Peripherally-acting cannabinoid receptor agonists for chronic pain
09656981 ยท 2017-05-23
Assignee
Inventors
Cpc classification
C07D215/12
CHEMISTRY; METALLURGY
C07D295/03
CHEMISTRY; METALLURGY
C07C49/788
CHEMISTRY; METALLURGY
C07D295/096
CHEMISTRY; METALLURGY
C07C49/84
CHEMISTRY; METALLURGY
C07D217/02
CHEMISTRY; METALLURGY
C07C13/465
CHEMISTRY; METALLURGY
C07D209/14
CHEMISTRY; METALLURGY
C07D307/52
CHEMISTRY; METALLURGY
C07D209/08
CHEMISTRY; METALLURGY
C07C43/215
CHEMISTRY; METALLURGY
International classification
C07D295/096
CHEMISTRY; METALLURGY
C07D295/073
CHEMISTRY; METALLURGY
C07D295/03
CHEMISTRY; METALLURGY
C07D217/02
CHEMISTRY; METALLURGY
C07D215/12
CHEMISTRY; METALLURGY
C07C13/465
CHEMISTRY; METALLURGY
C07D209/08
CHEMISTRY; METALLURGY
C07C43/215
CHEMISTRY; METALLURGY
C07C49/788
CHEMISTRY; METALLURGY
Abstract
Peripherally acting cannabinoid agonist compounds, pharmaceutical compositions, and methods of using them are presented.
Claims
1. A compound having the structure ##STR00102## wherein Ar.sup.1 is alkyl substituted 1-naphthyl; m.sup.1 is 1, 2, 3, 4, 5, or 6; R.sup.1 is morpholin-4-yl; and G.sup.1 is one, two, three, or four substituents, each independently selected from hydrogen, halogen, fluorine, hydroxyl, alkoxy, and methylenedioxy; and each R.sup.8 independently is H or alkyl.
2. The compound of claim 1, wherein m.sup.1 is 1 or 2.
3. The compound of claim 1, wherein G.sup.1 is one fluorine substituent.
4. The compound of claim 1, wherein Ar.sup.1 is selected from the group consisting of ##STR00103## and R.sup.6 is alkyl.
5. The compound of claim 1, wherein R.sup.8 is hydrogen.
6. The compound of claim 1, selected from: ##STR00104##
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
8. A method for treating a disease or disorder in a subject comprising administering to a subject a compound according to claim 1, wherein the disease or disorder may be treated by activating or blocking a peripheral cannabinoid receptor.
9. The method of claim 8, wherein the compound has less than 10% permeability across the blood brain barrier, as measured using the Madin-Darby canine kidney cell line assay.
10. The method of claim 8, wherein the disorder is pain.
11. The method of claim 10, wherein the pain is chronic, inflammatory, or neuropathic.
12. The method of claim 8, wherein said disease or disorder is hyperalgesia or allodynia.
13. The method of claim 8, wherein said disease or disorder is rheumatoid arthritis, inflammatory bowel disorders, soft tissue pain, bone cancer pain, chemotherapy-induced neuropathy, pain caused by thermal injury, pain caused by nerve injury, and pain caused by cancer.
14. The method of claim 8, wherein said disease or disorder is intraocular pressure.
15. The method of claim 8, wherein said treatment is anti-emetic, or anti-nausea treatment.
16. The method of claim 8, wherein said disease or disorder is a tumor.
17. The method of claim 8, wherein said disease or disorder is a bone disease associated with accelerated bone resorption.
18. The method of claim 17, wherein the bone disorder is osteoporosis, rheumatoid arthritis, or bone metastasis.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
Definitions
(11) As used herein, agent is a non-peptide, small molecule compound according to the invention.
(12) By control is meant a standard or reference condition.
(13) By disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, organ or subject.
(14) By effective amount is meant the amount of an agent required to ameliorate the symptoms of a disease relative to an untreated subject. The effective amount of an active therapeutic agent for the treatment of a disease or injury varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending clinician will decide the appropriate amount and dosage regimen.
(15) By modifies is meant alters. An agent that modifies a cell, substrate, or cellular environment produces a biochemical alteration in a component (e.g., polypeptide, nucleotide, or molecular component) of the cell, substrate, or cellular environment.
(16) As used herein, the terms prevent, preventing, prevention, prophylactic treatment and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
(17) By subject is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
(18) As used herein, the terms treat, treating, treatment, therapeutic and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
(19) As used herein, the terms reduce, and reducing when used in the context of a method of treatment mean decreasing the extent of or amount of, relative to a condition where no treatment is administered.
(20) As used herein, the term about when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of 0.20% or 10%, more preferably 5%, even more preferably 1%, and still more preferably 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
(21) The terms alkyl used alone or as part of a larger moiety (i.e. alkoxy, hydroxyalkyl, alkoxyalkyl, and alkoxycarbonyl) include both straight and branched chains containing one to ten carbon atoms (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), as well as cyclic structures such as cyclopropyl and cyclobutyl. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl (.sup.nPr or n-Pr), isopropyl (.sup.iPr or i-Pr) and cyclopropyl (.sup.cPr or c-Pr)), butyl (Bu) (including n-butyl (.sup.nBu or n-Bu), isobutyl (.sup.iBu or i-Bu), tert-butyl (.sup.tBu or t-Bu) and cyclobutyl (.sup.cBu or c-Bu)), pentyl (Pe) (including n-pentyl) and so forth. Alkyl groups also include mixed cyclic and linear alkyl groups, such as cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, etc., so long as the total number of carbon atoms is not exceeded.
(22) The term alkoxy refers to an O-alkyl radical, such as, for example O-Me, O-Et, OPr, and so on.
(23) The term hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl, such as, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, and so forth. The term thioalkyl refers to an S-alkyl group, such as, for example, example S-Me, S-Et, S-Pr.
(24) The term haloalkyl means alkyl, substituted with one or more halogen atoms, such as trifluoromethyl, chloromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2,-petanfluoroethyl, and so on.
(25) The term aminoalkyl means alkyl, substituted with an amine group (NH.sub.2), such as, for example, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl and so forth.
(26) The term alkoxyalkyl refers to an alkyl group, substituted with an alkoxy group, such as, for example, methoxymethyl, ethoxymethyl, methoxyethyl, and so forth.
(27) As used herein, the term alkylaminoalkyl refers to an alkyl group substituted with an alkylamine group, such as, for example, N-methylaminomethyl, N,N-dimethylaminomethyl, N,N-methylpentylaminomethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, and so forth.
(28) The term halogen or halo means F, Cl, Br, or I.
(29) The term nitro means (NO.sub.2).
(30) The term amine or amino used alone or as part of a larger moiety refers to unsubstituted (NH.sub.2). The term alkylamine refers to mono- (NRH) or di-substituted (NR.sub.2) amine where at least one R group is an alkyl substituent, as defined above. Examples include methylamino (NHCH.sub.3), dimethylamino (N(CH.sub.3).sub.2). As used herein, the term tertiary amine or tertiary amino means an amine-containing moiety where the nitrogen atom has three non-hydrogen substituents. Amino also includes quaternary amines (NR.sub.3.sup.+) bearing a permanent positive charge, and associated with a suitable counterion. The counterion may be any suitable counter ion, including halide (chloride, bromide, iodide) or sulfonate (methanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethylsulfonate). Examples include trialkylammonium (e.g. triethylammonium) substituents having three alkyl groups on the amine substituent.
(31) The term cycloamino used alone or as part of a larger moiety refers to a disubstituted amine (NR.sub.2), where the two R groups join to form a 3, 4, 5, 6, 7, or 8 membered monocyclic ring, or bicyclic ring having up to fourteen atoms or tricyclic ring system having up to fourteen atoms. The ring may be saturated or unsaturated, but not aromatic. The ring formed by the two R groups in the cycloamine substituent substitutent may be fused to an aromatic ring in a bicyclic or tricyclic system. The ring may include one or more additional heteroatoms, including N, S, O, P, or Si. Examples include morpholine, thiomorpholine, pyrrolidine, azetidine, piperidine, azepane, and so forth. Cycloamino also includes cycloammonium substituents (NR.sub.3.sup.+) having an additional substituent on the nitrogen atom, producing a permanent positive charge. The additional substituent on the nitrogen is an alkyl substituent having 1, 2, 3, or 4 carbon atoms. A counterion is associated with the positive charge. The counterion may be any suitable counterion, including halide (chloride, bromide, iodide) or sulfonate (methanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethylsulfonate).
