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  • 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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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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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  • C07D241/40—Benzopyrazines
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  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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  • C07D277/62—Benzothiazoles
  • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles 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 in position 2
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  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles 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 in position 2
  • C07D277/82—Nitrogen atoms
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Definitions

• the present invention is concerned with piperazine derivatives, therapeutic dosage forms including one or more of the derivatives, and methods for treating diseases in mammals, and in particular, in a human in a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
• a therapy selected from the group including protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart
• U.S Patent No. 4,561,264 discloses a class of substituted piperazine compounds that includes a compound known as ranolazine, ( ⁇ )-N- (2,6-dimethylphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)- propyl]-l-piperazineacetamide, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise-induced angina, and myocardial infarction.
• U.S. Patent No. 5,506,229 which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants, hi particular, ranolazine is particularly useful for treating arrhythmias, variant and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation.
• Conventional oral and parenteral ranolazine formulations are disclosed, including controlled release formulations.
• 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
• ranolazine is a very useful cardiac therapeutic agent, there remains a need for compounds that are partial fatty acid oxidation inhibitors that have a half-life greater than ranolazine and that have activities as least similar to ranolazine.
• This invention includes novel heteroaryl alkyl piperazine derivatives that are partial fatty acid oxidation inhibitors with good therapeutic half-lives.
• This invention also includes novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
• novel substituted piperazine compounds that can be administered to a mammal to protect skeletal muscles against damage resulting from trauma, to protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
• This invention includes a class of substituted piperazine compounds having the formula:
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , CMS alkyl, C 2 . 15 alkenyl, C 2 .
• alkynyl, heterocyclyl, aryl, and heteroaryl wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , and SO 2 R 22 and wherein R 1 and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 when taken together with the carbons to which they are attached may form a 6-membered aromatic ring that is optionally substituted by alkyl, trifluoroalkyl, alkoxy, or halogen; R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen or C1-3 alkyl;
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, CO 2 R 20 , CON(R 20 ) 2 , C ⁇ _. 4 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , CN, OR 20 , N(R 20 ) 2> CO 2 R 20 , CON(R 20 ) 2 or aryl, wherein R 9 and R 10 may together form a carbonyl, or R 11 and R 12 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl, or R 15 and R 16 may together form a carbonyl or R 11 and R 13 or R 9 and R 15 or R 9 and R 11 or R 11 and R 15 or R 9 and R 13 may join together to form a ring including from 1 to 3 carbon atoms;
• R 17 is heteroaryl that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , Ci.i 5 alkyl, C . 15 alkenyl, C 2 .
• alkynyl, heterocyclyl, aryl, or heteroaryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 ;
• R 20 is selected from the group consisting of H, C S alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl, CN, -O-C ⁇ .
• R 22 is selected from the group consisting of C S alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C ⁇ . . 6 alkyl, CF 3 , or heteroaryl.
• this invention is a substituted piperazine compound selected from the group consisting of N-(2,6-dimethyl-phenyl)-2-(4- ⁇ 2-hydroxy-3-[2-(3- rifluoromethylphenyl)-benzoxazol-5-yloxy]- ⁇ ropyl ⁇ - ⁇ iperazin-l-yl)acetamide, 2- ⁇ 4-[3-
• this invention is a method for administering one or more composition of this invention to a mammal in a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
• a treatment selected from the group consisting of protecting skeletal muscles against damage resulting from trauma, protecting skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
• a class of substituted piperazine compounds having the following formula:
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 0 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C M5 alkyl, C2-15 alkenyl, C 2 .
• alkynyl, heterocyclyl, aryl, and heteroaryl wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , and SO 2 R 22 and wherein R 2 and R 3 or R 3 and R 4 or R 4 and R 5 when taken together with the carbons to which they are attached may form a 6- membered aromatic ring that is optionally substituted by alkyl, trifluoroalkyl, alkoxy, or halogen;
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen or C1-3 alkyl
• R 9 , R 10 , R ⁇ , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, CO 2 R 20 , CON(R 20 ) 2 , CM alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , CN, OR 20 , N(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 or aryl, wherein R 9 and R 10 may together form a carbonyl, or R 11 and R 12 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl, or R or R 9 and R 11 or R 11 and R 15 or R 9 and R 13 may join together to form a ring including from 1 to 3 carbon atoms;
• R 17 is heteroaryl that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 )2, NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C MS alkyl, C2-15 alkenyl, C 2 .
