U.S. patent number RE36,256 [Application Number 08/988,005] was granted by the patent office on 1999-07-20 for bis mono- and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase.
This patent grant is currently assigned to Rhone-Poulenc Rorer Pharmaceuticals, Inc.. Invention is credited to Martin P. Maguire, Michael R. Myers, Paul E. Persons, Alfred P. Spada.
United States Patent |
RE36,256 |
Spada , et al. |
July 20, 1999 |
Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit
EGF and/or PDGF receptor tyrosine kinase
Abstract
This invention relates to bis mono- and/or bicyclic aryl and/or
heteroaryl compounds exhibiting protein tyrosine kinase inhibition
activity. More specifically, it relates to the method of inhibiting
abnormal cell proliferation in a patient suffering from a disorder
characterized by such proliferation comprising the administration
thereto of an EGF and/or PDGF receptor inhibiting effective amount
of said bis mono- and/or bicyclic aryl and/or heteroaryl compound
and to the preparation of said compounds and their use in
pharmaceutical compositions used in this method.
Inventors: |
Spada; Alfred P. (Lansdale,
PA), Myers; Michael R. (Reading, PA), Maguire; Martin
P. (Mont Clare, PA), Persons; Paul E. (King of Prussia,
PA) |
Assignee: |
Rhone-Poulenc Rorer
Pharmaceuticals, Inc. (Collegeville, PA)
|
Family
ID: |
46248895 |
Appl.
No.: |
08/988,005 |
Filed: |
December 10, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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988,515 |
Dec 10, 1992 |
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146,072 |
Nov 8, 1993 |
5409930 |
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PCT/US92/03736 |
May 6, 1992 |
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698,420 |
May 10, 1991 |
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988,515 |
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Reissue of: |
166199 |
Dec 10, 1993 |
05480883 |
Jan 2, 1996 |
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Current U.S.
Class: |
514/249;
514/234.8; 544/353; 544/356; 544/354 |
Current CPC
Class: |
C07D
239/91 (20130101); C07D 403/12 (20130101); C07D
215/50 (20130101); A61K 31/5377 (20130101); C07D
213/30 (20130101); C07D 215/233 (20130101); A61K
31/517 (20130101); C07C 43/2055 (20130101); C07D
241/42 (20130101); C07D 277/64 (20130101); C07D
215/20 (20130101); C07D 215/18 (20130101); C07D
239/88 (20130101); C07D 239/93 (20130101); C07D
265/22 (20130101); C07D 213/64 (20130101); C07D
239/74 (20130101); C07D 241/52 (20130101); C07D
405/04 (20130101); C07C 43/23 (20130101); C07D
471/04 (20130101); C07D 403/04 (20130101); C07D
215/14 (20130101); C07D 239/94 (20130101); C07C
43/225 (20130101); C07D 401/04 (20130101); C07D
409/04 (20130101); C07D 405/12 (20130101) |
Current International
Class: |
A61K
31/535 (20060101); C07D 241/00 (20060101); C07D
241/52 (20060101); C07D 241/54 (20060101); A61K
31/495 (20060101); A61K 031/495 (); A61K 031/535 ();
C07D 241/52 (); C07D 241/54 () |
Field of
Search: |
;544/353,354,356
;514/234.8,249,353 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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9331010 |
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Jan 1993 |
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AU |
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0520722 |
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Dec 1992 |
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EP |
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1543560 |
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Apr 1979 |
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GB |
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9220642 |
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Nov 1992 |
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WO |
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Other References
Tamao et al., "Nickel-Phosphine Complex-Catalyzed . . . ",
Tetrahedron, vol. 38, No. 22, pp. 3347-3354, 1982. .
Yamamoto et al., "General Method for Synthesis of Bipyridines:
Palladium . . . ", Synthesis, pp. 564-565, 1986. .
Yamamoto et al., "Studies on Organometallic Compounds. III.
Reaction of . . . ", Chem. Pharm. Bull., vol. 30, No. 6, pp.
2003-2010, 1982. .
Ishikura et al., "A Simple & Regioselective Preparation of 2-or
3-. . . ", Heterocycles, vol. 23, No. 9, pp. 2375-2386, 1985. .
Stem et al., "Potential-Dependent Surface Chemistry of . . . ", J.
Am. Soc., vol. III. No. 3, pp. 877-891, 1989. .
Yoshina, "Quinoline Derivatives", Chemical Abstracts, vol. 84,
Abstract #164632t, p. 453, 1976. .
Barker et al., "Dehalogenation of 1-Halothienyldi & tetra . . .
", Chemical Abstracts, vol. 103, Abstract #123292z, p. 709, 1985.
.
Epling et al., "Sulfur-Containing 2-Anylquinoline Methanols . . .
", Chemical Abstracts, vol. 108, Abstract #55860j, 704, 1988. .
Beilstein--band EIII/IV 21, p. 2436, 1978. .
Saeed et al., "Preparation of Phenylquinoxaline from .alpha.,
.alpha.-diamino . . . ", J. Heterocyclic Chem., vol. 20, pp.
1739-1740, 1983..
|
Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Bell, Boyd & Lloyd
Parent Case Text
BACKGROUND OF THE INVENTION
.[.This application is a continuation-in-part application of U.S.
Ser. No. 07/988,515 filed Dec. 10, 1992, now abandoned which is a
continuation-in-part application of U.S. Ser. No. 07/698,420, filed
May 10, 1991 now abandoned and a continuation-in-part application
of PCT International Application Ser. No. PCT/US92/03736 filed May
6, 1992..].
.Iadd.This application is a reissue of 08/166,199, filed Dec. 10,
1993, now U.S. Pat. No. 5,480,883, which, in turn, is a
continuation-in-part application of U.S. patent application Ser.
No. 07/988,515, filed Dec. 10, 1992, now abandoned, which, in turn,
is a continuation-in-part application of International Patent
Application No. PCT/US92/03736, filed May 6, 1992, now abandoned,
which, in turn, is a continuation-in-part application of U.S.
patent application Ser. No. 07/698,420, filed May 10, 1991, now
abandoned. This application is also a reissue of 08/166,199, filed
Dec. 10, 1993, now U.S. Pat. No. 5,480,883, which, in turn, is a
continuation-in-part of U.S. patent application Ser. No.
08/146,072, filed Nov. 8, 1993, now U.S. Pat. No. 5,409,930, which
is the National Stage of International Patent Application No.
PCT/US92/03736, filed May 6, 1992, now abandoned, which, in turn,
is a continuation-in-part application of U.S. patent application
Ser. No. 07/698,420, filed May 10, 1991, now abandoned. .Iaddend.
Claims
We claim:
1. A method of inhibiting cell proliferation in a patient suffering
from a disorder characterized by such proliferation comprising
administering to a patient a pharmaceutical composition comprising
an EGF and/or PDGF receptor inhibiting effective amount of a
compound of the formula ##STR80## wherein: Ar II is a substituted
or unsubstituted mono- or bicyclic aryl or heteroaryl ring system
of about 5 to about 12 atoms and where each monocyclic ring may
contain 0 to about 3 hetero atoms, and each bicyclic ring may
contain 0 to about 4 hetero atoms or at least one ring is a
substituted or unsubstituted saturated carbocyclic of about 3 to
about 7 atoms where each monocyclic ring may contain 0 to about 2
hetero atoms and where the hetero atoms are selected from N, O and
S provided said hetero atoms are not vicinal oxygen and/or sulfur
atoms and where the substituents may be located at any appropriate
position of the ring system and are described by R;
X is (CHR.sub.1).sub.0-4 or (CHR.sub.1).sub.m
--Z--(CHR.sub.1).sub.n :
Z is O, NR', S, SO or SO.sub.2 :
m and n are 0-3 and m+n=0-3;
R substitution besides hydrogen independently includes alkyl,
alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, aralkoxy, acyloxy, halo, haloalkyl, nitro, amino,
mono-and di-alkylamino, arylamino, carboxy, carboxyalkyl,
carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl,
aminoalkoxy, amido, mono- and di-alkylamido and
N,N-cycloalkylamido, phenyl, halophenyl, thienyl, halothienyl,
pyridyl, 1H-tetrazolyl or benzoyl;
R and R together may also be keto;
R.sub.1 and R' are hydrogen or alkyl; or
an N-oxide or a pharmaceutically acceptable salt thereof, in
admixture with a pharmaceutically acceptable carrier.
2. A method according to claim 1 where the compound is described
by: ##STR81## wherein Ar II is phenyl, naphthyl, thienyl,
cyclohexyl or cyclopentyl; and
X is a bond, methyl, ethyl, propyl or (CHR.sub.1).sub.m
--Z--(CHR.sub.1).sub.n where Z is O, S, SO, SO.sub.2 or NR', and n
and m are 0-1 and n+m is 0 or 1.
3. A method according to claim 2 comprising administering to said
patient a pharmaceutically effective amount of a pharmaceutical
composition containing, in admixture with a pharmaceutically
acceptable carrier, a compound, or a pharmaceutically acceptable
salt thereof, of the formulae: ##STR82##
4. A method according to claim 3 where said compound is described
by the formula: where:
X is a bond, O, NR', methyl, ethyl or propyl.
5. A method according to claim 3 where said compound is selected
from the formula: ##STR83## where: X is a bond, O, NR', methyl,
ethyl or propyl.
6. A method according to claim 4 where the compound administered is
selected from:
2-phenyl-6,7-dimethylquinoxaline,
2-phenyl-6,7-dichloroquinoxaline,
2-phenyl-6,7-dimethoxyquinoxaline,
2-phenyl-6,7-dimethoxyquinoxaline-4-N-oxide.
2-phenyl-6,7-diethoxyquinoxaline,
2-(4-fluorophenyl)-6,7-diethoxyquinoxaline,
2-(4-fluorophenyl)-6,7-dimethylquinoxaline,
2-(4-fluorophenyl)-6-aminoquinoxaline,
2-(4-fluorophenyl)-6-acetamidoquinoxaline,
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline,
2-phenethyl-6,7-diethoxyquinoxaline,
2-phenyl-6,7-dicarboxyquinoxaline,
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline and
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline-4-N-oxide.
7. A method according to claim 5 where the compound administered is
selected from:
2-(thien-3-yl)-6,7-dimethylquinoxaline,
2-(thien-3-yl)-6,7-dimethoxyquinoxaline,
2-(thien-3-yl)-6,7-diethoxyquinoxaline,
2-(5-chlorothien-2-yl)-6,7-diethoxyquinoxaline,
2-(5-chlorothien-2-yl)-6,7-dimethoxyquinoxaline,
2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline,
2-(thien-2-yl)-6,7-diethoxyquinoxaline,
2-(thien-2-yl)-6,7-dimethoxyquinoxaline and
2-(thien-2-yl)-6,7-dicarboxyquinoxaline.
8. A pharmaceutical composition for inhibiting cell proliferation
comprising an EGF and/or PDGF receptor inhibiting effective amount
of a compound or a pharmaceutically acceptable salt thereof
selected from:
2-(thien-3-yl)-6,7-dimethylquinoxaline;
2-(thien-3-yl)-6,7-dimethoxyquinoxaline;
2-(thien-3-yl)-6,7-diethoxyquinoxaline;
2-(5-chlorothien-2-yl)-6,7-diethoxyquinoxaline;
2-(5-chlorothien-2-yl)-6,7-dimethoxyquinoxaline;
2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline;
2-(thien-2-yl)-6,7-diethoxyquinoxaline;
2-(thien-2-yl)-6.7-dimethoxyquinoxaline;
2-(thien-2-yl)-6,7-dicarboxyquinoxaline;
2-phenyl-6,7-dimethylquinoxaline,
2-phenyl-6,7-dichloroquinoxaline,
2-phenyl-6,7-dimethoxyquinoxaline,
2-phenyl-6,7-dimethoxyquinoxaline-4-N-oxide,
2-phenyl-6,7-diethoxyquinoxaline,
2-(4-fluorophenyl)-6,7-diethoxyquinoxaline,
2-(4-fluorophenyl)-6,7-dimethylquinoxaline,
2-(4-fluorophenyl)-6-aminoquinoxalne,
2-(4-fluorophenyl)-6-acetamidoquinoxaline,
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline,
2-phenethyl-6,7-diethoxyquinoxaline,
2-phenyl-6,7-dicarboxyquinoxaline
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline and
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline4-N-oxide in admixture
with a pharmaceutically acceptable carrier.
9. A compound selected from:
2-phenyl-6,7-dimethylquinoxaline,
2-phenyl-6,7-dichloroquinoxaline,
.[.2-phenyl-6,7-dimethoxyquinoxaline,
2-phenyl-6,7-diethoxyquinoxaline,.].
2-(4-fluorophenyl)-6,7-diethoxyquinoxaline,
2-(4-fluorophenyl)-6,7-dimethylquinoxaline,
2-(4-fluorophenyl)-6-aminoquinoxaline,
2-(4-fluorophenyl)-6-acetamidoquinoxaline,
.[.2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline,.].
2-phenethyl-6,7-diethoxyquinoxaline,
2-phenyl-6,7-dicarboxyquinoxaline,
.[.2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline,.]. or
an N-oxide or a pharmaceutically acceptable salt thereof.
10. A compound selected from:
2-(thien-3-yl)quinoxaline,
.[.2-(thien-3-yl)-6,7-dimethylquinoxaline,
2-(thien-3-yl)-6,7,-dimethoxyquinoxaline,
2-(thien-3-yl)-6,7,-diethoxyquinoxaline,.].
2-(5-chlorothien-3-yl)-6,7,-diethoxyquinoxaline,
2-(5-chlorothien-3-yl)-6,7,-dimethoxyquinoxaline,
2-(5-fluorothien-3-yl)-6,7,-diethoxyquinoxaline,
2-(thien-2-yl)-6,7,-diethoxyquinoxaline,
2-(thien-2-yl)-6,7,-dimethoxyquinoxaline,
2-(thien-2-yl)-6,7-dicarboxyquinoxaline or
an N-oxide or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 9 which is
2-phenyl-6,7-dimethylquinoxaline or a pharmaceutically acceptable
salt thereof.
12. A compound according to claim 10 which is
2-(thien-2-yl)-6,7-diethoxyquinoxaline or a pharmaceutically
acceptable salt thereof.
13. A compound according to claim 10 which is
2-(thien-2-yl)-6,7dimethoxyquinoxaline or a pharmaceutically
acceptable salt thereof.
14. A compound according to claim 10 which is
2-(thien-3-yl)quinoxaline or a pharmaceutically acceptable salt
thereof.
15. A compound according to claim 9, which is
2-(4-fluorophenyl)-6,7-diethoxyquinoxaline or a pharmaceutically
acceptable salt thereof.
16. A compound according to claim 9 which is
2-(4-fluorophenyl)-6,7-dimethoxyquinoxaline or a pharmaceutically
acceptable salt thereof.
17. A compound according to claim 9 which is
2-(4-fluorophenyl)-6-acetamidoquinoxaline or a pharmaceutically
acceptable salt thereof.
18. A compound according to claim 9 which is
2-phenethyl-6,7-diethoxyquinoxaline or a pharmaceutically
acceptable salt thereof.
19. A compound according to claim 9 which is
2-phenyl-6,7-dichloroquinoxaline or a pharmaceutically acceptable
salt thereof.
20. A compound according to claim 10 which is
2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline or a
pharmaceutically acceptable salt thereof. ##STR84##
Description
FIELD OF THE INVENTION
This invention relates to the modulation and/or inhibition of cell
signaling, cell proliferation, cell inflammatory response, the
control of abnormal cell growth and cell reproduction. More
specifically, this invention relates to the use of bis mono- and/or
bicyclic aryl and/or heteroaryl compounds in inhibiting cell
proliferation, including compounds which are useful protein
tyrosine kinase (PTK) inhibitors.
