U.S. patent application number 12/688273 was filed with the patent office on 2010-06-03 for fused heteroaryl derivatives.
Invention is credited to Masahiko Hayakawa, Hiroyuki Kaizawa, Ken-Ichi Kawaguchi, Tomonobu Koizumi, Koyo Matsuda, Hiroyuki Moritomo, Mitsuaki Ohta, Minoru Okada, Mayumi Yamano.
Application Number | 20100137585 12/688273 |
Document ID | / |
Family ID | 27394158 |
Filed Date | 2010-06-03 |
United States Patent
Application |
20100137585 |
Kind Code |
A1 |
Hayakawa; Masahiko ; et
al. |
June 3, 2010 |
FUSED HETEROARYL DERIVATIVES
Abstract
The present invention provides a pharmaceutical composition
which is useful as a phosphatidylinositol 3 kinase (PI3K) inhibitor
and an antitumor agent, and it provides a novel bicyclic or
tricyclic fused heteroaryl derivative or a salt thereof which
possesses an excellent PI3K inhibiting activity and cancer cell
growth inhibiting activity.
Inventors: |
Hayakawa; Masahiko;
(Tsukuba-shi, JP) ; Kaizawa; Hiroyuki;
(Tsukuba-shi, JP) ; Moritomo; Hiroyuki;
(Tsukuba-shi, JP) ; Kawaguchi; Ken-Ichi;
(Tsukuba-shi, JP) ; Koizumi; Tomonobu;
(Tsukuba-shi, JP) ; Yamano; Mayumi; (Tsukuba-shi,
JP) ; Matsuda; Koyo; (Tsukuba-shi, JP) ;
Okada; Minoru; (Tsukuba-shi, JP) ; Ohta;
Mitsuaki; (Tsukuba-shi, JP) |
Correspondence
Address: |
FULBRIGHT & JAWORSKI L.L.P.
666 Fifth Avenue
New York
NY
10103
US
|
Family ID: |
27394158 |
Appl. No.: |
12/688273 |
Filed: |
January 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11544144 |
Oct 6, 2006 |
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12688273 |
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11250782 |
Oct 14, 2005 |
7173029 |
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11544144 |
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10918094 |
Aug 13, 2004 |
7037915 |
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11250782 |
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10459002 |
Jun 10, 2003 |
6838457 |
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10918094 |
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10243416 |
Sep 13, 2002 |
6608056 |
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10459002 |
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09843615 |
Apr 26, 2001 |
6608053 |
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10243416 |
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60200537 |
Apr 27, 2000 |
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60200481 |
Apr 28, 2000 |
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Current U.S.
Class: |
544/118 ;
544/117 |
Current CPC
Class: |
C07D 495/14 20130101;
A61K 31/519 20130101; C07D 471/04 20130101; C07D 491/14 20130101;
A61K 31/517 20130101; A61K 31/5377 20130101; C07D 471/14 20130101;
C07D 491/04 20130101; C07D 495/04 20130101; A61K 31/00
20130101 |
Class at
Publication: |
544/118 ;
544/117 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 491/048 20060101 C07D491/048; C07D 495/04 20060101
C07D495/04 |
Claims
1-21. (canceled)
22. A fused heteroaryl compound of the formula: ##STR00534##
wherein: B is furan or thiophene, selected from the structures;
##STR00535## R.sup.1 is independently selected from
C.sub.1-C.sub.10 alkyl, C.sub.6-C.sub.14 aryl, or 5- or 6-membered
monocyclic heteroaryl; R.sup.4b is C.sub.6-C.sub.14 aryl, 5- or
6-membered monocyclic heteroaryl, or bicyclic heteroaryl fused to a
benzene ring; where C.sub.6-C.sub.14 aryl, 5- or 6-membered
monocyclic heteroaryl and bicyclic heteroaryl fused to a benzene
ring are optionally and independently substituted with one or more
substituents selected from C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10
alkenyl, C.sub.1-C.sub.10 alkynyl, halogen, halogenated
C.sub.1-C.sub.10 alkyl, (C.sub.1-C.sub.10 alkylene)-OR, NO.sub.2,
CN, .dbd.O, OR, O-(halogenated C.sub.1-C.sub.10 alkyl),
O--(C.sub.1-C.sub.10 alkylene)-NRR', O--(C.sub.1-C.sub.10
alkylene)-OR, O--(C.sub.1-C.sub.10 alkylene)-(C.sub.6-C.sub.14
aryl), SR, SO.sub.2--(C.sub.1-C.sub.10 alkyl),
SO--(C.sub.1-C.sub.10 alkyl), COOR, COO--(C.sub.1-C.sub.10
alkylene)-(C.sub.6-C.sub.14 aryl), SO--(C.sub.1-C.sub.10 alkyl),
COR, CO--(C.sub.6-C.sub.14 aryl), C.sub.6-C.sub.14 aryl, CONRR',
SO.sub.2NRR', NRR', NR''-(C.sub.1-C.sub.10 alkylene)-NRR',
NR'--(C.sub.1-C.sub.10 alkylene)-OR, NR--(C.sub.1-C.sub.10
alkylene)-(C.sub.6-C.sub.14 aryl), NRCO--(C.sub.1-C.sub.10 alkyl),
NRSO.sub.2--(C.sub.1-C.sub.10 alkyl), C.sub.3-C.sub.8 cycloalkyl,
and C.sub.3-C.sub.8 cycloalkenyl; R, R', and R'' are independently
selected from H and C.sub.1-C.sub.10 alkyl; and n is 1 or 2; with
the proviso that when B is: ##STR00536## then R.sup.1 is not
C.sub.1-C.sub.10 alkyl.
23. The fused heteroaryl compound of claim 22, wherein R.sup.4b is
phenyl, pyridyl, pyrimidinyl, indolyl, or indazolyl.
24. The fused heteroaryl compound of claim 22, wherein R.sup.4b is
phenyl substituted with one or more substituents selected from Cl,
Br, methyl, ethyl, CN, CO.sub.2H, OH, OCH.sub.3, OCH.sub.2CH.sub.2
NH.sub.2, NH.sub.2, NHCH.sub.3, NHSO.sub.2CH.sub.3, SCH.sub.3,
SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, and
SO.sub.2N(CH.sub.3).sub.2.
25. A fused heteroaryl compound of the formula: ##STR00537##
wherein B is selected from the structures: ##STR00538## and R is
OH, CONHMe, CH.sub.2OH, or CONH.sub.2.
26. The fused heteroaryl compound of claim 25, wherein R is OH.
27. The fused heteroaryl compound of claim 26, wherein B is
##STR00539##
28. The fused heteroaryl compound of claim 25, wherein B is
##STR00540##
Description
FIELD OF THE INVENTION
[0001] The present invention relates to fused heteroaryl
derivatives which are useful as medicaments, more particularly as
phosphatidylinositol 3-kinase (PI3K) inhibitors and carcinostatic
agents.
BACKGROUND OF THE INVENTION
[0002] Phosphatidylinositol (hereinafter abbreviated as "PI") is
one of phospholipids in cell membranes. In recent years it has
become clear that PI plays an important role also in intracellular
signal transduction. It is well recognized in the art that
especially PI (4,5) bisphosphate (PI(4,5)P2) is degraded into
diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C
to induce activation of protein kinase C and intracellular calcium
mobilization, respectively [M. J. Berridge et al., Nature, 312, 315
(1984); Y Nishizuka, Science, 225, 1365 (1984)].
[0003] Turning back to the late 1980s, PI3K was found to be an
enzyme to phosphorylate the 3-position of the inositol ring of
phosphatidylinositol [D. Whitman et al., Nature, 332, 664
(1988)].
[0004] PI3K was originally considered to be a single enzyme at the
time when PI3K was discovered. Recently it was clarified that a
plurality of subtypes are present in the PI3K. Three major classes
of PI3Ks have now been identified on the basis of their in vitro
substrate specificity [B. Vanhaesebroeck, Trend in Biol. Sci., 22,
267 (1997)].
[0005] Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2.
In these substrates, PI(4,5)P2 is the most advantageous substrate
in cells. Class I PI3Ks are further divided into two groups, class
Ia and class Ib, in terms of their activation mechanism. Class Ia
PI3Ks, which include PI3K p110.alpha., p110.beta. and p110.delta.
subtypes, are activated, in the tyrosine kinase system. Class Ib
PI3K is a p110.gamma. subtype activated by a G protein-coupled
receptor.
[0006] PI and PI(4)P are known as substrates for class II PI3Ks but
PI(4,5)P2 is not a substrate for the enzymes of this class. Class
II PI3Ks include PI3K C2.alpha., C2.beta. and C2.gamma. subtypes,
which are characterized by containing C2 domains at the C terminus,
implying that their activity will be regulated by calcium ions. The
substrate for class III PI3Ks is PI only. A mechanism for
activation of the class III PI3Ks is not clarified yet. Since each
subtype has its own mechanism for the regulating activity, it is
considered that the respective subtypes will be activated depending
on their respective stimuli specific to each of them.
[0007] In the PI3K subtypes, the class Ia subtype has been most
extensively investigated to date. The three subtypes of class Ia
are hetero dimers of a catalytic 110 kDa subunit and regulatory
subunits of 85 kDa and 55 kDa. The regulatory subunits contain SH2
domains and bind to tyrosine residues phosphorylated by growth
factor receptors with a tyrosine kinase activity or oncogene
products thereby inducing the PI3K activity of the p110 catalytic
subunit. Thus, the class Ia subtypes are considered to be
associated with cell proliferation and carcinogenesis. Furthermore,
the class Ia PI3K subtypes bind to activated ras oncogene to
express their enzyme activity. It has been confirmed that the
activated ras oncogene is found to be present in many cancers,
suggesting a role of class Ia PI3Ks in carcinogenesis.
[0008] As explained above, PI3K inhibitors are expected to be a
novel type of medicaments useful against cell proliferation
disorders, especially as carcinostatic agents. As for the PI3K
inhibitor, wortmannin [H. Yano et al., J. Biol. Chem., 263, 16178
(1993)] and LY294002 [J. Viahos et al., J. Biol. Chem., 269, 5241
(1994)] which is represented by the formula below are known.
However, development of PI3K inhibitors having a more potent cancer
cell growth inhibiting activity is desired.
##STR00001##
[0009] Japanese Patent KOKAI (Laid-Open) No. 6-220059 discloses
fused heteroaryl derivatives shown by formula (a) below which
possess an activity of reducing the blood glucose level.
Furthermore, compounds shown by formula (b) and formula (c) below
are described in Indian J. Chem., Sect. B (1993), 32B (9), 965-8
and J. Heterocycl. Chem. (1992), 29 (7), 1693-702, respectively. In
addition, Al-AzharBull. Sci. (1992), 3(2), 767-75 discloses a
compound shown by formula (d) below. However, none of these prior
art publications disclose or suggest the PI3K inhibiting
activity.
##STR00002##
[0010] In formula (a) above, Z is O, S or .dbd.N--R0, R1 is an
amino which may be substituted, a heterocyclic group which may be
substituted, etc.; R2 is cyano, an amino which may be substituted,
or a heterocyclic group which may be substituted; and with respect
to the remaining substituents, see the specification of the patent.
In formula (b) and (c) above, R is a (substituted) amino or a
(substituted) nitrogen-containing saturated heterocyclic group.
[0011] Publication No. WO98/23613 discloses fused pyrimidine
derivatives, such as 7H-pyrrolo[2,3-d]pyrimidine derivatives, which
having a tyrosine kinase receptor inhibiting activity and which are
useful as carcinostatic agents, wherein the fused pyrimidine
derivatives have at its fourth position a
particular-heteroaryl-substituted amino, pheny-substituted amino,
or indole-1-yl, and have no substituent at its second position.
[0012] Following compounds are known among the compounds shown by
general formula (I), whereas "A" ring is a ring shown by (b);
[0013] (1) Ann. Pharm. Fr. (1974), 32(11), 575-9 discloses
4-(4-morpholinyl)-2-phenylpirido[2,3-d]pyrimidine as a compound
having antiinflammatory and spasmolytic activities,
[0014] (2) Chem. Pharm. Bull. (1976), 24(9), 2057-77 discloses
4-(4-morpholinyl)-2-phenylpirido[2,3-d]pyrimidine-7(1H)-one as a
compound having a diuretic activity,
[0015] (3) Khim.-Farm. Zh. (1993), 7(7), 16-19 and Khim.
Geterotsiki. Soedin. (1971), 7(3), 418-20 disclose
4-(4-morpholinyl)-2-phenyl-6-quinazolinol and
6-methoxy-4-(4-morpholinyl)-2-phenylquinazoline as compounds having
an antibiotic activity,
[0016] (4) Publication No. WO2000/41697 discloses
2,4-diamino-6-phenyl-8-piperidinopyrimido[5,4-d]pyrimidine as a
compound having celebral ischemia prevention and treatment
effects,
[0017] (5) Publication No. WO99/32460 discloses, as cardiovascular
drugs, compounds of general formula (Ib) described hereinafter
wherein B is a benzene ring, W is N, n is 2 or 3, existing R1's are
all --OMe, and R4b is an unsubstituted phenyl or a phenyl
substituted by 1 to 3 substituents which are selected from -a
halogen, NO2, -a lower alkyl, --O-a lower alkyl, -a halogenated
lower alkyl and --CONRaRc,
[0018] (6) Publication No. BE841669 discloses, as antiparasitics,
compounds of general formula (Ib) described hereinafter wherein B
is a benzene ring, W is N, n is 1, R1 is -a halogen or -a lower
alkyl, and R4b is -(an imidazolyl which may have one or more
substituents),
[0019] (7) Publication No. WO99/43682 discloses, as antianxiety
agents, compounds of general formula (Ib) described hereinafter
wherein B is a thiophene ring, and W is CH,
[0020] (8) Japanese Patents KOKAI (Laid-Open) Nos. 62-10085 and
61-158983 disclose compounds of general formula (Ib) described
hereinafter wherein B is an imidazole ring, and W is N, whereas the
compounds have an antiinflammatory activity, a platelet aggregation
inhibiting activity, etc.,
[0021] (9) U.S. Pat. No. 3,873,545 and Act Pol. Pharm. (1994),
51(4-5), 359-63 disclose compounds of general formula (Ib)
described hereinafter wherein B is a pyridine ring, and R4b is an
unsubstituted phenyl, an unsubstituted pyridyl, or -a lower
alkylene-(a nitrogen-containing saturated heterocyclic group which
may have one or more substituents), whereas the compounds have a
spasmolytic, diuretic or hypotensive activity,
[0022] (10) U.S. Pat. No. 2,940,972 discloses compounds of general
formula (Ib) described hereinafter wherein B is a pyrazine ring,
and R4b is an unsubstituted phenyl, or a benzyl, whereas the
compounds have a coronary dilating or sedative activity,
[0023] (11) U.S. Pat. No. 3,753,981 and German Patent Publication
No. 2,140,280 disclose compounds of general formula (Ib) described
hereinafter wherein B is a benzene ring, and R4b is a styryl or
2-(5-nitro-2-furyl)vinyl, whereas the compounds have an
antiinflammatory or antibiotic activity, and
[0024] (12) Eur. J. Med. Chem. (1996), 31(5), 417-425, discloses
compounds of general formula (Ib) described hereinafter wherein B
is a benzene ring, W is CH, and R2 and R3 are bonded together with
an adjacent N atom to form -(piperidinyl which may have one or more
substituents) or -(piperazinyl which may have one or more
substituents), as compounds working as a benzodiazepine receptor
ligand, U.S. Pat. No. 4,560,692 discloses them as those having a
spasmolytic and ataractic activity, and Japanese Patents KOKAI
(Laid-Open) No. 2-129169 discloses them as those having a
lipoperoxidation inhibiting activity.
[0025] Furthermore, compounds of general formula (Ib) described
hereinafter wherein B is a pyridine ring and n is 0 are disclosed
in Japanese Patent KOKAI (Laid-Open) No. 51-138689
(antiparasitics), Japanese Patent KOKAI (Laid-Open) No. 56-120768
(a dye component for thermosensitive recording materials),
Antimicrob. Agents Chemother., (1975), 8 (2), 216-19 (an
antibacterial activity), Cancer Res. (1975), 35 (12), 3611-17 (a
mutagenic activity), CA 64: 19608c, Collect. Czech. Chem. Commun.,
(1994), 59 (6), 1463-6, U.S. Pat. No. 5,304,554 (an anti-HIV
activity), Chem. Pharm. Bull., (1982), 30(6), 1974-9, and J.
Heterocycl. Chem. (1980), 17(5), 1029-34. However, none of the
prior publications teach or even suggest the PI3K inhibiting
activity and carcinostatic activity.
SUMMARY OF THE INVENTION
[0026] The present inventors have performed extensive
investigations on compounds with a PI3K inhibiting activity. As a
result, it has been found that novel fused heteroaryl derivatives
have an excellent PI3K inhibiting activity as well as a cancer cell
growth inhibiting activity. Based on the finding, it has been
discovered that the fused heteroaryl derivatives could be excellent
PI3K inhibitors and antitumor agents. The present invention has
thus been achieved.
[0027] Therefore, the present invention relates to pharmaceutical
compositions, which are PI3K inhibitors or antitumor agents,
comprising a fused heteroaryl derivative represented by general
formula (I) below or a salt thereof and a pharmaceutically
acceptable carrier.
##STR00003## [0028] [wherein:
##STR00004##
[0029] B represents a benzene ring, or a 5- or 6-membered
monocyclic heteroaryl containing 1 to 2 hetero atoms selected from
O, S and N;
[0030] R1 represents -a lower alkyl, -a lower alkenyl, -a lower
alkynyl, -a cycloalkyl, -an aryl which may have one or more
substituents, -a heteroaryl which may have one or more
substituents, -a halogen, --NO2, --CN, -a halogenated lower alkyl,
--ORb, --SRb, --SO2-Rb, --SO--Rb, --COORb, --CO--Rb, --CONRaRb,
--SO2NRaRb, --NRaRb, --NRa--CORb, --NRa--SO2Rb, --O--CO--NRaRb or
--NRaCO--COORb, --CO-a nitrogen-containing saturated heterocyclic
group, --CONRa-a lower alkylene-ORb, --CONRa-a lower alkylene-NRb,
--O-a lower alkylene-ORb, --O-a lower alkylene-O-a lower
alkylene-ORb, --O-a lower alkylene-NRaRb, --O-a lower alkylene-O-a
lower alkylene-NRaRb, --O-a lower allylene-NRc-a lower
alkylene-NRaRb, --NRc-a lower alkylene-NRaRb, --N(a lower
alkylene-NRaRb)2, --CONRa--ORb, --NRa--CO--NRbRc, or --OCORb;
[0031] each of R2 and R3, which may be the same or different,
represents --H, -a lower alkyl, -a lower alkylene-ORa or -a lower
alkylene-NRaRc, or R2 and R3 are combined together with the N atom
adjacent thereto to form a nitrogen-containing saturated
heterocyclic group as --NR2R3 which may have one or more
substituents;
[0032] each of Ra and Rc, which may be the same or different,
represents --H or -a lower alkyl;
[0033] Rb represents --H, -a lower alkyl, a cycloalkyl, an aryl
which may have one or more substituents or a heteroaryl which may
have one or more substituents;
[0034] n represents 0, 1, 2 or 3;
[0035] each of W and X, which may be same or different, represents
N or CH;
[0036] Y represents O, S or NH;
[0037] and,
[0038] R4 represents --H, -a lower alkyl, -a lower alkenyl, -a
lower alkynyl, -(an aryl which may have one or more substituents),
-a lower alkylene-(an aryl which may have one or more
substituents), -a lower alkenylene-(an aryl which may have one or
more substituents), -a lower alkynylene-(an aryl which may have one
or more substituents), -(a cycloalkyl which may have one or more
substituents), -(a cycloalkenyl which may have one or more
substituents), -a lower alkylene-(a cycloalkyl which may have one
or more substituents), a lower alkenylene-(a cycloalkyl which may
have one or more substituents), -a lower alkylene-(a
nitrogen-containing saturated heterocyclic group which may have one
or more substituents), -a lower alkenylene-(a nitrogen-containing
saturated heterocyclic group which may have one or more
substituerits), -(a heteroaryl which may have one or more
substituents), -a lower alkylene-(a heteroaryl which may have one
or more substituents), or -a lower alkenylene-(a heteroaryl which
may have one or more substituents). The same applies
hereinbelow.
