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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
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  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
  • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
  • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
  • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
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  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

• the present invention relates to novel ALDH-2 inhibitors, and to their use in treating mammals for dependence upon drugs of addiction, for example addiction to dopamine-producing agent such as cocaine, opiates, amphetamines, nicotine, and alcohol.
• ALDH-2 inhibitors have also been shown to be effective in treating obesity.
• the invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
• Alcohol abuse and alcohol dependency can cause liver, pancreatic and kidney disease, heart disease, including dilated cardiomyopathy, polyneuropathy, internal bleeding, brain deterioration, alcohol poisoning, increased incidence of many types of cancer, insomnia, depression, anxiety, and even suicide.
• Heavy alcohol consumption by a pregnant mother can also lead to fetal alcohol syndrome, which is an incurable condition.
• alcohol abuse and alcohol dependence are major contributing factors for head injuries, motor vehicle accidents, violence and assaults, and other neurological and other medical problems.
• Cigarette smoking is the most popular method of using nicotine, but there are smokeless tobacco products; for example, snuff, chewing tobacco.
• Nicotine addition is linked to disease states such as leukemia, cataracts, pneumonia, and is the cause of about one-third of all cancer deaths, the foremost of which is lung cancer.
• cigarette smoking also causes lung diseases, such as bronchitis and emphysema, exacerbates asthma symptoms, and is the cause of chronic obstructive pulmonary diseases in general. It is also well known that cigarette smoking increases the risk of cardiovascular diseases, including stroke, heart attack, vascular disease, aneurysm, and the like.
• Another major health problem is caused by cocaine abuse.
• Physical effects of cocaine use include constricted blood vessels, dilated pupils, and increased temperature, heart rate, and blood pressure.
• a user of cocaine can experience acute cardiovascular or cerebrovascular emergencies, such as a heart attack or stroke, potentially resulting in sudden death.
• Other complications associated with cocaine use include disturbances in heart rhythm, chest pain and respiratory failure, seizures and headaches, and gastrointestinal complications such as abdominal pain and nausea.
• cocaine has a tendency to decrease appetite, many chronic users can become malnourished. Repeated use of cocaine may lead to a state of increasing irritability, restlessness, and paranoia. This can result in a period of full-blown paranoid psychosis, in which the user loses touch with reality and experiences auditory hallucinations.
• Daidzein is the major active component obtained from extracts of Radix puerariae, a traditional Chinese medication that suppresses ethanol intake in Syrian golden hamsters. See Keung, W. M. and Vallee, B. L. (1993) Proc. Natl. Acad. Sci. USA 90, 10008-10012 and Keung, W. M., Klyosov, A. A., and Vallee, B. L. (1997) Proc. Natl. Acad. Sci. USA 94, 1675-1679, and U.S. Patents 5,624,910 and 6,121,010.
• U.S. Patents 5,624,910 and 6,121,010 disclosed ether derivatives of daidzin, which were shown to be effective in treating ethanol dependency. Daidzin and its analogs were shown to be potent and selective inhibitors of human mitochondrial aldehyde dehydrogenase (ALDH-2), which is an enzyme involved in the major enzymatic pathway responsible for ethanol metabolism in humans. It was also found that daidzin analogues that inhibit ALDH-2 but also inhibit the monamine oxidase (MOA) pathway were the least effective antidipsotropic activity.
• ALDH-2 human mitochondrial aldehyde dehydrogenase
• MOA monamine oxidase
• the invention relates to compounds of Formula I:
• R 1 is optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
• R 2 is hydrogen, hydroxy, halogen, optionally substituted lower alkoxy, optionally substituted lower alkyl, cyano, optionally substituted heteroaryl, C(O)OR 5 , -C(O)R 5 , -SO 2 R 15 , -B(OH) 2 , -OP(O)(OR 5 ) 2 , - C(NR 20 )NHR 22 , -NHR 4 , or C(O)NHR 5 , in which,
• R 4 is hydrogen, -C(O)NHR 5 , or -SO 2 R 15 , or -C(O)R 5 ;
• R 5 is hydrogen, optionally substituted lower alkyl
• R 15 is optionally substituted lower alkyl or optionally substituted phenyl
• R 2 is -O-Q-R 6 , in which Q is a covalent bond or lower alkylene and R 6 is optionally substituted heteroaryl;
• R is hydrogen, cyano, optionally substituted amino, lower alkyl, lower alkoxy, or halo;
• X, Y and Z are chosen from -CR 7 - and -N-, in which R 7 is hydrogen, lower alkyl, lower alkoxy, or halo;
• V is oxygen, sulfur, or -NH-; and W is -Q ⁇ T-Q 2 -, wherein
• T is a covalent bond, -O-, or -NH-, or
• T and Q 1 may together form a covalent bond
• R 20 and R 22 are independently selected from the group consisting of hydrogen, hydroxy, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, benzyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, benzyl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci_ 6 alkyl, CF 3 , OCF 3 , B(OH) 2 , Si(CH 3 ) 3 , aryl, and heteroaryl.
• compositions comprising a therapeutically effective amount of an ALDH-2 inhibitor of Formula I, and at least one pharmaceutically acceptable carrier.