Normal cellular reproduction is believed to be triggered by the
exposure of the cellular substrate to one or more growth factors,
examples of which are insulin, epidermal growth factor (EGF) and
platelet-derived growth factor (PDGF). Such growth factor receptors
are imbedded in and penetrate through the cellular membrane. The
inhibition of cellular reproduction is believed to occur when a
growth factor binds to the corresponding receptor on the external
surface of the cellular membrane. This growth factor-receptor
binding alters the chemical characteristics of that portion of the
receptor which exists within the cell and which functions as an
enzyme to catalyze phosphorylation of either an intracellular
substrate or the receptor itself, the latter being referred to as
autophosphorylation. Examples of such phosphorylation enzymes
include tyrosine kinases, which catalyze phosphorylation of
tyrosine amino acid residues of substrate proteins.
Many disease states that characterized by the uncontrolled
reproduction of cells. These disease states involve a variety of
cell types and include disorders such as leukemia, cancer,
psoriasis, inflammatory disease, bone diseases, atherosclerosis and
restenosis occuring subsequent to angioplastic procedures. This
inhibition of tyrosine kinase is believed to have utility in the
control of uncontrolled cellular reproduction, i.e., cellular
proliferative disorders.
Initiation of autophosphorylation, i.e., phosphorylation of the
growth factor receptor itself, and of the phosphorylation of a host
of intracellular substrates are some of the biochemical events
which are involved in mediator release mitogenesis and cell
proliferation. Autophosphorylation of the insulin receptor and
phosphorylation of substrate proteins by other receptors are the
earliest identifiable biochemical hormonal responses.
Elimination of the protein tyrosine kinase (PTK) activity of the
insulin receptor and of the epidermal growth factor (EGF) receptor
by site-directed mutagenesis of the cellular genetic material which
is responsible for generation of insulin and EGF results in the
complete elimination of the receptor's biological activity. This is
not particularly desirable because insulin is needed by the body to
perform other biological functions which are not related to cell
proliferation. Accordingly, compounds which inhibit the PTK portion
of the EGF and/or PDGF receptor at concentrations less than the
concentrations needed to inhibit the PTK portion of the insulin
receptor could provide valuable agents for selective treatment of
cell proliferation disorders.
REPORTED DEVELOPMENTS
It has been reported that the most potent inhibitors of EGF
receptors Inhibit EGF-induced proliferation of A431/clone 15 cells
with little or no effect on the proliferation of such cells when
induced by other growth factors. It has been reported also that
erbstatin inhibits the autophosphorylation of the EGF receptor in
membranes of A431 cells. Higher concentrations of erbstatin are
required to inhibit cyclic adenosine 3',5'-monophosphate
(cAMP)-dependent protein kinase.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a
method of inhibiting abnormal cell proliferation in a patient
suffering from a disorder characterized by such proliferation
comprising the administration to a patient of an EGF and/or PDGF
receptor inhibiting effective amount of a bis mono- and/or bicyclic
aryl compound exhibiting protein tyrosine kinase inhibition
activity wherein each aryl group is a ring system containing 0-4
hetero atoms, said compound being optionally substituted or
polysubstituted.
Another aspect of the present invention relates to pharmaceutical
compositions comprising, in admixture with a pharmaceutically
acceptable carrier, a pharmaceutically effective amount of a
compound of the aforementioned type. Another aspect of this
invention comprises compounds useful in the practice of the present
method.
With respect to the method aspects of this invention, the compounds
described by Formula I below constitute a class of the
aforementioned bis mono- and/or bicyclic aryl, heteroaryl,
carbocyclic or heterocarbocyclic compounds for use in the practice
of the present invention: ##STR1## where:
Ar I and Ar II are independently a substituted or unsubstituted
mono- or bicyclic ring, said rings optionally substituted with 0 to
about 3 R groups; and
X is (CHR.sub.1).sub.0-4 or (CHR.sub.1).sub.m
--Z--(CHR.sub.1).sub.n where Z is O, NR', S, SO or SO.sub.2, m and
n are 0-3 and m+n=0-3 and R.sub.1 and R' are independently hydrogen
or alkyl; or a pharmaceutically acceptable salt thereof.
Preferably, AR I is a substituted or unsubstituted mono- or
bicyclic aryl or heteroaryl ring system of about 5 to about 12
atoms and where each monocyclic ring may contain 0 to about 3
hetero atoms, and each bicyclic ring may contain 0 to about 4
hetero atoms selected from N, O and S provided said hetero atoms
are not vicinal oxygen and/or sulfur atoms and where the
substituents may be located at any appropriate position of the ring
system and are described by R.;
Ar II may be as described for Ar I or at least one ring is a
substituted or unsubstituted saturated carbocyclic of about 3 to
about 7 atoms where each monocyclic ring may contain 0 to about 2
hetero atoms, and each bicyclic ring may contain 0 to about 4
hetero atoms selected from N, O and S provided said hetero atoms
are not vicinal oxygen and/or sulfur atoms and where the
substituents may be located at any appropriate position of the ring
system and are described by R.
Preferred Ar I and Ar II monocyclic aryl or heteroaryl rings
include substituted or unsubstituted benzene, pyrrole, thiophene,
furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine,
2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine,
isothiazole, isoxazole, s-triazine, oxazole and tetrazole.
Preferred Ar II carbomonocyclic rings include substituted and
unsubstituted cycloalkanes such as cyclopentane, cyclohexane,
cycloheptane and partially unsubstituted cycloalkanes such as
cyclopent-1-ene and heteromonocyclic rings such as piperdine,
piperazine, morpholine and pyrrolidine.
Preferred Ar I and Ar II bicyclic rings include substituted and
unsubstituted bicyclic aryl and heteroaryl rings such as
naphthalene, naphthyridine, benzofuran, benzothiophene, indole,
1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole,
benzoxazole, purine, coumarin, chromone, quinoline, isoquinoline,
benzimidazole, quinazoline, pyrido[2,3-b]pyrazine,
pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine,
pyrido[3,4-b]-pyridine, pteridine, 2(1H)-quinolone, 1
(2H)-isoquinolone, 1,4-benzisoxazine, benzothiazole, quinoxaline,
quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide,
quinazoline-N-oxide, benzoxazine, phthalazine, or cinnoline.
Preferred Ar II carbobicyclic rings include substituted and
unsubstituted bicycloalkanes such as tetralin, decaline and
adamantane and preferred heterobicyclic rings such as
imidazolidine, chroman, indoline and quinuclidine
Preferred R substituents other than hydrogen include alkyl,
alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, aralkoxy, acyloxy, halo, haloalkyl, nitro, amino,
mono-and di-alkylamino, acylamino, carboxy, carboxyalkyl,
carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl,
aminoalkoxy, amido, mono- and di-alkylamido and
N,N-cycloalkylamido, phenyl, or benzoyl; and R and R together may
also form a ketone group.
Preferred X moieties are (CHR.sub.1).sub.0-2, CH.sub.2
--Z--CH.sub.2 or Z--CH.sub.2, where Z is O, NR' or S;
A special embodiment of this invention includes those compounds
where one of Ar I or Ar II is an azidophenyl moiety.
A further special embodiment of this invention includes those
compounds where Ar II is cycloalkyl. Preferred group include
cyclopentyl, cyclohexyl and cycloheptyl.
As employed above and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
"Monocyclic aryl" means a carbocyclic and/or heterocyclic aromatic
ring. Preferred rings include phenyl, thienyl, pyridyl,
2(1H)-pyridonyl, 4(1H)-pyridonyl, furyl, pyrimidinyl, imidazolyl,
thiazolyl, oxazolyl and tetrazolyl.
"Bicyclic aryl" means a bicyclic ring system composed of two fused
carbocyclic and/or heterocyclic aromatic rings. Preferred rings
include naphthyl, indolyl, benzothienyl, benzofuranyl, quinolinyl,
chromonyl, 1 (2H)-isoquinolonyl, isoquinolinyl, benzimidazolyl,
benzothiazolyl, quinoxalinyl, naphthyridinyl, cinnolinyl,
phthalazinyl, pyrido[2,3-b]pyrazine, pyrido[3,4b]pyrazine,
pyrido[3,2-c]pyridazine, pyrido[3,4-b]-pyridine, pteridine, and
quinazolinyl.
"Alkyl" means a saturated aliphatic hydrocarbon, either branched-
or straight-chained. Preferred alkyl is "loweralkyl" having about 1
to about 6 carbon atoms. Examples of alkyl include methyl, ethyl,
n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.
"Alkoxy" refers to an alkyl-O-group. Preferred alkoxy groups
include methoxy, ethoxy, propoxy and butoxy.
"Aryloxy" refers to an aryl-O-group. The preferred aryloxy group is
phenoxy.
"Aralkyl" means an alkyl group substituted by an aryl radical. The
preferred aralkyl groups are benzyl or phenethyl.
The preferred aralkoxy groups are benzyloxy and phenethoxy.
The preferred acyloxy groups are acetoxy and benzyloxy;
"Halo" means halogen. Preferred halogens include chloride, bromide
and fluoride.
The preferred haloalkyl group is trifluoromethyl.
The more preferred compounds of this invention include those
compounds of Formula I where Ar I and Ar II are independently
phenyl, naphthyl, 2(1H)-pyridonyl, pyridyl, quinolinyl, thienyl, 1
(2H)-isoquinolonyl, indolyl, napthyridenyl, pyrido[2,3-b]pyrazine,
pyrido[3,4-b]pyrazine, pyrido [3,2-c]pyridazine,
pyrido[3,4-b]-pyridine, pteridine, benzothiazolyl, quinoxalinyl,
benzimidazolyl, quinolinyl-N-oxide, isoquinolinyl-N-oxide,
quinazolinyl, quinoxalinyl-N-oxide, quinazolinyl-N-oxide,
benzoxazinyl, phthalazinyl, or cinnolinyl; and R is hydrogen,
alkyl, alkoxy, hydroxy, halo or trifluoromethyl.
More specifically the compounds described by this invention are
shown by the following representative subgeneric formulae Ia-Iw:
##STR2##
It should be understood that the R groups which are substituted in
the above formulae Ia-Iw are located at any suitable and compatible
position of each of the rings of the bicyclic system.
A special embodiment of this invention includes those compounds of
the above formulae Ia-Iw where Ar II is thienyl, phenyl, naphthyl,
pyridyl, quinolinyl, indolyl, furanyl, imidazolyl, 2(1H)-pyridonyl,
1 (2H)-isoquinolonyl, thiazolyl and cycloalkyl, Phenyl, thienyl
naphthyl,or cycloalkyl are preferred.
A further special embodiment of this invention includes those
compounds which are most preferred. These are described by the
following formulae: ##STR3## wherein
Ar II is phenyl, naphthyl, thienyl, cyclohexyl or cyclopentyl;
and
X is a bond, methyl, ethyl, propyl or (CHR.sub.1).sub.m
--Z--(CHR.sub.1).sub.n where Z is O, NR', and n and m are 0-1 and
n+m is 0 or 1.
The preferred classes of compounds include: ##STR4##
Compounds within the scope of this invention inhibit the growth
factor induced autophosphorylation of PDGF and/or EGF receptors. It
is believed that therapeutically useful PTK inhibiting compounds
should not have appreciable activity as inhibitors of serine or
threonine kinase systems. In addition these compounds should
inhibit growth factor-induced cell proliferation. Compounds meeting
these criteria are of considerable value and are particularly
useful in the practice of the present invention. Compounds
exhibiting selectivity for either of the above receptors are
described herein.
The most preferred compounds are described where R is hydroxy,
methoxy, ethoxy, chloro, bromo, fluoro or trifluoromethyl.
It is intended that the N-oxides of the above-described
N-heteroaryl rings are encompassed within the scope of this
invention.
The compounds of this invention may be useful in the form of the
free base, in the form of salts and as a hydrate. All forms are
within the scope of the invention. Acid addition salts may be
formed and are simply a more convenient form for use; and in
practice, use of the salt form inherently amounts to use of the
base form. The acids which can be used to prepare the acid addition
salts include preferably those which produce, when combined with
the free base, pharmaceutically acceptable salts, that is, salts
whose anions are non-toxic to the animal organism in pharmaceutical
doses of the salts, so that the beneficial properties inherent in
the free base are not vitiated by side effects ascribable to the
anions. Although pharmaceutically acceptable salts of said basic
compound 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 product as, for example, when the
salt is formed only for purposes of purification and
identification, or when it is used as an intermediate in preparing
a pharmaceutically acceptable salt by ion exchange procedures.
Pharmaceutically acceptable salts within the scope of the invention
include 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, citric acid, lactic
acid, tartaric acid, malonic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid, quinic acid, and the like.
The corresponding acid addition salts comprise the following:
hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate,
lactate, tartrate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and
quinate, respectively.
The acid addition salts of the compounds of this invention are
prepared either by dissolving the free base in aqueous or
aqueous-alcohol solution or other suitable solvents containing the
appropriate acid and isolating the salt by evaporating the
solution, or by reacting the free base and acid in an organic
solvent, in which case the salt separates directly or can be
obtained by concentration of the solution.
The compounds of this invention may be prepared by employing
procedures known in the literature starting from known compounds or
readily preparable intermediates. Exemplary general procedures
follow.
In general the compounds useful for the method of inhibiting cell
proliferation may be prepared by the coupling reaction of a
palladium catalyzed aryl or heteroaryistannane with an aryl or
heteroarylhalide or triflate. ##STR5## where X is halogen or
triflate and Y is trialkylstannane and R and n are as previously
described.
Preparation of aryl or heteroaryl substituted quinolines may be
prepared as follows. ##STR6##
The triflate may be prepared from the corresponding alcohol with
triflic anhydride (trifluoromethanesulfonic anhydride) in pyridine
##STR7##
Other triflates suitable for coupling with the aryl and
heteroarylstannanes may be prepared in a similar manner.
##STR8##
Triflates may also be prepared from 2(1 H) or 4(1 H) quinolones as
shown by the following. ##STR9##
The triflimide such as used in the above reaction may also be used
to prepare compounds having a particular substitution such as the
following compound. ##STR10##
The aryl and heteroarylstannanes may be prepared from the
corresponding halide (preferably bromide or iodide) by conversion
to the aryllithium (by reaction with t-butyl-lithium at decreased
temperatures, preferably about -78.degree. C. followed by reaction
with a halotrialkylstannane. The following reaction schemes give a
representative list of stannanes prepared and the reaction
conditions involved. ##STR11##
Further methods which may be employed in the preparation of
stannanes of this invention include the following.
(1.) by the action of trimethyltin sodium on aryl halides as
described in Chem. Pharm. Bull. 1982, 30, 1731-1737: ##STR12## (2.)
by heteroatom directed aromatic lithiation process: ##STR13## (3.)
by halogen-lithium exchange: ##STR14##
The following are representative coupling reactions which show the
preparation of compounds used for the inhibition of cell
proliferation ##STR15##
Of course various methods may be employed depending on the
reactants involved. Thus, for example, in order to prepare
##STR16## the following methods may be used: ##STR17##
When it is desired that the final product include a 2-(1H) pyridone
or 4-(1H) pyridone ring then it is convenient to carry out the
condensation on the 2- or 4-alkoxy pyridine followed by selective
dealkylation. This can be seen by the following representative
scheme. ##STR18##
More specifically preparation of aryl or heteroaryl substituted
2(1H)-pyridones may be found in U.S. Pat. Nos. 3,715,358;
3,718,743; 4,465,686 and 4,599,423. Substituted phenyl pyridine
preparation may be found in J. Am. Chem. Soc. 111, 877-891
(1989).
Thus it will be a matter of condensing two rings as shown above
under the methods described and/or in the art in order to obtain
the compounds useful in the practice of inhibition of cell
proliferation of this invention. The following representative
compounds are prepared as shown below:
5-(2,4,5-trihydroxyphenyl)-2(1H)-pyridone,
5-(1,4-dihydroxynaphth-2-yl)-2(1H)-pyridone,
5-(2,5-dihydroxyphenyl)-2(1H)-pyridone,
5-(2,5-dihydroxy-4-t-butylphenyl)-2(1H)-pyridone,
3-(2,5-dihydroxyphenyl)-4(1H)-pyridone,
3-(2,5-dihydroxy-4-t-butylphenyl)-4(1H)-pyridone,
3-(thien-3-yl)-6,7-dimethoxyquinoline,
3-(pyrid-3-yl)indole,
2-(2,5-dihydroxy-4t-butylphenyl)pyridine and
4-(2,5-dihydroxyphenyl)-1(2H)-isoquinolone. ##STR19##
The compounds of the present invention may be prepared by the
following representative examples.