[0039] The compounds (I) of the present invention encompass the
known compounds as well as commercially available compounds later
described in Compound Z, which are all included within the
definition of formula (I).
[0040] The present invention further relates to a novel fused
heteroaryl derivative represented by general formula (Ia) or (Ib)
or salts thereof, as well as a novel pharmaceutical composition
comprising the same and a pharmaceutically acceptable carrier:
##STR00005##
[0041] [wherein:
[0042] R1 represents -a lower alkyl, -a lower alkenyl, -a lower
alkynyl, -a cycloalkyl, -an aryl which may have one or more
substituents, -a heteroaryl which may have one or more
substituents, -a halogen, --NO2, --CN, -a halogenated lower alkyl,
--ORb, --SRb, --SO2-Rb, --SO--Rb, --COORb, --CO--Rb, --CONRaRb,
--SO2NRaRb, --NRaRb, --NRa--CORb, --NRa--SO2Rb, --O--CO--NRaRb or
--NRaCO--COORb, --CO-a nitrogen-containing saturated heterocyclic
group, --CONRa-a lower alkyl-ORb; --CONRa-a lower alkylene-ORb,
--O-a lower alkylene-NRb, --O-a lower alkylene-O-a lower
alkylene-ORb, --O-a lower alkylene-NRaRb, --O-a lower alkylene-O-a
lower alkylene-NRaRb, --O-a lower alkylene-NRc-a lower
alkylene-NRaRb, --NRc-a lower alkylene-NRaRb, --N(a lower
alkylene-NRaRb)2, --CONRa--ORb, --NRa--CO--NRbRc, or --OCORb;
[0043] each of R2 and R3, which may be the same or different,
represents --H or -a lower alkyl, or R2 and R3 are combined
together with the N atom adjacent thereto to form a
nitrogen-containing saturated heterocyclic group as --NR2R3 which
may have one or more substituents;
[0044] Ra and Rc, which may be the same or different, represent --H
or -a lower alkyl;
[0045] Rb represents --H, -a lower alkyl, a cycloalkyl, an aryl
which may have one or more substituents or a heteroaryl which may
have one or more substituents;
[0046] n represents 0, 1, 2 or 3;
[0047] X represents N or CH;
[0048] Y represents O, S or NH;
[0049] and,
[0050] R.sup.4a represents -(an aryl which may have one or more
substituents), -a lower alkylene-(an aryl which may have one or
more substituents), -a lower alkenylene-(an aryl which may have one
or more substituents), -a lower alkynylene-(an aryl which may have
one or more substituents), -(a cycloalkyl which may have one or
more substituents), -(a cycloalkenyl which may have one or more
substituents), -a lower alkylene-(a cycloalkyl which may have one
or more substituents), -a lower alkenylene-(a cycloalkyl which may
have one or more substituents), -a lower alkylene-(a
nitrogen-containing saturated heterocyclic group which may have one
or more substituents), -a lower alkenylene-(a nitrogen-containing
saturated heterocyclic group which may have one or more
substituents), -(a heteroaryl which may have one or more
substituents), -a lower alkylene-(a heteroaryl which may have one
or more substituents), or -a lower alkenylene-(a heteroaryl which
may have one or more substituents); with the proviso that the
following compounds are excluded:
[0051] (1) compounds in which X represents N, Y represents S, n is
3 and R1 represents a combination of --CN, --OEt and phenyl, and
R4a represents 2-nitrophenyl;
[0052] (2) compounds in which X represents CH, and R4a represents
-(a heteroaryl which may have one or more substituents);
[0053] (3) compounds in which X represents CH, Y represents O, n is
O and R4a represents an unsubstituted phenyl; and
[0054] (4) compounds in which X represents N, Y represents S, n is
2, R1 represents an unsubstituted phenyl and R4a represents
4-methoxyphenyl or an unsubstituted phenyl. The same applies
hereinbelow.
##STR00006##
[0055] [wherein:
[0056] B represents a benzene ring, or a 5- or 6-membered
monocyclic heteroaryl containing 1 to 2 hetero atoms selected from
O, S and N;
[0057] R1 represents -a lower alkyl, -a lower alkenyl, -a lower
alkynyl, -a cycloalkyl, -an aryl which may have one or more
substituents, -a heteroaryl which may have one or more
substituents, -a halogen, --NO2, --CN, -a halogenated lower alkyl,
--ORb, --SRb, --SO2-Rb, --SO--Rb, --COORb, --CO--Rb, --CONRaRb,
--SO2NRaRb, --NRaRb, --NRa--CORb, --NRa--SO2Rb, --O--CO--NRaRb,
--NRaCO--COORb, --NRaCOORb, --NRaCO-a lower alkylene-an aryl,
--NRa--SO2-a lower alkylene-an aryl, --NRa-a lower alkylene-an
aryl, -a lower alkylene-ORb, -a lower alkylene-NRaRb, --CO-a
nitrogen-containing saturated heterocyclic group, --CONRa-a lower
alkylene-ORb, --CONRa-a lower alkylene-NRcRb, --CONRa-a lower
alkylene-a nitrogen-containing saturated heterocyclic group, --O-a
lower alkylene-ORb, --O-a lower alkylene-NRaRb, --O-a lower
alkylene-a nitrogen-containing saturated heterocyclic group, --O-a
lower alkylene-O-a lower alkylene-ORb, --O-a lower alkylene-O-a
lower alkylene-NRaRb, --O-a lower alkylene-NRc-a lower
alkylene-NRaRb, --NRc-a lower alkylene-NRaRb, --N(a lower
alkylene-NRaRb)2, --CONRa--ORb, --NRa--CO--NRbRc, or --OCORb;
[0058] R2 and R3 are combined together with the N atom adjacent
thereto to form --NR2R3 which is a nitrogen-containing saturated
heterocyclic group which may have one or more substituents;
[0059] Ra and Rc, which may be the same or different, represent --H
or -a lower alkyl;
[0060] Rb represents --H, -a lower alkyl, -a cycloalkyl, -(an aryl
which may have one or more substituents) or -(a heteroaryl which
may have one or more substituents);
[0061] n represents 0, 1, 2 or 3, whereas n represents 1, 2 or 3
when B represents a benzene ring;
[0062] W represents N or CH;
[0063] and,
[0064] R4b represents -(an aryl which may have one or more
substituents), -a lower alkylene-(an aryl which may have one or
more substituents), -a lower alkenylene-(an aryl which may have one
or more substituents), -a lower alkynylene-(an aryl which may have
one or more substituents), -(a cycloalkyl which may have one or
more substituents), -(a cycloalkenyl which may have one or more
substituents), -a lower alkylene-(a cycloalkyl which may have one
or more substituents), -a lower alkenylene-(a cycloalkyl which may
have one or more substituents), -a lower alkylene-(a
nitrogen-containing saturated heterocyclic group which may have one
or more substituents), -a lower alkenylene-(a nitrogen-containing
saturated heterocyclic group which may have one or more
substituents), -(a heteroaryl which may have one or more
substituents), -a lower alkylene-(a heteroaryl which may have one
or more substituents), or -a lower alkenylene-(a heteroaryl which
may have one or more substituents); with the proviso that the
following compounds are excluded:
[0065] (1) 4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidine,
[0066] (2)
4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidin-7(1H)-one,
[0067] (3) 4-(4-morpholinyl)-2-pheny-6-quinazolinol and
6-methoxy-4-(4-morpholinyl)-2-phenyquinazoline,
[0068] (4)
2,4-diamino-6-phenyl-8-piperidinopyrimido[5,4-d]pyrimidine,
[0069] (5) compounds in which B represents a benzene ring, W
represents N, n is 2 or 3, existing R1's all represent --OMe, and
R4b is an unsubstituted phenyl or a phenyl which is substituted by
1 to 3 substituents selected from -halogen, --NO2, -a lower alkyl,
--O-a lower alkyl, -a hanogenated lower alkyl and --CONRaRc,
[0070] (6) compounds in which B represents a benzene ring, W
represents N, n is 1, R1 represents -halogen or -a lower alkyl, and
R4b represents -(imidazolyl which may have one or more
substituents),
[0071] (7) compounds in which B represents a thiophene ring, and W
represents CH,
[0072] (8) compounds in which B represents an imidazole ring, and W
represents N,
[0073] (9) compounds in which B represents a pyridine ring, and R4b
represents an unsubstituted phenyl, an unsubstituted pyridyl, or -a
lower alkylene-(a nitrogen-containing saturated heterocyclic group
which may have one or more substituents),
[0074] (10) compounds in which B represents a pyrazine ring, and
R4b represents an unsubstituted phenyl, or a benzyl,
[0075] (11) compounds in which B represents a benzene ring, and R4b
represents a styryl or 2-(5-nitro-2-furyl)vinyl, and
[0076] (12) compounds in which B represents a benzene ring, W
represents CH, and R2 and R3 are combined together with the N atom
adjacent thereto to form -(piperidinyl which may have one or more
substituents) or -(piperazinyl which may have one or more
substituents). The same applies hereinbelow.
[0077] Further teaching of the present invention provides a method
to treat disorders (especially cancers) which are associated with
PI3K, wherein the method comprises of administering to a patient an
effective amount of a fused heteroaryl derivative of formula (I),
(Ia) or (Ib) above or a salt thereof as well as a use of said fused
heteroaryl derivative or a salt thereof for producing a medicament
(especially a carcinostatic agent) which inhibit PI3K.
EMBODIMENTS
[0078] The compounds of general formula (I), (Ia) or (Ib) are
described below in more detail.
[0079] The term "lower" throughout the specification is used to
mean a straight or branched hydrocarbon chain having 1 to 10,
preferably 1 to 6, and more preferably 1 to 3 carbon atoms.
[0080] Preferred examples of the "lower alkyl" are an alkyl having
1 to 3 carbon atoms, more preferably methyl and ethyl. Preferred
examples of the "lower alkenyl" include vinyl, allyl, 1-propenyl,
isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl. Preferred examples
of the "lower alkynyl" include ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl. The terms
"lower alkylene", "lower alkenylene" and "lower alkynylene" are
used to mean bivalent groups of the lower alkyl, lower alkenyl and
lower alkynyl described above. Preferred examples of these groups
are methylene, ethylene, vinylene, propenylene, ethynylene and
propynylene. The terms "cycloalkyl" and "cycloalkenyl" refer to
cycloalkyl and cycloalkenyl groups preferably having 3 to 8 carbon
atoms. Preferred examples of these groups include cyclopropyl,
cyclopentyl, cyclohexyl and cyclopentenyl.
[0081] Examples of the "halogen" are F, Cl, Br and I. Examples of
the "halogenated lower alkyl" are the aforementioned lower alkyl
groups which are further substituted with one or more halogen atoms
described above, preferably --CF3.
[0082] The term "nitrogen-containing saturated heterocyclic group"
throughout the specification refers to a 5- to 7-membered
heterocyclic group containing one or two nitrogen atoms on the
ring, which may further contain one O or S atom and may form a
bridge structure or may be fused with one benzene ring. Preferred
examples of such heterocyclic group are pyrrolidinyl, piperazinyl,
piperidyl and morpholinyl. Preferred examples of the
nitrogen-containing saturated heterocyclic group as --NR2R3 are
1-pyrrolidinyl, 1-piperazinyl, piperidino and morpholino, with
particular preference to morpholino.
[0083] The term "aryl" is used throughout the specification to mean
an aromatic cyclic hydrocarbon group. An aryl having 6 to 14 carbon
atoms is preferable. Preferred examples of such aryl are phenyl and
naphthyl.
[0084] The term "heteroaryl" refers to a 5- or 6-membered
monocyclic heteroaryl containing 1 to 4 hetero atoms selected from
N, S and O as well as a bicyclic heteroaryl fused to a benzene
ring. The heteroaryl may be partially saturated. Preferred examples
of the monocyclic heteroaryl are furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, -thiazolyl, isothiazolyl, oxazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and
pyrazinyl. Examples of the bicyclic heteroaryl are preferably
benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,
benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl,
isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl and
benzodioxolyl. Specific examples of the partially saturated
heteroaryl are 1,2,3,4-tetrahydroquinolyl, etc. Particularly
preferred are 5- to 6-membered monocyclic groups, more preferably
imidazolyl, thiazolyl, triazolyl, pyridyl and pyrazinyl.
[0085] Examples of a "5- or 6-membered monocyclic heteroaryl
containing 1 or 2 hetero atoms selected from O, S and N" in B
include a furan, thiophene, pyrole, imidazole, pyrazole, thiazole,
isothiazole, oxazole, pyridine, pyrimidine, pyridazine and pyrazine
ring. Preferably, it is a pyridine, pyrazine or thiophene ring.
More preferable, it is a pyridine ring.
[0086] The substituents for the "aryl which may have one or more
substituents", "heteroaryl which may have one or more
substituents", "cycloalkyl which may have one or more
substituents", "cycloalkenyl which may have one or more
substituents" or "nitrogen-containing saturated heterocyclic group
which may have one or more substituents" are 1-5 substituents,
which may be the same or different. Preferably, these substituents
are selected from Group A described below. Each of R, R' and R'',
which may be the same or different, represents H or a lower alkyl
(the same shall apply hereinafter).
[0087] Group A: -a lower alkyl, -a lower alkenyl, -a lower alkynyl,
-a halogen, -a halogenated lower alkyl, -a lower alkylene-OR,
--NO2, --CN, .dbd.O, --OR, --O-- a halogenated lower alkyl, --O-a
lower alkylene-NRR', --O-a lower alkylene-OR, --O-a lower
alkylene-an aryl, --SR, --SO2-a lower alkyl, --SO-a lower alkyl,
--COOR, --COO-a lower alkylene-an aryl, --COR, --CO-an aryl, -an
aryl, --CONRR', --SO2NRR', --NRR', --NR''-a lower alkylene-NRR',
--NR'-a lower alkylene-OR, --NR-a lower alkylene-an aryl, --NRCO-a
lower alkyl, --NRSO2-a lower alkyl, -a cycloalkyl and -a
cycloalkenyl.
[0088] When R4, R4a and R4b represent "an aryl which may have one
or more substituents" or "a heteroaryl which may have one or more
substituents", the substituents are 1 to 5 groups selected from a)
through c) below, which may be the same or different.
[0089] a): -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a
halogen, -a halogenated lower alkyl, -a lower alkylene-OR, --NO2,
--CN, .dbd.O, --O-halogenated lower alkyl, --SO2-a lower alkyl,
--SO-a lower alkyl, --COOR, --COO-a lower alkylene-an aryl, --COR,
--CO-an aryl, --CONRR', --SO2NRR', -Cyc or -Alp-Cyc (wherein Alp
represents a lower alkylene, a lower alkenylene or a lower
alkynylene, and Cyc represents an aryl which may have 1 to 5
substituents selected from Group A, a heteroaryl which may have 1
to 5 substituents selected from Group A, a nitrogen-containing
saturated heterocyclic group which may have 1 to 5 substituents
selected from Group A, a cycloalkyl which may have 1 to 5
substituents selected from Group A, or a cycloalkenyl which may
havel to 5 substituents selected from Group A; the same shall apply
hereinafter).
[0090] b): --NR-E-F (wherein E represents --CO--, --COO--,
--CONR'--, --SO2NR'-- or --SO2-; F represents -Cyc or -(a lower
alkyl, a lower alkenyl or a lower alkynyl which may be substituted
by one or more substituents selected from the group comprising of
-a halogen, --NO2, --CN, --OR, --O-a lower alkylene-NRR', --O-a
lower alkylene-OR, --SR, --SO2-a lower alkyl, --SO-a lower alkyl,
--COOR, --COR, --CO-an aryl, --CONRR', --SO2NRR', --NRCO-a lower
alkyl, --NRR', --NR'-a lower alkylene-OR, --NR''-a lower
alkylene-NRR' and -Cyc); and the same shall apply hereinafter).
[0091] c): --Z--R', --Z-Cyc, --Z-Alp-Cyc, --Z-Alp-Z'--R' or
--Z-Alp-Z'-Cyc (wherein each of Z and Z', which may be the same or
different, independently represents O, S or NR; and the same shall
apply hereinafter).
[0092] The particularly preferred ones are -a lower alkylene-OR,
--CONRR', --NR--CO-Cyc1 (wherein Cyc1 is -an aryl which may have
1-5 substituents selected from Group A, -a heteroaryl which may
have 1-5 substituents selected from Group A, or -a
nitrogen-containing saturated heterocyclic group which may have 1-5
substituents selected from Group A, and the same applies
hereinbelow), --NR--SO2-Cyc1, --OR, --NRR', --O-a lower
alkylene-NRR' and --O-a lower alkylene-(a nitrogen-containing
saturated ring which may have 1.about.5 substituents selected from
Group A).
[0093] When n is 2 to 4, each R1 group may be the same or
different, independently.
[0094] In the compounds which are shown by formulas (I), (Ia) and
(Ib) of the present invention, the following compounds are
preferred:
[0095] (1) Compounds in which R2 and R3 forms --NR2R3 which is a
nitrogen-containing saturated heterocyclic group which may have 1-2
substituents selected from the group comprising of --OH, .dbd.O and
-a lower alkyl;
[0096] (2) Compounds in which R2 and R3 forms --NR2R3 which is
-morpholino;
[0097] (3) Compounds in which W is N;
[0098] (4) Compounds in which R4, R4a or R4b represents -(an aryl
which may have one or more substituents) or -(a heteroaryl which
may have one or more substituents);
[0099] (5) Compounds in which B represents a benzene ring; R1
represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a
cycloalkyl, -an aryl which may have one or more substituents, -a
heteroaryl which may have one or more substituents, -a halogen,
--NO2, --CN, -a halogenated lower alkyl, --ORb, --SRb, --SO2-Rb,
--SO--Rb, --COORb, --CO--Rb, --CONRaRb, --SO2NRaRb, --NRaRb,
--NRa--CORb, --NRa--SO2Rb, --O--CO--NRaRb or --NRaCO--COORb;
[0100] (6) Compounds in which B is a pyridine, pyrazine or
thiophene ring and n is 0;
[0101] (7) Compounds in which X represents N, Y represents O and n
is 0; and
[0102] (8) Compounds in which R4, R4a or R4b represents an aryl
which has one or more substituents selected from the group
comprising of -a lower alkylene-OR, --CONRR', --NR--CO-Cyc1,
--NR--SO2-Cyc1, --OR, --NRR', --O-a lower alkylene-NRR' and --O-a
lower alkylene-(a nitrogen-containing saturated heterocyclic group
which may have 1-5 substituents selected from Group A).
[0103] The particularly preferred compounds shown by general
formula (Ia) are those having R4a which is a phenyl having at least
one substituent which is selected from of the group comprising of
--OH, --NH2, --NH-a lower alkyl, --N(a lower alkyl)2, --O-a lower
alkylene-NH2 and --O-a lower alkylene-(a nitrogen-containing
saturated heterocyclic group which may be substituted by a lower
alkyl).
[0104] Moreover, the following compounds shown by general formula
(Ib) are particularly preferred:
[0105] (1) Compounds in which. W represents N, R4b represents -(an
aryl which may have one or more substituents), and R2 and R3 form
--NR2R3 which is -morpholino;
[0106] (2) Compounds in which B represents a benzene ring, n is 1
or 2, and R1 represents -a halogen, --NO2, --CN, -a halogenated
lower alkyl, --ORb, --SRb, --NRaRb, --NRa--CORb or --NRa--SO2Rb;
and
[0107] (3) Compounds in which B represents a pyridine, pyrazine or
thiophene ring, n is 0, and R4b represents a phenyl which has at
least one substituent which is selected from --OH, --CH2OH and
--CONH2.
