CA2657986A1 - Substituted piperazine compounds - Google Patents
Substituted piperazine compounds Download PDFInfo
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- CA2657986A1 CA2657986A1 CA002657986A CA2657986A CA2657986A1 CA 2657986 A1 CA2657986 A1 CA 2657986A1 CA 002657986 A CA002657986 A CA 002657986A CA 2657986 A CA2657986 A CA 2657986A CA 2657986 A1 CA2657986 A1 CA 2657986A1
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- 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
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- 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
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- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- 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
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- 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
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- 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
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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
- C07D241/04—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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- 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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- 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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- 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
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- 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
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- 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
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- 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
Abstract
Novel compounds of the general formula:
(see formula above) 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.
(see formula above) 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
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.
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, 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]-1-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, 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:
R
R3 R, Rlo 11 O Ra _'R12 I X
N N ~.
4 N --J~ Rza RI R7 Rs R13 OH
Rie Ris RU
wherein X is selected from the group consisting of:
m and m O
wherein m = 1 or 2 or 3;
Rõ Rz, Rõ R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF31 CN, OR23, SR23, N(RZ3)2, S(O)R22, SOzRZZ, SO2N(R23)Z, NR23CO2R72, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23S02R22, C,-,s alkyl, C2-,s 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, NOZ, CF31 CN, OR23, SR23, N(R23)2, S(O)R22, and S02R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R may join together to form -CH=CH-CH=CH-;
R6i R, and Re are each independently selected from the group consisting of hydrogen and C,_,S alkyl;
R9, R,o, R,,, R12, R13, R14, R,5 and R6 are each independently selected from the group consisting of hydrogen, COZR23, CON(R23)Z, C,.q alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF31 CN, OR2,, N(R2.,)2, C02R23i CON(R23)2 and aryl, wherein R, and R,o may together form a carbonyl, or Rõ and R,Z may together form a carbonyl, or Rõ and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rõ and Rõ
or R9 and R15 or R9 and Rõ or Rõ and R15 or F. and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R and R,o or Rõ and R12 or R13 and R14 or R,S
2o and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms.
R,z is selected from the group consisting of C1_,S alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl arnide, heteroaryl amide, CN, O-C,, alkyl, CF3, and heteroaryl;
R23 is selected from the group consisting of H, C1_15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -O-C1-4 allcyl, 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, OR23, SR23, S(O)R22, S02R22i SO2N(R23)2, NR23CO2R22, 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, CF31CN, OR23, and C,, alkyl, and Ria R,? R
Rp Rp ~
wherein R17, RtB, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NOz, CF3, CN, ORZ,, SR23, N(R23)2, S(O)R22, SOZR,2, SOZN(R23)2, NR23COZR22, NR23CON(Rz3)z, COR,_3, C02R23, CON(Rz3)2, NR23SO2R22, C,-,s alkyl, C2-,5 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 1 o halo, NO2, CF31CN, OR23, SRZ,, N(R23)2, S(O)R22, and SOZRZZ.
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.
U.S. Patent No. 5,506,229, 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:
R
R3 R, Rlo 11 O Ra _'R12 I X
N N ~.
4 N --J~ Rza RI R7 Rs R13 OH
Rie Ris RU
wherein X is selected from the group consisting of:
m and m O
wherein m = 1 or 2 or 3;
Rõ Rz, Rõ R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF31 CN, OR23, SR23, N(RZ3)2, S(O)R22, SOzRZZ, SO2N(R23)Z, NR23CO2R72, NR23CON(R23)2, COR23, CO2R23, CON(R23)2, NR23S02R22, C,-,s alkyl, C2-,s 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, NOZ, CF31 CN, OR23, SR23, N(R23)2, S(O)R22, and S02R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and R may join together to form -CH=CH-CH=CH-;
R6i R, and Re are each independently selected from the group consisting of hydrogen and C,_,S alkyl;
R9, R,o, R,,, R12, R13, R14, R,5 and R6 are each independently selected from the group consisting of hydrogen, COZR23, CON(R23)Z, C,.q alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF31 CN, OR2,, N(R2.,)2, C02R23i CON(R23)2 and aryl, wherein R, and R,o may together form a carbonyl, or Rõ and R,Z may together form a carbonyl, or Rõ and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rõ and Rõ
or R9 and R15 or R9 and Rõ or Rõ and R15 or F. and R13 may join together to form a bridging ring system having from 1 to 4 carbon atoms and wherein R and R,o or Rõ and R12 or R13 and R14 or R,S
2o and R16 may join to form a bridging ring system having from 1 to 5 carbon atoms.
R,z is selected from the group consisting of C1_,S alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl arnide, heteroaryl amide, CN, O-C,, alkyl, CF3, and heteroaryl;
R23 is selected from the group consisting of H, C1_15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylamino, dialkylamino, alkyl-CN, -O-C1-4 allcyl, 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, OR23, SR23, S(O)R22, S02R22i SO2N(R23)2, NR23CO2R22, 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, CF31CN, OR23, and C,, alkyl, and Ria R,? R
Rp Rp ~
wherein R17, RtB, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NOz, CF3, CN, ORZ,, SR23, N(R23)2, S(O)R22, SOZR,2, SOZN(R23)2, NR23COZR22, NR23CON(Rz3)z, COR,_3, C02R23, CON(Rz3)2, NR23SO2R22, C,-,s alkyl, C2-,5 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 1 o halo, NO2, CF31CN, OR23, SRZ,, N(R23)2, S(O)R22, and SOZRZZ.
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:
R
R3 R, R, Rt O Re R12 N N ---~ X
R4 N Rsa RI R7 Rs R13 OH
RS Rjs Ris R14 I
wherein X is selected from the group consisting of:
and O
m wherein m = 1 or 2 or 3;
R,, R2, R3, R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, S02R22, SO2N(R23)2, NR23C02R221 NR23CON(R23)21 COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 allCyl, 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, CF31 CN, OR23, SR23, N(R23)2, S(O)R22, and S02R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and RS may join together to form -CH=CH-CH=CH-;
R6, R7 and R. are each independently selected from the group consisting of hydrogen and C1.15 alkyl;
R9, R,a, R,,, R12, R13, R10 R,5 and R,6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, C,-4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF31 CN, OR23, N(R23)2, C02R23, CON(R23)2 and aryl, wherein R9 and R,o may together form a carbonyl, or Rõ 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 Rõ and R13 or R9 and R15 or R9 and Rõ or Rõ and R15 or R9 and R13 may join together to form a bridging ring system .iaving from 1 to 4 carbon atoms and wherein R9 and R,o or Rõ and R,Z or Rõ
and Rõ or R,s 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 C1-15 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, diallcylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,, alkyl, CF3, and heteroaryl;
RZ, is selected from the group consisting of H, C1-15 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-C1 -,, 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, OR23, SR23, S(O)R22, S02R22, SO2N(R23)2, NR23CO2RZ2, C,-Z 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, CF31 CN, OR23, and C,, alkyk and Rta Rt7 Rts Rzo wherein R,,, R18, R,9, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3, CN, OR23, SR23, N(R23)2, S(O)RZZ, S02R22, SOZN(R23)Z, NR23CO2R22, NR,3CON(R23)2, COR23, COZR,,, CON(RA, NR23SO2R22, C,_,s alkyl, CZ_,5 alkenyl, C245 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, CF31 CN, OR23, SRZõ N(R23)2, S(O)Ru, and SO2R,2.
This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA):
This invention includes a class of substituted piperazine compounds having the following formula:
R
R3 R, R, Rt O Re R12 N N ---~ X
R4 N Rsa RI R7 Rs R13 OH
RS Rjs Ris R14 I
wherein X is selected from the group consisting of:
and O
m wherein m = 1 or 2 or 3;
R,, R2, R3, R4 and RS are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R23)2, S(O)R22, S02R22, SO2N(R23)2, NR23C02R221 NR23CON(R23)21 COR23, CO2R23, CON(R23)2, NR23SO2R22, C1-15 allCyl, 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, CF31 CN, OR23, SR23, N(R23)2, S(O)R22, and S02R22 , wherein R2 and R3 may join together to form a fused ring system having from three to four carbon atoms, and wherein R4 and RS may join together to form -CH=CH-CH=CH-;
R6, R7 and R. are each independently selected from the group consisting of hydrogen and C1.15 alkyl;
R9, R,a, R,,, R12, R13, R10 R,5 and R,6 are each independently selected from the group consisting of hydrogen, C02R23, CON(R23)2, C,-4 alkyl, and aryl wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, CF31 CN, OR23, N(R23)2, C02R23, CON(R23)2 and aryl, wherein R9 and R,o may together form a carbonyl, or Rõ 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 Rõ and R13 or R9 and R15 or R9 and Rõ or Rõ and R15 or R9 and R13 may join together to form a bridging ring system .iaving from 1 to 4 carbon atoms and wherein R9 and R,o or Rõ and R,Z or Rõ
and Rõ or R,s 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 C1-15 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, diallcylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,, alkyl, CF3, and heteroaryl;
RZ, is selected from the group consisting of H, C1-15 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-C1 -,, 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, OR23, SR23, S(O)R22, S02R22, SO2N(R23)2, NR23CO2RZ2, C,-Z 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, CF31 CN, OR23, and C,, alkyk and Rta Rt7 Rts Rzo wherein R,,, R18, R,9, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3, CN, OR23, SR23, N(R23)2, S(O)RZZ, S02R22, SOZN(R23)Z, NR23CO2R22, NR,3CON(R23)2, COR23, COZR,,, CON(RA, NR23SO2R22, C,_,s alkyl, CZ_,5 alkenyl, C245 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, CF31 CN, OR23, SRZõ N(R23)2, S(O)Ru, and SO2R,2.
This invention also includes a subset of the class of substituted piperazine compounds identified in Formula I above having the following Formula (IA):
~~
R3 \ R m 0 R19 ` /
Rs RT Re OH
R
IA
wherein m = 1, 2;
R', RZ, R3, R 4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, ORz3 and Ci-4alkyl and wherein R23 is a C1_3 alkyl;
R6, R' and Ra each independently selected from the group consisting_of hydrogen and C,_, alkyl;
R9, R'o, R", R12, R13, R'a, R`s and R16 are each independently selected from the group consisting of hydrogen and C,., alkyl, or R4 and R1 may together form a carbonyl, or R" and R'2 may together form a carbonyl, or R" and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rõ and Rõ or R9 and R15 or R9 and Rõ or Rõ and R15 or R9 and Rõ 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, R", R'2, R", R14, Rls and R16 are not all simultaneously hydrogen, when RI7, R18, R19, R20 and R21 are all hydrogen.
R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, S(O)R22, S02R22, SO2N(R23)2, CON(R23)2, Ct-4 alkyl wherein R23 is C,_, alkyl, or R" and R'B may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In more preferred compounds of Formula IA, R', R; R'-, R4 and RS are each selected from the group consisting of hydrogen, halo, CF31 OR23 and Ci-4alkyl where R23 is a CI_3 alkyl; R6 is selected from hydrogen and methyl; R', Ra, R9, R10, R", R'2, R", R'4, R'S and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R" and R14 may together form a carbonyl with the proviso that R', R10, R", R'2, R13, R14, R15 and R16 are not all simultaneously hydrogen ; R", R'$, R19, R20 and W' are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and C,., alkyl, or R" and R18 may together form -CH=CH-CH=CH-, or R" and R19 may together form -OCHZO-.
In still more preferred compounds of Formula IA, R', R2, R', R4, R5, R6, R' and Rg are each independently selected from the group consisting of methyl and hydrogen;
R9, R10, R", 'Z, R13, R", R15 and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R" and R'4 may together form a carbonyl with the proviso that R9, R10, R", R'z, R", R", R'S and R'6 are not all sunultaneously hydrogen; R", R18, R19, R20 and Rz1 are each independently selected from the group consisting of hydrogen, halo, CF31 ORZ3 wherein R23 is methyl, or R" and R'a may together form -CH=CH-CH=CH-, or R' 8 and R19 may together form -OCHzO-In an even more preferred compounds of Fornnula IA, R' and RS are each methyl;
R2, R3, R4, R6, R', R8 are each hydrogen; R9, RtO, R", R1z, R", 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, R", R'z, R", R14, R's and R16 are not all simultaneously hydrogen; R", R'g, R19, R20 and Rz1 are each independently selected from the group consisting of hydrogen, halo, methyl, OR23 wherein R23 is methyl, or R" and R1e may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In still more preferred compounds of Formula IA, R' and RS are each methyl;
RZ, R3, R', R6, R', R8 are each hydrogen; R9, R10 are selected from hydrogen, methyl, or may together form a carbonyl; R" and R12 are selected from hydrogen and methyl; R" 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", R'Z, R", R'", R'S and R'6 are not all simultaneously hydrogen; R"
is selected from the group consisting of hydrogen, chloro, fluoro or methoxy;
R1e and R19 are each selected from the group consisting of hydrogen or methoxy, or R'$ and R19 may together form -OCH2O-1 or R" and R'g may together form -CH=CH-CH=CH-, R20 is hydrogen;
and RZ' 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 -di aza-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)propyl]-3,3-dimethylpiperazinyl} acetamide, 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1 S,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-dimethylphenyl)-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- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-indan-5-ylacetamide, 2- {(3 S)-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-4-2o methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(1-methylvinyl)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methylphenyl) acetamide, 2-{ (3 S)-4-[(2S)-3 -(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl } -N-[6-methyl-2-(methylethyl)phenyl] acetamide, 2- {(3 S)-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- {(3 S)-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]-methylpiperazinyl} -N-(3-chlorophenyl) acetamide, 2- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-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-{ (3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl } -N-(4-acetylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-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-morpholin-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- {(3 S)-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-(hydroxymethyl-6-methylphenyl]
acetamide.
