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HK1211295B - C17-heteroaryl derivatives of oleanolic acid and methods of use thereof - Google Patents

C17-heteroaryl derivatives of oleanolic acid and methods of use thereof Download PDF

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Publication number
HK1211295B
HK1211295B HK15112022.0A HK15112022A HK1211295B HK 1211295 B HK1211295 B HK 1211295B HK 15112022 A HK15112022 A HK 15112022A HK 1211295 B HK1211295 B HK 1211295B
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compound
disease
group
acid
compound according
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HK15112022.0A
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HK1211295A1 (en
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江昕
克里斯多福‧F‧班德
麦琳‧维斯尼克
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里亚塔医药公司
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Priority claimed from PCT/US2013/059015 external-priority patent/WO2014040056A1/en
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Description

C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
This application claims the benefit of U.S. provisional patent application No. 61/699,199, filed on 9/10/2012, the entire contents of which are incorporated herein by reference.
In accordance with 37c.f.r.1.821(c), herein is submitted a sequence listing of ASCII compliant text files named "REATP 0076US _ sequenceisting _ st25.txt (REATP0076US _ sequence listing _ st25. txt)" which was created on 9 months and 9 days of 2013 and has a size of about 1 KB. The entire contents of the above documents are incorporated herein by reference.
Background
I. Field of the invention
The present invention relates generally to the fields of biology and medicine. More particularly, the present invention relates to compounds, compositions and methods for the treatment and prevention of diseases, such as those associated with oxidative stress and inflammation.
Description of the related Art
The anti-inflammatory and anti-proliferative activity of the naturally occurring triterpenoid oleanolic acid has been improved by chemical modification. For example, 2-cyano-3, 12-dioxoolean-1, 9(11) -diene-28-oic acid (CDDO) and related compounds have been developed (Honda et al, 1997; Honda et al, 1998; Honda et al, 1999; Honda et al, 2000 a; Honda et al, 2000 b; Honda, et al, 2002; Suh et al, 1998; Suh et al, 1999; Place et al, 2003; Liby et al, 2005; and U.S. Pat. Nos. 8,129,429, 7,915,402, 8,124,799, 8,071,632, 8,338,618 and 7,943,778). The methyl ester, methylparabolone methyl (CDDO-Me), has been evaluated clinically in the treatment of cancer and chronic kidney disease (Pergola et al, 2011; Hong et al, 2012).
Synthetic triterpenoid analogs of oleanolic acid have also been shown to be inhibitors of cellular inflammatory processes such as the induction of Inducible Nitric Oxide Synthase (iNOS) and COX-2 by IFN- γ in mouse macrophages. See Honda et al (2000 a); honda et al (2000b) and Honda et al (2002). Although synthetic derivatives of another triterpenoid betulinic acid have not been characterized extensively, they have also been shown to inhibit cellular inflammatory processes (Honda et al, 2006). The pharmacology of these synthetic triterpenoid molecules is complex. Compounds derived from oleanolic acid have been shown to affect the function of a variety of protein targets and thus modulate the activity of several important cellular signaling pathways associated with oxidative stress, cell cycle control, and inflammation (e.g., Dinkova-kostowa et al, 2005; Ahmad et al, 2006; Ahmad et al, 2008; Liby et al, 2007 a). Although derivatives of betulinic acid have shown comparable anti-inflammatory properties, their pharmacology also appears to have significant differences compared to OA derivative compounds (Liby et al, 2007 b). Given that the biological activity spectrum of known triterpenoid derivatives varies, and in view of the diversity of diseases that can be treated or prevented with compounds having potent antioxidant and anti-inflammatory effects and the highly unmet medical needs represented within this disease diversity, there is a need to synthesize new compounds of different structures that can have an improved biological activity spectrum for the treatment of one or more indications.
Disclosure of Invention
The present disclosure provides novel synthetic triterpenoid derivatives with anti-inflammatory and/or antioxidant properties, pharmaceutical compositions and methods of making and using the same.
In one aspect, there is provided a compound of the formula:
wherein:
n is 0 to 3;
ar is a heteroaromatic diyl group(C≤8)Or substituted forms thereof; and is
Y is:
hydrogen, hydroxy, halo, amino or cyano or-NCO; or
Alkyl radical(C≤8)Alkenyl radical(C≤8)Alkynyl group(C≤8)Aryl radical(C≤12)Aralkyl group(C≤12)Heteroaryl group(C≤8)Heterocycloalkyl group(C≤12)Acyl group(C≤12)Alkoxy group(C≤8)Aryloxy group(C≤12)(iii) acyloxy group(C≤8)Alkylamino group(C≤8)Dialkylamino group(C≤8)Arylamino group(C≤8)Aralkylamino group(C≤8)Alkylthio group(C≤8)Acylthio groups(C≤8)Alkyl sulfonyl amino(C≤8)Or substituted versions of any of these groups.
In some embodiments, Y is — H. In some embodiments, Y is alkyl(C≤4)For example methyl, n-propyl, isopropyl or cyclopropyl. In some embodiments, Y is substituted alkyl(C≤4)Such as methoxymethyl.
In some embodiments, Ar is
In some embodiments, n ═ 0. In other embodiments, n ═ 1.
In some embodiments, the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the above formulas.
In some aspects, pharmaceutical compositions are provided comprising one or more of the above compounds and an excipient. In other aspects, there is provided a method of treating and/or preventing a disease or condition in a patient in need thereof, comprising administering to the patient one or more of the above compounds in an amount sufficient to treat and/or prevent the disease or condition.
Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound belongs to one particular formula does not mean that it cannot also belong to another formula.
Detailed Description
Disclosed herein are novel compounds and compositions having antioxidant and/or anti-inflammatory properties, methods for their manufacture, and methods for their use, including methods for treating and/or preventing diseases.
I. Definition of
When used in the context of chemical groups: "Hydrogen" means-H; "hydroxy" means-OH; "oxo/oxy (oxo)" means ═ O; "carbonyl" means-C (═ O) -; "carboxy" means-C (═ O) OH (also written as-COOH or-CO)2H) (ii) a "halo" independently means-F, -Cl, -Br, or-I; "amino" means-NH2(ii) a "hydroxyamino" means-NHOH; "nitro" means-NO2(ii) a Imino means ═ NH; "cyano" means-CN; "isocyanate group" means-N ═ C ═ O; "azido" means-N3(ii) a In a monovalent context, "phosphate group" means-OP (O) (OH)2Or a deprotonated form thereof; in a divalent context, "phosphate group" means-OP (O) (OH) O-or a deprotonated form thereof; "mercapto" means-SH; and "thio" means ═ S; "Sulfonyl" means-S (O)2-; and "sulfinyl" means-S (O) -.
In the context of chemical formulae, the symbol "-" means a single bond, "═ means a double bond, and" ≡ "means a triple bond. The symbol "- - -" represents an optional bond, which if present, is a single or double bond. SymbolRepresents a single bond or a double bond. Thus, for example, formulaComprises thatAndand it is to be understood that none of the ring atoms forms part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when linking one or two stereogenic atoms. Rather, it encompasses all stereoisomers as well as mixtures thereof. When drawn perpendicular to a bond (e.g., for methyl,) Symbol ofIndicating the point of attachment of the group. It should be noted that for larger groups, the point of attachment is generally only identified in this manner in order to assist the reader in clearly identifying the point of attachment. SymbolMeaning a single bond in which the group attached to the butt end of the wedge is "out of the paper". SymbolMeaning a single bond in which the group attached to the butt end of the wedge is "in the paper". SymbolMeaning a single bond in which the geometry (e.g., E or Z) around the double bond is undefined. Two options and combinations thereof are therefore contemplated. When one of the atoms linked by the bond is a metal atom (M), the above bond order is not limitingAnd (4) the nature is good. In such cases, it is understood that the actual bonding may comprise significant multiple bonding and/or ionic character. Thus, unless otherwise indicated, the formulae M-C, M ═ C, M — C andrefers to any type and order of bond between a metal atom and a carbon atom. Any undefined valency on an atom of a structure shown herein implicitly represents a hydrogen atom bonded to the atom. The thick dots on the carbon atoms indicate that the hydrogen attached to the carbon is oriented out of the plane of the paper.
