WO2000075110A1 - Pharmaceutical compositions and methods for use - Google Patents
Pharmaceutical compositions and methods for use Download PDFInfo
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- WO2000075110A1 WO2000075110A1 PCT/US2000/015560 US0015560W WO0075110A1 WO 2000075110 A1 WO2000075110 A1 WO 2000075110A1 US 0015560 W US0015560 W US 0015560W WO 0075110 A1 WO0075110 A1 WO 0075110A1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/63—One oxygen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Definitions
- the present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds that are capable of affecting nicotinic cholinergic receptors. More particularly, the present invention relates to compounds capable of activating nicotinic cholinergic receptors, for example, as agonists of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.
- Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J.
- CNS Central Nervous System
- CNS disorders are a type of neurological disorder.
- CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
- CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
- CNS disorders There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
- CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency.
- CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
- CNS diseases e.g., CNS diseases
- a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors, such as those which have the potential to affect the functioning of the CNS, but which compound when employed in an amount sufficient to affect the functioning of the CNS, does not significantly affect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle and ganglia sites).
- the present invention relates to aryl substituted amine compounds, and most preferably to aryl substituted olefinic amine compounds.
- Representative preferred compounds of the present invention include (3E)-N- methyl-4-[3-(5-nitro-6-aminopyridin)yl]-3-buten-1-amine, (3E)-N-methyl-4-[3- (5-(N-benzylcarboxamido)pyridin)yl]-3-buten-1 -amine, (4E)-N-methyl-5-[5-(2- aminopyrimidin)yl]-4-penten-2-amine, (4E)-N-methyl-5-(3-(5-aminopyridin)yl)- 4-penten-2-amine, (2S)-(4E)-N-methyl-5-[3-(5-isopropoxy-1-oxopyridin)yl)]-4- penten-2-amine, (3E)-N-methyl-4-(3-(5-isobutoxypyhdin
- the present invention also relates to methods for synthesizing certain aryl substituted amine compounds, such as the compounds of the present invention.
- certain aryl substituted amine compounds such as the compounds of the present invention.
- isolated enamiomeric compounds i.e., compounds in a substantially pure form, as opposed to racemic mixtures
- methods for synthesizing such enaniomeric compounds in substantially pure form are also relates to prodrug derivatives of compounds of the present invention.
- the present invention also relates to methods for the prevention or treatment of a wide variety of conditions or disorders, and particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release.
- the present invention also relates to methods for the prevention or treatment of disorders, such as central nervous system (CNS) disorders, which are characterized by an alteration in normal neurotransmitter release.
- CNS central nervous system
- the present invention also relates to methods for the treatment of certain conditions (e.g., a method for alleviating pain). The methods involve administering to a subject an effective amount of a compound of the present invention.
- the present invention in another aspect, relates to a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of a compound of the present invention.
- a pharmaceutical composition incorporates a compound which, when employed in effective amounts, has the capability of interacting with relevant nicotinic receptor sites of a subject, and hence has the capability of acting as a therapeutic agent in the prevention or treatment of a wide variety of conditions and disorders, particularly those disorders characterized by an alteration in normal neurotransmitter release.
- Preferred pharmaceutical compositions comprise compounds of the present invention.
- compositions of the present invention are useful for the prevention and treatment of disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release.
- the pharmaceutical compositions provide therapeutic benefit to individuals suffering from such disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions, when employed in effective amounts, have the potential to (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases.
- the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts do not cause appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, significant negative effects upon the gastrointestinal tract, and significant effects upon skeletal muscle).
- the pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of a wide variety of conditions and disorders.
- the compounds of the present invention include compounds of the formula:
- each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen (e.g., an N-oxide (N-O) functionality) or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1 , and generally greater than 0.2, and even greater than 0.3; less than 0 and generally less than -0.1 ; or 0; as determined in accordance with Hansch et al., Chem. Rev. 91 :165 (1991).
- N-O N-oxide
- X is CH, CBr or COR'.
- X is CH.
- X is nitrogen.
- both X' and X" are nitrogen.
- Y' and Y" each are carbon bonded to a substituent species, and it is preferred that Y' and Y" both are carbon bonded to a substituent species such as hydrogen.
- n is an integer such that the sum of m plus n is 1 , 2, 3, 4, 5 or 6, preferably is 1 , 2, or 3, and most preferably is 2 or 3. It is highly preferred that m is 1 and n is 1.
- those substituent species often has a sigma m value between about -0.3 and about 0.75, frequently between about -0.25 and about 0.6; and each sigma m value individually can be 0 or not equal to zero.
- B' is a substituted or unsubstituted two carbon atom bridging species and can be selected from the following:
- B' can be saturated or unsaturated (e.g., with R' and R") and can be part of a substituted or unsubstituted cycloalkyl ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.).
- Substituents of B' e.g., either R' or R
- the associated substituent species of X or Y" i.e., when each relevant X and Y" are carbon atoms bonded to a substituent species
- can combine to form a ring structure such as a 5 or 6 membered ring structure (e.g., cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl).
- a ring structure such as a 5 or 6 membered ring structure (e.g., cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl).
- the substituent species of carbon atom of the bridging species immediately adjacent of aromatic ring combines with X or Y" to form such a ring.
- substituents of B', at least one of E, E 1 , E" and E 1 ", and the intervening atoms can combine to form monocyclic ring structures (e.g., cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl structurces) or bicyclic ring structures.
- monocyclic ring structures e.g., cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl structurces
- E, E 1 , E" and E 1 " individually represent hydrogen, alkyl (e.g., straight chain or branched alkyl including C- ⁇ -C 8 , preferably C1-C 5 , such as methyl, ethyl, or isopropyl), substituted alkyl, halo substituted alkyl (e.g., straight chain or branched alkyl including C-i-Cs, preferably C 1 -C 5 , such as trifluoromethyl or trichloromethyl), cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; all of E, E 1 , E", E” 1 can be hydrogen, or at least one of E, E 1 , E", E 1 " is non-hydrogen (e.g., alkyl, substituted alkyl, hal
- R' and R" can be straight chain or branched alkyl, or R' and R" and the intervening atoms can combine to form a ring structure (e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or quinuclidinyl).
- Substituent species to the aromatic carbon atoms previously described for X, X', X", Y' and Y", when adjacent, can combine to form one or more saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic rings containing, but not limited to, ether, acetal, ketal, amine, ketone, lactone, lactam, carbamate, or urea functionalities.
- Y' is carbon bonded to hydrogen, and it is preferred that X is C-H.
- E, E 1 and E" are hydrogen.
- n is 1 , m is 1 or 2, E, E 1 and E" each are hydrogen, and E 1 " is alkyl (e.g., methyl). In another preferred embodiment, n is 1 , m is 1 or 2 and E, E 1 , E", E 1 " each are hydrogen. Depending upon the identity and positioning of each individual E, E 1 , E" and E 1 ", certain compounds can be optically active. Additionally, compounds of the present invention can have chiral centers within the side chain (e.g., the compound can have an R or S configuration).
- n, m, E, E 1 , E” and E 1 " is such that up to about 4, and frequently up to 3, and usually 0, 1 or 2, of the substituents designated as E, E 1 , E” and E 1 " are non-hydrogen substituents (i.e., substituents such as alkyl or halo-substituted alkyl).
- alkyl refers to straight chain or branched alkyl radicals including C ⁇ Cs, preferably C 1 -C 5 , such as methyl, ethyl, or isopropyl; "substituted alkyl” refers to alkyl radicals further bearing one or more substituent groups such as hydroxy, alkoxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like; "alkenyl” refers to straight chain or branched hydrocarbon radicals including C-i-Ca, preferably C Cs and having at least one carbon-carbon double bond; “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituent groups as defined above; "cycloalkyl” refers to saturated or unsaturated cyclic ring-containing radicals containing three to eight carbon atoms, preferably three to six carbon atoms; "substituted
- X, X', X", Y', Y", E, E 1 , Z, Z 1 , m and R' are as defined hereinbefore.
- the wavy line in the structure indicates that the compound can have the cis (Z) or trans (E) form, preferably the trans (E) form.
- both R' are hydrogen, or either or both of R' are methyl.
- Z is hydrogen and Z 1 is hydrogen or methyl.
- m is 1 or 2.
- each E is hydrogen, and preferably each E 1 is hydrogen or methyl, but most preferably all of E and E 1 are hydrogen.
- Y" is carbon bonded to a substituent species, and most preferably, that substituent species is hydrogen, halo, NR'R" or OR".
- X is nitrogen or carbon bonded to a substituent species such as NR'R", N0 2 or OR", but most preferably is nitrogen.
- X' is nitrogen, but also preferably is carbon bonded to a substituent species such as hydrogen, R', halo, OR', NR'R", CN, C 2 R' or CHCHR'.
