WO2001062744A2 - Substituted piperazine compounds - Google Patents

Substituted piperazine compounds Download PDF

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Publication number
WO2001062744A2
WO2001062744A2 PCT/US2001/005606 US0105606W WO0162744A2 WO 2001062744 A2 WO2001062744 A2 WO 2001062744A2 US 0105606 W US0105606 W US 0105606W WO 0162744 A2 WO0162744 A2 WO 0162744A2
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Prior art keywords
alkyl
group
hydrogen
aryl
carbonyl
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PCT/US2001/005606
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French (fr)
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WO2001062744A3 (en
Inventor
Jeff Zablocki
Elfatih Elzein
Grigory Nudelman
Tim Marquart
Vaibhav Varkhedkar
Prabha N. Ibrahim
Venkata P. Palle
Brent K. Blackburn
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Cv Therapeutics, Inc.
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Priority to NZ520782A priority Critical patent/NZ520782A/en
Priority to EP01911085A priority patent/EP1259493A2/en
Priority to CA002400176A priority patent/CA2400176C/en
Priority to JP2001562526A priority patent/JP3980885B2/en
Priority to AU2001238623A priority patent/AU2001238623B2/en
Priority to IL15117801A priority patent/IL151178A0/en
Application filed by Cv Therapeutics, Inc. filed Critical Cv Therapeutics, Inc.
Priority to AU3862301A priority patent/AU3862301A/en
Priority to MXPA02008213A priority patent/MXPA02008213A/en
Priority to BR0108592-1A priority patent/BR0108592A/en
Publication of WO2001062744A2 publication Critical patent/WO2001062744A2/en
Publication of WO2001062744A3 publication Critical patent/WO2001062744A3/en
Priority to NO20023954A priority patent/NO324837B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D241/06—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • 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
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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.

Abstract

Novel compounds of the general formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect 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, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.

Description

TITLE: SUBSTITUTED PIPERAZINE COMPOUNDS
BACKGROUND OF THE INVENTION
This application claims priority to U.S. Patent Application Nos. 60/184182 filed on February
22, 2000, 60/184457, filed on February 22, 2000, 60/206396, filed on May 23, 2000,
60/184306 filed on February 22, 2000, and to U.S. Patent Application 60/209262 filed on June 5, 2000, the specification of which is incorporated herein by reference. 1. Field of the Invention
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. 2. Description of the Art
U.S Patent No. 4,567,264, the specification of which is incorporated herein by reference, 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. In 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. In particular, 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.
Despite the important discovery that 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.
SUMMARY OF THE INVENTION
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:
Figure imgf000003_0001
wherein X is selected from the group consisting of:
Figure imgf000003_0002
^ o wherein m = 1 or 2 or 3;
R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CMS alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-; Rg, R7 and R8 are each independently selected from the group consisting of hydrogen and C,.15 alkyl;
Rg, R10, Rn, R]2, R13, RM, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C,^ alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R, and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Ru and R13 or Rg and R15 or Rg and R, j or Ru and R15 or Rg and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R, and R10 or Ru and R12 or R13 and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms.
R22 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, CF3, and heteroaryl; R23 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 CF3; and
R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C,.6 alkyl, and
Figure imgf000005_0001
wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.IS alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22.
In yet another embodiment, 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.
DETAILED DESCRIPTION OF THE INVENTION
This invention includes a class of substituted piperazine compounds having the following formula:
Figure imgf000006_0001
wherein X is selected from the group consisting of:
Figure imgf000006_0002
wherein m = 1 or 2 or 3;
R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CM5 alkyl, C2-15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
R^, R7 and R8 are each independently selected from the group consisting of hydrogen and C,.15 alkyl;
Rg, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R, and R]0 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rn and R13 or R, and R15 or Rg and R, , or R, , and R15 or R, and R,3 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein Rg and R10 or Ru and R12 or R13 and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms;
R22 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, CF3, and heteroaryl;
R23 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 CF3; and
R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C,.6 alkyl and
Figure imgf000007_0001
wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C 5 alkyl, C2.15 alkenyl, C2.I5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22.
This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA):
Figure imgf000008_0001
wherein m = 1, 2;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and CM alkyl and wherein R22 is a C,.3 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C,_3 alkyl;
R9, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and CM alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rn and R13 or R, and R15 or R, and Rn or Ru and R,5 or Rg and R13 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 R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen.
R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S(O)R22, SO2R22, SON(R22)2, CON(R22)2, C1 alkyl wherein R22 is C,.3 alkyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In more preferred compounds of Formula IA, R1, R2, R3, R4 and R5 are each selected from the group consisting of hydrogen, halo, CF3, OR22 and C alkyl where R22 is a C^ alkyl; R6 is selected from hydrogen and methyl; R7, R8, R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, Ru, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen.; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C,_3 alkyl wherein R22 is CU3 alkyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In still more preferred compounds of Formula IA, R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of methyl and hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, Ru, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 wherein R22 is methyl, methyl, or R17 and R18 may together form -CH=CH- CH=CH-, or R18 and R19 may together form -OCH2O-
In an even more preferred compounds of Formula I A, R1 and R5 are each methyl; R2, R\ R4, R6, R7, R8 are each hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl with the proviso that R9, R10, R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, methyl, OR22 wherein R22 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. In still more preferred compounds of Formula IA, R1 and R5 are each methyl; R2, R3,
R4, R6, R7, R8 are each hydrogen; R9, R10 are selected from hydrogen, methyl, or may together form a carbonyl; R11 and R12 are selected from hydrogen and methyl; R13 and R14 are selected from hydrogen and methyl or may together form a carbonyl; R15 and R16 are hydrogen with the proviso that R9, R10, R", R12, R13, R14, R15 and R16 are not all simultaneously hydrogen; R17 is selected from the group consisting of hydrogen, chloro, fluoro or methoxy; R18 and R19 are each selected from the group consisting of hydrogen or methoxy, or R18 and R19 may together form -OCH2O-, or R17 and R18 may together form -CH=CH-CH=CH-, R20 is hydrogen; and R21 is selected from hydrogen or chloro.
Most preferably, 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- dimethy lphenyl)-2- {4- [2-hydroxy-3 -(2-methoxyphenoxy)propyl] -3 - oxopiperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2- methoxyphenoxy)propyl]-3,3-dimethylpiperazinyl}acetamide, 2-{5-[(2S)-2-hydroxy-3-(2- methoxyphenoxy)propyl](lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6- dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2- methoxyphenoxy)butyl]- piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[4-(4- fluorophenoxy)-2-hydroxybutyl]- piperazinyl} acetamide, 2-(4- {4-[4-(tert-butyl)phenoxy]-2- hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl) acetamide, N-(2,6-dimethylphenyι)-2- {4- [2-hydroxy-4-(4-phenylphenoxy)butyl] piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4- [2-hydroxy-4-(4-methoxyphenoxy)butyl]- piperazinyl} acetamide, 2- {(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropy 1] -3 -methylpiperazinyl } -N-(2 ,6-dimethylpheny l)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6- dichlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(4-sulfamoylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-(5-methoxy-3-(trifluoromethyl)phenyl]acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-indan-5- ylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}- N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(4-chloronaphthyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl] -3 -methylpiperazinyl} -N-(2-pyrrolylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl] -3 -methylpiperazinyl} -N-phenylacetamide, 2- {(3S)-4-[(2S)- 3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chloro-4- methylphenyl)acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylρiρerazinyl}-N-[2-(l-methylvinyl)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2- fiuorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[6-methyl-2- (methylethyl)phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(3-methylthiophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloro-2-methoxy-5-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4- (dimethylamino) phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]- 3-methylpiperazinyl} -N-(2,4-dimethoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4-dichlorophenyl) acetamide,
2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4- chlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(3-chlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dichlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4- methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl} -N-(3-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(4-fluorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-cyanophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4- acetylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(2-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl] acetamide, 2-{(3S)-4- [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-chloro-3- (trifluoromethyl)phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]- 3-methylpiperazinyl}-N-(3,5-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-mo holin-4-ylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (3-fluoro-4-methoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(3,4,5-trimethoxyphenyl) acetamide, 2-{(3S)-4- [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (4-chloro-2-fluorophenyl) acetamide, and 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl] -3 -methylpiperazinyl } -N- [2-(hydroxymethy 1-6-methylphenyl] acetamide.