(32) The term arylamine refers to a mono (NRH) or di-substituted (NR.sub.2) amine, where at least one R group is an aryl group as defined below, including, for example, phenylamino, diphenylamino, and so forth.
(33) The term heteroarylamine refers to a mono (NRH) or di-substituted (NR.sub.2) amine, where at least one R group is a heteroaryl group as defined below, including, for example, 2-pyridylamino, 3-pyridylamino and so forth.
(34) The term aralkylamine refers to a mono (NRH) or di-substituted (NR.sub.2) amine, where at least one R group is an aralkyl group, including, for example, benzylamino, phenethylamino, and so forth.
(35) The term heteroaralkylamine refers to a mono (NRH) or di-substituted (NR.sub.2) amine, where at least one R group is a heteroaralkyl group.
(36) As used herein, the term alkylaminoalkyl refers to an alkyl group substituted with an alkylamine group.
(37) Analogously, arylaminoalkyl refers to an alkyl group substituted with an arylamine, and so forth, for any substituted amine described herein.
(38) The term alkenyl used alone or as part of a larger moiety include both straight and branched chains containing at least one double bond and two to ten carbon atoms (i.e. 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), as well as cyclic, non-aromatic alkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc. As used herein, alkenyl groups also include mixed cyclic and linear alkyl groups, such as cyclopentenylmethyl, cyclopentenylethyl, cyclohexenylmethyl, etc., so long as the total number of carbon atoms is not exceeded. When the total number of carbons allows (i.e. more than 4 carbons), an alkenyl group may have multiple double bonds, whether conjugated or non-conjugated, but do not include aromatic structures. Examples of alkenyl groups include ethenyl, propenyl, butenyl, butadienyl, isoprenyl, dimethylallyl, geranyl and so forth.
(39) The term aryl used alone or as part of a larger moiety, refers to monocyclic, bicyclic, tricyclic or tetracyclic aromatic hydrocarbon ring system having five to 18 members, such as phenyl, 1-naphthyl, 2-naphthyl, phenanryl, 1-anthracyl and 2-anthracyl. The term aryl may be used interchangeably with the term aryl ring. Aryl also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Polycyclic rings include naphthylene, anthracene, phenanthrene. Also included within the scope of the term aryl, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, dihydroacenaphthalene, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring. The term aryl also refers to aryl rings that are substituted such as, for example, 4-chlorophenyl, 3,4-dibromophenyl and so forth. An aryl group may have more than one substituent, up to the total number of free substitution positions. For example, an aryl group may have 1, 2, 3, 4, or 5 substituents. The substituents may the same or different. Substituents on an aryl group include hydrogen, halogen, alkyl, alkenyl, nitro, hydroxyl, amino, alkylamino, alkoxy, alkylthio, acyl, ester, amide, O-acyl, N-acyl, S-acyl as defined herein.
(40) The term aralkyl refers to an alkyl substituent substituted by an aryl group.
(41) The term aryloxy refers to an O-aryl group, such as, for example phenoxy, 4-chlorophenoxy and so forth.
(42) The term arylthio refers to an S-aryl group such as, for example phenylthio, 4-chlorophenylthio, and so forth.
(43) The term heteroaryl, used alone or as part of a larger moiety, refers to heteroaromatic ring groups having five to fourteen members, five to ten members, or five to six members, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term heteroaryl, as it is used herein, is a group in which a heteroaromatic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[3,4-d]pyrimidinyl. The term heteroaryl may be used interchangeably with the term heteroaryl ring or the term heteroaromatic. A heteroaryl group may have more than one substituent, up to the total number of free substitution positions. For example, a heteroaryl group may have 1, 2, 3, 4, or 5 substituents. The substituents may the same or different. Substituents on a heteroaryl group include hydrogen, halogen, alkyl, alkenyl, nitro, hydroxyl, amino, alkylamino, alkoxy, alkylthio, acyl, ester, amide, O-acyl, N-acyl, S-acyl as defined herein.
(44) The term heteroaralkyl refers to an alkyl group substituted by a heteroaryl, such as, for example, 2-pyridylmethyl, 3-pyridylmethyl, 1-imidazolomethyl, 2-imidazolomethyl and so forth. The term heteroaryloxy refers to an O-heteroaryl group. The term heteroarylthio refers to an S-aryl group.
(45) The term acyl refers to a C(O)-alkyl, C(O)-aryl, or C(O)-heteroaryl group. Accordingly, alkylacyl refers to a C(O)-alkyl, arylacyl refers to a C(O)-aryl, and heteroarylacyl refers to a C(O)-heteroaryl group.
(46) The term ester refers to a C(O)O-alkyl, C(O)O-aryl, or C(O)O-heteroaryl group. Accordingly, alkyl ester refers to a C(O)O-alkyl, aryl ester refers to a C(O)O-aryl and heteroaryl ester refers to a C(O)O heteroaryl group.
(47) The term amide refers to a C(O)NR-alkyl, C(O)NR-aryl, or C(O)NR-heteroaryl group where R is hydrogen or an alkyl, hydroxyl, or alkoxy group. Accordingly, alkyl amide refers to C(O)NR-alkyl, aryl amide refers to C(O)NR-aryl, and heteroarylamide refers to C(O)NR-heteroaryl group.
(48) The term O-acyl refers to an OC(O)-alkyl, OC(O)-aryl, or OC(O) heteroaryl group.
(49) The term N-acyl refers to an NRC(O)-alkyl, NRC(O)-aryl, or NRC(O)-heteroaryl where R is hydrogen, alkyl, hydroxyl, or alkoxy group.
(50) The term S-acyl refers to SC(O)-alkyl, SC(O)-aryl, or SC(O) heteroaryl.
(51) The term NO-acyl refers to an NOC(O)-alkyl, NOC(O)-aryl, or NOC(O)-heteroaryl group.
(52) As used herein, a substituted structure refers to a chemical structure where a hydrogen atom has been replaced by a substituent. A substituent is a chemical structure that replaces a hydrogen atom on the substituted structure. The term substituent does not imply that the substituent is smaller than the substituted structure. Substituents include hydrogen, halogen, alkyl, alkenyl, nitro, hydroxyl, amino, alkylamino, alkoxy, and alkylthio, acyl, ester, amide, O-acyl, N-acyl, S-acyl as defined herein.
(53) As used herein, the term tertiary amine or tertiary amino means an amine-containing moiety where the nitrogen atom has three non-hydrogen substituents. One of the non-hydrogen substituents may be the core structure of the compound. Tertiary amine containing substituents include dialkylamino, cycloamino where the nitrogen atom is bonded to the parent structure, and N-alkylcycloamino, where a non-nitrogen atom of the a cycloamine moiety is bonded to the parent structure.
(54) Compounds
(55) Embodiments include compounds having the structure
(56) ##STR00001##
wherein Ar.sup.1 is optionally substituted biphenyl, optionally substituted monocyclic aromatic or heteroaromatic, optionally substituted bicyclic aromatic or heteroaromatic, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic. m.sup.1 is 1, 2, 3, or 4. R.sup.1 is a non-aromatic tertiary amine containing substituent having three to ten atoms. Each R.sup.8 independently is H or alkyl.
(57) In some embodiments, Ar.sup.1 is optionally substituted biphenyl, optionally substituted bicyclic aromatic or heteroaromatic, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic; wherein the optional substituents are halo, alkyl, or alkoxy, provided that if Ar.sup.1 is naphthyl, then the optional substituents are alkyl. In some embodiments, R.sup.1 is morpholin-4-yl.
(58) In some embodiments, m.sup.1 is 1 or 2. In some embodiments, R.sup.8 is hydrogen.
(59) G.sup.1 may be one, two, three, or four substituents, each independently selected. In essence, the indene compound may be substituted by one or more substituents. In some embodiments, G.sup.1 may be, for example, hydrogen, halogen, fluorine, hydroxyl, or alkoxy. Alternatively, two substituents may join to form a ring structure, such as methylenedioxy. In some embodiments, the G.sup.1 is a single non-hydrogen substituent. In some embodiments, G.sup.1 is a fluorine substituent. In some embodiments, the substituent, G.sup.1 resides on the 4-position, on the 5-position, on the 6-position, or on the 7-position of the indene structure.