- X is carbon bonded to a substituent species, such as hydrogen.
- Representative compounds of the present invention include (3E)-N- methyl-4-[3-(5-nitro-6-aminopyridin)yl]-3-buten-1-amine, (3E)-N-methyl-4-[3- (5-(N-benzylcarboxamido)pyridin)yl]-3-buten-1-amine, (4E)-N-methyl-5-[5-(2- aminopyrimidin)yl]-4-penten-2-amine, (4E)-N-methyl-5-(3-(5-arninopyridin)yl)- 4-penten-2-amine, (2S)-(4E)-N-methyl-5-[3-(5-isopropoxy-1-oxopyridin)yl)]-4- penten-2-amine, (3E)-N-methyl-4-(3-(5-isobutoxypyridin)yl)-3-buten-1 -amine, (3E)-N-methyl-4-(3-(1-oxopyridin)yl)-3
- the following compounds also are representative compounds of the present invention: 4-(N-methylamino)-1-(3-(5-isopropoxypyridin)yl)-1-pentan- 1-ol, (2R)-(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine, (2S)-(4E)-N- methyl-5-(5-pyrimidinyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, (2S)-(4E)-N-methyl-5-[3-(5- methoxypyridin)yl]-4-penten-2-amine, (4E)-N-methyl-5-[3-(5- cyclopentyloxypyridin)yl]-4-penten-2-amine, (4E)-N-methyl-5-[3-(5- cyclohexyloxypyridin)y
- Yet other representative compounds of the present invention include the following: (1 -methyl-4-(3-pyridyl)but-3-enyl)(3-pyridylmethyl)amine, methyl(1-methyl-4-(2-(prop-2-ynyloxymehtyl)pyrimidin-5yl)but-3-enyl)amine and methyl(1-methyl-4-(2-(2-phenylvinyl)pyrimidin-5-yl)but-3-enyl)amine.
- aryl substituted olefinic amine compounds of the present invention are synthetically produced can vary. Exemplary techniques and procedures for providing compounds of the present invention are set forth in U.S. Patent No. 5,616,716 to Dull et al. and U.S. Patent Application Serial No. 09/098,285, filed June 16, 1998, which are incorporated herein by reference in their entirety.
- (E)-metanicotine-type compounds can be prepared using the techniques set forth by L ⁇ ffler et al., Chem. Ber., 42, pp. 3431-3438 (1909) and Laforge, J.A.C.S., 50, p. 2477 (1928) from substituted nicotine-type compounds.
- Certain 6-substituted metanicotine-type compounds can be prepared from the corresponding 6-substituted nicotine-type compounds using the general methods of Acheson et al., J. Chem. Soc, Perkin Trans. 1, 2, pp. 579-585 (1980).
- 6- substituted nicotine-type compounds can be synthesized from 6-substituted nicotinic acid esters using the general methods disclosed by Rondahl, Ada Pharm. Suec, 14, pp 113-118 (1977).
- Preparation of certain 5-substituted metanicotine-type compounds can be accomplished from the corresponding 5-substituted nicotine-type compounds using the general method taught by Acheson et al., J. Chem. Soc, Perkin Trans. 1, 2, pp. 579-585 (1980).
- the 5-halo-substituted nicotine-type compounds e.g., fluoro- and bromo- substituted nicotine-type compounds
- the 5-amino nicotine-type compounds can be prepared using the general procedures disclosed by Rondahl, Act. Pharm. Suec, 14, pp. 113-118 (1977).
- the 5-trifluoromethyl nicotine-type compounds can be prepared using the techniques and materials set forth in Ashimori et al., Chem. Pharm. Bull., 38(9), pp. 2446- 2458 (1990) and Rondahl, Ada Pharm. Suec, 14, pp.113-118 (1977).
- preparation of certain metanicotine-type compounds can be accomplished using a palladium catalyzed coupling reaction of an aromatic halide and a terminal olefin containing a protected amine substituent, removal of the protective group to obtain a primary amine, and optional alkylation to provide a secondary or tertiary amine.
- certain metanicotine-type compounds can be prepared by subjecting a 3-halo-substituted, 5-substituted pyridine compound or a 5-halo-substituted pyrimidine compound to a palladium catalyzed coupling reaction using an olefin possessing a protected amine functionality (e.g., such an olefin provided by the reaction of a phthalimide salt with 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or 6-halo-1-hexene).
- an olefin possessing a protected amine functionality e.g., such an olefin provided by the reaction of a phthalimide salt with 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or 6-halo-1-hexene.
- metanicotine-type compounds can be prepared by coupling an N-protected, modified amino acid residue, such as 4-(N-methyl-N- tert-butyloxycarbonyl)aminobutyric acid methyl ester, with an aryl lithium compound, as can be derived from a suitable aryl halide and butyl lithium.
- an aryl lithium compound as can be derived from a suitable aryl halide and butyl lithium.
- the resulting N-protected aryl ketone is then chemically reduced to the corresponding alcohol, converted to the alkyl halide, and subsequently dehydrohalogenated to introduce the olefin functionality. Removal of the N- protecting group then affords the desired metanicotine-type compound.
- (Z)-metanicotine-type compounds can be synthesized from nicotine-type compounds as a mixture of E and Z isomers; and the (Z)-metanicotine-type compounds can then be separated by chromatography using the types of techniques disclosed by Sprouse et al., Abstracts of Papers, p. 32, Coresta TCRC Joint Conference (1972).
- metanicotine-type compounds can be prepared by the controlled hydrogenation of the corresponding acetylenic compound (e.g., an N-methyl-4-(3-pyridinyl)-3-butyn-1 -amine type compound).
- certain 5-substituted (Z)-metanicotine-type compounds and certain 6-substituted (Z)-metanicotine-type compounds can be prepared from 5- substituted-3-pyridinecarboxaldehydes and 6-substituted-3- pyridinecarboxaldehydes, respectively.
- Representative synthetic techniques for (Z)-metanicotine-type compounds are set forth in U.S. Patent No. 5,597,919 to Dull et al. the disclosure of which is incorporated by reference in its entirety.
- the (Z)-olefinic isomers of aryl substituted olefinic amine compounds can be synthetically produced.
- the (Z)-isomers of aryl substituted olefinic amine compounds can be prepared by the controlled hydrogenation of the corresponding alkynyl compounds (e.g., a N-methyl-5-(3-pyridyl)-4-butyn-2-amine-type compound) using commercially available Lindlar catalyst (Aldrich Chemical Company) using the methodology set forth in H. Lindlar et al., Org. Syn. 46: 89 (1966).
- the requisite alkynyl compounds can be prepared by the palladium catalyzed coupling of an aromatic halide, preferably a 3-bromopyridine-type or a 3- iodopyridine-type compound with an alkynyl side chain compound (e.g., an N- methyl-4-pentyn-2-amine-type compound).
- an aromatic halide preferably a 3-bromopyridine-type or a 3- iodopyridine-type compound
- an alkynyl side chain compound e.g., an N- methyl-4-pentyn-2-amine-type compound.
- an alkynyl side chain compound e.g., an N- methyl-4-pentyn-2-amine-type compound.
- an alkynyl side chain compound e.g., an N- methyl-4-pentyn-2-amine-type compound.
- Alkynyl compounds such as N-methyl-4-pentyn-2-amine can be prepared from commercially available 4-pentyn-2-ol (Aldrich Chemical Company) by treatment with p-toluenesulfonyl chloride in pyridine, followed by reaction of the resulting 4-pentyn-2-ol p-toluenesulfonate with excess methylamine either as a 40% aqueous solution or as a 2.0 M solution in tetrahydrofuran.
- it may be necessary to protect the amino functionality of the N- methyl-4-pentyn-2-amine-type compound by treatment with di-tert-butyl dicarbonate to give the tert-butoxycarbonyl protected amine-type compound.
- Such protected amine compounds may undergo the palladium catalyzed coupling with aryl halides and the subsequent controlled hydrogenation of the resulting alkynyl compound more easily than the unprotected amine compounds.
- the tert-butoxycarbonyl protecting group can be easily removed using a strong acid such as trifluoroacetic acid to yield the (Z)-olefinic isomers of aryl substituted olefinic amine compounds.
- aryl substituted olefinic amine compounds of the present invention can be synthetically produced can vary.
- An olefinic alcohol such as 4-penten-2-ol
- an aromatic halide such as 3-bromopyridine or 3-iodopyridine.
- an aromatic halide such as 3-bromopyridine or 3-iodopyridine.
- the types of procedures set forth in Frank et al., J. Org. Chem., 43, pp. 2947-2949 (1978) and Malek et al., J. Org. Chem., 47, pp. 5395-5397 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used.
