Patent Grant
7071180
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2c receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the non-specific 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, causes weight loss in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Weight reduction has also been reported from clinical studies with other “serotonergic” agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2c receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs. 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
Information disclosure
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A 1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
J. Med. Chem. 1981, 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particularly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists particularly for use as anti-obesity agents.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
GB-B-1,457,005 discloses 1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives which exhibit anti-inflammatory activity.
Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT3 antagonists including 2-(4-methyl-1-piperazinyl)-4-phenoxyquinoxaline.
GB-B-1,440,722 discloses 2-(1′-piperazinyl)-quinoxaline compounds having pharmaceutical activity against depression.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 97/14689 discloses aryl-piperazine cyclic amine derivatives which are selective 5-HT1d receptor antagonists.
WO 98/42692 discloses piperazines derived from cyclic amines which are selective antagonists of human 5-HT1a, 5-HT1d and 5-HT1b receptors.
GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl and pyridyl compounds which are active as β-receptor blocking agents.
EP-A-711757 discloses [3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine and benzene derivatives as α-adrenoceptor antagonists.
WO 99/03833 discloses aryl-piperazine derivatives which are 5-HT2 antagonists and 5-HT1a receptor agonists and therefore are useful as remedies or preventives for psychoneurosis.
WO 96/02525 discloses aryl-piperazine-derived piperazide derivatives having 5-HT receptor antagonistic activity.
WO 99/58490 disloses aryl-hydronaphthalen-alkanamines which may effectuate partial or complete blockage of serotonergic 5-HT2c receptors in an organism.
According to the present invention, a class of novel compounds have been developed which bind to the 5-HT2c receptor (agonists and antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
In one aspect, the invention provides novel compounds of the general formula (I):
wherein
A limited group of compounds of the invention comprise compounds of formula (I) as defined above but with the further proviso that when Ar is optionally substituted phenyl, pyridyl or quinoxalinyl, then A is a group -Het—CH(R6)—CH(R6)—Het-, where each Het independently is selected from O, S and N(R6), and R6 is as defined above.
In case the compounds of formula (I) can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
In case the compounds of formula (I) contain groups which may exist in tautomeric forms, the invention comprises the tautomeric forms of the compounds as well as mixtures thereof, e.g. a 2-hydroxypyridine and its tautomer 1H-2-pyridone.
In case the compounds of formula (I) can be in the form of geometrical isomers, the invention comprises the geometrical isomers as well as mixtures thereof.
In another aspect, the invention provides the compounds according to formula (I) above for use in therapy.
Still another aspect of the invention provides a pharmaceutical composition comprising a compound according to formula (I) above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disease, particularly 5-HT2 receptor-related, especially eating disorders, particularly obesity; memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders.
Another aspect of the invention provides the use of the compounds according to formula (I) above for the manufacture of a medicament for the treatment of a serotonin-related disease, particularly 5-HT2 receptor-related, especially eating disorders, particularly obesity; memory disorders; schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders.
Still another aspect of the invention provides methods for the preparation of the compounds according to formula (I) above.
First, the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
By “heteroatom” is meant nitrogen, oxygen, sulphur, and in heterocyclic rings (including heteroaromatic as well as saturated and partially saturated heterocyclic rings), also selenium.
The term “aryl” is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl (substitutions may be in any ring).
The term “heteroaryl” means a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic, and substitutions may be in any ring) having from 5 to 14, preferably 5 to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, coumarin, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, 2,3-dihydro-1,4-benzodioxine, indane, 1,3-benzodioxole, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine, xanthene, 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine, and 2,3-dihydro-1,4-benzoxathiine. The heteroaryl ring may be linked to the divalent group A in formula (I) via a carbon or nitrogen atom thereof. If a bi- or tricyclic ring is substituted, it may be substituted in any ring.
The term “heteroalkylene” means an alkylene group which contains a terminal heteroatom at one or both ends and/or one or more carbon chain-interrupting heteroatom(s) selected from N, O and S. The number of heteroatoms is at least one, and usually from one to three, especially one or two. When heteroalkylene is substituted, it is usually substituted at a carbon atom by C1-4-alkyl or oxo, but it may alternatively or additionally be substituted at a nitrogen by C1-4-alkyl or at a sulphur atom by oxo (S═O or O═S═O), if present.
The term “heterocyclyl” is intended to include fully unsaturated (i.e. aromatic) as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, and containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, such as, for example, the heteroaryl groups mentioned above as well as their corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.
C1-6-alkyl, which may be straight or branched, is preferably C1-4-alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
C1-6-alkoxy, which may be straight or branched, is preferably C1-4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
C2-6-alkenyl, which may be straight or branched, is preferably C2-4-alkenyl, e.g. 1-propenyl, 2-propenyl, vinyl.
C2-6-alkynyl, which may be straight or branched, is preferably C2-4-alkynyl, e.g. propargyl, ethynyl.
C3-8-cycloalkyl is preferably C4-7-cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
C1-6-acyl may be saturated or unsaturated and is preferably C1-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl), hexenoyl (e.g. 5-hexenoyl).
C1-8-alkylene (wherein 1-8 is the number of chain carbon atoms) and heteroalkylene having 2 to 8 chain atoms, which may contain one or more unsaturations (double and/or triple bonds), are preferably C1-4-alkylene and heteroalkylene of 2 to 4 chain atoms, respectively. Exemplary alkylene groups include methylene, ethylene, propylene, butylene and their isomers (e.g. 1,3-butlene, 2-methyl-1,3-propylene). Exemplary heteroalkylene groups include oxymethylene (and methylenoxy), oxyethylene (and ethylenoxy), oxypropylene (and propylenoxy), oxybutylene (and butylenoxy), ethylenedioxy, propylenedioxy, butylenedioxy, oxyallyl (and allyloxy), etc. An exemplary alkyl-substituted heteroalkylene group is methylethylenedioxy.
Hydroxy-C1-6-alkyl may be straight or branched. Exemplary hydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.
Exemplary aryl-C1-6-acyl groups include benzoyl, 1-naphthoyl, 2-naphthoyl, cinnamoyl and phenylacetyl.
Exemplary C1-6-alkylcarbonyl-C1-6-alkyl groups include 2-oxobutyl.
Exemplary C1-6-alkoxy-C1-6-alkyl groups include 2-ethoxyethyl.
Exemplary C1-6-alkoxycarbonyl-C1-6-alkyl groups include ethoxycarbonylbutyl.
Exemplary C1-6-acyloxy-C1-6-alkyl groups include propanoyloxypropyl.
Exemplary saturated and unsaturated (partially and fully) azacyclic and saturated azabicyclic rings include azetidine, pyrrolidine, piperidine, morpholine, hexahydroazepine, tetrahydropyridine, pyridine and 1-azabicyclo[2.2.2]octane. The azacyclic and azabicyclic rings are coupled via a ring carbon atom when n=0.
Exemplary saturated and unsaturated aminoazacyclic rings include aminopiperidine (e.g. 4-aminopiperidine), aminoazetidine (e.g. 3-aminoazetidine), aminopyrrolidine (e.g. 3-aminopyrrolidine), and aminopyridine (e.g. 4-aminopyridine). The aminoazacyclic rings are preferably coupled to B or Ar in formula (I) via either the aza nitrogen atom or the amino nitrogen atom. An example of a saturated aminoazabicyclic ring is 3-aminoazabicyclo[2.2.2]octane, and the coupling is preferably via the 3-amino nitrogen atom.
An example of a saturated aminodiazacyclic ring is 1-aminopiperazine, and the coupling is preferably via either the 4-aza nitrogen atom or the 1-amino nitrogen atom.
Exemplary saturated diazacyclic rings include piperazine and homopiperazine, and an example of a diazabicyclic ring is diazabicyclo[2.2.1]heptane. The diazacyclic and diazabicyclic rings are preferably coupled via one of the ring nitrogens.
The group —[C(R4)(R5)]xN(R2a)(R3a) is preferably linked to Ar in formula (I) via a heteroatom (i.e. when n=1 and B is oxygen, nitrogen or sulphur).
As indicated by the expression “independently for each substituted carbon atom” with regard to substitutents R4 and R5, each individual carbon atom in the chain —[C(R4)(R5)]x-may be differently substituted than the adjacent carbon atom(s). An exemplary chain, werein x=3, illustrating this is —CH(CH3)—CH2—C(CH3)(CH3)—.
Halogen includes fluorine, chlorine, bromine and iodine.
Where it is stated above that aryl, heteroaryl and heterocyclyl residues may be substituted, this applies to aryl, heteroaryl and heterocyclyl per se as well as to any combined groups containing aryl, heteroaryl or heterocyclyl residues, such as aryl-C1-6-acyl, heteroaryl-C2-4-alkenyl, heterocyclylthio, etc.
The term “N-oxides” means that one or more nitrogen atoms, when present in a compound, are in N-oxide form (N→O).
The term “prodrug forms” means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15.
“Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
“A” in formula I is preferably a C2-8-alkylene chain or a heteroalkylene chain having at least two chain atoms.
More preferably, “A” in formula I is a divalent group of the general formula (II):
wherein
The expression “independently for each substituted carbon atom” means that if in formula (II) the integers o and/or g are 2 or 3, each carbon atom in question may be differently substituted. Thus, in the case of R9 and R10, for example, if o is 2 or 3, for each of the two or three carbons atoms, the meanings of R9 and R10 may be chosen independently of the meanings for R9 and R10 on the other two or three carbon atoms. For example, when o=2, the coupling to X is via a single bond, and R9 and R10 are independently selected from hydrogen and methyl, then e.g. R9 may be hydrogen and R10 methyl on the first carbon atom and both R9 and R10 may be hydrogen on the second carbon atom. i.e. the group 1-methylethylene. If R9 and R10 on the first carbon atom are hydrogen and, on the second carbon atom R9 is hydrogen and R10 is methyl, the group 2-methylethylene is obtained. Exemplary groups for o=3, when R9 and R10 are independently selected from e.g. hydrogen, methyl and oxo, are 2-oxo-1,3-butanediyl, 1-oxo-2-methyl-1, 3-propanediyl, 1-oxo-1,3-butanediyl and 1-oxo-2-methyl-1,3-butanediyl. The corresponding applies, of course, also to Y and Z in formula (II) when Y and Z are other than —O— or —S— and the integers p and r, respectively, are 2 or 3.
When formula (II) contains a carbon—carbon double bond(s) and/or a triple bond(s), one or both substituents on each participating carbon atom is, of course, omitted (for double bonds: R9 and R13 and/or R11 and R16, respectively; and for triple bonds: R9, R10, R13 and R14 and R11, R12, R16 and R17, respectively).
In a preferred embodiment, A in formula (I) is a group -Het—CH(R6)—CH(R6)—Het-, where each Het independently is selected from O, S and N(R6), and R6 is as defined above, preferably hydrogen or methyl, particularly hydrogen.
The presently most preferred group A is —O—CH2—CH2—O—. Other preferred groups A include —S—CH2—CH2—O—, —O—CH2—CH2—S—, and —O—CH2—CH2—CH2—.
In another preferred embodiment, A is —O—CH2— and R is optionally substituted heteroaryl, e.g. 2,3-dihydro-1,4-benzodioxine, 3,4-dihydro-2H-1,4-benoxazine, 2,3-dihydro-1,4-benzoxathiine, quinoline, benzofuran, 3,4-dihydro-2H-pyrido(3,2-b)-1,4-oxazine.
R in formula (I) is preferably optionally substituted aryl or heteroaryl. When R is aryl, it is preferably phenyl which is substituted or unsubstituted, preferably substituted. When R is substituted phenyl, it is preferably substituted in the meta-position. When R is heteroaryl, it is preferably selected from pyridine, isoquinoline, quinoline, quinoxaline, 2,3-dihydro-1,4-benzodioxine, benzoxazole, 2,1,3-benzothiadiazole, coumarin, 3,4-dihydro-2H-1,4-benzoxazine and quinazoline. Especially R is a substituted (especially meta-substituted) phenyl ring, or an unsubstituted or substituted pyridine ring.
Ar in formula (I) is preferably unsubstituted or substituted pyrazine, quinoxaline, 1,2,5-thiadiazole, pyridyl or phenyl.
When Ar is substituted it is usually mono- or (independently) di-substituted. Preferred substituents on Ar are selected from C1-4-alkyl. C1-4-alkoxy, C1-4-alkylthio. C1-4-alkylsulphonyl, cyano, hydroxy, C2-4-alkenyl, C2-4-alkynyl, trifluoromethyl, trifluoromethylthio, halogen, amino, methylamino, dimethylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, wherein any aryl and heterocyclyl residues in turn may be substituted in one or more positions independently of each other by halogen, methyl, methoxy, methylthio, methylsulphonyl, nitro, trifluoromethyl, cyano, hydroxy, amino, methylamino and dimethylamino or acetamido.
R1 in formula (I) is preferably a saturated diazacyclic ring, especially piperazine, unsubstituted or substituted by C1-4-alkyl, e.g. mono-substituted, particularly by methyl (at any position).
The integer n in formula (I) is preferably 0. When n=1, B is preferably —N(R6)—, —O—, —S— or —SO2—, where R6 is as defined above.
The integer o in formula (II) is preferably 2.
The integer p in formula (II) is preferably 1.
The integer q in formula (II) is preferably 0.
The integer r in formula (II) is preferably 0.
X, Y and Z are preferably oxygen.
R9 to R12 are preferably hydrogen.
In a preferred subgroup of compounds of formula I, Ar is a pyrazine ring, i.e. compounds of formula (Ia):
wherein
When R20 and R21 in formula (Ia) form a 5- or 6-membered aromatic or heteroaromatic ring together with the pyrazine ring carbons, such a ring may, for example, be selected from the aryl and heteroaryl rings mentioned above.
R20 and R21 are preferably (independently) hydrogen, halogen or methyl. When R20 and R21 form a ring together with the ring carbons to which they are bound, such a ring is preferably benzene (to give quinoxaline) or thiophene (to give thieno[3,4-b]pyrazine). When substituted, the rings are preferably mono- or (independently) disubstituted, such as by halogen or methyl.
The integers m1 and m2 are preferably both zero (i.e. the pyrazine nitrogens are not in oxidized form).
A subgroup of the compounds of formula (Ia) consists of compounds of formula (Ib):
wherein:
Exemplary ring systems formed when R26 is linked to Ra are 2,3-dihydro-1,4-benzodioxine 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1,4-benzoxathiine and benzofuran.
In formula (Ib), R22 is preferably hydrogen, and R23 and R24 are preferably C1-4-alkyl, especially methyl, or hydrogen. Particularly, R23 is methyl (especially in the 2-position of the piperazine ring; and preferably with (R)-configuration at the chiral carbon atom), z is 1 and R24 is hydrogen. When R23 or R24 are other than hydrogen and at least one of y and z is 2, or y and z both are I, then R23 or R24, respectively, may be on the same or different carbon atoms.
R25 is preferably hydrogen.
Presently preferred compounds of the general formula (I) above are:
As mentioned above, the compounds of the present invention are useful for the treatment (including prophylactic treatment) of serotonin-related disorders, especially 5-HT2 receptor-related, in a human being or in an animal (including e.g. pets), such as eating disorders, especially obesity; memory disorders, such as Alzheimer's disease; schizophrenia; mood disorders, including, but not restricted to, major depression and bipolar depression, including both mild and manic bipolar disorder, seasonal affective disorder (SAD): anxiety disorders, including situational anxiety, generalised anxiety disorder, primary anxiety disorders (panic disorders, phobias, obsessive-compulsive disorders, and post-traumatic stress disorders), and secondary anxiety disorders (for example anxiety associated with substance abuse); pain; sexual dysfunctions; and urinary disorders, such as urinary incontinence.
The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
The compounds of the general formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods.
Method A:
Compounds of formula (I) above in which A is bound to Ar via an O, S or N atom in A, and (i) n=0 and R1 is a saturated aminoazacyclic, aminodiazacyclic, diazacyclic or diazabicyclic residue, or (ii) n=1, B is —N(R6)— or —N(R6)C(R4)(R5)—, wherein R4, R5 and R6 are as defined above, and R1 is a saturated or unsaturated azacyclic, or a saturated azabicyclic, residue, are prepared by reacting a compound of the structural formula (III):
wherein Ar is as defined above and Hal is halogen, with a compound R—A′—X′—H or its corresponding anion where X′ is —O—, —S— or —N(R15)—, A′ is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom binding to R, said heteroatoms being selected from N, O and S, and R and R15 are as defined above, to produce a compound of the formula (IV):
wherein Ar, X′, A′, R and Hal are as defined above. The compound R—A′—X′—H may be converted completely or partially to its corresponding anion by treatment with bases, such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, K2CO3, NaOH, NaH, KO-t-Bu, lithium diisopropylamide or the like. The reaction is carried out in a solvent, such as dioxane, tetrahydrofuran or N,N-dimethylformamide (DMF), at 0-200° C. for 1-24 hours. The compound of formula (IV) is reacted with 1 to 10 molar equivalents of the appropriate amine in a solvent, such as acetonitrile, dioxane, tetrahydrofuran, n-butanol, DMF, or in a mixture of solvents such as DMF/dioxane, optionally in the presence of a base, such as K2CO3, Na2CO3, Cs2CO3, NaOH, triethylamine, pyridine or the like, at 0-200° C. for 1-24 hours to produce the compound of formula (I).
Exemplary amines have the following structures:
wherein R23, R24, y and z are as defined above, and Z has the meanings defined for R22 in formula (Ib) above or is a suitable protecting group such as tert-butoxycarbonyl, trityl or benzyl.
Method B:
Compounds of formula (I) in which n=1, B is oxygen, sulphur and R1 is a saturated azacyclic or azabicyclic residue, or a group —[C(R4)(R5)]x (R2a)(R3a), wherein R2, R3, R4, R5 and x are as defined above, are prepared by reacting a compound of formula (IV) above with a corresponding hydroxy- or mercapto-substituted azacyclic or azabicyclic compound, or with a compound HO—R1 or HS—R1, where R1 is —[C(R4)(R5)]xN(R2a)(R3a). Exemplary hydroxy- and mercapto-substituted compounds have the following, structures:
wherein Z is as defined above.
The reaction is carried out in a solvent, such as toluene, DMF or dioxane, in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, KOH, KO-t-Bu, NaH or the like, at 0-200° C. for 1-24 hours.
Method C:
Compounds of formula (I), wherein A is bound to R via an oxygen or sulphur atom in A, are prepared by reacting a compound of formula (V):
wherein Ar, R1, B and n are as defined above, A″ is C1-8-alkylene wherein the carbon chain may be interrupted by one or more heteroatoms and which may have a terminal heteroatom bound to Ar, said heteroatoms being selected from N, O and S, and L is a hydroxy, thiol or a leaving group such as, for example, halogen, tosyloxy, mesyloxy and the like, with a compound R—OH or R—SH, where R is as defined above, to produce the compound of formula (I).
When L is a free hydroxy or thiol group, the reaction may be carried out in the presence of diethyl azodicarboxylate (DEAD) or 1,1′-azobis(N,N-dimethylformamide) (cf. Tetrahedron Lett. 1995, 36, 3789-3792), preferably DEAD, and triphenylphosphine (PPh3) in a solvent such as tetrahydrofuran or dichloromethane (Mitsunobu reaction, see Org. React. 1992, 42, 335-656).
When L is a leaving group, the reaction may be carried out in the presence of a suitable base, such as Na2CO3, K2CO3, Cs2CO3, KOH, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like, in a solvent, such as acetonitrile or DMF, at 0-200° C. for 1-24 hours.
In case the group —(B)nR1 in formula (V) contains a primary or secondary amino group, the nitrogen may be protected with a suitable protecting group, preferably tert-butoxycarbonyl, trityl or benzyl. N-Deprotection is then carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley & Sons. 1991.
Method D:
Compounds of formula (I), in which A is bound to Ar via an O, S or N atom in A, and wherein n=0, or n=1 and B is oxygen, nitrogen, sulphur, —N(R6)C(R4)(R5)—, wherein R4, R5 and R6 are as defined above, are prepared by reacting a compound of formula (III) above with an appropriate amine, or an appropriate hydroxy- or mercapto-substituted compound to produce a compound of formula (VI):
The reaction conditions may be those described for method A above.
Exemplary amines, hydroxy- and mercapto-substituted compounds include those shown in connection with methods A and B above as well as a compound HO—R1 or HS—R1, where R1 is —[C(R4)(R5)]xN(R2a)(R3q), and wherein R2, R3, R4, R5 and x re as defined above.
Compounds of formula (I), in which Ar represents an optionally substituted phenyl, naphthyl, pyridyl, or quinolinyl nucleus and (i) A is oxygen or (ii) A is bound to Ar via an oxygen atom in A, may be prepared by methods well known in the art, as illustrated in Examples 184 and 185 below.
An obtained compound of formula (I) may be converted to another compound of formula (I) by methods well known in the art (illustrated in e.g. Example 216).
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds. For example, the aryloxy- and heteroaryloxyethanols used in the preparation of the novel compounds of formula (I) may be prepared using the methods depicted in Scheme 1 below.
In accordance with the present invention, the compounds of formula (I), in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) in association with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transdermal preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders in a human being or an animal, such as eating disorders, particularly obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders. The compounds may also be useful for treating gastrointestinal disorders, such as gastrointestinal mobility disorders, e.g. irritable bowel syndrome (IBS), or glaucoma. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
The invention will now be further illustrated by the following non-limiting Examples.
General:
The structures of the prepared compounds were confirmed by standard spectroscopical methods, and elemental analysis and/or high resolution MS. The NMR data were obtained on a JEOL JNM-EX 270, a Bruker 400 DPX or a Bruker DRX 500 spectrometer. IR spectra were obtained on a Perkin Elmer SPECTRUM 1000 FT-IR spectrometer. High resolution MS were obtained on a Micromass LCT spectrometer. Elemental analysis was performed by Mikro Kemi AB. Uppsala, Sweden. Melting points, when given, were obtained on a Büchi or a Gallenkamp melting point apparatus and are uncorrected.
Step 1: 2-Chloro-3-(2-phenoxyethoxy)pyrazine.
NaO-t-Bu (2.91 g, 30.29 mmol) was added to a mixture of 2,3-dichloropyrazine (4.75 g, 31.9 mmol) and 2-phenoxyethanol (4.18 g, 30.3 mmol) in dioxane (25 mL). The reaction mixture was stirred at ambient temperature for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure and the crystalline residue obtained was dried in a vacuum oven affording 4.4 g (62%) of the title compound as white waxy crystals: mp 55-54° C. Anal. (C12H11CIN2O2) C, H, N.
Step 2: 2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
A mixture of the product from Step 1 (1.705 g, 6.80 mmol), piperazine (1.75 g, 20.3 mmol), and K2CO3 (1.16 g, 8.39 mmol) in acetonitrile (10 mL) was stirred at 50° C. for 1.5 h and for a further 3 h at 80° C. The reaction mixture was diluted with CH2Cl2, filtered, and concentrated. Purification of the semi-solid residue by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent gave a beige oil. This material was redissolved in ether/CHCl3 (9:1), dried over K2CO3, and filtered through a short (3 cm) plug of alumina. The filtrate was concentrated in vacuo to afford 1.33 g (65%) of the title compound as the free base. The free base was converted to the maleate and recrystallized from MeOH/ether: mp 155-157° C.; HRMS m/z calcd for C16H20N4O2 (M)+300.1586, found 300.1573. Anal. (C16H20N4O2.C4H4O4) C, H, N.