• a third aspect of the invention methods of using the compounds of Formula I in the treatment of addition to a dopamine-producing agent.
• the method comprises administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I.
• diseases include, but are not limited to, the treatment of cocaine, opiate, amphetamine, nicotine, and alcohol dependency.
• the invention relates to a group of compounds of Formula I in which X, Y and Z are all -CR 6 -, in which R 6 is hydrogen.
• preferred compounds include a class in which R 1 is optionally substituted phenyl, R 2 is 4-hydroxyl, R 3 is hydrogen, V is oxygen, and W is methylene.
• R 1 is phenyl substituted with from 1 to 3 substituents, which are independently selected from the group consisting of carboxyl, carboxylic ester, carboxamido, cyano, tetrazolyl, halo, or lower alkyl substituted by halo, particularly monosubstituted compounds in which the substitution is at the 3 -position and disubstituted compounds in which the substitutions are at the 3,5-positions.
• R 1 is optionally substituted phenyl
• R 2 is 4-NHR 4
• R 3 is hydrogen
• V oxygen
• W is methylene.
• R 1 is phenyl substituted with from 1 to 3 substituents which are independently selected from the group consisting of carboxyl, carboxamido, cyano, tetrazolyl, halo, or lower alkyl substituted by halo, particularly monosubstituted compounds in which the substitution is at the 3- position and disubstituted compounds in which the substitutions are at the 3,5- positions. More preferred are those compounds where R 4 is -SO 2 R 5 , more preferably where R 5 is methyl.
• R 1 is optionally substituted heteroaryl, particularly where R 1 is a five or six membered heteroaryl ring that includes oxygen and nitrogen atoms, V is oxygen, W is methylene, preferably where R 2 is 4-hydroxy and R 3 is hydrogen.
• one preferred subgroup includes those compounds in which R 1 is 1,3-oxazolyl, 1,3-thiazolyl, or (l,2,4-oxadiazol-3-yl), which are optionally substituted by phenyl substituted by carboxyl, carboxamido, cyano, tetrazolyl, halo, or lower alkyl substituted by halo, for example trifluoromethyl, particularly monosubstituted compounds in which the substitution is at the 3 -position and disubstituted compounds in which the substitutions are at the 3,5-positions.
• the compounds for use in the invention include, but are not limited to:
• FIG 1 depicts how increasing doses of 3-[(3- ⁇ 4-
• alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
• substituted alkyl refers to:
• alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO 2 -alkyl,
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is O, 1 or 2; or
• alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR a -, where R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
• lower alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t- butyl, n-hexyl, and the like.
• substituted lower alkyl refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.
• alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
• This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and-CH(CH 3 )CH 2 -) and the like.
• lower alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
• lower alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.
• substituted alkylene refers to:
• an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO 2 -alkyl, SO 2 -aryl and
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
• an alkylene group as defined above that is interrupted by 1 -20atoms independently chosen from oxygen, sulfur and NR 3 -, where R a is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
• alkylene group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1 -20 atoms as defined above.
• substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH 2 )CH 2 -), methylaminoethylene (-CH(NHMe)CH 2 -), 2- carboxypropylene isomers(-CH 2 CH(CO 2 H)CH 2 -), ethoxyethyl (-CH 2 CH 2 O- CH 2 CH 2 -), ethylmethylaminoethyl (-CH 2 CH 2 N(CH 3 )CH 2 CH 2 -), 1 -ethoxy-2-(2- ethoxy-ethoxy)ethane (-CH 2 CH 2 O-CH 2 CH 2 -OCH 2 CH 2 -OCH 2 CH 2 -), and the like.
• aralkyl refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
• Optionally substituted aralkyl refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group.
• Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
• alkoxy refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
• Preferred alkoxy groups are optionally substituted alkyl-O- and include, by way of example, methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2- dimethylbutoxy, trifluoromethoxy, and the like.
• the term "lower alkoxy” refers to the group R-O-, where R is optionally substituted lower alkyl as defined above.
• alkylthio refers to the group R-S-, where R is as defined for alkoxy.
• alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl).
• lower alkenyl refers to alkenyl as defined above having from 2 to 6 carbon atoms.
• substituted alkenyl refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl,
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation.
• Preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (or prop-l-yn-3-yl, -CH 2 C ⁇ CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
• substituted alkynyl refers to an alkynyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• aminocarbonyl refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• acylamino refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• acyloxy refers to the groups -O(O)C-alkyl, -O(O)C-cycloalkyl, - O(O)C-aryl, -O(O)C-heteroaryl, and -O(O)C-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• aryl refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
• Preferred aryls include phenyl, naphthyl and the like.
• arylene refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, l,4'-biphenylene, and the like.
• aryl or arylene groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• aryloxy refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
• arylthio refers to the group R-S-, where R is as defined for aryl.
• amino refers to the group -NH 2 .
• substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• Carboxyalkyl refers to the groups -C(O)O-alkyl or -C(O)O- cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(O) n R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• cycloalkyl refers to carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
• Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2. l]heptane, l,3,3-trimethylbicyclo[2.2. l]hept-2-yl, (2,3,3- trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
• substituted cycloalkyl refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl,
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is O, 1 or 2.