When the group "R" is depicted as a "floating group" on a ring system such as in the following formula:
r may replace any hydrogen atom attached to any ring atom, including the depicted hydrogen, an implied hydrogen, or a well-defined hydrogen, so long as a stable structure is formed. When the group "R" is depicted as a "floating group" on a fused ring system such as in the following formula:
unless otherwise indicated, R may replace any hydrogen attached to any ring atom of any fused ring. Alternative hydrogens include the depicted hydrogen (e.g., the hydrogen of the nitrogen to which the formula is attached), implied hydrogens (e.g., hydrogens not shown in the formula above but understood to be present), well defined hydrogens, and optional hydrogens whose presence depends on the nature of the ring atoms (e.g., the hydrogen attached to group X when X is equal to-CH-), so long as a stable structure is formed. In the depicted example, R may be located on a 5-or 6-membered ring of the fused ring system. In the above formula, the subscript letter "y" immediately following the group "R" in parentheses represents a numerical variable. Unless otherwise specified, this variable may be 0,1, 2, or any integer greater than 2, limited only by the maximum number of replaceable hydrogen atoms of the ring or ring system.
For the following groups and classes, the following subscripts in parentheses further define the groups/classes as follows: "(Cn)" defines the exact number of carbon atoms (n) in the group/class. "(C.ltoreq.n)" defines the maximum number of carbon atoms (n) that can be in the group/class, the minimum number for the group in question being as small as possible, for example, it is to be understood that the group "alkenyl(C≤8)"or class" olefins(C≤8)"the minimum number of carbon atoms is 2. For example, "alkoxy group(C≤10)"indicates those alkoxy groups having 1 to 10 carbon atoms. (Cn-n ') defines the minimum (n) and maximum (n') numbers of carbon atoms in the group. Similarly, "alkyl group(C2-10)"indicates those alkyl groups having 2 to 10 carbon atoms.
The term "saturated" as used herein means that the compound or group so modified has no carbon-carbon double bonds and no carbon-carbon triple bonds, unless specified below. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not excluded when such bonds are present.
When used without the modifier "substituted," the term "aliphatic" means that the compound/group so modified is an acyclic or cyclic but non-aromatic hydrocarbon or group. In aliphatic compounds/groups, the carbon atoms may be joined together in straight chain, branched or non-aromatic rings (alicyclic). Aliphatic compounds/groups may be saturated, i.e. bound by single bonds (alkane/alkyl), or unsaturated, having one or more double bonds (alkene/alkenyl) or having one or more triple bonds (alkyne/alkynyl).
The term "alkyl" when used without a "substituted" modifier means having a carbon atom as a linkageA monovalent saturated aliphatic group having a linear or branched, cyclic, or acyclic structure and no atoms other than carbon and hydrogen. Thus, a cycloalkyl group as used herein is a subset of alkyl groups that form the carbon atom of the point of attachment or are members of one or more non-aromatic ring structures, wherein the cycloalkyl group does not consist of atoms other than carbon and hydrogen. The term as used herein does not preclude the presence of one or more alkyl groups (allowing carbon number limitation) attached to the ring or ring system. group-CH3(Me (methyl)), -CH2CH3(Et (ethyl)), -CH2CH2CH3(n-Pr (n-propyl) or propyl), -CH (CH)3)2(i-Pr、iPr or isopropyl), -CH (CH)2)2(cyclopropyl), -CH2CH2CH2CH3(n-Bu (n-butyl)), -CH (CH)3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C (CH)3)3(tert-butyl, t-Bu ortBu)、-CH2C(CH3)3(neopentyl), cyclobutyl, cyclopentyl, cyclohexyl and cyclohexylmethyl are non-limiting examples of alkyl groups. The term "alkanediyl", when used without a "substituted" modifier, refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as the point of attachment, having a linear or branched, cyclic, or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. group-CH2- (methylene), -CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2CH2-andare non-limiting examples of alkanediyl groups. When used without the "substituted" modifier, the term "alkylene" refers to a divalent group ═ CRR ', where R and R ' are independently hydrogen, alkyl, or R and R ' taken together represent an alkanediyl group having at least two carbon atoms. Of alkylene radicals other thanLimiting examples include: CH (CH)2、＝CH(CH2CH3) And ═ C (CH)3)2. "alkane" refers to the compound H-R, where R is alkyl, as that term is defined above. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH、-CH2Cl、-CF3、-CH2CN、-CH2C(O)OH、-CH2C(O)OCH3、-CH2C(O)NH2、-CH2C(O)CH3、-CH2OCH3、-CH2OC(O)CH3、-CH2NH2、-CH2N(CH3)2and-CH2CH2And (4) Cl. The term "haloalkyl" is a subgroup of substituted alkyl groups in which one or more hydrogen atoms have been replaced with a halo group and no other atoms than carbon, hydrogen, and halogen are present. group-CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subgroup of alkyl groups that are substituted in which one or more hydrogens have been replaced with a fluoro group and no other atoms than carbon, hydrogen, and fluorine are present. group-CH2F、-CF3and-CH2CF3Are non-limiting examples of fluoroalkyl groups.
The term "alkenyl", when used without a "substituted" modifier, refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, having a straight or branched, cyclic, or acyclic structure, having at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. Non-limiting of alkenyl groupsIllustrative examples include: -CH ═ CH2(vinyl), -CH ═ CHCH3、-CH＝CHCH2CH3、-CH2CH＝CH2(allyl), -CH2CH＝CHCH3and-CH ═ CHCH ═ CH2. The term "alkenediyl" when used without a "substituted" modifier refers to a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, having a linear or branched, cyclic, or acyclic structure, having at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The radicals-CH-, -CH-C (CH)3)CH2-、-CH＝CHCH2-andare non-limiting examples of alkenediyl groups. It should be noted that although the alkenediyl group is aliphatic, once it is attached at both ends, it is not excluded that this group forms part of an aromatic structure. The term "alkene (alkene or olefin)" is synonymous and refers to a compound having the formula H-R, wherein R is alkenyl, as that term is defined above. "terminal olefin" refers to an olefin having only one carbon-carbon double bond, wherein the bond forms a vinyl group at one end of the molecule. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、–C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、–C(O)NH2、–OC(O)CH3or-S (O)2NH2Independently replaced. The groups-CH ═ CHF, -CH ═ CHCl and-CH ═ CHBr are non-limiting examples of substituted alkenyl groups.
The term "alkynyl", when used without a "substituted" modifier, refers to a straight or branched chain, cyclic, or acyclic, group having a carbon atom as the point of attachmentA cyclic structure, a monovalent unsaturated aliphatic group having at least one carbon-carbon triple bond and no atoms other than carbon and hydrogen. The term alkynyl as used herein does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The group-C.ident.CH, -C.ident.CCH3and-CH2C≡CCH3Are non-limiting examples of alkynyl groups. "alkyne" refers to the compound H-R where R is alkynyl. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、–C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、–C(O)NH2、–OC(O)CH3or-S (O)2NH2Independently replaced.
The term "aryl", when used in the absence of a "substituted" modifier, refers to a monovalent unsaturated aromatic group having as the point of attachment an aromatic carbon atom that forms part of one or more six-membered aromatic ring structures in which the ring atoms are all carbon, and in which the group is not composed of atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. This term as used herein does not preclude the presence of one or more alkyl or aralkyl groups (allowing carbon number limitations) attached to the first aromatic ring or any additional aromatic rings present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl) phenyl, -C6H4CH2CH3(ethylphenyl), naphthyl, and monovalent radicals derived from biphenyl. The term "aryldiyl," when used without a "substituted" modifier, refers to a divalent aromatic group having two aromatic carbon atoms as points of attachment, the carbon atoms forming part of one or more six-membered aromatic ring structures in which all of the ring atoms are carbon, and in which the monovalent group does not consist of atoms other than carbon and hydrogen. Such asThe term as used herein does not preclude the presence of one or more alkyl, aryl or aralkyl groups (allowing carbon number limitations) attached to the first aromatic ring or any additional aromatic rings present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected by one or more of the following: covalent bonds, alkanediyl or alkenediyl groups (allowing carbon number limitation). Non-limiting examples of aryldiyl groups include:
"arene" refers to the compound H-R wherein R is aryl, which is the term as defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、–C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、–C(O)NH2、–OC(O)CH3or-S (O)2NH2Independently replaced.
