use.
One aspect of the present invention relates to a method of stopping or reducing smoking and/or chewing of tobacco or nicotine-containing products in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3; r1 and R2 are independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein cessation or reduction of smoking and/or chewing of tobacco or nicotine-containing products is facilitated.
Another aspect of the invention relates to a method of preventing relapse of smoking and/or chewing tobacco or a nicotine-containing product in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or ester thereof;
wherein R is a group selected from the group consisting of: alkyl of 1 to 8 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, thioalkoxy of 1 to 3 carbon atoms;
x is an integer of 0 to 3, provided that R may be the same or different when x is 2 or 3; r1 and R2 are independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, cycloalkyl of 3 to 7 carbon atoms; or
R1And R2May together form a 5-7 membered heterocyclic ring optionally unsubstituted or substituted with one or more alkyl or aryl groups, wherein the heterocyclic ring may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly attached to each other or to an oxygen atom;
wherein relapse of smoking and/or chewing tobacco or nicotine-containing products is prevented.
In some embodiments of the above method, R is a group selected from the group consisting of: alkyl of 1 to 3 carbon atoms, halogen, alkoxy of 1 to 3 carbon atoms, nitro, hydroxy and trifluoromethyl. In some embodiments of the above method, R is a group selected from the group consisting of: alkyl of 1-3 carbon atoms, halogen, alkoxy of 1-3 carbon atoms.
In some embodiments of the above methods, R1And R2May be the same or different and is independently selected from the group consisting of: hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl, and cycloalkyl of 3 to 7 carbon atoms. In some embodiments of the above methods, R1And R2Independently selected from: hydrogen and alkyl of 1 to 8 carbon atoms. In some embodiments of the above methods, R1And R2Independently selected from: hydrogen and alkyl of 1 to 3 carbon atoms.
It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized using techniques known in the art and methods described herein.
In one embodiment, the compound of formula (I) is a compound of formula Ia:
or a pharmaceutically acceptable salt or ester thereof.
In one embodiment, the formula I is a derivative ofThe compound is the (D) enantiomer, wherein R1And R2Is hydrogen and x is 0 (compound Ib).
Or a pharmaceutically acceptable salt or ester thereof. The compound is the (R) enantiomer; if named for structure, is (R) - (beta-amino-phenylpropyl) carbamate. This compound is the dextro enantiomer and is therefore also referred to as O-carbamoyl- (D) -phenylaminopropanol. These designations may be used interchangeably throughout this specification.
The invention encompasses the use of isolated enantiomers of compounds of formula I (e.g., compounds of formula Ia or Ib). In one embodiment, a pharmaceutical composition comprising the isolated S-enantiomer of formula I is used to provide treatment to a subject. In another embodiment, a pharmaceutical composition comprising the isolated R-enantiomer of formula I is used to provide treatment to a subject.
The invention also includes the use of mixtures of enantiomers of formula I. In one aspect of the invention, one enantiomer predominates. The predominant enantiomer in the mixture is present in the mixture in an amount greater than any other enantiomer present in the mixture, e.g., in an amount greater than 50%. In one aspect, one enantiomer predominates to the extent of 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater. In one embodiment, the predominant enantiomer in a composition comprising a compound of formula I is the S-enantiomer of formula I.
The present invention provides methods of using enantiomers and mixtures of enantiomers of compounds represented by formula I. The carbamate enantiomer of formula I contains an asymmetric chiral carbon at the benzyl position (i.e., the second aliphatic carbon adjacent to the phenyl ring).
An isolated enantiomer is an enantiomer substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is isolated by separation techniques or prepared without the corresponding enantiomer.
The term "substantially free" as used herein means that the compound is made up of a significantly larger proportion of one enantiomer. In a preferred embodiment, the compound comprises at least about 90% by weight of one enantiomer. In other embodiments of the invention, the compounds comprise at least about 99% by weight of one enantiomer.
The compounds of formula I can be synthesized by methods known to those skilled in the art. Salts and esters of compounds of formula I may be prepared by treating the compounds with a suitable mineral or organic acid (HX) in a suitable solvent or by other methods well known to those skilled in the art.
