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HK1097532B - Tricyclic delta opioid modulators - Google Patents

Tricyclic delta opioid modulators Download PDF

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Publication number
HK1097532B
HK1097532B HK07103171.8A HK07103171A HK1097532B HK 1097532 B HK1097532 B HK 1097532B HK 07103171 A HK07103171 A HK 07103171A HK 1097532 B HK1097532 B HK 1097532B
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HK
Hong Kong
Prior art keywords
ethyl
compound
formula
pain
neuralgia
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HK07103171.8A
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Chinese (zh)
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HK1097532A1 (en
Inventor
John R. Carson
Ellen Codd
Christine M. Razler
Andrea Works
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Janssen Pharmaceutica N.V.
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Priority claimed from PCT/US2004/019911 external-priority patent/WO2005003131A1/en
Publication of HK1097532A1 publication Critical patent/HK1097532A1/en
Publication of HK1097532B publication Critical patent/HK1097532B/en

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Description

Tricyclic delta opioid modulators
Cross Reference to Related Applications
This application claims priority from U.S. provisional patent application 60/483,389, filed on 27/6/2003, which is incorporated herein by reference in its entirety.
Statement regarding federally favored research and development
The research and development of the present invention described below is not federally sponsored.
Background
The term "opioid" generally refers to all natural and synthetic drugs having morphine-like effects. Previously, the term "opiate" refers to drugs extracted from opiates (e.g., morphine, codeine) and many semisynthetic homologs of morphine. After isolation of the peptide compounds having morphine-like action, the term opioid is introduced, which refers to all drugs having morphine-like action. Opioids include various peptides with morphine-like activity (e.g., endorphins, enkephalins, and dynorphins). However, some documents continue to use the term "opiate" in its ordinary sense, where opiate and opioid are interchangeable. In addition, the term opioid also refers to antagonists of morphine-like narcotic drugs, and also serves to characterize the receptors or binding sites that bind to such drugs.
Opioids are commonly used as analgesics, but they also have many other pharmacological effects. Morphine and related opioids primarily act on the central nervous system and the digestive system. These effects are diverse and include analgesia, lethargy, mood changes, respiratory depression, dizziness, mental confusion, dysphoria, pruritus, increased biliary tract pressure, decreased gastrointestinal motility, nausea, vomiting, and changes in the endocrine and autonomic nervous systems.
One of the obvious features of opioid-induced analgesia is that there is no loss of consciousness. When therapeutic doses of morphine are administered to pain patients, they respond with reduced pain, reduced discomfort or complete loss of pain. In addition to alleviating pain, some patients feel psychologically happy. However, when pain-relieving doses of morphine are administered to pain-free individuals, the sensation is not always pleasant; nausea and possibly vomiting are common. This in turn leads to drowsiness, mental inattention, difficulty thinking, apathy, reduced physical activity, reduced visual acuity and somnolence.
Two different types of opioid molecules can bind to opioid receptors: opioid peptides (e.g., enkephalins, dynorphins and endorphins) and the alkaloids opiates (e.g., morphine, etorphine, diprenorphine and naloxone). After initial confirmation of the opiate binding site (Pert, C.B. and Snyder, S.H., Science (1973) 179: 1011-. Accordingly, 3 anatomically and pharmacologically distinct opioid receptor types have been described: δ, κ, and μ. Furthermore, each type is believed to have a subtype (Wollemann, M., J neurohem (1990) 54: 1095-499; Lord, J.A., et al., Nature (1977) 267: 495-499).
These 3 opioid receptor types appear to have the same functional mechanism at the cellular level. For example, opioid receptors inhibit adenylate cyclase and inhibit Ca by activating potassium channels2+The channel thereby inhibits the release of neurotransmitters (Evans, C.J., In: biologic)cal Basis of Substance Abuse，S.G.Korenman &Barchas, eds, Oxford University Press (to be published); north, a.r., et al, Proc natl acad Sci USA (1990) 87: 7025-29; gross, r.a., et al, Proc Natl acadsi USA (1990) 87: 7025-29; shama, s.k., et al, Proc Natl Acad SciUSA (1975) 72: 3092-96). Despite the same functional mechanism, the efficacy of receptor-selective drugs appears quite different (Gilbert, P.E.&Martin, w.r., J Pharmacol ExpTher (1976) 198: 66-82). Such differences may be due in part to the anatomical location of the different receptors.
In the mammalian CNS, the distribution of delta receptors is more discontinuous relative to mu or kappa receptors, with high concentrations in the amygdala complex, striatum, substantia nigra, olfactory bulb, olfactory tubercle, hippocampal structure and cerebral cortex (Mansour, A., et al., Trends in Neurosci (1988) 11: 308-14). The rat cerebellum is significantly deficient in opioid receptors, including the delta opioid receptor.
D. delorme, e.roberts and z.wei in world patent WO/28275(1998) disclose the opioid analgesics diarylmethylenepiperidines, but do not disclose or suggest the compounds of the present invention.
5-HT is disclosed in U.S. Pat. No. 0166672(2003), world patent WO/035646(2003) and EP 1321169(2003), L.Hermann, C.Ullmer, E.Bellott et al2BThe receptor antagonists 4- (thio-or seleno-xanthen-9-ylidene) -piperidine or acridine, but the compounds of the present invention are not disclosed.
Partial piperidylidene derivatives of thioxanthene, xanthene, dibenzoxepin and 9, 10-dihydroacridine, which are antipsychotic drugs, are disclosed by Kaiser et al, J.Med.chem.1974, volume 17, pages 57-61. However, the authors do not disclose or suggest the structure or activity of the compounds of the present invention.
British patent GB 1128734(1966) discloses 6, 11-dihydrodibenzo [ b, e ] oxepin derivatives which are anticholinergics, anticonvulsants, muscle relaxants, sedatives, diuretics and/or circulation active agents. However, these drugs are both structurally and pharmacologically distinct from the compounds of the present invention.
There remains a need for novel delta-opioid receptor modulators as analgesics. There is also a need for delta-opioid receptor selective agonists as analgesics with fewer side effects. Delta-opioid receptor antagonists are also needed as immunosuppressive agents with fewer side effects, anti-inflammatory agents, agents for treating neurological and psychiatric disorders, agents for treating drugs and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for treating respiratory diseases.
Summary of The Invention
The present invention relates to compounds of the following structural formula (I) and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein:
R1and R2Is independently selected from hydrogen and C1-8A substituent of an alkyl group;
R3selected from hydrogen, C1-8Alkyl, halo1-3(C1-8) Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, cycloalkyl (C)1-8) Alkyl radical, C1-8Alkyl alkoxy (C)1-8) Alkyl radical, C1-8Alkanylthio radical (C)1-8) Alkyl, hydroxy C1-8Alkyl radical, C1-8Alkyl oxy carbonyl, halo1-3(C1-8) Alkyl carbonyl, formyl, thioaldehyde, amidino (carbamimidoyl), phenylimino (C)1-8) Alkyl, phenyl (C)1-8) Alkyl radicalPhenyl (C)1-8) Alkenyl, phenyl (C)1-8) Alkynyl, naphthyl (C)1-8) Alkyl and heteroaryl (C)1-8) An alkyl group; wherein phenyl, naphthyl and heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: c1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl carbonyl amino group, C1-6Alkylthio alkyl radical, C1-6Alkanesulfonyl, halogen, hydroxy, cyano, fluoroalkane, thiourea and fluoroalkyloxy; alternatively, when the phenyl and heteroaryl groups are optionally substituted with 2 substituents on adjacent carbon atoms, the 2 substituents may together form 1 fused moiety; wherein the fused moiety is selected from- (CH)2)3-5-and-O (CH)2)1-3O-；
R4Is 1-3 substituents independently selected from: hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl oxycarbonyl radical, C1-6Alkyl aminocarbonyl, di (C)1-6Alkyl) aminocarbonyl, C1-6Alkyl carbonyl amino group, C1-6Alkylthio alkyl radical, C1-6Alkanesulfonyl, halogen, hydroxy, cyano, hydroxycarbonyl, C6-10Aryl, chromanyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl, fluoroalkyloxy, and fluoroalkyloxy; or when R is4When there are 2 substituents attached to adjacent carbon atoms, the 2 substituents are optionally joined together to form1 fused moiety; wherein the fused moiety is selected from- (CH)2)3-5-and-O (CH)2)1-3O-；
R5Is 1-2 substituents independently selected from: hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl oxycarbonyl radical, C1-6Alkyl aminocarbonyl group, C1-6Alkyl carbonyl amino group, C1-6Alkylthio alkyl radical, C1-6Alkanesulfonyl, halogen, hydroxy, cyano, fluoroalkane and fluoroalkyloxy;
a is- (CH)2)m-, where m is 0, 2 or 3; preferably m is 2 or 3, most preferably m is 2;
y is- (CH)2)nX-or-X (CH)2)n-；
X is O or S;
n is 0 or 1;
z is O or S.
Finally, the present invention relates to veterinary and pharmaceutical compositions comprising a compound of formula (I), wherein said compositions are useful for the treatment of mild to severe pain in a warm-blooded animal.
Detailed Description
The following underlining terms used herein have the following meanings:
term "C a-b "(wherein a and b are integers) refers to groups containing a-b carbon atoms. E.g. C1-3Represents a group containing 1 to 3 carbon atoms.
"alkyl" refers to a saturated or unsaturated, branched, straight chain or cyclic monovalent hydrocarbon radical derived from a carbon atom of a parent alkane, alkene or alkyneDerived by removing one hydrogen atom. Typical alkyl groups include, but are not limited to, methyl; ethyl groups such as ethyl, vinyl, and ethynyl; propyl such as propan-1-yl, propan-2-yl, cyclopropane-1-yl, propan-1-en-2-yl, propan-2-en-1-yl, cycloprop-1-en-1-yl; cyclopropyl-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butyl radicals such as the butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutane-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like. When referring to a particular saturation level, the designations "alkanyl", "alkenyl" and/or "alkynyl" are used, as defined below. In a preferred embodiment, the alkyl group is (C)1-C6) Alkyl, especially preferred is (C)1-C3) An alkyl group.
“Alkanyl (alkanyl)"refers to a saturated branched, straight chain or cyclic monovalent hydrocarbon radical derived from a parent alkane by the removal of one hydrogen atom from one carbon atom of the parent alkane. Typical alkyl groups include, but are not limited to, methyl; an ethyl group; a propyl group such as propan-1-yl, propan-2-yl, cyclopropane-1-yl, etc.; butyl groups such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutane-1-yl and the like. In a preferred embodiment, the alkyl group is (C)1-8) An alkyl group, particularly preferably (C)1-3) An alkyl group.
“Alkenyl radical"refers to an unsaturated branched or straight chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived from a parent olefin by the removal of one hydrogen atom from one carbon atom of the parent olefin. The alkenyl group may be in the cis or trans conformation of the double bond. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, for example prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, prop-1-en-1-yl; cyclopropyl-2-en-1-yl; butenyl, e.g. but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-ylA-group, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like.
“Alkynyl radical"refers to an unsaturated branched or straight chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived from a parent alkyne by the removal of one hydrogen atom from one carbon atom. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl groups such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like.
“Heteroalkyl radicals"and"Heteroalkanyl radical"refers to an alkyl or an alkyl group, respectively, in which one or more carbon atoms (and any necessary hydrogen atoms) are independently replaced with the same or different heteroatoms (including any necessary hydrogen or other atoms). Typical heteroatoms used to replace carbon atoms include, but are not limited to N, P, O, S, Si, etc., with the preferred heteroatoms being O, N and S. Thus, a heteroalkanyl group may contain one or more identical or different heteroatomic groups, including, for example, but not limited to, oxo (-O-), oxo (-O-), thioether (-S-), oxo-disulfide (-SS-), oxo-sulfide (-O-S-), oxo-imino (-O-NR ' -), imino (-NR ' -, hydrazo (-NR ' -, azino (- (N-N) ═ O '), azo (-N ═ N-), azoxy (-N-O-N-), azido (-NR ' -N ═ N-), phosphinous (phosphino) (-PH-), λ (-N ═ N-), and the like4-sulfano(-SH2-), sulfonyl (-S (O)2-) etc., wherein each R' is independently hydrogen or (C)1-C6) An alkyl group.
“Parent aromatic ring system:"refers to an unsaturated or polycyclic ring system having a conjugated pi electron system. "Mother bodyThe definition of "aromatic ring system" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as indane, indene, phenalene (phenalene), and the like. Typical ofMother bodyAromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexylene, hexalene, asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indaneIndene, naphthalene, octabenzene, octaphene, octalene, ovalene, pentalene (penta-2, 4-diene), pentacene, pentalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, benzo [9, 10 ] pleiadene]Phenanthrene, binaphthyl, and the like.
“Aryl radicals"refers to a monovalent aromatic hydrocarbon radical derived from a parent aromatic ring system by the removal of one hydrogen atom from one carbon atom. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexylene, hexalene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, benzo [9, 10 ] azulene]Phenanthrene, binaphthyl, and the like. In a preferred embodiment, aryl is (C)5-20) Aryl, especially preferred is (C)5- 10) And (4) an aryl group. Particularly preferred aryl groups are phenyl and naphthyl.
“Arylalkyl:"refers to an alkyl-opening hydrocarbon group in which a hydrogen atom attached to a carbon atom (usually the terminal carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, and the like. When referring to a particular alkyl moiety, the nomenclature arylalkylene, arylalkenyl, and/or arylalkynyl is used. In a preferred embodiment, arylalkyl is (C)6-26) Arylalkyl, e.g. arylalkyl, having an alkyl, alkenyl or alkynyl moiety of (C)1-6) And the aromatic base is (C)5-20). In a particularly preferred embodiment, arylalkyl is (C)6-13) For example, the alkyl, alkenyl or alkynyl moiety of an arylalkyl group is (C)1- 3) And the aromatic base is (C)5-10). More preferably, the arylalkyl group is phenylalkyl.
“An alkyl alkoxy group:"means saturated branched, straight or branched chainA cyclic monovalent hydrocarbon alcohol radical derived from the removal of a hydrogen atom from the hydroxyl oxygen of an alcohol. Typical alkyl alkoxy groups include, but are not limited to, methyl alkoxy; an ethoxy group; propyleneoxy radicals, e.g. propan-1-yloxy (CH)3CH2CH2O-), propan-2-yloxy ((CH)3)2CHO-), cyclopropane-1-yloxy, etc.; butyalkoxy groups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy, cyclobutane-1-yloxy and the like. In a preferred embodiment, the alkyloxy group is (C)1-8) Alkylhydrocarbyloxy radicals, particularly preferably (C)1-3) An alkyl-oxy group.
“The parent heteroaromatic ring system:"refers to a parent aromatic ring system in which one carbon atom is replaced with a heteroatom. Heteroatoms which may replace carbon atoms include N, O and S. The definition of "parent heteroaromatic ring system" specifically includes fused ring systems where one or more rings are aromatic and one or more rings are saturated or unsaturated, e.g., arsenoline, chroman, benzopyran, indole, indoline, xanthene, and the like. Typical parent heteroaromatic ring systems include, but are not limited to, carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
“Heteroaryl group:"refers to a monovalent heteroaromatic group derived from a parent heteroaromatic ring system by the removal of one hydrogen atom from one atom. Typical heteroaryl groups include, but are not limited to, groups derived from the following heteroaryl rings: carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazolazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In a preferred embodiment, the heteroaryl groupThe radical is 5-to 20-membered heteroaryl, particularly preferably 5-to 10-membered heteroaryl.
“Cycloheteroalkyl group:"refers to a saturated or unsaturated monocyclic or bicyclic alkyl group having one carbon atom replaced with N, O or S. In certain particular embodiments, the cycloheteroalkyl group may contain up to 4 heteroatoms independently selected from N, O or S. Typical cycloheteroalkyl moieties include, but are not limited to, groups derived from the following cycloheteroalkyl: imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. In a preferred embodiment, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.
“A cycloheteroalkyl group:"refers to a saturated monocyclic or bicyclic alkane having one carbon atom replaced by N, O or SHydrocarbonsAnd (4) a base. In certain particular embodiments, the cycloheteroalkyl is a cycloheteroalkylHydrocarbonsThe group may contain up to 4 heteroatoms independently selected from N, O or S. Typical cycloheteroalkanesHydrocarbonsRadical moieties include, but are not limited to, those derived from cycloheteroalkanesHydrocarbonsThe group of (a): imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. In a preferred embodiment, the cycloheteroalkyl is cycloheteroalkylHydrocarbonsThe radical being a 3-to 6-membered cycloheteroalkylHydrocarbonsAnd (4) a base.
“Heterocycloalkenyl:"refers to a saturated monocyclic or bicyclic alkenyl group having one carbon atom replaced with N, O or S. In certain particular embodiments, the heterocycloalkenyl can comprise up to 4 heteroatoms independently selected from N, O or S. Typical heterocycloalkenyl moieties include, but are not limited to, groups derived from the following cycloheteroalkenes: imidazolines, pyrazolines, pyrrolines, indolines, pyrans, and the like. In a preferred embodiment, the cycloheteroalkyl is cycloheteroalkylHydrocarbonsThe radical being a 3-to 6-membered cycloheteroalkylHydrocarbonsAnd (4) a base.
