U.S. patent application number 09/850685 was filed with the patent office on 2001-10-18 for method of treating a patient having precancerous lesions with quinazoline derivatives.
Invention is credited to Pamukcu, Rifat, Piazza, Gary.
Application Number | 20010031760 09/850685 |
Document ID | / |
Family ID | 23895049 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031760 |
Kind Code |
A1 |
Pamukcu, Rifat ; et
al. |
October 18, 2001 |
Method of treating a patient having precancerous lesions with
quinazoline derivatives
Abstract
Derivatives of Quinazoline are useful for the treatment of
patients having precancerous lesions. These compounds are also
useful to inhibit growth of neoplastic cells.
Inventors: |
Pamukcu, Rifat; (Spring
House, PA) ; Piazza, Gary; (Highlands Ranch,
CO) |
Correspondence
Address: |
Cell Pathways, Inc.
702 Electronic Drive
Horsham
PA
19044
US
|
Family ID: |
23895049 |
Appl. No.: |
09/850685 |
Filed: |
May 7, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09850685 |
May 7, 2001 |
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09055829 |
Apr 6, 1998 |
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6262059 |
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09055829 |
Apr 6, 1998 |
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08477227 |
Jun 7, 1995 |
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Current U.S.
Class: |
514/266.22 |
Current CPC
Class: |
A61K 31/517
20130101 |
Class at
Publication: |
514/259 ;
514/260 |
International
Class: |
A61K 031/517 |
Claims
We claim:
1. A method of treating a patient having precancerous lesions
sensitive to compounds below and in the need of treatment,
comprising administering to the patient a pharmacologically
effective amount of a compound of the formula: 123wherein R1, R2,
R3 and R4, each of which may be the same or different, are selected
from a hydroxyalkyl group, an acylamino group, a carboxyl group
which may be protected, or two of R1, R2, R3 or R4 may together
form methylenedioxy, ethylenedioxy, or a phenyl ring; R5 and R6,
each of which may he the same or different, are selected from a
hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a
hydroxyalkyl group having from 1 to 6 carbon atoms, an aminoalkyl
grouid having from 1 to 6 carbon atoms, a carboxyalkyl group which
may be protected, an alkylcarbamoyl group having 2 to 8 carbon
atoms, a 1,3-benzdioxolyalkyl group or 1,4-benzdioxylalkyl group,
or further R5 and R6 may form a ring which may contain another
nitrogen atom and/or oxygen atom together with the nitrogen atom to
which they are bonded, which may be substituted; R7 is selected
from an acyl group, an alkoxyalkyl group having 2 to 8 carbon
atoms, a carboxyalkyl group having 2 to 8 carbon atoms which may be
protected or a hydroxyalkyl group having 2 to 8 carbon atoms; R8 is
selected from a hydrogen atom, a hydroxyl group, a carboxyl group
which may be protected, a cyano group, an acyl group, a heteroaryl
group which may be substituted, said substitutions, which may be
the same or different, are selected from a hydrogen atom, a halogen
atom, a hydroxyl group, an amino group, a nitro group, an alkyl
group having from 1 to 6 carbon atoms, an alkoxy group having from
1 to 6 carbon atoms, an alkoxyalkyl group having from 2 to 8 carbon
atoms, an alkenyl group having from 2 to 8 carbon atoms, an acyl
group, an acylamino group, an alkylsulfonylamino group, a
hydroiminoalkyl group, an alkyloxy-carbonylamino group, an
alkyloxybarbonyloxy group or a heteroaryl group which may be
substituted; or two of said substitutions may together form a
saturated or unsaturated ring which may contain a nitrogen, a
sulfer atom or an oxygen atom; and Y is a group represented by the
formula --(CH2)q-- (wherein q is 0 or an integer of 1 to 8), when q
is an integer of 1 to 8, each carbon atom may have from 1 to 2
substituents, or Y is a group represented by the formula: 124
2. The method of claim 1, wherein R1, R2, R3, and R4, each of which
may be the same or different from one another, are selected from a
hydrogen atom, a cyano group, a halogen atom, or a lower alkoxy
group.
3. The method of claim 2, wherein one of R1, R2, R3 and R4 is a
cyano group, a halogen atom or a methoxy group.
4. The method of claim 3, wherein R2 is a halogen atom.
5. The method of claim 4, wherein R2 is a chlorine atom.
6. The method of claim 5, wherein R1, R3 and R4 are hydrogen
atoms.
7. The method of claim 6, wherein Y is a group represented by the
formula --(CH2)q--, wherein q is an integer of 1 to 8.
8. The method of claim 7, wherein R8 is benzyl group which may be
substituted, said substitutions, each of which may be the same or
different, are each selected from a hydrogen atom, a halogen atom,
a hydroxy group, an amino group, a nitro group, a lower alkyl
group, a lower alkoxy group, a lower alkoxyalkyl group, a lower
alkenyl group, an acyl group, an acylamino group, an
alkylsulfonylamino group, a hydroxyiminoalkyl group, an
alkyloxycarbonylamino group, an alkyloxycarbonyloxy group or a
heteroaryl group which may be substituted, or two of the
substitutions may together form a saturated or unsaturated ring
which may contain a nitrogen atom, a sulfer atom or an oxygen atom;
and q is an integer of 1 to 8.
9. The method of claim 8, wherein R8 is a group represented by the
formula: 125
10. The method of claim 9, wherein R7 is a hydrogen atom.
11. The method of claim 10, wherein R5 and R6 form a ring
represented by the formula: 126wherein R9 is selected from a
hydroxyl group which may be protected, a halogen atom, a alkyl
group having 1 to 8 carbon atoms, a lower alkoxy group, a carboxyl
group which may be protected, a hydroxyalkyl group, a carboxyalkyl
group and a heteroacyl group.
12. The method of claim 10, wherein said compound is
2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl)
amino-6-choroquinazolin.
13. The method of claim 1, wherein Y is a group represented by the
formula --(CH2)q--, wherein q is an integer of 1 to 8.
14. The method of claim 13, wherein R8 is a group represented by
the formula: 127
15. The method of claim 14, wherein one of R1, R2, R3 and R4 is a
cyano group, a chlorine atom or a methoxy atom.
16. The method of claim 15, wherein R2 is a halogen atom.
17. The method of claim 16, wherein R2 is a chlorine atom.
18. The method of claim 17, wherein R1, R3 and R4 are hydrogen
atoms.
19. The method of claim 18, wherein R5 and R6 form a ring which is
represented by the formula: 128wherein R9 is selected from a
hydroxyl group which may be protected, a halogen atom, a alkyl
group having 1 to 8 carbon atoms, a lower alkoxy group, a carboxyl
group which may be protected, a hydroxyalkyl group, a carboxyalkyl
group and a heteroacyl group.
20. The method for inhibiting the growth of neoplastic cells
sensitive to a compound below, comprising exposing said cells to an
effective amount of a compound of the formula: 129wherein R1, R2,
R3 and R4, each of which may be the same or different, are selected
from a hydroxyalkyl group, an acylamino group, a carboxyl group
which may be protected, or two of R1, R2, R3 or R4 may together
form methylenedioxy, ethylenedioxy, or a phenyl ring; R5 and R6,
each of which may be the same or different, are selected from a
hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a
hydroxyalkyl group having from 1 to 6 carbon atoms, an aminoalkyl
group having from 1 to 6 carbon atoms, a carboxyalkyl group which
may be protected, an alkylcarbamoyl group having 2 to 8 carbon
atoms, a 1,3-benzdioxolyalkyl group or 1,4-benzdioxylalkyl group,
or further R5 and R6 may form a ring which may contain another
nitrogen atom and/or oxygen atom together with the nitrogen atom to
which they are bonded, which may be substituted; R7 is selected
from an acyl group, an alkoxyalkyl group having 2 to 8 carbon
atoms, a carboxyalkyl group having 2 to 8 carbon atoms which may be
protected or a hydroxyalkyl group having 2 to 8 carbon atoms; R8 is
selected from a hydrogen atom, a hydroxyl group, a carboxyl group
which may be protected, a cyano group, an acyl group, a heteroaryl
group which may be substituted, said substitutions, which may be
the same or different, are selected from a hydrogen atom, a halogen
atom, a hydroxyl group, an amino group, a nitro group, an alkyl
group having from 1 to 6 carbon atoms, an alkoxy group having from
1 to 6 carbon atoms, an alkoxyalkyl group having from 2 to 8 carbon
atoms, an alkenyl group having from 2 to 8 carbon atoms, an acyl
group, an acylamino group, an alkylsulfonylamino group, a
hydroiminoalkyl group, an alkyloxy-carbonylamino group, an
alkyloxybarbonyloxy group or a heteroaryl group which may be
substituted; or two of said substitutions may together form a
saturated or unsaturated ring which may contain a nitrogen, a
sulfer atom or an oxygen atom; and Y is a group represented by the
formula --(CH2)q-- (wherein q is 0 or an integer of 1 to 8), when q
is an integer of 1 to 8, each carbon atom may have from 1 to 2
substituents, or Y is a group represented by the formula: 130
21. The method of claim 20 wherein R1, R2, R3 and R4 may
independently be a cyano group, a halogen or a methoxy group.
22. The method of claim 21, wherein R2 is a halogen.
23. The method of claim 22, wherein R8 is represented by the
formula: 131
24. The method of claim 23, wherein R5 and R6 form a ring which is
represented by the formula: 132
25. The method of claim 24, wherein said compound is
2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl)
amino-6-chloroquinazolin.
26. The method of claim 21 wherein R7 and R8 are each hydrogen; q
is zero; and R5 and R6 form a substituted ring represented by the
structure: 133and R10 is hydrogen, amino, lower alkyl group, or
NHCO2R11 in which R11 is a lower alkyl group.
27. The method of regulating apoptosis in human cells, comprising
exposing said cells to an effective amount of a compound of
formula: 134wherein R1, R2, R3 and R4, each of which may be the
same or different, are selected from a hydrogen atom, a alkoxy
group having from 1 to 6 carbon atoms, a hydroxyalkyl group, a
cyano group, an acylamino group, a carboxyl group which may be
protected or two of R1, R2, R3 or R4 may together form
methylenedioxy, ethylenedioxy, or a phenyl ring; R5 and R6, each of
which may be the same or different, are selected from a hydrogen
atom, a lower alkyl group having 1 to 6 carbon atoms, a
hydroxylakyl group having from 1 to 6 carbon atoms, an aminoalkyl
group having from 1 to 6 carbon atoms, a carboxyalkyl group which
may be protected, alkylcarbamoyl group having 2 to 8 carbon atoms,
a 1,3-benzdioxolyalkyl group or a 1,4-benzdioxylalkyl group, or
further R5 and R6 may form a ring which may contain another
nitrogen atom and or oxygen atom together with the nitrogen atom to
which they are bonded, and which may be substituted; R7 is selected
from a hydrogen atom, a alkyl group having 1 to 6 carbon atoms, an
acyl group, a alkoxyalkyl group having 2 to 8 carbon atoms, a
carboxyalkyl group having 2 to 8 carbon atoms which may be
protected or a hydroxyalkyl group having 2 to 8 carbon atoms; R8 is
selected from a hydrogen atom, a hydroxyl group, a carboxyl group
which may be protected, a cyano group, an acyl group, a heteroaryl
group which may be substituted or a benzyl group which may be
substituted, said substitutions, which may be the same or
different, are selected from a hydrogen atom, a halogen atom, a
hydroxyl group, an amino group, a nitro group, a alkyl group having
from 1 to 6 carbon atoms, a alkoxy group having from 1 to 6 carbon
atoms, a alkoxyalkyl group having from 2 to 8 carbon atoms, a
alkenyl group having from 2 to 8 carbon atoms, an acyl group an
acylamino group, an alkylsulfonylamino group, a hydroiminoalkyl
group, an alkyloxy-carbonylamino group, an alkyloxybarbonyloxy
group or a heteroaryl group which may be substituted: or two of
said substitutions may together from a saturated or unsaturated
ring which may contain a nitrogen, a sulfer atom or an oxygen atom;
and Y is a group represented by the formula --(CH2)q-- (wherein q
is 0 or an integer of 1 to 8), when q is an integer of 1 to 8, each
carbon atom may have from 1 to 2 substituents, or Y is a group
represented by the formula: 135
28. The method of claim 26, wherein R2 is a halogen.
29. The method of claim 27, wherein R8 is represented by the
formula: 136
30. The method of claim 28, wherein R5 and R6 form a ring which is
represented by the formula: 137
31. The method of claim 29, wherein said compound is
2-(4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl)
amino-6-chloroquinazolin.
Description
[0001] This application is a Continuation of prior U.S. application
Ser. No. 09/055,829 filed Apr. 6, 1998, entitled "Method of
Treating a Patient Having Precancerous Lesions with Quinazoline
Derivatives," which is a continuation of prior U.S. application
Ser. No. 08/477,227 filed Jun. 7, 1995, entitled "Method of
Treating a Patient Having Precancerous Lesions with Quinazoline
Derivatives."
TECHNICAL FIELD
[0002] This invention relates to methods for treatment or
prevention of precancerous lesions.
BACKGROUND OF THE INVENTION
[0003] Each year in the United States alone, untold numbers of
people develop precancerous lesions. These lesions exhibit a strong
tendency to develop into malignant tumors, or cancer. Such lesions
include lesions of the breast (that can develop into breast
cancer), lesions of the skin (that can develop into malignant
melanoma or basal cell carcinoma), colonic adenomatous polyps (that
can develop into colon cancer), and other such neoplasms. Compounds
which prevent or induce the remission of existing precancerous or
cancerous lesions or carcinomas would greatly reduce illness and
death from cancer.
[0004] Approximately 60,000 people die from colon cancer, and over
150,000 new cases of colon cancer are diagnosed each year. For the
American population as a whole, individuals have a six percent
lifetime risk of developing colon cancer, making it the second most
prevalent form of cancer in the country. Colon cancer is also
prevalent in Western Europe. It is believed that increased dietary
fat consumption is increasing the risk of colon cancer in
Japan.
[0005] In addition, the incidence of colon cancer reportedly
increases with age, particularly after the age of 40. Since the
mean ages of populations in America and Western Europe are
increasing, the prevalence of colorectal cancer should increase in
the future.
[0006] To date, little progress has been made in the prevention and
treatment of colorectal cancer, as reflected by the lack of change
in the five-year survival rate over the last few decades. The only
cure for this cancer is surgery at an extremely early stage.
Unfortunately, most of these cancers are discovered too late for
surgical cure. In many cases, the patient does not experience
symptoms until the cancer has progressed to a malignant stage.
[0007] In view of these grim statistics, efforts in recent years
have concentrated on colon cancer prevention. Colon cancer usually
arises from pre-existing benign neoplastic growths known as polyps.
Prevention efforts have emphasized the identification and removal
of colonic polyps. Polyps are identified by x-ray and/or
colonoscopy, and usually removed by devices associated with the
colonoscope. The increased use of colon x-rays and colonoscopies in
recent years has detected clinically significant precancerous
polyps in four to six times the number of individuals per year that
acquire colon cancer. During the past five years alone, an
estimated 3.5 to 5.5 million people in the United States have been
diagnosed with adenomatous colonic polyps, and it is estimated that
many more people have or are susceptible to developing this
condition, but are as yet undiagnosed. In fact, there are estimates
that 10-12 percent of people over the age of 40 will form
clinically significant adenomatous polyps.