EXAMPLE 1
2-methoxy-5-trimethylstannylpyridine
A solution of 1.74 g (9.26 mmol) of 2-methoxy-5-bromopyridine, 3.84
mL (6.07 g; 18.5 mmol) of hexamethylditin and 516 mg (0.446 mmol)
of Pd (PPh3)4 in mL of dry toluene is flushed thoroughly with
nitrogen and heated to 90.degree. C. for 4 hours. The mixture is
then evaporated and chromatographed on silica gel (eluting with
hexane and then with 95:5 hexane/ethyl acetate) to give
2-methoxy-5-trimethylstannylpyridine as a colorless oil which is
used directly in the next step.
EXAMPLE 2
When the procedure of Example 1 is followed and
2-methoxy-5-bromopyridine is replaced by the compounds of Table I
below, then the compounds of Table II below are prepared. (Methods
outlined on pages 14 and may also be used.)
TABLE I
2-methoxyphenyl bromide
3-methoxyphenyl bromide
4-methoxyphenyl bromide
2,3-dimethoxyphenyl bromide
2,4-dimethoxyphenyl bromide
2,5-dimethoxyphenyl bromide
2,6-dimethoxyphenyl bromide
3,4-dimethoxyphenyl bromide
3,5-dimethoxyphenyl bromide
3,4,5-trimethoxyphenyl bromide
2,3,4-trimethoxyphenyl bromide
2,5-dimethoxy-4-t-butylphenyl bromide
2,5-dimethoxy-4-phenylphenyl bromide
2,4dimethylphenyl bromide
2,5-dimethylphenyl bromide
2-methyl-5-methoxyphenyl bromide
4-chlorophenyl bromide
4-fluorophenyl bromide
2,5-dichlorophenyl bromide
3,4-dichlorophenyl bromide
4-dimethylaminophenyl bromide
4-acetylaminophenyl bromide
4-(N,N-dimethylaminocarbonyl)phenyl bromide
4-t-butoxycarbonylphenyl bromide
4-(pyrrolidinocarbonyl)phenyl bromide
3,5-bis(trifluoromethyl)phenyl bromide
4-bromobiphenyl
2-bromopyridine
3-bromopyridine
4-bromopyridine
2-methoxy-5-bromopyridine
4-methoxy-5-bromopyridine
6-methoxy-5-bromopyridine
2,3-dimethoxy-5-bromopyridine
2,4-dimethoxy-5-bromopyridine
2-acetylamino-5-bromopyridine
2-bromothiophene
3-bromothiophene
2-methoxy-3-bromothiophene
2-methoxy-4-bromothiophene
2-methoxy-5-bromothiophene
3-methoxy-5-bromothiophene
4-methoxy-2-bromothiophene
3-bromofuran
t-butyl 5-bromo-2-furoate
2-bromothiazole
2-bromooxazole
1-methyl-3-bromopyrazole
5-bromopyrimidine
2-bromopyrazine
4-bromopyridazine
'-bromonaphtbalene
2-bromonaphthalene
2-bromo-6-methoxynaphthalene
2-bromo-6,7-dimethoxynaphthalene
2-bromoquinoline
3-bromoquinoline
4-bromoquinoline
5-bromoquinoline
6-bromoquinoline
6,7-dimethoxy-3-bromoquinoline
6-methoxy-3-bromoquinoline
7-methoxy-3-bromoquinoline
7,8-dimethoxy-3-bromoquinoline
6,7-dichloro-3-bromoquinoline
4-bromoisoquinoline
3-bromoisoquinolihne
1-bromoisoquinoline
6,7-dimethoxy-3-bromoisoquinoline
N-methanesulfonyl-3-bromoindole
N-methanesulfonyl-5-brqmoindole
N-methanesulfonyl-3-bromo-5-methoxyindole
N-methanesulfonyl-3-bromo-5-chloroindole
2-bromobenzothiophene
3-bromobenzothiophene
8-bromopurine
7-methyl-2-bromopurine
3-bromopyrido-[3,4-b]-pyridine
TABLE II
2-methoxyphenyl trimethylstannane
3-methoxyphenyl trimethylstannane
4-methoxyphenyl trimethylstannane
2,3-dimethoxyphenyl trimethylstannane
2,4-dimethoxyphenyl trimethylstannane
2,5-dimethoxyphenyl trimethylstannane
2,6-dimethoxyphenyl trimethylstannane
3,4dimethoxyphenyl trimethylstannane
3,5-dimethoxyphenyl trimethylstannane
3,4,5-trimethoxyphenyl trimethylstannane
2,3,4-trimethoxyphenyl trimethylstannane
2,5-dimethoxy-4-t-butylphenyl trimethylstannane
2,5-dimethoxyphenylphenyl trimethylstannane
2,4-dimethylphenyl trimethylstannane
2,5-dimethylphenyl trimethylstannane
2-methyl-5-methoxyphenyl trimethylstannane
4-chlorophenyl trimethylstannane
4-fluorophenyl trimethylstannane
2,5-dichlorophenyl trimethylstannane
3,4-dichlorophenyl trimethylstannane
4-dimethylaminophenyl trimethylstannane
4-acetylaminophenyl trimethylstannane
4-(N,N-dimethylaminocarbonyl)phenyl trimethylstannane
4-t-butoxycarbonylphenyl trimethylstannane
4-(pyrrolidinocarbonyl)phenyl trimethylstannane
3,5-bis(trifluoromethyl)phenyl trimethylstannane
4-trimethylstannylbiphenyl
2-trimethylstannylpyridine
3-trimethylstannylpyridine
4-trimethylstannylpyridine
2-methoxy-5-trimethylstannylpyridine
4-methoxy-5-trimethylstannylpyridine
6-methoxy-5-trimethylstannylpyridine
2,3-dimethoxy-5-trimethylstannylpyridine
2,4-dimethoxy-5-trimethylstannylpyridine
2-acetylamino-5-trimethylstannylpyridine
2-trimethylstannylthiophene
3-trimethylstannylthiophene
2-methoxy-3-trimethylstannylthiophene
2-methoxy-4-trimethylstannylthiophene
2-methoxy-5-trimethylstannylthiophene
3-methoxy-5-trimethylstannylthiophene
4-methoxy-2-trimethylstannylthiophene
3-trimethylstannylfuran
t-butyl 5-trimethylstannyl-2-furoate
2-trimethylstannylthiazole
2-trimethylstannyloxazole
1-methyl-3-trimethylstannylpyrazole
5-trimethylstannylpyrmidine
2-trimethylstannylpyrazine
4-trimethylstannylpyridazine
1-trimethylstannylnaphthalene
2-trimethylstannylnaphthalene
2-trimethylstannyl-6-methoxynaphthalene
2-trimethylstannyl-6,7-dimethoxynaphthalene
2-trimethylstannylquinoline
3-trimethylstannylquinoline
4-trimethylstannylquinoline
5-trimethylstannylquinoline
6-trimethylstannylquinoline
6,7-dimethoxy-3-trimethylstannylquinoline
6-methoxy-3-trimethylstannylquinoline
7-methoxy-3-trimethylstannylquinoline
7,8-dimethoxy-3-trimethylstannylquinoline
6,7-dichloro-3-trimethylstannylquinoline
4-trimethylstannylisoquinoline
3-trimethylstannylisoquinoline
1-trimethylstannylisoquinoline
6,7-dimethoxy-3-trimethylstannylisoquinoline
N-methanesulfonyl-3-trimethylstannylindole
N-methanesulfonyl-5-trimethylstannylindole
N-methanesulfonyl-3-trimethylstannyl-5-methoxyindole
N-methanesulfonyl-3-trimethylstannyl-5-choroindole
2-trimethylstannylbenzothiophene
3-trimethylstannylbenzothiophene
8-trimethylstannylpurine
7-methyl-2-trimethylstannylpurine
3-trimethylstannylpyrido-[3,4-b]-pyridine
EXAMPLE 3
6,7-dimethoxyquinolin-3-yl trifluoromethanesulfonate,
A solution of 1.84 g (8.98 mmol) of
3-hydroxy-6,7-dimethoxyquinoline in mL of dry pyridine is cooled to
0.degree. C. and 3.20 mL (5.38 g; 19.1 mmol) of
trifluoromethanesulfonic anhydride is added via syringe. The
solution is allowed to warm to 22.degree. C. and stirred for 4
hours. The solution is then partitioned between ethyl acetate (150
mL) and water (100 mL). The aqueous layer is back extracted with
ethyl acetate (100 mL) and the combined organics dried (Na.sub.2
SO.sub.4) and evaporated. The resulting residue is chromatographed
on silica gel (eluting with chloroform) to give a white solid which
is recrystallized from hexane to give 6,7-dimethoxyquinolin- 3-yl
trifluoromethane-sulfonate. mp 82.5.degree.-85.degree. C.)
EXAMPLE 4
When the procedure of Example 3 is followed and
3-hydroxy-6,7-dimethoxyquinoline is replaced by the compounds of
Table III below, then the products of Table IV are prepared
TABLE III
phenol
2-methoxyphenol
3-methoxyphenol
4-methoxyphenol
2,3-dimethoxyphenol
3,4-dimethoxyphenol
3,5-dimethoxyphenol
3,4,5-trimethoxyphenol
2-chlorophenol
3-chlorophenol
4-chlorophenol
4-bromophenol
2,4-dichlorophenol
2,5-dichlorophenol
3,5-dichlorophenol
3,5-bis(trifluoromethyl)phenol
3-dimethylaminophenol
o-cresol
m-cresol
p-cresol
.alpha.,.alpha.,.alpha.-trifluoro-p-cresol
3-ethylphenol
4-tert-butylphenol
2,4-dimethylphenol
2,5-dimethylphenol
3,4-dimethylphenol
4-benzyloxyphenol
4-phenylphenol
2-phenylphenol
2,3,5-trimethyphenol
4-nitrophenol
4-acetylaminophenol
2-bromo-4-methylphenol
3'-hydroxyacetophenone
4'-hydroxyacetophenone
methyl 3-hydroxybenzoate
methyl 4-hydroxy-3-methoxybenzoate
N,N-dimethyl-4-hydroxybenzamide
1-naphthol
2-naphthol
6-methoxy-1-naphthol
6-methoxy-2-naphthol
6,7-dimethoxy-1-naphthol
6,7-dimethoxy-2-naphthol
5,8-dimethoxy-2-naphthol
6-bromo-2-naphthol
2-hydroxyquinoline
2-hydroxy-4-methylquinoline
6,7-dimethoxy-2-hydroxyquinoline
3-hydroxyquinoline
4-hydroxyquinoline
6,7-dimethoxy-4-hydroxyquinoline
7-chloro-4-hydroxyquinoline
1-hydroxyisoquinoline
5-hydroxyisoquinoline
2-hydroxypyridine
3-hydroxypyridine
4-hydroxypyridine
2,3-dimethoxy-5-hydroxypyridine
5-chloro-2-pyridinol
5-chloro-3-pyridinol
3-hydroxypicolinamide
TABLE IV
phenyl trifluoromethane sulfonate
2-methoxyphenyl trifluoromethane sulfonate
3-methoxyphenyl trifluoromethane sulfonate
4-methoxyphenyl trifluoromethane sulfonate
2,3-dimethoxyphenyl trifluoromethane sulfonate
3,4-dimethoxyphenyl trifluoromethane sulfonate
3,5-dimethoxyphenyl trifluoromethane sulfonate
3,4,5-trimethoxyphenyl trifluoromethane sulfonate
2-chlorophenyl trifluoromethane sulfonate
3-chlorophenyl trifluoromethane sulfonate
4-chlorophenyl trifluoromethane sulfonate
4-bromophenol trifluoromethane sulfonate
2,4-dichlorophenyl trifluoromethane sulfonate
2,5-dichlorophenyl trifluoromethane sulfonate
3,5-dichlorophenyl trifluoromethane sulfonate
3,5-bis(trifluoromethyl)phenyl trifluoromethane sulfonate
3-dimethylaminophenyl trifluoromethane sulfonate
o-cresyl trifluoromethane sulfonate
m-cresyl trifluoromethane sulfonate
p-cresyl trifluoromethane sulfonate
.alpha.,.alpha.,.alpha.-trifluoro-p-cresyl trifluoromethane
sulfonate
3-ethylphenyl trifluoromethane sulfonate
4-tert-butylphenyl trifluoromethane sulfonate
2,4dimethylphenyl trifluoromethane sulfonate
2,5-dimethylphenyl trifluoromethane sulfonate
3,4-dimethylphenyl trifluoromethane sulfonate
4-benzyloxyphenyl trifluoromethane sulfonate
2-phenylphenyl trifluoromethane sulfonate
4-phenylphenyl trifluoromethane sulfonate
2,3,5-trimethyphenyl trifluoromethane sulfonate
4-nitrophenyl trifluoromethane sulfonate
4-acetamidophenyl trifluoromethane sulfonate
2-bromo-4-methylphenyl trifluoromethane sulfonate
3-acetylphenyl trifluoromethane sulfonate
4-acetylphenyl trifluoromethane sulfonate
3-methoxycarbonylphenyl trifluoromethane sulfonate
2-methoxy-4-methoxycarbonylphenyl trifluoromethane sulfonate
4-N,N-dimethylaminocarbonylphenyl trifluoromethane sulfonate
naphth-1-yl trifluoromethane sulfonate
naphth-2-yl trifluoromethane sulfonate
6-methoxynaphth-1-yl trifluoromethane sulfonate
6-methoxynaphth-2-yl trifluoromethane sulfonate
6,7-dimethoxynaphth-1-yl trifluoromethane sulfonate
6,7-dimethoxynaphth-2-yl trifluoromethane sulfonate
5,8-dimethoxynaphth-2-yl trifluoromethane sulfonate
6-bromonaphth-2-yl trifluoromethane sulfonate
quinolin-2-yl trifluoromethane sulfonate
4-methylquinolin-2-yl trifluoromethane sulfonate
6,7-dimethoxyquinolin-2-yl trifluoromethane sulfonate
quinolin-2-yl trifluoromethane sulfonate
quinolin-4-yl trifluoromethane sulfonate
6,7-dimethoxyquinolin-4-yl trifluoromethane sulfonate
7-chloroquinolin-4-yl trifluoromethane sulfonate
isoquinolin-1-yl trifluoromethane sulfonate
isoquinolin-5-yl trifluoromethane sulfonate
pyridin-2-yl trifluoromethane sulfonate
pyridin-3-yl trifluoromethane sulfonate
pyridin-4-yl trifluoromethane sulfonate
2,3-dimethoxypyridin-5-yl trifluoromethane sulfonate
5-chloro-2-pyridin-2-yl trifluoromethane sulfonate
5-chloro-3-pyridinyl trifluoromethane sulfonate
picolin-3-amido trifluoromethane sulfonate
EXAMPLE 5
2.5-dimethoxy-4-t-butylphenyl iodide
A stirred solution of 3.00 g (15.5 mmol) of
1,4-dimethoxy-2-t-butylbenzene (obtained by methylation of t-butyl
hydroquinone with sodium hydride and methyl iodide in
tetrahydrofuran) and 2.52 g (21.7 mmol) of
tetramethylethylenediamine in 50 mL of anhydrous ether under
nitrogen is cooled to 0.degree. C. and 8.66 mL (21.7 mmol) of
n-butyllithium (2.5M in hexane) is added over a 5 minute period.
The mixture is warmed to 22.degree. C., stirred for 18 hours and
then cooled back to 0.degree. C. The reaction is quenched with 7.86
g (30.9 mmol) of iodine in 30 mL of tetrahydrofuran and partitioned
between ethyl acetate (200 mL) and 10% NaHSO3 (300 mL). The organic
layer is washed with water (50 mL), brine (50 mL), dried (MgSO4)
and evaporated to give a brown, partially crystalline oil which is
chromatographed on silica gel (eluting with 98:2 hexane/ethyl
acetate) to give crude product which is recrystallized from hexane
to obtain 2,5-dimethoxy-4-t-butylphenyl iodide m p
8.5.degree.-82.5.degree. C.)