This invention includes a subset of substituted piperazine compounds of formula I
having the following formula IB:
2 R~ R Rlo R11 1~
R12 R~$
Rs R7 s OH
IB
wherein m 0, 1 or 2 or 3;
R', RZ, R3, R and RS are each independently selected from the group consisting of hydrogen, halo, NOZ, CF31 CN, OR23, SRZ3, N(R23)2, S(O)R22, SO,RZ2, SOzN(Rz3)z, NR23C0ZR22, NR23CON(R23)2, COR23 CO2R23, CON(R23)21 NR23SOzR22, Ci-t5 aIkY" C2-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, NOZ, CFõ CN, OR23, SR,3, N(RZ,)z, S(O)R22, and SO2RZ2;
R6, R' and Rg are each independently selected from the group consisting of hydrogen an,' C,_,s alkyl;
R9, R10, R", R'z, R`3, R,a, R's and R`6 are each independently selected from the group 1 o consisting of hydrogen, C02R23, CON(R23)Z, 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(RZ,)Z, COZR23, CON(R23)2 and aryl, wherein R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R'S and R16 may together form a carbonyl wherein R" and R13 or R9 and R15 or R9 and R" 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 R" and R'Z or R'3 and R'4 or R'S and R'6 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R", R'a, R", R20, and RZ' are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23 SR23, N(R2,)2, S(O)R22, S02R22, SO2N(R23)2, NR23CO2R22, NR23CON(R2,)2, COR23, CO2RZ3, CON(R23)2, NR23S02R22I C,-is alkyl, alkenyl, C2_15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with I substituent selected from the group consisting of halo, NO2, CF31 CN, OR23, SR23, N(R23)21 S(O)R221 and SO2R22 or wherein R" and R'8 may join together may join together to form -CH=CH-CH=CH- or wherein R" and R1e or R18 and R19 or RL9 and R20 or RZ0 and RZ' 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 I to 3 substituents selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R")Z, S(O)R
22, S02R22, SOZN(R'3)2, NR23CO2 R22, NRZ'CON(R23)2, COR23, CO2R23, CON(RZ')2, NR23SOZR23, Cl_ls alkyl, C2.15 alkenyl, CZ.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, CFõ CN, OR23, SR23, N(R23)2, S(O)R22, or S02R22;
R21 is selected from the group consisting of 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, allcyl amide, aryl amide, heteroaryl amide, CN, O-C,-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, C1_15 alkyl, aryl, or heteroaryl, wherein the allcyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl-CN, -O-C1_6 alkyl, or CF3.
In preferred compositions of this invention, m= 0, 1 or 2 or 3; R', R2, R', R4 and RS
are each independently selected from the group consisting of hydrogen, halo, CF3, OR2,3 and C,4 alkyl; R6, R' and Re each independently selected from the group consisting of hydrogen and C,_3 alkyl; R9, R10, R", R'Z, R", R'4, R15 and R'6 are each independently selected from the group consisting of hydrogen and C,.4 alkyl, or R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R14 may together form a carbonyl, or R's and R16 may together form a carbonyl, or wherein R" and R13 or R9 and R15 or R9 and R" or R" and R15 or R9 and R" may join together to form a ring including from I to 4 carbon atoms wherein R9, R10, R", R'2, R'3, R'4, R'5 and R'6 are not all hydrogen; and R", R'e, R'9, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF31 CN, OR23, S(O)R22, S02R22, SOZN(R23)Z, CON(RZ3)Z,C, , alkyl or R" and R18 may together form -CH=CH-CH=CH-, and phenyl.
In other preferred compounds, R', RZ, and RS are each independently selected from the group consisting of hydrogen, halo, CF31 OR23 and C1_2 alkyl wherein R23 is a Ct_3 alkyl; R6, R' and Ra are each independently selected from the group consisting of hydrogen and methyl; R9, R10, R", R'Z, R'3, R'4, R'S and R`6 are each independently selected from the group consisting of hydrogen and C,_Z 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", R'2, R'3, R'4, R'5 and R" are not all simultaneously hydrogen and wherein R" and R" or R9 and R15 or R9 and R" or R" and R'S or R' and R13 may join to form a ring including from 1 to 4 carbon atoms and R", R'g, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C alkyl and wherein R" and 3o R" may together form a substituent selected from the group consisting of -CH=CH-CH=CH-and phenyl.
In still other preferred compounds, m= I or 2; R', RZ, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and Ci.a alkyl where R23 is a C1.3 alkyl; R6, R', R', R9, R10, R", R`Z, R'3, R'4, R'S and R'6 are each independently selected from hydrogen and methyl; R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CFõ OR22, C_, alkyl where R22 is methyl, or R" and R18 may together form -CH=CH-CH=CH-, or R1e and R19 nlay together form -OCH2O-.
In more preferred compounds, m = 1 or 2; R', RZ, R', R4, R5, R6, R' and Rfl are each independently selected from methyl and hydrogen; R9, R10, R", R'z, R", R'4, R'5 and R'6 are each hydrogen; and R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, and OR23 wherein R23 is methyl, or R" and R18 may together form -CT-I=CH-CH=CH-, or R18 and R19 may together form -OCHzO-.
In yet other preferred compounds, m = 1 or 2; R' and RS are methyl; R2, R', R4 R6, R7, R8,R9, R10, R", R'2, R'3, R'4, R'5 and R'6 are hydrogen; R", R'B, R'9, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, and OR23 wherein R23 is methyl, or R" and R1e may together form -CH=CH-CH=CH-, or R1e and R19 may together form -OCHZO-.
In still other preferred compounds, R' and RS are methyl; R2, R3, R4, R6; R', R8,R9, R10, R", R1z, R13, Rt4, R15 and R16 are hydrogen; R" is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected fiom hydrogen and methoxy; R19 is selected from hydrogen and methoxy; R20 is hydrogen; R21 is selected from hydrogen and chloro, or R" and R18 may together form -CH=CH-CH=CH-, or R'a and R'9 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] 1,3-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, 1-I-(2,6-dimethylphenyl)-2-[4-(2-hyd.roxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl} -2-metliylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2- f 4-[5-(2-flucropl:enyl)- 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:
Ft2 ~3 , ~10 ~11 _._ ~2 ~9 N N m O~ ft2a I O
$ 3 OFi IC
wherein m 1, 2, or 3;
R', R2, R3, R4 and RS are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3, CN, OR20, SRZO, N(R20)2, S(O)R22, S02R22, SO2N(R20)Z, NR20C02R22, NR20CON(R.Z)2, COR20, C02R2o, CON(RZ0)Z, NRZ0S02RZ2, C,-õ alkyl, Czas alkenyl, C2-4 5 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(RZ0)2, S(O)R22, and SO2R22 ;
R6, R' and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R', R10, R", R'Z, R", R'4, R15 and R'6 are each independently selected from the group consisting of hydrogen, COZR20, CON(R20)2, C,-4 alkyl, and 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, . COZR20, CON(RZ0)2 or aryl, wherein R' and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R14 may together form a carbonyl, or R15 and Rt6 may together form a carbonyl, wherein R" and R13 or R9 and R15 or R9 and R" or R" and R15 or R9 and R" may join together to form a ring including from I to 3 carbon atoms;
R24 is selected from the group consisting of alkyl, eyeloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, :,ycloalkyl, and fused phenylcycloalkyl are optionally substituted with from I
to three substituents selected from the group consisting of halo, CF3, CN, OR20, SRzO, S(O)RZZ, SOZRZ', SOZN(R20)z, NR20CO2R21, C,_Z alkyl, and aryl wtierein the optional aryl substituent is optionally substituted with from I to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C, , alkyl;
Rz is selected from the group consisting of H, C,_,S alkyl, aryl,and heteroaryl,wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, mono- or dialkylamiiio, alkyl-CN, -O-C1_6 alkyl, and CF3; and RZ' is selected from the group consisting of C1_15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylanuno, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,-, alkyl, CF3, and heteroaryl.
In Formula IC, it is preferred that m = 1 or 2 and most preferred when m = 1.
In preferred compositions of Fonnula IC, R', R2, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C, alkyl and wherein R22 is C,_, alkyl. In other preferred compositions, R', RZ, R', R' and RS are each independently selected from the group consisting of hydrogen, CFõ OR20, and C1_2 alkyl. More preferably R', R2, R', R4 and RS are each independently selected from the group consisting of hydrogen, and methyl with RZ, R', and R' as hydrogen and R' and RS as methyl being preferred.
In other preferred compositions of Formula IC, R6, R' 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, R", R'Z, R", R'4, R'S and R16 are each independently selected from the group consisting of hydrogen, CON(R2)2, C1 I
alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with I
substituent selected from the group consisting of halo, CFõ OR20, N(RZ0)2, CON(R2)2 and aryl wherein R9 and R10 may together form a carbonyl, or R" and R'2 may.together form a carbonyl, or R13 and R14 may together fonn a carbonyl, or R15 and R16 may together form a carbonyl, wherein R' 1 and R 13 or R9 and R15 or R9 and R" 1 or R" and RIS or R9 and R13 may join together to form a ring having from 1 to 3 carbon atoms. In alternative preferred compositions, R9, Rio~ Rtt~ Rt2~ R13~ Rta, Rts and R16 are each independently selected from the group consisting of hydrogen and C1_4 alkyl, or R9 and R10 together foi-m a carbonyl, or R" and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl, R10 and R' 1 together form -CH2CH2CH2CH2-. In another embodiment, R9, R1O, Rl 1, R12, R13, R14, R15 and R" are each independently selected from the group consisting of hydrogen, and CI_2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)z.and arylor wherein R9 and R10 may together form a carbonyl.
More preferably, R9, R10, R", R'Z, R", R'4, R'5 and R'6 are each independently selected from the group consisting of hydrogen and C,_z alkyl, or wherein R9 and R10 may together form a carbonyl. In another embodiment, R" and R15 are each selected from the group consisting of hydrogen or methyl, R9, R10, R'z, R'3, R'-0 and R'6 are each hydrogen and R9 and R'0 may together form a carbonyl, or, R9, R10, R", R'2, R", R'4, R'S and R'6 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 I to three substituents selected from the group consisting of halo, CF3, CN, OR20, SRZO, S(O)R22, S02R 22, SOZN(RZ)Z, NR20C02 R22, C1_2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from I 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, CFõ CN, OR20, SRZO, S(O)R22, S02 R22, C1_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,., alkkyl. 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, CF31 CN, OR20, and C,, alkyl.
In still other preferred compounds of Formula IC, R24 is selected from the group consisting of alkyl having from I 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, CF31 OH, methyl, and aryl, and aryl that is optionally substituted with from I to 2 substituents selected from the group consisting of halo, CFõ OH, C1_2 alkyl, and aryl. In still other preferred compounds of Formula IC, R24 is alkyl having from I 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, CF31 OR20, C,_Z alkyl, and aryl or R24 is phenylmethyl that is optionally substituted with from I
to 2 substituents selected from the group consisting of halo, CF31 OR20, C,, alkyl, and aryl.
In the compounds of Formula IC, R20 is selected from the group consisting of H, C1_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, R20 is selected from the group consisting of H or C1_3 alkyl and most preferably, RZ0 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-hydxoxy-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-rnethoxyphenyl)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}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} 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 I
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 I 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, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, 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 defmed below.
"Alkoxy" denotes the group -OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloallcyl, 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 I 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 furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, 0 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 0, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, atkylsulfonyl, 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, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.
"Heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of 0, 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 :ffective 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 IA-7A. A general synthesis of the compounds of this invention is outlined in Scheme 1A. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetylchloride M. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnC12 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 H 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.
R2 Rt cl C' R2 Rt O
III /
R NH R7 R8 R / \ N CI
- RB _ Re R7 R8 R, RS R, R5 u tv R1o R11 Ra~1 I/Riz H-N/7-~\N-P R2 R, ReRto Rt1R
tz R1eRt5R14Ru R N N N-P
V
loom RB R7 Rej~
P BOC,CBZaBmzyl R4 R5 R1e R15Rt4Rt3 vi R9R1a R11Rtz R Rt O
Dc{avtoa R N N - H )MP I Y
R6 R7 Re R4 R5 Rts R15R14R13 VII
R / \ O~''6~
t m - R1o Rtt R Rt O R4\I ~R12 R17 R1E
R~ R21 'T- (`
VIII R / ~ i N N~O R79 RB R R-1Y OIH m R4 Rg R16 R15RuRts R21 R
I
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 10 cases, compound V can be obtained from commercial resources. Examples of commercially available compounds corresponding 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).
Rie R17 R18 R17 O
X acetone, K SCO3 O
R19 OH + R~e m X
X = C1 or Br ix VIII
Epoxide VIII (where m = I or 2) can be prepared as outlined in Scheme 2.
Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-1,2-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 IX 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 VIlI can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure VIII 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 methylphenyl ether, glycidyl 3,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.
O
Rio Re TFA
_ t-BuLi , R 9,IOBr DeQrotecho^
Bn-N BOC Bn-N BOC
R ' R 9 O R Rto Diborane Bn-N flH ~ Bn-N NH
\~_XIv// \t_J/
v 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 XIH 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].
1 o SCHEME 4A
toR9 o e R10 O R13 O R`~4 R14~~4 l.coupling H-N N-Bn + i~R1s Boc--NH OH
Bn~NH OR Z, T'FA, ring dosure O R14 XVI XVII XVIII
It=MeorEt R~~Rs diborane ~
H-N N-Bn \-~ Rts xlx R 14 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 (1S,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.
HN NH HN NH H NH
Commercially available bicyclic analogs include (1 S,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, SS, 1684-1687).
A specific example of the preparation of a compound of Formula IA is disclosed in Schemes 5A, 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 K2C03 as described in Scheme 6.
C Ci sat NaHCO 3/ Et ZO (1:1) H EtOH DrPEA refluz 24 hrs.
CO
O
O
HLb O /,--< 6 N NH
N
H EtOI-); Rcflux H~C
N NO
H
OH
CHs O
OH O
CI acetone, K2C03 8 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 dichioromethane 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 3 as described above afforded compound 14.
~ ~c H OCH, HN. J~IHz + O H~ O
5,~
v HN- fl v 6 il H 1.TFA
chbroacetyl chloride Yoc T-~f O
HN~ O OCH, DCM, DIPEA jw- 2. EtOH, DIPEA
H
OCH, 3 I - OCH, O \~ N~ O
HN \ j ' n I' EtOA,DIPEA 0 The compounds having the general formula I and IB can be prepared as outlined in 5 Schemes 1B-7B. A general synthesis of the compounds of this invention is outlined in Scheme 1B. 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.
lo 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.
2 R' C IQR~ Ra CI *2,W
O
Ra ~ ` i Ra H R N RR RRR5 II IV
Rio Rtt Ro~' 4 J _R' 2 H,^N/ \N_P RsRto R" i2 RZ Rt O )L__~R
R
18~ 15R1 ,4Ria Ra N N-P
R
V Ra R~ Ra P=BOC,CBZorBenzy R4 5 Rta RISR14Rt9 ~
RgRto Rtt 12 R2 Rt I/R
Deprotect R N NN-H
Ra R7 Re Ra R5 R1e RuRt4 Rta VII
Rte Rt7 Rt ~ `
n - O 2 R ReRto RttR12 Rt7 Rie R2o R2t VIII R3 N N Rta ~
' Ra Rt Re OH
R4 6 Rta Rt5RtaRt3 ~1 R2o R
I
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, EtOIT).
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).
R \ CHO R18 I ~ \ CI
R1 ~ R21 R1 ~ R21 ~/MgBr PhgPCH2Br, NaH, THF
Diethylether Ri8 R1a 0 \ mCPBA,DCM
Rtg I~ R~ R1 R21 XI Vlll 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 Homer 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-chiorostyrene, 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.
R10Ra O
n-SuLi, Rg,ipBr ~ Deprotection Bn-N~-2-BOC Bn-N_ JJ--BOC
XII XIvII
Ri oR9 O R' R9 ~4 ~
BH3 Bn~N_ J~H lo= Bn--N_ rIH
jav \~~, J/
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 Pohiman 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).
R14~\~/ // 1.coupling H-N N-~Bn + ~.~((` lob ~R13 Boa--=-NH OH
Bn~ NH OR Z TFp, ringdosure O 14 XVIII R
XVI XVII
IZ=MeorEt RloRs diborane ~
H-N N-Bn ~R13 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 (1S,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.
\
HN H H -\H H H
Commercially available bicyclic analogs include (1S,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.
o /-\
-j~ HN- NH
v cl cl (NH2 Z fLci 4 sat NaHCOS1 Et2O (175 EtOH, DIPEA, reflux 24 hrs.
0 ---> RT
J
__ O
O
O
'~` H
N
H EtOH, Reflux O
O^1 NN N
H OH
Compound 8 is commercially available and was epoxidized using 3-chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6B.
Scheme 6B
OH Q....o Nl~ + C acetone, K=C0= m y 6a.
m=1 8 OCH3 6b. m= 2 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.
CI MgBr I f - I~
H3CO Ethylether OCH3 mCPBA, DCM 1--0)~ OCH3 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 1C.
U
R Rj CI Ci R 0 III
R3 / ` NH R,Rs R 0", N CI _ RB Re R7 RB
s II IV
Rio Rit R"~Rtz H-N --P ReRto RttRIz R R~ O
RtsRisR14R~a R3 N N p V
P= BOC, CBZ or Benz R4 R5 RB R7 RA
~e R~sRt~ u VI
R Rt O Ip---E' ' l R9Rto RttRtz Deprotect R3 N N ~ H
I JY
s R7 R
R4 Rs R A 16 RuRt4Rta VII
~ Rto Rt~R1z Rt7 R R' o R9`
V 111 ~/R'T
R oH
R6 R7 Rts Rta R4 Rs RtsR14 I
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/SnC12 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, 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).
X NaH, DMF O
R~7 ~-OH +
X
IX
X=ClorBr VIII
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 2o 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 Pohlmanet. 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).
O RioRe O
I~ n-BuLi. R9103r /~ TFA
Bn-N N-BOC Bn-NN-BOC )OW
XI XII
R, oRa O R Ry Diborane l~~
,~
Bn-N NH 00 Bn- N NH
\xiII
v 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.
1 o SCHEME 4C
s R'O O R1s O ~
R74 i.coupung H-N N-Bn + ~ Rt3 Boo-NH OIH
B~NH OR
2. TFA, ring dos nre 0 R14 xiv xv xvi R=Me or Flt oR9 diborane H-NN-Bn Rta 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.
HN H
y C CI
1(NH2 (Lc N
set NeHC03/ Et20 (1:1) H EtOH, DIPEA, rcflux 24 hro.
0 ---> RT
QocO
N NH
:enux N EtOH, H
s OH
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.
-oH
NaH, DMF
$ 6 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. The effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal. 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 1ike, 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 adniinistration 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.
In another recent approach, the compositions of this invention can be administered orally in a sustained release dosage form.
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 sldlled 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-meth oxy)propyl] -3,5-dimethylpiperazinyl}acetamide (7).
O
~ ~ N~/N N p OH
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.
=
=
NH
O N O
`
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). KZC03 (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 MgSOq 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.
NH
IrN OH OCH3 O N O
2-{(5S,2R)-4-[2-hydroxy-3-(2-meth oxyphen oxy)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_ &":" H
~N OH OCH 3 O N O
`
N-(2,6-dimethylphenyl)-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+1) = 442.41.
NH
*'r' N "") OH OCH3 O N O
O
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 17: Mass spectrum (M+1) = 482.4.
O edrO
000"~ OH
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+1) _ 456.51 Q~H ~^
N
O ` /
HN r 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1 S,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 (IS,4S)-(+)-2,5-Diazabicyclo[2.2.1]heptane for 2,6-dimethylpiperazine 4 in part B to afford compound 19:
Mass spectrum (M+1) = 481.5 O O Z
N JL-.-~ N N
OH
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy)butyll-piperazinyl}acetamide (20) Compound 20 was prepared in the manner of compound 7 substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 20: Mass spectrum (M+1) = 442.37 F
O
N NOH
c N
N-(2,6-dimethylphenyl)-2-{4-[4-(4-flu orophenoxy)-2-hydroxybu tyl] -piperazinyl}acetamide (21) Compound 21 was prepared in the manner of compound substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21: Mass spectrum (M+1) = 430.35 o N J"'., N N
4)4 H
OH
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-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 22: Mass spectrum (M+1) = 468.32 ..~*
O Z
Z
CS\ NJL~= N ~N
OH
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-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 23: Mass spectrum (1VI+1)=488.41 JL,,., N N
N
H OH
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-4-(4-meth oxyphenoxy)butyl]-piperazinyl}acetamide (24) Compound 24 was prepared in the manner of compound 7 substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 24: Mass spectrum (M+1) = 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- methoxyphenoxy)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 witll diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled in an ice water bath. 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 1-[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)propyl]-3-oxopiperazinyl}acetatnide (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+1) 442.34 Example 3 S .,,.=~` F
H N S
R..- y 0*141~ N N O
O OH
The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2.
Table 1 R NIIT~
25 2,6-dimeth 1 hen l 430.3 26 2,6-dichloro hen l 471 27 4-aminosulfon 1 hen l 481.2 28 3-trifluorometh 1-5methox hen 1 500.2 29 5-indanyl 442.2 30 1-na hth 1 452.3 31 1 - 4-chlorona hth 1 486.3 32 2-N- ol l- hen l 467.3 33 Phenyl 402.2 34 2-chloro hen 1 436.2 35 2-chloro-4-meth 1 hen 1 450.2 36 2- 1-meth lethen 1 hen l 442.3 37 2-meth 1 hen 1 416.2 38 2-iso ro 1-6-meth 1 hen l 458.4 39 3-meth lthio hen 1 448.2 40 2-methox -4-chloro-5-meth 1 hen 1 480.2 41 4-dimeth lamino hen 1 445.3 42 2,4-dimethox hen 1 462.3 43 3,4-dichloro hen l 471.1 44 4-chloro hen 1 436.3 45 3-chloro hen 1 436.2 46 3,5-dichloro hen 1 471.1 47 4-methox hen l 432.3 48 4-meth 1 hen l 416.2 49 3-meth l hen l 416.2 50 4-fluoro hen 1 420.2 51 4-c ano hen 1 427.3 52 4-ace 1 hen 1 444 53 2-methox hen 1 432.4 54 4-trifluorometh i hen 1 470.2 55 3-trifluorometh l-4-chloro hen 1 504.1 56 3,5-dimethox hen 1 462.3 57 4-N-mo holin 1 hen 1 487.4 58 3-fluoro-4-methox hen 1 450.2 59 3,4,5-trimethox hen 1 492.3 60 3,4-dimethox hen 1 490 61 2-fluoro-4-chloro hen 1 454.2 62 2-h drox eth 1-6-meth 1 hen 1 446 Example 4 2-[4-(3-(2H-benzo [d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinylJ-N-(2,6-dimethylphenyl)acetamide (7B).
NH
~, N OH I
O N /
\~/ O
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 colunm chromatography (10:1 dichloromethane: methanol) to afford compound 5B.
Part C.
Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[dj1,3-dioxane (6B).
To an ice cold solution of 8 (1.0 g, 6.17 mmol) in dichioromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL
dichioromethane 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 (200m1), 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] 1,3-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 dichioromethane: methanol) to afford compound 7B: Mass spectrum (MH+1) =
426.34.
NH
'\ N OH
01,10 O N
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9B).
Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 9B: Mass spectrum (MH+1) = 396.32.
NH O
I ~ N 100 OH
/ O N
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)-propyl]piperazinyl}acetamide (10B) Compound lOB was prepared in the manner of compound 7B substituting 3-(2-methoxyphenyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C
to afford compound 10B: Mass spectrum (MH+1) = 412.35.
CA 02657986 2009-03-10 , *) NH N OH OCH3 ( \ ( \
O N /
N-(2,6-dimethylphenyl)-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)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C
to afford compound 11B: Mass spectrum (MIi+l) = 412.35.
NH
\
Jro'o~ N OH
/ O N
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-l-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 12B:
Mass spectrum (MH+1) = 382.
NH
X 00~ N -100 OH
~ o- N
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-(1-naphthyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 13:Mass spectrum (MH+l) = 432.55.
Part A
Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether (10 niL), 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 9lmL) 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 (200m1), 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-methoxyphenyl)-2-hydroxybntyl]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+1) = 426.3 H
~ H
N ON
F
2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl] piperazinyl}-N-(2,6-dimethylphenyl)acetamide(17B) Compound 17B was prepared in a manner similar to that of compound 16B
substituting 2,6-difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) 432.2 H
N
N OH ~
O N
\ ~
C
N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide(18B) Compound 18B was prepared in a manner similar to that of compound 16B
substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) = 430.2 H
N H
O N
2-(4-{4-[4-(tert-butyl)phenyl)-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide(19B) 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 H
N ~ N H
O N
F
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-fluorobenzy] chloride for 4-methoxybenzyl chloride. (M + 1) = 414.2 H
\ N N H ~
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl] butyl}piperazinyl)acetamide(21 B) Compound 21B was prepared in a manner similar to that of compound 16B
substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 464.2 O-\
H
H
2-[4-(3-(2H-benzo[d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-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+1) = 454.54 q1i7coO
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinylJ-2-methylpropanamide (23B) This compound was prepared in a manner similar to that of 7B, substituting 2-cbloro-2-methylpropionyl chloride for chloroacetyl chloride in part A and allylbenzene for 8B. (M+1) = 410.34.
cLr\j:,HaCH:
~ OCH3 H
N-(2,6-dimethylphen yl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propylJpiperazinyl}-2-methylpropanamide (24B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2-methylpropionyl chloride for chioroacetyl chloride in part A and 3,4,5-trimethoxy alkybenzene for 8B. (M+1) = 472.54 H
NY' C~JH~ 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+1) = 410.4.
