Classifications

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  • 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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  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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  • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
  • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
  • C07D241/40—Benzopyrazines
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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
  • C07D295/08—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 singly bound oxygen or sulfur atoms
  • C07D295/084—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—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 singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/54—Radicals substituted by oxygen atoms
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  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/58—Radicals substituted by nitrogen atoms
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention is concerned with substituted piperazine compounds, therapeutic dosage forms including one or more of the compounds, 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. 4,567,264 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.
• 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.
• Example 7D of U.S. Patent No. 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
• This invention includes novel substituted piperazine compounds 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.
• This invention includes a class of substituted piperazine compounds having the following formula:
• R Consider 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C MS alkyl, C 2 . 15 alkenyl, C 2 .
• Rg, R 10 , R n , R] 2 , R 13 , R M , R 15 and R 16 are each independently selected from the group consisting of hydrogen, CO 2 R 23 , CON(R 23 ) 2 , C, ⁇ alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , CN, OR 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 2 and aryl, wherein R, and R 10 may together form a carbonyl, or R n 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 wherein R u and R 13 or Rg and R 15 or Rg and R, j or R u and R 15 or Rg and R 13 may join together to form a bridging ring system having from 1 to 4
• R 22 is selected from the group consisting of C,. 15 alkyl, aryl, and 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 , and heteroaryl;
• R 23 is selected from the group consisting of H, C, .15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-C,. 6 alkyl, and CF 3 ; and
• R 24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C 2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C,. 6 alkyl, and
• R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C,. IS 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , and SO 2 R 22 .
• 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.
• This invention includes a class of substituted piperazine compounds having the following formula:
• R Consider 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C M5 alkyl, C 2-15 alkenyl, C 2 .
• R ⁇ , R 7 and R 8 are each independently selected from the group consisting of hydrogen and C,. 15 alkyl;
• Rg, R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, CO 2 R 23 , CON(R 23 ) 2 , C alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , CN, OR 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 2 and aryl, wherein R, and R ]0 may together form a carbonyl, or R n 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 wherein R n and R 13 or R, and R 15 or Rg and R, , or R, , and R 15 or R, and R, 3 may join together to form a bridging ring system having from 1 to
• R 22 is selected from the group consisting of C,. 15 alkyl, aryl, and 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 , and heteroaryl;
• R 23 is selected from the group consisting of H, C, .15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl, CN, -O-C, ⁇ alkyl, and CF 3 ; and
• R 24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C,.
• R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C 5 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , and SO 2 R 22 .
• 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 22 and C M alkyl and wherein R 22 is a C,. 3 alkyl;
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen and C,_ 3 alkyl;
• R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen and C M alkyl, or 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 wherein R n and R 13 or R, and R 15 or R, and R n or R u and R, 5 or Rg and R 13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms with the proviso that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen.
• R 1 , R 2 , R 3 , R 4 and R 5 are each selected from the group consisting of hydrogen, halo, CF 3 , OR 22 and C alkyl where R 22 is a C ⁇ alkyl;
• R 6 is selected from hydrogen and methyl;
• R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl or R 9 and R 10 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl with the proviso that R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen.
• R 17 , R 18 , R 19 , R 20 and R 21 are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 22 , C,_ 3 alkyl wherein R 22 is C U3 alkyl, or R 17
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of methyl and hydrogen;
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl or R 9 and R 10 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl with the proviso that R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen;
• R 1 and R 5 are each methyl;
• R 2 , R ⁇ R 4 , R 6 , R 7 , R 8 are each hydrogen;
• R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl or R 9 and R 10 may together form a carbonyl, or R 13 and R 14 may together form a carbonyl with the proviso that R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen;
• R 1 and R 5 are each methyl;
• R 4 , R 6 , R 7 , R 8 are each hydrogen;
• R 9 , R 10 are selected from hydrogen, methyl, or may together form a carbonyl;
• R 11 and R 12 are selected from hydrogen and methyl;
• R 13 and R 14 are selected from hydrogen and methyl or may together form a carbonyl;
• R 15 and R 16 are hydrogen with the proviso that R 9 , R 10 , R", R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen;
• R 17 is selected from the group consisting of hydrogen, chloro, fluoro or methoxy;
• R 18 and R 19 are each selected from the group consisting of hydrogen or methoxy, or R 18 and R 19 may together form -OCH 2 O-, or
• R 20 is hydrogen; and
• R 21 is selected from hydrogen or chloro.