Details of reaction schemes for synthesizing compounds of formula I and representative examples for the preparation of specific compounds have been described in U.S. patent 5,705,640, U.S. patent 5,756,817, U.S. patent 5,955,499, U.S. patent No. 6,140,532, all of which are incorporated herein by reference in their entirety.
As can be seen from formula I, some of the compounds of the present invention have at least one and possibly more asymmetric carbon atoms. It is understood that stereochemically pure isomeric forms of the compounds and racemates thereof are included within the scope of the present invention. Stereochemically pure isomeric forms may be obtained by applying the principles known in the art. Diastereomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from one another by selective crystallization of diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers can also be prepared from suitable stereochemically pure starting materials, or by synthesis using stereoselective reactions.
During the preparation process of any of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by means of conventional protecting Groups, see for example protecting Groups in Organic Chemistry (Protective Groups in Organic Chemistry), ed.f.w.mcomie, Plenum Press, 1973; and t.w.greene & p.g.m.wuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), third edition, John Wiley & Sons, 1999. The protecting group may be removed in a convenient subsequent stage using methods known in the art.
The compounds may be administered to a subject by any conventional route of administration, including, but not limited to: oral, buccal, topical, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, transdermal, or intravenous injection). Compounds for direct administration to the nervous system can include intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal, or paraspinal routes of administration, for example, using intracranial or intraspinal needle or catheter delivery, with or without the use of pump devices. Depending on the route of administration, the compounds of formula I may be formulated in any form. For example, forms suitable for oral administration include solid forms such as pills, gel capsules, tablets, caplets, capsules, granules and powders (including immediate release, timed release and sustained release formulations). Forms suitable for oral administration also include liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. In addition, forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.
In certain embodiments, the pharmaceutical compositions of the present invention comprise one or more compounds of formula I or salts or esters thereof without any pharmaceutically acceptable carriers or excipients. In other embodiments, the pharmaceutical compositions of the present invention comprise one or more compounds of formula I or salts or esters thereof, in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The carrier is an inert pharmaceutically acceptable excipient including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. In preparing the compositions for oral administration, any conventional pharmaceutical carrier may be employed. For example, for liquid oral formulations, suitable carriers and additives include: water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like; for solid oral preparations, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
The composition may take the form of: tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols or any other suitable composition; and comprises at least one compound of the invention, optionally in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those of ordinary skill in the art, and excipients and methods of formulating compositions can be found in standard references such as: remington's Pharmaceutical Sciences (Remington Pharmaceutical Sciences), 17 th edition, Mark Publishing Co., Mack Publishing Co., Italyton, Pa, 1985, the entire contents of which are incorporated herein by reference for all purposes. Suitable liquid carriers (particularly for injectable solutions) include water, aqueous saline solutions, aqueous dextrose solutions, and glycols.
The carbamate compound may be provided as an aqueous suspension. The aqueous suspensions of the present invention may contain a carbamate compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Suitable excipients may include, for example: suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example, phospholipids of natural origin (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyoxyethylene sorbitan monooleate).
The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. The formulation may be osmotically regulated.
The oily suspensions used in the method of the present invention may be formulated by suspending the carbamate compound in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (such as liquid paraffin) or a mixture thereof. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. See Minto, J.Pharmacol. exp.Ther.281:93-102,1997 for an example of an injectable oily vehicle. The pharmaceutical formulations of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil, as described above, or a mixture thereof.
Suitable emulsifiers include: gums of natural origin, such as gum acacia and gum tragacanth, phospholipids of natural origin, such as soya lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents, as in syrups and elixirs. Such formulations may also contain a demulcent, a preservative, or a coloring agent.
In some embodiments, the compound may be provided in the form of a personal nebulizer (e.g., an electronic cigarette) that vaporizes a liquid solution containing the compound into an aerosol mist for inhalation or insufflation.
The selected compound (alone or in combination with other suitable ingredients) may be formulated as an aerosol formulation (i.e., it may be in "aerosolized" form) for administration by inhalation. The aerosol formulation may be placed in a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations of the invention suitable for parenteral administration, e.g., by the intra-articular (intra-articular), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Acceptable carriers and solvents that may be employed are water and ringer's solution, isotonic sodium chloride, and sterile, fixed oils are generally employed as a solvent or suspending medium. For this purpose, any non-volatile oil that is less irritating, including synthetic mono-or diglycerides, may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. These solutions are sterile and generally free of undesirable substances.