(60) In some embodiments, R.sup.1 may be a substructure depicted below:
(61) ##STR00002##
wherein X may be CH.sub.2, O, S, NR.sup.11, SO, or SO.sub.2. R.sup.4 may be H or alkyl, R.sup.5 may be H or alkyl. R.sup.11 may be an acyl group, C(O)N(R.sup.7).sub.2, C(O)OR.sup.7, S(O).sub.2-alkyl, S(O).sub.2-aryl, C(O)NR.sup.7S(O).sub.2-alkyl, or C(O)NR.sup.7S(O).sub.2-aryl where R.sup.7 is H or alkyl. In some embodiments, R.sup.1 may be one of
(62) ##STR00003##
wherein X may be CH.sub.2, O, S, NR.sup.5, SO, and SO.sub.2 and R.sup.4 is alkyl, R.sup.5 is alkyl. In some embodiments, R.sup.1 is morpholine (e.g., morpholin-4-yl), having the structure
(63) ##STR00004##
where X is O.
(64) In some embodiments, Ar.sup.1 may be an aromatic structure shown below
(65) ##STR00005##
where R.sup.6 may be H, alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide. Y may be O, S, S(O), S(O).sub.2, NR.sup.10, or CH.sub.2. R.sup.10 may be H or alkyl.
(66) In some embodiments, Ar.sup.1 may be selected from the group consisting of
(67) ##STR00006##
where R.sup.6 is H, alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide; Y is O, S, S(O), S(O).sub.2, NR.sup.10, or CH.sub.2; and R.sup.10 is H or alkyl.
(68) In some embodiments, Ar.sup.1 may be
(69) ##STR00007##
where R.sup.6 may be alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide. In some embodiments, R.sup.6 can be alkyl, or alkoxy. In some embodiments, Ar.sup.1 may be
(70) ##STR00008##
(71) In some embodiments, the compound can be selected from:
(72) ##STR00009## ##STR00010## ##STR00011##
(73) In some embodiments, the compound is not (E)-4-(2-(1-((4-methoxynaphthalen-1-yl)methylene)-1H-inden-3-yl)ethyl)morpholine; (E)-4-(2-(1-(naphthalen-1-ylmethylene)-1H-inden-3-yl)ethyl)morpholine; (E)-4-(2-(2-methyl-1-(naphthalen-1-ylmethylene)-1H-inden-3-yl)ethyl)morpholine; (E)-4-(2-(2-methyl-1-(quinolin-4-ylmethylene)-1H-inden-3-yl)ethyl)morpholine; (E)-4-(3-(1-(naphthalen-1-ylmethylene)-1H-inden-3-yl)propyl)morpholine; (E)-4-(3-(1-(4-methoxynaphthalen-1-ylmethylene)-1H-inden-3-yl)propyl)morpholine; (E)-4-(2-(1-((4-methoxynaphthalen-1-yl)methylene)-2-methyl-1H-inden-3-yl)ethyl)morpholine; (E)-4-(2-(1-((1H-indol-4-yl)methylene)-1H-inden-3-yl)ethyl)morpholine; or (E)-4-(2-(1-(anthracen-9-ylmethylene)-1H-inden-3-yl)ethyl)morpholine. Embodiments include compounds having the structure
(74) ##STR00012##
wherein Ar.sup.2 is optionally substituted biphenyl, optionally substituted monocyclic aromatic or heteroaromatic, optionally substituted bicyclic aromatic or heteroaromatic, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic. m.sup.2 is 2, 3, 4, 5, or 6. R.sup.2 is CH.sub.3, CO.sub.2R.sup.3, CON(R.sup.4).sub.2, halogen (F, Cl, Br, I), hydroxyl, nitro, amino, monoalkylamino, or non-aromatic tertiary amine containing substituent having three to ten atoms. R.sup.3 is H or alkyl. R.sup.4 is, independently, hydrogen or alkyl. G.sup.2 is one, two, three, or four substituents, each independently selected from hydrogen, halogen, fluorine, hydroxyl, alkoxy, and methylenedioxy. R.sup.9 is H or alkyl.
(75) In some embodiments, Ar.sup.2 is optionally substituted biphenyl, optionally substituted bicyclic aromatic or heteroaromatic, optionally substituted tricyclic aromatic or heteroaromatic, or optionally substituted tetracyclic aromatic or heteroaromatic; wherein the optional substituents are halo, alkyl, O-alkyl, CO-alkyl, COOR.sup.4, or CON(R.sup.4).sub.2, provided that if R.sup.8 is methyl, then Ar.sup.2 is not 4-halonaphth-1-yl. In some embodiments, R.sup.2 is CH.sub.3, CO.sub.2R.sup.3, CON(R.sup.4).sub.2, F, Cl, I, hydroxyl, nitro, amino, monoalkylamino, or morpholin-4-yl.
(76) In some embodiments, m.sup.2 is 2, 3, 4 or 5. In some embodiments, m.sup.2 is 2. In some embodiments, R.sup.9 is H.
(77) G.sup.2 may be one, two, three, or four substituents, each independently selected. In essence, the indole compound may be substituted by one or more substituents. In some embodiments, G.sup.2 may be, for example, hydrogen, halogen, fluorine, hydroxyl, or alkoxy. Alternatively, two substituents may join to form a ring structure, such as methylenedioxy. In some embodiments, the G.sup.2 is a single non-hydrogen substituent. In some embodiments, G.sup.2 is a fluorine substituent. In some embodiments, the substituent, G.sup.2 resides on the 4-position, on the 5-position, on the 6-position, or on the 7-position of the indole structure.
(78) In some embodiments, R.sup.2 may be fluorine, CH.sub.3, CO.sub.2R.sup.3 where R.sup.3 is alkyl, CO.sub.2H or a substructure shown below
(79) ##STR00013##
where X may be CH.sub.2, O, S, NR.sup.6, SO, and SO.sub.2. R.sup.4 may be H or alkyl, R.sup.5 may be H or alkyl. R.sup.6 is an acyl group, C(O)N(R.sup.7).sub.2, C(O)OR.sup.7, S(O).sub.2-alkyl, S(O).sub.2-aryl, C(O)NRS(O).sub.2-alkyl, or C(O)NR.sup.7S(O).sub.2-aryl where R.sup.7 is H or alkyl.
(80) In some embodiments, R.sup.2 may be fluorine, CH.sub.3, CO.sub.2H, CO.sub.2CH.sub.2CH.sub.3 or a substructure shown below
(81) ##STR00014##
where X may be CH.sub.2, O, S, NR.sup.5, SO, and SO.sub.2. R.sup.4 is alkyl, R.sup.5 is alkyl. In some embodiments, R.sup.2 is methyl (CH.sub.3). In some embodiments, R.sup.2 is morpholine.
(82) In some embodiments, R.sup.2 may be fluorine, CH.sub.3, CO.sub.2R.sup.3 where R.sup.3 is alkyl, CO.sub.2H or morpholin-4-yl.
(83) In some embodiments, Ar.sup.2 may be
(84) ##STR00015##
wherein R.sup.6 is H, alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide. Y is O, S, S(O), S(O).sub.2, NR.sup.10, or CH.sub.2 where R.sup.10 is H or alkyl.
(85) In some embodiments, Ar.sup.2 may be
(86) ##STR00016##
where R.sup.6 is H, alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide; and Y is O, S, S(O), S(O).sub.2, NR.sup.10, or CH.sub.2; and R.sup.10 is H or alkyl.
(87) In some embodiments, Ar.sup.2 may be
(88) ##STR00017##
where R.sup.6 may be alkyl, alkoxy, alkylacyl, alkyl ester, or alkyl amide.
(89) In some embodiments, Ar.sup.2 may be
(90) ##STR00018##
(91) In some embodiments, Ar.sup.2 may be
(92) ##STR00019##
R.sup.2 is CH.sub.3 or halogen; and R.sup.9 is H.
(93) In some embodiments, the compound is selected from:
(94) ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
(95) In some embodiments, the compound is not (1-(3-bromopropyl)-2-methyl-1H-indol-3-yl)(naphthalen-1-yl)methanone; (4-chloronaphthalen-1-yl)(7-methoxy-2-methyl-1-pentyl-1H-indol-3-yl)methanone; (4-bromonaphthalen-1-yl)(7-methoxy-2-methyl-1-pentyl-1H-indol-3-yl)methanone; or (4-bromonaphthalen-1-yl)(7-fluoro-2-methyl-1-pentyl-1H-indol-3-yl)methanone.