H
H
O
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+1) =
428.1.
H
' N)rN H
O N
CI
N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyt)- 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+1) = 444.3 Example 6 N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]
acetamide (7C) Part A.
Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3C).
2,6-dimethylaniline (9.8g, 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 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 MgSOõ 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 (l Oml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1.l lg, 8.18mmol) in DMF (1m1) was added dropwise. The reaction was allowed to warm to room temperature and stirred 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-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl] acetamide (7C) To a solution of 6C (0.43g, 2.3mmol) in ethanol(4m1) was added 5C (0.405g, 1.64mmo1).
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+1) = 438.36.
Q ~
N N O
H
OH
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-({2,6-dimethylphenyl)acetamide (lOC) Compound 10C 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 10C : Mass spectrum MS (MH+) = 364.37.
NH
N .01 OH ' N O ~
~ O
(4-,~ %~
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-3 (phenylmethoxy)propyl] 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+1) = 412.36.
O
N ~=~'_= O
N
H
l.~
OH
2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]- N-(12,6-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
(1VIH+) _ 390.
2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)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.
H
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+1) = 468.44 H
NO N
J!~QDO
N-(2,6-dimethylphenyl)-2-(4-{3- [(2-f luorophenyl)meth oxy]-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+1) = 430.39 H
NH F
O
2-(4-{3- [(2,4-diiluorophenyl)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+1) = 448.38 H
Nj_--~N H / F
O
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{ [4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide (17C): Compound was prepared in a similar manner to compound 7C, substituting the commercially available 4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+1) = 480.37 H
O
O ~ \ I
N-(2,6-dimethylphenyl)-2-(4-{2-hyd roxy-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+1) = 442.41 H O/
, H / I \
O ~I
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+1) = 472.42 H
N --C
O
ON,~, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-5 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+1) = 442.42 H
N~ ~N^ H
O ~N" 0 / IF
~
N-(2,6-dimethylp h enyl)-2-(4- {3- [(4-flu oroph enyl)meth oxy] -2-hydroxypropyl}piperazinyl)acetamide (21C) Compound 21C was prepared in a similar 10 manner to compound 7C, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+1) = 430.40 O ~N-'I _ NJ OH
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-15 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+1) = 426.41 O rJ O
N OH
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide (23C) Compound 23C was prepared in a similar manner to compound 7C, substituting the commercially available 4-phenyl-benzylalcohol for 2-propanol in part C. MS
(M+1) = 488.42 N-"~O
NK~N J OH
H
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 cxLCrC0iX
N-(2,6-dimethylphenyl)-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+1) = 462.41 H
NH
O "0 1V -(2,6-dimethylp henyl)-2- {4- [3-(cyclohexylmeth oxy)-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+1) = 418.55 H
I \ ~N H
/ O N O
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)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+1) = 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 KCI, 33 mM
Tris buffer at pH 8, 2 mM KPi, 2 mM MgCIZ1 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 Inhibition of mitochondrial fatty acid oxidation using palmitoyl CoA as substrate -% of Control at 3 concentrations.
Compound # 100 M 30 M 3 M
Ranolazine 75% 90% --7 85% 98% 107%
15 78% 97% 103%
17 89% 98% 100%
16 100% 96% --18 17%
22 25%
9B 84% 84% --l OB -- -- --11B 83% 92% --12B 42% 95%
16B 37%
17B 78%
18B 78%
19B 35%
20B 56%
21B 56%
23B 70%
24B 72%
lOC 100% 97% --7C 68% -- --11 C 79% -- --12C 41%
-- --13C 30% -- --14C 21% - -15C 100% - -16C 97% - -17C 35% - -18C 96% - -19C 97% - -20C 100% - -21C 87% - -22C 45% - -23C 12% - -24C 15% - -25C 38% - -26C 70% - -27C 73% - -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 KCI, 33 mM Tris buffer at pH 8, 2 mM
KPi, 2 mM
MgCIZ1 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 camitine (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 supematant 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 Inhibition of mitochondrial fatty acid oxidation using palmitoyl carnitine as substrate -% of Control At 3 concentrations.
Compound # 100 M 30 12M 3 M
Ranolazine 63% 98% --7 95% 102% 109%
15 82% 98% 106%
17 80% 88% 103%
16 64% 8 -- --12B 56% -- --lOC 80% -- --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; P-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. 1mM of ranolazine or Compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain 100 M in 10% ACN; Human S9 stock: 20mgImL from Gentest.
Procedure:
Incubation mixtures were prepared as follows:
Table 3 Component Volume per 0.25mL of Incubation Final Mixture concentration compounds MgC12 25 L 0.005 M
NADPH 25 L 0.002 M
S9 25 L 2 mg/mL
Incubation Buffer 25 L 0.05 M
Water 125 L ----* 1% organic solvent (acetonitrile) was used in incubation mixture. Generally, 30 incubates were prepared at a time by pre-mixing 0.75 niL of MgC121 0.75 mL of incubation buffer, 0.75 5 mL of NADPH, 3.75 mL of water. Then pipette 200 L/incubate, add 25 L of compound being tested, mix, and initiate reaction by addition of S-9.
Combine all components with incubation buffer and re-pipette 200 L/tube +
25 L of the compound being tested along with 25 L of S-9.
10 After 5 min of pre-incubation at 37 C, at 0 and 30min after starting the reaction, a 50 l aliquot of the incubation mixture was removed and added to 100 L of 9:1 acetonitrile:
methanol containing the internal standard.
The mixture was centrifuged and a 100 L 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 LClMS
(injected 10 L).
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 mi/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 1Ø If a compound is less stable than ranolazine, than the stability factor will be less than 1Ø
Table 4 Compound # Liver S9 Stabili Factor Ranolazine 1.0 0.45 7 1.51 1.20 16 0.15 17 0.45 9B 1.18 lOB 1.03 7B 1.46 11B 1.33 12B 1.38 13B 0.10 16B 0.99 17B 0.71 18B 0.68 22B 1.49 23B 0.5 24B 1.05 22C 0.61 23C 0.05 24C 0.02 25C 0.01
R3 \ R m 0 R19 ` /
Rs RT Re OH
R
IA
wherein m = 1, 2;
R', RZ, R3, R 4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, ORz3 and Ci-4alkyl and wherein R23 is a C1_3 alkyl;
R6, R' and Ra each independently selected from the group consisting_of hydrogen and C,_, alkyl;
R9, R'o, R", R12, R13, R'a, R`s and R16 are each independently selected from the group consisting of hydrogen and C,., alkyl, or R4 and R1 may together form a carbonyl, or R" and R'2 may together form a carbonyl, or R" and R14 may together form a carbonyl, or R15 and R16 may together form a carbonyl wherein Rõ and Rõ or R9 and R15 or R9 and Rõ or Rõ and R15 or R9 and Rõ 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, R", R'2, R", R14, Rls and R16 are not all simultaneously hydrogen, when RI7, R18, R19, R20 and R21 are all hydrogen.
R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, S(O)R22, S02R22, SO2N(R23)2, CON(R23)2, Ct-4 alkyl wherein R23 is C,_, alkyl, or R" and R'B may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In more preferred compounds of Formula IA, R', R; R'-, R4 and RS are each selected from the group consisting of hydrogen, halo, CF31 OR23 and Ci-4alkyl where R23 is a CI_3 alkyl; R6 is selected from hydrogen and methyl; R', Ra, R9, R10, R", R'2, R", R'4, R'S and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R" and R14 may together form a carbonyl with the proviso that R', R10, R", R'2, R13, R14, R15 and R16 are not all simultaneously hydrogen ; R", R'$, R19, R20 and W' are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and C,., alkyl, or R" and R18 may together form -CH=CH-CH=CH-, or R" and R19 may together form -OCHZO-.
In still more preferred compounds of Formula IA, R', R2, R', R4, R5, R6, R' and Rg are each independently selected from the group consisting of methyl and hydrogen;
R9, R10, R", 'Z, R13, R", R15 and R'6 are each independently selected from hydrogen and methyl or R9 and R10 may together form a carbonyl, or R" and R'4 may together form a carbonyl with the proviso that R9, R10, R", R'z, R", R", R'S and R'6 are not all sunultaneously hydrogen; R", R18, R19, R20 and Rz1 are each independently selected from the group consisting of hydrogen, halo, CF31 ORZ3 wherein R23 is methyl, or R" and R'a may together form -CH=CH-CH=CH-, or R' 8 and R19 may together form -OCHzO-In an even more preferred compounds of Fornnula IA, R' and RS are each methyl;
R2, R3, R4, R6, R', R8 are each hydrogen; R9, RtO, R", R1z, R", 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, R", R'z, R", R14, R's and R16 are not all simultaneously hydrogen; R", R'g, R19, R20 and Rz1 are each independently selected from the group consisting of hydrogen, halo, methyl, OR23 wherein R23 is methyl, or R" and R1e may together form -CH=CH-CH=CH-, or R18 and R19 may together form -OCH2O-.
In still more preferred compounds of Formula IA, R' and RS are each methyl;
RZ, R3, R', R6, R', R8 are each hydrogen; R9, R10 are selected from hydrogen, methyl, or may together form a carbonyl; R" and R12 are selected from hydrogen and methyl; R" 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", R'Z, R", R'", R'S and R'6 are not all simultaneously hydrogen; R"
is selected from the group consisting of hydrogen, chloro, fluoro or methoxy;
R1e and R19 are each selected from the group consisting of hydrogen or methoxy, or R'$ and R19 may together form -OCH2O-1 or R" and R'g may together form -CH=CH-CH=CH-, R20 is hydrogen;
and RZ' 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 -di aza-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)propyl]-3,3-dimethylpiperazinyl} acetamide, 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1 S,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-dimethylphenyl)-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- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-indan-5-ylacetamide, 2- {(3 S)-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-4-2o methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(1-methylvinyl)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methylphenyl) acetamide, 2-{ (3 S)-4-[(2S)-3 -(2-fluorophenoxy)-2-hydroxypropyl] -3-methylpiperazinyl } -N-[6-methyl-2-(methylethyl)phenyl] acetamide, 2- {(3 S)-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- {(3 S)-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]-methylpiperazinyl} -N-(3-chlorophenyl) acetamide, 2- {(3 S)-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- {(3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-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-{ (3 S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl } -N-(4-acetylphenyl) acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-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-morpholin-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- {(3 S)-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-(hydroxymethyl-6-methylphenyl]
acetamide.
This invention includes a subset of substituted piperazine compounds of formula I
having the following formula IB:
2 R~ R Rlo R11 1~
R12 R~$
Rs R7 s OH
IB
wherein m 0, 1 or 2 or 3;
R', RZ, R3, R and RS are each independently selected from the group consisting of hydrogen, halo, NOZ, CF31 CN, OR23, SRZ3, N(R23)2, S(O)R22, SO,RZ2, SOzN(Rz3)z, NR23C0ZR22, NR23CON(R23)2, COR23 CO2R23, CON(R23)21 NR23SOzR22, Ci-t5 aIkY" C2-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, NOZ, CFõ CN, OR23, SR,3, N(RZ,)z, S(O)R22, and SO2RZ2;
R6, R' and Rg are each independently selected from the group consisting of hydrogen an,' C,_,s alkyl;
R9, R10, R", R'z, R`3, R,a, R's and R`6 are each independently selected from the group 1 o consisting of hydrogen, C02R23, CON(R23)Z, 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(RZ,)Z, COZR23, CON(R23)2 and aryl, wherein R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R13 and R14 may together form a carbonyl, or R'S and R16 may together form a carbonyl wherein R" and R13 or R9 and R15 or R9 and R" 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 R" and R'Z or R'3 and R'4 or R'S and R'6 may join to form a spiro ring system wherein the two R groups together comprise of from 1 to 5 carbon atoms;
R", R'a, R", R20, and RZ' are each independently selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23 SR23, N(R2,)2, S(O)R22, S02R22, SO2N(R23)2, NR23CO2R22, NR23CON(R2,)2, COR23, CO2RZ3, CON(R23)2, NR23S02R22I C,-is alkyl, alkenyl, C2_15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl and aryl substituent are optionally substituted with I substituent selected from the group consisting of halo, NO2, CF31 CN, OR23, SR23, N(R23)21 S(O)R221 and SO2R22 or wherein R" and R'8 may join together may join together to form -CH=CH-CH=CH- or wherein R" and R1e or R18 and R19 or RL9 and R20 or RZ0 and RZ' 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 I to 3 substituents selected from the group consisting of hydrogen, halo, NO2, CF3, CN, OR23, SR23, N(R")Z, S(O)R
22, S02R22, SOZN(R'3)2, NR23CO2 R22, NRZ'CON(R23)2, COR23, CO2R23, CON(RZ')2, NR23SOZR23, Cl_ls alkyl, C2.15 alkenyl, CZ.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, CFõ CN, OR23, SR23, N(R23)2, S(O)R22, or S02R22;
R21 is selected from the group consisting of 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, allcyl amide, aryl amide, heteroaryl amide, CN, O-C,-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, C1_15 alkyl, aryl, or heteroaryl, wherein the allcyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl-CN, -O-C1_6 alkyl, or CF3.