• alkynyl, heterocyclyl, aryl, or heteroaryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 ;
• R 20 is selected from the group consisting of H, C S alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl, CN, -O-C ⁇ .
• R 22 is selected from the group consisting of CM S alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C ⁇ .. 6 alkyl, CF 3 , or heteroaryl.
• q NH or O.
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , SO 2 N(R 20 ) 2 , CO 2 R 20 ,
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , - 5 alkyl, C 2 -s alkenyl, or C 2 . 5 alkynyl, wherein the alkyl substituent is optionally substituted with CF 3 .
• R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , - 5 alkyl, C 2 -s alkenyl, or C 2 . 5 alkynyl, wherein the alkyl substituent is optionally substituted with CF 3 .
• R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , or C1 . . 3 alkyl wherein the alkyl substituent is optionally substituted with CF 3 . More preferably R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, CF 3 , OR 20 , or . 2 alkyl, with hydrogen, OR 20 , or methyl being more preferred and hydrogen or methyl being most preferred.
• any one of R 1 and R 2 or R 2 and R 3 or R 3 and R or R and R 5 when taken together with the carbons to which they are attached may form a 6-membered aromatic ring that is optionally substituted by alkyl, trifluoroalkyl, alkoxy, or halogen with the remaining substituents defined as set forth in the paragraph above, h this embodiment, it is most preferred that R and R when taken together with the carbons to which they are attached form a 6-membered aromatic ring.
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen or C 1 . 3 alkyl and most preferably hydrogen or methyl.
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, CON(R 20 ) 2 , C ⁇ _ 4 alkyl, or wherein R 9 and R 10 may together form a carbonyl, or R 11 and R 12 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl, or R 15 and R 16 may together form a carbonyl.
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen or d- 2 alkyl, wherein R 9 and R 10 may together form a carbonyl, or R u and R 12 may together form a carbonyl, or R 3 and R 14 may together form a carbonyl, or R 15 and R 16 may together form a carbonyl.
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, or methyl, wherein R 9 and R 10 may together form a carbonyl, or R 11 and R 12 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl, or R 15 and R 1 may together form a carbonyl.
• R , R , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, or C ⁇ _- 2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R 20 ) 2 , or aryl or wherein R 9 and R 10 may together form a carbonyl.
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen or d. 2 alkyl, or wherein R 9 and R 10 may together form a carbonyl.
• R 11 and R 15 are each selected from the group consisting of hydrogen or methyl
• R 9 , R , R 2 , R 13 , R 14 and R 16 are each hydrogen and R 9 and R 10 may together form a carbonyl.
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each hydrogen.
• R 17 is a heteroaryl that is optionally substituted with
• R is a heteroaryl that is a fused 6,5 membered ring system containing from 1 to 5 heteroatoms each selected from the group consisting of N, O, or S that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C MS alkyl, C 2 .
• alkenyl C 2 - ⁇ s alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent independently selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 .
• R 17 is preferably a heteroaryl that is a fused 6,5 membered ring system containing from 1 to 3 heteroatoms selected from the group consisting of N, O, or S that is optionally substituted with from 1 to 2 substituents selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 , C ⁇ . 8 alkyl, C 2 . 8 alkenyl, C 2 .
• alkynyl aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent independently selected from the group consisting of halo, CF 3 , OR 20 , or N(R 20 ) 2 .
• R 17 is a heteroaryl that is a fused 6,5 membered ring system containing from 1 to 2 heteroatoms selected from the group consisting of N, O, or S that is optionally substituted with from 1 to 2 substituents selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 ) 23 CON(R 20 ) 2 , C alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , or OR 20 .