- the olefinic alcohol optionally can be protected as a t-butyldimethylsilyl ether prior to the coupling. Desilylation then produces the olefinic alcohol.
- the alcohol condensation product then is converted to an amine using the type of procedures set forth in deCosta et al., J. Org. Chem., 35, pp. 4334-4343 (1992).
- the alcohol condensation product is converted to the aryl substituted olefinic amine by activation of the alcohol using methanesulfonyl chloride or p- toluenesulfonyl chloride, followed by mesylate or tosylate displacement using ammonia, or a primary or secondary amine.
- an aryl substituted olefinic primary amine compound is provided; when the amine is a primary amine such as methylamine or cyclobutylamine, an aryl substituted olefinic secondary amine compound is provided; and when the amine is a secondary amine such as dimethylamine or pyrrolidine, an aryl substituted olefinic tertiary amine compound is provided.
- olefinic alcohols include 4-penten-1-ol, 5-hexen-2-ol, 5-hexen-3-ol, 3-methyl- 3-buten-1-ol, 2-methyl-3-buten-1-ol, 4-methyl-4-penten-1-ol, 4-methyl-4- penten-2-ol, 1-octen-4-ol, 5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol, 5- methyl-5-hexen-2-ol, 5-hexen-2-ol and 5-methyl-5-hexen-3-ol.
- Trifluormethyl- substituted olefinic alcohols such as 1 ,1 ,1-trifluoro-4-penten-2-ol
- 1 ,1 ,1-trifluoro-4-penten-2-ol can be prepared from 1-ethoxy-2,2,2-thfluoro-ethanol and allyltrimethylsilane using the procedures of Kubota et al., Tetrahedron Letters, Vol. 33(10), pp. 1351- 1354 (1992), or from trifluoroacetic acid ethyl ester and allyltributylstannane using the procedures of Ishihara et al., Tetrahedron Letters, Vol. 34(56), pp. 5777-5780 (1993).
- Certain olefinic alcohols are optically active, and can be used as enantiomeric mixtures or as pure enantiomers in order to provide the corresponding optically active forms of aryl substituted olefinic amine compounds.
- an olefinic allylic alcohol such as methallyl alcohol
- an aromatic halide an aryl substituted olefinic aldehyde is produced; and the resulting aldehyde can be converted to an aryl substituted olefinic amine compound by reductive amination (e.g., by treatment using an alkyl amine and sodium cyanoborohydride).
- Preferred aromatic halides are 3- bromopyridine-type compounds and 3-iodopyridine-type compounds.
- substituent groups of such 3-halopyridine-type compounds are such that those groups can survive contact with those chemicals (e.g., tosylchloride and methylamine) and the reaction conditions experienced during the preparation of the aryl substituted olefinic amine compound.
- substituents such as -OH, -NH 2 and -SH can be protected as corresponding acyl compounds, or substituents such as -NH 2 can be protected as a phthalimide functionality.
- sequential palladium-catalyzed (Heck-type) couplings to two different olefinic side chains are possible.
- N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine can be synthesized as follows: (i) Commercially available 4-penten-2-ol (Aldrich Chemical Company, Lancaster Synthesis Inc.) can be treated with p-toluenesulfonyl chloride in pyridine to yield 4-penten-2-ol p-toluenesulfonate, previously described by T. Michel, et al., Liebigs Ann. 11: 1811 (1996). (ii) The resulting tosylate can be heated with 20 molar equivalents of methylamine as a 40% aqueous solution to yield N- methyl-4-penten-2-amine.
- the resulting amine such as previously mentioned by A. Viola et al., J. Chem. Soc, Chem. Commun. (21): 1429 (1984), can be allowed to react with 1.2 molar equivalents of di-tert-butyl dicarbonate in dry tetrahydrofuran to yield the side chain, N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine.
- the halo-substituted pyridine (e.g., 5- bromo-3-isopropoxypyridine) can be synthesized by two different routes.
- 5-bromo-3-isopropoxypyridine is heated at 140°C for 14 hours with 2 molar equivalents of potassium isopropoxide in dry isopropanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube to yield 5-bromo-3-isopropoxypyridine.
- a second preparation of 5- bromo-3-isopropoxypyridine from 5-bromonicotinic acid can be performed as follows: (i) 5-Bromonicotinic acid is converted to 5-bromonicotinamide by treatment with thionyl chloride, followed by reaction of the intermediate acid chloride with aqueous ammonia, (ii) The resulting 5-bromonicotinamide, previously described by C. V.
- the resulting 3- amino-5-bromopyridine previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761 (1970), can be converted to 5-bromo-3- isopropoxypyridine by diazotization with isoamyl nitrite under acidic conditions, followed by treatment of the intermediate diazonium salt with isopropanol to yield 5-bromo-3-isopropoxypyridine.
- the palladium-catalyzed coupling of 5-bromo-3-isopropoxypyridine and N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine is carried out in acetonitrile-triethylamine (2:1 , v,v) using a catalyst consisting of 1 mole % palladium(ll) acetate and 4 mole % tri-o-tolylphosphine.
- the reaction can be carried out by heating the components at 80°C for 20 hours to yield (4E)-N-methyl-N-(tert- butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.
- Removal of the tert-butoxycarbonyl protecting group can be accomplished by treatment with 30 molar equivalents of trifluoroacetic acid in anisole at 0°C to afford (4E)-N- methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.
- (4E)-N- methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine is available from 3,5- dibromopyridine using this type of technology (i.e., treatment with sodium or potassium alkoxides or aryloxides and subsequent Heck coupling and deprotection).
- aryl substituted olefinic amine compounds possessing a branched side chain can vary.
- a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4- penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5- bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine.
- the resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0°C to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p- toluensulfonate.
- the tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3- pyridyl)-4-penten-2-amine.
- optically active forms of certain aryl substituted olefinic amine compounds such as (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten- 2-amine, are provided can vary.
- the latter type of compound is synthesized by coupling a halo-substituted pyridine, 3- bromopyridine, with an olefin possessing a chiral, secondary alcohol functionality, (2R)-4-penten-2-ol, under Heck reaction conditions.
- the chiral side chain, (2R)-4-penten- 2-ol can be prepared by treatment of the chiral epoxide, (R)-(+)-propylene oxide (commercially available from Fluka Chemical Company) with vinylmagnesium bromide in tetrahydrofuran at low temperatures (-25 to -10°C) using the general synthetic methodology of A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991), to afford (2R)-4-penten-2-ol.
- the resulting chiral alcohol is subjected to a Heck reaction with 3-bromopyridine in acetonitrile-triethylamine (1 :1 , v/v) using a catalyst consisting of 1 mole % palladium(ll) acetate and 4 mole % tri-o-tolylphosphine.
- the reaction is done by heating the components at 140°C for 14 hours in a sealed glass tube, to produce the Heck reaction product, (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol.
- the resulting chiral pyridyl alcohol is treated with 3 molar equivalents of p- toluenesulfonyl chloride in dry pyridine at 0°C, to afford the tosylate intermediate.
- the p-toluenesulfonate ester is heated with 82 molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent, to produce (2S)-(4E)-N-methyl-5-(3- pyridyl)-4-penten-2-amine.
- the corresponding aryl substituted olefinic amine enantiomer such as (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine
- (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine can be synthesized by the Heck coupling of 3-bromopyridine and (2S)-4-penten-2- ol.
- the resulting intermediate, (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol is converted to its p-toluenesulfonate, which is subjected to methylamine displacement.
- the chiral alcohol, (2S)-4-penten-2-ol is prepared from (S)-(-)- propylene oxide (commercially available from Aldrich Chemical Company) using a procedure analogous to that described for the preparation of (2R)-4- penten-2-ol from (R)-(+)-propylene oxide as reported by A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).
- such compounds as (3E)-N-methyl-4-(3-(6-aminopyridin)yl)-3-buten-1 -amine can be prepared by subjecting a 3-halo-substituted pyridine such as 2-amino-5- bromopyridine (Aldrich Chemical Company) to a palladium-catalyzed coupling reaction with an olefin possessing a protected amine functionality, such as N- methyl-N-(3-buten-1-yl)benzamide.
- a 3-halo-substituted pyridine such as 2-amino-5- bromopyridine (Aldrich Chemical Company)
- an olefin possessing a protected amine functionality such as N- methyl-N-(3-buten-1-yl)benzamide.
- Compounds of the present invention may contain an azacyclic functionality, such as pyrrolidine or quinuclidine.
- the methods of synthesis of such compounds may vary.
- the Heck reaction can be used for the coupling a vinyl-substituted or allyl-substituted nitrogen heterocycle to a 3-halopyridine.