Step 1: 2-Chloro-3-(2-furylmethoxy))pyrazine.
The title compound was prepared according to the procedure described in Example 1. Step 1, starting from 2-furanmethanol (4.18 g, 42.7 mmol), 2,3-dichloropyrazine (2.05 g, 13.8 mmol) and KO-t-BuO (1.82 g, 16.2 mmol). The product, which was obtained as a yellowish oil in 68% yield, was used directly in the next step.
Step 2: 2-(2-Furylmethoxy)-3-(1-piperazinyl)pyrazine, Maleate.
The title compound was prepared according to the procedure described in Example 1, Step 2, starting from 2-chloro-3-(2-furylmethoxy)pyrazine (1.47 g, 7.0 mmol): yield 0.62 g (34%) as the free base. A portion of the free base was converted to the maleate salt: mp 118-120° C.; HRMS m/z calcd for C13H16N4O2(M)+260.1273, found 260.1270. Anal. (C13H16N4O2.C4H4O4) C, H, N.
Step 1: 2-Chloro-3-(2-phenoxyethoxy)quinoxaline.
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-phenoxyethanol (3.7 g, 26.8 mmol), 2,3-dichloroquinoxaline (1.33 g, 6.7 mmol) and KO-t-Bu (0.75 g, 6.7 mmol): yield 0.74 g (37%); mp 99.5-101.5° C., HRMS m/z calcd for C16H13CIN2O2(M)+300.0666, found 300.0672. Anal. (C16H13CIN2O2) C, H, N.
Step 2: 2-(2-Phenoxyethoxy)-3-(1-piperazinyl)quinoxaline, Hydrochloride.
The title compound vas prepared according to the procedure described in Example 1, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)quinoxaline (0.65 g, 2.15 mmol): yield 0.44 g (58%) as the free base. A portion of the free base was converted to its hydrochloride salt: mp 123-126° C.; HRMS m/z calcd for C20H22N4O2(M)+350.1743, found 350.1748. Anal. (C20H22N4O2.1.75 HCl.0.5H2O)C, H, N.
Step 1: 2-Chloro-3-[2-(2-naphthyloxy)ethoxypyrazine.
Sodium hydride (55% dispersion in mineral oil; 44 mg, 1.0 mmol) was added to a mixture of 2-(2-naphthoxy)ethanol (188 mg, 1.00 mmol) and 2,3-dichloropyrazine (149 mg, 1.00 mmol) in dioxane (0.5 mL), and the reaction mixture was stirred at 40° C. for 15 h. The crude material was used directly in Step 2.
Step 2: 2-[2-(2-Naphthyloxy)ethoxy]-3-(1-piperazinyl)pyrazine, Trifluoroacetate.
A solution of piperazine (430 mg, 5.00 mmol) in a mixture of dioxane (0.5 mL) and DMF (1 mL) was added to the crude material from Step 1. The reaction mixture was stirred at 60° C. for 15 h, then diluted with EtOAc, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using EtOAc/MeOH/HOAc/H2O (20:3:3:2) as eluent. The product-containing fractions were combined and concentrated. The residue was further purified by C-18 HPLC using CH3CN/H2O/TFA (gradient: CH3CN 0% to 100%, TFA 0.1%) to give 34.5 mg (10%) of the title product. HRMS m/z calcd for C20H22N4O2(M)+350.1743, found 350.1742.
Examples 5-20 were prepared in an analogous manner starting from 2,3-dichloropyrazine (1 mmol) and the appropriate alcohol (1 mmol).
The title compound was prepared starting from 2-(4-bromophenoxy)ethanol to give 47 mg (12%). HRMS m/z calcd for C16H19BrN4O2(M)+378.0691, found 378.0698.
The title compound was prepared starting from 2-(2-chlorophenoxy)ethanol to give 32 mg (10%). HRMS m/z calcd for C16H10CIN4O2 (M)+334.1197, found 334.1195.
The title compound was prepared starting from 2-(4-chlorophenoxy)ethanol to give 56 mg(17%). HRMS m/z called for C16H19CIN4O2(M)+33.1197, found 334.1182.
The title compound was prepared starting from 2-phenoxypropanol to give 24 mg (6%). HRMS m/z calcd for C17H22N4O2(M)+314.1743, found 314.1742.
The title compound was prepared starting from 1-phenoxy-2-propanol to give 29 mg (9%). HRMS m/z calcd for C17H22N4O2(M)+314.1743, found 314.1732.
The title compound was prepared starting from 1-(2-methoxyphenoxy)-2-propanol to give 25 mg (5%). HRMS m/z calcd for C18H24N4O3(M)+344.1848, found 344.1852.
The title compound was prepared starting from 1-(3-methoxyphenoxy)-2-propanol to give 38 mg (11%). HRMS m/z calcd for C18H24N4O3(M)+344.1848, found 344.1842.
The title compound was prepared starting from 1-(2-methylphenoxy)-2-propanol to give 60 mg (18%). HRMS m/z calcd for C18 H24N4O2(M)+328.1899, found 328.1898.
The title compound was prepared starting from 1-(4-methylphenoxy)-2-propanol to give 12 mg (3%). HRMS m/z calcd for C18H24N4O2(M)+328.1899, found 328.1896.
The title compound was prepared starting from 2-(phenylthio)ethanol to give 30 mg (10%). HRMS m/z calcd for C16H20N4OS (M)+316.1358, found 316.1359.
The title compound was prepared starting from 2-anilinoethanol to give 48 mg (16%). HRMS m/z calcd for C16H2lN5O (M)+299.1746, found 299.1754.
The title compound was prepared starting from 2-(N-ethylanilino)ethanol to give 7 mg (2%). HRMS m/z calcd for C18H25N5O (M)+327.2059, found 327.2057.
The title compound was prepared starting from 2-hydroxymethyl-1,4-benzodioxane to give 22 mg (5%). HRMS m/z calcd for C17H20N4O3(M)+328.1535, found 328.1519.
The title compound was prepared starting from 3-phenyl-1-propanol to give 9 mg (2%). HRMS m/z calcd for C17H22N4O (M)+298.1794, found 298.1795.
The title compound was prepared starting from 4-phenyl-1-butanol to give 10 mg (2%). HRMS m/z calcd for C18H24N4O (M)+312.1950, found 312.1963.
The title compound was prepared starting from 2-benzyloxyethanol to give 31 mg (7%). HRMS m/z calcd for C17H22N4O2(M)+314.1743, found 314.1739.
Step 1: 4-(2-Hydroxyethoxy)-2-amino-1,3-benzoxazol.
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 4-hydroxy-2-amino-1,3-benzoxazol*(0.97 g, 6.5 mmol) and ethylene carbonate (0.63 g, 7.1 mmol). Solid; yield 46%; mp 124-126° C. Anal. (C9H10N2O3) C, H, N.
*Previously described in J. Chem. Soc. 1960, 2369-2370.
Step 2: 4-{2-[(3-Chloro-2-pyrazinyl)oxy]ethoxy}-1,3-benzoxazol-2-amine.
The title compound was prepared according to the procedure of Example 4, Step 1, except that 4 equiv of both NaH and 2,3-dichloropyrazine were used, starting from the product of Step 1. The reaction temperature was 90° C. The crude product was used directly in the next step.
Step 3: 4-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1,3-benzoxazol-2-amine Fumarate.
The title compound was prepared according to the procedure of Example 1. Step 2, starting from the product of Step 2 above. Yield of free base 24%. The free base was converted to the fumarate salt: mp 138-140° C. Anal. (C17H20N6O3.C4H4O4.0.25H2O)C, H, N.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and 3-aminopyrrolidine (270 mg, 3.13 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 121 mg (67%) of the title product. Anal. (C16H19N4O2) C, H; N: calcd, 18.65; found, 18.0.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 3-aminopyrrolidine (252 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg(56%) of the title product. Anal. (C16H19CIN4O2) C, H; N: calcd, 16.73; found, 16.0.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 3-aminopyrrolidine (247 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 123 mg (69%) of the title product. Anal. (C16H19CIN4O2) H, N; C: calcd. 57.40; found, 56.9.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and homopiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 141 mg (75%) of the title product. Anal. (C17H22N4O2.0.35EtOAc) C, H, N.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and homopiperazine (266 mg, 2.66 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 105 mg (57%) of the title product. Anal. (C18H24N4O3) H, N; C: calcd, 63.14; found, 62.70.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and homopiperazine (287 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (69%) of the title product. HRMS m/z calcd for C17H21CIN4O2(M)+348.1353, found 348.1353. Anal. (C17H21CIN4O2) C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4. Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol, from Example 1, Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (73%) of the title product. Anal. (C17H22N4O2) C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 2-methylpiperazine (256 mg, 2.56 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 143 mg (77%) of the title product. HRMS m/z calcd for C17H21CIN4O2(M)+348.1353, found 348.1370. Anal. (C17H21CIN4O2)C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (65%) of the title product. HRMS m/z calcd for C19H26N4O3M)+358.2005, found 358.2018. Anal. (C19H26N4O3) C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and 2-methylpiperazine (293 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (64%) of the title product. HRMS m/z calcd for C18H22N4O3(M)+342.1692, found 342.1678. Anal. (C18H22N4O3) H, N; C: calcd, 63.14; found, 62.30.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and N-ethylpiperazine (250 mg, 2.19 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (64%) of the title product. Anal. (C18H24N4O2) C, H, N.
The title compound was prepared in an analogous manner to Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg (52%) of the title product. Anal. (C18H24Cl4O2) C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4. Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 138 mg (72%) of the title product. HRMS m/z calcd for C18H23CIN4O2(M)+362.1510, found 362.1526. Anal. (C18H23CIN4O2)C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and N-ethylpiperazine (219 mg, 1.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (66%) of the title product. HRMS m/z calcd for C19H24N4O3(M)+356.1848, found 356.1848. Anal. (C19H24N4O3) C, H, N.
*Prepared according to the procedure described in Example 4, Step 1.
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and N-ethylpiperazine (222 mg, 1.94 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (67%) of the title product. HRMS m/z calcd for C20H28N4O3(M)+372.2161, found 372.2174. Anal. (C20H28N4O3) C, H, N.
*Prepared according to the procedure described in Example 4, Step I.
Step 1: 2-(3-Bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether.
A mixture of 3-bromophenol (1.73 g, 10.0 mmol), ethylene oxide (0.44 g, 10 mmol). Et3N (3 drops) and dioxane (4 mL) was heated at 100° C. in a sealed tube for 2 d. The solution was cooled in an ice-bath and KO-t-Bu (1.07 g, 9.50 mmol) followed by 2,3-dichloropyrazine (1.34 g, 9 mmol) were added along with dioxane (1 mL). The mixture was stirred at room temperature for 90 min, diluted with CH2Cl2 and filtered. The filtrate was concentrated and the residue was purified by chromatography-on silica gel (gradient: isohexane to 25% EtOAc/isohexane) to give 2.21 g (75%) of the title product as a white solid: mp 57-58° C. Anal. (C12H10BrCIN2O2) C, H, N.
Step 2: 2-(3-Bromophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
Piperazine (1.29 g, 15.0 mmol) and K2CO3 (0.69 g, 5.0 mmol) were added to a solution of 2-(3-bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether (1.65 g, 5.00 mmol) in acetonitrile (25 mL) at room temperature. The mixture was heated at reflux for 21 h, allowed to cool, concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with water and brine, and dried over MgSO4. Purification by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) gave 1.61 g (85%) of the title compound as a pale yellow oil that slowly solidified on standing: mp 62-63° C. Anal. (C16H19BrN4O2) C, H, N.
Step 1: 2-Chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline.
2-(2-Chlorophenoxy)ethanol (0.229 g, 1.33 mmol) was treated with NaH (55% dispersion in mineral oil; 0.058 g, 1.33 mmol) in dioxane (2 mL). After stirring at room temperature for 3 h, the mixture was added dropwise to a slurry of 2,3-dichloroquinoxaline (0.320 g, 1.60 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 15 h to produce the intermediate 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline which was used directly in the next step.
Step 2: 2-[2-(2-Chlorophenoxy)ethoxy]-3-(1-piperazinyl)quinoxaline.
Piperazine (0.580 g, 6.65 mmol) was added to the crude material from Step 1 and the resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the crude mixture was dissolved in DMSO and precipitated with water. The precipitate was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (40:3:3:2) as eluent to afford 0.100 g (22%) of the title compound as a yellow oil. HRMS m/z calcd for C20H21CIN4O2(M)+384.1353, found 384.1334.
Examples 39-45 were prepared according to the procedure of Example 38, starting from 2,3-dichloroquinoxaline and the appropriate alcohol.
The title compound was prepared starting from 2-(4-chlorophenoxy)ethanol (0.229 g, 1.33 mmol) to give 0.250 g (56%) of a yellow solid: mp 108-112° C.; HRMS m/z calcd for C20H21CIN4O2(M)+384.1353, found 384.1347.
The title compound was prepared starting from 2-(phenylthio)ethanol (0.205 g, 1.33 mmol) to give 0.045 g (9%) of a yellow oil. HRMS m/z calcd for C20H22N4OS (M)+366.1514, found 366.1509.
The title compound was prepared starling from 1-methyl-2-phenoxyethanol (0.202 g, 1.33 mmol) to give 0.084 g (17%) of a yellow oil. HRMS m/z calcd for C21H24N4O2(M)+364.1899, found 364.1908.
The title compound was prepared starting from 1-methyl-2-(4-methylphenoxy)ethanol (0.221 g, 1.33 mmol) to have 0.047 g (9%) of a yellow oil. Anal. (C22H26N4O2)C, H, N.
The title compound was prepared starting from 1-methyl-2-(2-methoxyphenoxy)ethanol (0.242 g, 1.33 mmol) to give 0.072 g (14%) of a yellow oil. Anal. (C22H26N4O3) C, H, N: calcd, 14.20; found, 13.70.
The title compound was prepared starting from 2,3-dihydro-1,4-benzodioxin-2-ylmethanol (0.221 g, 1.33 mmol) to give 0.18 g (35%) of a yellow oil. Anal. (C21H22N4O3) C, H, N.
The title compound was prepared starting from 2-(2-naphthyloxy)ethanol (0.250 g, 1.33 mmol) to give 0.22 g (41%) of a yellow solid. HRMS m/z calcd for C24H24N4O2(M)+400.1899, found 400.1902.
Step 1: 2-Chloro-3-(2-phenoxyethylamino)pyrazine.
A mixture of 2-phenoxyethylamine (2.65 g, 19.3 mmol), 2,3-dichloropyrazine (2.88 g, 19.3 mmol) and K2CO3 (2.67 g, 19.3 mmol) in acetonitrile (8 mL) was stirred in a sealed tube for 12 h at room temperature, and for a further 9.5 h at 80° C. The reaction mixture was diluted with ether, filtered, and concentrated. The residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 2.36 g (49%) of the title compound as a yellowish oil that solidified on standing: mp 51-53° C.; HRMS m/z called for C12H12CIN3O (M)+249.0669, found 249.0659, Anal. (C12H12CIN3O)C, H, N.
Step 2: 2-(2-Phenoxyethylamino)-3-(1-piperazinyl)pyrazine.
A mixture of the product from Step 1 above (1.59 g, 6.37 mmol), piperazine (1.56 g, 18.2 mmol), and K2CO3 (0.88 g, 6.4 mmol) in acetonitrile (10 mL) was stirred at 140° C. for 12 h in a sealed tube. After cooling, the reaction mixture was diluted with CH2Cl2, filtered, and concentrated. The semisolid residue %% as purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give a beige oil. This oil was redissolved in CHCl3, and filtered through a short (3 cm) plug of alumina covered with K2CO3. The pad was washed with several portions of CHCl3 and the resulting filtrate was concentrated to afford 1.48 g (78%) of the title product as a pale yellow oil. HRMS m/z calcd for C16H21N5O (M)+299.1746, found 299.1753. Anal. (C16H21N5O.⅓H2O)C, H, N.
Step 1: 3-Chloro-N-methyl-N-(2-phenoxyethyl)-2-pyrazinamine.
A mixture of 2,3-dichloropyrazine (6.64 g, 44.6 mmol) and N-methyl-N-(2-phenoxyethyl)amine* (4.5 g, 29.8 mmol) in DMF (5 mL) was placed in a sealed Pyrex tube and heated in a microwave oven (Labwell MW10) for 1×2 min followed by 2×1 min at 75 W. The mixture was concentrated and the resulting oil was purified by column chromatography on silica using hexane/EtOAc (95:5 followed by 93:7) to give 5.56 g (71%) of the title product as a colorless oil. HRMS m/z calcd for C13H14CIN3O (M)+263.0825, found 263.0824.
*Previously described in J. Chem. Soc. 1963, 1385-1400.
Step 2: N-Methyl-N-(2-phenoxyethyl)-3-(1-piperazinyl)-2-pyrazinamine, Fumarate.
A mixture of the product obtained in Step 1 (5.0 g, 19 mmol) and piperazine (5.0 g, 59.4 mmol) in DMF (10 mL) was placed in a sealed Pyrex tube and heated in a microwave oven (Labwell MW10) for 2.5 min at 75 W. The mixture was concentrated and the remaining yellow oil was partitioned between water and CHCl3. The water phase was extracted with CHCl3 (×2) and the combined organic phases were extracted with 0.5 M aqueous HCl (×2). The combined aqueous phases were made alkaline (11M NaOH) and extracted with CHCl3 (×3). The combined organic phases were washed with water and brine, dried (MgSO4), and concentrated to give the free base of the title product as a light yellow oil. The free base was converted to its fumarate salt. Yield 1.38 g (17%) of off-white crystals from methanol; mp 154° C. Anal. (C17H23N5O.C4H4O4) H, N; C: calcd, 58.7, found, 58.05.
2-Chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) was added to a stirred mixture of 3-pyrrolidinol (260 mg, 2.99 mmol) and NaH (55% dispersion in mineral oil; 110 mg, 2.50 mmol) in dioxane (2 mL), and the reaction was stirred at room temperature for 2 h. EtOAc was added and the mixture was washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using EtOAc/MeOH/HOAc/H2O (50:40:9:1) as eluent to give 38 mg (22%) of the title compound. Anal. (C16H19N3O3) H; C: calcd, 63.77; found, 62.20; N: calcd, 13.94; found, 13.0.
Step 1: 2-(Phenoxy)ethyl 3-[N-tert-butoxycarbonyl (3R)-pyrrolidinyloxy]-2-pyrazinyl ether.
2-Chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) was added to a mixture of N-Boc-(R)-3-pyrrolidinol (225 mg, 1.20 mmol) and KO-t-Bu (140 mg, 1.25 mmol) in toluene (5 mL), and the reaction was stirred at 95° C. for 30 min. The reaction mixture was diluted with toluene, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc (9:1) as eluent to give 261 mg (65%) of the title product which was used in the next step without further characterization.
Step 2: 2-(Phenoxy)ethyl 3-[(3R)-pyrrolidinyloxy]-2-pyrazinyl ether.
The product from Step 1 above was treated with CH2Cl2/trifluoroacetic acid/H2O (50:45:5; 4 mL) for 30 min. The mixture was concentrated and the residue was partitioned between 5% aqueous NaOH and CH2Cl2. After separation, the organic layer was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using CH2Cl2/MeOH (8:2) as eluent to give 44 mg (15%) of the title product: [α]D=−4.6° (c 0.017, MeOH); HRMS m/z calcd for C16H19N3O3 (M)+301.1426, found 301.1427.
The title compound was prepared according to the procedure described in Example 49 starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) and N-Boc-4-hydroxypiperidine (234 mg, 1.16 mmol) to give 112 mg (35%) of the title product. HRMS m/z calcd for C17H23N3O3(M)* 315.1583, found 315.1570.
The title compound was prepared according to the procedure described in Example 49, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) and N-Boc-L-prolinol (250 mg, 1.24 mmol). The intermediate product 2-(phenoxy)ethyl 3-[N-tert-butoxycarbonyl (2S)-pyrrolidinylmethoxy]-2-pyrazinyl ether was not characterized. Yield 23 mg (7%); [α]D=13.2° (c 0.016, MeOH). HRMS m/z calcd for C17H21N3O3(M)+315.1583, found 315.1598.
Step 1: 2-Chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine.
A mixture of N-Boc-piperazine (11.47 g, 61.5 mmol), K2CO3 (8.5 g, 61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile (100 mL) was stirred at 100° C. for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the title product. HRMS m/z calcd for C13H19N4O2(M)+298.1197, found 298.1206.
Step 2: 2-[3-(4-tert-Butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol.
KO-t-Bu (9.92 g, 103 mmol) was added to a mixture of the product obtained in Step 1 (18.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448 mmol) in pyridine (125 mL) at 85° C. The reaction mixture was stirred for 15 h and then poured into ice-water and extracted with toluene. The organic phase was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 16.9 g (85%) of the title product. HRMS m/z calcd for C15H24N4O4(M)+324.1798, found 324.1784.
Step 3: 2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
1,1′-Azobis(N,N-dimethylfomamide) (TMAD; 60 mg, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and added to a stirred solution of the product from Step 2 (100 mg, 0.31 mmol), 2-methoxyphenol (124 mg, 1.00 mmol) and triphenylphosphine (92 mg, 0.35 mmol) in THF (1 mL). The reaction mixture was stirred for 15 h and then concentrated under reduced pressure. The residue was passed through a bed of silica gel using toluene/EtOAc/MeOH (45:45:10) as eluent, and the pure fractions were combined, concentrated and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min. The mixture was concentrated and the residue was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The combined product-containing fractions were concentrated and partioned between 5% aqueous NaOH and CH2Cl2. The organic phase was concentrated, and the residue was purified by chromatography on silica gel using CH2Cl2/MeOH (8:2) as eluent to give 11.2 mg (11%) of the title product. HRMS m/z calcd for C17H22N4O3(M)+330.1692, found 330.1707.
Examples 53-68 were prepared according to the procedure described in Example 52, Step 3, starting from 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol and the requisite phenolic compound (1 mmol unless otherwise noted).
The title compound was prepared starting from p-butoxyphenol, but no extraction with NaOH and without the third chromatographic step, to give 92 mg (19%) as the trifluoroacetate salt. HRMS m/z calcd for C20H28N4O3(M)+372.2161, found 372.2162.
The title compound was prepared starting from 2-isopropoxyphenol to give 216 mg (60%). HRMS m/z calcd for C19H26N4O3(M)+358.2005, found 358.2006.
The title compound was prepared starting from 1-naphthol to give 142 mg (40%). HRMS m/z calcd for C20H22N4O2(M)+350.1743, found 350.1758.
The title compound was prepared starting from 2,5-difluorophenol, but no extraction with NaOH and without the third chromatographic step, to give 21 mg (6%) as the trifluoroacetate salt. HRMS m/z calcd for C16H18F2N4O2(M)+336.1398. Found 336.1407.
The title compound was prepared starting from 3,5-dimethoxyphenol to give 52 mg (14%). HRMS m/z calcd for C18H24N4O4(M)+360.1798, found 360.1808.
The title compound was prepared starting from 2-methoxy-5-nitrophenol (0.524 g, 3.08 mmol) to give 0.53 g (42%). Pos-EI-MS shows M+ and 10 ions supporting the stated structure. HRMS m/z calcd for C17H21N5O5(M)+375.1543, found 375.1561. Anal. (C17H21N5O5.0.5HCl.1.3H2O)C, H, N.