• the substituted piperazine compounds of Formula IA are selected from the group consisting of N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-(2- methoxyphenoxy)propyl]-3-oxopiperazinyl ⁇ acetamide, N-(2,6-dimethylphenyl)-2- ⁇ 4-[2- hydroxy-3-(2-methoxyphenoxy)propyl]-3,5-dimethylpiperazinyl ⁇ acetamide, 2- ⁇ (5S,2R)-4-[2- hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl ⁇ -N-(2,6- dimethylphenyl)acetamide, 2- ⁇ 2,5-diaza-5-[2-hydroxy-3-(2- methoxyphenoxy)propyl]bicyclo[4.4.0]dec-2-yl ⁇ -N-(2,6-dimethylphenyl)acetamide, N-(2,6- dim
• This invention includes a subset of substituted piperazine compounds of formula I having the following formula IB:
• 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C,. IS 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 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , and SO 2 R 22 ;
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen or C,. 15 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 23 , CON(R 23 ) 2 , C, ⁇ 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 23 , N(R 23 ) 2 , CO 2 R 23 , CON(R 23 ) 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 wherein R u and R 13 or R 9 and R 15 or R 9 and R 11 or R" and R 15 or R 9 and R 13 may join together to form a bridging ring system wherein the two R groups together comprise of from
• R 17 , R 18 , R 19 , R 20 , and R 21 are each independently selected from the group consisting of hydrogen, halo, NO 2 , CF 3 , CN, OR 23 , SR 23 , N(R 23 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 23 ) 2 , NR 23 CO 2 R 22 , NR 23 CON(R 23 ) 2 , COR 23 , CO 2 R 23 , CON(R 23 ) 2 , NR 23 SO 2 R 22 , C,. 15 alkyl, C 2-15 alkenyl, C 2 .
• 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; and R 23 is selected from the group consisting of H, C, .15 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, ⁇ alkyl, or CF 3 .
• m 0, 1 or 2 or 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 22 and C M alkyl;
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen and C,.
• 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 22 and C,. 2 alkyl wherein R 22 is a C,_ 3 alkyl; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen and methyl; R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen and C j .
• R 9 and R 10 may together form a carbonyl
• R 15 and R 16 may together form a carbonyl with the proviso that R 9 , R 10 , R", R 12 , R 13 , R 14 , R 15 and R 16 are not all simultaneously hydrogen and wherein R u 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 to form a ring including from 1 to 4 carbon atoms
• m 1 or 2;
• 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 22 and C, ⁇ alkyl where R 22 is a C,.
• R 6 , R 7 , R 8 , R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen and methyl;
• R 8 ,R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are hydrogen;
• R 1 and R 5 are methyl;
• R" R 12 , R 13 , R 14 , R 15 and R 16 are hydrogen;
• R 17 is selected from the group consisting of hydrogen, chloro, fluoro and methoxy;
• R 18 is selected from hydrogen and methoxy;
• R 19 is selected from hydrogen and methoxy;
• R 20 is hydrogen;
• R 21 is selected from hydrogen and chloro, or
• the substituted piperazine compounds of this invention are selected from N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6- dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl ⁇ acetamide; 2-[4- (3-(2H-benzo[d]l,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-(4- methoxyphenyl)propyl]piperazinyl ⁇ acetamide; N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-phenylpropyl]piperazinyl ⁇ acetamide; N-
• This invention further includes a subset of compounds of Formula I above having the following Formula IC:
• R ⁇ 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 ).