- N-(tert-butoxycarbonyl)-2-allylpyrrolidine and 3-bromopyridine Aldrich Chemical Company
- W. C. Frank et al. J. Org. Chem. AZ: 2947 (1978)
- 2-allylquinuclidine can be coupled with 3-bromopyridine, under Heck conditions, to give 2-(3-(3-pyridyl)-(2E)-propen-1-yl)quinuclidine.
- the required 2-allylquinuclidine can be prepared from 3-quinuclidinone (Aldrich Chemical Company) by alkylation and deoxygenation.
- 3- quinuclidinone can be converted into its isopropylimine with isopropylamine and molecular sieves.
- Treatment of the imine with lithium diisopropylamide and allyl bromide, followed by hydrolysis gives 2-allyl-3-quinuclidinone.
- Deoxygenation by conversion of the ketone into its p- toluenesulfonylhydrazone and reduction with sodium borohydride, gives 2- allylquinuclidine.
- Compounds of the present invention may contain a pyrazine or pyridazine ring.
- 2-methylpyrazine or 3- methylpyridazine can be condensed with N-methyl-N-(tert-butoxycarbonyl)-3-aminobutanal to give (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(2-pyrazinyl)-4-penten-2-amine and (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-pyridazinyl)-4-penten-2-amine respectively.
- the alcohol N-methyl- N-(tert-butoxycarbonyl)-3-amino-1-butanol, can be made from commercially available 4-hydroxy-2-butanone (Lancaster Synthesis, Inc.) by sequential reductive amination (with methylamine and sodium cyanoborohydride, using chemistry reported by R. F. Borch in Org. Syn.52, 124 (1974)) and protection with di-tert-butyl dicarbonate.
- bromo-imidazopyridine, 6-bromo-2-methyl-1 H- imidazo[4,5-b]pyridine can be prepared in 82% yield by heating 2,3-diamino- 5-bromopyridine with acetic acid in polyphosphoric acid according to the methods described by P. K. Dubey et al., Indian J. Chem. 16B(6):531-533 (1978).
- 2,3-Diamino-5-bromopyridine can be prepared in 97% yield by heating 2-amino-5-bromo-3-nitropyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) with tin(ll) chloride dihydrate in boiling ethanol according to the techniques described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997).
- a bromo fused-ring heterocycle such as 6-bromo- 1 ,3-dioxolo[4,5-b]pyridine can be coupled with the previously mentioned olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine using the Heck reaction.
- the resulting Boc-protected intermediate can be deprotected with a strong acid such as trifluoroacetic acid to produce (4E)-N- methyl-5-(6-(1 ,3-dioxolo[4,5-b]pyridin)yl)-4-penten-2-amine.
- the requisite bromo compound, 6-bromo-1 ,3-dioxolo[4,5-b]pyridine can be synthesized from 5-bromo-2,3-dihydroxypyridine, also known as 5-bromo-3-hydroxy- 2(1 H)-pyridinone, via a methylenation procedure using bromochloromethane, in the presence of potassium carbonate and N,N-dimethylformamide according to the methodology of F. Dallacker et al., Z. Naturforsch. 34 b:1729- 1736 (1979).
- 5-Bromo-2,3-dihydroxypyridine can be prepared from furfural (2-furaldehyde, commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) using the methods described in F. Dallacker et al., Z. Naturforsch. 34 b: 1729-1736 (1979).
- 5-bromo-2,3- dihydroxypyridine can be prepared according to the techniques described in EP 0081745 to D. Rose and N. Maak.
- the bromo compound, 7-bromo-2,3-dihydro-1 ,4-dioxino[2,3- bjpyridine (also known as 7-bromo-5-aza-4-oxachromane) can be condensed with the previously mentioned olefinic amine side chain, N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine using the Heck reaction.
- the resulting Boc-protected compound can be deprotected with strong acid such as trifluoroacetic acid to produce (4E)-N-methyl-5-(7-(2,3-dihydro-1 ,4-dioxino[2,3- b]pyridin)yl-4-penten-2-amine.
- the required bromo compound, 7-bromo-2,3- dihydro-1 ,4-dioxino[2,3-b]pyridine can be prepared by treating 5-bromo-2,3- dihydroxypyridine with 1 ,2-dibromoethane and potassium carbonate in N,N- dimethylformamide according to the methodology of F. Dallacker et al., Z. Naturforsch. 34 b: 1729-1736 (1979).
- 5-Bromo-2,3-dihydroxypyridine can be prepared from furfural as described above.
- polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction.
- certain compounds can be synthesized by the palladium-catalyzed coupling of a bromo fused-ring heterocycle, such as 6-bromo-1 H-imidazo[4,5-b]pyridine-2-thiol with the previously mentioned olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine.
- the Boc-protected intermediate, resulting from the Heck reaction, can be subjected to treatment with a strong acid, such as trifluoroacetic acid to produce (4E)-N-methyl-5-(6-(2-thio-1 H-imidazo[4,5-b]pyridin)yl)-4-penten-2- amine.
- a strong acid such as trifluoroacetic acid
- the requisite bromo compound, 6-bromo-1 H-imidazo[4,5-b]pyridine- 2-thiol can be prepared by treating 6-bromo-1 H-imidazo[4,5-b]pyridine with sulfur at 230-260°C according to the methods described in Y. M. Yutilov, Khim. Geterotsikl Doedin. 6: 799-804 (1988).
- 6-Bromo-1 H-imidazo[4,5- bjpyridine can be obtained from Sigma-Aldrich Chemical Company.
- 6-bromo-1 H-imidazo[4,5-b]pyridine can be prepared by treating 2,3-diamino-5-bromopyridine with formic acid in polyphosphoric acid using methodology similar to that described by P. K. Dubey et al., Indian J. Chem. 16B(6):531-533 (1978).
- 2,3-Diamino-5-bromopyridine can be prepared in 97% yield by heating 2-amino-5-bromo-3-nitropyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc) with tin(ll) chloride dihydrate in boiling ethanol according to the techniques described by S. X. Cai et al., J. Med. Chem., 40(22): 3679-3686 (1997).
- 6-bromo-1 H- imidazo[4,5-b]pyridine-2-thioi can be prepared by heating 2,3-diamino-5- bromopyridine with K + " SCSOEt in aqueous ethanol using methodology similar to that described by T. C. Kuhler et al., J. Med Chem. 38(25): 4906-4916 (1995).
- 2,3-Diamino-5-bromopyridine can be prepared from 2-amino-5-bromo- 3-nitropyridine as described above.
- 6-bromo-2-phenylmethylthio-1 H-imidazo[4,5- bjpyridine can be coupled via Heck reaction with the previously mentioned olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine.
- the resulting Boc-protected intermediate can be subjected to treatment with a strong acid, such as trifluoroacetic acid to produce (4E)-N-methyl-5-(6-(2- phenylmethylthio-1 H-imidazo[4,5-b]pyridin)yl)-4-penten-2-amine.
- the required bromo compound, 6-bromo-2-phenylmethylthio-1 H-imidazo[4,5- bjpyridine can be prepared by alkylating the previously described 6-bromo- 1 H-imidazo[4,5-b]pyridine-2-thiol with benzyl bromide in the presence of potassium carbonate and N,N-dimethylformamide.
- 6-bromooxazolo[4,5-b]pyridine when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine.
- the requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5- bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C.
- 5-Bromooxazolo[5,4-b]pyridine isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine.
- the required 5-bromooxazolo[5,4-b]pyridine is synthesized from 3-amino-5-bromo-2- pyridinol (3-amino-5-bromo-2-pyridone) by the condensation with formic acid (or a derivative thereof) as described above.
- 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41 : 729-741 (1967)) and subsequent tin(l I) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem.
- the requisite 5-bromofuro[2,3-b]pyridine and 5-bromo-1 H- pyrrolo[2,3-b]pyridine can be made from 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine respectively, by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone), using chemistry described by E. C. Taylor et al., Tetrahedron AZ: 5145-5158 (1987).
- 2,3-Dihydrofuro[2,3-b]pyridine and 2,3- dihydropyrrolo[2,3-b]pyridine are, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company), as described by A. E. Frissen et al., Tetrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of 3-butyn-1-ol or with 4-amino-1-butyne) and subsequent intramolecular Diels-Alder reaction.
- 2,3- dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are also produced from 3-methylthio-1 ,2,4-triazene (E. C. Taylor et al., Tetrahedron AZ: 5145-5158 (1987)), which in turn is made from glyoxal and S- methylthiosemicarbazide (W. Paudler et al., J. Heterocyclic Chem. 7: 767-771 (1970)).
- Brominated dihydrofuropyridines, dihydropyrrolopyridines, and dihydropyranopyridines are also substrates for the palladium catalyzed coupling.