The title compound was prepared starting from 2,6-dimethoxyphenol to give 142 mg (30%). HRMS m/z calcd for C18H24N4O4(M)+360.1798, found 360.1797.
The title compound was prepared starting from 2,3-dimethoxyphenol to give 110 mg (31%). HRMS m/z calcd for C18H24N4O4(M)+360.1798, found 360.1800.
The title compound was prepared starting from 2-hydroxyacetophenone (170 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325 mg, 1 mmol, prepared in Example 52, Step 2), but no extraction with NaOH and without the third chromatographic step, to give 170 mg (37%) of the trifluoroacetate. HRMS m/z calcd for C18H22N4O3(M)+42.1692, found 342.1704.
The title compound was prepared starting from 2-hydroxy-4-methoxy-acetophenone (208 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325 mg, 1 mmol; prepared in Example 52, Step 2), but no extraction with NaOH and without the third chromatographic step, to give 128 mg (26%) of the trifluoroacetate. HRMS m/z calcd for C19H24N4O4(M)+372.1798, found 372.1810.
The title compound was prepared starting from 2-hydroxy-4,6-dimethoxyacetophenone (245 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325 mg, 1.00 mmol; prepared in Example 52, Step 2), but no extraction with NaOH and without the third chromatographic step, to give 216 mg (42%) of the trifluoroacetate. HRMS m/z calcd for C20H26N4O5(M)+402.1903, found 402.1886.
The title compound was prepared starting from 5,6,7,8-tetrahydro-2-naphthol (185 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325 mg, 1.00 mmol; prepared in Example 52, Step 2), but no extraction with NaOH and without the third chromatographic step, to give 155 mg (33%) of the trifluoroacetate. HRMS m/z calcd for C20H26N4O2(M)+354.2056, found 354.2068.
The title compound was prepared starting from 2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17 mmol; prepared in Example 52, Step 2) to give 230 mg (66%) of a yellow oil. HRMS m/z calcd for C17H21FN4O3(M)+348.1598, found 348.1602.
The title compound was prepared starting from 2-methoxy-4-methylphenol (162 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 mmol; prepared in Example 52, Step 2) to give 233 mg (67%) of a yellow solid. HRMS m/z calcd for C18H24N4O3(M)+344.1848, found 344.1839.
The title compound was prepared starting from 7-hydroxyisoquinoline (435 mg, 3.00 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 mmol; prepared in Example 52, Step 2). The free base of the title compound was converted to its fumarate salt. Yield 45 mg (2%); mp 157° C. (dec). HRMS m/z calcd for C19H21N5O2(M)+351.1695, found 351.1695. Anal. (C19H21N5O2.2.3C4H4O4).
The title compound was prepared starting from 2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61 mmol; prepared in Example 52, Step 2) according to the procedure described in Example 52, Step 3, but utilizing diethyl azodicarboxylate (DEAD) instead of TMAD. Yield 50 mg (21%) HRMS m/z calcd for C17H21CIN4O3(M)+364.1302, found 364.1307.
2-Fluoro-5-(trifluoromethyl)phenol (0.54 g, 3.0 mmol) was added to a stirred solution of DEAD (0.52 g, 3.0 mmol), PPh3 (0.79 g, 3.0 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.49 g, 1.5 mmol; prepared in Example 52, Step 2) in THF (50 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography on silica using isohexane/EtOAc (80:20) as eluent. The N-Boc protected intermediate obtained was treated with CH2Cl2/TFA (75:25; 5 mL) for 1 h at room temperature and concentrated. The residue was purified by column chromatography on silica using EtOAc/MeOH/Et3N (80:15:5) as eluent to give 0.22% g (38%) of the title compound. MS m/z 387 (M+H)+. HRMS m/z calcd for C17H18F4N4O2(M)+386.1366, found 386.1367.
Step 1: 8-Hydroxy-2H-1,4-benzoxazin-3(4H)-one.
The title compound was prepared according to procedure described in J. Med. Chem. 1996, 39, 3533-3538 by replacing 2-amino-m-cresol with 3-amino-pyrocatechol.*The crude product was purified by column chromatography on silica gel using EtOAc/isohexane (1:2 to 2:1) as eluent. Solid; yield 70%. MS m/z 165 (M)+. Anal. (C8H7NO3) C, H, N.
*Previously reported in Liebigs Ann. Chem. 1957, 608, 128 and Synth. Commun. 1997, 27, 1661-1668.
Step 2: 8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-1,4-benzoxazin-3(4H)-one, Maleate.
The title compound was prepared according to the procedure of Example 69 starting from the product of Step 1 above. Yield 42%. MS m/z 372 (M+H)+. Anal. (C18H21N5O4.C4H4O4) C, H, N.
Step 1: 3-(Methylsulfonyl)phenol.
The title compound was prepared by a slightly modified literature procedure.*3-aminophenyl methyl sulfone hydrochloride (1.18 g, 5.70 mmol) was suspended in water/CH2Cl2. The mixture was neutralized with 25% aqueous NaOH. The CH2Cl2 layer was isolated and evaporated to dryness. Aqueous H2SO4 (60%; 10 mL) was added to the residue and the solution was cooled to 0° C. A solution of NaNO2 (0.345 g, 5.00 mmol) in water (5 mL) was added dropwise. The solution was stirred at 0° C. for 30 min. and at 90° C. for 30 min. The reaction mixture was allowed to come to room temperature. Extraction with CH2Cl2, drying (MgSO4), and concentration gave 0.39 g (40%) of the title compound as a solid. MS m/z 172 (M)+. HRMS m/z calcd for C7H8O3S (M)+172.0194, found 172.0198.
*J. Chem. Soc. 1938, 899-905.
Step 2. 2-{2-[3-(Methylsulfonyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.
The title compound was prepared according the procedure of Example 69 starting from the product of Step 1. Yield 26%. MS m/z 379 (M+H)+. HRMS m/z calcd for C17H22N4O4S (M)+378.1362, found 378.1343.
The title compound was prepared according to the procedure of Example 69 starting from 7-hydroxy-2H-chromen-2-one. Yield 29%. MS m/z 369 (M+H)+. HRMS m/z calcd for C19H20N4O4(M)+368.1485, found 368.1478
The title compound was prepared according to the procedure of Example 69 starting from 2,3,6-trifluorophenol. Yield 46%. MS m/z 355 (M+H)+. HRMS m/z calcd for C16H17F3N4O2(M)+354.1304, found 354.1288.
The title compound was prepared according to the procedure of Example 69 starting from 2,4,5-trifluorophenol. Yield 43%. MS m/z 355 (M+H)+. HRMS m/z calcd for C16H17F3N4O2(M)+354.1304, found 354.1304.
The title compound was prepared according to the procedure of Example 69 starting from catechol. Yield 37%. MS m/z 317 (M+H)+. HRMS m/z calcd for C16H20N4O3 (M)−316.1535, found 316.1535.
The title compound was prepared according to the procedure of Example 69 starting from resorcinol. Yield 36%. MS m/z 317 (M+H)+. HRMS m/z calcd for C16H20N4O3(M)+316.1535, found 316.1525.
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400 mg, 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol (441 mg, 1.23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by repeated chromatography on silica gel using toluene and toluene/EtOAc (8:2) as eluents. Solvents were evaporated and the residue was treated with CH2Cl2/TFA/H2O (1:0.9:0.1; 5 mL) at room temperature for 0.5 h After concentration 5 M NaOH was added followed by extraction with CH2Cl2. The organic phase was dried (K2CO3), filtered, and concentrated. The residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 50 mg (10%) of the title product as on oil. HRMS m/z calcd for C20H27N5O3(M)+385.2114, found 385.2100.
Examples 78-82 were prepared according to the procedure of Example 77 starting from 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol and the requisite phenolic compound.
The title compound was prepared starting from 1,3-benzodioxol-4-ol*(340 mg, 1.24 mmol) to give 125 mg (29%) of an oil. HRMS m/z calcd for C17H20N4O4(M)+344.1485, found 344.1487.
*Prepared as described in Chem. Pharm. Bull. 1980, 28, 2414-2421.
The title compound was prepared starting from 2,3-dihydro-1,4-benzodioxin-5-ol*(374 mg, 1.24 mmol) to give 260 mg (59%) of a solid: mp 98-99° C. HRMS m/z calcd for C18H22N4O4(M)+358.1641, found 358.1648.
*Prepared as described in J. Am. Chem Soc. 1959, 81, 5199-5201.
The title compound was prepared starting from 2-allylphenol (330 mg, 1.24 mmol) to give 200 mg (47%) of an oil. HRMS m/z calcd for C19H24N4O2(M)+340.1899, found 340.1888.
The title compound was prepared starting from 3-aminophenol (268 mg, 1.24 mmol) to give 49 mg (13%) of an oil. HRMS m/Z calcd for C16H21N5O2(M)+315.1695, found 315.1705.
The title compound was prepared starting from 4-hydroxy-1-indanone (365 mg, 1.24 mmol) to give 19 mg (4%) of an oil. HRMS m/z calcd for C19H22N4O3(M)+354.1692, found 354.1705.
The title compound was prepared according to the procedure of Example 77 starting from 2,6-difluorophenol (239 mg, 1.84 mmol), TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (600 mg, 1.86 mmol; prepared in Example 52, Step 2), and triphenylphosphine (969 mg, 3.69 mmol) to give 279 mg (45%) of a solid: mp 101-102° C. HRMS m/z calcd for C16H18F2N4O2(M)+336.1398, found 336.1403.
DEAD (0.485 mL, 3.08 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbon)-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 8-hydroxy-5-nitroquinoline (0.589 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (10 mL). The mixture was stirred at room temperature for 2 h, and concentrated. The residue was passed through a silica column using toluene/EtOAc (1:1) as eluent. The N-Boc protected intermediate obtained was treated with CH2Cl2/TFA/H2O (50:45:5; 15 mL) for 30 min at room temperature and concentrated. The residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was concentrated to give 0.206 g (15%) of the title product. Pos-EI-MS shows M+ and 7 ions supporting the stated structure: HRMS m/z calcd for C19H20N6O4(M)+396.1546, found 396.1557.
DEAD (0.50 mL, 3.2 mmol) was added dropwise to a stirred mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), scopoletin (0.60 g, 3.1 mmol) and triphenylphosphine (0.87 g, 3.3 mmol) in THF (10 mL) at room temperature. After 1 h, the reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried, (MgSO4), concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was diluted with 0.2 M aqueous HCl and washed with EtOAc (×3). The aqueous layer was concentrated to give 0.075 g (5%) of the title product. Pos-EI-MS shows M+ and 15 ions supporting the stated structure. Anal (C20H22N4O5.1.3 HCl.1.4H2O)C, H, N.
Step 1: tert-Butyl 4-{3-[2-(2,1,3-benzothiadiazol-4-yloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.
DEAD (0.52 mL, 3.3 mmol) was added to a slurry of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 4-hydroxy-2,1,3-benzothiadiazole*(0.46 g, 3.0 mmol) and resin bound PPh3 (1.1 g, 3.3 mmol) and shaken until HPLC showed no starting material. The mixture was filtered to remove the resin, concentrated and purified by column chromatography on silica to give 0.163 g (12%) of the title compound. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C21H26N6O4S (M)+458.1736, found 458.1716.
*The starting material 4-hydroxy-2,1,3-benzothiadiazole was obtained as described in Khim. Geterotsikl Soedin 1973, 7, 926-9).
Step 2: 4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2,1,3-benzothiadiazole, Dihydrochloride.
The product from Step 1 above (0.163 g, 0.356 mmol) was treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) at room temperature for 30 min. The reaction mixture was concentrated and diluted with 0.1 M aqueous HCl and washed with toluene. The water phase was concentrated and the residue crystallized from MeOH/diethyl ether to give 0.088 g (57%) of the title product. Pos-EI-MS shows M+ and 7 ions supporting the stated structure; HRMS m/z calcd for C16H18N6O2S (M)+358.1212, found 358.1207. Anal (C18H18N6O2S.2HCl H2O)C, H, N.
DEAD (0.657 mL, 4.00 mmol) was added to a stirred solution of 8-quinazolinol*(0.55 g, 3.76 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.216 g, 3.75 mmol; prepared in Example 52, Step 2) and PPh3 (1.048 g, 4.00 mmol) in THF (12 mL). The reaction was stirred at room temperature for 2 h and then poured into 5% aqueous NaOH and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc/MeOH (49:50:1). The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) at room temperature for 30 minutes, poured into 0.5 M aqueous HCl and washed with EtOAc. The water phase was alkalinized to pH 12 and extracted with EtOAc, dried (MgSO4), and concentrated to give 0.499 g (1.40 mmol) of the free base of the title compound. The free base was dissolved in dioxane (10 mL), and maleic acid (0.162 g, 1.40 mmol) in dioxane (2 mL) was added and the solution concentrated to give 0.65 g (37%) of the title product. Pos-EI-MS shows M+ and 9 ions supporting the stated structure. Anal (C18H20N6O2.1.3C4H4O4) C, H, N.
*The starting material 8-quinazolinol was obtained as described in J. Chem. Soc. 1952, 4985-4993.
TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline*(0.45 g, 3.08 mmol) and PPh3 (0.85 g, 3.24 mmol) in THF (20 mL). The reaction was stirred at room temperature for 1.5 h and at 65° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica using toluene/EtOAc (1:1) as eluent. The resulting solid was crystallized twice from diethyl ether/petroleum ether to remove PPh3O. The recrystallized material (0.50 g) was dissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resulting mixture was stirred at room temperature for 4 h (only 10% N-Boc-deprotection had occurred according to HPLC/MS). The mixture was concentrated and the residue was treated with CH2Cl2/TFA/H2O (50:45:5; 20 mL) for 1 h. After concentration in vacuo, the residue was dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was lyophilized to give a yellow oil that was dissolved in 1 M HCl. The solution was concentrated and MeOH and diethyl ether was added. The precipitate formed was collected and dried in vacuum to give 0.32 g (76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting the stated structure. HRMS m/z calcd for C18H20N6O2(M)+352.1648, found 352.1662.
*The starting material 5-hydroxyquinoxaline was obtained as described in J. Org. Chem. 1951, 16, 438-442.
DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5.0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by column chromatography oil silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4(M)+382.1641, found 382.1631.
Step 1: 2-Chloro-3-(1-piperazinyl)pyrazine.*
A mixture of 2,3-dichloropyrazine (1.35 g, 15.32 mmol), piperazine (2.34 g, 27.2 mmol) and K2CO3 (1.25 g, 9.04 mmol) in acetonitrile (5.5 mL) was stirred at 110° C. for 1.25 h in a sealed tube. The reaction mixture was diluted with CH2Cl2, filtered, and concentrated to give a yellowish semisolid residue which was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. The obtained solid was redissolved in CHCl3 and applied to a short (3 cm) plug of alumina. Elution with ether/CHCl3 (9:1) afforded 1.24 g (69%) of the title product as a white solid: mp 47-53° C. HRMS m/z calcd for C8H11CIN4(M)+198.0672, found 198.0673.
*Previously reported in J. Med. Chem. 1978, 21, 536-542.
Step 2: 3-(Phenoxy)propyl 3-(1-piperazinyl)-2-pyrazinyl ether, Dihydrochloride.
2-Chloro-3-(1-piperazinyl)pyrazine (608 mg, 3.1 mmol; from Step 1 above) and 3-phenoxypropanol (570 mg, 3.7 mmol) was dissolved in dioxane (10 mL). KO-t-Bu (870 mg, 7.7 mmol) was added and the mixture was stirred at 95° C. for 6 h. The solvent was evaporated and the residue was purified by chromatography on silica gel using CH2Cl2/MeOH (9:1) as eluent to give the free base of the title compound as a yellow oil. The free base was converted to the dihydrochloride salt: yield 0.380 g (32%): mp 146-146.5° C. Anal. (C17H22N4O2.2HCl) C, H, N.
Examples 91-161 were prepared according to the procedure of Example 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine and the appropriate alcohol. Purification was by column chromatography on silica gel using CHC3/MeOH (9:1) or CHCl3/MeOH/NH4OH (95:5:0.5) or other appropriate solvent system.
Step 1: 2-(2-Trifluoromethylphenoxy)ethanol.
A mixture of 2-trifluoromethylphenol (2.00 g, 12.3 mmol), K2CO3 (1.71 g, 12.3 mmol) and ethylene carbonate (1.20 g, 13.6 mmol) in dry DMF (30 mL) was heated at 150° C. for 1 h. After cooling, the reaction was quenched by addition of water (10 mL). The mixture was concentrated in vacuo and the residue partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with additional portions of EtOAc (3×30 mL). The combined organic layers were treated with charcoal, dried over MgSO4, and filtered through Celite. The filtrate was concentrated in vacuo and the remaining oil was purified by chromatography on silica gel using n-hexane/EtOAc (80:20) as eluent to give 0.50 g (20%) of the title product as white crystals: mp 74-77° C. Anal. (C9H9F3O2) C, H.
Step 2: 2-(2-Trifluoromethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
Yield 48%, mp 79-80° C. Anal. (C17H19F3N4O2) C, H, N.
Step 1: 2-(2-Methylthiophenoxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-(methylthio)phenol. Yield 63%: nip 47-49° C. Anal. (C9H12O2S) C, H.
*Previously described in U.S. Pat. No. 3,932,498.
Step 2: 2-(2-Methylthiophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 68%; mp 160-162° C. Anal. (C17H22N4O2S.C4H4O4.0.1 THF) C, H, N.
Step 1: 2-(2-Methylphenoxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from o-cresol. Oil; yield 59%. HRMS m/z calcd for C9H12O2(M)+152.0837, found 152.0840.
*Previously described in Tetrahedron 1996, 52, 177-184.
Step 2: 2-(2-Methylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 33%; mp 151-152° C. Anal. (C17H22N4O2.C4H4O4.0.5H2O)C, H, N.
Step 1: 2-(2,5-Dimethylphenoxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2,5-dimethylphenol. Yield 60%; mp 45-48° C. Anal. (C10H14O2) C, H.
*Previously described in J. Chem. Soc. 1914, 2117-2139.
Step 2: 2-(2,5-Dimethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
Oil, yield 65%. Anal. (C18H24N4O2) C, H, N.
Step 1: 2-(2-Fluorophenoxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-fluorophenol. Oil; yield 71%. MS m/z 156 (M)+.
*Previously described in J. Indian Chem. Soc. 1962, 39, 5-8.
Step 2: 2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 46%, mp 171-173° C. Anal. (C16H19FN4O2.C4H4O4) C, H, N.
Step 1: 2-(2-Cyanophenoxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-cyanophenol. Oil; yield 26%. MS m/z 163 (M)+.
*Previously described in J. Chem. Soc. 1914, 2117-2139.
Step 2: 2-(2-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 40%; mp 165-166° C. Anal. (C17H19N5O2.C4H4O4) C, H, N.
Step 1: 2-[(1,1′Biphenyl)-2-yloxy]ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-phenylphenol. Yield 52%; mp 71-75° C. Anal. (C14H14O2) C, H.
*Previously described in J. Med. Chem. 1987, 30, 939-943.
Step 2: 2-[(1,1′Biphenyl)-2-yloxy]ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
Yield 53%; mp 101-103° C. Anal. (C22H24N4O2) C, H, N.
Yield 49%; mp 129-131° C. Anal. (C18H24N4O2.2HCl) C, H, N.
*The starting material 4-phenoxybutanol was obtained as described in J. Org. Chem. 1965, 30, 2441-2447.
Step 1: 2-(2-Fluoro-5-methylphenoxy)ethanol.
The title compound was prepared according to the procedure described in Example 91. Step 1, starting from 2-fluoro-5-methylphenol. Oil; yield 94%. MS m/z 170 (M)+.
Step 2: 2-[2-(2-Fluoro-5-methylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Fumarate.
Yield 71%; mp 145-146° C. Anal. (C21H25FN4O6.0.3H2O)C, H, N.
Step 1: 2-(5-Fluoro-2-methoxyphenoxy)ethanol*.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 5-fluoro-2-methoxyphenol**. Yield 89%. MS m/z 186 (M)+. Anal. (C9H11FO3) C, H.
*Previously described in EP 331943.
** Prepared as described in Bull. Soc. Chim. Belg. 1993, 102, 217-226.
Step 2: 2-[2-(5-Fluoro-2-methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Fumarate.
Yield 76%; mp 172-176° C. Anal. (C17H21FN4O3.C4H4O4.0.3H2O)C, H, N.
Step 1: 2-(3-Fluorophenoxy)ethanol*.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 3-fluorophenol. Oil; yield 83%. MS m/z 156 (M)+.
*Previously described in Magn. Reson. Chem. 1992, 30, 723-732.
Step 2: 2-[2-(3-Fluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Solid, yield 51%; mp 141-143° C. Anal. (C16H19FN4O2.C4H4O4) C, H, N.
Step 1: 2-(3-Methoxyphenoxy)ethanol*.
The title compound was prepared according to the procedure described in Example 91. Step 1, starting from 3-methoxyphenol. Oil; yield 64%; MS m/z 168 (M)+. Anal. (C9H12O3) C, H.
*Previously described in J. Chem. Soc. 1935, 1098-1101 and in U.S. Pat. No. 5,025,031.
Step 2: 2-[2-(3-Methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, p-Toluenesulfonate.
Solid; yield 20%; mp 131-133° C. Anal. (C17H22N4O3.C7H8O3S)C, H, N.
Step 1: 2-(3-Acetylphenoxy)-1-ethanol.*
The title compound was prepared according to the procedure described in Example 91. Step 1, starting from 3-hydroxyacetophenone. Oil; yield 82%. MS m/z 180 (M)+. HRMS m/z calcd for C10H12O3(M)+180.0786, found 180.0787.
*Previously described in Helv. Chim Acta 1989, 72, 1216-1224.
Step 2: 2-[2-(3-Acetylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield of free base 68%. Part of the free base was converted to the maleate salt. MS m/z 343 (M+H)+. Anal. (C18H22N4O3.C4H4O4) C, H, N.
Step 1:2-(3-Cyanophenoxy)-1-ethanol.*
The title compound was prepared according to the procedure described in Example 91. Step 1, starting from 3-cyanophenol. Oil: yield 63%. MS m/z 163 (M)−. Anal. (C9H9NO2)C, H, N.
*Previously described J. Chem. Soc. 1914.2117-2139 and Pharmazie 1975.30.353-357.
Step 2: 2-[2-(3-Cyanophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine. Solid; yield 74%. MS m/z 326 (M+H)+. Anal. (C17H19N5O2) C, H, N.
Step 1: 2-(2,3-Difluorophenoxy)-1-ethanol.
The title product was prepared according to the procedure described in Example 91, Step 1, starting from 2,3-difluorophenol. Oil; yield 92%. MS m/z 174 (M)+. Anal (C8H8F2O2) C, H.
Step 2: 2-[2-(2,3-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Fumarate.
Yield 35%; mp 125-130° C. Anal. (C16H18F2N4O2.C4H4O4) C, H, N.
Step 1: 2-(2,3,5-Trifluorophenoxy)-1-ethanol.
The title product was prepared according to the procedure described in Example 91, Step 1, starting from 2,3,5-trifluorophenol. Oil; yield 83%. MS m/z 192 (M)+. Anal. (C8H7F3O2) C, H.
Step 2: 2-[2-(2,3,5-Trifluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Fumarate.
Yield 35%; mp 158-159° C. MS m/z 354 (M)+; HRMS m/z calcd for C16H17F3N4O2(M)+354.1304, found 354.1303. Anal. (C16H17F3N4O2.C4H4O4) C, H, N.