• R 17 is a heteroaryl that is a fused 6,5 membered ring system selected from the group consisting of indole, benzothiazole, and benzoxazole that is optionally substituted with from 1 to 2
• R 17 is preferably benzothiazole that is optionally substituted with 1 substituent selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 , C1- 3 alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo or CF 3 .
• R 17 is benzothiazole that is optionally substituted at the 2-position with 1 substituent selected from the group consisting of hydrogen, methyl or phenyl.
• R 17 is 5-substituted benzothiazole that is optionally substituted with 1 substituent selected from the group consisting of hydrogen, halo, CF , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 , C 1 - 3 alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo or CF 3 .
• the 5-substituted benzothiazole is preferably substituted at the 2-position with 1 substituent selected from the group consisting of hydrogen, methyl or phenyl.
• R is a heteroaryl that is a fused 6, 6 membered ring system containing from 1 to 4 nitrogen atoms that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C MS alkyl, C 2 .
• alkenyl C 2 - ⁇ s alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent independently selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 .
• R 17 is a heteroaryl that is a fused 6, 6 membered ring system containing from 1 to 3 nitrogen atoms that is optionally substituted with from 1 to 2 substituents selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 )2, CON(R 20 ) 2 , Ct- 8 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent independently selected from the group consisting of halo, CF 3 , OR 20 , or N(R 20 ) 2 .
• R 17 is a heteroaryl that is a fused 6, 6 membered ring system containing from 1 to 2 nitrogen atoms that is optionally substituted with methyl;
• R 17 is a 5 or 6-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of N, S, or O that is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , C MS alkyl, C 2 - 15 alkenyl, C 2 .
• alkynyl, heterocyclyl, aryl, or heteroaryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent independently selected from the group consisting of halo, NO 2 , CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , or SO 2 R 22 .
• R 17 is a 5 or 6 membered ring including from 1 to 3 heteroatoms selected from N, S, or O nitrogen atoms that is optionally substituted with from 1 to 2 substituents selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 , .g alkyl, C 2 .
• R 17 is a 6 membered ring including from 1 to 2 nitrogen atoms that is optionally substituted with from 1 to 2 substituents selected from the group consisting of hydrogen, halo, CF 3 , OR 20 , N(R 20 ) 2 , CON(R 20 ) 2 , C M alkyl, C 2 .
• R 17 is a 6 membered ring containing from 1 to 2 nitrogen atoms that is optionally substituted with methyl.
• R 17 is a heteroaryl that is a fused 6,5 membered ring system selected from the group consisting of benzothiazole, and benzoxazole that is optionally substituted with 1 substituent selected from the group consisting of hydrogen, CF 3 , OR 20 , C alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo or CF 3 and preferably optionally substituted with methyl.
• R 20 is selected from the group consisting of H, CMS alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkylcyano, -O-C ⁇ . . 6 alkyl, or CF 3 .
• R 20 is selected from the group consisting of H, CM alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -OMe, or CF 3 .
• R 20 is selected from the group consisting of H, CM alkyl, or aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, -OMe, and CF 3 . Most preferably, R 20 is selected from the group consisting of H or C M alkyl and most preferably H or methyl.
• R 22 is selected from the group consisting of C MS alkyl, aryl, or heteroaryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O- - ⁇ alkyl, CF 3 , or heteroaryl.
• this invention is a substituted piperazine compound selected from the group consisting of N-(2,6-dimethyl-phenyl)-2-(4- ⁇ 2-hydroxy-3-[2-(3- trifluoromethylphenyl)-benzoxazol-5-yloxy]-propyl ⁇ -piperazin-l-yl)acetamide, 2- ⁇ 4-[3-
• Halo or “Halogen” - alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).
• Hydroxyl refers to the group -OH.
• Thiol or “mercapto” refers to the group -SH.
• Alkyl - alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined). It is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6, yet more preferably 1-4 and most preferably 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
• the term "lower alkyl” is used herein to describe the straight chain alkyl groups described immediately above.
• cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
• Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl.