- both 5-bromo-2,3-dihydrofuro[2,3-b]pyridine and 5- bromo-2, 3-d ihyd ropy rrolo[2,3-b]pyridine from bromination of 2,3- dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine, as described above
- 6-bromo-2,3- dihydrofuro[3,2-b]pyridine can be made from 5-bromo-2-methyl-3-pyridinol by sequential treatment with two equivalents of lithium diisopropylamide (to generate the 2-methylenyl, 3-oxy dianion) and one equivalent of dibromomethane.
- two equivalents of lithium diisopropylamide to generate the 2-methylenyl, 3-oxy dianion
- dibromomethane Alternatively, using chemistry similar to that described by M. U. Koller et al., Synth. Commun.
- silyl-protected pyridinol (5-bromo-2-methyl-3-trimethylsilyloxypyridine) can be treated sequentially with one equivalent of lithium diisopropylamide and an alkyl or aryl aldehyde to produce a 2-(2-(1 -alkyl- or 1-aryl-1-hydroxy)ethyl)-5-bromo-3- (trimethylsilyloxy)pyridine.
- Such materials can be converted, by methods (such as acid catalyzed cyclization or the Williamson synthesis) known to those skilled in the art, into the corresponding cyclic ethers (2-alkyl- or 2-aryl- 6-bromo-2,3-dihydrofuro[3,2-b]pyridines.
- Similar chemistry in which epoxides (instead of aldehydes) are used in reaction with the pyridylmethyl carbanion, leads to 2-alkyl- and 2-aryl-7-bromo-2,3-dihydropyrano[3,2-b]pyridines.
- These 2-substituted, brominated dihydrofuro- and dihydropyranopyridines are also substrates for the Heck reaction.
- 6-bromo-2,3-dihydro-2- phenylfuro[3,2-b]pyridine can be coupled, in a palladium catalyzed process, with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, and the coupling product treated with trifluoroacetic acid (to remove the tert-butoxycarbonyl group), to give (4E)-N-methyl-5-(6-(2,3-dihydro-2-phenylfuro[3,2-b]pyridin)yl)- 4-penten-2-amine.
- the 5-bromo-2-methyl-3-pyridinol required for the syntheses of the brominated dihydrofuro- and dihydropyranopyridines, is produced by standard transformations of commercially available materials.
- 2-methylnicotinic acid Aldrich Chemical Company
- thionyl chloride, bromine, and ammonia Methodology described by C. V. Greco et al., J. Heterocyclic Chem. 7: 761-766 (1970)
- the aryl substituted olefinic amine compounds of the present invention can be prepared by coupling an N-protected aminoaldehyde, such as 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal with an aryllithium.
- N-protected aminoaldehyde such as 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal
- the required aldehyde can be prepared according to methodology described by Otsuka et al., J. Am Chem. Soc. 112: 838-845 (1990), starting from commercially available 1 ,5-dimethyl-2-pyrrolidinone (Aldrich Chemical Company).
- 3-lithio-5-isopropoxypyridine (from 3-bromo-5- isopropoxypyridine and n-butyllithium) can be condensed with 4-(N-methyl-N- (tert-butoxycarbonyl)amino)pentanal to give 1-(3-(5-isopropoxypyridin)yl)-4- (N-methyl-N-(tert-butoxycarbonyl)amino)-1-pentanol, which can subsequently be converted into (4E)-N-methyl-5-(3-(5-isopropoxypyridin)yl)-4-penten-2- amine.
- the R and S enantiomers of 1 ,5-dimethyl-2-pyrrolidinone can be made from commercially available (R)- and (S)-5-(hydroxymethyl)-2-pyrrolidinone (Aldrich Chemical Company).
- R room temperature
- S hydroxymethyl-2-pyrrolidinone
- reaction of the enantiomerically pure hydroxymethylpyrrolidinone with carbon tetrabromide and triphenylphosphine in acetonitrile gives the corresponding 5-(bromomethyl)-2-pyrrolidinone (Pfaltz et al., Helv. Chim.
- Ada 79: 961 (1996)
- Ada 79: 961 (1996)
- is reduced to the 5- methylpyrrolidinone by tri-n-butyltin hydride in toluene (Otsuka et al., J. Amer. Chem. Soc. 112: 838 (1990)).
- Subsequent methylation using sodium hydride and methyl iodide in tetrahydrofuran gives the enantiomerically pure 1 ,5- dimethyl-2-pyrrolidinone.
- the resulting (S)- or (R)-l-p-toluenesulfonyloxy-N-methyl-N-(tert-butoxycarbonyl)- 2-propanamine can be used to alkylate lithium acetylide to give the corresponding (S)- or (R)-N-methyl-N-(tert-butoxycarbonyl)-4-pentyn-2- amines.
- These, in turn, can be hydroborated and oxidized, by methods described by H. C. Brown et al., J. Amer. Chem. Soc. 97: 5249 (1975), to give (S)- or (R)-4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal.
- Fused ring heterocycles can also be lithiated and condensed with 4-(N- methyl-N-(tert-butoxycarbonyl)amino)pentanal.
- 6-chloro-2- phenylfuro[3,2-b]pyridine can be treated sequentially with n-butyllithium and with 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal to give 1-(6-(2- phenylfuro[3,2-b]pyridin)yl)-4-(N-methyl-N-(tert-butoxycarbonyl)amino)-1- pentanol.
- the 5-chloro-2-iodo-3-pyridinol can be made by iodination of commercially available 5-chloro-3-pyridinol (Aldrich Chemical Company) using methods described by V. Koch et al., Synthesis, 497 (1990).
- the present invention relates to a method for providing prevention of a condition or disorder to a subject susceptible to such a condition or disorder, and for providing treatment to a subject suffering therefrom.
- the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of a CNS disorder (i.e., provide protective effects), amelioration of the symptoms of a CNS disorder, and amelioration of the recurrence of a CNS disorder.
- the method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore.
- the present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore.
- Optically active compounds can be employed as racemic mixtures or as enantiomers.
- the compounds can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts).
- suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt
- the salts may be in some cases hydrates or ethanol solvates.
- Representative salts are provided as described in U.S. Patent Nos. 5,597,919 to Dull et al., 5,616,716 to Dull et al. and 5,663,356 to Ruecroft et al.
- Compounds of the present invention are useful for treating those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest.
- Compounds of the present invention can be used as analgesics, to treat ulcerative colitis, and to treat convulsions such as those that are symptomatic of epilepsy.
- CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
- the pharmaceutical composition also can include various other components as additives or adjuncts.
- exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants, buffering agents, anti-inflammatory agents, anti-pyretics, time release binders, anaesthetics, steroids and corticosteroids.
- Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition.
- a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular disorder.
- the manner in which the compounds are administered can vary.
- the compounds can be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al.); topically (e.g., in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids); intrathecally; intracerebro ventricularly; or transdermally (e.g., using a transdermal patch).
- inhalation e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks
- each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
- exemplary methods for administering such compounds will be apparent to the skilled artisan.
- the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule.
- the compounds can be delivered transdermally using the types of patch technologies available from Novartis and Alza Corporation.
- the administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey); but advantageously is preferably administered to a human being.
- a warm-blooded animal e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
- the time of day and the number of times per day that the pharmaceutical formulation is administered can vary.
- Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that affect the functioning of the CNS.
- administering preferably is such so as to optimize the effect upon those relevant receptor subtypes which have an effect upon the functioning of the CNS, while minimizing the effects upon muscle-type receptor subtypes.
- Other suitable methods for administering the compounds of the present invention are described in U.S. Patent No. 5,604,231 to Smith et al., the disclosure of which is incorporated herein by reference in its entirety.
- an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to activate relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
- an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to activate relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
- Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder. Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the recurrence of the symptoms of the disorder.
- the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
- the effective dose of typical compounds generally requires administering the compound in an amount sufficient to activate relevant receptors to effect neurotransmitter (e.g., dopamine) release but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
- the effective dose of compounds will of course differ from patient to patient but in general includes amounts starting where CNS effects or other desired therapeutic effects occur, but below the amount where muscular effects are observed.
- the effective dose of compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight.
- the compounds of the present invention are administered in an amount from less than about 1 mg/kg patient weight, and usually less than about 100 ug/kg of patient weight, but frequently between about 10 ug to less than 100 ug/kg of patient weight, and preferably between about 10 ug to about 50 ug/kg of patient weight.
- the effective dose is less than 5 mg/kg of patient weight; and often such compounds are administered in an amount from 50 ug to less than 5 mg/kg of patient weight.
- the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hour period.
- the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 ug/ 24 hrJ patient.
- the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 ug/ 24 hrJ patient.
- administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
- the compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient.
- the log P values of typical compounds, which are useful in carrying out the present invention are generally greater than about 0, often are greater than about 0.5, and frequently are greater than about 1.