Step 1: 2-(3-Anilinophenoxy)-1-ethanol.*
The title product was prepared according to the procedure described in Example 91. Step 1, starting from 3-anilinophenol. Oil: yield 75% HRMS m/z calcd for C14H15NO2(M)+229.1103, found 229.1111.
*Previously described in U.S. Pat. No. 2,077,322 and EP 585500.
Step 2: N-Phenyl-3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)aniline, Fumarate.
Yield of free base 24%. Part of the base was converted into its fumarate salt: mp 78-81° C.; HRMS m/z calcd for C22H25N5O2(M)+391.2008, found 391.2001. Anal (C22H25N5O2.C4H4O4) C, H, N.
Step 1: 3-(2-Hydroxyethoxy)benzaldehyde*
The title product was prepared according to the procedure described in Example 91, Step 1, starting from 3-hydroxybenzaldehyde. Oil; yield 88%; MS m/z 166 (M)+. Anal. (C9H10O3.0.2H2O)C, H, N.
*Previously described in WO 9733202.
Step 2: 2-[3-(Dimethoxymethyl)phenoxy]-1-ethanol.
p-TsOH (165 mg, 0.87 mmol) was added to a solution of the product obtained in Step 1 (1.45 g, 8.73 mmol) in dry MeOH (60 mL). After being stirred for 23 h at room temperature, more p-TsOH (170 mg, 0.89 mmol) was added. After additional 4 h of stirring, the reaction was quenched by the addition of NaHCO3 (saturated aqueous solution, 70 mL) and H2O (50 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine and dried (MgSO4). Evaporation of the solvents afforded a yellow oil that was used in the next step without purification. Yield 1.59 g (86%). The product contained about 5% of starting material (1H NMR).
Step 3: 2-{2-[3-(Dimethoxymethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.
Oil, yield 63%: MS m/z 344 (M—CH2O)−. HRMS m/z calcd for C18H24N4O3(M—CH2O)+344.1848, found 344.1847.
Step 4: 3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)benzaldehyde.
HOAc (12 mL) and H2O (4 mL) was added to a solution of the product obtained in Step 3 (858 mg, 2.29 mmol) in THF (4 mL). The reaction mixture was stirred at 45° C. for 1.5 h and then diluted with EtOAc (150 mL). The organic phase was washed with brine (x 2), aqueous saturated NaHCO3 and brine. Drying (MgSO4) followed by evaporation of the solvents afforded the title product (0.41 g) as an acetate salt (1.7·HOAc as determined by 1H NMR). This product was used in the next step without purification.
Step 5: [3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenyl]methanol, Maleate.
The product obtained in Step 4 (408 mg, 1.24 mmol) was dissolved in EtOH (99%, 35 mL). Immediately upon addition of NaBH4 (293 mg, 7.75 mmol) the solution turned white. The reaction mixture was stirred at room temperature for 5 h and then quenched by addition of H2O (7 mL). The mixture was filtered, and the filtrate diluted with aqueous saturated NaCl (30 mL) and H2O (20 mL). The aqueous solution was extracted with EtOAc (×4). The combined organic phases were washed with brine and dried (MgSO4). Evaporation of the solvents gave a semi-solid residue (330 mg) that was purified by column chromatography on silica using gradient elution with EtOAc/MeOH (9:1)+1% NH3 to EtOAc/MeOH (8:2)+1% NH3. This afforded 76 mg (16%) of the free base of the title product as a semi-solid which was converted to its maleate salt: mp 123.2-123.5° C.; MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3(M)+330.1692, found 330.1692.
Step 1: 2-[(3-(Methoxymethyl)phenoxy]-1-ethanol.
Et3SiH (4.0 mL, 25.0 mmol) was added to a solution of the product of Example 108. Step 1 (1.33 g, 8.00 mmol) in MeOH (14 mL). The mixture was cooled to 0° C. and concentrated H2SO4 (1.5 mL) was added dropwise over 1.5 min. The reaction mixture was stirred at room temperature for 4.5 h. More Et3SiH (1.5 mL, 9.4 mmol) was added, and the stirring was continued for 1 h. After solvent removal in vacuo. H2O was added to the residue and pH was adjusted to pH 4 by addition of 2 M aqueous NaOH. The aqueous solution was extracted with CH2Cl2 (×3). The combined organic phases were washed with brine, dried (MgSO4) and concentrated to give an oil (1.8 g). NMR analysis of the crude product showed only 40% conversion. Therefore, the procedure was repeated by treating the residue with Et3SiH (3 mL), MeOH (8 mL) and concentrated H2SO4 (1.2 mL). After being stirred for 4 h at room temperature more H2SO4 (1.2 mL) was added. The stirring was continued for a further hour and worked up as above. The crude product was purified by column chromatography on silica [gradient 100% isohexane to isohexane/EtOAc (1:1)] to give the title compound as a colorless oil. Yield 0.98 g (67%); MS m/z 182 (M)+. Anal. (C10H14O3.0.1H2O) C, H.
Step 2: 2-{2-[3-(Methoxymethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine, Maleate.
Yield of free base of the title compound 0.61 g (80%). Part of this material was converted to the maleate salt: mp 114-115° C.; MS m/z 345 (M+H)+. Anal. (C18H24N4O3.C4H4O4) C, H, N.
Step 1: 3-(2-Hydroxyethoxy)benzamide.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 3-hydroxybenzamide. Yield 62%; MS m/z 181 (M)+. HRMS m/z calcd for C9H11NO3(M)+181.0739, found 181.0739.
*Previously reported in WO 8606628.
Step) 2: 3-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)benzamide, Maleate.
Yield of free base of the title compound 43%. The maleate salt was prepared: mp 134-137° C. MS m/z 344 (M+H)+. Anal. (C17H21N5O3.C4H4O4) C, H, N.
Step 1: 2-(4-Anilinophenoxy)ethanol.*
The title product was prepared according to the procedure described in Example 91, Step 1, starting from 4-anilinophenol. Solid; yield 0.85 g (75%); MS m/z 229 (M)+. Anal. (C14H11NO2) C, H, N.
*Previously described in EP 420790.
Step 2: N-Phenyl-4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)aniline, Maleate.
Yield of free base of the title compound 44%. The maleate salt was prepared: mp 132-133° C.; MS m/z 392 (M+H)+. Anal. (C22H25N5O2.C4H4O4) C, H, N.
Step 1: N-[4-(2-Hydroxyethoxy)phenyl]acetamide.*
The title product was prepared according to the procedure described in Example 91, Step 1, starting from 4-acetamidophenol. Solid; yield 1.38 g (52%); MS m/z 195 (M)+. Anal. (C10H13NO3.0.1H2O)C, H, N.
*Previously described in J. Heterocycl. Chem. 1994, 31, 457-480.
Step 2: N-[4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenyl]acetamide.
Solid; yield 0.47 g (53%); MS m/z 357 (M)+. HRMS m/z calcd for C18H23N5O3(M)+357.1801, found 357.1810.
Step 1: 2-[3-(Trifluoromethoxy)phenoxy]ethanol.
The title product % vas prepared according to the procedure described in Example 91, Step 1, starting from 3-trifluoromethoxyphenyl. Oil: yield 0.75 g (60%): MS m/z 222 (M)+. Anal. (C9H9F3O3) C, H.
Step 2: 2-(1-piperazinyl)-3-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}pyrazine, Maleate.
Yield of free base of the title compound 61%. The maleate salt was prepared: mp 150-152° C.; MS m/z 326 (M+H)+. Anal. (C17H19N5O2.C4H4O4) C, H, N.
Step 1: 2-(3,5-Difluorophenoxy)-1-ethanol.
In a sealed Pyrex tube, a mixture of 3,5-difluorophenol (2.19 g, 16.8 mmol), ethylene carbonate (1.0 g, 11.4 mmol), a catalytic amount of NaH (60% in mineral oil) in DMF (1 mL) was reacted in a Labwell MW-10 microwave reactor at 50 W for 3 min. The reaction mixture was diluted with toluene and washed with 5% aqueous NaOH. The organic phase was dried (MgSO4) and concentrated: This gave 1.59 g (80%) of the title compound as a light red oil. MS m/z 174 (M)+.
Step 2: 2-[2-(3,5-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine p-Toluenesulfonate.
Yield 14%; mp 118-119° C. Anal. (C16H18F2N4O2.C7H8O3S)C, H, N.
Step 1: 2-(1,3-Benzodioxol-5-yloxy)ethanol.*
The title compound was prepared according to the procedure of Example 114, Step 1 starting from sesamol (2.0 g, 14.5 mmol) and ethylene carbonate (1.0 g, 11.4 mmol): solid; yield 99%. MS m/z 182 (M)+.
*Previously described in J. Org. Chem. 1960, 25, 626-632.
Step 2: 2-[2-(1,3-Benzodioxol-5-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine.
Solid: yield 71%. MS m/z 345 (M+H)+. Anal. (C17H20N4O4) C, H, N.
Step 1: 2-(3-Butoxyphenoxy)ethanol.
The title compund was prepared according to the procedure of Example 114, Step 1 starting from 3-n-butoxyphenol (2.0 g, 12 mmol) and ethylene carbonate (0.88 g, 10 mmol). Oil; yield 85%. MS m/z 210 (M)+.
Step 2: 2-[2-(3-Butoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield of free base of the title compound 77%. Part of the free base was converted to the maleate salt. MS m/z 373 (M+H)+. Anal. (C20H28N4O3.C4H4O4) C, H, N.
Step 1: 2-(3-Trifluoromethylphenoxy)ethanol.
The title compound was prepared according to the procedure of Example 114, Step 1 starting from 3-trifluoromethylphenol (3.89 g, 24 mmol) and ethylene carbonate (1.76 g, 20 mmol) with the exception that no DMF was used. Oil; yield 64%. MS m/z 206 (M)+.
Step 2: 2-[2-(3-Trifluoromethylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield of free base of the title compound 65%. Part of the free base was converted to the maleate salt. MS m/z 369 (M+H)+. HRMS m/z calcd for C17H19F3N4O2(M)+368.1460, found 368.1460.
Step 1: 2-(3-Phenylphenoxy)ethanol.*
The title compound was prepared according to the procedure of Example 114, Step 1 starting, from 3-phenylphenol (1.72 g, 0.1 mmol) and ethylene carbonate (0.80 g, 9.1 mmol) and DMF (3 mL). Semi-solid; yield 86%. MS m/z 214 (M)+.
*Previously described in U.S. Pat. No. 2,140,824.
Step 2: 2-[2-([1,1′-Biphenyl]-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield of free base 70%. Part of the free base was converted to the maleate salt. MS m/z 377 (M+H)+. Anal. (C22H24N4O2.C4H4O4) C, H, N.
Step 1: 2-(3-Acetamidophenoxy)-1-ethanol*.
The title product was prepared according to the procedure described in Example 114, Step 1, starting from 3-acetamidophenol (2.10 g, 13.9 mmol) and ethylene carbonate (0.88 g, 10 mmol). The crude product was purified by column chromatography on silica using toluene/EtOAc/MeOH (49:49:2). Oil; yield 99%. MS m/z 195 (M)+.
*Previously described in J. Am. Chem. Soc. 1939, 61, 355-357.
Step 2: 2-[2-(3-Acetamidophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield 38%; mp 154-155° C. Anal. (C18H23N5O3.C4H4O4) C, H, N.
The title product was prepared from 1,4-bis(2-hydroxyethoxy)benzene. Yield of free base of the title compound 51%. The maleate salt was prepared: mp 127-129° C. MS m/z 361 (M+H). Anal. (C18H24N4O4.C4H4O4) C, H, N.
The title product wasp prepared from 1,3-bis(2-hydroxyethoxy)benzene. Yield of free base of the title compound 45%. The maleate salt was prepared: nip 111-114° C.; MS m/z 361 (M+H)+. Anal. (C18H24N4O4.C4H4O4.0.1H2O) C, H, N.
Yield 44%; nip 160-161° C. Anal. (C17H18N4O2.HCl) C, H, N.
*The starting material benzofuran-2-ylmethanol was obtained from benzofuran-2-carboxaldehyde by reduction with sodium borohydride.
Yield 33%; mp 172-174° C. Anal. (C17H20N4O2.2HCl) C, H, N. The starting material 2,3-dihydrobenzofuran-2-ylmethanol*was obtained from benzofuran-2-carboxaldehyde by reduction with sodium borohydride and subsequent catalytic hydrogenation.*Previously described in Bioorg. Med. Chem. Lett. 1999, 9, 401-406.
The title compound was prepared starting from tetrahydrofurfuryl alcohol. Yield 65%; mp 130-136° C. Anal. (C13H20N4O2.HCl.H2O)C, H, N.
The title compound was prepared starting from 2-pyridinepropanol. Yield 51% nip 147-148° C. Anal. (C16H21N5O.1.05C4H4O4) C, H, N.
The title compound was prepared starting from 3-pyridinepropanol. Yield 43%; mp 128-130° C. Anal. (C16H21N5O.C4H4O4) C, H, N.
The title compound was prepared starting from 4-pyridinepropanol. Yield 41%; mp 90-91° C. Anal. (C16H21N5O.C4H4O4.0.7H2O) C, H, N.
The title compound was prepared starting from 6-methyl-2-pyridinepropanol. Yield 30%; mp 134-136° C. Anal. (C17H23N5O.C4H4O4) C, H, N.
The title compound was prepared starting from cinnamyl alcohol. Oil; yield 39%. Anal. (C17H20N4O.0.2H2O)C, H, N.
Dihydrochloride. Yield 22%; mp 171-175° C. Anal. (C17H2lN5O5.2HCl) C, H, N.
*The starting material 3,4-dihydro-2H-1,4-benzoxazin-2-ylmethanol was prepared as described in J. Heterocycl. Chem. 1996, 33, 191-196.
Yield 49%; mp 119° C. (dec). Anal. (C18H23N5O2.1.33HCl) C, H, N.
*The starting material 3,4-dihydro-4 methyl-2H-1,4-benzoxazin-2-ylmethanol has previously been described in J. Heterocycl. Chem. 1996, 33, 191-196.
Yield 41%; mp 178-79° C. Anal. (C17H20N4O2S.C4H4O4) C, H, N.
*The starting material 2,3-dihydro-1,4-benzoxathiin-2-yl)-methanol was prepared as described in J. Pharm. Sci. 1972, 61, 228-231.
Yield 45%; mp 170-175° C. Anal. (C18H23N4O2.HCl) C, H, N.
*The starting material 3,4-dihydro-2H-chromen-2-ylmethanol was prepared as described in Eur. J. Med. Chem. 1985, 20, 117-120.
Step 1: 2-(5-Isoquinolinyloxy)ethanol.
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl3 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.
Step 2: 2-(5-Isoquinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 55% as the free base. The free base was converted to the maleate salt: mp 178-180.5° C.; HRMS m/z calcd for C19H21N5O2(M)+351.1695, found 351.1694. Anal. (C19H21N5O2.C4H4O4) C, H, N.
Step 1: 2-(5-Quinolinyloxy)ethanol
The title compound was prepared according to the procedure described in Example 134, Step 1, starting from 5-hydroxyquinoline (0.93 g, 6.40 mmol). Yield 1.19 g (91%); mp 109-111° C.; HRMS m/z calcd for C11H11NO2(M)−189.0790, found 189.0786. Anal. (C11H11NO2) C, H, N.
Step 2: 2-(5-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 61% as the free base. The free base was converted to the maleate salt: mp 132-135° C.; HRMS m/z calcd for C19H21N5O2(M)+351.1695, found 351.1681. Anal. (C19H21N5O2.1.8C4H4O4) C, H, N.
Step 1: 2-(6-Quinolinyloxy)ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 6-hydroxyquinoline. Yield 78%; mp 68-70° C. Anal. (C11H11NO2) C, H, N.
Step 2: 2-(6-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 33%; mp 167-169° C. Anal. (C19H21N5O2.C4H4O4) C, H, N.
Step 1: 2-(7-Quinolinyloxy)ethanol.
The title compound % vas prepared according to the procedure described in Example 91. Step 1, starting from 7-hydroxyquinoline. Yield 76%; mp 93-95° C. Anal. (C11H11NO2) C, H, N.
Step 2: 2-(7-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 39%: mp 156-158° C. Anal. (C19H21N5O2.C4H4O4) C, H, N.
Step 1: 2-(8-Quinolinyloxy)ethanol.*
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 8-hydroxyquinoline. Yield 48%; mp 82-84° C. Anal. (C11H11NO2) C, H, N.
*Previously described in Pharm. Chem. J. 1994, 28, 934-936.
Step 2: 2-(8-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.
Yield 62%; mp 98-100° C. Anal. (C19H21N5O2.0.05 EtOAc) C, H, N.
Step 1: 2-[(5-Chloro-8-quinolinyl)oxy]-1-ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 5-chloro-8-hydroxyquinoline (3.59 g, 20 mmol). Yield 48%. Pos-EI-MS shows M+ and 5 ions supporting the stated structure; HRMS m/z calcd for C11H10CINO2(M)+223.0400, found 223.0392. Anal. (C11H10CINO2) C, H, N.
Step 2: 5-Chloro-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine, Fumarate.
The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (90:10:0.3) as eluent. After evaporation of solvents from the combined pure fractions, the resulting free base was converted to its fumaric acid salt. Recrystallization from water afforded 1.22 g (50%) of the title product as white crystals: mp 178° C. (dec). Anal. (C19H20N5O2.C4H4O4) C, H, N.
Step) 1: 2-(Benzofuran-7-yloxy)ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 7-hydroxybenzofuran* and was isolated as a semi-solid; yield 79%.
*Prepared as described in J. Med. Chem. 1987, 30, 62-67.
Step 2: 2-(Benzofuran-7-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.
Yield 42% as the free base. A portion of the free base was converted to the maleate salt: mp 177-179° C.; MS m/z 341 (M+H)+. Anal. (C18H20N4O3.C4H4O4) C, H, N.
Step 1: 2-(1H-Indol-7-yloxy)-1-ethanol.
A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethylene oxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reaction tube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reaction mixture was stirred at 100° C. for 5 days. The reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product. Pos-EI-MS shows M+ and 5 ions supporting the stated structure. HRMS m/z calcd for C10H11NO2 (M)+177.0790, found 177.0799.
Step 2: 7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole
The product obtained in Step 1 above (0.200 g, 1.13 mmol) and dioxane (4 mL) was placed in a reaction tube and NaH (60% in oil; 0.060 g, 1.50 mmol) was added. When the gas evolution had ceased, 2-chloro-3-(1-piperazinyl)pyrazine (0.228 g, 1.15 mmol; from Example 90, Step 1) was added and the tube sealed. The mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was extracted with 0.5 M aqueous HCl. The pH of the aqueous phase was adjusted to pH 11 with NaOH and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 0.31 g (81%) of the title product. Pos-EI-MS shows M+ and 9 ions supporting the stated structure. HRMS m/z calcd for C18H21N5O2(M)−339.1695, found 339.1696.
Step 1: 2-(1H-Indol-6-yloxy)-1-ethanol.
A mixture of 6-hydroxyindole (2.66 g, 20 mmol) and K2CO3 (3.04 g, 22 mmol) was stirred in DMF (10 mL) at 80° C. for 10 min. A solution of ethylene carbonate (1.94 g, 22 mmol) in DMF (4 mL) was added and the mixture was heated at 125° C. for 3 h. The mixture was concentrated, diluted with water, and extracted with toluene. The organic phase was washed with 1 M aqueous Na2CO3 and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/toluene (1:4→36:65) as eluent. Yield 1.02 g (29%); mp 74-77° C.; HRMS m/z calcd for C10H11NO2(M)+177.0790, found 177.0784. Anal. (C10H11NO2) C, H, N.
Step 2: 6-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole.
Yield 59%; mp 111-113° C.; MS-EI m/z 339 (M)+. Anal. (C18H21N5O2) C, H, N.
Step 1: 2-[(2-Methyl-1,3-benzothiazol-5yl)oxy]ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-methyl-1,3-benzothiazol-5-ol. Yield 61%; mp 67-68° C. HRMS m/z calcd for C10H11NO2S (M)+209.0510, found 209.0502. Anal. (C10H11NO2S)C, H, N.
Step) 2: 2-Methyl-5-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1,3-benzothiazole, Hydrochloride.
Yield 58%; mp 188-190° C. HRMS m/z calcd for C18H21N5O2S (M)+371.1416, found 371.1421. Anal. (C18H21N5O2S.HCl.0.3H2O) C, H, N.
Step 1: 2-(2-Methoxy-5-methylphenoxy)ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 2-methoxy-5-methylphenol. Yield 56%; mp 42-43° C. Anal. (C10H14O3) C, H.
Step 2: 2-[2-(2-Methoxy-5-methylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Yield 56%; mp 148-149° C. Anal. (C18H24N4O3.C4H4O4) C, H, N.
Step 1: 2-[(8-Amino-2-naphthyl)oxy]ethanol, Hydrochloride.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 8-amino-2-naphthol. Yield 40%; mp 185° C. (dec). Anal. (C12H13NO2.HCl) C, H, N.
Step 2: 7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1-naphthylamine, Maleate.
Yield 21%; mp 120° C. (dec). Anal. (C20H23N5O2.1.7C4H4O4) C, H, N.
Step 1: 7-Nitro-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.
Trifluoroacetic anhydride (20 mL, 149 mmol) was added dropwise to solution of 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine (6.64 g, 40 mmol) and NH4NO3(84.8 g, 60 mmol) in CH2Cl2(300 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give a small fraction (0.3 g, 4%) of the pure title compound and 6.5 g of a mixture of the C6- and C7 regioisomeric nitro derivatives. The regioisomeric mixture was taken on to Example 147 Step 1, without separation.
Step 2: 2-(7-Nitro-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy) 3-(1-piperazinyl)pyrazine.
The title compound was prepared starting from the pure product obtained in Step 1 above. Oil; yield 43%; mp 133-135° C. HRMS m/z calcd for C17H19N5O5(M)+373.1386, found 373.1367.
Step 1: 7-Amino-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.
A mixture of 6- and 7-nitro-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine (6.3 g, 30 mmol; from Example 146, Step 1), ammonium formate (2.8 g, 45 mmol), and 10% Pd/C (0.4 g) in MeOH (200 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite. The pad was washed with several portions of MeOH and the filtrate was concentrated in vacuo. The mixture of 6- and 7-amino substituted-2,3-dihydro-1,4-benzodioxin derivatives was separated by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 2.8 g (58%) of the title product as an oil which was used directly in the next step.
Step 2: 7-Acetamido-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.
Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirred mixture of the title compound from Step 1 above (0.30 g, 1.66 mmol) and Et3N (0.70 g, 6.9 mmol) in CH2Cl2(30 mL). The reaction was stirred at room temperature for 15 h. More acetic anhydride (0.10 g, 1.0 mmol) was added and the mixture was stirred for a further 5 h at room temperature. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 170 mg (46%) of the title product as an oil.
Step 3: 2-(7-Acetamido-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy),3-(1-piperazinyl)pyrazine.
Oil; yield 45%. HRMS m/z calcd for C19H23N5O4(M)+385.1750, found 385.1741.
Mp 160° C. (dec). Anal. (C17H20N4O3.HCl) C, H, N.
*The starting material (S)-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine was prepared as described in Tetrahedron Lett. 1988, 29, 3671-3674.
Mp 165° C. (dec). Anal. (C17H20N4O3.HCl) C, H, N.