In preferred compositions of this invention, m= 0, 1 or 2 or 3; R', R2, R', R4 and RS
are each independently selected from the group consisting of hydrogen, halo, CF3, OR2,3 and C,4 alkyl; R6, R' and Re each independently selected from the group consisting of hydrogen and C,_3 alkyl; R9, R10, R", R'Z, R", R'4, R15 and R'6 are each independently selected from the group consisting of hydrogen and C,.4 alkyl, or R9 and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R14 may together form a carbonyl, or R's and R16 may together form a carbonyl, or wherein R" and R13 or R9 and R15 or R9 and R" or R" and R15 or R9 and R" may join together to form a ring including from I to 4 carbon atoms wherein R9, R10, R", R'2, R'3, R'4, R'5 and R'6 are not all hydrogen; and R", R'e, R'9, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF31 CN, OR23, S(O)R22, S02R22, SOZN(R23)Z, CON(RZ3)Z,C, , alkyl or R" and R18 may together form -CH=CH-CH=CH-, and phenyl.
In other preferred compounds, R', RZ, and RS are each independently selected from the group consisting of hydrogen, halo, CF31 OR23 and C1_2 alkyl wherein R23 is a Ct_3 alkyl; R6, R' and Ra are each independently selected from the group consisting of hydrogen and methyl; R9, R10, R", R'Z, R'3, R'4, R'S and R`6 are each independently selected from the group consisting of hydrogen and C,_Z 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", R'2, R'3, R'4, R'5 and R" are not all simultaneously hydrogen and wherein R" and R" or R9 and R15 or R9 and R" or R" and R'S or R' and R13 may join to form a ring including from 1 to 4 carbon atoms and R", R'g, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C alkyl and wherein R" and 3o R" may together form a substituent selected from the group consisting of -CH=CH-CH=CH-and phenyl.
In still other preferred compounds, m= I or 2; R', RZ, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and Ci.a alkyl where R23 is a C1.3 alkyl; R6, R', R', R9, R10, R", R`Z, R'3, R'4, R'S and R'6 are each independently selected from hydrogen and methyl; R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CFõ OR22, C_, alkyl where R22 is methyl, or R" and R18 may together form -CH=CH-CH=CH-, or R1e and R19 nlay together form -OCH2O-.
In more preferred compounds, m = 1 or 2; R', RZ, R', R4, R5, R6, R' and Rfl are each independently selected from methyl and hydrogen; R9, R10, R", R'z, R", R'4, R'5 and R'6 are each hydrogen; and R", R18, R19, R20 and RZ' are each independently selected from the group consisting of hydrogen, halo, CF3, and OR23 wherein R23 is methyl, or R" and R18 may together form -CT-I=CH-CH=CH-, or R18 and R19 may together form -OCHzO-.
In yet other preferred compounds, m = 1 or 2; R' and RS are methyl; R2, R', R4 R6, R7, R8,R9, R10, R", R'2, R'3, R'4, R'5 and R'6 are hydrogen; R", R'B, R'9, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, and OR23 wherein R23 is methyl, or R" and R1e may together form -CH=CH-CH=CH-, or R1e and R19 may together form -OCHZO-.
In still other preferred compounds, R' and RS are methyl; R2, R3, R4, R6; R', R8,R9, R10, R", R1z, R13, Rt4, R15 and R16 are hydrogen; R" is selected from the group consisting of hydrogen, chloro, fluoro and methoxy; R18 is selected fiom hydrogen and methoxy; R19 is selected from hydrogen and methoxy; R20 is hydrogen; R21 is selected from hydrogen and chloro, or R" and R18 may together form -CH=CH-CH=CH-, or R'a and R'9 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] 1,3-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, 1-I-(2,6-dimethylphenyl)-2-[4-(2-hyd.roxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl} -2-metliylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide, N-(2,6-dimethylphenyl)-2- f 4-[5-(2-flucropl:enyl)- 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:
Ft2 ~3 , ~10 ~11 _._ ~2 ~9 N N m O~ ft2a I O
$ 3 OFi IC
wherein m 1, 2, or 3;
R', R2, R3, R4 and RS are each independently selected from the group consisting of hydrogen, halo, NOZ, CF3, CN, OR20, SRZO, N(R20)2, S(O)R22, S02R22, SO2N(R20)Z, NR20C02R22, NR20CON(R.Z)2, COR20, C02R2o, CON(RZ0)Z, NRZ0S02RZ2, C,-õ alkyl, Czas alkenyl, C2-4 5 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(RZ0)2, S(O)R22, and SO2R22 ;
R6, R' and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R', R10, R", R'Z, R", R'4, R15 and R'6 are each independently selected from the group consisting of hydrogen, COZR20, CON(R20)2, C,-4 alkyl, and 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, . COZR20, CON(RZ0)2 or aryl, wherein R' and R10 may together form a carbonyl, or R" and R'Z may together form a carbonyl, or R" and R14 may together form a carbonyl, or R15 and Rt6 may together form a carbonyl, wherein R" and R13 or R9 and R15 or R9 and R" or R" and R15 or R9 and R" may join together to form a ring including from I to 3 carbon atoms;
R24 is selected from the group consisting of alkyl, eyeloalkyl, and fused phenylcycloalkyl wherein the point of attachment is on the cycloalkyl wherein the alkyl, :,ycloalkyl, and fused phenylcycloalkyl are optionally substituted with from I
to three substituents selected from the group consisting of halo, CF3, CN, OR20, SRzO, S(O)RZZ, SOZRZ', SOZN(R20)z, NR20CO2R21, C,_Z alkyl, and aryl wtierein the optional aryl substituent is optionally substituted with from I to 3 substituents selected from the group consisting of halo, phenyl, CF3, CN, OR20, and C, , alkyl;
Rz is selected from the group consisting of H, C,_,S alkyl, aryl,and heteroaryl,wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, mono- or dialkylamiiio, alkyl-CN, -O-C1_6 alkyl, and CF3; and RZ' is selected from the group consisting of C1_15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with I substituent selected from the group consisting of halo, alkyl, monoalkylanuno, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C,-, alkyl, CF3, and heteroaryl.
In Formula IC, it is preferred that m = 1 or 2 and most preferred when m = 1.
In preferred compositions of Fonnula IC, R', R2, R', R4 and RS are each independently selected from the group consisting of hydrogen, halo, CF3, OR22 and C, alkyl and wherein R22 is C,_, alkyl. In other preferred compositions, R', RZ, R', R' and RS are each independently selected from the group consisting of hydrogen, CFõ OR20, and C1_2 alkyl. More preferably R', R2, R', R4 and RS are each independently selected from the group consisting of hydrogen, and methyl with RZ, R', and R' as hydrogen and R' and RS as methyl being preferred.
In other preferred compositions of Formula IC, R6, R' 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, R", R'Z, R", R'4, R'S and R16 are each independently selected from the group consisting of hydrogen, CON(R2)2, C1 I
alkyl, and aryl wherein the alkyl and aryl substituents are each optionally substituted with I
substituent selected from the group consisting of halo, CFõ OR20, N(RZ0)2, CON(R2)2 and aryl wherein R9 and R10 may together form a carbonyl, or R" and R'2 may.together form a carbonyl, or R13 and R14 may together fonn a carbonyl, or R15 and R16 may together form a carbonyl, wherein R' 1 and R 13 or R9 and R15 or R9 and R" 1 or R" and RIS or R9 and R13 may join together to form a ring having from 1 to 3 carbon atoms. In alternative preferred compositions, R9, Rio~ Rtt~ Rt2~ R13~ Rta, Rts and R16 are each independently selected from the group consisting of hydrogen and C1_4 alkyl, or R9 and R10 together foi-m a carbonyl, or R" and R12 together form a carbonyl, or R13 and R14 together form a carbonyl, or R15 and R16 together form a carbonyl, R10 and R' 1 together form -CH2CH2CH2CH2-. In another embodiment, R9, R1O, Rl 1, R12, R13, R14, R15 and R" are each independently selected from the group consisting of hydrogen, and CI_2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)z.and arylor wherein R9 and R10 may together form a carbonyl.
More preferably, R9, R10, R", R'Z, R", R'4, R'5 and R'6 are each independently selected from the group consisting of hydrogen and C,_z alkyl, or wherein R9 and R10 may together form a carbonyl. In another embodiment, R" and R15 are each selected from the group consisting of hydrogen or methyl, R9, R10, R'z, R'3, R'-0 and R'6 are each hydrogen and R9 and R'0 may together form a carbonyl, or, R9, R10, R", R'2, R", R'4, R'S and R'6 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 I to three substituents selected from the group consisting of halo, CF3, CN, OR20, SRZO, S(O)R22, S02R 22, SOZN(RZ)Z, NR20C02 R22, C1_2 alkyl, and aryl wherein the optional aryl substituent is optionally substituted with from I 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, CFõ CN, OR20, SRZO, S(O)R22, S02 R22, C1_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,., alkkyl. 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, CF31 CN, OR20, and C,, alkyl.
In still other preferred compounds of Formula IC, R24 is selected from the group consisting of alkyl having from I 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, CF31 OH, methyl, and aryl, and aryl that is optionally substituted with from I to 2 substituents selected from the group consisting of halo, CFõ OH, C1_2 alkyl, and aryl. In still other preferred compounds of Formula IC, R24 is alkyl having from I 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, CF31 OR20, C,_Z alkyl, and aryl or R24 is phenylmethyl that is optionally substituted with from I
to 2 substituents selected from the group consisting of halo, CF31 OR20, C,, alkyl, and aryl.
In the compounds of Formula IC, R20 is selected from the group consisting of H, C1_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, R20 is selected from the group consisting of H or C1_3 alkyl and most preferably, RZ0 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-hydxoxy-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-rnethoxyphenyl)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}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} 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 I
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 I 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, alkylsulfmyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, 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 defmed below.
"Alkoxy" denotes the group -OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloallcyl, 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 I 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 furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, 0 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 0, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, atkylsulfonyl, 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, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.
"Heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of 0, 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 :ffective 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 IA-7A. A general synthesis of the compounds of this invention is outlined in Scheme 1A. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetylchloride M. Compound II is available commercially or readily prepared through reduction of the corresponding nitrobenzene derivative (acid/SnC12 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 H 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.
R2 Rt cl C' R2 Rt O
III /
R NH R7 R8 R / \ N CI
- RB _ Re R7 R8 R, RS R, R5 u tv R1o R11 Ra~1 I/Riz H-N/7-~\N-P R2 R, ReRto Rt1R
tz R1eRt5R14Ru R N N N-P
V
loom RB R7 Rej~
P BOC,CBZaBmzyl R4 R5 R1e R15Rt4Rt3 vi R9R1a R11Rtz R Rt O
Dc{avtoa R N N - H )MP I Y
R6 R7 Re R4 R5 Rts R15R14R13 VII
R / \ O~''6~
t m - R1o Rtt R Rt O R4\I ~R12 R17 R1E
R~ R21 'T- (`
VIII R / ~ i N N~O R79 RB R R-1Y OIH m R4 Rg R16 R15RuRts R21 R
I
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 10 cases, compound V can be obtained from commercial resources. Examples of commercially available compounds corresponding 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).
Rie R17 R18 R17 O
X acetone, K SCO3 O
R19 OH + R~e m X
X = C1 or Br ix VIII
Epoxide VIII (where m = I or 2) can be prepared as outlined in Scheme 2.
Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-1,2-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 IX 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 VIlI can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure VIII 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 methylphenyl ether, glycidyl 3,4-dichlorophenyl ether and glycidyl 4-fluorophenyl ether.
O
Rio Re TFA
_ t-BuLi , R 9,IOBr DeQrotecho^
Bn-N BOC Bn-N BOC
R ' R 9 O R Rto Diborane Bn-N flH ~ Bn-N NH
\~_XIv// \t_J/
v 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 XIH 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].
1 o SCHEME 4A
toR9 o e R10 O R13 O R`~4 R14~~4 l.coupling H-N N-Bn + i~R1s Boc--NH OH
Bn~NH OR Z, T'FA, ring dosure O R14 XVI XVII XVIII
It=MeorEt R~~Rs diborane ~
H-N N-Bn \-~ Rts xlx R 14 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 (1S,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.
HN NH HN NH H NH
Commercially available bicyclic analogs include (1 S,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, SS, 1684-1687).
A specific example of the preparation of a compound of Formula IA is disclosed in Schemes 5A, 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 K2C03 as described in Scheme 6.
C Ci sat NaHCO 3/ Et ZO (1:1) H EtOH DrPEA refluz 24 hrs.
CO
O
O
HLb O /,--< 6 N NH
N
H EtOI-); Rcflux H~C
N NO
H
OH
CHs O
OH O
CI acetone, K2C03 8 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 dichioromethane 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 3 as described above afforded compound 14.
~ ~c H OCH, HN. J~IHz + O H~ O
5,~
v HN- fl v 6 il H 1.TFA
chbroacetyl chloride Yoc T-~f O
HN~ O OCH, DCM, DIPEA jw- 2. EtOH, DIPEA
H
OCH, 3 I - OCH, O \~ N~ O
HN \ j ' n I' EtOA,DIPEA 0 The compounds having the general formula I and IB can be prepared as outlined in 5 Schemes 1B-7B. A general synthesis of the compounds of this invention is outlined in Scheme 1B. 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.
lo 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.