• 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 5 alkyl, C 2-15 alkenyl, C 2 . 15 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 ;
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen or C,_ 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, ⁇ 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 n 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 with the proviso that R 11 and R 13 or R 9 and R 15 or R 9 and R 11 or R u and R 15 or R 9 and R 13 may join together to form a ring including from 1 to 3 carbon atoms;
• R 24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C,_ 2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C M alkyl;
• R 20 is selected from the group consisting of H, C,. 15 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,_ 6 alkyl, or CF 3 ; and R 22 is selected from the group consisting of C,.
• 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 ⁇ alkyl, CF 3 , or heteroaryl.
• 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 22 and C M alkyl and wherein R 22 is a C U3 alkyl.
• 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 C,. 2 alkyl. More preferably R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, or methyl with R 2 , R 3 , and R 4 as hydrogen and R 1 and R 5 as methyl being preferred.
• R 6 , R 7 and R 8 each independently selected from the group consisting of hydrogen and C ⁇ alkyl with hydrogen or methyl being preferred and hydrogen being most preferred.
• 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 alkyl, or aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo, CF 3 , OR 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 with the proviso that R n 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.
• R 9 , R 10 , R 11 , R 12 are each independently selected from the group consisting of hydrogen, CON(R 20 ) 2
• R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, or R 9 and R 10 together form a carbonyl, or R 11 and R 12 together form a carbonyl, or R 13 and R 14 together form a carbonyl, or R 15 and R 16 together form a carbonyl,
• R 10 and R 11 together form -CH 2 CH 2 CH 2 CH 2 -.
• 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, 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. More preferably, R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen or C,.
• 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 10 , R 12 , R 13 , R 14 and R 16 are each hydrogen and R 9 and R 10 may together form a carbonyl, or, R 9 , R 10 , R ⁇ , R 12 , R 13 , R 14 , R 15 and R 16 may each be hydrogen.
• R 24 may be selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to three substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , C,.
• R 24 is selected from the group consisting of alkyl , cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , Cj.
• R 24 is selected from the group consisting of alkyl, cycloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, cycloalkyl, and fused phenylcycloalkyl are optionally substituted with from 1 to two substituents selected from the group consisting of halo, CF 3 , OR 20 , and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF 3 , CN, OR 20 , and C 6 alkyl.
• R 24 is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms, fused phenylcycloalkylwith a phenyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo,
• R 24 is alkyl having from 1 to 6 carbon atoms and cycloalkyl or R 24 is a fused phenylcycloalkyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OR 20 , Cj. 2 alkyl, and aryl or R 24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF 3 , OR 20 , C, ⁇ alkyl, and aryl.
• R 20 is selected from the group consisting of H, C, .3 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 More preferably, R 20 is selected from the group consisting of H or C ⁇ alkyl and most preferably, R 20 is methyl or H.
• the substituted piperazine compounds of Formula IC are selected from the group consisting of 2-( ⁇ 2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-( ⁇ 2,6- dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2- yloxypropyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2- ⁇ 4-[2-hydroxy-3-
• Halo or “Halogen” - alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).
• Haldroxyl 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, alkylsulfinyl, 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, heteroarylcarbon
• 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, alkylsulfinyl, 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,
• 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, alkylsulfinyl, 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, heteroarylcarbonylamin
• Alkyl alkynyl refers to a groups -RC ⁇ 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.
• 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, alkylsulfinyl, 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, alkylcarbony
• 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 fury! 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, within 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.
• 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, alkylsulfinyl, 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
• Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, 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, quinohnyl, 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 sulfinyl, 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.
• 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, alkylthio, acetylene, 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.
• “Optional” and “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
• optional pharmaceutical excipients indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.
• Treating and “treatment” refer to any treatment of a disease in a mammal, particularly a human, and include:
• compositions of this invention are useful for treating mammals in a therapy 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.