*The starting material (R)-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine was prepared as described in Tetrahedron Lett. 1988, 29, 3671-3674.
Step 1: 2-(3-Pyridyloxy)ethanol.*
A mixture of 3-hydroxypyridine (2.00 g, 21 mmol), 2-chloroethanol (1.69 g, 21 mmol) and K2CO3(8.7, 63 mmol) in DMF (10 mL) was stirred at 130° C. for 3 h. After cooling, the black mixture was filtered through a short bed of alumina using acetone as eluent to afford a brown oil which was partitioned between water (30 mL) and CH2Cl2 (40 mL). The aqueous phase was extracted with CH2Cl2(3×40 mL), and the combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated to give, 0.55 g (19%) of the title compound as a light brown oil. Anal. (C7H9NO2.0.2H2O)C, H, N.
*Previously described in EP 286242(A2).
Step 2: 2-(3-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.
Yield 41%; mp 170-175° C. Anal. (C15H19N5O2.2HCl.2H2O)C, H, N.
Step 1: 2-(4-Pyridyloxy)ethanol.*
The title compound was prepared according to the procedure described in Example 150, Step 1. Yield 19%; mp 119-121° C. Anal. (C7H9NO2) C, H, N.
*Previously described in J. Chem. Soc., Perkin Trans 2, 1987, 1867-1870.
Step 2: 2-(4-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.
Yield 58%; mp 170° C. (dec). Anal. (C15H19N5O2.2HCl.2H2O)C, H, N.
Step 1: 2-(2-Pyridyloxy)ethanol, Hydrochloride.*
A mixture of ethylene carbonate (2.78 g, 31.5 mmol), 2-hydroxypyridine (3.00 g, 31.5 mmol) and potassium carbonate (4.36 g, 31.5 mmol) in DMF (50 mL) was heated at 150° C. for 1 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and applied to a column with hydromatrix material. The column was eluted with EtOAc. The elute was concentrated and the remaining oil was purified by silica gel chromatography using isohexane/EtOAc (6:4) as eluent. This furnished the free base of the title compound as an oil which was converted to the hydrochloride salt: yield 1.00 g (18%); mp 97-98° C. Anal. (C7H9NO2.HCl) C, H, N.
*The free base of the title compound has been reported in J. Org. Chem. 1977, 42, 1500-1508.
Step 2: 2-(2-Pyridyloxy)ethyl 3-(1-piperizinyl)-2-pyrazinyl ether, Maleate.
Yield 27%; mp 130-132° C. Anal. (C15H19N5O2.C4H4O4) C, H, N.
Step 1: 2-(6-Methyl-3-pyridyloxy)ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1, starting from 3-hydroxy-6-methylpyridine. Yield 25%, mp 49-51° C. Anal. (C8H11 NO2) C, H, N.
Step 2: 2-(6-Methyl-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.
Yield 50%; mp 157° C. (dec). Anal. (C16H21N5O2.2.3HCl.0.2 Et2O)C, H, N.
Step 1: 2-(2-Methyl-3-pyridyloxy)ethanol.
The title compound was prepared according to the procedure described in Example 150, Step 1, starting from 3-hydroxy-2-methylpyridine. Yield 36%; mp 75-80° C. Anal. (C8H11NO2) C, H, N.
Step 2: 2-(2-Methyl-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.
Yield 36%; mp 50° C. (dec). Anal. (C16H21N5O2.3.1HCl.0.2 Et2O)C, H, N.
Step 1: 2-(5-Chloro-3-pyridyloxy)ethanol.
The title compound was prepared according to The procedure described in Example 150. Step 1, starting from 5-chloro-3-pyridinol. Yield 25%; mp 38-40° C. HRMS m/z calcd for C7H8CINO2(M)+173.0244, found 173.0244.
Step 2: 2-(5-Chloro-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.
Yield 65%; mp 104° C. (dec). Anal. (C15H18CIN5O2.1.9HCl.0.3Et2O)C, H, N.
Step 1: 2-(1-Benzothien-3-yloxy)ethanol.
A mixture of 3-bromobenzothiophene (3.00 g, 14.1 mmol), KO-t-Bu (4.74 g, 42.2 mmol), copper (II) oxide (0.56 g, 7.0 mmol) and potassium iodide (2.34 g, 14.1 mmol) in ethylene glycol (10 mL) was stirred at 140° C. for 24 h. The reaction was quenched with water (100 mL) and filtered through a pad of Celite. The water phase was extracted with EtOAc (3×50 mL). The organic phase was treated with MgSO4 and silica, filtered through Celite and concentrated. The remaining oil was purified by column chromatography on silica using isohexane/EtOAc (6:4) as eluent. The product crystallized on standing to give 1.63 g (60%) of the title product: mp 55-56° C. Anal. (C10H10O2S)C, H.
Step 2: 2-[2-(1-Benzothien-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.
Solid; yield 0.23 g (32%): mp 147-149° C. Anal. (C18H20N4O2S.C4H4O4) C, H, N.
Yield 39%, mp 75-85° C. Anal. (C14H18N4O2S.2.1HCl) C, H, N.
*The starting material 2-(3-thienyloxy)ethanol was prepared as described in Synth. Met. 1988, 26, 153-168.
A mixture of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (0.82 g, 5.0 mmol), ethylene oxide (0.22 g, 5.0 mmol), triethylamine (3 drops) and dioxane (4 mL) was heated at 100° C. in a sealed tube for 3 d. The solution was cooled in an ice-bath and KO-t-Bu (0.56 g, 5 mmol) followed by 2-chloro-3-(1-piperazinyl)pyrazine (0.79 g, 4.0 mmol; from Example 90, Step 1) were added. The mixture was stirred at room temperature for 30 min and at 100° C. for 4 h, allowed to cool, diluted with CH2Cl2 and filtered. The filtrate was concentrated and purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give 1.46 g of a beige viscous oil. Maleic acid (0.46 g, 4.0 mmol) and dry MeOH (10 mL) was added. The mixture was heated until a clear solution formed. Upon cooling, the maleate salt of the title compound crystallized as a pale beige solid: yield 1.40 g (72%); mp 156-157° C. Anal. (C20H26N4O3.C4H4O4) C, H, N.
Step 1: 2-(1,3-Benzoxazol-4-yloxy)ethanol.
K2CO3 (254 mg, 1.84 mmol) was added to a stirred solution of 4-hydroxybenzoxazole* (248 mg, 1.84 mmol) in DMF (5 mL) at room temperature. The mixture was heated at 90° C. for 15 min and ethylene carbonate (176 mg, 2.00 mmol) was added. The mixture was stirred at 150° C. for 2 h and allowed to attain room temperature. The mixture was diluted with water (2 mL) and MeOH (2 mL), and concentrated. The residue was partitioned between water and CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The organic phases were pooled and washed with water and brine, and dried over MgSO4. The filtrate was concentrated to give the product as a brown oil that slowly solidified: yield 278 mg (84%); mp 47-49° C. Anal. (C9H9NO3) C, H, N.
*Prepared as described in J. Med. Chem. 1987, 30, 62-67.
Step 2: 2-(1,3-Benzoxazol-4-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate. KO-t-Bu (146 mg, 1.30 mmol) was added in one portion to a stirred solution of 2-(1,3-benzoxazol-4-yloxy)ethanol (223 mg, 1.24 mmol) in dioxane (5 mL) at room temperature. After 15 min, 2-chloro-3-(1-piperazinyl)pyrazine (247 mg, 1.24 mmol; from Example 90, Step 1) was added in one portion followed by dioxane (3 mL). The mixture was stirred at room temperature for 10 min and at 100° C. for 3 h, allowed to cool, diluted with CH2Cl2 and filtered through Celite. The filtrate was concentrated and purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give the product (70 mg, 17%) as a beige viscous oil. The maleate salt was prepared as described in Example 158: mp 191-193° C. Anal. (C17H19N5O3.C4H4O4) C, H, N.
Step 1: 2-[(2-Amino-4-quinolinyl)oxy]-1-ethanol.
To a mixture of 2-amino-4-hydroxyquinoline (0.505 g, 3.15 mmol) and K2CO3 (0.87 g, 6.3 mmol) in DMF (10 mL) was added of 2-bromoethanol (0.470 g, 3.78 mmol). The mixture was stirred at 150° C. for 7 h. The reaction mixture was concentrated and the residue purified by column chromatography on silica using MeOH/CHCl3 (1:9) as eluent. The resulting brown oil (0.30 g, 30%), which was used directly in the next step, contained 75% of the desired product and 25% of unreacted starting material. MS m/z 205 (M+H)+.
Step 2: 4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine, Trihydrochloride.
The product obtained in Step 1 (0.30 g, 1.5 mmol) was dissolved in DMF (4 mL) and treated with NaH (55% dispersion in mineral oil; 0.12 g, 3.0 mmol). After beeing stirred for 5 min at room temperature, 2-chloro-3-(1-piperazinyl)pyrazine (0.212 g, 1.07 mmol; from Example 90, Step 1) was added. The reaction mixture was stirred at 70° C. for 4 h and at room temp for 14 h. Purification by column chromatography on silica gel using 20% MeOH in CHCl3 as eluent furnished 0.102 g (25%) of the free base of the title compound which was converted to a hydrochloric acid salt: mp 156° C. (dec). HRMS m/z calcd for C19H22N6O2(M)+366.1804, found 366.1795.
Step 1: 3,4-Dihydro-3-oxo-2H-pyrido[3,2-b]-1,4-oxazin-2-carboxylic acid ethyl ester.
Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirred mixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine (6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixture was heated at reflux for 17 h and allowed to attain room temperature. The precipitate formed was filtered off, washed with EtOH and dried to give the product as a white solid: yield 3.85 g (35%); mp 160-162° C. Anal. (C10H10N2O4) C, H, N.
Step 2: 3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethanol.
A solution of 3,4-dihydro-3-oxo-2H-pyrido[3,2-b]-1,4-oxazin-2-carboxylic acid ethyl ester (1.10 g, 5.0 mmol) in THF (50 mL) was added over 5 min to a stirred mixture of LiAlH4 (0.38 g, 10 mmol) and THF (20 mL) at 40° C. The mixture was stirred at 45° C. for 30 min and at reflux for 4 h. The mixture was allowed to attain room temperature and excess LiAlH4 decomposed with 50% aqueous NaOH. The mixture was filtered through Celite, and the filtrate was concentrated. The residue (0.42 g) was extracted with CH2Cl2 and the extract was concentrated and purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give the product as a white solid: yield 0.11 g (13%); mp 123-124° C. Anal. (C8H10N2O2) C, H, N.
Step 3: 2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine, Maleate.
The title compound was prepared in an analogous manner to Example 159, Step 2, starting from 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethanol and was isolated as a brownish solid. Yield 47%: nip 154-158° C. Anal. (C16H20N6O2.1.2C4H4O4) C, H, N.
Step 1: 2-Chloro-3-(1-piperazinyl)quinoxaline, Maleate.*
A mixture of 2,3-dichloroquinoxaline (3.05 g, 15.3 mmol), piperazine (2.64 g, 30.6 mmol) and K2CO3 (2.12 g, 15.3 mmol) in acetonitrile (20 mL) was stirred at 55° C. for 1 h. The reaction mixture was diluted with CHCl3, filtered, and concentrated to give a yellowish solid which was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. The resulting solid was redissolved in CHCl3 and applied to a short (4 cm) plug of alumina. Elution with CHCl3 afforded 3.08 g (81%) of the free base of the title compound, which was isolated as a light yellow solid. A portion of the free base was converted to the maleate and recrystallized from MeOH/ether: mp 165-166° C.; HRMS m/z calcd for C12H13CIN4 (M)+248.0829, found 248.0830. Anal. (C12H13CIN4.C4H4O4) C, H, N.
*The corresponding hydrochloride salt has been reported in J. Med. Chem. 1981, 24, 93-101.
Step 2: 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline, Maleate.
KO-t-Bu (0.57 g, 5.1 mmol) was added to a stirred solution of 2-(3-pyridyloxy)ethanol (0.97 g, 7.0 mmol; from Example 150, Step 1) in dioxane (20 mL) and the mixture was stirred for 3 min at room temperature. The free base from Step 1 above (0.97 g, 3.89 mmol) was then added and the resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was diluted with CH2Cl2, filtered, and concentrated to give a yellowish oil which was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and applied to a short (4 cm) plug of alumina. Elution with CHCl3 afforded 1.20 g (88%) of the free base of the title compound as a light beige oil. The free base was converted to the maleate salt and recrystallized from MeOH/ether: mp 137-139° C.; HRMS m/z calcd for C19H21N5O2 (M)+351.1695, found 351.1701. Anal. (C19H21N5O2.1.3C4H4O4) C, H. N.
Step 1: 2-Chloro-3-(1-piperazinyl)-6,7-difluoroquinoxaline.
Piperazine (0.86 g, 10 mmol) was added to a stirred suspension of 6,7-difluoro-2,3-dichloroquinoxaline*(1.18 g, 5 mmol) in EtOH (50 mL) at room temperature. The mixture was heated at 75° C. for 17 h, allowed to cool and filtered to give the product as a pale yellow solid: yield 0.40 g (28%); mp 294-297° C. (dec). MS m/z 285/287 (M+H)+.
*Previously described in J. Med. Chem. 1990, 33, 2240-2254.
Step 2: 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline, Maleate.
The title compound was prepared) according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)-6,7difluoroquinoxaline (230 mg, 0.8 mmol) and 2-(3-pyridinyloxy)ethanol (140 mg, 1 mmol; from Example 150, Step 1). Yield 95 mg (31%). The maleate salt was obtained as described in Example 158: mp 110-5° C. Anal. (C19H19F2N5O2.1.5C4H4O4) C, H, N.
Step 1: 3-(1-piperazinyl)-2,6,7-trichloroquinoxaline.
Piperazine (0.69 g, 8.06 mmol) was added to a stirred suspension of 2,3,6,7-tetrachloroquinoxaline (1.08 g, 4.03 mmol) in EtOH (125 mL) at room temperature. The mixture was stirred at room temperature for 8 h and filtered to give the product as a pale yellow solid: yield 0.88 g (69%), mp>300° C. MS m/z 316/318 (M)+.
Step 2: 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-dichloroquinoxaline, Maleate.
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 3-(1-piperazinyl)-2,6,7-trichloroquinoxaline (270 mg, 1.00 mmol) and 2-(3-pyridinyloxy)ethanol (170 mg, 1.20 mmol; from Example 150, Step 1). Yield 135 mg (32%). The maleate salt was obtained as described in Example 158: mp 187-189° C. Anal. (C19H19Cl2N5O2.C4H4O4) C, H. N.
Step 1: 2,3-Dichlorothieno[3,4-b]pyrazine.
1,4-Dihydro-thieno[3,4-pyrazine-2,3dione* (1.26 g, 7.5 mmol) and POCl3 (6.9 mL, 75 mmol) was stirred at reflux for 21 h. The dark mixture was poured onto ice and extracted with CH2Cl2 (4×30 mL). The organic extracts were pooled and concentrated to give 0.11 g (7%) of the title product which was used in the next step without purification.
*Previously described in Bull. Soc. Chim. Fr. 1983, 159-163.
Step 2: 2-Chloro-3-(1-piperazinyl)-thieno[3,4-b]pyrazine.
Piperazine (92 mg, 1.07 mmol) was added to a stirred suspension of 2,3-dichlorothieno[3,4-b]pyrazine (110 mg, 0.54 mmol) in EtOH (5 mL) at room temperature. The mixture was stirred at reflux for 16 h and filtered. The solid was purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give 40 mg (29%) of the product as an orange solid. The material was used without further purification in the next step.
Step 3: 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno [3,4-b]pyrazine, Maleate.
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)-thieno[3,4-b]pyrazine (40 mg, 0.16 mmol; from Step 2 above) and 2-(3-pyridinyloxy)ethanol (44 mg, 0.31 mmol; from Example 150, Step 1. Yield 38 mg (66%). The maleate was obtained as described in Example 158: mp 152-156° C. Anal. (C17H19N5O2S.1.8C4H4O4) C, H. N.
Step 1: 2-(5-Pyrimidinyloxy)ethanol.
KO-t-Bu (7.70 g, 68.6 mmol) was added to ethylene glycol (10.45 g, 168.4 mmol) under stirring. The mixture was gently heated in order to consume all KO-t-Bu. 5-Bromopyrimidine (8.45 g, 53.1 mmol) was added to the light brownish mixture. After 8 h of stirring at 130° C., CH2Cl2 (50 mL) was added to the brownish reaction mixture and two layers were formed. The CH2Cl2 layer was saved and the other layer was extracted with additional portions of CH2Cl2. The combined CH2Cl2 layers were concentrated in vacuo and the oily residue purified by column chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 0.45 g (6%) of the title product as an oil sufficiently pure for the next step. HRMS m/z calcd for C6H8N2O2(M)+140.0586, found 140.0589.
Step 2: 2-[2-(5-Pyrimidinyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline.
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (0.66 g, 2.65 mmol; from is Example 162, Step 1) and 2-(5-pyrimidinyloxy)ethanol (0.45 g, 3.20 mmol). Yield 0.55 g (59%); mp 115-117° C.; HRMS m/z calcd for C18H20N6O2 (M)+352.1648, found 352.1654. Anal. (C18H20N6O2) C, H, N.
The title product was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1) and 3,4-dihydro-2H-1,4-benzoxazin-2-ylmethanol.* Yield 41%; mp 125-134° C. (dec). Anal. (C21H23N4O4.0.5C4H4O4.2H2O)C, H, N.
*See Example 130.
The title product was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1) and 3,4-dihydro-2H-chromen-2-ylmethanol.* The product was obtained as a yellow amorphous substance: yield 23%; mp 202-204° C.; HRMS m/z calcd for C13H16N4O2(M)+376.1899, found 376.1899. Anal. (C22H24N4O2.HCl) H; C: calcd, 61.32; found. 60.7; N: calcd, 13.00; found 13.5.
*See Example 133.
Step 2: 1-(3-Chloro-2-pyrazinyl)-4-methylpiperazin
A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) and N-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/brine. The dried (MgSO4) organic layer was concentrated and the remaining oil was purified by chromatography on silica gel using CHCl3/MeOH (95:5) as eluent to give 10.7 g (75%) of the title compound as an oil that crystallized upon standing: mp 34-36° C. Anal. (C9H13CIN4) C, H, N.
Step 2: 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl 3-(4-methyl-1 piperazinyl)-2-pyrazinyl ether, Dihydrochloride.
The title compound was prepared according to the procedure described in Example 90, Step 2, starting from 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example 169, Step 1) and 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine. Yield 87%; mp 160-167° C. Anal. (C18H22N4O3.2 HCl) H, N; C: calcd, 52.06; found, 52.6.
The title compound was prepared according to the procedure described in Example 90, Step 2, starting from 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example 169, Step 1) and 2-phenoxyethanol. Yield 79%; mp 172-174° C. Anal. (C17H22N4O2.HCl) C, H, N.
Step 1: 3-Chloro-2-(4-benzyl-2-methyl-1-piperazinyl)pyrazine.
A mixture of 2,3-dichloropyrazine (0.332 g, 2.23 mmol), 1-benzyl-3-methylpiperazine* (0.423 g, 2.23 mmol), and K2CO3 (0.339 g, 2.45 mmol) in acetonitrile (2.5 mL) was stirred at 115° C. for 17 h in a sealed tube. The reaction mixture was diluted with ether, filtered, and concentrated. The brownish oily residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 0.19 g (28%) of the title product as a viscous oil that was sufficiently pure for the next step.
*Previously described in J. Med. Chem. 1996, 39, 2962-2970.
Step 2: 2-(2-Phenoxy)ethyl 3-(4-benzyl-2-methyl-1-piperazinyl)-2-pyrazinyl ether.
KO-t-Bu (0.087 g, 0.77 mmol) was added in one portion to a stirred solution of 2-phenoxyethanol (0.164 g, 1.19 mmol) in dioxane (5 mL) at room temperature. After being stirred for 5 min at 90° C., a solution of the product obtained in Step 1 above (0.18 g, 0.59 mmol) in dioxane (3 mL) was added. The mixture was stirred at room temperature for 10 min and at 85° C. for 2 h. The reaction mixture was diluted with ether, filtered, and concentrated. The remaining beige oil was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 0.22 g (93%) of the title product as an oil. HRMS m/z calcd for C24H28N4O2 (M)+404.2212, found 404.2232.
Step 3: 2-(2-Phenoxy)ethyl 3-(2-methyl-1-piperazinyl)-2-pyrazinyl ether, Maleate.
Ammonium formate (0.18 g, 2.85 mmol) was added to a solution of the product from Step 2 above (0.22 g, 0.54 mmol) in ethanol (5 mL). The mixture was purged with nitrogen and 5% Pd/C (0.15 g) was added. The flask was sealed and the mixture was stirred at 90° C. for 2.5 h. The reaction mixture % vas filtered through Celite and concentrated. The residue %% as purified by chromatography on silica gel using CHCl3/MeOH (10:1) to give 0.12 g (72%) of the free base of the title compound as an oil. The free base was convened to the maleate and recrystallized from MeOH/ether: mp 102-103° C.; HRMS m/z calcd for C17H22N4O2(M)+314.1743, found 314.1754. Anal. (C17H22N4O2.C4H4O4) C, H, N.
Step 1: 4-tert-Butoxycarbonyl-(2R)-methylpiperazine.
Glacial acetic acid (6.3 g, 105 mmol), followed by di-tert-butyldicarbonate (23.11 g, 106 mmol), were added to a stirred solution of (2R)-methylpiperazine (10.3 g, 103 mmol) in MeOH (200 mL) at 0° C., and the resulting mixture was stirred for 1 h. The reaction mixture was allowed to warm to room temperature and stirred for further 15 h. An excess of triethylamine (20 mL, 140 mmol) was added and the reaction mixture was concentrated under reduced pressure. The residue was suspended in CHCl3 and filtered through a fritted glass filter. The filtrate was concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH (85:15) as eluent to give 21 g (65%) of the title product as an oil that crystallized upon standing. The product was used in the next step without further characterization.
Step 2: 3-Chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine.
A mixture of 2,3-dichloropyrazine (22.0 g, 148 mmol), 4-tert-butoxycarbonyl-(2R)-methylpiperazine (21 g, 105 mmol) and K2CO3 (30.4 g, 220 mmol) in DMF was heated at 95° C. for 15 h. The black reaction mixture was filtered through a bed of silica gel, and the filtrate was concentrated. The residue was purified by chromatography on silica gel using petroleum ether/EtOAc (9:1) as eluent to afford 3.2 g (10% over two steps) of the title compound as a colourless oil. HRMS m/z calcd for C14H21CIN4O2 (M)+312.1353, found 312.1358.
Step 3: (2R)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, Hydrochloride.
KO-t-Bu (0.52 g, 4.66 mmol) was added to a solution of 2-phenoxyethanol (0.42 g, 3.0 mmol) in dioxane (15 mL) and the mixture was stirred at room temperature for 15 minutes. 4-tert-Butoxycarbonyl-(2R)-methylpiperazine (0.73 g, 2.33 mmol: from Step 1 above) was added to the suspension and the reaction was stirred at 85° C. for 15 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (97:3:0.2) as eluent. The resulting oil was dissolved in CH2Cl21TFA (1:1) and the mixture was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure and the remaining oil was partitioned between 1 M NaOH/CHCl3. The organic phase was dried (MgSO4) and the solvent evaporated. The resulting oil was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent to provide the free base of the title compound. The free base was precipitated as its hydrochloride salt with HCl/ether to give 0.36 g (44%) of the title compound as white crystals: mp 164-166° C.; HRMS m/z calcd for C17H22N4O2 (M)+314.1731, found 314.1743. Anal. (C17H22N4O2.HCl) C, H, N.