[0008] Removal of polyps has been accomplished either with surgery
or fiber-optic endoscopic polypectomy--procedures that are
uncomfortable, costly (the cost of a single polypectomy ranges
between $1,000 and $1,500 for endoscopic treatment and more for
surgery), and involve a small but significant risk of colon
perforation. Overall, about $2.5 billion is spent annually in the
United States in colon cancer treatment and prevention.
[0009] As indicated above, each polyp carries with it a chance that
it will develop into a cancer. The likelihood of cancer is
diminished if a polyp is removed. However, many of these patients
demonstrate a propensity for developing additional polyps in the
future. They must, therefore, be monitored periodically for the
rest of their lives for polyp reoccurrence.
[0010] In most cases (i.e. the cases of so-called common sporadic
polyps), polyp removal will be effective to reduce the risk of
cancer. In a small percentage of cases (i.e. the cases of the
so-called polyposis syndromes), removal of all or part of the colon
is indicated. The difference between common sporadic polyps and
polyposis syndromes is dramatic. Common sporadic polyp cases are
characterized by relatively few polyps, each of which can usually
be removed leaving the colon intact. By contrast, polyposis
syndrome cases can be characterized by many (e.g. hundreds or more)
of polyps--literally covering the colon in some cases--making safe
removal of the polyps impossible short of surgical removal of the
colon.
[0011] Because each polyp carriers with it the palpable risk of
cancerous development, polyposis syndrome patients invariably
develop cancer if left untreated. Surgical removal of the colon is
the conventional treatment. Many of these patients have undergone a
severe change in lifestyle as a result of the disfiguring surgery.
Patients have strict dietary restrictions, and many must wear
ostomy appliances to collect their intestinal wastes.
[0012] The search for drugs useful for treating and preventing
cancer is intensive. Indeed, much of the focus of cancer research
today is on the prevention of cancer because therapy is often not
effective and has severe side effects. Cancer prevention is
important for recovered cancer patients who retain a risk of cancer
reoccurrence. Also, cancer prevention is important for people who
have not yet had cancer, but have hereditary factors that place
them at risk of developing cancer. With the development of new
diagnostic screening technologies, it is possible to identify those
with high risk factors, such as the potential for polyposis
syndrome, who would greatly benefit from chemopreventive drugs.
Therefore, finding such anti-cancer drugs that can be used for
prolonged preventive use is of vital interest to many people.
[0013] One way to find such drugs is to screen thousands of
compounds for the same biological activity found in known
chemopreventive and chemotherapeutic drugs. Most such drugs are now
believed to kill cancer cells by inducing apoptosis, or as
sometimes referred to as "programmed cell death." Apoptosis
naturally occurs in virtually all tissues of the body, and
especially in self-renewing tissues such as bone marrow, gut, and
skin. Apoptosis plays a critical role in tissue homeostasis, that
is, it ensures that the number of new cells produced are
correspondingly offset by an equal number of cells that die. For
example, the cells in the intestinal lining divide so rapidly that
the body must eliminate cells after only three days in order to
prevent the overgrowth of the intestinal lining.
[0014] Recently, scientists have realized that abnormalities of
apoptosis can lead to the formation of precancerous lesions and
carcinomas. Also, recent research indicates that defects in
apoptosis plays a major role in other diseases in addition to
cancer. Consequently, compounds that modulate apoptosis could be
used to prevent or control cancer, as well as used in the treatment
of other diseases.
[0015] Unfortunately, even though known chemotherapeutic drugs may
exhibit such desirable apoptotis effects, most chemotherapeutic
drugs have serious side effects that prohibit their long term use,
or use in otherwise healthy individuals with precancerous lesions.
These side effects, which are a result of the high levels of
cytotoxicity of the drugs, include hair loss, weight loss, vomiting
and bone marrow immune suppression. Therefore, there is a need to
identify new drug candidates for therapy that do not have such
serious side effects in humans.
SUMMARY OF THE INVENTION
[0016] This invention is a method of treating patients with
precancerous lesions or neoplasms by administering a
pharmacologically effective amount of a compound of Formula I below
to a patient in need of such treatment. Such compositions are
effective in modulating apoptosis, and eliminating and inhibiting
precancerous lesions, and neoplastic cells.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0017] As discussed above, this invention is a method of treating a
patient with precancerous lesions or neoplasms by administering a
pharmacologically effective amount of the quinazoline derivative
represented by the following formula (I), or the pharmacologically
acceptable salt thereof; 1
[0018] wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4, each of which
may be the same or different from one another, represent each a
hydrogen atom, a halogen atom, a alkyl group having 1 to 6 carbon
atoms, a alkoxy group having 1to 6 carbon atoms, a hydroxyalkyl
group having 1 to 6 carbon atoms, a cyano group, an acylamino
group, or a carboxyl group which may be protected, or two of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may together form
methylenedioxy, ethylenedioxy, or a phenyl ring;
[0019] R5 and R6, each of which may be the same or different, are
selected from a hydrogen atom, a lower alkyl group having 1 to 6
carbon atoms, a hydroxylalkyl group having from 1 to 6 carbon
atoms, an aminoalkyl group having from 1 to 6 carbon atoms, a
carboxyalkyl group which may be protected, alkylcarbamoyl group
having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkyl group or a
1,4-benzdioxylalkyl group, or further R5 and R6 may form a ring
which may contain another nitrogen atom and or oxygen atom together
with the nitrogen atom to which they are bonded, and which may be
substituted;
[0020] R7 is selected from a hydrogen atom, a alkyl group having 1
to 6 carbon atoms, an acyl group, a alkoxyalkyl group having 2 to 8
carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which
may be protected or a hydroxyalkyl group having 2 to 8 carbon
atoms;
[0021] R8 is selected from a hydrogen atom, a hydroxyl group, a
carboxyl group which may be protected, a cyano group, an acyl
group, a heteroaryl group which may be substituted or a benzyl
group which may be substituted, said substitutions, which may be
the same or different, are selected from a hydrogen atom, a halogen
atom, a hydroxyl group, an amino group, a nitro group, a alkyl
group having from 1 to 6 carbon atoms, a alkoxy group having from 1
to 6 carbon atoms, a alkoxyalkyl group having from 2 to 8 carbon
atoms, a alkenyl group having from 2 to 8 carbon atoms, an acyl
group an acylamino group, an alkylsulfonylamino group, a
hydroiminoalkyl group, an alkyloxy-carbonylamino group, an
alkyloxycarbonyloxy group or a heteroaryl group which may be
substituted: or two of said substitutions may together form a
saturated or unsaturated ring which may contain a nitrogen, a
sulfer atom or an oxygen atom; and
[0022] Y is a group represented by the formula --(CH2) q-- (wherein
q is 0 or an integer of 1 to 8), when q is an integer of 1 to 8,
each carbon atom may have from 1 to 2 substituents, or Y is a group
represented by the formula: 2
[0023] Preferably, R1, R2, R3, and R4, each of which may be the
same or different from one another, are selected from a hydrogen
atom, a cyano group, a halogen atom, or a lower alkoxy group. More
preferably, one of R1, R2, R3 and R4 is a cyano group, a halogen
atom or a methoxy group. Still more preferably, R2 is a halogen
atom. Most preferably, R2 is a chlorine atom, and R1, R3 and R4 are
hydrogen atoms.
[0024] It is preferred that Y is a group represented by the formula
--(CH.sub.2)q--, wherein q is an integer of 1 to 8. When such
occurs, R8 is benzyl group which may be substituted, said
substitutions, each of which may be the same or different, are each
selected from a hydrogen atom, a halogen atom, a hydroxy group, an
amino group, a nitro group, a lower alkyl group, a lower alkoxy
group, a lower alkoxyalkyl group, a lower alkenyl group, an acyl
group, an acylamino group, an alkylsulfonylamino group, a
hydroxyiminoalkyl group, an alkyloxycarbonylamino group, an
alkyloxycarbonyloxy group or a heteroaryl group which may be
substituted, or two of the substitutions may together form a
saturated or unsaturated ring which may contain a nitrogen atom, a
sulfer atom or an oxygen atom; and q is an integer of 1 to 8.
However, it is preferred that R8 is a group represented by the
formula: 3
[0025] In which case, preferably, R7 is a hydrogen atom, and R5 and
R6 form a ring represented by the formula: 4
[0026] wherein R9 is selected from a hydroxyl group which may be
protected, a halogen atom, a alkyl group having 1 to 8 carbon
atoms, a lower alkoxy group, a carboxyl group which may be
protected, a hydroxyalkyl group, a carboxyalkyl group and a
heteroacyl group.
[0027] Also, R5 and R6 may form a substituted ring structure
represented by the formula: 5
[0028] wherein Z is represented by the formula: 6
[0029] wherein X is S or O;
[0030] or Z is a cycloalkyl having 3 to 8 ring carbon atoms or a
cycloalkenyl having 4 to 8 ring carbon atoms;
[0031] wherein R10 and R11 are independently selected from
hydrogen, amino, lower alkyl, lower alkoxy and lower alkylthio; and
X is either sulfur or oxygen.
[0032] Also, R5 and R6 may form a substituted ring structure
represented by the formula: 7
[0033] wherein A represents a group selected from the following (i)
and (ii):
[0034] (i) R12--CO--:
[0035] wherein R12 represents a lower alkyl group; phenyl
substituted with a halogen atom, methoxy group or methanesulfonyl
group; a styryl group unsubstituted or ring substituted with a
halogen atom, methoxy group or 3,4-methylenedioxy group or 2-furyl
group; and
[0036] (ii) R13--:
[0037] wherein R13 represents a lower alkyl group of C1-C4; benzyl
group substituted with a halogen atom or methoxy group; or
B--(2-pyridyl)ethyl group.
[0038] "Alkyl group" refers to straight or branched chain
C.sub.1-C.sub.12 groups such as methyl, ethyl, propyl, iso-propyl,
n-butyl, t-butyl and amyl. "Alkoxy group" refers to
hydroxy-substituted alkyl groups such as methoxy, ethoxy, propoxy,
butoxy and amyloxy. "Alkoxycarbonyl group" refers to
carbonyl-substituted alkoxy groups such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl,
etc. "Alkylcarbonyl group" refers to carbonyl-substituted alkyl
groups such as acetyl, propionyl, butyryl or others. "Halogen"
refers to fluorine, chlorine, bromine and iodine.
[0039] The pharmacologically acceptable salt includes inorganic
acid salts such as hydrochloride, hydrobromide, sulfate and
phosphate; organic acid salts such as acetate, maleate, tartrate,
methanesulfonate, benzenesulfonate and toluenesulfonate; and amino
acid salts such as argininate, aspartate and glutamate. Further,
some of the compounds may form metal salts such as Na, K, Ca or Mg,
and the pharmacologically acceptable salt of formula (I) also
includes these metal salts.
[0040] Although the compound of formula I may be present as various
isomers including geometrical isomers, i.e., cis-isomer and
trans-isomer. and optical isomers, i.e., d-isomer and 1-isomer
depending upon the kinds and combination of the substituents, it is
needless to say that the compounds include all of the isomers.
[0041] As used herein, the term "precancerous lesion" refers to
lesions that exhibit histologic changes which are associated with
an increased risk of cancer development. Examples include
adenomatous polyps of the colon, dysplastic nevi of the skin and
atypical hyperplasia of the breasts. Certain syndromes that
commonly display precancerous lesions are also referred to by the
term "precancerous" including dysplastic nevus syndrome and the
colonic polyposis syndromes. "Precancerous" refers to these lesions
or syndromes of various tissues whether or not the lesions are
clinically identifiable.
[0042] As used herein, the term "carcinomas" refers to lesions
which are cancerous. Examples include malignant melanomas, breast
cancer, and colon cancer.
[0043] As used herein, the term, "neoplasm" refers to both
precancerous and cancerous lesions.
[0044] As used herein, the term "halo" or "halogen" refers to
chloro, bromo, fluoro and iodo groups, and the term "alkyl" refers
to straight, branched or cyclic alkyl groups.
[0045] Compounds of formula I may be formulated into compositions
together with pharmaceutically acceptable carriers for injection,
oral administration in solid or liquid form, or for rectal
administration, although carriers for oral administration are most
preferred.
[0046] Pharmaceutically acceptable carriers for oral administration
include capsules, tablets, pills, powders, troches and granules. In
such solid dosage forms, the carrier can comprise at least one
inert diluent such as sucrose, lactose or starch. Such carriers can
also comprise, as is normal practice, additional substances other
than diluents, e.g., lubricating agents such as magnesium stearate.
In the case of capsules, tablets, troches and pills, the carriers
may also comprise buffering agents. Carriers such as tablets, pills
and granules can be prepared with enteric coatings on the surfaces
of the tablets, pills or granules. Alternatively, the enterically
coated compound can be pressed into a tablet, pill, or granule, and
the tablet, pill or granules for administration to the patient.
Preferred enteric coatings include those that dissolve or
disintegrate at colonic pH such as shellac or Eudraget S.
[0047] Pharmaceutically acceptable carriers include liquid dosage
forms for oral administration, e.g. pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0048] Pharmaceutically acceptable carriers for rectal
administration are preferably suppositories which may contain, in
addition to the compounds of Formula I, excipients such as cocoa
butter or a suppository wax.
[0049] The pharmaceutically acceptable carrier and compounds of
Formula I are formulated into unit dosage forms for administration
to a patient. The dosage levels of active ingredient (i.e.
compounds of Formula I) in the unit dosage may be varied so as to
obtain an amount of active ingredient effective to achieve
polyp-eliminating activity in accordance with the desired method of
administration (i.e. oral or rectal). The selected dosage level
therefore depends upon the nature of the active compound
administered, the route of administration, the desired duration of
treatment, and other factors. If desired, the unit dosage may be
such that the daily requirement for active compound is in one dose,
or divided among multiple doses for administration, e.g. two to
four times per day.
[0050] In another form, the invention is a method of inhibiting the
growth of neoplastic cells by exposing them to an effective amount
of the compound of formula [I] above.
[0051] In still another form, the invention is a method of inducing
apoptosis in human cells by exposing those cells to an effective
amount of the compound of formula [I] above where such cells are
sensitive to this compound.
[0052] Additionally, in yet another form, the invention is a method
of treating a patient having a disease which would benefit from
regulation of apoptosis by treating the patient with an effective
amount of the compound of formula [I] above. The regulation of
apoptosis is believed to play an important role in diseases
associated with abnormalities of cellular growth patterns such as
benign prostatic hyperplasia, neurodegenerative diseases such as
Parkinson's disease, autoimmune diseases including multiple
sclerosis and rheumatoid arthritis, infectious diseases such as
AIDS, and other diseases, as well.
[0053] The foregoing may be better understood from the following
examples, which are presented for purposes of illustration and are
not intended to limit the scope of the invention. As used in the
following examples, the references to substituents such as R,
R.sup.1, R.sup.2 etc., refer to the corresponding compounds and
substituents in the Formula above.
[0054] Preferable specific examples of the compound will now be
described in order to facilitate the understanding of the present
invention, though it is needless to say that the compounds of the
present invention are not limited to these examples.
Preparation Process
[0055] Representative processes for the preparation of the
compounds utilized in the present invention will now be described
below. A representative quinazoline skeleton as shown following is
useful to represent the processes. 8
[0056] Though compounds having a quinazoline skeleton are mainly
described in the following explanation, the following explanation
can be applied for compounds having a skeleton other than the
quinazoline skeleton.