EXAMPLE 6
When the procedure of Example 5 is followed and the appropriate
starting material is used, the following compounds of Table V may
be prepared.
TABLE V
2,3-dimethoxyphenyl iodide
2,3,4-trimethoxyphenyl iodide
2,4-dimethoxy-3-t-butylphenyl iodide
4-iodo-1,3-benzodioxole
EXAMPLE 7
5-(3,4-dimethoxyphenyl)-2-methoxypyridine
A solution of 2.00 g (6.64 mmol) of 4-trimethylstannylveratrole,
2.49 g (13.2 mmol) of 2-methoxy-5-bromopyridine and 370 mg (0.332
mmol) of Pd (PPh.sub.3).sub.4 in 30 mL of dry dimethylformamide is
flushed thoroughly with nitrogen and heated to 90.degree. C. for 12
hours. The reaction mixture is partitioned between ethyl acetate
(150 mL) and water (100 mL). The aqueous layer is back extracted
with ethyl acetate (100 mL) and the combined organics are washed
with brine (75 mL), dried (MgSO.sub.4) and evaporated to give a
crude yellow oil. The oil is chromatographed on silica gel (eluting
with 95:5 hexane/ethyl acetate and then with 9:1 hexane/ethyl
acetate) which gives 5-(3,4-dimethoxy-phenyl)-2-methoxypyridine m.p
83.degree.-84.degree. C.)
EXAMPLE 8
When the procedure of Example 7 is followed and
2-methoxy-5-bromopyridine is replaced with the bromo compounds of
Example 2, Table I, then the corresponding products are
obtained.
EXAMPLE 9
When the procedure of Example 7 is followed and
4-trimethylstannylveratrole is replaced by the stannanes of Example
2, Table II, then the corresponding products are obtained.
EXAMPLE 10
When the procedure of Example 7 is followed and
2-methoxy-5-bromopyridine is replaced with the bromo compounds of
Example 2, Table I and 4-trimethylstannylveratrole is replaced by
the stannanes of Example 2, Table II, then the corresponding
products are obtained. A representative list of compounds so
prepared are shown below In Table VI.
TABLE VI
2-(2,3,4-trimethoxyphenyl)pyridine
2,3-dimethoxy-6-(thien-3-yl)naphthaylene
3-(2,3-dimethoxypbenyl)quinoline
3-(benzothien-3-yl)quinoline
4-(phenyl)phenyl-1,4-dimethoxybenzene
2-(2,5-dimethoxyphenyl)naphthaylene
5-(2,5-dimethoxyphenyl)pyrimidine
5-phenyl-1,2,4-trimethoxybenzene
2-methoxy-5-(2,3,5-trimethoxyphenyl)pyridine
2-methoxy-5-(1,4-dimethoxynaphth-2-yl)pyridine
3-(2,5-dimethoxyphenyl)thiophene
2-methoxy-5-(2,5-dimethoxy-4-phenyl)phenylpyridine
3,6-dihydroxy-4-phenylveratrole
4-(2,5-dimethoxyphenyl)veratrole
EXAMPLE 11
3-(2-methoxypyridin-5,yl)-6,7-dimethoxyquinoline
A mixture of 800 mg (2.94 mmol) of
2-methoxy-5-trimethylstannyl-pyridine, mg (2.94 mmol) of
6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82
mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of
Pd(PPh.sub.3)hd in 15 mL of anhydrous dioxane is flushed thoroughly
with nitrogen and refluxed for 6 hours. The mixture is diluted with
ethyl acetate (100 mL), washed with saturated NaHCO.sub.3 (75 mL),
dried (Na.sub.2 SO.sub.4) and evaporated. The resulting residue is
chromatographed on silica gel (eluting with chloroform) to give a
solid material which is recrystallized from ethyl acetate to give
3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline m.p.
170.5.degree.-171.5.degree. C.
EXAMPLE 12
When the procedure of Example 11 is followed and
2-methoxy-5-trimethylstannylpyridine is replaced by the stannanes
of Example 2, Table II, then the corresponding products are
obtained.
EXAMPLE 13
When the procedure of Example 11 is followed and
6,7-dimethoxy-quinolin-3-yl trifluoromethane sulfonate is replaced
by the triflates of Example 4, Table IV, then the corresponding
products are prepared.
EXAMPLE 14
When the procedure of Example 11 is followed and
2-methoxy-5-trimethylstannylpyridine is replaced by the stannanes
of Example 2, Table II, and 6,7-dimethoxyquinolin-3-yl
trifluoromethane sulfonate is replaced by the triflates of Example
4, Table IV, then the corresponding products are prepared. A
representative list of compounds so prepared is shown below in
Table VII.
TABLE VII
3-(thien-3-yl)-6,7-dimethoxyquinoline, mp. 116.degree.-118.degree.
C.
2-methoxy-5-(3,4,5-trimethoxyphenyl)pyridine, m.p.
71.degree.-72.degree. C.
4-(thien-3-yl)-6,7-dimethoxyquinoline, m.p. 134.degree.-135.degree.
C.
2-(thien-3-yl)-6,7-dimethoxyquinoline, 135.5.degree.-138.degree.
C.
3-(quinolin-3-yl)-6,7-dimethoxyquinoline, m.p.
190.5.degree.-191.degree. C.
3-(thien-3-yl)-6,7-dichloroquinoline, m.p.
167.degree.-167.5.degree. C.
3-(thien-3-yl)-7-methoxyquinoline, m.p. 122.degree.-124.degree.
C.
3-(3,4-dichlorophenyl)-6,7-dimethoxyquinoline, m.p.
184.degree.-186.degree. C.
3-(4-methoxyphenyl)-6,7-dimethoxyquinoline, m.p.
162.5.degree.-164.5.degree. C.
3-(naphth-2-yl)-6,7-dimethoxyquinoline, m.p.
162.50.degree.-165.degree. C.
3-(4-phenyl)phenyl-6,7-dimethoxyquinoline, m.p.
143.degree.-145.degree. C.
3-(thien-2-yl)-6,7-dimethoxyquinoline, m.p.
122.5.degree.-124.degree. C.
3-(5-methoxythien-2-yl)-6,7-dimethoxyquinoline
(111.degree.-113.degree. C.
4-phenyl-6,7-dimethoxyquinoline, m.p. 124.degree.-125.degree.
C.
3-(5-chlorothien-2-yl)-6,7-dimethoxyquinoline
(131.5.degree.-132.degree. C.
3-(furan-3-yl)quinoline, m.p. 87.degree.-90.degree. C.
5-(2,5-dimethoxyphenyl)pyridine, m.p. 92.5.degree.-94.5.degree.
C.
5-(2,5-dimethoxyphenyl)-2-methoxypyridine (oil)
EXAMPLE 15
2.methoxy-5-[(2,5-dimethoxy-4-t-butyl)phenyl]pyridine
When the procedure of Example 7 is followed and
4-trimethylstannylveratrole is replaced with
2-methoxy-5-trimethylstannylpyridine and 2-methoxy-5-bromopyridine
is replaced with 2,5-dimethoxy-4-t-butylphenyl iodide from Example
5, then the compound prepared is
2-methoxy-5-[(2,5-dimethoxy-4-t-butyl)phenyl] pyridine as an
oil.
EXAMPLE 16
5[(2,5-dimethoxy-4-t-butyl)phenyl]pyridine
When 2-methoxy-5-trimethylstannylpyridine in Example 15 is replaced
by 5-trimethylstannylpyridine, the compound prepared is
5-[(2,5-dimethoxy-4-t-butyl)phenyl] pyridine m.p.
92.5.degree.-94.5.degree. C.
EXAMPLE 17
5-[(2,5-dihydroxy-4t-butyl)phenyl]-2(1H)-pyridone
A mixture of 252 mg (0.837 mmol) of
2-methoxy-5-[(2,5-dimethoxy-4-t-butyl)-phenyl] pyridine and 7.0 g
of pyridine hydrochloride is heated to 210.degree. C. for 1 hour,
cooled and diluted with 60 mL of water. The mixture is cooled lo
0.degree. C., filtered, and recrystallized from methanol to obtain
5-[(2,5-dihydroxy4-t-butyl)-phenyl]-2(1H)-pyridone [m.p.
270.degree.-5.degree. C.(softens)>300.degree. C.(dec)].
EXAMPLE 18
5-[(2,5-dihydroxy-4-t-butyl)phenyl)pyridine
When the procedure of Example 17 is followed and
2-methoxy-5-[(2,5-dimethoxy-4-t-butyl)phenyl]pyridine is replaced
by 5-[2,5-dimethoxy-4-t-butyl)phenyl] pyridine, the product
obtained is 5-[(2,5-dihydroxy-4-t-butyl)phenyl] pyridine m.p.
202.degree.-204.degree. C.
EXAMPLE 19
5-(2,5-dihydroxyphenyl)-2(1H)-pyridone
A solution of 502 mg (2.05 mmol) of
2-methoxy-5-(2,5-dimethoxyphenyl)pyridine in 20 mL of 48%
hydrobromic acid (aqueous) is refluxed for 6 hours, cooled to ca.
25.degree. C. and diluted with 150 mL of water. The mixture is
neutralized with solid NaHCO.sub.3, cooled to 0.degree. C. and the
resulting solid product collected by filtration. The solid is
washed well with water, collected by centrifugation, then further
purified by recrystalization in methanol to obtain
5-(2,5-dihydroxyphenyl)-2(1H)-pyridone m.p. 303.degree.-306.degree.
C. dec).
EXAMPLE 20
When the procedure of Example 19 is followed and
2-methoxy-5-(2,5dimethoxyphenyl)pyridine is replaced by
2-methoxy-5-(3,4-dimethoxyphenyl)pyridine,
2-methoxy-5-(3,4,5-trimethoxyphenyl)pyridine or
5-(2,5-dimethoxyphenyl)pyridine, then the compounds prepared are
5-(3,4-dihydroxy-phenyl)-2(1H)-pyridone m.p.
307.degree.-310.degree. C.);
5-(3,4,5-trihydroxyphenyl)-2(1H)-pyridone m.p. 300.degree. C.) and
5-(2,5-dihydroxyphenyl)pyridine m.p. 216.degree.-218.degree.
C.).
EXAMPLE 21
When the procedure of Example 17 is followed and
2-methoxy-5-[(2,5-dimethoxy-4-t-butyl)phenyl]pyridine is replaced
by 2-methoxy-5-(6,7-dimethoxy-quinolin-3-yl)pyridine and the
reaction is carried out at 160.degree. C. for 5 minutes, then the
product prepared is 5-(6,7-dimethoxyquinolin-3-yl)-2(1H)-pyridone
m.p. 259.degree.-261.degree. C.).
EXAMPLE 22
3-(6.7-dimethoxyquinolin-3-yl)pyridine
A solution of 600 mg (3.37 mmol) of methyl
N-2-(pyrid-3-yl)vinylcarbamate in 10 mL of 6N H.sub.2 SO.sub.4 is
refluxed for 10 minutes, cooled to 0.degree. C. and basified to pH
11 with 50% NaOH. A solution of 400 mg (2.03 mmol) of
2-amino-4,5-dimethoxybenzaldehyde is immediately added and the
mixture refluxed for 2.5 hours, cooled to 22.degree. C. and
partitioned between ether (150 mL) and water (100 mL). The aqueous
layer is back extracted with chloroform and the combined organics
are dried (MgSO.sub.4) and evaporated to obtain an oil which is
recrystallized from hexane/ethyl acetate twice to give
3-(6,7-dimethoxyquinolin-3-yl)pyridine m.p. 131.degree.-132.degree.
C.).
EXAMPLE 23
3-(indol-3-yl)-6.7-dimethoxyquinoline
A solution of 800 mg (5.03 mmol) of indol-3-ylacetaldehyde
(obtained from diisobutylaluminum hydride reduction of the ester
and used immediately) and 800 mg (4.42 mmol) of
2-amino-4,5-dimethoxybenzaldehyde in 15 mL of ethanol is flushed
thoroughly with nitrogen, treated with 0.5 mL of 1M NaOH and heated
to 80.degree. C. for 3 hours. The mixture is cooled to 22.degree.
C. and partitioned between chloroform (150 ml) and brine (100 mL).
The organic layer is dried (MgSO.sub.4) and evaporated and the dark
brown residue that results is chromatographed on silica gel
(eluting with 97.5:2.5 chloroform/methanol). The product obtained
is further chromatographed on silica gel (eluting with 98:2 ethyl
acetate/methanol) and the resulting product is recrystallized from
ethyl acetate to give 3-(indol-3-yl)-6,7-dimethoxyquinoline m.p.
204.degree.-206.degree. C.).
EXAMPLE 24
When the procedure of Example 23 is followed and
2-amino-4,5-dimethoxybenzaldehyde is replaced with
2-aminobenzaldehyde, then the product prepared is
3-(indol-3-yl)quinoline m.p. 173.degree.-175.degree. C.).
EXAMPLE 25
When the procedure of Example 23 is followed and
indol-3-yl-acetaldehyde is replaced by phenylacetaldehyde then the
product prepared is 3-phenyl-6,7-dimethoxyquinoline m.p.
126.5.degree.-128.degree. C.)
EXAMPLE 26
6,7-dimethoxy-4-hydroxy-3-(thien-3-yl)-2(1H)-quinoline
A mixture of (0.632g) 3,4-dimethoxyaniline, (1.00 g) diethyl
thien-3-ylmalonate and (20 ml) diphenyl ether are heated at
approximately 200.degree. C. for 4 hours. The reaction mixture is
extracted with 0. IN NaOH solution and the alkaline solution then
acidified with IN HCl and cooled in an ice water bath. The
precipitate is collected, washed with ether and dried. The solid is
then heated in EtOH, filtered and the filtrate evaporated in vacuo
to give a light brown solid which is triturated with ether,
filtered, and dried to give
6,7-dimethoxy-4-hydroxy-3-(thien-3-yl)-2(1H)quinoline m.p.
300.degree. C. dec.).
EXAMPLE 27
2-(thien-2-yl)-4-carboxy-6,7-dimethoxyquinoline
To a boiling solution of 2-thiophenecarboxaldehyde (1.22 ml),
pyruvic acid (0.904 ml) and 50 ml absolute EtOH is added dropwise a
solution of 3,4-dimethoxyaniline (2.00 g) in 100 ml EtOH. The
mixture is refluxed for approximately 4 hours, then stored at room
temperature overnight. The greenish-yellow precipitate is collected
by filtration, washed with fresh EtOH then with ether and allowed
to air dry to obtain 2-(thien-2-yl) carboxy-6,7-dimethoxyquinoline
m.p. 260.degree.-263.degree. C.).
EXAMPLE 28
When the procedure of Example 26 is followed and
2-thiophenecarboxaldehyde is replaced with 3-pyridinecarboxaldehyde
or 2-midazolcarboxaldehyde, then the products prepared are
2-(pyrid-3-yl)-4-carboxy-6,7-dimethoxyquinoline m.p. 275.degree. C.
dec) and 2-(imidazol-2-yl)-4-carboxy-6,7-dimethoxyquinoline m.p.
300.degree. C. dec).
EXAMPLE 29
2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline
Pyruvic acid (0.486 ml) is added to a suspension of (2.00 g) of
N-phenyl-sulfonyl-3-indolecarboxaldehyde in 100 ml absolute EtOH.
The mixture is heated to reflux and a solution of
3,4dimethoxyaniline (1.074 g) in 50 ml absolute EtOH is added
dropwise. The reaction is then refluxed for approximately three
hours and stirred at RT for 72 hours. The yellow precipitate is
collected by filtration, washed with EtOH then with ether and the
solid collected. This is triturated with EtOAC/EtOH and dried and
used directly in the next step.
