MXPA01005318A - Quinoline and quinoxaline compounds as pdgf-r and/or lck tyrosine kinase inhibitors - Google Patents
Quinoline and quinoxaline compounds as pdgf-r and/or lck tyrosine kinase inhibitorsInfo
- Publication number
- MXPA01005318A MXPA01005318A MXPA/A/2001/005318A MXPA01005318A MXPA01005318A MX PA01005318 A MXPA01005318 A MX PA01005318A MX PA01005318 A MXPA01005318 A MX PA01005318A MX PA01005318 A MXPA01005318 A MX PA01005318A
- Authority
- MX
- Mexico
- Prior art keywords
- optionally substituted
- compound according
- ylamino
- further characterized
- dimethoxy
- Prior art date
Links
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- 229940121358 tyrosine kinase inhibitors Drugs 0.000 title description 8
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Abstract
This invention is directed to quinoline/quinoxaline compounds of formula (I) wherein X is L1OH or L2Z2;L1 is (CR3aR3b)r or (CR3aR3b)m-Z3-(CR3'aR3'b)n;L2 is (CR3aR3b)p-Z4-(CR3'aR3'b)q or ethenyl;Z1 is CH or N;Z2 is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl;Z3 is O, NR4, S, SO or SO2;Z4 is O, NR4, S, SO, SO2 or a bond;m is 0 or 1;n is 2 or 3, and n + m=2 or 3;p and q are independently 0, 1, 2, 3 or 4, and p + q=0, 1, 2, 3 or 4 when Z4 is a bond, and p + q=0, 1, 2 or 3 when Z4 is other than a bond;r is 2, 3 or 4;which inhibit platelet-derived growth factor or p56lck tyrosine kinase activity, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or T cell activation and proliferation.
Description
QUINOLINE AND QUINOXALINE COMPOUNDS AS GROWTH FACTOR INHIBITORS DERIVED FROM PLATELETS AND / OR LCK TIROSIN KINASE
RECIPROCAL REFERENCE TO RELATED APPLICATIONS This is a continuation of the patent application of E.U.A. No. 09 / 198,720, filed on November 24, 1998 which, in turn, is a continuation in part of the international patent application No. ^ PCT / US98 / 11000, filed on May 28, 1998 which, at its time, it's a
continuation in part of the document of E.U.A. series No. 08 / 972,614, presented on November 18, 1997 now abandoned which, in turn, is a continuation in part of the document of E.U.A. series No. 08 / 864,455, presented on May 18, 1997, now abandoned.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION This invention is directed to the inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis)
and / or activation and proliferation of T cells, using quinoline / quinoxaline compounds, which are useful inhibitors of tyrosine kinase proteins (TKIs).
Cell signaling is mediated through a system of interactions that include contact between cell and cell or contact between matrix and cell or contact between substrate and extracellular receptor. The signal
• extracellular is frequently communicated to other parts of cell 5 by an event of tyrosine kinase mediated phosphorylation, which affects substrate proteins downstream of the signaling complex bound to cell membrane. A specific series of receptor enzymes such as the insulin receptor, epidermal growth factor receptor (EGF-R) or platelet-derived growth factor receptor (PDGF-R), are
examples of tyrosine kinase enzymes involved in cell signaling. Autophosphorylation of the enzyme is required for efficient enzyme-mediated phosphorylation of substrate proteins containing tyrosine residues. It is known that these substrates are responsible for a variety of cellular events that include cell proliferation, production
of cellular matrix, cell migration and apoptosis, to name a few. It is known that a large number of disease states are
• caused by uncontrolled reproduction of cells or matrix overproduction or poorly regulated programmed cell death (apoptosis). These disease states involve a variety of cell types, and include 20 disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and restenosis that occurs subsequent to angioplasty of the coronary, femoral arteries. or kidney, or such fibroproliferatiya disease
fr - * - * - * • as in arthritis, fibrosis of the lung, kidney and liver. In addition, dysregulated cell proliferative conditions result from coronary bypass surgery. It is thought that the inhibition of tyrosine kinase activity has
• utility in the control of reproduction without control of cells or overproduction of matrix or programmed cell death poorly regulated (apoptosis). It is also known that certain tyrosine kinase inhibitors can interact with more than one type of tyrosine kinase enzyme. Several tyrosine kinase enzymes are critical to the normal functioning of the
• 10 body. For example, Sei would not wish to inhibit the action of insulin in most circumstances; < s normal. Therefore, compounds that inhibit the tyrosine kinase activity of PDGF-R at concentrations lower than the effective concentrations "to inhibit the insulin receptor kinase, could provide valuable agents for the selective treatment of
diseases characterized by cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) such as restenosis, • This invention relates to the modulation and / or inhibition of cell signaling, cell proliferation, extracellular matrix production , chemotaxis, and control of the cellular inflammatory response and growth
cellular abnormal. More specifically, this invention relates to the use of substituted quinoxaline compounds which exhibit selective inhibition of differentiation, proliferation or release of the mediator, effectively inhibiting the tyrosine kinase activity of the platelet-derived growth factor receptor (PDGF-R) and / or the tyrosine kinase activity of Lck.
• Progress reported 5 Several reports in the literature describe tyrosine kinase inhibitors that are selective for tyrosine kinase receptor enzymes such as EGF-R or PDGF-R or non-receptor cytosolic tyrosine kinase enzymes such as v-abl, p56lck or c-src . Recent reviews by Spada and Myers
_ ^ (Exp. Opin. Ther.Patents 1995, 5 (8), 805) and Bridges (Exp. Opin. Ther. Patents
W '10 1995, 5 (12), 1245) summarize the literature for tyrosine kinase inhibitors and selective EGF-R inhibitors, respectively. In addition, Law and Lydon have summarized the anticancer potential of tyrosine kinase inhibitors
(Emerging Drugs: The Prospect For Improved Medicines 1996, 241-260). The known inhibitors of the tyrosine kinase activity of
PDGF-R include quinoline-based inhibitors reported by Maguire et al. (J. Med. Chem. 1994, 37, 2129), and by Dolle et al. (J. Med. Chem. 1994, 37,
• 2627). A class of phenylamino-pyrimidine-based inhibitors was recently reported by Traxler et al. in EP 564409, and by Zimmerman, J .; and Traxler, P. et al. (Biorg. & Med. Chem. Lett. 1996, 6 (11),
1221-1226), and by Buchdunger, E. et al. (Proc. Nat. Acad. Sci. 1995, 92, 2558). Despite advances in the field, there are no agents for these classes of compounds that have been approved for use in humans for the treatment of proliferative disease.
The correlation between the multifactorial disease of restenosis with PDGF and PDGF-R, is well documented throughout the scientific literature. However, recent advances in the knowledge of
• fibrotic diseases of the lung (Antoniades, HN et al., J. Clin, Invest 5 1990, 86, 1055), kidney and liver (Peterson, TC Hepatology, 1993, 17, 486), have also indicated that PDGF and PDGF- R play a role. For example, glomerulonephritis is a major cause of renal failure, and PDGF has been identified as a potent mitogen for mesanglial cells in vitro, as demonstrated by Shultz et al. (Am. J. Physiol.
Wf 10 1988, 255, F674) and by Floege, et al. (Clin Exp Immun 1991, 86, 334). It has been reported by Thornton, S.C. et al. (Clin. Exp. Immun., 1991, 86, 79) that FNT-alpha and PDGF (obtained from human patients suffering from rheumatoid arthritis) are the main cytokines involved in the proliferation of! synovial cells. In addition, specific types of "elulas" have been identified
tumors (see Silver, B. J., BioFactors, 1992, 3, 217), such as glioblastoma and Kaposi's sarcoma, which overexpress the protein or
• PDGF receptor, thus leading to the uncontrolled growth of cancer cells by an autocrine or paracrine mechanism. therefore, it is anticipated that a PDGF tyrosine kinase inhibitor would be useful in the
treatment of a variety of apparently unrelated human disease conditions that can be characterized p ^ > r the participation of PDGF and / or PDGF-R in its etiology.
* »* - i I¡« ^^^ B &M ___ I.
The function of several non-receptor tyrosine kinases such as p56; lck (hereinafter "Lck") in conditions related to inflammation, involving activation and proliferation of T cells, has been reviewed by Hanke, et al (Inflamm. Res. 44, 357) and by Bolen and Brugge (Ann. Rev. Immunol., 1997, 15, 371). These inflammatory conditions include allergy, autoimmune disease, rheumatoid arthritis and rejection of transplants. Another recent review summarizes several classes of tyrosine kinase inhibitors that include compounds that have Lck inhibitory activity (Groundwater, et al.
Progress in Medicinal Chemistry, 1996, 33-233). The inhibitors of
The Lck tyrosine kinase activity includes several natural products which are generally nonselective tyrosine kinase inhibitors such as staurosporine, genistein, certain flavones and erbstatin. It was recently reported that damnacantol is an Lck inhibitor of low nM levels (Faltynek, et al, Biochemistry, 1995, 34, 12404). Examples of synthetic Lck inhibitors include: a series of dihydroxy isoquinoline inhibitors reported to have low micromolar to submicromolar activity (Burke, et al.
• J. Med. Chem. 1993, 36, 425); and a quinoline derivative which has been found to be much less active and which has an IC 50 of Lck of 610 micromolar. Researchers have also discovered a series of 20 4-substituted quinazolines that inhibit Lck on the low micromolar to submicromolar scale (Myers et al, W095 / 15758 and Myers, et al., Bioorg, Med. Chem. Lett., 1997, 7 , 417). Researchers at Pfizer (Hanke, et al J. Biol. Chem. 1996, 271, 695) have described two specific pyrazolopyrimidine inhibitors known as PP1 and PP2, which have low nanomolar potency against Lck and Fyn (other kinases of the Src family). No inhibitory activity of Lck has been reported with respect to quinoline or quinoxaline-based compounds. Therefore, it is anticipated that a quincine or quinoxaline-based inhibitor of Lck tyrosine kinase activity might be useful in the treatment of several apparently unrelated human disease conditions, which may be characterized by the involvement of signaling tyrosine kinase of Lck in its etiology.
BRIEF DESCRIPTION OF THE INVENTION
This invention is directed to a compound of formula
wherein: Li is (CR3aR3b) r O (CR3aR3b) m -Z3- (CR3'aR3'b) n; L2 is (CR3aR3b, p-Z ^ CRa-aR ^ q or ethenyl, Zi is CH or N;
Z2 is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl;
• Z3 is O, NR4) S, SO or S02; 5 Z is O, NR ^ S, SO, S02 or a bond: m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3 or
4 when Z is a bond, v p + q = 0, 1, 2 or 3 when Z4 is different from a
• 10 link; r is 2, 3 or 4; RIA and R.b.pn independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally cycloalkyloxy
Substituted, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, c-ano, RsRßN- or aciIRsN-, or one of R a and R.b is hydrogen or halogen, and e # other is optionally substituted alkyl; optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy,
Optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, RsRβN- or aciIRsN-.
R c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halogen, cyano , RsRßN- or aciIRsN-; R3a, R3b. R ^ a and R ^ b are independently hydrogen or alkyl; R 4 is hydrogen, alkyl or acyl; and R5 and e are independently hydrogen or alkyl, or R5 and Re
taken together with the nitrogen atom to which they are attached, form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is directed to a composition
Pharmaceutical comprising a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. The invention is also directed to intermediates useful in the preparation of compounds of formula I, methods for the preparation of intermediates and compounds of formula I, and the use of a compound of formula I for the
treatment of a patient suffering from, or subject to, disorders / conditions involving cell differentiation, proliferation, production of extracellular matrix or release of mediators.
DETAILED DESCRIPTION OF THE INVENTION
As used above and throughout the description of the invention, it should be understood that the following terms, unless otherwise indicated, have the following meanings:
Definitions "Patient" includes humans and other mammals. "Effective amount" means an amount of the compound of the present invention effective to inhibit the tyrosine kinase activity of
PDGF-R and / or the tyrosine kinase activity of Lck, thereby producing the desired therapeutic effect. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain having from about 1 to about 10 carbon atoms. The preferred alkyl is "lower alkyl," having from about 1 to about 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halogen, carboxy, hydroxy or RsRßN- Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched chain having from about 2 to about 10 carbon atoms in the chain. Preferred alkenyl groups have 2 to
about 6 carbon atoms in the chain, and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Alkenyl
"lower" means from about 2 to about 4 carbon atoms
F 10 in the chain, which can be straight or branched. The alkenyl group can be substituted by carbalkoxy. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. "Ethylenyl" means a group -CH = CH-. "Cycloalkyl" means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group can be substituted by one or more, preferably from 1 to 3, more preferably from one to two, of the following "cycloalkyl substituents", alkyl, hydroxy, acyloxy, alkoxy, halogen substituents, R5R6N-, acyl R5N-, carboxy or R5R6NCO-; the most preferred substituents are alkyl, hydroxy, acyloxy, alkoxy and R5R6NCO-. In addition, when the cycloalkyl group is substituted with at least two hydroxy substituents, then at least two of the hydroxy substituents can be hydroxy [2.2.2] bicyclooctanyl ketalates. "Cycloalkenyl" means a monocyclic ring system or
A non-aromatic multicyclic containing a carbon-carbon double bond and having from about 3 to about 10 carbon atoms. The cycloalkenyl group can be substituted by one or more, preferably one to 3, more preferably 1 to 2 cycloalkyl substituents as described above. "Hydroxycycloalkenyl" means HO-cycloalkenyl, wherein the cycloalkyl can be substituted as described above. Preferred substituted or unsubstituted monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, hydroxycyclopentenyl, hydroxycyclohexepyl and cycloheptenyl; more preferred are hydroxycyclopentenyl and hydroxydichexenyl. Preferred multicyclic cycloalkenyl rings include [2.2.1 jbicycloheptenyl (norbomenyl) and [2.2.1] bicyclooctenyl. "Aryl" means an aromatic carbocyclic radical containing from about 6 to about 10 carbon atoms. Examples of aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more arylc group substituents which may be identical or different, wherein "aryl group substituent" includes hydrogen, hydroxy, halogen, alkyl, alkoxy, carboxy, alkoxycarbonyl or Y1Y2NCO-, wherein Y1 and Y2 are independently hydrogen or alkyl. Preferred substituents of aryl group include hydrogen, halogen and alkoxy. "Heteroaryl" means an apical multi-cyclic or monocyclic hydrocarbon ring system of about 5 to about 10 members, in which one or more of the carbon atoms in the ring system are different carbon elements, eg, nitrogen , oxygen and sulfur. The "heteroaryl" may also be substituted by one or more of the "aryl group substituents" mentioned above. Examples of heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, midazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl benzothienyl, quinolinyl , imidazolyl and isoquinolinyl. "Heterocyclyl" means a monocyclic or multicyclic ring system of about 4 to about 10 members, where one or more of the atoms in the ring system is a different element of carbon selected from nitrogen, oxygen or sulfur. The heterocyclyl group can be substituted by one or more, preferably 1 to 3, more preferably 1 to 2 cycloalkyl substituents as described above. "Hydroxyheterocyclyl" means HO-heterocyclyl, wherein the heterocyclyl can be substituted as mentioned above. "Azaheterocyclyl" means a heterocyclyl as described herein, wherein at least one of the ring atoms is nitrogen. Examples of the heterocyclyl moieties include quinuclidyl, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl or 7-oxabicyclo [2.2.1] heptanyl. "Heterocyclycarbonyloxy" means a heterocyclyl group as defined herein, which is attached to the original molecular moiety by a carbonyloxy group (-C (O) O-). The heterocyclic moiety is optionally substituted by one or more, preferably 1 to 3, more preferably a cycloalkyl substituent as defined above. A representative heterocyclylcarbonyloxy is [1, 4 '] - bipiperidin-1' -carbonyloxy. "Heterocyclenyl" means a heterocyclyl ring system as defined herein, which contains at least one carbon-carbon or carbon-nitrogen double bond. The heterocyclenyl group can be substituted by one or more, preferably 1 to 3, more preferably 1 to 2 cycloalkyl substituents as described above. "Hydroxyheterocyclenyl" means HO-heterocyclenyl, wherein the
• Heterocyclenyl can be substituted as described above. "Azaheterocyclenyl" means a heterocyclenyl as described herein, wherein at least one of the ring atoms is nitrogen. Representative monocyclic heterocyclenyl groups include 1, 2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6- • tetrahydropyridine, 1, 4,5,6-tetrahydropyrimidine, 3 , 4-dihydro-2H-pyran, 2-10 pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. "Acyl" means a group H-CO- or alkyl-CO-, in which the alkyl group is as described above. Preferred acyls contain a lower alkyl. Examples of acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. "Aroyl" means an aryl-CO- group, in which the alkyl group is as described above. Examples of aryl groups include benzoyl and 1 - and 2-naphthoyl. "Alkoxy" means an alkyl-O- group, in which the alkyl group
is as described above. The preferred alkoxy is "lower alkoxy" having from about 1 to about 6 carbon atoms. The alkoxy may be optionally substituted by one or more amino, alkoxy, carboxy, alkoxycarbonyl, carboxiaryl, carbamoyl or heterocyclyl groups. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, / -propoxy, n-butoxy, heptoxy, 2- (morpholin-4-yl) ethoxy, 2- (ethoxy) ethoxy, 2- (4-methylpiperazin-1-) il) ethoxy, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, carboxymethoxy and methoxycarbonylmethoxy. "Cycloalkyloxy" means a cycloalkyl-O- group, in which the cycloalkyl group is as described above. Examples of cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, hydrocyclopentyloxy and hydroxycyclohexyloxy. "Heterocyclyloxy" means a heterocyclyl-O- group, wherein the heterocyclyl group is as described above. Examples of heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfidesoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy or 7-oxabicyclo [2.2.1] heptanyloxy, hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo [2.2.1 jheptanyloxy. "Aryloxy" means aryl-O- group, in which the aryl group is as described above. "Heteroaryloxy" means heteroaryl-O- group, wherein the heteroaryl group is as described above. "Acyloxy" means an acyl-O- group, in which the acyl group is as described above. "Carboxy" means a group HO (0) C- (carboxylic acid). I "RsRßN-" means a substituted or unsubstituted amino group, wherein R5 and Re are as described above. Examples are amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.