• halogen refers to fluoro, bromo, chloro, and iodo.
• acyl denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
• heteroaryl refers to a radical derived from an aromatic cyclic group (i.e., fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
• Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl).
• heteroaryls include, but are not limited to, [l,2,4]oxadiazole, [l,3,4]oxadiazole, [l,2,4]thiadiazole, [l,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, thiazole, isothiazole, phenazine, oxazole, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazo
• heteroaryl or heteroarylene groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• heteroarylkyl refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.
• Optionally substituted heteroaralkyl refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group.
• Such heteroaralkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.
• heteroaryloxy refers to the group heteroaryl-O-.
• heterocyclyl refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
• Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholino, oxathiane, thiomorpholino, tetraydropthiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, triazolidino, piperazinyl, dihydropyridino, pyrrolidinyl, imidazolidino, heyxahydropyrimidine, hezahydropyridazine, imidazoline, and the like.
• heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO
• substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(O) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
• thiol refers to the group -SH.
• substituted alkylthio refers to the group -S-substituted alkyl.
• heteroarylthiol refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
• sulfoxide refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl.
• substituted sulfoxide refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
• sulfone refers to a group -S(O ⁇ R, in which R is alkyl, aryl, or heteroaryl.
• substituted sulfone refers to a group -S(O ⁇ R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
• keto refers to a group -C(O)-.
• thiocarbonyl refers to a group -C(S)-.
• carboxyl refers to a group -C(O)-OH.
• compound of Formula I is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers).
• the individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means.
• the individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non- racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
• "Isomers" are different compounds that have the same molecular formula.
• Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
• Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture.
• the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
• Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
• the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
• Parental administration is the systemic delivery of the therapeutic agent via injection to the patient.
• therapeutically effective amount refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
• the therapeutically effective amount will vary depending upon the specific activity of the therapeutic agent being used, and the age, physical condition, existence of other disease states, and nutritional status of the patient. Additionally, other medication the patient may be receiving will effect the determination of the therapeutically effective amount of the therapeutic agent to administer.
• treatment means any treatment of a disease in a mammal, including:
• the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable.
• Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkeny
• Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
• Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
• solvents used in the reactions of the present invention are inert organic solvents.
• q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
• the compound of formula (1) (daidzein, commercially available) is dissolved in an inert solvent, for example N,N-dimethylformamide, and reacted with about an equimolar amount of a compound of formula R 1 WX, where W is lower alkylene of 1-3 carbon atoms and X is iodo, bromo or chloro, in the presence of a base, for example potassium carbonate, cesium carbonate, or the like.
• the reaction may be conducted at a temperature of about 50-100 0 C, for about 1-10 hours or may also be conducted at room temperature for 3 to 24 hours.
• the product of Formula I in which R 2 is hydroxy is isolated by conventional means, for example by precipitating the product out of solution by addition of water.
• the compound of formula (1) is dissolved in an inert solvent, for example acetone, and an aqueous base added, for example 2N potassium hydroxide, and the mixture sonicated for about 5-30 minutes.
• the mixture is then reacted with about an equimolar amount of a compound of formula R 1 WX, where W is lower alkyene of 1-3 carbon atoms and X is iodo, bromo or chloro, in the presence of about an equimolar amount of potassium iodide, and the mixture reacted at about reflux temperature for about 1-5 days.
• R 1 WX a compound of formula R 1 WX
• X is iodo, bromo or chloro
• R is phenyl -yl
• the purified product of formula (2) is suspended in an aqueous solvent, for example acetonitrile/water, and a catalytic amount of a strong acid added, for example trifluoroacetic acid. Removal of the solvents provides the compound of Formula I in which R 1 is phenyl substituted by tetrazol-5-yl.
• an aqueous solvent for example acetonitrile/water
• a catalytic amount of a strong acid for example trifluoroacetic acid
• a nitro derivative of formula (3) (commercially available) is suspended in an aqueous solvent, for example a mixture of tetrahydrofuran and water, and reacted with sodium dithionite. The reaction is conducted at a temperature of about 50-70 0 C overnight. When the reaction is substantially complete, the amine of Formula I is isolated by conventional means, for example by chromatography on silica gel.
• the carboxyl group is better protected as an allyl ester before carrying out the reduction of the nitro group.
• a protecting group protects the carboxyl group in any subsequent reaction in which the amine is, for example acylated, and is easily removed after acylation, whereas an alkyl ester is more difficult to hydrolyze under conventional hydrolysis conditions.
• the compound of Formula I in which R 2 is amino is suspended in an inert solvent, for example dichloromethane, and a tertiary base added, for example pyridine.
• an inert solvent for example dichloromethane
• a tertiary base for example pyridine
• the mixture is cooled to about 0 0 C, a compound of formula R 5 SO 2 Cl added, and the mixture reacted for about 1-2 hours.
• the compound of Formula I in which R 4 is -SO 2 R 5 is isolated by conventional means, for example by chromatography on silica gel.