The term "aralkyl", when used without a "substituted" modifier, refers to a monovalent group-alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definition provided above. Non-limiting examples of aralkyl groups are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the modifier "substituted", one or more hydrogen atoms from the alkanediyl and/or aryl group have been replaced by-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl) -methyl and 2-chloro-2-phenyl-eth-1-yl.
The term "heteroaryl", when used without a "substituted" modifier, refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as the point of attachment, said carbon or nitrogen atom forming part of one or more aromatic ring structures wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the heteroaryl does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. The term as used herein does not preclude the presence of one or more alkyl, aryl and/or aralkyl groups (allowing carbon number limitations) attached to an aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl (Im)Azolyl, methylpyridyl, oxazolyl, and morpholinyl,Oxazolyl, phenylpyridyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the point of attachment. The term "heteroaryldiyl," when used without a "substituted" modifier, refers to a divalent aromatic group having two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two points of attachment, the atoms forming part of one or more aromatic ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, thenThe rings may be fused or unfused. Unfused rings may be connected by one or more of the following: covalent bonds, alkanediyl or alkenediyl groups (allowing carbon number limitation). The term as used herein does not preclude the presence of one or more alkyl, aryl and/or aralkyl groups (allowing carbon number limitations) attached to an aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl diradicals include:
"heteroarene" refers to the compound H-R where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the modifier "substituted", one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、–C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、–C(O)NH2、–OC(O)CH3or-S (O)2NH2Independently replaced.
The term "heterocycloalkyl," when used without a "substituted" modifier, refers to a monovalent non-aromatic group having as a point of attachment a carbon or nitrogen atom that forms part of one or more non-aromatic ring structures in which at least one ring atom is nitrogen, oxygen, or sulfur, and in which the heterocycloalkyl is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, the rings may be fused or unfused. The term as used herein does not preclude the presence of one or more alkyl groups (allowing carbon number limitation) attached to the ring or ring system. Furthermore, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains a non-aromatic group. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term "N-heterocycloalkyl" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. The term "heterocycloalkandiyl" when used without a "substituted" modifier refers to a divalent cyclic group having two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as two points of attachment, the atoms forming part of one or more ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected by one or more of the following: covalent bonds, alkanediyl or alkenediyl groups (allowing carbon number limitation). The term as used herein does not preclude the presence of one or more alkyl groups (allowing carbon number limitation) attached to the ring or ring system. Furthermore, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains a non-aromatic group. Non-limiting examples of heterocycloalkyl diyl groups include:
when these terms are used with the modifier "substituted", one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3、-S(O)2NH2or-C (O) OC (CH)3)3(tert-butoxycarbonyl, BOC) is independently substituted.
When in the absence of a "substituted" modifierWhen used below, the term "acyl" refers to the group-C (O) R, where R is hydrogen, alkyl, aryl, aralkyl, or heteroaryl, as those terms are defined above. The group-CHO, -C (O) CH3(acetyl, Ac), -C (O) CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)2、-C(O)CH(CH2)2、-C(O)C6H5、-C(O)C6H4CH3、-C(O)CH2C6H5and-C (O) (imidazolyl) is a non-limiting example of an acyl group. "Thioacyl" is defined in a similar manner, except that the oxygen atom of the group-C (O) R has been replaced with a sulfur atom (-C (S) R). The term "aldehyde" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by a-CHO group. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms (including the hydrogen atom directly attached to a carbonyl or thiocarbonyl group, if any) have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced. The radical-C (O) CH2CF3、-CO2H (carboxyl), -CO2CH3(methyl carboxyl), -CO2CH2CH3、-C(O)NH2(carbamoyl) and-CON (CH)3)2Are non-limiting examples of substituted acyl groups.
The term "alkoxy" when used without a "substituted" modifier refers to the group-OR, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkoxy groups include: -OCH3(methoxy), -OCH2CH3(ethoxy), -OCH2CH2CH3、-OCH(CH3)2(isopropoxy), -O (CH)3)3(tert-butoxy), -OCH (CH)2)2-O-cyclopentyl and-O-cyclohexyl. When used without the "substituted" modifier, the terms "alkenyloxy," "alkynyloxy," "aryloxy," "aralkyloxy," "heteroaryloxy," "heterocycloalkoxy," and "acyloxy" refer to a group defined as-OR, wherein R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term "alkoxydiyl" refers to the divalent radicals-O-alkanediyl-, -O-alkanediyl-O-or-alkanediyl-O-alkanediyl-. When used without the "substituted" modifier, the terms "alkylthio" and "acylthio" refer to the group-SR, wherein R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by an alkoxy group. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced.
The term "alkylamino", when used without a "substituted" modifier, refers to the group-NHR, wherein R is alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: -NHCH3and-NHCH2CH3. When used without a "substituted" modifier, the term "dialkylamino" refers to the group-NRR ', where R and R ' may be the same or different alkyl groups or R and R ' may together represent an alkanediyl group. Non-limiting examples of dialkylamino groups include: -N (CH)3)2、-N(CH3)(CH2CH3) And N-pyrrolidinyl. When there is no getWhen used in the context of a substitute "modifier," the terms "alkoxyamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino", and "alkylsulfonylamino" refer to the group defined as — NHR, wherein R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is-NHC6H5. The term "acylamino" (acylamino), when used without a "substituted" modifier, refers to the group-NHR, wherein R is acyl, as that term is defined above. A non-limiting example of an amide group is-NHC (O) CH3. The term "alkylimino", when used without a "substituted" modifier, refers to a divalent group, NR, where R is alkyl, as that term is defined above. The term "alkylaminodiyl" refers to the divalent radical-NH-alkanediyl-, -NH-alkanediyl-NH-or-alkanediyl-NH-alkanediyl-. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced. The group-NHC (O) OCH3And NHC (O) NHCH3Are non-limiting examples of substituted amide groups.
When used without the modifier "substituted," the terms "alkylsulfonyl" and "alkylsulfinyl" refer to the group-S (O), respectively2R and-S (O) R, wherein R is alkyl, as that term is defined above. The terms "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl" and "heterocycloalkylsulfonyl" are defined in an analogous manner. When any of these termsOne in the case of the "substituted" modifier, one or more hydrogen atoms have been replaced by-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced.
The term "alkylphosphate group" when used without a "substituted" modifier refers to the group-OP (O) (OH) (OR) wherein R is an alkyl group, as that term is defined above. Non-limiting examples of alkylphosphate groups include: -OP (O) (OH) (OMe) and-OP (O) (OH) (OEt). When used without a "substituted" modifier, the term "dialkylphosphate group" refers to the group-OP (O) (OR) (OR '), wherein R and R ' may be the same OR different alkyl groups OR R and R ' may together represent an alkanediyl group. Non-limiting examples of dialkylphosphate groups include: -OP (O) (OMe)2-OP (O) (OEt) (OMe) and-OP (O) (OEt)2. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms have been replaced with-OH, -F, -Cl, -Br, -I, -NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3or-S (O)2NH2Independently replaced.
The use of the word "a/an" when used in conjunction with the term "comprising" in the claims and/or the specification can mean "a", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one".
Throughout this application, the term "about" is used to indicate that a value includes variations in the inherent error of the device, method used to determine the value, or variations that exist between study subjects.
As used herein, "chiral auxiliary" refers to a removable chiral group that is capable of affecting the stereoselectivity of the reaction. The compounds are familiar to the person skilled in the art and many are commercially available.
The terms "comprising", "having" and "including" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "singular/has/include", "going/having/including", is also open-ended. For example, any method that "comprises," "has/contains," or "includes" one or more steps is not limited to having only that one or more steps and also encompasses other, non-listed steps.
The term "effective" when used in this specification and/or claims means sufficient to achieve a desired, expected, or intended result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" means the amount of the compound that is sufficient to effect the treatment of a disease when administered to a subject or patient to treat the disease.
The term "IC" as used herein50"refers to an inhibitory dose that is 50% of the maximal response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical, or chemical process (or component of a process, i.e., enzyme, cell, cellular receptor, or microorganism) by half.
An "isomer" of a first compound is a separate compound that contains the same constituent atoms as the first compound per molecule, but which differs in the configuration of those atoms in three dimensions.
The term "patient" or "subject" as used herein refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, adolescents, infants and fetuses.