EXAMPLE 30
2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline
A stirred solution of (0.547 g) of
2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline,
K.sub.2 CO.sub.3 (0.380 g), MeOH (40 ml) and H.sub.2 O (10 ml) are
heated to reflux. The MeOH is evaporated in vacuo, and the aqueous
residue diluted with more H.sub.2 O, and acidified with 0.IN HCl to
pH between 6.degree.-7 while contained in an ice-bath. An orange
solid precipitates. This is collected, washed with ether then dried
under vacuum (0.1 mm at 22.degree. C.) for a few hours to obtain
2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline m.p. 286.degree. C.
dec).
EXAMPLE 31
3-cyclohexylethyl-6,7-dimethoxyquinoline
Step A 3-cyclohexylethynyl-6,7-dimethoxyquinoline
This reaction is carried out under anhydrous conditions.
Cyclohexylacetylene (700 mg; 6.47 mmol) in 10 mL. THF is cooled to
0.degree. C. To this is added 2.5M n-BuLi (3.0 mL; 7.44 mmol) and
stirred for 30 min. at 0.degree. C. under N.sub.2 atm and then 1.0M
ZnCl.sub.2 (7.4 mL; 7.44 mmol). This is allowed to warm to room
temperature and stirred for 3/4 hour. The reaction mixture is
transferred via cannula to a flask containing
6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate (500 mg; 1.48
mmol) and Pd(PPh.sub.3)4 (83 mg; 0.074 mmol) in 4 mL of THF. This
is then heated to 50.degree. C. under N.sub.2 for 41/2 hours. The
reaction mixture is then poured into 90 mL of 10% NH.sub.4 OH,
diluted with CHCl.sub.3 and stirred for 20 min. The aqueous layer
is separated, and the organic layer washed with brine, dried over
MgSO.sub.4, filtered, evaporated and chromatographed with 4:1
hexane: EtOAc to obtain 3-cyclohexylethynyl-6,7-dimethoxyquinoline,
which is recrystallized from hexane, identified by NMR and used
directly in the next step.
Step B 3-cyclohexylethyl-6,7-dimethoxyquinoline
To 3-cyclohexylethynyl-6,7-dimethoxyquinoline (215 mg; 0.73 mmol)
in 10mL CH.sub.3 OH and 20 mL glacial acetic acid is added 22 mg
10% Pd/C. H.sub.2 is bubbled through the reaction mixture and then
filtered, evaporated to dryness and diluted with distilled water.
This is then neutralized with Na.sub.2 CO.sub.3, extracted with
EtOAc, washed with brine, dried (MgSO.sub.4), evaporated to dryness
and chromatographed with 8:2/hexane: EtOAc to obtain
3-cyclohexyl-ethyl-6,7-dimethoxyquinoline.
Calc'd: C: 76.22; H: 8.47; N: 4.69
Found: C: 75.08; H: 8.32; N: 4.59
EXAMPLE 32
3-benzyloxy-6,7-dimethoxyquinoline
To 3-hydroxy-6,7-dimethoxyquinoline (150 mg; 0.73 mmol) in 3 mL THF
is added benzyl bromide (0.13 mL; 188 mg; 1.10 mmol) and Nail (59
mg; 1.46 mmol). This is stirred at room temperature for 1 hour and
25 mg of NaH added followed by
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU)(255 mg;
2.07 mmol) and stirred at room temperature for 31/2 hours. The
reaction mixture is partitioned between EtOAc and distilled H.sub.2
O and extracted 2.times. with EtOAc. The latter is washed with
brine, dried (MgSO.sub.4), filtered, evaporated to dryness and
chromatographed with 1% MeOH/CHCl.sub.3 to obtain
3-benzyloxy-6,7-dimethoxyquinoline m.p. 146.5.degree.-148.5.degree.
C.).
EXAMPLE 33
2,(thien-3-yl)-6,7-dimethylquinoxaline
Step A 3-thienylglyoxaldehyde hydrate
A mixture of selenium dioxide (5.276 g; 0.048 mol) in dioxane:
water; 95:5 is heated to solution. To this is added
3-acetylthiophene (4.00 g; 0.032 mol) and the mixture refluxed for
5 hours. The precipitated selenium is filtered off and the filtrate
concentrated in vacuo to give a yellow oil which is purified by
FPLC using 20%: 30%; EtoAc: hexane to obtain a yellow solid which
is then recrystalized from water to obtain 3-thienylglyoxaldehyde
hydrate, which is used directly in the next step.
Step B 2-(thien-3-yl)-6,7-dimethylquinoxaline
To a cooled stirring solution of 4,5-diamino-o-xylene (1.00g; 6.3
mmol) in 20 ml. absolute ethanol is slowly added a solution of
3-thienylglyoxaldehyde hydrate (0.662 g; 4.9 mmol) in 20 ml.
absolute ethanol. The mixture is refluxed for 1.5 hours, cooled in
an ice bath, filtered and the collected material is washed with
hexane and dried in vacuo to obtain
2-(thien-3-yl)-6,7-dimethylquinoxaline m.p.
142.degree.-143.5.degree. C.).
EXAMPLE 34
When the procedure of example 33 is followed, and
3-thienylglyoxaldehyde of Step B is replaced by the compounds of
Table VIII, below and 4,5-diamino-.sigma.-xylene of Step B is
replaced by the compounds of Table IX, below, then the
corresponding products are obtained.
Table VIII
3-thienylglyoxaldehyde
glyoxal
phenylglyoxal
4-methoxy-.alpha.-oxobenzeneacetaldehyde
3-fluoro-4-methoxy-.alpha.-oxobenzeneacetaldehyde
.alpha.-oxo-.gamma.-phenylbutyraldehyde
.alpha.-oxo-4-pyridineacetaldehyde
.alpha.-oxo-3-pyridineacetaldehyde
.alpha.-oxo-2-pyridineacetaldehyde
3,4-dimethoxy-.alpha.-oxobenzeneacetaldehyde
.alpha.-oxo-2-thiopheneacetaldehyde
.alpha.-oxo-3-thiopheneacetaldehyde
5-chloro-.alpha.-oxo-2-thiopheneacetaldehyde
5-fluoro-.alpha.-oxo-2-thiopheneacetaldehyde
2,3-butanedione
pyravic aldehyde
5-(4-chlorophenyl)-.alpha.-oxo-2-thiopheneacetaldehyde
5-(5-chloro-2-thienyl)-.alpha.-oxo-2-thiopheneacetaldehyde
4-cyano-.alpha.-oxobenzeneacetaldehyde
4-(1H-tetrazol-5-yl)-.alpha.-oxobenzeneacetaldehyde
5-bromo-.alpha.-oxo-2-thiophenacetaldehyde
TABLE IX
4,5-diamino-.sigma.-xylene
1,2-diaminobenzene
4,5-dimethyl-1,2-diaminobenzene
4,5-dimethoxy-1,2-diaminobenzene
3,5-dimethyl-1,2-diaminobenzene
3,5-dimethoxy-1,2-diaminobenzene
2,3-diaminopyridine
3,4-diaminopyridine
3,4-diaminotoluene
4,5-diaminopyrimidine
4,5-diethyl-1,2-diaminobenzene
4,5-diethoxy-1,2-diaminobenzene
3,4-diaminobenzotrifluoride
4-tert-butyl-1,2-diaminobenzene
4-(4-pyridyl)-1,2-diaminobenzene
4-(3-pyridyl)-1,2-diaminobenzene
5-bromo-2,3-diaminopyridine
5-bromo-3,4-diaminopyridine
4-fluoro-1,2-diaminobenzene
2-bromo-4,5 -diamopyridine
3,4-diaminothiophene
1,2-diaminocyclohexane
EXAMPLE 35
3-phenoxy-6,7-dimethylquinoline
To a solution of Nail (1.2g; 60% disp in oil) in DMF (3 ml) is
added 3-hydroxy-6.7-dimethoxyquinoline (150 mg; 0.73 tool) and the
reaction mixture is allowed to stir for 30 minutes at room
temperature. To this is added the tetrafluoroborate salt of
chlorobenzene manganese tricarbonyl complex (prepared by J.O.C. 24:
1991;7092) (183 mg) and stirred for 3 hours. To this is added 20 ml
of acetonitrile and stirred overnight. The reaction mixture is
dissolved in EtOAc: brine and extracted 2.times. with EtOAc, washed
with water 2.times., washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo to obtain a material which is purified by
FPLC using 1% methanol: chloroform to obtain a solid which NMR
indicates to be 3-phenoxy-6.7-dimethoxyquinoline. The hydrochloride
salt is then prepared in the usual manner m.p. 224-226).
EXAMPLE 36
(6,7-dimethoxyquinazolin-4-yl)-alpha-naphthalenylamine
To a 25 mL flask with 10 ml of abs. EtOH is added 0.137 g of
4-chloro-6,7-dimethoxyquinazoline and 0.087 g of
1-aminonaphthalene. The solution is heated to reflux whereupon the
insoluble materials dissolve. After 5 minutes at reflux a
precipatate forms. The solution is allowed to stir an additional 10
min before cooling and isolation of the product as the
hydrochloride salt by simple filtration. High-vacuum drying of the
solid provided analytically pure
(6,7-dimethoxy-quinazolin-4-yl)-alpha-naphthalenylamine (0.142 g,
white powder, m.p. 271.degree.-273.degree. C.
EXAMPLE 37
4-(m-chlorophenoxy)-6.7-dimethoxyquinazoline
THF (5 ml) and Nail (60% disp in oil, approx. 28 mg) is added to a
dry flask maintained under inert atmosphere at room temperature.
m-Chlorophenol (0.09 g) is added as a soln. in THP (1 mL) and
stirring is continued until the solution became clear.
4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the
solid) and stirring was maintained overnight at RT. The solution is
partitioned between CH.sub.2 CL.sub.2 and 5% NaOH. The organic
layer is washed with, brine, dried (Na.sub.2 SO.sub.4) and
concentrated. Flash column chromatography (40% EtOAc/Hex) provided
the pure compound. An analytical sample is obtained by
recrystallization from EtOAc/Hex to provide
4-m-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g, white needles,
m.p. 152.degree.-153.degree. C.
EXAMPLE 38
The above examples may be followed to prepare any of the desired
compounds of this invention. A representative list of compounds
which may be prepared are shown below in Table X.
TABLE X
3-(thien-3-yl)-6,7-dimethylquinoline, m.p. 132.degree.-138.degree.
C.
3-(1-cyclopent-1-enyl)-6,7-dimethoxyquinoline hydrochloride, m.p.
213.degree.-215.degree. C.
3-cyclopentyl-6,7-dimethoxyquinoline hydrochloride, m.p.
213.5.degree.-215.degree. C.
4-(3-phenylpropyloxy)-6,7-dimethoxyquinoline, m.p.
90.degree.-91.5.degree. C.
3-(thien-3-yl)-6,7-dimethoxy-2(1H)-quinolone, m.p.
264.degree.-266.degree. C.
3-(thien-3-yl)-6,7-dimethoxyquinoline-N-oxide, m.p.
207.degree.-208.degree. C.
3-(2-chlorothien-5-yl)-5,7-dimethoxyquinoline, m.p.
153.degree.-154.degree. C.
3-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinoline, m.p.
165.5.degree.-167.degree. C.
3-phenyl-4-carboxy-6,7-dimethoxyquinoline, m.p.
259.degree.-262.degree. C.
3-(3-fluorophenyl)-6,7-dimethoxyquinoline, m.p.
156.degree.-158.degree. C.
4-(2-phenylethoxy)-6,7-dimethoxyquinoline, m.p.
117.5.degree.-118.5.degree. C.
3-(4-methoxybenzyloxy)-6,7-dimethoxyquinoline, m.p.
115.5.degree.-118.degree. C.
3-(3-fluoro-4-methoxyphenyl)-7-fluoroquinoline, m.p.
138.degree.-140.5.degree. C.
2-chloro-3-(thien-3-yl)-6,7-dimethoxyquinoline, m.p.
138.5.degree.-139.5.degree. C.
2-methyl-3-(thien-3-yl)-6,7-dimethoxyquinoline, m.p.
132.degree.-132.5.degree. C.
3-(thien-3-yl)-5-fluoroquinoline, m.p, 87.5.degree.-89.degree.
C.
ethyl 4-(6,7-dimethoxyquinolin-3-yl)benzoate, m.p.
165.degree.-166.degree. C.
4-phenylpropyl-6,7-dimethoxyquinoline hydrochloride, m.p.
144.degree.-147.degree. C.
3-(thien-3-yl)-5,7-dimethylquinoline, m.p.
109.50.degree.-111.degree. C.
3-(5-chlorothien-2-yl)-6,7-dimethylquinoline, m.p.
131.5.degree.-132.5.degree. C.
3-(3-fluoro-4-methoxyphenyl)-7-methoxy4(1H)-quinolone, m.p.
291.degree.-293.degree. C.
3-(3-fluoro-4-methoxyphenyl)-5,7-dimethylquinoline, m.p.
109.degree.-110.degree. C.
3-(thien-3-yl)-6,7-difluoroquinoline, m.p.
141.5.degree.-143.5.degree. C.
3-benzyloxy-6,7-dimethoxyquinoline, m.p.
146.5.degree.-148.5.degree. C.
3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline, m.p.
170.5.degree.-171.5.degree. C.
3-cyclohexylethyl-6,7-dimethoxyquinoline (oil) (Calc'd/Fnd; C:
76.22175.10; H: 8.42/8.30; N: 4.68/4.60)
4-[3-(3-fluorophenyl)quinolin-6-yl]benzoic acid,
m.p.>285.degree. C.
2-phenyl-1-[3-(3-fluorophenyl)quinolin-6-yl)ethylene, m.p.
157.5.degree.-159.degree. C.
ethyl-4-[3-(3-fluorophenyl)quinolin-6-yl]benzoate, m.p.
168.degree.-170.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-6-yl]propanoate, m.p.
83.degree.-85.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-6-yl]propanoate, m.p.
184.degree.-186.degree. C.
3-(3-fluorophenyl)-6-(thien-3-yl)quinoline, m.p.
122.degree.-124.degree. C.
1-phenyl-2-[3-(3-fluorophenyl)quinolin-5-yl]ethylene, m.p.
101.degree.-102.degree. C.
3-(3-fluorophenyl)-6-methoxycarbonylquinoline, m.p.
196.degree.-196.5.degree. C.
3-(3-fluorophenyl)quinoline-6-carboxylic acid, m.p.
283.degree.-284.degree. C.
3-(3-fluorophenyl)-6-(N-ethylaminocarbonyl)quinoline, m.p.
184.degree.-185.degree. C.
1-dimethylamino-3-[3-(3-fluorophenyl)quinolin-6-yl]-2-propyne, m.p.
73.degree.-74.degree. C.
N-ethyl-3-[3-(3-fluorophenyl)quinoline-5-yl]propionamide, m.p.
147.5.degree.-149.5.degree. C.
4-[3-(3-fluorophenyl)quinolin-5-yl]benzoic acid,
m.p.>280.degree. C.
N-ethyl-3-[3-(3-fluorophenyl)quinoline-6-yl]propionamide, m p.
141.degree.-142.5.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-5-yl]propenoate, m.p.
128.degree.-130.degree. C.
3-(3-fluorophenyl)-5-(thiophen-3-ylquinoline, m.p.
102.degree.-103.5.degree. C.
1-dimethylamino-313-(3-fluorophenyl)quinolin-6-yl]propane
dihydrochloride, m.p. 194.degree.-198.degree. C.
1-[3-(3-fluorophenyl)quinolin-6-yl]-1-hexyne hydrochloride, m.p.
165.degree.-169.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-5-yl]propanoate hydrochloride,
m.p. 196.degree.-198.degree. C.
ethyl-4-[3-(3-fluorophenyl)quinolin-5-yl]benzoate, m.p.
132.degree.-134.degree. C.
1-[3-(3-fluorophenyl)quinolin-6-yl]n-hexane hydrochloride, m.p.
147.5.degree.-149.5.degree. C.
1-[3-(3-fluorophenyl)quinolin-5-yl]-1-hexyne hydrochloride, m.p.
168.degree.-170.5.degree. C.
1-[3-(3-fluorophenyl)quinolin-5-yl]-n-hexane hydrochloride, m.p.