(96) Examples of compounds according to the invention include those shown in Table 1.
(97) Peripherally Acting Compounds
(98) Current clinical treatments with FDA-approved cannabinoid-based analgesics can provide relief from chronic pain symptoms, but also produce several important CNS-mediated side effects which greatly limit their usefulness.
(99) Peripherally-acting cannabinoids compounds may have limited permeability at the blood-brain barrier (BBB) while possessing high affinity for cannabinoid receptors. In preclinical testing example compounds were effective in alleviating chronic pain of inflammatory and neuropathic origin without any centrally-mediated side effects.
(100) Compounds described herein have an indole or indene core and substituted about these rings. Examples have substitution on the indole at N-1 with alkyl groups (e.g. n-pentyl), C-3 with 1-naphthoyl that is substituted in the 4-position with various moieties such as alkyl, ether, acyl, or halo. Other examples include other C-3 aroyl (C(O)Ar) substituents. Further examples include indole core substituted on the benzene ring with fluorines. The indenes may be substituted in the C-3 position with an ethyl-4-morpholino group, at the C-1-position with a 1-naphthalenylmethylene that is substituted in the 4-position as above for the indoles or with other aryl-methylidene or -ethylidene groups. The indene core may be substituted on the benzene ring with fluorines. The compounds have affinity for the CB1 receptor and exhibit minimal penetration of the MDCK model of the blood-brain barrier.
(101) Some compounds having an indole or indene core are described in U.S. Pat. Nos. 6,013,648; 5,292,736; and 5,013,837, each of which is incorporated by reference in its entirety.
(102) Compounds described herein are those with an indene or indole core, substituted on the 2-indene ring at C-1, C-3 and either or multiple of the 4-7 indene ring positions and for the indole ring on the N-1, C-3 and either or multiple of the 4-7 indole ring positions. Specific to these are those compounds exhibiting the properties of affinity for the cannabinoid CB1 receptor (Ki300 nM), peripheral selectivity as indicated by the MDCK assay and/or behavioral testing showing minimal or no CNS penetration or tetrad effects respectfully, and reduced neuropathic pain as demonstrated by SNE and/or CFA inflammatory pain testing. Representative examples are given in the appended spreadsheet.
(103) The indene C-1 substituent is a polycyclic arylidene system or heteroaromatic system with N, O, or S as the heteroatom(s) singly or in combination. Such polycyclic systems are those that fit the abcd template (shown below) with some or all of the rings. For a non-limiting example, the non-heteroaromatic system can formally be derived from phenanthrene-4-carboxaldehyde, naphthylene-2-carboxaldehyde or o-phenyl-benzaldehyde heteroaromatic system. The heteroaromatic system can be quinoline, isoquinoline, indole, benzofuran or benzothiophene that is suitably substituted for formal condensation with the indene at C-1 via a carboxaldehyde moiety.
(104) ##STR00025## abcd system can involve some or all of the rings. abc: where a and c are aromatic, b is aromatic or non-aromatic as c6 or c5 carbocyclic or heterocyclic or absent (e.g. 196-41, 138-139). abd: where a and b are aromatic or heteroaromatic, d is aromatic or c6 or c5 carbocyclic (e.g. 174-38 derived from acenaphthene-5-carboxaldehyde; analogs derived from acenaphthylene-5-carboxaldehyde or fluorene-4-carboxaldehyde) or heterocyclic pyran or lactone. ac: e.g. o-phenylbenzylidene derived from o-phenylbenzaldehyde (138-39). =(CH.sub.2).sub.n=0,1; O, S, NR(RH, alkyl).
(105) Substituents on the 1-naphthylene aromatic system at the indene C-1 are most favored at the 4-position and are carboxy esters of small alcohols, primary and secondary amides, acyl moieties from acetyl through pentanoyl, and ethers as methoxy through pentyloxy, and alkyl as methyl, ethyl, n-propyl and butyl.
(106) The indene 3-substituent in the examples provided is the morpholino-N-ethyl moiety, which surprisingly conferred peripheral selectivity in the indene series. Other beta-amino ethyl groups with other hetero atoms or groups such as sulfone are extensions that are claimed.
(107) The indene 4-7 positions can be substituted with either or multiple halogens (fluorine being a favored example) or oxygens such as hydroxyl, methoxyl or methylenedioxy.
(108) The indole core scaffold follows similar structural patterns except that in lieu of arylidene moieties the C-3 of the indoles are substituted with aroyl moieties following the abcd template in (2) above.
(109) Modified 1-arylidene indenes (A1) and 3-aroyl indoles (A2) as peripherally selective CB1R agonists are described herein. The first four areas focus on the pendant 3-aroyl and the 1-arylidene moieties, which have been majorly implicated in the CB1R binding that stabilizes the active state of CB1R (Figure A). Analogs should be able to adopt the bioactive conformation, similar to the archetypical WIN 55,212-2, aligning the naphthyl rings in the X-Z plane (into the plane of the paper horizontally) (relative to the X-Y plane of the paper for the indole or indene ring) and stack with aromatic residues in the helices of the CB1R transmembrane region TM 3-4-5-6. The four areas contribute to binding affinity and potentially receptor subtype selectivity (CB1R vs CB2R) by 1) optimally juxtaposing aromatic stacking interaction surface, 2) enhancing the strength of the interaction by increasing or decreasing the electron density of the pendant aryl groups, 3) the productive effect of 4-position substituents of 1-naphthyl rings beyond those currently reported, and 4) conformational constraint via atropisomers that favor the binding and activation conformation.
(110) The first area, Aromatic Stacking Interactions demonstrate that favorable binding interactions extend beyond the naphthyl moiety to our current and evolving annotated template A3 for indenes. Numbers 1, 2, 3, 5 and 6 represent regions/rings associated with good binding (Ki=1-83 nM) and underlined numbers (i.e. 4, 7) represent regions of decreased binding (Ki1 M).
(111) ##STR00026##
(112) Mapped areas include: the 2/1 ring pair, the naphthyl system (Ki=4.69 nM); the 3/1 non-fused ring pair, 2-phenyl benzylidene (Ki=82.9 nM); the 2/1/5 (or 2/1/6) groupings, which are the possible templates for 4-propyl- or 4-ethyl-1-naphthylidene systems (acyclic propyl and ethyl) (Ki=1.18 and 0.86 nM, respectively), while the 1/4 is the inactive m-phenyl benzylidene (Ki=2603 nM) and the 2/1/7 is the putatively inactive 9-anthracene based on the inactive 9-anthracenoyl system in the indoles.sup.120.
(113) The A3 template may be used as a guide to select aryl carboxaldehydes to couple with 3-(morpholinoethyl)-2-indene to prepare the target indenes. Using this template, the analog 1/2/3 (from phenanthrene-4-carboxaldehyde) was prepared and found to be active (Ki=22.9 nM). Further, based on the 4-ethyl- and the 4-propyl-1-naphthylidene, described above, the ethyl and propyl moieties could be part of either of two additional non-aromatic rings (i.e. 1/2/5 or 1/2/6). This was tested with a, ring constrained, ethyl analog of the 1/2/5 ring configuration from acenaphthene-carboxaldehyde that gave an active, but less active, analog (Ki=15.9 nM). This suggests the possibility that the ethyl might have an out of plane interaction or that the conformation of the ethyl (or propyl) is more like 1/2/6. This suggests preparing a 1/2/6 analog with the number 6 ring as 5- or 6-membered aliphatic. It is understood that as results from analogs are obtained, the template may change towards a more refined SAR that systematically explores enhanced affinity and potential CB1R vs CB2R selectivity.