As used generally herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is pharmaceutically acceptable as defined above and which has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts with organic acids such as: 1, 2-ethanedisulfonic acid, 2-isethionic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentylpropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, dodecylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o- (4-hydroxybenzoyl) benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, benzoic acid, Phenyl substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, t-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when an acidic proton present is capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It will be appreciated that the particular anion or cation forming part of any salt of the invention is not critical, so long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable Salts and methods for their preparation and Use are presented in Handbook of pharmaceutical Salts: Properties, and Use (edited by P.H.Stahl and C.G.Wermuth, VerlagHelvetica Chimica Acta, 2002).
The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in the transport or delivery of a chemical agent.
"Prevention (Prevention or preventing)" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk for and/or predisposed to developing the disease, but does not yet experience or exhibit any or all pathology (pathology) or symptom (symptomatology) of the disease; and/or (2) slowing the onset of pathology or symptomatology of a disease in a subject or patient who may be at risk for and/or predisposed to developing the disease, but does not yet experience or exhibit any or all of the pathology or symptomatology of the disease.
suitable esters that can be converted in vivo to hydroxy compounds include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis- β -hydroxynaphthoate, cholate, isethionate, di-p-toluoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinate (quinate), amino acid ester, and the like.
"stereoisomers" or "optical isomers" are the following isomers of a given compound: wherein the same atom is bonded to the same other atom, but the configuration of those atoms in three dimensions is different. "enantiomers" are stereoisomers of a given compound that are mirror images of each other as left and right handed. "diastereoisomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also known as a stereocenter (stereocenter) or a stereogenic center, which is any point in the molecule with groups that cause the interchange of any two groups to produce a stereoisomer, but the point is not necessarily an atom. In organic compounds, the chiral center is typically a carbon atom, a phosphorus atom, or a sulfur atom, although in organic and inorganic compounds, other atoms may also be stereocenters. The molecule may have multiple stereocenters, giving it many stereoisomers. In compounds where the stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry typically have less than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomerically enriched such that one enantiomer is present in an amount greater than 50%. Generally, enantiomers and/or diastereomers may be resolved or separated using techniques known in the art. It is contemplated that for any stereocenter or chiral axis for which stereochemistry has not yet been defined, the stereocenter or chiral axis may exist as its R form, S form, or as a mixture of said R and S forms, including racemic and non-racemic mixtures. The phrase "substantially free of other stereoisomers" as used herein means that the composition contains 15% or less, more preferably 10% or less, even more preferably 5% or most preferably 1% or less of other stereoisomers.
"treating" includes (1) inhibiting (e.g., arresting further development of) a disease in a subject or patient experiencing or exhibiting a pathology or symptom of the disease, (2) ameliorating (e.g., reversing) the disease in a subject or patient experiencing or exhibiting a pathology or symptom of the disease, and/or (3) achieving any measurable decline in the disease in a subject or patient experiencing or exhibiting a pathology or symptom of the disease.
Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; (COCl)2Oxalyl chloride; EtN3Or TEA, triethylamine; DMAP, dimethylaminopyridine; et (Et)2O, diethyl ether; n-PrCONHNH2Hydrazine butyrate; i-PrCONHNH2Hydrazine isobutyrate; c-PrCONHNH2cyclopropane hydrazine, p-TsOH, p-toluenesulfonic acid, DMF, dimethylformamide, EDCl, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, NO, nitric oxide, iNOS, inducible nitric oxide synthase, COX-2, cyclooxygenase-2, FBS, fetal bovine serum, IFN gamma or IFN-gamma, interferon-gamma, TNF α or TNF- α, tumor necrosis factor α, IL-1 β, interleukin-1 β, HO-1, inducible heme oxygenase.
The above definitions supersede any conflicting definition in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be taken to indicate that any undefined terms are undefined. Rather, it is to be understood that all terms used are intended to be interpreted as clearly describing the invention, so that those skilled in the art can understand the scope and practice the invention.
Compounds and methods of synthesis
Compounds provided by the present disclosure are set forth in the summary above, in the claims, and in the sections below. They can be made using the methods outlined in the examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. The principles and techniques are taught, for example, in March's advanced Organic Chemistry: Reactions, mechanics, and Structure (2007), which is incorporated herein by reference.
The compounds of the invention may contain one or more asymmetrically substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of a formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. The compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the compounds of the present invention may have either the S configuration or the R configuration.
The chemical formulae used to represent the compounds of the present invention will generally show only one of several different tautomers that are possible. For example, many types of keto groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which is the most prevalent, all tautomers of a given formula are intended.
The atoms that make up the compounds of the present invention are intended to include all isotopic forms of the atoms recited. The compounds of the invention include those in which one or more atoms have been altered or enriched by isotopic abundance, particularly those having a pharmaceutically acceptable isotope or those useful in pharmaceutical research. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. As a general example and not by way of limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon include13C and14C. similarly, it is contemplated that one or more carbon atoms of the compounds of the present invention may be replaced by silicon atoms. Furthermore, it is contemplated that one or more oxygen atoms of the compounds of the present invention may be replaced by oneOne or more sulfur or selenium atoms.
The compounds of the present invention may also exist in prodrug form. Because prodrugs are known to enhance numerous desirable pharmaceutical qualities (e.g., solubility, bioavailability, manufacturing, etc.), the compounds used in some methods of the invention may be delivered in prodrug form, if desired. Thus, the present invention encompasses prodrugs of the compounds of the present invention as well as methods of delivering the prodrugs. Prodrugs of the compounds used in the present invention may be prepared by modifying functional groups present in the compounds in the following manner: the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Thus, prodrugs include, for example, compounds described herein wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.
It will be appreciated that the particular anion or cation forming part of any salt of the invention is not critical, so long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable Salts and methods for their preparation and Use are presented in the Handbook of Pharmaceutical Salts, Properties, and Use (2002), which is incorporated herein by reference.
It will be further appreciated that the compounds of the present invention include those that have been further modified to include substituents that can be converted to hydrogen in vivo. This includes those groups that can be converted to hydrogen atoms by enzymatic or chemical means, including but not limited to hydrolysis and hydrogenolysis. Examples include hydrolyzable groups such as acyl groups, groups having oxycarbonyl groups, amino acid residues, peptide residues, o-nitrophenylsulfinyl groups, trimethylsilyl groups, tetrahydropyranyl groups, diphenylphosphinyl groups, and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of the group having an oxycarbonyl group include an ethoxycarbonyl group, a tert-butoxycarbonyl group (-C (O) OC (CH)3)3Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, β - (p-toluenesulfonyl) ethoxycarbonyl and the likethe amino acid residues of (A) include, but are not limited to, residues of Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine) and β -Ala3)3Boc), and the like. Suitable peptide residues include peptide residues comprising two to five amino acid residues. The residues of these amino acids or peptides may exist in stereochemical configuration in D-form, L-form or mixtures thereof. In addition, the residues of amino acids or peptides may have asymmetric carbon atoms. Examples of suitable amino acid residues having asymmetric carbon atoms include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having asymmetric carbon atoms include peptide residues having one or more constituent amino acid residues having asymmetric carbon atoms. Examples of suitable amino acid protecting groups include those commonly used in peptide synthesis, including acyl groups (e.g., formyl and acetyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonyl (-C (O) OC (CH)3)3) other examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl (e.g., o-toluenesulfonyl), methyl substituted with phenyl or benzyloxy (e.g., benzyl, trityl, and benzyloxymethyl), arylmethoxycarbonyl (e.g., benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl), and haloethoxycarbonyl (e.g., β, β, β -trichloroethoxycarbonyl and β -iodo-ethoxycarbonyl)Ethoxycarbonyl).
The compounds of the invention may also have the following advantages: whether used in the indications described herein or in other indications, they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties relative to, compounds known in the art.
Biological Activity
The results of the assays for inhibition of IFN γ -induced NO production by several compounds of the present invention are shown in table 1 below. The results were compared with those of methyl bardoxolone (RTA 402, CDDO-Me) under the title RAW264.7 in the right column of the table. Details regarding this assay are provided in the examples section below.
Table 1 inhibition of IFN γ -induced NO production.
Diseases associated with inflammation and/or oxidative stress
inflammation is a biological process that provides resistance to infectious or parasitic organisms and repairs damaged tissue, inflammation is generally characterized by local vasodilation, redness, swelling, and pain, recruitment of leukocytes to the site of infection or injury, production of inflammatory cytokines, such as TNF- α and IL-1, and production of reactive oxygen or nitrogen species, such as hydrogen peroxide, superoxide, and peroxynitrite (peroxynitrite). at a later stage of inflammation, tissue remodeling, angiogenesis, and scarring (fibrosis) may occur as part of the wound healing process.