[0108] Among the compounds of the present invention, the preferred
ones which are shown by general formula (Ia) are (Co 17)
6-amino-3'-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)nicoti-
nanilide, (Co 33)
4-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)aniline,
(Co 50)
3-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)phenol,
(Co 69)
4-morpholino-2-[3-(2-piperazin-1-ylethoxy)phenyl]pyrido[3',2':4,5]fur-
o[3,2-d]pyrimidine, (Co 73)
3'-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl)acrylanilide,
and salts thereof. The preferred ones which are shown by general
formula (Ib) are (Co 144)
N-[2-(3-benzenesulfonylaminophenyl)-4-morphoniloquinazolin-6-yl]acetamide-
, (Co 164) 3-(4-morpholinopyrido[4,3-d]pyrimidin-2-yl)phenol, (Co
172) 3-(4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenol, (Co 174)
3-(4-morpholinopyrido[3,4-d]pyrimidin-2-yl)phenol, (Co 186)
3-(6-methoxy-4-morpholinoquinazolin-2-yl)phenol, (Co 190)
3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol, (Co 191)
3-(4-morpholinopteridin-2-yl)phenol, and salts thereof.
[0109] The compound of this invention may exist in the form of
geometrical isomers or tautomers depending on the kinds of
substituent groups, and these isomers in separated forms or
mixtures thereof are included in the present invention. Also, the
compound of the present invention may have asynmmetric carbon
atoms, so that optical isomer forms may exist based on such carbon
atoms. All of the mixtures and the isolated forms of these optical
isomers are included in the present invention.
[0110] Some of the compounds of the invention may form salts. There
is no particular limitation so long as the formed salts are
pharmacologically acceptable. Specific examples of acid salts are
salts with inorganic acids such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid,
etc., organic acids such as formic acid, acetic acid, propionic
acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic
acid, etc. Specific examples of basic salts include salts with
inorganic bases containing metals such as sodium, potassium,
magnesium, calcium, aluminum, etc., or salts with organic bases
such as methylamine, ethylamine, ethanolamine, lysine, ornithine,
etc. In addition, various hydrates and solvates and polymorphism of
the compound (I), (Ia) or (Ib) and salts thereof are also included
in this invention.
[0111] (Processes for Producing Compounds)
[0112] Hereinafter representative processes for producing the
compounds of the present invention are described below. In these
processes, functional groups present in the starting materials or
intermediates may be suitably protected with protective groups,
depending upon the kinds of functional groups. In view of the
preparation technique, it may be advantageous to protect the
functional groups with groups that can be readily reverted to the
original functional groups. When required, the protective groups
are removed to give the desired products. Examples of such
functional groups are amino, hydroxy, carboxyl, etc. Examples of
the protective groups which may be used to protect these functional
groups are shown in, e.g., Greene and Wuts, "Protective Groups in
Organic Synthesis", second edition. These protective groups may be
appropriately employed depending upon reaction conditions.
##STR00007##
[0113] (Here and Hereinafter, L Represents a Leaving Group.)
[0114] This process for producing the compounds (I) of the present
invention comprises converting the compounds shown by general
formula (II) to reactive derivatives thereof (III) in a
conventional manner and then reacting an amine (IV) with the
reactive derivatives. When another reactive site containing the
leaving group L also exists on the ring A or the substituent R4 in
the reactive derivatives (III), the same or different amine (IV)
may be reacted again, if necessary. In a similar manner, when the A
ring or R4 of the compounds of the present invention has a leaving
group L such as a chloro or fluoro, transformations of functional
groups may be conducted such as a hydrolysis reaction according to
a method described in J. Am. Chem. Soc., 68, 1288 (1946) or an
ipso-substitution reaction using alkoxide as a reacting agent
according to a method described in Tetrahedron Lett., 40, 675
(1999).
[0115] The leaving group shown by L is preferably a halogen, or an
organic sulfonyloxy group, e.g., methanesulfonyloxy,
p-toluenesulfonyloxy, etc.
[0116] The reaction for preparing the reactive derivatives (III)
can be carried out by the usual procedures. Where the leaving group
is chlorine, phosphorus oxychloride, oxalyl chloride or thionyl
chloride can be reacted under cooling or heating or at room
temperature in an inert organic solvent or without. As such an
inert organic solvent, there is an aromatic hydrocarbon solvent
such as benzene or toluene; an ethereal solvent such as
tetrahydrofuran (THF), 1,4-dioxane, etc.; a halogenated hydrocarbon
solvent such as dichloromethane, chloroform, etc.; and a basic
solvent such as pyridine or collidine. These solvents may be used
alone or as a mixture of two or more. The solvent is optionally
selected depending on the kinds of starting compounds. The addition
of a base (preferably a dialkylaniline, triethylamine, ammonia,
lutidine, collidine, etc.), phosphorus chloride (e.g., phosphorus
pentachloride), a quaternary ammonium salt (e.g.,
tetraethylammonium chloride), or an N,N-dialkylamide compound
(e.g., dimethylformamide (DMF)) may be advantageous in some cases
from the viewpoint of accelerating the reaction. Where the leaving
group is sulfonyloxy, the active intermediates (III) can be
synthesized from the corresponding sulfonyl chloride by the usual
procedures, e.g., using a method described in Tetrahedron Lett. 23
(22), 2253 (1982) or Tetrahedron Lett. 27 (34), 4047 (1986).
[0117] The reaction for producing the compounds (I) from the
reactive derivatives (III) and the amine (IV) can be carried out by
reacting the amine (IV) in an inert organic solvent or in the
absence of any solvents under cooling or heating or at room
temperature. The solvent described above is available and it may be
used singly or as a mixture of two or more. The addition of an
inorganic base such as sodium hydride, or an organic base such as
triethylamine (TEA), pyridine or 2,6-lutidine, may be advantageous
in some cases from the viewpoint of accelerating the reaction
##STR00008##
[0118] (Wherein Rd is a lower alkyl which may have one or more
substituents and Rb has the same definition as defined above; and
the same shall apply hereinafter.)
[0119] This process comprises O-alkylation of the
hydroxy-substituted compounds shown by general formula (Ia) or (Ic)
in a conventional manner to obtain the compounds (Ib) or (Id).
[0120] The reaction may be carried out, e.g., by reacting the
compounds (Ia) or (Ic) with an alkylating agent such as an alkyl
halide or a sulfonic acid ester in the presence of a base such as
triethylamine, potassium carbonate, sodium carbonate, cesium
carbonate, sodium hydroxide, sodium hydride or potassium
t-butoxide. The reaction temperature can be under cooling or
heating or at room temperature, and can be appropriately chosen
depending on the kinds of starting compounds. When water is used or
contained as a solvent in an O-alkylation reaction, the reaction
may be accelerated by the addition of a phase transfer catalyst
such as tetra n-butylammoniurn hydrogensulfate.
[0121] Another method for the O-alkylation reaction is Mitsunobu
reaction. For example, methods described in Synthesis, 1 (1981) or
modified methods may be used. For the hydroxyethylation of a
hydroxyl group, methods using carbonate ester such as
[1,3]dioxolane-2-one are also effective. As an example, methods
described in J. Am. Chem. Soc., 68, 781 (1946) can be used.
[0122] Moreover, when functional groups exist on Rb and Rd of the
compounds (Ib) and (Id) of the present invention, known reactions
may be employed to convert the functional group. For example, when
a hydroxyl group is present on Rb and Rd, the aforementioned
O-alkylation reaction can be conducted, and when a leaving group is
present such as a halogen, an appropriate alcohol or amine can be
reacted with utilizing the conditions of said O-alkylation or
N-alkylation described hereinafter in Production Method 4. When an
ester group is present, the functional group can be converted to a
carboxylic acid, hydroxymethyl group, and amido, using a method
described hereinafter in Production Method 3.
[0123] The starting compounds (Ia) and (Ic) used in this process
can be prepared by the method described for Production Method 1,
using starting compounds whose OH group has been protected by an
acyl type protective group (e.g., acetyl or tosyl). Further, when
phosphorus oxychloride is used as a reacting agent for synthesizing
reactive derivatives (III) and then a desired amino is reacted to
synthesize (I), protective groups for OH group may be removed and
O-phosphoramides may be produced, depending on the kind of starting
compounds, a protective group, reaction conditions and conditions
for work-up. In that case, for example, using a method described in
Chem. Pharm. Bull., 37, 2564 (1989), phosphoramides groups can be
removed. Other general protective groups can be introduced and
removed by the methods described in "Protective Groups in Organic
Synthesis" supra.
##STR00009##
[0124] (Wherein Rf is a lower alkyl and Rg is a lower alkyl which
may have one or more substituents; and the same shall apply
hereinafter.)
[0125] Production Method 3 comprises transformations of the
functional groups of the ester compounds of the present invention
shown by general formula (Ie) to produce the hydroxymethyl
compounds (If), carboxylic acid derivatives (Ig) and amide
derivatives (Ih) of the present invention, respectively. Each of
the reactions can be carried out in a conventional manner, e.g., as
described in Jikken Kagaku Kouza (Encyclopedia for Experimental
Chemistry) edited by Nihon Kagaku Kai (Japanese Association of
Chemistry) and published by Maruzen Co., Ltd., and "Protective
Groups in Organic Synthesis" supra.
[0126] Preferably, the reduction to give the hydroxymethyl
compounds (If) can be conducted in an inert organic solvent to the
reactions, e.g., an ethereal solvent or an aromatic hydrocarbon
solvent, using a reducing agent such as lithium aluminum hydride,
lithium borohydride, zinc borohydride, boran, Vitride, etc. The
hydrolysis to give the carboxylic acid derivatives (Ik) can be
conducted by reacting with lithium hydroxide, sodium hydroxide or
potassium hydroxide in a single solvent selected from methanol,
ethanol, THF and water, or a mixture of two or more. The amidation
to give the amide compounds (Ih) may be performed by converting
carboxylic acids to reactive derivatives such as acyl halides (acyl
chlorides, etc.) or acid anhydrides, and then reacting the reactive
derivatives with amines. In the reaction with amines, it is
preferred to conduct the reaction in an inert organic solvent in
the presence of a base (an inorganic base such as sodium hydroxide,
or an organic base such as TEA, diisopropylethylamine or pyridine).
Furthermore, the amidation using the carboxylic acid as a starting
compound can also be carried out in an inert organic solvent in the
presence of a condensation agent such as
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),
1,1'-carbonylbis-1H-imidazole (CDI), etc.). In this case, an
additive such as 1-hydroxybenzotriazol (HOBt) or the like may also
be added to the reaction. The reaction temperature and solvent can
be appropriately chosen depending on the kinds or the like of
starting compounds.
##STR00010##
(Wherein R' has the same definition as defined above, Rh is -a
lower alkyl which may have one or more substituents, Ri is -Cyc or
-Alp which may have one or more substituents, a C ring is a
nitrogen-containing saturated heterocyclic group which may have one
or more substituents, and Rj is --H, -a lower alkyl, -an aryl,
etc.; and the same shall apply hereinafter.)
[0127] Production Method 4 comprises the reduction of the nitro
compounds shown by general formula (Ii) to the corresponding amino
compounds (Ij) and then subjecting the amino compounds (Ij) to
various modification reactions including N-alkylation, amidation,
sulfonamidation, conversion to the corresponding urea, conversion
to the corresponding carbamic acid, imidation or conversion to the
corresponding thiazoles, to give the compounds (Ik), (Ir), (In),
(Io), (Ip), (Iq) and (Ir), respectively. These products can be
appropriately subjected to further known modification reactions
such as N-alkylation, if necessary.
[0128] These reactions can all be carried out in a conventional
manner, e.g., using the methods described in "Jikken Kagaku Kouza"
supra, or "Protective Groups in Organic Synthesis" supra. Preferred
procedures in these methods are described below.
[0129] The reduction of the nitro compounds can be carried out in
an alcoholic solvent such as methanol in a gaseous hydrogen
atmosphere using palladium on carbon (Pd--C).
[0130] When various aldehydes are employed as the starting
compounds, the N-alkylation can be conducted by reductive amination
using aldehydes and reducing agents such as sodium borohydride,
sodium triacetoxyborohydride or sodium cyanoborohydride. Reducting
amination using Dean-Stark apparatus could be useful, too. When an
alkyl halide such as methyl iodide or benzyl bromide, or dimethyl
sulfate is employed as an alkylating agent, the reaction can be
carried out in an inert organic solvent, e.g., DMF, acetonitrile or
toluene, in the presence of base such as potassium carbonate,
sodium hydroxide or sodium hydride, under cooling or heating or at
room temperature. For monoalkylation, an example of useful
procedure is as follows: protection of amino group by acyl group
such as trifluoroacetyl, alkylation of acylamide by conventional
methods using halogenated alkyl, and removal of protection. The
dialkylation can be conducted by reacting 2 equivalents or more of
a halogenated alkyl. For dimethylation, the reaction with formalin
in formic acid at room temperature or under heating is also
useful.
[0131] The amidation reaction may be performed in a similar manner
to that described above for Production Method 3. The
sulfonamidation can be carried out in an inert organic solvent
using a reactive derivative such as an acid halide (acid chloride,
etc.) or an acid anhydride. The conversion to the corresponding
urea can be conducted by reacting with isocyanates in an inert
organic solvent, e.g., an aromatic hydrocarbon solvent, under
cooling or heating or at room temperature. The conversion to the
corresponding carbamic acids can be conducted by reacting
chloroformate derivatives in an inert organic solvent under cooling
or heating or at room temperature. The imidation can be carried out
using agents such as succinic anhydride or maleic anhydride.
[0132] The conversion to the corresponding aminothiazole compounds
can be conducted by converting the amino compounds to the
corresponding thiourea derivatives and then reacting the
derivatives with an .alpha.-halogenated ketone. Compounds (Ij) can
be converted into the thiourea derivatives by methods described in,
e.g., Synth. Cornmun. 1998, 28 (8), 1451; J. Org. Chem., 1984, 49
(6), 997, Org. Synth., 1963, IV, 180; J. Am. Chem. Soc., 1934, 56,
1408, etc. The conversion of the thiourea derivatives into the
thiazole derivatives can be conducted by reacting the thiourea
derivatives with the .alpha.-halogenated ketone in an alcoholic
solvent such as ethanol or a carbonyl solvent such as methyl ethyl
ketone, under cooling or heating or at room temperature. The
addition of a base (potassium carbonate, sodium carbonate, etc.)
may be effective in some cases from the viewpoint of accelerating
the reaction.
##STR00011##
[0133] (Wherein Rk and Rm each represents -a lower alkyl which may
have one or more substituents.)
[0134] Production Method 5 comprises converting the nitro compounds
of the invention shown by general formula (Is) to the corresponding
amino compounds (It) and then subjecting them to various
modification reactions to obtain the other compounds of the present
invention. Each reaction can be carried out as described for
Production Method 4.
[0135] Other Production Method
[0136] Other compounds included in the present invention can be
obtained in the same manner as described above or by using methods
well known to those skilled in the art. For instance, the reactions
are carried out appropriately using methods described in "Jikken
Kagaku Kouza" supra, or "Protective Groups in Organic Synthesis"
supra.
[0137] For example, the demethylation reaction of compounds with an
aryl group into the corresponding phenol derivatives can be carried
out by the methods described in "Protective Groups in Organic
Synthesis" supra, i.e., the method of reacting with a demethylating
agent such as sodium cyanide or potassium cyanide in a solvent such
as dimethylsulfoxide (DMSO), etc., at room temperature or under
heating.
[0138] Processes for Preparing Starting Compounds The starting
compounds (II) for the synthesis of the present invention can be
performed in conventional manners, e.g., by the reactions shown in
the following synthetic routes.
##STR00012##
[0139] (Wherein Rn is a lower alkyl; and the same shall apply
hereinafter.)
[0140] The starting compounds (IIc) can be synthesized by a
cyclization reaction of amide intermediates (5) or cyclization
conducted by reacting anthranylic acid derivatives (1) as the
starting compounds with imidates (6). Conventional cyclization
reactions for preparing pyrimidine ring are available for the
cyclization reaction for this purpose. For instance, the method
described in Chem. Pharm. Bull., 39 (2), 352 (1991) can be used for
the cyclization of the intermediates (5) and the intermediates (1)
and (6) as the starting materials can be cyclized by the method
described in J. Med. Chem., 9, 408 (1966). The amide intermediates
(5) can be synthesized by amidation of the aniline derivatives (4)
in a conventional manner, or by sequential conversions of
esterification of a carboxylic acid in (1), acylation of an amino,
and amidation of the ester group according to conventional methods.
For example, the amide intermediates (5) can be obtained in
accordance with the methods described in J. Med. Chem., 33, 1722
(1990), Eur. J. Med. Chem.-Chim. Ther., 9(3), 305 (1974), etc. When
(3) is obtained by acylation using (2) as the starting materials,
diacylation may take place depending on the starting compounds and
reaction conditions. In such a case, treatment with basic
conditions will give desired monoacyl compounds (3).
##STR00013##
[0141] The starting compounds (IId) can be synthesized by
cyclization of the amide intermediates (12) or by cyclization of
the ester intermediates (7) and the amide compounds (10). The
intermediates (12) can be cyclized in the same manner as described
above; where the intermediates (7) and (10) are used as the
starting compounds, the cyclization can be carried out by the
method described in, e.g., J. Med. Chem., 37, 2106 (1994). The
amide intermediates (12) can be prepared by conversion of the
functional group in ester compounds (7) in a conventional manner.
The bicyclic ester intermediates (9) can be synthesized by
formation of a 5-membered ring by reacting nitrile compounds (7)
with ester compounds (8) in the presence of a base, for example, in
accordance with the method described in J. Org. Chem., 37, 3224.
(1972) or J. Heterocycl. Chem., 11 (6), 975 (1974), etc.
##STR00014##
[0142] The starting compounds (IIe) can be synthesized, e.g., by
cyclization of the starting compounds (14). Preferably, the
compounds (14) are heated in a solvent with a high boiling point
such as diphenyl ether or in the absence of any solvents. The
starting compounds (14) can be synthesized in a conventional
manner, e.g., by condensation of the corresponding anilines (13)
with the compounds (15).
[0143] Each of the reaction products obtained by the aforementioned
production methods is isolated and purified as a free base or a
salt thereof. The salt can be produced by a usual salt forming
method. The isolation and purification are carried out by employing
usually used chemical techniques such as extraction, concentration,
evaporation, crystallization, filtration, recrystallization,
various types of chromatography and the like.
[0144] Various forms of isomers can be isolated by the usual
procedures making use of physicochemical differences among isomers.
For instance, racemic compounds can be separated by means of a
conventional optical resolution method (e.g., by forming
diastereomer salts with a conventional optically active acid such
as tartaric acid, etc. and then optically resolving the salts) to
give optically pure isomers. A mixture of diastereomers can be
separated by conventional means, e.g., fractional crystallization
or chromatography. In addition, an optical isomer can also be
synthesized from an appropriate optically active starting
compound.
INDUSTRIAL APPLICABILITY
[0145] The compounds of the present invention exhibit a PI3K
inhibitory activity and therefore, can be utilized in order to
inhibit abnormal cell growths in which PI3K plays a role. Thus, the
compounds are effective in the treatment of disorders with which
abnormal cell growth actions of PI3K are associated, such as
restenosis, atherosclerosis, bone disorders, arthritis, diabetic
retinopathy, psoriasis, benign prostatic hypertrophy,
atherosclerosis, inflamation, angiogenesis, immunological
disorders, pancreatitis, kidney disease, cancer, etc. In
particular, the compounds of the present invention possess
excellent cancer cell growth inhibiting effects and are effective
in treating cancers, preferably all types of solid cancers and
malignant lymphomas, and especially, leukemia, skin cancer, bladder
cancer, breast cancer, uterus cancer, ovary cancer, prostate
cancer, lung cancer, colon cancer, pancreas cancer, renal cancer,
gastric cancer, brain tumor, etc.
[0146] The pharmacological effect of the compounds according to the
invention have been verified by the following pharmacological
tests.