(114) Stacking of aromatic rings can be in a parallel, offset parallel or edge-to-face (T-stacked) mode that maximizes an attraction between the relatively positive -bond carbon framework and the relatively negative -bond electron cloud.sup.121. In stacking aromatic rings, attractive interactions can be enhanced by increasing or decreasing the electron density of the ligand's pendant ring relative to that of the receptor ring with which it is stacked. Such altered electron density is observed in heteroaromatic rings that are electron poorer when N is in a 6-member ring (relative to an all carbon 6-member ring) or electron richer (than phenyl) when the heteroatom is in a smaller (i.e. 5-member) ring (e.g. pyrrole, furan). CB1R binding and activation may be modified with indole and indene ligands containing heteroaromatic rings with altered electron density that also match the mapping described previously in the pendant aryl ring systems. Some such substitutions have been examined (e.g., electron-rich 7-coupled indole and electron-poor 5-coupled isoquinoline both of which placed the heteroring distal to the point of coupling, while maintaining the oriented overlap matching the parent naphthyl rings) and found increased affinity with an electron-rich distal ring. The reported.sup.120 electron-rich distal 4- or 7-coupled-benzofuran aromatic ring with good IC.sub.50 values supports our observations with the 7-coupled indole above. Similarly, we found an electron-poor proximal ring of 4-coupled quinoline to have good affinity (Ki=23 nM) while others reported.sup.120 a good IC.sub.50 with an electron-poor proximal 2-coupled quinoline. These consistent few examples suggest potential improvement in both binding and activation, by appropriate adjustment of electron density of stacking aromatic rings pendant to indole and indene systems. These merit further examination since the few examples that are available for comparison cross both core templates (indoles and indenes) and position of coupling and hence the positioning of the heteroatom, both of which could influence binding and activation.
(115) The scope of the aryl substituent may enhance ligand properties. We have prepared and screened a 1-naphthoyl-4-carbomethoxy-indole that exhibited good CB1 binding affinity (Ki=20 nM) and <1% MDCK permeability, then significantly improved affinity as the 4-propionyl analog (Ki=5.7 nM). In the indene class of analogs, a 4-methoxy-1-naphthylidene-indene (13339-135-35) had superior affinity (Ki=2.4 nM) and <1% MDCK permeability. Further, the 4-n-propyl- and 4-ethyl-naphthylidene indenes had 1 nM CB1R affinity in accord with results with the corresponding naphthoyl-indole analogs.sup.118. Peripheral in vivo activity was demonstrated for 4-substituted 1-naphthylidene indenes (see 13339-135-35 results in
(116) The binding conformation of a ligand in a receptor active site might not be the same conformation as the ground state of the ligand, thus requiring a conformational change that is done at the expense of the binding energy and reduced ligand-receptor affinity. Further, ligand conformation can also affect receptor selectivity (i.e. CB1R and CB2R). Therefore, when a ligand is conformationally constrained, if the restricted conformation is that of the binding conformation, the binding affinity will be improved and potentially the receptor selectivity will be enhanced in favor of one or the other receptors. For the E-naphthylidene indenes (A1), this has been demonstrated by the exocyclic double bond that locks the molecule into an E-configuration, equivalent to the active s-trans conformation of 3-naphthoyl-indoles (A2).sup.117. Yet, there is further conformational freedom that can be addressed; rotation about the single bond that links the naphthyl ring to the vinyl group. Computational modeling of the CB1R binding of indoles and indenes, such as those we propose here, supports alignment of the naphthoyl ring with the X-Z plane.sup.115. Two such alignments, with the distal phenyl of the naphthyl ring into or out of the X-Y plane of the indole or indene, are possible. In the receptor active site, one conformation would favor binding and the other would not.
(117) Some embodiments include analogs of active naphthylidene indenes that are constrained into each of the non-interconverting isomers in the form of atropisomers (isomers formed due to limited rotation about a single bond, e.g. tetra-ortho-substituted biphenyls, B3). Analogous to B3, wherein a-d are of sufficient size (>H) (and are non-identical moieties in B3) and thus lock B3 into enantiomeric atropisomers that can't rotate past the steric blockade, the naphthylidene indene analogs B1 and B2 are similarly locked. All the atoms of each connected ring are rigidly coplanar thus serving the same paradigm as the tetra substituted phenyl rings in B3 in inducing atropisomerism. It can be seen that the moieties a-f in B1 and B2 serve the same steric interplay as a-d in B3 to induce atropisomerism. In analog B2 the extension of e (i.e. e=Me), which replaces the steric role of d in B1, represents an E-naphthylidene-2-methyl-indene that is also active.sup.126. The synthesis of the B1 analogs will follow that discussed herein but will employ suitably substituted ketones (to provide moieties f, b and d) instead of aldehydes. The E-isomer may be favored for analogs B1 and be chromatographically separable from the Z-isomer that could be present. The resulting mixture of the two enantiomers of the E-isomer would be subsequently resolved on chiral columns. The E-analogs B2, from 2-methyl-indenes may be less favored than the Z-isomer favored in 2-methyl-indenes. Photochemical isomerization has been used in naphthylidene indenes to produce mixtures from either isomer and could be employed to generate E/Z-mixtures from Z-fractions.sup.117.
(118) ##STR00027##
(119) The 1-n-pentyl-3-(1-naphthoyl)-indole family (A2) of CB1R agonists have been widely synthesized.sup.118 as CB1R/CB2R agonist ligands but little has been scientifically pursued in the areas of pharmacology and behavior. The metabolism of the parent A2 and an analog has been investigated.sup.127,128 and found to be rapidly and extensively metabolized (predominantly hydroxylated at indole 4-7 positions) affording full and partial agonists and neutral antagonists. The potential for many active metabolites could create a polypharmacology, which would best be avoided. The introduction of electron drawing substituents at and proximal to metabolism sites inhibit metabolism. We have observed improved metabolic stability in selected fluoro-indoles (i.e. 7-fluoro) while maintaining high CB1R affinity and non-permeability of the MDCK model. Accordingly, substitution of the indene ring may improve metabolic stability.
(120) The morpholinoethyl-indene family (e.g. A1) has shown peripheral selectivity indicated by the MDCK in vitro model and by behavioral studies in rats (see
(121) ##STR00028##
Pharmaceutical Compositions
(122) A further embodiment includes pharmaceutical compositions comprising any compound, discussed herein or pharmaceutically acceptable salts thereof.
(123) In certain embodiments the compositions may include one or more than one compound described herein, and may further contain other suitable substances and excipients, including but not limited to physiologically acceptable buffering agents, stabilizers (e.g. antioxidants), flavoring agents, agents to effect the solubilization of the compound, and the like.
(124) In certain embodiments, the composition may be in any suitable form such as a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use. The composition may include suitable parenterally acceptable carriers and/or excipients.
(125) In certain embodiments, the compositions may comprise an effective amount of a compound in a physiologically-acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for a particular route of administration. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin.
(126) In certain embodiments, the compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for parenteral (e.g., subcutaneously, intravenously, intramuscularly, or intraperitoneally) or oral administration route. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
(127) In certain embodiments, the compositions may be in a form suitable for administration by sterile injection. To prepare such a composition, the compositions(s) are dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution and dextrose solution. The aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate). For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
(128) Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
(129) Parenteral administration may comprise any suitable form of systemic delivery or localized delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
(130) In certain embodiments, the compositions may be in a form suitable for oral administration. In compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. If desired, tablets may be sugar coated or enteric coated by standard techniques.
(131) Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the compound as a powder or granules. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught. Formulations for oral use include tablets containing active ingredient(s) in a mixture with pharmaceutically acceptable excipients. Such formulations are known to the skilled artisan. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.
(132) A syrup may be made by adding the compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
(133) In some embodiments, the composition may be in a form of nasal or other mucosal spray formulations (e.g. inhalable forms). These formulations comprise purified aqueous solutions of the compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
(134) In some embodiments, the composition may be in a form suitable for rectal administration. These formulations may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
(135) In some embodiments, the composition may be in a form suitable for transdermal administration. These formulations may be prepared by incorporating the compound in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
(136) In addition to the aforementioned ingredients, compositions of the invention may further include one or more accessory ingredient(s) selected from encapsulants, diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
(137) In some embodiments, compositions may be formulated for immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
(138) In some embodiments, the pharmaceutical composition may be formulated to release the compound substantially immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain action during a predetermined time period by maintaining a relatively constant, effective level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active substance (sawtooth kinetic pattern); (iv) formulations that localize action by, e.g., spatial placement of a controlled release composition adjacent to or in the central nervous system or cerebrospinal fluid; (v) formulations that allow for convenient dosing, such that doses are administered, for example, once every one or two weeks; and (vi) formulations that target the site of a pathology. For some applications, controlled release formulations obviate the need for frequent dosing to sustain activity at a medically advantageous level.
(139) Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the compound is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the compound in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.
(140) In some embodiments, the composition may comprise a vectorized form, such as by encapsulation of the compound in a liposome or other encapsulate medium, or by fixation of the compound, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
(141) In some embodiments, the composition can be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release. Furthermore, the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, tonicity adjusting agents, and/or dispersing, agents. Alternatively, the compound may be incorporated in biocompatible carriers, implants, or infusion devices.