"RsRßNCO-" means a substituted or unsubstituted carbamoyl group, wherein R5 and R6 are as described above. Examples are carbamoyl (H2NCO-), N-methylcarbamoyl (MeNHCO-) and N, N- • dimethylaminocarbamoyl (Me2NCO-). 5"ACÍI0R5N-" means an acylamino group wherein R5 and acyl are as defined above. "Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred, and more preferred are fluorine or chlorine. "Prodrug" means a form of the compound of formula I
suitable for administration to a patient without undue toxicity, irritation or allergic response and the like, and effective for its intended use, including ketal, ester and zwitterionic forms. A prodrug is
Transformed in vivo to produce the original compound of the above formula, for example, by hydrolysis in the blood. A full description is
provides in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the symposium series of A. C. S., and in Edward B. Roche, ed., Bioreversible
• Carriers in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, citations that are incorporated herein by reference. "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical association involves variable degrees of ionic and covalent binding, including hydrogen bonding. In certain cases, the solvate will be able to undergo isolation, for example, when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. "Solvate" covers insoluble solvates and phase solvates. Representative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecules are H20.
DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
A preferred aspect of the compound of the invention is a compound of formula I, wherein: Li is (CRaaRatJm-ZHCRa-aRa-bJn; L2 is (CR3aR3t and Z_r (CR3 _ 3 _); Z2 is optionally hydroxycycloalkyl substituted, or optionally substituted hydroxyheterocyclyl, Z4 is O and NR4, m is O; n is 2 or 3, p + q = 0 or 1; RIA and Ri is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, heterocyclyloxy optionally substituted or RsRßN, or one of R? and R-ib is hydrogen or halogen; R-ic is hydrogen, optionally substituted alkyl or optionally substituted klkoxy;
-! * - «R3a. R3b. R3 a and R3 b are independently hydrogen or lower alkyl; R ^ t is hydrogen; and R5 and Re taken together with the nitrogen atom to which they are attached, form azaheterocyclic, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. Another preferred aspect of the compound of the invention is a compound of formula I, wherein: • 10 X is L2Z2; L2 eS (CR3aR3b) p-Z4- (CR3-aR3'b) q; Z2 is optionally substituted hydroxycycloalkyl; Z4 is O and NR4; weight; 15 q is 0 or 1; R-ia and R-ib are independently alkyl optionally
• substituted, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclic loxy, or one of R-? A and R-ib is hydrogen or halogen and the other of R? And Ri is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy; R-ic is hydrogen; R3_ and R3'b are independently hydrogen; and R4 is hydrogen, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. Another preferred aspect of the compound of the invention is a
Compound of formula I, wherein R-? A and Rib are independently lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy or heterocyclyloxy optionally substituted by hydroxy, or one of R a and R e is hydrogen or halogen, and the other of
Ria and R.b is optionally lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy
A or heterocyclyoloxy substituted by hydroxy. Another preferred aspect of the compound of the invention is a compound of formula I wherein R a and R b are independently heterocyclylcarbonyloxy or optionally substituted lower alkoxy; more preferably, the lower alkoxy is methoxy or ethoxy. Another preferred aspect of the compound of the invention is a compound of formula I wherein R-? A and R.b are lower alkyl; more preferably, the lower alkyl is methyl or ethyl. • Another preferred aspect of the compound of the invention is a compound of formula I wherein one of R a and Rib is lower alkoxy, and the other R a and Rib is halogen; more preferably, the lower alkoxy is methoxy or ethoxy, and the halogen is chloro or bromo. Another preferred aspect of the compound of the invention is a compound of formula I wherein one of R a and R-ib is lower alkyl, and the other of R a and R y is lower alkoxy; more preferably, the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl. Another preferred aspect of the compound of the invention is a
• compound of formula I wherein one of R a and R-ib is lower alkoxy, and the other of R a and Rib cycloalkyloxy; more preferably, the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. Another preferred aspect of the compound of the invention is a compound of formula I wherein one of Ria and R-ib is hydrogen, and the other of
A R1a and Rib is lower alkoxy, cycloalkyloxy or heterocyclyloxy; more preferable,
The lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and the heterocyclyloxy is furanyloxy. Another preferred aspect of the compound of the invention is a compound of formula I wherein R.sup.a and R.sup.b are lower alkoxy, wherein the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. Another preferred aspect of the compound of the invention is a
• compound of formula I wherein one of R a and R-ib is unsubstituted lower alkoxy, and the other of R-? A and Ri is optionally substituted heterocyclylcarbonyloxy, or is lower alkoxy substituted with alkoxy, heterocyclyl, carboxy,
Alkoxycarbonyl or carbamoyl. Another preferred aspect of the compound of the invention is a compound of formula I wherein one of R a and Ri is methoxy, and the other of R a and Ri is [1, 4 '] - bipiperidin-1' -carbonyloxy, - (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy, 2- (4-methylpiperazin-1-yl) ethoxy, carbonylmethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy, N-methylaminocarbonylmethoxy or N, N-dimethylaminocarbonylmethoxy. • Another preferred aspect of the compound of the invention is a compound of formula I wherein R-? C is hydrogen, lower alkyl or lower alkoxy; more preferably, the lower alkoxy is methoxy or ethoxy. Another preferred aspect of the compound of the invention, ps a compound of formula I wherein Zi is CH. Another preferred aspect of the compound of the invention is a
• Compound of formula I wherein Zi is N. Another preferred aspect of the compound of the invention is a compound of formula I wherein Z2 is optionally substituted hydroxycycloalkyl. Another preferred aspect of the compound of the invention is a compound of formula I wherein p and q are 0. Another preferred aspect of the compound of the invention is a
• compound of formula I wherein p + q = 1. Another preferred aspect of the compound of the invention is a compound of formula I wherein Z is O. Another preferred aspect of the compound of the invention is a compound of formula I wherein Z is O, ypyq are 0. Another preferred aspect of the compound of the invention is a compound of formula I wherein Z4 is O, and p + q = 1.
Another preferred aspect of the compound of the invention is a compound of formula I wherein Z is NR4. Another preferred aspect of the compound of the invention is a
• compound of formula I wherein Z_t is NR-t, ypyq are 0. Another preferred aspect of the compound of the invention is a compound of formula I wherein Z is NR, and m + n = 1. Another preferred aspect of the compound of the invention, is a compound of formula I wherein Z is S. • Another preferred aspect of the compound of the invention, it is a
The compound of formula I in Count Z is S, and p and q are 0. Another aspect of the compound of the invention is a compound of formula I where Z is S, and p + q = 1. Another aspect. The compound of the invention is a compound of formula I ei wherein Z 2 is hydroxycycloalkyl substituted with hydroxy or alkyl, and more preferred is hydroxycycloalkyl substituted with lower alkyl. • Compounds -referred in accordance with the invention are selected from the following species: 7rans-4- (7-chloro-6-methoxyquinolalin-2-ylamino) -cyclohexanol; 20 rrans-4- (6-chloro-7-methoxyquinolalin-2-ylamino) -cyclohexanol; Rrans-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexanol; C / s-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexanol;
I (2endo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) bicyclo [2.2.1] - heptan-2-ol; (2exo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) bicyclo [2.2.1] - • heptan-2-ol; 5 (2endo, 3exo, 5exo) -5- (6,7-dimethoxy-cyanoxalin-2-ylamino) bicyclo- [2.2.1] heptan-2,3-diol; C / s-2- (6-methoxyquinolalin-2-ylamino) -cyclopentanol; Trans-2- (6-methoxyquinol-2-yn-2-ylamino) -cyclopentanol; • Trans-4- (6-methoxyquinolalin-2-ylamino) -cyclohexanol; 10 Ethylamide [3aR, 4S, 6R, 6aS] -6- (6,7-dimethoxy-quinxoalin-2-ylamino) -2,2-dimethyl-tetrahydro-cyclopenta [1, 3] dioxol-4-carboxylic acid; 2- (1, 4-dioxa-spiro [4.5] dec-8-yloxy) -6,7-dimethoxy-quinotoxaline; 4- (6,7-dimethoxy-quinotoxalin-2-yloxymethyl) -cyclohexanol; 3- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol; 15 4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexanol; 5- (6,7-Dimethoxy-cyanoxalin-2-yloxy) -bicyclo [2.2.1] heptane-2,3-diol; (2exo, 3exo, 5exo) -5- (6,7-dimethoxy-quinxoalin-2-ylamino) -bicyclo [2.2.1] heptane-2,3-diol; Ester c / s-4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexyl of acetic acid; C / 's-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol; 4- (6,7-Dimethoxy-cyanoxalin-2-yloxy) -cyclohexyl ester of dimethylcarbamic acid;
Trans-4- (6,7-dimethoxy-4-oxyquinolalin-2-ylammon) -cyclohexanol; Ester frans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexyl acetic acid; (2exo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) -bicyclo [2.2.1] - heptan-2-ol; (2endo, 5exo) -5- (6,7-dimethoxyquinolin-2-ylamino) bicyclo [2.2.1] heptan-2-ol; (2exo, 6exo) -6- (6,7-dimethoxyquinolin-2-ylamino) -bicyclo [2.2.1] heptan-2-ol; 4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2trans, 4.rans) -4- (6,7-dimethoxy-quinxoalin-2-ylamino) -2-methyl-cyclohexanol; (+) - (2trans, 4.rans) -4- (6,7-dimethoxyquinolalin-2-ylamino) -2-methyl-cyclohexanol; (-) - (2trans, 4frans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2-trans, 4-trans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2cis, 4c / s) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2c / s, 4.rans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; 4- (6,7-dimethylquinoxalin-2-ylamino) cyclohexanol; Y
(1S, 2R, 4S, 5R) -5- (6,7-dimethoxyquinolalin-2-ylamino) -bicyclo [2.2.1] -heptan-2-ol. The most preferred compounds are the following: i rrans-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexanol; C / s-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexanol; 4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (-) - (2-trans, 4 -rans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2exo, 5exo) -5- (6,7-dimethoxy-quinxoalin-2-ylamino) -bicyclo [2.2.1] heptan-2-ol; 7rans-4- (7-chloro-6-methoxyquinolalin-2-ylamino) -cyclohexanol; 4- (6,7-dimethoxyquinolin-3-ylamino) -cyclohexanol; and (1S, 2R, 4S, 5R) -5- (6,7-dimethoxy-cyanoxalin-2-ylamino) -bicyclo [2.2.1] -heptan-2-ol. It will be understood that this invention encompasses all appropriate combinations of the particular and preferred groups referred to herein. The compounds of this invention can be prepared using procedures known in the literature starting from known compounds or readily prepared intermediates. Examples of general procedures are given below. In addition, the compounds of formula I are prepared according to the following l-X schemes, wherein the variables are as described above, except those variables that the person skilled in the art would appreciate that are inconsistent with the described method.
SCHEME I
• 10 SCHEME II
fifteen
SCHEME IV
SCHEME V
SCHEME VI
RCOCI
wherein at least one of R a, R and R is lower alkoxy and X '"is LiOP' or
L2Z2, wherein P 'is a suitable protecting group to protect a hydroxyl portion in the presence of base and an alkylating agent.
wherein at least one of R a, Rib and Rie is as defined herein, and where X is L? OP \ the protecting group P "is then removed to provide the corresponding OH portion.
In Schemes VI, VII and VIII, R represents a precursor group for R a, R e or R c as defined herein, so that the reaction of RBr, ROH or RCOCI with the aromatic hydroxy group under the conditions described in the diagrams VI, VII and VIII, results in the formation of
Representative RBr includes bromoacetic acid and methyl and ethyl bromoabutyl acetate. Representative ROH includes 2-ethoxyethanol, 2- (4-morpholinyl) ethanol and 3- (4-methylpiperazinyl) propanol. A representative RCOCI is [1, 4'j-bipiperidin-1-ylcarbonyl chloride.
SCHEME Vil
as described in Schemes I, II, III or IX
wherein X "'is L1OP" or L2Z2, wherein P "is a suitable group to protect a hydroxyl portion under the reaction conditions described in
the schemes I, II, III and IX.
wherein X "'is L1OP" or L22_, wherein P "and P" are suitable groups to protect a hydroxyl portion under the reaction conditions described in Schemes I, II, III and IX.
X '"is (LiOP' or L2Z2), where P 'is an appropriate group to protect a hydroxy portion in the presence of a Grignard reagent.
wherein X '"is L1OP', and then the OP 'portion can be converted to the corresponding OH portion using an appropriate deprotection agent.
A mixture of 2-chloro-6,7-dimethoxyquinoxalpa (1 equivalent) and an amine (from about 1 to about 5 equivalents) is heated from about 160 to about 180 ° C by dissolving about 3 hours until the night. The dark brown residue is dissolved in methanol / methylene chloride (0% -10%), and chromatographed on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride
• (0% -100%), to give the desired product. The desired product can be further purified by recrystallization from methanol, methylene chloride or methanol / water.
2. Coupling of 2-chloro substituted quinoxaline and alcohols or phenols A suspension of an alcohol or mercaptan (1 equivalent) and sodium hydride (from about 1 to about 3 equivalents) in anhydrous DMF / THF (0% -50%) is reflux for 1 hour before the addition of 2-chloro-6,7-dimethoxyquinolaline (1 equivalent). The resulting mixture is refluxed for about 1 a
approximately 4 hours. The suspension is neutralized to a pH of about 5 to 8, and separated between methylene chloride and brine. He
• residue after concentration of methylene chloride was chromatographed on silica gel eluted with hexane / ethyl acetate or methanol / methylene chloride (0% -100%), to give the desired product. 20 I 3. Reductive amination reaction with amino-guinolines and aldehydes or ketones An appropriately substituted 3-amino quinoline (1 equivalent) is stirred with an equivalent of the appropriate aldehyde or ketone in methanol (or other suitable solvent mixture), until TLC indicates that the formation of the imine has ended. Excess NaCNBH4 or NaBH4 or other suitable reducing agent is added, and the mixture is stirred until the TLC shows the consumption of the intermediate imine. The mixture is concentrated, and the residue is chromatographed on silica gel with hexane / ethyl acetate (0-1? P%) or chloroform / methanol (0-20%), to give the desired product.
4. Coupling reaction of 3-amino substituted guinolines and bromophenyl compounds An appropriately substituted 3-amino quinoline (1 equivalent) is stirred with about 1.4 equivalents of a strong base such as sodium b-butoxide, 1 equivalent of the appropriate bromophenyl compound, and catalytic amounts of 2,2'-bis (diphenylphosphino) -1 -1 * -bubityl (S-BINAP) and bis (dibenzylideneacetone) -palladium (Pd (dba) 2) are mixed in an inert organic solvent such as low toluene. an inert atmosphere such as argon, and are heated to about 80 ° C overnight. The mixture is cooled, diluted with a solvent such as ether, filtered, concentrated and chromatographed with 50% EtOAc / hexane to give the desired product.
. Formation of ether from 3-hydroxy-substituted guinolines by Mitsunobu conditions A THF solution of an appropriately substituted hydroxyquinhoxaline (from about 0 to about 25 ° C) is treated with 1
equivalent of each of the desired alcohol, triphenylphosphine and finally diethyl azodicarboxylate (DEAD), or an appropriate equivalent. The progress of the reaction is monitored by TLC, and after the end of the reaction (from about 1 to about 24 hours), the mixture is concentrated, and the residue is chromatographed on silica gel to give the
desired product.