Test Example 1
Inhibition of PI3K (p110.alpha. Subtype)
[0147] Inhibition was determined using enzyme (bovine p110.alpha.)
prepared in the baculovirus expression system. Bovine p110 was
prepared according to a modification from the method by I. Hiles et
al., Cell, 70, 419 (1992). Each compound to be assayed was
dissolved in DMSO and the obtained 10 mM DMSO solution was serially
diluted with DMSO.
[0148] The compound (0.5 .mu.l) to be assayed and enzyme were mixed
in 25 .mu.l of buffer solution (40 mM Tris-HCl (pH 7.4), 200 mM
NaCl, 2 mM dithiothreitol, 5 mM MgCl2). Then, 25 .mu.l of 5 mM
Tris-HCl (pH 7.4) buffered solution supplemented with 10 .mu.g PI
(Sigma), 2.mu. Ci [.gamma.-32P]ATP (Amersham Pharmacia) and 80
.mu.M non-radiolabeled ATP (Sigma) was added to the mixture to
initiate the reaction. After reacting at 37.degree. C. for 15
minutes, 200 .mu.l of 1M HCl and 400 .mu.l of CHCl3/MeOH (1:1) were
added to the reaction mixture. The resulting mixture was stirred
and then centrifuged. After the organic layer was again extracted
twice with 150 .mu.l of MeOH/1M HCl (1:1). The radioactivity was
measured using Cerenkov light.
[0149] The IC50 inhibition activity was defined by a 50% inhibition
concentration of each compound assayed, which was converted from
the radioactivity determined as 100% when DMSO alone was added and
as 0% when no enzyme was added.
[0150] The compounds of the prevent invention exhibited an
excellent p110.alpha. subtype inhibition activity. For example,
IC50 of Compound (hereinafter, abbreviated as Co) 10, Co 17, and Co
24 were less than 1 .mu.M.
[0151] Moreover, compounds of the prevent invention were confirmed
to have inhibiting activities against other subtypes (such as a C2
.beta. subtype).
Test Example 2
Colon Cancer Cell Growth Inhibition
[0152] HCT116 cells from a colon cancer cell line were cultured in
McCoy's 5A medium (GIBCO) supplemented with 10% fetal bovine serum.
HCT116 cells were inoculated on a 96 well plate (5000 cells/well)
followed by overnight incubation. The test compound diluted with
the medium was added to the medium in a final concentration of 0.1
to 30M (final DMSO concentration, 1%). After incubation over 72
hours, Alamar Blue reagent was added to the medium. Two hours after
the addition, a ratio of fluorescent intensity at an excitation
wavelength of 530 nm to that at an emission wavelength of 590 nm
was measured to determine the IC50. Co 14, Co 24, Co 25, Co 31, Co
46 and Co 47 of the present invention exerted an excellent cancer
cell growth inhibition activity.
Test Example 3
Melanoma Cell Growth Inhibition
[0153] A375 cells from a melanoma cell line were cultured in DMEM
medium (GIBCO) supplemented with 10% fetal bovine serum. A375 cells
at 10,000 cells/100 .mu.l were added to a 96 well plate which
contained 1 .mu.l/well of the test compounds (final concentration
of 0.001 .about.30 .mu.M). After incubation for over 46 hours,
Alamar Blue reagent was added to the medium (10 .mu.l/well). Two
hours after the addition, a ratio of fluorescent intensity at an
excitation wavelength of 530 nm to that at an emission wavelength
of 590 nm was measured to determine the IC50 of the test compounds
in the same manner as in the above examples.
[0154] The compounds of the prevent invention exhibited an
excellent cancer cell growth inhibition activity. For example, Co
17, Co 33, Co 50, Co 69, Co 164, Co 172, Co 174, Co 186, Co 190 and
Co 191 exerted a good melanoma cell growth inhibition activity.
Their IC50 values were 0.33-4.26 .mu.M. Contrarily, the known PI3K
inhibitor LY294002 showed a value of 8.39 .mu.M.
[0155] In addition to the above cancer cell lines, the compounds of
the present invention exhibited excellent cancer cell growth
inhibiting activities against Hela cells from a cervix cancer cell
line, A549, H460 cells from a lung cancer cell line, COLO205, WiDr,
Lovo cells from a colon cancer cell line, PC3, LNCap cells from a
prostate cancer cell line, SKOV-3, OVCAR-3, CH1 cells from an ovary
cancer cell line, U87 MG cells from a glioma cell line and BxPC-3
cells from a pancreas cancer cell line.
Test Example 4
In Vivo Cancer Cell Growth Inhibition
[0156] A single-cell suspension of HelaS3 (5.times.106 cells), a
human cervix cancer cell line, was inoculated into the flank of
female Balb/c nude mice by subcutaneously injection. When the tumor
reached 100-200 mm3 in volume, test compounds were
intraperitoneally administered once a day for two weeks. 20%
Hydroxypropyl-.beta.-cyclodextrin/saline was intraperitoneally
administered with the same schedule as a control group. The
diameter of the tumors was measured with a vernier caliper at
certain time intervals until one day after the final doze
administration. The tumor volume was calculated by the following
formula: 1/2.times.(a shorter diameter)2.times.(a longer
diameter).
[0157] In the present test, test compounds exhibited superior
anti-tumor activities as compared with the control group.
[0158] The pharmaceutical composition of the present invention can
be prepared in a conventional manner by mixing one or more
compounds of the invention shown by general formula (I) with a
carrier for medical use, a filler and other additives usually used
in pharmaceutical preparation. The pharmaceutical composition of
the invention may be administered either orally in the form of
tablets, pills, capsules, granules, powders, liquid, etc., or
parenterally such as by intravenous or intramuscular injection, in
the form of suppositories, or through pernasal, permucosal or
subcutaneous route.
[0159] For oral administration of the composition in the present
invention, a solid composition in the form of, e.g., tablets,
powders or granules is available. In such a solid composition, one
or more active or effective ingredients are blended with at least
one inert diluent such as lactose, mannitol, glucose, hydroxypropyl
cellulose, microcrystalline cellulose, starch, polyvinyl
pyrrolidone or magnesium aluminate metasilicate. The composition
may further contain additives other than the inert diluent by the
usual procedures. Examples of such additives include a lubricant
such as magnesium stearate, a disintegrating agent such as calcium
cellulose glycolate, a solubilization assisting agent such as
glutaniic acid or aspartic acid. Tablets or pills may be coated, if
necessary, with films of sugar or a gastric or enteric substance
such as sucrose, gelatin, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose phthalate, etc.
[0160] A liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, elixirs, etc. and contains an inert diluent conventionally
employed, e.g., purified water or ethanol. In addition to the inert
diluent above, the liquid composition may further contain an
auxiliary agent such as a moistening agent or a suspending agent, a
sweetener, a flavor and/or a preservative.
[0161] A composition for parenteral administration contains a
sterile aqueous or non-aqueous solution, a suspension and an
emulsion. Examples of the aqueous solution and suspension include
distilled water for injection use and physiological saline. Typical
examples of the non-aqueous solution and suspension are propylene
glycol, polyethylene glycol, vegetable oil such as olive oil, an
alcohol such as ethanol, polysorbate 80, and the like. These
compositions may further contain a preservative, a moistening
agent, an emulsifier, a dispersing agent, a stabilizer and a
solubilization assisting agent. These compositions are sterilized,
e.g., by filtering them through a bacteria retention filter,
incorporating a bactericide or through irradiation. Alternatively,
they may be prepared into a sterile solid composition, which is
dissolved in sterile water or a sterile solvent for injection prior
to use.
[0162] In the case of oral administration, suitable daily does is
usually about 0.0001 to 50 mg/kg body weight, preferably about
0.001 to 10 mg/kg, more preferably about 0.01 to 1 mg/kg, and the
daily does is administered once a day or divided into 2 to 4 doses
per day. In the case of intravenous injection, suitable daily dose
is usually about 0.0001 to 1 mg/kg body weight, preferably about
0.0001 to 0.1 mg/kg. And the daily does is administered once a day
or divided into a plurality of doses per day. The dose may be
appropriately determined for each case, depending on conditions,
age, sex, etc.
[0163] The compounds of the present invention can be utilized
alone, or in conjunction with other treatments (e.g., radiotherapy
and surgery). Moreover, they can be utilized in conjunction with
other antitumor agents, such as alkylation agents (cisplatin,
carboplatin, etc.), antimetabolites (methotrexate, 5-FU, etc.),
antitumor antibiotics (adriamymnycin, bleomycin, etc.), antitumor
vegetable alkaloids (taxbol, etoposide, etc.), antitumor hormones
(dexamethasone, tamoxifen, etc.), antitumor immunological agents
(interferon .alpha., .beta., .gamma., etc.), and so forth.
EXAMPLES
[0164] The present invention will be described in more detail by
referring to the following EXAMPLES but is not deemed to be limited
thereto.
[0165] The following Tables 1.about.3 and 13.about.161 show
starting compounds which were used in EXAMPLES, and Tables
4.about.11 and 17.about.24 show structural formulas as well as
physicochemical properties of the compounds of the present
invention. Moreover, the compounds of the present invention with
structural formulas shown in Tables 12 and 25.about.26 can be
easily produced in the same manner as in the EXAMPLES mentioned
hereinafter or in accordance with the Production Methods mentioned
hereinabove, or by applying thereto some modifications which are
obvious to those skilled in the art.
[0166] In the tables, abbreviations are used to mean the
following.
[0167] Rco: starting compounds number
[0168] Rex: Production method of Reference Example compounds (a
following number represents a Reference Example number described
hereinafter, indicating that the compound was prepared using the
method described in the Reference Example or the one similar
thereto.)
[0169] Co: compounds number of the present invention
[0170] Str: structural formula
[0171] Sal: salt
[0172] Syn: production method (a following number represents a
number of an EXAMPLE described hereinbelow, indicating that the
associated compound is produced using the method described in the
EXAMPLE or a similar method.)
[0173] Dat: physicochemical properties wherein:
[0174] F: FAB-MS (M+H)+
[0175] FN: FAB-MS (M-H)-
[0176] E: EI-MS
[0177] M: melting point [.degree. C.]
[0178] (dec.): Decomposition
[0179] N1: characteristic peaks .delta. ppm of NMR (DMSO-d6, TMS
internal standard)
[0180] Ac: acetyl
[0181] Bn: benzyl
[0182] Ph: phenyl
[0183] Ts: 4-toluenesulfonyl
[0184] Ms: methanesulfonyl
[0185] Me: methyl
[0186] Et: ethyl
[0187] Where two or more positions to permit substitution are
present, the position substituted is indicated as a prefix (e.g.,
6-MeO-7-HO represents 6-methoxy-7-hydroxy.).
TABLE-US-00001 TABLE 1 Rco Rex Str DAT 1 1 ##STR00015## F: 249 2 1
##STR00016## F: 277 3 2 ##STR00017## F: 206 4 3 ##STR00018## F: 327
5 3 ##STR00019## F: 353 6 3 ##STR00020## F: 341 7 3 ##STR00021## F:
398 8 3 ##STR00022## F: 381 9 3 ##STR00023## F: 310 10 3
##STR00024## F: 341 11 4 ##STR00025## F: 356 12 4 ##STR00026## F:
375 13 5 ##STR00027## F: 299 14 5 ##STR00028## FN: 311 15 5
##STR00029## FN: 281 16 5 ##STR00030## FN: 311
TABLE-US-00002 TABLE 2 Rco Rex Str DAT 17 5 ##STR00031## FN: 326 18
5 ##STR00032## F: 282 19 5 ##STR00033## F: 311 20 5 ##STR00034##
FN: 326 21 6 ##STR00035## F: 298 22 6 ##STR00036## FN: 279 23 6
##STR00037## FN: 325 24 6 ##STR00038## F: 282 25 6 ##STR00039## F:
310 26 6 ##STR00040## F: 312 27 6 ##STR00041## F: 312 28 6
##STR00042## FN: 325 29 7 ##STR00043## F: 188 30 8 ##STR00044## E:
279 31 8 ##STR00045## E: 308 32 8 ##STR00046## F: 264
TABLE-US-00003 TABLE 3 Rco Rex Str DAT 33 8 ##STR00047## F: 309 34
8 ##STR00048## F: 292 35 8 ##STR00049## F: 263 36 8 ##STR00050## F:
294 37 8 ##STR00051## E: 293 38 9 ##STR00052## F: 322 39 9
##STR00053## E: 321 40 3 ##STR00054## F: 341 41 4 ##STR00055## FN:
344 42 5 ##STR00056## FN: 311 43 5 ##STR00057## FN: 316 44 6
##STR00058## F: 312 45 6 ##STR00059## F: 317 46 8 ##STR00060## F:
293 47 8 ##STR00061## FN: 297 48 9 ##STR00062## F: 322 49 19
##STR00063## F: 207
TABLE-US-00004 TABLE 4 Co Syn Str DAT 1 1 ##STR00064## F: 378 2 1
##STR00065## E: 377 3 2 ##STR00066## F: 593 4 2 ##STR00067## N1:
4.15 (4H, t, J = 4.4 Hz), 8.52 (1H, s), 10.41 (1H, s). 5 2
##STR00068## F: 593 6 2 ##STR00069## F: 497 7 12 ##STR00070## M:
206- 208 Z -- ##STR00071## : SPECS and BioSPECS B.V. :
AE-848/3855062)
TABLE-US-00005 TABLE 5 Co Syn X Y NR.sup.2R.sup.3 R.sup.4 Sal DAT 8
3 N O ##STR00072## ##STR00073## -- M: 229-230; N1: 3.85 (4H, t, J =
4.8 Hz), 7.22-7.25 (1H, m), 10.47 (1H, s) 9 3 N O ##STR00074##
##STR00075## -- M: 291-293; N1: 2.74 (3H, s), 7.39 (1H, t, J = 7.8
Hz), 8.23 (1H, s) 10 4 N O ##STR00076## ##STR00077## -- M: 266-268;
N1: 3.87 (4H, t, J = 4.8 Hz), 7.51 (1H, t, J = 7.8 Hz), 10.78 (1H,
s) 11 4 N O ##STR00078## ##STR00079## -- F: 487 12 5 N O
##STR00080## ##STR00081## HCl N1: 3.87 (4H, t, J = 4.8 Hz), 8.87
(1H, s), 11.06 (1H, s) 13 5 N O ##STR00082## ##STR00083## HCl N1:
3.88 (4H, t, J = 4.8 Hz), 9.34 (1H, s), 10.88 (1H, s) 14 5 N O
##STR00084## ##STR00085## 2HCl N1: 3.86 (4H, t, J = 4.8 Hz), 8.14
(1H, s), 10.85 (1H, s) 15 5 N O ##STR00086## ##STR00087## 2HCl N1:
3.87 (4H, t, J = 4.4 Hz), 7.56 (1H, t, J = 7.8 Hz), 11.26 (1H, s)
16 5 N O ##STR00088## ##STR00089## HCl N1: 3.87 (4H, t, J = 4.4
Hz), 8.84 (1H, s), 10.72 (1H, s) 17 5 N O ##STR00090## ##STR00091##
2HCl M: 203-207; N1: 3.86 (4H, t, J = 4.9 Hz), 7.52 (1H, t, J = 7.8
Hz), 10.71 (1H, s) 18 5 N O ##STR00092## ##STR00093## -- N1:
1.35-1.48 (1H, m), 3.85 (4H, t, J = 4.4 Hz), 10.19 (1H, s)
TABLE-US-00006 TABLE 6 Co Syn X Y NR.sup.2R.sup.3 R.sup.4 Sal DAT
19 5 N O ##STR00094## ##STR00095## 2HCl M: 203-206 20 5 N O
##STR00096## ##STR00097## -- F: 487 21 5 N O ##STR00098##
##STR00099## 2HCl MS: 173-175; N1: 7.53 (1H, t, J = 7.8 Hz),
8.24-8.29 (2H, m), 11.01 (1H, s) 22 5 N O ##STR00100## ##STR00101##
HCl N1: 3.87 (4H, m), 8.30 (2H, s), 10.06 (1H, s) 23 5 N O
##STR00102## ##STR00103## 2HCl N1: 4.39 (2H, s), 7.47 (1H, t, J =
7.7 Hz), 10.87 (1H, s) 24 6 N O ##STR00104## ##STR00105## -- N1:
2.09 (3H, s), 3.87 (4H, t, J = 4.9 Hz), 10.11 (1H, s) 25 7 N O
##STR00106## ##STR00107## 2HCl M: 213-217 26 7 N O ##STR00108##
##STR00109## 3HCl M: 203-205 27 7 N O ##STR00110## ##STR00111##
2HCl N1: 1.50-1.90 (5H, m), 3.86 (4H, t, J = 4.9 Hz), 11.00 (1H, s)
28 7 N O ##STR00112## ##STR00113## 2HCl N1: 1.83-2.06 (4H, m), 3.86
(4H, t, J = 4.4 Hz), 10.37 (1H, s) 29 8 N O ##STR00114##
##STR00115## -- N1: 2.84 (4H, s), 3.85 (4H, t, J = 4.9 Hz),
7.38-7.40 (1H, m) 30 9 N O ##STR00116## ##STR00117## HCl M: 293-295