141.degree.-144.degree. C.
3-[3-(3-fluorophenyl)quinolin-5-yl]propanoic acid, m.p.
249.degree.-251.degree. C.
N-(2-Phenylethyl)-3-[3-(3-fluorophenyl)-quinolin-5-yl]propionamide,
m.p. 137.5.degree.-140.degree. C.
1-dimethylamino-3-[3-(3-fluorophenyl)quinolin-5-yl]propane
dihydrochloride, m.p. 193.degree.-198.degree. C.
1-dimethylamino-3-[3-(3-fluorophenyl)quinolin-5-yl]-2-propane
dihydrochloride, m.p. 77.degree.-77.5.degree. C.
3-(3-fluorophenyl)-5-(N-ethylaminocarbonyl)quinoline, m.p.
227.degree.-227.5.degree. C.
3-(3-fluorophenyl)-5-methoxycarbonylquinoline, m.p.
144.degree.-145.5.degree. C.
3-(3-fluorophenyl)quinolin-5-carboxylic acid, m.p. >280.degree.
C. (dec)
N-(2-phenylethyl)-3-[3-(3-fluorophenyl)quinolin-6-yl]propionamide,
m.p. 139.5.degree.-140.degree. C.
3-(3-fluorophenyl)-7-(thien-3-yl)quinoline, m.p.
186.degree.-187.5.degree. C.
3-[3-(3-fluorophenyl)quinolin-6-yl]propanoic acid, m.p.
138.5.degree.-141.degree. C.
ethyl-4-[3-(3-fluorophenyl)quinolin-7-yl]benzoate, m.p.
134.degree.-136.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-7-yl]propenoate, m.p.
164.degree.-166.degree. C.
3-(3-fluorophenyl)-7-methoxycarbonylquinoline, m.p.
163.5.degree.-165.degree. C.
1-[3-(3-fluorophenyl)quinolin-7-yl]hexyne hydrochloride, m.p.
183.degree.-185.degree. C.
3-(3-fluorophenyl)quinolin-7-carboxylic acid, m.p. >250.degree.
C.
4-[3-(3-fluorophenyl)quinolin-7-yl]benzoic acid hydrochloride,
m.p.>250.degree. C.
3-(3-fluorophenyl)-7-(N-ethylaminocarbonyl)quinoline, m.p.
193.degree.-195.degree. C.
N-(2-phenylethyl)-3-[3-(3-fluorophenyl)quinolin-7-yl]propionamide,
mp. 157.degree.-158.5.degree. C.
3-[3-(3-fluorophenyl)quinolin-7-yl]propanoic acid hydrochloride,
m.p.>250.degree. C.
N-ethyl-3-[3-(3-fluorophenyl)quinolin-7-yl]propionamide, mp.
148.degree.-149.5.degree. C.
methyl-3-[3-(3-fluorophenyl)quinolin-7-yl]propanoate, m.p.
111.5.degree.-113.degree. C.
1-dimethylamino-3-[3-(3-fluorophenyl)quinolin-7-yl]propane
dihydrochloride, m.p. 225.5.degree.-228.degree. C.
1-[3-(3-fluorophenyl)quinolin-7-yl]-n-hexane hydrochloride, m.p.
158.degree.-160.degree. C.
1-dimethylamino-3-[3-(3-fluorophenyl)quinolin-7-yl]-2-propyne, m.p.
86.5.degree.-88.5.degree. C.
3-(3-fluorophenyl)-6-carboxamidoquinoline, m.p.
225.degree.-227.degree. C.
5-[3-(3-fluorophenyl)quinolin-6-oxy]pentanoic acid, m.p.
216.degree.-217.degree. C.
3-(3-fluorophenyl)-6-[1 -(1-pyrrolidin-1-yl)-propan-3-yl]quinoline
dihydrochloride, m.p. 238.degree.-242.degree. C.
3-(3-fluorophenyl)-7-(1-diethylamino-propan-3-yl)quinoline
dihydrochloride, mp. 219.degree.-222.degree. C.
3-(3-fluorophenyl)-7-(1-diethylamino-2-propyn-3-yl)quinoline, m.p.
84.degree.-86.degree. C.
3-(3-fluorophenyl)-6-(1-diethylamino-propan-3-yl)quinoline
dihydrochloride, m.p. 237.degree.-241.degree. C.
3-(3-fluorophenyl)-6-[1-(1-methylpiperazin-4-yl)propan-3-yl]quinoline
trihydrochloride, m.p. 245.degree.-248.degree. C. (dec)
3-(3-fluorophenyl)-7-[1-(1-methylpiperazin-4-yl)propan-3-yl]quinoline
trihydrochloride, m.p. >280.degree. C.
3-(3-fluorophenyl)-6-(1-diethylamino-2-propyn-3-yl)quinoline
dihydrochloride, m.p. 208.degree.-211.degree. C. (dec)
3-(3-fluorophenyl)-7-[1-(morpholin-4-yl)-propan-3-yl]quinoline
dihydrochloride, m.p. 190.degree.-193.degree. C. (dec)
3-(3-fluorophenyl)-6-[1-(morpholin-4-yl)-propan-3-yl]quinoline
dihydrochloride, m.p. 267.degree.-270.degree. C. (dec)
3-(3-fluorophenyl)-7-[1-(4methylpiperazin-1-yl)-2-propyn-3-yl]quinoline,
m.p. 139.5.degree.-141.degree. C.
3-(3-fluorophenyl)-7-[1-(morpholin-4-yl)-2-propyn-3-yl]quinoline,
mp. 137.5.degree.-140.degree. C. (dec)
3-(3-fluorophenyl)-6-[1-(morpholin-4-yl)-2-propyn-3-yl]quinoline,
m.p. 134.degree.-136.degree. C. (dec)
3-(3-fluorophenyl)-7-[1-(1-pyrrlidino)-propan-3-yl]quinoline
dihydrochloride, m.p. 245.degree.-248.degree. C. (dec)
3-(3 -fluorophenyl)-6-[1-(1-pyrollidino)-2-propyn-3 -yl]quinoline
dihydrochloride, m.p. 214.degree.-216.degree. C. (dec)
3-(3-fluorophenyl)-7-[1-(1-pyrollidino)-2-propyn-3-yl]quinoline,
m.p. 84.degree.-87.degree. C.
3-(3-fluorophenyl)-6-[1-(4-methylpiperazin-1
-yl)-2-propyn-3-yl]quinoline, m.p. 132.degree.-134.degree. C.
3- (3-fluorophenyl)-6-[4-(N,N-dimethylamino)butyloxy]quinoline
dihydrochloride, m.p. 245.degree.-248.degree. C.
3-(3-fluorophenyl)-6-(1-hydroxy-2-propyn-3-yl)quinoline, m.p.
159.degree.-160.degree. C.
3-(3-fluorophenyl)-6-(4-hydroxy-butoxy)quinoline, m.p.
84.degree.-86.degree. C.
3-(3-fluorophenyl)-6-[1-(t-butyldimethylsilyloxy)-2-propyn-3-yl]quinoline,
m.p. 100.5.degree.-102.degree. C.
methyl-5-[3-(3-fluorophenyl)quinolin-6-oxy]pentanoate, m.p.
70.degree.-71.degree. C.
3-(3-fluorophenyl)-6-(4-chlorobutoxy)quinoline hydrochloride, m.p.
179.degree.-182.5.degree. C.
3-(3-fluorophenyl)-7-[(2s)-2,3-dihydroxypropoxy-2-propyn-3-yl]quinoline
hydrochloride, m.p. 170.degree.-173.degree. C.
6,7-dimethoxy-3-p-tolyloxyquinoline, m.p. 215.degree.-217.degree.
C. (dec)
6,7-dimethoxy-3-phenoxyquinoline, m.p. 224.degree.-226.degree.
C.
5,7-dimethoxy-3-phenoxyquinoline, m.p. 201.degree.-203.degree.
C.
methyl 3-[3-(3-fluorophenyl)quinolin-6-yl]propenoate, m.p.
184.degree.-186.degree. C.
ethyl 4-[3-(3-fluorophenyl)quinolin-6-yl]benzoate, m.p.
168.degree.-170.degree. C.
2-phenyl-6,7-dimethylquinoxaline, m.p. 128.degree.-131.degree.
C.
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline hydrochloride, m.p.
212.degree.-16.degree. C.
2-(thien-3-yl)-6,7-dimethoxyquinoxaline hydrochloride, mp.
228.degree.-231.degree. C.
2-(thien-3-yl)quinoxaline, m.p. 87.5.degree.-89.degree. C.
2-phenyl-6,7-dimethoxyquinoxaline hydrochloride, m.p. 200.degree.
C.
6,7-dimethyl-2-(thien-3-yl)-quinoxaline, m.p.
142.degree.-143.5.degree. C.
2-phenyl-6,7-diethoxyquinoxaline hydrochloride, m.p.
180.degree.-185.degree. C.
2-(4-methoxyphenyl)-6,7-dimethoxyquinoxaline-4-N-oxide, m.p.
224.degree.-226.degree. C.
2-phenyl-6,7-dimethoxyquinoxaline-4-N-oxide, m.p.
219.degree.-222.degree. C.
2-phenyl-6,7-dimethylquinoxaline, m.p. 128.degree.-131.degree.
C.
2-phenyl-6,7-dichloroquinoxaline, m.p. 158.degree.-160.degree.
C.
2-phenyl-6,7-dimetoxyquinoxaline, m.p. 200.degree. C.
2-phenyl-6,7-diethoxyquinoxaline, m.p. 180.degree.-185.degree.
C.
2-phenethyl-6,7-diethoxyquinoxaline, m.p. 148.degree.-155.degree.
C.
2-(thien-3-yl)-6,7-dimethylquinoxaline, m.p.
142.degree.-143.5.degree. C.
2-(thien-3-yl)-6,7-diethoxyquinoxaline, mp. 217.degree.-224.degree.
C.
2-(5-chlorothien-2-yl)-6,7-diethoxyquinoxaline, m.p.
189.degree.-194.degree. C.
2-(5-chlorothien-2-yl)-6,7-dimethoxyquinoxaline, m.p.
218.degree.-225.degree. C.
2-(5-fluorothien-2-yl)-6,7-diethoxyquinoxaline,
2-(thien-2-yl)-6,7-diethoxyquinoxaline,
2-(thien-2-yl)-6,7-dimethoxyquinoxaline, m.p.
214.degree.-220.degree. C.
2-(thien-2-yl)-6,7-dicarboxyquinoxaline,
6,7-dimethyl-2-[4-1-tetrazol-5-yl)phenyl]quinoxaline, m.p.
278.degree.-280.degree. C. (dec.)
6,7-dimethyl-2-[5-(5-chloro-2-thien-2-yl)-2-thienyl]quinoxaline,
m.p. 180.degree.-183.degree. C.
6,7-dimethyl-2-[5-(5-chloro-2-thien-2-yl)-2-thienyl]quinoxaline,
m.p. 174.degree.-177.degree. C.
6,7-dimethyl-2-[4-(1-methyl-tetrazol-5-yl)phenyl]quinoxaline, m.p.
235.degree.-238.degree. C.
2-(3-fluoro-4-methoxy-phenyl)-7-(4-pyridyl)quinoxaline, m.p.
173.degree.-175.degree. C.
2-(3-fluoro-4-methoxy-phenyl)-6-(-pyrid-4-yl)quinoxaline, m.p.
210.degree.-216.degree. C.
2-(5-chloro-2-thien-2-yl)-7-(4-pyridyl)quinoxaline, m.p.
214.degree.-215.degree. C.
2-(5-chloro-2-thien-2-yl)-6-(pyrid-4-yl)quinoxaline, m.p.
260.degree.-263.degree. C.
7-(4-pyridyl-2-(3-thien-3-yl)quinoxaline, m.p.
210.degree.-212.degree. C.
6-(pyrid-4-yl)-2-(3-thienyl)quinoxaline, m.p.
234.degree.-236.degree. C.
2-(3-chloro-4methoxyphenyl)pyrido[3,4-b]pyrazine,
3-5-chlorothien-2-yl)pyrido[2,3-b]pyrazine, m.p.
194.degree.-196.degree. C.
2-3-fluoro-4-methoxyphenyl)pyrido[3,4-b]pyrazine, m.p.
214.degree.-216.degree. C.
2-3,4-dimethoxyphenyl)pyrido[3,4-b]pyrazine, m.p.
124.degree.-127.degree. C.
2-5-chlorothien-2-yl)pyrido[3,4-b]pyrazine, m.p.
203.degree.-206.degree. C.
2-(thien-2-yl)pyrido[3,4-b]pyrazine,
2-(thien-3-yl)pyrido[3,4-b]pyrazine,
2-(5-chlorothien-3-yl)pyrido[3,4-b]pyrazine,
2-(3-fluoro4-methoxyphenyl)thienyl[3,4-b]pyrazine, m.p.
187.degree.-189.degree. C.
3-(3'-thien-3-yl)-7-methoxy-pyrido-2,3b)-pyrazine, m.p.
215.degree.-220.degree. C.
7-(3'-thien-3-yl)pyrido-(2,3b)-pyrazine, m.p.
171.degree.-173.degree. C.
7-(3'-thien-3-yl)-2,3-dimethylpyrido-(2,3b)-pyrazine, m.p.
200.degree.-205.degree. C. (dec)
3-(3'-thien-3-yl)-7-bromo-pyrido-2,3b)-pyrazine, m.p.
205.degree.-206.5.degree. C.
2-(3,4-dimethoxyphenyl)pyrido[3,4-b]pyrazine, m.p.
124.degree.-127.degree. C.
3-(5-chloro-2-thien-2-yl)pyrido[2,3-b]pyrazine, m.p.
194.degree.-196.degree. C.
3-(3-fluoro-4-methoxyphenyl)pyrido[2,3-b]pyrazine, m.p.
217.degree.-219.degree. C.
2-(3-fluoro-4-methoxypehenyl)pyrido[3,4-b]pyrazine, m.p.
214.degree.-216.degree. C.
2-(5-chloro-2-thien-2-yl)pyrido[3,4-b]pyrazine, m.p.
203.degree.-206.degree. C.
6,7-dimethoxy-4-naphthalen-2-ylethynylquinazoline, m.p.
158.degree.-161.degree. C.
4-(4-hydroxyphenyl)-6,7-dimethoxyquinazolinehydrochloride,
m.p.>270.degree. C. (dec)
4-(naphthalen-1-yl)-6,7-dimethoxyquinazoline, m.p.
144.degree.-147.degree. C.
4-(naphthalen-2-yl)-6,7-dimethoxyquinazoline, m.p.
115.degree.-118.degree. C.
4-phenylacetylenyl-6,7-dimethoxyquinazoline, m.p.
146.degree.-148.degree. C.
4-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinazoline, m.p.
207.degree.-210.degree. C.
4-(3-phenylphenyl)-6,7-dimethoxyquinazoline, m.p.
160.degree.-163.degree. C.
4-(2-phenylethylenyl)-6,7-dimethoxyquinazoline, m.p.
168.degree.-169.degree. C.
4-(2-methoxypyridin-5-yl)-6,7-dimethoxyquinazoline, m.p.
175.degree.-176.degree. C.
4-(1-benzyl-indol-3-yl)-6,7-dimethoxyquinazoUne, m.p.
148.degree.-150.degree. C.
4-(indol-3-yl)-6,7-dimethoxyquinazoline, m.p.>240.degree. C.
(dec)
4-(1-methylindol-3-yl)-6,7-dimethoxyquinazoline hydrochloride,
m.p.>230.degree. C. (dec)
4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline,
m.p.>220.degree. C. (dec)
4-(4-phenylpiperidin-1 -yl)-6,7-dimethoxyquinazoline, m.p.
150.degree.-151.degree. C.
4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline, m.p.
155.degree.-156.degree. C.
4-(N-methyl-3,4,5-trimethoxyanilino)-6,7-dimethoxyquinazoline, m.p.
149.degree.-151.degree. C.