(142) Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and, poly(lactic acid). Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters) or combinations thereof).
(143) Unless the context clearly indicates otherwise, compositions of all embodiments can comprise various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the compound. Certain embodiments can comprise all individual enantiomers, diastereomers, racemates, and other isomer of compounds of the invention. The invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.
(144) Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or inorganic ligands, such as quaternary ammonium salts.
(145) Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate salts of the compound of the present invention.
(146) The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy.
(147) Methods of Treatment
(148) A further embodiment includes uses of compounds described herein for treating a disease in a subject. Embodiments include methods for treating a disease by administering a subject a therapeutically effective amount of a compound described herein.
(149) Embodiments include methods for treating a disease or disorder in a subject comprising administering to a subject a compound described herein, wherein the disease or disorder may be treated by activating or blocking a peripheral cannabinoid receptor.
(150) Other potential therapeutic applications for peripherally-acting CB1R ligands include: 1) pain symptoms of rheumatoid arthritis, inflammatory bowel disorders, soft tissue and bone cancer pain, and chemotherapy-induced neuropathy, particularly since classical CBs have been shown to ameliorate the pain symptoms of cancer and chemotherapy-induced neuropathies mainly by peripheral mechanisms.sup.161-168; 2) decreasing intraocular pressure in glaucoma resistant to conventional therapies.sup.169; 3) anti-emetic and anti-nausea actions via CB1R activation in area postrema, which are located outside the blood-brain barrier.sup.170; 4) antidiarrheal actions.sup.171; 5) antitumorigenic actions.sup.172; and 6) treatment of bone diseases associated with accelerated osteoclastic bone resorption including osteoporosis, rheumatoid arthritis and bone metastasis.sup.173.
(151) In some embodiments, the compound has less than about 10% permeability across the blood brain barrier, as measured using the Madin-Darby canine kidney cell line assay. In some embodiments, the compound has less than about 7% permeability, less than about 5% permeability, less than about 4% permeability, less than about 3% permeability, less than about 2% permeability or less than about 1% permeability across the blood brain barrier, as measuring using the Madin-Darby canine kidney cell line assay. In some embodiments, the disorder is pain. The pain may be chronic, inflammatory, or neuropathic. In some embodiments, the disease or disorder is hyperalgesia or allodynia, and the compound alleviates the symptoms of hyperalgesia or allodynia.
(152) In some embodiments, the disease or disorder is one or more of rheumatoid arthritis, inflammatory bowel disorders, soft tissue pain, bone cancer pain, chemotherapy-induced neuropathy, pain caused by thermal injury, pain caused by nerve injury, and pain caused by cancer. In some embodiments, the disease or disorder is intraocular pressure. In some embodiments, the disease or disorder is a tumor.
(153) In some embodiments, the compound acts an anti-emetic, or anti-nausea agent.
(154) In some embodiments, the disease or disorder is a bone disease associated with accelerated bone resorption. Examples include osteoporosis, rheumatoid arthritis, or bone metastasis.
(155) Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.
EXAMPLES
Ligand Screening Assays
(156) Compounds were first screened for: a) CB1R and CB2R binding, b) CB1R agonist activity using the human CB1R (hCB1R) calcium flux assay, and c) BBB permeability using the Madin-Darby canine kidney (MDCK-MDR1) cell line assay. Results are shown in Table 1. Compounds 1, 19, 39, 42, 44, 69, 70 are standards. After identifying ligands with high affinity and agonist activity at CB1Rs and low BBB permeability, ligands were tested for stability in rat plasma and in the rat S9 fraction. Results are shown in Table 2. Subsequently, the most promising candidate compounds were tested in rat models of chronic inflammatory and neuropathic pain. Results are shown in Table 3.
Example 1
In Vitro Assays
(157) 1) CB1/CB2R Binding Assays.
(158) Detailed radioligand displacement assays (using the well-characterized CBR agonist CHFCP55940 as the radioligand) were conducted to determine the affinity (Ki) of the test compounds for CB1R and CB2R as has been previously described by our group.sup.112,113. Heterologous competition binding assays were performed to calculate receptor affinities. Unlabeled SR141716 or SR144528 were used as appropriate controls for non-specific binding (NSB) in the assay. Calculation of the equilibrium dissociation constant (Ki) was performed using the Cheng-Prusoff equation.
(159) 2) Calcium Flux Assay.
(160) The calcium 3 dye assays were run according to manufacturer's specifications (http://www.moleculardevices.com/Products/Assay-Kits/GPCRs/FLIPR-Calcium.html) and as reported in our previous publications.sup.112,113. Briefly, wells of black clear-bottom 96-well tissue culture-treated plates are seeded with 20,000 cells the afternoon before assay. The day of assay, the cells are incubated with the Ca.sup.2+ indicator dye for 1 hr @ 37 C. For antagonist assays, the test compound is preincubated with the cells during the last 10 min of the dye incubation. Basal or unstimulated fluorescence intensity is recorded in the FlexStation @ 37 C. for 13 sec followed by the addition of test compound or CP 55,940 (depending on the assay endpoint). Fluorescence intensity is recorded for an additional 47 sec. The effect of test compound in each well is determined by subtracting the minimum from the maximum fluorescence during the 47-sec recording period.
(161) 3) Permeability Assay.
(162) Potential substrates for crossing the BBB and apparent permeability (Papp) are assessed for various new chemical entities (NCEs) using the MDCK-MDR1 epithelial cell line. Papp of a compound in this particular model is defined as the rate of flux of a molecule across the monolayer and is predictive of potential blood brain barrier penetration.sup.114. In a typical assay, cells are grown to confluence on Transwell filters and the test compound added to the apical side in a transport buffer. Following incubation for 1 hr at 37 C., samples are collected from both compartments and analyzed for transport using LC-MS/MS. Cells are plated onto semi-permeable membranes in a system. NCE is dissolved in dimethyl sulfoxide or ethanol. For screening purposes, two concentrations of NCE are assessed, typically 3 M and 10 M, each for 60 min, in triplicate for both concentrations. Samples are analyzed by HPLC. Results are reported as a Papp value and NCEs are rank ordered accordingly.
(163) 4) Plasma Stability Assay.
(164) Compounds are incubated at 10 M in rat plasma at 37 C. A solution of each compound is prepared in ethanol at a concentration of 1 mM. A 2.5 L volume of the 1 mM solution is added to 247.5 L of rat plasma (male Sprague Dawley) in a glass test tube in a 37 C. water bath. Samples (50 L) are removed at 0, 30 and 60 min and immediately extracted with 3 volumes (150 L) of methanol. Samples are centrifuged (2500 rpm for 10 min at 4 C.) to pellet protein and supernatants transferred to LC/MS vials for analysis. Samples are stored at 80 C. prior to analysis.
(165) 5) S9 Fraction Stability Assay.
(166) Compounds are incubated at 10 M in rat (male Sprague Dawley) liver S9 at 37 C. Each compound is prepared in ethanol at a concentration of 1 mM. An assay mixture containing S9 (1 mg protein/mL final concentration) and an NADPH regenerating system (NADP [1 mM final], glucose 6-phosphate [5 mM final] and glucose 6-phosphate dehydrogenase [1 U/mL final]) in a buffer consisting of 50 mM KPO4 phosphate buffer, pH 7.4 with 3 mM MgCl2 is prepared and preincubated at 37 C. for 5 min. A 10 L volume of the 1 mM solution is added to 990 L of assay mixture in a glass test tube @ 37 C. to initiate the assay. Samples (50 L) are removed at 0, 15, 30, 60 and 120 min and immediately extracted with 3 volumes (150 L) of methanol, centrifuged to pellet protein and supernatants transferred to LC/MS vials for analysis.
Example 2
Indene Synthesis
(167) General Methods
(168) 1H and 13C NMR spectra were run on a Bruker Avance 300 MHz or a Varian Unity Inova 500 MHz NMR spectrometer. Mass spectra (MS) were run on a Perkin-Elmer Sciex API 150 EX mass spectrometer. High resolution mass spectra (HRMS) were run on a Waters Synapt G2 Q-TOF mass spectrometer in high-resolution mode. Column chromatography was carried out using a Teledyne Isco Combiflash Rf system with RediSep Rf silica cartridges. Preparative thin layer chromatography was carried out using Analtech TLC Uniplates (silica gel, 1000 m, 2020 cm). High pressure liquid chromatography was performed using a system consisting of a Waters 1525 pump unit, driven by Empower software, and a Waters 2487 detector. Microwave chemistry was carried out using a CEM Discover SP microwave with 10 mL irradiation tubes.