31 10 N O ##STR00118## ##STR00119## 2HCl M: 237-240
TABLE-US-00007 TABLE 7 Co Syn X Y NR.sup.2R.sup.3 R.sup.4 Sal DAT
32 10 N O ##STR00120## ##STR00121## 2HCl N1: 3.87 (4H, t, J = 4.4
Hz), 7.51-7.55 (2H, m), 10.68 (1H, s) 33 10 N O ##STR00122##
##STR00123## HCl M: 262-266; N1: 3.86 (4H, t, J = 4.4 Hz), 8.37
(2H, d, J = 8.8 Hz), 8.70 (1H, dd, J = 1.5, 4.9 Hz) 34 11 N O
NH.sub.2 H -- N1: 7.59 (1H, dd, J = 4.8, 7.8 Hz), 7.72 (2H, br s),
8.45 (1H, s) 35 12 N O ##STR00124## ##STR00125## -- M: 237-239 36
12 N NH ##STR00126## ##STR00127## -- M: 248-250 37 12 N S
##STR00128## ##STR00129## -- M: 201-202 38 12 N O ##STR00130## H --
M: 182-183 39 12 CH S ##STR00131## H HCl M: 202-205 40 13 N O
##STR00132## ##STR00133## 2HCl M: 237-240; N1: 3.09-3.14 (2H, m),
7.50 (1H, t, J = 7.8 Hz), 10.59 (1H, s) 41 13 N O ##STR00134##
##STR00135## 3HCl M: 178 (dec.); N1: 3.13-3.16 (2H, m), 7.54 (1H,
t, J = 7.8 Hz), 11.04 (1H, s) 42 13 N O ##STR00136## ##STR00137##
2HCl M: 282-285; N1: 3.09 (3H, s), 7.51 (1H, t, J = 7.8 Hz), 10.79
(1H, s) 43 13 N O ##STR00138## ##STR00139## 2HCl M: 257-261; N1:
4.81 (2H, s), 7.33- 7.53 (6H, m), 10.76 (1H, s) 44 14 N O
##STR00140## ##STR00141## 2HCl M: 234-237; N1: 3.32 (6H, s), 7.53
(1H, t, J = 7.8 Hz), 10.75 (1H, s) 45 15 N O ##STR00142##
##STR00143## HCl M: 244-245; N1: 3.87 (4H, t, J = 4.9 Hz),
7.49-7.67 (5H, m), 10.47 (1H, s)
TABLE-US-00008 TABLE 8 Co Syn X Y NR.sup.2R.sup.3 R.sup.4 Sal DAT
46 15 N O ##STR00144## ##STR00145## 2HCl N1: 3.87 (4H, t, J = 4.9
Hz), 7.53 (1H, t, J = 7.8 Hz), 10.73 (1H, s) 47 15 N O ##STR00146##
##STR00147## 2HCl N1: 3.87 (4H, t, J = 4.9 Hz), 7.55 (1H, t, J =
7.8 Hz), 10.86 (1H, s) 48 15 N O ##STR00148## ##STR00149## HCl M:
195-197; N1: 3.62 (3H, s), 7.44 (1H, t, J = 7.8 Hz), 10.25 (1H, s)
49 16 N O ##STR00150## ##STR00151## HCl M: 164-167; N1: 2.55-2.64
(4H, m), 7.43 (1H, t, J = 7.8 Hz), 10.17 (1H, s) 50 17 N O
##STR00152## ##STR00153## HCl M: 270-272; N1: 4.15 (4H, t, J = 4.8
Hz), 7.32 (1H, t, J = 7.8 Hz), 8.70 (1H, dd, J = 1.9, 4.9 Hz) 51 17
N O ##STR00154## ##STR00155## HCl M: 182-184; N1: 3.87 (3H, s),
7.45 (1H, t, J = 7.8 Hz), 8.69 (1H, dd, J = 1.5, 4.9 Hz) 52 17 N O
##STR00156## ##STR00157## HCl M: 306 (dec.); N1: 3.85 (4H, t, J =
4.9 Hz), 6.91 (2H, d, J = 8.8 Hz), 8.32 (2H, d, J = 8.8 Hz) 53 17 N
O ##STR00158## ##STR00159## HCl N1: 2.18 (3H, s), 8.11 (1H, s),
12.50 (1H, s) 54 18 N O ##STR00160## ##STR00161## 2HCl M: 186-190;
N1: 4.15 (4H, t, J = 4.4 Hz), 4.59 (2H, t, J = 4.8 Hz), 7.49 (1H,
t, J = 7.8 Hz) 55 18 N O ##STR00162## ##STR00163## 2HCl M: 283-286;
N1: 1.35-1.47 (1H, m), 4.56 (2H, t, J = 4.9 Hz), 7.49 (1H, t, J =
7.8 Hz) 56 18 N O ##STR00164## ##STR00165## 2HCl M: 233-235; N1:
1.30 (6H, t, J = 7.3 Hz), 4.53 (2H, t, J = 4.9 Hz), 7.49 (1H, t, J
= 7.8 Hz) 57 18 N O ##STR00166## ##STR00167## 2HCl M: 275-277; N1:
3.19-3.28 (2H, m), 7.15 (2H, d, J = 8.8 Hz), 8.46 (2H, d, J = 8.8
Hz)
TABLE-US-00009 TABLE 9 (Ia) ##STR00168## Co Syn R Sal DAT 58 47
##STR00169## HCl N1: 3.29-3.34 (2H, m), 7.46 (1H, t, J = 7.8 Hz),
8.68-8.71 (2H, m) 59 48 ##STR00170## 2HCl M: 206-210; N1: 4.17 (4H,
t, J = 4.9 Hz), 7.73 (1H, d, J = 7.8 Hz), 7.81 (1H, s) 60 49
NHCOCF.sub.3 -- N1: 3.86 (4H, t, J = 4.9 Hz), 7.64 (1H, dd, J =
5.0, 7.7 Hz), 11.43 (1H, s) 61 18 ##STR00171## -- N1: 7.56-7.67
(3H, m), 8.48-8.53 (2H, m), 8.62-8.65 (1H, m) 62 50 ##STR00172## --
N1: 3.83-3.88 (6H, m), 7.45 (1H, t, J = 7.9 Hz), 8.67-8.72 (2H, m)
63 50 ##STR00173## -- N1: 1.85-2.07 (4H, m), 4.10-4.14 (6H, m),
8.65-8.70 (2H, m) 64 51 ##STR00174## 3HCl N1: 2.85 (3H, br s), 4.16
(4H, t, J = 4.4 Hz), 7.66 (1H, dd, J = 4.9, 7.8 Hz) 65 18
##STR00175## -- N1: 4.19 (2H, t, J = 4.9 Hz), 7.62 (1H, t, J = 7.8
Hz), 7.96 (1H, s) 66 51 ##STR00176## 2HCl M: 196-198; N1: 3.33 (6H,
s), 7.50 (1H, t, J = 7.8 Hz), 8.07-8.11 (2H, m) 67 51 ##STR00177##
HCl N1: 4.12 (4H, t, J = 4.3 Hz), 8.09 (1H, d, J = 8.0 Hz),
8.65-8.69 (2H, m) 68 51 ##STR00178## 2HCl M: 243-248; N1: 3.01-3.10
(2H, m), 3.15- 3.20 (2H, m), 7.65 (1H, dd, J = 4.9, 7.8 Hz) 69 52
##STR00179## 3HCl M: 250-253; N1: 4.56 (2H, t, J = 4.9 Hz), 7.49
(1H, t, J = 7.8 Hz), 8.10 (1H, d, J = 7.8 Hz) 70 53 ##STR00180##
2HCl N1: 3.05 (3H, s), 4.19 (4H, t, J = 4.4 Hz), 7.91 (1H, br
s)
TABLE-US-00010 TABLE 10 Co Syn R Sal DAT 71 15 ##STR00181## 2HCl M:
244-245; N1: 1.84 (3H, s), 4.11-4.18 (6H, m), 7.64-7.72 (3H, m) 72
51 ##STR00182## 2HCl M: 196-201; N1: 4.15 (4H, t, J = 4.4 Hz), 7.74
(1H, s), 9.34 (1H, s) 73 15 ##STR00183## HCl N1: 5.79 (1H, d, J =
10.8 Hz), 6.30 (1H, d, J = 17.1 Hz), 10.40 (1H, s) 74 51
##STR00184## 2HCl N1: 4.15 (4H, t, J = 4.9 Hz), 4.53-4.56 (2H, m),
8.05 (1H, s) 75 18 ##STR00185## HCl N1: 1.24 (3H, t, J = 6.8 Hz),
4.22 (2H, q, J = 6.8 Hz), 4.89 (2H, s) 76 16 ##STR00186## HCl M:
264-267; N1: 4.79 (2H, s), 7.45 (1H, t, J = 7.8 Hz), 7.64 (1H, dd,
J = 4.9, 7.8 Hz) 77 54 ##STR00187## HCl M: 243-244; N1: 3.78 (2H,
t, J = 4.9 Hz), 4.14 (4H, t, J = 4.9 Hz), 7.98-7.99 (1H, m)
TABLE-US-00011 TABLE 11 (Ia) ##STR00188## Co Syn R.sup.4 Sal DAT 78
47 ##STR00189## 2HCl N1: 3.05-3.14 (2H, m), 3.26-3.31 (2H, m), 7.10
(2H, d, J = 8.8 Hz) 79 55 ##STR00190## -- N1: 4.15 (4H, t, J = 4.9
Hz), 7.66 (1H, dd, J = 4.9, 7.8 Hz), 8.15 (1H, dd, J = 1.5, 7.8 Hz)
80 12 ##STR00191## -- N1: 4.16 (4H, t, J = 4.9 Hz), 7.67 (1H, dd, J
= 4.9, 7.3 Hz), 8.34-8.35 (2H, m) 81 56 ##STR00192## -- M: 343-347;
N1: 7.64 (1H, dd, J = 4.9, 7.3 Hz), 8.66-8.69 (2H, m), 11.72 (1H,
br)
TABLE-US-00012 TABLE 12 (Ia) ##STR00193## Co X Y R.sup.4 A1 N S
##STR00194## A2 N S ##STR00195## A3 N S ##STR00196## A4 N S
##STR00197## A5 N S ##STR00198## A6 N S ##STR00199## A7 N S
##STR00200## A8 N S ##STR00201## A9 N S ##STR00202## A10 N S
##STR00203## A11 N S ##STR00204## A12 N S ##STR00205## A13 N S
##STR00206## A14 N S ##STR00207## A15 N S ##STR00208## A16 N S
##STR00209## A17 N S ##STR00210## A18 N S ##STR00211## A19 N S
##STR00212## A20 N S ##STR00213## A21 N S ##STR00214## A22 N S
##STR00215## A23 N S ##STR00216## A24 N S ##STR00217## A25 N S
##STR00218## A26 N S ##STR00219##
TABLE-US-00013 TABLE 13 Rco Rex Str DAT 50 10 ##STR00220## F: 208
51 10 ##STR00221## F: 240 52 11 ##STR00222## E: 324 53 11
##STR00223## F: 321 54 11 ##STR00224## F: 283 55 11 ##STR00225## F:
253 56 11 ##STR00226## F: 241 57 11 ##STR00227## F: 321 58 11
##STR00228## F: 280 59 11 ##STR00229## FN: 282 60 11 ##STR00230##
FN: 282 61 11 ##STR00231## F: 297 62 11 ##STR00232## FN: 227 63 11
##STR00233## F: 297 64 11 ##STR00234## F: 329 65 11 ##STR00235## F:
290 66 11 ##STR00236## F: 329 67 12 ##STR00237## F: 259 68 12
##STR00238## F: 313 69 12 ##STR00239## F: 279
TABLE-US-00014 TABLE 14 Rco Rex Str DAT 70 12 ##STR00240## F: 271
71 12 ##STR00241## F: 254 72 13 ##STR00242## F: 255 73 13
##STR00243## F: 293 74 14 ##STR00244## F: 407 75 14 ##STR00245## F:
317 76 14 ##STR00246## F: 393 77 15 ##STR00247## F: 299 78 15
##STR00248## F: 281 79 15 ##STR00249## F: 397 80 15 ##STR00250## F:
287 81 15 ##STR00251## F: 321 82 15 ##STR00252## F: 282 83 16
##STR00253## FN: 324 84 16 ##STR00254## F: 271 85 16 ##STR00255##
F: 371 86 16 ##STR00256## F: 339 87 16 ##STR00257## FN: 369 88 16
##STR00258## F: 332 89 16 ##STR00259## F: 339
TABLE-US-00015 TABLE 15 Rco Rex Str DAT 90 16 ##STR00260## F: 326
91 16 ##STR00261## F: 400 92 17 ##STR00262## F: 339 93 17
##STR00263## F: 341 94 17 ##STR00264## F: 369 95 18 ##STR00265##
FN: 359 96 3 ##STR00266## F: 286 97 3 ##STR00267## F: 287 98 3
##STR00268## F: 287 99 3 ##STR00269## F: 292 100 3 ##STR00270## F:
302 101 3 ##STR00271## F: 422 102 8 ##STR00272## F: 254 103 8
##STR00273## F: 254 104 8 ##STR00274## F: 382 105 8 ##STR00275## F:
269 106 9 ##STR00276## F: 281 107 9 ##STR00277## F: 283 108 9
##STR00278## F: 282 109 9 ##STR00279## F: 282
TABLE-US-00016 TABLE 16 Rco Rex Str DAT 110 9 ##STR00280## F: 299
111 9 ##STR00281## F: 410 112 9 ##STR00282## F: 286 113 9
##STR00283## F: 282 114 9 ##STR00284## F: 282 115 11 ##STR00285##
F: 286 116 20 ##STR00286## F: 254 117 21 ##STR00287## F: 272 118 21
##STR00288## F: 272 119 22 ##STR00289## F: 329 120 22 ##STR00290##
F: 400 121 23 ##STR00291## F: 311 122 24 ##STR00292## F: 259 123 24
##STR00293## F: 255 124 24 ##STR00294## F: 269
TABLE-US-00017 TABLE 17 (Ib) ##STR00295## Co Syn X R.sup.1
NR.sup.2R.sup.3 R.sup.4 Sal DAT 82 19 N H ##STR00296## ##STR00297##
-- M: 111-412; N2: 3.86 (4H, m), 3.95 (4H, m), 8.56 (2H, m) 83 19 N
6-F ##STR00298## ##STR00299## -- M: 157-159; N2: 3.80 (4H, t, J =
4.7 Hz), 3.94 (4H, t, J = 4.7 Hz), 8.50- 8.54 (2H, m) 84 19 N
6-MeO- 7-MeO ##STR00300## ##STR00301## -- M: 182-186. 85 19 N
6-NO.sub.2 ##STR00302## ##STR00303## -- M: 238-240; N1: 3.83 (4H,
t, J = 4.9 Hz), 7.99 (1H, d, J = 8.8 Hz), 8.82 (1H, d, J = 2.4 Hz)
86 19 N 6-AcHN ##STR00304## ##STR00305## -- M: 121-124 87 19 N
6-McO ##STR00306## ##STR00307## -- M: 145-146; N1: 3.79 (4H, m),
3.87 (4H, m), 3.94 (3H, s) 88 19 N 6-AcHN ##STR00308## ##STR00309##
-- N1: 8.52 (1H, s), 8.86 (1H, m), 10.36 (1H, s) 89 19 N 6-MeO
##STR00310## ##STR00311## -- M: 161-163 89 19 N 6-MeO ##STR00312##
##STR00313## -- M: 218-220 90 19 N 6-MsHN ##STR00314## ##STR00315##
-- N1: 3.10 (3H, s), 3.80-3.90 (8H, m), 10.18 (1H, br) 91 19 CH
6-MeO ##STR00316## ##STR00317## -- N1: 3.92 (8H, m), 7.96 (1H, d, J
= 8.8 Hz), 8.22 (2H, m) 92 20 N 6-MeO- 7-OH ##STR00318##
##STR00319## -- M: 202-204; N1: 3.70 (4H, t, J = 4.4 Hz), 3.98 (3H,
s), 7.07 (1H, s) 93 20 N 6-HO ##STR00320## ##STR00321## -- M:
203-205; N1: 3.79 (4H, m), 3.87 (4H, m), 10.22 (1H, s) 94 20 N 6-HO
##STR00322## ##STR00323## -- M: 222-225 (dec.); N1: 3.72 (4H, m),
4.82 (1H, brs), 8.01 (1H, brs)
TABLE-US-00018 TABLE 18 Co Syn X R.sup.1 NR.sup.2R.sup.3 R.sup.4
Sal DAT 96 20 N 6-HO ##STR00324## ##STR00325## -- M: 296-305 (dec.)
97 21 N 6-H.sub.2N ##STR00326## ##STR00327## -- M: 184-186 98 22 N
6-OHCHN- ##STR00328## ##STR00329## -- M: 218-222; N1: 3.79 (4H, t,
J = 4.2 Hz), 8.41 (1H, d, J = 1.5 Hz), 10.59 (1H, s) 99 23 N 6-HO
##STR00330## ##STR00331## -- M: 243-249; N1: 4.07 (2H, s), 7.67
(1H, d, J = 8.8 Hz), 10.00 (1H, s) 100 23 N 6-HO ##STR00332##
##STR00333## -- M: 258-262 (dec.) 101 23 N 6-HO ##STR00334## H --
M: 259-260; N1: 3.57 (4H, t, J = 4.7 Hz), 8.55 (1H, s) 10.12 (1H,
s) 102 23 N 6-HO ##STR00335## ##STR00336## -- M: 249-250; N1: 3.82
(1H, m), 7.77 (1H, d, J = 9.6 Hz), 10.08 (1H, s) 103 23 N 6-HO
##STR00337## ##STR00338## -- M: 221-225; N1: 1.20 (6H, d, J = 6.4
Hz), 7.80 (1H, d, J = 8.8 Hz), 10.12 (1H, s) 104 23 N 6-HO
##STR00339## ##STR00340## -- M: 139-141 105 24 N 6-AcMeN-
##STR00341## ##STR00342## -- M: 204-206 106 25 N 6-TsHN-
##STR00343## ##STR00344## -- M: 199-200; N1: 2.32 (3H, s) 3.62 (4H,
t, J = 4.4 Hz), 10.65 (1H, s) 107 26 N 6-Me.sub.2N- ##STR00345##
##STR00346## -- M: 124-125 108 27 N 6-HO ##STR00347## ##STR00348##
0.5 HCl M: 268-271 109 28 N 6-HO ##STR00349## Me -- M: 281-284
TABLE-US-00019 TABLE 19 Co Syn X R.sup.1 NR.sup.2R.sup.3 R.sup.4
Sal DAT 110 29 N 7-HO ##STR00350## ##STR00351## -- M: 245-246 111
29 N 6-HO ##STR00352## ##STR00353## -- M: 266-269; N1: 3.74 (4H, t,
J = 4.4 Hz), 8.66 (2H, d, J = 9.1 Hz), 10.29 (1H, s) 112 29 N 6-HO
##STR00354## ##STR00355## -- M: 226-227 113 29 N 6-HO ##STR00356##
##STR00357## -- N1: 1.94 (2H, m), 2.69 (1H, m), 7.65 (1H, d, J =
8.8 Hz) 114 29 N 6-HO ##STR00358## ##STR00359## -- M: 275-277; N1:
7.83 (1H, d, J = 8.8 Hz), 9.58 (1H, d, J = 1.5 Hz), 10.09 (1H, brs)
115 29 N 6-HO ##STR00360## ##STR00361## -- M: 280 (dec.) 116 29 N
6-HO ##STR00362## ##STR00363## -- M: 239-241 117 29 N 6-HO
##STR00364## ##STR00365## -- M: 184-186; N1: 3.92 (3H, s), 9.03
(1H, br), 10.19 (1H, s) 118 29 N 6-HO ##STR00366## ##STR00367## --
M: 280-284; N1: 3.68 (4H, t, J = 4.5 Hz), 9.49 (1H, s), 10.12 (1H,
s) 119 29 N 6-HO ##STR00368## ##STR00369## -- M: 306-311 (dec.);
N1: 7.75 (1H, d, J = 8.8 Hz), 9.29 (2H, s), 10.10 (1H, s) 120 29 N
6-HO ##STR00370## ##STR00371## -- M: 254-255 121 29 N 6-HO
##STR00372## ##STR00373## -- M: 288-290 122 29 N 6-HO ##STR00374##
##STR00375## -- M: 188-190; N1: 3.80 (3H, s), 13.83 (3H, s), 10.06
(1H, s) 123 29 N 6-HO ##STR00376## ##STR00377## -- M: 224-227
TABLE-US-00020 TABLE 20 Co Syn X R.sup.1 NR.sup.2R.sup.3 R.sup.4
Sal DAT 124 29 N 6-HO ##STR00378## ##STR00379## -- M: 285-288; N1:
3.88 (3H, s), 9.37 (1H, s), 10.03 (1H, s) 125 29 N 6-HO
##STR00380## ##STR00381## -- M: 310-313 N1: 3.71 (4H, m) 3.87 (4H,
m), 10.23 (1H, s) 126 29 N 6-HO ##STR00382## ##STR00383## -- M:
178-180 127 30 N 6-HO ##STR00384## ##STR00385## -- M: 260-263; N1:
3.64 (4H, m), 3.86 (4H, m), 1H, 10.12 (1H, s) 128 30 N 6-HO
##STR00386## ##STR00387## -- M: 280-282 129 31 N 6-HO ##STR00388##
##STR00389## -- M: 285 (dec.); N1: 3.62 (4H, t, J = 4.7 Hz), 5.51
(2H, br), 9.95 (1H, s) 130 32 N 6-HO ##STR00390## ##STR00391## --
M: 305 (dec.) 131 32 N 6-HO ##STR00392## ##STR00393## -- M:
306-309; N1: 3.71 (4H, t, J = 4.9 Hz), 10.18 (1H, s), 13.08 (1H, s)
132 33 N 6-HO ##STR00394## ##STR00395## -- M: 204-206; N1: 4.78
(2H, d, J = 5.9 Hz), 5.28 (1H, t, J = 5.9 Hz), 10.13 (1H, s) 133 34
N 6-HO ##STR00396## ##STR00397## -- M: 274-277; N1: 5.17 (2H, brs),
6.66 (1H, m), 10.08 (1H, s) 134 34 N 6-MsHN ##STR00398##
##STR00399## -- N1: 3.07 (3H, s), 3.72-3.77 (4H, m), 10.07 (1H, br
s) 135 35 N 6-HO ##STR00400## ##STR00401## -- M: 266-267 136 36 N
6-HO ##STR00402## ##STR00403## -- M: 261-264; N1: 8.10 (1H, br),
8.91 (1H, t, J = 1.4), 10.17 (1H, s) 137 36 N 6-HO ##STR00404##
##STR00405## -- M: 306-309 138 37 N 6-HO ##STR00406## ##STR00407##
-- M: 245-248
TABLE-US-00021 TABLE 21 Co Syn X R.sup.1 NR.sup.2R.sup.3 R.sup.4
Sal DAT 139 38 N 6-HO ##STR00408## ##STR00409## -- M: 296-299; N1:
2.08 (3H, s), 10.08 (1H, s), 10.11 (1H, s) 140 39 N 6-HO
##STR00410## ##STR00411## -- M: 152-157 141 40 N 6-HO ##STR00412##
##STR00413## -- M: 225-228; N1: 8.21 (1H, m), 10.16 (1H, brs),
10.44 (1H, brs) 142 40 N 6-HO ##STR00414## ##STR00415## -- M:
206-207; N1: 8.33 (1H, s), 10.12 (1H, s), 10.18 (1H, s) 143 40 N
6-HO ##STR00416## ##STR00417## -- M: 172-174 144 40 N 6-AcHN
##STR00418## ##STR00419## -- M: 145-150; N1: 8.48 (1H, d, J = 2.0
Hz), 10.33 (1H, brs), 10.44 (1H, brs) 145 40 N 6-MsHN ##STR00420##
##STR00421## -- M: 234-236; N1: 3.08 (3H, s), 3.74-3.79 (4H, m),
10.30 (2H, br) 146 40 N 6-AcHN ##STR00422## ##STR00423## -- M:
145-148; N1: 2.12 (3H, s), 10.34 (1H, s), 10.56 (1H, s) 147 40 N
6-AcHN ##STR00424## ##STR00425## -- M: 290 (d); N1: 2.12 (3H, s),
10.32 (1H, s), 10.83 (1H, s) 148 41 N 6-HO ##STR00426##
##STR00427## -- M: 167-169 149 42 N 6-HO ##STR00428## ##STR00429##
-- M: 144-147 150 43 N 6-HO ##STR00430## ##STR00431## -- M:
175-178; N1: 3.71-3.73 (4H, m), 10.17 (1H, s), 10.68 (1H, s) 151 43
N 6-HO ##STR00432## ##STR00433## -- M: 239-243; N1: 2.33-2.42 (1H,
m), 3.66-3.69 (4H, m), 9.96 (1H, s)
TABLE-US-00022 TABLE 22 Co Ex X R.sup.1 NR.sup.2R.sup.3 R.sup.4 Sal
DAT 152 43 N 6-HO ##STR00434## ##STR00435## -- M: 214-216; N1:
3.68-3.70 (6H, m), 10.14 (1H, s), 10.34 (1H, s) 153 43 N 6-HO
##STR00436## ##STR00437## -- M: 246-247 154 43 N 6-HO ##STR00438##