Many serious and refractory human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis, and diabetes, which are not traditionally considered inflammatory conditions. In the case of cancer, inflammatory processes are associated with tumor formation, progression, metastasis and resistance to therapy. Atherosclerosis, which has long been considered a disorder of lipid metabolism, is now understood to be an inflammatory condition in which primarily activated macrophages play a significant role in the formation and eventual rupture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance and in peripheral tissue damage associated with diabetic hyperglycemia. Overproduction of reactive oxygen species and reactive nitrogen species, such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite, are hallmarks of inflammatory conditions. Evidence of a dysregulated peroxynitrite production has been reported in a variety of diseases (Szabo et al, 2007; Schulz et al, 2008; Forstermann, 2006; Pall, 2007).
Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, resulting from dysfunction of the recognition and response mechanisms of the immune system self versus non-self. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage is associated with activation of microglia and elevated levels of proinflammatory proteins such as Inducible Nitric Oxide Synthase (iNOS). Chronic organ failure, such as renal failure, heart failure, liver failure and chronic obstructive pulmonary disease, is closely associated with the presence of chronic oxidative stress and inflammation leading to the development of fibrosis and eventual loss of organ function. Oxidative stress in vascular endothelial cells lining large and small blood vessels can lead to endothelial dysfunction and is considered to be an important contributor to the development of systemic cardiovascular disease, diabetic complications, chronic kidney disease and other forms of organ failure, as well as many other age-related diseases including degenerative diseases of the central nervous system and retina.
Many other conditions involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; graft failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of bone and joints, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; paroxysmal disorders; and neuropsychiatric conditions including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder (autism-spectrum disorder), and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is considered to be a major factor in the pathology of muscle wasting diseases including muscular dystrophy and various forms of cachexia.
Inflammatory signaling disorders are also implicated in a variety of life-threatening acute conditions, including acute organ failure involving the pancreas, kidneys, liver or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns and anaphylaxis.
while an inflammatory response can kill invading pathogens, an excessive inflammatory response can also be quite destructive and in some cases can be a major source of damage in infected tissues.
Aberrant or overexpression of iNOS or cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many disease processes. For example, it is clear that NO is a potent mutagen (Tamir and Tannebaum, 1996), and that nitric oxide can also activate COX-2(Salvemini et al, 1994). In addition, there was a significant increase in iNOS in rat colon tumors induced by the carcinogen azoxymethane (Takahashi et al, 1997). A series of synthetic triterpenoid analogs of oleanolic acid have been shown to be potent inhibitors of cellular inflammatory processes such as the induction of Inducible Nitric Oxide Synthase (iNOS) and COX-2 by IFN-. gamma.in mouse macrophages. See Honda et al (2000 a); honda et al (2000b) and Honda et al (2002), all of which are incorporated herein by reference.
In one aspect, the compounds disclosed herein are characterized in that they are capable of inhibiting nitric oxide production induced by exposure to interferon-gamma in RAW264.7 cells derived from macrophages. They are further characterized by the ability to induce the expression of antioxidant proteins such as NQO1, and to decrease the expression of pro-inflammatory proteins such as COX-2 and Inducible Nitric Oxide Synthase (iNOS). These properties are relevant to the treatment of a wide variety of diseases and conditions involving oxidative stress and dysregulation of inflammatory processes, including cancer, complications from local or systemic exposure to ionizing radiation, mucositis from radiation or chemotherapy, autoimmune diseases, cardiovascular diseases (including atherosclerosis), ischemia-reperfusion injury, acute and chronic organ failure (including renal failure and heart failure), respiratory diseases, diabetes and diabetic complications, severe allergy, transplant rejection, graft-versus-host disease, neurodegenerative diseases, diseases of the eye and retina, acute and chronic pain, degenerative bone diseases (including osteoarthritis and osteoporosis), inflammatory bowel disease, dermatitis and other skin diseases, sepsis, burns, episodic diseases, and neuropsychiatric conditions.
Without being bound by theory, it is believed that activation of the antioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway is related to both anti-inflammatory and anti-cancer properties of the compounds disclosed herein.
In another aspect, the compounds disclosed herein are useful for treating a subject having a condition caused by an increase in the level of oxidative stress in one or more tissues. Oxidative stress results from abnormally high or prolonged levels of reactive oxygen species, such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite (formed by the reaction of nitric oxide with superoxide). Oxidative stress may be accompanied by acute or chronic inflammation. Oxidative stress can be caused by: mitochondrial dysfunction, such as activation of immune cells of macrophages and neutrophils; brief exposure to external agents such as ionizing radiation or cytotoxic chemotherapeutic agents (e.g., doxorubicin); trauma or other acute tissue injury; ischemia/reperfusion; poor circulation or anemia; hypoxia or hyperoxia, either local or systemic; elevated levels of inflammatory cytokines and other inflammation-related proteins; and/or other abnormal physiological states such as hyperglycemia or hypoglycemia.
In animal models of many such conditions, expression of the target genes of the stimulus-induced heme oxygenase (HO-1), the Nrf2 pathway, has been shown to have significant therapeutic effects, including models of myocardial infarction, renal failure, graft failure and rejection, stroke, cardiovascular disease, and autoimmune disease (e.g., Sacerdoti et al, 2005; Abraham and Kappas, 2005; Bach, 2006; Araujo et al, 2003; Liu et al, 2006; Ishikawa et al, 2001; Kruger et al, 2006; Satoh et al, 2006; Zhou et al, 2005; Morse and Choi, 2002). This enzyme breaks down free heme into iron, carbon monoxide (CO) and biliverdin, which is subsequently converted into the potent antioxidant molecule bilirubin.
In another aspect, the compounds of the invention are useful in the prevention or treatment of acute and chronic tissue damage or organ failure resulting from oxidative stress exacerbated by inflammation. Examples of diseases belonging to this category include: examples of diseases belonging to this category include heart failure, liver failure, graft failure and rejection, renal failure, pancreatitis, fibrotic pulmonary diseases (especially cystic fibrosis, COPD, and idiopathic pulmonary fibrosis), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune diseases, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies have shown that increased oxidative stress in the central nervous system can lead to the development of the disease (Chauhan and Chauhan, 2006).
Evidence also associates oxidative stress and inflammation with the occurrence and pathology of many other disorders of the central nervous system, including psychiatric disorders such as psychosis, major depression, and bipolar disorder; seizure disorders such as epilepsy; pain and sensory syndromes, such as migraine, neuropathic pain or tinnitus; and behavioral syndromes, such as attention deficit disorder. See, e.g., Dickerson et al, 2007; hanson et al, 2005; kendall-tatkett, 2007; lencz et al, 2007; dudhgaonkar et al, 2006; lee et al, 2007; morris et al, 2002; ruster et al, 2005; McIver et al, 2005; sarcoleilli et al, 2006; kawakami et al, 2006; ross et al, 2003, which are all incorporated herein by reference. For example, elevated levels of inflammatory cytokines, including TNF, interferon-gamma and IL-6, are associated with severe psychiatric disorders (Dickerson et al, 2007). Microglial activation has also been associated with severe psychiatric disorders. Thus, down-regulation of inflammatory cytokines and inhibition of excessive activation of microglia may be beneficial to patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder, and other neuropsychiatric conditions.
Thus, in pathologies involving oxidative stress alone or exacerbated by inflammation, treatment may comprise administering to the subject a therapeutically effective amount of a compound of the invention, such as those described above or throughout this specification. The treatment may be administered prophylactically prior to a predictable oxidative stress state (e.g., organ transplantation or administration of radiation therapy to a cancer patient), or may be administered therapeutically in a setting involving established oxidative stress and inflammation.
The compounds disclosed herein may be broadly useful in the treatment of inflammatory conditions such as sepsis, dermatitis, autoimmune diseases, and osteoarthritis. In one aspect, the compounds of the invention are useful for treating inflammatory pain and/or neuropathic pain, for example, by inducing Nrf2 and/or inhibiting NF- κ B.