“Substituted (of): "refers to a group wherein one or more hydrogen atoms are each independently replaced by the same or different substituents. Typical substituents include, but are not limited to, -X, -R, -O-、＝O、-OR、-O-OR、-SR、-S-、＝S、-NRR、＝NR、-CX3、-CN、-OCN、-SCN、-NCO、-NCS、-NO、-NO2、＝N2、-N3、-NHOH、-S(O)2O-、-S(O)2OH、-S(O)2R、-P(O)(O-)2、-P(O)(OH)2、-C(O)R、-C(O)X、-C(S)R、-C(S)X、-C(O)OR、-C(O)O--C (S) OR, -C (O) SR, -C (S) SR, -C (O) NRR, -C (S) NRR, and-C (NR) NRR, wherein each X is independently halogen (preferably-F, -Cl, OR-Br), and each R is independently-H, alkyl, alkanyl, alkenyl, alkynyl, alkylene, alkynylene, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, OR heteroaryl-heteroalkyl, as defined herein. Preferred substituents include hydroxy, halogen, C1-8Alkyl radical, C1-8Alkyl alkoxy, fluoro alkyl, C1-8Alkylthio radical, C3-8Cycloalkyl radical, C3-8Cycloalkyloxy, nitro, amino, C1-8Alkylamino radical, C1-8Dialkylamino radical, C3-8Cycloalkylamino, cyano, carboxyl, C1-7Alkyl oxycarbonyl radical, C1-7Alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroyl, carbamoyl, amidino, (C)1-8Alkylamino) carbonyl, (arylamino) carbonyl and aryl (C)1-8Alkyl) carbonyl.
With respect to substituents, the term "Independently of each other"means that when there may be more than 2 of said substituents, said substituents may be the same as or different from each other.
In this context, the terminal portion of the designated side chain is first recited, and then the adjacent functional group in the direction of the point of attachment is recited. Thus, for example, "phenyl C1-6Alkyl aminocarbonyl C1-6Alkyl "substituents refer to groups of the formula:
one embodiment of the present invention is directed to compounds of structural formula (I), wherein the structural numbering is as shown in the following figure.
Structural formula (I)
The present invention relates to the analgesic and antipyretic use of a compound of the following structural formula (I) or enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein:
R1and R2Is independently selected from hydrogen and C1-8A substituent of an alkyl group;
R3selected from hydrogen, C1-8Alkyl, halo1-3(C1-8) Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, cycloalkyl (C)1-8) Alkyl radical, C1-8Alkyl alkoxy (C)1-8) Alkyl radical, C1-8Alkylmercapto (C)1-8) Alkyl, hydroxy C1-8Alkyl radical, C1-8Alkyl oxy carbonyl, halo1-3(C1-8) Alkyl carbonyl, formyl, thioaldehyde, amidino, phenylimino (C)1-8) Alkyl, phenyl (C)1-8) Alkyl, phenyl (C)1-8) Alkenyl, phenyl (C)1-8) Alkynyl, naphthyl (C)1-8) Alkyl and heteroaryl (C)1-8) An alkyl group; wherein phenyl, naphthyl and heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: c1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl carbonyl amino group, C1-6Alkylthio alkyl radical, C1-6Alkyl sulfonyl, halogenElements, hydroxyl, cyano, fluoroalkyloxy, thiourea and fluoroalkyloxy; or when phenyl and heteroaryl are optionally substituted with 2 substituents on adjacent carbon atoms, optionally the 2 substituents together form 1 fused moiety; wherein the fused moiety is selected from- (CH)2)3-5-and-O (CH)2)1-3O-；
R4Is 1-3 substituents independently selected from: hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl oxycarbonyl radical, C1-6Alkyl aminocarbonyl, di (C)1-6Alkyl) aminocarbonyl, C1-6Alkyl carbonyl amino group, C1-6Alkylthio alkyl radical, C1-6Alkanesulfonyl, halogen, hydroxy, cyano, hydroxycarbonyl, C6-10Aryl, chromanyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl, fluoroalkyloxy, and fluoroalkyloxy; or when R is4When there are 2 substituents attached to adjacent carbon atoms, optionally the 2 substituents together form 1 fused moiety; wherein the fused moiety is selected from- (CH)2)3-5-and-O (CH)2)1-3O-；
R5Is 1-2 substituents independently selected from: hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkyl alkoxy, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyl, C1-6Alkyl carbonyl oxy, C1-6Alkyl oxycarbonyl radical, C1-6Alkyl aminocarbonyl group, C1-6Alkane(s)Aminocarbonylamino group, C1-6Alkylthio alkyl radical, C1-6Alkanesulfonyl, halogen, hydroxy, cyano, fluoroalkane and fluoroalkyloxy;
a is- (CH)2)m-, where m is 0, 2 or 3;
y is- (CH)2)nX-or-X (CH)2)n-；
X is O or S;
n is 0 or 1;
z is O or S.
For the embodiments of the present invention, it is preferred that:
a)R1and R2Is independently selected from hydrogen and C1-4A substituent of an alkyl group;
b)R1and R2Is a substituent independently selected from hydrogen, methyl, ethyl and propyl;
c)R1and R2Is a substituent independently selected from hydrogen and ethyl;
d)R3selected from hydrogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkyl alkoxy (C)1-8) Alkyl radical, C1-8Alkylmercapto (C)1-8) Alkyl, hydroxy C1-8Alkanyl, thioaldehyde, phenylimino (C)1-8) Alkyl, phenyl (C)1-8) Alkyl and heteroaryl (C)1-8) An alkyl group; wherein phenyl and heteroaryl are optionally substituted with 1-3 substituents independently selected from: c1-6Alkoxy and hydroxy; or when phenyl and heteroaryl are optionally substituted with 2 substituents on adjacent carbon atoms, optionally the 2 substituents together form 1 fused moiety; wherein the moiety is selected from the group consisting of-O (CH)2)1-3O-；
e)R3Selected from hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioEthyl, methoxyethyl, thioaldehyde, phenyliminomethyl, phenethyl and heteroaryl (C)1-8) An alkyl group; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
f)R3is hydrogen, methyl, allyl or heteroarylmethyl;
g)R4is 1-3 substituents independently selected from: hydrogen, C1-6Alkyl radical, C1-6Alkyl alkoxy, C1-6Alkyl aminocarbonyl group, C1-6Alkyl carbonyl amino, halogen, hydroxy, C6-10Aryl, chromanyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl;
h)R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
i)R4is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy;
j)R5is 1-2 substituents independently selected from hydrogen and halogen;
k)R5is hydrogen;
1) a is- (CH)2)0-2-；
m) A is — (CH2)2-；
n) X is O or S;
o) n is 0;
p) Z is O; and
q) combinations of the above a) to p).
One embodiment of the present invention is a compound of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein:
R1is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from hydrogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkyl alkoxy (C)1-8) Alkyl radical, C1-8Alkylmercapto (C)1-8) Alkyl, hydroxy C1-8Alkanyl, thioaldehyde, phenylimino (C)1-8) Alkyl, phenyl (C)1-8) Alkyl and heteroaryl (C)1-8) An alkyl group; wherein phenyl and heteroaryl are optionally substituted by 1-3 substituents independently selected from C1-6Substituted with alkyl oxy and hydroxy; or when phenyl and heteroaryl are optionally substituted with 2 substituents on adjacent carbon atoms, optionally the 2 substituents together form 1 fused moiety; wherein the moiety is selected from the group consisting of-O (CH)2)1-3O-；
R4Is 1-3 substituents independently selected from: hydrogen, C1-6Alkyl radical, C1-6Alkyl alkoxy, C1-6Alkyl aminocarbonyl group, C1-6Alkyl carbonyl amino, halogen, hydroxy, C6-10Aryl, chromanyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridazinyl, thiazolyl, and the like,Pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl;
R5is 1-2 substituents independently selected from hydrogen and halogen;
a is absent or CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
Yet another embodiment of the present invention is a compound of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein:
R1is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, oxyethyl, methylthioethyl, thioaldehyde, phenyliminomethyl, phenethyl and heteroaryl (C)1-8) An alkyl group; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
R5is hydrogen;
a is absent or CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
Yet another embodiment of the present invention is directed to compounds of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein R is1Is ethyl; r2Is ethyl or hydrogen; r3Is a substituent selected from: benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, thien-2-ylmethyl; r4Is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group; a is absent or CH2CH2(ii) a Y is O or S; and Z is O.
Yet another embodiment of the present invention is a compound of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein:
R1is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from hydrogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkyl alkoxy (C)1-8) Alkyl radical, C1-8Alkylmercapto (C)1-8) Alkyl, hydroxy C1-8Alkanyl, thioaldehyde, phenylimino (C)1-8) Alkyl, phenyl (C)1-8) Alkyl and heteroaryl (C)1-8) An alkyl group; wherein phenyl and heteroaryl are optionally substituted with 1-3 substituents independently selected from: c1-6Alkoxy and hydroxy; or when phenyl and heteroaryl are optionally substituted with 2 substituents on adjacent carbon atoms, optionally the 2 substituents together form 1 fused moiety; wherein the moiety is selected from the group consisting of-O (CH)2)1-3O-；
R4Is 1-3 substituents independently selected from: hydrogen, C1-6Alkyl radical, C1-6Alkyl alkoxy, C1-6Alkyl aminocarbonyl group, C1-6Alkyl carbonyl amino, halogen, hydroxy, C6-10Aryl, chromanyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl;
R5is 1-2 substituents independently selected from hydrogen and halogen;
a is CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
Yet another embodiment of the present invention is a compound of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein:
R1is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methoxyethyl, methylthioethyl, thioaldehyde, and mixtures thereof,Phenyliminomethyl, phenylethyl and heteroaryl (C)1-8) An alkyl group; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
R5is hydrogen;
a is CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
Yet another embodiment of the present invention is directed to compounds of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein R is1Is ethyl; r2Is ethyl or hydrogen; r3Is a substituent selected from: benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxy-ethyl, methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl, thien-2-ylmethyl; r4Is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group and a hydroxyl group(ii) a A is CH2CH2(ii) a Y is O or S; and Z is O.
Yet another embodiment of the present invention is directed to compounds of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein R is1Is ethyl; r2Is ethyl; r3Is a substituent selected from: benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl and phenethyl; r4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy; a is CH2CH2(ii) a Y is O or S; and Z is O.
Yet another embodiment of the present invention is directed to compounds of structural formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein R is1Is ethyl; r2Is ethyl; r3Is a substituent selected from: H. benzo [1, 3]]Dioxol-5-ylmethyl, 1-H-imidazol-4-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl and phenyliminomethyl; r4Is a substituent independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy; a is CH2CH2(ii) a Y is O or S; and Z is O.
A further embodiment of the present invention relates to compounds of formula (I), wherein R is preferred4Substituted at the 5-position or 6-position of formula (I).
Yet another embodiment of the present invention relates to the following compounds and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof:
1) knotA compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
2) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
3) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
4) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is benzo [1, 3]]Dioxol-5-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
5) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
6) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
7) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
8) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
9) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is methyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
10) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1, 1, 1-trichloroethoxycarbonyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
11) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
12) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-but-2-enyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
13) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is thien-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
14) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
15) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is cyclopropylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
16) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
17) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
18) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 4-hydroxy-3-methoxyphenyl-methyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
19) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
20) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
21) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
22) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
23) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
24) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is furan-3-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
25) a compound of formula (I) wherein R1Is aRadical, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is CH2O and Z is O;
26) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
27) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is furan-3-ylmethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
28) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
29) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 2-hydroxyphenyl-methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
30) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is amidino, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
31) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
32) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-prop-2-ynyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
33) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is methylcarbonylamino, R5Is H, A is absent, Y is O, and Z is O;
34) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is hydroxy-ethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
35) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenyliminomethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
36) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is a thioaldehyde group, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
37) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
38) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methoxyethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
39) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methylthioethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
40) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is methylcarbonylamino, R5Is H, A is absent, Y is O, and Z is O;
41) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H，R5Is H, A is absent, Y is O, and Z is O;
42) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
43) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
44) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is hydroxyethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
45) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
46) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is benzo [1, 3]]Dioxol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
47) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
48) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is cyclopropylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
49) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methylthiopropyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
50) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is hydroxy-ethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
51) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
52) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
53) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
54) a compound of formula (I) wherein R1Is methyl, R2Is methyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
55) a compound of formula (I) wherein R1Is isopropyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
56) a compound of formula (I) wherein R1Is methyl, R2Is isobutyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
57) a compound of formula (I) wherein R1Is a n-propyl group, and is,R2is n-propyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
58) a compound of formula (I) wherein R1Is n-propyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
59) a compound of formula (I) wherein R1Is methyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
60) a compound of formula (I) wherein R1Is H, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
61) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
62) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
63) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
64) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-fluoro, R5Is H, A is CH2CH2Y is O and Z is O;
65) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
66) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
67) a compound of formula (I) wherein R1Is methyl, R2Is n-butyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
68) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
69) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
70) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
71) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is trifluoromethyl carbonyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
72) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
73) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
74) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
75) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-phenyl, R5Is H, A is CH2CH2Y is O and Z is O;
76) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
77) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
78) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-benzothien-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
79) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7- (N-tert-butoxycarbonyl) pyrrol-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
80) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
81) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
82) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7- (3, 5-dimethyl) isoxazol-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
83) a compound of formula (I) wherein R1Is methyl, R2Is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
84) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyrrol-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
85) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
86) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-phenyl, R5Is H, A is CH2CH2Y is O and Z is O;
87) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
88) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
89) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-quinolin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
90) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
91) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
92) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O; and
93) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-fluoro, R5Is H, A is CH2CH2Y is O and Z is O.
Yet another embodiment of the present invention relates to the following compounds and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof:
1) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
2) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-but-2-enyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
3) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is thien-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
4) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
5) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
6) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
7) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
8) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
9) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
10) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
11) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
12) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
13) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
14) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
15) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
16) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
17) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
18) a compound of formula (I) wherein R1Is a methyl group, and the compound is,R2is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
19) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
20) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
21) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
22) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
23) a compound of formula (I) wherein R1Is n-propyl, R2Is n-propyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
24) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-fluoro, R5Is H, A is CH2CH2Y is O and Z is O;
25) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
26) a compound of the formula (I),wherein R is1Is methyl, R2Is isobutyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
27) a compound of formula (I) wherein R1Is methyl, R2Is n-butyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
28) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-quinolin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
29) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O; and
30) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-phenyl, R5Is H, A is CH2CH2Y is O and Z is O.
Yet another embodiment of the present invention is a composition comprising the dextrorotatory enantiomer of a compound of formula (I), wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O; wherein the composition is substantially free of the levorotatory isomer of the compound. Substantially free in this context means that the calculated levorotatory isomer of the formula is less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1%:
yet another embodiment of the present invention is a composition comprising the levorotatory enantiomer of a compound of formula (I), wherein R is1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O; wherein said composition is substantially free of the dextrorotatory isomer of said compound. Substantially free in this context means that the calculated dextroisomer is less than 25%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% and even more preferably less than 1% of the formula:
the compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For medical use, a salt of a compound of the invention refers to a non-toxic "pharmaceutically acceptable salt" (see International J.pharm., 1986, 33, 201-217; J.pharm.Sci., 1997(Jan), 66, 1, 1). However, other salts known to those skilled in the art may still be used to prepare the compounds of the present invention or their pharmaceutically acceptable salts. Typical organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Typical organic or inorganic bases include, but are not limited to, basic or cationic salts, such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, methylamine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
The present invention includes prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives that are readily converted to the desired compound in vivo. Thus, in the methods of treatment of the present invention, the term "administering" includes treating the various disorders with the specific compounds disclosed or with compounds which, although not specifically disclosed, are capable of being converted in vivo to the specific compounds of the present invention after their administration to a patient. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of produgs", ed.h. bundgaard, Elsevier, 1985.
The compounds of the present invention have at least one chiral center and therefore they may exist as enantiomers. When the compounds of the present invention have 2 or more chiral centers, they may also exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are within the scope of the present invention. In addition, certain crystalline forms of the compounds of the present invention may be polymorphic, and such polymorphs are also within the scope of the present invention. In addition, certain compounds may form solvates with water (i.e., hydrates) or conventional organic solvents, and such solvates are also within the scope of the present invention.
For the mixture of stereoisomers produced during the preparation of the compounds of the invention, these isomers may be separated using conventional techniques (e.g. preparative chromatography). The compounds of the invention may be prepared in racemic form, or the individual enantiomers may be prepared by enantiospecific synthesis or by resolution. These compounds can be resolved into their individual enantiomers by standard methods, for example, by first forming diastereomeric pairs by salt formation with an optically active acid (e.g., (-) -di-p-toluoyl-d-tartaric acid and/or (+) -di-p-toluoyl-1-tartaric acid), followed by fractional crystallization and finally regeneration of the free base. These compounds can also be broken down as follows: diastereomeric esters or amides are first formed, then chromatographed, and finally the chiral auxiliary is removed. Alternatively, these compounds can be resolved by a chiral HPLC column.
In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups of any molecule involved. Protection can be effected by conventional protecting group methods, see, for exampleProtective Groups in Organic Chemistry，ed.J.F.W.McOmie，Plenum Press, 1973; and t.w.greene& P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley &Sons, 1991. These protecting groups may be removed at a later appropriate time by methods known in the art.
Although the compounds of the present invention (including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof) may be administered alone, they are generally administered in admixture with a pharmaceutically acceptable carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmacological or veterinary practice. Accordingly, the present invention relates to pharmaceutical and veterinary compositions comprising a compound of structural formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
For example, in the pharmaceutical and veterinary compositions of the present invention, the compounds of the present invention may be mixed with any suitable binder, lubricant, suspending agent, coating agent and/or solubilizing agent.