• a substituted alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbony
• Alkenyl - alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2 to 4 carbon atoms with at least one, preferably 1-3, more preferably 1-2, and most preferably one, carbon to carbon double bond.
• a cycloalkyl group conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring.
• Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion.
• alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like.
• a substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, al
• Alkynyl - alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond.
• alkynyl groups include ethynyl, propynyl, butynyl and the like.
• a substituted alkynyl refers to the straight chain alkynyl or branched alkynyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N- mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino
• Alkyl alkynyl refers to a groups -RG ⁇ CR' where R is lower alkyl or substituted lower alkyl, R' is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.
• Alkoxy denotes the group -OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.
• Alkylthio denotes the group -SR, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.
• Acyl denotes groups -C(O)R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl and the like as defined herein.
• Aryloxy denotes groups -OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.
• Amino denotes the group NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined herein or acyl.
• “Amido” denotes the group -C(O)NRR', where R and R' may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.
• “Carboxyl” denotes the group -C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.
• Aryl - alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,
• Substituted aryl refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• functional groups e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Heterocycle refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, witlnn the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• a single ring e.g., morpholino,
• Heteroaryl alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alky
• Heteroaryl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
• a carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained.
• heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
• a substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.
• Heterocyclyl - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl.
• Heterocycyl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom.
• heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like.
• a substituted hetercyclyl contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.
• Substituted heteroaryl refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• functional groups e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Aryl refers to the group -R-Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group.
• Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Heteroalkyl refers to the group -R-Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Heteroarylalkyl refers to the group -R-HetAr where HetAr is an heteroaryl group and
• R lower alkyl or substituted lower alkyl.
• Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Cycloalkyl refers to a divalent cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.
• Substituted cycloalkyl refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, all ylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Cycloheteroalkyl refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).
• Substituted cycloheteroalkyl refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• substituents such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Alkyl cycloalkyl denotes the group -R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl.
• Cycloalkyl groups can- optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Alkyl cycloheteroalkyl denotes the group -R-cycloheteroalkyl where R is a lower alkyl or substituted lower alkyl.
• Cycloheteroalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.
• Treating” and “treatment” refer to any treatment of a disease in a mammal, particularly a human, and include: (i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
• All of the aforementioned embodiments include the pharmaceutically acceptable acid addition salts thereof, particularly the mono- and dihydrochlorides, and mixtures thereof.
• a general synthesis of the compounds of this invention is outlined in Scheme 1.
• Compound IV can be prepared by N-acylation of substituted aniline II with 2- substituted chloroacetylchloride III.
• Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley- Interscience).
• Some examples of commercially available substituted anilines corresponding to general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4- methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3 -chloroaniline, 4-acetoxyaniline.
• SCHEME 1 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4- methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-
• Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V through warming in an appropriate solvent (e.g. DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of Compound V with compound IV. In some cases, compound V can be obtained from commercial resources.
• an appropriate solvent e.g. DMF, EtOH.
• Examples of commercially available compounds corresponding to general structure V include 2-methylpiperazine, 2,5- dimethylpiprazine, 2,6-dimethylpiperazine, 2,3,5,6-tetramethylpiperazine, piperazine-2- carboxylic acid, perhydroquinoxaline, 2-aminomethyl-6-methylpiperazine, 2- aminomethylpiperazine, 2-(o-chlorophenyl)piperazine, and 2-(m-chlorophenyl)piperazine.
• Deprotection of compound VI can be accomplished using the standard conditions (e.g. for Boc group use TFA, for CBZ and benzyl use hydrogenation).
• Compound la or Ic can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF, CHCI 2 , THF) or by stirring at room temperature in the presence of a lanthamide (IH) Lewis acid (Chini, Met al, Tetrahedron Lett., 35: 433-36 (1994).
• an appropriate solvent ethanol, DMF, CHCI 2 , THF
• IH lanthamide
• Compound IX can be obtained from commercial resources. Examples of commercially available compounds corresponding to structure XI include 2-methyl-5- hydroxybenzothiazole, 2-hydroxybenzothiazole, 8-hydroxyquinolidine, 6-hydroxyquinoline, 4-hydroxyquinoline, 5-hydroxyisoquinoline, 3-hydroxypyridine, 2-quinoxalinol, and 4- (imidazol-l-yl)phenol. In some cases compound VIII can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure VIII include 4-glycidyloxy-2-indolecarboxamide.