##STR00439## -- M: 251-252 155 43 N 6-HO ##STR00440## ##STR00441##
-- N1: 3.86 (3H, s), 10.14 (1H, s), 10.26 (1H, s) 156 43 N 6-HO
##STR00442## ##STR00443## -- M: 182-183 157 43 N 6-HO ##STR00444##
##STR00445## -- N1: 3.72-3.74 (4H, m), 9.70- 9.99 (1H, br), 10.45
(1H, br s) 158 43 N 6-HO ##STR00446## ##STR00447## -- M: 232-233
159 44 N ##STR00448## ##STR00449## ##STR00450## -- M: 182-183 160
45 N ##STR00451## ##STR00452## ##STR00453## -- M: 224-227 161 45 N
##STR00454## ##STR00455## ##STR00456## -- M: 199-202; N1: 8.76 (1H,
d, J = 2.4 Hz), 8.49 (2H, m), 10.74 (1H, brs) 162 46 CH 6-HO
##STR00457## ##STR00458## -- M: 250-253
TABLE-US-00023 TABLE 23 (Ib) ##STR00459## Co Syn B R Sal DAT 163 17
##STR00460## OMe 2HCl N1: 3.84 (4H, t. J = 4.9 Hz), 3.89 (3H, s),
9.55 (1H, s) 164 17 ##STR00461## OH HCl M: 261-266; N1: 3.84 (4H,
t, J = 4.9 Hz), 7.91 (1H, s), 9.53 (1H, s) 165 18 ##STR00462##
##STR00463## 3HCl M: 167-170; N1: 3.61 (2H, br s), 4.61 (2H, t, J =
4.9 Hz); 9.54 (1H, s) 166 47 ##STR00464## ##STR00465## 3HCl N1:
3.26-3.31 (2H, m), 7.54 (1H, t, J = 7.8 Hz), 9.53 (1H, s) 167 17
##STR00466## NO.sub.2 HCl M: 272-273; N1: 4.20 (4H, t, J = 4.9 Hz),
7.97 (1H, d, J = 6.4 Hz), 9.52 (1H, s) 168 34 ##STR00467## NH.sub.2
2HCl M: 195-200; N1: 4.25 (4H, t, J = 4.9 Hz), 7.64 (1H, t, J = 7.8
Hz), 9.55 (1H, s) 169 57 ##STR00468## NHAc HCl N1: 2.10 (3H, s),
9.52 (1H, s), 10.32 (1H, s) 170 3 ##STR00469## NHSO.sub.2Ph HCl N1:
8.75 (1H, d, J = 6.4 Hz), 9.49 (1H, s), 10.62 (1H, s) 171 2
##STR00470## ##STR00471## 2HCl M: 200-203; N1: 8.89-8.90 (1H, m),
9.53 (1H, s), 10.84 (1H, s) 172 17 ##STR00472## OH HCl M: 233-238;
N1: 4.73 (4H, br), 7.43 (1H, t, J = 7.8 Hz), 10.02 (1H, br) 173 18
##STR00473## ##STR00474## 2HCl M: 201-206; N1: 3.19-3.29 (2H, m),
7.65 (1H, t, J = 7.8 Hz), 8.60 (1H, br) 174 17 ##STR00475## OH HCl
M: 269-274; N1: 7.39 (1H, t, J = 7.8 Hz), 8.06 (1H, d, J = 5.9 Hz),
9.44 (1H, s) 175 18 ##STR00476## ##STR00477## 2HCl N1: 3.20-3.29
(2H, m), 4.60 (2H, t, J = 4.9 Hz), 9.50 (1H, s)
TABLE-US-00024 TABLE 24 Co Syn B R Sal DAT 176 17 ##STR00478## OMe
HCl M: 159-162; N1: 3.89 (3H, s), 7.55 (1H, t, J = 7.8 Hz), 8.02
(1H, d, J = 7.8 Hz) 177 17 ##STR00479## OH HCl M: 274-279; N1: 4.22
(4H, t, J = 4.9 Hz), 7.41 (1H, t, J = 7.8 Hz), 10.05 (1H, br) 178
18 ##STR00480## ##STR00481## 2HCl N1: 4.59 (2H, t, J = 4.9 Hz),
7.57 (1H, t, J = 7.8 Hz), 7.68 (1H, dd, J = 4.9, 8.3 Hz) 179 17
##STR00482## OH HCl M: 235-237; N1: 4.19 (4H, br s), 7.43 (1H, t, J
= 7.8 Hz), 8.27-8.34 (1H, m) 180 18 ##STR00483## ##STR00484## 2HCl
N1: 4.19 (4H, br s), 8.28 (1H, br s), 8.57 (1H, br) 181 17
##STR00485## NO.sub.2 HCl N1: 3.78-3.79 (4H, m), 7.83-7.89 (3H, m),
8.88 (1H, d, J = 7.8 Hz) 182 34 ##STR00486## NH.sub.2 2HCl N1: 4.11
(4H, br s), 7.47 (1H, d, J = 7.8 Hz), 7.62 (1H, t, J = 7.8 Hz) 183
57 ##STR00487## NHAc HCl N1: 2.10 (3H, s), 7.52 (1H, t, J = 7.8
Hz), 10.25 (1H, s) 184 3 ##STR00488## NHSO.sub.2Ph HCl N1: 4.10
(4H, br s), 8.17-8.28 (3H, m), 10.83 (1H, s) 185 2 ##STR00489##
##STR00490## 2HCl M: 196-201; N1: 4.15 (4H, br s), 8.85-8.87 (2H,
m), 10.97 (1H, s) 186 17 ##STR00491## OH HCl M: 252-258; N1: 3.95
(3H, s), 4.23 (4H, br s), 10.04 (1H, br) 187 18 ##STR00492##
##STR00493## 2HCl N1: 4.67 (2H, t, J = 4.9 Hz), 8.12 (1H, d, J =
7.8 Hz), 8.49 (1H, br) 188 17 ##STR00494## ##STR00495## 2HCl M:
266-267; N1: 4.60-4.63 (2H, m), 8.16 (1H, s), 10.68 (1H, br) 189 17
##STR00496## OH HCl M: 214-220; N1: 4.26 (4H, br), 7.45 (1H, t, J =
7.8 Hz), 7.82 (1H, s) 190 17 ##STR00497## OH HCl M: 207-210; N1:
7.40 (1H, t, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.51 (1H, d, J
= 5.3 Hz) 191 17 ##STR00498## OH HCl M: 262-268 (d); N1: 4.58 (4H,
br), 8.87 (1H, d, J = 2.0 Hz), 9.09 (1H, d, J = 2.0 Hz) 192 58
##STR00499## OH 2HCl M: 270-273; N1: 4.66-4.68 (2H, m), 7.55 (1H,
br s), 10.05 (1H, br)
TABLE-US-00025 TABLE 25 (Ib) ##STR00500## Co R.sup.4 B1
##STR00501## B2 ##STR00502## B3 ##STR00503## B4 ##STR00504## B5
##STR00505## B6 ##STR00506##
TABLE-US-00026 TABLE 26 Co B R B7 ##STR00507## CO.sub.2NHMe B8
##STR00508## OH B9 ##STR00509## OH B10 ##STR00510## CH.sub.2OH B11
##STR00511## CH.sub.2OH B12 ##STR00512## CH.sub.2OH B13
##STR00513## CONH.sub.2 B14 ##STR00514## CONH.sub.2 B15
##STR00515## CONH.sub.2 B16 ##STR00516## OH B17 ##STR00517## OH B18
##STR00518## OH B19 ##STR00519## CH.sub.2OH B20 ##STR00520##
CH.sub.2OH B21 ##STR00521## CH.sub.2OH B22 ##STR00522## CONH.sub.2
B23 ##STR00523## CONH.sub.2 B24 ##STR00524## CONH.sub.2 B25
##STR00525## OH B26 ##STR00526## OH B27 ##STR00527## OH B28
##STR00528## CH.sub.2OH B29 ##STR00529## CH.sub.2OH B30
##STR00530## CH.sub.2OH B31 ##STR00531## CONH.sub.2 B32
##STR00532## CONH.sub.2 B33 ##STR00533## CONH.sub.2
[0188] Production methods of the starting compounds shown in the
foregoing tables are explained in the following Reference
Examples.
Reference Example 1
[0189] A suspension of 2-chloro-3-cyanopyridine, ethyl glycolate
and sodium carbonate in 3-methyl-1-butanol was refluxed for 3 days.
The solvent was evaporated and water was added to the residue to
crystallize to give Reference Example Compound (hereinbelow,
abbreviated as Rco) 1.
Reference Example 2
[0190] A suspension of 2-chloro-3-cyanopyridine, glycine ethyl
ester hydrochloride and sodium carbonate in 3-methyl-1-butanol was
refluxed for 6 days. The solvent was evaporated. After the obtained
residue was diluted with ethyl acetate and water, insoluble solids
were filtered off. The separated organic layer was concentrated
under reduced pressure. The residue was dissolved in ethanol,
sodium ethoxide was added, and the mixture was stirred at room
temperature for 15 minutes. The reaction solution was concentrated,
and ethyl acetate saturated aqueous sodium hydrogencarbonate were
added. The separated organic layer was concentrated under reduced
pressure and the residue was purified with silica gel column
chromatography to give Rco 3.
Reference Example 3
[0191] Dimethylaminopyridine and benzoyl chloride were added to a
solution of 3-aminothieno[2,3-b]pyridine-2-carboxylic acid ethyl
ester in pyridine. The reaction mixture was stirred at room
temperature for 18 hours, and concentrated. 1M Hydrochloric acid
was added, and the mixture was extracted with chloroform. The
organic layer was concentrated under reduced pressure. The obtained
residue was purified with silica gel column chromatography to give
Rco 4.
Reference Example 4
[0192] Phosphorous oxychloride was added to a solution of Rco 49
and 4-nitrobenzoic acid and the reaction mixture was stirred at -15
C for 15 minutes. Ice and water was added to this reaction mixture.
The precipitated crystals were collected to give Rco 11.
Reference Example 5
[0193] 1M Sodium hydroxide was added to a solution of Rco 4 in
methanol. The reaction mixture was stirred at room temperature for
2 hours, and 1M hydrochloric acid was added. The precipitated
crystals were collected to give Rco 13.
Reference Example 6
[0194] Thionyl chloride was added to Rco 13. The mixture was
refluxed for 2 hours, cooled to room temperature and then
concentrated. DMF and aqueous ammonia were added to the obtained
residue and the reaction mixture was stirred at room temperature
for 2 hours. Water was added to the resulting mixture and extracted
with chloroform. The organic layer was concentrated under reduced
pressure to give Rco 21.
Reference Example 7
[0195] Formamide was added to Rco 1 and the mixture was stirred at
200 C for 2 hours. After the mixture was cooled to room
temperature, the precipitated crystals were collected to give Rco
29.
Reference Example 8
[0196] 2M potassium hydroxide was added to a solution of Rco 21 in
methanol and the mixture was stirred at 100 C for 1 hour. After
being cooled to room temperature, hydrochloric acid was added. The
precipitated crystals were collected to give Rco 30.
Reference Example 9
[0197] Acetic acid and 48% hydrobromic acid were added to Rco 36
and the mixture was refluxed for 17 hours. After the reaction
solution was concentrated under reduced pressure, diethyl ether was
added and the reaction mixture was concentrated under reduced
pressure. Sodium acetate and acetic anhydride were added to the
obtained residue, and the mixture was stirred at 110 C for 2 hours.
Ice and then water were added to this reaction mixture under ice
cooling. The precipitated crystals were collected to give Rco
38.
Reference Example 10
[0198] Ethanol was added to a solution of 3-cyanobenzoic acid
methyl ester in chloroform and gaseous hydrogen chloride was passed
into the mixture at 0 C for 15 minutes. Further, the solution was
sealed and the solution was stirred at 0 C for 17 hours. The
reaction mixture was concentrated, ether was added, and the
precipitated crystals were collected to give Rco 50.
Reference Example 11
[0199] 2-Propanol was added to a mixture of 5-acetoamidoanthranilic
acid, 3-nitrobenzimidic acid ethyl ester hydrochloride and sodium
methoxide, and the mixture was refluxed for 3 days. The reaction
solution was allowed to cool to room temperature. The obtained
solid was collected to give Rco 52.
Reference Example 12
[0200] A solution of cyclohexanecarbonyl chloride in benzene was
added in dropwise to a solution of 2-amino-5-methoxybenzamide and
dimethylaminopyridine in pyridine at room temperature, and the
mixture was stirred for 2 hours. The reaction mixture was
concentrated, and the residue was dissolved with ethyl acetate.
After the organic layer was washed with 1M hydrochloric acid and
saturated aqueous sodium hydrogencarbonate, it was concentrated and
the obtained residue was dissolved with methanol. 2M Sodium
hydroxide was added. After the reaction solution was refluxed for 2
hours, it was neutralized with 12M hydrochloric acid. The solvent
was evaporated and the crystals were filtered to give Rco 67.
Reference Example 13
[0201] THF and DMF were added to a mixture of
2-amino-5-methoxybenzamide, EDCI hydrochloride, HOBt and
pyrazinecarboxylic acid, and the mixture was stirred at room
temperature for 3 days. The solvents were evaporated, and the
crystals were collected and dissolved in methanol and 2M sodium
hydroxide. The reaction solution was refluxed for 3 hours and
neutralized with 12M hydrochloric acid. The obtained crystals were
collected to give Rco 72.
Reference Example 14
[0202] Dimethylaminopyridine, TEA, ethanol and tosyl chloride were
added to a suspension of Rco 55 in chloroform, and the reaction
mixture was stirred at room temperature for 12 hours. DMSO was
added to it to give a solution. Then, the reaction solution was
stirred for 12 hours. Again, dimethylaminopyridine, TEA and tosyl
chloride were added and the reaction solution was stirred for 18
hours. The reaction solution was concentrated, and the residue was
diluted with ethyl acetate and purified according to a conventional
method to give Rco 74.
Reference Example 15
[0203] 48% Hydrobromic acid was added to a solution of Rco 70 in
acetic acid, and the mixture was refluxed for 2 days. After the
reaction solution was allowed to cool, it was concentrated, and
sodium acetate and acetic anhydride were added to the obtained
residue. The reaction solution was refluxed for 3 hours. After the
reaction solution was allowed to cool, it was concentrated and
ether was added to the solution, followed, by collection of
crystals to give Rco 77.
Reference Example 16
[0204] Sodium acetate and acetic anhydride were added to Rco 60,
and the mixture was refluxed for 40 minutes. After the reaction
mixture was allowed to cool, the precipitated crystals were
collected to give Rco 83.
Reference Example 17
[0205] Sodium methoxide was added to a solution of
3-hydroxybenzimidate ethyl ester hydrochloride and
5-hydroxyanthranilic acid in methanol, and the mixture was refluxed
for 30 minutes. After the reaction solution was cooled to room
temperature, the precipitate was collected. Sodium acetate and
acetate anhydride were added to the obtained precipitate and the
mixture was refluxed for 30 minutes. After the reaction solution
was allowed to cool, the precipitated crystals were collected to
give Rco 92.
Reference Example 18
[0206] Concentrated hydrochloric acid was added to Rco 52, and the
mixture was stirred at 80 C. The reaction mixture was allowed to
cool, filtered, and concentrated under reduced pressure to give
6-amino-2-(3-nitrophenyl)-3H-quinazoline-4-one hydrochloride. After
the obtained compound was neutralized, pyridine,
dimethylaminopyridine and methanesulfonyl chloride were added. The
reaction solution was stirred at room temperature for 20 hours, the
solvent was evaporated and the crystals were collected to give Rco
95.
Reference Example 19
[0207] 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) was added to a
solution of 2-chloro-3-cyanopyridine and ethyl glycolate in ethanol
and the reaction mixture was refluxed for 21 hours. The resulting
mixture was evaporated under reduced pressure, diluted with ethyl
acetate and then, washed with water and brine. The organic layer
was concentrated under reduced pressure and crystallized to give
Rco 49.
Reference Example 20
[0208] Aqueous ammonia was added to a solution of Rco 96 in
methanol, and the reaction solution was stirred at room temperature
for 3 hours. Methanol in the reaction mixture was evaporated under
reduced pressure and the crystals were collected to give Rco
116.
Reference Example 21
[0209] Aqueous ammonia was added to a solution of Rco 98 in
methanol, and the reaction solution was stirred at room temperature
overnight. Methanol in the reaction mixture was evaporated under
reduced pressure and the crystals were collected to give Rco
117.
Reference Example 22
[0210] EDCI hydrochloride and HOBt were added to a solution of
3-acetoxybenzoic acid in DMF, and the reaction mixture was stirred
at room temperature for 10 minutes. Then,
2-amino-5-methoxybenzamide was added, and the reaction mixture was
stirred at room temperature for 1 hour. The solvent was evaporated
under reduced pressure, and waster and THF were added. After the
extraction with ethyl acetate, the organic layer was washed with
brine, evaporated under reduced pressure, and crystallized to give
Rco 119.
Reference Example 23
[0211] Acetic anhydride was added to Rco 105 and sodium acetate,
and the reaction mixture was stirred at 110 C for 1 hour and 15
minutes. Under cooling, the precipitated crystals were collected to
give Rco 121.
Reference Example 24
[0212] Aqueous ammonia was added to a solution of Rco 99 in
dioxane, and the reaction mixture was stirred at room temperature
for 13 days. The solvent was evaporated under reduced pressure and
the crystals were collected to give a mixture of amido
3-(3-methoxybenzoylamino)thiophene-2-carboxylate and Rco 122. 2M
aqueous sodium hydroxide was added to a solution of this mixture in
2-propanol and the reaction solution was refluxed for 21 hours.