This invention includes a subset of substituted piperazine compounds of formula I having the following formula IB:
Figure imgf000011_0001
IB
wherein m = 0, 1 or 2 or 3; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.IS alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,.15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C,^ alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 or aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Ru and R13 or R9 and R15 or R9 and R11 or R" and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or Ru and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.15 alkyl, C2-15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 or wherein R17 and R18 may join together may join together to form -CH=CH-CH=CH- or wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 3 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein the ring may be optionally substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R23, CM5 alkyl, C2-ι5 alkenyl, C2-15 alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, or SO2R22; R22 is selected from the group consisting of 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, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,_6 alkyl, CF3, or heteroaryl; and R23 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 CF3.
In preferred compositions of this invention, m = 0, 1 or 2 or 3; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and CM alkyl; R6, R7 and R8 each independently selected from the group consisting of hydrogen and C,.3 alkyl; R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and CM alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl, or wherein R11 and R13 or R9 and R15 or R9 and Ru or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 4 carbon atoms wherein R9, R10, R11, R12, R13, R14, R15 and R16 are not all hydrogen; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, S(O)R22, SO2R22, SON(R22)2, CON(R22)2, CM alkyl or R17 and R18 may together form - CH=CH-CH=CH-, and phenyl. In other preferred compounds, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C,.2 alkyl wherein R22 is a C,_3 alkyl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl; R9, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and Cj.2 alkyl, or R9 and R10 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R9, R10, R", R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein Ru and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR22, and CM alkyl wherein R22 is C,.3 alkyl, and wherein R17 and R18 may together form a substituent selected from the group consisting of -CH=CH-CH=CH- and phenyl.
In still other preferred compounds, m = 1 or 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C,^ alkyl where R22 is a C,.3 alkyl; R6, R7, R8, R9, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from hydrogen and methyl; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22, C,.3 alkyl where R22 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. In more preferred compounds, m = 1 or 2;; R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from methyl and hydrogen; R9, R10, R", R12, R13, R14, R15 and R16 are each hydrogen; and R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 wherein R22 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-. In yet other preferred compounds, m = 1 or 2;; R1 and R5 are methyl; R2, R3, R4 R6, R7,
R8,R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen; R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, OR22 wherein R22 is methyl, or R17 and R18 may together form -CH=CH-CH=CH-, or R'8 and R19 may together form -OCH2O-. In still other preferred compounds, R1 and R5 are methyl; R2, R3, R4, R6, R7, R8,R9, R10,
R", R12, R13, R14, R15 and R16 are hydrogen; R17 is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected from hydrogen and methoxy; R19 is selected from hydrogen and methoxy; R20 is hydrogen; R21 is selected from hydrogen and chloro, or R17 and R18 may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
Most preferably, 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-(2,6-dimethylphenyl)-2- {4-[4-(4-methoxyphenyl)-2- hydroxybutyljpiperazinyl} acetamide, 2- {4-[4-(2,6-difluorophenyl)-2- hydroxybutyljpiperazinyl} -N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, 2-(4- {4-[4-(tert-butyl)phenyl]-2- hydroxybutyl} piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-(4- {2- hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d] 1,3- dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2 ,6-dimethy lpheny l)-2- [4-(2-hydroxy-3 -phenylpropyl)piperazinyl] -2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2- methylpropanamide,
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6- dimethylphenyl)-2-{4-[5-(2-fluorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide, and N- (2,6-dimethylphenyl)-2- (4-[5-(2-chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide.
This invention further includes a subset of compounds of Formula I above having the following Formula IC:
Figure imgf000015_0001
IC wherein m = 1, 2, or 3;
R\ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR20, SR20, N(R20)2, S(O)R22, SO2R22, SO2N(R20).
NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22, C 5 alkyl, C2-15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR20, SR20, N(R20)2, S(O)R22, and SO2R22 ;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,_3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON(R20)2, C,^ alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N(R20)2ι CO2R20, CON(R20)2 or aryl, wherein R9 and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R11 and R13 or R9 and R15 or R9 and R11 or Ru and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms;
R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and CM alkyl;
R20 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 CF3; and R22 is selected from the group consisting of 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, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O'C^ alkyl, CF3, or heteroaryl.
In Formula IC, it is preferred that m = 1 or 2 and most preferred when m = 1.
In preferred compositions of Formula IC, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and CM alkyl and wherein R22 is a CU3 alkyl. In other preferred compositions, R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, or C,.2 alkyl. More preferably R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, or methyl with R2, R3, and R4 as hydrogen and R1 and R5 as methyl being preferred. In other preferred compositions of Formula IC, R6, R7 and R8 each independently selected from the group consisting of hydrogen and C^ alkyl with hydrogen or methyl being preferred and hydrogen being most preferred.
In yet other preferred compositions of Formula IC, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)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, CF3, OR20,
Figure imgf000016_0001
CON(R20)2 or aryl wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that Rn and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a ring. In alternative preferred compositions, R9, R10, R11, R12,
R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-4 alkyl, or R9 and R10 together form a carbonyl, or R11 and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl,
R10 and R11 together form -CH2CH2CH2CH2-. In another embodiment, R9, R10, R", R12, R13, R14, R15 and R16 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(R20)2 or aryl or wherein R9 and R10 may together form a carbonyl. More preferably, R9, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen or C,.2 alkyl, or wherein R9 and R10 may together form a carbonyl. In another embodiment, R11 and R15 are each selected from the group consisting of hydrogen or methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen and R9 and R10 may together form a carbonyl, or, R9, R10, Rπ, R12, R13, R14, R15 and R16 may each be hydrogen.
In compounds of Formula IC, R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C,^ alkyl. In certain preferred compounds of Formula IC, R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, Cj.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, CF3, CN, OR20, and C,.6 alkyl. In other preferred compounds of Formula IC, R24 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, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C 6 alkyl. In still other preferred compounds of Formula IC, R24 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, CF3, OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo,
CF3, OH, C,_2 alkyl, and aryl. In still other preferred compounds of Formula IC, R24 is alkyl having from 1 to 6 carbon atoms and cycloalkyl or R24 is a fused phenylcycloalkyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, Cj.2 alkyl, and aryl or R24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, C,^ alkyl, and aryl. In the compounds of Formula IC, R20is 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 CF3 More preferably, R20is selected from the group consisting of H or C^ alkyl and most preferably, R20 is methyl or H.
Most preferably, 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-
(phenylmethoxy)propyl]piperazinyl}acetamide, 2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2- hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4- {3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, 2-(4-{3-[(2,4- difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-
(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl] acetamide, N-(2,6-dimethylphenyl)-2- (4- {2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, 2-(4- {3-[(2,4- dimethoxyphenyl)methoxy] -2-hydroxypropy 1 } piperaziny l)-N-(2 ,6-dimethy lphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4- fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2- (4- {2-hydroxy-3-[(4-methylphenyl)methoxy]propyl} piperaziny l)acetamide, N-(2,6- dimethylphenyl)-2-(4- {2-hydroxy-3-[(4- phenylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2- hydroxypropyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydoxy-3-(2- naphthylmethoxy)propyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[3- (cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide, and N-(2,6-dimethylphenyl)-
2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.
The following definitions apply to terms as used herein.
"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. Preferably, 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, heteroarylcarbonylamino, or the like.
"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. In the case of 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. Examples of 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, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.
"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. Examples of 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, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound. "Alkyl alkenyl" refers to a group -R-CR'=CR'" R"", where R is lower alkyl, or substituted lower alkyl, R', R'", R"" may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.
"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. "Alkylthio" denotes the group -SR, -S(O)n=1.2-R, 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, 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, heteroarylcarbonylamino, or the like. "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.
"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, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. 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. Examples of 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. Examples of 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.
"Aralkyl" 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. For example, "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:
(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.
The 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/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-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.
SCHEME 1
Figure imgf000025_0001
Figure imgf000025_0002
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. Examples of commercially available compounds coπesponding 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).
SCHEME 2A
Figure imgf000026_0001
Epoxide VIII (where m = 1 or 2) can be prepared as outlined in Scheme 2. Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-l,2-epoxybutane and potassium carbonate in acetone can afford epoxide VIII. Compound IX can be obtained from commercial resources. 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. In some cases compound VIII can be obtained from commercial sources. Examples of commercially available compounds coπesponding 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.
SCHEME 3A
Figure imgf000027_0001
XII XIII
Figure imgf000027_0002
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]. SCHEME 4A
Figure imgf000027_0003
R=MeorEt
diborane
Figure imgf000027_0004
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.