Preparation Process 1
[0057] When R.sup.5 is a hydrogen atom, a halogen atom or a group
selected from among those which are directly bonded to the
quinazoline skeleton through a carbon atom in the general formula
(I), a compound similar to the general formula (I) can also be
prepared by the following process: 9
[0058] (in a series of formulas, R.sup.5.sub.a is a hydrogen atom,
a halogen atom or a group selected from among those which are
directly bonded to the quinazoline skeleton through a carbon atom
in R.sup.5 described above; and R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above.
[0059] That is, this process is one for preparing a quinazoline
derivative represented by the general formula (III) by reacting a
quinazoline derivative represented by the general formula (II) with
phosphorus oxychloride or by reacting it with phosphorus
oxychloride in the presence of phosphorus pentachloride under
heating.
Preparation Process 2
[0060] When R.sup.5 is a group selected from among a hydrogen atom,
a halogen atom, a group represented by the formula: 10
[0061] (wherein R.sup.8 and m are each as defined above), a group
represented by the formula --O--R.sup.9 (wherein R.sup.9 represents
a hydroxyalkyl group which may be protected, a carboxyalkyl group
which may be protected or a benzyl group), a heteroaryl group which
may be substituted and a group which is directly bonded to the ring
through a carbon atom (for example, a lower alkyl group, a carboxyl
group which may be protected, a 1,3-benzodioxolyl group which may
be substituted, a 1,4-benzodioxyl group which may be substituted, a
1,3-benzodioxolylalkyl group which may be substituted and a
1,4-benzodioxylalkyl group which may be substituted); and R.sup.6
is a group selected from among those defined above with respect to
NR.sup.7YR.sup.8 except a hydrogen atom, halogen atoms and lower
alkyl groups in the general formula (I), a compound similar the
general formula (I) can be prepared by the following process:
11
[0062] [in a series of formulas R.sup.1, R.sup.2, R.sup.3 and
R.sup.4, are each as defined above; R.sup.5.sub.b represents a
group selected from among a hydrogen atom, a halogen atom, a group
represented by the formula 12
[0063] (wherein R.sup.8 and m are each as defined above), a group
represented by the formula --O--R.sup.9 (wherein R.sup.9 is as
defined above), a heteroaryl group which may be substituted and a
group which is directly bonded to the ring through a carbon atom
(for example, a lower alkyl group, a carboxyl group which may be
protected, a 1,3-benzodioxolyl group which may be substituted, a
1,4-benzodioxyl group which may be substituted, a
1,3-benzodioxylalkyl group which may be substituted and
1,4-benzodioxylalkyl group which may be substituted); R.sup.6.sub.a
represents a group selected from among those defined above with
respect to R.sup.6 except a hydrogen atom, halogen atoms and lower
alkyl groups; and E represents an eliminable group].
[0064] That is, this process is one for preparing an objective
compound (V) by condensing a quinazoline derivative represented by
the general formula (IV) with a compound represented by the general
formula (VI).
[0065] The eliminable group represented by E in the formula
includes halogen atoms and alkoxy groups.
[0066] This process may be conducted in the presence of a base at
need.
[0067] The base includes organic bases such as triethylamine,
pyridine and diisopropylethylamine; inorganic bases such as sodium
carbonate, potassium carbonate, sodium hydrogencarbonate, sodium
hydroxide and sodium hydride; and alkoxides such as sodium
methoxide and potassium t-butoxide.
[0068] As the reaction solvent, every solvent which is inert to the
reaction can be used and examples thereof include ethanol,
isopropyl alcohol, tetrahydrofuran, dimethylformamide and dimethyl
sulfoxide. This process can be conducted even in the absence of any
solvent in some cases.
[0069] The reaction temperature preferably ranges from -20 to
300.degree. C.
Preparation Process 3
[0070] When R.sup.5 is a group selected from among those defined
above with respect to NR.sup.5R.sup.6 except a hydrogen atom,
halogen atoms and groups which are directly bonded to the
quinazoline skeleton through a carbon atom; and R.sup.6 is a group
selected from among those defined above with respect to R.sup.6
except halogen atoms in the general formula (I), a compound similar
to the general formula (I) can be prepared by the following
process: 13
[0071] (in a series of formulas, R.sup.1, R.sup.2.sub.1 R.sup.3 and
R.sup.4 are each as defined above; R.sup.5.sub.c is a group
selected from among those defined above with respect to R.sup.5
except a hydrogen atom, halogen atoms and groups which are directly
bonded to the quinazoline skeleton through a carbon atom;
[0072] R.sup.6.sub.b is a group selected from among those defined
above with respect to R.sup.6, except halogen atoms; and
[0073] F represents an eliminable group).
[0074] That is, this process is one for preparing an objective
compound (VIII) by condensing a compound represented by the general
formula (VII) with a compound represented by the general formula
(IX).
[0075] The eliminable group represented by F in the formula
includes, for example, halogen atoms, alkylthio groups and so
forth.
[0076] This process may be conducted in the presence of a base at
need.
[0077] The base includes organic bases such as triethylamine,
pyridine and diisopropylethylamine; inorganic bases such as sodium
carbonate, potassium carbonate, sodium hydrogencarbonate, sodium
hydroxide and sodium hydride; and alkoxides such as sodium
methoxide and potassium t-butoxide.
[0078] As the reaction solvent, every solvent which is inert to the
reaction can be used and examples thereof include ethanol,
isopropanol, tetrahydrofuran, dimethylformamide and dimethyl
sulfoxide.
[0079] The reaction temperature preferably ranges from 0 to
300.degree. C.
Preparation Process 4
[0080] When R.sup.5 is a group represented by the formula 14
[0081] (wherein R.sup.24 is a hydrogen atom or a lower alkyl group
in the general formula (I), a compound similar to the general
formula (I) can also be prepared by the following process: 15
[0082] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 and R.sup.6 are each as defined above; and R.sup.24 and
R.sup.25, each of which may be the same or different from each
other, represent each a hydrogen atom or a lower alkyl group).
[0083] That is, this process is one for preparing an objective
compound (XI) by reacting a compound represented by the general
formula (X) with an ordinary reducing agent or an ordinary
nucleophilic reagent, either directly or through the oxidation of
an alcohol (XII).
[0084] The reducing agent includes lithium aluminum hydride, sodium
borohydride, diisobutylaluminum hydride and so forth.
[0085] The nucleophilic reagent includes lower alkyl metals such as
methyllithium, methylmagnesium bromide and so forth.
[0086] The oxidizing agent to be used when the reaction is
conducted through the alcohol (XII) includes potassium
bichromate/sulfuric acid, dimethyl sulfoxide/oxalyl chloride and so
forth.
[0087] As the reaction solvent, every solvent which is inert to the
reaction can be used.
[0088] The reaction temperature ranges from 0.degree. C. to the
refluxing temperature of the solvent.
Preparation Process 5
[0089] When R.sup.5 is a group represented by the formula 16
[0090] (wherein R.sup.10 and R.sup.24 are each as defined above) in
the general formula (I), a compound represented by the general
formula (I) can also be prepared by the following process 17
[0091] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.10 and R.sup.24 are each as defined
above).
[0092] That is, this process is one for preparing a compound
represented by the formula (XIII) by reacting a compound
represented by the general formula (XI) with hydroxyamine.
[0093] As the reaction solvent, every solvent which is inert to the
reaction can be used.
[0094] The reaction temperature ranges from 0.degree. C. to the
refluxing temperature of the solvent.
Preparation Process 6
[0095] When R.sup.5 is a group represented by the formula 18
[0096] (wherein R.sup.24 is as defined above; R.sup.26 represents a
hydrogen atom or a lower alkyl group; and R.sup.27 represents a
hydrogen atom, a lower alkyl group, a carboxyl group which may be
protected or a carboxyalkyl group which may be protected) in the
general formula (I), a compound represented by the formula (I) can
also be prepared by the following process: 19
[0097] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.24, R.sup.26 and R.sup.27 are each as
defined above; and Ph represents a phenyl group).
[0098] That is, this process is one for preparing a compound
represented by the general formula (XV) by reacting a compound
represented by the general formula (XIV) with a compound
represented by the general formula (XVI) or the general formula
(XVII) through the Wittig reaction.
[0099] As the reaction solvent, every solvent which is inert to the
reaction can be used.
[0100] The reaction temperature ranges from 0.degree. C. to the
refluxing temperature of the solvent.
Preparation process 7
[0101] When R.sup.5 is a group represented by the formula 20
[0102] (wherein R.sup.24, R.sup.26, and R.sup.27 are each as
defined above) in the general formula (I), a compound represented
by the formula (I) can also be prepared by the following process:
21
[0103] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.24, R.sup.26 and R.sup.27 are each as
defined above).
[0104] That is, this process is one for preparing an objective
compound (XVIII) by reducing the compound represented by the
general formula (XV) prepared in the Preparation process 6.
[0105] The reduction can be conducted by conventional means, for
example, catalytic reduction using palladium/carbon or platinum
catalyst.
[0106] As the reaction solvent, every solvent which is inert to the
reaction is used.
Preparation Process 8
[0107] When R.sup.6 is a group represented by the formula 22
[0108] (wherein R.sup.19, R.sup.20, R.sup.21 and r are each as
defined above) in the general formula (I), a compound represented
by the general formula (I) can also be prepared by the following
process: 23
[0109] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.19, R.sup.20, R.sup.21 and r are each as
defined above).
[0110] That is, this process is one for preparing an objective
compound (XX) by reducing a compound represented by the general
formula (XIX).
[0111] The reduction is conducted by conventional means, e.g.,
catalytic reduction using palladium/carbon or platinum catalyst or
reduction with iron or tin.
[0112] As the reaction solvent, every solvent which is inert to the
reaction can be used.
Preparation Process 9
[0113] When R.sup.5 is a group represented by the formula
--O--R.sup.9 (wherein R.sup.9 is a carboxyl group which may be
protected) in the general formula (I), a compound represented by
the formula (I) can be prepared by the following process:
[0114] The first step 24
[0115] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.6 are each as defined above; and m represented 0 or an
integer of 1 to 2).
[0116] That is, this process is one for preparing a compound
represented by the general formula (XXII) by oxidizing a compound
represented by the general formula (XXI) by conventional means.
[0117] As the oxidizing agent, everyone can be used so far as it is
conventionally used and examples thereof include chromium (VI),
dimethyl sulfoxide and oxalyl chloride.
[0118] As the reaction solvent, every solvent which is inert to the
reaction can be used.
[0119] The reaction temperature ranges from 0.degree. C. to the
refluxing temperature of the solvent.
[0120] The second step 25
[0121] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6 and m are each as defined above; and R.sup.28,
R.sup.29 and R.sup.30, each of which may be the same or different
from one another, represent each a hydrogen atom or a lower alkyl
group).
[0122] That is, this process is one for preparing a compound
represented by the general formula (XXIV) by reacting the compound
(XXII) prepared in the first step with the Wittig reagents (XXIII)
or (XXIII)'.
[0123] As the reaction solvent, everyone which is inert to the
reaction can be used.
[0124] The reaction temperature ranges from 0.degree. C. to the
refluxing temperature of the solvent.
[0125] The third step 26
[0126] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.29, R.sup.30 and m are each as defined
above).
[0127] That is, this process is one for preparing the objective
compound (XXV) by reducing the compound (XXIV) prepared in the
second step.
[0128] The reduction may be conducted by conventional means, and
examples thereof include catalytic reduction using palladium/carbon
or platinum catalyst.
Preparation Process 10
[0129] When R.sup.6 is a group represented by the formula 27
[0130] (wherein R.sup.19, R.sup.20, R.sup.21 and r are each as
defined above; and R.sup.31 represents an acyl group, a lower
alkylsulfonyl group or a lower alkyloxycarbonyl group) in the
general formula (I), a compound represented by the general formula
(I) can also be prepared by the following process: 28
[0131] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 R.sup.19, R.sup.20, R.sup.21 and R.sup.31, and r
are each as defined above).
[0132] That is, this process is one for preparing an objective
compound (XXVI) by subjecting the compound represented by the
general formula (XX) prepared in the Preparative process 8 to the
conventional acylation, sulfonylation or alkoxycarbonylation in the
presence of a base.
[0133] As the acylating agent, every acylating agent which is
conventionally used, for example, activated derivatives of
carboxylic acids such as acid chloride, acid anhydride and mixed
acid anhydride; and condensing agents such as
dicyclohexylcarbodiimide is used.
[0134] As the sulfonylating agent, every sulfonylating agent which
is conventionally used can be used and examples thereof include a
lower alkylsulfonyl chloride and a lower alkylsulfonic
anhydride.
[0135] The alkoxycarbonylating agent includes every
alkoxycarbonylating agent which is conventionally used, for
example, a lower alkyloxycarbonyl chloride and a lower alkyl
pyrocarbonate.
[0136] At the base, every base can be used and examples thereof
include organic bases such as pyridine and triethylamine; and
inorganic bases such as sodium carbonate, potassium carbonate,
sodium hydroxide and sodium hydride.
Preparation Process 11
[0137] When a compound similar to formula (I) is desired, except
having 2 rings A and B, the ring A is selected from any of a
benzene ring, a pyridine ring and a cyclohexane ring, the ring B is
selected from among a pyridine ring, a pyrimidine ring and an
imidazole ring, R.sup.5 represents a group selected from among
those defined above with respect to R.sup.5 except groups which are
directly bonded to the ring portion through a carbon atom; and
R.sup.6 represents a group selected from among those defined above
with respect to R.sup.5 except groups which are directly bonded to
the ring portion through a carbon atom in the general formula (I),
the compound represented by the general formula (I) can also be
prepared by the following process. The case in which the ring
portion forms a quinazoline skeleton is shown below as the
representative of the above:
[0138] The first step 29
[0139] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above; R.sup.5.sub.a represents a group
selected from among those defined above with respect to R.sup.5
except groups which are directly bonded to the ring portion through
a carbon atom; and X represents a halogen atom).
[0140] That is, the first step is a condensation reaction according
to a conventional process.
[0141] Alcohol solvents such as isopropyl alcohol, ether solvents
such as tetrahydrofuran and dimethylformamide are preferably used
as the reaction solvent. However, every solvent which is inert to
the reaction can be used.
[0142] In the case where R.sup.5.sub.a is bonded to the ring
portion through a nitrogen atom, it is preferred that the reaction
is proceeded by heating under reflux in the presence of a tertiary
amine such as triethylamine while removing HCI generated. While in
the case where R.sup.5.sub.a is bonded to the ring portion through
an oxygen atom or a sulfur atom, it is preferred that the reaction
is proceeded by heating under reflux in the presence of an alkali
such as sodium hydroxide and sodium carbonate.
[0143] The second step 30
[0144] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5.sub.a and X are each as defined above:
R.sup.6.sub.a represents a group selected from among those defined
above with respect to R.sup.6 except groups which are directly
bonded to the ring portion through a carbon atom).
[0145] The second step is a reaction wherein the compound (XXVIII)
obtained in the first step is condensed with a compound represented
by the formula R.sup.6.sub.a--H according to a conventional
process.
[0146] Alcohol solvents such as isopropyl alcohol, ether solvents
such as tetrahydrofuran and dimethylformamide are preferably used
as the reaction solvent. However, every solvent which is inert to
the reaction can be used.
[0147] In the case where R.sup.6.sub.a is bonded to the ring
portion through a nitrogen atom, it is preferred that the reaction
is proceeded by heating under reflux in the presence of an organic
base such as triethylamine, pyridine and ethyldiisopropylamine, an
inorganic base such as sodium carbonate, potassium carbonate,
sodium hydrogencarbonate, sodium hydride and sodium hydroxide or an
alkoxide such as sodium methoxide and potassium t-butoxide. While
in the case where R.sup.6.sub.a is bonded to the ring portion
through an oxygen atom or a sulfur atom, it is preferred that the
reaction is proceeded by heating under reflux in the presence of an
alkali such as sodium hydroxide and sodium carbonate.