After being cooled, it was neutralized and the precipitated
crystals were collected to give Rco 122.
Example 1
[0213] Phosphorous oxychloride was added to Rco 33 and the mixture
was refluxed for 20 minutes. The reaction mixture was concentrated
under reduced pressure, and, was azeotropically concentrated with
toluene. Morpholine was added to the obtained residue and the
mixture was refluxed for 10 minutes. The reaction solution was
concentrated under reduced pressure and the obtained crystals were
washed with chloroform and water to give Compound (hereinafter,
abbreviated as Co) 1.
Example 2
[0214] 1-Benzyl piperidine-1,2-dicarboxylate, HOBt and EDCI
hydrochloride were added to a solution of a free form of Co 31 in
DMF, and the mixture was stirred at room temperature for 7 hour.
The solvent was evaporated under reduced pressure. After being
diluted with ethyl acetate, the organic layer was washed with
saturated aqueous sodium hydrogencarbonate and brine. After the
solution was dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure. The obtained residue was
purified with silica gel column chromatography and crystallized to
give Co 3.
Example 3
[0215] Benzenesulfonyl chloride (6.02 ml) was added to a solution
of a free form of C 31 (13.6 g) in pyridine (480 ml) at 0 C and the
mixture was stirred at room temperature for 1.5 hours. The solvent
was evaporated under reduced pressure. The obtained residue was
dissolved in ethyl acetate and the solution was washed with
saturated aqueous sodium hydrogencarbonate and brine. After the
solution was dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure. The obtained residue was
purified with silica gel column chromatography (eluent;
chloroform:methanol=96:4) and recrystallized (ethanol) to give Co 8
(15.6 g).
Example 4
[0216] Picolinoyl chloride hydrochloride (9.40 g) and TEA (14.7 ml)
were added to a solution of a free form of Co 31 (15.3 g) in THF (1
L) at 0 C and the mixture was stirred at room temperature for 1.5
hours. Then, additional picolinoyl chloride hydrochloride (4.00 g)
was added and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was concentrated under reduced
pressure. After dissolving in ethyl acetate, the solution was
washed with saturated aqueous sodium hydrogencarbonate and brine.
After being dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure and the obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=96:4) and recrystallized (ethanol) to give Co
10 (15.4 g).
Example 5
[0217] 3-Hydroxypicolinic acid (140 mg), EDCI hydrochloride (190
mg) and HOBt (135 mg) were added to a solution of a free form of Co
31 (300 mg) in DMF (20 ml) and the mixture was stirred at room
temperature for 2 hours. The solvent was evaporated under reduced
pressure. The obtained residue was dissolved with ethyl acetate and
THF. The solution was washed with water and saturated aqueous
sodium hydrogencarbonate. After the organic layer was dried over
anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was purified with silica gel
column chromatography (chloroform:methanol=100:1). 4M Hydrogen
chloride/ethyl acetate was added to a solution of the obtained
residue in chloroform and methanol. The solvent was evaporated
under reduced pressure, and the obtained solid was crystallized
from methanol to give Co 12 (207 mg).
Example 6
[0218] A suspension of a free form of Co 31 (300 mg), succinic
anhydride (519 mg) and acetic acid (1 ml) was stirred at 100 C for
30 minutes. The solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column chromatography
(chloroform:methanol=98:2) and recrystallized (methanol) to give Co
24 (106 mg).
Example 7
[0219] To a solution of Co 18 (300 mg) in THF (12 ml) and ethanol
(12 ml), 10% Pd--C (35 mg) was added, and the mixture was stirred
at room temperature under hydrogen atmosphere (latm) for 4 hours.
The reaction solution was filtered by Celite. After the filtrate
was concentrated under reduced pressure, the obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=98: 2-80:20) to give a free form of Co 25 (178
mg). 1M Hydrochloric acid (1.00 ml) was added to a solution of the
obtained free form (153 mg) in THF (35 ml) and methanol (20 ml).
The reaction solution was stirred at room temperature, then
concentrated under reduced pressure, and recrystallized (methanol)
to give dihydrochloride of Co 25 (119 mg).
Example 8
[0220] A suspension of a free form of Co 31 (300 mg), succinic
anhydride (519 mg) and acetic acid (1 ml) was stirred at 100 C for
30 minutes. The solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column chromatography
(chloroform:methanol=98:2) and recrystallized (methanol) to give Co
29 (57 mg).
Example 9
[0221] N-Carboethoxyphthalimide (262 mg) and TEA (0.166 ml) were
added to a solution of a free form of Co 31 (346 mg) in THF (60 ml)
and the mixture was stirred at 80 C for 1 day. After the reaction
mixture was allowed to cool, water was added, and collected to give
a free form of Co 30 (374 mg). 1M Hydrochloric acid (1.55 ml) was
added to a solution of the obtained free form (371 mg) in THF (200
ml) and the solution was stirred at room temperature. The
precipitated crystals were collected to give hydrochloride of Co 30
(287 mg).
Example 10
[0222] Co 1 (22.4 g) and ammonium chloride (1.59 g) were suspended
in a mixture of ethanol (717 ml) and water (269 ml). Then, iron
(33.2 g) was added and the solution was refluxed for 9 hours. While
the reaction solution was still hot, hot THF was added, and the
mixture was filtered with Celite. After most of the solvent was
evaporated under reduced pressure, the precipitate was collected,
and washed with diethyl ether to give a free form of Co 31 (18.9
g). 1M Hydrochloric acid (0.870 ml) was added to a solution of the
obtained free form (101 mg) in THF (25 ml) and the solution was
stirred at room-temperature. The precipitated crystals were
collected, and washed with methanol to give dihydrochloride of Co
31 (75 mg).
Example 11
[0223] A solution of Rco 1 (1.03 g) in formamide (12 ml) was
refluxed for 2 hours. After the reaction mixture was cooled to room
temperature, the obtained solids were collected to give Rco 29 (648
mg). Phosphorous oxychloride (7 ml) was added to a solution of
obtained Rco 29 (630 mg) in pyridine (3.5 ml). The reaction mixture
was refluxed for 2.5 hours. After being cooled to room temperature,
the solvent was evaporated. Toluene (7 ml) was added to the
obtained residue. After morpholine (7 ml) was slowly added in
dropwise under ice cooling, the reaction mixture was refluxed for
3.5 hours. Further, THF (3 ml) and morpholine (20 ml) were added,
and the reaction mixture was refluxed for 5 days, and then
concentrated under reduced pressure. After the residue was diluted
with ethyl acetate, the crystals were collected, washed with ethyl
acetate, saturated aqueous sodium hydrogencarbonate and water, and
recrystallized (ethanol) to give Co 34 (372 mg).
Example 12
[0224] Phosphorous oxychloride (5 ml) was added to Rco 32 (396 mg)
and the mixture was refluxed for 50 minutes. The solvent was
evaporated under reduced pressure. After morpholine (10 ml) was
slowly added in dropwise into the obtained residue under ice
cooling, the reaction mixture was refluxed for 30 minutes. The
reaction mixture was concentrated under reduced pressure. The
obtained crystals were washed with ethyl acetate and water, and
recrystallized (ethanol) to give Co 35 (411 mg).
Example 13
[0225] Ethylenediamine (1.85 ml) was added to Co 11 (303 mg) and
the mixture was stirred at 90 C for 2 hours. The solvent was
evaporated under reduced pressure, The obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=80:20) and crystallized (methanol) to give a
free form of Co 40 (269 mg). The obtained free form (266 mg) was
subjected to salt formation as described in EXAMPLE 7, and the
obtained residue was recrystallized (methanol) to give
dihydrochloride of Co 40 (153 mg).
Example 14
[0226] DMF (10 ml) was added to Co 11 (285 mg) and the solution was
stirred at 110 C for 2 hours and at 80 C for 27 hours. The solvent
was evaporated under reduced pressure. The obtained residue was
dissolved in ethyl acetate and THF. The reaction solution was
washed with aqueous sodium hydrogencarbonate and brine, dried over
anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified with silica gel
column chromatography (chloroform:methanol=98:2) to give a free
form of Co 44 (167 mg). 1M Hydrochloric acid (0.283 ml) was added
to a solution of the obtained free form (70 mg) in THF (5 ml) and
methanol (10 ml), and the solution was stirred at room temperature.
The precipitated crystals were collected to give dihydrochloride of
Co 44 (72 mg).
Example 15
[0227] Benzoyl chloride (0.1-18 ml) was added to a solution of a
free form of Co 31 (297 mg) in pyridine (20 ml) under ice cooling
and the mixture was stirred at room temperature for 20 minutes. The
solvent was evaporated under reduced pressure. The obtained residue
was dissolved in ethyl acetate and THF. The reaction solution was
washed with aqueous sodium hydrogencarbonate and brine. After being
dried over anhydrous sodium sulfate, the solvent was evaporated
under reduced pressure. The obtained residue was recrystallized
(methanol) to give a free form of Co 45 (301 mg). The obtained free
form (287 mg) was subjected to salt formation as described in
EXAMPLE 7 to give hydrochloride crystals of Co 45 (249 mg).
Example 16
[0228] 1M Sodium hydroxide (11 ml) was added in two portions to a
solution of a free form of Co 48 (171 mg) in methanol (60 ml) and
THF (30 ml), and the mixture was stirred at room temperature for
2.5 hours. The reaction mixture was acidified with 1M hydrochloric
acid, and the organic solvent was evaporated under reduced
pressure. The precipitate was collected, and washed with water and
diethyl ether. The obtained crystals were recrystallized
(methanol/diethyl ether) to give Co 49 (116 mg).
Example 17
[0229] Phosphorous oxychloride (5 ml) was added to Rco 38 (452 mg),
and the mixture was refluxed for 30 minutes. After the reaction
solution was cooled to room temperature, it was concentrated under
reduced pressure. After adding THF (5 ml) and then slowly adding
morpholine (4 ml) in dropwise to the obtained residue under ice
cooling, the ice bath was removed and the solution was refluxed for
1 hour. After the reaction mixture was cooled to room temperature.
the solvent was evaporated under reduced pressure. The obtained
solid was washed with water and diethyl ether and purified, with
silica gel column chromatography (chloroform:methanol=98:2) to give
a free form of Co 50 (411 mg). The obtained free form (183 mg) was
subjected to salt formation as described in EXAMPLE 7 and
recrystallized (methanol) to give hydrochloride of Co 50 (129
mg).
Example 18
[0230] 4-(2-Chloroethyl)morpholine hydrochloride (1.53 g) and
potassium carbonate (1.90 g) were added to a solution of a free
form of Co 50 (956 mg) in DMF (35 ml), and the mixture was stirred
at 70 C for 2.5 days. After the reaction solution was cooled to
room temperature, the solvent was evaporated under reduced
pressure. The obtained solid was washed with water and diethyl
ether and purified with silica gel column chromatography
(chloroform:methanol=98:2) and crystallized (methanol) to give a
free form of Co 54 (1.16 g). 4M Hydrochloric acid/ethyl acetate
(1.14 ml) was added to a solution of the obtained free form (1.05
g) in THF (140 ml) and methanol (70 ml), and the solution was
stirred at room temperature. The solvents were evaporated under
reduced pressure, and the material was recrystallized (methanol) to
give dihydrochloride crystals of Co 54 (1.18 g).
Example 19
[0231] Phosphorous oxychloride (5 ml) was added to
2-phenyl-3H-quinazoline-4-one (450 mg), and the mixture was
refluxed for 3 hours. The reaction mixture was concentrated.
Saturated aqueous sodium hydrogencarbonate was added and extracted
with ethyl acetate. After the organic layer was dried over
anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained colorless crystals were dissolved in
benzene (10 ml) and morpholine (325 mg) was added. The reaction
mixture was refluxed overnight. Insoluble materials were filtered
off and the filtrate was diluted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium hydrogencarbonate,
dried over anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The obtained residue was purified with column
chromatography (hexane:ethyl acetate=5:1) and recrystallized
(hexane-benzene) to give Co 82 (136 mg).
Example 20
[0232] Sodium cyanide (132 mg) was added to a solution of Co 84
(190 mg) in DMSO (5 ml), and the mixture was stirred at 180 C for 2
hours. After the reaction mixture was allowed to cool, water was
added to it and the mixture was extracted with ethyl acetate. After
the organic layer was washed with brine and dried over anhydrous
sodium sulfate, the solvent was evaporated under reduced pressure.
The obtained residue was recrystallized (hexane/ethyl acetate) to
give Co 92 (40 mg).
Example 21
[0233] Iron (415 mg) was added to a solution of Co 85 (500 mg) in
acetic acid (12 ml), and the mixture was stirred at 105 C for 1
hour. After the reaction solution was allowed to cool, chloroform
and 1M sodium hydroxide were added. The solution was filtered with
Celite and the filtrate was extracted with chloroform. The organic
layer was Washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. 1M Hydrochloric
acid (10 ml) was added to the obtained residue and the mixture was
stirred at 85 C for 90 minutes. After the mixture was allowed to
cool, 1M sodium hydroxide was added and extracted with chloroform,
and the organic layer was washed with brine. After the solution was
dried over anhydrous sodium sulfate, the solvept was evaporated
under reduced pressure. The obtained residue was purified with
silica gel column chromatography (eluent;
chloroform:methanol=50:1), and recrystallized (chloroform/hexane)
to give Co 97 (374 mg).
Example 22
[0234] Acetic anhydride (3 ml) was added to a solution of Co 97
(149 mg) in formic acid (3 ml), and the mixture was stirred at room
temperature for 2 hours. Water was added and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium hydrogencarbonate and brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified with silica gel column chromatography
(eluent; chloroform:methanol=50:1), and recrystallized
(chloroform/hexane) to give Co 98 (46 mg).
Example 23
[0235] Phosphorous oxychloride (3 ml) was added to Rco 74 (270 mg),
and the mixture was refluxed for 0.5 hours. The reaction mixture
was concentrated under reduced pressure, and morpholine (10 ml) was
added. After the reaction mixture was refluxed for 1 hour, the
reaction mixture was concentrated under reduced pressure and
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium hydrogencarbonate, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. After
purifying by silica gel column chromatography (eluent; hexane:ethyl
acetate=5:1), ethanol (2 ml) and 20% potassium hydroxide (100 mg)
were added, and the mixture was stirred at room temperature for 40
minutes. The reaction mixture was extracted with ethyl acetate, and
the organic layer was washed with saturated aqueous sodium
hydrogencarbonate, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained crystals were
washed with a mixture of ethyl acetate and hexane, and
recrystallized (ethyl acetate/hexane) to give Co 99 (30 mg).
Example 24
[0236] Sodium hydroxide (43 mg), potassium carbonate (37 mg) and
tetra-n-butylammonium hydrogensulfate (2 mg) were added to a
solution of Co 86 (95 mg) in toluene (15 ml), and the mixture was
stirred at 35 C for 0.5 hour, followed by addition of
dimethylsulfate (34 mg) and stirring at 35 C for 2 hours. The
reaction solution was filtered and the filtrated was concentrated
under reduced pressure. The residue was purified with silica gel
column chromatography (eluent; chloroform:methanol=20:1), and
recrystallized (chloroform/hexane) to give Co 105 (62 mg).
Example 25
[0237] p-Toluenesulfonyl chloride (124 mg) and pyridine (1 ml) were
added to a solution of Co 97 (200 mg) in chloroform (6 ml), and the
mixture was stirred at room temperature for 45 minutes. 1M
Hydrochloric acid was added and extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium
hydrogencarbonate and brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure.
[0238] The residue was recrystallized (chloroform/hexane) to give
Co 106 (165 mg).
Example 26
[0239] 35% Formalin (5 ml) and formic acid (5 ml) were added to Co
97 (250 mg), and the mixture was stirred at 100 C. for 90 minutes.
After the mixture was allowed to cool, 1M sodium hydroxide was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
residue was purified with silica gel column chromatography (eluent;
hexane:ethyl acetate=4:1), and recrystallized (chloroform/hexane)
to give Co 107-(133 mg).
Example 27
[0240] Phosphorous oxychloride (50 ml) was added to Rco 76 (6.2 g),
and the mixture was refluxed for 1 hour. The reaction solution was
concentrated under reduced pressure and the residue was dissolved
in chloroform. The chloroform layer was washed twice with saturated
aqueous sodium hydrogencarbonate, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure to give 6.0 g of
crystals. To 802 mg of the crystals, thiomorpholine (500 mg) and
benzene (10 ml) were added. The reaction mixture was heated with
stirring at 70 C for 1 hour, and then diluted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium
hydrogencarbonate and brine, dried over anhydrous magnesium
sulfate, concentrated under reduced pressure, and purified with
silica gel column chromatography (hexane:ethyl acetate=5:1) to give
p-toluenesulfonic acid 4-thiomorpholino 2-phenylquinazoline-6-yl
(828 mg). 802 mg of this compound was dissolved in methanol (10 ml)
and THF (10 ml). 20% Potassium hydroxide (1.0 g) was added to the
solution and the mixture was stirred at 70 C for 1 hour. Water and
1M hydrochloric acid was added to neutralize the solution. Then,
the solution was extracted with ethyl acetate, and the organic
layer was washed with brine. After the solution was dried over
anhydrous magnesium sulfate, the solution was concentrated under
reduced pressure and recrystallized (ethyl acetate-hexane) to give
Co 108 (151 mg).
Example 28
[0241] Ammonium acetate (1.2 g) was added to acetic acid
2-methyl-4-oxo-4H-benzo[d][1,3]oxazine-6-yl ester (3 g), and the
mixture Was stirred at 150 C for 30 minutes. After cooling to 80 C,
methanol was added to the mixture and the mixture was stirred at 80
C for 1 hour. After the mixture was allowed to cool, the
precipitated crystals were collected and washed with methanol to
give crystals (930 mg). To a solution of the obtained crystals (918
mg) in DMSO (10 ml)/chloroform (5 ml), toluenesulfonyl chloride (1
ml), TEA (1 ml) and a catalytic amount of dimethylaminopyridine
were added. The mixture was stirred at room temperature for 8
hours, and then extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium hydrogencarbonate and brine,
dried over anhydrous sodium sulfate, and the solvent was evaporated
under reduced pressure. Phosphorous oxychloride (15 ml) was added
to the obtained residue and the mixture was refluxed for 15 hours.
After the reaction solution was allowed to cool, phosphorous
oxychloride was evaporated under reduced pressure. The residue was
extracted with chloroform and washed with saturated aqueous sodium
hydrogencarbonate. The organic layer was dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
residue was purified with silica gel column chromatography (eluent;
chloroform:methanol=50:1) to give a liquid material (577 mg). To a
solution of the obtained material (577 mg) in toluene (20 ml),
morpholine (2 g) was added, and the mixture was refluxed for 16
hours. The reaction solution was allowed to cool, and concentrated
under reduced pressure. To a solution of the obtained residue in
ethanol (15 ml), 20% potassium hydroxide (1 ml) was added, and the
mixture was stirred at room temperature for 1 hour. The solvent was
evaporated under reduced pressure. The residue was purified with
silica gel column chromatography (eluent;
chloroform:methanol=20:1), and recrystallized
(chloroform/methanol/hexane) to give Co 109 (207 mg).
Example 29
[0242] Phosphorous oxychloride (10 mg) was added to Rco 78 (590
mg), and the mixture was refluxed for 0.5 hours. The reaction
mixture was concentrated, diluted with chloroform, and washed with
saturated aqueous sodium hydrogencarbonate. The organic layer was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. To the obtained colorless crystals, morpholine
(10 ml) was added, and the mixture was refluxed for 12 hours. The
reaction mixture was diluted with chloroform, washed with water and
saturated aqueous sodium hydrogencarbonate, and dried over
anhydrous magnesium sulfate. The obtained organic layer was
concentrated under reduce pressure. The residue was crystallized
from chloroform-methanol, and further recrystallized to give Co 110
(126 mg).