Examples 173-177 were prepared according to the procedure of Example 172, step 3.
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine (from Example 172, Step 2). The pure free base was precipitated as its hydrochloride salt with HCl/ether to give the title compound as white crystals: yield 31%; mp 180-183° C.; HRMS m/z calcd for C16H21N5O2 (M)+315.1695, found 315.1689. Anal. (C16H21N5O2.1.33HCl) C, H, N.
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine (prepared according to the procedure of Example 172, Step 2, with the exception that (2S)-methyl piperazine was substituted for (2R)-methylpiperazine). MS m/z 316 (M+H)+. Yield 58%; mp 170-172° C. Anal. (C16H21N5O2.1.45HCl) C, H, N.
The title compound was prepared starting from 2-phenoxy-1-ethanol and 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine (prepared according to the procedure of Example 172, Step 2, with the exception that (2S)-methylpiperazine was to substituted for (2R)-methylpiperazine). MS m/z 315 (M+H)+. Yield 68%; mp 162-163° C. Anal. (C17H22N4O2.HCl) C, H, N.
The title product was prepared from 2-(6-methyl-3-pyridyloxy)ethanol (from Example 153, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine (from Example 172, Step 2). The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent. After evaporation of the solvent from the combined pure fractions, the resulting free base was precipitated as its fumaric acid salt. Recrystallization from MeOH/ether gave 46% of the title product as an amorphous solid: mp 115° C. (dec). Anal. (C17H23N5O2.C4H4O4) C, H, N.
Step 1: 2-(2-Amino-8-quinolinyloxy)-ethanol.
A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylene carbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20 mL) was stirred at 90° C. for 15 h. The mixture was poured into brine, extracted with EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc/MeOH (50:50:2) as eluent to give 1.13 g (28%) of the title product as a solid HRMS m/z calcd for C11H12N2O2(M)+204.0899, found 204.0906.
Step 2: (2R)-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine, Fumarate.
The title compound was prepared starting from 2-(2-amino-8-quinolinyloxy)ethanol and 3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine (from Example 172, Step 2). The pure free base was precipitated as its fumaric acid salt to give the title compound as yellow, slightly hygroscopic, crystals: yield 5%; mp 160-163° C. (dec). HRMS m/z calcd for C20H24N6O2 (M)+380.1961, found 380.1958.
Step 1:1-Benzyl-3-ethylpiperazine.
Benzyl bromide (38.7 g, 0.22 mol) was added in portions to an ice cold (˜0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150 mL) with such a rate that the temperature did not exceed 20° C. The mixture was stirred for 1 h, the solvent was evaporated and the residue was partitioned between CHCl3/0.5 M HCl. The aqueous phase was made alkaline (11M NaOH) and extracted three times with CHCl3. The combined organic phases were dried (MgSO4) and concentrated. The resulting oil was purified by column chromatography on silica using CHCl3, followed by CHCl3/MeOH/NH4OH (95:5:0.3) as eluents to give 31.6 g (70%) of the title compound as a yellowish oil. Anal. (C13H20N2) H, N; C: calc, 76.42 found 75.85; H, N.
Step 2: 4-Benz-1-(3-chloro-2-pyrazinyl)-2-ethylpiperazine.
A mixture of 2,3-dichloropyrazine (3.9 g, 27 mmol), 1-benzyl-3-ethylpiperazine (4.6 g, 22.5 mmol; from Step 1) and K2CO3 (6.2 g, 45 mmol) in DMF (10 mL) was stirred at 100° C. for 4 days. The solvent from the filtered reaction mixture was evaporated off and the residue was purified by column chromatography on silica using heptane/EtOAc (90:10) as eluent to yield 5.0 g (71%) of the title compound as a light yellow oil. HRMS m/z calcd for C17H21CIN4 (M)+316.1455, found 316.1448.
Step 3:1-(3-Chloro-2-pyrazinyl)-2-ethylpiperazine, Hydrochloride.
1-Chloroethyl chloroformate (2.11 g, 15.2 mmol) was added with a syringe during 1 h to an ice cold (˜0° C.) solution of 4-benzyl-1-(3-chloro-2-pyrazinyl)-2-ethylpiperazine (3.22 g, 10.1 mmol, from Step 2) in dry CH2Cl2 (30 mL). The reaction-was-allowed to slowly reach room temperature and stirred for 48 h. The solvent was evaporated from the reaction mixture and MeOH was added to the resulting oil. The mixture was heated to reflux for 2 h, the solvent was evaporated and the resulting oil was partitioned between CHCl3/H2O. The aqueous phase was made alkaline and extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4), and the solvent was evaporated. The resulting oil was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent to give a quantitative yield (2.35 g) of the free base of the title compound as a slightly yellow oil. An analytical sample was prepared as its hydrochloric acid salt (from HCl/ether): mp 195-197° C. Anal. (C10H15CIN4.HCl) C, H, N.
Step 4. 2-Ethyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, Fumarate.
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and the product obtained in Step 3 according to the procedure described in Example 162, Step 2. The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (90:10:0.3) as eluent. After evaporation of the solvent from the combined pure combined fractions, the resulting free base was converted to its fumarate salt and crystallized from MeOH to afford 0.21 g (8%) of the title compound as light yellow crystals: mp 125-127° C.; HRMS m/z calcd for C17H23N5O2 (M)+329.1852, found 329.1845. Anal. (C17H23N5O2.C4H4O4) C, H, N.
Step: 1-Benzyl-cis-3,5-dimethylpiperazine.*
To an ice cold (˜0° C.) suspension of cis-2,6-dimethylpiperazine (4.0 g, 35 mmol) in DMF (100 mL) was benzyl bromide (6.0 g, 35.0 mmol) added in portions under a period of 45 min and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated from the suspension and the residue was dissolved in aqueous HCl and washed twice with CHCl3. The aqueous phase was made alkaline and extracted twice with CHCl3. The combined organic phases were washed with H2O and brine, dried (MgSO4), and concentrated to give 4.9 g (68%) of the title product as a colorless oil.
*Previously described in J. Med. Chem. 1964, 7, 241-242 and Org. Prep. Proc. Int. 1976, 8, 19-23.
Step 2: 4-Benzyl-1-(3-chloro-2-pyrazinyl)-cis-2,6-dimethylpiperazine.
A mixture of 2,3-dichloropyrazine (4.9 g, 32.9 mmol), 1-benzyl-cis-3,5-dimethylpiperazine (5.9 g, 29.0 mmol), tributylamine (5.9 g, 32 mmol) and diphenyl ether (70 mL) was heated in a sealed tube at 220° C. for 3 days. The reaction mixture was cooled to ambient temperature and EtOAc (200 mL) and toluene (100 mL) were added. The organic phase was extracted with 5 M aqueous HCl (×3) and the combined aqueous phases were extracted with CHCl3 (×3). The combined organic layers, which contained the product, were washed with aqueous NaOH (5 M), dried (MgSO4), and the solvent was evaporated. The crude product (0.96 g), about 80% pure based on GC, was used in the next step without further purification.
Step 3. 1-(3-Chloro-2-pyrazinyl)cis-2,6-dimethylpiperazine, Hydrochloride.
The title compound was prepared by treating the product obtained in Step 2 with 1-chloroethyl chloroformate according to the procedure described in Example 178, Step 3. The crude product % vas purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2, followed by 90:10:0.5) as eluent to give 0.50 g (8% over two steps) of the free base of the title compound as a colorless oil. An analytical sample was precipitated as its HCl salt with HCl/ether: mp 199-200° C. Anal. (C10H15CIN4.HCl) C, H, N.
Step 4: cis-2,6-Dimethyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, Fumarate.
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and the product obtained in Step 3 according to the procedure of Example 162, Step 2. The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent. After evaporation of the solvent from the combined pure fractions, the resulting oil was crystallized as its fumaric acid salt from MeOH/ether to afford 0.29 g (36%) of the title compound as white crystals: mp 157° C. (dec). Anal. (C17H23N5O2.C4H4O4) C, H, N.
Step 1: tert-Bu tyl 4-(3-{2-[(2-amino-8-quinolinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.
The product of Example 177, Step 1 (503 mg, 2.46 mmol) and 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (659 mg, 2.21 mmol, from Example 52, Step 1) were dissolved in dry dioxane (20 mL). K-t-Bu (305 mg, 2.72 mmol) was added and the reaction mixture was heated. The reaction mixture was heated at 80° C. under inert atmosphere for 3.5 h (monitoring by MS). The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with H2O and the aqueous phase was back-extracted with CH2Cl2. The combined organic phases were washed with brine and dried (MgSO4). Evaporation of the solvents gave a yellow oil (1.37 g), that was purified by column chromatography using EtOAc/Et3N (95:5) as eluent to give the title compound as a yellow solid: yield 898 mg (87%); MS m/z 467 (M+H)+. Anal. (C24H30N6O4.0.9H2O)C, H, N.
Step 2: tert-Butyl 4-[3-(2-{[2-(acetylamino)-8-quinolinyl]oxy}ethoxy)-2-pyrazinyl]-1-piperazinecarboxylate.
The product obtained in Step 1 (502 mg, 1.08 mmol) was dissolved in pyridine. Ac2O (0.42 mL, 4.45 mmol) was added, and the reaction mixture was stirred under inert atmosphere at room temperature for 5 h. Concentration in vacuo afforded a yellow oil, which was purified by column chromatography using EtOAc/Et3N (95:5) as eluent to give the title product as a yellow solid: yield 531 mg (97%); MS m/z 509 (M+H)+. Anal. (C26H32N6O5.0.4H2O)C, H, N.
Step 3: N-[8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinyl]acetamide.
TFA (1.5 mL) was added to a solution of the product from Step 2 (112 mg, 0.22 mmol) in CH2Cl2(1.5 mL) at 0° C. and the mixture was stirred under inert atmosphere for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 2 M aqueous NaOH (×4) and brine. The organic layer was dried (MgSO4) and concentrated. The crude solid product (83 mg) was purified by column chromatography on silica using CHCl3/MeOH (9:1)+1% NH3 as eluent to give the title compound as an oil that solidified after repeated additions of pentane: yield 67 mg (75%); MS m/z 409 (M+H)+. Anal. (C21H24N6O3.0.6H2O.0.1C5H12) C, H, N.
Step 1: 2-(Methylamino)-8-quinolinol.
To a solution of 2-chloro-8-hydroxyquinoline*(2.0 g, 11.1 mmol) in EtOH (40 mL) was added H2NMe (40% aqueous solution, 40 mL, 464 mmol). The mixture was heated in a sealed Pyrex tube at 100° C. for 24 h. The solvent was evaporated and the resulting crude product was purified by column chromatography [gradient: CH2Cl2/MeOH (99:1) to 1% NH4OH in C H2Cl2/MeOH (80:20)] to give the title compound as a black-green solid. Yield 1.31 g (67%); MS m/z 174 (M)+. Anal. (C10H10N2O)C, H, N.
*Prepared as described in J. Org. Chem. 1971, 36, 3490-3493.
Step) 2: 2-{[2-(Methylamino)-8-quinolinyl]oxy}-1-ethanol.
The title compound was prepared according to the procedure of Example 91, Step 1, starting form the product obtained in Step 1 above. The crude product was purified by, column chromatography on silica gel using EtOAc/MeOH (95:5) containing Et3N (2%). Solid, yield 1.21 g (88%); MS m/z 218 (M)+. Anal. (C12H14N2O2.0.6H2O)C, H, N.
Step 3: N-Methyl-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 2 above and 2-chloro-3-(1-piperazinyl)piperazine (from Example 90, Step 1). The crude product was purified by column chromatography (gradient: 1% NH4OH in EtOAc/MeOH (90:10) to 1% NH4OH in EtOAc/MeOH (80:20) in first purification step and gradient 0.5% NH4OH in CHCl3/MeOH (95:5) to 1% NH4OH in CHCl3/MeOH (90:10) in second purification). Yield 31%; mp 54.0-56.5° C.; MS m/z 381 (M+H)+. Anal. (C20H24N6O2.0.5H2O)C, H, N.
Step 1: Step 1: 4-tert-Butoxycarbonyl-2-methylpiperazine.*
The title compound was prepared according to the procedure described in Example 172, Step 1, except that racemic 2-methylpiperazine was used instead of (2R)-methylpiperazine. Yield 82% of the free base. An analytical sample was prepared by conversion to the hydrochloride salt: mp 162° C. (dec). Anal. (C10H20N2O2.HCl) C, H, N.
*Previously described in J. Med. Chem. 1993, 36, 690-698.
Step 2: tert-Butyl 4-(3-chloro-2-quinoxalinyl)-3-methyl-1-piperazinecarboxylate.
A mixture of the title product from Step 1 above (12.3 g, 61.4 mmol), 2,3-dichloroquinoxaline (14.4 g, 72.2 mmol), and K2CO3 (13.8 g, 100 mmol) in DMF (100 mL) was stirred at 85° C. for 15 h. The mixture was filtered and the resulting filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel using petroleum ether/EtOAc (94:6) as eluent to give 5.8 g (36%) of a reddish oil that crystallized on standing: mp 93-97° C. Anal. (C18H23CIN4O2)C, H, N.
Step 3: 2-(1,3-Benzodioxol-4-yloxy)ethanol.
A mixture of 1,3-benzodioxol-4-ol*(0.74 g, 5.36 mmol), ethylene carbonate (0.47 g, 5.3 mmol) and K2CO3 (0.67 g, 4.8 mmol) in DMF (30 mL) was heated at 150° C. After the evolution of carbon dioxide had ceased (1 h), the reaction mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/EtOAc (70:30) as eluent to give 0.64 g (65%) of the title product as an oil which spontaneously crystallized to a white solid: mp 56-57° C. Anal. (C9H10O4) C, H.
*See Example 78.
Step 4: 2-[2-(1,3-Benzodioxol-4-yloxy)ethoxy]-3-(2-methyl-1-piperazinyl)quinoxaline, Hydrochloride.
KO-t-Bu (0.41 g, 3.7 mmol) was added to a solution of 2-(1,3-benzodioxol-4-yloxy)ethanol (0.33 g, 1.8 mmol; from Step 3 above) in dioxane (15 mL). After 15 min of stirring at room temperature, the title compound from Step 2 above (0.73 g, 2.0 mmol) was added and the mixture was stirred at 95° C. for 1.5 h. The reaction mixture was filtered through a pad of Celite, concentrated in vacuo, and the residue was purified by chromatography on silica gel using petroleum ether/EtOAc (9:1) as eluent. The resulting oil was dissolved in CH2Cl2/TFA (1:1, 20 mL) and stirred at room temperature for 15 h. The mixture was concentrated and the resulting oil was co-evaporated twice with 2 M HCl. The residue was recrystallized from water to give 0.22 g (26%) of the title compound as white crystals: mp 133-138° C.; HRMS m/z calcd for C17H22N4O2 (M)+408.1798, found 408.1782. Anal. (C22H24N4O4.HCl H2O)C, H, N;
Step 1. 2-Chloro-5,6-dimethyl-3-(1-piperazinyl)pyrazine.
The title compound was prepared according, to the procedure described in Example 90. Step 1, starting from 2,3-dichloro-5,6-dimethylpyrazine*(0.60 g, 3.39 mmol) and piperazine (0.88 g, 10.2 mmol). Yield 0.51 g (66%). MS m/z 226 (M)+.
*Prepared as described in J. Am. Chem. Soc. 1956, 78, 4071-4077.
Step 2: 5,6-Dimethyl-2-(2-phenoxyethoxy)-3-(1-piperazinyl)pyrazine, Dihydrochloride.
The product from Step 1 above (506 mg, 2.20 mmol) and 2-phenoxyethanol (370 mg, 2.70 mmol) was dissolved in dioxane (10 mL). KO-t-Bu (626 mg, 5.60 mmol) was added and the resulting mixture was stirred at 95° C. for 4 h. The solvent was evaporated and the residue was purified by chromatography on silica gel to give the free base as a yellow oil. The free base was converted to the dihydrochloride salt which was obtained as a monohydrate: yield 0.46 g (50%); mp 138-140° C. Anal. (C18H24N4O2.2HCl.H2O)C, H, N.
Step 1: tert-Butyl 4-(2-hydroxyphenyl)-1-piperazinecarboxylate.
Triethylamine (8.23 mL, 59.5 mmol) was added to a stirred solution of 2-(1-piperazinyl)phenol dihydrobromide (9.87 g, 29.0 mmol) in a mixture of water and dioxane (1:1, 60 mL). The reaction mixture was cooled on an ice-bath (0° C.) and di-tert-butyldicarbonate (6.33 g, 29.0 mmol) was added in one portion. The resulting mixture was allowed to warm to room temperature and stirred for 15 h. The mixture was concentrated to a small volume. Water (20 mL) was added and the white crystals formed were filtered off and dried (1 mm Hg, 70° C.) to give a quantitative yield (7.24 g) of the title compound: mp 115-117° C. Anal. (C15H22N2O3) C, H, N.
Step 2: 1-[2-(2-Phenoxyethoxy)phenyl]piperazine, Hydrochloride.
The product from Step 1 above (0.55 g, 2.0 mmol) was added to a stirred solution of NaO-t-Bu (0.55 g. 2.0 mmol) in DME (5 mL). After 5 min, β-bromophenetole (0.56 g, 2.8 mmol) was added, and the reaction was stirred at 55° C. for 15 h, 2 M HCl was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 2 M NaOH/CHCl3. The aqueous phase was extracted with CHCl3 (×3). The combined organic layers were dried (MgSO4), concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting hydrochloride salt was dried (80° C., 1 mmHg) to afford 0.254 g (35%) of the title compound as a light brown semi-solid material that solidified upon standing. Anal. (C18H22N2O2.HCl.H2O)H, N, C: calc, 61.27; found, 61.9.
Step 1: 2-Chloro-3-(2-phenoxyethoxy)pyrid ine.
A mixture of 2-chloro-3-hydroxypyridine (3.0 g, 23.1 mmol), β-bromophenetole (4.66 g, 23.2 mmol), and K2CO3 (8.0 g, 57.9 mmol) in DMF (50 mL) was heated at 100° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The organic phase was dried (MgSO4), filtered, and the solvent evaporated. The solid residue was triturated with a small amount of ether and dried (65° C., 1 mmHg) to afford 4.23 g (74%) of the title product as white crystals: mp 77-78° C. Anal. (C13H12CINO2) C, H, N.
Step 2: 1-[3-(2-Phenoxyethoxy)-2-pyridinyl]piperazine, Dihydrochloride.
A mixture of the product from Step 1 above (0.84 g, 3.1 mmol) and piperazine hexahydrate (5.3 g, 27.3 mmol) was heated in a sealed tube at 165° C. for 1 h. After cooling, the mixture was diluted with water (100 mL) and extracted twice with EtOAc. The combined and dried (MgSO4) organic phases were concentrated in vacuo and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting dihydrochloride salt was dried (80° C., 1 mmHg) to afford 0.598 g (52%) of the title compound as a light yellow solid: mp 91-120° C. Anal. (C17H21N3O2.2HCl) C, H, N.
The title compound obtained in Example 140, Step 2, (390 mg, 0.85 mmol) was dissolved in MeOH (50 mL) and hydrogenated over 10% Pd/C (50 mg) at atmospheric pressure for 7 h. The reaction mixture was filtered through Celite and concentrated. The residue was purified by chromatography on silica gel using EtOAc/MeOH/Et3N (9:1:0.25) as eluent to give 57 mg (20%) of the free base of the title compound. The free base was converted to the maleate and recrystallized from MeOH/ether: mp 149-154° C.; MS m/z 343 (M+H)+. Anal. (C18H22N4O3.1.1C4H4O4.0.6H2O)C, H, N.
Step 1: 3,5-Dichloro-2-(1-piperazinyl)pyrazine.
To a suspension of 2-chloro-3-(1-piperazinyl)pyrazine (11.7 g, 58.7 mmol; from Example 90, Step 1) in CHCl3 (50 mL) was N-chlorosuccinimid (14.4 g, 108 mmol) added and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and extracted twice with water. The combined aqueous phases were made alkaline (11M NaOH), saturated with NaCl, cooled, and extracted with EtOAc (×3). Concentration of the combined, dried (MgSO4), organic phases afforded 6.12 g (45%) of the title compound as a brown oil which crystallized upon standing: mp 89-97° C. Anal. (C8H10Cl2N4.⅓H2O)C, H, N.
Step 2: 5-Chloro-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine, Fumarate
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and the product from Step 1 according to the procedure described in Example 162, Step 2. The crude product was purified by column chromatography on silica using CHCl3/MeOH/NH4OH (95:5:0.2, followed by 90:10:0.3) as eluent. After evaporation of the solvent from the combined pure fractions, the resulting oil was crystallized as its fumaric acid salt from MeOH/ether to afford 3.06 g (39%) of the title compound as light yellow crystals mp 162° C. (dec). Anal. (C15H18CIN5O2.C4H4O4)
Step 1: 5-Bromo-3-chloro-2-(1-piperazinyl)pyrazine.
To a mixture of 2-chloro-3-(1-piperazinyl)pyrazine (5.94 g, 30 mmol, from Example 90, Step 1) and Na2CO3 (6.0 g, 57 mmol) in AcOH (25 mL) was added a solution of Br2 (6.00 g 38.0 mmol) in AcOH (25 mL) dropwise at room temperature. The reaction mixture was stirred overnight. Water (50 mL) was added and the solution was stirred for 30 min and then concentrated to a small volume. Water (20 mL) was added and the solution was basified to pH 9 by adding solid Na2CO3. The mixture was extracted with CH2Cl2 containing 10% MeOH. The combined extract was evaporated to dryness and the residue was recrystallized from MeOH to give 7.43 g (89%) of the title compound: mp 114-115° C. HRMS m/z calcd for C8H10BrCIN4 (M)+275.9777, found 275.9765.
Step 2: 5-Bromo-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine, Acetate.
To a solution of the product obtained in Step 1 above (3.73 g, 13.5 mmol) and 2-(3-pyridyloxy)ethanol (2.06 g, 14.8 mmol, from Example 150, Step 1) in DMSO (10 mL) was added NaH (50% in mineral oil; 0.93 g, 20 mmol) at room temperature. The mixture was stirred at room temperature overnight. EtOAc (100 mL) was added and the mixture was washed with water, dried over Na2CO3 and filtered. AcOH (1.0 mL) was added to the filtrate. Crystals were formed upon cooling. The crystals were collected, washed with ethyl ether, and dried in vacuum to give 2.45 g (41%) of the title product: nip 108-109° C. Anal. (C15H18BrN5O2.CH3COOH)C, H, N.
Step 1: tert-Butyl 4-(5-bromo-3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl)-1-piperazinecarboxylate.
To a solution of the free base of the product obtained in Example 188. Step 2, (0.70 g. 1.85 mmol) in EtOAc (10 mL) and Et3N (2 mL) was added (T-BuOC)2O (0.46 g, 2.0 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with 2 M aqueous NaOH and brine, dried over Na2CO3 and concentrated. The residue was purified by column chromatography on silica gel, using ethyl ether/hexane (1:3 to 3:1) as eluent to give 0.64 g (72%) of the title product as an oil. MS m/z 481 (M)+.