Figure imgf000028_0001
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).
A specific example of the preparation of a compound of Formula IA is disclosed in Schemes 5 A, 6A and 7A to further illustrate how to prepare the compounds of this invention. In particular, 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 2,6-dimethyl piperazine afforded compound 5 through warming in ethanol. Reaction of compound 5 with epoxide 6 by warming both components in ethanol at reflux afforded 2,6-dimethyl piperazine derivative 7. Compound 6 in turn was prepared by warming epichlorohydrin with 2-methoxyphenol in acetone in the presence of K2CO3 as described in Scheme 6.
SCHEME 5A
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
SCHEME 6A
Figure imgf000029_0004
A specific synthesis of compound 14 is described in Scheme 7. Compound 11 was prepared by opening of epoxide 6 with Boc-ethylenediamine through warming in EtOH. Acylation of compound 11 was accomplished using chloroacetyl chloride in dichloromethane using diisopropylethyl amine as a base. Removal of the Boc group using TFA followed by ring closure through warming in EtOH afforded compound 13. Reaction of compound 13 with 6 as described above afforded compound 14.
Figure imgf000030_0001
12
Figure imgf000030_0002
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/SnCl2 or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available 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,. 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.
Figure imgf000031_0001
IV
Figure imgf000031_0002
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. In some cases, 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).
SCHEME 2B
Figure imgf000032_0001
XI VIII
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. In some cases compound XI can be obtained from commercial sources. Examples of commercially available compounds corresponding to the general structure XI include (where m = 0) 3-fluorostyrene, 4- fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,6-dichlorostyrene, 3,4- dichlorostyreneand 3,4-dimethoxystyrene. Other examples of commercially available compounds with the general structure XI include (where m = 1) 4-methoxyallylbenzene, 2- hydroxyallylbenzene, 4,5-dimethoxyallylbenzene, 2-methylallylbenzene safrole and 1- allylnaphthalene.
SCHEME 3B
Figure imgf000033_0001
XII XIII
Figure imgf000033_0002
XIV xv Compound V can be prepared as described in Scheme 3B. 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 XIII 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).
SCHEME 4B
Bn
Figure imgf000034_0001
=MeorEt
diborane
Figure imgf000034_0002
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 [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.
Figure imgf000034_0003
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).
A specific example of the preparation of a compound from this invention is disclosed in Scheme 5B to further illustrate how to prepare the compounds of this invention. In particular, 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. SCHEME 5B s
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000035_0003
Compound 8 is commercially available and was epoxidized using 3- chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6B. Scheme 6B
Figure imgf000035_0004
Four carbon epoxide 15 can be prepared by coupling commercially available 4- methoxybenzyl chloride with allylmagnesium bromide followed by oxidation with mCPBA as illustrated in Scheme 7B. SCHEME 7B
Figure imgf000036_0001
14 mCPBA, DCM
Figure imgf000036_0002
15
The compounds having the general Formula I and IC can be prepared as outlined in Schemes 1C-6C. A general synthesis of the compounds of this invention is outlined in Scheme IC.
Figure imgf000037_0001
VII
Figure imgf000037_0002
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 aniline 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.
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 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). SCHEME 2C
Figure imgf000038_0001
IX
V]
X = Cl or Br
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). SCHEME 3C
Figure imgf000039_0001
XI XII
Figure imgf000039_0002
XIII
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
Figure imgf000039_0003
R=Me or Et
diborane
Figure imgf000039_0004
A specific example of the preparation of a compound from this invention is disclosed in Schemes 5C and 6C to further illustrate how to prepare the compounds of this invention.
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
In particular, 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.
SCHEME 6C
Figure imgf000040_0004
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. 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.
Depending on the intended mode, the 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. 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.
For solid compositions, 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. If desired, 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. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. The composition 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. For oral administration, 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. In 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. A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Pat. No. 3,710,795, which is incorporated herein by reference. In another recent approach, the 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.
It is within the scope of this invention to administer one or more compounds of this invention to a mammal, and preferably to a human by other known routes of pharmaceutical dosage form administration including, but not limited to by bolus, intravenously, transdermally, through inhalation, sub-cutaneously, or any other therapeutic agent administration method or route know to one skilled in the art.
The following Examples are representative of the invention, but are not to be construed as limiting the scope of the claims.
Example 1
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5- dimethylpiperazinyl} acetamide (7).
Figure imgf000044_0001
Part A.
Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3).
2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3 X 50). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3 as a white solid. Part B.
Synthesis of N-(2,6-dimethylphenyl)-2-(3,5-dimethylpiperazinyl)acetamide (5). To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6- dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM: MeOH) to afford compound 5.
Figure imgf000045_0001
Part C.
Synthesis of glycidyl 4-methoxyphenyl ether (6).
2-methoxyphenol (1.0 g, 8.0 mmol) and epichlorohydrin (3.7 g, 40.0 mmol) were dissolved in acetone (20 mL). K2CO3 (2.2 g, 16.0 mmol) was added and the mixture was heated at 70 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved 100 mL of EtOAc , washed with 100 mL water, dried over MgSO4 and filtered. The mixture was evaporated to dryness and the residue was purified using column chromatography (2:1, hexane: ethyl acetate) to afford compound 6. Part D.
Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5- dimethylpiperazinyl} acetamide (7).
To a solution of compound 5 in 10 mL EtOH (0.4 g, 1.4 mmol) was added compound 6 (0.27 g, 1.5 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 7.
Figure imgf000045_0002
2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6- dimethylphenyl)acetamide (15) Compound 15 was prepared in the manner of compound 7 substituting (2R, 5S)- dimethylpiperazine for 2,6-dimethylpiperazine 4 in part B to afford compound 15: Mass spectrum (M+l) = 456.4.
Figure imgf000046_0001
N-(2,6-dimethylphenyI)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2- oxopiperazinyl} acetamide (16)
Compound 16 was prepared substituting 4-benzyloxycarbonyl-2-oxo-piperazine for 2,6- dimethylpiperazine 4 in part B of compound 7 that was carried on to the final target in the manner of compound 7 after removal of the CBZ protecting group (hydrogenation - 20 psi, 10% palladium on carbon) to afford compound 16: Mass spectrum (M+l) = 442.41.
Figure imgf000046_0002
2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyl]bicyclo[4.4.0]dec-2-yl}-N-(2,6- dimethylphenyl)acetamide (17)
Compound 17 was prepared in the manner of compound 7 substituting perhydroquinoxaline for 2,6-dimethylpiperazine 4 in part B to afford compound 15: Mass spectrum (M+l) = 482.4.
Figure imgf000047_0001
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3- dimethylpiperazinyl} acetamide (18)
Compound 18 was prepared in the manner of compound 7 substituting 2,2-dimethylpiperazine for 2,6-dimethylpiperazine 4 in part B to afford compound 18: Mass spectrum (M+l) = 456.51
Figure imgf000047_0002
2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](lS,4S)-2,5-diazabicyclo[2.2.1]hept- 2-yl}-N-(2,6-dimethylphenyl)acetamide (19)
Compound 19 was prepared in the manner of compound 7 substituting (lS,4S)-(+)-2,5- Diazabicyclo[2.2.1]heptane for 2,6-dimethylpiperazine 4 in part B to afford compound 19: Mass spectrum (M+l) = 481.5
Figure imgf000047_0003
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy)butyl]- piperazinyl} acetamide (20) Compound 20 was prepared in the manner of compound 7 substituting 4-bromo-l,2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 20: Mass spectrum (M+l) = 442.37
Figure imgf000048_0001
N-(2,6-dimethylphenyI)-2-{4-[4-(4-fmorophenoxy)-2-hydroxybutyl]- piperazinyl} acetamide (21) Compound 21 was prepared in the manner of compound 7 substituting 4-bromo-l,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21: Mass spectrum (M+l) = 430.35
Figure imgf000048_0002
2-(4-{4-[4-(tert-butyl)phenoxy]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl) acetamide (22)
Compound 22 was prepared in the manner of compound 7 substituting 4-bromo-l,2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 22: Mass spectrum (M+l) = 468.32
Figure imgf000048_0003
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-phenylphenoxy)butyl] piperazinyl} acetamide (23)
Compound 23 was prepared in the manner of compound 7 substituting 4-bromo-l,2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 23: Mass spectrum (M+l) = 488.41
Figure imgf000049_0001
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-methoxyphenoxy)butyl]- piperazinyl} acetamide (24)
Compound 24 was prepared in the manner of compound 7 substituting 4-bromo-l,2- epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 24: Mass spectrum (M+l) = 442.37
Example 2 N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3- oxopiperazinyl} acetamide (14)
Part E. Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2- methoxy phenoxy)propyl] amino} ethyl)carboxamide (11).