• reaction of a compound of Formula I in which R 2 is amino with an acylating agent of formula ClC(O)R 5 provides compounds of Formula I in which R 2 is
• an allyl ester derivative of Formula I is dissolved in an inert solvent, for example tetrahydrofuran, and a base, for example morpholine, and tetrakis(triphenyl-phosphine)palladium(0) added.
• an inert solvent for example tetrahydrofuran
• a base for example morpholine
• tetrakis(triphenyl-phosphine)palladium(0) added.
• the reaction is conducted at about room temperature for about 1-12 hours.
• the compound of Formula I in which R 1 is a benzoic acid derivative is isolated by conventional means, for example by flash chromatography on silica gel.
• the compounds of formula R 1 WCl are either commercially available, or are made by methods well known in the art.
• the synthesis starts from a compound of formula (4) (which is a compound of formula R 1 WCl in which R 1 is optionally substituted 1,3 -oxazole and W is methylene), the preparation of which is shown in Reaction Scheme VI.
• R is optionally substituted phenyl.
• 1,3-dichloroacetone (a) is reacted with an appropriately substituted benzamide derivative of formula (b), in which R is optionally substituted phenyl.
• the reaction is conducted at a temperature of about 100-140 0 C, for about 1-6 hours.
• the compound of formula (4) is isolated by conventional means, for example by flash chromatography on silica gel or recrystallization from an inert solvent.
• R is optionally substituted phenyl
• R is optionally substituted phenyl and R 5 is hydrogen or lower alkyl
• the nitrile of formula (e) in which R is optionally substituted phenyl, is reacted with aqueous hydroxy lamine (formula (f)) in a protic solvent, for example ethanol.
• a protic solvent for example ethanol.
• the reaction is conducted at a temperature of about 50-100 0 C, for about 2 hours.
• the compound of formula (g) is isolated by conventional means.
• a compound of formula R 1 WCl in which R 1 is optionally substituted 1,2,4-oxadiazole and W is alkylene may also be prepared as shown in Reaction Scheme VIB' REACTION SCHEME VIB'
• the compound of formula (g) is reacted with the compound of formula (h 1 ), in which R 5 is hydrogen or lower alkyl.
• the compound of formula (h 1 ) is placed in as suitable solvent such a dichloromethane and cooled to approximately 0 0 C. After 20 to 40 minutes, the compound of formula (g 1 ) is added and the coupling reaction allowed to proceed fro 1 to 2 hours. CBr 4 and Ph 3 P are then added and the dehydration allowed to proceed for an additional 4 to 6 hours. Solid triphenylphosine oxide is removed and the remaining solvent evaporated and the compound of formula (4b) is isolated by conventional means.
• the acetylene derivative of formula (i), in which R is optionally substituted phenyl, is reacted with ethyl chlorooximidoacetate (formula (j)) in an inert solvent, for example tetrahydrofuran, in the presence of a base, for example triethylamine.
• an inert solvent for example tetrahydrofuran
• a base for example triethylamine
• ester derivative of formula (k), in which R is optionally substituted phenyl is reacted with a reducing agent, for example sodium borohydride in a protic solvent, for example ethanol.
• a reducing agent for example sodium borohydride in a protic solvent, for example ethanol.
• the reaction is initially conducted at a temperature of about 0 0 C, and then at room temperature for about 1-2 hours.
• the compound of formula (1) is isolated by conventional means.
• the hydroxymethyl derivative of formula (1) in which R is optionally substituted phenyl, is reacted with a brominating agent, for example carbon tetrabromide in the presence of triphenylphosphine.
• a brominating agent for example carbon tetrabromide
• the reaction is conducted at a temperature of about 0 0 C for about 1-2 hours.
• the compound of formula (4c) is isolated by conventional means.
• the compound of formula (5) 7-hydroxy-3-iodochromen-4-one, is reacted with a compound of formula R 1 WCl in a polar solvent, for example N,N- dimethylformamide, in the presence of sodium iodide and a mild base, for example potassium carbonate.
• a polar solvent for example N,N- dimethylformamide
• the reaction is conducted at a temperature of about 40-80 0 C, for about 1 hour or may be conducted at room temperature for a longer period, 2 to 24 hours.
• the compound of formula (6) is isolated by conventional means, for example by flash chromatography on silica gel or recrystallization from an inert solvent.
• the compound of formula (6) is then reacted with the boronic acid of formula (7), which are either commercially available or prepared by means well known in the art.
• the reaction is conducted in an inert solvent, for example dimethoxymethane, in the presence of tetrakistriphenylphosphine palladium and aqueous sodium carbonate.
• the reaction is conducted at a temperature of about 60- 100 0 C, for about 1 hour.
• the compound of Formula I is isolated by conventional means, for example by flash chromatography on silica gel or recrystallization from an inert solvent.
• the compound of fomula (7) may first be reacted with the compound of formula (5) to produce a desired compound of formula (5a) as shown below:
• the compound of formula (8) l-(2-hydroxy-4-methoxyphenyl)ethan- 1-one, is reacted with the dimethylacetal of N,N-dimethylformamide.