Preparation Process 12
[0148] When the compound represented by the general formula (1) is
a compound represented by the following general formula (XXXII):
31
[0149] the compound can also be prepared by the following process.
32
[0150] (in a series of formulas R.sup.1, R.sup.2, R.sup.3, R.sup.4,
and R.sup.5 are each as defined above; and R.sup.6.sub.b represents
a group selected from among groups which are directly bonded to the
ring portion through a carbon atom in those defined above with
respect to R.sup.6) .
[0151] That is, this process is one for preparing an objective
compound by reacting, for example, piperonyl chloride (XXXI) with a
benzimidazole derivative represented by the general formula (XXX)
in the presence of an alkali by a conventional process.
[0152] Sodium iodide is preferred as alkali.
[0153] Although every solvent which is inert to the reaction can be
used as the reaction solvent, polar solvents such as
dimethylforamide can be cited as preferable ones.
[0154] The reaction temperature is preferably about 60 to
100.degree. C., particularly preferably about 70 to 80.degree.
C.
Preparation Process 13
[0155] Additional compounds can also be prepared by the following
process:
[0156] The first step 33
[0157] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above; R.sup.6.sub.d represents a group
selected from among those defined above with respect to R.sup.6
except groups which are directly bonded to the ring portion through
a carbon atom; and Q and Q' represent halogen atoms).
[0158] The first step is a condensation reaction according to a
conventional process.
[0159] In the case where R.sup.6.sub.d is bonded to the ring
portion through a nitrogen atom, it is preferred that the reaction
is proceeded by heating under reflux in the presence of an organic
base such as triethylamine, pyridine and duisopropylethylamine, an
inorganic base such as sodium carbonate, potassium carbonate,
sodium hydrogencarbonate, sodium hydroxide and sodium hydride or an
alkoxide such as sodium methoxide and potassium t-butoxide. While
in the case where R.sup.6.sub.d is bonded to the ring portion
through an oxygen atom or a sulfur atom, it is preferred that the
reaction is proceeded by heating under reflux in the presence of an
inorganic base such as sodium hydroxide and sodium carbonate.
[0160] Every solvent which is inert to the reaction can be used as
the reaction solvent, and examples thereof include alcohol solvents
such as ethanol and isopropyl alcohol, ether solvents such as
tetrahydrofuran, dimethylformamide and dimethylsulfoxide. Further,
in the present process, the reaction can be proceeded in the
absence of a reaction solvent in some cases.
[0161] The second step 34
[0162] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3, R.sup.4
R.sup.6.sub.d and Q are each as defined above; and R.sup.5.sub.d
represents a group selected from among those defined above with
respect to R.sup.5 except groups which are directly bonded to the
ring portion through a carbon atom).
[0163] That is, the second step is a process for preparing an
objective compound in which the compound obtained in the first step
is condensed with a compound represented by the general formula
R.sup.5.sub.d--H.
[0164] In the present process, the reaction can be processed in the
presence of a base at need.
[0165] As the base, organic bases such as triethylamine, pyridine
and diisopropylethylamine, inorganic bases such as sodium
carbonate, potassium carbonate, sodium hydrogencarbonate, sodium
hydroxide and sodium hydride and alkoxides such as sodium methoxide
and potassium t-butoxide can be cited.
[0166] Every solvent which inert to the reaction can be used as the
reaction solvent, and examples thereof include alcohol solvents
such as ethanol and isopropanol, ether solvents such as
tetrahydrofuran, dimethylformamide and dimethylsulfoxide.
[0167] The reaction temperature is preferably 0.degree. C. to
300.degree. C.
[0168] In the case where R.sup.5.sub.d is a group which is bonded
to the ring portion through a nitrogen atom, it is preferred that
the reaction is proceeded by heating under reflux in the presence
of a tertiary amine such as triethylamine. While in the case where
R.sup.5.sub.d is a group which is bonded to the ring portion
through a oxygen atom or a sulfur atom, it is preferred that the
reaction is proceeded by heating under reflux in the presence of an
alkali such as sodium hydroxide and sodium carbonate.
[0169] The compounds thus obtained in the preparation processes 1
to 13 described above can form salts thereof by a conventional
process, for example, by adding sodium hydroxide, potassium
hydroxide or methanesulfonic chloride.
[0170] Next, the preparation processes for the raw compounds used
in the preparation processes will be shown.
Preparation Process A
[0171] Among the starting materials used in the preparation process
13, the compound in which the ring portion is a quinazoline ring
and Q and Q' are chlorine atoms can also be prepared by the
following process: 35
[0172] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above; and X' represents any group
among a hydroxyl group, an alkoxy group and an amino group).
[0173] That is, this process is one for preparing the objective
compound (c) by cyclizing the compound (a) by a conventional
process to obtain the compound (b) and then chlorinating it by a
conventional process.
[0174] The first step is a cyclization reaction. It is a step in
which urea is reacted with the compound (a) to obtain the compound
(b). In this case, the reaction temperature is preferably about 170
to 190.degree. C., and although every solvent can be used as long
as it is inert to the reaction, preferable examples thereof include
N-methylpyrrolidone and the like. In this step, the reaction can
also be proceeded in the absence of the solvent.
[0175] Further, the compound (b) can also be obtained by cyclizing
with carbonyldiimidazole or by cyclizing under an acidic or basic
condition after converting to urethane with a chloroformic ester
when X' is an amino group.
[0176] The second step is a chlorination reaction. This step can be
carried out by a conventional manner, and examples thereof include
a process in which the compound (b) is heated under reflux with
phosphorus pentachloride and phosphorus oxychloride, or phosphorus
oxychloride while stirring to chlorinate.
Preparation Process B
[0177] The starting material (II) used in the preparation process 1
can be prepared by the following process: 36
[0178] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above; and R.sup.5.sub.c represents a
halogen atom or a group selected from among groups which are
directly bonded to the ring portion through a carbon atom in those
defined with respect to above R.sup.5).
[0179] That is, the above process is a reaction in which an amide
product is obtained by a conventional process in the first step and
a cyclization is carried out in the presence of an acid or a base
in the second step.
[0180] The amide produce (e) can be obtained by a conventional
process, and it can be obtained, for example, by reacting the
compound (d) with an acylating agent such as an acid chloride
represented by R.sup.5.sub.c--COCI in the presence of a base.
[0181] Tertiary amines such as triethylamine and organic bases such
as pyridine are preferably cited as the base.
[0182] Specific examples of the acylating agent include acid
chlorides such as benzoyl chloride, acetyl chloride, ethyloxalyl
chloride and benzyloxyacetyl chloride.
[0183] The reaction temperature is preferably about 0.degree. C. to
30.degree. C.
[0184] In the second step, the compound (e) obtained in the first
step is heated under reflux in the presence of an acid or a base to
obtain the compound (f).
[0185] The acid includes acetic anhydride and the like.
[0186] The base includes sodium hydroxide and the like.
Preparation Process C
[0187] The starting material (II) can also be prepared by the
following process when R.sup.5.sub.a is a hydrogen atom in the
preparation process 1: 37
[0188] (in a series of formulas, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are each as defined above; and X" represents a hydroxyl
group or a lower alkoxy group).
[0189] That is, the above process is a cyclization reaction by a
conventional process.
[0190] The objective compound (h) can be synthesized, for example,
by condensing the raw compound (g) with formamide by heating under
reflux, or by heating it together with formic acid.
[0191] Examples of the present invention will now be described,
though it is needless to say that the present invention is not
limited to them. In advance of Examples, preparative examples of
the raw compound for compounds according to the present invention
will be described. In the Examples, Me represents a methyl group,
Et an ethyl group, Bzl a benzyl group and Ac an acetyl group.
EXAMPLES
Preparative Example 1
2-Ethoxycarbonyl-6-chloroquinazolin-4(3H)-one
[0192] 38
[0193] 2.50 g (0.0147 mol) of 2-amino-5-chlorobenzamide was
dissolved in 15 ml of pyridine. 2.0 ml of ethyloxalyl chloride was
dropped into the obtained solution under stirring at room
temperature. The obtained mixture was stirred for several hours and
distilled under a reduced pressure to remove the solvent. The
obtained residue was used as such in the subsequent reaction.
[0194] The residue was dissolved in 50 ml of acetic acid, followed
by the addition of 5 ml of acetic anhydride. The obtained mixture
was heated under reflux for 24 hours. The solvent was distilled
away under a reduced pressure and ethanol was added to the obtained
crystalline residue. The obtained mixture was filtered to recover
the crystal. The crystal was washed with ethanol and ether and
air-dried to give 2.78 g of the title compound as a pale-yellow
crystal.
[0195] yield (i); 75
[0196] m.p. (.degree. C.); 239.about.240
[0197] Mass; 253 (M+H).sup.+
[0198] NMR .delta. (DMSO-d.sub.6);
[0199] 1.36 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 7.86 (1H, d,
J=8.8 Hz), 7.92 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.11(1H,d,J=2.4 Hz),
12.85(1H,brs)
Example 1
2-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline
[0200] 39
[0201] A mixture comprising 338 mg of
2-chloro-4-(3,4-methylenedioxybenzyl- )amino-6-cyanoquinazoline,
435 mg of morpholine and 20 ml of isopropyl alcohol was heated
under reflux for 3 hours, followed by the addition of 30 ml of
water under heating. The precipitate thus formed was recovered by
filtration and washed with 30 ml of water and 30 ml of ethyl
acetate. Thus, 310 mg of the title compound was obtained.
[0202] molecular formula; C.sub.21H.sub.19N.sub.5O.sub.3 (389)
[0203] yield (%); 80
[0204] m.p. (.degree. C.); 270.about.272 (dec.)
[0205] Mass; 390 (M+1).sup.+
[0206] NMR .delta. (DMSO-d.sub.6)
[0207] 3.57-3.61 (4H, m), 3.73.about.3.79 (4H, m), 4.57 (2H, d,
J=5.6 Hz), 5.95 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0
Hz), 6.93 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.8 Hz,
1.6 Hz), 8.56 (1H, d, J=1.6 Hz), 8.75 (1H, brt, J=5.6 Hz)
Examples 2 to 3
[0208] The following compounds were prepared in a similar manner to
that of Example 1.
Example 2
2-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline
[0209] 40
[0210] molecular formula; C.sub.20H.sub.19N.sub.4O.sub.3Cl
(398.850)
[0211] yield (%); 96
[0212] m.p. (.degree. C.); 208.about.209
[0213] Mass; 399 (MH).sup.+
[0214] NMR .delta. (DMSO-d.sub.6);
[0215] 3.61 (4H, t, J=5 Hz), 3.72 (4H, t, J=5 Hz), 4.58 (2H, d,
J=5.7 Hz), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.28 (1H, d,
J=9.0 Hz), 7.51 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.18 (1H, d, J=2.4 Hz),
8.60 (1H, t, J=5.7 Hz)
Example 3
2-Morpholino-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline
[0216] 41
[0217] molecular formula; C.sub.21H.sub.20N.sub.5O.sub.2Cl
(407.5)
[0218] yield (%); 51
[0219] m.p. (.degree. C.) ; 222.about.223
[0220] Mass; 410 (M+1).sup.+
[0221] NMR .delta. (DMSO-d.sub.6);
[0222] 3.56.about.3.61 (4H, m), 3.74.about.3.80 (4H, m), 3.80 (3H,
s), 4.58 (2H, d, J=5.2 Hz), 7.27.about.7.32 (2H, m), 7.44 (1H, d,
J=1.6 Hz), 7.75 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.55 (1H, d, J=1.6 Hz),
8.80 (1H, brt, J=5.2 Hz)
Example 4
2-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-cyanoquinazol-
ine
[0223] 42
[0224] A mixture comprising 339 mg of
2-chloro-4-(3,4-methylenedioxybenzyl- )amino-6-cyanoquinazoline,
500 mg of 4-hydroxypiperidine and 20 ml of N,N-dimethyl-formamide
was heated under reflux for 5 hours and poured into 50 ml of water,
followed by the addition of 50 ml of ethyl acetate. The obtained
mixture was filtered to remove insolubles. The organic layer of the
filtrate was dried over magnesium sulfate and concentrated under a
reduced pressure to give a crystalline residue. This residue was
washed with chloroform to give 145 mg of the title compound.
[0225] molecular formula; C.sub.22H.sub.21N.sub.5O.sub.3 (403)
[0226] yield (%); 36
[0227] m.p.(.degree. C.); 229
[0228] Mass; 404 (M+1).sup.+
[0229] NMR .delta. (DMSO-d.sub.6);
[0230] 1.19.about.1.30 (2H, m), 1.64.about.1.77 (2H, m),
3.21.about.3.30 (2H, m), 3.63.about.3.75 (1H, m), 4.34.about.4.38
(2H, m), 4.55 (2H, d, J=5.6 Hz), 4.66 (1H, d, J=4.0 Hz), 5.94 (2H,
s), 6.80.about.6.86 (2H, m), 6.93 (1H, d, J=0.8 Hz), 7.24 (1H, d,
J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.52 (1H, d, J=1.6 Hz),
8.70 (1H, br)
Examples 5 to 11
[0231] The following compounds were prepared in a similar manner to
that of Example 4.