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.
Synthesis of N-{2-[(tert-butoxy)carbonylamino]ethyl}-2-chloro-N[2-hydroxy-3-(2- methoxyphenoxy)propyl] acetamide (12)
Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled to °C. To the cold mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12. Synthesis of l-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-2-one (13).
Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was allowed to stir at RT for 2 h. TFA was removed under reduced pressure. The residue was dissolved in 20 mL EtOH and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure to afford compound 13 which was used without further purification. Part F.
Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2- methoxyphenoxy)propyI]-3-oxopiperazinyI} acetamide (14) To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added compound 3 (0.7 g, 0.36 mmol) and diisopropylethyl amine (0.76 g, 0.36 mmol). The reaction mixture was heated at reflux for 24 h. The mixture was concentrated in vacuo and the residue was purified by using Prep. TLC (10:1, DCM:MeOH) to afford compound 14: Mass spectrum (M+l) = 442.34 Example 3
Figure imgf000051_0001
The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2.
Table 1
Figure imgf000051_0002
Figure imgf000052_0001
Example 4
2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yI)-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl)acetamide (7B).
Figure imgf000053_0001
Part A. Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3B).
2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2B (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3 X 50). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3B as a white solid. Part B. Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5B). To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added compound 4B (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 dichloromethane: methanoi) to afford compound 5B. Part C. Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo [d\ 1 ,3-dioxane (6B).
To an ice cold solution of 8 (1.0 g, 6.17 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3x100ml). The organic layer was dried over MgSO4 , and concentrated in vacuo . The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 6B. Part D. 2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl)acetamide (7B)
To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound 6B (0.38 g, 2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichloromethane: methanol) to afford compound 7B: Mass spectrum (MH+1) = 426.34.
Figure imgf000054_0001
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyI]acetamide (9B). Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 9B: Mass spectrum (MH+1) = 396.32.
Figure imgf000054_0002
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)- propyl] piperazinyl} acetamide (10B)
Compound 10B was prepared in the manner of compound 7B substituting 3-(2- methoxyphenyl)-l-propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 10B: Mass spectrum (MH+1) = 412.35.
Figure imgf000055_0001
N-(2,6-dimethyIphenyl)-2-{4-[2-hydroxy-3-(4- methoxyphenyl)propyl]piperazinyl} acetamide (11B).
Compound 11B was prepared in the manner of compound 7B substituting 3-(4- methoxyphenyl)-l-propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 11B: Mass spectrum (MH+1) = 412.35.
Figure imgf000055_0002
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide (12B) Compound 12B was prepared in the manner of compound 7B substituting 3 -phenyl- 1-propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 12B: Mass spectrum (MH+1) = 382.
Figure imgf000055_0003
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-naphthylpropyl)piperazinyl]acetamide (13B). Compound 13B was prepared in the manner of compound 7B substituting 3-(l-naphthyl)-l- propene for 3-(3,4-methylendioxyphenyl)-l-propene in part C to afford compound 13:Mass spectrum (MH+1) = 432.55. EXAMPLE 5
Part A
Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2 -mmol) in anhydrous ether
(10 mL), was added allylmagnesium bromide ( 4 mL, 1M solution in THF) and the reaction mixture was allowed to stir for 16h at room temperature. Sat. ammonium chloride solution
91mL) was added and the ether layer was separated, washed with water and dried.
Evaporation of ether under reduced pressure afforded olefin 14B as an oil. It was used in the next reaction without purification.
Part B Intermediate (15B): To an ice cold solution of 15B (2 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200ml), and it was washed with saturated sodium bicarbonate (3x100ml). The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 15B.
Part C
Synthesis of N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyι)-2- hydroxybutyl]piperazinyl}acetamide(16B) To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound
15B (2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichloromethane: methanol) to afford compound 16. (M+l) = 426.3
Figure imgf000056_0001
2-{4-[4-(2,6-difluorophenyι)-2-hydroxybιιtyl]piperazinyl}-N-(2,6- dimethylphenyl)acetamide(l 7B)
Compound 17B was prepared in a manner similar to that of compound 16B substituting 2,6- difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+l) 432.2
Figure imgf000057_0001
N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyι)-2- hydroxybutyl] piperazinyl} acetamide(l 8B)
Compound 18B was prepared in a manner similar to that of compound 16B substituting 2- chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+l) = 430.2
Figure imgf000057_0002
19 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6- dimethylphenyl)acetamide(l 9B)
Compound 19B was prepared in a manner similar to that of compound 16B substituting 4-t- butylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 452.3
Figure imgf000057_0003
N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2- hydroxybutyl] piperazinyl} acetamide(20B)
Compound 20B was prepared in a manner similar to that of compound 16B substituting 2- fluorobenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 414.2
Figure imgf000058_0001
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4- (trifluoromethyl)phenyI]butyl}piperazinyl)acetamide(21B)
Compound 21 B was prepared in a manner similar to that of compound 16B substituting 4- trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 464.2
Figure imgf000058_0002
2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yι)-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethyIphenyl)-2-methylpropanamide (22B)
This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A. (M+l) = 454.54
Figure imgf000058_0003
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2- methylpropanamide (23B)
This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A and allylbenzene for 8B. (M+l) = 410.34.
Figure imgf000059_0001
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5- trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide (24B)
This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2- methylpropionyl chloride for chloroacetyl chloride in part A and 3,4,5-trimethoxy alkybenzene for 8B. (M+l) = 472.54
Figure imgf000059_0002
25
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide (25B)
This compound was prepared in a manner similar to that of 16B, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. (M+l) = 410.4.
Figure imgf000059_0003
N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)- 2-hydroxy- pentyl] piperazinyl} acetamide(26B)
This compound was prepared in a manner similar to that of 16B, substituting 2- fluorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+l) = 428.1.
Figure imgf000060_0001
2-hydroxy- pentyl] piperazinyl} acetamide(27B)
This compound was prepared in a manner similar to that of 16B, substituting 2- chlorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+l) = 444.3
Example 6
N-(2,6-dimethyIphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide
(7C) Part A. Synthesis of N-(2,6-dimethylphenyι)-2-chIoroacetamide (3C).
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 MgSO4, filtered and concentrated to afford compound 3C as a white solid. Part B.
Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5C). To a solution of compound 3C in 100 mL EtOH (5 g, 25.2 mmol) was added compound 4C (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography ( 10:1, DCM:MeOH) to afford compound 5C. Part C. Synthesis of 2-(oxiran-2-ylmethoxy) propane (6C) To a solution of 60% NaH (0.18g, 4.5mmol) in DMF (10ml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1.1 lg, 8.18mmol) in DMF (1ml) was added dropwise. The reaction was allowed to warm to room temperature and stured for 48 h. The solvent was removed in vacuo and the residue was purified using Prep TLC (30:1, DCM:MeOH) to afford compound 6C. Part D
Synthesis of N-(2,6-dimethyIphenyl)-2-[4-(2-hydroxy-3-indan-2- yIoxypropyl)piperazinyl] acetamide (7C)
To a solution of 6C (0.43g, 2.3mmol) in ethanol(4ml) was added 5C (0.405g, 1.64mmol). The solution was heated to reflux and stirred for 24 h. Upon completion the solution was concentrated in vacuo and purified using Prep TLC (10: 1, DCM:MeOH) to yield 7C. Mass Spectrum (M+l) = 438.36.
Figure imgf000062_0001
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-({2,6-dimethylphenyl)acetamide (IOC)
Compound IOC was prepared in a similar manner to compound 7C, substituting the commercially available glycidyl isopropyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford IOC : Mass spectrum MS (MH+) = 364.37.
Figure imgf000062_0002
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3 (phenylmethoxy)propy 1] piperazinyl} acetamide (11 C)
Compound 11C was prepared in a similar manner to compound 7C, substituting the commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 11C. Mass Spectrum (M+l) = 412.36.
Figure imgf000062_0003
2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyϊ)piperazinyl]- N-({2,6- dimethylphenyl)acetamide (12C) Compound 12C was prepared in a similar manner to compound 7C, substituting the commercially available cyclopentanol for 2-indanol in part C to afford 12C: MS (MH+) = 390.