• the reaction is conducted at a temperature of about 50-100 0 C, for about 2 hours.
• the compound of formula (9) is isolated by conventional means, for example by filtration of the precipitated product, 3-(dimethylamino)-l-(2-hydroxy- 4-methoxyphenyl)prop-2-en- 1 -one.
• the compound of formula (9) is then reacted with N-iodosuccinimide in an inert solvent, for example chloroform, in the presence of silica gel.
• an inert solvent for example chloroform
• the reaction is conducted at a temperature of about 0 0 C, for about 1 hour.
• the compound of formula (5a), 3-iodo-7-methoxychromen-4- one is isolated by conventional means, for example by filtering off the silica gel, washing the solid with chloroform, and removal of the solvent.
• the compound of formula (5a) is then reacted with boron tribromide to convert the methoxy group to a hydroxyl group.
• the compound of formula (5 a) is dissolved in an inert solvent, for example chloroform, cooled to about -80 0 C, and reacted with boron tribromide for about 1 hour. The mixture is then allowed to warm to about room temperature, and stirred for about 2-5 days.
• an inert solvent for example chloroform
• the commercially available compound of formula (1) is dissolved in an inert solvent, for example acetone, and an aqueous base added, for example 2N potassium hydroxide.
• an inert solvent for example acetone
• an aqueous base for example 2N potassium hydroxide
• the mixture is then reacted with about an equimolar amount of a compound of formula X 1 Q 2 X 2 , where X 1 and X 2 are independently iodo, bromo or chloro.
• the mixture is reacted at about reflux temperature for about 1-5 days.
• the solvent is then evaporated and the residue purified using conventional methods such as column chromatography to provide the compound of formula (10).
• the compound of formula (10) is the reacted with a compound of formula R 1 Q 1 -NU 2 in an inert solvent such as DMF.
• the reaction takes place at a temperature of approximately 50 0 C to 80 0 C for 12 to 48 hours.
• the compound of Formula I is isolated by conventional means, for example by solvent evaporation followed byt TLC.
• this type of reaction can be modified so that a modified Q 1 linking group is added to an appropriately halogenated R 1 derivative according the the method described in Step 2 to provide a compound of the formula R 1 -Q 1 Ot.
• oxirane derivatives of desired Q 1 and/or Q 2 linking groups may be used to produce compounds of Formula I wherein either or both of the Q moieties are hydroxy substituted.
• a method of making compounds wherein Q 1 is methylene, T is NH, and Q 2 is 2-hydroxy propylene is shown in Reaction Scheme X:
• the compound of formula (5') is reacted with epichlorohydrin and K 2 CO3 in a suitable solvent such as DMF.
• a suitable solvent such as DMF.
• the reaction takes place at a temperature ranging from 6O 0 C to 90 0 C and is carried out for 1 to 6 hours.
• the solvent is removed by evaporation and the compound of formula (11) collected as a precipitate from the residue by treatedment with H 2 O.
• the precipitate may be collected conventional means, for example by flash chromatography on silica gel or recrystallization from an inert solvent.
• the compound of formula (11) is then reacted with an amino derivative of the desired R 1 Q 1 segment, such as the R/methylamino compound shown in Reaction Scheme X.
• the reactents are dissolved in a protic solvent such as ethanol and a catalytic amound of base such as DIPEA (N,N'-diisopropylethylamine) is added.
• a catalytic amound of base such as DIPEA (N,N'-diisopropylethylamine) is added.
• DIPEA N,N'-diisopropylethylamine
• the reaction may be carried out by stirring overnight at at emperature of 70 0 C to 85°C.
• the solvent is removed by evaporation and the compound of Formula I collected and purified by conventional means such as silica gel column chromatography followed by recrystalization from an inert solvent.
• the compound of formula (11) can be reacted with a magnesioum brominde derivative of the desired R 1 Q 1 segment.
• the magnesium bromide derivative is slowly added to a cooled (-60° to -30 0 C) solution of CuI in THF.
• To this solution is then slowly added the compound of formula (11) in THF.
• the reaction mixture is stirred at -60° to -30 0 C 1 to 2 hours then quenched with saturated NH 4 Cl aqueous solution and H 2 O and extracted with EtOAc.
• the organic layer is further washed with brine, then dried over Na 2 SO 4 and evaporated in vacuo.
• the compound of Formula I is then collected and purified by conventional means such as prep-TLC.
• the compounds of Formula I are generally effective in the treatment of conditions that respond to administration of ALDH-2 inhibitors. Specifically, the compounds of Formula I are useful in the treatment of addictions to dopamine- producing agents of addiction such as, for example, cocaine, opiates, amphetamines, nicotine, and alcohol.
• ALDH-2 inhibitors are effective in treating addiction as a consequence of their ability to normalize the increased dopamine levels associated with various addictive behaviors. See, N.D. Volkow et ah, Dopamine in drug abuse and addiction: results from imaging studies and treatment implications, MoI. Psychiatry 9 (2004), pp. 557-569; and BJ. Everitt and M.E. Wolf, Psychomotor stimulant addiction: a neural systems perspective, J. Neurosci. 22 (2002), pp. 3312-3320.