In some embodiments, the compounds disclosed herein are useful for the treatment and prevention of diseases such as: cancer, inflammation, alzheimer's disease, parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseases (e.g. rheumatoid arthritis, lupus, Crohn's disease and psoriasis), inflammatory bowel disease, all other diseases whose pathogenesis is believed to involve overproduction of nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or exacerbated by inflammation.
Another aspect of inflammation is the production of inflammatory prostaglandins, such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, local pain, elevated temperature and other inflammatory symptoms. The induced form of the enzyme COX-2 is associated with their production and high levels of COX-2 are found in inflamed tissues. Thus, inhibition of COX-2 can alleviate many symptoms of inflammation, and many important anti-inflammatory drugs (e.g., ibuprofen (ibuprofen) and celecoxib (celecoxib)) act by inhibiting COX-2 activity. However, recent studies have demonstrated that a class of cyclopentenone prostaglandins (cypgs) (e.g., 15-deoxy prostaglandin J2, also known as PGJ2) plays a role in stimulating the coordinated resolution of inflammation (e.g., Rajakariar et al, 2007). COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 can interfere with complete resolution of inflammation, potentially promoting persistence of activated immune cells in the tissue and leading to chronic "smoldering" inflammation. This effect can lead to an increased incidence of cardiovascular disease in patients who have been administered selective COX-2 inhibitors for an extended period of time.
in one aspect, the compounds disclosed herein can be used to control the production of proinflammatory cytokines in cells by selectively activating Regulatory Cysteine Residues (RCR) on proteins that modulate the activity of redox-sensitive transcription factors.activation of RCR by cyPG has been shown to initiate a pro-resolution program in which the activity of antioxidant and cytoprotective transcription factors Nrf2 is strongly induced and the activities of pro-oxidative and proinflammatory transcription factors NF- κ B and STAT are inhibited.
Pharmaceutical formulations and routes of administration
The compounds of the present disclosure can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, intraperitoneally, etc.). Depending on the route of administration, the active compound may be coated with a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. They may also be administered by continuous perfusion/infusion to the disease or wound site.
In order to administer a therapeutic compound parenterally, it may be necessary to coat the compound with a material that prevents its inactivation, or to co-administer the compound with the material. For example, the therapeutic compound may be administered to the patient in a suitable carrier such as a liposome or diluent. Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al, 1984).
The therapeutic compound may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under normal conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
Pharmaceutical compositions suitable for injectable use include: sterile aqueous solutions (where water soluble), dispersions and sterile powders for the on-site preparation of sterile injectable solutions or dispersions. See, for example, U.S. patent application entitled "Amorphous Solid Dispersions of CDDO-Me for Delayed Release Oraldosage Compositions" filed by J.Zhang on 13.2.2009, which is incorporated herein by reference. In all cases, the composition must be sterile and must flow to the extent that ready syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal (thimerosal), and the like). In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride or polyalcohols such as mannitol and sorbitol in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a solution thereof which has been previously sterile-filtered.
The therapeutic compound may be administered orally using, for example, an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or added directly to the diet of the subject. For oral therapeutic administration, the therapeutic compound may be added with excipients and used in the following forms: ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Of course, the percentage of therapeutic compound in the compositions and formulations can vary. The amount of therapeutic compound in the therapeutically useful composition is such that a suitable dosage will be obtained.
It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention depends on and directly depends on the following factors: (a) the unique characteristics of a therapeutic compound and the particular therapeutic effect to be achieved, and (b) limitations inherent in the art of formulating the therapeutic compound for the treatment of a selected condition in a patient.
Therapeutic compounds may also be topically applied to the skin, eye or mucosa. Alternatively, if local delivery to the lungs is desired, the therapeutic compound may be administered by inhalation in a dry powder or aerosol formulation.
The active compound is administered in a therapeutically effective dose sufficient to treat a condition associated with the condition in the patient. For example, the efficacy of a compound can be assessed in an animal model system (e.g., the model systems shown in the examples and figures) that can predict efficacy in treating human diseases.
The actual dosage amount of a compound of the present disclosure or a composition comprising a compound of the present disclosure administered to a subject can be determined by physical and physiological factors such as age, sex, body weight, severity of the condition, type of disease being treated, prior or concurrent therapeutic intervention, specific disease of the subject, and route of administration. These factors can be determined by one skilled in the art. The practitioner responsible for administration will typically determine the concentration of the active ingredient in the composition and the appropriate dosage for the individual subject. The dosage may be adjusted by the individual physician if any complications occur.
An effective amount will typically vary from about 0.001mg/kg to about 1000mg/kg, from about 0.01mg/kg to about 750mg/kg, from about 100mg/kg to about 500mg/kg, from about 1.0mg/kg to about 250mg/kg, from about 10.0mg/kg to about 150mg/kg, administered in one or more doses per day for one or more days (depending, of course, on the mode of administration and factors discussed above). Other suitable dosage ranges include 1mg to 10000mg per day, 100mg to 10000mg per day, 500mg to 10000mg per day, and 500mg to 1000mg per day. In some particular embodiments, the amount is less than 10,000 mg/day, ranging from 750mg to 9000mg per day.
The effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day, or less than 10 mg/kg/day. Alternatively, it may be in the range of 1 mg/kg/day to 200 mg/kg/day. For example, with respect to treatment of a diabetic patient, a unit dose may be an amount that lowers blood glucose by at least 40% compared to an untreated subject. In another embodiment, the unit dose is an amount that lowers blood glucose to a level that is ± 10% of the blood glucose level of the non-diabetic subject.
In other non-limiting examples, the dose can further include about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein. In non-limiting examples of ranges derivable from the numbers listed herein, ranges of about 5mg/kg body weight to about 100mg/kg body weight, about 5 micrograms/kg body weight to about 500 milligrams/kg body weight, and the like, may be administered based on the numbers listed above.
In certain embodiments, a pharmaceutical composition of the disclosure may comprise, for example, at least about 0.1% of a compound of the disclosure. In other embodiments, the compounds of the present disclosure may, for example, comprise from about 2% to about 75% or from about 25% to about 60% of the stated weight of the unit, and any range derivable therein.
Single or multiple doses of the agent are contemplated. The desired time interval for delivery of multiple doses can be determined by one skilled in the art using only routine experimentation. As an example, the subject may be administered two doses per day at about 12 hour intervals. In some embodiments, the agent is administered once daily.
The agents may be administered according to a conventional schedule. A conventional schedule, as used herein, refers to a predetermined specified period of time. A regular schedule may cover periods of time that are the same or different in length, as long as the schedule is predetermined. For example, a conventional schedule may involve twice daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once monthly, or any set number of days or weeks therebetween. Alternatively, the predetermined regular schedule may involve twice daily administration for the first week, once daily administration for months thereafter, and the like. In other embodiments, the invention provides that the medicament can be taken orally and that the timing is dependent or independent on food intake. Thus, for example, the medicament may be taken every morning and/or every night, whether the subject has eaten or is about to eat at that time.
Combination therapy
In addition to being used as monotherapy, the compounds of the invention may also be used in combination therapy. Effective combination therapy can be achieved with a single composition or pharmacological formulation comprising two agents, or with two different compositions or formulations administered simultaneously, wherein one composition comprises a compound of the invention and the other composition comprises a second agent. Alternatively, the therapy may be performed before or after the treatment with another agent, with time intervals ranging from minutes to months.
Non-limiting examples of such combination therapies include one or more compounds of the present invention in combination with: another anti-inflammatory agent, chemotherapeutic agent, radiation therapy, antidepressant, antipsychotic agent, anticonvulsant agent, mood stabilizer, anti-infective agent, antihypertensive agent, cholesterol lowering agent or other lipid regulating agent, agent for promoting weight loss, antithrombotic agent, agent for treating or preventing cardiovascular events such as myocardial infarction or stroke, antidiabetic agent, agent for reducing transplant rejection or graft versus host disease, antiarthritic agent, analgesic, antiasthmatic agent or other treatment for respiratory diseases, or agent for treating or preventing skin conditions. The compounds of the invention may be combined with agents designed to improve the immune response of a patient to cancer, including (but not limited to) cancer vaccines. See Lu et al (2011), which is incorporated herein by reference.