2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyI)piperazinyl]- N-({2,6- dimethylphenyl)acetamide (13C)
Compound 13C was prepared in a similar manner to compound 7C, substituting the commercially available cyclohexanol for 2-indanol in part C to afford 13C - MS (MH+) = 404.
Figure imgf000063_0001
2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6- dimethylphenyl)acetamide (14C): Compound 14C was prepared in a similar manner to compound 7C, substituting the commercially available 4-t-bu-benzylalcohol for 2-propanol in part C. MS (M+l) = 468.44
Figure imgf000063_0002
N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2- hydroxypropyl}piperazinyl)acetamide(15C): Compound 15C was prepared in a similar manner to compound 7C, substituting the commercially available 2-fluorobenzylalcohol for 2-propanol in part C. MS (M+l) = 430.39
Figure imgf000063_0003
2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6- dimethylphenyl)acetamide(16C): Compound 16C was prepared in a similar manner to compound 7, substituting the commercially available 2,4-difluorobenzylalcohol for 2- propanol in part C. MS (M+l) = 448.38
Figure imgf000064_0001
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-
(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl] acetamide (17C): Compound 17C was prepared in a similar manner to compound 7C, substituting the commercially available 4- trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+l) = 480.37
Figure imgf000064_0002
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2- methoxyphenyl)methoxy]propyl}piperazinyl)acetamide (18C): Compound 18C was prepared in a similar manner to compound 7C, substituting the commercially available 2- methoxy-benzylalcohol for 2-propanol in part C. MS (M+l) = 442.41
Figure imgf000064_0003
19
2-(4-{3-[(2,4-dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6- dimethylphenyl)acetamide (19C): Compound 19C was prepared in a similar manner to compound 7C, substituting the commercially available 2,4-dimethoxy-benzylalcohol for 2- propanol in part C. MS (M+l) = 472.42
Figure imgf000065_0001
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- methoxyphenyl)methoxy]propyl}piperazinyl)acetamide(20C): Compound 20C was prepared in a similar manner to compound 7C, substituting the commercially available 4- methoxy-benzylalcohol for 2-propanol in part C. MS (M+l) = 442.42
Figure imgf000065_0002
21 N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2- hydroxypropyl}piperazinyl)acetamide (21C) Compound 21C was prepared in a similar manner to compound 7C, substituting the commercially available 4-fluoro-benzylalcohol for
2-propanol in part C. MS (M+l) = 430.40
Figure imgf000065_0003
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- methylphenyl)methoxy]propyl}piperazinyl)acetamide (22C): Compound 22C was prepared in a similar manner to compound 7C, substituting the commercially available 4- methyl-benzylalcohol for 2-propanol in part C. MS (M+l) = 426.41
Figure imgf000065_0004
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- phenylphenyl)methoxy]propyl}piperazinyl)acetamide (23C) Compound 23C was prepared in a similar mariner to compound 7C, substituting the commercially available 4-phenyl- benzylalcohol for 2-propanol in part C. MS (M+l) = 488.42
Figure imgf000066_0001
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2- hydroxypropyl}piperazinyl)acetamide (24C): Compound 24C was prepared in a similar manner to compound 7C, substituting the commercially available 4-n-bu-benzylalcohol for 2- propanol in part C. MS (M+l) = 468.45
Figure imgf000066_0002
N-(2,6-dimethyIphenyl)-2-{4-[2-hydroxy-3-(2- naphthylmethoxy)propyl] piperazinyl} acetamide (25C) Compound 25C was prepared in a similar manner to compound 7C, substituting the commercially available 2-naphthylmethanol for 2-propanol in part C. MS (M+l) = 462.41
Figure imgf000066_0003
N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2- hydroxypropyl] piperazinyl} acetamide (26C) Compound 26C was prepared in a similar manner to compound 7C, substituting the commercially available cyclohexylmethanol for 2- propanol in part C. MS (M+l) = 418.55
Figure imgf000067_0001
27 N-(2,6-dimethyIphenyl)-2-(4-{3-[(4-fluorophenyI)methoxy]-2-hydroxypropyl}-3,3- dimethylpiperazinyl)acetamide (27C) Compound 27C was prepared in a similar manner to compound 7C, substituting the commercially available 4-fluorobenzylalcohol for 2-propanol in part C and 2,2-dimethylpiperazine for compound 4 part B. MS (M+l) = 458.5
Example 7 Mitochondrial Assays
Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
Palmitoyl CoA oxidation - The Palmityl 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 MgCl2, 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. In each assay, a DMSO control was used. After 15 min at 30 oC, 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 C14 trapped as C14 bicarbonate ion.
Table 1
Figure imgf000068_0001
Figure imgf000069_0001
Example 8 Palmitoyl Carnitine Oxidation
The 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 MgCl2, 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. In each assay, 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 C14 trapped as C14 bicarbonate ion. The data are presented as % activity of control. Table 2
Figure imgf000070_0001
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. Reagents:
The following reagents were used; Potassium phosphate, 0.5M pH 7.4 (incubation buffer), kept at room temperature; 0.05M MgCl2 kept at 4°C; β-Nicotinamide adenine dinucleotide phosphate, tetrasodium salt, reduced form (NADPH), 0.02M solution in water (~16.6mg/mL) from Sigma Lot # 79H7044 prepared on day of use. lmM of ranolazine or Compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain lOOμM in 10% ACN; Human S9 stock: 20mg/mL from Gentest. Procedure:
Incubation mixtures were prepared as follows:
Table 3
Figure imgf000072_0001
* 1% organic solvent (acetonitrile) was used in incubation mixture. Generally, 30 incubates were prepared at a time by pre-mixing 0.75 mL of MgCl2, 0.75 mL of incubation buffer, 0.75 mL of NADPH, 3.75 mL of water. Then pipette 200 μL/incubate, add 25 μL of compound being tested, mix, and initiate reaction by addition of S-9.
Combine all components with incubation buffer and re-pipette 200 μL/tube +
25μL of the compound being tested along with 25μL of S-9. After 5 min of pre-incubation at 37°C, at 0 and 30min after starting the reaction, a 50 μl aliquot of the incubation mixture was removed and added to 100 μL of 9:1 acetonitrile: methanol containing the internal standard.
The mixture was centrifuged and a 100 μL aliquot of the supernatant was diluted in lmL of solvent C (0.1% Formic Acid in water). Then samples were analyzed for change between the ratio of compound to internal standard at time zero and 30 minutes by LC/MS
(injected 10 μL).
Analytical and Data Calculations:
Samples were analyzed for the starting compounds and potential metabolite/s by
LC/MS using an internal standard and an ODS-C18 column with a flow rate of 0.25 ml/min. Following the above procedure resulted in the following relative stability factors as compared to ranolazine for the compounds of this invention as illustrated in Table 4. If a compound is more stable than ranolazine in the liver S9 assay, than the stability factor will be greater than
1.0. If a compound is less stable than ranolazine, than the stability factor will be less than 1.0. Table 4
Figure imgf000073_0001

Claims

A substituted piperazine compounds having the following formula:
Figure imgf000074_0001
wherein X is selected from the group consisting of:
Figure imgf000074_0002
wherein m = 1 or 2 or 3;
Rl5 R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CM5 alkyl, CW5 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R^ and R5 may join together to form -CH=CH-CH=CH-; Rg, R7 and R8 are each independently selected from the group consisting of hydrogen and Cι.,5 alkyl;
Rg, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C^ alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein Rg and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rn and R13 or R, and
R15 or Rg and Rπ or Rn and R15 or R, and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein Rg and R10 or Ru and R12 or R13 and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that Rg, R10, Rπ, R12, R13, R14, R15 and R16 are not all hydrogen when R24 is phenyl and when X is
R22 is sel -ectetdi frobm. 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, CF3, and heteroaryl;
R23 is selected from the group consisting of H, C 5 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 CF3; and
R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C,.6 alkyl and
Figure imgf000075_0001
wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CMS alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
2. The substituted piperazine compound of claim having the following formula:
Figure imgf000076_0001
I wherein m = 1 or 2 or 3;
Rj, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CM5 alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
Rg, R7 and R8 are each independently selected from the group consisting of hydrogen and C ι5 alkyl;
Rg, R10, Rπ, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein Rg and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rπ and R,3 or R, and R15 or Rg and R, , or R, , and R15 or Rg and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R, and R10 or Ru and R12 or R13 and R14 or R15 and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that Rg, R10, Rn, R12, R13, R14, R15 and R16 are not all hydrogen;
R17, Rlg, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CM5 alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R22 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, CF3, and heteroaryl; and
R23 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 CF3.