• the treatment is accomplished using a therapeutically effective amount of at least one compound of this invention and/or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable excipient.
• Compounds falling within the scope of this invention include the optical isomers (+) and (-) and R- and S- isomers of the above-identified compounds and mixtures thereof.
• This invention includes the individual isomers and all possible mixtures thereof.
• All of the aforementioned embodiments include the pharmaceutically acceptable acid addition salts thereof, particularly the mono- and dihydrochlorides, and mixtures thereof.
• the compounds having the general Formula I and IA can be prepared as outlined in Schemes 1A-7A.
• a general synthesis of the compounds of this invention is outlined in Scheme 1 A.
• 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/SnCl 2 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-dimethylanihne, 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-fiuoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.
• 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.
• compound V can be obtained from commercial resources. Examples of commercially available compounds co ⁇ esponding to general structure V include 2-methyl piperazine, 2,5- dimethyl piprazine and 2,6-dimethyl 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 I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF).
• Example of commercially available compounds of compounds XI include 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, 2-methylphenol, sesamol, 2,6- dichlorophenol, 3,5-dichlorophenol, 2,6-difluorophenol, 2,4-difluorophenol5-indanol, 3- chloro-4-fluorophenol, 2,chloro-4-fluorophenol and 5,6,7,8-tetrahydro-2-naphthol.
• compound VIII can be obtained from commercial sources.
• Examples of commercially available compounds co ⁇ esponding to general structure Vffl include benzyl glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chlorophenyl ether, glycidyl 2-chlorophenyl ether, glycidyl 2-methoxyphenyl ether, glycidyl 4- methylphenyl ether, glycidyl 3,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.
• Compound V can be prepared as described in Scheme 3. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et. al. (J. Org. Chem, (1997), 62, 1016-1022). Reduction of XTV using diborane can afford N- benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA) [ for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144].
• TFA trifluoroacetic acid
• Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection as outlined in Scheme 4 [For preparations of diketopiperazines see - P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford compound XIX the N-benzyl protected version of compound V.
• 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.
• 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 compounds having the general formula I and IB can be prepared as outlined in Schemes 1B-7B.
• a general synthesis of the compounds of this invention is outlined in Scheme IB.
• Compound IV can be prepared by N-acylation of substituted anilines of general structure II with 2-substituted chloroacetylchloride III.
• Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnCl 2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience).
• substituted anilines of general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2- methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4-dichloroaniline, .
• Compound VI can be obtained by reacting compound IV with a 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.
• compound V can be obtained from commercial sources. Examples of commercially available compounds of general structure V include 2-methyl piperazine, 2,5-dimethyl piperazine and 2,6-dimethyl 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 I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF).
• Epoxide VIII can be prepared as outlined in Scheme 2B. Epoxidation of substituted allylbenzene XI using mCPBA or hydrogen peroxide can afford epoxide VIII (G. Majetich, R. Hicks, G. Sun and P. McGill, (1998), 63, 2564-2573). Compound XI in turn can be prepared by reacting aldehyde IX with methylenetriphenylphosphorane under Wittig conditions or Horner Emmons conditions [Advanced Organic Chemistry, Eds. J. March, (1992), Wiley-Interscience publication and S. Pine, G. Shen and H. Hoang, Synthesis, (1991), 1].
• the compound XI can also be conveniently prepared by coupling a halide with the general formula X with allyl magnesium bromide.
• compound XI can be obtained from commercial sources.
• Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids and standard deprotection (e.g., Boc removal by TFA treatment) as outlined in Scheme 4
• standard coupling e.g. EDC or PyBroP
• deprotection e.g., Boc removal by TFA treatment
• Scheme 4 For preparations of diketopiperazines see - P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374].
• Reduction of the diketopiperazine with diborane can afford the N-benzyl protected version of compound V.
• 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.
• 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).
• 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/SnCl 2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience).