Step 2: tert-Butyl 4-{5-Methyl-3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.
To a mixture of the product obtained in Step 1 (0.38 g, 0.8 mmol) and NiCl2(dppp) (0.054 g, 0.10 mmol) in dry THF (3 mL) was added dropwise 2N dimethylzinc in toluene (0.5 mL, 1 mmol) at room temperature under stirring. [The reaction was monitored by TLC on SiO2 using ethyl ether/n-hexane (1:1)]. After 4 h, an additional portion (0.3 mL, 0.6 mmol) of the dimethylzinc solution was added. The reaction was stirred for another 2 h and quenched with water (3 mL). The mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2CO3 and concentrated to give 0.29 g of a yellowish oil. Column chromatography on silica gel, using ethyl ether/n-hexane (1:1 to 4:1) as eluent, gave 0.19 g (57%) of the title product as an oil. MS m/z 415 (M)+. HRMS m/z calcd for C21H29N5O4 (M)+415.2220, found 415.2200.
Step 3: 5-Methyl-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine.
To a solution of the product obtained in Step 2 (0.507 g, 1.22 mmol) in CH2Cl2 (3.0 mL) was added TFA (1.5 mL) at 5° C. The solution was stirred for 2 h and evaporated to dryness. The residue was dissolved in water (5 mL) and the solution was basified with 50% aqueous NaOH to pH>13 and extracted with EtOAc. The organic extract was dried over Na2CO3. Evaporation of the solvent gave 0.51 g of the free base. Attempts to prepare a salt of the free base from oxalic acid, fumaric acid or acetic acid failed. The free base was re-generated [treatment with 10% NH3 aqueous solution, extraction with EtOAc and drying (Na2CO3)]to give 0.15 g (40%) of the title compound as an oil. MS m/z 315 (M)+. HRMS m/z calcd for C16H21N5O2 (M)+315.1695, found 311.1701.
Step 1: tert-Butyl 4-(3-{2-[(3-Chloro-2-pyrazinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.
NaH (50% in mineral oil; 0.153 g, 3.50 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2) and 2,3-dichloropyrazine (1.0 g, 6.71 mmol) in dioxane (10 mL). The reaction was stirred in a sealed tube at 100° C. overnight. The reaction mixture was poured into water and extracted with diethyl ether. The ether phase was dried (MgSO4), concentrated and purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.823 g (61%) of the title product: Pos-EI-MS shows M+ and 14 ions supporting the stated structure. HRMS m/z calcd for C19H25CIN6O4 (M)+436.1626, found 436.1606.
Step 2: tert-Butyl 4-(3-{2-[(3-methoxy-2-pyrazinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.
NaH (50% in mineral oil; 0.010 g, 2.1 mmol) was added to a stirred solution of the product from Step 1 (0.38 g, 0.87 mmol) in dioxane (8 mL) and MeOH (2 mL) in a reaction tube. As the gas evolution had ceased, the tube was sealed and the mixture was stirred at 100° C. for 15 min. The reaction was poured into water and extracted with toluene, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.178 g (47%) of the title product. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C20H28N6O5 (M)+432.2121, found 432.2126.
Step 3: 2-{2-[(3-Methoxy-2-pyrazinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Maleate.
The product from Step 2 (0.175 g, 0.40 mmol) product was treated with CH2Cl2/TFA/H2O (50:45:5: 10 mL) for 30 min at room temperature, poured into 0.11M aqueous HCl and washed with toluene (×2). The aqueous phase was alkalinized to pH 11 with NaOH, and extracted with diethyl ether (×3). The organic layers were dried (MgSO4) and concentrated to give 0.120 g (0.36 mmol) of the free base of the title product. Maleic acid (0.042 g, 0.36 mmol) in dioxane (0.5 mL) was added to a solution of the free base in dioxane (3 mL) and left to crystallize to give 0.147 g (82%) of the title product. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C15H20N6O3 (M)+332.1597, found 332.1607.
Step 1: 2-Bromo-3-(2-hydroxyethoxy)pyridine.
The title compound was prepared from 2-bromo-3-hydroxypyridine according to the procedure described in Example 91, Step 1. Oil; yield 2.33 g (76%).
Step 2: 3-(2-Hydroxyethoxy)-2-methoxypyridine.
A mixture of the product obtained in Step 1 (2.33 g, 10.7 mmol) and NaOMe (0.634 mg, 11.8 mmol) in MeOH (50 mL) was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica, using CH2Cl2/MeOH/heptane (4:1:5) as eluent, to give 0.81 g (45%) of the title compound as a colorless oil.
Step 3: 2-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Fumarate.
2-Chloro-3-(1-piperazinyl)pyrazine (0.454 g, 2.13 mmol, from Example 90, Step 1) was added to a mixture of the product obtained in Step 2 (0.380 g, 2.25 mmol) and NaOt-Bu (0.432 g, 4.50 mmol) in dioxane (25 mL). The reaction mixture was stirred at 90° C. for 2 h and then quenched by adding MeOH (0.6 mL, 13.3 mmol). Silica gel was added and the mixture was filtered and concentrated in vacuo). The residue was purified by column chromatography using CHCl3/MeOH/heptane (4:1:5) containing 0.2% aqueous NH3 as eluent to give 0.257 g (40%) of the free base of the title compound as a colorless oil. The free base was dissolved in MeOH (3 mL) and converted into its fumarate salt by adding fumaric acid (0.104 g, 0.87 mmol) in MeOH (3 mL) followed by addition of ether to obtain 0.214 g (56%) of the title compound as white needles: mp 181-183° C.; Anal. (C20H25N5O7) C, H, N.
Step 1: (R)-3-Methyl-1-tritylpiperazine.
(2R)-Methylpiperazine-L-(+)-tartrate* (300 g, 1.2 mol) was added to a hot stirred solution of KOH (240 g, 4.3 mol) in H2O (240 mL). Two phases were formed and the mixture was cooled to room temperature and extracted with CH2Cl2 (3×400 mL). The extracts were dried over K2CO3 and filtered. Trityl chloride (260 g, 0.93 mol) was slowly added to a well-stirred solution of the generated (R)-2-metyhylpiperazine* in CH2Cl2 under cooling (exotermic). After 45 min, the solution was poured into a solution of K2CO3 (140 g, 1.00 mol) in water (500 mL). The resulting organic phase was separated and dried over K2CO3, and the solvent was evaporated. This gave 370 g of the title product as an oil, which was used without purification.
*Previously reported in J. Med. Chem. 1990, 33, 1645-1656.
Step 2: (2R)-1-(3-Chloro-2-pyrazinyl)-2-methylpiperazine.
A mixture of the product obtained in Step 1 above, 2,3-dichloropyrazine (154 g, 1.00 mmol) and K2CO3 (160 g, 1.20 mol) in DMF (1 L) was heated at 110° C. for 20 h with vigorous stirring. (TLC monitoring system: CHCl3: EtOH (20:1); silica). The mixture was cooled and poured slowly into water (6 L) with stirring. The solid was collected, washed with water, dried, dissolved in CHCl3 (1 L), diluted with n-heptane (1 L), and filtered through SiO2. Solvents were evaporated off. The resulting oil was dried under vacuum (3 mm/50° C., 30 min) to remove the DMF. The oil was dissolved in hot ethanol (1 L.), and HCl (10% aqueous solution, 300 mL) was added slowly. Trityl carbinol began to crystallize out after 10 min. After 30 min, the formed trityl carbinol was filtered off and the ethanol was evaporated. The aqueous solution was extracted by ether (2×200 mL) and made basic by addition of K2CO3 to pH 12. The alkaline layer was extracted with CHCl3 (3×200 mL). The combined organic layers were dried (K2CO3) and concentrated to give 140 g (66%) of the title compound.
Step 3: (2R)-1-(3-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine, Fumarate.
The product obtained in Step 2(0.494 g, 2.18 mmol) was added to a solution of 3-(2-hydroxyethoxy)-2-methoxypyridine (0.410 g, 2.42 mmol; from Example 191, Step 2) and NaOt-Bu (0.349 g, 3.63 mmol) in dioxane (25 mL) at 90° C. The reaction mixture was stirred at 90° C. for 2 h and then quenched by adding MeOH (0.6 mL, 13.3 mmol). Silica gel was added and the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using CHCl3/MeOH/n-heptane (4:1:5) containing 0.2% aqueous NH3 as eluent to give 0.382 g (45%) of the free base of the title compound as a colorless oil. Part of the free base (0.150 g, 0.48 mmol) was converted to its fumarate salt to give 0.061 g (28%) of the title compound: mp 141-143° C. Anal. (C21H27N5O7.0.25H2O)C, H, N.
Step 1: 2-[(2-Chloro-3-pyridinyl)oxy]ethanol.
The title compound was prepared from 2-chloro-3-hydroxypyridine according to the procedure described in Example 91, Step 1. Oil; yield (77%; purity about 80% according to 1H NMR). This material was used without further purification in the next synthetic step. HRMS m/z calcd for C7H8CINO2 (M)+173.0240. Found: 173.0244.
Step 2: 2-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Fumarate.
The title compound was prepared according to the procedure of Example 90, Step 2, except that the reaction was carried out at room temperature, starting from the product obtained in Step 1 above and 2-chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1). The crude product was purified by column chromatography on silica. Using CHCl3/MeOH/NH4OH(95:5:0.25, followed by 90:10:03) as eluent. The free base of the title compound was converted to the fumarate salt. Yield 41%; mp 200° C. Anal. (C18H18CIN5O2.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 192, Step 3, except that the reaction was carried out at room temperature and replacing 3-(2-hydroxyethoxy)-2-methoxypyridine with 2-[(2-chloro-3-pyridinyl)oxy]ethanol (obtained in Example 193, Step 1). The crude product was purified by column chromatography on silica, using CHCl3/MeOH/NH4OH (97:3:0.2, followed by 95:5:0.25) as eluent. The free base of the title compound was converted to the fumarate salt: yield 25%; mp 147° C. Anal. (C16H20CIN5O2.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 90, Step 2, except that the reaction was carried out at room temperature, starting from 2-bromo-3-(2-hydroxyethoxy)pyridine (obtained in Example 191, Step 1) and 2-chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1). Yield 39%; mp 202° C. Anal. (C15H18BrN5O2).C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 192, Step 3, except that the reaction was carried out at room temperature, starting from 2-bromo-3-(2-hydroxyethoxy)pyridine (obtained in Example 191, Step 1) and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192. Step 2). Yield 23%: mp 154° C. Anal. (C16H20BrN5O2).C4H4O4) C, H, N,
Step 1: 2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethanol.
To a suspension of sodium thiomethoxide (3.01 g, 42.9 mmol) in dry DMF (30 mL) was 2-[(2-chloro-3-pyridinyl)oxy]ethanol (7.82 g, 45.1 mmol, from Example 193, Step 1) added and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between brine/1 M aqueous NaOH and CHCl3. The aqueous phase was extracted with an additional portion of CHCl3 and the combined organic layers were dried (MgSO4) and concentrated. The resulting red oil was purified by column chromatography on silica using toluene/Et3N/MeOH (96:2:2) as eluent to give 3.0 g (36%) of the title compound as brownish crystals: mp 80° C. Anal. (C7H11, NO2S)C, H, N.
Step 2: 2-(2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine, Fumarate.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from from 2-chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1) and the product obtained in Step 1 above. The free base of the title compound was converted to its fumarate salt: yield 47%; mp 201° C. Anal. (C16H21N5O2S.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 192. Step 3, starting from (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192, Step 2) and the product of Example 197, Step 1. The free base of the title compound was converted to the fumarate salt: yield 39%: mp 179° C. Anal. (C17H23N5O2S.C4H4O4) C, H, N.
Step 1: 2-Bromo-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridine.
A solution of dimethyl-t-butylsilyl chloride (11.1 g, 74 mmol) in DMF (30 mL) was added to a suspension of 2-bromo-3-(2-hydroxyethoxy)pyridine (15.3 g, 70 mmol; obtained in Example 191, Step 1) and imidazole (10.0 g, 147 mmol) in DMF (30 mL). The reaction mixture was stirred at ambient temperature for 2 h, diluted with 0.5 M aqueous NaOH (0.7 L), and extracted twice with toluene. The combined organic phases were washed once with water, dried (MgSO4), and concentrated. The resulting oil was treated with a mixture of petroleum ether and ethyl acetate (95:5; 50 mL) and an analytical sample of white crystals was collected. The remaining crystals were mixed with the filtrate, the solvent was evaporated and the resulting crude product was used directly in the next step. Solid; yield 18.3 g (78%); mp 81° C. Anal. (C13H22BrNO2Si) C, H, N.
Step 2: 2-[(2-Ethoxy-3-pyridinyl)oxy]ethanol.
The product obtained in Step 1 above (13.2 g, 39.7 mmol) was added to sodium ethoxide in EtOH [prepared from Na (10.5 g, 457 mmol) and EtOH (200 mL)]. The resulting mixture was heated at 70° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ice water (0.8 L) and extracted with EtOAc (×4). The combined organic phases were washed twice with brine, dried (MgSO4) and concentrated. The resulting dark red oil was purified by column chromatography on silica using toluene/Et3N (95:5), followed by (90:10), as eluent to give 3.0 g (41%) of the title product as a red oil. HRMS m/z calcd for C9H13NO3 (M)+183.0896. Found: 183.0895.
Step 3: 2-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Fumarate.
The title compound was prepared according to the procedure of Example 90 Step 2, starting from 2-Chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1) and the product obtained in Step 2 above. The free base of the title compound was converted to its fumarate salt: yield 30%; mp 186° C. Anal. (C17H23N5O3.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 192, Step 3, starting from (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192, Step 2) and 2-[(2-ethoxy-3-pyridinyl)oxy]ethanol (from Example 199, Step 2). The free base of the title compound was converted to its fumarate salt: yield 17%; mp 179° C. Anal. (C18H25N5O3.C4H4O4) C, H, N.
Step 1: 2-[(5-Ethoxy-3-pyridinyl)oxy]-1-ethanol.
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 5-ethoxy-3-pyridinol (1.0 g, 7.2 mmol). Yield: 1.23 g (93%). MS m/z 184 (M+H)+.
Step 2: 5-Ethoxy-3-pyridinyl 2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethyl ether, Fumarate.
To a stirred solution of the product obtained in Step 1 (660 mg, 3.60 mmol) in dioxane (6 mL) was added K-t-BuO (438 mg, 3.90 mmol). After 15 min, (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (638 mg, 3.0 mmol: from Example 192, Step 2) was added and the solution was stirred at 85° C. for 2 h. After cooling, CHCl3 was added and the mixture filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using Cl2Cl2/methanol (9:1) as eluent to give the free base of the title compound (0.60 g, 56%). The free base was converted to the hydrochloride salt: yield 0:53 g (37%); mp. 101-104° C.; MS m/z 360 (M+H)+. HRMS m/z calcd for C18H25N5O3 (M)+359.1957, found 359.1943.
The title product was prepared according to the procedure of Example 201, Step 2, starting from 2-(5-pyrimidinyloxy)-1-ethanol (505 Mg, 3.60 mmol; from Example 166, Step 1) and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (638 mg, 3.00 mmol; from Example 192, Step 2). The residue was purified by column chromatography on silica gel using CH2Cl2/methanol (9:1) as eluent to give 456 mg (48%) of the free base of the title compound. The free base was converted to the hydrochloride: mp. 145-147° C.; MS m/z 317 (M+H)+. Anal. (C15H20N6O2.1.3C4H4O4) C, H, N.
Example 203
Step 1: 2-[(6-Chloro-3-pyridinyl)oxy]-1-ethanol.
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 2-chloro-5-hydroxypyridine. Solid; yield 78%. MS m/z 173 (M)+. Anal. (C7H8CINO2) C, H, N.
Step 2: 2-{2-[(6-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Maleate.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 1 above. The crude product was purified by column chromatography (gradient: EtOAc/MeOH (90:10)+1% NH3 to EtOAc/MeOH (80:20)+1% NH3) on silica to give 22% of the free base of the title compound as a colorless oil. Part of this material was converted to its maleate salt: mp 145.9-146.3° C.; MS m/z 336 (M+H)+. Anal. (C15H18CIN5O.C4H4O4) C. H, N.
Step) 1: 2-[(6-Methoxy-3-pyridinyl)oxy]-1-ethanol.
A mixture of the product of Example 203, Step 1 (513 mg. 2.96 mmol) and freshly prepared NaOMe (3.06 g, 56.6 mmol) in dry dioxane (25 mL) was heated in a sealed Pyrex tube at 130° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The organic phase was washed with brine, dried (MgSO4), and concentrated to give the crude product as an oil (430 mg). Purification by column chromatography, using isohexane/EtOAc (1:1) as an eluent, gave the title product as a white solid. Yield 258 mg (51%); MS m/z 169 (M)+. Anal. (C8H11NO3) C, H, N.
Step 2: 2-{2-[(6-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Maleate.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 1 above. Yield of free base of the title product 90%. Part of this material was converted to its maleate salt: mp 151.8-152.6° C.; MS m/z 332 (M+H)+. Anal. (C16H21N5O3.C4H4O4) C, H, N.
Step 1: 5-(Dimethylamino)-2-methoxyphenol.
To a stirred solution of 5-amino-2-methoxyphenol (5.0 g, 36 mmol) in ethanol (250 mL), was added 33% formaldehyde (4×1.5 mL at times 0, 60 min, 140 min and 185 min) and sodium cyanoborohydride (4×0.8 g, at times 30 min, 120 min, 165 min and 210 min). After each addition of the hydride, pH was adjusted to ˜6 using acetic acid. The mixture was stirred for an additional 2 h and then concentrated in vacuo. The residue was partitioned between brine/diethyl ether and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel using hexane/EtOAc (7:3) as eluent to give 1.17 g (20%) of the title compound. MS m/z 168 (M+H)+.
Step 2: 2-[5-(Dimethylamino)-2-methoxyphenoxy]-1-ethanol.
The title compound was prepared according to the procedure of Example 91. Step 1, starting from 5-(dimethylamino)-2-methoxyphenol (1.17 g, 7.0 mmol; front Step 1 above): Yield: 1.44 g (97%).
Step 3: 4-Methoxy-N,N-dimethyl-3-[2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethoxy]aniline, Fumarate.
The title product was prepared according to the procedure of Example 192, Step 3, starting from the product obtained in Step 2 above (700 mg, 3.30 mmol) and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (585 mg. 2.75 mmol; from Example 192, Step 2). The crude product was purified by column chromatography on silica gel using CH2Cl2/CH3OH (9:1) as eluent to give the free base of the title compound. The free base was converted to the fumaric acid salt. Yield: 135 mg (10% over all); mp. 147-149° C.; MS m/z 388 (M+H)+. Anal. (C20H29N5O3.C4H4O4) C, H, N.
Step 1: 2-(2,5-Dimethoxyphenoxy)-1-ethanol*.
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 2,5-dimethoxyphenol.** Yield 85%; mp 50-52° C. Anal (C10H14O4) C, H.
*Previously reported in J. Med. Chem. 1963, 6, 63-69. However, no experimental details were given.
**Prepared as described in Synth. Commun. 1995, 25, 2121-2134.
Step 2: (2R)-Methyl-1-[3-(2,5-dimethoxyphenoxyethoxy)-2-pyrazinyl]piperazine, Maleate.
The title product was prepared according to the procedure of Example 192, Step 3 starting from the product obtained in Step 1 above and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192, Step 2). Yield 26%; nip 105-109° C. Anal (C19H26N4O4.C4H4O4) C, H, N.
The title product was prepared according to the procedure of Example 90, Step 2, starting from 1,2,3,4-tetrahydro-naphtalenylmethanol* (0.79 g, 4.88 mmol) and 2-chloro-3-(1-piperazinyl)pyrazine (0.99 g, 4.6 mmol; from Example 90, Step 1). Oil; yield 57% of the free base. The free base was converted to the fumarate: mp 186-188° C.; Anal. (C19H24N4O.C4H4O4.0.25H2O) C, H, N.
*Previously described in Aust. J. Chem. 1992, 45, 289-308.
The title product was prepared according to the procedure of Example 192, Step 3, starting from 1,2,3,4-tetrahydro-naphthalenylmethanol (0.98 g, 6.04 mmol) and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (1.3 g, 5.7 mmol; from Example 192, Step 2). The product was isolated as a mixture of two diastereomers. Yield of the free base was 63%. The free base was converted to the fumarate salt: mp 169-172° C. Anal (C20H26N4O.C4H4O4) C, H, N.
Step 1: 3-Chloro-4-(1-piperazinyl)-1,2,5-thiadiazole, Hydrochloride.
A mixture of 3,4-dichloro-1,2,5-thiadiazole (4.00 g, 25.8 mmol) and piperazine hexahydrate (25.0 g, 130 mmol) in DMF (25 mL) was heated at 70° C. for 20 minutes. After cooling to ambient temperature, the reaction mixture was basified (11M NaOH) and brine was added. The resulting mixture was extracted with CHCl3 (×3). The combined organic phases were washed twice with brine/water (1:1), dried (MgSO4) and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel using CHCl3 as eluent to give 2.77 g (52%) of the title compound as a colourless oil which was converted to its hydrochloride salt: mp 231° C. (dec). Anal. (C6H9CIN4S.HCl), calc 29.89, found 30.4. H, N.
Step 2: 1-{4-[2-(3-Pyridinyloxy)ethoxy]-1,2,5-thiadiazol-3-yl}piperazine, Maleate.
The product from Step 1 above (0.70 g, 3.42 mmol), 2-(3-pyridinyloxy)-1-ethanol (0.57 g, 4.10 mmol; from Example 150, Step 1) and sodium hydride (60% in mineral oil, 0.19 g, 4.79 mmol) was stirred at 70° C. in dioxane for 14 h. The reaction mixture was filtered through a pad of silica gel and concentrated. The remaining oil was purified by by C-18 HPLC using CH3CN/H2O (gradient: CH3CN 0% to 100%). This furnished the free base of the title compound as an oil which was converted to the maleate salt: yield 0.16 g (11%); mp 116-118° C. Anal. (C13H17N5O2S.C4H4O4) C, H, N.
Step 1: 2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethanol.
The title compound was prepared according to the procedure described in Example 91, Step 1 starting from 6-hydroxy-1,4-benzodioxane.* Oil; yield 55%. MS m/z 196 (M)+. HRMS m/z calcd for C10H12O4 (M)+196.0736, found 196.0735.
*Prepared as described in Eur. J. Med. Chem. 1989, 24, 619-22.
Step 2: tert-butyl 4-{3-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.
To a solution of the product obtained in Step 1 (0.22 g, 1.12 mmol) and 2-chloro-3-(1-piperazinyl)pyrazine (0.25 g, 1.26 mmol; from Example 90, Step 1) in dioxane (5 mL) was added NaH (50% in mineral oil, 0.05 g, 1.1 mmol). The solution was heated at 90° C. overnight. After cooling, EtOAc (10 mL) %%,as added and the solution was washed with water, dried over Na2CO3 and concentrated. The oily residue (0.51 g) was dissolved in a mixture of EtOAc (2 mL) and Et3N (1 mL) and (t-BuOC)2O (0.32 g, 1.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel using MeOH/EtOAc (2:1) as eluent to give 0.43 g (93%) of the title product as an oil. MS m/z: 458 (M) HRMS m/z calcd for C23H30N4O6 (M)+458.2165, found 458.2178.