3. The compound of claim 2 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.8 alkyl, C2.8 alkenyl, C2.8 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, SR23, and N(R23)2, wherein R2 and R3 may join together to form a fused ring system wherein having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
Rg, R7 and R8 are each independently selected from the group consisting of hydrogen and Cj.g alkyl;
Rg, RI0, Rπ, R12, R13, R14, R15 and R16are each independently selected from the group consisting of hydrogen, CM alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein Rg and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein RH and R13 or Rg and R15 or R, and Ru or Rn and R15 or Rg and R13 may join together to form a bridging ring including from 1 to 4 carbon atoms ; and
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CM5 alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22
4. The compound of claim 2 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C,.6 alkyl, C2.6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of CF3, and OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-; Rg, R7 and R8 are each independently selected from the group consisting of hydrogen or C,.3 alkyl;
Rg, R10, Ru, R12, R,3, R14, R15 and R16are each independently selected from the group consisting of hydrogen, C,^ alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 and aryl, wherein R, and R10 may together form a carbonyl, or Rπ and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rn and R13 or R, and R15 or R, and Ru or Rn and R15 or Rg and R13 may join together to form a ring including from 1 to 4 carbon atoms; R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, CMS alkyl, C2.I5 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22;
R22is 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, CF3, and heteroaryl; and
R23 is selected from the group consisting of hydrogen, CU8 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -O-C,_3 alkyl, and CF3.
5. The compound of claim 2 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2,
SO2N(R23)2, COR23, CO2R23, CON(R23)2, CM alkyl, C2.6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
Rg, R7 and R8 each independently selected from the group consisting of hydrogen and methyl; Rg, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,.2 alkyl, wherein R, and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R,g may together form a carbonyl;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, C,.8 alkyl, C2.8 alkenyl, C2.8 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, and
OR23;
R22is selected from the group consisting of C alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, O-Cj_3 alkyl, and CF3; and
R23 is selected from the group consisting of H, C,.5 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -OMe, and CF3
6. The compound of claim 5 wherein m = 1 or 2.
7. The compound of claim 5 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C,.3 alkyl, C2.6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent are optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-;
Rg, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
Rg, R10, R,„ R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,.2 alkyl, wherein Rg and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and C s alkyl; R22 is CM alkyl; and
R23 is selected from the group consisting of hydrogen and C,.5 alkyl .
8. The compound of claim 5 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C,.3 alkyl, C2.6 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-; Rg, R7 and R8 are each hydrogen; Rg, R10, R,„ R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,_2 alkyl, wherein R, and R10 may together form a carbonyl, or Rπ and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, COR23, CO2R23, CON(R23)2, and C,.8 alkyl; R22is CU2 alkyl; and R23 is selected from the group consisting of hydrogen and C,_2 alkyl .
9. The compound of claim 5 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C,.3 alkyl, C2.3 alkenyl, heterocyclyl, and heteroaryl, wherein the alkyl substituent is optionally substituted with OR23, wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-; R6, R7 and R8 are each hydrogen; Rg, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl, wherein Rg and R]0 may together form a carbonyl, or R13 and R14 may together form a carbonyl;
R17, R18, R,g, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C,_2 alkyl; R22 is methyl; and
R23 is selected from the group consisting of hydrogen and methyl.
10. The compound of claim 5 wherein R18, R19, R20, and R21 are each hydrogen, and R17 is selected from the group consisting of halo and OR2
11. The compound of claim 10 wherein R12 is (S)-methyl and Rg, R10, Ru, R]3, R14, R15 and R16 are each hydrogen.
12. The compound of claim 10 wherein Rg and R10 together form a carbonyl Rn, R12, R,3, R14, R15 and R16 are each hydrogen.
13. The compound of claim 10 wherein Rg, R10, Rπ, R12, R15 and R16 are each hydrogen and R13 and R14 together form a carbonyl.
14. The compound of any one of claims 3 to 13 wherein m = 1.
15. The compound of claim 10 wherein R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, SO2N(R23)2, COR23, CO2R23, CON(R23)2, C,.3 alkyl, C2.3 alkenyl, N-morpholino, and pyrrolyl, wherein the alkyl substituent is optionally substituted with OH, wherein R2 and R3 may join together to form a fused ring system having three carbon atoms, and wherein R4 and R5 may join together to form -CH=CH-CH=CH-.
16. The compound of claim 2 wherein m = 1 or 2; R,, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C,_2 alkyl wherein R22 is a C^ alkyl;
Rg, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
Rg, R10, R,„ R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C Λ alkyl, or R, and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that Rg, R10, Ru, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein Ru and R13 or Rg and R15 or Rg and Rπ or Ru and R15 or Rg and R13 may join to form a ring including from 1 to 4 carbon atoms. R17, R18, R]9, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, OR23, Cl alkyl, C2^, alkenyl, C2A alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, and OR23 wherein R23 is C,.2 alkyl.
17. The compound of claim 16 wherein Rj, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl.
18. The compound of claim 16 wherein R6, R7 and R8 are each hydrogen.
19. The compound of claim 16 wherein R,, R10, Rn, R]2, R,3, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,.2 alkyl, or Rg and R10 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that Rg, R10, Rn, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein Ru and R13 or Rg and R15 or R, and Rπ or Ru and R15 or R, and R13 may join to form a ring having from 1 to 2 carbon atoms.
20. The compound of claim 16 wherein Rg, R10, Rπ, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,_2 alkyl, or R, and
R10 may together form a carbonyl, or Rπ and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl.
21. The compound of claim 16 wherein R, and RI0 together form a carbonyl, R15 and R16 together form a carbonyl or both Rg and R10 together form a carbonyl and R15 and R16 together form a carbonyl.
22. The compound of claim 16 wherein R17, R]8, R,9, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, Cl alkyl and OR22 wherein R22 is C,.2 alkyl.
23. The compound of claim 2 wherein m = l;
R„ R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl;
Rg, R7 and R8 are each hydrogen;
Rg, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C alkyl, or R, and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R,, R10, Rπ, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen and wherein Rπ and R13 or Rg and R15 or Rg and Ru or Rn and R15 or Rg and Rπ may join to form a ring including from 1 to 4 carbon atoms; R,7, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C1-4 alkyl and OR22; and
R22 is C,.2 alkyl.
24. The compound of claim 23 wherein R] and R5 are each methyl and R2, R3, and R4 are each hydrogen.
25. The compound of claim 23 wherein Rπ, R12, R13, R14, R15 and R16 are each hydrogen and Rg and R10 together form carbonyl.
26. The compound of claim 23 wherein Rg, R10, Ru, R12, R15 and R16 are each hydrogen and R13 and Ru together form carbonyl.
27. The compound of claim 23 wherein Rg, R10, Ru, R12, R13 R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl.
28. The compound of claim 23 wherein Rg, R12, R13 R,4, R15 and R16 are each hydrogen and R10 and Rn together form a ring having from 1 to 4 carbon atoms.
29. The compound of claim 23 wherein Rg, R10, R12 R13, R14 and R16 are each hydrogen and Ru and R15 together form a ring having from 1 to 3 carbon atoms.
30. The compound of claim 23 wherein, R18, R19 and R21 are each hydrogen and R17 and R18 are each methyl.
31. The compound of claim 23 wherein, R17 is -OCH3, and R18, R19, R20 and R21 are each hydrogen.
32. The compound of claim 23 wherein, R17, R18, R20 and R21 are each hydrogen and R19is selected from the group consisting of-OCH3, -F, C,.4 alkyl and unsubstituted aryl.