6. Desalting a Guinoline or Guinoxaline Lower Alkoxy Substituted, and Subsequent Alkylation An Appropriate Substituted Substituted Quinoxine or Quinoxaline (1)
equivalent) in DMF is treated with an excess of sodium ethantiolate (usually about two or more equivalents), and the reaction mixture is
• stir with heating from about 1 to about 24 hours. The mixture is separated between water and ethyl acetate. The extractive preparation followed by chromatography, if necessary, provides the quinoline product or
The corresponding desired hydroxy-substituted quinoxaline. The quinoline or hydroxy substituted quinoxaline product can be alkylated using the conditions for the Mitsunobu reaction as detailed above. In alternative form, a simple alkylation using methods well known in the art with a reactive alkyl or benzyl halide using NaH or other appropriate base, in a suitable solvent, provides the desired alkylated product. • 5 7. Oxidation of a nitrogen in a guinoline or quinoxaline to the corresponding N-oxide A mine portion (= N-) in a quinoxane or quinoxaline compound of formula (I), can be converted to the corresponding compound , where the imine portion is oxidized to an N-oxide,
Preferably by reaction with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as dichloromethane, at a temperature close to room temperature to reflux, preferably at an elevated temperature. The compounds of the present invention are useful in the form of the free base or acid, or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the
• invention. When the compound of the present invention is substituted with a basic portion, acid addition salts are formed and are simply a more convenient form for use; and in practice, the use of salt inherently forms quantities that will be used as the free base form. The acids that can be used to prepare the acid addition salts preferably include those which, when combined with the free base, produce pharmaceutically acceptable salts, that is, salts whose non-toxic anions are not toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free base, are not
• vitiated by side effects attributable to anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate, for example, as when the salt is formed solely for purification and identification purposes, or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange process. The pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, acid
citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acid
• cyclohexylsulfamic, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalogenides, for example, hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulphamate, acetate, citrate,
Lactate, tartrate, malonate, oxalate, silicone, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoates, gentisatos, mesylates, isethionates and di-p-toluoyltartrates methanesulfonate, ethanesulfonate, benzenesulfonate, p-I toluenesulfonate, cyclohexyl sulfamate and quinato, respectively.
According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared by dissolving the free base in aqueous or non-aqueous alcohol solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or reacting the Free base and acid in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution. The compounds of this invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, original compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, for example, aqueous solution of sodium bicarbonate or aqueous solution of ammonia. When the compound of the invention is substituted with an acidic portion, basic addition salts can be formed, and are simply a more convenient use form; and in practice, the use of salt inherently forms quantities that will be used as the free acid form. Bases that can be used to prepare the basic addition salts preferably include those that produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical dosages of the salts, so that the beneficial inhibitory effects on PDGF inherent in the free acid, not be vitiated by side effects attributable to the Wm cations. The pharmaceutically acceptable salts, including for example
alkali metal and alkaline earth metal salts, within the scope of the invention, are those derived from the following bases: hydride of? Hate sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonic, triethylammonic, ethylenediamine, n-methyl-glucamine,
Lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloropropain, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide, and the like. Metal salts of the compounds of the present invention can be obtained by contacting a hydride, hydroxide, carbonate or
similar reactive compound of the chosen metal, in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent
• used may be water or may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as
ethyl acetate. Said reactions are usually carried out at room temperature but, if desired, they can be carried out with heating.
Amine salts of the compounds of the present invention can be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Aqueous solvents
• suitable include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts can be prepared in a similar manner. The compounds of this invention can be regenerated from the basic addition salts by the application or adaptation of
known methods. For example, original compounds of the invention can be regenerated from their basic addition salts by treatment with an acid, for example, hydrochloric acid. Also being useful as active compounds, the salts of the compounds of the invention are useful for the purification purposes of
compounds, for example, exploiting differences in solubility between salts and original compounds, by-products and / or materials
• starting, using techniques well known to experts in the field. The compounds of the present invention can have asymmetric centers. These asymmetric centers can be
independently in the R or S configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometric isomerism. Geometric isomers include the cis and trans forms of the compounds of the invention, ie, compounds having alkenyl portions or substituents in the ring systems. In addition, the bicyclic ring systems include the endo and exo isomers. The present invention comprises the enantiomers, stereoisomers, geometric isomers
• Individuals, and mixtures thereof. Said isomers can be separated from their mixtures by the application or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates, for example, by the application or adaptation of the methods described in
present. Starting materials and intermediates are prepared by the application or adaptation of known methods, for example, methods such as those described in the reference examples or their obvious chemical equivalents, or by methods described in accordance with
present invention. The present invention is further exemplified, but not limited
• a, the following illustrative examples, which describe the preparation of the compounds according to the present invention. In addition, the following examples are representative of the
procedures used to synthesize the compounds of this invention! EXAMPLE 1 3-cyclohexyloxy-6-dimethoxyquinoline
f To a solution of THF (30 ml) at 0 ° C is added 3-hydroxy-6,7-5-dimethoxy-quinoline (0.237 g, 1.15 mmol), cyclohexanol (0.347 g, 3.46 mmol) and Ph3P (0.908 g, 3.46 g). mmoles). Diethyl azodicarboxylate is added in portions until the solution retains a deep red color (0.663 g, 3.81 mmol). After 4 hours, the solution is concentrated, and the residue is chromatographed (50% EtOAc in hexanes). The product is recrystallized from isopropanol / hexanes as the hydrochloride salt as a white solid (mp 229-232 ° C, decomposition).
EXAMPLE 2 2-Anilino-6-isopropoxy-quinoxaline hydrochloride 15 To NaH (0.033 g, 0.84 mmol) under argon is added 1 ml of f DMF. 2-Anilino-6-quinoxalinol (0.1 g, 0.42 mmol) is added in portions
1. 5 ml of DMF. After 30 minutes, 2- bromopropane is added dropwise, and the solution is heated to 50 ° C for 1.5 hours. The cooled reaction mixture is quenched with water and separated between EtOAc and H20, washed with H20 (3X), brine, dried (MgSO4) and concentrated. The resulting residue is chromatographed (30% EtOAc / hexanes) to provide 0.05 g of dialkylated product and 0.1 g of the title compound. You get an i
analytical sample of the HCl salt by the addition of IPA (isopropanol) / HCI to an Et20 / IPA solution of the free base to provide the HCl salt (mp 205-210 ° C, decomposition). Analysis calculated for C? 7H17N30? HCl: C, 64.65; H, 5.74; N, 13.31. Found: C, 64.51; H, 5.90; N; 13.09.
EXAMPLE 3 2-Anilino-6-methoxy-quinoxaline hydrochloride
To 2-chloro-6-methoxy-quinoxaline (0.93 g, 4.08 mmol) under argon is added aniline (1.3 ml, 14.3 mmol). The reaction mixture is heated at 120 ° C for 2 hours, and then at 150 ° C for 1.5 hours. The mixture is cooled and CH2Cl2 is added. The resulting suspension is stirred, and the orange solid is filtered, washed with CH2Cl2 / Et20, then stirred vigorously in H20 for 40 minutes, filtered and washed with Et20 to provide a bright yellow solid.
EXAMPLE 4 2-anilino-6-quinoxalinol
By the method of Feutrill, G. I .; Mirrington, R. N. Tet. Lett. 1970, 1327; the arylmethyl ether is converted to the phenoxy derivative. To 2-anilino-6-methoxy-quinoxaline (0.27g, 1.07 mmol) under argon in DMF is added the sodium salt of ethanethiol (0.19 g, 2 mmol). The reaction mixture is heated to 110 ° C overnight. The mixture is concentrated and separated between EtOAc and H20 / tartaric acid at 5%, so that the pH of the aqueous layer if is approximately 4. The organic layer is washed with H20 (J4X) and
then with 2.5% NaOH (4X). The basic layers are combined, washed with EtOAc (2X), acidified again with 5% tartaric acid, and washed with multiple portions of EtOAc. The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated. The resulting solid is chromatographed (50% EtOAc / hexanes). An analytical sample is obtained by triturating the product with Et20 to provide a yellow powder (mp 211-213 ° C). Analysis calculated for C? 4 HnN30: C, 70.88; H, 4.67; N, JI7.71; Found: C, 70.64; H, 4.85; N, 17.58.
EXAMPLE 5 Phenyl-r6- (tetrahydrofuran-3- (R) -yl-oxy) quinoxalin-2-ylamine
To a solution of THF at 0 ° C under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S) - (+) - 3-hydroxytetrahydrofuran (0.086 ml, 20 1.3 mmol) and triphenylphosphine ( 0.31 g 1.2 mmol). It is added in portions DEAD (0.18 ml, 1.2 mmol). The reaction is allowed to warm to room temperature and is stirred for 1.5 hours. The mixture is concentrated and separated between EtOAc and H20. The organic layer is washed with H20, brine, dried (MgSO) and concentrated. The resulting yellow oil is chromatographed (50% EtOAc / hexanes) and taken up in Et20 / IPA. HCl / Et20 solution is added dropwise, and the resulting orange-red powder is dried in vacuo. The powder is liberated from the base by stirring in MeOH with washed ion exchange basic resin (3X H20, 5X MeOH). The mixture is stirred for 30 minutes, filtered, concentrated and recrystallized from EtOAc / hexanes to provide the product in two crops (mp 173-175 ° C). Analysis calculated for d8H? 7N302: C, 70.35; H, 5.57; N,; I3.67; Found: C, 70.19; H, 5.60; N, 13.66.
EXAMPLE 6 2,7-bis-cyclohexyloxy-6-methoxy-quinoxaline
To a solution of DMF (5 ml) of NaH (0.32 g, 8 mmol) under argon, cyclohexanol (0.7 ml, 6.7 mmol) is added dropwise. The mixture is stirred at room temperature for 25 minutes, and then 2-chloro-6,7-dimethoxyquinolaline is added in portions. The reaction is stirred for 15 minutes at room temperature, at 90 ° C for 2 hours, and at 110 ° C for 1 hour. The mixture is cooled, quenched with H20, and separated between EtOAc / H20. The organic layer is washed with H20 and brine, dried (MgSO4) and chromatographed (10% EtOAc / hexanes) to provide a white waxy solid (mp 75-78 ° C).
Analysis calculated for C2? H28N203: C, 70.76; H, 7.92; N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70.
f EXAMPLE 7 5 Cyclohexyl- (6,7-dimethoxyquinolalin-2-ylmethyl) -amine
To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2: 1 MeOH / 1,2-dichloroethane (7.5 mL, 0.5 mmol), cyclohexylamine (0.11 mL, 0.9 mmol) is added. The reaction is left stirring at
F 10 room temperature overnight, and then NaBH (0.038 g,
1 mmol), and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc / hexanes-MeOH to about 5% in 50% EtOAc / hexanes). The oil dissolves in
EtOAc / hexanes, and treated with HCl in EtOH. The resulting solution is
The mixture is concentrated, and the solids are triturated with isopropanol to provide a white solid after drying under vacuum at 60 ° C (mp 185-190 ° C, decomposition). Analysis calculated for C? 7H23N302 »HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07. EXAMPLE 8 (6,7-Dimethoxyquinol-3-yl, -frans- (3- (R) -methyl-cyclohexyl) -amine v (6,7-dimethoxyquinolin-3-M) -cs- ( 3- (R) -metl-ci ohexyl) -amine
• The reaction is carried out in a manner similar to the previous preparation, using the free base of 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and (R) - (+) - 3-methylcyclohexanone ( 0.23 ml, 1.9 mmol). The mixture of products obtained is chromatographed (70% EtOAc / hexanes) and recrystallized from EtOAc / hexanes to obtain a white solid (1: 1 mixture of cis and trans isomers) (mp 153-160 ° C). ). Analysis calculated for C? 8H24N202: C, 71.97; H, 8.05; N, 9.33; Found: C, 72.12; H, 7.85; N, 9.29.
EXAMPLE 9 15 3- (6,7-dimethoxyquinolin-3-yl-amino) -2,2-dimethyl-propan-1-ol
• The reaction is carried out in a similar manner to the preparation of Example 7. To a MeOH solution of pulverized molecular sieves up to 4Á (0.35 g), under argon, 3-amino-6,7-dimethoxy-quinoline (0.32) is added.
g, 1.6 mmol) and 2,2-dimethyl-3-hydroxypropionaldehyde (0.19 g, 1.9 mmol). The product mixture is chromatographed (3% MeOH / CHCl3), to produce
0. 10 g of material which is separated between CH2Cl2 / 10% NaOH. The organic layer is washed with 10% NaOH, H20 and brine, and then dried (MgSO4) and recrystallized from EtOAc / hexanes to provide a light orange solid (mp 170-173.5 ° C). Analysis calculated for C? 6H22N203: C, 66.18; H, 7.64; N, 9.65; Found: C, 66.11, H, 7.49; N, 9.33.
EXAMPLE 10 Cyclohexyl-fß-methoxy-7-morpholin-4-yl-quinoxalin-2-yl) -amine
This preparation is based on an adaptation of the method described by Buchwald, et al, J. Am. Chem. Soc, 1996, 118, 7215. To a toluene solution of 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline ( 0.1 g, 0.3 mmol) under argon, morpholine (0.1 g, 0.3 mmol), sodium urea-butoxide (0.04 g, 0.42 mmol), S - (-) - BINAP (cat., 0.001 g) are added. and bis (dibenzylideneacetone) -palladium (cat., 0.001 g). The reaction mixture is heated to 80 ° C overnight. The mixture is cooled, diluted with Et20, filtered, concentrated and chromatographed (50% EtOAc / hexanes). The product is recrystallized from EtOAc / hexanes to provide, in two crops, a yellow solid (mp 194-196 ° C). Analysis calculated for C? 9H26N402: C, 66.64; H, 7.65; N, 16.36; Found: C, 66.60; H, 7.60; N, 16.51.
EXAMPLE 11
Trans-4- (7-chloro-6-methoxy-quinoxalin-2-amino) -cyclohexanol v trans 4- (6-chloro-7-methoxy-quinoxalin-2-yl-amino) -cyclohexanol i
To a reaction flask under argon adapted with a trap of
Dean-Stark and a condenser, is added 6: 1 of 2,7-dichloro-6-methoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline (0.30 g, 1.3 mmol) and trans-4-amino- cyclohexanol (0.35 g, 3 mmol). The reaction mixture is heated to 170 ° C for about 10 hours, and then concentrated and chromatographed twice (7% MeOH / CHCl3, then 5% MeOH / CHCl3). The product is recrystallized from EtOAc / hexanes to provide a light yellow solid (mp 144-147 ° C). Analysis calculated for C? 9H26N4O2 »0.4 H20: C, 57.20; H, 6.02; N, 13.34; Found: C, 57.21; H, 5.97; N, 13.08. Analysis of 1 H NMR revealed that the product is a 2: 1 mixture of frans-4- (7-chloro-6-methoxy-quinoxalin-2-amino) -cyclohexanol: .rans-4- (6-chloro-7- methoxy-quinoxalin-2-ylamino) -cyclohexanol.
EXAMPLE 12 rrans-4- (6,7-D-methoxy-quininoal-2-ylamino) -cyclohexanol
Frans-4-aminocyclohexanol (0.11 g, 2 equivalents) and 2-chloro-6,7-dimethoxyquinolaline (0.1 g, 1 equivalent) are combined and heated to 160-180 ° C for a period of 4 to 8 hours. The dark brown suspension is filtered and concentrated. The residue is purified on a flash column eluted with 3% methanol / methylene chloride to provide the product as a yellow powder with the melting point of
119-123 ° C. Analysis calculated for C16H2? N303: C, 62.33; H, 7.05; N, 13.63; Found: C, 62.35; H, 7.09; N, 13.18. The compound could be recrystallized by the following method. Starting with 0.2 g of yellow powder with a mixture of 2.5 10 ml of water and 1.25 ml of meianol, a light orange solution is obtained after reflux. The hot solution is allowed to settle and gradually cooled. Orange-shaped needle-like crystals are collected by filtration and dried under high vacuum to give a yellow solid (mp 119-120 ° C). Alternatively, the hydrochloride salt of the title compound is prepared in the following manner: to a solution of trans-4- (6,7-dimethoxyquinolalin-2-ylamine) -cyclohexanol in isopropanol, a solution of HCl is added. at 0 ° C. The mixture is stirred for 15 minutes before filtering. The collected solid is dried under high vacuum to provide the hydrochloric acid salt of frans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexanol. Analysis calculated for C? 6H22CIN303 »1.2 H20: C, 53.19; H, 6.80; N, 11.63; Cl, 9.81; Found: C, 53.14; H, 6.85; N, 11.24; Cl, 10.28.
Alternatively, the sulfate salt of the title compound is prepared in the following manner: in a typical procedure, trans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexanol is dissolved in acetone or another suitable organic solvent. with heating to 45 ° C, as necessary, To the resulting solution, aqueous H 2 SO 4 (1 equivalent, 1 M solution) is added with rapid stirring. The salt formed in this manner is collected and dried to provide the sulfate with more than 80% yield. In a similar manner, the following compounds are prepared starting from the appropriate starting material: I
• 10 3- (6,7-dimethoxyquinolalin-2-ylamino) -propan-1-ol (p.f. 1 | 54.5-156 ° C). Analysis calculated for C? 3H? 7N303: C, 59.30; H, 6.51; N, 15.96; Found: 59.30; H, 6.46; N, 15.87. 3- (6,7-Dimethoxy-cyanoxalin-2-ylamino) -2,2-dimethyl-propan-1-ol (mp 174-176.5 ° C). Analysis calculated for C? 5H21N303: C, 61.84; H, 7.27; N, 14.42; Found: C, 61.67; H, 7.22; N, 14.22. 4- (6,7-dimethylquinoxalin-2-ylamino) -cyclohexanol (mp 168-171 ° C). Analysis calculated for C16H2? N30: C, 70.82; H, 7.80; N, 15.48; 20 Found: C, 70.76; H, 7.90; N, 15.20.