Example 30
[0243] Acetic acid (20 ml) and 48% hydrogen bromide (20 ml) were
added to Rco 67 (957 mg), and the mixture was stirred at an oil
bath temperature of 135 C for 13 hours. After the mixture was
allowed to cool to room temperature, precipitate was collected as a
mixture of a starting material and a desired compound. To the
obtained solid, acetic anhydride (30 ml) and sodium acetate (112
mg) were added and the reaction mixture was refluxed for 30
minutes. The reaction solution was allowed to cool, precipitate was
collected. To the obtained solids, phosphorous oxychloride (10 ml)
was added, and the mixture was refluxed for 30 minutes and
concentrated under reduced pressure. The obtained residue was
dissolved in chloroform and the solution was washed with saturated
aqueous sodium hydrogencarbonate. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. To the obtained residue, morpholine (20 ml) was added and
the mixture was refluxed for 15 hours. The reaction mixture was
concentrated under reduced pressure and purified with silica gel
column chromatography (eluent; chloroform methanol=50:1). The
obtained crystals were washed with a mixture of chloroform and
ether to give Co 127 (193 mg).
Example 31
[0244] Iron (396 mg) was added to a solution of Co 111 (500 mg) in
acetic acid (12 ml), and the mixture was stirred at 105 C for 45
minutes. The reaction solution was allowed to cool. Chloroform and
1M sodium hydroxide were added to it. The mixture was filtered and
extracted with chloroform. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The obtained residue was purified with silica gel column
chromatography (eluent; chloroform:methanol=10:1) and
recrystallized (chloroform/methanol/hexane) to give Co 129 (120
mg).
Example 32
[0245] 1M Sodium hydroxide (8 ml) was added to a solution of Co 116
(564 mg) in ethanol (8 ml) and THF (8 ml), and the reaction mixture
was stirred at room temperature for 15 hours. 1M Hydrochloric acid
(8 ml) was added and the solution was extracted with ether. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
recrystallized (methanol I ether/hexane) to give Co 1.30 (163
mg).
Example 33
[0246] Lithium aluminum hydride (67 mg) was added to a solution of
Co 117 (325 mg) in THF (40 ml), and the reaction mixture was
stirred at 0 C for 2 hours. Water (0.1 ml), 1M sodium hydroxide
(0.1 ml), and then water (0.3 ml) were added and the mixture was
stirred at room temperature for 30 minutes. The mixture was dried
over anhydrous sodium sulfate, filtered through silica gel, and
concentrated under reduced pressure. The residue was recrystallized
(THF/hexane) to give Co 131 (158 mg).
Example 34
[0247] Co 112 (860 mg) was dissolved in a mixture of TH (30 ml),
methanol (30 ml) and ethanol (30 ml). 10% Pd--C (130 mg) was added
and the reaction mixture was stirred under hydrogen atmosphere (1
atm) at room temperature for 2 hours. Insoluble materials were
removed by filtration and the filtrate was concentrated to give 780
mg of solid.
[0248] Of the solid, 202 mg was recrystallized (ethanol/methanol)
to give Co 133 (148 mg).
Example 35
[0249] Co 133 (202 mg) was dissolved in pyridine (10 ml).
Methanesulfonyl chloride (96 mg) was added to the reaction
solution. The reaction mixture was stirred for 15 hours, and
concentrated under reduced pressure. The obtained residue was
dissolved in ethyl acetate. The organic layer was washed with
water, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The obtained crystals were purified with
column chromatography (chloroform-methanol=100:1) and
recrystallized (ethanol-ethyl acetate-hexane) to give Co 135.
Example 36
[0250] HOBt (75 mg) and EDCI hydrochloride (106 mg) were added to a
solution of Co 131-(177 mg) in DMF (12 ml), and the reaction
solution was stirred at 0 C for minutes and then at room
temperature for 30 minutes. Aqueous ammonia (2 ml) was added and
the mixture was stirred at room temperature for 3 hours. The
reaction mixture was extracted with chloroform, and the organic
layer was washed with water, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure. The residue was purified
with silica gel column chromatography (eluent;
chloroform:methanol=10:1) and recrystallized
(chloroform/methanol/hexane) to give Co 136 (39 mg).
Example 37
[0251] Phosphorous oxychloride (15 ml) was added to Rco 87 (1.1 g),
and the mixture was refluxed for 1 hour. The reaction mixture was
allowed to cool, and concentrated under reduced pressure. The
mixture was diluted with chloroform and the organic layer was
washed with saturated aqueous sodium hydrogencarbonate, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
To a solution of the obtained residue in toluene (40 ml),
morpholine (5 g) was added and the reaction solution was refluxed
for 17 hours, allowed to cool, and concentrated under reduced
pressure. The residue was purified with silica gel column
chromatography (eluent; chloroform:methanol=30:1), and
recrystallized (chloroform/ether/hexane) to give Co 138 (869
mg).
Example 38
[0252] Acetic anhydride (0.75 ml) and pyridine (1 ml) were added to
a solution of Co 129 (457 mg) in DMF (10 ml), and the reaction
mixture was stirred at room temperature for 1 hour. 1M Sodium
hydroxide (15 ml) and water were added and the reaction mixture was
extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified with silica gel column chromatography
(eluent; chloroform:methanol=10:1), recrystallized
(chloroform/methanol/hexane), and washed with ether to give Co 139
(358 mg).
Example 39
[0253] Benzene (10 ml), benzaldehyde (249 mg) and THF (10 ml) were
added to Co 133 (476 mg). The reaction mixture was azeotropically
refluxed for 2 hours and concentrated under reduced pressure, and
the obtained residue was dissolved in methanol (20 ml). Under ice
cooling, sodium borohydride (50 mg) was added. The reaction mixture
was stirred at room temperature for 1 hour, and concentrated under
reduced pressure. The residue was dissolved in ethyl acetate, and
the organic layer was washed with water and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified with silica gel column
chromatography (chloroform:methanol=100:1), and recrystallized
(ethyl acetate/hexane) to give Co 140 (259 mg).
Example 40
[0254] Co 133 (3.0 g) was dissolved in pyridine (50 ml).
Benzenesulfonyl chloride (1.9 g) was added to the mixture at room
temperature. After stirring the mixture for 2 hours, the solvent
was evaporated under reduced pressure. Ethyl acetate and water were
added to the obtained residue and then the organic layer was washed
with brine three times. The obtained organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained solid was purified with silica gel column
chromatography (chloroform:methanol=100:1) and recrystallized
(ethanol) to give Co 141 (3.0 g).
Example 41
[0255] THF (15 ml) and phenyl isocyanate (207 mg) were added to Co
133 (540 mg). After the mixture was refluxed for 3 hours, phenyl
isocyanate (500 mg) was again added. The mixture was then refluxed
for 4 hours. 1M Sodium hydroxide (5 ml) was added. After the
mixture was stirred for 15 minutes, 1M hydrochloric acid (5 ml) was
added to neutralize it. The reaction mixture was extracted with
chloroform, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=50:1) and recrystallized (2-propanol/diethyl
ether/hexane) to give Co 148 (180 mg).
Example 42
[0256] THF (15 ml) and TEA (520 mg) were added to Co 133 (440 mg).
Phenyl chloroformate (498 mg) was added in dropwise to the reaction
solution at room temperature, and stirred at room temperature for 2
hours. After adding methanol, 1M sodium hydroxide (5 ml) was added
under ice cooling and the reaction mixture was stirred for 20
minutes. 1M Hydrochloric acid (5 ml) was added to neutralize it.
The reaction mixture was extracted with chloroform, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified with silica gel column
chromatography (chloroform:methanol=50:1) and recrystallized (ethyl
acetate) to give Co 149 (189 mg).
Example 43
[0257] Isonicotinoyl chloride hydrochloride (280 mg) and pyridine
(0.127 ml) were added to a solution of Co 133 (253 mg) in THF (10
ml), and the reaction mixture was stirred at room temperature for
5.5 hours. Further, TEA (0.1 ml) was added and the mixture was
stirred at room temperature for 2.5 hours. Then, 1M sodium
hydroxide (0.786 ml) and methanol (4 ml) were added, and the
reaction mixture was stirred at room temperature for 30 minutes to
cleave the ester. After neutralization, most of the solvent was
evaporated, the resulting precipitate was collected, washed with
ethyl acetate and Water, and recrystallized (ethanol) to give Co
150 (71 mg).
Example 44
[0258] Chlorooxoacetic acid ethyl ester (190 mg) and TEA (1 ml)
were added to a solution of Co 97 (285 mg) in chloroform (12 ml),
and the mixture was stirred at room temperature for 16 hours. The
reaction mixture was extracted with chloroform, washed with water,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified with silica gel column
chromatography (eluent; chloroform:methanol=50:1), and
recrystallized (chloroform/methanol/hexane) to give Co 159 (103
mg).
Example 45
[0259] Benzoyl isothiocyanate (1.2 ml) was added to a solution of
Co 97 (1.2 g) in chloroform (30 ml) under ice cooling, and the
mixture was stirred at room temperature for 3 hours. The
precipitated crystals were collected. To the obtained crystals, 40%
methylamine/methanol was added and the reaction mixture was stirred
at room temperature for 1 hour, concentrated under reduced
pressure, and purified with silica gel column chromatography to
give 1-(4-morpholino-2-phenylquinazoline-6-yl)thiourea (1.1 g). To
266 mg of this compound, ethanol (5 ml), methanol (3 ml) and 40%
chloroacetaldehyde (300 mg) were added. The reaction mixture was
stirred for 4 days, diluted with ethyl acetate, washed with
saturated aqueous sodium hydrogencarbonate, and dried over
anhydrous magnesium sulfate. The residue was purified with silica
gel column chromatography (hexane:ethyl acetate=2:1), and
recrystallized (ethanol/hexane) to give Co 160 (49 mg).
Example 46
[0260] Acetic acid (5 ml) and 48% hydrobromic acid (5 ml) were
added to Co 91 (500 mg), and the reaction solution was refluxed for
13 hours, and then concentrated. The reaction mixture was
neutralized with 1M sodium hydroxide and saturated aqueous sodium
hydrogencarbonate, and extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The obtained solid was purified with silica
gel column chromatography (hexane:ethyl acetate=1:1), and
recrystallized (ethanol) to give Co 162 (12 mg).
Example 47
[0261] 3-Morpholinopropanol (93 mg) and a free form of Co 50 (203
mg) were added to a solution of diethyl azodicarboxylate (0.101 ml)
and triphenylphosphine (168 mg) in THF (20 ml) and the mixture
solution was stirred at 60 C for 13 hours. Additional diethyl
azodicarboxylate (0.1 ml), triphenylphosphine (170 mg) and
3-morpholinopropanol (93 mg) were added and the mixture was stirred
at 60 C. This addition of the reagents was repeated again. After
the reaction mixture was allowed to cool, water and ethyl acetate
were added, and the reaction mixture was basified with saturated
aqueous sodium hydrogencarbonate. After extraction with ethyl
acetate, the solution was washed with brine. After the solution was
dried over anhydrous sodium sulfate, the solvent was evaporated
under reduced pressure. The obtained residue was purified with
silica gel column chromatography (chloroform:methanol=98:2), and
recrystallized (methanol) to give a free form of Co 58 (174 mg).
The obtained free form (71 mg) was subjected to salt formation as
described in EXAMPLE 18, and recrystallized (methanol) to give
hydrochloride of Co 58 (68 mg).
Example 48
[0262] Potassium carbonate (1.10 g) was added to a solution of Co
61 (1.48 g) in methanol (15 ml) and water (15 ml). After the
mixture was stirred at 80 C, additional methanol (8 ml) and water
(8 ml) were added and the mixture was stirred at 80 C for 12 hours.
After the reaction mixture was allowed to cool, crystals were
collected, purified with silica gel column chromatography
(chloroform:methanol=98:2), and crystallized (methanol) to give a
free form of Co 59 (1.13 g). The obtained free form (160 mg) was
subjected to salt formation as described in EXAMPLE 18, and
recrystallized (methano) to give dihydrochloride of Co 59 (146
mg).
Example 49
[0263] Anhydrous trifluoroacetic acid (1.07 ml) and
dimethylaminopyridine (78 mg) were added to a solution of a free
form of Co 31 (2.21 g) in pyridine (70 ml) under ice cooling. After
the mixture solution was stirred for 1 hour, more anhydrous
trifluoroacetic acid (0.5 ml) and dimethylaminopyridine (30 mg)
were added, and the mixture was stirred under ice cooling for 1
hour. The solvent was evaporated under reduced pressure, water and
ethyl acetate were added, and the precipitated crystals were
filtered and washed with ethyl acetate to give Co 60 (2.66 g).
Example 50
[0264] Water (0.645 ml), dibromoethane (1.11 ml),
tetrabutylammonium hydrogensulfate (22 mg) and 2M aqueous sodium
hydroxide (2.58 ml) were added to a free form of Co 50 (1.29 g),
and the mixture was stirred 60 C for 6 hours. Chloroform was added
to the mixture, unsoluble materials were filtered, and the filtrate
was extracted with chloroform and then washed with brine. After the
solution was dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure, and the obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=98:2) to give Co 62 (376 mg).
Example 51
[0265] 1-Methylpiperazine (139 mg) and potassium carbonate (256 mg)
were added to a solution of Co 62 (211 mg) in DMF (5 ml) and the
mixture solution was stirred at 60 C for 4 hours. The solvent was
evaporated under reduced pressure, water and THF were added to the
obtained residue, the mixture was extracted with ethyl acetate, and
then the solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column chromatography
(chloroform:methanol=97:3.about.95:5) to give a free form of Co 64
(198 mg). The obtained free form (198 mg) was subjected to salt
formation as described in EXAMPLE 18, and recrystallized (methanol)
to give trihydrochloride of Co 64 (160 mg).
Example 52
[0266] tert-Butyl piperazine-1-carboxylate (285 mg) and potassium
carbonate (282 mg) were added to a solution of Co 62 (232 mg) in
DMF (5 ml) and the mixture solution was stirred at 60 C for 17
hours. The solvent was evaporated under reduced pressure, water was
added to the obtained residue, and the resulting mixture was
extracted with ethyl acetate and then washed with brine. After the
solution was dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure and the obtained residue was
purified with silica gel column chromatography
(chloroform:methanol=99:1) to give solid (227 mg). 4M Hydrogen
chloride/ethyl acetate (1 ml) were added to a solution of the
obtained solid (212 mg) in dioxane (3 ml) and methanol (3 ml), and
the mixture was stirred at room temperature for 4 hours. The
resulting mixture was concentrated and the residue was
recrystallized (methanol) to give Co 69 (144 mg).
Example 53
[0267] Paraformaldehyde (15 mg) and acetic acid (81 ml) were added
to a solution of a free form of Co 59 (216 mg) in THF (3 ml). After
the mixture was stirred at room temperature for 10 minutes, sodium
triacetoxyborohydride (199 mg) was added and the mixture was
stirred at room temperature for 21 hours. Then, liquid formaldehyde
(0.44 ml), acetic acid (5.5 ml) and sodium triacetoxyborohydride
(704 mg) were added in 3 divided portions, and the reaction
solution was stirred at room temperature for 4 days. The reaction
mixture was neutralized with 2M aqueous sodium hydroxide, and THF
was added. After the reaction solution was extracted with ethyl
acetate, it was washed with brine. After it was dried over
anhydrous sodium sulfate, the solvent was evaporated under reduced
pressure, and the obtained residue was purified with silica gel
column chromatography (chloroform:methanol=98:2) to give a free
form of Co 70 (162 mg). The obtained free form (48 mg) was
subjected to salt formation as described in EXAMPLE 18, and
recrystallized (methanol) to give dihydrochloride of Co 70 (53
mg).
Example 54
[0268] After a free form of Co 50 (322 mg), 1,3-dioxolane-2-one
(814 mg) and potassium carbonate (192 mg) were stirred at 100 C for
2 hours, more 1,3-dioxolane-2-one (680 mg) was added and the
mixture was stirred at 100 C for 17 hours. Then, DMF (3 ml) was
added and the mixture was stirred at 100 C for 2 hours, and further
1,3-dioxolane-2-one (670 mg) was added and the mixture was stirred
at 100 C for 20 hours. After the reaction mixture was allowed to
cool, the solvent was evaporated under reduced pressure, and water
was added. Then, 1M aqueous hydrochloric acid was added until
bubbles no longer appeared. The precipitated crystals were
collected and recrystallized (methanol) to give Co 77 (164 mg).
Example 55
[0269] Phosphorus oxychloride (10 ml) was added to Rco 48 (1.07 g),
and the mixture was refluxed for 2.5 hours. The solvent was
evaporated, and the reaction mixture was azeotropically
concentrated with toluene. THE (15 ml) was added to the obtained
residue. After morpholine (10 ml) was slowly added in dropwise
under ice cooling, the ice bath was removed and the reaction
mixture was refluxed for 30 minutes. Ethyl acetate and THF were
added to the reaction mixture and the mixture was washed with water
and brine. After it was dried over anhydrous sodium sulfate, the
solvent was evaporated under reduced pressure and the obtained
residue was purified with silica gel column chromatography
(chloroform:methanol=98:2) to give
bis(morpholinoamido)2-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]py-
rimidine-2-yl)phenylphosphonate (594 mg). Formic acid (4 ml) was
added to this compound (360 mg) and the mixture was stirred at 100
C for 3 days. The solvent was evaporated under reduced pressure,
ethyl acetate and water were added, and the mixture was neutralized
with saturated aqueous sodium hydrogencarbonate under ice cooling.
The precipitated crystals were filtered to give crystals (162 mg).
The obtained crystals (123 mg) were recrystallized (methanol-THF)
to give Co 79 (122 mg).
Example 56
[0270] Dioxane (3.9 ml) and 6M hydrochloric acid (5.5 ml) were
added to Co 80 (220 mg), and the mixture was refluxed for 3 days.
After the reaction mixture was allowed to cool, it was neutralized,
extracted with a mixture solution of ethyl acetate and THF, and
washed with brine. After it was dried over anhydrous sodium
sulfate, the solvent was evaporated under reduced pressure, and the
obtained residue was purified with silica gel column chromatography
(chloroform:methanol=96:4) to give crystals (83 mg). The obtained
crystals (81 mg) were recrystallized (THF-methanol) to give Co 81
(53 mg).
Example 57
[0271] After a solution of a free form of Co 168 (151 mg) in
pyridine (9 ml) was cooled in an ice bath, acetic anhydride (4.5
ml) was added, and the mixture was stirred under ice cooling. After
the reaction completed, the reaction mixture was poured into water
with ice, extracted with ethyl acetate, and washed with brine.
After it was dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure to give a free form of Co 183
(158 mg). The obtained free form (156 mg) was subjected to salt
formation as described in EXAMPLE 18, and the obtained crystals
were recrystallized (methanol) to give hydrochloride of Co 169 (93
mg).
Example 58
[0272] 2-Morpholinoethanol (806 mg) was added in dropwise to a
solution of 60% sodium hydroxide (63 mg) in DMF (5 ml), and the
mixture solution was stirred at room temperature for 15 minutes.
Then, a free form of Co 179 (285 mg) was added and the mixture was
stirred at 60 C for 23 hours. Then, a mixture, which was prepared
by adding 2-morpholinoethanol (806 mg) in dropwise to 60% sodium
hydroxide (63 mg) in DMF (1 ml) and stirring at room temperature
for 15 minutes, was added in dropwise to the reaction mixture and
the resulting mixture was stirred at 60 C. This addition of sodium
2-morpholinoethoide was conducted 3 times. The solvent was
evaporated under reduced pressure, water and THF were added to the
obtained residue, and the mixture was extracted with ethyl acetate
and then washed with brine. After it was dried over anhydrous
sodium sulfate, the solvent was evaporated under reduced pressure,
and the obtained residue was purified with silica gel column
chromatography (chloroform:methanol=95:5) to give a free form of Co
192 (529 mg). The obtained free form (404 mg) was subjected to salt
formation as described in EXAMPLE 18, and the obtained crystals
were recrystallized (methanol) to give dihydrochloride of Co 192
(320 mg).
* * * * *