33. The compound of claim 2 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-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3- oxopiperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(2- methoxyphenoxy)propy 1] -3 ,3 -dimethylpiperaziny 1 } acetamide, 2- { 5 - [(2S)-2-hydroxy-3 -(2- methoxyphenoxy)propyl](lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2,6- dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2- methoxyphenoxy)butyl]- piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(4- fluorophenoxy)-2-hydroxybutyl]- piperazinyl} acetamide, 2-(4- {4-[4-(tert-butyl)phenoxy]-2- hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl) acetamide, N-(2,6-dimethylphenyl)-2- {4- [2-hydroxy-4-(4-phenylphenoxy)butyl] piperazinyl} acetamide, N-(2,6-dimethylphenyι)-2- {4- [2-hydroxy-4-(4-methoxyphenoxy)butyl]- piperazinyl} acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6- dichlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl} -N-(4-sulfamoylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-(5-methoxy-3-(trifluoromethyl)phenyl]acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-indan-5- ylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}- N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(4-chloronaphthyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(2-pyrrolylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-phenylacetamide, 2-{(3S)-4-[(2S)- 3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chlorophenyl) acetamide, 2- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-chloro-4- methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3 -(2-fluorophenoxy)-2-hydroxypropyl] -3 - methylpiperazinyl}-N-[2-(l-methylvinyl)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(2-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[6-methyl-2- (methylethyl)phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl} -N-(3-methylthiophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3 -methylpiperazinyl} -N-(4-chloro-2-methoxy-5-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4- (dimethylamino) phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]- 3-methylpiρerazinyl}-N-(2,4-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl] -3 -methylpiperazinyl } -N-(3 ,4-dichlorophenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4- chlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(3-chlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dichlorophenyl) acetamide, 2- {(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxyρroρyl]-3-methylpiperazinyl} -N-(4- methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(3-methylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl} -N-(4-fluorophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2- fluorophenoxy)-2-hydroxypropyl] -3 -methylpiperazinyl } -N-(4-cyanophenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4- acetylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl} -N-(2-methoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl] acetamide, 2- {(3S)-4-
[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-chloro-3- (trifluoromethyl)phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]- 3 -methylpiperazinyl} -N-(3,5-dimethoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2- fiuorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-moφholin-4-ylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N- (3-fluoro-4-methoxyphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl] -3 -methylpiperazinyl} -N-(3,4,5-trimethoxyphenyl) acetamide, 2- {(3S)-4- [(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4-dimethoxyphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N- (4-chloro-2-fluorophenyl) acetamide, and 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxyprdpyl]-3-methylpiperazinyl}-N-[2-(hydroxymethyl-6-methylphenyl] acetamide.
34. A substituted piperazine compound having the following formula:
Figure imgf000085_0001
wherein m = or 1 or 2 or 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, CMS alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22; R6, R7 and R8 each independently selected from the group consisting of hydrogen or
C-,.,5 alkyl;
R9, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, N(R23)2, CO2R23, CON(R23)2 or aryl, wherein R9 and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R1 Or R" and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms and wherein R9 and R10 or R11 and R12 or R13 and R14 or R15 and R16 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.15 alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, and SO2R22 and wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-;
R22 is selected from the group consisting of 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, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN,
Figure imgf000086_0001
alkyl, CF3, or heteroaryl; and R23 is selected from the group consisting of H, C,.,5 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 CF3.
35. The compound of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23SO2R22, C,.^ alkyl, heterocyclyl, aryl, and heteroaryl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,_8 alkyl;
R9, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C,^ alkyl, or aryl, wherein R9 and R10 may together form a carbonyl, or Rπ and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or
R9 and R15 or R9 and R1 Or R" and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 4 carbon atoms ; R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, COR23, CO2R23, CON(R23)2, C,.,5 alkyl, C2.6 alkenyl, C2.6 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR23, and wherein R17 and R18 or R18 and R19 or R19 and R20 or R20 and R21 may combine to form a saturated ring including from 5 to 6 carbon atoms wherein from 0 to 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form - CH=CH-CH=CH-;
R22 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, CN, CF3,; and
R23 is selected from the group consisting of H, C,_8 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, alkyl, CN, or CF3.
36. The compound of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, SR23, N(R23)2, Cj.8 alkyl, aryl, and heteroaryl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,.5 alkyl; R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CM alkyl, or aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and Rπ or R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 2 carbon atoms ;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, C,_8 alkyl, aryl, and heteroaryl, and R19 and R20 may combine to form a saturated ring including from 5 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH- CH=CH-;
R22is selected from the
Figure imgf000087_0001
alkyl, aryl; and R23is selected from the group consisting of H, C,.6 alkyl, aryl;
37. The composition of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, C,.6 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,.3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C,.3 alkyl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Ru and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 2 carbon atoms ;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; R22is selected from the group consisting of C^-, alkyl; and R23 is selected from the group consisting of H, Cj.3 alkyl;
38. The compound of claim 37 wherein m = 1 or 2 or 3.
39. The compound of claim 37 wherein R9, R'°, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, methyl, wherein R9 and
R10 may together form a carbonyl, R13 and R14 may together form a carbonyl, wherein R11 and R13 or R9 and R15 or R11 and R15 or R9 and R13 may join together to form a bridging ring system wherein the two R groups together comprise of from 1 to 2 carbon atoms.
40. The compound of claim 37 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl.
41. The compound of claim 39 or 40 wherein R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl. .
42. The compound of claim 37 wherein R9, R10, Ru, R12, R13, R14, R15 and R16 are hydrogen.
43. The compound of claim 37 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, C,.2 alkyl;
R6 is hydrogen; and
R7 and R8 each independently selected from the group consisting of hydrogen or methyl; and R9, R10, Rn, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C,.3 alkyl, wherein R9 and R10 may together form a carbonyl, or R13 and R14 may together form a carbonyl;
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, C,.6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-; R22is selected from the group consisting of methyl; and R23 is selected from the group consisting of H, methyl;
44. The compound of claim 43 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl.
45. The compound of claim 43 wherein R9, R10, R", R12, R13, R14, R15 and R16 are hydrogen.
46. The compound of claim 43 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, C,^ alkyl, and
R19 and R20 may combine to form a saturated ring including from 5 carbon atoms wherein 2 carbon atoms may be substituted with an oxygen atom and wherein R17 and R18 may together form -CH=CH-CH=CH-.
47. The compound of claim 43 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, C alkyl, and
R19 and R20 may combine to form -O-CH2-O- or -OCH2CH2O- and wherein R17 and R18 may together form -CH=CH-CH=CH-;
48. The compound of claim 34 wherein m = 1 or 2;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C,.2 alkyl wherein R22 is a C 2 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,_2 alkyl, or R9 and R10 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms; and
R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, OR23, C^ alkyl, C2.4 alkenyl, C2_4 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein R23 is C,^ alkyl and wherein R17 and R18 or R18 and R19 may together form a ring selected from the group consisting of -CH=CH-CH=CH-, -O-CH2-O, and -O-CH2-CH2-O-.
49. The compound of claim 48 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl.
50. The compound of claim 48 wherein R6, R7 and R8 are each hydrogen.
51. The compound of claim 48 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,.3 alkyl.
52. The compound of claim 48 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl.
53. The compound of claim 15 wherein R9 and R10 together form a carbonyl, R15 and R16 together form a carbonyl or both R9 and R10 together form a carbonyl and R15 and R16 together form a carbonyl.
54. The compound of claim 48 wherein R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C,^ alkyl and OR22 wherein R22 is C,.2 alkyl.
55. The compound of claim 48 wherein R17 and R18 or R18 and R19 together form a ring selected from the group consisting of -CH=CH-CH=CH-, -O-CH2-O.
56. The compound of claim 34 wherein m = 1 or 2; R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl;
R6, R7 and R8 are each hydrogen;
R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C,^ alkyl, or R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl and wherein R11 and R13 or R9 and R15 or R9 and R11 or R11 and
R15 or R9 and R13 may join to form a ring including from 1 to 4 carbon atoms;
R17, R18, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, ClΛ alkyl, CF3 and OR22 ; and R22 is C,.2 alkyl.
57. The compound of claim 56 wherein R1 and R5 are each methyl and R2, R3, and R4 are each hydrogen.
58. The compound of claim 56 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen or methyl.
59. The compound of claim 56 wherein R9, R10, Ru, R12, R13 R14, R15 and R16 are each hydrogen.
60. The compound of claim 56 wherein, R17, R18, R19, R20, and R21 are each selected from the group consisting of hydrogen, Cl, F, -OCH3, -CF3 and C alkyl.
61. The compound of claim 60 wherein R18, and R20 are each hydrogen.
62. The compound of claim 60 wherein R19 is -OCH3.
63. The compound of claim 56 wherein, R17 is -OCH3, and R18, R19, R20 and R21 are each hydrogen.
64. The compound of claim 56 wherein, R17, R18, R20 and R21 are each hydrogen and R19 is selected from the group consisting of -OCH3, -F, CF3, C,^ .