Example 5
2-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazo-
line
[0232] 43
[0233] molecular formula; C.sub.21H.sub.21N.sub.4O.sub.3Cl
(412.877)
[0234] yield (%); 56
[0235] m.p. (.degree. C.) ; 157.about.158
[0236] Mass; 413 (MH.sup.+)
[0237] NMR .delta. (DMSO-d.sub.6);
[0238] 1.2.about.1.3 (2H, m), 1.6.about.1.8 (2H, m), 3.1.about.3.2
(2H, m), 3.6.about.3.7 (1H, m), 4.3.about.4.4 (2H, m), 4.55 (2H, d,
J=5.7 Hz), 4.65 (1H, d, J=4.4 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.95
(1H, s), 7.24 (1H, d, J=9.0 Hz), 7.47 (1H, dd, J=2.4 Hz, 9.0 Hz),
8.13 (1H, d, J=2.4 Hz), 8.53 (1H, t, J=5.7 Hz)
Example 6
2-(4-Hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-cyanoquinazol-
ine
[0239] 44
[0240] molecular formula; C.sub.22H.sub.22N.sub.5O.sub.2Cl
(423.5)
[0241] yield (%); 80
[0242] m.p. (.degree. C.); 207.about.208
[0243] Mass; 424 (M+1).sup.+
[0244] NMR .delta. (DMSO -d.sub.6);
[0245] 1.18.about.1.30 (2H, m), 1.65.about.1.76 (2H, m),
3.21.about.3.33 (2H, m), 3.30 (3H, s), 3.64.about.3.72 (1H, m),
4.29.about.4.37 (2H, m), 4.57 (2H, d, J=5.6 Hz), 4.66 (1H, d, J=1.8
Hz), 7.07 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.8 Hz), 7.29 (1H, dd,
J=8.4 Hz, 2.0 Hz), 7.43 (1H, d, J=2.0 Hz), 7.71 (1H, dd, J=8.8 Hz,
2.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.74 (1H, brt, J=1.8 Hz)
Example 7
2- (2-Hydroxyethyl)amino-4- (3,4-methylenedioxybenzyl)
-amino-6,7,8- trimethoxyquinazoline
[0246] 45
[0247] molecular formula; C.sub.21H.sub.24N.sub.4O.sub.6
[0248] yield (%); 38
[0249] m.p.(.degree. C.); amorphous
[0250] Mass; 429 (M+H).sup.+
[0251] NMR .delta. (CDCl.sub.3);
[0252] 3.60 (2H, m), 3.88 (3H, s&1H, m) , 3.99 (3H, s), 4.01
(3H, s), 4.67 (2H, d, J=5.6 Hz), 5.32 (1H, brs), 5.53 (1H, brs),
5.97 (2H, s), 6.55 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d,
J=8.0 Hz), 6.89 (1H, s)
Example 8
2-
(2-Hydroxyethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinaz-
oline
[0253] 46
[0254] molecular formula; C.sub.18H.sub.17N.sub.4O.sub.3Cl
[0255] yield (%); 47
[0256] m.p.(.degree. C.); 138.about.139
[0257] Mass m/e; 373 (M+1)
[0258] NMR .delta. (CDCl.sub.3(+DMSO-d.sub.6));
[0259] 3.60 (2H, m), 3.79 (2H, t, J=4.8 Hz), 4.65 (2H, d, J=5.2
Hz), 5.94 (2H, s), 6.76 (1H, d, J=8.0 Hz), 6.85 (1H, dd, J=8.0 Hz,
2.0 Hz), 6.90 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.44 (1H,
dd, J=8.8 Hz, 2.4 Hz), 8.02 (2H, brs)
Example 9
2-[N-(2-Hydroxyethyl)-N-methylaminol-4-(3,4-methylene-dioxybenzyl)amino-6--
chloroquinazoline
[0260] 47
[0261] molecular formula; C.sub.19H.sub.19N.sub.4O.sub.3Cl
[0262] yield (%); 48
[0263] m.p. (.degree. C.); 146.about.148
[0264] Mass m/e; 387 (M+1)
[0265] NMR .delta. (CDCl.sub.3(+DMSO-d.sub.6));
[0266] 3.27 (3H, s), 3.82 (2H, t, J=4.8 Hz) 3.89 (2H, t, J=4.8 Hz),
4.67 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86
(1H, dd, J=8.0 Hz, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.43 (2H, m),
7.76 (1H, brs)
Example 10
2-(2-Hydroxymethylpyrrolidin-1-yl)-4-(3,4-methylene-dioxybenzyl)amino-6-ch-
loroquinazoline
[0267] 48
[0268] molecular formula; C.sub.21H.sub.21N.sub.4O.sub.3Cl
(412.877)
[0269] yield (%); 70
[0270] m.p. (.degree. C.); 182.about.183
[0271] Mass; 413 (MH.sup.+)
[0272] NMR .delta. (DMSO-d.sub.6);
[0273] 1.8.about.2.0 (4H, br 2 peaks), 3.4.about.3.7 (3H, br 2
peaks), 4.1.about.4.2 (1H, brs), 4.58 (2H, d, J=5.8 Hz), 5.96 (2H,
s), 6.84 (1H, d, J=8.0 Hz), 6.88 (1H, dd, J=1.3 Hz, 8.0 Hz), 6.96
(1H, d, J=1.3 Hz), 7.23 (1H, d, J=8.8 Hz), 7.47 (1H, dd, J=2.4 Hz,
8.8 Hz), 8.15 (1H, d, J=2.4 Hz), 8.4.about.8.6 (1H, brs)
Example 11
2-Bis
(2-hydroxyethyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroqui-
nazoline
[0274] 49
[0275] molecular formula; C.sub.20H.sub.21N.sub.4O.sub.4Cl
(416.865)
[0276] yield (%); 56
[0277] m.p. (.degree. C.) ; 167.about.168
[0278] Mass; 417 (MH.sup.+)
[0279] NMR .delta. (DMSO-d.sub.6);
[0280] 3.5.about.3.7 (8H, br 2 peaks), 4.56 (2H, d, J=5.7 Hz), 5.96
(2H, s), 6.85 (2H, s), 6.93 (1H, s), 7.22 (1H, d, J=9.0 Hz), 7.47
(1H, dd, J=2.4 Hz, 9.0 Hz), 8.15 (1H, d, J=2.4 Hz), 8.55 (1H, brt,
J=5.7 Hz)
Example 12
2-(1-Imidazolyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline
[0281] 50
[0282] 103 mg of imidazole was added to a suspension of 66 mg of
sodium hydride in 6 ml of dimethylformamide at 0.degree. C. The
obtained mixture was stirred for 10 minutes. 500 mg of
2,6-dichloro-4-(3,4-methylenedioxyb-
enzyl)-amino-6-chloroquinazoline was added to the resulting mixture
at room temperature. The mixture thus prepared was stirred at
100.degree. C. for 20 minutes, followed by the addition of water.
The crystals precipitated were recovered by filtration and washed
with water and ethanol/acetone successively to give 325 mg of the
title compound.
[0283] molecular formula; C.sub.19H.sub.14N.sub.5O.sub.2Cl
[0284] yield (%); 59
[0285] m.p.(.degree. C.); 275.about.276 (dec.)
[0286] Mass m/e; 380 (M+1)
[0287] NMR .delta. (DMSO-d.sub.6);
[0288] 4.74 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.85 (1H, d, J=8.0
Hz), 6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.03 (1H, d, J=1.6 Hz), 7.08
(1H, d, J=1.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.78 (1H, dd, J=8.8 Hz,
2.4 Hz), 7.94 (1H, d, J=1.2 Hz), 8.47 (1H, d, J=2.4 Hz), 8.58 (1H,
t, J=2.4 Hz), 9.28 (1H, t, J=5.6 Hz)
Examples 13 to 17
[0289] The following compounds were prepared in a similar manner to
that of Example 12.
Example 13
2-(Imidazol-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline
[0290] 51
[0291] molecular formula; C.sub.20H.sub.14N.sub.6O.sub.2 (370)
[0292] yield (%); 81
[0293] m.p. (.degree. C.) ; >290
[0294] Mass; 371 (M+1).sup.+
[0295] NMR .delta. (DMSO-d.sub.6);
[0296] 4.74 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.86 (1H, d, J=8.0
Hz), 6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.04 (1H, d, J=1.6 Hz), 7.09
(1H, d, J=1.6 Hz), 7.73 (1H, d, J=8.4 Hz), 7.95 (1H, d, J=1.6 Hz),
8.06 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.61 (1H, d, J=1.6 Hz), 8.87 (1H,
d, J=1.6 Hz), 9.47 (1H, brt, J=6.0 Hz)
Example 14
2-Pentylamino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline
[0297] 52
[0298] molecular formula; C.sub.21H.sub.23N.sub.4O.sub.2Cl
[0299] yield (%); 97
[0300] m.p. (.degree. C.) ; 194.about.195
[0301] Mass m/e; 399 (M+1)
[0302] NMR .delta. (CDCl.sub.3);
[0303] 0.86 (3H, t, J=7.2 Hz), 1.29 (4H, m), 1.58 (2H, quintet,
J=6.8 Hz), 3.47 (2H, q, J=6.8 Hz), 4.78 (2H, d, J=5.6 Hz), 5.87
(2H, s), 6.66 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=8.0 Hz), 6.94 (1H,
s), 7.26 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.90 (1H, t,
J=5.6 Hz), 8.55 (1H, s), 9.53 (1H, brs)
Example 15
2-(2-Aminoethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6,7,8-trimethoxyq-
uinazoline
[0304] 53
[0305] molecular formula; C.sub.21H.sub.25N.sub.5O.sub.5
[0306] yield (%); 87
[0307] m.p. (.degree. C.); amorphous
[0308] Mass; 428 (M+H).sup.+
[0309] NMR .delta. (CDCl.sub.3);
[0310] 1.44 (2H, s), 2.93 (2H, t, J=6.0 Hz), 3.57 (2H, brs), 3.88
(3H, s), 4.00 (3H, s), 4.07 (3H, s), 4.70 (2H, d, J=4.8 Hz), 5.16
(1H, brs), 5.51 (1H, brs), 5.96 (2H, s), 6.56 (1H, s), 6.80 (1H, d,
J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.90 (1H, s)
Example 16
2-Hydrazino-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline
[0311] 54
[0312] molecular formula; C.sub.19H.sub.21N.sub.5O.sub.5
[0313] yield (%); 12
[0314] m.p. (.degree. C.); oily substance
[0315] Mass; 400 (M+H).sup.+
[0316] NMR .delta. (CDCl.sub.3);
[0317] 3.88 (3H, s), 3.99 (3H, s), 4.05 (3H, s), 4.66 (2H, d, J=3.6
Hz), 5.92 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.83 (1H, d, J=8.0 Hz),
6.87 (1H, s), 7.04 (2H, brs)
Examale 17
2-(Carbamoylmethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinaz-
oline
[0318] 55
[0319] molecular formula; C.sub.18H.sub.16N.sub.5O.sub.3Cl
[0320] yield (%); 63
[0321] m.p. (.degree. C.); 259.about.260 (dec.)
[0322] Mass m/e; 386 (M+1)
[0323] NMR .delta. (DMSO-d.sub.6);
[0324] 4.02 (2H, d, J=4.8 Hz), 4.66 (2H, d, J=5.6 Hz), 5.97 (2H,
s), 6.86 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 6.99 (1H, s),
7.19 (1H, s), 7.50 (1H, d, J=8.8 Hz), 7.61 (1H, S), 7.83 (1H, d,
J=8.8 Hz), 8.09 (1H, brs), 8.49 (1H, brs), 10.03 (1H, brs)
Example 18
2-(3,4-Methylenedioxybenzyl)amino-4,6,7,8-tetramethoxy-quinazoline
[0325] 56
[0326] 1.00 g (3.51 mmol) of
2-chloro-4,6,7,8-tetra-methoxyquinazoline, 0.60 g (3.97 mmol) of
piperonyl-amine and 0.60 g of sodium carbonate were mixed with 30
ml of isopropyl alcohol. The obtained mixture was heated under
reflux for 24 hours and distilled under a reduced pressure to
remove the solvent. The residue was purified by silica gel column
chromatography (ethyl acetate/n-hexane) to give 0.12 g of the title
compound as an oily substance.
[0327] molecular formula; C.sub.20H.sub.21N.sub.3O.sub.6
[0328] yield (%); 9
[0329] m.p. (.degree. C.); oily substance
[0330] NMR .delta. (CDCl.sub.3) ;
[0331] 3.91 (3H, s), 4.02 (3H, s), 4.04 (6H, s), 4.63 (2H, d, J=6.0
Hz), 5.30 (1H, brs), 5.93 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.86
(1H, dd, J=8.0 Hz, 1.6 Hz), 6.92 (1H, d, J=1.6 Hz), 7.06 (1H,
s)
Example 19
2-Chloro-4,6,7,8-tetramethoxyquinazoline
[0332] 57
[0333] 5.00 g (17.3 mmol) of
2,4-dichloro-6,7,8-trimethoxyquinazoline was suspended in 100 ml of
methanol, followed by the gradual addition of 1.5 g of sodium
hydride. The obtained mixture was heated under reflux. After
several hours, the reaction mixture was concentrated under a
reduced pressure, followed by the addition of water. The crystal
thus precipitated was recovered by filtration, washed with water
and air-dried to give 4.80 g of the title compound as a pale-pink
crystal.
[0334] yield (%); 97
[0335] m.p. (.degree. C.); 119.about.120
[0336] Mass; 285 (M+1).sup.+
[0337] NMR .delta. (CDCl.sub.3);
[0338] 3.98 (3H, s), 4.06 (3H, s), 4.12 (3H, s), 4.19 (3H, s), 7.17
(1H, s)
Example 20
2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline
[0339] 58
[0340] 2.0 g of
2.6-dichloro-4-(3,4-methylenedioxy-benzyl)aminoquinazoline was
heated to 120.degree. C. in 50 ml of ethanolic ammonia put in a
pressure vessel for 18 hours, cooled and concentrated under a
reduced pressure. The obtained residue was introduced to a silica
gel column and eluted with a chloroform/methanol (9:1) mixture to
give 830 mg of the title compound.
[0341] molecular formula; C.sub.16H.sub.13N.sub.4O.sub.2Cl
[0342] yield (%); 44
[0343] m.p. (.degree. C.); 285 (dec.)
[0344] Mass; 329 (M+1).sup.+
[0345] NMR .delta. (CDCl.sub.3);
[0346] 4.67 (2H, d, J=5.6 Hz), 4.98 (2H, br), 5.74 (1H, br), 5.96
(2H, s), 6.78 (1H, d, J=7.6 Hz), 6.83 (1H, dd, J=7.6 Hz, 1.6 Hz),
6.86 (1H, d, J=1.6 Hz), 7.38 (1H, d, J=9.6 Hz), 7.46.about.7.49
(2H, m)
Example 21
2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-cyano-quinazoline
[0347] The title compound was prepared in a similar manner to those
of Examples 19 and 20. 59
[0348] molecular formula; C.sub.17H.sub.13N.sub.5O.sub.2 (319)
[0349] yield (%); 60
[0350] m.p. (.degree. C.); 284 (dec.)
[0351] Mass; 320 (M+1).sup.+
[0352] NMR .delta. (CDCl.sub.3);
[0353] 4.31 (2H, d, J=5.6 Hz), 5.25 (2H, brs), 5.58 (2H, s), 6.40
(1H, d, J=7.6 Hz), 6.51 (1H, dd, J=7.6 Hz, 1.2 Hz), 6.57 (1H, d,
J=1.2 Hz), 6.95 (1H, d, J=8.4 Hz), 7.25 (1H, dd, J=8.4 Hz, 1.6 Hz),
8.00 (1H, br), 8.20 (1H, d, J=1.6 Hz)
Example 22
2-(Methylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinaz-
oline
[0354] 60
[0355] 4 ml of dimethyl sulfoxide and 260 mg of methyl isocyanate
were added to 500 mg of
2-amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquin- azoline.
The obtained mixture was stirred at 50.degree. C. for 3 hours and
distilled under a reduced pressure to remove excess methyl
isocyanate, followed by the addition of chloroform and water. The
mixture thus obtained was filtered and the filtrate was extracted
with chloroform twice. The organic layers were combined, washed
with water twice, dried over magnesium sulfate and distilled under
a reduced pressure to remove the solvent. The residue was purified
by silica gel column chromatography (benzene/acetone) and
recrystallized (from benzene/chloroform/ethanol) to give 72 mg of
the title compound.
[0356] molecular formula; C.sub.18H.sub.16N.sub.5O.sub.3Cl
[0357] yield (%); 12
[0358] m.p. (.degree. C.); 245.about.247
[0359] Mass m/e; 386 (M+1)
[0360] NMR .delta. (DMSO-d.sub.6);
[0361] 2.75 (3H, d, J=4.4 Hz), 4.56 (2H, d, J=6.0 Hz), 5.95 (2H,
s), 6.82 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.4 Hz), 7.11 (1H, s),
7.56 (1H, d, J=8.8 Hz), 7.67 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.27 (1H,
d, J=1.6 Hz), 8.90 (1H, t, J=6.0 Hz), 9.20 (1H, s), 9.38 (1H, d,
J=4.4 Hz)
Examples 23 and 24
[0362] The following compounds were prepared in a similar manner to
that of Example 22.