- the log P values of such typical compounds generally are less than about 3.5, often are less than about 3, and sometimes are less than about 2.5.
- Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).
- the compounds useful according to the method of the present invention have the ability to bind to, and in most circumstances, cause activation of, nicotinic cholinergic receptors of the brain of the patient (e.g., such as those receptors that modulate dopamine release). As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists.
- the receptor binding constants of typical compounds useful in carrying out the present invention generally exceed about 0.1 nM, often exceed about 1 nM, and frequently exceed about 10 nM.
- the receptor binding constants of such typical compounds generally are less than about 1 uM, often are less than about 100 nM, and frequently are less than about 50 nM.
- Receptor binding constants provide a measure of the ability of the compound to bind to half of the relevant receptor sites of certain brain cells of the patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).
- the compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic function by effectively eliciting ion flux through, and/or neurotransmitter secretion from, nerve ending preparations (e.g., thalamic or striatal synaptosomes). As such, such compounds have the ability to cause relevant neurons to become activated, and to release or secrete acetylcholine, dopamine, or other neurotransmitters.
- nerve ending preparations e.g., thalamic or striatal synaptosomes
- typical compounds useful in carrying out the present invention effectively provide for relevant receptor activation in amounts of at least about 30 percent, often at least about 50 percent, and frequently at least about 75 percent, of that maximally provided by (S)-(-)-nicotine.
- typical compounds useful in carrying out the present invention are more potent than (S)-(-)-nicotine in eliciting relevant receptor activation.
- typical compounds useful in carrying out the present invention effectively provide for the secretion of dopamine in amounts of at least about 50 percent, often at least about 75 percent, and frequently at least about 100 percent, of that maximally provided by (S)-(-)-nicotine.
- Certain compounds of the present invention can provide secretion of dopamine in an amount which can exceed that maximally provided by (S)-(-)-nicotine.
- typical compounds useful in carrying out the present invention are less potent than (S)-(-)-nicotine in eliciting neurotransmitter secretion, such as dopamine secretion.
- the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, lack the ability to elicit activation of nicotinic receptors of human muscle to any significant degree.
- the compounds of the present invention demonstrate poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations expressing muscle-type nicotinic acetylcholine receptors.
- receptor activation constants or EC50 values i.e., which provide a measure of the concentration of compound needed to activate half of the relevant receptor sites of the skeletal muscle of a patient
- EC50 values i.e., which provide a measure of the concentration of compound needed to activate half of the relevant receptor sites of the skeletal muscle of a patient
- typical preferred compounds useful in carrying the present invention activate isotopic rubidium ion flux by less than 10 percent, often by less than 5 percent, of that maximally provided by S(-) nicotine.
- the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects.
- a particular dose of compound resulting in prevention and/or treatment of a CNS disorder is essentially ineffective in eliciting activation of certain ganglionic-type nicotinic receptors.
- This selectivity of the compounds of the present invention against those receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue.
- Such compounds have poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from the adrenal gland.
- typical preferred compounds useful in carrying out the present invention activate isotopic rubidium ion flux by less than 10 percent, often by less than 5 percent, of that maximally provided by S(-) nicotine.
- Compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of the progression of CNS disorders, amelioration of the symptoms of CNS disorders, and amelioration to some degree of the recurrence of CNS disorders.
- effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as is demonstrated by decreased effects on preparations believed to reflect effects on the cardiovascular system, or effects to skeletal muscle.
- administration of compounds of the present invention provides a therapeutic window in which treatment of certain CNS disorders is provided, and side effects are avoided.
- an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
- effective administration of a compound of the present invention resulting in treatment of CNS disorders occurs upon administration of less 1/3, frequently less than 1/5, and often less than 1/10, that amount sufficient to cause any side effects to a significant degree. amount sufficient to cause certain side effects to any significant degree.
- the pharmaceutical compositions of the present invention can be employed to prevent or treat certain other conditions, diseases and disorders.
- diseases and disorders include inflammatory bowel disease, acute cholangitis, aphteous stomatitis, arthritis (e.g., rheumatoid arthritis and ostearthritis), neurodegenerative diseases, cachexia secondary to infection (e.g., as occurs in AIDS, AIDS related complex and neoplasia), as well as those indications set forth in PCT WO 98/25619.
- the pharmaceutical compositions of the present invention can be employed in order to ameliorate may of the symptoms associated with those conditions, diseases and disorders.
- compositions of the present invention can be used in treating genetic diseases and disorders, in treating autoimmune disorders such as lupus, as anti-infectious agents (e.g, for treating bacterial, fungal and viral infections, as well as the effects of other types of toxins such as sepsis), as anti-inflammatory agents (e.g., for treating acute cholangitis, aphteous stomatitis, asthma, and ulcerative colitis), and as inhibitors of cytokines release (e.g., as is desirable in the treatment of cachexia, inflammation, neurodegenerative diseases, viral infection, and neoplasia),
- the compounds of the present invention can also be used as adjunct therapy in combination with existing therapies in the management of the aforementioned types of diseases and disorders.
- administration preferably is such that the active ingredients of the pharmaceutical formulation act to optimize effects upon abnormal cytokine production, while minimizing effects upon receptor subtypes such as those that are associated with muscle and ganglia.
- Administration preferably is such that active ingredients interact with regions where cytokine production is affected or occurs.
- compounds of the present invention are very potent (i.e., affect cytokine production and/or secretion at very low concentrations), and are very efficacious (i.e., significantly inhibit cytokine production and/or secretion to a relatively high degree).
- Effective doses for such applications are most preferably at very low concentrations, where maximal effects are observed to occur. Concentrations, determined as the amount of compound per volume of relevant tissue, typically provide a measure of the degree to which that compound affects cytokine production. Typically, the effective dose of compounds generally requires administering the compound in an amount of much less than 100 ug/kg of patient weight, and even less than 10 ug/kg of patient weight. The foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hour period.
- the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 ug / 24 hr. / patient.
- the effective dose of typical compounds requires administering the compound which generally does not exceed about 1 , often does not exceed about 0.75, often does not exceed about 0.5, frequently does not exceed about 0.25 mg / 24 hr. / patient.
- administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 pg/ml, often does not exceed 300 pg/ml, and frequently does not exceed 100 pg/ml.
- compounds of the present invention When employed in such a manner, compounds of the present invention are dose dependent, and as such, cause inhibition of cytokine production and/or secretion when employed at low concentrations but do not exhibit those inhibiting effects at higher concentrations. Compounds of the present invention exhibit inhibitory effects upon cytokine production and/or secretion when employed in amounts less than those amounts necessary to elicit activation of relevant nicotinic receptor subtypes to any significant degree.
- CHCI 3 for chloroform
- CH 2 CI 2 for dichloromethane
- CH 3 OH for methanol
- DMF for N,N- dimethylformamide
- EtOAc for ethyl acetate
- THF for tetrahydrofuran
- Et 3 N for triethylamine
- Binding of the compounds to relevant receptor sites was determined in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al. Inhibition constants (Ki values), reported in nM, were calculated from the IC 50 values using the method of Cheng et al., Biochem, Pharmacol. 22:3099 (1973).
- Neurotransmitter release was measured using techniques similar to those previously published (Bencherif M, et al.:. JPET 279: 1413-1421 , 1996).
- Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% C0 2 . Brains are dissected, and hippocampus, striatum, and thalamus isolated, and homogenized in 0.32 M sucrose containing 5 mM HEPES pH 7.4 using a glass/glass homogenizer. The tissue was then centrifuged for 1000 x g for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000 x g for 20 minutes. The resultant pellet was resuspended in perfusion buffer (128 mM NaCI, 1.2 mM KH2PO4, 2.4 mM KCI,
- E max The maximal activation for individual compounds (E max ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine. Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
- the determination of the interaction of the compounds with ganglionic receptors was carried out in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al.
- the maximal activation for individual compounds (Em ax ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
- Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
- Sample No. 1 is (3E)-N-methyl-4-[3-(5-nitro-6-aminopyridin)yl]-3-buten-1- amine, which was prepared in accordance with the following techniques:
- anhydrous DMF 40 mL
- methylamine 40 mL, 43.2 g, 1.4 mol, condensed from the gas phase
- Anhydrous potassium carbonate (19.36 g, 140 mmol) was added to the stirring solution, followed by 4-bromo-1-butene (18.9 g, 140 mmol).
- the resulting mixture was allowed to slowly warm to room temperature overnight.
- the mixture was poured into water (150 mL) and extracted with ether (8 x 50 mL).
- N-methyl-3-buten-1 -amine (6.86 g, 80.6 mmol) in dichloromethane (100 mL) was cooled to 0°C, and triethylamine (17.93 g, 177.2 mmol) and 4-(N,N-dimethylamino)pyridine (207 mg) were added.