EXAMPLE 13! C.s-4- (6,7-dimethoxyquinol-2-ylamino) -cyclohexanol
A mixture of c / s-4-aminocyclohexanol (400 mg, 3.48 mmol) and 2-chloro-6,7-dimethoxyquinolaline (450 mg, 2 mmol) in 5 ml of ethanol is placed in a sealed tube, and then heated at 180 ° C for 3 hours. The dark brown mixture is chromatographed on silica gel and eluted with ethyl acetate to provide the desired product (mp 65-67 ° C). Analysis calculated for C? 6H2? N3O3 »0.6 H20: C, 61.17; H, 7.12; N, 13.37; Found: C, 61.22; H, 7.19; N, 12.19.
EXAMPLE 14 (±) -bicyclor2.2.phept-2-yl-.6,7-dimethoxy-cyanoxalin-2-yl-amine
Method A: A mixture of 2-chloro-6,7-dimethoxyquinolaline (5 g, 22.3 mmol) and (±) -exo-norbomil-2-amine (10 g, 90 mmol) is heated to 160-180 ° C for last night The dark brown residue is dissolved in 200 ml of methylene chloride and washed with 1 N NaOH (50 ml). The organic layer is dried over magnesium sulfate and then filtered. The residue after concentration is chromatographed on silica gel eluted with hexane / ethyl acetate (80%) to provide the desired product as a yellow solid which can be recrystallized from methanol.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ Procedure B: A mixture of 2-chloro-6,7-dimethoxyquinolaline (9 g, 40.1 mmol) and (±) -exo-norbomil-2-amine (5.77 g, 52 mmol), sodium t-butoxide
• (4.22 g, 44 mmol), 2,2'-bis (diphenylphosphino) -1-1 '-bubfthyl (BINAP, 120 mg) and 5 bis (dibenzylideneacetone) -palladium Pd (dba) 2, 40 mg in 80 ml of toluene is heated at 80 ° C for 8 hours. Another portion of BINAP (60 mg) and Pd (dba) 2 (20 mg) are added, and the mixture is heated at 100 ° C overnight. After being diluted with 200 ml of methylene chloride, the reaction mixture is washed with 1 N NaOH (100 ml). The organic layer is dried over sodium sulfate
magnesium and filtered. The residue after concentration is chromatographed on silica gel eluted with hexane / ethyl acetate (80%), to project the desired product as a light yellow solid (mp 188-189 ° C). Analysis calculated for d7H2? N303: C, 68.20; H, 7.07; N, 14.04; Found: C, 68.18; H, 7.03; N, 14.03. In a similar manner, the following compounds are prepared starting with the appropriate starting material (procedure A): • exo-bicyclo [2.2.1] hept-5-en-2-yl- (6,7-dimethoxy-quin-2-yl) - amine (mp 175-177 ° C). Analysis calculated for C? 7H? 9N3O2 »0.4 H20: C, 60.94; H, 6.56; 20 N, 13.78; Found: C, 66.98; H, 6.62; N, 12.73. | (2endo, 5exo) -5- (6,7-dimethoxy-quinxoalin-2-ylamino) -bicyclo [2.2.1] -heptan-2-ol (mp 90-93 ° C). (2exo, 5exo) -5- (6,7-dimethoxy-quinxoalin-2-ylamino) -bicyclo [2.2.1] -heptan-2-ol (p.p. 97-1 OOX). (2endo, 3exo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) - • bicyclo [2.2.1] heptane-2,3-diol (p.f. 220-222X). 5 Analysis calculated for C? 7H2? N3O4 «0.2 H20: C, 60.96; H, 6.44; N, 12.54; Found: C, 60.93; H, 6.06; N, 11.60. Cyclohexyl- (6,8-dimethyl-quinoxalin-2-yl) -amine [MS m / z: 255 (M +)]. Analysis calculated for C? 6H2? N3: C, 75.26; H, 8.29; N, 16.46; Found: C, 75.08; H, 8.28; N, 15.86. 10 c / s .rans-2- (6-methoxy-quinoxalin-2-ylamino) cyclopentanol (mp 137- 139X). Analysis calculated for C? 4H? 7N302: C, 64.85; H, 6.61; N, 16.20; Found: C, 64.87; H, 6.45; N, 16.22. .rans-4- (6-methoxy-quinoxalin-2-ylamino) -cyclohexanol (mp 70- 15 75X). Analysis calculated for C? 5H? 9N3O2 * 0.3 H20: C, 64.64; H, 7.09;
• N, 15.08; Found: C, 64.68; H, 7.06; N, 14.77. Etylamide [3aR, 4S, 6R, 6aS] -6- (6,7-dimethoxy-quinxoalin-2-ylamino) -2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxolo-4-carboxylic acid (mp 94-97X) . 20 Analysis calculated for C2? H28N4O5 «0.3 H20: C, 59.79; H, | 6.83;
N, 13.28; Found: C, 59.80; H, 6.89; N, 12.03. (6,7-dimethoxyquinolalin-2-yl) - (4-methoxy-cyclohexyl) -amine (mp 58- I 68X).
_____________________________________ Analysis calculated for C17H23N3O3 * 0.5 H20: C, 62.56; H, 7.41; N, 12.87; Found: C, 62.53; H, 7.22; N, 12.22.
EXAMPLE 15 exo-2- (bicyclo2.2.nhept-2-yloxy) -6,7-dimethoxyquinolaline
A mixture of exo-2-norborneol (223 mg, 2 mmol) and NaH (60%, 100 mg, 2.5 mmol) in 10 ml of anhydrous THF is refluxed for 0.5 hours before the addition of 2-chloro-6 , 7-dimethoxyquinolaline (336 mg, 1.5 mmol). The resulting mixture is refluxed for 2 hours. The residue after filtration and concentration is chromatographed on silica gel (50% ether / hexane) to provide the desired product as a white solid (mp 135-137X). Analysis calculated for C? 7H20N2O3: C, 67.98; H, 6.71; N, 9.33; Found: C, 67.96; H, 6. ^ 62; N, 9.19. In a similar manner, the following compounds are prepared starting from the appropriate starting material: xx-2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinotoxaline (mp 108-110X) ). Analysis calculated for C? 7H? 8N203: C, 68.44; H, 6.08; N, 9.39;
Found: C, 68.54; H, 6.23, N, 9.27. 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxyquinolaline (pj.f 93-95X).
Analysis calculated for C? 7H? 8N203: C, 68.44; H, 6.08; N, 9.39; Found: C, 68.32; H, 5.98; N, 9.25. 2- (1, 4-dioxa-spiro [4.5] dec-8-yloxy) -6,7-dimethoxy-quinotoxaline (m.p. 124-125X). ! Analysis calculated for C? 8H22N205: C, 62.42; H, 6.40; N, 8.09;
Found: C, 62.63; H, 6.46; N, 7.79.
EXAMPLE 16 Acid c / s / frans-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanecarboxylic acid
A mixture of c / s? Tens-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1 mmol) and NaH (60%, 160 mg, 4 mmol) in anhydrous THF / DMF (10 ml / 2 ml) is subjected to reflux for 1 hour before the addition of 2-chloro-6,7-dimethoxyquinolaline (225 mg, 1 mmol). The resulting mixture is refluxed for 2 hours. The reaction mixture is neutralized to pH 5, and extracted with ethyl acetate (2 x 50 ml). The combined organic solutions are dried over magnesium sulfate and filtered. The residue after concentration is chromatographed on silica gel (ethyl acetate, followed by methanol) to provide the desired product as a white solid (mp 90-93X). Analysis calculated for C? 7H20N2O5 «0.5 H20: C, 58.89; H, 6.19; N, 8.22; Found: C, 59.91; H, 6.62; N, 7.90.
In a similar manner, the following compounds are prepared starting from the appropriate starting material: 4- (6,7-dimethoxy-quinxoalin-2-yloxymethyl) -cyclohexanol (pf | 118-121 X. | Analysis calculated for C? 7H22N2O4 »0.3 H20 : C, 63.15, H 7.03;
N, 8.66; Found: C, 63.13; H; H, 6.65; N, 9.01. 3- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexanol (mp 151-153X). Analysis calculated for C? 6H20N2O4: C, 63.14, H, 6.62; N, 9.20; Found: C, 62.56; H; 6.58; N, 8.67. 4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexanol (mp 162-164 X). Analysis calculated for C? 6H20N2O4: C, 63.14; H, 6.62; NJ 9.20; Found: C, 62.52: H; 6.80; N, 8.88.
EXAMPLE 17 5- (6-dimethoxy-quinotoxal-2-yloxy) -biciclof2.2.1..heptane-2,3-diol
To a solution of 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dir-ethoxy-quinoxaline (149 mg, 0.5 mmol) and 4-methylmorpholine N-oxide (234 mg, 2 mmol) at room temperature in 5 ml of THF, a solution of Os0 in t-butanol (2.5% by weight, 0.2 ml) is added. The brown solution is stirred vigorously for 2 hours before being quenched with saturated NaHS203 (2 ml). Ether (3 x 100 ml) is used to perform the extraction, and then dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (50% ethyl acetate / hexane) to provide the desired product (mp 85-88X). Analysis calculated for C? 7H20N2O5 «0.9 H20: C, 58.73; H, 6.29; N, 8.06; Found: C. 58.74; H, 5.91; N, 7.53. It is prepared in a similar manner (2exo, 3exo, 5exo) -5- (6,7-dimethoxyquinolinoin-2-ylamino) -bicyclo [2.2.1] heptane-2,3-diol (mp 150-153X).
EXAMPLE 18 Ester C / S-4- (6,7-D-Methoxy-Chinoxalin-2-yloxy) -cyclohexyl-acetic acid and C / S-4- (6,7-dimethoxy-cyanoal-2-yloxy) -cyclohexanol
A mixture of c / s-4-acetoxy-cyclohexanol (632 mg, 4 mmcl) and NaH (60%, 220 mg, 5.5 mmol) in 15 ml of anhydrous THF is refluxed for 0.5 hour before the addition of 2-chloro-6,7-dimethoxyquinolaline (674 mg, 3 mmol). The resulting sample is refluxed for two hours. The residue after filtration and concentration is chromatographed on silica gel (ether) to provide: a) c / s-4- (6,7-dimethoxy-quinotoxal-2-yloxy) -cyclohexyl acetic acid ester (mp 150-) 152X). Analysis calculated for C? 8H22N205: C, 62.42; H, 6.40; N, | 8.09;
Found: C, 62.39; H, 6.55; N, 7.82, and b) cis-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol (mp 148-150X).
. ^ ¿I -----------.---------------------------------- ---------------------- ------, Analysis calculated for C? 6H20N2O4: C, 63.14; H, 6.62; N, 9.20; Found: C, 62.80; H, 6.76; N, 8.67. Similar trans-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol [MS m / z: 304 (M +)] is prepared in a similar manner.
EXAMPLE 19 Ester 4-.6.7-dimethoxyquinolaln-2-yloxy) -cyclohexyl of dimethylcarbamic acid I I i
A mixture of 4- (6,7-dimethoxy-quinxoalin-2-yloxy) -cyclohexanol
(100 mg, 0.33 mmol), dimethylcarbamyl chloride (90 μL, 1.2 mmol) and NaH (60%, 19.6 mg, 0.49 mmol) in 5 mL of THF are stirred at room temperature for three days to provide a white solid. (mp 152-155X) isolated by chromatography (50% ethyl acetate / hexane). Analysis calculated for C? 9H25N305: C, 60.79; H, 6.71; N, 11.19;
Found: C, 60.38; H, 6.54; N, 10.43.
EXAMPLE 20 1-3-cyclohexyloxy-6,7-dimethoxyquinolutin oxide
A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinolaline (11.0 mg, 0.38 mmol) and meta-chlorobenzoic acid (70%, 113 mg, 0.46 mmol) in 10 ml of methylene chloride is stirred at room temperature for one day .
The solution after filtering is concentrated, and the residue is
chromatography on silica gel (20% ethyl acetate / hexane) to provide the desired product (mp 167-169X). f 'It is prepared in a similar way .rans-4- (6,7-dimethoxy-4-oxy-
-quinoxalin-2-ylamino) -cyclohexanol (p.p. 220-222X).
Analysis calculated for C? 6H2? N304 »0.2 H20: C, 59.42; Hj 6.69;
N, 12.99; Found: C, 59.43; H, 6.64; N, 12.95.
EXAMPLE 21 • 10 Acetic acid ester frans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexyl ester
A mixture of frans-4- (6,7-dimethoxyquinolalin-2-ylamino) -cyclohexanol (303 mg, 1 mmol), acetic anhydride (2 ml) and pyridine (2 ml) in 10 ml.
ml of dichloromethane is aortated at room temperature overnight. The mixture is quenched with water (5 ml) and extracted with dichloromethane (2 x 30 ml).
• After drying over magnesium sulfate and filtration, the solution is concentrated in a rotary evaporator. The residue is chromatographed on gel
of silica (ethyl acetate) to provide the desired acetate as a solid of
light yellow color (p.f 176-177X). Analysis calculated for C? 8H23N304: C, 62.59; H, 6.71; N, 1 2.17;
Found: C, 62.89; H, 6.67; N, 11.95.
EXAMPLE 22 II (2exo 5exo) -5- (6,7-dimethoxy-quinxoalin-2-ylamino) -biciclof2.2.nheptan-2- 1 A mixture of (2exo, 5exo) -5-aminobicyclo [2.2.1] heptan -2- 5 Acetate (127 mg, 0.75 mmol) and 2-chloro-6,7-dimethoxyquinoline (224 mg, 1
mmol) is heated up to 180X for six hours. After that time, the
The mixture is cooled to room temperature, dissolved in methylene chloride and
it is purified by a flash column. The recovered product (20 mg, 7.5% yield) is dissolved in methanol (2 ml), and
F 10 adds a new solution of sodium methoxide at 1 N (0.063 ml, 0.063 mmol). The reaction mixture is refluxed for ninety minutes.
The crude mixture is purified by preparative gada layer chromatography to provide the product as a yellow solid with a 97-1 OOX melting point. 15 C? 7H2? N303 (m / z): 315. Similarly, the following compounds are prepared
• Starting with the appropriate starting material: (2endo, 5exo) -5- (6,7-dimethoxyquinolin-2-ylamino) -bicyclo [2.2.1] - heptan-2-ol, as a yellow solid. 20 C17H2? N303 (m / z): 315. I (2exo, 6exo) -6- (6,7-dimethoxyquinolin-2-ylamino) -bicyclo [2.2.1] t
heptan-2-ol, as a yellow solid (30 mg, 21% in total). C? 7 H 21 N 303 (m / z): 315.
Analysis calculated for C? 7H2? N303: C, 64.74; H, 6.71; N, 13.32; Found: C, 58.42; H, 6.26; N, 11.56.
• EXAMPLE 23 ¡5 (Itrans, 4c / s) -4- (6,7-dimethoxy-quinxoalin-2-ylamino) -2-methyl-cyclohexanol and I (2trans, 4frans) -4- (6,7-dimethoxyquinoline-2) -ylamino) -2-methyl-cyclohexanol
A mixture of 2-chloro-6,7-dimethoxyquinolaline (1.08 g, 4.81 I mmol) and (2-trans) -4-amino-2-methylcyclohexanol (620 mg, 4.81 mmol) is heated to 180X for six hours. The reaction produced two
diastereomers The main isomer is isolated as a yellow solid, assigned as (2trans, 4.rans) -4- (6,7-dimethoxyquinolalin-2-ylamino) -2-methyl-cyclohexanol (240 mg, 0.76 mmol). 15 C? 7 H23N303 (m / z): 317.
Analysis calculated for C? 7H23N303 »2H20: C, 58.00; H, 7.69; N,
• 11.94; Found: C, 58.0; H, 6.58; N, 11.24. The minor isomer is also a yellow solid, assigned as (2trans, 4c / s) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-1-cyclohexanol. C? 7 H23N303 (m / z): 317.
Analysis calculated for C? 7H23N303 »H20: C, 60.08; H, 6.94; N,
12. 53; Found: C, 61.21; H, 6.94; N, 11.56.
The (2-trans, 4-trans) -4- (6,7-dimethoxy-quinxoalin-2-ylamino) -2-methyl-cyclohexanol is further separated by chiral HPLC and its individual enantiomers. The first enantiomer has a rotation (+) - (order of elution on Chiracel OJ). The second enantiomer has a rotation (-) - (order of elution on Chiracel OJ). The analytical conditions using a Chiracel OD column resulted in the (+) enantiomer eluting in second. The (-) - enantiomer exhibits a preferred activity in a PDGF-R ELISA test. I
EXAMPLE 24 (2c / s, 4c / s) -4- (6-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol and (2c / s.4.rans) -4- (6.7-d.methoxyquinolxin) -2-ylamino-2-methyl-cyclohexanol
To a solution of a 2: 1 mixture of (2trans, 4trans) -4- (6,7-dimethoxy-quinoxalin-2-ylamino) -2-methyl-cyclohexanol and (2trans, 4c / s) -4- (6 , 7-dimethoxyquinolalin-2-ylamino) -2-methyl-cyclohexanol (120 mg, 0.38 mmol) in THF (7 mL) is added triphenylphosphine (110 mg, 0.42 mmol) and diethyl azodicarb-oxylate (0.066 mL, 0.42 mmol) and acid benzoic (46.4 mg, 0.38 mmbles). The mixture is stirred at room temperature overnight and the residue after handling is separated on silica gel (30% ethyl acetate / hexane) to provide a mixture of benzoates. To a solution of the main benzoate (50 mg, 0.12 mmol) in methanol (2 mL) is added 1 N sodium hydroxide (0.12 mL, 0.12 mmol). The pure product (13 mg, 32% yield) is isolated from the thin layer of preparative chromatography as a yellow solid (mp 85-88X), assigned as (2c / s, 4c / s) -4- (6, 7-dimethoxy-quinoxalin-2-ylamino) -2-methyl-cyclohexanol. C? 7H23N303 (m / z): 317.