• substituted aniline II examples 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.
• 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.
• compound V can be obtained from commercial sources. Examples of commercially available compound corresponding to the general structure V include 2-methyl piperazine, 2,5-dimethyl piperazine, 2,6-dimethyl piperazine and 4-benzyloxycarbonylpiperazin-2-one. 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 I can be prepared by reacting compound VII with epoxide VIII through warming in an appropriate solvent (ethanol, DMF).
• Epoxide VIII can be prepared as outlined in Scheme 2C. Heating alkyl alcohol IX with epichlorohydrin or epibromohydrin and sodium hydride in DMF can afford epoxide VIII. In some cases compound VIII can be obtained from commercial resources. Examples of commercially available compounds of general structure VIII include glycidyl isopropyl ether, N butyl glycidyl ether, T butyl glycidyl ether and iso-butyl glycidyl ether.
• Compound V can be prepared as described in Scheme 3C. Alkylation of compound XII with alkyl halides using t-BuLi as base can afford compound XIII as described by Pohlman et. al. (J. Org. Chem, (1997), 62, 1016-1022). Reduction of XIV using diborane can afford N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA , for the diborane reduction see Jacobson et. al, J. Med. Chem, (1999), 42, 1123-1144).
• TFA trifluoroacetic acid
• Compound V can also be prepared through standard coupling (eg. EDC or PyBroP) of D or L amino acids as outlined in Scheme 4C [For preparations of diketopiperazines see - P. Cledera et al. Tetrahedron, (1998) p. 12349-12360 and R. A. Smith et al Bioorg. Med. Chem. Lett. (1998) p. 2369-2374]. Reduction of the diketopiperazine with diborane can afford the N- benzyl protected version of compound V. SCHEME 4C
• 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1:1) as base and co-solvent, respectively to afford the chloroacetamide derivative 3.
• Further reaction of compound 3 with piperazine afforded compound 5 through warming in ethanol.
• Reaction of compound 5 with epoxide 6 by warming both components in ethanol at reflux afforded piperazine derivative 7.
• Compound 6 in turn was prepared by warming epibromohydrin with 2-indanol in DMF in presence of NaH as described in Scheme 6C.
• 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 administration 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. However, 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.
• 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%.
• Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• Injectables 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.
• 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.
• Epoxide 6 (1.0 g, 5.5 mmol) and Boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL EtOH and the mixture was heated at reflux for 24 h. The solvent was evaporated and the residue was purified using column chromatography (1:1, Hex:EtOAc) to afford compound 11.
• 2,6-dimethylaniline (9.8g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCOj (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2C (9.17 g, 81.2 mmol) dropwise over a period of 2h. The mixture was allowed to warm to RT over 14 h. The mixture was diluted with 100 mL ether and the organic layer was dried over MgSO 4 , filtered and concentrated to afford compound 3C as a white solid. Part B.
• 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, 30 microM, and 3 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.
• Palmitoyl carnitine oxidation was carried out in a total volume of 100 microliters containing the following agents: 110 mM KCl, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl 2 , 0.1 mM EDTA, 0.1 mg/ml of defatted BSA, 0.5 mM malic acid, 3 mM ADP, 52 micrograms of mitochondrial protein, and 43 microM 1-C14 palmitoyl carnitine (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, 30 microM, and 3 microM.
• a DMSO control was used. After 15 min at 30 °C, 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. The data are presented as % activity of control. Table 2
• Example 9 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 compound with a stability number greater than 1.2 has a better stability than ranolazine in the liver S-9 assay.
• a compound with a stability number between 1.2 and 0.8 has an equivalent stability in the liver S-9 assay.
• a compound with a stability number less than 0.8 is less stable than ranolazine in the liver S-9 assay.
• the purpose of this experiment is to compare the percentages remaining for compounds of this invention with the percentage remaining for ranolazine after 30 minutes of incubation with human liver S9 fractions.

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