Example 23
2-Bis(methylcarbamoyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroqui-
nazoline
[0363] 61
[0364] molecular formula; C.sub.20H.sub.19N.sub.6O.sub.4Cl
[0365] yield (%); 8
[0366] amt. of product (mg); 45
[0367] m.p. (.degree. C.); 243.about.245
[0368] Mass m/e; 443 (M+1)
[0369] NMR .delta. (DMSO-d.sub.6);
[0370] 2.71 (6H, d, J=4.8 Hz), 4.53 (2H, d, J=6.0 Hz), 5.94 (2H,
s), 6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.95 (1H, s),
7.66 (1H, d, J=8.8 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.32 (1H,
dd, J=2.0 Hz), 8.85 (1H, dd, J=4.8 Hz), 9.01 (1H, t, J=6.0 Hz)
Example 24
2-(n-Butylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquina-
zoline
[0371] 62
[0372] molecular formula; C.sub.21H.sub.22N.sub.5O.sub.3Cl
[0373] yield (%); 40
[0374] m.p. (.degree. C.); 209.about.210
[0375] Mass m/e; 428 (M+1)
[0376] NMR .delta. (DMSO-d.sub.6);
[0377] 0.89 (3H, t, J=7.2 Hz), 1.33 (2H, sextet, J=7.2 Hz), 1.45
(2H, quintet, J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 4.56 (2H, d, J=6.0
Hz), 5.95 (2H, s), 6.83 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz),
7.09 (1H, s), 7.46 (1H, d, J=8.8 Hz), 7.66 (1H, dd, J=8.8 Hz, 2.0
Hz), 8.27 (1H, d, J=2.0 Hz), 8.90 (1H, t, J=6.0 Hz), 9.17 (1H, s),
9.58 (1H, t, J=7.2 Hz)
Example 25
2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloro-
quinazoline
[0378] 63
[0379] 3.61 g of methyl isonipecotate, 2.32 g of triethylamine and
5 ml of 2-propanol were added to 1 g of
2,6-dichloro-4-(3,4-methylenedioxybenzyl)- amino-quinazoline
prepared in Example 92. The obtained mixture was refluxed for 100
minutes. The mixture thus obtained was extracted with chloroform
twice. The organic layers were combined, washed with water, dried
over magnesium sulfate and freed from the solvent by distillation.
The residue was recrystallized (from ethanol/water) to give 1.31 g
of the title compound.
[0380] molecular formula; C.sub.24H.sub.25ClN.sub.4O.sub.4
[0381] yield (%); 97
[0382] m.p. (.degree. C.); 118.about.119
[0383] Mass; 469 (M+1)
[0384] NMR .delta. (DMSO-d.sub.6);
[0385] 1.18 (3H, t, J=7.2 Hz), 1.42 (2H, m), 2.58 (1H, m), 2.98
(2H, m), 4.06 (2H, q, J=7.2 Hz), 4.56 (2H, m, J=5.6 Hz), 4.62 (2H,
m), 5.96 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz,
1.6 Hz), 6.94 (1H, d, J=1.6 Hz), 7.26 (1H, d, J=9.2 Hz), 7.48 (1H,
dd, J=9.2 Hz, 2.4 Hz), 8.15 (1H, d, J=2.4 Hz), 8.56 (1H, brt, J=5.6
Hz)
Example 26
2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloro-
quinazoline hydrochloride
[0386] 64
[0387] The title compound was prepared from the
2-(4-Ethoxycarbonylpiperid-
ino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline
prepared in Example 205 by the use of ethanol-hydrochloric
acid-ethanol.
[0388] molecular formula; C.sub.24H.sub.25ClN.sub.4O.sub.4.HCl
[0389] yield (%); 97
[0390] m.p. (.degree. C.); 174.about.175
[0391] NMR .delta. (DMSO-d.sub.6);
[0392] 1.20 (3H, t, J=7.2 Hz), 1.59 (2H, m), 1.97 (2H, m), 2.75
(1H, m), 3.31 (2H, m), 4.09 (2H, q, J=7.2 Hz), 4.53 (2H, m), 4.67
(2H, d, J=5.6 Hz), 5.98 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.90 (1H,
dd, J=8.0 Hz, 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.83 (1H, dd, J=8.8
Hz, 2.0 Hz), 7.91 (1H, d, J=8.8 Hz), 8.52 (1H, d, J=2.0 Hz), 10.15
(1H, brs), 12.28 (1H, brs)
Example 27
2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-cyanoq-
uinazoline
[0393] 65
[0394] 3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and
10 ml of 2-propanol were added to 1 g of 2-chloro-4-
(3,4-methylenedioxybenzyl) amino-6-cyanoquinazoline. The obtained
mixture was refluxed for 1 hour and cooled to room temperature. The
crystals thus precipitated were recovered by filtration and washed
with water and ether successively to give 1.126 g of the title
compound.
[0395] molecular formula; C.sub.25H.sub.25N.sub.5O.sub.4
[0396] yield (%); 83
[0397] m.p. (.degree. C.); 192.about.193
[0398] Mass; 460 (M+1)
[0399] NMR .delta. (CDCl.sub.3);
[0400] 1.26 (3H, t, J=7.2 Hz), 1.71 (2H, m), 1.99 (2H, m), 2.59
(1H, m), 3.12 (2H, brt, J=12.0 Hz), 4.15 (2H, q, J=7.2 Hz), 4.67
(2H, d, J=5.2 Hz), 4.82 (2H, dt, J=13.2 Hz, 3.6 Hz), 5.96 (2H, s)r
6.79 (1H, d, J=8.0 Hz), 6.85 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.88 (1H,
d, J=1.6 Hz), 7.42 (1H, brs), 7.61 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.84
(1H, brs)
Example 28
2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-cyanoq-
uinazoline
[0401] 66
[0402] 3.5 g of ethyl isonipecotate, 2.25 g of triethylamine and 30
ml of 2-propanol were added to 1 g of
2-chloro-4-(3-chloro-4-methoxybenzyl)amin- o-6-cyano-quinazoline.
The obtained mixture was refluxed for 30 minutes and cooled to room
temperature. The crystals thus precipitated were recovered by
filtration and washed with water and ethanol successively to give
1.13 g of the title compound.
[0403] molecular formula; C.sub.25H.sub.26N.sub.5O.sub.3Cl
[0404] yield (%); 85
[0405] m.p. (.degree. C.) ; 202.about.203
[0406] Mass; 480 (M+1)
[0407] NMR .delta. (CDCl.sub.3);
[0408] 1.26 (3H, t, J=7.2 Hz), 1.72 (2H, m), 1.99 (2H, m), 2.59
(1H, m), 3.13 (2H, brt, J=11.2 Hz), 3.90 (3H, s), 4.15 (2H, q,
J=7.2 Hz), 4.69 (2H, d, J=5.6 Hz), 4.80 (2H, m), 6.91 (1H, d, J=8.4
Hz), 7.25 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.42 (1H, d, J=2.4 Hz), 7.43
(1H, brs), 7.61 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.87 (1H, brs)
Example 29
2-[N-(3-Ethoxycarbonylpropyl)-N-methylaminol-4-(3,4-methylenedioxybenzyl)a-
mino-6-cyanoquinazoline
[0409] 67
[0410] 858 mg of ethyl N-methyl-4-aminobutyrate hydrochloride, 238
mg of triethylamine, 4 ml of 2-propanol and 2 ml of
N,N-dimethylformamide were added to 400 mg of
2-chloro-4-(3,4-methylenedioxybenzyl)-amino-6-cyanoqui- nazoline.
The obtained mixture was refluxed for 1 hour, cooled to room
temperature and filtered. The filtrate was distilled under a
reduced pressure to remove the solvent and the residue was
recrystallized (from ethanol/water) to give 410 mg of the title
compound.
[0411] molecular formula; C.sub.24H25N.sub.5O.sub.4
[0412] yield (%); 78
[0413] m.p. (.degree. C.); 152.about.153
[0414] Mass; 448 (M+1)
[0415] NMR .delta. (CDCl.sub.3);
[0416] 1.22 (3H, t, J=6.8 Hz), 1.97 (2H, brs), 2.30 (2H, brs), 3.24
(3H, s), 3.75 (2H, brs), 4.10 (2H, q, J=6.8 Hz), 4.68 (2H, d, J=5.2
Hz), 5.96 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz),
6.87 (1H, s), 7.42 (1H, brs), 7.60 (1H, d, J=8.8 Hz), 7.81 (1H,
brs)
Examples 30 to 41
[0417] The following compounds were prepared in a similar manner to
that of Examples 25 to 29.
Example 30
2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6,7,8-tr-
imethoxyquinazoline hydrochloride
[0418] 68
[0419] molecular formula; C.sub.27H.sub.32N.sub.4O.sub.7.HCl
[0420] yield (%); 65
[0421] m.p. (.degree. C.) ; 148.about.150
[0422] Mass; 525 (M+1)
[0423] NMR .delta. (CDCl.sub.3);
[0424] 1.275 (3H, t, J=7.2 Hz), 1.76 (2H, m), 2.03 (2H, m), 2.63
(1H, m), 3.38 (2H, m), 3.99 (3H, s), 4.08 (3H, s), 4.12 (3H, s),
4.17 (2H, q, J=7.2 Hz), 4.28 (2H, m), 4.63 (2H, d, J=6.0 Hz), 5.88
(2H, s), 6.68 (1H, d, J=8.0 Hz), 6.92 (1H, dd, J=8.0 Hz, 1.6 Hz),
6.97 (1H, d, J=1.6 Hz), 8.23 (1H, s), 9.38 (1H, brs), 11.1 (1H,
s)
Example 31
2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6,7,8-tr-
imethoxyquinazoline hydrochloride
[0425] 69
[0426] molecular formula; C.sub.27H.sub.33N.sub.4O.sub.6Cl.HCl
[0427] yield (%); 93
[0428] m.p.(.degree. C.); 177.about.178
[0429] Mass; 545 (M+1)
[0430] NMR .delta. (CDCl.sub.3);
[0431] 1.27 (3H, t, J=7.2 Hz), 1.80 (2H, m), 2.06 (2H, m), 2.67
(1H, m), 3.40 (2H, m), 3.82 (3H, s), 3.98 (3H, s), 4.07 (3H, s),
4.11 (3H, s), 4.17 (2H, q, J=7.2 Hz), 4.27 (2H, m), 4.65 (2H, d,
J=6.0 Hz), 6.84 (1H, d, J=8.8 Hz), 7.40 (1H, d, J=2.0 Hz), 7.48
(1H, dd, J=8.8 Hz, 2.0 Hz), 8.23 (1H, s), 9.26 (1H, s), 11.27 (1H,
brs)
Example 32
2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-chloro-
quinazoline hydrochloride
[0432] 70
[0433] molecular formula;
C.sub.24H.sub.26N.sub.4O.sub.3Cl.sub.2.HCl
[0434] yield (%); 97
[0435] m.p. (.degree. C.) ; 201.about.204
[0436] Mass; 489 (M+1)
[0437] NMR .delta. (DMSO-d.sub.6);
[0438] 1.17 (3H, t, J=7.2 Hz),, 1.56 (2H, m) 1.93 (2H, m), 2.71
(1H, m), 3.30 (2H, m), 3.80 (3H, s), 4.06 (2H, q, J=7.2 Hz), 4.48
(2H, m), 4.66 (2H, d, J=5.2 Hz), 7.09 (1H, d, J=8.4 Hz), 7.34 (1H,
dd, J=8.4 Hz, 2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.83 (2H, brs), 8.48
(1H, brs), 10.8 (1H, brs)
Example 33
2-(Ethoxycarbonylmethyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroq-
uinazoline
[0439] 71
[0440] molecular formula; C.sub.20H.sub.19N.sub.4O.sub.4Cl
[0441] yield (%); 55
[0442] m.p.(.degree. C.); 218.about.219 (dec.)