Similarly, the minor benzoate (4.4 mg) is hydrolyzed and the desired product (3.3 mg, 100%) is also isolated from the thin layer of preparative chromatography as a yellow solid, assigned as i (2c / s, 4írans) -4 - (6,7-dimethoxyquinolalin-2-ylamino) -2-methyl-cyclohexanol. C? 7H¿N303
(m / z): 317.
EXAMPLE 25 (1R, 2R, 4S) - (+) - b.cichlor.2.2.nhept-2-yl- (6,7-dimetoxiquinoxalin-2-inamine)
(±) -bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amine
from example 14 is resolved on a chiral HPLC column (Chiralpac AD, 25x2 cm, 60% heptane / 40% ethanol with 10 mM (1S) - (+) - camphorsulfonic acid,
12 mL / minute) and the product of the previous title is obtained as the first eluent. The collected fractions are combined and washed with 50 mL of 1 N NaOH before drying (MgSO4). The solution after filtration is
concentrate on a rotary evaporator and then dry under high vacuum. HE
get a yellow solid. [α] d 20 + 19.5 ° (c = 0.20, CH 2 Cl 2) m.p. 184-1¡86X.
Anal, calculated for C17H2? N302 x 0.3 H20: C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.
EXAMPLE 26 Biotransformative preparation of (1S, 2R, 4S, 5R) -5- (6,7-I-dimethoxy-quin-2-ylamino) -bicyclor2.2.nheptan-2-ol | ! I Strains of fungi F 2052 (Mortierella isab llina) were acquired
of Northen Utilization Research and Development Division (NRRL). The fungi were stored at -25X. Conical flasks d ^ 250
mL each containing 50 mL of seed culture medium (medium
216) are injected with 2 mL of fungal suspension and incubated on a
Rotary agitator (200 rpm) at 23X for 3 days. 250 mL conical flasks each containing 5 mL of the same medium were inoculated with 2 r? L of the seed culture and incubated on a rotary shaker (200 rpm) at 23X.
After 24 hours (1 R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl- (6,7-dimethoxyquinolalin-2-yl) -amipa of Example 25 is dissolved in MeOH and HE
add to the flasks at a final concentration of 300 mg / L. The crops are harvested after 24 hours of incubation. (Medium 216: glucose 0.4%,
yeast extract 0.05 ° ^, soy flour 0.05%, NaCl 0.05%, Kh 2P04
0. 05). Extraction is performed using 2 volumes of acetonitrile, 1 volume of tert-butyl methyl ether and 1 volume of n-heptane were added to one volume of culture broth. After magnetic stirring at 22X, the
The extract is separated into 3 layers. The intermediate layer is collected and evaporated to dryness, and dissolved again in ethyl acetate. The ethyl acetate extract is separated on silica gel (0.04-0.063 mm) using ethyl acetate as eluent. Fractions containing the biotransformation product are separated on C18 silica using a gradient of H20 / MeOH as eluent. This chromatography produces the pure compound of the heading
• as an amorphous yellow powder, m.p. 190-192X.
EXAMPLE 27 frans-4-f7-methoxy-6- (2-morpholin-4-yl-ethoxy) -quinoxalin-2-ylamino-cyclohexanol and frans-4-r6-methoxy-7-, 2-morpholin-4- il-ethoxy) -quinoxalin-2-ylaminol-cyclohexanol 10 The compound of the heading is prepared by coupling Mitsunobu of 6-hydroxy-7-methoxy-2-chloroquinoxaline: 7- (2-morpholin-4-ylethoxy) -6 -methoxy-2-chloroquinoxaline and 2- (morpholin-4-yl) ethanol using the procedure of Example 1 and the reaction of 6- (2-morphine-4-ylethoxy) -7-methoxy-2-chloroquinoxaline: 7- (2-morpholin-4-ylethoxy) -6-methoxy-2-chloroquinoxaline and trans-4-amino-cyclohexanol resulting using the procedure of Example 11.!
EXAMPLE 28, 2-f2- (frans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6-yloxy-1-acetic acid and 2-f2-trans-4-hydroxy-cyclohexylamino acid) - 6-methoxy-quinoxalin-7-yloxy-1-acetic acid The title compound is prepared by dealkylation of 4- (6,7-dimethoxy-quinotoxal-2-ylamino) -cyclohexanol using the sodium salt of ethanediol in DMF as described in US Pat. example 4,
^ followed by alkylation with bromoacetic acid in the presence of base as
is described in general procedure 6.
EXAMPLE 29
2- [2- (Irans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6- 15-yloxy] -N, N-dimethyl-acetamide and 2- [2- (trans-4-hydroxy-cyclohexylamino) - 6-methoxy-quinoxalin-7-yloxyl] -N, N-dimethyl-acetamide • The title compound is prepared by aminjolysis of the compound of example 28 using dimethylamine.
INTERMEDIATE EXAMPLE 1
4-Bromo-5-methoxy-benzene-1,2-diamine dihydrochloride.
To a solution of EtOAc (50 mL) and 5-bromo-4-methoxy-2-nh.ro-phenylamine (2.5 g, 10 mmol) under argon is added 5% Pd / C (0.5 g). The reaction mixture is hydrogenated at 3.51 kg / cm2 for 1 hour. The mixture is filtered through Celite in an HCI / IPA EtOAc solution, and the pad washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid. i
INTERMEDIATE EXAMPLE 2
7-Bromo-6-methoxy-quinoxalin-2-ol and 6-Bromo-7-rtj? Ethoxy-quinoxalin-2-ol. To a solution of MeOH (15 mL) under argon, powdered NaOH pellets (0.86 g, 21 mmol) and 4-bromo-5-methoxy-benzene-1,2-diamine dihydrochloride (2.7 g, 9.3 mmol) are added. . The mixture is stirred for 10 minutes, then a solution of 45% ethyl glyoxylate in toluene (2.7 g, 12 mmol) is added in portions. The reaction mixture is refluxed for 1 hour, and then cooled. Water is added, and then the suspension is filtered. The resulting solid is washed successively with H20, MeOH, IPA, and Et20 to provide a yellow powder.
I I
INTERMEDIATE EXAMPLE 3 I
7-Bromo-2-chloro-6-methoxy-quinoxaline and 6-Bromo-2-cl ro-7-methoxy-quinoxaline. To a mixture of 7-Bromo-6-methoxy-quinoxalin-2-ol and 6-brorno-7-methoxy-quinoxalin-2-ol (1 g, 3.9 mmol) is added POCI3 (5 mL). The reaction mixture is refluxed for 1 hour, poured into ice-cooled water, filtered, then washed with water to provide a clear tan solid. The ratio of 7-bromo-2-chloro-6-methoxy-quinoxaline: 6-bromo-2-chloro-7-methoxy-quinoxaline is about 7: 1 by 1 H NMR.
INTERMEDIATE EXAMPLE 4
-Chloro-4-methoxy-2-nitroaniline. To a solution of N- (5-chloro-4-methoxy-2-nitrophenyl) -acetamicla (2 g, 8.2 mmol) in 5N HCl (20 mL) is added 1,4-dioxane (10 mL), and the mixture stir at 60 ° C for 1.5 hours. The reaction mixture is concentrated! and it is partitioned between EtOAc / 2 N NaOH. The aqueous layers are washed with EtOAc (3X), brine, dried (MgSO), absorbed on silica gel, and chromatographed (70% EtOAc / hexanes) to provide an orange powder.
INTERMEDIATE EXAMPLE 5
4-Chloro-5-methoxy-benzene-1,2-diamine dihydrochloride. F. To a solution of EtOAc (25 mL) and 5-chloro-4-methoxy-2-nitro-5-phenylamine (1.6 g, 7.9 mmol) under argon is added 5% Pd / C (0.5 g). The reaction mixture is hydrogenated at 3.51 kg / cm2 for 1 hour. The mixture is filtered under N2 through Celite in a solution of 1 N HCl / Et20 in EtOAc, and the pad is washed with additional EtOAc. The resulting precipitate is filtered to provide a white solid. ^ 10 INTERMEDIATE EXAMPLE 6
7-Chloro-6-methoxy-quinoxalin-2-ol and 6-chloro-7-methoxy-quinoxalin-2-ol. 15 To a solution of 4-chloro-5-methoxy-benzene-1, 2-diamine dihydrochloride (1.8 g, 7.2 mmol) in EtOH (15 mL) under argon is added TEA (2.5 f mL, 18 mmol) to OX. . The mixture is stirred for 20 minutes, and then a solution of 45% ethyl glyoxylate in toluene (2.1 g, 9.3 mmol) is added in portions. The reaction mixture is heated to room temperature, refluxed for 1.5 hours, and then cooled. Water is added, then the suspension is filtered and washed successively with H20, IPA, and Et20 to provide a light yellow powder. The product is subjected to acetopy several times with toluene and dried in vacuo before being used. l!
INTERMEDIATE EXAMPLE 7 2,7-Dichloro-6-methoxy-quinoxaline and 2,6-D-chloro-7-methoxy-quinoxaline. To a mixture of 7-chloro-6-methoxy-quinoxalin-2-ol and 6-clpro-7-methoxy-quinoxalin-2-ol (1 g, 4.7 mmol) under a CaCl2 drying tube is added POCI3 (5 g). mL). The reaction mixture is refluxed for 30 minutes, poured into cold saturated NaHC03 solution, filtered, and then washed with water to provide a solid. The ratio of 2,7-dichloro-6-rnetoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline is about 6: 1 by 1 H NMR.
INTERMEDIATE EXAMPLE 8
c / s-4-Aminocyclohexanol! c / s-4-aminocyclohexanol is made according to the literature procedure with minor modification [J. Med. Chem. 18 (6) 634
1975].
INTERMEDIATE EXAMPLE 9
exo-Bicyclo [2.2.1] hept-5-en-2-amine The exo-bicyclo [2.2.1] hept-5-en-2-amine is prepared with the same procedure as in the intermediate example 15 from 5-norbornen-2-ol by means of a versatile intermediate of exo-2-bicyclo [2.2.1] hept-5-n-2-yl-isoindole-1,3-dione.
INTERMEDIATE EXAMPLE 10
(2exo, 6exo) -2- (6-Hydroxy-bicyclo [2.2.1] hept-2-yl isoindole-1,3-dione and (2exo, 5exo) -2- (5-hydroxy-bicyclo [2.2.1 ] hept-2-yl isoindole-1,3-dione To a mixture of exo-2-bicyclo [2.2.1] hept-5-en-2-yl isoindol ^ -1, 3-dione (320 mg, 1.31 mmoles) in 5 ml of THF to OX is added a solution of BH3 / THF (1 M, 2 ml, 2 mmol) The mixture is stirred at room temperature for two hours before the addition of water (2 ml) and NaBO3 «4H20 (900 mg) The resulting suspension is stirred overnight.Ether (3x5 ml) is used to extract and dried over magnesium sulfate, the residue after filtration and concentration is chromatographed on silica gel (ether) provide the desired products that can be further separated.
INTERMEDIATE EXAMPLE 11 (2 exo 5endo) -2 - (5-hydroxy-biciclor2.2.1lhept-2-yl-isoindole-1,3-dione
(a): A mixture of (2exo, 6exo 2- (6-hydroxy-bicyclo [2.2.1] ript-2-yl isoindole-1,3-dione and (2exo, 5exp -2- (5- hydroxy-bicyclo [2.2.1] hept-2-yl isoindole-1,3-dione (800 mg, 3.3 mmol), and pyridinium chlorochromate (21 g) in 10 ml of methylene chloride is stirred at room temperature for the purpose After dilution with ether (100 ml) the suspension is filtered and the solution is concentrated, the residue is chromatographed on silica gel] (ether) to give 750 mg (95%) of the corresponding ketones. further separated by reverse phase HPLC (CH3CN / H20, 10-70%) to provide exo-2- (5-oxy-bicyclo [2.2.1] hept-2-yl -indole-1, 3-dione. (B): To a solution of exo-2- ( 5-oxy-bicyclo [2.2.1] hept-2-yl isoindole-1,3-dione (250 mg, 0.98 mmol) in 10 ml of 0X methanol was added NaBH (38 mg, 1 mmol). stir for an additional half hour and quench with 1 N HCl (1 ml) After concentration, the residue is extracted with methylene chloride (2 × 50 ml) The evaporation of the methylene chloride gave the desired product used directly without further purification. INTERMEDIATE EXAMPLE 12 (2endo 5exo.-5-Amino-biciclor2.2.1 lheptan-2-ol. (2exo 5exo_-5-amino-biciclor2.2.11heptan-2-ol, 2in o, 6exo) -6- amino-biciclof2.2.11heptan-2-ol, fy (2exo. 6exo) -6-amino-biciclor2.2.11heptan-2-ol
The compounds of the heading are prepared from suitable starting material by application of the above procedure of intermediate example 11.
INTERMEDIATE EXAMPLE 13 2-Methyl-6,7-dimethoxy-quinotoxaline
The compound of the heading is prepared using] an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38,
3347-3354. To a solution of THF under argon is added 2-chlor? -6,7-dimethoxyquinolaline (5 g, 26 mmol) and NiCI2 (dppp) (0.14 g 0.26 mmol). The f. The reaction mixture is cooled to OX, and a solution of 3 M MeMgBr in Et20 (13 ml, 39 mmol) is added in portions. The reaction mixture is allowed to warm to room temperature, stirred for 1 hour, and then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred for 10 minutes, and then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture is stirred during the nbche. Then CH2Cl2, H20, and additional NaCl are added and the mixture is filtered. The resulting solution is poured into a separating funnel, and the aqueous layers are washed 3X with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated on silica gel, and chromatographed (50% -80% EtOAc hexanes) to provide an orange solid (49% yield).
INTERMEDIATE EXAMPLE 14 6.7-Dimethoxy-2-quinoxaline carboxaldehyde
To a reaction flask under argon is added 1,4-dioxazole (20 ml), 2-methyl-6,7-dimethoxyquinolaline (1.09 g, 5.3 mmol) and Se? 2 (1.8 g, 16 mmol). The mixture is heated to 100X for 2 hours 45 minutes, cooled, and filtered through Celite. The pad is washed with portions of EtOAc and CH2Cl2. The resulting solution is concentrated, taken up in MeOH / CH2Cl2, loaded onto a column of silica gel, and chromatographed (30% E.OAC / CH2CI2) to provide an off-white solid (73% yield).
INTERMEDIATE EXAMPLE 15 (2exo 5exo) -5-Aminobicyclo2.2.11heptan-2-acetate
exo-5-Acetoxibicyclo [2.2.1] heptan-2-one and exo-6-acetoxy-benzyl [2.2.1] heptan-2-one are obtained from the bicyclo [2.2.1] Hepta- I i 2.5- diene according to the procedure of R. Gagnon (J. Chem. Soc, Perkin trans. 1, 1505 1995) with minor modification. To a solution of exo-5-acetoxy-cyclo [2.2.1] heptan-2-one (350 mg, 2.08 mmol) in 10 ml of THF at room temperature is added an I 1 solution of 1 M borane / THF (1.2 ml). , 1.2 mmol). The mixture is stirred for 0.5 hour before quenching to 0X with methanol (3 ml) and 1 N HCl (1.5 ml). Ethyl acetate (3x30 ml) is used to extract and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel to provide (2endo, 5exoJ-5-acetoxybicyclo [2.2.1] heptan-2-ol) to a solution of (2endo, 5exo,) - 5-acetox. Cyclo [2.2.1] heptan-2-ol (350 mg, 2.06 mmol) in THF (10 mL) is added to phthalimide (454 mg, 3.09 mmol), triphenylphosphine (810 mg, 3.09 mmol) and diethyl azodicarboxylate. (0.49 mL, 3.09 mmol) at 0 ° C. The reaction is allowed to stir overnight and then condenses on the rotovap and the residue is purified by column chromatography (20% ethyl acetate / hexane) | f provide the desired product as a yellow solid.A mixture of the above solid (300 mg, 1 mmol) and hyd azine
(0.126 ml, 2.2 mmol) in 5 ml of methanol is heated to reflux for six 20 hours. After removal of methanol, dichloromethane (3x30 ml) is used to extract the residue. The concentration of the solvent affords (exoexop) -5-aminobicyclo [2.2.1] heptan-2-acetate (127 mg, 75%) which is used in the coupling reaction without further purification.