(+-)-4-(2-methyl-1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline
hydrochloride, m.p. 198.degree.-201.degree. C. (dec)
4-(1,2,3,4-tetrahydroquinolin-1-yl)-6,7-dimethoxyquinazoline
hydrochloride, m.p. 195.degree.-197.degree. C. (dec)
4-(N-methyl-4-methoxy-anilino)-6,7-dimethoxyquinazoline
hydrochloride, m.p. 202.degree.-265.degree. C.
4-(N-methyl-4-chloro-anilino)-6,7-dimethoxyquinazoline
hydrochloride, m.p. 220.degree.-222.degree. C.
4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline hydrochloride,
m.p. 226.degree.-229.degree. (dec)
(6,7-dimethoxyquinazolin4-yl)methyl-(3-trifluoromethylphenyl)amine
hydrochloride, m.p. 240.degree.-243.degree. C.
(3-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)methylamine
hydrochloride, m.p. 235.degree.-237.degree. C.
(3-chlorophenyl)methylquinazolin-4-yl-amine hydrochloride, m.p.
233.degree.-235.degree. C.
6,7-dimethoxy-4-naphthalen-1-yl-ethynylquinazoline, m.p.
175.degree.-177.degree. C.
4-(thien-3-yl)-6,7-dimethoxyquinazoline, m.p.
148.5.degree.-151.5.degree. C.
4-benzyl-6,7-dimethoxyquinazoline, m.p. 122.5.degree.-125.degree.
C.
2-(4-methylphenyl)-3-methyl-4(3H)quinazolinone, m.p.
139.degree.-141.degree. C.
2-(4-methoxyphenyl)quinazolin-4(3H)-one, m.p.
244.degree.-247.degree. C.
2-(4-methoxyphenyl)-6,7-dimethoxyquinazolin-4(3H)-one, m.p.
288.degree.-291.degree. C.
(6,7-dimethoxyquinazolin-4-yl)-5-indazol-5-yl hydrochloride, m.p.
261.degree.-263.degree. C. (dec)
N-phenyl-N-(6,7,8-trimethoxyquinazolin-4-yl)methylamine, m.p.
122.5.degree.-124.5.degree. C.
(6,7-dimethoxyquinazolin-4-yl)-N-phenylethylamine hydrochloride, m
p. 227.degree.-230.degree. C. (dec)
benzyl-(6,7-dimethoxyquinazolin-4-yl)phenylamine hydrochloride,
m.p. 269.degree.-271 .degree. C.
(6-chloroquinazolin-4-yl)methylphenylamine, m.p.
106.degree.-108.degree. C.
(3-chloro-phenyl)-(6,7-dimethoxyquinazolin-4-yl)ethylamine
hydrochloride, m.p. 261.degree.-263.degree. C.
(6,7-dimethoxyquinazolin-4-yl)methyl-p-tolyl-amine hydrochloride,
m.p. 230.degree.-234.degree. C. (dec)
benzyl-(6,7-dimethoxyquinazolin-4-yl)amine, m.p.
220.degree.-225.degree. C.
(4-methoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine, m.p.
194.degree.-198.degree. C.
(3,5-dimethoxybenzyl)-(6,7-dimethoxyquinazolin-4-yl)amine
hydrochloride, m.p. 265.degree.-269.degree. C.
4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, m.p.
228.degree.-232.degree. C.
methylphenyl-(9H-purin-6-yl)amine, m.p. 229.degree.-232.degree.
C.
(quinazolin-4-yl)-N-phenylmethylamine hydrochloride, m.p.
242.degree.-246.degree. C. (dec)
(6,8-dimethylquinazolin-4-yl)-N-phenylmethylamine, m.p.
120.degree.-121.degree. C.
(6,7-dimethoxyquinazolin-4-yl)-4-morpholin-4-yl-phenyl)amine
hydrochloride, m.p. 231.degree.-235.degree. C. (dec)
4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline, m.p.
139.5.degree.-141.5.degree. C.
4-[N-(indan-5-yl)amino]-6,7-dimethoxyquinazoline hydrochloride,
m.p. 244.degree.-246.degree. C. (dec)
3-chlorophenyladenine hemi-hydrochloride, m.p. >260.degree.
C.
4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline, m.p.
152.degree.-153.5.degree. C.
4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline hydrochloride, m.p.
262.degree.-264.degree. C. (dec)
4-(3,6-dioxananilino)-6,7-dimethoxyquinazoline hydrochloride, m.p.
267.degree.-269.degree. C. (dec)
N.sup.6 -(3,4,5-dimethoxyphenyl)adenine hydrochloride,
m.p.>250.degree. C.
6,7-dimethoxy-4-(.alpha.-naphthylamino)quinazoline hydrochloride,
m.p.>250.degree. C.
6,7-dimethoxy-4-(.beta.-naphthylamino)quinazoline hydrochloride,
m.p.>250.degree. C.
4-(cyclohexylanilino)-6,7-dimethoxyquinazoline, m.p.
239.degree.-244.degree. C.
4-(3,4,5-trimethoxyanilino)-6,7-dimethoxyquinazoline hydrochloride,
m.p. 260.degree.-265.degree. C.
6,7-dimethoxy-4-(N-methylanilino)quinazoline hydrochloride,
m.p.>230.degree. C.
4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline, m.p.
152.degree.-153.degree. C.
(4-methoxyphenyl)methyl-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amine
hydrochloride, m.p. 223.degree.-226.degree. C.
6-(thien-3-yl)-1,8-naphthyridin-2(1H)-one, m.p.
250.degree.-250.degree. C.
6-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one, m.p.
251.degree.-253.degree. C.
7-(3,4-dimethoxyphenyl)pteridine, m.p. 198.degree.-199.degree.
C.
7-(4-methoxyphenyl)pteridine, m.p. 210.degree.-213.degree. C.
7-(5-chloro-2-thien-2-yl)pteridine, m.p. 231 .degree. C. (dec)
7-(3-fluoro-4-methoxy-phenyl)pteridine
7-(5-chlorothien-2-yl)pteridine, m.p. 231.degree. C. dec.),
7-(thien-2-yl)pteridine
5,6-dimethoxy-2-(2-phenylethenyl)benzothiazole, m.p.
133.degree.-135.degree. C.
methyl-(1H-pyrazole[3,4-d]pyrimidin-4-yl)-(3-trifluoromethylphenyl)amine,
m.p. 226.degree.-227.degree. C.
3-benzyl-5-(thien-3-yl)pyridine, m.p. 81.degree.-82.degree. C.)
3-(thien-3-yl)-6,7-dimethoxyisoquinoline-N-oxide, m.p.
197.degree.-200.degree. C.
3-(thien-3-yl)-6,7-dimethoxyisoquinoline-N-oxide, m.p.
197.degree.-200.degree. C.
3-(thien-3-yl)-6,7-dimethoxy-1(2H)-isoquinolone, m.p.
213.degree.-216.degree. C.
4-(thien-3-yl)isoquinoline hydrochloride, m.p.
179.degree.-183.degree. C.
4-(4-methoxyphenyl)isoquinoline hydrochloride, m.p.
196.degree.-199.degree. C.
2-phenyl-6,7-dimethoxy-4H-3,1-benzoxazin-4-one, m.p.
198.degree.-201.degree. C.
3-(4-methoxyphenyl)-7-methoxy-1-naphthalenol, m.p.
155.degree.-159.degree. C.
1-phenylphthalazine, m.p. 139.5.degree.-141.degree. C.
(4-methoxyphenyl)methyl-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)amine
hydrochloride, m p. 223.degree.-226.degree. C.
EXAMPLE 39
The procedures described in the above examples may be followed to
prepare the following representative compounds If TABLE XI.
TABLE XI
5-(6,7-Dimethoxy-quinolin-3-yl)-2-hydroxy-benzoic acid
5-(6,7-Dimethoxy-quinolin-3-yl)-2-methoxy-benzoic acid
5-(6,7-Dimethoxy-quinolin-3-yl)-2-methoxy-benzamide
5-(6,7-Dimethoxy-quinolin-3-yl)-2-hydroxy-benzamide
4-(6,7-Dimethoxy-quinolin-3-yl)-2-hydroxy-benzoic acid
8-Fluoro-6,7-dimethoxy-3-(4-methoxy-phenyl)-quinoline
N-(6,7-Dimethoxy-quinolin-4-yl)-N-phenyl-methylamine
N-(6,7-Dimethoxy-quinolin-4-yl)-aniline
5-(6,7-Dimethoxy-quinolazolin-4-yl)-2-hydroxy-benzoic acid
2-Benzyloxy-5-(6,7-dimethoxy-quinazolin-4-yl)-benzoic acid
5-(6,7-Dimethoxy-quinolazolin-4-yl)-2-methoxy-benzoic acid
5-(6,7-Dimethoxy-quinolazolin-4-yl)-2-hydroxy-benzamide
5-(6,7-Dimethoxy-quinolazolin-4-yl)-2-hydroxy-benzamide
4-(6,7-Dimethoxy-quinolazolin-4-yl)-2-hydroxy-benzoic acid
6,7-dimethoxy-4-(1-naphthylthio)-quinazoline
6,7-dimethoxy-4-(2-naphthylthio)-quinazoline
6,7-dimethoxy-4-(1-naphthyloxy)-quinazoline
6,7-dimethoxy-4-(2-naphthyloxy)-quinazoline
6,7-Dimethoxy-quinolazolin-4-yl)-2-naphthyl-ethylamine
6,7-dimethoxy-4-(naphthalene-2-sulfinyl)-quinazoline
6,7-dimethoxy-4-(naphthalene-2-sulfonyl)-qinazoline
4-(4-Methoxyphenyl)-7,8-dimethoxyisoquinoline
4-(3-Fluoro-4-methoxyphenyl)-7-chloroisoquinoline
4-(3-Fluoro-4-methoxyphenyl)-8-chloroisoquinoline
1-Anilinoisequinoline
1-(N-Methyl-3,4,5-trimethoxyanilino)isoquinoline
Preparation of Pharmaceutical Compositions and Pharmacological Test
Section
Compounds within the scope of this invention exhibit significant
activity as protein tyrosine kinase inhibitors and possess
therapeutic value as cellular antiproliferative agents for the
treatment of certain conditions including psoriasis,
atherosclerosis and restenosis injuries. It is expected that the
invention will be particularly applicable to the treatment of
atherosclerosis. With regard to the treatment of some conditions,
for example, atherosclerosis, certain people may be identified as
being at high risk, for example, due to genetic, environmental or
historical factors. Compounds within the scope of the present
invention exhibit the modulation and/or inhibition of cell
signaling, cell proliferation, cell inflammatory response, the
control of abnormal cell growth and cell reproduction can and can
be used in preventing or delaying the occurrence or reoccurrence of
such conditions or otherwise treating the condition.
To determine the effectiveness of compounds of this invention, the
following pharmacological tests described below, which are accepted
in the art and recognized to correlate with pharmacological
activity in mammals, are utilized. Compounds within the scope of
this invention have been subjected to these various tests, and the
results obtained are believed to correlate to useful cellular
antiproliferative activity. The below described tests are useful in
determining the EGF receptor kinase, PDGF receptor kinase and
insulin receptor kinase inhibition activities of compounds
disclosed herein. The results of these tests are believed to
provide sufficient information to persons skilled in the
pharmacological and medicinal chemistry arts to determine the
parameters for using the studied compounds in one or more of the
therapies described herein.
EGF-Receptor Purification
EGF-receptor purification is based on the procedure of Yarden and
Schlessinger. A431 cells are grown in 80 cm.sup.2 bottles to
confluency (2.times.10.sup.7 cells per bottle). The cells are
washed twice with PBS and harvested with PBS containing 11.0 mmol
EDTA (1 hour at 37.degree. C., and centrifuged at 600g for 10
minutes. The cells arc solubilized in 1 ml per 2.times.10.sup.7
cells of cold solubilization buffer (50 mmol Hepes buffer, pH 7.6,
1% Triton X-100, 150 mmol NaCl, 5 mmol EGTA, 1 mmol PMSF, 50
.mu.g/ml aprotinin, 25 mmol benzamidine, 5 .mu.g/ml leupeptic, and
10 .mu.g/ml soybean trypsin inhibitor) for 20 minutes at 4.degree.
C. After centrifugation at 100,000 g for 30 minutes, the
supernatant is loaded onto a WGA-agarose column (100 .mu.l of
packed resin per 2.times.10.sup.7 cells) and shaken for 2 hours at
4.degree. C. The unabsorbed material is removed and the resin
washed twice with HTN buffer (50 mmol Hepes, pH 7.6, 0.1% Triton
X-100, 150 mmol NaCl), twice with HTN buffer containing 1M NaCl,
and twice with HTNG buffer (50 mmol Hepes, pH 7.6, 0.1% Triton
X-100, 150 mmol NaCl, and 10% glycerol). The EGF receptor is eluted
batchwise with HTNG buffer containing 0.5M N-acetyl-D-glucosamine
(200 .mu.l per 2.times.10.sup.7 cells.). The eluted material is
stored in aliquots at -70.degree. C. and diluted before use with
TMTNG buffer (50 mmol Tris-Mes buffer, pH 7.6, 0.1% Triton X-100,
150 mmol NaCl, 10% glycerol).
ATP and EGF Dependence of Autophosphorylation
WGA-purified EGF receptor from A431 cells (0.5 .mu.g/assay is
activated with EGF (0.85 .mu.M) for 20 minutes at 4.degree. C.. The
assay is performed at 15.degree. C. and initiated by addition of
Mg(Ac).sub.2 (60 mmol), Tris-Mes buffer, pH 7.6 (50 mmol), [.sup.32
P]ATP (carrier free, 5 .mu.Ci/assay), and increasing concentrations
of nonradioactive ATP. The assay is terminated after 10-sec by
addition of SDS sample buffer. The samples are run on a 6% SDS
polyacrylamide gel. The gel is dried and autoradiographed as
described above. The relevant radioactive bands are cut and counted
in the Cerenkov mode. The Km for ATP determined in this fashion is
found to be 7.2 .mu.(M. With use of the 10-sec assay protocol, the
EGF concentration dependence of EGF-RK autophosphorylation is
determined.
Inhibition of EGF-R Autophosphorylation
A431 cells were grown to confluence on human fibronectin coated
tissue culture dishes. After washing 2 times with ice-cold PBS,
cells were lysed by the addition of 500 .mu.l/dish of lysis buffer
(50 mmol Hepes, pH 7.5,150 mmol NaCl, 1.5 mmol MgCl.sub.2, 1 mmol
EGTA, 10% glycerol, 1% triton X-100, 1 mmol PMSF, 1 mg/ml
aprotinin, 1 mg/ml leupeptin) and incubating 5 minutes at 4.degree.
C. After EGF stimulation (500 .mu.g/ml 10 minutes at 37.degree. C.)
immunoprecipitation was performed with anti EGF-R (Ab 108) and the
autophosphorylation reaction (50 .mu.l aliquots, 3 .mu.Ci
[.gamma.-.sup.32 P]ATP) sample was carried out in the presence of 2
or 10 .mu.M of compound of the present invention, for 2 minutes at
4.degree. C. The reaction was stopped by adding hot electrophoresis
sample buffer. SDA-PAGE analysis (7.5% els) was followed by
autoradiography and the reaction was quantitated by densitometry
scanning of the x-ray films.
In order to test the present compounds for selective inhibition,
the procedure is repeated using PDGF stimulation in place of EGF
stimulation. "IC.sub.50," as used below refers to the concentration
of inhibitor mM) at which the rate of autophosphorylation is
halved, compared with media containing no inhibitor.
Inhibition of PDGF-R Autophosphorylation
Lysate from NIH 3T3 cells was diluted one-third in Triton-free
buffer and stimulated with 10 ng/ml PDGF for 30 minutes at
4.degree. C. The equivalent of 1/15 of a 175-cm.sup.2 plate of
lysate was used per sample. The stimulated lysate was then
immunoprecipitated with rabbit polyclonal anti-PDGF-receptor
antibodies raised against a synthetic peptide from the
COOH-terminal region (amino acids 1094-1106) or the human
PDGF-receptor B-subunit and added to increasing concentrations of
test compound of the present invention. After 10 minutes at
4.degree. C., 10 .mu.Ci of [.gamma.-.sup.32 P]ATP were added and
further incubated for 10 minutes at 4.degree. C. Samples were
separated by SDS-PAGE on 6% gels.