• Compound IX can in turn be prepared by the deprotection of the corresponding methyl or benzyl ethers (X) using Lewis acids as shown in Scheme 3 (BBr 3 , BF 3j etc.- see Advanced Organic Chemistry, Ed. J. March (1992) A. Wiley Intersciences, p 434).
• Benzyl ethers can also be deprotected by refluxing with palladium hydroxide in ethanol/cyclohexene (see Catalytic hydrogenation over platinum metals, P. N. Rylander, Academic Press, New York, NY, (1976) p 464).
• Commercially available methyl ethers include 6-methoxy-2-methyl- benzothiazole. SCHEME 3
• Compound IX can also be prepared by the diazotization of the corresponding amino compounds (XI) as shown in Scheme 4 (Boggust, W. A and Cocker, W. J. Chem. Soc. 1949, 355).
• Commercially available amines include 6-amino-benzothiazole.
• the 6, 5 fused ring system of compound X can be prepared by the cyclization of commercially available ethers of 2-aminophenols, 2-aminothiophenols, or 2-aminoanilines (XII) with orthoesters (XIII) (Musser, J. H. et al, J. Med. Chem. 1985, 28, 1255-1259) or imidates (XIV) (Gregory, G. I. Et al, J. Chem. Soc. Perkin Trans. 1, 1973, 47-51) as shown in Scheme 5 and 6 respectively.
• ethers of aminophenols include 4- methoxy-2-aminophenol
• orthoesters include trimethyl orthoformate and trimethyl orthoacetate
• imidates include ethyl acetimidate hydrochloride, and ethyl benzimidate hydrochloride.
• the thiophenol analog of compound XII can be prepared from the commercially available compound XV by reacting with sodium disulfide hydrate followed by reduction using tin and hydrochloric acid ( Dannley, R. L. and Zazaris, D. A; Can. J. Chem. 1965, 43, 2610-2612) as shown in Scheme 7.
• Commercially available nitro compounds include 3-nitro- 4-chloroanisole.
• Benzyl Imidate XIV can be prepared by bubbling HC1 gas through an alcoholic solution of the commercially available nitriles XVI as shown in Scheme 8.
• Commercially available nitriles include, benzonitrile, 4-trifluoromethylbenzonitrile and 3-trifluoromethylbenzonitrile.
• Sulfur containing 6,5 fused ring system of compound X can also be prepared from the commercially available ethers of anilines XVII (Stevens, M. F. G. et al, J. Med. Chem. 1994, 37, 1689-1695) as shown in Scheme 9.
• Thioamide XX can be obtained by the reaction of Lawesson's reagent with amide XIX which in turn can be prepared by the reaction of compound XVII with compound XVIII. Cyclization of XX with potassium ferrocyanide under basic conditions can afford compound XXI.
• Commercially available ethers of anilines include benzyloxyanilines and anisidines.
• a general synthesis of the compound XXV of this invention is outlined in Scheme 10.
• Compound XXIV can be prepared by the deprotection of compound XXIII using the standard conditions (e. g. for BOC group use TFA, for CBZ and benzyl use hydrogenation).
• Compound XXIII in turn can be prepared by the reaction of the commercially available protected monoketopiperazine analog compound XXII with compound IV and sodium hydride in an appropriate solvent (DMF, THF).
• An example of the commercially available monoketopiperazines include 4-benzyloxycarbonylpiperazine-2-one.
• Compound XXVII can be prepared by refluxing compound VII with the epoxide XXVI in a suitable solvent (ethanol, THF). Deprotection of compound XXVII can be accomplished by using standard conditions (e. g. for BOC group use TFA; for CBZ use hydrogenation or Pd(OH) 2 ).
• Compound lb can be prepared by refluxing compound XXVIII with compound XXIX in a suitable solvent (ethanol, THF).