Similarly, (2endo, 5exo) -5-aminobicyclo [2.2.1] heptan-2-acetate, (2endo, 6exo) -6-aminobicyclo [2.2.1] heptane-2-acetate and (2exo, eexo) - 6-Aminobicyclo [2.2.1] heptan-2-acetate are prepared from the material of
proper departure. !
INTERMEDIATE EXAMPLE 16 I (2frans) -4-Amino-2-methylcyclohexanol
___________ A mixture of 3-methyl-2-cyclohexenone (4 g, 36.36 mmole),
Toluenesulfonic acid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene were added.
it refluxes overnight and the water formed is removed by a Dean-Stark trap. The residue after concentration is chromatographed on silica gel (10% ethyl acetate / hexane) to give
3. 36 g (62%) of 7-methyl-1,4-dioxa-spiro [4.5] dec-7-ene.
To a stirred solution of 7-methyl-1,4-dioxa-spiro [4.5] dec? 7-ene
(3.36 g, 22.47 mmol) er: tetrahydrofuran (THF) (125 mL) is added
solution 1 M of borane ef. THF (22.47 mL, 22.47 mmol) at room temperature
ambient. The mixture is stirred for one hour, and the reaction is quenched by adding H20 (10 mL) to 0X followed by sodium perborate tetrahydrate.
(10.0 g, 66 mmol). The mixture is allowed to stir overnight. The two layers are separated, and the aqueous layer is washed several times with ethyl acetate.
(4x150 mL). The desired alcohol is obtained as a clear liquid after flash column chromatography. 'The above alcohol (1.8 g, 10.5 mmol) is dissolved in methanol
(50 mL) and 1 N HC1 (16 mL). The reaction mixture is allowed to stir overnight. The acid solution is neutralized with 1 N sodium hydroxide (18 m) and is followed by normal aqueous handling. The crude mixture is purified
by flash column (50% ethyl acetate) to yield 4-hydroxy-3-methyl-cyclohexenone. To a solution of trans 4-hydroxy-3-methyl-cyclohexenone (78.0 mg, 6.1 mmol) is added water (3 mL) hydroxylamine hydrochloride (550 mg, 7.92 mmol) followed by the slow addition of a saturated solution of carbonate
™ 10 sodium (326 mg, 3.8 mmol) in water (1.02 mL). After stirring for 30 minutes, ether is added to the reaction mixture, and the two layers are separated. The organic layer is condensed and dissolved in ethanol (10 mL). To the refluxing ethanol solution is added sodium (1.8 g, 78.3 mmol) over a period of one hour and the resulting mixture is heated for an additional 2.5 hours. After the ethanol removal, n-propanol (10 mL) ether (25 mL) and water (3 mL) are added. The organic solution is dried over magnesium sulfate and filtered. The concentration of solvents gives a mixture of (2-trans-4-amino-2-methylcyclohexanol as a white solid.
INTERMEDIATE EXAMPLE 17 2-Methoxy-4,5-diaminophenol dihydrochloride
^ The header compound is prepared by
hydrogenation of 2-methoxy-4,5-dinitrophenol according to the procedure of Ehrlich et al., J. Org. Chem., 1947, 12, 522.
INTERMEDIATE EXAMPLE 18 7-hydroxy-6-methoxy-quinoxaline-2-ol and 6-hydroxy-7-methoxy-quinoxaline-2-ol I The compounds of the heading are prepared for 4-methoxy-5-dihydrochloride hydroxybenzene-1,2-diamine by reaction with NaOH and ethyl glyoxalate using the procedure of intermediate example 2.!
INTERMEDIATE EXAMPLE 19
• 7-hydroxy-6-methoxy-2-chloroquinoxaline and 6-hydroxy-7-methoxy-2-chloroquinoxaline
The compounds of the heading are prepared from 7- I hydroxy-6-methoxy-quinoxaline-2-ol and 6-hydroxy-7-methoxy-quinoxalin-2-ol by reaction with POCI3 using the procedure of intermediate example 3.
The compounds of formula 1 as described herein inhibit the inhibition of cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) by inhibition of PDGF-R tyrosine kinase activity. A large number of disease states are caused either by uncontrolled cell reproduction or matrix overproduction or programmed cell death (apoptosis) poorly regulated. These disease states involve a variety of cell types and include disorders such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases,
F ^ 10 fibrotic diseases, atherosclerosis and occur after I angioplasty of coronary, femoral or kidney arteries or, fibroproliferative diseases such as in arthritis, fibrosis of the lung, kidney and liver. In particular, PDGF and PDGF-R have been reported to be involved in specific types of cancers and tumors such as brain cancer, cancer
ovarian cancer, colon cancer, prostate cancer, lung cancer, sarcoma
Kaposi and malignant melanoma. In addition, cellular proliferative conditions f. Unregulated follow-up from coronary bypass surgery. The inhibition of tyrosine kinase activity is believed to be useful in the control of uncontrolled cell reproduction or overproduction of matrix or
programmed cell death (apoptosis) poorly regulated. This invention relates to the modulation and / or inhibition of cell signaling, cell proliferation and / or cell matrix production, and / or cell movement (chemotaxis), the control of abnormal cell growth and inflammatory cell response. More specifically, this invention relates to the use of substituted quinoline and quinoxaline compounds that exhibit selective inhibition of differentiation, proliferation, matrix production, I f chemotaxis or mediator release by effectively inhibiting factor receptor activity. of platelet-derived growth (PDGF-R) tyrosine kinase. The initiation of autophosphorylation, that is, phosphorylation of 1! The growth factor receptor itself, and the phosphorylation of a host of intracellular substrates, are some of the biochemical events that are involved in cell signaling, cell proliferation, matrix production, chemotaxis and mediator release. By effectively inhibiting the activity of Lck tyrosine kinase, the compounds of this invention are also useful in the treatment of transplant resistance and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft vs. host disease, in hyperproliferative disorders such as tumors and psoriasis, and in diseases in which cells receive proinflammatory signals such as asthma, inflammatory bowel disease and pancreatitis. In the treatment of transplantation resistance, a compound of this invention can be used either prophylactically or in response to an adverse reaction by the human subject I I to a transplanted organ or tissue. When used prophylactically, a compound of this invention is administered to the patient or to the tissue or organ that will be transplanted in advance of the transplant operation. Prophylactic treatment may also include administering the medication prior to the transplant operation but before any signs of an adverse reaction to the transplant are observed. When
administered in response to an adverse reaction, a compound of this invention is administered directly to the patient in order to cross the resistance to transplantation after external signs of resistance have been manifested. According to a further feature of the invention,
F ^ 10 provides a method for inhibiting the activity of PDGF tyrosine kinase comprising contacting a compound according to the claim
1 with a composition containing a PDGF of tyrosine kinase. According to a further feature of the invention there is provided a method for inhibiting the activity of Lck tyrosine kinase which comprises contacting a compound according to claim 1 with a composition containing an Lck tyrosine kinase. According to a further feature of the invention, a method is provided for the treatment of a patient suffering from, or undergoing, conditions that can be alleviated or prevented by the administration of an inhibitor of PDGF-R activity. tyrosine kinase and / or Lck tyrosine kinase activity, for example conditions as described above, comprising administering to the patient an effective amount II of the compound of formula I or a composition containing a compound of formula I, or a pharmaceutically acceptable salt of the same. The reference herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions. The present invention also includes within its scope pharmaceutical compositions comprising a pharmaceutically acceptable I I amount of at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier., for example, an auxiliary, diluent, coating and excipient. In practice, the compounds or compositions for treatment according to the present invention can be administered in a variety of suitable forms, for example, by inhalation, topically, parenterally, rectally or orally; more preferably orally. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, colonic, peritoneal, transepithelial including transdermal, ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation by means of insufflation, and aerosol. The compounds of formula I can be presented in forms that allow administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one compound I according to the invention which is suitable for use as a medicament in a patient. These compositions can be prepared according to the usual methods, using one or more auxiliaries or pharmaceutically acceptable excipients. The auxiliaries comprise, inter alia, diluents, sterile aqueous medium and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of sweeteners such as sucrose, lactose, fructose, saccharin. or Nutrasweet R, flavors such as peppermint oil, wintergreen oil, or cherry or orange flavors, colorants, or stabilizers such as methyl- or propylparaben in order to obtain pharmaceutically acceptable preparations. The selection of the vehicle and the content of active substance in the vehicle is determined in general according to the solubility and chemical properties of the product, the particular mode of administration and the provisions that must be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used to prepare tablets, troches, pills, capsules and the like. To prepare a capsule, it is advantageous to use lactose and liquid carrier, such as polyethylene glycols of high molecular weight. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. When used, aqueous suspensions may contain emulsifying agents or agents that facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof can also be used. In addition, the active compound can be incorporated into sustained release formulations and formulations. For oral administration, the active compound can be administered, for example, with an inert diluent or with an edible carrier
F ^ 10 assimilable, or it can be enclosed in hard gelatin capsules! or of soft cover, or it can be compressed into tablets, or it can be incorporated directly with the food of the diet, or it can be incorporated with excipient and used in the form of edible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups , wafers, and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention are used in vegetable oil, for example safflower oil, peanut oil or olive oil, or aqueous-organic solutions such as water and propylene. glycol, injectable organic esters such as ethyl oleate, as well as solutions
Aqueous sterile salts of the pharmaceutically acceptable salts. The injectable drugs must be fluid to the extent that they can be easily injected, and the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be attracted by the use of absorption delaying agents, by
Example 4, aluminum monostearate and gelatin. Solutions of salts of
The products according to the invention are especially useful for administration by intramuscular or subcutaneous injection! Solutions of the active compound as a free base or pharmaceutically acceptable salt can be prepared in water mixed in a suitable manner with a surfactant such as hydroxypropylcellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof and in oil. Aqueous solutions, which also comprise solutions of the salts in pure distilwater, can be used for intravenous administration with the proviso that their pH is adjusted appropriately, that they are regulated in a judicious manner and pH.
that become isotonic with a sufficient amount of glucose or sodium chloride and that are sterilized by heating, irradiation, microfiltration, f and / or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal , and similar. I Sterile injectable solutions are prepared by incorporating the
Active compound in the required amount in the appropriate solvent with several of the ingredients listed above, as required, followed by filter sterilization. In general, the dispersions are prepared by incorporating I the various sterilized active ingredients into a sterile vehicle containing,
the basic dispersion medium and the other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods f are vacuum drying and the freeze drying technique which
produces a powder of the active ingredient plus any additional ingredients i desired from the previously sterilized solution by filter thereof. Topical administration, gels, (based on water or alcohol), creams or ointments containing compound of this invention can be used. The I compounds of the invention can also be incorporated into a matrix gel or base for applications in a patch, which would allow a controlrelease of the compound through a transdermal barrier For administration by inhalation, the compounds of the invention can be dissolved or suspended in a suitable carrier for use in a nebulizer or aerosol suspension or solution, or
can absorb on a suitable solid carrier to be used as a dry powder inhaler. Solid compositions for rectal administration include suppositories formulated according to known methods and containing at least one compound of formula I. The compositions according to the invention can also be formulated in a manner that will resist rapid release of the vascular wall ( arterial or venous) by convection and / or diffusion, thereby increasing the residence time of the viral particles at the desired site of action. A periadvencial deposit comprising a compound according to the invention can be used for sustained release. One such deposit useful for administering a compound according to the invention may be a copolymer matrix, such as vinyl ethylene acetoate, or a polyvinyl alcohol gel surrounded by a Silastic sheath. Alternatively, a compound according to the invention can be delivered locally from a silicon polymer implanted in the adventitia. An alternative method for minimizing the disappearance of a compound according to the invention during percutaneous, transvascular delivery, comprises the use of non-diffusible, drug-eluting microparticles. The microparticles can be constituted of a variety of synthetic polymers, such as polylactide for example, or natural substances, including proteins or polysaccharides. Said microparticles
allow the strategic manipulation of variables including the total dose of drug and the syn- thetics of its release. The microparticles can be faithfully injected efficiently into the arterial or venous wall via a porous balloon catheter or balloon-on-stent, and are retained in the vascular wall and periadvential tissue for at least two weeks. The formulations and
methodologies for local, site-specific intravascular delivery of therapeutic agents are discussed in Reissen et al. (J. Am. Coil, Cardiol., 1994; 23: 1234-1244), the complete contents of which are incorporated herein by reference.
A composition according to the invention can also comprise a hydrogel which is prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polymer of polyacrylic acid which can act as an absorption sponge drug. Such polymers have been described, for example, in the application
WO93 / 08845, the entire contents of which is incorporated herein by reference. Certain of them, such as, in particular, those obtained from ethylene oxide and / or propylene are commercially available. In the use of compounds according to the invention to treat pathologies that are linked to hyperproliferative disorders, the compounds according to the invention can be administered in different ways. For the treatment of restenosis, the compounds of the invention are administered directly to the wall of the blood vessel by means of an angioplasty balloon which is coated with a hydrophilic film (for example a hydrogel) which is saturated with the compound, or by of any other catheter containing an infusion chamber for the compund, which can therefore be applied in a precise manner to the site to be treated and allow the compound to be released locally and efficiently at the location in the cells to be treated. This method of administration advantageously makes it possible for the compound to rapidly contact the cells in need of treatment.
The method of treatment of the invention preferably consists of introducing a compound according to the invention at the site to be treated. For example, a hydrogel containing the composition can be deposited directly on the surface of the tissue to be treated, for example during a surgical procedure. Advantageously, the hydrogel is introduced into the desired intravascular site by coating a catheter, for example a balloon catheter and delivery to the vascular wall, preferably at the time of angioplasty. In a particularly advantageous manner, the saturated hydrogel is introduced into the site
^ 10 which will be treated by means of a balloon catheter. The balloon may be accompanied by a protective cover as the catheter advances toward the target passage, in order to minimize the disappearance of the drug after the catheter enters the bloodstream. Another embodiment of the invention provides a composite according to
with the invention that will be administered by means of perfusion balloons.
These perfusion balloons, which make it possible to maintain a blood flow and thus decrease the risk of myocardial ischemia, with balloon inflation, also allow the compound to be delivered locally at normal pressure for a relatively long time, more than twenty minutes. minutes, that 20 may be necessary for its optimal action. Alternatively, a channeled balloon catheter ("channeled balloon angioplasty catheter", Mansfield Medical, Boston Scientific Corp., Watertown, MA) can be used. The latter consists of a conventional balloon covered with a layer of 24 perforated I channels that are perfused by an independent lumen through an additional infusion port. Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, balloon with channel, balloon-on-stent and hydrogel catheters, all of which can be used to practice the invention, are described in Reissen et al. (1994), the complete content of which is incorporated herein by reference. The use of a perfusion balloon catheter is especially advantageous, since it has the advantages of keeping the balloon inflated for a longer period of time while retaining the facilitated slip properties and site specificity of the hydrogel, which are obtained simultaneously . Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the invention and poloxamer, such as Poloxamer 407 is a non-toxic, biocompatible, commercially available polyol (BASF, Parsippany, NJ). A poloxamer impregnated with a compound according to the invention can be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer I possesses essentially the same advantages as the hydrogel while having a lower viscosity. The use of a balloon catheter with a channel with a ooloxamer impregnated with a compound according to the invention is especially advantageous. In this case, the advantages of keeping the balloon inflated for a longer period of time while retaining the facilitated slip properties and site specificity of the poloxamer are obtained simultaneously. The percentage of active ingredient in the compositions! of the invention may vary, it being necessary that a proportion be formed so that a suitable dose can be obtained.