2 R' C IQR~ Ra CI *2,W
O
Ra ~ ` i Ra H R N RR RRR5 II IV
Rio Rtt Ro~' 4 J _R' 2 H,^N/ \N_P RsRto R" i2 RZ Rt O )L__~R
R
18~ 15R1 ,4Ria Ra N N-P
R
V Ra R~ Ra P=BOC,CBZorBenzy R4 5 Rta RISR14Rt9 ~
RgRto Rtt 12 R2 Rt I/R
Deprotect R N NN-H
Ra R7 Re Ra R5 R1e RuRt4 Rta VII
Rte Rt7 Rt ~ `
n - O 2 R ReRto RttR12 Rt7 Rie R2o R2t VIII R3 N N Rta ~
' Ra Rt Re OH
R4 6 Rta Rt5RtaRt3 ~1 R2o R
I
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, EtOIT).
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).
R \ CHO R18 I ~ \ CI
R1 ~ R21 R1 ~ R21 ~/MgBr PhgPCH2Br, NaH, THF
Diethylether Ri8 R1a 0 \ mCPBA,DCM
Rtg I~ R~ R1 R21 XI Vlll 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 Homer 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-chiorostyrene, 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.
R10Ra O
n-SuLi, Rg,ipBr ~ Deprotection Bn-N~-2-BOC Bn-N_ JJ--BOC
XII XIvII
Ri oR9 O R' R9 ~4 ~
BH3 Bn~N_ J~H lo= Bn--N_ rIH
jav \~~, J/
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 Pohiman 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).
R14~\~/ // 1.coupling H-N N-~Bn + ~.~((` lob ~R13 Boa--=-NH OH
Bn~ NH OR Z TFp, ringdosure O 14 XVIII R
XVI XVII
IZ=MeorEt RloRs diborane ~
H-N N-Bn ~R13 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 (1S,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.
\
HN H H -\H H H
Commercially available bicyclic analogs include (1S,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.
o /-\
-j~ HN- NH
v cl cl (NH2 Z fLci 4 sat NaHCOS1 Et2O (175 EtOH, DIPEA, reflux 24 hrs.
0 ---> RT
J
__ O
O
O
'~` H
N
H EtOH, Reflux O
O^1 NN N
H OH
Compound 8 is commercially available and was epoxidized using 3-chloroperoxybenzioc acid in dichloromethane as illustrated in Scheme 6B.
Scheme 6B
OH Q....o Nl~ + C acetone, K=C0= m y 6a.
m=1 8 OCH3 6b. m= 2 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.
CI MgBr I f - I~
H3CO Ethylether OCH3 mCPBA, DCM 1--0)~ OCH3 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 1C.
U
R Rj CI Ci R 0 III
R3 / ` NH R,Rs R 0", N CI _ RB Re R7 RB
s II IV
Rio Rit R"~Rtz H-N --P ReRto RttRIz R R~ O
RtsRisR14R~a R3 N N p V
P= BOC, CBZ or Benz R4 R5 RB R7 RA
~e R~sRt~ u VI
R Rt O Ip---E' ' l R9Rto RttRtz Deprotect R3 N N ~ H
I JY
s R7 R
R4 Rs R A 16 RuRt4Rta VII
~ Rto Rt~R1z Rt7 R R' o R9`
V 111 ~/R'T
R oH
R6 R7 Rts Rta R4 Rs RtsR14 I
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/SnC12 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, 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).
X NaH, DMF O
R~7 ~-OH +
X
IX
X=ClorBr VIII
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 2o 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 Pohlmanet. 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).
O RioRe O
I~ n-BuLi. R9103r /~ TFA
Bn-N N-BOC Bn-NN-BOC )OW
XI XII
R, oRa O R Ry Diborane l~~
,~
Bn-N NH 00 Bn- N NH
\xiII
v 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.
1 o SCHEME 4C
s R'O O R1s O ~
R74 i.coupung H-N N-Bn + ~ Rt3 Boo-NH OIH
B~NH OR
2. TFA, ring dos nre 0 R14 xiv xv xvi R=Me or Flt oR9 diborane H-NN-Bn Rta 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.
HN H
y C CI
1(NH2 (Lc N
set NeHC03/ Et20 (1:1) H EtOH, DIPEA, rcflux 24 hro.
0 ---> RT
QocO
N NH
:enux N EtOH, H
s OH
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.
-oH
NaH, DMF
$ 6 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. The effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal. 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 1ike, 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 adniinistration 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.
In another recent approach, the compositions of this invention can be administered orally in a sustained release dosage form.
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 sldlled 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-meth oxy)propyl] -3,5-dimethylpiperazinyl}acetamide (7).
O
~ ~ N~/N N p OH
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.
=
=
NH
O N O
`
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). KZC03 (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 MgSOq 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.
NH
IrN OH OCH3 O N O
2-{(5S,2R)-4-[2-hydroxy-3-(2-meth oxyphen oxy)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_ &":" H
~N OH OCH 3 O N O
`
N-(2,6-dimethylphenyl)-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+1) = 442.41.
NH
*'r' N "") OH OCH3 O N O
O
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 17: Mass spectrum (M+1) = 482.4.
O edrO
000"~ OH
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+1) _ 456.51 Q~H ~^
N
O ` /
HN r 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1 S,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 (IS,4S)-(+)-2,5-Diazabicyclo[2.2.1]heptane for 2,6-dimethylpiperazine 4 in part B to afford compound 19:
Mass spectrum (M+1) = 481.5 O O Z
N JL-.-~ N N
OH
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy)butyll-piperazinyl}acetamide (20) Compound 20 was prepared in the manner of compound 7 substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 20: Mass spectrum (M+1) = 442.37 F
O
N NOH
c N
N-(2,6-dimethylphenyl)-2-{4-[4-(4-flu orophenoxy)-2-hydroxybu tyl] -piperazinyl}acetamide (21) Compound 21 was prepared in the manner of compound substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 21: Mass spectrum (M+1) = 430.35 o N J"'., N N
4)4 H
OH
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-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 22: Mass spectrum (M+1) = 468.32 ..~*
O Z
Z
CS\ NJL~= N ~N
OH
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-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 23: Mass spectrum (1VI+1)=488.41 JL,,., N N
N
H OH
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-4-(4-meth oxyphenoxy)butyl]-piperazinyl}acetamide (24) Compound 24 was prepared in the manner of compound 7 substituting 4-bromo-1,2-epoxybutane 6b for epichlorohydrin 6a in part B to afford compound 24: Mass spectrum (M+1) = 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- methoxyphenoxy)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 witll diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled in an ice water bath. 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 1-[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)propyl]-3-oxopiperazinyl}acetatnide (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+1) 442.34 Example 3 S .,,.=~` F
H N S
R..- y 0*141~ N N O
O OH
The compounds listed in Table 1, below were made in the manner of compound 14 of Example 2.
Table 1 R NIIT~
25 2,6-dimeth 1 hen l 430.3 26 2,6-dichloro hen l 471 27 4-aminosulfon 1 hen l 481.2 28 3-trifluorometh 1-5methox hen 1 500.2 29 5-indanyl 442.2 30 1-na hth 1 452.3 31 1 - 4-chlorona hth 1 486.3 32 2-N- ol l- hen l 467.3 33 Phenyl 402.2 34 2-chloro hen 1 436.2 35 2-chloro-4-meth 1 hen 1 450.2 36 2- 1-meth lethen 1 hen l 442.3 37 2-meth 1 hen 1 416.2 38 2-iso ro 1-6-meth 1 hen l 458.4 39 3-meth lthio hen 1 448.2 40 2-methox -4-chloro-5-meth 1 hen 1 480.2 41 4-dimeth lamino hen 1 445.3 42 2,4-dimethox hen 1 462.3 43 3,4-dichloro hen l 471.1 44 4-chloro hen 1 436.3 45 3-chloro hen 1 436.2 46 3,5-dichloro hen 1 471.1 47 4-methox hen l 432.3 48 4-meth 1 hen l 416.2 49 3-meth l hen l 416.2 50 4-fluoro hen 1 420.2 51 4-c ano hen 1 427.3 52 4-ace 1 hen 1 444 53 2-methox hen 1 432.4 54 4-trifluorometh i hen 1 470.2 55 3-trifluorometh l-4-chloro hen 1 504.1 56 3,5-dimethox hen 1 462.3 57 4-N-mo holin 1 hen 1 487.4 58 3-fluoro-4-methox hen 1 450.2 59 3,4,5-trimethox hen 1 492.3 60 3,4-dimethox hen 1 490 61 2-fluoro-4-chloro hen 1 454.2 62 2-h drox eth 1-6-meth 1 hen 1 446 Example 4 2-[4-(3-(2H-benzo [d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinylJ-N-(2,6-dimethylphenyl)acetamide (7B).
NH
~, N OH I
O N /
\~/ O
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 colunm chromatography (10:1 dichloromethane: methanol) to afford compound 5B.
Part C.
Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[dj1,3-dioxane (6B).
To an ice cold solution of 8 (1.0 g, 6.17 mmol) in dichioromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 mL
dichioromethane 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 (200m1), 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] 1,3-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 dichioromethane: methanol) to afford compound 7B: Mass spectrum (MH+1) =
426.34.
NH
'\ N OH
01,10 O N
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9B).
Compound 9B was prepared in the manner of compound 7B substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 9B: Mass spectrum (MH+1) = 396.32.
NH O
I ~ N 100 OH
/ O N
N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)-propyl]piperazinyl}acetamide (10B) Compound lOB was prepared in the manner of compound 7B substituting 3-(2-methoxyphenyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C
to afford compound 10B: Mass spectrum (MH+1) = 412.35.
CA 02657986 2009-03-10 , *) NH N OH OCH3 ( \ ( \
O N /
N-(2,6-dimethylphenyl)-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)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C
to afford compound 11B: Mass spectrum (MIi+l) = 412.35.
NH
\
Jro'o~ N OH
/ O N
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-l-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 12B:
Mass spectrum (MH+1) = 382.
NH
X 00~ N -100 OH
~ o- N
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-(1-naphthyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 13:Mass spectrum (MH+l) = 432.55.
Part A
Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether (10 niL), 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 9lmL) 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 (200m1), 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-methoxyphenyl)-2-hydroxybntyl]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+1) = 426.3 H
~ H
N ON
F
2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl] piperazinyl}-N-(2,6-dimethylphenyl)acetamide(17B) Compound 17B was prepared in a manner similar to that of compound 16B
substituting 2,6-difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) 432.2 H
N
N OH ~
O N
\ ~
C
N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide(18B) Compound 18B was prepared in a manner similar to that of compound 16B
substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1) = 430.2 H
N H
O N
2-(4-{4-[4-(tert-butyl)phenyl)-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide(19B) 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 H
N ~ N H
O N
F
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-fluorobenzy] chloride for 4-methoxybenzyl chloride. (M + 1) = 414.2 H
\ N N H ~
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl] butyl}piperazinyl)acetamide(21 B) Compound 21B was prepared in a manner similar to that of compound 16B
substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M + 1) = 464.2 O-\
H
H
2-[4-(3-(2H-benzo[d] 1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-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+1) = 454.54 q1i7coO
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinylJ-2-methylpropanamide (23B) This compound was prepared in a manner similar to that of 7B, substituting 2-cbloro-2-methylpropionyl chloride for chloroacetyl chloride in part A and allylbenzene for 8B. (M+1) = 410.34.
cLr\j:,HaCH:
~ OCH3 H
N-(2,6-dimethylphen yl)-2- {4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propylJpiperazinyl}-2-methylpropanamide (24B) This compound was prepared in a manner similar to that of 7B, substituting 2-chloro-2-methylpropionyl chloride for chioroacetyl chloride in part A and 3,4,5-trimethoxy alkybenzene for 8B. (M+1) = 472.54 H
NY' C~JH~ 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+1) = 410.4.
H
H
O
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+1) =
428.1.
H
' N)rN H
O N
CI
N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyt)- 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+1) = 444.3 Example 6 N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]
acetamide (7C) Part A.
Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3C).
2,6-dimethylaniline (9.8g, 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 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 MgSOõ 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 (l Oml) cooled to 0 degrees was added 2-propanol (0.5g, 3,73mmol) in DMF (2ml) dropwise. After stirring for 30minutes epibromohydrin (1.l lg, 8.18mmol) in DMF (1m1) was added dropwise. The reaction was allowed to warm to room temperature and stirred 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-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl] acetamide (7C) To a solution of 6C (0.43g, 2.3mmol) in ethanol(4m1) was added 5C (0.405g, 1.64mmo1).
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+1) = 438.36.
Q ~
N N O
H
OH
2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]- N-({2,6-dimethylphenyl)acetamide (lOC) Compound 10C 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 10C : Mass spectrum MS (MH+) = 364.37.
NH
N .01 OH ' N O ~
~ O
(4-,~ %~
N-(2,6-dimethylphenyl)-2-{4- [2-hydroxy-3 (phenylmethoxy)propyl] 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+1) = 412.36.
O
N ~=~'_= O
N
H
l.~
OH
2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]- N-(12,6-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
(1VIH+) _ 390.
2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)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.