• compound XXIX includes 2-chlorobenzothiazole, 2-chlorobenzoxazole, 2-chloropyridine, 2- chloropyrimidine, 2-chloro-4-(trifluoromethyl)pyrimidine, and chloropyrazine.
• Epoxide XXVI in turn can be prepared as shown in Scheme 12.
• Commercially available compound XXX can be protected using the standard conditions (for BOC protection use BOC anhydride; for CBZ protection use CBZ-Cl).
• Compound XXV can be prepared by the reaction of compound XXXI using m-chloroperbenzoic acid in a suitable solvent (e. g. dichloromethane).
• An example of a commercially available compoxmd XXX includes by is not limited to allylamine.
• Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of
• aldehydes include isobutyraldehyde.
• Compound V also includes the bicyclic homologs of piperazine (lS,4S)-(+)-2,5- diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1] octane 84, and 2,5-diazabicyclo[2.2.2] octane 85.
• 83 84 85 Commercially available bicyclic analogs include (lS,4S)-(+)-2,5- diazabicyclo[2.2.1]heptane 83.
• Compounds 84, 85, and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85- see Sturm, P. A. et al, J. Med. Chem. 1974, 17, 481-487; for 83 see- Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687).
• the benzoxazole derivative 8 was prepared by the deprotection of compound 13 as shown in Scheme 18.
• Compound 10 was prepared by condensation of 2-amino-4- methoxyphenol 12.
• Compoxmd 12 was obtained by the catalytic hydrogenation of the commercially available 4-methoxy-2-nitrophenol 11, and the benzimidate derivative 13 as shown in Scheme 19.
• Compound 13 was obtained from 3-trifluoromethylbenzonitrile 14 using a Pinner reaction (ethanol/anhydrous HC1).
• Compoxmd 19 was prepared by condensation of compound 12 with trimethyl orthoacetate 18 as shown in Scheme 22.
• Compoxmd 22 can be prepared by the reduction of compound 21 with tin and hydrochloric acid as shown in Scheme 23.
• Compound 21 was synthesized by reacting compound 20 with sodium disulfide hydrate.
• Compound 26 was prepared by the reaction of compound 25 with Lawesson's reagent as shown in Scheme 24.
• Compound 25 was prepared by the reaction of the aniline 23 with benzoyl chloride 24. Cyclization of the thioamide 26 with potassium ferrocyanide in aqueous sodium hydroxide gave a mixture of compounds 27 and 28. Compounds 27 and 28 were separated by column chromatography. SCHEME 24
• Epoxide 35 was synthesized as described in Scheme 28. Allylamine 40 was reacted with benzyl chloroformate in dichloromethane to afford compound 42. Reaction of m- chloroperbenzoic acid with 42 gave the epoxide 35.
• the acid addition salts of the compounds of this invention may be converted to the corresponding free base by treating with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0 degrees C and 100 degrees C.
• a suitable base such as potassium carbonate or sodium hydroxide
• the free base form is isolated by conventional means, such as extraction with an organic solvent.
• Salts of the compounds of this invention may be interchanged by taking advantage of differential solubilities and volatilities, or by treating with the appropriately loaded ion exchange resin. This conversion is carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure.
• Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes.
• the preferred method of admimstration is oral, except in those cases where the subject is unable to ingest, by himself, any medication. In those instances it may be necessary to administer the composition parentarally.
• compositions may be in the form of solid, semi- solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages.
• the compositions may include one or more conventional pharmaceutical excipients and at least one active compound of this invention or the pharmaceutically acceptable salts thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
• the amount of active compound administered will, of course, be dependent on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
• an effective dosage is in the range of 0.1-30 mg/kg/day, preferably 0.5-20 mg/kg/day. For an average 70 kg human, this would amount to 7-2100 mg per day, or preferably 35-1400 mg/day. Since many of the effects of the compounds herein (protect skeletal muscles against damage resulting from trauma; protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication; treat shock conditions; preserve donor tissue and organs used in transplants; and treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, and myocardial infarction) are achieved through a similar mechanism (partial fatty acid oxidation inhibition) dosages (and forms of administration) are all generally within the same general and preferred ranges for all these utilities.