• ALDH-2 inhibitors such as the compounds of Formula I will be useful in the treatment of all addictive and compulsive behaviors and neurological conditions associated with increased dopamine levels.
• Such behaviors and conditions include, but are not limited to, compulsive gambling, overeating, and shopping, obsessive compulsive disorder (OCD), schizophrenia, attention deficit hyperactivity disorder, and the like.
• the compounds of Formula I are usually administered in the form of pharmaceutical compositions.
• This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
• the compounds of Formula I may be administered alone or in combination with other therapeutic agents.
• Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17 th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3 rd Ed. (G.S. Banker & CT. Rhodes, Eds.). Administration
• the compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneous Iy, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
• agents having similar utilities for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneous Iy, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
• One mode for administration is parental, particularly by injection.
• the forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
• Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention.
• Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
• the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Sterile injectable solutions are prepared by incorporating the compound of Formula I in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• Oral administration is another route for administration of the compounds of Formula I.
• Administration may be via capsule or enteric coated tablets, or the like.
• the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
• a carrier that can be in the form of a capsule, sachet, paper or other container.
• the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
• excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
• the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
• compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
• Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.
• Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
• compositions are preferably formulated in a unit dosage form.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
• suitable pharmaceutical excipient e.g., a tablet, capsule, ampoule.
• the compounds of Formula I are effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
• each dosage unit contains from 10 mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of a compound of Formula I, more preferably about 50-200 mg.
• the amount of the compound of Formula I actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids [0148] and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
• compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
• the product can be purified by flash chromatography over silica gel, eluting with ethyl acetate/hexanes (1/4).
• This product (9.36g, 30.98 mmol) was dissolved in anhydrous chloroform (10ml), and cooled to -78°C. To this solution was added a 1.0 M solution of boron tribromide in methylene chloride (90 ml, 90 mmol), and the mixture stirred for 1 hour at -78°C. The mixture was allowed to warm to room temperature, and stirred for 4 days. The mixture was then poured into water (200 ml), and the brown solid filtered off, washed with water (4 x 100 ml), and chloroform (3 x 20 ml).
• Step 1 Preparation of a Compound of Formula (6) in which R 1 is 4-Methyl-2-[4- (trifluoromethyl)phenyll(X3-thiazol-5-yl), and W is Methylene
• Step 2 Preparation of a Compound of Formula I in which R 1 is Phenyl1(l,3-thiazol-5- yl), R 2 is 4-Methylsulfonamide, R 3 is Hydrogen, V is Oxygen, X, Y, and Z are -CH-, and W is Methylene
• the mixture was refluxed for 1 hour, cooled to ambient temperature, filtered through celite (3 g), and the celite washed with ethyl acetate (50 ml). The filtrate was washed with brine (30 ml), and dried over sodium sulfate.
• V is Oxygen
• W is Methylene
• reaction mixture was then dry-loaded onto a pre-packed column using silica gel and purified (silica gel, gradient, 100% CH 2 Cl 2 to CH 2 Cl 2 /Me0H, 3:1) by flash chromatography to obtain the desired product protected by trimethylsilyl.
• This intermediate was suspended in acetonitrile (2 ml) and water (1 ml) and one drop of trifluoroacetic acid added. The volatile solvents were removed under vacuum to afford 3-(4-hydroxyphenyl)-7- ⁇ [5-(3-(l,2,3,4-tetraazol-5-yl)phenyl)(l,2,4-oxadiazol-3- yl)]methoxy ⁇ chromen-4-one (4 mg).
• the reaction mixture was mixed with silica gel (2 g), solvent removed under reduced pressure, and the mixture applied to a column.
• the silica gel mixture was purified by flash chromatography, eluting with methylene chloride/methanol (98/2) to give prop-2-enyl 3- ⁇ [3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl ⁇ benzoate as a yellow solid (99.6 mg, 65%);.
• (ESI) m/z 428 (M + H) + .
• Step 1 The product of Step 1 was used without further purification.
• the product 606.7 mg, 1.50 mmol was placed in a 50 mL round bottomed flask, and lithium chloride (127.6 mmol, 3.01 mmol, 2 equiv.), dimethylsulfoxide (5 mL) and water (0.5 mL) added, and the mixture heated at 190-195 0 C for 3 hours.
• To the reaction mixture was added water (30 mL) and the whole was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate.
• Step 1 To a solution of cuprous iodide (0.14 g, 0.74 mmol) in tetrahydrofuran (2 ml) was added phenylmagnesium bromide in tetrahydrofuran (IM, 2.22 ml, 2.22 mmol) dropwise at -40°C. After 5 minutes 3-(4-methoxyphenyl)-7-(oxiran-2- ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol) in tetrahydrofuran (4 ml) was added slowly, and stirred at -40 0 C for 1 hour.
• IM phenylmagnesium bromide in tetrahydrofuran
• step 1 The product of step 1 was then reacted with boron tribromide as shown in Example 15, step 3, to provide 3-(4-hydroxyphenyl)-7-(2-hydroxy-3- phenylpropoxy)chromen-4-one.