Tablets or capsules of the compounds may be administered one tablet (granule), two tablets (granules) or more at a time, as appropriate. Sustained release formulations of the compounds may also be administered.
Alternatively, the compounds of formula (I) may be administered by inhalation or in the form of suppositories or pessaries, or they may be applied topically in the form of: lotions, solutions, creams, ointments or dusting powders. An alternative to transdermal administration is the use of skin patches. For example, they may be incorporated into creams consisting of aqueous emulsions of polyethylene glycol or liquid paraffin. They may also be incorporated in the form of ointments consisting of white wax or white soft paraffin base at a concentration of 1 to 10% by weight, with stabilizers and preservatives and the like if necessary.
For certain applications, it is preferred that the compositions be administered orally in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules (ovule) alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
The compositions (and individual compounds) may also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. In such a case, the composition should contain a suitable carrier or diluent.
For parenteral administration, the compositions are preferably used in the form of sterile aqueous solutions which may contain other substances, for example, enough salts or monosaccharides to formulate an isotonic solution of blood.
For buccal and sublingual administration, the compositions may be administered in the form of tablets or lozenges formulated in conventional manner.
By way of further example, pharmaceutical and veterinary compositions containing one or more compounds of the invention as active ingredients may be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations (e.g., suspensions, elixirs and solutions), suitable carriers and additives include water, glycols, oils, monohydric alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral formulations (e.g., powders, capsules, and tablets), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Solid oral formulations may also be coated with carbohydrates or enteric coatings to regulate absorption at the primary site. For parenteral administration, the carrier will usually comprise sterile water, although other ingredients may be added to increase solubility or to preserve. Injectable suspensions or solutions may also be prepared using aqueous carriers and appropriate additives.
Conveniently, the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be divided into 2-4 divided doses per day. In addition, the compounds of the present invention may be administered topically using suitable intranasal vehicles in intranasal dosage forms, or in the form of transdermal patches well known to those skilled in the art. For transdermal delivery system forms of administration, the dosage administration is, of course, continuous rather than intermittent throughout the dosage regimen.
It will also be apparent to those skilled in the art that the therapeutically effective dose of the active compounds of the present invention or pharmaceutical compositions thereof will vary depending upon the desired effect. Thus, one skilled in the art can quickly determine the optimal dosage that should be administered and adjust the dosage depending on the particular compound used, the mode of administration, the potency of the formulation, and the extent of the disease. In addition, the dosage must be adjusted to the appropriate level depending on the relevant factors for the particular patient being treated, including the age, weight, diet and time of administration of the patient. The above dosages are therefore examples in the usual case. Individual instances will, of course, be given higher or lower dosage ranges, and such dosage ranges are within the scope of the invention.
Whenever a patient is in need of using a compound of the present invention as an analgesic or antipyretic, the compound of the present invention may be administered in any of the aforementioned composition forms and dosage regimens, or according to those compositions and dosage regimens identified in the art.
The invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with a pharmaceutical or veterinary composition of one or more ingredients of the invention. Optionally, instructions are given with such containers (which conform to the regulatory format of a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products) that mandate approval for human administration by the governmental agency regulating the manufacture, use or sale.
The compounds of the present invention can be administered in an analgesically effective dose to treat mild to severe pain in a warm-blooded animal such as a human. In a regimen for 1-4 administrations per day of an average human (70kg), the dosage range is about 0.01mg to 15,000mg of active ingredient, preferably about 0.1mg to 3500mg, or more preferably about 0.1mg to 1000mg of active ingredient; however, one skilled in the art will recognize that the therapeutically effective dose of the active compounds of the present invention will vary depending on the type of pain being treated.
Preferably, the pharmaceutical composition for oral administration is a tablet comprising 0.01, 10.0, 50.0, 100, 150, 200, 250 and 500mg of active ingredient, the dosage being adjusted according to the symptoms of the patient to be treated.
Examples of pain within the scope of the present invention include, but are not limited to, inflammatory pain, central pain, peripheral pain, pain associated with structural or soft tissue injury, pain associated with progressive disease, neuropathic pain, as well as acute pain (caused, for example, by acute injury, trauma, or surgery) and chronic pain (caused, for example, by headache and by neuropathy, stroke sequela, and migraine).
The compounds of the present invention are also useful as immunosuppressants, anti-inflammatory agents, agents for the treatment and prevention of neurological and psychiatric disorders such as depression and parkinson's disease, agents for the treatment of drug abuse and alcohol abuse, agents for the treatment of gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.
The compounds of the invention are also useful in the treatment of pain caused by: osteoarthritis, rheumatoid arthritis, fibromyalgia (fibrosyalgia), migraine, headache, toothache, burn, sunburn, snake bite (particularly venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post-operative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, sensory femoral pain, causalgia syndrome, post-herpetic neuralgia (post-herpetic neuralgias), trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, post-mastectomy pain syndrome, post-traumatic pain syndrome, cluster headache, migraine, peripheral neuropathy, and pain syndrome, Bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia (postherpetic neuralgia), trigeminal neuralgia, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Studis neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged canal neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
When using the compounds of the invention to treat, for example, the diseases or conditions described above, one skilled in the art can determine a therapeutically effective amount using established animal models. The dosage of the active ingredient administered to an average human (70kg)1-4 times per day may range from about 0.01mg to about 15,000 mg.
General synthetic method
Representative compounds of the invention can be synthesized according to the general synthetic methods described below, and the following schemes illustrate these methods. Because the schemes are illustrative, the invention is not limited by the chemical reactions and conditions described below. The person skilled in the art knows how to prepare the various starting materials used in the schemes.
Schemes 1 and 2 illustrate how the compounds of the present invention can be prepared. Both procedures were carried out in the same overall scheme. In stage 1, intermediate 1 is prepared by linking two phenyl rings with a linker-Y-. The linking group-Y-should be- (CH)2)nThe form-X-wherein X may be oxygen or sulfur and n may be 0 or 1. One benzene ring carries a group Q which is readily converted to a carboxylic acid amide. Examples of such Q groups are fluoro, bromo, iodo or trifluoromethanesulfonyloxy. One benzene ring must carry the carboxylic acid adjacent to the linker-Y-. The atom X may be bound to a phenyl ring having a Q group or a phenyl ring having no Q group. Schemes 1 and 2 differ in that the carboxylic acid of scheme 1 is on the phenyl ring with the Q group (1A and 1B), while the carboxylic acid functional group of scheme 2 is on the phenyl ring without the Q group (1C, D and E).
Scheme 1
Scheme 2
In stage 1, a linker-Y-is constructed between two monocyclic intermediates. In stage 1 of scheme 1, a bridge can be formed by nucleophilic aromatic displacement of the fluorine of intermediate int 2 (where Q' is an electron withdrawing group that is readily converted to a carboxylic acid, such as cyano or alkoxycarbonyl) with a phenolate, thiophenolate, benzylalkoxide or benzylthiolate int 1. Then hydrolyzed with an alkali metal hydroxide to obtain the 1A compound. To construct a bridge for type 1B compounds, the benzyl halide intermediate compound (int 5) was prepared by NBS bromination of the corresponding toluene (int 4). int 5 reacts with phenate or thiophenolate to give int 6. The 1B compound is prepared by hydrolysis of int 6 with an alkali metal hydroxide.
Scheme 1, stage 1
In stage 1 of scheme 2, to prepare the 1C compound, 2-benzo [ C ] furanone (int7) is reacted with a phenate or thiophenolate (int 8). To prepare the 1D compound, the bridge can be built up by nucleophilic aromatic displacement of the fluorine of intermediate int 9 with a phenolate or thiophenolate (int 8). Int 10 is then hydrolyzed with an alkali metal hydroxide to obtain the 1D compound. To construct the bridge for the type 1E compound, the benzyl bromide intermediate compound (int 12) is reacted with a phenate or thiophenolate (int 11) to obtain int 13. Int 13 is then hydrolyzed with an alkali metal hydroxide to obtain the 1E compound.
Scheme 2, stage 1
After stage 1, both procedures are the same. In stage 2, with, for example, BF3·Et2O-trifluoroacetic acid or polyphosphoric acid cycloacylation compound 1, which is converted to ketone 2. Alternatively, the cyclization is accomplished by converting the acid 1 to an acid chloride with, for example, thionyl chloride, followed by Friedel-Crafts ring closure in the presence of a Lewis acid such as aluminum chloride.
Alternatively, stages 1 and 2 may be reversed to obtain compound 2, ready to enter stage 3. For example, dimethyl ether (int 14) is cycloacylated with an appropriately substituted acid chloride to give ketone (int 16), which has been simultaneously demethylated under Friedel-Crafts reaction conditions. The bridge-Y-is then formed by nucleophilic aromatic displacement to give compound 2 ready for stage 3.
Scheme 3, stages 1 and 2
In stage 3, the Q functionality of compound 2 is converted to a carboxylic acid amide group to obtain the compound of formula 3. The conversion proceeds as follows: first converted to an ester by alkoxycarbonylation using, for example, carbon monoxide, an aliphatic alcohol, a trialkylamine and a palladium catalyst such as bis (triphenylphosphine) palladium (II) dichloride. The ester can be hydrolyzed to an acid and finally converted to a primary, secondary or tertiary amide by coupling reaction with ammonia, a primary or secondary amine. The conversion of the acid to the amide can be carried out as follows: first converted to an acid chloride with, for example, thionyl chloride, and then subjected to a Schotten-Baumann reaction with ammonia or an amine and an alkali metal hydroxide. Alternatively, the ester can be converted directly to the amide by reaction with aluminum dimethylamide. An alternative method of preparing compound 3 via an ester is to use a nitrile to convert the group Q to a carboxylic acid amide. With Zn (CN)2And palladium catalysts such as (Ph)3P)4The Pd treatment of compound 2 can synthesize nitrile, or the high temperature treatment of compound 2 with CuCN can synthesize nitrile. Hydrolysis of nitriles with alkali metal hydroxides yields the same acids as the acid derived from the ester.
To carry out stage 4, the 4-piperidylidene or 8-tropylidene function is attached to the tricyclic system (replacement of the ketone) to give a compound of type 4 (in the case of piperidylidene, the function is-A-is absent, whereas in the case of a tropylene group it represents- (CH)2)2-). The reaction can be carried out as follows: the McMurray condensation reaction of ketone 3 with 4-piperidone or 8-tropinone is carried out by means of a low-valent titanium reagent, such as a reagent obtained by the addition of titanium tetrachloride to zinc powder. Alternatively, a 4-piperidyl magnesium halide or an 8-thienylidene magnesium halide may be added to a ketone to obtain methanol. Such methanol is dehydrated with an acidic reagent (e.g., formic acid, sulfuric acid, or trifluoroacetic acid) to obtain a type 4 compound.
The operations of stages 3 and 4 may be performed in reverse order, if desired.
As shown in schemes 1 and 2, the nitrogen atom of compound 4 carries a group P. Such groups may be alkyl, alkenyl or aralkenyl groups, in which case they are the therapeutically useful products of the invention. The group P may also be an alkoxycarbonyl or aralkoxycarbonyl group. The latter group can be converted to secondary amine 5 as shown in stage 5. These conversions can be carried out with certain acidic reagents such as hydrogen bromide or trimethylsilyl iodide. The type 4 compound having a group liable to be cleaved (e.g., methyl, allyl or benzyl) can be converted to the above alkoxycarbonyl derivative by treating with an alkyl chloroformate (e.g., ethyl chloroformate or 1-chloroethyl chloroformate), thereby acting as a source of the compound 5.
Finally, the secondary amine 5 can be converted to any desired end product 6 of the invention as shown in stage 6. These transformations may be carried out by reductive alkylation using a carbonyl compound and a reducing agent, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. They may also be alkylated with alkyl, alkenyl or aralkyl halides and organic or inorganic bases.
Desired end products of the invention may include R4Chemical modification of (3). Such conversion may include dealkylation of the lower alkyl ether with a reagent (e.g., boron trihalide) to obtain the corresponding alcohol. R4Compounds that are halogen atoms may participate in transition metal element mediated coupling reactions, such as Suzuki, Stille or Negishi reactions.
bridge-A-is- (CH)2)2The compound of (a) is a chiral compound. They can be separated into their enantiomers by chiral stationary phase chromatography after stages 4, 5 or 6. Alternatively, basic compounds of types 4, 5 and 6 can be converted into diastereomeric salts by mixing with a chiral acid and then resolved into their enantiomers by fractional crystallization.
It is generally preferred that the corresponding product of each reaction step be separated from the other components of the reaction mixture and purified before use as starting material for a subsequent step. Typical separation methods include evaporation, extraction, precipitation and filtration. Typical purification methods include column chromatography (Still, w.c.et.al, j.org.chem.1978, 43, 2921), thin layer chromatography, crystallization and distillation. The structures of the final products, intermediates and starting materials were confirmed by spectroscopic, spectrometric and analytical methods, including Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS) and liquid chromatography (HPLC). In the description of the preparation of the compounds of the present invention, diethyl ether, tetrahydrofuran and dioxane are ether solvents of general examples; benzene, toluene, hexane and cyclohexane are typical hydrocarbon solvents, and dichloromethane and dichloroethane are representative halogenated hydrocarbon solvents. In case the product is isolated as an acid addition salt, the free base may be obtained by methods known to the person skilled in the art. In case the product is isolated as an acid addition salt, said salt may comprise 1 or several equivalents of said acid.
Enantiomers of the compounds of the invention can be separated by chiral HPLC.
Representative compounds of the present invention can be synthesized according to the general synthetic methods described above, and are more specifically exemplified in the following schemes. The chemical reactions and conditions of the present invention should not be construed as limiting the invention, as the schemes are illustrative. The person skilled in the art knows how to prepare the various starting materials used in the schemes.
Examples
Example A
Step 1
4-bromo-2-phenoxy-benzonitrile, 1a
Sodium hydride (12g, 300mmol) (60% by weight) was weighed into the flask and washed several times with hexane to wash off the oil. The hexane was decanted and discarded, and DMF was added to the flask. A solution of phenol (23.5g, 250mmol in 100mL DMF) in DMF was added dropwise to the NaH mixture, stirring at room temperature. To the phenate was added dropwise a solution of 4-bromo-2-fluoro-benzonitrile (50g, 250mmol in 100mL DMF). After the addition was complete, the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and poured into cooled 1N NaOH. A fine tan precipitate formed and was collected by vacuum filtration to give 62.04g (226mmol) of compound 1 a. MS m/z (MH)+)277。
Step 2
4-bromo-2-phenoxy-benzoic acid, 2a
4-bromo-2-phenoxy-benzonitrile (35.3g, 129mmol) was added to 130mL EtOH followed by 340mL 20% aqueous NaOH. The reaction was heated to reflux for 20 hours. The mixture was cooled to room temperature and poured into 6N HCl to form a precipitate. The solid was collected by vacuum filtration, dissolved in 3:1 THF-ether and washed with brine. The organic phase is dried over magnesium sulfate and concentrated. The solid was dried in a vacuum oven at 60 ℃ overnight to yield 35.1g (128mmol) of the desired product. MS m/z (MH)+)292。
Step 3
3-bromo-xanthen-9-one, 3a
To 4-bromo-2-phenoxy-benzoic acid (35.1g, 120mmol) in CH2Cl2(350mL) the suspension was added dropwise trifluoroacetic anhydride (20.3mL, 144mmol) at 0 deg.C and the reaction stirred for 15 min. Boron trifluoride etherate (1.46mL, 12) was then added dropwise.0 mmol). The reaction was stirred at room temperature for 1 hour to homogenize the reaction. After completion, the reaction was poured into 1N NaOH and the organic phase was dried over magnesium sulfate, filtered and concentrated to yield compound 3a (32.14g, 116 mmol). MS m/z (MH)+)275。
Step 4
9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 4a
A sample of compound 3a (20g, 72.2mmol) was dissolved in 2:1 MeOH/DMF solution (600 mL). To this solution triethylamine (40mL, 290mmol) was added and the solution degassed with argon. To this solution was added bis (triphenylphosphine) palladium (II) dichloride (2.0g, 2.85mmol), the reaction was transferred to a pressure vessel and charged with 150psi CO (g). The reaction was stirred at 90 ℃ for 24 hours. After completion, the reaction was cooled to 40 ℃ and CH was added2Cl2. The reaction was filtered while warming and evaporated to give the crude product. Recrystallization from ethanol gave 16.62g (65.4mmol) of Compound 4 a. MS m/z (MH)+)255。
Step 5
9-oxo-9H-xanthene-3-carboxylic acid, 5a
A sample of compound 4a 9-oxo-9H-xanthene-3-carboxylic acid methyl ester (16.6g, 65.3mmol) was suspended in 250mL of 3N NaOH and 250mL of EtOH and heated at reflux for 1 hour. EtOH was then evaporated and the reaction poured into 6N ice HCl and extracted with copious amounts of 1:1 THF/ether. The combined organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated to yield 13.35g of compound 5a (55.6mmol) after drying in a vacuum oven at 50 ℃ overnight.