If the compounds have sufficient solubility, they may be dissolved directly in physiological saline, with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds are prepared in aqueous starch or sodium carboxymethylcellulose solution, or in a suitable oil, for example arachis oil. These preparations may be sterilized by a conventionally known sterilization technique. The formulations may contain pharmaceutically acceptable auxiliary substances as required to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.
The concentration of the carbamate compound in these formulations can vary widely, and will be selected primarily based on fluid volume, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For intravenous administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. The recommended formulations may be presented in unit-dose or multi-dose sealed containers (e.g., ampoules and vials). Injectable solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Carbamate compounds suitable for use in the practice of the present invention may be administered orally. Compositions the amount of a compound of the invention may vary widely, depending on the type of composition, unit dose size, type of excipient, and other factors well known to those skilled in the art. In general, the final composition may comprise, for example, 0.000001% to 100% by weight (% w) of the carbamate compound, for example, 0.00001% to 50% by weight, with the remainder being excipients.
Pharmaceutical formulations for oral administration may be formulated using pharmaceutically acceptable carriers well known in the art, in appropriate dosages for oral administration. Such carriers enable the pharmaceutical preparations to be formulated as tablets, pills, powders, coatings, capsules, liquids, lozenges, gels, syrups, slurries, suspensions and the like, in unit dosage forms suitable for ingestion by a subject. In other embodiments, the pharmaceutical formulation may be formulated for oral administration without any pharmaceutically acceptable carrier.
Formulations suitable for oral administration may consist of: (a) a liquid solution, such as an effective amount of a pharmaceutical formulation dissolved in a diluent (e.g., water, saline, or PEG 400); (b) capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as a liquid, solid, granules or gelatin; (c) suspensions in suitable liquids; and (d) a suitable emulsion.
Pharmaceutical preparations for oral use can be obtained by: the compounds according to the invention are mixed with solid excipients, the mixture obtained is optionally ground, and after addition of suitable complementary compounds the mixture is processed to granules, if desired to obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein fillers including, but not limited to: sugars, including lactose, sucrose, mannitol, or sorbitan; starch from corn, wheat, rice, potato, or other crops; cellulose, such as methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose; gums including acacia and tragacanth; and proteins such as gelatin and collagen. .
If desired, disintegrating or solubilizing agents may be added, for example, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Tablet forms may contain one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrants, and pharmaceutically compatible carriers. Lozenge forms may comprise the active ingredient in a flavor, such as sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and similar forms containing, in addition to the active ingredient, carriers known in the art.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration. Such formulations may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of the invention may also be administered by intranasal, intraocular, intravaginal and intrarectal routes (including suppositories, insufflation, powder and aerosol formulations) (e.g. steroid inhalants, see Rohatagi, J.Clin. Pharmacol.35:1,187 (1995); Tjwa, Ann. allergy Asthma immunol.75:107 (1995)).
The compounds of the invention may be delivered transdermally, by a topical route, formulated in the form of sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, patches and aerosols.
The compounds of the present invention may also employ an encapsulating material and the term "composition" may include the active agent and encapsulating material in the form of a formulation, with or without other carriers. For example, the compounds of the present invention may also be delivered in the form of microspheres for sustained release in vivo. In one embodiment, the microspheres may be administered by intradermal injection of microspheres containing the drug (e.g., mifepristone), with slow release subcutaneously (see Rao, J.Biomater.Sci.Polym. Ed.7:623 (1995)), as biodegradable and injectable gel formulations (see, e.g., Gao, pharm.Res.12: 857(1995)), or as microspheres for oral administration (see, e.g., Eyles, J.pharm.Pharmacol.49: 669(1997)), both transdermal and intradermal routes achieving sustained delivery for weeks or months.
In another embodiment, the compounds of the invention may be delivered by using liposomes that are fused to the cell membrane or are endocytosed, i.e. by binding the surface membrane protein receptor of the cell using a ligand attached to the liposome resulting in endocytosis. The active agent may also be administered in the form of a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearamide, or phosphatidylcholine.