- a solution of benzoyl chloride (11.89 g, 84.6 mmol) in dichloromethane (60 mL) was added drop-wise via addition funnel over 1 h at 0-5°C. The resulting turbid mixture was stirred 3h at 0°C.
- An analytical sample was prepared by the successive recrystallization of 1.28 g of material from the following solvents: benzene-petroleum ether (1 :1 , v/v), benzene, including a Darco ® G-60 charcoal (0.10 g) and Hyflo Super Cel (0.10 g) treatment, and finally benzene (twice).
- the recrystallized product was air dried and further dried in a vacuum oven at 50°C for 5 h to give 0.77 g of an orange powder, mp 162.5-164°C.
- Sample No. 1 exhibits a Ki of 3 nM.
- the low binding constant indicates that the compound exhibits good high affinity binding to certain CNS nicotinic receptors.
- Sample No. 1 exhibits an E max value of 0% for dopamine release, indicating that the compound is selective in elicting neurotransmitter release.
- the sample exhibits an EC 50 value of 26,000 nM and an E max value of 22% in the rubidium ion flux assay.
- the sample exhibits a neurotransmitter release E max value of 33%.
- Sample No. 1 exhibits an E max of 10% (at a concentration of 100 uM) at muscle-type receptors, indicating that the compound does not significantly induce activation of muscle-type receptors.
- the sample exhibits an E max of 11% (at a concentration of 100 uM) at ganglionic-type receptors.
- the compound has the capability to bind to human CNS receptors without activating muscle-type and ganglionic-type nicotinic acetylcholine receptors to any significant degree.
- the compound begins to cause muscle effects and ganglion effects only when employed in amounts greater than those required to bind to certain CNS receptors, thus indicating a lack of undesirable side effects in subjects receiving administration of this compound.
- Sample No. 2 is (3E)-N-methyl-N-[3-(5-(N-benzylcarboxamido)pyridin)yl]- 3-buten-1 -amine, which was prepared in accordance with the following techniques:
- anhydrous DMF 40 mL
- methylamine 40 mL, 43.2 g, 1.4 mol, condensed from the gas phase
- Anhydrous potassium carbonate (19.36 g, 140 mmol) was added to the stirring solution, followed by 4-bromo-1-butene (18.9 g, 140 mmol).
- the resulting mixture was allowed to slowly warm to room temperature overnight.
- the mixture was poured into water (150 mL) and extracted with ether (8 x 50 mL).
- thionyl chloride (4.12 g, 34.65 mmol) was added drop-wise via addition funnel to a cold (0°C), stirring mixture of 5- bromonictinic acid (7.00 g, 34.65 mmol) (Acros Organics), pyridine (5.48 g, 69.28 mmol), and toluene (6 mL).
- the stirring mixture was heated to 105°C (oil bath temperature), held at this temperature for 1 h, and then cooled to 70- 75°C.
- a solution of benzylamine (3.71 g, 34.65 mmol) in toluene (10 mL) was added drop-wise over 5 min.
- the recrystallized material was filtered, washed with cold ethanol (2 x 20 mL), vacuum dried at 45°C for 15 h to give 4.26 g of a light-beige, slightly pink, crystalline powder, mp 118-120°C. More product was obtained from the HCI- toluene filtrate: The toluene phase was separated and extracted with 1 M HCI solution (2 x 50 mL). The combined HCI extracts were cooled to 0°C, basified with 18% Na 2 C0 3 solution to pH 9, extracted with toluene (50 mL), and extracted with CH 2 CI 2 (4 x 50 mL).
- the combined peach-colored toluene- CH 2 CI 2 extracts were dried (Na 2 SO ), filtered, concentrated on a rotary evaporator, and further vacuum dried at 45°C for 15 h.
- the resulting reddish beige solids were recrystallized from a minimum amount ( ⁇ 5 mL) of absolute ethanol.
- the recrystallized second batch was filtered, washed with cold ethanol (2 x 10 mL), and vacuum dried at 45°C for 3 h to give 2.09 g of a light- beige, slightly pink, crystalline powder, mp 118-120°C, bringing the total yield to 6.35 g (62.9%).
- the dark-brown mixture was allowed to cool to ambient temperature, diluted with water (20 mL) and CH 2 CI 2 (20 mL).
- the light-brown CH 2 CI 2 layer was separated, and the aqueous layer was extracted with CH 2 CI 2 (2 x 20 mL).
- the combined CH 2 CI 2 extracts were washed with water (10 mL), dried (Na 2 S0 ), filtered, concentrated by rotary evaporation, and further vacuum dried for 3 h at 0.6 mm Hg to give 3.41 g of a brown oil.
- the crude product was purified by column chromatography on silica gel (150 g), eluting with 50-100% (v/v) ethyl acetate in hexane.
- Sample No. 2 exhibits a Ki of 192 nM, indicating that the compound exhibits binding to certain CNS nicotinic receptors. Sample No. 2 exhibits an EC 50 value of 100,000 nM and an E max value of 12% for dopamine release.
- Sample No. 1 exhibits an E max of 11% (at a concentration of 100 uM) at muscle-type receptors, indicating that the compound does not significantly induce activation of muscle-type receptors.
- the sample exhibits an E max of 16% (at a concentration of 100 uM) at ganglionic-type receptors.
- the compound has the capability to bind to human CNS receptors without activating muscle-type and ganglionic-type nicotinic acetylcholine receptors to any significant degree.
- Sample No. 3 is (4E)-N-Methyl-5-[5-(2-aminopyrimidin)yl]-4-penten-2- amine Hemigalactarate, which was prepared in accordance with the following techniques:
- tosyl chloride (16.92 g, 88.75 mmol) was added to a cold (2°C), stirring solution of 4-penten-2-ol (7.28 g, 84.52 mmol) in pyridine (60 mL). The solution was stirred at 2-5°C for 2 h and allowed to warm to ambient temperature over several hours. The mixture, containing white solids was poured into cold 3 M HCI solution (250 mL) and extracted with CHCI 3 (4 x 75 mL).
- a 185 mL thick-walled glass pressure tube was charged with 4-penten- 2-ol p-toluenesulfonate (17.30 g, 71.99 mmol) followed by a 40% solution of aqueous methylamine (111.85 g, 1.44 mol). The tube was sealed and the mixture was stirred and heated at 122°C (oil bath temperature) for 16 h. The solution was cooled to ambient temperature and further cooled to 0-5°C. The light-yellow solution was saturated with NaCI and extracted with diethyl ether (6 x 40 mL, inhibitor-free). The combined ether extracts (light-yellow) were dried (Na 2 S0 ) and filtered.
- the ether was removed by distillation at atmospheric pressure using a 6-inch Vigreaux column and a short-path distillation apparatus.
- the residual light-yellow oil was distilled at atmospheric pressure collecting 2.59 g (36.3%) of a colorless oil, bp 75-105°C.
- Di-tert-butyl dicarbonate (6.84 g, 31.35 mmol) was quickly added in several portions to a cold (0-5°C), stirring solution of N-methyl-4-penten-2- amine (2.55 g, 25.68 mmol) in THF (25 mL, freshly distilled from sodium and benzophenone). The resulting light-yellow solution was stirred and allowed to warm to ambient temperature over several hours. The solution was concentrated on a rotary evaporator. The resulting oil was vacuum distilled using a short-path distillation apparatus, collecting 4.61g (90.0%) of an almost colorless oil, bp 85-86°C at 5.5 mm Hg.
- a 185 mL thick-walled glass pressure tube was charged with 2-amino- 5-bromopyrimidine (1.222 g, 7.025 mmol), palladium(ll) acetate (15.77 mg, 0.070 mmol), tri-o-tolylphosphine (85.53 mg, 0.281 mmol), N-methyl-N-(tert- butoxycarbonyl)-4-penten-2-amine (1.400 g, 7.025 mmol), triethylamine (2.5 mL, 1.815 g, 17.937 mmol) and acetonitrile (5 mL). The tube was flushed with nitrogen, sealed and heated at 114°C (oil bath temperature) for 17 h.
- Impure fractions were combined and concentrated to a residue that was re-chromatographed on silica gel (65 g) in the same manner to yield an additional 0.09 g of a tan semi-solid. Impure fractions were combined and concentrated to a yellow oil that was re-chromatographed on silica gel (65 g), eluting with CH 3 OH-NH 4 OH (10:1 , v/v). Fractions containing the product (R f 0.48) were combined and concentrated to give an additional 0.07 g of a tan semi-solid. All of the purified material was dissolved in CHCI 3 .
- Sample No. 3 exhibits a Ki of 542 nM.