Step 6
9-oxo-9H-xanthene-3-N, N-diethyl-carboxamide, 6a
A sample of Compound 5a (13.4g, 55.6mmol) was suspended in 220mLCH2Cl224.4mL of thionyl chloride (330mmol) was added. The mixture was refluxed for 6 hours, adding about 10mL thionyl chloride every hour until the reaction became homogeneous. However, the device is not suitable for use in a kitchenAfter this time thionyl chloride and solvent were removed in vacuo and the residue was taken up in 220mL CH2Cl2And (6) diluting. To the suspension was added 100mL ice-cold 1.5N NaOH, 100mL CH2Cl2And 17mL diethylamine (166 mmol). After stirring at room temperature for 15 min, the phases were separated and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to give compound 6a (14.7g, 49.8 mmol). MS m/z (MH)+)296。
9-oxo-9H-xanthene-3-N-ethyl-carboxamide, 7a
Compound 6a was converted to its monoethylamide according to step 6, replacing diethylamine with ethylamine. MS m/z (MH)+)267.9。
Step 7
3- (3-Diethylcarbamoyl-xanthen-9-ylidene) -8-aza-bicyclo [3.2.1] octane-8-carboxylic acid ethyl ester, 8a
To a suspension of zinc metal powder (24.2g, 370mmol) in THF (325mL) was added dropwise titanium tetrachloride (IV) (20.3mL, 180mmol) at 5 ℃ under argon. The reaction was then refluxed for 2 hours. Heating was removed and a solution of compound 6a (13.69, 46mmol) and N-ethoxycarbonylnortropinone (9.21g, 46mmol) in 100mL THF was added dropwise. The reaction was refluxed for 2 hours. The reaction was then cooled and ice water containing excess potassium carbonate was added. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 22g of gum. The crude product was purified by chromatography with 1:1 EtOAc/hexane to afford 17g (36.9mmol) of compound 8 a. MS m/z (MH)+)461.8。
9- (8-phenylethyl) -8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3-N-ethyl-carboxamide, 9a
The title compound was synthesized according to step 7, substituting compound 7a for compound 6a and N-phenethyl-4-tropinone for ethoxycarbonylnortropinone. MS M/z 465.1(M + 1);1HNMR 300MHz(DMSO-d6)δ 1.1(t，3H)，1.3(m，2H)，2.1(m，2H)，2.5(q，2H)，3.0-3.4(m，8H)，4.05(m，2H)，7.1-7.7(m，11H)，8.5(m，1H)。
step 8
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 10a
A sample of compound 8a (16.0g, 34.8mmol) was dissolved in 35mL of acetic acid, 100mL of 30% HBr in acetic acid was added to the reaction under argon, and then heated on a steam bath for 1 hour. The reaction was cooled, ice cold NaOH added and CH added2Cl2And (4) extracting. The combined organics were washed with brine and dried over potassium carbonate. Evaporation of the solvent gave 12g of crude compound 10a, which was purified by column chromatography over 7% 2N NH3Methanol/93% CH2Cl2Purification gave 7.66g (19.7mmol) of Compound 10 a. MS M/z 389.3(M + 1);1H NMR 300MHz(CDCl3)δ1.1-1.4(m，6H)，1.7(m，2H)，2.7-3.0(m，4H)，3.4(br s，4H)，3.5-3.7(m，4H)，7.0-7.3(m，7H)。
9- (8-methyl-8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 11a
Compound 6a was converted to the title compound according to step 7, substituting tropinone for N-ethoxycarbonyl nortropinone. MS M/z 403.2(M + 1);1H NMR 300MHz(CDCl3)δ1.2(br s，6H)，1.9(m，2H)，2.5(s，3H)，2.8(m，2H)，3.1(m，2H)，3.3(m，2H)，3.4(br s，2H)，3.6(m，4H)，7.0-7.3(m，7H)。
step 9
9- (8-furan-3-ylmethyl-8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 12a
To dissolve in 20mL CH2Cl2A sample of compound 10a (0.65g, 1.7mmol) was charged with sodium triacetoxyborohydride (0.53g, 2.5mmol) and 3-furfural (0.17mL, 2.0 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was quenched with 10mL CH2Cl2Diluting, washing with 1N NaOH. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using 5% 0.5M NH3methanol/CH2Cl2Elution gave compound 12a (0.25g, 0.53 mmol). MS M/z 469.0(M + 1);1H NMR 300MHz(DMSO-d6)δ 1.1(br s，6H)，1.35(m，2H)，2.1(m，2H)，2.5(m，2H)，3.0(m，2H)，3.2(m，2H)，3.5(m，2H)，3.85(br s，2H)，4.05(d，2H)，6.8(s，1H)，7.1-7.5(m，7H)，7.8(s，1H)，7.9(s，1H)。
step 10
9- [8- (methylthio-ethyl) -8-aza-bicyclo [3.2.1] oct-3-ylidene ] -9H-xanthene-3-N, N-diethyl-carboxamide, 13a
To a 20mL aqueous solution of p-toluenesulfonic acid monohydrate (1.4g, 7.5mmol) was added (methylthio) acetaldehyde diethyl acetal (1.0mL, 7.5mmol) dissolved in 15mL CH2Cl2The solution was stirred and the reaction was stirred vigorously for 4 hours. Separating the aqueous phase, adding NaCl until saturation, and then adding CH2Cl2And (4) extracting. The organic extracts were washed successively with saturated aqueous sodium bicarbonate and brine. The extract was dried over magnesium sulfate and filtered. To the filtrate were added compound 10a (0.060g, 0.15mmol) and sodium triacetoxyborohydride (0.040g, 0.19mmol), and the reaction was stirred at room temperature overnight. The reaction was washed with 1M NaOH and the organic phase was dried over magnesium sulfate. The solution was concentrated and purified by flash chromatography on silica gel. The product was purified over 10% 0.5M NH3methanol/CH2Cl2Eluting and concentrating. Trituration with chloroform and diethyl ether afforded the pure compound 13a (0.040g, 0.086 mmol). MS M/z 463.8(M + 1).
Step 11
9- (8-allyl-8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 14a
To a sample (0.37g, 0.95mmol) of compound 10a in 6mL acetonitrile was added potassium carbonate (0.53g, 3.81mmol) and allyl bromide (80. mu.L, 0.95 mmol). The mixture was stirred at room temperature for 20 hours. Diluting the reactant with water and then using CH2Cl2And (4) extracting. The combined organic extracts were dried over magnesium sulfate and concentrated. Purifying the product by silica gel flash column chromatography with 10% 0.5MNH3methanol/CH2Cl2Elution gave 0.11g (0.25mmol) of compound 14 a. The product was converted to its HCl salt with hydrogen chloride in ether. MS M/z 429.0(M + 1);1H NMR300MHz(CDCl3)δ 1.1-1.4(m，6H)，1.7(m，2H)，2.3(m，2H)，3.1(m，2H)，3.4(m，2H)，3.6(m，4H)，4.0(m，2H)，4.4(m，2H)，4.7(m，2H)，5.5-5.9(m，4H)，6.3(m，2H)，7.1-7.4(m，7H)。
9- [8- (2-methoxy-ethyl) -8-aza-bicyclo [3.2.1] oct-3-ylidene ] -9H-xanthene-3-N, N-diethyl-carboxamide, 15a
Compound 10a was converted to the title compound 15a according to step 11, substituting 3 equivalents of 2-bromoethyl methyl ether for allyl bromide. The product was converted to its HCl salt with hydrogen chloride in ether. MS M/z 447.4(M + 1);1H NMR 300MHz(CDCl3)δ 1.0-1.2(m，6H)，1.3(m，2H)，2.0(m，2H)，2.95(m，2H)，3.1-3.2(m，2H)，3.3(s，3H)，3.4(m，2H)，3.6(m，4H)，3.8(m，2H)，4.0(m，2H)，7.1-7.4(m，7H)。
example B
9-piperidin-4-ylidene-9H-xanthene-3-N, N-diethyl-carboxamide, fumarate 1b
According to step 7, compound 1b was synthesized in 1 step with compound 6a and the Boc-protecting group was removed simultaneously, replacing N-ethoxycarbonylnortropanone with N-Boc-piperidone. Purifying by silica gel flash chromatography. The product was passed through 10% 2N NH3methanol/CH2Cl2And (4) eluting. Fumarate is prepared from 2-PrOH. MS m/z (MH)+)363.2；1H NMR 300MHz(DMSO-d6)δ 1.1(br s，6H)，2.8(m，4H)，2.95(m，4H)，3.3-3.4(br s，4H)，6.4(s，2H)，7.1-7.5(m，7H)。
9-piperidin-4-ylidene-9H-xanthene-3-N-ethyl-carboxamide, 2b
The title compound 2b was synthesized according to step 7, substituting compound 7a for compound 6a and N-Boc-piperidone for N-ethoxycarbonylnortropinone. MS m/z (MH)+)334.8。
9- (1-furan-3-ylmethyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, hydrochloride salt 3b
Compound 1b was converted to the title compound 3b according to step 9. The crude product was purified by flash chromatography on silica gel with 3% methanol/CH2Cl2Eluting to obtain the product. With Et2O/HCl to make the hydrochloride salt. MS m/z (MH)+)363.2；1H NMR 300MHz(DMSO-d6)δ1.2(br d，6H)，2.4(m，2H)，3.3-3.6(m，10H)，4.0(s，2H)，6.8(s，1H)7.1-7.3(m，7H)，7.5(s，1H)，7.7(s，1H)，13.1(s，1H)。
Step 12
9- (1-amidino-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 4b
A solution of compound 2b (0.025g, 0.069mmol) and c (0.015g, 0.36mmol) in 4mL of water was refluxed. After 3 hours, the reaction was 50% complete. Cyanamide was added and the mixture was heated for 24 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude material was purified by HPLC (15-70% acetonitrile/water/0.1% TFA). The TFA salt of Compound 4b (1.4mg, 3.5. mu. mol) was isolated. MS M/z405.1(M + 1);1H NMR 300MHz(DMSO-d6)δ 1.1(brs，6H)，2.8(m，4H)，3.2(m，2H)，3.5(m，6H)，7.1-7.5(m，7H)。
9-(R3-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 5b-8b
According to step 9, the following compound was prepared, replacing 3-furfural with the appropriate aldehyde:
ex # aldehyde R MSm/z(MH)
5b 2-Pyridinecarboxaldehyde pyridin-2-ylmethyl 454.5
6b salicylaldehyde 2-hydroxybenzyl 469.2
7b formalin methyl 377.26
8b Phenylacetaldehyde phenethyl 467.33
9- (1-prop-2-ynyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide hydrochloride, 9b
Compound 1b12 was refluxed in acetonitrile according to step 11, substituting propargyl bromide for allyl bromide. The crude product was purified by flash column chromatography on silica gel using 3% methanol/CH2Cl2Eluted and then converted to the hydrochloride salt with a solution of hydrogen chloride in ether. MS m/z (MH)+)401.4；1H NMR 300MHz(CDCl3)δ 1.2(br d，6H)，2.6(s，1H)，2.9(m，2H)3.1-3.6(m，10H)，3.9(s，2H)，7.15-7.3(m，7H)，13.5(s，1H)。
9- [1- (2-hydroxy-ethyl) -piperidin-4-ylidene ] -9H-xanthene-3-N, N-diethyl-carboxamide, 10b
The title compound was prepared according to step 11 using compound 1b, substituting 2-iodo-ethanol for allyl bromide. MS m/z (MH)+)407.0；1H NMR 300MHz(CDCl3)δ 1.2(br d，6H)，1.7(m，2H)，2.8(m，2H)，3.1(m，2H)，3.2-3.8(m，8H)，4.0(m，2H)，4.8(m，1H)，7.15-7.3(m，7H)。
Step 13
9- (1-Sulfoaldehyde-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 11b
A sample of compound 1b (0.77g, 2.1mmol) was refluxed with N, N-dimethyl-thiocarboxamide (0.36mL, 4.24mmol) in 2mL toluene for 5 hours. The crude product was purified by flash column chromatography on silica gel eluting with 45% ethyl acetate/hexane to give 0.66g (1.6mmol) of compound 11 b. By passing1Two rotamers were observed by H-NMR. MS m/z (MH)+)406.9。1HNMR 300MHz(CDCl3)δ 1.2(br d，6H)，2.9(m，3H)，3.3(m，2H)3.4-3.7(m，3H)，3.9(m，2H)，7.1-7.4(m，7H)，9.3(s，1H)。
Step 14
9- (1-Phenyliminomethyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 12b
A sample (0.1g, 0.25mmol) of compound 11b in 1mL of chloroform was added to the pressure tube and treated with methyl tosylate (0.037mL, 0.25 mmol). The reaction was heated for 1 hour in a steam bath. The reaction was then cooled to room temperature, aniline (0.023mL, 0.25mmol) was added, and the reaction was heated in a steam bath for 2 hours. After 2 hours, the reaction was cooled, washed with 1N NaOH and evaporated. The crude material was purified by flash chromatography on silica gel with 5% methanol/CH2Cl2The product was eluted and then converted to the hydrochloride salt with hydrogen chloride in ether (0.004g, 0.009 mmol). MS m/z (MH)+)466.3。1H NMR 300MHz(CDCl3)δ 1.2(br s，6H)，3.1(m，4H)，3.3(d，2H)3.4-3.8(m，4H)，4.3(s，2H)，)7.1-7.4(m，10H)，7.7(s，2H)，8.0(s，1H)，13.6(s，1H)。
9- (1-allyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 13b
Compound 1b was converted to the title compound 13b according to step 11, substituting compound 1b for compound 10 a. MS m/z (MH)+)403.3。1H NMR 300MHz(CDCl3)δ1.2(br d，6H)，2.5(m，2H)，3.1-3.7(m，12H)，5.4(m，2H)，6.2(m，1H)，7.1-7.3(m，7H)。
Example C
Step 15
2- (3-bromo-phenoxymethyl) -benzoic acid, 1c
A solution of m-bromo-phenol (9.4mL, 0.100mmol) in 25mL THF was added dropwise to sodium hydride (4.0g, 0.10mmol) which had been washed free of oil with hexane. When bubbling was stopped, the solvent was evaporated and 2-benzo [ c ] furanone (13g, 0.1mmol) was added. The oil bath heated the reaction to 200 ℃ for 1 hour. The reaction was cooled, diluted with water, washed with ether and acidified with HCl. The solid was collected and air-dried to obtain 22.3g (72.9mmol) of Compound 1 c. MS M/z305.31 (M-H).
3-bromo-6H-dibenzo [ b, e ] oxaheptin-11-one, 2c
According to modified step 3, compound 1c (22.3g, 72.6mmol) was converted to the title compound 2c (15.2g, 52.3 mmol). MS m/z (MH)+)289。
11-oxo-6, 11-dihydro-dibenzo [ b, e ] oxepin-3-carboxylic acid methyl ester, 3c
A sample (5.0g, 17mmol) of compound 2c was converted to the desired methyl ester (3.0g, 11.2mmol) according to modified step 4.
11-oxo-6, 11-dihydro-dibenzo [ b, e ] oxepin-3-carboxylic acid, 4c
A sample (6.0g, 22mmol) of compound 3c was converted to the corresponding carboxylic acid (5.5g, 21.6mmol) according to modified step 5.
11-oxo-6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N, N-diethyl-carboxamide, 5c
A sample of compound 4c (5.5g, 21.6mmol) was converted to its corresponding diethylamide (4.28g, 13.8mmol) according to modified step 6.
11- (1-methyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N, N-diethyl-carboxamide, 0.5 fumarate, 6c
A sample of compound 5c was converted to the title compound according to step 7, substituting compound 5c (3.85g, 12.5mmol) for compound 6a and N-methyl-piperidone for N-ethoxycarbonylnortropinone. The reaction yielded 2.5g (6.4mmol) of Compound 6 c. MS m/z (MH)+)391.28；1H NMR 300MHz(DMSO)δ 1.0(br s，6H)，2.5(m，2H)，3.1-3.7(m，12H)，5.4(m，2H)，6.2(m，1H)，7.1-7.3(m，7H)。
Step 16
4- (3-Diethylcarbamoyl-6H-dibenzo [ b, e ] oxaheptin-11-ylidene) -piperidine-1-carboxylic acid 2, 2, 2-trichloro-ethyl ester, 7c
A sample of compound 6c (2.58g, 6.41mmol), trichloroethyl chloroformate (1.33mL, 9.7mmol) and potassium carbonate (3.34g, 24.2mmol) were refluxed in benzene for 3.5 hours. 4mL of trichloroethyl chloroformate was added and the reaction refluxed for 1 hour. Dimethylaminopropylamine (5mL) was added and the reaction was complete. The mixture was extracted with 2N HCl, washed with brine, the organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was recrystallized from acetone/hexane to obtain 2g (3.6mmol) of compound 7 c. MS m/z (MH)+)551.31。
Step 17
11-piperidin-4-ylidene-6, 11-dihydro-dibenzo [ b, e ] oxaheptin-11-ylidene-piperidine-1-N, N-diethyl-carboxamide, 8c
A sample of compound 7c (1.75g, 3.17mmol) and zinc (1.51g, 23.1mmol) were stirred at room temperature in acetic acid (17.5 mL). The resulting solid was collected by filtration and washed with acetic acid. Concentrating the filtrateIn NaOH and CH2Cl2Are distributed among the devices. The organic phase was collected, dried over potassium carbonate and evaporated. The crude product was recrystallized from acetonitrile to yield compound 8c (1.2g, 3.2 mmol). MS m/z (MH)+)377.28；1H NMR 300MHz(CDCl3)δ 1.2(br d，6H)，2.3(m，2H)，2.4-3.1(m，6H)3.4(br d，4H)，4.8(d，1H)，5.8(d，1H)6.8(d，1H)，7.0(m，1H)，7.1(d，1H)，7.2-7.4(m，4H)。
11- (1-benzo [1, 3] dioxol-5-ylmethyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N, N-diethyl-carboxamide hydrochloride, 9c
According to step 9, with benzo [1, 3]]The title compound was prepared by substituting dioxole-5-carbaldehyde for 3-furfural and compound 8c for compound 10 a. The crude product was converted to its HCl salt with hydrogen chloride in ether. MS m/z (MH)+)511.34；1H NMR 300MHz(CDCl3)δ 1.2(br d，6H)，2.3-2.7(m，12H)，2.4-3.1(m，6H)，4.05(s，2H)，4.8(d，1H)，5.7(d，1H)6.8-7.4(m，10H)。
11- (1-Phenylethylpiperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N, N-diethyl-carboxamide hydrochloride 10c
Compound 8c was converted to the title compound according to step 9, substituting phenylacetaldehyde for 3-furfural and compound 8c for compound 10 a. The crude product was converted to its HCl salt with hydrogen chloride in ether. MS m/z (MH)+)481.35；1H NMR 300MHz(CDCl3)δ1.2(br d，6H)，2.3-2.7(m，12H)，2.4-3.7(m，16H)，4.8(d，1H)，5.7(d，1H)，6.8-7.4(m，12H)。
11-oxo-6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N-ethyl-carboxamide, 11c
Compound 4c was converted to its monoethylamide according to modified step 6, substituting ethylamine for diethylamine.