Delivery of carbamate compounds can be focused to target cells in vivo by using liposomes, particularly where the liposomes are surface-loaded with ligands specific for the target cells, or otherwise preferentially directed to a particular organ (see, e.g., Al-Muhammed, J.Microencapsu.13: 293 (1996); Chonn, Curr. Opin. Biotechnol.6:698 (1995); Ostro, am.J.Hosp. Pharm.46:1576 (1989)).
The active drug may also be delivered by coupling the compound molecule using the monoclonal antibody as a separate carrier. The active drug may also be coupled to soluble polymers as targetable drug carriers. Such polymers include: polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyoxyethylene-polylysine substituted with palmitoyl residues. In addition, the active drug may be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.
In certain embodiments, the composition may be in unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, patch, autoinjector device or suppository for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
Alternatively, the composition may be presented as a form suitable for once weekly or once monthly administration; for example, an insoluble salt of the active compound, such as a decanoate salt, can be adapted as a depot formulation for intramuscular injection.
The pharmaceutical compositions contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository, and the like, the amount required to deliver an effective dose of the active ingredient as described above. For example, the pharmaceutical compositions described herein may contain from about 10 to 1000mg of active ingredient per dosage unit, such as from about 25 to 600mg of active ingredient, for example from about 75 to 400mg of active ingredient, such as from about 25,50,75,100,125,150,175,200,225,250,275,300, 325,350,375,400,425,450,475,500,525,550,575,600mg or more, or any range therein.
In some embodiments of the invention, carbamate compounds suitable for use in the practice of the invention can be administered alone or in parallel with at least one or more other compounds or therapeutic agents, e.g., in parallel with other agents that promote cessation or reduction of smoking or prevention of relapse. Examples include, but are not limited to
The method comprises the following steps: administration of an effective amount of one of the carbamate compounds described herein to a patient in need of treatment, as well as an effective amount of one or more other compounds or therapeutic agents that provide a beneficial combined therapeutic effect, for example, can enhance the effect of the compounds of the present invention.
Pharmaceutically acceptable salts and esters refer to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. These salts include salts formed by the reaction of an acidic proton present in the compound with an inorganic or organic base. Suitable inorganic salts include those formed with alkali metals (e.g., sodium and potassium), magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as amines (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like). Pharmaceutically acceptable salts can also include acid addition salts formed by the reaction of the amine group of the parent compound with inorganic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, malic acid, alkylsulfonic acids, and arylsulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compound. If two acidic groups are present, the pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly if more than two acidic groups are present, some or all of these groups may form salts or esters.
The compounds of the present invention may exist in the unsalified or unsalified form, or in the salt-forming and/or ester-forming form of such compounds, and the nomenclature of such compounds is intended to include the original (unsalified and unsalified) compounds and their pharmaceutically acceptable salts and esters. The invention includes pharmaceutically acceptable salt and ester forms of formula (la). More than one crystalline form of the enantiomer of formula I may be present and these are also included within the scope of the present invention.
The pharmaceutical compositions of the present invention may optionally include, in addition to the carbamate compound, at least one other therapeutic or beneficial agent for promoting smoking cessation or reduction or preventing relapse. For example, the carbamate compounds of formula I can be physically mixed with other compounds in a fixed dose combination to simplify their administration.
Methods of formulating pharmaceutical compositions have been described in a number of published documents, such as pharmaceutical dosage forms: tablets (Pharmaceutical Dosage Forms: tables), second edition, revised and expanded, volumes 1-3, compiled by Lieberman et al; dosage form of the drug: parenteral drugs (Pharmaceutical Dosage Forms: Parenteral medicines), Vol.1-2, eds. Avis et al; and "pharmaceutical dosage form: dispersions (Pharmaceutical Dosage Forms: Dispersesystems), volumes 1-2, eds. Lieberman et al; published by massalder (Marcel Dekker, Inc), all of which are incorporated herein by reference in their entirety and for all purposes.
The pharmaceutical compositions are generally formulated to be sterile, substantially isotonic and in full compliance with the Good Manufacturing Practice (GMP) regulations of the U.S. food and drug administration.
The treatment provided by the methods provided herein uses a carbamate compound to promote cessation or reduction of tobacco/nicotine use or prevention of relapse in a mammal. The amount of carbamate compound required to provide a benefit is defined as the effective dose. The dosage regimen and the amount effective for the application, i.e., the amount administered or the dosage regimen, will depend on a variety of factors including the disease state, the physical state of the patient, age, and the like. The mode of administration should also be considered when calculating the dosage regimen for the patient.