H
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+1) = 468.44 H
NO N
J!~QDO
N-(2,6-dimethylphenyl)-2-(4-{3- [(2-f luorophenyl)meth oxy]-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+1) = 430.39 H
NH F
O
2-(4-{3- [(2,4-diiluorophenyl)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+1) = 448.38 H
Nj_--~N H / F
O
N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{ [4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide (17C): Compound was prepared in a similar manner to compound 7C, substituting the commercially available 4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+1) = 480.37 H
O
O ~ \ I
N-(2,6-dimethylphenyl)-2-(4-{2-hyd roxy-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+1) = 442.41 H O/
, H / I \
O ~I
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+1) = 472.42 H
N --C
O
ON,~, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-5 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+1) = 442.42 H
N~ ~N^ H
O ~N" 0 / IF
~
N-(2,6-dimethylp h enyl)-2-(4- {3- [(4-flu oroph enyl)meth oxy] -2-hydroxypropyl}piperazinyl)acetamide (21C) Compound 21C was prepared in a similar 10 manner to compound 7C, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+1) = 430.40 O ~N-'I _ NJ OH
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-15 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+1) = 426.41 O rJ O
N OH
N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide (23C) Compound 23C was prepared in a similar manner to compound 7C, substituting the commercially available 4-phenyl-benzylalcohol for 2-propanol in part C. MS
(M+1) = 488.42 N-"~O
NK~N J OH
H
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 cxLCrC0iX
N-(2,6-dimethylphenyl)-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+1) = 462.41 H
NH
O "0 1V -(2,6-dimethylp henyl)-2- {4- [3-(cyclohexylmeth oxy)-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+1) = 418.55 H
I \ ~N H
/ O N O
N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)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+1) = 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 KCI, 33 mM
Tris buffer at pH 8, 2 mM KPi, 2 mM MgCIZ1 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 Inhibition of mitochondrial fatty acid oxidation using palmitoyl CoA as substrate -% of Control at 3 concentrations.
Compound # 100 M 30 M 3 M
Ranolazine 75% 90% --7 85% 98% 107%
15 78% 97% 103%
17 89% 98% 100%
16 100% 96% --18 17%
22 25%
9B 84% 84% --l OB -- -- --11B 83% 92% --12B 42% 95%
16B 37%
17B 78%
18B 78%
19B 35%
20B 56%
21B 56%
23B 70%
24B 72%
lOC 100% 97% --7C 68% -- --11 C 79% -- --12C 41%
-- --13C 30% -- --14C 21% - -15C 100% - -16C 97% - -17C 35% - -18C 96% - -19C 97% - -20C 100% - -21C 87% - -22C 45% - -23C 12% - -24C 15% - -25C 38% - -26C 70% - -27C 73% - -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 KCI, 33 mM Tris buffer at pH 8, 2 mM
KPi, 2 mM
MgCIZ1 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 camitine (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 supematant 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 Inhibition of mitochondrial fatty acid oxidation using palmitoyl carnitine as substrate -% of Control At 3 concentrations.
Compound # 100 M 30 12M 3 M
Ranolazine 63% 98% --7 95% 102% 109%
15 82% 98% 106%
17 80% 88% 103%
16 64% 8 -- --12B 56% -- --lOC 80% -- --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; P-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. 1mM of ranolazine or Compounds 43, 45, 47, 52, 70, 74, 76, 78, and 80 in ACN further diluted to obtain 100 M in 10% ACN; Human S9 stock: 20mgImL from Gentest.
Procedure:
Incubation mixtures were prepared as follows:
Table 3 Component Volume per 0.25mL of Incubation Final Mixture concentration compounds MgC12 25 L 0.005 M
NADPH 25 L 0.002 M
S9 25 L 2 mg/mL
Incubation Buffer 25 L 0.05 M
Water 125 L ----* 1% organic solvent (acetonitrile) was used in incubation mixture. Generally, 30 incubates were prepared at a time by pre-mixing 0.75 niL of MgC121 0.75 mL of incubation buffer, 0.75 5 mL of NADPH, 3.75 mL of water. Then pipette 200 L/incubate, add 25 L of compound being tested, mix, and initiate reaction by addition of S-9.
Combine all components with incubation buffer and re-pipette 200 L/tube +
25 L of the compound being tested along with 25 L of S-9.
10 After 5 min of pre-incubation at 37 C, at 0 and 30min after starting the reaction, a 50 l aliquot of the incubation mixture was removed and added to 100 L of 9:1 acetonitrile:
methanol containing the internal standard.
The mixture was centrifuged and a 100 L 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 LClMS
(injected 10 L).
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 mi/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 1Ø If a compound is less stable than ranolazine, than the stability factor will be less than 1Ø
Table 4 Compound # Liver S9 Stabili Factor Ranolazine 1.0 0.45 7 1.51 1.20 16 0.15 17 0.45 9B 1.18 lOB 1.03 7B 1.46 11B 1.33 12B 1.38 13B 0.10 16B 0.99 17B 0.71 18B 0.68 22B 1.49 23B 0.5 24B 1.05 22C 0.61 23C 0.05 24C 0.02 25C 0.01
Claims (56)
1. A substituted piperazine compound having the following formula:
wherein X is:
wherein m= 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, C1-125 alkyl, 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-;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 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 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 R11 or R11 and R15 or R9 and R13 may join together to form a bridging ring system having 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 bridging ring system having from 1 to 5 carbon atoms;
R22 is selected from the group consisting of C1-15 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-C1-6 alkyl, CF3, and heteroaryl;
R23 is selected from the group consisting of H, C1-15 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-C1-6 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, OR23, SR23, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, C1-2 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, OR23, and C1-6 alkyl, and 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, C02R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 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.
wherein X is:
wherein m= 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, C1-125 alkyl, 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-;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 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 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 R11 or R11 and R15 or R9 and R13 may join together to form a bridging ring system having 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 bridging ring system having from 1 to 5 carbon atoms;
R22 is selected from the group consisting of C1-15 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-C1-6 alkyl, CF3, and heteroaryl;
R23 is selected from the group consisting of H, C1-15 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-C1-6 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, OR23, SR23, S(O)R22, SO2R22, SO2N(R23)2, NR23CO2R22, C1-2 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, OR23, and C1-6 alkyl, and 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, C02R23, CON(R23)2, NR23SO2R22, C1-15 alkyl, C2-15 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.
2. A substituted piperazine compound having the following formula:
wherein m = 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, C1-15 alkyl, 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;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 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 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 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 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, C1-15 alkyl, 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 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 C1-15 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-C1-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, C1-15 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-C1-6 alkyl, or CF3.
wherein m = 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, C1-15 alkyl, 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;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-15 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 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 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 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 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, C1-15 alkyl, 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 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 C1-15 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-C1-6 alkyl, CF3, and heteroaryl; and R23 is selected from the group consisting of H, C1-15 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-C1-6 alkyl, or CF3.
3. The compound of claim 2 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, C1-15 alkyl, heterocyclyl, aryl, and heteroaryl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-8 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, and 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 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 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, C1-15 alkyl, C2-6 alkenyl, C2-6 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, CN, and 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 C1-8 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, CN, and CF3; and R23 is selected from the group consisting of H, C1-8 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, and CF3.
R6, R7 and R8 each independently selected from the group consisting of hydrogen or C1-8 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R23, CON(R23)2, C1-4 alkyl, and 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 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 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, C1-15 alkyl, C2-6 alkenyl, C2-6 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, CN, and 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 C1-8 alkyl, aryl, or heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, CN, and CF3; and R23 is selected from the group consisting of H, C1-8 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, and CF3.
4. The compound of claim 2 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, C1-8 alkyl, aryl, and heteroaryl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-5 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and 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 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, C1-8 alkyl, aryl, and heteroaryl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is selected from the group consisting of C1-6 alkyl, and aryl; and R23 is selected from the group consisting of H, C1-6 alkyl, and aryl.
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-5 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and 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 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, C1-8 alkyl, aryl, and heteroaryl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is selected from the group consisting of C1-6 alkyl, and aryl; and R23 is selected from the group consisting of H, C1-6 alkyl, and aryl.
5. The composition of claim 2 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, CN, OR23, and C1-6 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 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 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 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, and C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is C1-3 alkyl; and R23 is selected from the group consisting of H and C1-3 alkyl.
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 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 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 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, and C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is C1-3 alkyl; and R23 is selected from the group consisting of H and C1-3 alkyl.
6. The compound of claim 5 wherein m = 1 or 2 or 3.
7. The compound of claim 5 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and 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.
8. The compound of claim 5 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl.
9. The compound of claim 7 or 8 wherein R6, R7 and R8 are each independently selected from the group consisting of hydrogen and methyl.
10. The compound of claim 5 wherein R9, R10, R11, R12, R13, R14 R15 and R16 are hydrogen.
11. The compound of claim 5 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, and C1-2 alkyl;
R6 is hydrogen; and R7 and R8 are each independently selected from the group consisting of hydrogen and methyl; and R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 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, C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is methyl; and R23 is selected from the group consisting of H, and methyl.
R6 is hydrogen; and R7 and R8 are each independently selected from the group consisting of hydrogen and methyl; and R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-3 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, C1-6 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-;
R22 is methyl; and R23 is selected from the group consisting of H, and methyl.
12. The compound of claim 11 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and methyl.
13. The compound of claim 11 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are hydrogen.
14. The compound of claim 11 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, and C1-4 alkyl, and R19 and R20 may combine to form a saturated ring including from 5 to 6 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-.
15. The compound of claim 11 wherein R17, R18, R19, R20, and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, and C1-4 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-.
16. The compound of claim 2 wherein m = 1 or 2;
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and C1-2 alkyl wherein R23 is a C1-2 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 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, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein R23 is C1-2 alkyl and wherein R'7 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 CH2-O-.
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 and C1-2 alkyl wherein R23 is a C1-2 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 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, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein R23 is C1-2 alkyl and wherein R'7 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 CH2-O-.
17. The compound of claim 16 wherein R1, 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 R9 R10 R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 alkyl.
20. The compound of claim 16 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl.
21. The compound of claim 16 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 R1 together form a carbonyl.
22. The compound of claim 16 wherein R17, R18, R19, R20 and R 21 are each independently selected from the group consisting of hydrogen, halo, C1-3 alkyl and OR23 wherein R23 is C1-2 alkyl.
23. The compound of claim 16 wherein R17 and R18 or R18 and R19 together form a ring selected from the group consisting of -CH=CH-CH=CH-, and -O-CH2-O.
24. The compound of claim 2 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, 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 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, C1-4 alkyl, CF3 and OR23; and R23 is C1-2 alkyl.
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, 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 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, C1-4 alkyl, CF3 and OR23; and R23 is C1-2 alkyl.
25. The compound of claim 24 wherein R1 and R5 are each methyl and R2, R3, and R4 are each hydrogen.
26. The compound of claim 24 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and methyl.
27. The compound of claim 24 wherein R9, R10 R11 R12, R13 R14, R15 and R16 are each hydrogen.
28. The compound of claim 24 wherein, R17, R18, R19, R20, and R2 are each selected from the group consisting of hydrogen, Cl, F, -OCH3, -CF3 and C1-4 alkyl.
29. The compound of claim 28 wherein R18 and R20 are each hydrogen.
30. The compound of claim 28 wherein R19 is -OCH3.
31. The compound of claim 24 wherein R17 is -OCH3, and R18, R19, R20 and R21 are each hydrogen.
32. The compound of claim 24 wherein, R17 , R18, R20 and R21 are each hydrogen and R19 is selected from the group consisting of -OCH3, -F, CF3, and C1-4 alkyl.
33. A substituted piperazine compound of claim 2 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]1,3-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-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide.
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]1,3-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-pentyl]piperazinyl}acetamide, and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide.
34. A substituted piperazine compound having the following formula:
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, NR2OCO2R12, NR20CON(R20)2, CO2R20, CON(R20)2, NR20SO2R22, C1-15 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, OR20, SR20, N(R20)2, S(O)R22, and SO2R22;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON(R20)2, C1-4 alkyl, and 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 and 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 R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms, or R10 and R11 together form -CH2CH2CH2CH2-;
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, 2R22, SO2N(R20)2, NR20CO2R22, C1-2 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 C1-6 alkyl;
R20 is selected from the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl -CN, -O-C1-6 alkyl, and CF3; and R22 is selected from the group consisting of C1-15 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-C1-6 alkyl, CF3, and heteroaryl.
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, NR2OCO2R12, NR20CON(R20)2, CO2R20, CON(R20)2, NR20SO2R22, C1-15 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, OR20, SR20, N(R20)2, S(O)R22, and SO2R22;
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CO2R20, CON(R20)2, C1-4 alkyl, and 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 and 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 R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms, or R10 and R11 together form -CH2CH2CH2CH2-;
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, 2R22, SO2N(R20)2, NR20CO2R22, C1-2 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 C1-6 alkyl;
R20 is selected from the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, alkyl, mono- or dialkylamino, alkyl -CN, -O-C1-6 alkyl, and CF3; and R22 is selected from the group consisting of C1-15 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-C1-6 alkyl, CF3, and heteroaryl.
35. 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, OR20, SR20, N(R20)2, SO2N(R20)2, CO2R20, CON(R20)2, C1-8 alkyl, C2-4 alkenyl, C2-4 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, OR20, SR20, N(R20)2, S(O)R22, and SO2R22;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, and C1-4 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; and R20 is selected from the group consisting of H, C1-15 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, alkylcyano, -O-C1-6 alkyl, and CF3.