11- (8-phenethyl-8-aza-bicyclo [3.2.1] oct-3-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N-ethyl-carboxamide, 12c
A sample of compound 11c was converted to the title compound according to step 7, substituting compound 11c for compound 6a and N-phenethyl-4-tropinone for N-ethoxycarbonylnortropinone. The title compound was isolated as its TFA salt. MS M/z 479.1(M + 1);1H NMR 300MHz(DMSO-d6)δ 1.1(t，3H)，1.35(m，1H)，1.8(m，1H)，2.2(m，2H)，2.5(m，2H)，2.8(dd，2H)，3.1(m，2H)，3.3(m，2H)，3.75(m，2H)，4.1(m，2H)，5.0(m，1H)，5.7(m，1H)，7.0-7.7(m，11H)，8.4(7，1H)，10.0(br s，1H)。
11- (1-allyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N, N-diethyl-carboxamide, 13c
The title compound was prepared according to step 11 substituting compound 8c for compound 10 a. MSm/z (MH)+)417.33；1H NMR 300MHz(CDCl3)δ 1.2(br d，6H)，2.4(m，1H)，2.6(n，1H)，2.8(m，2H)，3.0-3.8(m，10H)，4.8(d，1H)，5.3-5.7(m，3H)，6.2(m，1H)，6.8-7.4(m，7H)。
Example D (Grignard method)
Step 18
3-bromo-11- (1-methyl-piperidin-4-yl) -6, 11-dihydro-dibenzo [ b, e ] oxaheptin-11-ol, 1d
Basification of a sample of 4-chloro-1-methyl-piperidine hydrochloride with KOH followed by CH2Cl2And (4) extracting. The organic phase is dried over magnesium sulfate and concentrated in vacuo. Crude product with CaH2Distilling at 50 deg.C under 1 mmHg.
Magnesium turnings (3.42g, 143mmol) were suspended in 15mL dry THF under nitrogen. To the direction ofThis liquid is added to CH2Br2(1.25mL, 14.5mmol) a vigorous reaction was observed. The reaction was heated to reflux and 4-chloro-1-methyl-piperidine (21mL, 128mmol) was added. The reaction was refluxed for 1 hour. The reaction was allowed to cool and the supernatant was cannulated at room temperature to a stirred solution of compound 2c (8g, 128mmol) in THF. The slurry was washed with 2X 20mL THF and the supernatant transferred. At this point, all of the starting material ketone has been consumed. Saturated sodium bicarbonate solution was added to the reaction, and the mixture was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. The crude product, compound 1d, was used without further purification. MS m/z (MH)+)388.14。
Step 19
4- (3-bromo-6H-dibenzo [ b, e ] oxaheptin-11-ylidene) -1-methyl-piperidine, 2d
A solution of compound 1d (9.53g, 24.6mmol) in 50mL of formic acid was heated at reflux for 5 hours. The reaction was concentrated, diluted with ethyl acetate and washed successively with 3N HCl and 3N KOH to give compound 2d (9.0 g). MS m/z (MH)+)370.0。
11- (1-methyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-carboxylic acid methyl ester, 3d
The title compound 3d was synthesized according to modified step 4. MS m/z (MH)+)350.2。
11- (1-methyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-carboxylic acid, 4d
The title compound 4d was synthesized according to modified step 5 using compound 3 d.
11- (1-methyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N-ethyl-carboxamide, 5d
The title compound was synthesized according to modified step 6, substituting ethylamine for diethylamine and compound 4 d. MS m/z (MH)+)363.0。
4- (3-ethylcarbamoyl-6H-dibenzo [ b, e ] oxaheptin-11-ylidene) -piperidine-1-carboxylic acid 2, 2, 2-trichloro-ethyl ester, 6d
The title compound was synthesized according to modified step 16, using compound 5 d. MS m/z (MH)+)523.0。
11-piperidin-4-ylidene-6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N-ethyl-carboxamide, 7d
Compound 6d was converted to the title compound according to modified step 17. MS m/z (MH)+)349.0。
Compound 7d is converted according to step 9, replacing 3-furfural with the appropriate aldehyde, to the following compound:
ex aldehyde R MS m/z# (MH)
8d 4-methyl-but-3-enal 2-methyl-but-2-ene 417.1
9d thiophene-2-carbaldehyde thiophen-2-ylmethyl 445.1
10d 2-methyl-propenal 2-methyl-allyl 403.1
11d Cyclopropanecarboxaldehyde cyclopropylmethyl 403.1
12d 2-Pyridinecarboxaldehyde pyridin-2-ylmethyl 440.1
13d 1H-imidazole-4-carbaldehyde 1H-imidazol-4-ylmethyl 429.1
14d 4-hydroxy-3-methoxy-benzaldehyde 4-hydroxy-3-methoxy-phenylmethyl 485.1
15d phenyl-acetaldehyde phenethyl 453.2
11- (1-allyl-piperidin-4-ylidene) -6, 11-dihydro-dibenzo [ b, e ] oxepin-3-N-ethyl-carboxamide, 16d
The title compound 16d was prepared according to step 11, substituting compound 7d for compound 10 a. MS m/z (MH)+)389.1。
Example E (McMurry, bromide)
4- (3-bromo-xanthen-9-ylidene) -1-methyl-piperidine, 1e
Compound 3a was converted to the title compound 1e by substituting compound 3a for compound 6a and N-methyl-piperidone for N-ethoxycarbonylnortropinone according to modified step 7. MS m/z (MH)+)356。
9- (1-methyl-piperidin-4-ylidene) -9H-xanthene-3-carboxylic acid methyl ester, 2e
Compound 1e was converted to its methyl ester 2e according to modified step 4. MS m/z (MH)+)336.1。
9- (1-methyl-piperidin-4-ylidene) -9H-xanthene-3-carboxylic acid, 3e
Compound 2e is converted to the corresponding carboxylic acid compound 3e according to modified step 5. MS m/z (MH)+)321.1。
9- (1-methyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 7b
Compound 3e was converted to the title compound, diethylamide compound 7b, according to modified step 6.
Example F
N- [4- (5-bromo-2-cyano-phenoxy) -phenyl ] -acetamide, 1f
Compound 1f was synthesized according to the synthesis described for compound 1a in step 1, substituting phenol with N- (4-hydroxyphenyl) -acetamide.
2- (4-amino-phenoxy) -4-bromo-benzoic acid, 2f
The title compound 2f was synthesized in quantitative yield according to the procedure described for step 2, substituting compound 1f for compound 1 a. CIMS M/z 307(M + 1).
Step 20
2- (4-acetylamino-phenoxy) -4-bromo-benzoic acid, 3f
Compound 2f (500mg, 1.6mmol) was treated with acetyl chloride (0.15mL, 2.08mmol) and triethylamine (0.22mL, 2.08mmol) in 10mL of THF. After stirring for 2.5 hours, the solid was collected. The filtrate was evaporated in vacuo to yield 0.48g of Compound 3 f. MS M/z 331(M + 1).
N- (6-bromo-9-oxo-9H-xanthen-2-yl) -acetamide, 4f
The title compound was synthesized according to modified step 3, substituting compound 3f for compound 2 a.
7-Acetylamino-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 5f
The title compound was synthesized according to modified step 4, substituting compound 4f for compound 3 a.
7-Acetylamino-9-oxo-9H-xanthene-3-carboxylic acid, 6f
The title compound was synthesized according to modified step 5, substituting compound 5f for compound 4 a.
Step 21
7-acetylamino-9-oxo-9H-xanthene-3-N, N-diethyl-carboxamide, 7f
Compound 6f (2g, 6.7mmol) was treated with HATU (2.5g, 6.7mmol), diethylamine (0.2mL, 8.7mmol) and diisopropylethylamine (4.75mL, 26.8mmol) in 35mL of DMF. After stirring for 3 hours, the reaction was poured into water and the solid was collected to give the product compound 7 f. The filtrate was extracted with ether/THF (1: 1). The combined organic phases were washed with water, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and combined with the above solid to give a total of 1.5g of compound 7 f. MS M/z 353(M + 1).
7-acetylamino-9-hydroxy-9- (1-methyl-piperidin-4-yl) -9H-xanthene-3-N, N-diethyl-carboxamide, 8f
The title compound was synthesized according to modified step 18, substituting compound 7f for compound 2 c.
Step 22
7-acetylamino-9- (1-methyl-piperidin-4-ylidene) -9H-xanthene-3-N, N-diethyl-carboxamide, 9f
Compound 8f (0.3g, 0.66mmol) and trifluoromethanesulfonic acid (2mL) were added to the flask. After heating in a steam bath for 1 hour, the reaction was poured into 3N NaOH and ice. Passing the aqueous solution through CH2Cl2Extraction and drying with sodium sulfate. The solvent was evaporated in vacuo and the residue purified by flash column (silica; 90:10:1 CH)2Cl2:CH3OH:NH4OH) to yield 0.01g of compound 9 f. MSm/z 435(M + 1).
7-acetylamino-9-piperidin-4-ylidene-9H-xanthene-3-N, N-diethyl-carboxamide, 10f
Compound 10f was synthesized according to modified step 7, substituting compound 7f for compound 6a and N-Boc-piperidone for N-ethoxycarbonylnortropinone. MS M/z 420.3(M + 1).
Example G
Step 23
9-piperidin-4-yl-9H-xanthene-3-N, N-diethyl-carboxamide, hydrochloride salt
A sample of hydrochloric acid of Compound 1b (0.19g, 0.52mmol) was dissolved in 3mL of CHCl3Treated with iodotrimethylsilane (0.15mL), the pressure tube was sealed and heated in a steam bath for 2 hours. The pressure tube was opened after cooling the mixture. Further, iodotrimethylsilane (0.15mL) was added, the pressure tube was sealed, and the vessel was heated via a steam bath for 3 hours. After cooling the reaction 3ml of MeOH was added. Reaction mixture in CH2Cl2And the NaOH solution. The organic layer was washed with sodium dithionite solution. The solvent was evaporated and the residue was purified by flash chromatography (90% CH)2Cl2：10％2NNH3MeOH) to obtain the title compound. With Et2O/HCl to make the hydrochloride salt. MS m/z (MH)+)364.9；1HNMR 300MHz(CDCl3)δ 1.2(br s，6H)，1.5(m，2H)，1.7(m，2H)，2.8(m，2H)，3.2-3.4(m，4H)，3.5(br s，2H)，3.7(d，1H)，7.1-7.3(m，7H)。
9- (1-methylpiperidin-4-yl) -9H-xanthene-3-N, N-diethyl-carboxamide, hydrochloride
The title compound was obtained according to the procedure of step 23, substituting the hydrochloride salt of compound 7b for the hydrochloride salt of compound 1 b. MS m/z (MH)+)364.9；1H NMR 300MHz(CDCl3)δ1.2(br s，6H)，1.4(m，1H)，1.7(m，2H)，2.05(q，2H)，2.7(s，3H)，3.1-3.5(m，6H)，3.7(d，1H)，7.1-7.3(m，7H)，12.2(s，1H)。
Example H
Step 24
4-bromo-2-phenylsulfanyl-benzonitrile for 1h
Sodium hydride (2.40g, 60mmol) (60% by weight) was weighed into the flask and washed with several hexanes. The hexane was decanted and discarded, and 20mL of DMF was added to the flask. A solution of thiophenol in DMF (5.1mL, 50mmol in 50mL DMF) was added dropwise to the NaH mixture, which was stirred at room temperature. To 4-bromo-2-fluoro-benzonitrile (10.0g, 50mmol in 40mL of DMF) was added dropwise the benzenethiolate (benzanethiopenoxide) (above) over 30 minutes. After the addition was complete, the reaction was stirred at room temperature for 20 minutes. The mixture was then poured into cold 1N NaOH. A precipitate formed and was collected by vacuum filtration to yield 14.0g (48.4mmol) of compound for 1 h.
4-bromo-2-phenylsulfanyl-benzoic acid, 2h
Compound 1h was substituted for compound 1a according to step 2 to give compound 2 h.
3-bromo-thioxanthen-9-one, 3h
Compound 2h was substituted for compound 2a according to step 3 to give compound 3 h.
9-oxo-9H-thioxanthene-3-carboxylic acid methyl ester for 4H
Compound 3a was replaced with compound 3h according to step 4 to give compound 4 h.
9-oxo-9H-thioxanthene-3-carboxylic acid, 5H
Compound 4h was substituted for compound 4a according to step 5 to give compound 5 h.
9-oxo-9H-thioxanthene-3-N, N-diethyl-carboxamide, 6H
Compound 5h was substituted for compound 5a according to step 6 to give compound 6 h.
9-oxo-9H-thioxanthene-3-N-ethyl-carboxamide, 7H
Compound 7h was obtained according to step 6, substituting ethylamine for diethylamine and compound 5h for compound 5 a.
3- (3-Diethylcarbamoyl-thioxanthen-9-ylidene) -8-aza-bicyclo [3.2.1] octane-8-carboxylic acid ethyl ester, 8h
Compound 8c was obtained according to the procedure described for step 7, substituting compound 6a with compound 6 h. MS m/z 477.1 (MH)+)。
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-thioxanthene-3-N, N-diethyl-carboxamide, 9H
Compound 8h was substituted for compound 8a according to step 8 to give compound 9 h. The product is then converted to its fumarate salt. MS m/z (MH)+)＝405.4。1H NMR 300MHz(CDCl3)δ 1.05-1.3(m，6H)，1.40(m，2H)，1.9(m，2H)，2.75(m，2H)，3.1(m，2H)，3.3(m，2H)，3.6(m，2H)，3.90(br s，2H)，7.2(m，5H)，7.5(m，2H)。
9- (8-benzo [1, 3] dioxol-5-ylmethyl-8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-thioxanthene-3-N, N-diethyl-carboxamide, 10H
According to step 9, compound 9h was used instead of compound 10a and piperonal was used instead of 3-furfural to obtain compound 10 h. The product is then converted to its fumarate salt. MS m/z (MH)+) 439.4. Fumarate salt:1H NMR 300MHz(DMSO-d6)δ 0.9-1.2(m，8H)，1.90(m，2H)，2.55(m，2H)，2.95(m，2H)，3.19(m，2H)，3.4(m，4H)，3.80(br s，2H)，6.05(s，2H)，6.65(s，2H)，6.9(m，2H)，7.2(s，1H)，7.35(m，5H)，7.6(m，2H)。
9-(R3-8-aza-bicyclo [3.2.1]Oct-3-ylidene) -9H-thioxanthene-3-N, N-diethyl-carboxamide, 11H-12H
The following compounds were prepared according to step 9, substituting the appropriate aldehyde for 3-furaldehyde:
9- [8- (2 hydroxy-ethyl) -8-aza-bicyclo [3.2.1] oct-3-ylidene ] -9H-thioxanthene-3-N, N-diethyl-carboxamide, 13H
Compound 13h was obtained according to step 11, substituting compound 9h for compound 10a and 2-iodoethanol for allyl bromide. MS m/z (MH)+)＝449.2。1H NMR 300MHz(CDCl3)δ 1.05-1.4(m，8H)，1.8(m，2H)，2.6-2.8(m，4H)，3.0(m，2H)，3.5(m，4H)，3.80(m，2H)，4.8(br s，1H)，7.2(m，5H)，7.5(m，2H)。
Step 25
The (+) and (-) enantiomers of compound 24 in table 1 herein (compounds 52 and 53) were isolated as follows: hexane/methanol/ethanol (50/25/25) was used as eluent on a preparative chiralpak AD column (500g, 20 micron material, 5X 41 cm). The analyte was monitored at a wavelength of 220 nm. For the analytical procedure, the same column material (chiralpak AD, 4, 6 × 50mm) and the same solvent were used, but in a ratio of 80/10/10.