• R Enantiomer of a Compound of Formula I in which R 1 is3- r5-Fluoro-3-(trifluoromethyl)phenyl "
• R 3 is Hydrogen.
• X. Y and Z are -CH-.
• V is Oxygen, and W is -CH(CHQ-).
• Step 2 Preparation of di-tert-butyl (4-(7-((2-(3-fluoro-5- (trifluoromethyl)phenyl)oxazol-4-yl)methoxy)-4-oxo-4H-chromen-3- yl)phenoxy)methyl phosphate
• Step 3 Preparation of (4-(7-((2-(3-fluoro-5-(trifluoromethyl)phenyl)oxazol-4- yl)methoxy)-4-oxo-4H-chromen-3-yl)phenoxy)methyl dihydrogen phosphate
• the above ingredients are mixed and filled into hard gelatin capsules.
• a dry powder inhaler formulation is prepared containing the following components:
• the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
• the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
• Suspensions each containing 50 mg of active ingredient per 5.0 mL dose are made as follows:
• a subcutaneous formulation may be prepared as follows:
• EXAMPLE 27 [0240] An injectable preparation is prepared having the following composition:
• a topical preparation is prepared having the following composition: Ingredients grams
• Microcrystalline cellulose (filler) 1-35 5-15 10.6 Methacrylic acid copolymer 1-35 5-12.5 10.0
• the sustained release formulations of this invention are prepared as follows: compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnesium stearate), and compressed into tablets.
• Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols).
• the resulting tablets may be coated with an optional film- forming agent, for identification, taste-masking purposes and to improve ease of swallowing.
• the film forming agent will typically be present in an amount ranging from between 2% and 4% of the tablet weight.
• Suitable film-forming agents are well known to the art and include hydroxypropyl. methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers - Eudragit® E - R ⁇ hm. Pharma), and the like.
• These film- forming agents may optionally contain colorants, plasticizers, and other supplemental ingredients.
• the compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression.
• the tablet size will depend primarily upon the amount of compound in the tablet.
• the tablets will include from 300 to 1100 mg of compound free base.
• the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg, and 900-1100 mg.
• the time during which the compound containing powder is wet mixed is controlled.
• the total powder mix time i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes.
• the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60 0 C.
• a mitochondrial pellet obtained from 5 g of hamster liver was resuspended in 10 mL of 10 mM sodium phosphate buffer (pH 7.4), kept on ice, and sonicated for 3-15 seconds at 90 Wof power with a Branson Sonifier cell disruptor. This suspension was centrifuged at 105000g for 70 min in a Beckman L8 ultracentrifuge and the supernatant, which contained ALDH-2 activity, was used for the ALDH-2 assay. The pellet, which contained mainly mitochondrial membrane, was washed 3 times in 30 mL TKK buffer (10 mM Tris, 10 mM KCl, and 10 mM KPi, pH 7.4).
• TKK buffer 10 mM Tris, 10 mM KCl, and 10 mM KPi, pH 7.4
• the final pellet which contained only MAO but not ALDH-2 activity, was used for MAO assay.
• ALDH-2 activity was assayed in 0.1 M NaPPi, pH 9.5, containing 0.15 M KCl, 1.2 mM NAD+, 0.6 mM formaldehyde, and specified concentrations of daidzin or its structural analogues.
• Activity was determined by following the increase in absorbance at 340 nm with a Varian Cary 1 spectrophotometer at 25 °C23 MAO activity was assayed in TKK buffer containing 10 iM 5-HT, 0.4 mM sodium bisulfite, specified concentrations of daidzin or its structural analogues, and MAO. Enzyme reaction was initiated by the addition of enzyme and was allowed to proceed at 37 0 C for 30 min. The reaction was terminated by centrifugation at 4 0 C in a Sorvall Microspin at top speed for 15 min.
• the reaction product 5-HIAL present in the supernatant as its stable bisulfite complex, was liberated by diluting the supernatant 10-100-fold in 50 mM NaPPi, pH 8.8 and analyzed by HPLC. Since 5-HIAL is relatively unstable at alkaline pH, 5-HIAL was liberated not more than 4 h before HPLC analysis.
• the overall recovery of 5-HIAL and 5-HIAA in assay samples spiked with standard analytes were 0.78 and 0.86, and the intra-assay coefficient of variation of the analytical methods determined with samples spiked with 2 micromolar of the respective analytes are 11.2% and 7.5%.
• the strains of alcohol-preferring rats are housed individually in stainless-steel wire mesh cages (26 ' 34 '20 cm) under constant temperature of 21 ⁇ 1°C and reversed 12 hour light— 12 hour dark cycle (10:00-22:00 dark). These rats consume significantly more alcohol than their respective control strains: the selectively -bred alcohol non- preferring (NP), the low alcohol-drinking (LAD) rat, and the Wistar rat.
• the FH and P rats were derived from the Wistar rat. Water and food (Agway Prolab Rat/Mouse/Hamster 3000 formula, Agway, Syracuse, USA) were provided ad lib.