65. A substituted piperazine compound of claim 34 selected from the group consisting of: 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-(2,6-dimethylphenyl)-2- {4-[4-(4-methoxyphenyl)-2- hydroxybutyl]piperazinyl} acetamide, 2- {4-[4-(2,6-difluorophenyl)-2- hydroxybutyl]piperazinyl} -N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, 2-(4- {4-[4-(tert-butyl)phenyl]-2- hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4- [4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-(4- {2- hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3-(2H-benzo[d] 1 ,3- dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2- methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5- phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2- (4-[5-(2-fluorophenyl)- 2- hydroxy-pentyljpiperazinyl} acetamide, and N-(2,6-dimethylphenyl)-2- {4-[5-(2- chlorophenyl)- 2-hydroxy-pentyl]piperazinyl} acetamide.
66. A substituted piperazine compound having the following formula:
Figure imgf000092_0001
I wherein m = 1, 2, or 3;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR20, SR20, N(R20)2, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, NR20CON(R20)2, COR20, CO2R20, CON(R20)2, NR20SO2R22, C 5 alkyl, C2.15 alkenyl, C2.15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR20, SR20, N(R 0)2, S(O)R22, and SO2R22 ;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C,.3 alkyl; R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON(R20)2, C alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF3, CN, OR20, N(R20)2 CO2R20, CON(R20)2 or aryl, wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that Rn and R13 or R9 and R15 or R9 and R11 or Ru and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms;
R24 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, CF3, CN, OR20, SR20, S(O)R22, SO2R22, SO2N(R20)2, NR20CO2R22, 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, CF3, CN, OR20, and C,.6 alkyl;
R20 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 CF3; and R22 is selected from the group consisting of 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, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,.6 alkyl, CF3, or heteroaryl.
67. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR20, SR20, N(R20)2, SO2N(R20)2, CO2R20, CON(R20)2, C,.8 alkyl, C^ alkenyl, CM alkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, NO2, CF3, CN, OR20, SR20, N(R20)2, S(O)R22, or SO2R22 ;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-3 alkyl;
R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, CM alkyl, or wherein R9 and R10 may together form a carbonyl, or Ru and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl; and
R20 is selected from the group consisting of H, C 5 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 CF3
68. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, C,.5 alkyl, C2_ 3 alkenyl, or C2.3 alkynyl, wherein the alkyl substituent is optionally substituted with CF3;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen or C,.3 alkyl;
R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, or C,^ alkyl wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl; R24 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, CF3, CN, OR20, SR20, S(O)R22,
SO2R22, 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, CF3, CN, OR20, and Cj.6 alkyl; and
R20 is selected from the group consisting of H, C,-g alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -O-C,_3 alkyl, or CF3.
69. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, C,.3 alkyl, C2_ 3 alkenyl, or C2.3 alkynyl, wherein the alkyl is optionally substituted with CF3;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or methyl;
R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen or C,_2 alkyl, wherein R9 and R10 may together form a carbonyl, or Rn and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl; R24 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, CF3, OR20, S(O)R22, 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, CF3, CN, OR20, and .g alkyl; and
R20 is selected from the group consisting of H, C,_5 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 CF3
70. The compound of claim 66 wherein m = 1 or 2;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and CM alkyl and wherein R22 is a C1-3 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and
C,.3 alkyl; R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, CM alkyl, or aryl wherein the alkyl and aryl substituents are each optionally substituted with 1 substituent selected from the group consisting of halo,
CF3, OR20, N(R20)2 CON(R20)2 or aryl wherein R9 and R10 may together form a carbonyl, or
R11 and R12 may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl with the proviso that R11 and R13 or R9 and R15 or R9 and R" or R11 and R15 or R9 and R13 may join together to form a ring;
R24 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, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C 6 alkyl; and
R20is 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 CF3
71. The compound of claim 70 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C alkyl, or R9 and R10 together form a carbonyl, or R11 and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl, R10 and R11 together form - CH2CH2CH2CH2-.
72. The compound of claim 70 wherein R9, R10, Ru, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, C,_3 alkyl, or aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, N(R20)2 and aryl or wherein R9 and R10 may together form a carbonyl, or R11 and R12 may together form a carbonyl with the proviso that R11 and R13 or R9 and R15 or R9 and R11 or R11 and R15 or R9 and R13 may join together to form a ring.
73. The compound of claim 70 wherein R9, R10, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, or C,^ alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)2 or aryl or wherein R9 and R10 may together form a carbonyl.
74. The compound of claim 66 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, or CU3 alkyl wherein the alkyl substituent is optionally substituted with CF3
75. The compound of claim 66 wherein R6, R7 and R8 each independently selected from the group consisting of hydrogen or methyl.
76. The compound of claim 66 wherein m=l . R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, or d.2 alkyl;
R6, R7 and R8 are each hydrogen;
R9, R'°, R", R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen or C^ alkyl, or wherein R9 and R10 may together form a carbonyl;
R24 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, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and C,^ alkyl; and
R20is selected from the group consisting of H or C,.3 alkyl.
77. The compound of claim 76 wherein R24 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 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and C alkyl.
78 The compound of claim 66 wherein R24 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 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and C,^ alkyl.
79. The compound of claim 76 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OCH3, or methyl.
80. The compound of claim 76 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, or methyl.
81. The compound of claim 76 wherein R11 and R15 are each selected from the group consisting of hydrogen or methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen and
R9 and R10 may together form a carbonyl.
82. A compound of claim 66 wherein m = 1 ;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, or methyl; R6, R7 and R8 are each hydrogen;
R11 and R15 are each selected from the group consisting of hydrogen or methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen and R9 and R10 may together form a carbonyl;
R24 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 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, phenyl, CF3, OR20, and CM alkyl; and R20 is methyl or H.
83. The compound of claim 82 wherein R24 is alkyl having from 1 to 6 carbon atoms and cycloalkyl.
84. The compound of claim 82 wherein R24 is a fused phenylcycloalkyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, C,_2 alkyl, and aryl.
85. The compound of claim 82 wherein R24 is phenylmethyl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, CM alkyl, and aryl.
86. The compound of claim 82 wherein R2, R3, and R4 are each hydrogen and R1 and R5 are each methyl.
87. The compound of claim 66 wherein m=l ;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen or methyl;
R6, R7 and R8 each hydrogen; R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen; and
R24 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,
CF3, OH, methyl, and aryl, and aryl that is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, Cj_2 alkyl, and aryl.
88. The compound of claim 66 selected from the group consisting of substituted piperazine compound 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-(phenylmethoxy)propyl]piperazinyl} acetamide, 2-( {2-[4-(3-cyclopentyloxy-2- hydroxypropyl)piperazinyl]- N-( {2,6-dimethylphenyl)acetamide, 2-( {2-[4-(3-cyclohexyloxy- 2-hydroxypropyl)piperazinyl]- N-( {2,6-dimethylphenyl)acetamide, 2-[4-(3- {[4-(tert- butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide, N- (2,6-dimethylphenyl)-2-(4- {3-[(2-fluorophenyl)methoxy]-2- hydroxypropyl}piperazinyl)acetamide, 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2- hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-[4- (2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide, N-(2,6- dimethylphenyl)-2-(4- {2-hydroxy-3-[(2- methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, 2-(4-{3-[(2,4- dimethoxyphenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- methoxyphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4- fluorophenyl)methoxy]-2-hydroxypropyl} piperaziny l)acetamide, N-(2,6-dimethylphenyl)-2- (4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6- dimethylphenyl)-2-(4-{2-hydroxy-3-[(4- phenylphenyl)methoxy]propyl}piperazinyl)acetamide, N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2- hydroxypropyl} piperaziny l)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydoxy-3-(2- naphthylmethoxy)propyl]piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[3-
(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide, and N-(2,6-dimethylphenyl)- 2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.
89. A method of treatment comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of 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, treating shock conditions, preserving donor tissue and organs used in transplants, or treating cardiovascular diseases.
90. The method of claim 89 wherein the cardiovascular disease is selected from the group consisting of atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise induced angina, congestive heart disease, or myocardial infarction.
91. The method of claim 89 wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.
92. The method of claim 89 wherein the mammal is a human.
93. A pharmaceutical composition of matter comprising the compound of claim 1 and one or more pharmaceutical excipients.
94. The pharmaceutical composition of matter of claim 93 wherein the pharmaceutical composition is in the form of a solution.
95. The pharmaceutical composition of matter of claim 93 wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet or a capsule.
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