The (+) and (-) enantiomers of compound 54 in table 1 herein (compounds 55 and 56) were isolated as follows: heptane/ethanol (85/15) was used as eluent on a preparative Chiralpak AD column (500g, 20 micron material, 5 × 41 cm). The analyte was monitored at a wavelength of 220 nm.
Example I
Step 26
(2, 4-difluoro-phenyl) - (2-hydroxy-4-methoxy-phenyl) -methanone, 3i
Aluminum chloride (2.03g, 15.2mmol) was added portionwise at 0 deg.C to a solution of 1, 3-dimethoxybenzene (1.86mL, 15.2mmol) and 2, 4-difluorobenzoyl chloride (1.86mL, 15.2mmol) in 1, 2-dichloroethane. The mixture was allowed to warm to room temperature over 3 hours and then heated at reflux for 6 hours. The resulting mixture was allowed to cool to room temperature and then poured into a mixture of ice (about 100g) and concentrated hydrochloric acid (about 20 mL). The organic layer was separated. The aqueous solution was stirred at room temperature overnight and extracted with dichloromethane. The organic layer was washed with an aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford the crude product. Purification of a portion of the product by flash chromatography on silica gel with a gradient of 1% to 10% EtOAc/heptane as eluent gave the title compound 3i (1.8 g).
MS：m/z 264.9(MH+)。1H NMR(CDCl3): δ 3.90(s, 3H), 6.42(dd, 1H, J ═ 9.0 and 2.5Hz), 6.50(d, 1H, J ═ 2.5Hz), 6.91-7.04(m, 2H), 7.27-7.29(m, 1H), 7.44-7.50(m, 1H) and 12.44(s, 1H).
Step 27
3-fluoro-6-methoxy-xanthen-9-one, 4i
A mixture of potassium carbonate (2.13g, 15.4mmol) and (2, 4-difluoro-phenyl) - (2-hydroxy-4-methoxy-phenyl) -methanone (3.4g, 12.9mmol) in N, N-dimethylformamide (50mL) was heated at 100 ℃ for 2 hours. The mixture was cooled and poured into water (about 150 mL). The solid was collected by filtration, washed with water and dried in vacuo to give the title compound (2.8g), which was used directly in the next step without purification. MS: m/z 244.9 (MH)+)。1H NMR(CDCl3)：δ3.94(s，1H)，6.88(d，1H，J＝2.4Hz)，6.96(dd，1H，J＝2.4 &8.9Hz), 7.07(m, 2H), 8.24(d, 1H, 8.9Hz) and 8.34(dd, 1H, J ═ 6.5& 8.8Hz)。
Step 28
6-methoxy-9-oxo-9H-xanthene-3-carbonitrile, 5i
Adding fine sodium cyanide (1.3g, 26.5mmol) and 3-fluoro-6-methoxy-xanthen-9-one (2.3g, 9.42mmol) in N, N-dimethyl formamideThe mixture in amide (30mL) was heated at 100 ℃ for 4 hours. Sodium cyanide (0.7g, 14.3mmol) was added and heating continued for 1 hour. The mixture was allowed to cool to room temperature and then poured into ice water (about 150 mL). The product was collected by filtration, washed with water and air-dried to obtain 1.42g of compound 5i (60%). MS: m/z 251.9 (MH)+)。1HNMR(CDCl3)：δ 3.96(s，3H)，6.91(d，1H，J＝2.3Hz)，7.00(dd，1H，J＝2.3 & 8.9Hz)，7.61(dd，1H，J＝1&8.1Hz), 7.79(d, 1H, J ═ 1Hz), 8.24(d, 1H, J ═ 8.9Hz) and 8.42(d, 1H, J ═ 8.1 Hz).
6-methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 6i
The title compound (0.75g) was prepared according to the procedure described for step 2, substituting compound 5i for compound 1 a. MS: m/z 270.9 (MH)+)。1H NMR(DMSO-d6)：δ 3.95(s，3H)，7.06(dd，1H，2.4 & 8.9Hz)，7.17(d，1H，J＝2.4Hz)，7.94(dd，1H，J＝1.4 &8.2Hz), 8.03(d, 1H, J ═ 14Hz), 8.10(d, 1H, J ═ 8.9Hz), 8.24(d, 1H, J ═ 8.2Hz) and 13.65(br s, 1H).
Step 29
6-methoxy-9-oxo-9H-xanthene-3-N, N-diethyl-carboxamide, 7i
A mixture of compound 6i (0.707g, 2.62mmol) and O-benzotriazol-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate (HBTU, 1.05g, 2.74mmol) in N, N-dimethylformamide (10mL) was treated with N, N-diisopropylethylamine (DIEA, 0.685mL, 3.92mmol), and stirred at room temperature for 15 minutes. Diethylamine (0.541mL, 5.23mL) was added and the resulting mixture was stirred for 2 hours. The mixture was poured into ice water. The solid was collected by filtration, washed with water and air-dried to obtain the title compound (0.445 g). MS: m/z 326.0 (MH)+)。1HNMR(DMSO-d6)：δ 1.07(br t，3H)，1.19(br t，3H)，3.20(br q，2H)，3.48(br t，2H)，3.95(s，3H)，7.08(m，1H)，7.17(d，1H，J＝2.1Hz)，7.40(dd，1H，J＝1.3 & 8.1Hz)，7.59(d，1H，J＝1.2Hz)，8.12(dd，1H，J＝1.3 &8.9Hz) and 8.21(d, 1H, J ═ 8.1 Hz).
Step 30
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -6-methoxy-9H-xanthene-3-N, N-diethyl-carboxamide, 8i
To a suspension of zinc powder (0.626g, 9.60mmol) in THF (20mL) was added titanium tetrachloride (0.525mL, 4.79mmol) dropwise at 0 ℃. The resulting mixture was heated at reflux for 2 hours. The resulting solution was cooled to room temperature and 3-oxo-8-aza-bicyclo [3.2.1] was added]Octane-8-carboxylic acid tert-butyl ester (0.270g, 1.20mmol) and compound 7i (0.390, 1.20mmol) were heated under reflux for 2 hours. Sodium potassium tartrate (2.98g, 1056mmol) dissolved in a minimum amount of water was added to the reaction mixture and stirred at room temperature overnight. The inorganic solid was removed by filtration and washed thoroughly with THF. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and 10% aqueous ammonium hydroxide. The organic layer was separated and dried over sodium sulfate. The solvent was evaporated in vacuo. The residue was dissolved in DMSO and subjected to reverse phase preparative HPLC (C)18) Purification (with a gradient of acetonitrile (10% -90%)/water + TFA (0.1%)) afforded the trifluoroacetate salt of the title compound (0.50 g). MS: m/z 419.1 (MH)+)。1HNMR(DMSO-d6)：δ 1.0-1.2(br m，6H)，1.32(br d，2H)，1.78(br m，2H)，2.85-3.02(br m，4H)，3.2-3.55(br m，4H)，3.80(s，3H)，3.96-4.05(br s，2H)，6.81(dd，1H，J＝2.5 & 8.6)，6.88(d，1H，J＝2.5Hz)，7.15(dd，1H，J-1.4 &7.8Hz), 7.20(d, 1H, J ═ 1.4Hz), 7.31(d, 1H, J ═ 8.6Hz), 7.41(d, 1H, J ═ 7.8hZ), 8.81(br s, 1H) and 9.12(br d, 1H).
Step 31
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -6-hydroxy-9H-xanthene-3-N, N-diethyl-carboxamide, 9i
A1.0M solution of boron tribromide in dichloromethane (2.14mL, 2.14mmol) was added to 9- (8-aza-bicyclo [3.2.1] at 0 deg.C]Oct-3-ylidene) -6-methoxy-9H-xanthene-3-N, N-diethyl-carboxamideWas dissolved in dichloromethane (10mL) to obtain a solution of trifluoroacetate salt (0.285g, 0.535 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 ℃ and treated with 10% aqueous ammonium hydroxide (about 20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, the residue dissolved in DMSO and loaded in reverse phase C18The column was purified by HPLC using a gradient of acetonitrile (10% to 90%)/water + trifluoroacetic acid (0.1%) as eluent. The fractions containing the title compound were combined and further purified by reverse phase HPLC to give the purified title compound (0.035 g). MS: m/z405.1 (MH)+)。1HNMR(DMSO-d6): δ 1.0-1.2(br m, 6H), 1.29(d, 12H, J ═ 8.1Hz), 1.7-1.8(br m, 2H), 2.8-3.0(br m, 4H), 3.1-3.5(br m, 4H), 3.99(br s, 2H), 6.63-6.65(m, 2H), 7.13(d, 1H, J ═ 7.9Hz), 7.18-7.21(m, 3H), 7.41(d, 1H, J ═ 7.9Hz), 8.70(br s, 1H), 9.01(br d, 1H) and 9.93(br s, 1H).
Example J
Step 32
2- (2-bromo-phenoxy) -terephthalic acid dimethyl ester, 3j
A mixture of 2-fluoro-terephthalic acid dimethyl ester 2j (10g, 47.1mmol), 2-bromophenol 1j (6.0mL, 51.8mmol) and potassium carbonate (7.16g, 51.8mmol) in N, N-dimethylformamide (100mL) was heated at 100 ℃ for 36 hours. The mixture was allowed to cool to room temperature and then poured into cold dilute hydrochloric acid (0.5N, 350 mL). The product was extracted with EtOAc, washed with water (4 ×) and brine (1 ×), and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using dichloromethane as eluent. The crude product (10.5g) was isolated and used directly in the next reaction without further purification. MS: m/z 365 (MH)+)。
Step 33
5-bromo-9-oxo-9H-xanthene-3-carboxylic acid, 5j (via 4j)
2- (2-bromo-phenoxy) -terephthalic acid dimethyl ester (10g) was added dropwise to hot (100 ℃ C.) polyphosphoric acid (280g) over 5 minutes. The solution was heated at 155 ℃ for 2 hours and at 180 ℃ for 2 hours. The solution was mixed with a large amount of ice water. The resulting solid was collected by filtration, washed with water and purified by silica gel flash chromatography (gradient methanol (1% -10%)/dichloromethane + acetic acid (0.1%)) to afford compound 4j (1.25 g). The acid compound 5j was isolated from the latter part (3.52 g).
A solution of ester compound 4j (1.25g, 3.75mmol) and 3N sodium hydroxide (1.37mL, 4.12mmol) in MeOH (30mL) was heated at reflux for 2 h. The solution was cooled to room temperature and acidified with 2N hydrochloric acid (ca. 2.5 mL). The mixture was concentrated in vacuo and then diluted with water. The resultant solid was collected by filtration, washed with water and then air-dried to obtain 1.08g of compound 5 j. MS: m/z318.7 (MH)+)。1H NMR(DMSO-d6)：δ 7.43(t，1H，J＝7.8Hz)，7.98(dd，1H，J＝1.4 &8.2), 8.09(d, 1H, J ═ 1.3Hz), 8.17-8.23(m, 2H) and 8.28(d, 1H, J ═ 8.2 Hz).
5-bromo-9-oxo-9H-xanthene-3-N, N-diethyl-carboxamide, 6j
The title compound was prepared according to the procedure described for step 29, substituting compound 5j for compound 6 i. Purification by flash chromatography using dichloromethane as eluent gave compound 6j (4.4 g). MS: m/z 373.8 (MH)+)。1H NMR(CDCl3)：δ 1.16(t，3H，J＝6.8Hz)，1.30(t，3H，J＝6.8Hz)，3.28(q，2H，J＝6.8Hz)，3.60(q，2H，J＝6.8Hz)，7.30(d，1H，J＝7.9Hz)，7.40(dd，1H，J＝1.4&8.0Hz)，7.64(d，1H，J＝1.4Hz)，7.98(dd，1H，J＝1.6 & 7.9Hz)，8.30(dd，1H，J＝1.6 &8.0Hz) and 8.36(d, 1H, J ═ 8.1 Hz).
Step 34
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-bromo-9H-xanthene-3-N, N-diethyl-carboxamide, 7j
To a suspension of zinc powder (5.59g, 85.5mmol) in tetrahydrofuran (THF, 100mL) was added titanium tetrachloride (IV) (4.69mL, 42.8mmol) dropwise at 0 ℃. The resulting mixture was heated at reflux for 2 hours. The resulting solution was cooled to 0 ℃. Adding 3-oxo-8-aza-bicyclo [3.2.1]]Octane-8-carboxylic acid tert-butyl ester (2.4g, 10.7mmol) and 5-bromo-9-oxo-9H-xanthene-3-N, N-diethyl-carboxamide (4.0g, 10.7mmol) were heated to reflux for 4 hours. Sodium potassium tartrate tetrahydrate (30g, 106mmol) was added to the reaction mixture and stirred at room temperature overnight. The inorganic solid was removed by filtration and washed sequentially with THF, EtOAc and dichloromethane. The solvent was evaporated in vacuo. Purification by flash chromatography using a gradient of 1% to 10% methanol (+ ammonia, 2N)/dichloromethane as eluent afforded compound 7j (3.65 g). The crude product was purified by reverse phase preparative HPLC using a gradient of acetonitrile (10% to 90%)/water + trifluoroacetic acid (0.1%) to afford the trifluoroacetate salt of compound 7 j. MS: m/z 467.0 (MH)+)。1H NMR(DMSO-d6): δ 1.0-1.2(br m, 6H), 1.32(d, 2H, J ═ 7.9Hz), 1.75-1.85(br m, 2H), 2.85-3.10(m, 4H), 3.15-3.50(br m, 4H), 4.01(br s, 2H), 7.15-7.26(m, 3H), 7.42(d, 1H, J ═ 6.7Hz), 7.49(d, 1H, J ═ 7.9Hz), 7.66(d, 1H, J ═ 7.9Hz), 8.81(br s, 1H) and 9.12(br d, 1H).
Step 35
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-phenyl-9H-xanthene-3-N, N-diethyl-carboxamide, 8j
Reacting 9- (8-aza-bicyclo [3.2.1]]Oct-3-ylidene) -5-bromo-9H-xanthene-3-N, N-diethyl-carboxamide (0.170, 0.363mmol), phenylboronic acid (0.049g, 0.40mmol), and cesium carbonate (0.236g, 0.726mmol) in a mixture of dioxane (4mL) and ethanol (1mL) with dichloro [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) methylene chloride adduct (13mg), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, filtered to remove inorganic materials, washed with dioxane, ethanol andthe dichloromethane washes were in turn. The solvent was evaporated in vacuo. The residue is reversed phase (C)18) Preparative HPLC purification using gradient acetonitrile (10% to 90%)/water + trifluoroacetate salt (0.1%) as eluent gave the title compound as a colourless solid (0.153 g). MS: m/z 465.3 (MH)+)。1H NMR(DMSO-d6)：δ 1.05-1.20(br m，6H0，1.31d，2H，J＝8、2Hz)，1.75-1.85(br m，2H)，2.90-3.10(m，4H)，3.15-3.50(brm，4H)，4.03(br s，2H)，7.10(d，1H，J＝1.5Hz)，7.20(dd，1H，J＝1.5&7.9Hz), 7.32(t, 1H, J ═ 7.5Hz), 7.40-7.63(m, 8H), 8.83(br s, 1H0 and 9.16(br d, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-methoxy-9H-xanthene-3-N, N-diethyl-carboxamide
The title compound was prepared according to example J substituting 2-methoxyphenol for 2-bromophenol of step 32. MS: m/z 419.1 (MH)+)。1H NMR(DMSO-d6): δ 1.0-1.2(m, 6H), 1.29(br m, 1H), 1.73-1.82(m, 2H), 2.87-3.15(m, 4H), 3.22(br m, 2H), 3.42(br m, 2H), 3.88(s, 3H), 4.00(br s, 2H), 6.95(d, J ═ 7.5Hz, 1H), 7.07-7.19(m, 3H), 7.22(d, J ═ 1.5Hz, 1H), 7.44(d, J ═ 7.9Hz, 1H), 8.77(br s, 1H) and 9.08(br s, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-hydroxy-9H-xanthene-3-N, N-diethyl-carboxamide
According to modified step 31, with 9- (8-aza-bicyclo [3.2.1]]Oct-3-ylidene) -5-methoxy-9H-xanthene-3-N, N-diethyl-carboxamide the title compound was prepared. MS: m/z405.0 (MH)+)。1H NMR(DMSO-d6)：δ 1.0-1.2(m，6H)，1.29(br m，1H)，1.73-1.84(m，2H)，2.95-3.15(m，4H)，3.20(br m，2H)，3.42(brm，2H)，4.00(br s，2H)，6.80(d，J＝7.6Hz，1H)，6.87(d，J＝7.9Hz，1H)，7.02(t，J＝7.9Hz，1H)，7.15(dd，J＝1.5 &7.9Hz, 1H), 7.25(d, J ═ 1.5Hz, 1H), 7.42(d, J ═ 7.9Hz, 1H), 8.78(br s, 1H), 9.08(br s, 1H) and 9.67(br s, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-pyridin-4-yl-9H-xanthene-3-N, N-diethyl-carboxamide
The title compound was prepared according to the procedure described for example J substituting pyridin-4-ylboronic acid for phenylboronic acid of step 35. MS: m/z 466.1 (MH)+)。1H NMR(DMSO-d6): δ 1.0-1.2(m, 6H), 1.32(br m, 2H), 1.80(br m, 2H), 2.88-3.42(br m, 8H), 4.03(br s, 2H), 7.22(d, J ═ 7.8Hz, 1H), 7.27(d, J ═ 1.2Hz, 1H), 7.42(t, J ═ 7.6Hz, 1H), 7.51(d, J ═ 7.8Hz, 1H), 7.58(d, J ═ 7.6Hz, 1H), 7.63(d, J ═ 6.8Hz, 1H), 8.06(d, J ═ 6.1Hz, 2H), 8.90(br m, 3H) and 9.22(brd, J ═ 9.4, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-furan-3-yl-9H-xanthene-3-N, N-diethyl-carboxamide
The title compound was prepared according to the procedure described for example J substituting furan-3-ylboronic acid for phenylboronic acid of step 35. MS: m/z 455.1 (MH)+)。1H NMR(DMSO-d6): δ 1.0-1.2(m, 6H), 1.30(br m, 2H), 1.78(br m, 2H), 2.89-3.05(m, 4H), 3.20(br m, 2H), 3.44(br m, 2H), 4.02(br s, 2H), 7.15(s, 1H), 7.19(d, J ═ 7.8Hz, 1H), 7.26-7.31(m, 2H), 7.47(d, J ═ 7.8Hz, 1H), 7.56(d, J ═ 1.1Hz, 1H), 7.69-7.72(m, 1H), 7.82(s, 1H), 8.59(s, 1H), 8.83(br d, 1H) and 9.15(br d, J ═ 9.3, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-pyridin-3-yl-9H-xanthene-3-N, N-diethyl-carboxamide
The title compound was prepared according to the procedure described for example J substituting pyridin-3-ylboronic acid for phenylboronic acid of step 35. MS: m/z 466.1 (MH)+)。1H NMR(DMSO-d6)：δ 1.0-1.2(m，6H)，1.32(m，2H)，1.80(br m，2H)，2.90-3.02(m，4H)，3.20(br m，2H)，3.42(br m，2H)，4.03(br s，2H)，7.16(d，J＝1.5Hz，1H)，7.20(dd，J＝1.5 & 7.8Hz，1H)，7.38(t，J＝7.7Hz，1H)，7.49-7.56(m，3H)，7.76(dd，J＝5.0 & 7.9Hz，1H)，8.31(d，J＝8.0Hz，1H)，8.74(dd，J＝1.5 &5.0Hz, 1H), 8.82(br s, 1H), 8.95(s, 1H) and 9.13(br d, 1H).