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, and C1-4 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; and R20 is selected from the group consisting of H, C1-15 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, alkylcyano, -O-C1-6 alkyl, and 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, OR20, C1-5 alkyl, C2-3 alkenyl, and 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 and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, and C1-4 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, C1-2 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 C1-6 alkyl; and R20 is selected from the group consisting of H, C1-8 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -O-C1-3 alkyl, and CF3.
R6, R7 and R8 are each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, and C1-4 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, C1-2 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 C1-6 alkyl; and R20 is selected from the group consisting of H, C1-8 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -O-C1-3 alkyl, and CF3.
37. The compound of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, wherein the alkyl is optionally substituted with CF3;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 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, OR20, S(O)R22, C1-2 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 C1-6 alkyl;
and R20 is selected from the group consisting of H, C1-5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -OMe, and CF3.
R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen and C1-2 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, OR20, S(O)R22, C1-2 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 C1-6 alkyl;
and R20 is selected from the group consisting of H, C1-5 alkyl, aryl, and heteroaryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent selected from the group consisting of halo, -OMe, and CF3.
38. 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, OR20 and C1-4 alkyl and wherein R20 is a C1-3 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, C1-4 alkyl, and 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 and 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 R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms, or R10 and R11 together form -CH2CH2CH2CH2-;
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 C1-6 alkyl; and R20 is selected from the group consisting of H, C1-3 alkyl, and aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, -OMe, and CF3.
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20 and C1-4 alkyl and wherein R20 is a C1-3 alkyl;
R6, R7 and R8 each independently selected from the group consisting of hydrogen and C1-3 alkyl;
R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R20)2, C1-4 alkyl, and 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 and 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 R11 or R11 and R15 or R9 and R13 may join together to form a ring including from 1 to 3 carbon atoms, or R10 and R11 together form -CH2CH2CH2CH2-;
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 C1-6 alkyl; and R20 is selected from the group consisting of H, C1-3 alkyl, and aryl, wherein the alkyl and aryl substituents are optionally substituted with 1 substituent individually selected from the group consisting of halo, -OMe, and CF3.
39. The compound of claim 38 wherein 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, or R10 and R11 together form -CH2CH2CH2CH2-.
40. The compound of claim 38 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, CON(R 20)2, C1-3 alkyl, and 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, wherein 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 including from 1 to 3 carbon atoms.
41. The compound of claim 38 wherein R9, R10, R11, R12, R13, R14, R15 and R16 are each independently selected from the group consisting of hydrogen, and C1-2 alkyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of N(R20)2, and aryl or wherein R9 and R10 may together form a carbonyl.
42. The compound of claim 34 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OR20, and C1-3 alkyl wherein the alkyl substituent is optionally substituted with CF3.
43. The compound of claim 34 wherein R6, R7 and R8 each independently selected from the group consisting of hydrogen and methyl.
44. The compound of claim 34 wherein m=1.
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, and C1-2 alkyl;
R6, R7 and R8 are each hydrogen;
R9, R10, R11, R12, R13, R14, R15 and R16are each independently selected from the group consisting of hydrogen and C1-2 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 C1-4 alkyl; and R20 is selected from the group consisting of H and C1-3 alkyl.
R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, CF3, OR20, and C1-2 alkyl;
R6, R7 and R8 are each hydrogen;
R9, R10, R11, R12, R13, R14, R15 and R16are each independently selected from the group consisting of hydrogen and C1-2 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 C1-4 alkyl; and R20 is selected from the group consisting of H and C1-3 alkyl.
45. The compound of claim 44 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 C1-4 alkyl.
46. The compound of claim 34 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 C1-4 alkyl.
47. The compound of claim 44 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halo, CF3, OCH3, and methyl.
48. The compound of claim 44 wherein R1, R2, R3, R4 and R5 are each independently selected from the group consisting of hydrogen, and methyl.
49. The compound of claim 44 wherein R11 and R15 are each selected from the group consisting of hydrogen and methyl, R9, R10, R12, R13, R14 and R16 are each hydrogen, or R9 and R10 may together form a carbonyl.
50. A compound of claim 34 wherein m = 1;
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;
R11 and R15 are each selected from the group consisting of hydrogen and 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 C1-4 alkyl; and R20 is methyl or H.
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;
R11 and R15 are each selected from the group consisting of hydrogen and 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 C1-4 alkyl; and R20 is methyl or H.
51. The compound of claim 50 wherein R24 is alkyl having from 1 to 6 carbon atoms or cycloalkyl.
52. The compound of claim 50 wherein R24 is a fused phenylcycloalkyl that is optionally substituted with 1 substituent selected from the group consisting of halo, CF3, OR20, and aryl.
53. The compound of claim 50 wherein R24 is phenylmethyl wherein the phenyl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OR20, C1-4 alkyl, and phenyl.
54. The compound of claim 50 wherein R2, R3, and R4 are each hydrogen and R1 and R5 are each methyl.
55. The compound of claim 34 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 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, and fused phenylcycloalkyl wherein the phenyl of the fused phenylcycloalkyl is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, methyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, C1-2 alkyl, and phenyl.
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, and fused phenylcycloalkyl wherein the phenyl of the fused phenylcycloalkyl is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, methyl, and aryl, wherein the optional aryl substituent is optionally substituted with from 1 to 2 substituents selected from the group consisting of halo, CF3, OH, C1-2 alkyl, and phenyl.
56. The compound of claim 34 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}piperazinyl)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}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.
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
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| US18430600P | 2000-02-22 | 2000-02-22 | |
| US18445700P | 2000-02-22 | 2000-02-22 | |
| US18418200P | 2000-02-22 | 2000-02-22 | |
| US60/184,306 | 2000-02-22 | ||
| US60/184,457 | 2000-02-22 | ||
| US60/184,182 | 2000-02-22 | ||
| US20639600P | 2000-05-23 | 2000-05-23 | |
| US60/206,396 | 2000-05-23 | ||
| US20926200P | 2000-06-05 | 2000-06-05 | |
| US60/209,262 | 2000-06-05 | ||
| CA002400176A CA2400176C (en) | 2000-02-22 | 2001-02-22 | Substituted piperazine compounds |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CA002400176A Division CA2400176C (en) | 2000-02-22 | 2001-02-22 | Substituted piperazine compounds |
Publications (1)
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|---|---|
| CA2657986A1 true CA2657986A1 (en) | 2001-08-30 |
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| CA002400176A Expired - Fee Related CA2400176C (en) | 2000-02-22 | 2001-02-22 | Substituted piperazine compounds |
| CA002657986A Abandoned CA2657986A1 (en) | 2000-02-22 | 2001-02-22 | Substituted piperazine compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
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| Country | Link |
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| EP (1) | EP1259493A2 (en) |
| JP (2) | JP3980885B2 (en) |
| KR (1) | KR100595942B1 (en) |
| CN (1) | CN1404471A (en) |
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| AU (2) | AU2001238623B2 (en) |
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| CA (2) | CA2400176C (en) |
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| MX (1) | MXPA02008213A (en) |
| NO (1) | NO324837B1 (en) |
| NZ (1) | NZ520782A (en) |
| TW (1) | TWI236471B (en) |
| WO (1) | WO2001062744A2 (en) |
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| JP2004505886A (en) * | 2000-02-18 | 2004-02-26 | スィーヴィー セラピューティクス インコーポレイテッド | Partial fatty acid oxidation inhibitors in the treatment of congestive heart failure |
| EP1406898B1 (en) | 2001-07-19 | 2005-04-06 | Cv Therapeutics, Inc. | Substituted piperazine compounds and their use as fatty acid oxidation inhibitors |
| US7001909B2 (en) | 2001-07-19 | 2006-02-21 | Cv Therapeutics, Inc. | Substituted heterocyclic compounds |
| EP1806346B1 (en) * | 2002-12-05 | 2009-07-22 | Cv Therapeutics, Inc. | Substituted piperazine compounds and their use as fatty acid oxidation inhibitors |
| ES2287574T3 (en) * | 2002-12-05 | 2007-12-16 | Cv Therapeutics, Inc. | SUBSTITUTED PIPERACINE COMPOUNDS AND ITS USE AS INHIBITORS OF OXIDATION OF FATTY ACIDS. |
| NZ541069A (en) * | 2003-01-03 | 2008-09-26 | Cv Therapeutics Inc | Piperazine derivatives as fatty acid oxidation inhibitors |
| US7208496B2 (en) * | 2003-06-23 | 2007-04-24 | Cv Therapeutics, Inc. | Substituted heterocyclic compounds |
| AU2004303882A1 (en) * | 2003-12-18 | 2005-07-07 | Gilead Palo Alto, Inc. | 1-akan-2-ol substituted piperazine and piperidine compounds |
| KR20070051305A (en) * | 2004-09-08 | 2007-05-17 | 씨브이 쎄러퓨틱스, 인코포레이티드 | Substituted piperazine compounds and their use as fatty acid oxidation inhibitors |
| CN102875490A (en) * | 2012-10-19 | 2013-01-16 | 四川大学 | Synthetic method used for preparing ranolazine |
| CN107043361B (en) * | 2017-05-25 | 2019-07-02 | 合肥医工医药股份有限公司 | Treat anginal compound, Preparation method and use |
Family Cites Families (8)
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| JPS584774A (en) * | 1981-06-23 | 1983-01-11 | ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ | N-aryl-piperadine alkane amides |
| US4766125A (en) * | 1981-06-23 | 1988-08-23 | Janssen Pharmaceutica N.V. | N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia |
| US4567264A (en) * | 1983-05-18 | 1986-01-28 | Syntex (U.S.A.) Inc. | Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry |
| US4558129A (en) * | 1983-05-18 | 1985-12-10 | Syntex (U.S.A.) Inc. | Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade |
| FR2552083B1 (en) * | 1983-09-15 | 1986-05-09 | Cerm Cent Europ Rech Mauvernay | (ALKYNYLOXY-3 HYDROXY-2-PROPYL) -4 PIPERAZINYL-1 N-PHENYL ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| ZA904842B (en) * | 1989-06-23 | 1992-02-26 | Syntex Pharma Ltd | Novel methods of treatment using ranolazine and related piperazine derivatives |
| JPH03141258A (en) * | 1989-10-25 | 1991-06-17 | Kowa Co | Novel piperazine derivative |
| HU209723B (en) * | 1990-10-31 | 1994-10-28 | Richter Gedeon Vegyeszet | Process for producing of piperazine derivatives |
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2001
- 2001-02-22 WO PCT/US2001/005606 patent/WO2001062744A2/en active IP Right Grant
- 2001-02-22 BR BR0108592-1A patent/BR0108592A/en not_active Application Discontinuation
- 2001-02-22 EP EP01911085A patent/EP1259493A2/en not_active Withdrawn
- 2001-02-22 AU AU2001238623A patent/AU2001238623B2/en not_active Ceased
- 2001-02-22 CN CN01805442A patent/CN1404471A/en active Pending
- 2001-02-22 AU AU3862301A patent/AU3862301A/en active Pending
- 2001-02-22 CA CA002400176A patent/CA2400176C/en not_active Expired - Fee Related
- 2001-02-22 AR ARP010100804A patent/AR029229A1/en unknown
- 2001-02-22 JP JP2001562526A patent/JP3980885B2/en not_active Expired - Lifetime
- 2001-02-22 NZ NZ520782A patent/NZ520782A/en unknown
- 2001-02-22 KR KR1020027011014A patent/KR100595942B1/en not_active IP Right Cessation
- 2001-02-22 MX MXPA02008213A patent/MXPA02008213A/en active IP Right Grant
- 2001-02-22 CA CA002657986A patent/CA2657986A1/en not_active Abandoned
- 2001-02-22 IL IL15117801A patent/IL151178A0/en unknown
- 2001-04-13 TW TW090104080A patent/TWI236471B/en not_active IP Right Cessation
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2002
- 2002-08-20 NO NO20023954A patent/NO324837B1/en not_active IP Right Cessation
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- 2007-01-15 JP JP2007005347A patent/JP2007211009A/en active Pending
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| AR029229A1 (en) | 2003-06-18 |
| NZ520782A (en) | 2004-03-26 |
| JP2007211009A (en) | 2007-08-23 |
| JP3980885B2 (en) | 2007-09-26 |
| IL151178A0 (en) | 2003-04-10 |
| KR100595942B1 (en) | 2006-07-03 |
| TWI236471B (en) | 2005-07-21 |
| MXPA02008213A (en) | 2004-04-05 |
| NO20023954D0 (en) | 2002-08-20 |
| JP2003531116A (en) | 2003-10-21 |
| NO20023954L (en) | 2002-09-30 |
| BR0108592A (en) | 2004-06-29 |
| CA2400176C (en) | 2009-04-28 |
| WO2001062744A3 (en) | 2002-02-07 |
| AU3862301A (en) | 2001-09-03 |
| KR20020079893A (en) | 2002-10-19 |
| CN1404471A (en) | 2003-03-19 |
| WO2001062744A2 (en) | 2001-08-30 |
| EP1259493A2 (en) | 2002-11-27 |
| CA2400176A1 (en) | 2001-08-30 |
| NO324837B1 (en) | 2007-12-17 |
| AU2001238623B2 (en) | 2004-09-23 |
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