Based on conventional techniques and The disclosure of The present invention, one skilled in The Art can determine without undue experimentation an effective amount of a particular substituted carbamate compound for use in The practice of The present invention (see, e.g., Lieberman, Pharmaceutical Dosage Forms (volumes 1-3, 1992); Lloyd,1999, Science and Technology of Pharmaceutical Compounding (The Art, Science and Technology of Pharmaceutical Compounding); and Pickar,1999, dose calculation (Dosage Calculations)). An effective amount is also one in which the beneficial effects of the active agent outweigh any toxic or detrimental side effects in the clinical context. It is also understood that for each specific subject, specific dosage regimens should be evaluated and adjusted over time based on the individual need and the professional judgment of the person administering or supervising the administration of the compounds.
For therapeutic purposes, the compositions or compounds described herein can be administered to a subject as a single bolus, via continuous delivery over an extended time period, or in a repeated dosing regimen (e.g., an hourly, daily, or weekly repeated dosing regimen). The pharmaceutical formulations of the present invention may be administered, for example, one or more times per day, 3 times per week, or once per week. In one embodiment of the invention, the pharmaceutical formulation of the invention is administered orally once or twice daily.
In the present invention, an effective dose of a bioactive agent can include repeated doses within an extended treatment regimen that produces clinically significant results. Determination of an effective dose herein is generally based on animal model experiments and subsequent human clinical experiments, and is guided by determining an effective dose and dosing regimen that significantly reduces the occurrence or severity of the targeted exposure symptom or condition in the subject. Suitable models in this regard include, for example, murine, rat, porcine, feline, primate other than human, and other acceptable animal model subjects known in the art. Alternatively, an effective dose can be determined using in vitro models (e.g., immunological and histopathological analysis).
Using these models, appropriate concentrations and dosages can generally be determined with only ordinary calculation and adjustment to administer an effective amount of the biologically active agent (e.g., an orally, intranasally, transdermally, intravenously, or intramuscularly effective amount to elicit the desired response). However, effective amounts can also vary based on the particular compound employed, the mode of administration, the strength of preparation, the mode of administration, the level of nicotine dependence. In addition, factors associated with the particular patient being treated, including patient age, weight, diet, time of administration, may result in the need to adjust the dosage.
In exemplary embodiments of the invention, unit dosage forms of the compounds may be prepared for standard dosing regimens. In this way, the composition can be easily subdivided into smaller doses according to the physician's instructions. For example, a unit dose may be formulated as a packaged powder, vial or ampoule, preferably in capsule or tablet form.
Effective administration of the carbamate compounds of the invention can be, for example, an oral or parenteral dosage of about 0.01 mg/kg/dose to 150 mg/kg/dose. For example, administration can be from about 0.1 mg/kg/dose to about 25 mg/kg/dose, such as from about 0.2 to 18 mg/kg/dose, such as from about 0.5 to about 10 mg/kg/dose. Thus, for a subject with an average body weight of 70 kg, a therapeutically effective amount of the active ingredient may be, for example, about 1 mg/day to 7000 mg/day, such as about 10 to 2000 mg/day, such as about 50 to 600 mg/day, such as about 10, 25,50,75,100,125,150,175,200,225,250,275,300, 325,350,375,400,425,450,475,500,525,550,575, or 600 mg/day or more, or any range therein. In one embodiment, the compound of formula I is administered in the form of a capsule in a dosage of about 10 mg to about 1000mg without any excipients.
The methods of the invention also provide kits for promoting cessation or reduction of tobacco/nicotine use or prevention of relapse. After formulating a pharmaceutical composition comprising one or more of the carbamate compounds of the invention and possibly one or more additional compounds of benefit in a suitable carrier, it is placed in a suitable container and labeled for promoting cessation or reduction of tobacco/nicotine use or prevention of relapse. In addition, another medicament containing at least one other therapeutic or beneficial agent may also be placed in the container and labeled for treatment of a designated disease. Such labels may include, for example, instructions regarding the dosage, frequency of administration, and method of administration of each drug.
All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety for the purpose of disclosing the contents relating to the sentences and/or paragraphs of the cited references, and for any other purpose that might be used.
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