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -5-thiophen-3-yl-9H-xanthene-3-N, N-diethyl-carboxamide
The title compound was prepared according to the procedure described for example J substituting thiophen-3-ylboronic acid for phenylboronic acid of step 35. MS: m/z 471.0 (MH)+)。1H NMR(DMSO-d6): δ 1.0-1.2(m, 6H), 1.31(m, 2H), 1.78(br m, 2H), 2.95-3.05(m, 4H), 3.21(br m, 2H), 3.43(br m, 2H), 4.02(br s, 2H), 7.21(dd, J ═ 1.5 and 7.8Hz, 1H), 7.28(t, J ═ 7.6Hz, 1H), 7.34(dd, J ═ 1.4H)& 7.6Hz，1H)，7.38(d，J＝1.4Hz，1H)，7.48(d，J-7.8Hz，1H)，7.63-7.70(m，3H)，8.13(dd，J＝1.4 &2.8Hz, 1H), 8.80(br s, 1H) and 9.12(br d, J ═ 10Hz, 1H).
Example K
9- (8-aza-bicyclo [3.2.1] oct-3-ylidene) -9H-xanthene-3- (N-isopropyl-N-methyl) -carboxamide
Step 36
2-phenoxy-terephthalic acid dimethyl ester. 2-iodo-terephthalic acid dimethyl ester (10g, 31mmol), phenol (3.23g, 34mmol), tetraethyl nitrile copper hexafluorophosphate (2.9g, 7.8mmol) and cesium carbonate (10.2g, 31mmol) were charged to a 1L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and containing toluene (350 mL). The reaction was refluxed under nitrogen for 5 hours while stirring. After cooling, EtOAc (200mL) was added and the mixture was filtered. The filtrate was concentrated to obtain the crude title compound (9.2g), which was used without further purification.
According to modified step 33, 2-phenoxy-terephthalic acid dimethyl ester is converted into 9-oxo-9H-xanthene-3-carboxylic acid.
9-oxo-9H-xanthene-3- (N-isopropyl-N-methyl) -carboxamide was prepared with 9-oxo-9H-xanthene-3-carboxylic acid according to modified step 29, substituting N-isopropyl-N-methyl-amine for diethylamine.
The title compound of example K was prepared according to the procedure described for step 34 substituting 9-oxo-9H-xanthene-3- (N-isopropyl-N-methyl) -carboxamide for compound 6 j. The crude product was purified by preparative reverse phase chromatography on a C-18 column eluting with water/acetonitrile/0.1% TFA to afford the product, trifluoroacetate salt. MSm/z (MH)+)389.2；1H NMR 300MHz(DMSO-d6)δ 1.12(s，6H)，1.2-1.3(m，2H)，1.79(m，2H)，2.82(m，3H)，2.95(q，4H)，4.00(s，2H)，7.18-7.21(m，1H)，7.24(d，2H)，7.30(d，1H)，7.36(d，1H)，7.40-7.46(m，2H)，8.77(m，1H)，9.09(d，1H)。
Compounds 1-102 in the table below were synthesized by the above method.
TABLE 1
Biological examples
Rat brain mu opioid receptor binding assay
The method comprises the following steps: with CO2Male Sprague Dawley rats (150-. The forebrain is separated from the rest of the brain by a coronal transection, which begins at the dorsal thalamus by the midbrain-bridge junction to the ventral side. After dissection, the forebrain is usedThe glass homogenizer homogenized in Tris buffer. The homogenate was diluted to 1g forebrain tissue/80 ml of tris and centrifuged at 39,000 Xg for 10 min. Resuspending the centrifuged pellet in the same amount of 5mM MgCl2Is treated several times with short pulses of a Polytron homogenizer. This microparticle formulation was used in the μ -opioid binding assay. Then contacted with a mu-selective peptide ligand of about 0.8nM in a 96-well plate3H]DAMGO (total volume 1ml) was incubated at 25 ℃ for 2.5 hours and the contents passed through a Tomtec 96 well harvester, Wallac filtermat B plate filter plate. The filter was washed 3 times with 2mL of 10mM HEPES (pH 7.4) and dried 2 times for 1.75 minutes in a 650W microwave oven. To each sample area 2X 40. mu.L of Betaplate Scint scintillation fluid (LKB) was added and analyzed by LKB (Wallac)1205 Betaplate liquid scintillation counter.
And (3) analysis: the data from the scintillation counter is used to calculate the percent inhibition (when only one concentration of test compound is evaluated) or Ki value (when a range of concentrations of compound is tested) of binding relative to the control. Percent inhibition was calculated as follows: [ (total dpm-test compound dpm)/(total dpm-nonspecific dpm) ]. 100. Kd and Ki values were calculated using the GraphPad PRISM data analysis program.
Of CHO-h [ mu ] cell membrane35S]GTP γ S binding assay
Preparation of the film
CHO-h μ cell membranes were purchased from Receptor Biology, Inc. (Baltimore, Md.). Approximately 10mg/ml membrane protein was suspended in 10mM TRIS-HC pH 7.2, 2mM EDTA, 10% sucrose.
The membrane was maintained at 4-8 ℃. Add 1ml of membrane to 15ml of cooled binding assay buffer. This assay buffer contained 50mM HEPES pH7.6, 5mM MgCl2100mM NaCl, 1mM DTT and 1mM EDTA. The membrane suspension was homogenized 2 times by Polytron and centrifuged at 3000rpm for 10 minutes. The supernatant was then centrifuged at 18,000rpm for 20 minutes. The centrifuged pellet was stored in a tube and 10ml of assay buffer was added to the tube. The pellet and buffer were mixed using a Polytron.
Incubation step
The spun down membrane (20. mu.g/ml) was preincubated with SPA (10mg/ml) in assay buffer for 45 minutes at 25 ℃. SPA (5mg/ml) coupled to a membrane (10. mu.g/ml) was mixed with 0.5nM [ alpha ], [ solution ]35S]GTPgS was incubated in the same HEPES buffer (containing 50. mu.M GDP) in a total volume of 200. mu.l. Increasing concentrations of a receptor agonist for stimulation35S]GTPgS binding. Basal binding values were determined in the absence of agonist, and non-specific binding was determined in the presence of 10 μ M unlabeled GTR γ S. Data were analyzed with a Top counter.
Data of
Percent relative to basal binding value (stimulated binding value-non-specific binding value) 100/(basal binding value-non-specific binding value). Percent inhibition was calculated using the following formula: percent inhibition (percent of 1 μ M DAMGO to basal binding value-percent of compound to basal binding value) 100/(percent of 1uM DAMGO to basal binding value-100)
Of CHO-h delta cell membrane35S]GTP γ S binding assay
Preparation of the film
CHO-h delta cell membranes were purchased from Receptor Biology, Inc. (Baltimore, Md.). 10mg/ml membrane protein was suspended in 10mM Tris-HC pH 7.2, 2mM EDTA, 10% sucrose.
The membrane was maintained at 4-8 ℃.1ml of membrane was added to 15ml of cooled binding assay buffer. This assay buffer contained 50mM HEPES pH7.6, 5mM MgCl2100mM NaCl, 1mM DTT and 1mM EDTA. The membrane suspension was homogenized 2 times by Polytron and centrifuged at 3000rpmFor 10 minutes. The supernatant was then centrifuged at 18,000rpm for 20 minutes. The centrifuged pellet was stored in a tube and 10ml of assay buffer was added to the tube. The pellet and buffer were mixed using a Polytron.
Incubation step
The spun down membrane (20. mu.g/ml) was preincubated with SPA (10mg/ml) in assay buffer for 45 minutes at 25 ℃. SPA (5mg/ml) coupled to a membrane (10. mu.g/ml) was mixed with 0.5nM [ alpha ], [ solution ]35S]GTPgS was compared with 0.5nM [ 2 ] in the same HEPES buffer (containing 50. mu.M GDP ]35S]GTPgS incubation was performed in a total volume of 200. mu.l. Increasing concentrations of a receptor agonist for stimulation35S]GTPgS binding. Basal binding values were determined in the absence of agonist, and non-specific binding was determined in the presence of 10 μ M unlabeled GTP γ S. Data were analyzed with a Top counter.
Of NG108-15 cell membrane35S]GTP γ S binding assay
Preparation of the film
NG108-15 Cell membranes were purchased from Applied Cell Sciences (Rockville, Md.). 8mg/mL of membrane protein was suspended in 10mM TRIS-HC pH 7.2, 2mM EDTA, 10% sucrose.
The membrane was maintained at 4-8 ℃.1ml of membrane was added to 10ml of cooled binding assay buffer. This assay buffer contained 50mM Tris pH7.6, 5mM MgCl2100mM NaCl, 1mM DTT and 1mM EGTA. The membrane suspension was homogenized 2 times by Polytron and centrifuged at 3000rpm for 10 minutes. The supernatant was then centrifuged at 18,000rpm for 20 minutes. The centrifuged pellet was stored in a tube and 10ml of assay buffer was added to the tube. The pellet and buffer were mixed using a Polytron.
Incubation step
The spun down membrane (75. mu.g/ml) was preincubated with SPA (10mg/ml) in assay buffer for 45 min at 25 ℃. SPA (5mg/ml) coupled to a membrane (37.5. mu.g/ml) was mixed with 0.1nM [ alpha ], [ solution ]35S]GTP γ S was incubated in the same Tris buffer (containing 100. mu.M GDP) in a total volume of 200. mu.l. Increasing concentrations of a receptor agonist for stimulation35S]GTP γ S binding. Basal binding values were determined in the absence of agonist, and non-specific binding was determined in the presence of 10 μ M unlabeled GTP γ S. Data were analyzed with a Top counter.
Data of
Percent relative to basal binding value (stimulated binding value-non-specific binding value) 100/(basal binding value-non-specific binding value). EC50 values were calculated using the Prism program.
Mouse abdominal stimulation test (MAIT)
The procedure used is described in the literature by Collier et al (1968), with minor modifications. 30 minutes after administration of the test compound, the animals are injected i.p. with 5.5mg/kg acetylcholine bromide. Mice were then filled into large glass jars for animals and observed for the first appearance of characteristic behavioral responses (torsion and extension to body extension of the entire hind limb) for a prescribed observation period of 10 minutes. The percent inhibition of this reaction was calculated as follows:
percent inhibition of 100 × (number of no reaction)/(number of experimental animals)
Estimated ED50The values (calculated agonist dose yielding 50% antinociceptive pain) and corresponding 95% confidence intervals were determined by probabilistic analysis of Litchfield and Wilcoxon (1949).
Data of
Percent relative to basal binding value (stimulated binding value-non-specific binding value) 100/(basal binding value-non-specific binding value). EC50 values were calculated using the Prism program.
Rat zymosan bolometry
After an overnight fast, rats were acclimatized to a warm glass-bottom experimental box. The radiant thermal stimulus (beam) was then focused sequentially on the plantar surface of each hind paw and the initial (basal) response time to the thermal stimulus was recorded for each rat. The optical stimulus is automatically switched off by a photo-relay when the foot is moved or when a cut-off time is reached (20 seconds of radiant heat, 5 Amp). The subplantar tissue of the left hind paw of the rat was injected subcutaneously with zymosan A (100. mu.L, 25mg/mL) to stimulate an acute inflammatory response.
After 3 hours, the response time of the animals to the thermal stimulus was evaluated and compared to the basal response time of the animals. The response time is usually shortened and the results are reported as the percentage hyperalgesia (% H). The cut-off value% H (about 75%) was used to ensure animal hyperalgesia. The rats are then administered the test compound or vehicle. After a certain time (usually 60 minutes), the animals are again evaluated for their response time to the thermal stimulus.
CFA thermal hyperalgesia
The intraplantar injections of Complete Freund's Adjuvant (CFA) in rodents produce a severe, persistent inflammatory response characterized by significant chronic hyperalgesia to both thermal and mechanical stimuli. These effects are maximal between 24-72 hours after injection and may last from several days to several weeks. To evaluate the ability of JNJ compounds to resist thermal hyperalgesia, the left hind paw of male Sprague-Dawley rats (200-350g) was injected intraplantarly with CFA (1:1 CFA: saline, 100. mu.L). After a 24 hour latency period, response latencies were obtained by radiant heat paw stimulators (RH) and compared to basal (before CFA administration) latencies. When the rat lifts the paw off the glass surface, the response is automatically recorded by the RH device. Further analysis was performed using only rats with response latency reduced by at least 25% from basal response time (i.e. hyperalgesia). After a defined incubation period following CFA administration, rats are given oral (2.5mL/kg) test compound or vehicle (hydroxypropylmethylcellulose, HPMC). The percentage of anti-hyperalgesia for each animal was calculated as follows: (post-treatment reaction-reaction after administration of CFA)/(reaction before administration of CFA-reaction after administration of CFA). times.100. Thus, a pre-CFA threshold to return to normal is defined as 100% efficacy, while a non-changing, post-CFA threshold is 0% efficacy. The average% of anti-hyperalgesia was calculated for each treatment group (n ═ 6-8 rats/group). The dose response curve at which the maximum effect is obtained subsequently. ED (electronic device)50Values and related statistics were calculated using PharmTools Plus software (The McCary; Group).
Biological and mass spectral data
TABLE 2
rDOR Ki: rat brain delta opioid receptor binding
rMOR Ki: rat brain mu opioid receptor binding
hDOR gtp: functional assay for human delta opioid receptor GTP γ S
hMOR gtp: functional assay for human mu opioid receptor GTP gamma S
DOR gtp: functional assay for the delta opioid receptor GTP γ S
MAIT: mouse abdominal stimulation test
Compounds 1 and 5 non-explicitly stimulated GTP binding at 10 uM. However, at 10uM they inhibited GTP binding induced by 1uM DPDPDPDPPE with 61% and 19% inhibition, respectively. These results indicate that these two compounds may be delta opioid receptor antagonists.

Claims (117)

1. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein:
R1and R2Is independently selected from hydrogen and C1-8A substituent of an alkyl group;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioaldehyde, phenyliminomethyl, phenylethyl and heteroaryl C1-8An alkyl group; wherein heteroaryl is selected from carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole and xanthene; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
R5is hydrogen;
a is- (CH)2)m-, where m is 0, 2 or 3;
y is- (CH)2)nX-or-X (CH)2)n-；
X is O or S;
n is 0 or 1;
z is O.
2. The compound of claim 1, wherein R1And R2Is independently selected from hydrogen and C1-4A substituent of an alkyl group.
3. The compound of claim 1, wherein R1And R2Is a substituent independently selected from: hydrogen, methyl, ethyl and propyl.
4. The compound of claim 1, which isIn R1And R2Are substituents independently selected from hydrogen and ethyl.
5. The compound of claim 1, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl.
6. The compound of claim 1, wherein R4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy.
7. The compound of claim 6, wherein Y is O or S.
8. The compound of claim 1, wherein A is (CH)2)mWherein m is 0 or 2.
9. The compound of claim 1, wherein A is- (CH)2)2-。
10. The compound of claim 1, wherein X is O.
11. The compound of claim 1, wherein n is 0.
12. The compound of claim 1, wherein X is S.
13. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein R is1Is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioaldehyde, phenyliminomethyl, phenylethyl and heteroaryl C1-8An alkyl group; wherein heteroaryl is selected from carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole and xanthene; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
R5is hydrogen;
a is absent or CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
14. The compound of claim 13, wherein R1Is ethyl; r2Is ethyl or hydrogen; and R is3Is benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl or thien-2-ylmethyl.