VII. examples
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Method and material
RAW264.7 mouse macrophages were seeded at 30,000 cells/well in 96-well plates (in triplicate) in RPMI1640+ 0.5% FBS and 5% CO at 37 ℃, 5%2And (4) incubating. The following day, cells were pretreated with DMSO or drug (0-200nM dose range) for 2 hours, followed by recombinant mouse IFN γ (R)&D Systems) for 24 hours. The nitric oxide concentration in the medium was determined using the Griess reagent system (Promega). Cell viability was determined using WST-1 reagent (Roche). Determination of IC based on inhibition of IFN gamma-induced nitric oxide production normalized to cell viability50The value is obtained.
The NQO1-ARE luciferase reporter assay this assay allows for the quantitative assessment of endogenous activity of Nrf2 transcription factor in cultured mammalian cells. Expression of firefly luciferase from the NQO1-ARE luciferase reporter plasmid is controlled by Nrf2 in combination with specific enhancer sequences corresponding to the Antioxidant Response Element (ARE) identified in the promoter region of the human NADPH: quinone oxidoreductase 1(NQO1) gene (Xie et al, 1995). The plasmid was constructed by inserting the sequence 5'-CAGTCACAGTGACTCAGCAGAATCTG-3' encompassing human NQO1-ARE (SEQ ID NO:1) into the pLuc-MCS vector (GenScript, Inc., Piscataway, NJ) using the HindIII/XhoI cloning site. The assay was performed in HuH7 cells maintained in DMEM (Invitrogen) supplemented with 10% FBS and 100U/ml (respectively) of penicillin and streptomycin. To perform the assay, cells were seeded at 17,000 cells/well in 96-well plates. After 24 hours, the cells were co-transfected with 50ng each of the NQO1-ARE reporter plasmid and the pRL-TK plasmid using Lipofectamine 2000 transfection reagent (Invitrogen). The pRL-TK plasmid constitutively expresses Renilla (Renilla) luciferase and serves as an internal control to normalize transfection levels. 30 hours after transfection, the cells were treated with compounds (at concentrations ranging from 0. mu.M to 1. mu.M) for 18 hours. The activities of firefly and Renilla luciferases were determined by Dual-Glo Luciferase Assay (Promega corporation, Madison, Wis.) and luminescence signals were measured on an L-Max II luminometer (Molecular Devices). Firefly luciferase activity was normalized to renilla activity, and fold induction of normalized firefly activity relative to vehicle control (DMSO) was calculated. Fold induction at a concentration of 62.5nM was used to compare the relative potency of compounds to induce Nrf2 transcriptional activity. See Xie et al, 1995, which is incorporated herein by reference.
Synthetic schemes, reagents and yields
Scheme 1
Reagents and conditions: (a) (COCl)2DMF (catalyst), CH2Cl2From 0 ℃ to rt, 2 h; (b) CH (CH)3CONHNH2，Et3N，Et2O, 97% at 0 ℃ to rt for 30 min; (c) p-TsOH, toluene, reflux, 1.5h, 74%.
Scheme 2
Reagents and conditions: (a) n-PrCONHNH2，Et3N，CH2Cl2Rt, 2.5h, 98%; (b) p-TsOH, toluene, reflux, 2.5h, 83%.
Scheme 3
Reagents and conditions: (a) i-PrCONHNH2，Et3N，CH2Cl2Rt, 3h, 91%; (b) p-TsOH, toluene, reflux, 1h, 85%.
Scheme 4
Reagents and conditions: (a) c-PrCONHNH2，Et3N，CH2Cl2Rt, 3.5h, 86%; (b) p-TsOH, toluene, reflux, 2.5h, 83%.
Scheme 5
Reagents and conditions: (a) CH (CH)3OCH2CONHNH2，Et3N，CH2Cl2Rt, 3.5h, 86%; (b) p-TsOH, toluene, reflux, 1h, 56%.
Scheme 6
Reagents and conditions: (a) CHONHNH2，Et3N，CH2Cl2Rt, 1.5h, 48%; (b) p-TsOH, toluene, reflux, 1h, 49%.
Scheme 7
Reagents and conditions: (a) acetamide oxime, Et3N，CH2Cl2Rt, 5h, 93%; (b) toluene, microwave, reflux, 0.5h, 46%.
Scheme 8
Reagents and conditions: (a) CH (CH)3CONH2NH2，EDCI，DMAP，Et3N,CH2Cl2Rt, 17h, 57%; (b) p-TsOH, toluene, microwave, reflux, 1h, 46%.
Synthesis and characterization of Compounds and intermediates
Compound 1: compound RTA401 (1.00g,2.03mmol) was dissolved in CH2Cl2(20mL) and the solution was cooled to 0 ℃. Oxalyl chloride (0.55mL,6.50mmol) was added followed by DMF (2 drops). The reaction mixture was stirred at room temperature for 2h, then the reaction mixture was concentrated. The residue is reacted with CH2Cl2Azeotropy 2 x gave compound 1 as a yellow foam, which compound 1 was used directly in the next step.
Compound 2: dissolve Compound 1(2.03mmol) in Et2O (20mL) and the solution was cooled to 0 ℃. Et was added to the reaction mixture3N (0.565mL,4.05mmoL) and acethydrazide (226mg,3.05mmoL) in CH2Cl2Solution (10 mL). The reaction mixture was stirred at room temperature for 30min, then extracted with EtOAc and washed with water, 1N HCl and again with water. The organic extract was purified over MgSO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 2(1.08g, 97%, from RTA401) as an off-white foamy solid: m/z 548.3(M + 1).
Compound TX 63384: to a solution of compound 2(548mg,1.00mmol) in toluene (20mL) was added p-TsOH (95mg,0.50 mmol). The reaction was heated at 135 ℃ for 1.5h using an attached Dean-Stark condenser. After cooling to room temperature, the reaction mixture was washed with water and over MgSO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give compound TX63384(390mg, 74%) as an off-white foamy solid:1H NMR(400MHz,CDCl3)δ8.02(s,1H),5.96(s,1H),3.13(m,1H),2.94(d,1H,J＝4.5Hz),2.53(s,3H),2.19(m,1H),1.20-2.05(m,14H),1.45(s,3H),1.25(s,3H),1.19(s,3H),1.16(s,3H),1.06(s,3H),1.05(s,3H),0.95(s,3H)；m/z 530.3(M+1)。
compound 3: to butyryl hydrazine (156mg,1.53mmol) and Et3N (0.58mL,4.16mmol) in CH2Cl2To the solution (5mL) of (1, 510mg,1.00mmol) in CH was added2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 3(566mg, 98%) as a white solid: m/z 576.4(M + 1).
Compound TX 63475: to a solution of compound 3(197mg,0.342mmol) in toluene (12mL) was added p-TsOH (33mg,0.174 mmol). The reaction was heated at 135 ℃ for 2.5h using an attached dean-stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc and with saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 100% EtOAc in hexanes) to give compound TX63475(159mg, 83%) as a white solid:1H NMR(400MHz,CDCl3)δ8.01(s,1H),5.95(s,1H),3.14(td,1H,J＝4.3,13.4Hz),2.94(d,1H,J＝4.7Hz),2.81(t,2H,J＝7.6Hz),2.19(m,1H),1.93(m,3H),1.50(m,13H),1.45(s,3H),1.25(s,3H),1.16(s,3H),1.15(s,3H),1.05(s,3H),1.04(s,3H),0.99(t,3H,J＝7.4Hz),0.95(s,3H)；m/z 558.4(M+1)。
compound 4: to isobutyrylhydrazide (153mg,1.50mmol) and Et3N (0.58mL,4.16mmol) in CH2Cl2To the solution (5mL) of (1, 510mg,1.00mmol) in CH was added2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 4(525mg, 91%) as a white solid: m/z 576.4(M + 1).
Compound TX 63476: to a solution of compound 4(282mg,0.490mmol) in toluene (12mL) was added p-TsOH (48mg,0.253 mmol). The reaction was heated at 135 ℃ for 1h using an attached dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc and with saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound TX63476(233mg, 85%) as a white solid:1H NMR(400MHz,CDCl3)δ8.02(s,1H),5.95(s,1H),3.17(m,2H),2.99(d,1H,J＝4.7Hz),2.18(dt,1H,J＝4.2,14.8Hz),1.90(m,3H),1.45(m,11H),1.45(s,3H),1.37(d,6H,J＝7.0Hz),1.25(s,3H),1.16(s,3H),1.15(s,3H),1.05(s,3H),1.04(s,3H),0.95(s,3H)；m/z 558.3(M+1)。
compound 5: to cyclopropane carboxylic acid hydrazide (155mg,1.55mmol) and Et3N (0.58mL,4.16mmol) in CH2Cl2To the solution (5mL) of (1, 510mg,1.00mmol) in CH was added2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 5(495mg, 86%) as a white solid: m/z 574.3(M + 1).