Obviously, several unit dosage forms can be administered at about the same time. A dose used can be determined by a qualified physician or medical professional, and depends on the desired therapeutic effect, the route of administration and the duration of treatment, and the condition of the patient. In the adult, the doses are generally from 0.001 to 50, preferably from 0.001 to 5, mg / kg of body weight per day for inhalation, from 0.01 to 100, preferably from 0.1 to 70, more especially from 0.5 to 10, mg / kg of body weight per day for oral administration, and from p.001 to 10, preferably from 0.01 to 10 mg / kg of body weight per day for intravenous administration. In each particular case, the doses are determined according to the distinguishing factors of the patient to be treated, (such as age, weight, general state of health and other characteristics that can influence the efficiency of the compound according to the invention. / compositions according to the invention can be administered as frequently as necessary in order to obtain the desired therapeutic effect.Some patients may respond rapidly to a higher or lower dose and may find that maintenance doses are adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, according to the physiological requirements of each particular patient.In general, the active product can be administered orally from 1 to 4 times a day Of course, for other patients, it will be necessary to prescribe no more than 1 or 2 doses per day. The compounds of the present invention can also be formulated to be used in conjunction with other therapeutic agents such as agents or in connection with the application of therapeutic techniques to face pharmacological conditions that can be alleviated through the application of a compound of formula 1, such as in the following: The compounds of the present invention can be used in the treatment of post angioplasty restenosis using any device such as balloon, excision techniques or laser. The compounds of the present invention can be used in the treatment of restenosis following stent placement in the vasculature either as 1) primary treatment for vascular blockage, or 2) in the case where angioplasty using any device fails to give an artery. patent. The compounds of the present invention can be used orally, by parenteral administration or the compound could be applied topically through the intervention of a specific device or as a suitably formulated coating on a stent device. In one aspect, the coating on a stent device is formed by applying polymeric material in which the compound of the invention is incorporated into at least one surface of the stent device. Suitable polymeric materials for incorporating the compound of the invention include polymers having relatively low processing temperatures such as polycaprolactone, poly (ethylene-co-vinyl acetate) or poly (vinyl acetate) or silicone gum and polymers having similar relatively low processing temperatures. Other suitable polymers include non-degradable polymers capable of carrying and delivering therapeutic drugs such as latexes, urethanes, polysiloxanes, sterene-ethylene / butylene-styrene block copolymers
(SEBS) and biodegradable, bioabsorbable polymers capable of carrying and delivering therapeutic drugs, such as poly-DL-lactic acid (DL-PLA), and poly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates, and aliphatic polycarbonates and polyphosphazenes. A porosigen can also be incorporated into the drug loaded polymer by adding the porosigen to the polymer together with the therapeutic drug to form a porous polymer membrane, loaded with drug. "Porosigen" means any portion, such as microgranules of sodium chloride, lactose, or sodium heparin, for example, which will be dissolved or otherwise degraded when immersed in body fluids to leave behind a porous network in the body. polymeric material !. The pores left by said porosigenes can typically be as large as 10 microns. Pores formed by porosigenes such as polyethylene glycol (PEG) polyethylene oxide / polypropylene oxide copolymers (PEO / PPO), for example, may also be smaller than one miera, although other similar materials form 5-phase separations from of the continuous polymer matrix loaded with drug and that can subsequently be leached by body fluids may also be suitable to form smaller pores of a miera. The polymeric material can be applied to the stent while the therapeutic drug and the porosigen material are contained within the polymeric material, for
F 10 allows the porosigen to be dissolved or degraded by body fluids when the stent is placed in a blood vessel, or alternatively, the porosigen can be dissolved and removed from the polymeric material to form pores in the polymeric material before placing the polymeric material combined with the stent inside a blood vessel. If desired, a velocity control membrane may also be applied on the drug loaded polymer, to limit the rate f of release of the compound of the invention. The speed control membrane can be added by applying a coating that forms a solution, or a lamination. The velocity control membrane applied on the
Polymeric material can be formed to include a uniform dispersion of a porosigen in the membrane to control the velocity, and the porosigen in the membrane to control the velocity can be dissolved to leave pores in the membrane to control the velocity typically as long as 10 minutes. micras, or as small as 1 miera, for example, although the pores are smaller than 1 miera. The porosigen in the membrane to control the velocity can be, for example, sodium chloride, lactose, sodium heparin,
^ polyethylene glycol, polyethylene oxide / polypropylene oxide copolymers, and
mixtures thereof. In another aspect, the coating on the stent device can be formed by applying the compound of the invention to at least one surface of the stent device to form a bioactive layer and then applying one or more layers of porous polymeric material on the bioactive layer 10 , so that the porous polymeric material has a suitable thickness to provide a controlled release of the compound. In one aspect, the porous polymeric material is composed of a polyamide, parylene or a parylene derivative applied by deposition of catalyst-free steam. "Parylene" refers to a polymer based on p-xylylene and made by vapor phase polymerization as described in the U.S. patent. No. 5,824,049, incorporated in f. present by reference. Alternatively, the porous polymeric material is applied by plasma deposition. The suitable representative polymers
for plasma deposition include poly (ethylene oxide), poly (ethylene glycol), poly (propylene oxide), and polymers of methane, silicone, tetrafluoroethylene tetramethyldisiloxane, and the like.
Other suitable polymer systems derived from photopolymerizable monomers such as preferably having at least two interlazab double bonds C-C
(carbon to carbon), and a non-gaseous ethylenically unsaturated compound being polymerizable, having a boiling point above 100X, at atmospheric pressure, a molecular weight of 100-1500 and being capable of forming easily high molecular weight addition polymers. More preferably, the monomer is preferably a photopolymerizable polyethylenically unsaturated acrylic or methacrylic acid ester containing two or more acrylate or methacrylate groups per molecule or mixtures thereof. Representative examples of said multifunctional acrylates are ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylpropane triacrylate, trimethylpropane trimethacrylate, pentaerythritol tetracrylate or pentaerythritol tetramethacrylate, 1,6-hexanediol dimethacrylate, and diethylene glycol dimethacrylate. Also useful in some special instances are monoacrylates such as n-butyl acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate, lauryl acrylate and 2-hydroxy-propyl acrylate. Also suitable are small amounts of (meta) acrylic acid amides] such as N-methoxylol, butyl methacrylamide ether, N-vinyl compounds | such as N-vinyl pyrrolidone, butanediol-1,4-divinyl ether, vinyl esters of aliphatic monocarboxylic acids such as vinyl oleate, virile ethers of diols such as butanediol-1,4-divinyl ether and allyl ether and allylic ester i. They are also suitable. Also included are other monomers such as the reaction products of di- or polyepoxides such as butanediol-1,4-diglycidyl ether or diglycidyl-biphenol-ether with (meta) acrylic acid. The characteristics of the polymerizable liquid dispersion medium can be modified for the specific purpose by a suitable selection of monomers or mixtures thereof. Other useful polymer systems include a polymer that is bicompatible and minimizes irritation to the vessel wall when the stent is implanted. The polymer can be a biostable or bioabsorbable polymer depending on the desired release rate or the desired degree of polymer stability. The bioabsorbable polymers that could be used include poly (L-lactic acid), polycaprolactone, poly (lactide-co-glycolide), poly (hydroxybutyrate), poly (hydroxybutyrate-co-valerate), polydioxanone, pol orthoester, polyanhydride, poly (glycolic acid), poly (D, L-lactic acid), poly (glycolic acid-cotrimethylene carbonate), polyphosphonate, polyphosphbest urethane, poly (amino acids), cyanoacrylates, poly (trimethylene carbonate), poly (iminocarbonate), copol (ether esters) (eg, PEO / PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid. In addition, biostable polymers with a relatively low chronic tissue response I such as polyurethanes, silicones and polyesters could be used and polymers could also be used if they can be dissolved and cured or polymerized on the stent such as polyolefins, polyisobutylery and | I! ethylene-alpha-olefin copolymers; adipic polymers and copolymers, and polymers and copolymers of vinyl halide, such as polyvinyl chloride; I polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinyl idene chloride; polyacrylonitrile, polyvinyl, polyvinyl aromatic ketones, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with one another and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS I resins and ethylene-vinyl acetate copolymers; polyamides, such as Nylone 66 and polycaprolactam; alkyl resins, polycarbonates; polyoxymethylenes; polyimides, polyethers; epoxy resins, polyurethanes; rayon; rayon triacetate; cellulose, cellulose acetate, cellulose butyrate, cellulose butyrate acetate; cellophane, cellulose nitrate; cellulose propionate; I cellulose ethers; and carboxymethylcellulose. ! In addition to plasma deposition and vapor phase deposition, other techniques can be used to apply the various coatings on the surfaces of the stent. For example, a polymer solution can be applied to the stent and allow the solvent to evaporate, thereby leaving a coating of the polymer and the therapeutic substance on the surface of the stent. Typically, the solution can be applied to the stent by spraying the solution onto the stent or immersing the stent in the solution. The compounds of the present invention can be used in the treatment of restenosis in combination with any anticoagulant, antiplatelet, antithrombotic, or profibrinolytic agent. Patients are often treated concurrently before, during and after interventional procedures with agents of those classes either in order to safely perform the intervention procedure to avoid detrimental effects of thrombus formation. Some examples of classes of agents known to be anticoagulant, antiplatelet, antithrombotic or profibrinolytic agonists include any heparin formulation, low molecular weight heparins, pentasaccharides, fibrinogen receptor antagonists, inhibitors of
F ^ 10 thrombin, Factor Xa inhibitors, or Factor Vlla inhibitors. The compounds of the present invention can be used in combination with any antihypertensive agent or cholesterol or lipid regulating agent in the treatment of restenosis or atherosclerosis concurrently with the treatment of high blood pressure or atherosclerosis.
Some examples of agents that are useful in the treatment of high blood pressure include compounds of the following classes; beta blockers, ACE inhibitors, calcium channel blockers and alpha receptor antagonists. Some examples that are useful in the treatment of elevated cholesterol levels or deregulated lipid levels include compounds known to be inhibitors of HMGCoA reductase, compounds of the fibrate class.
| The compounds of the present invention can be used in the treatment of various forms of cancer either alone or with compounds known to be useful in the treatment of cancer. It is understood that the present invention includes combinations of
compounds of the present invention with one or more of the therapeutic class agents mentioned above. Compounds within the scope of the present invention exhibit pharmacological activities labeled according to tests described in the literature whose test results are believed to be
• 10 correlate with pharmacological activity in humans and other mammals. The following results of pharmacological tests in vitro and in vivo are typical for characterizing compounds of the present invention.
Preparation of Pharmaceutical Compositions and Pharmacological Test Section Compounds within the scope of this invention exhibit significant activity as inhibitors of protein tyrosine kinase and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis, atherosclerosis and vascular lesions.
restenosis. Compounds within the scope of the present invention exhibit modulation and / or inhibition of cellular signaling and / or cell proliferation and / or matrix production and / or chemotaxis and / or inflammatory cell response and can be used to prevent or delay occurrence or reoccurrence of said conditions or otherwise treat the condition. To determine the effectiveness of the compounds of! this invention, those accepted in the art and recognized for relating to pharmaceutical activity in mammals were used. The compounds within the scope of this invention have been subjected to these various tests, and the results obtained are believed to correlate with useful cell differentiation mediator activity. The results of these tests are believed to provide sufficient information for persons skilled in the pharmacological and medical chemistry techniques to determine the parameters for using the compounds studied in one or more of the therapies described herein.
1. ELISA test for autophosphorylation of PDGF-R tyrosine kinase The header test is performed as described by Dolle et al. (J. Med. Chem. 1994, 37, 2627), which is incorporated herein by reference, with the exception that cell lysates derived from human aortic soft muscle (HAMSC) cells were used as described below.
I 2.- General procedure of myogenesis test a. Cell culture Human aortic soft muscle cells (step 4-9) are formed in 96-well plates in a growth medium at 6000 cells / well and allowed to grow for 2-3 days. At approximately 85% confluence, cell growth was stopped with serum free medium (SMF). b. Mitogenesis test After 24 hours of serum deprivation, the medium is removed and replaced with test / vehicle compound in SFM (200 μl / well). The compounds are solubilized in DMSO cell culture at a concentration of 10 mM and further dilutions are made in SFM. After 30 minutes of preincubation with the compound, the cells are stimulated with PDGF at 10 ng / mL. The determinations are made in duplicate with stimulated and unstimulated wells in each compound concentration. Four hours later, 1 μCi 3 H thymidine / well was added. Cultures finished 24 hours after the addition of growth factor. Cells are harvested with trypsin and harvested on a filter mat using an automated cell harvester (Vyallac
Machll96). The filter mat is counted in a scintillation counter
(Wallac Betaplate) to determine the built-in DNA tag.
3. - Chymathaxis test I Human soft aortic muscle cells (HASMC) ai initial steps I are obtained from ATCC. Cells grow in Clonetics SrnGM 2
SingleQuots (medium and cells of steps 4-10 are used). When cells i are at 80% confluence, a fluorescent, calcein AM probe (5 mM, molecular probe) is added to the medium and the cells are incubated for 30 minutes. After washing with pH regulated saline from HEPES, cells are harvested with trypsin and neutralized with MCDB pH regulator
131 (Gibco) with 0.1% BSA, 10 mM glutamine and 10% fetal bovine serum. After centrifugation, the cells are washed once more! and resuspended in the same pH regulator without fetal bovine serum at 30,000 cells / 50 ml. The cells are incubated with different concentrations of a compound of formula I (final concentration of DMSO = 1%) for 30 minutes at 37X. For chemotaxis studies, modified 96-well Boyden chambers (Neuroprobe, Inc.) and a polycarbonate membrane with an 8-mm pore size (Poretics, CA) are used. The membrane is coated with collagen (Sigma C3657, 0.1 mg / ml). PDGF-β (3 ng / ml) in pH regulator with and without a compound of formula I are placed in the lower chamber. The I cells (30,000), with and without inhibitor, are placed in the upper chamber. The cells are incubated for 4 hours. The filter membrane is removed1 and the cells on the upper membrane side are removed. After drying, fluorescence is determined on the membrane using Cytofluor II (Millipore) at excitation / emission wavelengths of 485/530 nm. In each experiment, an average cell migration is obtained from 6 duplicates. The percent inhibition is determined from control values treated with DMSO. From 5 points of concentration-dependent inhibitions, the IC50 value is calculated. The results are presented as 5 ± SEM means of these five experiments.
4. Purification of EGF receptor The purification of EGF receptor is based on the procedure of Yarden and Schlessinger. A431 cells are grown in bottles of 80 em a
^ 10 confluence (2 x 107 cells per bottle). The cells are washed twice with
PBS and are harvested with PBS containing 11.0 mmol EDTA (1 hour at 37X, and centrifuged at 600 g for 10 minutes). Cells are solubilized in 1 ml by 2 x 10 7 cold solubilizing pH regulator cells (50 mmoles Hepes pH regulator, pH 7.6, 1% Triton X-100, 150 mmoles NaCl, 5
mmol EGTA, 1 mmol PMSF, 50 mg / ml aprotinin, 25 mmol benzamidine,
mg / ml leupeptic, and 10 mg / ml soybean trypsin inhibitor) for 20 f minutes at 4X. After centrifugation at 100,000g for 30 minutes, the superfluid is loaded onto a WGA-agarose column (100 ml of resin packed by 2 x 10 7 cells) and stirred for 2 hours at 4X. The material does not
absorbed is removed and the resin is washed twice with pH regulator HTN
(50 mmoles Hepes, pH 7.6, 0.1% Triton X-100, 150 mmoles NaCl), twice with pH regulator HTN containing 1 M NaCl and twice with pH regulator HTNG (50 mmoles Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol!! I
NaCl, and 10% glycerol). The EGF receptor is eluted in batches with HTNG pH regulator I containing 0.5 M N-cetyl-D-glucosamine (200 ml per 2 x 10 7 cells). The eluted material is stored in aliquots at -70X and diluted anj.es I • to be used with TMTNG pH regulator (50 mmol Tris pH regulator - 5 Month, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, 10% glycerol).
. Inhibition of autophosphorylation of EGF-R Cells A431 are grown to confluence on tissue culture dishes coated with human fibronectin. After washing twice with
PBS cooled by ice, the cells are crippled by adhesion of 500 ml / lysis buffer plate pH (50 mmoles Hepes, pH 7.5, 150 mmoles NaCl, 1.5 mmoles MgCl 2, 1 mmole EGTA, 10% glycerol, 1% triton X-100, 1 mmol PMSF, 1 mg / ml aprotinin, 1 mg / ml leupeptin) and incubating 5 minutes at 4X. After stimulation of EGF (500 mg / ml, 10 minutes at 37X)
performs immunoprecipitation with anti-EGF-R (Ab 108) and the autophosphorylation reaction (50 ml aliquots, 3 mCi [g "32P] ATP) sample is carried out in the presence of 2 or 10 mM compound of the present invention, for 2 minutes at 4X.The reaction is stopped by adding a hot electrophoresis sample pH regulator.The SDA-PAGE analysis (7.5% els) is
follows by autoradiography and the reaction is quantified by densitometry evaluation of the X-ray films.
to. Cell culture The cells called HER 14 and K721A were pre-transfected with NIH3T3 cells (clone 2.2) (from C. Fryling, NCI, NIH) which have endogenous EGF receptors, with wild-type EGF receptor cDNA constructs. or mutant EGF receptor that lacks tyrosine kinase activity (in which Lys 721 at the ATP binding site is replaced by an Ala residue, respectively). All cells are cultured in DMEM with 10% calf serum (Hyclone, Logan, Utah).