[0443] Mass m/e; 415 (M+1)
[0444] NMR .delta. (DMSO-d.sub.6) 1.13 (3H, t, J=7.2 Hz), 4.07 (2H,
q, J=7.2 Hz), 4.18 (2H, brs), 4.63 (2H, brd, J=4.0 Hz), 5.97 (2H,
s), 6.85.about.6.92 (3H, m), 7.53 (1H, brs), 7.84 (1H, brd, J=8.0
Hz), 8.35 (1H, brs), 8.50 (2H, m)
Example 34
2-(3-Ethoxycarbonylpropyl)amino-4- (3,4-methylenedioxy-benzyl)amino
-6-chloroquinazoline
[0445] 72
[0446] molecular formula; C.sub.22H.sub.23N.sub.4O.sub.4Cl
[0447] yield (%); 44
[0448] m.p. (.degree. C.); 96.about.98
[0449] Mass m/e; 443 (M+1)
[0450] NMR .delta. (CDCl.sub.3);
[0451] 1.24 (3H, t, J=6.8 Hz), 1.96 (2H, quintet, J=7.2 Hz), 2.41
(2H, t, J=7.2 Hz), 3.54 (2H, q, J=7.2 Hz), 4.12 (2H, q, J=6.8 Hz),
4.66 (2H, q, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84
(1H, d, J=8.0 Hz), 6.87 (1H, s), 7.30 (1H, d, J=8.0 Hz), 7.44 (1H,
s), 7.47 (1H, d, J=8.0 Hz)
Example 35
2-[N-(3-Ethoxycarbonylpropyl)-N-methylaminol-4-(3,4-methylenedioxybenzyl)a-
mino-6-chloroquinazoline hydrochloride
[0452] 73
[0453] molecular formula; C.sub.23H.sub.25N.sub.4O.sub.4Cl.HCl
[0454] yield (%); 67
[0455] m.p. (.degree. C.); 182.about.183
[0456] Mass; 457 (M+1)
[0457] NMR .delta. (CDCl.sub.3+DMSO-d.sub.6);
[0458] 1.23 (3H, t, J=7.2 Hz), 1.90 (2H, brs), 2.25 (2H, brs), 2.84
(3H, brs), 3.56 (2H, brs), 4.10 (2H, q, J=7.2 Hz), 4.70 (2H, d,
J=5.6 Hz), 5.94 (2H, s), 6.76 (1H, d, J=7.6 Hz), 6.87 (2H, m), 7.54
(1H, dd, J=9.2 Hz, 2.0 Hz), 8.40 (1H, d, J=2.0 Hz), 8.66 (1H, d,
J=9.2 Hz), 9.69 (1H, brs)
Example 36
2-(5-Ethoxycarbonylpentyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloro-
quinazoline
[0459] 74
[0460] molecular formula; C.sub.24H.sub.27N.sub.4O.sub.4Cl
[0461] yield (%); 46
[0462] m.p. (.degree. C.); 109.about.110
[0463] Mass m/e; 471 (M+1)
[0464] NMR .delta. (CDCl.sub.3) ;
[0465] 1.25 (3H, t, J=7.2 Hz), 1.43 (2H, quintet, J=7.6 Hz), 1.66
(4H, m), 2.31 (2H, t, J=7.6 Hz), 3.49 (2H, q, J=7.6 Hz), 4.12 (2H,
q, J=7.2 Hz), 4.68 (2H, d, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d,
J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.43 (3H, m)
Example 37
(S)-2-(N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amin-
o-6-chloroquinazoline hydrochloride
[0466] 75
[0467] molecular formula; C.sub.23H.sub.23N.sub.4O.sub.4Cl.HCl
[0468] yield (%) ; 52
[0469] m.p. (.degree. C.) ; 206.about.208
[0470] Mass; 455 (M+1)
[0471] NMR .delta. (CDCl.sub.3) ;
[0472] 1.19 (3H, t, J=7.2 Hz), 2.17 (3H, m), 2.32 (1H, m), 4.12
(2H, m), 4.24 (2H, m), 4.62 (2H, m), 4.67 (1H, m), 5.93 (2H, s)
6.77 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.89 (1H,
d, J=1.6 Hz), 7.54 (1H, d, J=8.8 Hz), 8.38 (1H, s), 8.64 (1H, d,
J=8.8 Hz), 9.67 (1H, brs), 13.38 (1H, brs)
Example 48
2-(N-Ethoxycarbonylmethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-
-6-cyanoquinazoline
[0473] 76
[0474] molecular formula; C.sub.22H.sub.21N.sub.5O.sub.4
[0475] yield (%); 75
[0476] m.p. (.degree. C.); 171.about.172
[0477] Mass; 420 (M+1)
[0478] NMR .delta. (DMSO-d.sub.6);
[0479] 1.12 (3H, m), 3.18 (3H, s), 4.03 (2H, m), 4.38 (2H, m), 4.51
(2H, m), 5.95 (2H, s), 6.84 (3H, m), 7.30 (1H, m), 7.76 (1H, m),
8.58 (1H, s), 8.79 (1H, m)
Example 39
2-[N-Ethyl-N-(3-ethoxycarbonylpropyl)aminol-4-(3,4-methylenedioxybenzyl)am-
ino-6-cyanoquinazoline
[0480] 77
[0481] molecular formula; C.sub.25H.sub.27N.sub.5O.sub.4
(461.522)
[0482] yield (%); 61
[0483] m.p. (.degree. C.); 142.about.143
[0484] Mass; 462 (M+1)
[0485] NMR .delta. (DMSO-d.sub.6);
[0486] 1.0.about.1.15 (3H, br 2 peaks), 1.13 (3H, t, J=7.1 Hz),
1.65.about.1.9 (2H, br 2 peaks), 2.15.about.2.35 (2H, br 2 peaks),
3.58 (4H, brs), 4.01 (2H, q, J=7.1 Hz), 4.58 (2H, d, J=5.7 Hz),
5.96 (2H, s), 6.84 (2H, s), 6.93 (1H, s), 7.25 (1H, brs), 7.72 (1H,
dd, J=1.8 Hz, 8.8 Hz), 8.56 (1H, d, J=1.8 Hz), 8.72 (1H, t, J=5.7
Hz)
Example 40
2-[N-(3-Ethoxycarbonylpropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)a-
mino-6-cyanoquinazoline
[0487] 78
[0488] molecular formula; C.sub.24H.sub.26N.sub.5O.sub.3Cl
[0489] yield (%); 72
[0490] m.p. (.degree. C.); 127.about.128
[0491] Mass; 468 (M+1)
[0492] NMR .delta. (DMSO-d.sub.6);
[0493] 1.11 (3H, t, J=7.2 Hz), 1.74 (2H, brs), 2.14 (2H, brs), 3.09
(3H, s), 3.62 (2H, brs), 3.81 (3H, s), 3.98 (2H, q, J=7.2 Hz), 4.61
(2H, d, J=6.0 Hz), 7.07 (1H, d, J=8.8 Hz), 7.20.about.7.36 (2H, m),
7.42 (1H, s), 7.72 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.75 (1H, t,
J=6.0 Hz)
Example 41
(S)-2-(N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amin-
o-6-cyanoquinazoline hydrochloride
[0494] 79
[0495] molecular formula; C.sub.24H.sub.23N.sub.5O.sub.4.HCl
[0496] yield (%); 44
[0497] m.p. (.degree. C.); 231.about.232
[0498] Mass; 446 (M+1)
[0499] NMR .delta. (CDCl.sub.3) ;
[0500] 1.21 (3H, t, J=7.2 Hz), 2.19 (3H, m), 2.36 (1H, m), 4.15
(2H, m) , 4.28 (2H, m), 4.62 (2H, m), 4.76 (1H, m), 5.95 (2H, s),
6.79 (1H, d, J=8.0 Hz) , 6.86 (1H, d, J=8.0 Hz), 6.88 (1H, s), 7.80
(1H, dd, J=8.8 Hz, 1.6 Hz), 8.82 (1H, d, J=1.6 Hz), 8.87 (1H, d,
J=8.8 Hz), 9.85 (1H, brs), 13.81 (1H, s)
Example 42
2- (4-Carboxypiperidino)-4-
(3,4-methylenedioxybenzyl)amino-6-chloroquinaz- oline
[0501] 80
[0502] 10 ml of ethanol, 5 ml of water and 820 mg of sodium
hydroxide were added to 1 g of
2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzy-
l)amino-6-chloroquinazoline. The obtained mixture was refluxed for
20 minutes, concentrated under a reduced pressure and neutralized
with 1 N hydrochloric acid. The crystals thus precipitated were
recovered by filtration to give 920 mg of the title compound.
[0503] molecular formula; C.sub.22H.sub.21N.sub.4O.sub.4Cl
[0504] yield (%); 98
[0505] m.p. (.degree. C.); 221.about.222
[0506] Mass m/e; 441 (M+1)
[0507] NMR .delta. (DMSO-d.sub.6)
[0508] 1.38 (2H, m), 1.80 (2H, dd, J=13.2 Hz, 2.4 Hz), 2.48 (1H,
m), 2.96 (2H, t, J=12.0 Hz), 4.54 (2H, d, J=5.6 Hz), 4.56 (2H, dt,
J=12.0 Hz, 3.2 Hz), 5.94 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.84 (1H,
d, J=8.0 Hz), 6.93 (1H, s), 7.24 (1H, d, J=9.2 Hz), 7.46 (1H, dd,
J=9.2 Hz, 2.0 Hz), 8.13 (1H, d, J=2.0 Hz), 8.55 (1H, t, J=5.6
Hz)
Example 43
Sodium
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroq-
uinazoline
[0509] 81
[0510] 12 ml of a 1N aqueous solution of sodium hydroxide and 40 ml
of water were added to 5.00 g (11.3 mmol) of the 2-
(4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl)amino-6-
chloroquinazoline prepared in Example 222. The obtained mixture was
dissolved by heating and cooled by allowing to stand. The crystals
thus precipitated were recovered by filtration under suction,
washed with a small amount of water, and vacuum-dried in the
presence of phosphorus pentaoxide to give 4.34 g of the title
compound.
[0511] molecular formula; C.sub.22H.sub.20ClN.sub.4O.sub.4Na
[0512] yield (%); 98
[0513] NMR .delta. (DMSO-d.sub.6);
[0514] 1.42(2H, m), 1.73(2H, m), 2.06 (1H, M), 2.95 (2H, M), 4.52
(2H, m), 4.56 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.81 (1H, d, J=8.0
Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.22
(1H, d, J=9.2 Hz), 7.44 (1H, dd, J=9.2 Hz, 2.4 Hz), 8.13 (1H, d,
J=2.4 Hz), 8.58 (1H, brt, J=5.6 Hz)
Example 44
Potassium
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chlo-
roquinazoline
[0515] 82
[0516] 12.5 ml of a 1N aqueous solution of potassium hydroxide and
40 ml of water were added to 5.50 g (12.5 mmol) of the 2-
(4-carboxypiperidino) -4-
(3,4-methylene-dioxybenzylamino)-6-chloroquinazoline prepared in
Example 222. The obtained mixture was dissolved by heating and
filtered. The filtrate was concentrated in a vacuum. Ethanol and
ether were added to the obtained residue to precipitate crystals.
The crystals were recovered by filtration, washed with ether, and
vacuum-dried in the presence of phosphorus pentaoxide to give 4.69
g of the title compound.
[0517] molecular formula; C.sub.22H.sub.20ClN.sub.4O.sub.4K
[0518] yield (%); 78
[0519] m.p. (.degree. C.); 230.about.234 (dec.)
[0520] NMR .delta. (DMSO-d.sub.6);
[0521] 1.39 (2H, m), 1.69 (2H, m), 1.96 (1H, m), 2.94 (2H, m), 4.48
(2H, m), 4.55 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.81 (1H, d, J=8.0
Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.94 (1H, d, J=1.6 Hz), 7.22
(1H, d, J=8.8 Hz), 7.43 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.11 (1H, d,
J=2.4 Hz), 8.50 (1H, brt, J=5.6 Hz)
Example 45
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazo-
line hydrochloride
[0522] 83
[0523] 2.00 g (4.54 mmol) of the 2-(4-carboxypiperidino)-4-
(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline prepared in
Example 222 was dissolved in a mixture comprising 25 ml of
tetrahydrofuran and 25 ml of ethanol under heating, followed by the
dropwise addition of 1.0 ml of an 8M ethanolic solution of
hydrochloric acid. The obtained mixture was cooled by allowing to
stand to precipitate crystals. The crystals were recovered by
filtration, washed with tetrahydrofuran, and air-dried to give 1.87
g of the title compound.
[0524] molecular formula; C.sub.22H.sub.21N.sub.4O.sub.4Cl.HCl
[0525] yield (%) ; 86
[0526] m.p. (.degree. C.); 284.about.286
[0527] NMR .delta. (DMSO-d.sub.6);
[0528] 1.58 (2H, m) , 1.96 (2H, m), 2.65 (1H, m), 3.3 (2H, m), 4.47
(2H, m), 4.67 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.87 (1H, d, J=8.0
Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.00 (1H, d, J=1.6 Hz), 7.83
(2H, brs), 8.49 (1H, brs), 10.09 (1H, brs), 12.11 (1H, brs), 12.40
(1H, brs)
Example 46
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazo-
line methanesulfonate
[0529] 84
[0530] 2.00 g (4.54 mmol) of the 2-(4-carboxypiperidino)-4-
(3,4methylenedioxybenzyl)amino-6-chloroquinazoline prepared in
Example 222 was dissolved in a mixture comprising 25 ml of
tetrahydrofuran and 25 ml of ethanol under heating, followed by the
dropwise addition of 0.31 ml (4.78 mmol) of methanesulfonic acid.
The obtained mixture was cooled by allowing to stand to precipitate
crystals. The crystals were recovered by filtration, washed with
tetrahydrofuran, and air-dried to give 2.21 g of the title
compound.
[0531] molecular formula;
C.sub.22H.sub.21N.sub.4O.sub.4Cl.CH.sub.4O.sub.3- S
[0532] yield (%); 91
[0533] m.p. (.degree. C.) ; 265.about.266
[0534] NMR .delta. (DMSO-d.sub.6);
[0535] 1.59 (2H, m), 1.97 (2H, m), 2.32 (3H, s), 2.65 (1H, m), 3.3
(2H, m), 4.40 (2H, m), 4.68 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.87
(1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.98 (1H, d,
J=1.6 Hz), 7.67 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=8.0 Hz, 2.0 Hz),
8.42 (1H, d, J=2.0 Hz), 9.95 (1H, brs), 11.76 (1H, brs), 12.37 (1H,
brs)
Example 47
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoli-
ne
[0536] 85
[0537] 20 ml of ethanol and 2.0 ml of a 1N aqueous solution of
sodium hydroxide were added to 318 mg of
2-(4-ethoxycarbonylpiperidino)-4-(3,4-m-
ethylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture
was stirred at 50.degree. C. for 30 minutes and neutralized with 1N
hydrochloric acid. The crystal thus precipitated was recovered by
filtration and purified by silica gel column chromatography
(chloroform/methanol) to give 116 mg of the title compound.
[0538] molecular formula; C.sub.23H.sub.21N.sub.5O.sub.4
[0539] yield (%); 39
[0540] m.p. (.degree. C.); 269.about.271
[0541] Mass m/e; 432 (M+1)
[0542] NMR .delta. (DMSO-d.sub.6);
[0543] 1.40 (2H, m), 1.79 (2H, m), 2.41 (1H, m), 3.04 (1H, dt,
J=11.2 Hz, 1.2 Hz), 4.55 (2H, d, J=5.6 Hz), 4.57 (2H, m), 5.95 (2H,
s), 6.82 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.94 (1H, s),
7.25 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 8.53 (1H, s), 8.72
(1H, t, J=5.6 Hz)
Example 48
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoli-
ne
[0544] 86
[0545] 30 ml of tetrahydrofuran, 30 ml of ethanol and 14 ml of a 1N
aqueous solution of sodium hydroxide were added to 1.0 g of
2-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoq-
uinazoline. The obtained mixture was stirred at room temperature
for 16 hours and neutralized with 1 N hydrochloric acid, followed
by the addition of 100 ml of water. The crystals thus precipitated
were recovered by filtration and recrystallized from
tetrahydrofuran/ethanol/w- ater to give 860 mg of the title
compound.
[0546] molecular formula; C.sub.23H.sub.22N.sub.5O.sub.3Cl
[0547] yield (%); 91
[0548] m.p. (.degree. C.); 277.about.278 (dec.)
[0549] Mass m/e; 452 (M+1)
[0550] NMR .delta. (DMSO-d.sub.6);
[0551] 1.40 (2H, m), 1.84 (2H, m), 2.51 (1H, m), 3.05 (2H, dt, J=12
Hz, 2.4 Hz), 3.82 (3H, s), 4.59 (2H, d, J=5.6 Hz), 4.63 (2H, m),
7.08 (1H, d, J=8.4 Hz), 7.28 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=8.4
Hz, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=8.8 Hz, 2.0
Hz), 8.54 (1H, d, J=2.0 Hz), 8.79 (1H, t, J=5.6 Hz)
Example 49
Sodium
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoqu-
inazoline
[0552] 87
[0553] 1.00 g (2.21 mmol) of the 2-(4-carboxypiperidino)-4-
(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline prepared in
Example 228 was dissolved in a mixture comprising 30 ml of
tetrahydrofuran and 40 ml of ethanol under heating, followed by the
addition of 2.3 ml of a 1N aqueous solution of sodium hydroxide and
100 ml of water. The obtained mixture was concentrated in a vacuum
to precipitate crystals. The crystals were recovered by filtration,
washed with water, and air-dried to give 0.45 g of the title
compound.
[0554] molecular formula; C.sub.23H.sub.21N.sub.5O.sub.3ClNa
[0555] yield (%); 43
[0556] NMR .delta. (DMSO-d.sub.6);
[0557] 1.45 (2H, m), 1.75 (2H, m), 2.12 (1H, m), 3.06 (2H, m), 3.81
(3H, s), 4.52 (2H, m), 4.58 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.8
Hz), 7.24 (1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.45
(1H, d, J=2.0 Hz), 7.69 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.54 (1H, d,
J=2.0 Hz), 8.86 (1H, brt, J=5.6 Hz)
Example 50
2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6--
cyanoquinazoline
[0558] 88
[0559] 20 ml of ethanol and 2.61 ml of a 1N aqueous solution of
sodium hydroxide were added to 389 mng of 2-[N-
(3-ethoxycarbonylpropyl)-N-metho- xyamino]-4-
(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained
mixture was stirred at room temperature for 4 hours and at
50.degree. C. for 10 minutes and neutralized with 1N hydrochloric
acid. The crystals precipitated were recovered by filtration,
purified by silica gel columnn chromatography (chloroform/methanol)
and recrystallized from ethanol/acetone/water to give 305 mg of the
title compound.
[0560] molecular formula; C.sub.22H.sub.21N.sub.5O.sub.4
[0561] yield (%); 84
[0562] m.p. (.degree. C.); 138.about.140
[0563] Mass m/e; 420 (M+1)
[0564] NMR .delta. (CDCl.sub.3(+DMSO-d.sub.6));
[0565] 1.96 (2H, brs), 2.31 (brs), 3.24 (3H, s), 3.76 (2H, brs),
4.67 (2H, d, J=5.6 Hz), 5.94 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86
(1H, d, J=8.0 Hz), 6.91 (1H, s), 7.58 (1H, brs), 7.61 (1H, d, J=8.4
Hz), 8.48 (2H, m)
Examples 51 to 65
[0566] The following compounds were prepared in a similar manner to
those of Examples 222 to 230.