15. The compound of claim 13, wherein R1Is ethyl; r2Is ethyl; and R is3Is benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl or phenethyl.
16. The compound of claim 13, wherein R1Is ethyl; r2Is ethyl; and R is3Is H, benzo [1, 3]]Dioxol-5-ylmethyl, 1-H-imidazol-4-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl or phenyliminomethyl.
17. The compound of claim 13, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl.
18. The compound of claim 13, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl; r4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy.
19. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein R is1Is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from hydrogen, methyl, allyl2-methyl-allyl, propynyl, hydroxyethyl, thioaldehyde, phenyliminomethyl, phenethyl and heteroaryl C1-8An alkyl group; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4An alkyloxy group, a halogen, a phenyl group, a furyl group, an imidazolyl group, an indazolyl group, an indolyl group, an indolinyl group, an isoindolinyl group, an isoquinolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrazolyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, a quinolyl group, a tetrazolyl group, a thiazolyl group, a thienyl group, and a hydroxyl group;
R5is hydrogen;
a is CH2CH2；
Y is O or S;
z is O.
20. The compound of claim 19, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl.
21. The compound of claim 19, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl; r4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy.
22. A compound of formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof,
structural formula (I)
They are selected from the following compounds and enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof:
1) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
2) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
3) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
4) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-benzo [1, 3]]Dioxol-5-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
5) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
6) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
7) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
8) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
9) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
10) a compound of the formula (I),wherein R is1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
11) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
12) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is furan-3-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
13) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is furan-3-ylmethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
14) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
15) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 2-hydroxyphenyl-methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
16) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is a 1-amidino group, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
17) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-prop-2-ynyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
18) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is methylcarbonylamino, R5Is H, A is absent, Y is O, and Z is O;
19) a compound of formula (I), whereinR1Is ethyl, R2Is ethyl, R3Is hydroxy-ethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
20) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is phenyliminomethyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
21) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is a thioaldehyde group, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
22) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is allyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
23) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methoxy-ethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
24) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methylthioethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
25) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
26) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methyl, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
27) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
28) a compound of formula (I), whichIn R1Is ethyl, R2Is ethyl, R3Is 2-hydroxy-ethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
29) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
30) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is benzo [1, 3]]Dioxol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
31) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
32) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is cyclopropylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
33) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is methylthio-propyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
34) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 2-hydroxy-ethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
35) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
36) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is a compound of formula (I) in the formula (H),R5is H, A is CH2CH2Y is O and Z is O;
37) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
38) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-but-2-enyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
39) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
40) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 4-hydroxy-3-methoxyphenyl-methyl, A is absent and Y is CH2O and Z is O;
41) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
42) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1, 1, 1-trichloroethoxycarbonyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
43) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is cyclopropylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
44) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
45) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
46) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is methyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
47) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
48) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is CH2O and Z is O;
49) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
50) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
51) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is thien-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
52) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
53) a compound of formula (I) wherein R1Is methyl, R2Is methyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
54) a compound of formula (I) wherein R1Is methyl, R2Is isobutyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
55) a compound of formula (I) wherein R1Is n-propyl, R2Is n-propyl, R3Is H, R4Is H, R5Is H, A is CH2H2Y is O and Z is O;
56) a compound of formula (I) wherein R1Is n-propyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
57) a compound of formula (I) wherein R1Is methyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
58) a compound of formula (I) wherein R1Is H, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
59) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
60) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
61) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
62) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-fluoro, R5Is H, A is CH2CH2Y is O and Z is O;
63) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
64) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
65) a compound of formula (I) wherein R1Is methyl, R2Is n-butyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
66) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
67) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
68) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
69) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is trifluoromethyl carbonyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
70) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
71) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
72) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
73) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-phenyl, R5Is H, A is CH2CH2Y is O and Z is O;
74) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
75) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
76) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-benzothien-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
77) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7- (N-tert-butoxycarbonyl) pyrrol-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
78) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
79) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
80) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7- (3, 5-dimethyl) isoxazol-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
81) a compound of formula (I) wherein R1Is methyl, R2Is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
82) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-pyrrol-2-yl, R5Is H, A is CH2CH2Y is O and Z is O;
83) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
84) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-phenyl, R5Is H, A is CH2CH2Y is O and Z is O;
85) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
86) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
87) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-quinolin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
88) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-thiophen-3-yl, R5Is H, A is CH2CH2Y is O, andz is O;
89) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
90) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
91) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-fluoro, R5Is H, A is CH2CH2Y is O and Z is O.
23. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof,
structural formula (I)
They are selected from the following compounds and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
1) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
2) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
3) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
4) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-but-2-enyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
5) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is 2-methyl-allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
6) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is allyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
7) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
8) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is phenethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
9) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is pyridin-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
10) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is thien-2-ylmethyl, R4Is H, R5Is H, A is absent, Y is CH2O and Z is O;
11) a compound of formula (I) wherein R1Is ethyl, R2Is H, R3Is H, R4Is H, R5Is H, A is absent, Y is O, and Z is O;
12) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-5-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
13) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
14) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is 1-H-imidazol-4-ylmethyl, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
15) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
16) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
17) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
18) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
19) a compound of formula (I) wherein R1Is methyl, R2Is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
20) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-bromo, R5Is H, A is CH2CH2Y is O and Z is O;
21) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
22) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
23) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is S and Z is O;
24) a compound of formula (I) wherein R1Is n-propyl, R2Is n-propyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
25) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-fluoro, R5Is H, A is CH2CH2Y is O and Z is O;
26) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
27) a compound of formula (I) wherein R1Is methyl, R2Is isobutyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
28) a compound of formula (I) wherein R1Is methyl, R2Is n-butyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O;
29) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-quinolin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
30) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is a compound of formula (I) in the formula (H),R4is 5-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
31) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-phenyl, R5Is H, A is CH2CH2Y is O and Z is O;
32) a compound of formula (I) wherein R1Is methyl, R2Is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O.
24. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
They are selected from the following compounds and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
1) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-hydroxy, R5Is H, A is CH2CH2Y is O and Z is O;
2) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-methoxy, R5Is H, A is CH2CH2Y is O and Z is O;
3) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-4-yl, R5Is H, A is CH2CH2Y is O and Z is O;
4) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-furan-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
5) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 6-methyl, R5Is H, A is CH2CH2Y is O and Z is O;
6) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 7-fluoro, R5Is H, A is CH2CH2Y is O and Z is O;
7) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-pyridin-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
8) a compound of formula (I) wherein R1Is ethyl, R2Is ethyl, R3Is H, R4Is 5-thiophen-3-yl, R5Is H, A is CH2CH2Y is O and Z is O;
9) a compound of formula (I) wherein R1Is methyl, R2Is isopropyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O.
25. A composition comprising the dextrorotatory enantiomer of a compound of formula (I),
structural formula (I)
Wherein R is1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O; wherein the composition is substantially free of the levorotatory isomer of the compound.
26. A composition comprising the levorotatory enantiomer of a compound of formula (I),
structural formula (I)
Wherein R is1Is ethyl, R2Is ethyl, R3Is H, R4Is H, R5Is H, A is CH2CH2Y is O and Z is O; wherein said composition is substantially free of the dextrorotatory isomer of said compound.
27. A pharmaceutical composition comprising a compound, salt, according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.
28. A veterinary composition comprising a compound, salt, according to claim 1, and a veterinarily acceptable carrier, excipient, or diluent.
29. Use of a therapeutically effective amount of a compound or salt of claim 1 in the manufacture of a medicament for treating or preventing a disease or condition alleviated by modulation of the δ opioid receptor in a mammal.
30. The use of claim 29, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
31. The use of claim 29, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
32. The use of claim 29, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
33. Use of a therapeutically effective amount of a compound or salt of claim 1 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
34. The use of claim 33, wherein the pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain caused by acute injury, acute pain caused by trauma, acute pain caused by surgery, chronic pain caused by headache, chronic pain caused by neuropathy, chronic pain caused by post-stroke syndrome, and chronic pain caused by migraine.
35. The use of claim 33, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
36. Use of a therapeutically effective amount of a compound or salt of claim 1 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
37. The use of claim 33, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
38. The use of claim 33, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
39. The use of claim 33, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
40. A kit comprising one or more containers filled with an effective amount for treating or preventing mild to severe pain of a compound of formula (I) according to claim 1 and enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.
41. A pharmaceutical composition comprising a compound, salt, according to claim 13, and a pharmaceutically acceptable carrier, excipient or diluent.
42. A veterinary composition comprising a compound, salt of claim 13 and a veterinarily acceptable carrier, excipient, or diluent.
43. Use of a therapeutically effective amount of a compound or salt of claim 13 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
44. The use of claim 43, wherein said pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
45. The use of claim 43, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
46. Use of a therapeutically effective amount of a compound or salt of claim 13 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cancer/pain, cardiovascular diseases and respiratory diseases.
47. The use of claim 43, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
48. The use of claim 43, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
49. The use of claim 43, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
50. A kit comprising one or more containers filled with an effective amount for treating or preventing mild to severe pain of a compound of formula (I) according to claim 13 and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof.
51. A pharmaceutical composition comprising a compound, salt, according to claim 19 and a pharmaceutically acceptable carrier, excipient or diluent.
52. A veterinary composition comprising a compound, salt, and a veterinarily acceptable carrier, excipient, or diluent of claim 19.
53. Use of a therapeutically effective amount of a compound or salt of claim 19 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
54. The use of claim 53, wherein said pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
55. The use of claim 53, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
56. Use of a therapeutically effective amount of a compound or salt of claim 19 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
57. The use of claim 53, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
58. The use of claim 53, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
59. The use of claim 53, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
60. A kit comprising one or more containers filled with an effective amount for treating or preventing mild to severe pain of a compound of formula (I) according to claim 19 and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof.
61. A pharmaceutical composition comprising a compound, salt, according to claim 22 and a pharmaceutically acceptable carrier, excipient or diluent.
62. A veterinary composition comprising a compound, salt, and a veterinarily acceptable carrier, excipient, or diluent of claim 22.
63. Use of a therapeutically effective amount of a compound or salt of claim 22 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
64. The use of claim 63, wherein the pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
65. The use of claim 63, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
66. Use of a therapeutically effective amount of a compound or salt of claim 22 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
67. The use of claim 63, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
68. The use of claim 63, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
69. The use of claim 63, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
70. A kit comprising one or more containers filled with an effective amount for treating or preventing mild to severe pain of a compound of formula (I) according to claim 22 and enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.
71. A pharmaceutical composition comprising a compound, salt, according to claim 23 and a pharmaceutically acceptable carrier, excipient or diluent.
72. A veterinary composition comprising a compound, salt, according to claim 23 and a veterinarily acceptable carrier, excipient, or diluent.
73. Use of a therapeutically effective amount of a compound or salt of claim 23 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
74. The use of claim 73, wherein said pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
75. The use of claim 73, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
76. Use of a therapeutically effective amount of a compound or salt of claim 23 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
77. The use of claim 73, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
78. The use of claim 73, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
79. The use of claim 73, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
80. A kit comprising one or more containers filled with an effective amount for treating or preventing mild to severe pain of a compound of formula (I) according to claim 23 and enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.
81. A pharmaceutical composition comprising a compound, salt, according to claim 25 and a pharmaceutically acceptable carrier, excipient or diluent.
82. A veterinary composition comprising a compound, salt, and a veterinarily acceptable carrier, excipient, or diluent of claim 25.
83. Use of a therapeutically effective amount of a compound or salt of claim 25 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
84. The use of claim 83, wherein said pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
85. The use of claim 83, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
86. Use of a therapeutically effective amount of a compound or salt of claim 25 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
87. The use of claim 83, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
88. The use of claim 83, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
89. The use of claim 83, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
90. A kit comprising one or more containers filled with an effective amount of the composition of claim 25 for treating or preventing mild to severe pain.
91. A pharmaceutical composition comprising a compound, salt, according to claim 26, and a pharmaceutically acceptable carrier, excipient, or diluent.
92. A veterinary composition comprising a compound, salt, and a veterinarily acceptable carrier, excipient, or diluent of claim 26.
93. Use of a therapeutically effective amount of a compound or salt of claim 26 in the manufacture of a medicament for the prevention or treatment of mild to severe pain.
94. The use of claim 93, wherein said pain is selected from the group consisting of inflammatory pain, centrally mediated pain, peripherally mediated pain, structurally related pain, cancer/pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain, acute pain resulting from acute injury, acute pain resulting from trauma, acute pain resulting from surgery, chronic pain resulting from headache, chronic pain resulting from neuropathy, chronic pain resulting from post-stroke syndrome, and chronic pain resulting from migraine.
95. The use of claim 93, wherein the pain is caused by a disease or condition selected from the group consisting of: osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergy, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, postoperative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, charcot pain, reflex sympathetic dystrophy, guillain's syndrome, paresthesias pain, causalgia syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, neurodynia, post-herpetic neuralgia, post-herpetic neuralgia, post, Trigeminal neuralgia, optic neuritis, postfebrile neuritis, wandering neuritis, segmental neuritis, axonal neuritis, neuronitis, cervicobrachial neuralgia, cerebral neuralgia, geniculate ganglionic neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, erythromelalgia, Sprayder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, winged tube neuralgia, sinus headache, tension headache, labor pain, childbirth, dysmenorrhea, and cancer.
96. Use of a therapeutically effective amount of a compound or salt of claim 26 in the manufacture of a medicament for treating or preventing a disease or condition selected from the group consisting of: depression, parkinson's disease, drug abuse, alcohol abuse, gastritis, urinary incontinence, premature ejaculation, diarrhea, cardiovascular diseases and respiratory diseases.
97. The use of claim 93, wherein the therapeutically effective dose is in the range of 0.001mg to 1,000 mg.
98. The use of claim 93, wherein the therapeutically effective dose is in the range of 0.1mg to 500 mg.
99. The use of claim 93, wherein the therapeutically effective dose is in the range of 1mg to 250 mg.
100. A kit comprising one or more containers filled with an effective amount of the composition of claim 26 for treating or preventing mild to severe pain.
101. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein:
R1and R2Is independently selected from hydrogen and C1-8A substituent of an alkyl group;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioaldehyde, phenyliminomethyl, phenylethyl and heteroaryl C1-8An alkyl group; wherein heteroaryl is selected from carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole and xanthene; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4Alkyl alkoxy, halogen, phenyl, furyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinylA group selected from the group consisting of phenyl, isoquinolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy;
R5is hydrogen;
a is- (CH)2)m-, where m is 2 or 3;
y is- (CH)2)nX-or-X (CH)2)n-；
X is O or S;
n is 0 or 1;
z is O.
102. The compound of claim 101, wherein R1And R2Is independently selected from hydrogen and C1-4A substituent of an alkyl group.
103. The compound of claim 101, wherein R1And R2Is a substituent independently selected from: hydrogen, methyl, ethyl and propyl.
104. The compound of claim 101, wherein R1And R2Are substituents independently selected from hydrogen and ethyl.
105. The compound of claim 101, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl.
106. The compound of claim 101, wherein R4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy.
107. The compound of claim 101, wherein Y is O or S.
108. Claim 101 wherein A is (CH)2)mWherein m is 0 or 2.
109. The compound of claim 101, wherein X is O.
110. The compound of claim 101, wherein n is 0.
111. The compound of claim 101, wherein X is S.
112. A compound of the following structural formula (I) and enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof:
structural formula (I)
Wherein R is1Is C1-3An alkyl group;
R2is C1-3An alkyl group or hydrogen;
R3selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, thioaldehyde, phenyliminomethyl, phenylethyl and heteroaryl C1-8An alkyl group; wherein heteroaryl is selected from carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole and xanthene; wherein the phenyl group of any phenyl-containing substituent is optionally substituted with 1 hydroxyl group;
R4is 1-2 substituents independently selected from: hydrogen, C1-4Alkyl radical, C1-4Alkyl alkoxy, halogen, phenyl, furyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolyl, isoquinolinylThiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy;
R5is hydrogen;
a is CH2CH2；
Y is O, S, CH2O or OCH2；
Z is O.
113. The compound of claim 112, wherein R1Is ethyl; r2Is ethyl or hydrogen; and R is3Is benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-ylmethyl or thien-2-ylmethyl.
114. The compound of claim 112, wherein R1Is ethyl; r2Is ethyl; and R is3Is benzo [1, 3]]Dioxol-5-ylmethyl, amidino, 1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl, thioaldehyde, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl, furan-3-ylmethyl, H, Me, methylthioethyl or phenethyl.
115. The compound of claim 112, wherein R1Is ethyl; r2Is ethyl; and R is3Is H, benzo [1, 3]]Dioxol-5-ylmethyl, 1-H-imidazol-4-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl or phenyliminomethyl.
116. The compound of claim 112, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl.
117. The compound of claim 112, wherein R3Is hydrogen, methyl, allyl or heteroarylmethyl; r4Is 1-2 substituents independently selected from: hydrogen, methyl, methoxy, bromo, fluoro, 5-phenyl, 6-phenyl, 5-pyridyl, 6-pyridyl, 5-furyl, 6-furyl and hydroxy.
HK07103171.8A 2003-06-27 2004-06-22 Tricyclic delta opioid modulators HK1097532B (en)

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