• a chronic experiment is conducted with adult male P rats. After establishment of stable baselines for alcohol and water intakes, and following a cross-over design, the test drug or vehicle is given i.p. once a day for 10 consecutive days. Alcohol and water intakes are measured at 6 and 24 hours after the treatment, whereas food intake is measured 24 hours after the treatment. Each rat receives both treatments, and a washout period of 3 days is imposed between treatments.
• Alcohol intake (g/kg) is calculated by multiplying the volume of alcohol consumed by 10% and 0.7893 (ethanol density)/animal body weight in kg. Alcohol preference, expressed as a percentage, is calculated as follows:
• Intravenous cocaine (0.35mg/kg/inj) was used in an operant self administration and reinstatement model in rats.
• rats addicted to cocaine repeatedly pressed a lever to obtain an intravenous dose (iv) of cocaine.
• iv intravenous dose
• rats resumed lever pressing for cocaine (reinstatement) if subjected to a small intraperitoneal (ip) dose (10mg/kg) of cocaine that normally has no effect in na ⁇ ve animals.
• ip intraperitoneal
• Cocaine reinforcement was delivered on a modified FRl schedule such that each drug infusion was accompanied by illumination of a stimulus over the active lever and a 20 second timeout during which active lever presses were counted but did not result in reinforcer delivery. After 20 seconds the stimulus light turned off and the first lever press again resulted in drug delivery. Depression of the inactive lever did not have any consequence.
• Daily training sessions for each group lasted 2 hours, or until a subject earned 200 drug infusions, whichever came first. The subjects remained in drug self-administration training mode until acquisition criterion was met (average presses on the active lever varied by ⁇ 10% over 3 consecutive training days). This typically takes 10-14 days.
• the Wistar-derived rats received several doses of 3-[(3- ⁇ 4- [(methylsulfonyl)amino]phenyl ⁇ -4-oxochromen-7-yloxy)methyl]benzoic acid (0.00, 7.5, 10, and 15 mg/kg) administered intraperitonealy (Lp.), and a positive control compound, mecamylamine (1.5 mg/kg, subcutaneously (s.c). The compounds were administered 30 minutes prior to SA sessions. 3-[(3- ⁇ 4-[(methylsulfonyl)amino]phenyl ⁇ -4-oxochromen-7-yloxy)methyl]benzoic acid (0.00, 7.5, 10, and 15 mg/kg) administered intraperitonealy (Lp.), and a positive control compound, mecamylamine (1.5 mg/kg, subcutaneously (s.c). The compounds were administered 30 minutes prior to SA sessions. 3-[(3- ⁇ 4-[(methylsulfonyl)amino]phenyl ⁇ -4-
• [(methylsulfonyl)amino]phenyl ⁇ -4-oxochromen-7-yloxy)methyl]benzoic acid was administered at 2 ml/kg for the 7.5 mg/kg (3.75 mg/ml) and 10 mg/kg (5 mg/ml), doses, and at 3 ml/kg for the 15 mg/kg dose (5 mg/ml).
• the compound was dissolved in corn oil (VEH), and sonicated for at least 30-minutes, up to 2 hours prior to administration.
• I l l Mecamylamine was dissolved in 0.09% isotonic saline and administered at a volume of 1 ml/kg.
• Lever pressing was established as demonstrated by the method of Hyytia et al, (1996). Initially, rats were restricted to 15 grams of food daily (approximately 85% of their free-feeding body weight). After the second day of food restriction, rats were trained to respond for food under a fixed-ratio 1 (FRl) schedule of reinforcement (1 food pellet for each lever press) with a 1 second time-out (TO-Is) after each reinforcement. Training sessions were given twice per day, and TO periods were gradually increased to 20 seconds. Once rats obtained a steady baseline responding at a FRl-TO20s schedule of reinforcement, they were returned to ad libitum food prior to preparation for intravenous jugular catheter implant surgery.
• FRl fixed-ratio 1
• TO-Is 1 second time-out
• Rats were anesthetized with a ketamine/xylazine mixture and chronic silastic jugular catheters were inserted into the external jugular vein and passed subcutaneously to a polyethylene assembly mounted on the animal's back.
• the catheter assembly consisted of a 13-cm length of silasitic tubing (inside diameter 0.31 mm; outside diameter 0.64 mm), attached to a guide cannula that was bent at a right angle.
• the cannula was embedded into a dental cement base and anchored with a 2 x 2 cm square of durable mesh.
• the catheter was passed subcutaneous Iy from the rats back to the jugular vein where it was inserted and secured with a non-absorbable silk suture.
• rats Upon successful completion of surgery, rats were given 3-5 days to recover before self- administration sessions started. During the recovery period, rats remained ad libitum food access, and had catheter lines flushed daily with 30 units/ml of heparinized saline containing 66 mg/ml of Timentin to prevent blood coagulation and infection in the catheters.
• Rats were allowed to self-administer nicotine after treatment with each dose of 3-[(3- ⁇ 4-[(methylsulfonyl)amino]phenyl ⁇ -4-oxochromen-7-yloxy)methyl]benzoic acid for 1 test session, and subsequently "rebaselined” for 1-3 days before the next dose probe during one test self-administrations sessions.
• rats received the positive control compound, mecamylamine (1.5 mg/kg), administered according to a crossover design.

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