Synthesis of ENMI 4-{2-[(1E)-1-(Naphthalen-1-ylmethylidene)-1H-inden-3-yl]ethyl}morpholine (26)
(169) ##STR00029##
(170) 4-[2-(1H-Inden-3-yl)ethyl]morpholine (30) (2.82 g, 12.3 mmol) was dissolved in methanol (75 mL) and cooled in a ice bath to 0 C. The reaction mixture was purged with nitrogen and sodium methoxide (25.8 mL, 0.5M in MeOH; 1.22 mmol) was added dropwise over 5 minutes and the solution stirred at room temperature for 30 minutes. Naphthaldehyde (31) (1.67 mL, 12.3 mmol) was then added dropwise over several minutes. After the addition was complete, the solution was stirred under reflux for 18 hours. At the end of this time the mixture was allowed to cool to room temperature. The resulting solid was removed by filtration and recrystallized from methanol to give a golden solid (2.2 g). The original filtrate and the filtrate from the recrystallization were combined and the solvent removed. This residue was recrystallized twice from methanol to give a golden solid which was combined with the initial recrystallization product (780 mg, 2.98 g total, 65.9%). .sup.1H NMR (300 MHz, CDCl.sub.3) 2.41 (t, J=4.2 Hz, 4H), 2.54-2.64 (m, 2H), 2.71-2.82 (m, 2H), 3.56 (t, J=4.5 Hz, 4H), 3H), 6.67 (s, 1H), 7.26-7.41 (m, 3H), 7.55-7.71 (m, 4H), 7.93-8.08 (m, 3H), 8.22-8.31 (m, 2H). .sup.13C NMR (75.5 MHz, CDCl.sub.3) 24.65, 53.15 (2C), 56.74, 66.20 (2C), 118.76, 119.86, 122.11, 124.44, 124.52, 125.32, 125.65, 126.22, 126.55, 127.54, 128.47, 128.51, 128.87, 131.58, 133.21, 133.54, 137.31, 140.67, 142.28, 146.74. HPLC 99.8% (Waters X-Bridge C-18 5 m, 4.6100 mm column, 10 mM aqueous NH.sub.4OAcCH.sub.3CN, 40:60, UV detection at 254 nm). HRMS: Calculated for C.sub.26H.sub.26NO (M+H): 368.2014. Found: 368.2013 (M+H).
Example 3
Indole Synthesis
(171) ##STR00030##
Synthesis of 6-Fluoro-3-[(naphthalen-1-yl)carbonyl]-1-pentyl-1H-indole (40)
(172) Sodium hydride (207 mg, 60% in oil, 5.18 mmol) was added to DMF (20 mL) at 0 C. and the mixture stirred for 10 minutes. A solution of 6-fluoro-3-[(naphthalen-1-yl)carbonyl]-1H-indole (36) (750 mg, 2.59 mmol) in DMF (10 mL) was added dropwise over 5 minutes and the resulting solution stirred at 0 C. for 30 minutes. A solution of 1-bromopentane (431 mg, 2.85 mmol) in DMF (1 mL) was then added dropwise to the stirred mixture. Cooling was continued for an additional 10 minutes before allowing the solution to warm to room temperature and stir overnight. The reaction was quenched with water (75 mL), and EtOAc (50 mL) was added. The mixture was shaken and the organic layer removed. The aqueous layer was then extracted with additional EtOAc (50 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent removed under reduced pressure. The residue was purified over silica gel (Isco, 120 g column, gradient from 100% hexane to 30% EtOAc/70% hexane) to give the title compound as a colorless resin (840 mg, 90.1%). .sup.1H NMR (300 MHz, CDCl.sub.3) 0.85 (t, J=6.8 Hz, 3H), 1.18-1.40 (m, 4H), 1.72-1.87 (m, 2H), 4.00 (t, J=7.2 Hz, 2H), 7.02-7.16 (m, 2H), 7.32 (s, 1H), 7.43-7.58 (m, 3H), 7.61-7.69 (m, 1H), 7.87-7.95 (m, 1H), 7.98 (d, J=8.2 Hz, 1H), 8.14-8.22 (m, 1H), 8.39-8.48 (m, 1H). .sup.13C NMR (75.5 MHz, CDCl3) 13.82, 22.15, 28.88, 29.35, 47.32, 96.64 (d, J=26.6 Hz, 1C), 111.34 (d, J=23.9 Hz, 1C), 117.70, 123.38, 124.09 (d, J=9.9 Hz, 1C), 124.51, 125.91 (d, J=2.6 Hz, 1C), 126.35, 126.83, 128.21, 130.13, 130.80, 133.79, 137.31 (d, J=11.7 Hz, 1C), 138.13 (d, J=2.6 Hz, 1C), 138.83, 160.57 (d, J=241.0 Hz, 1C), 191.88. HPLC 98.7% (Waters X-Bridge C-18 5 m, 4.6100 mm column, H.sub.2OCH.sub.3CN, 35:65, UV detection at 254 nm). HRMS: Calculated for C.sub.24H.sub.23NOF (M+H): 360.1764. Found: 360.1758 (M+H).
Example 4
Repeated Systemic Treatment with Different Novel Compounds with Agonist Activity at CB1 Receptors Reversibly Attenuates Symptoms of Mechanical Allodynia in a Rat Model of Neuropathic Pain
(173) The effectiveness of CBR agonists was tested for alleviating the painful symptoms of neuropathy induced by unilateral sciatic nerve entrapment (SNE).sup.131. The peripheral neuropathy induced by SNE is highly comparative to that of chronic constriction injury (CCI), which uses chromic gut suture materials instead of polyethylene cuffs.sup.132. SNE was demonstrated to produce consistent pain behaviors.sup.131, 133, a bona fide transient loss of varicosities in nociceptive fibers.sup.134, and increases in evoked excitability of sciatic nerve compound action potentials.sup.135. This increased excitability is at least in part attributable to injury-induced post-transcriptional transport of the voltage-gated sodium channel 1.8 (NaV1.8) mRNA, axonal accumulation of NaV1.8 mRNA, and its local protein translation leading to the increased NaV1.8 functional expression in injured nerve.sup.136. The hyperexcitability and ectopic burst discharge of primary sensory neurons are widely considered to be the major contributors to pain symptomatology of peripheral neuropathy models. The SNE-induced mechanical allodynia effectively models the most common complaint of human neuropathy patients of dynamic mechanical allodynia. Behavioral measurements of mechanical sensitivity were conducted before and after induction of SNE as follows:
(174) Mechanical Sensitivity Testing.
(175) Rats are placed in a plastic-walled cage (102013 cm) with a metal mesh floor (0.60.6 cm holes) and allowed to acclimate for 10 min. The amount of pressure (g) needed to evoke a hindpaw withdrawal response is measured 4 times on each paw separated by 30-s intervals using a von Frey-type digital meter (Model 1601C, IITC Instr.). Results of 4 tests/session are averaged for each paw.
(176)
(177) In the same group of rats we also tested several other novel CB1R ligands (at 3 day intervals) for effectiveness against symptoms of mechanical allodynia.
Example 5
At Systemic Doses that Relieve Neuropathy Symptoms CBR Agonists Show a Complete Lack of Side Effects in the Assays that Test for CNS-Mediated Side Effects of Catalepsy, Hypothermia and Motor Incoordination
(178) The CNS-mediated psychotropic actions of CB1R ligands represent their most troubling side effects. The cannabinoid agonists such as 9-THC or anandamide produce a complex pattern of behavioral effects which are unique to this class of compounds: at low doses a mixture of stimulatory and depressant effects is observed, while at higher doses central depression predominates.sup.137,138. The tetrad of tests which is classically predictive of cannabinoid receptor activation includes: catalepsy, motor performance, hypothermia, and analgesia tests.sup.139-141. Effects observed in all four tests have been thought to be mediated by the activation of central CBRs, but it is now well established that peripheral CBRs make a major contribution to the analgesic effects of cannabinoids.sup.142-144. The catalepsy and motor deficits induced by CB1R ligands are likely produced by their action on CB1Rs within the basal ganglia and cerebellum, while hypothermia is thought to be mediated mainly through hypothalamic and brainstem CB1Rs.sup.137, 145-150. If the novel analgesic compounds possess activity consistent with activation of central CB1Rs this could limit their usefulness as clinical analgesics. Therefore, tetrad tests were used to determine whether the novel CB1R ligands have antinociceptive effects and side-effect profile consistent with the activation of central CB1Rs. We first studied the potent CB1R agonist, HU-210, to determine its CNS actions in order to allow comparisons of this positive control with the putatively brain-impermeant analogs which we developed. The experiments were performed using the classic tetrad tests modified for rats, with rotarod substituting for the spontaneous activity test as follows:
(179) Tail-Flick Test.