Inhibition of Cell Proliferation as Measured by Inhibition Of DNA
Synthesis
EGF receptor overexpressing (HER14) cells were seeded at
1.times.10.sup.5 cells per well in 24-well Costar dishes pre-coated
with human fibronectin (by incubating for 30 minutes at room
temperature with 10 .mu.g/0.5 ml/well). The cells were grown to
confluence for 2 days. The medium was changed to DMEM containing
0.5 calf serum for 36-48 hours and the cells were then incubated
with EGF (Toyobo, New York, N.Y.) (20 ng/ml), PDGF (Amgen) (20 ng/m
1) or serum (10% calf serum, FCS) and different concentrations of
the compound of the present invention. [3H] thymidine, (NEN,
Boston, Mass.) was added 16-24 hours later at 0.51 .mu.Ci/ml for 2
hours. TCA precipitable material was quantitated by scintillation
counting (C Results of this assay are determined. "IC.sub.50 " of
the concentration of inhibitor (nM) at which [.sup.3 H] thymidine
incorporation is halved, compared with media containing no buffer
is calculated As FCS contains a broad range of growth factors, the
IC.sub.50 values for PDGF should be lower than for FCS, indicating
that the compounds of the present invention do not act as general
inhibitors.
These results indicate that compounds within the scope of the
invention inhibit the EGF and/or PDGF growth factor receptors
selectively.
Cell Culture
Cells termed HER 14 and K721A (=DK) were prepared by transfecting
NIH3T3 cells (clone 2.2) (From C. Fryling, NCl, NIH), which lack
endogenous EGF-receptors, with cDNA constructs of wild-type
EGF-receptor or mutant EGF-receptor lacking tyrosine kinase
activity (in which Lys 721 at the ATP-binding site was replace by
an Ala residue, respectively). All cells were grown in DMEM with
10% calf serum (Hyclone, Logan, Utah).
Further tests which show the effectiveness and selectivity of
compounds of this invention to inhibit cell proliferation are as
follows.
CSF-1R CELL-FREE AUTOPHOSPHORYLATION ASSAY
For a regular 28 tube assay (14 samples per 15 well gel):
In 2 ml eppendorf tube: 140 mg protein A sepharose (5
mg/sample)
Swell in 20 mM Hepes pH 7.5 and wash 2.times. in Hepes
Add 280 .lambda..alpha.-CSF-1R (from rabbit 3: C1-3-?)
20 min RT shaking
Wash 3.times. in HNTG pH 7.5:20 mM Hepes
150 mM NaCl
0.1% triton X-100
10 % glycerol
In 15 ml tube: 2.8 ml lysate (100 .lambda./sample of lysate made
from unstarved, subconfluent cfm Y cells)
lysis buffer: 20 mM Hepes
1.5 mM MgCl.sub.2
150 mM NaCl
1 mM EGTA
10% glycerol
1% triton X-100
Protease inhibitors added fresh:
PMSF: 8 mg/ml-2500.times. in 100% EtOH, store frozen, add
100.lambda./10 ml lysis buffer Aprotinin: 10 mg/ml=250.times. in
H.sub.2 O, store frozen (expires in about 6 months), add
40.lambda./10 ml lysis buffer
Leupeptin: 1 mg/ml=250.times. in H.sub.2 O, store frozen (expires
in about 6 months), add 40.lambda./10 ml lysis buffer
Add washed beads to stimulated lysate and incubate 90 min 4.degree.
C. on rotator or shaking (anywhere from 1 to 2.5 hours OK)
Meanwhile:
prepare 28 compound tubes:
make 40 mM solutions of compounds in 100% DMSO
make serial dilutions in 50 mM Tris pH 7.5+10 mM MnCl.sub.2
aliquot 10.lambda. compound solution into each I ml eppendorf
reaction tube waiting on ice, control blanks get 10.lambda.
buffer
Wash beads 1.times. HNTG, 2.times.10 mM Tris pH 7.5 (can transfer
beads to 2 ml eppendorf tube for washing)
Remove all liquid with gel loading pipette tip or Hamilton
syringe
Add back 560.lambda. 50 mM Tris pH 7.5+10 mM MnCl.sub.2
(20.lambda./sample)
Dole out into waiting reaction tubes (approx. 28.lambda./tube using
large bore tip)
Vortex, incubate 10 min on ice
Add 10.lambda. ATP solution: 312.lambda. 50 mM Tris pH 7.5+10 mM
MnCl.sub.2
2.7.lambda. cold ATP (stock of 10 mM in 50 mM
Tris=20 .mu.M final)
351 .sup.32 P-ATP (10 .mu.Ci/sample)
Vortex, incubate 10 min on ice
Add 45.lambda. 2.times. SDS-sample buffer, heat 95.degree. C. 6
min
7.5% SDS-PAGE, fix, dry, expose (usually 4 hrs)
*Note: it is important to keep lysate cold at all times: when
thawing, don't use water which is too warm and use cold buffer for
wash steps.
Ick Kinase: Immunoprecipitated from Jurkat lysate..sup.5.6
A. Jurkat cells (human T-cell leukemia, ATCC clone #E6-1) were
grown in suspension in RPMI 1640 medium with 10% fetal calf serum,
100 U/ml penicillin/streptomycin, and 2 mM L-glutamine in a
37.degree. C. incubator at 5% CO.sub.2.
B. Cells were grown to 1-1.5.times.10.sup.6 cells/ml media,
pelleted by centrifugation, and lysed in lysis buffer at 10.sup.8
cells/ml buffer (50 mM tris (pH 8), 150 mM NaCl, 5 mM EDTA, 10%
glycerol, and 1% NP-40, to which fresh protease and phosphatase
inhibitors were added as described above for A431 lysate). Lysates
stored at -70.degree. C.
C. Immunoprecipitation [#5264:12]: 3-4 mg Protein-A
sepharose/sample washed 2.times.20 mM Hepes (pH 7.5). 1 ul
.alpha.-lck antibody (prepared as polyclonals in rabbits using a
peptide antigen corresponding to the N-terminal region of human
lck) per sample added to the Protein-A and shaken 20 min at room
temperature. After washing 3.times. HNTG, lysate from
2.times.10.sup.6 cells was added to each sample, rotated 2 hr at
4.degree. C., then washed 3.times. HNTG (2nd wash containing 0.5 N
NaCl). If all samples contain identical concentrations of the
enzyme, then the immuno-precipitation can be done in bulk and
alloquoted to appropriate numbers of tubes prior to assay
set-up.
D. Compound screening in the cell-free/ck kinase assay [#5264:12]:
RPR compounds (40 mM stocks in DMSO) were initially screened at
concentrations of 10 and 100 uM in samples containing Ick
immuno-precipitated from 2.times.10.sup.6 cells, 5 uM cdc2 (a
p34.sup.cdc2 -derived synthetic peptide (N6-20) prepared by R.
Howk, RPR).sup.7, 5 mM MnCl.sub.2, 5 uM ATP and 30 uCi g.sup.32
p-ATp (6000Ci/mmol, NEN) in 20 mM hepes (pH 7.5) for 5 min at
30.degree. C. Samples were analyzed by 5-15% SDS-PAGE and
autoradiography as described for EGFR kinase assays.
E. Intact cell activation/inhibition studies.sup.8,9
[#5264:31]:.about.5.times.10.sup.7 cells per sample in 1 ml media
were activated with either 10 ug a-CD3 (clone Cris 7, Biodesign)
for 1 min at 37.degree. C. or 20 ng PMA and 10 ug PHA for 20 min at
37.degree. C. in the presence and absence of compound (added
earlier so that the total time of compound incubation is 30 min).
Incubations were terminated by centrifugation and lysis (as
described). Samples were analyzed by immunoprecipitation (aPY (100
ul/10.sup.8 cells), a-PLC (100 ul/10.sup.8 cells), or azeta (20
ul/10.sup.8 cells)), followed by SDS-PAGE and western blotting onto
nitrocellulose and inimunoblotting using RC20 recombinant aPY-HRP
Transduction Labs) and ECL (Amersham).
cAMP-dependent Protein Kinase (PKA) Assay.sup.10
Selectivity assay for compounds is performed as follows. Each
sample contains 0.4 pmolar units PKA (from rabbit muscle, Sigma), 1
uM cAMP, 50 uM Tris-HCL (pH7), 10 mM MgAc, 50 ug BSA, 16 uM
Kemptide substrate (specific cAMP kinase phosphate acceptor whose
sequence corresponds to the pig liver pyruvate kinase
phosphorlyation site), 16 uM ATP, 16 uCi .sup.32 P-ATP
(6000Ci/mmol, NEN), +/- compound and dH.sub.2 O to a final volume
of 200 ul. Reactions proceed for 5 min. at 30.degree. C., and are
terminated by the addition of 100 ul 375 mM H.sub.3 PO.sub.4. 50 ul
each sample spotted onto Whatman P81 phosphocellulose filters,
which are washed 3.times. (15 min.) in 75 mM H.sub.3 PO.sub.4,
followed by an acetone rinse and dry (Cerenkov) counting.
In view of the results of the above test, compounds of the present
invention can be shown to be selective.
The preferred class of compounds exhibiting CSF-1 inhibition and
lck Kinase inhibition are the 6,7-dialkoxy quinazolines, and most
preferred are the 4-arylamino, 6,7-dimethoxyquinazolines. The most
preferred lck inhibitory compound is
4-(3,4,5-trimethoxyphenylamino)-6,7-dimethoxyquinazoline, (m.p.
260.degree.-265.degree. C. (HCl)), which is prepared according to
the procedure described in Example 36 using 1.6 g of
3,4,5-trimethoxyaniline and 0.2g of
4-chloro,-6,7-dimethoxyquinazoline, under similar reaction
conditions. The most preferred CSF-1 inhibitory compound is
4-(N-methyl, N-phenylamino)-6,7-dimethoxyquinazoline,
(m.p>230.degree. C.(HCl)), which is prepared according to the
procedure described in Example 36 using 140mg of N-methylaniline
and 300 mg of 4-chloroquinazoline, under similar reaction
conditions.
The following tables show examples of representative compounds of
this invention and their test results as determined by the above
inhibition of PDGF-R cell-free autophosphorylation procedure.
__________________________________________________________________________
Inhibition of PDGF-R cell-free Autophosphorylation COMPOUND
IC.sub.50 (.mu.M)
__________________________________________________________________________
1 #STR20## 0.003-0.015 2 #STR21## 0.050-0.10 3 #STR22## 0.007 4
#STR23## 0.2-1 5 #STR24## 0.06-0.08 6 #STR25## 1.0-2.0 7 #STR26##
0.015 8 #STR27## 15-20 9 #STR28## 0.02 0 #STR29## 0.01 1 #STR30##
0.030-0.070 2 #STR31## 0.02-0.08 3 #STR32## 0.05-0.1 4 #STR33##
0.005-0.030 5 #STR34## 0.02-0.05 6 #STR35## 0.7-1.0 7 #STR36##
0.7-1.0 8 #STR37## 0.04 9 #STR38## 0.010-0.060 0 #STR39## 7-12 1
#STR40## 0.015 2 #STR41## 15-20 3 #STR42## 0.005-0.030 4 #STR43##
0.04 5 #STR44## 0.010-0.060 6 #STR45## 7-12 7 #STR46## 0.015 8
#STR47## 15-20 9 #STR48## 0.005-0.030 0 #STR49## 0.02-0.05 1
#STR50## 0.7-1.0 2 #STR51## 0.7-1.0 3 #STR52## 0.04 4 #STR53##
0.010-0.060 5 #STR54## 7-12 6 #STR55## >50 7 #STR56## 10-20 8
#STR57## 0.025-0.3 9 #STR58## 0.05-0.2 0 #STR59## >50 1 #STR60##
>50 2 #STR61## 0.5-3 3 #STR62## 9 4 #STR63## 7 5 #STR64## 0.6 6
#STR65## 0.25 7 #STR66## 2 8 #STR67## 2 9 #STR68## <2 0 #STR69##
<2
__________________________________________________________________________
4-Substituted-6,7-di-methoxyquinazolines EGF-R PDGF-R
__________________________________________________________________________
1 #STR70## 0.02 1.5 2 #STR71## 0.1 >50 3 #STR72## 2 4 #STR73##
4.0 15 5 #STR74## -- 25 6 #STR75## 0.35 15 7 #STR76## -- 5-20 8
#STR77## <1.0 >20 9 #STR78## 0.050 10 0 #STR79## 0.010 20
__________________________________________________________________________
The results obtained by the above experimental methods evidence the
useful protein tyrosine kinase inhibition properties of compounds
within the scope of the present invention and possess therapeutic
value as cellular antiproliferative agents. The above
pharmacological test results may be used to determine the dosage
and mode of administration for the particular therapy sought.
The compounds of the present invention can be administered to a
mammalian host in a variety of forms adapted to the chosen route of
administration, i.e., orally, or parenterally. Parenteral
administration in this respect includes administration by the
following routes: intravenous, intramuscular, subcutaneous,
intraocular, intrasynovial, transepithelial including transdermal,
ophthalmic, sublingual and buccal; topically including ophthalmic,
dermal, ocular, rectal and nasal inhalation via insufflation and
aerosol and rectal systemic.
The active compound may be orally administered, for example, with
an inert diluent or with an assimilable edible carder, or it may be
enclosed in hard or soft shell gelatin capsules, or it may be
compressed into tablets, or it may be incorporated directly with
the food of the diet. For oral therapeutic administration, the
active compound may be incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. Such
compositions and preparations should contain at least 0.1% of
active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be
between about 2 to about 6% of the weight of the unit. The amount
of active compound in such therapeutically useful compositions is
such that a suitable dosage will be obtained. Preferred
compositions or preparations according to the present invention are
prepared so that an oral dosage unit form contains between about 1
and 1000 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain
the following: A binder such as gum tragacanth, acacia, corn starch
or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin may be added
or a flavoring agent such as peppermint, oil of wintergreen, or
cherry flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier. Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For
instance, tablets, pills, or capsules may be coated with shellac,
sugar or both. A syrup or elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and flavoring such as cherry or orange flavor.
Of course, any material used in preparing any dosage unit form
should be pharmaceutically pure and substantially non-toxic in the
amounts employed. In addition, the active compound may be
Incorporated into sustained-release preparations and
formulations.
The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compound as a free base
or pharmacologically acceptable salt can be prepared in water
suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersion can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases the for must be sterile and must be fluid
to the extent that easy syringability exists. It may be stable
under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (for
example, glycerol, propylene glycol, and liquid polyethylene
glycol, and the like), suitable mixtures thereof, and vegetable
oils. The proper fluidity can be maintained, for example, by the
use of a coating such as lecithin, by the maintenance of the
required particle size in the case of dispersion and by the use of
surfactants. The prevention of the action of microorganisms can be
brought about by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
and the like. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. Prolonged
absorption of the injectable compositions can be brought about by
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the
active compound in the required amount in the appropriate solvent
with various of the other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredient into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and the freeze drying technique
which yield a powder of the active ingredient plus any additional
desired ingredient from previously sterile-filtered solution
thereof.
The therapeutic compounds of this invention may be administered to
a mammal alone or in combination with pharmaceutically acceptable
carriers, as noted above, the proportion of which is determined by
the solubility and chemical nature of the compound, chosen route of
administration and standard pharmaceutical practice.
The dosage of the present therapeutic agents which will be most
suitable for prophylaxis or treatment will vary with the form of
administration, the particular compound chosen and the
physiological characteristics of the particular patient under
treatment. Generally, small dosages will be used initially and if
necessary, will be increased by small increments until the optimum
effect under the circumstances is reached. The therapeutic human
dosage, based on physiological studies using rats, will generally
be from about 0.01 mg to about 100 mg/kg of body weight per day or
from about 0.4 mg to about 10 g or higher although it may be
administered in several different dosage units from once to several
times a day. Oral administration requires higher dosages.
* * * * *