- the low binding constant indicates that the compound exhibits good high affinity binding to certain CNS nicotinic receptors.
- Sample No. 4 is (4E)-N-Methyl-5-(3-(5-aminopyridin)yl)-4-penten-2- amine Hemigalactarate, which was prepared in accordance with the following techniques:
- Sample No. 4 exhibits a Ki of 1137 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- Sample No. 5 is (2S)-(4E)-N-methyl-5-[3-(5-isopropoxy-1- oxopyridin)yl)]-4-penten-2-amine, which was prepared in accordance with the following techniques:
- Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2- propanol (60.0 mL) under nitrogen.
- the resulting potassium isopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) at 140°C in a sealed glass tube for 14 h.
- the reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4 x 200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation.
- the resulting crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1 :9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing a pale-yellow oil (12.99 g, 71.2%).
- (2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propylene oxide according to procedures set forth in A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).
- the light-yellow solution was treated with 1 M NaOH solution (10 mL) and 10% NaHSO 3 solution (2 mL).
- the CH 2 CI 2 phase was separated; the aqueous phase was extracted with CH 2 CI 2 (2 x 10 mL). All CH 2 CI 2 extracts were combined, dried (Na 2 S0 4 ), filtered, concentrated by rotary evaporation, and vacuum dried briefly at 1 mm Hg to give 221.7 mg of a light-yellow oil.
- the crude product was purified by column chromatography on silica gel (20.8 g, Merck 70-230 mesh) eluting with EtOAc-CH 3 OH (9:1 , v/v).
- Sample No. 5 exhibits a Ki of 1400 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- the sample exhibits a neurotransmitter release E max value of 19%.
- Sample No. 5 exhibits an E max of 7% (at a concentration of 100 uM) at muscle-type receptors, indicating that the compound does not induce activation of muscle-type receptors.
- the sample exhibits an E max of 8% (at a concentration of 100 uM) at ganglionic-type receptors.
- the compound has the capability to activate human CNS receptors without activating muscle-type and ganglionic-type nicotinic acetylcholine receptors to any significant degree.
- a therapeutic window for utilization in the treatment of CNS disorders That is, at certain levels the compound shows CNS effects to a significant degree but does not show undesirable muscle and ganglia effects to any significant degree.
- Sample No. 6 is (3E)-N-methyl-4-(3-(5-isobutoxypyridin)yl)-3-buten-1- amine hemigalactarate, which was prepared in accordance with the following techniques: 3-Bromo-5-isobutoxy pyridine
- Sample No. 6 exhibits a Ki of 20 nM. The low binding constant indicates that the compound exhibits good high affinity binding to certain CNS nicotinic receptors. Sample No. 6 exhibits an EC 50 of 15,000 nM and an E max value of 25% for dopamine release. The sample exhibits an EC 50 value of 1 ,000 nM and an E max value of 15% in the rubidium ion flux assay.
- Sample No. 6 exhibits an E max of 6% (at a concentration of 100 uM) at muscle-type receptors.
- the sample exhibits an E max of 13% (at a concentration of 100 uM) at ganglionic-type receptors.
- Sample No. 7 is (3E)-N-methyl-4-(3-(1-oxopyridin)yl)-3-buten-1 -amine, which was prepared in accordance with the following techniques:
- Sample No. 8 is (4E)-N-methyl-5-(3-(1-oxopyridin)yl)-4-penten-2- amine, which was prepared in accordance with the following techniques:
- Sample No. 8 exhibits a Ki of 5900 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- the sample exhibits a neurotransmitter release E max value of 9%.
- Sample No. 8 exhibits an E max of 0% (at a concentration of 100 uM) at muscle-type receptors, indicating that the compound does not induce activation of muscle-type receptors.
- the sample exhibits an E max of 8% (at a concentration of 100 uM) at ganglionic-type receptors.
- the compound has the capability to activate human CNS receptors without activating muscle-type and ganglionic-type nicotinic acetylcholine receptors to any significant degree.
- a therapeutic window for utilization in the treatment of CNS disorders That is, at certain levels the compound shows CNS effects to a significant degree but do not show undesirable muscle or ganglion effects to any significant degree.
- Sample No. 9 is (3E)-N-methyl-4-(3-(5-ethylthiopyridin)yl)-3-buten-1- amine hemigalactarate, which was prepared in accordance with the following techniques:
- Sample No. 9 exhibits a Ki of 28 nM. The low binding constant indicates that the compound exhibits good high affinity binding to certain CNS nicotinic receptors. Sample No. 9 exhibits an EC 50 value of 875 nM and an E max value of 39% for dopamine release, indicating that the compound elicts neurotransmitter release. The sample exhibits an EC 5 o value of 191 nM and an E max value of 40% in the rubidium ion flux assay.
- Sample No. 9 exhibits an E max of 7% (at a concentration of 100 uM) at muscle-type receptors.
- the sample exhibits an E max of 22% (at a concentration of 100 uM) at ganglionic-type receptors.
- Sample No. 10 is of (4E)-N-methyl-5-(3-(5-trifluoromethylpyridin)yl)-4- penten-2-amine, which was prepared in accordance with the following techniques:
- Sample No. 10 exhibits a Ki of 3942 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- the sample exhibits an EC 5 o value of 100,000 nM and an E max value of 0% in the rubidium ion flux assay.
- the sample exhibits a neurotransmitter release E max value of 50%.
- Sample No. 10 exhibits an E max of 0% (at a concentration of 100 uM) at muscle-type receptors.
- the sample exhibits an E max of 0% (at a concentration of 100 uM) at ganglionic-type receptors.
- Sample No. 11 is (4E)-N-methyl-5-(3-(5- ((carboxymethyl)oxy)pyridin)yl)-4-penten-2-amine, which was prepared in accordance with the following techniques:
- Sample No. 111 is determined to exhibit a Ki of 100,000 nM.
- Sample No. 12 is (4E)-5-(3-(5-isopropoxypyridin)yl)-4-penten-2-amine hemigalactarate, which was prepared in accordance with the following techniques:
- benzene extracts were dried (Na 2 S0 ), evaporated and column chromatographed on 7 g of Merck silica gel 60 (70-230 mesh) with 5-10% (v/v) methanol, 2.5% (v/v) triethylamine in benzene. This provided 118 mg (72.8% yield) of light yellow oil.
- Second and third crops of 50 mg and 5 mg were isolated by concentrating the supernatant, bringing the total yield to 108 mg (65.5% yield).
- the three salt samples were slurried together in hot 100% ethanol, cooled, and filtered to give an analytical sample of 27 mg of fine, white powder, mp 170-172° C.
- Sample No. 12 exhibits a Ki of 413 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- Sample No. 12 exhibits an E max of 13% (at a concentration of 100 uM) at muscle-type receptors.
- the sample exhibits an E max of 5% (at a concentration of 100 uM) at ganglionic-type receptors.
- the sample exhibits a neurotransmitter E max of 32%.
- Sample No. 13 is of (4E)-N-methyl-5-(3-(5-hydroxypyridin)yl)-4-penten- 2-amine sesquioxalate, which was prepared in accordance with the following techniques:
- 3-Bromo-5-hydroxypyridine was prepared in 35.0% yield from furfurylamine according to the procedure described in U.S. Patent No. 4,192,946 to Clauson-Kaas et al.
- Sample No. 13 exhibits a Ki of 504 nM.
- the binding constant indicates that the compound exhibits binding to certain CNS nicotinic receptors.
- the sample exhibits a neurotransmitter release E max value of 80%.
- Sample No. 13 exhibits an E max of 21% (at a concentration of 100 uM) at muscle-type receptors.
- the sample exhibits an E ma of 12% (at a concentration of 100 uM) at ganglionic-type receptors.
Abstract
Description
Claims
Priority Applications (4)
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JP2001501591A JP2003501416A (en) | 1999-06-07 | 2000-06-06 | Pharmaceutical compositions and uses thereof |
AU53261/00A AU5326100A (en) | 1999-06-07 | 2000-06-06 | Pharmaceutical compositions and methods for use |
EP00938183A EP1185514A1 (en) | 1999-06-07 | 2000-06-06 | Pharmaceutical compositions and methods for use |
CA002376061A CA2376061A1 (en) | 1999-06-07 | 2000-06-06 | Pharmaceutical compositions and methods for use |
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US32714199A | 1999-06-07 | 1999-06-07 | |
US09/327,141 | 1999-06-07 | ||
US09/327,774 | 1999-06-07 | ||
US09/327,774 US6492399B1 (en) | 1998-06-16 | 1999-06-07 | Pharmaceutical compositions and methods for use |
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EP (1) | EP1185514A1 (en) |
JP (1) | JP2003501416A (en) |
AU (1) | AU5326100A (en) |
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WO (1) | WO2000075110A1 (en) |
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