• conventional non-toxic solid include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
• the active compound as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc.
• an active compound as defined above and optional pharmaceutical adjuvants in a excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
• a excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
• the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
• wetting or emulsifying agents such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
• compositions or formulation to be administered will, in any event, contain a quantity of the active compound(s), a therapeutically effective amount, i.e. in an amount effective to alleviate the symptoms of the subject being treated.
• a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
• Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
• Such compositions may contain 10%-95% active ingredient, preferably 1-70%.
• hijectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like, i addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
• compositions of this invention can be administered orally in a sustained release dosage form using the compositions and/or methods disclosed in U.S. Patent Application Serial No. 09/321,522, filed on May 27, 1999, the specification of which is incorporated herein by reference.
• Compoxmd 44 was prepared in the manner of compound 6 substituting 2-hydroxy- benzothiazole for compound 8 inpartC-5 of Example 1.
• Example 3 N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-(2-methyl-benzothiazol-5-yloxy)-propyl]- piperazin-l-yl ⁇ acetamide (45):
• Compoxmd 33 was prepared in the manner of compound 6 substituting 2-methyl- benzothiazol-5-ol for compoxmd 8 in partC-5 of Example 1.
• Compoxmd 48 was prepared in the manner of compound 6 substituting compound 16 for compound 8 in partC-5 of Example 1.
• Compound 51 was prepared in the manner of compound 6 substituting compound 50 for compound 8 in partC-5 of Example 1.
• Compoxmd 53 was prepared in the manner of compound 3 substituting 2,6- dimethylpiperazine for piperazine in part A of Example 1.
• Compoxmd 57 was prepared as described in part B of Example 1 substituting compound 56 for compound 3.
• Compoxmd 63 was prepared in the manner of compound 59 substituting deprotected compound 28 for compoxmd 29 in example 9.
• Compoxmd 75 was prepared in the manner of compound 6 substituting 4-hydroxyquinoline for compomid 8 in part C-5 of Example 1.
• Example 19 N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-(quinolin-6-yloxy)-propyl]-piperazin-l- yl ⁇ acetamide (78):
• Compoxmd 79 was prepared in the mamier of compound 6 substituting 6-hydroxy- quinoline for compoxmd 8 in part C-5 of Example 1.
• Compoxmd 81 was prepared in the manner of compound 6 substituting 7-hydroxy-2- methyl-quinoline for compound 8 in part C-5 of Example 1.
• Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
• Palmitoyl CoA oxidation was carried out in a total volume of 100 micro liters containing the following agents: 110 mM KC1, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl 2 , 0.1 mM EDTA, 14.7 microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms of mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA (Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters per assay).
• the compounds of this invention were added in a DMSO solution at the following concentrations: 100 microM, and 50 microM.
• a DMSO control was used.
• the enzymatic reaction was centrifuged (20,000 g for 1 min), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (approximately 0.5 ml of silicic acid).
• the column was eluted with 2 ml of water, and 0.5 ml of the eluent was used for scintillation counting to determine the amount of C 14 trapped as C 14 bicarbonate ion.
• Metabolic Stability As a measure of metabolic stability the compounds of this invention were incubated with human liver S-9 microsomal fractions. After, 30 minutes at 37 C, the amount of parent drug remaining was determined using LC-mass spec. The response factors for each compound was determined by establishing a standard curve and using an internal standard during the analysis of the samples. An average of five experiments for percentage of ranolazine remaining at the 30 minute time point is 57%. The compounds of this invention were assayed as described in the protocol below and the percentage of parent remaining was divided by the average % of ranolazine remaining (57%) affording a metabolic stability factor. A compoxmd with a stability number greater than 1.2 has a better stability than ranolazine in the liver S-9 assay. A compoxmd with a stability number between 1.2 and 0.8 has an equivalent stability in the liver S-9 assay. A compomid with a stability number less than 0.8 is less stable than ranolazine in the liver S-9 assay.

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