Step 3: 2-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine, Dihydrochloride.
To a solution of the product obtained in Step 2 (0.43 g, 0.94 mmol) in CH2Cl2 (2 mL) was added CF3COOH (1.5 mL) at room temperature. The solution was stirred at room temperature for 5 h and evaporated to dryness. The residue was dissolved in EtOAc. The solution was washed with 25% aqueous NaOH and dried over K2CO3. A solution of HCl in Et2O was dropped into the solution until no more precipitate formed. The precipitate was collected, washed with ethyl ether, and dried in vacuum to give 251 mg (62%) of the title product: mp 158-160° C. MS m/z 358 (M)+. HRMS m/z calcd for C18H22N4O4 (M)+358.1641, found 358.1647.
A mixture of 2-chloro-3-(1-piperazinyl)pyrazine (0.40 g, 2.0 mmol; from Example 90 Step 1), 3-(2-methoxyphenyl)-propan-1-ol (0.50 g, 3.0 mmol), and KO-t-Bu (1 M in t-BuOH; 3 mL, 3 mmol) in dry dioxane (30 mL) was stirred at reflux for 20 h. The reaction was quenched by addition of water (2 mL). The solvent was evaporated and the crude mixture was passed through a column of hydromatrix material with CH2Cl2 as eluent. The elute was concentrated and the remaining oil was purified by silica gel chromatography using EtOAc/MeOH/Et3N (8:1:1) as eluent. This furnished the free base of the title compound as an oil which was converted to the maleate salt: yield 0.20 g (22%); mp 132-133° C. Anal. (C18H24N4O2.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 90. Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (0.50 g, 2.5 mmol, from Example 90. Step 1) and 2-methoxy-cinnamyl alcohol (0.54 g, 3.3 mmol). Yield 0.45 g (41%); mp 136° C. (dec). Anal. (C18H22N4O2.C4H4O4) C, H, N.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (1.2 g, 5.6 mmol, from Example 90, Step 1) and 6-quinolinemethanol* (0.89 g, 5.6 mmol). Yield 0.80 g (94%); mp 207-209° C. Anal. (C18H19N5O.C4H4O4.0.25H2O)C, H, N.
*Previously described in J. Org. Chem. 1953, 18, 55-58.
A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (50 mg, 0.20 mmol; from Example 1, Step 1) and N N-dimethylethylenediamine (0.2 mL, 1.9 mmol) was heated in a MicroWell 10 microwave reactor for 6 min at 100 W. The reaction mixture was partitioned between water and EtOAc and applied to a hydromatrix column. The column was eluted with EtOAc and the elute was concentrated. The product was purified by Amberchrom CG-161 m LC using CH3CN/H2O (gradient: CH3CN 0% to 100%). Yield 2 mg (4%). MS m/z 303 (M+H)+.
A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (100 mg, 0.40 mmol, from Example 1, Step 1), dimethylaminoethanethiol hydrochloride (56 mg, 0.40 mmol) and sodium hydride (60% in mineral oil; 32 mg, 0.80 mmol) was stirred at 60° C. for 12 h. The reaction mixture was concentrated and partitioned between water and EtOAc and applied on a hydromatrix column. The column was eluted with EtOAc and the elute vas concentrated. The product was purified by Amberchrom CG-161 m LC using CH3CN/H2O (gradient: CH3CN 0% to 100%). Yield 24 mg(24%). MS m/z 320 (M+H)+.
Step 1: tert-Butyl (3R)-3-methyl-4-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.
Di-tert-butyl dicarbonate (1.01 g, 4.64 mmol) in dioxane (50 mL) was added to a solution of the fumararate salt of (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine* (2.0 g, 4.64 mmol) in a mixture of dioxane/10% aqueous NaHCO3 (1:1; 1100 mL). The reaction mixture was stirred overnight at room temperature and extracted with EtOAc (3×100 mL). The organic phase was concentrated and the residue purified by column chromatography on silica using isohexane/EtOAc (3:1 to 1:1) as eluent. This furnished 1.48 g (77%) of the title product as an oil. MS m/z 416 (M+H)+. HRMS m/z calcd for C21H29N5O4 (M)+415.2220 found 415.2224.
*The corresponding hydrochloride salt is described in Example 173.
Step 2: tert-Butyl (3R)-methyl-4-(3-{2-[(1-oxido-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.
MCPBA (2.91 g, 16.9 mmol) was added to the solution of the product obtained in Step 1 above (1.4 g, 3.37 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred for 1 h at room temperature. This gave a mixture of two unknown di-oxidized derivatives (MS). Aqueous sodium metabisulfite (10%, 50 mL) was added and the reaction mixture was stirred at room temperature until the di-oxidized products had converted to a single mono-oxidized derivative. Extraction with EtOAc (3×50 mL), concentration, and purification of the residue by column chromatography on silica, using isohexane/EtOAc (3:1 to 1:1) as eluent, furnished 0.96 g (66%) of the title product as an oil. MS m/z: 432 (M+H)+. HRMS m/z calcd for C21H29N5O5 (M)+431.2169, found 431.2171.
Step 3: (2R)-2-methyl-1-(3-{2-[(1-oxido-3-pyridinyl)oxy]ethoxy)})-2-pyrazinyl)piperazine.
The product obtained in Step 2 (0.86 g, 2.0 mmol) was treated with CH2Cl2/TFA (75:25; 10 mL) for 1 h at room temperature. After concentration, the residue was purified by column chromatography on silica using EtOAc/MeOH/Et3N (80:15:5) as eluent to give 0.32 g (48%) of the title compound as an oil. MS m/332 (M+H)+. HRMS m/calcd for C16H21N5O3 (M)+331.1644, found 331.1655.
Step 1: tert-Butyl 4-{3-[(2-hydroxyethyl)sulfanyl]-2-pyrazinyl}-1-piperazinecarboxylate.
Sodium hydroxide (0.92 g, 23 mmol) was dissolved in water (9 mL) and dioxane (15 mL). 2-Mercaptoethanol (0.54 mL, 7.7 mmol) was added while stirring and 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (2.3 g, 7.7 mmol, from Example 52, step 1) in dioxane (10 mL) was added. The reaction mixture was heated at 100° C. for 22 h. After cooling to room temperature, it was extracted with EtOAc. The organic layer was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) as eluent to give 1.71 g (65%) of the title compound as an orange oil. MS m/z 341 (M+H)+.
Step 2: tert-Butyl 4-{3-[(2-phenoxyethyl)sulfanyl]-2-pyrazinyl}-1-piperazinecarboxylate.
The product obtained in Step 1 (0.135 g, 0.39 mmol), triphenylphosphine (0.134 g, 0.51 mmol) and phenol (48 mg, 0.51 mmol) were dissolved in dry THF (4 mL). Diethyl azodicarboxylate (80 μL, 0.51 mmol) was then added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure. The residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) followed by a second column using (CH2Cl2→CH3OH). This gave 29 mg (18%) of the title compound as a yellow oil.
Step 3: 2-[(2-Phenoxyethyl)sulfanyl]-3-(1-piperazinyl)pyrazine, Trifluoroacetate.
The product obtained in Step 2 (30 mg, 0.072 mmol) was dissolved in CH2Cl2 (0.75 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.25 mL) was then added and the reaction mixture was stirred for 40 min at 5° C. The solvent was evaporated under vacuum. It gave a beige solid 26 mg of the crude product. Purification by reverse phase preparative HPLC on a SymmetryPrep C18 column (150×19 mm, 7 μm), eluting with a gradient of 5% CH3CN in 95% water to 95% CH3CN in 5% water (0.2% TFA buffer), of a 13 mg sample gave 6 mg (39%) of the title product as a white solid. MS m/z 317 (M+H)+; HRMS m/z calcd for C16H20N4OS (M)+316.1358, found 316.1355. Anal. (C16H2N4OS.C2HF3O2.0.5H2O)C, H, N.
Step 1: tert-Butyl 4-(4-chloro-1,2,5-thiadiazol-3-yl)-1-piperazinecarboxylate.
A mixture of N-Boc-piperazine (2.97 g, 15.9 mmol), K2CO3 (2.20 g, 15.9 mmol) and 3,4-dichloro-1,2,5-thiadiazole (1.5 mL, 15.9 mmol) in CH3CN (30 mL) was stirred at 100° C. for 19 h and at room temperature for 4 days. The reaction mixture was then diluted with EtOAc and water. The organic phase was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on two successive silica gel columns eluting with hexane/EtOAc (1:1) and (7:3), respectively. This gave 1.54 g (31%) of the title product as a yellow solid.
Step 2: tert-Butyl 4-[4-(2-hydroxyethoxy)-1,2,5-thiadiazol-3-yl]-1-piperazinecarboxylate.
K-t-BuO (1.24 g, 1 mmol) was added to a mixture of the product obtained in Step 1 (198 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5 mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C. for 6 h and at room temperature overnight. The solution was then poured into ice-water and diluted with EtOAc. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue %% as purified by chromatography on silica gel eluting hexane/EtOAc (1:1) to give 1.71 g (65%) of title product as an orange oil. MS m/z 331 (M+H)+.
Step 3: tert-Butyl 4-(4-{2-[(2-oxo-2H-chromen-7-yl)oxy]ethoxy}-1,2,5-thiadiazol-3-yl)-1-piperazinecarboxylate.
Diethyl azodicarboxylate (DEAD, 61 μl, 0.39 mmol) was added drop wise to a mixture of the product obtained in Step 2 (100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol) and 7-hydroxycoumarin (63 mg, 0.39 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 5 days. After solvent removal, the residue was purified by chromatography on silica gel eluting with hexane/EtOAc (1:1) to give the title product as a white solid (176 mg) which had low purity (67% by HPLC). This material was used directly in the following step without further purification.
Step 4: 7-(2-{[4-(1-piperazinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)-2H-chromen-2-one.
The product obtained in Step 3 (176 mg) was diluted in CH2Cl2 (1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred for 1 h at 5° C. After solvent removal in vacuo, the residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) followed by CH2Cl2/MeOH/Et3N (90:5:5) as eluents This furnished 45 mg (40%) of the title product as a white solid. MS m/z 375 (M+H)+.
Step 1: tert-Butyl 4-{4-[2-(7-isoquinolinyloxy)ethoxy]-1,2,5-thiadiazol-3-yl}-1-piperazinecarboxylate.
The title compound was prepared according to the procedure of Example 218, Step 3 starting from the product of Example 218, Step 2 (100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol), 7-hydroxyisoquinoline (57 mg, 0.39 mmol) and diethyl azodicarboxylate (61 μl, 0.39 mmol) except that the reaction mixture was stirred at room temperature for 5 days. It gave an orange oil (0.34 g) of low purity (63% by HPLC). It was used directly in the following step without further purification.
Step 2: 7-(2-{[4-(1-piperazinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)isoquinoline.
The product obtained in Step 1 (340 mg) %%,as dissolved in CH2Cl2 (1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred at 5° C. for 1 h. After solvent removal in vacuo, the residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) followed by CH2Cl2/CH3OH/Et3,N (90:5:5) as eluents. This furnished 59 mg (55%) of the title product as a yellow oil. MS m/z (M+H)+358.
Step 1: tert-Butyl 4-{3-[2-(3-hydroxyphenoxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.
To a stirred solution of 2-(3-hydroxyphenoxy)ethanol (7.71 g, 0.05 mol) in dry DMF to (100 mL) at ˜0° C. (ice bath) was added NaH (3.90 g, 0.163 mol) in portions under N2. When the H2-evolution had ceased, a solution of 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (0.05 mol, 14.9 g; from Example 52, Step 1) in dry DMF (70 mL) was added in one portion. The mixture was stirred at 65° C. for 1.75 h. After cooling, the reaction was quenched by addition of H2O in DMF. The mixture was filtered and concentrated, in vacuo. The residue was dissolved in EtOAc, washed with 1 M KHSO4 and water, dried (Na2SO4+Norit), and concentrated in vacuo to give the title compound as a beige sticky oil. Yield 94%. This product was used directly in the next step without further purification.
Step 2: 2-{2-[3-(2-Fluoroethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine, Trifluoroacetate.
The product obtained in Step 1 above (83 mg, 0.20 mmol) was dissolved in CH2Cl2 (8.0 mL) and treated first with polymer supported triphenylphosphine (3.0 mmol/g) (133 mg, 0.40 mmol), 2-fluoroethanol (26 mg, 0.40 mmol) and then diethyl azodicarboxylate (DEAD; 70 mg, 0.40 mmol). The reaction mixture was shaken at room temperature, for 18 h, then filtered to remove the solid support. The filtrate was concentrated under reduced pressure then diluted with MeOH (1.5 mL) and purified by preparative C-18 HPLC using CH3CN/H2O/TFA (gradient: CH3CN 60% to 90%, TFA 0.1%) to give the Boc-protected intermediate. This material was not isolated but treated directly with a solution of 25% TFA in CH2Cl2 for 30 min then concentrated under reduced pressure to afford 24 mg (25%) of the title compound. MS m/z 363 (M+H)+.
The title compound was prepared according to the procedure of Example 220, Step 2, starting from 4-methyl-5-thiazolylethanol (57 mg, 0.40 mmol) and the product obtained in Example 220, Step 1, (83 mg, 0.20 mmol) to give 57 mg (51%) of the title compound. MS m/z 442 (M+H)+.
The title compound was prepared according to the procedure of Example 220, Step 2, starting from cyclopropylmethanol (29 mg, 0.40 mmol) and the product obtained in 1 s Example 220, Step 1, (83 mg, 0.20 mmol) to give 30 mg (31%) of the title compound. MS m/z 371 (M+H)+.
The title compound was prepared according to the procedure of Example 220, Step 2, starting from 3-buten-1-ol (29 mg, 0.40 mmol) and the product obtained in Example 220, Step 1 (83 mg, 0.20 mmol) to give 57 mg (59%) of the title compound. MS m/z 371 (M+H)+.
The title compound was prepared according to the procedure of Example 220: Step 2, starting from 2-dimethylaminoethanol (36 mg, 0.40 mmol) and the product obtained in Example 220, Step 1 (83 mg, 0.20 mmol) to give 37 mg (37%) of the title product. MS (ES+) m/z 388 (M+H)+.
A solution of the product obtained in Example 220. Step 1 (208 mg, 0.50 mmol) in CH2Cl2 (8.0 mL) was treated first with polymer supported triphenylphosphine (3.0 mmol/g) (200 mg, 0.60 mmol), tetrahydro-4H-pyran-4-ol (51 mg, 0.50 mmol) and then diethyl azodicarboxylate (87 mg, 0.50 mmol). The reaction mixture was shaken at room temperature for 18 h, then filtered to remove the solid support. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel. Elution with CH2Cl2/Et2O (10:1) gave the crude N-Boc-protected intermediate which was further purified by preparative C-18 HPLC using CH3CN/H2O/TFA (gradient: CH3CN 60% to 90%, TFA 0.1%). This material was not isolated but treated directly with a solution of 25% TFA in CH2Cl2 for 30 min then concentrated under reduced pressure to afford the title compound 19.0 mg (7%), MS m/z 401 (M+H)+.
Step 1: tert-Butyl 4-(3-{2-[3-(2-methoxyethoxy)phenoxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.
NaH (80% dispersion in mineral oil; 66 mg, 2.75 mmol) was added to a stirred solution of the product obtained in Example 220, Step 1 (716 mg, 1.84 mmol) in dry DMF (10 mL). When the H2-evolution had ceased, 2-bromoethyl methyl ether (256 mg, 1.84 mmol) was added, and the mixture was stirred at 60° C. for 2.5 h. The reaction was quenched by addition of a mixture of HOAc (0.065 mL) and DMF (0.5 mL) followed by a mixture of water (0.065 mL) and DMF (0.50 mL). The resulting mixture was filtered, concentrated in vacuo, and the residue was dissolved in toluene. The solution was washed with 1 M aqueous KHSO4: dried (Na2SO4) and concentrated in vacuo to give 0.60 g (69%) of the title compound as an oil which %% as used in the next step without further purification.
Step) 2: 2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy-}-3-(1-piperazinyl)pyrazine.
The product obtained in Step 1 above was dissolved in a mixture of EtOAc (18 mL) and ether (9 mL) and 5 M HCl/ether (9 mL) was added. The mixture was stirred at room temperature for 3 h. The precipitated hydrochloride salt was filtered off and washed thoroughly with ether. The hydrochloride was dissolved in EtOAc/MeOH/Et3N (100:40:5) and purified by column chromatography) on silica using NH3-satd. EtOAc/CH3OH (100:15) as eluent. The combined pure fractions were concentrated in vacuo and the resulting oil was dried (˜0.8 torr, room temperature) to give 0.36 g (69%) of the title product. HRMS m/z calcd for C19H26N4O4 (M)+374.1954, found 374.1947.
Diethyl azodicarboxylate (DEAD; 575 mg, 3.30 mmol), dissolved in dry THF (5 mL), was added to a stirred mixture of the compound obtained in Example 220, Step 1 (983 mg, 2.36 mmol), 1-(2-hydroxyethyl)-2-pyrrolidinone (427 mg, 3.30 mmol) and Ph3P (867 mg, 3.30 mmol) in dry THF (50 mL). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was treated with EtOAc/hexane (1:1) and solids were filtered off. The filtrate was washed with 0.5 M aqueous Na2CO3, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica to give 1.1 g (88%) of the r-Boc protected intermediate. This material was directly N-Boc deprotected as described in Example 220, Step 2, to give 0.50 g (50% over two steps) of the title product as an oil. HRMS m/z calcd for C22H29N5O4 (M)+427.2220, found 427.2227.
The title compound was prepared according to the procedure of Example 227 starting from the product of Example 220, Step 1, and 3-hydroxytetrahydrofuran. Yield 29% over two steps. HRMS m/z calcd for C20H26N4O4 (M)+386.1954, found 386.1963.
The title compound was prepared according to the procedure of Example 227 starting from the product of Example 220, Step 1, and tetrahydro-3-furanmethanol. Yield 48% over two steps. HRMS m/z calcd for C21H28N4O4(M)+400.2111, found 400.2098.
A suspension of the product obtained in Example 220, Step 1 (62 mg, 0.15 mmol), 2-cyanobenzyl bromide (20 mg, 0.10 mmol) and polymer supported triazabicyclodecene (PTBD) (400 mg) in MeCN (8 mL) was shaken at room temperature for 48 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give the crude N-Boc protected intermediate which still contained some unreacted phenol (by HPLC). This material was dissolved in MeCN (8 mL) then retreated with PTBD (300 mg) and shaken at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was then treated directly with a solution of 25% TFA in CH2Cl2 for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure to afford 32 mg (59%) of the title compound. MS m/z 432 (M+H)+.
The title compound was prepared according to the procedure of Example 230 starting from the product obtained in Example 220, Step 1 (62 mg, 0.15 mmol), and benzyl bromide (17 mg, 0.10 mmol) to give 14 mg (27%) of the title compound. MS m/z 407 (M+H)30.
A solution of the product obtained in Example 220. Step 1 (208 mg, 0.50 mmol) in CH2Cl2 (8 mL) was treated first with polymer supported triphenylphosphine (3.0 mmol/g) (200 mg; 0.60 mmol), 2-(2-hydroxyethyl)pyridine (62 mg, 0.50 mmol) and then diethyl azodicarboxylate (87 mg, 0.50 mmol). The reaction mixture was shaken at room temperature for 3 h, then filtered to remove the solid support. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel. Elution with diethyl ether gave the crude N-Boc-protected intermediate which was treated directly with a solution of 25% TFA in CH2Cl2 for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure to afford 54 mg (20%) of the title compound. MS m/z 422 (M+H)+.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (0.80 g, 4.0 mmol; from Example 90, Step 1) and 4-methoxybenzyl alcohol (0.88 g, 6.4 mmol). Oil; yield 72%. MS m/z 301 (M+H)+.
The title compound was prepared according to the procedure of Example 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (0.15 g, 0.75 mmol; from Example 90, Step 1) and 1-phenyl-2-propanol (163 mg, 1.2 mmol). MS m/z 299 (M+H)+. The crude product was purified by reverse phase preparative HPLC on a SymmetryPrep C18 column (150×19 mm, 7 μm), eluting with a gradient of 5% CH3CN in 95% water to 95% CH3CN in 5% water (0.2% TFA buffer) to give gave 55 mg (18%) of the title product as a white solid. MS m/z 299 (M+H)+.
The title compound was prepared according to the procedure of Example 90. Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (0.50 g, 2.5 mmol; from Example 90, Step 1) and 1 naphthaleneethanol (0.69 g, 4.0 mmol). The crude product was purified by reverse phase preparative HPLC on a SymmetryPrep C18column (150×19 mm, 7 μm), eluting with a gradient of 5% CH3CN in 95% water to 95% CH3CN in 5% water (0.2% TFA buffer) to give gave 290 mg (26%) of the title product as a white solid. MS m/z 335 (M+H)+. Anal. (C20H22N4O.C2HF3O2) C, H, N.
Preparation of Pharmaceutical Compositions
The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
The ability of a compound of the invention to bind or act at specific 5-HT receptor subtypes can be determined using in vitro and in vivo assays known in the art. The biological activity of compounds prepared in the Examples was tested using different tests.
Affinity Assay
The 5-HT2c receptor affinity of compounds in the Examples was determined in competition experiments, where the ability of each compound in serial dilution to displace 3H-labelled 5-HT, bound to membranes prepared from a transfected HEK293 cell line stably expressing the human 5-HT2c receptor protein was monitored by Scintillation Proximity Assay technology. Non-specific binding was defined using 5 μM mianserin. Results obtained for exemplary compounds of the invention are illustrated in Table 1 below. Typically, the 5HT2c receptor affinity values (Ki, nM) were in the range of 1 nM to 1500 nM.
The agonist efficacy at the 5-HT2c receptor of the compounds in the Examples was determined by the ability of each compound to mobilise intracellular calcium in transfected HEK293 cells, stably expressing the human 5-HT2c receptor protein, using the calcium-chelating fluorescent dye FLUO-3 (Sigma. St. Louis, Mo. U.S.A.).
Typically, the maximum responses of 5-HT2c agonists were in the range of 20-100% relative to the maximum response of 5-HT (serotonin) at a concentration of 1 μM.
Acute toxicity studies in mice following oral administration of a number of compounds in the Examples showed that mortality typically occurred at doses between about 200 mg/kg body weight to about 450 mg/kg body weight.
| Number | Date | Country | Kind |
|---|---|---|---|
| 9901884 | May 1999 | SE | national |
This application is a continuation of U.S. application Ser. No. 10/269,670, filed on Oct. 11, 2002, which is a divisional of U.S. application Ser. No. 09/589,282, filed Jun. 8, 2000 (now U.S. Pat. No. 6,465,467, issued Oct. 15, 2002), which is a continuation-in-part of U.S. application Ser. No. 09/573,348, filed on May 19, 2000, abandoned, which claims the benefit of U.S. Provisional application Ser. No. 60/137,527, filed on Jun. 3, 1999, and of Swedish Application No. 9901884-8, filed on May 21, 1999, the entire contents each of which are incorporated by reference in their entirety.
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| Number | Date | Country | |
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| 20040242554 A1 | Dec 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60137527 | Jun 1999 | US |
| Number | Date | Country | |
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| Parent | 09589282 | Jun 2000 | US |
| Child | 10269670 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10269670 | Oct 2002 | US |
| Child | 10873852 | US |
| Number | Date | Country | |
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| Parent | 09573348 | May 2000 | US |
| Child | 09589282 | US |