6. Selectivity against PKA and PKC is determined using commercial equipment a) Colorimetric PKA test kit from Pierce Spinzime Format. Protocol Summary: PKA enzyme (bovine heart) 1 U / test tube Kemptide peptide substrate (labeled with dye) 45 minutes @ 30X Adsorbance at 570 nm b) Pierce Spinzyme Colorimetric PKC test kit Protocol summary:, Enzyme PKC (rat brain) 0.025U / test tube neurogranin peptide substrate (labeled with dye) 30 minutes @ 30X i Adsorbance at 570 nm. ]
7. Measurements of inhibition activity of p56lck tyrosine kinase I 5 The inhibition activity of p56lck tyrosine kinase was determined according to the procedure described in U.S. Patent No. 5,714,493, incorporated herein by reference. In the alternative, the tyrosine kinase inhibition activity is determined according to the following method. A substrate (substrate that contains 10 tyrosine, Biot- (ß Ala) 3-Lys-Val-Glu-Lys-lle-Gly-Glu-Gly-Thr-T? R-Glu-Val-Val-Tyr-Lys- (NH2) recognized by P56lck, 1 μM) is first phosphorylated in the presence or absence of a given concentration of the test compound, by a given amount of enzyme (the enzyme is produced by expression of the P56lck gene in a yeast construct)
purified from cloned yeast (the purification of the enzyme sel is done following classical methods), in the presence of ATP (10 μM) MgC12 (2.5 i mM),
• MnC12 (2.5 mM), NaCl (25 mM), DTT (0.4 mM) in 50 mM Hepes, p? 7.5, i for 10 minutes at room temperature. The total reaction volume is
50 μl, and the reactions are performed in a 96-well black fluoroplate. The
The reaction is stopped by the addition of 150 μl of stop buffer (100 mM Hepes pH 7.5, 400 mM KF, 133 mM EDTA, 1 g / L BSA) containing an antibody selected from anti-tyrosine labeled with the cryptate of Europium (PY20-K) at 0.8 μg / ml and streptavidin marked by allophycocyanin (XL665) at 4 μg / ml. The labeling of streptavidin and anti-tirosis I I antibodies was carried out by Cis-Bio International (France). The mix is counted using a Packard Discovery counter that is capable of measuring transfer! of homogeneous fluorescence resolved by time (excitation at 337 nm, Ijecture at 620 nm and 665 nm). The ratio of the signal 665 nm / signal 620 nm is a measure of the concentration of phosphorylated tyrosine. The preform is obtained by replacing enzyme by pH regulator. The specific signal ¡is the difference between the ratio obtained without inhibitor and the relation with the preform. The percentage of specific signal is calculated. The IC50 is calculated with 10 concentrations of inhibitor in duplicate using mild XIfit. The reference compound is staurosporine (Sigma) and exhibits an IC50 of 30 ± 6 nM (n = 20).
8. Measurement of tumor inhibition in vitro The inhibition of tumor growth in vitro by the compounds of this invention is determined as follows: Rat glioma cell line C6 (provided by ATCC) is cultured as monolayers in modified Eagle's medium from Dubelcco containing 2 mM L-glutamine, 200 U / ml penicillin, 200 μg / ml, streptomycin and i supplemented with 10% (v / v) of fetal calf serum inactivated by heat.
The cells in exponential growth phase are subjected to trypsinization, washed with PBS and diluted to a concentration of 6500 cells / ml in complete medium. The drug to be tested or the control solvent is added to the suspension (2.5 ml) under a volume of 50 μl and 0.4 ml of 2.4% agar] Noble
Difco maintained at 45X is added and mixed. The mixture is immediately poured into Petri dishes and left to stand for 5 minutes at 4X.
The number of cell clones (> 60 cells) is measured after 12 days of incubation at 37X under 5% C02 atmosphere. Each drug is tested at 10, 1, 0.1, and 0.01 μg / ml (final concentration on the agar) in duplicate. The results are expressed in percent inhibition of clonogenicity in relation to untreated controls. The IC50 are determined graphically from semi-logarithmic planes of the mean value determined for drug concentration.
9. Measurement of tumor inhibition in vivo The inhibition of tumor growth in vivo by the I compounds of this invention is determined using a subcutaneous xenograft model as described in the patents of E.U.A.1 Nos.
,700,823 and 5,760,066 in which mice are implanted with C6 glioma cells and tumor growth is measured using venier calipers. The results obtained by the above experimental methods prove that the compounds within the scope of the present invention possess useful inhibition properties of PDGF protein receptor tyrosine kinase or inhibition properties of p56 / c * tyrosine kinase, and therefore possess therapeutic value. The results of previous pharmacological tests can be used to determine the dosage and I mode of administration for the particular therapy sought. The present invention can be realized in other specific forms without departing from the spirit or essential attributes thereof.
•
•
Claims (60)
1. - A compound of formula I:
wherein: X is LiOH or L2Z2; Li is (CR3aR3) r or (CR3aR3) m-Z3- (CR3 aR3'b) n; L2 is or ethenyl; Zi is CH or N; Z2 is optionally substituted hydroxycycloalkyl, optionally substituted hydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl or optionally substituted hydroxyheterocyclenyl; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S ^ SO, S02 or a bond: m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1, 2, 3 or 4, and p + q = 0, 1, 2, 3 or 4 when ZL »is a bond, and p + q = 0, 1, 2 or 3 when Z is different from a link; r is 2, 3 or 4; R.a and R-ib are independently optionally substituted alkyl,! optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, substituted optionally substituted heteroaryloxy, cyano, R5ReN- or acylR5N-, or one of Rα and Rib is hydrogen or halogen, and the other is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally alkoxy su. Jutido, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, RsRβN- or aciIRsN; R c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halogen, cyano, RSRTN- OR aciIRsN; R3a, R3b. R3.3 and R3 are independently hydrogen or alkyl; R is hydrogen, alkyl or acyl; and R5 and Re are independently hydrogen or alkyl, or R5 and R & taken together with the nitrogen atom to which they are attached, they form azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, further characterized in that L1 is (CR3aR3b) m-Z3- (CR3 aR3) n; L2 is (CR3aR3b) p- (CR3"to 3 ') q; Z2 is optionally substituted hydroxycycloalkyl, or optionally substituted hydroxyheterocyclyl; Z4 is O and NR; m is 0; n is 2 or 3; p + q = 0 or Ria and Rb are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy or RsRβN, or one of R? And R ^ is hydrogen or halogen, R ?c is hydrogen, optionally substituted alkyl or alkoxy optionally substituted R3a, R3b, R3 a and R3 b are independently hydrogen or lower alkyl, R is hydrogen, and R5 and Re are considered together with the nitrogen atom to which they are attached, form azaheterocyclic, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof
3. The compound according to claim 1, further characterized in that X is L2Z2; L2 is Z2 is optionally hydroxycycloalkyl; uido; Z is O and NR4; p is 0; q is 0 or 1; Ria and Rib are optionally optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy or optionally substituted heterocyclyloxy, or R a and R y is hydrogen or halo and the other R a and R y is optionally substituted alkyl, optionally substituted alkoxy, cycloalkyloxy optionally substituted or optionally substituted heterocyclyloxy; R? C is hydrogen; R3-a and R ^ b are independently hydrogen; and R 4 is hydrogen, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, further characterized in that Z1 is CH.
5. The compound according to claim 1, further characterized in that Z1 is N.
|
6. The compound according to claim 1, further characterized in that Z2 is optionally substituted hydroxycycloalkyl.
7. The compound according to claim 1, further characterized in that p and q are 0.
8. The compound according to claim 1, further characterized in that p + q = 1.
9. The compound according to claim 1, further characterized in that Z4 is O. ^^ 10 10. The compound according to claim 1, further characterized in that ZA is O, and p and p are 0. 11. The compound according to claim 1, further characterized because Z is O, and p + q = 1. 12. The compound according to claim 1, characterized in that ZA is NR. 13. The compound according to claim 1, further characterized in that ZA is NR, and p and p are 0. 14. The compound according to claim 1, further characterized in that Z is NR », and p + q = 1. 15. The compound according to claim 1, further characterized in that ZA is S. 16. The compound according to claim 1, further characterized in that Z is S, and p and p are 0.
17. The compound according to claim 1, further characterized in that Z is S, and p + q = 1. 18. The compound according to claim 1, further characterized in that R and Ay are independently lower alkyl, hydroxy, alkoxy lower, cycloalkyloxy, heterocyclyloxy optionally substituted by hydroxy, or one of R &a and Rib is hydrogen or halo and the other of! R? A and
Rib is lower alkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy optionally substituted by hydroxy. 19. The compound according to claim 1, further characterized in that R a and R b are independently optionally substituted heterocyclylcarbonyloxy or optionally substituted lower alkoxy. 20. The compound according to claim 19, further characterized in that the lower alkoxy is methoxy or ethoxy. 21. The compound according to claim 1, further characterized in that R a and Rib are lower alkyl. 22. The compound according to claim 21, further characterized in that the lower alkyl is methyl or ethyl. 23. The compound according to claim 1, further characterized in that one of R? A and R? B is lower alkoxy, and the other of
Ría and R-ib is halo.
24. The compound according to claim 23, further characterized in that the lower alkoxy is methoxy or ethoxy, and the halo is chloro or bromo. f 25. The compound according to claim 1,
5 further characterized in that one of R a and Rib is lower alkyl, and the other of
Ria and R-ib is lower alkoxy. 26. The compound according to claim 25, further characterized in that the lower alkoxy is methoxy or ethoxy, and the lower alkyl is methyl or ethyl. The compound according to claim 1, further characterized in that one of R a and R. b is lower alkoxy, and the other of R a and R-ib is cycloalkyloxy. 28. The compound according to claim 27, further characterized in that the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy. 29. The compound according to claim 1, characterized in that one of R? A and Rib is hydrogen, and the other of R? A and
Rib is lower alkoxy, cycloalkyloxy or heterocyclyloxy. 30. The compound according to claim 29, further characterized in that the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and the heterocyclyloxy is furanyloxy.
31. The compound according to claim 1, further characterized in that R? C is hydrogen, lower alkyl or lower alkoxy. 32. The compound according to claim 31, further characterized in that the lower alkyl is methyl or ethyl and the lower alkoxy is methoxy or ethoxy. 33. The compound according to claim 1, further characterized in that Z2 is hydroxycycloalkyl optionally substituted with hydroxy or alkyl. 34. The compound according to claim 33, further characterized in that Z2 is hydroxycycloalkyl optionally substituted with lower alkyl. The compound according to claim 19, further characterized in that the lower alkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl. 36. The compound according to claim 35, further characterized in that one of R a and R b is unsubstituted lower alkoxy and the other of R and R 1b optionally substituted heterocyclylcarbonyloxy or lower alkoxy substituted with alkoxy, heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl 37.- The compound according to claim 36, further characterized in that one of R1a and Rib is methoxy and the other of R? Ay Rib is [1,4 '] -bipiperadin- -carbonyloxy, 2- (ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy, 2- (4-
l_-M-Ki < _-- ll-l ---- É? methylpiperazin-1-yl) ethoxy, carboxymethoxy, methoxycarbonyl ethoxy, aminocarbonylmethoxy, N-methylaminocarbonylmethoxy or N, N-dimethylaminocarbonylmethoxy. 38. The compound according to claim 1, wherein 5 is Trans-4- (7-chloro-6-methoxyquinolalin-2-ylamino) -cyclohexanol; Rrans-4- (6-chloro-7-methoxy-quinol-2-ylamino) -cyclohexanol; 7rans-4- (6,7-dimethoxy-quinotoxalin-2-ylamino) -cyclohexanol; C / s-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexanol; (2endo, 5exo) -5- (6,7-dimethoxy-quinotoxalin-2-ylamino) bicyclo [2.2.1] -heptan-2-ol; (2exo, 5exo) -5- (6,7-dimethoxy-cyanoxalin-2-yl-10-ylamino) bicyclo [2.2.1] -heptan-2-ol; (2endo, 3exo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) bicyclo- [2.2.1] heptan-2,3-diol; C / s-2- (6- methoxy-quinol-2-ylamino) -cyclopentanol; 7rans-2- (6-methoxyquinolalin-2-ylamino) -cyclopentanol; Trans-4- (6-methoxyquinolalin-2-ylamino) -cyclohexanol; Etylamide [3aR, 4S, 6R, 6aS] -6- (6,7-dimethoxy-quinxoalin-2-ylamino) -2,2-dimethyl-15-tetrahydro-cyclopenta [1,3] dioxol-4-carboxylic acid; 2- (1, 4-dioxa-spiro [4.5] dec-8-yloxy) -6,7-dimethoxy-quinotoxaline; 4- (6,7-Dimethoxy-cyanoxalin-2-yloxymethyl) -phthoxyhexanol; 3- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol; 4- (6,7-dimethoxy-quinotoxalin-2-yloxy) -cyclohexanol; 5- (6,7-Dimethoxy-cyanoxalin-2-yloxy) -bicyclo [2.2.1] heptane-2,3-diol; (2exo, 3exo, 5exo) -5- (6,7-dimethoxy-quinotoxalin-2-ylamino) -bicyclo [2.2.1] heptane-2,3-diol; Ester c / s-4- (6,7-dimethoxy-cyanoxalin-2-yloxy) -cyclohexylic acid acetic acid; C / s-4- (6,7-dimethoxyquinolalin-2-yloxy) -cyclohexanol; 4- (6,7-Dimethoxy-cyanoxalin-2-yloxy) -cyclohexyl ester of dimethylcarbamic acid; Rrans-4- (6,7-dimethoxy-4-oxy-quinol-2-ylamino) -cyclohexanol; Ester frans-4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -cyclohexylic acid acetic acid; (2exo, 5exo) -5- (6,7-dimethoxyquinolalin-2-ylamino) -bicyclo [2.2.1] - heptan-2-ol; (2endo, 5exo) -5- (6,7-dimethoxyquinolin-2-ylamino) -bicyclo [2.2.1] heptan-2-ol; (2exo, 6exo) -6- (6,7-dimethoxyquinolin-2-ylamino) -bicyclo [2.2.1] heptan-2-ol; 4- (6,7-dimethoxyquinolalin-2-ylamino) -2-methyl-cyclohexanol; (2trans, 4.rans) -4- (6,7-dimethoxy-quinxoalin-2-ylamino) -2-methyl-cyclohexanol; (+) - (2trans, 4.rans) -4- (6,7-dimethoxy-quinxoalin-2-ylamino) -2-methyl-cyclohexanol; (-) - (2-trans, 4 -rans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2-trans, 4-trans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; (2cis, 4c / 's) -4- (6,7-dimethoxy-quinol-2-ylamino) -2-HT-ethyl-cyclohexanol; (2c / s, 4frans) -4- (6,7-dimethoxy-cyanoxalin-2-ylamino) -2-methyl-cyclohexanol; 4- (6,7-dimethylquinoxalin-2-ylamino) cyclohexanol; and (1S, 2R, 4S, 5R) -5- (6,7-dimethoxyquinolalin-2-ylamino) -bicyclo [2.2.1] -heptan-2-ol, an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof. 39. The compound according to claim 1, which is trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanol, or an N-oxidp thereof, hydrate thereof, solvate same, prodrug thereof, or pharmaceutically acceptable salt thereof. The compound according to claim 1, which is c / s-4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.
41. The compound according to claim 1, which is 4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof , or pharmaceutically acceptable salt thereof. The compound according to claim 1, which is (2exo, 5exo 5- (6,7-dimethoxy-quinoxalin-2-ylamino) -bicyclo [2.2.1] heptan-2-ol, or an N -hydroxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically acceptable salt thereof.- The compound according to claim 1, which is frans-4- (7-chloro-6-) methoxyquinolalin-2-ylamino) -cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically accble salt thereof. The compound according to claim 1, which is 4- (6,7-dimethoxy-quinoxalin-2-ylamino) -cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug the same, or pharmaceutically accble salt thereof. 45.- The compound according to claim 1, which is (-) - (2trans, 4frans) -4- (6,7-Dimetoxiquinoxalin-2-ylamino) -2-methyl-cyclohexanol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically accble salt thereof. 46. The compound according to claim 1, which is (1S, 2R, 4S, 5R) -5- (6,7-Dimetoxiquinoxalin-2-ylamino) -Bicyclo [2.2.1] -hn- 2- ol, or an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof, or pharmaceutically accble salt thereof. 47.- A pharmaceutical composition characterized in that it comprises a compound according to claim 1, and a pharmaceutically accble carrier. 48. A method for inhibiting the activity of PDGF tyrosine kinase, comprising contacting a compound according to claim 1, with the composition containing a PDGF tyrosine kinase. 49. A method for inhibiting the activity of Lck tyrosine kinase comprising contacting a compound as claimed in claim 1, with a composition containing an Lck tyrosine kinase. 50.- The use of one of a compound according to claim 1, for the manufacture of a medicament for inhibiting cell differentiation proliferation, or mediator release in a patient. 51.- The use of a compound according to claim 1, for preparing a medicament for inhibiting cell proliferation, cell differentiation, or mediator release in a patient. 52. The use according to claim 51, wherein said pathology is restenosis. 53. The use of a compound as claimed in claim 1, for preparing a medicament for treating restenosis in a patient.
54. The use according to claim 53, wherein said medicament is administered to a site of mechanical injury to an arterial wall produced by treatment of an atherosclerotic lesion by angioplasty. 55. The use according to claim 53, wherein the compound as claimed in claim 1, is administered by means of an angioplasty balloon coated with a hydrophilic film saturated with the compound as claimed in claim 1. 56. The use according to claim 53, wherein the compound as claimed in claim 1, is administered by means of a catheter comprising an infusion chamber containing a solution of the compound as claimed in claim 1. The use according to claim 53, wherein the compound as claimed in claim 1, is administered by means of a coating on a stent device, wherein the coating comprises a compound such as which is claimed in claim 1. 58.- The use according to claim 51, wherein the pathology associated with a hyperproliferative disorder is a cancer susce ptible to treatment by inhibition of PDGF tyrosine kinase. 59. The use according to claim 58, wherein the cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma or malignant melanoma.
_ _. ___. "___! £ - i-J-miT
60. - The use of a compound as claimed in claim 1, for preparing a medicament for treating inflammation in a patient. !
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Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US09198720 | 1998-11-24 |
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MXPA01005318A true MXPA01005318A (en) | 2002-05-09 |
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