Compound TX 63477: to a solution of compound 5(288mg,0.502mmol) in toluene (12mL) was added p-TsOH (55mg,0.289 mmol). The reaction was heated at 150 ℃ for 2.5h using an attached dean-stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc and with saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4DryingFiltered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound TX63477(231mg, 83%) as a white solid:1H NMR(400MHz,CDCl3)δ8.02(s,1H),5.95(s,1H),3.10(td,1H,J＝3.6,13.2Hz),2.98(d,1H,J＝4.7Hz),2.12(m,2H),1.90(m,3H),1.45(s,3H),1.43(s,15H),1.25(s,3H),1.18(s,3H),1.16(s,3H),1.04(s,3H),1.04(s,3H),0.94(s,3H)；m/z 556.3(M+1)。
compound 6: to methoxy acethydrazide (166mg,1.59mmol) and Et3N (0.56mL,4.02mmol) in CH2Cl2To the solution (5mL) of (1, 510mg,1.00mmol) in CH was added2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 6(495mg, 86%) as a white foamy solid: m/z578.4(M + 1).
Compound TX 63478: to a solution of compound 6(292mg,0.505mmol) in toluene (12mL) was added p-TsOH (48mg,0.253 mmol). The reaction was heated at 150 ℃ for 1h using an attached dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc and with saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound TX63478(158mg, 56%) as a white solid:1H NMR(400MHz,CDCl3)δ8.02(s,1H),5.96(s,1H),4.63(s,2H),3.43(s,3H),3.18(td,1H,J＝4.2,13.7Hz),3.01(d,1H,J＝4.7Hz),2.21(m,1H),1.91(m,3H),1.50(m,11H),1.45(s,3H),1.24(s,3H),1.16(s,3H),1.15(s,3H),1.05(s,3H),1.05(s,3H),0.95(s,3H)；m/z 560.3(M+1)。
compound 7: to a mixture of formyl hydrazine (92mg,1.53mmol) and Et3N (0.56mL,4.02mmol) in CH2Cl2To the solution (5mL) of (1)Compound 1(510mg,1.00mmol) in CH2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was then extracted with EtOAc and washed with 1N HCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 7(257mg, 48%) as a white solid: m/z 534.3(M + 1).
Compound TX 63479: to a solution of compound 7(256mg,0.480mmol) in toluene (12mL) was added p-TsOH (48mg,0.253 mmol). The reaction was heated at 150 ℃ for 1h using an attached dean-Stark condenser. After cooling to room temperature, the reaction mixture was extracted with EtOAc and with saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound TX63479(120 mg, 49%) as a white solid:1H NMR(400 MHz,CDCl3)δ8.36(s,1H),8.01(s,1H),5.96(s,1H),3.20(td,1H,J＝3.8,13.3 Hz),2.91(d,1H,J＝4.8 Hz),2.23(m,1H),1.93(m,3H),1.46(m,11H),1.44(s,3H),1.25(s,3H),1.15(s,3H),1.14(s,3H),1.06(s,3H),1.05(s,3H),0.96(s,3H)；m/z 516.3(M+1)。
compound 8: to acetamide oxime (113 mg,1.53mmol) and Et3N (0.56mL,4.02mmol) in CH2Cl2To the solution (5mL) of (1, 510mg,1.00mmol) in CH was added2Cl2Solution (5.0 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to give compound 8(510 mg, 93%) as a white solid: m/z 548.3(M + 1).
Compound TX 63501: compound 8(27 mg,0.049 mmol) was dissolved in toluene (1 mL) and the solution was heated by microwave heating at 170 ℃ for 10 min, followed by heating at 200 ℃ for 20 min. After cooling to room temperature, the reaction mixture was concentrated. The purification of the crude product by flash chromatography (silica gel,0% to 80% EtOAc in hexanes) to afford compound TX63501(12 mg, 46%) as a white solid:1H NMR(400 MHz,CDCl3.)δ8.01(s,1H),5.95(s,1H),3.14(m,1H),3.02(d,1H,J＝4.7 Hz),2.21(s,3H),2.14(m,1H),1.93(m,3H),1.50(m,13H),1.45(s,3H),1.25(s,3H),1.18(m,1H),1.16(s,3H),1.15(s,3H),1.04(s,3H),0.98(s,3H)；m/z 530.3(M+1)。
compound 9: to compound TX63199(52 mg,0.103 mmol) in CH2Cl2To the solution (2mL) of (1), acethydrazide (18.6 mg,0.251 mmol) and Et were added3N (28. mu.L, 0.201 mmol) and DMAP (24.4 mg,0.200 mmol). EDCI (40 mg,0.209 mmol) was then added and the reaction stirred at room temperature for 17 h. The reaction mixture was extracted with EtOAc and washed with saturated 1NHCl and brine. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. By flash chromatography (silica gel, on CH)2Cl20% to 10% MeOH) to afford compound 9 as a white solid (33mg, 57%): m/z512.3(M + 1).
Compound TX 63593: to a solution of compound 9(25mg,0.045mmol) in toluene (1.5mL) was added p-TsOH (4.8mg,0.025 mmol). The reaction mixture was heated by microwave heating at 125 ℃ for 1 h. After cooling to room temperature, the reaction mixture was extracted with EtOAc and saturated NaHCO3And a brine wash. Subjecting the organic extract to Na2SO4Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20% to 100% EtOAc in hexanes) to give compound TX63593(11mg, 46%) as an off-white solid:1H NMR(400MHz,CDCl3)δ8.04(s,1H),6.01(s,1H),3.12(d,1H,J＝5.0Hz),3.12(d,1H,J＝14.1Hz),2.69(d,1H,J＝14.5Hz),2.52(s,3H),2.27(m,1H),1.98(m,2H),1.78(m,3H),1.56(m,3H),1.56(s,3H),1.52(s,3H),1.27(s,3H),1.19(m,7H),1.19(s,3H),1.04(s,3H),0.91(s,3H),0.88(s,3H)；m/z 544.3(M+1)。
all of the compounds, compositions, and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the present disclosure has been described in terms of only certain embodiments, it will be apparent to those of skill in the art that variations may be applied to the compounds, compositions, and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would still be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Reference to the literature
The following references are expressly incorporated herein by reference to the extent that they provide exemplary procedural or other details supplementary to those set forth herein.
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Claims (16)

1. A compound of the formula:
wherein:
ar isAnd is
Y is:
hydrogen, hydroxy, halo, or amino; or
Alkyl radicalC≤8Cyclopropyl, alkoxyC≤8Or substituted versions of any of these groups.
2. The compound of claim 1, wherein Y is-H.
3. The compound of claim 1, wherein Y is alkylC≤4。
4. The compound of claim 3, wherein Y is methyl, n-propyl, or isopropyl.
5. The compound of claim 1, wherein Y is methoxymethyl.
6. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1, further defined as:
or a pharmaceutically acceptable salt thereof.
13. A compound of the formula:
14. a pharmaceutical composition comprising:
a) a compound according to any one of claims 1-13; and
b) and (3) an excipient.
15. Use of a compound according to any one of claims 1-13 in the manufacture of a medicament for treating and/or preventing a disease or disorder in a patient in need thereof, wherein the medicament comprises the compound in an amount sufficient to treat and/or prevent the disease or disorder, wherein the disease or disorder is cancer, mucositis, rheumatoid arthritis, psoriasis, multiple sclerosis, amyotrophic lateral sclerosis, huntington's disease, lupus, crohn's disease, cardiovascular disease, ischemia reperfusion injury, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, diabetes, chronic kidney disease, graft-versus-host disease, alzheimer's disease, parkinson's disease, osteoarthritis, osteoporosis, inflammatory bowel disease, dermatitis, sepsis, uveitis, glaucoma, macular degeneration, retinopathy, uveitis, and/or inflammatory bowel disease, Asthma, schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism, anorexia nervosa, epilepsy, muscular dystrophy, cachexia, or influenza.
16. The use of claim 15, wherein the cardiovascular disease is atherosclerosis.
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