(180) A modified Hargreaves apparatus (Model 390, IITC Instr.) is used to measure tail-flick latency (TFL). Radiant heat is directed to a point 3 cm from the tail tip and the TFL observed and timed with a photo cell counter. The intensity of the radiant heat is adjusted for a baseline TFL of approximately 5-7 seconds for nave rats, with a 25 s cutoff set to avoid tissue damage (see
(181) Rotarod.
(182) Rats were tested for motor function and the ataxic effects of novel drugs as described previously.sup.151-153. To determine drug effects on motor coordination, rats are trained 72 h before the test (3 sessions 24 h apart) to remain for at least 180 s on a rotarod revolving at an acceleration of 4-40 revs over 5 min). Rats are tested immediately before vehicle or drug injections and tested again at 2, 6, 24 and 48 hrs after injection. The time for which the rats are able to remain on the rotarod is recorded up to a cut-off of 5 min.
(183) Hypothermia.
(184) Rats are acclimated to a plastic restrainer apparatus (Model RTV-180 Braintree Scientific Inc.) on the day of testing by placing them in the restrainer twice for 5 min separated by 20 min. Baseline core temperature is taken before treatment, and the rectal temperature is measured again at various times after injection of the CB1R ligands.
(185) Catalepsy (ring) test. Catalepsy was determined with a ring immobility test.sup.154, modified for rats.sup.139, 153. Rats are placed with their forepaws on a horizontal metal ring (12 cm diameter) at a height that allows their hindpaws to just touch the bench surface. Immobility is recorded as the time for the rat to move off the ring with a 100 s cutoff. Rats are tested before vehicle/drug injections and again at various times after injection.
(186) We used systemic doses of HU-210 consistent with its demonstrated effectiveness in alleviating painful neuropathy symptoms after peripheral or systemic injection (
(187)
(188) These data show the potent CNS side effects of the brain-permeant cannabinoid HU-210 in the tetrad assays at doses which are effective in relieving painful symptoms of peripheral neuropathy.
(189) The activity of CBR ligands were tested in the tetrad assays using the 0.3 mg/kg doses which were effective in reversibly attenuating mechanical allodynia symptoms of peripheral neuropathy (see
(190)
(191)
Example 6
Repeated Treatment with CB1 Receptor Agonists Reversibly Attenuates Symptoms of Mechanical Allodynia in a Rat Model of Chronic Inflammatory Pain
(192) Compounds were tested in a well-established model of chronic inflammation. In this model, unilateral intraplantar injection of complete Freund's adjuvant (CFA) leads to long-lasting symptoms of mechanical allodynia and thermal hyperalgesia of the affected hindpaw, which is alleviated by local, but not systemic administration of CB1R ligands.sup.125, 155. We show that even after systemic injection of our novel CB1R ligands, there is a small but significant relief of mechanical allodynia symptoms (
(193) Based on the above data, peripherally-acting CBR agonists will be particularly useful in alleviating chronic pain of inflammatory and neuropathic origin. Peripherally-acting CB1R-selective analgesics are unlikely to replace non-steroidal anti-inflammatory analgesics (NSAIAs) and opioids as the mainstay treatment for acute or post-operative pain. Indeed, several studies demonstrated the relatively poor response of cannabinoids in post-operative pain relief.sup.156,157. However, CB1R-selective analgesics may be a panacea for the treatment of various types of chronic pain in situations where NSAIAs or opioids may be contraindicated. For example, patients with G-I ulcers treated with CB1R agonists could benefit from the demonstrated anti-ulcer effects of cannabinoids.sup.158. Similarly, asthmatic patients in need of pain relief could benefit from the bronchodilator properties of cannabinoids.sup.159, which are not dependent on prostaglandins.sup.160.
Example 7
Anti-Allodynic Effects of PrNMI in the SNE Neuropathy are Mediated by CB1Rs
(194) The PRCBRLs shown in Table 1 had similar affinities for the CB1Rs and CB2Rs (Table 1). Therefore, it was important to determine which receptor subtype was responsible for the anti-allodynic effects of our the CBR ligands in the SNE neuropathy. To that end, the ability of a representative ligand, 13339-145-35 (PrNMI) to suppress mechanical allodynia in SNE rats in the presence of either CB1R or CB2R selective antagonists was measured. PrNMI was administered alone or after pretreatment with CBR blockers at 3 day intervals in SNE rats. Pretreatment with a CB2R selective inverse agonist, SR144528 had little effect on suppression of allodynia by PrNMI, whereas pretreatment with a CB1R inverse agonist, SR141617A (rimonabant), completely blocked the anti-allodynic effect of PrNMI (
Example 8
Pharmacokinetic Profiling
(195) Pharmacokinetic profiling of novel compounds is prerequisite to their clinical development. Analysis of plasma samples after PrNMI injections provided initial pharmacokinetic profile data (
(196) Measurements of brain levels are a must for putative peripherally-restricted analogs. Total brain levels include drug partitioned into brain lipids+unbound drug in equilibrium with extracellular fluid. Therefore, cerebrospinal fluid (CSF)/plasma ratios are considered to be more precise estimates of brain penetration of a given drug because of the continuity of CSF with extracellular space.sup.174. However, both measures are needed to confirm minimal CNS access and to compare with other reported peripherally-restricted CB1R ligands.sup.110, 111. Analysis of plasma, brain and cerebrospinal fluid (CSF) samples confirmed the minimal penetration of PrNMI into the CNS after systemic administration (Table 2). Plasma, brain and CSF samples were obtained at 75 min after PrNMI administration. Data presented as meanSEM, n=3 rats.
(197) TABLE-US-00001 TABLE 2 Drug CSF: Plasma Brain: Plasma PrNMI 0.001 0.0005 0.182 0.043 (0.3 mg/kg, i.p.)
Example 9
Reversible Suppression of Neuropathy Symptoms by Orally Administered PrNMI
(198) In other experiments we demonstrated that PrNMI was also effective in suppressing neuropathy symptoms after oral administration. The high oral dose of PrNMI (3 mg/kg) likely accounted for its potent anti-allodynic effects at the 24 hr time point.
Example 10
(199) In another set of rats, we showed that after systemic injection of 13339-135-35 (MoNMI, Compound 10 in Table 1), there was a relatively small effect on mechanical allodynia and robust relief of heat hyperalgesia symptoms (
(200) Thermal Sensitivity.
(201) The Hargreaves method was used to assess paw-withdrawal latency to a thermal nociceptive stimulus.sup.175. Rats were acclimated (10 min) within Plexiglas enclosures (102020 cm) on a clear glass plate preheated to 30 C. A radiant heat source (adjustable infrared lamp) and a timer were used to measure paw withdrawal latency (Model 390, IITC Instruments). Each paw was tested 4 times at 30% maximal intensity allowing 5 min between each test. This intensity setting resulted in a baseline withdrawal of 8-10 s. Results of 4 tests were averaged for each paw for that session.
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(203) TABLE-US-00002 TABLE 1 Ca Flux IUPAC % # Structure Name CB1_KI_CP CB2_KI_CP MDCK_BA Ca_Flux Emax 1
(204) TABLE-US-00003 TABLE 2 S9% Plasma % remaining @ remaining @ # Structure IUPAC Name xy min xy min 11
(205) TABLE-US-00004 TABLE 3 SNE Neuropath Catalepsy % Hypo- Rotarod Assay-% change thermia % return from % change to pre-drug (0.3 pre- change from from pre- mg/kg) drug (0.3 predrug drug (0.3 contralateal mg/kg) (0.3 mg/kg) mg/kg) # Structure IUPAC Name threshold at 2-3 h at 1-3 hrs at 2-3 hr at 2-3 hr 9
(206) While the invention has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.