Example 51
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxy-
quinazoline
[0567] 89
[0568] molecular formula; C.sub.25H.sub.28N.sub.4O.sub.7
[0569] yield (%); 73
[0570] m.p. (.degree. C.); 216.about.217
[0571] Mass m/e; 297 (M+1)
[0572] NMR .delta. (CDCl.sub.3);
[0573] 1.80 (2H, m), 2.05 (2H, m), 2.65 (1H, m), 3.39 (2H, dt,
J=10.8 Hz, 2.8 Hz), 3.98 (3H, s), 4.07 (3H, s), 4.13 (3H, s), 4.26
(2H, m), 4.70 (2H, d, J=6.0 Hz), 5.88 (2H, s), 6.69 (1H, d, J=7.6
Hz), 6.95 (1H, dd, J=7.6 Hz, 1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 8.38
(1H, s), 9.36 (1H, s), 11.24 (1H, t, J=6.0 Hz)
Example 52
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7,8-trimethoxy-
quinazoline
[0574] 90
[0575] molecular formula; C.sub.25H.sub.23N.sub.4O.sub.6Cl
[0576] yield (%); 90
[0577] m.p. (.degree. C.); 197.about.198
[0578] Mass m/e; 517 (M+1)
[0579] NMR .delta. (DMSO-d.sub.6) ;
[0580] 1.45 (2H, brs), 1.90 (2H, brs), 2.59 (1H, brs), 3.22 (2H,
brs), 3.80 (3H, s), 3.90 (6H, s), 3.92 (3H, s), 4.39 (2H, brs),
4.65 (2H, d, J=5.2 Hz), 7.05 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=8.4
Hz), 7.45 (1H, s), 7.76 (1H, brs), 10.70 (1H, brs)
Example 53
2-(4-Carboxypioeridino)-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazo-
line
[0581] 91
[0582] molecular formula; C.sub.23H.sub.24N.sub.4O.sub.5(436)
[0583] yield (%); 79
[0584] m.p. (.degree. C.); 263 (dec.)
[0585] Mass; 437 (M+1).sup.+
[0586] NMR .delta. (DMSO-d.sub.6);
[0587] 1.51.about.1.59 (2H, m), 1.86.about.195 (2H, m),
2.59.about.2.64 (1H, m) 3.21.about.3.28 (2H, m), 4.39.about.4.44
(2H, m), 4.67 (2H, d, J=5.6 Hz), 5.78 (2H, s), 6.85 (1H, d, J=7.6
Hz) , 6.89 (1H, d, J=7.6 Hz), 6.99 (1H, s), 7.42 (1H, dd, J=9.2 Hz,
1.6 Hz), 7.72 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=1.6 Hz), 10.02 (1H,
br), 11.89 (1H, s)
Example 54
2- (4-Carboxypiperidino)-4-
(3-chloro-4-methoxybenzyl)amino-6-methoxyquina- zoline
[0588] 92
[0589] molecular formula; C.sub.23H.sub.25N.sub.4O.sub.4Cl
(456.930)
[0590] yield (%); 81
[0591] m.p. (.degree. C.); 245 (dec.)
[0592] Mass; 457 (MH.sup.+)
[0593] NMR;
[0594] 1.3.about.1.5 (2H, m), 1.79 (2H, d, J=10 Hz), 2.4.about.2.5
(1H, m), 2.91 (2H, t, J=11 Hz), 3.81 (3H, s), 4.56 (2H, d, J=13
Hz), 4.60 (2H, d, J=5.7 Hz), 7.09 (1H, d, J=8.6 Hz), 7.18 (1H, dd,
J=2.7 Hz, 9.2 Hz), 7.24 (1H, d, J=9.2 Hz), 7.32 (1H, dd, J=2.2 Hz,
8.6 Hz), 7.45 (1H, d, J=2.2 Hz), 7.49 (1H, d, J=2.7 Hz), 8.42 (1H,
t, J=5.7 Hz), 12.15 (1H, brs)
Example 55
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazol-
ine
[0595] 93
[0596] molecular formula;
C.sub.22H.sub.22N.sub.4O.sub.3Cl.sub.2
[0597] yield (%); 92
[0598] m.p. (.degree. C.) ; 280.about.281
[0599] Mass m/e; 461 (M+1)
[0600] NMR .delta. (DMSO-d.sub.6);
[0601] 1.59 (2H, M), 1.94 (2H brd, J=11.6 Hz), 2.62 (1H, brs), 3.32
(2H, m), 3.79 (3H, s), 4.52 (2H, d, J=13.6 Hz), 4.64 (2H, d, J=4.8
Hz), 6.99 (1H, d, J=8.4 Hz), 7.30 (1H, d, J=8.4 Hz), 7.42 (1H, s),
7.69 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.51 (1H, s), 10.24
(1H, s), 12.42 (1H, s)
Example 56
2-
(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-chloroquinazol-
ine
[0602] 94
[0603] molecular formula; C.sub.22H.sub.21N.sub.6O.sub.2Cl
(436.903)
[0604] yield (%); 99
[0605] m.p. (.degree. C.); 230(dec.)
[0606] Mass; 437 (MH).sup.+
[0607] NMR .delta. (DMSO-d.sub.6);
[0608] 1.3.about.1.5 (2H, m), 1.82 (2H, d, J=10 Hz), 2.4.about.2.5
(1H, m), 2.98 (2H, t, J=11 Hz), 4.60 (2H, d, J=13 Hz), 4.77 (2H, d,
J=5.7 Hz), 7.2.about.7.3 (2H, m), 7.45.about.7.6 (3H, m), 8.16 (1H,
s), 8.19 (1H, d, J=2.4 Hz), 8.68 (1H, t, J=5.7 Hz), 12.17 (1H,
brs), 12.33 (1H, brs)
Example 57
2-(Carboxymethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoli-
ne
[0609] 95
[0610] molecular formula; C.sub.18H.sub.15N.sub.4O.sub.4Cl
[0611] yield (%); 64
[0612] m.p. (.degree. C.); 260.about.261 (dec.)
[0613] Mass m/e; 387 (M+1)
[0614] NMR .delta. (DMSO-d.sub.6);
[0615] 4.00 (2H, brs), 4.57 (2H, d, J=5.6 Hz), 5.93 (2H, s), 6.79
(1H, d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.35 (1H,
brs), 7.50 (1H, brs), 8.30.about.8.50 (2H, m)
Example 58
2-(3-Carboxypropyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazo-
line
[0616] 96
[0617] molecular formula; C.sub.20H.sub.19N.sub.4O.sub.4Cl
[0618] yield (%); 88
[0619] m.p. (.degree. C.); 170.about.172
[0620] Mass m/e; 415 (M+1)
[0621] NMR .delta. (DMSO-d.sub.6) ;
[0622] 1.71 (2H, brs), 2.23 (2H, brs), 3.27 (2H, brs), 4.56 (2H, d,
J=5.6 Hz), 5.95 (2H, s), 6.82 (3H, m), 6.95 (1H, s), 7.20 (1H,
brs), 7.46 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.12 (1H, d, J=1.6 Hz)
Example 59
2- (5-Carboxypentyl)amino-4-
(3,4-methylenedioxybenzyl)amino-6-chloroquina- zoline
[0623] 97
[0624] molecular formula; C.sub.22H.sub.23N.sub.4O.sub.4Cl
[0625] yield (%); 80
[0626] m.p. (.degree. C.); 190.about.192
[0627] Mass m/e; 443 (M+1)
[0628] NMR .delta. (DMSO-d.sub.6);
[0629] 1.25 (2H, brs), 1.47 (4H, brs), 2.16 (2H, brs), 3.31 (2H,
brs), 4.60 (2H, brs), 5.94 (2H, s), 6.84 (2H, s), 6.96 (1H, s),
7.33 (1H, brs), 7.60 (1H, brs), 8.25 (1H, brs)
Example 60
2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6--
chloroquinazoline
[0630] 98
[0631] molecular formula; C.sub.21H.sub.21N.sub.4O.sub.4Cl
[0632] yield (%); 92
[0633] m.p. (.degree. C.); 143.about.144
[0634] Mass m/e; 429 (M+1)
[0635] NMR .delta. (DMSO-d.sub.6(+CD.sub.3OD));
[0636] 1.79 (2H, brs), 2.20 (2H, brs), 3.21 (3H, s), 3.71 (2H, t,
J=7.2 Hz), 4.65 (2H, s), 5.95 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.86
(1H, d, J=8.0 Hz), 6.95 (1H, s), 7.79 (1H, d, J=8.8 Hz), 7.85 (1H,
d, J=8.8 Hz), 8.49 (1H, s)
Example 61
2-(N-Carboxymethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-6-cyan-
oquinazoline
[0637] 99
[0638] molecular formula; C.sub.20H.sub.17N.sub.5O.sub.4
[0639] yield (%); 68
[0640] m.p. (.degree. C.); 268.about.270
[0641] Mass m/e; 392 (M+1)
[0642] NMR .delta. (DMSO-d.sub.6);
[0643] 3.11 (3H, s), 4.13 (2H, brs), 4.56 (2H, m), 5.94 (2H, s),
6.83 (2H, m), 6.93 (1H, d, J=14.4 Hz), 7.20 (1H, m), 7.66 (1H, m),
8.51 (1H, s), 8.62 (1H, m)
Example 62
2-[N-Ethyl-N-(3-carboxypropyl)amino]-4-(3,4-methylene-dioxybenzyl)amino-6--
cyanoquinazoline
[0644] 100
[0645] molecular formula; C.sub.23H.sub.23N.sub.5O.sub.4
(433.468)
[0646] yield (%); 96
[0647] m.p. (.degree. C.) ; 186.about.187
[0648] Mass; 434 (M+1)
[0649] NMR .delta. (DMSOd.sub.6);
[0650] 1.0.about.1.15 (3H, br 2 peaks), 1.65.about.1.85 (2H, br 2
peaks), 2.1.about.2.25 (2H, br 2 peaks), 3.57 (4H, brs), 4.58 (2H,
d, J=5.7 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.93 (1H, s), 7.26 (1H,
d, J=8.8 Hz), 7.72 (1H, dd, J=1.8 Hz, 8.8 Hz), 8.56 (1H, d, J=1.8
Hz), 8.71 (1H, brs)
Example 63
2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)amino-6--
cyanoquinazoline
[0651] 101
[0652] molecular formula; C.sub.22H.sub.22N.sub.5O.sub.3Cl
[0653] yield (%); 88
[0654] m.p. (.degree. C.); 108.about.109
[0655] Mass; 440 (M+1)
[0656] NMR .delta. (DMSOd.sub.6);
[0657] 1.73 (2H, brs), 2.13 (2H, brs), 3.11 (3H, s), 3.63 (2H,
brs), 3.82 (3H, s), 4.61 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.4 Hz),
7.27 (1H, d, J=8.8 Hz), 7.31 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.72
(1H, s), 8.55 (1H, s), 8.74 (1H, brt, J=5.6 Hz), 12.02 (1H,
brs)
Example 64
2-(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-cyanoquinazolin-
e
[0658] 102
[0659] molecular formula; C.sub.23H.sub.21N.sub.7O.sub.2 (427)
[0660] yield (%); 50
[0661] m.p. (.degree. C.); >290
[0662] Mass; 428 (M.sup.++1)
[0663] NMR .delta. (DMSO-d.sub.6);
[0664] 1.29.about.1.42 (2H, m), 1.76.about.2.20 (2H, m),
2.39.about.2.51 (2H, m), 2.99.about.3.07 (3H, m), 4.60.about.4.64
(2H, m), 4.76 (2H, d, J=5.6 Hz), 7.23 (1H, d, J=8.4 Hz), 7.25 (1H,
d, J=8.8 Hz), 7.51 (1H, d, J=8.4 Hz), 7.56 (1H, s), 7.71 (1H, dd,
J=8.4 Hz, 1.6 Hz), 8.14 (1H, s), 8.57 (1H, d, J=1.6 Hz), 8.82 (1H,
brt, J=5.6 Hz)
Example 65
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-carbamoylquin-
azoline
[0665] 103
[0666] molecular formula; C.sub.23H.sub.23N.sub.5O.sub.5 (449)
[0667] yield (%); 6
[0668] m.p. (.degree. C.); 180.about.182 (dec.)
[0669] Mass; 450 (M+1)
[0670] NMR .delta. (DMSO-d.sub.6);
[0671] 1.39 (2H, m), 1.81 (2H, m), 2.48 (1H, m), 2.99 (2H, m) ,
4.55 (2H, d, J=5.6 Hz), 4.62 (2H, m), 5.93 (2H, s), 6.81 (1H, d,
J=7.6 Hz), 6.85 (1H, dd, J=7.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.20
(1H, d, J=8.8 Hz), 7.27 (1H, br), 7.71 (1H, br), 7.92 (1H, dd,
J=8.8 Hz, 2.0 Hz), 8.57 (1H, d, J=2.0 Hz), 8.59 (1H, brt, J=5.6
Hz), 12.09 (1H, br)
Example 66
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)oxy-6-chloroquinazoli-
ne
[0672] 104
[0673] molecular formula; C.sub.22H.sub.20ClN.sub.3O.sub.5
[0674] yield (%); 84
[0675] m.p. (.degree. C.); 145.about.147
[0676] Mass m/e; 442 (M+1)
[0677] NMR .delta. (DMSO-d.sub.6) ;
[0678] 1.47 (2H, m), 1.88 (2H, m), 2.49 (1H, m), 3.10 (2H, brt,
J=13.2 Hz), 4.60 (2H, brd, J=13.2 Hz), 5.43 (2H, s), 6.01 (2H, s),
6.91 (1H, d, J=8.0 Hz), 7.02 (1H, d, J=8.0 Hz), 7.11 (1H, s), 7.39
(1H, d, J=8.8 Hz), 7.61 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.77 (1H, d,
J=2.4 Hz)
Example 67
2-
(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-thio-6-chloroquinazo-
line
[0679] 105
[0680] molecular formula; C.sub.22H.sub.20ClN.sub.3O.sub.4S
[0681] yield (%); 98
[0682] m.p. (.degree. C.); 153.about.154
[0683] Mass m/e; 458 (M+1)
[0684] NMR .delta. (DMSO-d.sub.6);
[0685] 1.50 (2H, m), 1.82 (2H, m), 2.39 (1H, brs), 3.18 (2H, m),
4.48 (2H, s), 4.55 (2H, brs), 5.96 (2H, s), 6.82 (1H, d, J=8.0 Hz),
6.92 (1H, d, J=8.0 Hz), 6.99 (1H, s), 7.41 (1H, brd, J=8.8 Hz),
7.62 (1H, brd, J=8.8 Hz), 7.69 (1H, brs)
Example 68
2-(4-Nitroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazo-
line
[0686] 106
[0687] molecular formula; C.sub.21H.sub.20ClN.sub.5O.sub.5
[0688] yield (%); 11
[0689] m.p. (.degree. C.); oily substance
[0690] Mass m/e; 458 (MH.sup.+)
[0691] NMR .delta. (CDCl.sub.3);
[0692] 1.71.about.1.82(2H, m), 2.02.about.2.10(2H, m),
3.56.about.3.63(2H, m), 4.39.about.4.44(2H, m), 4.66(2H, d, J=5.2
Hz), 5.18.about.5.22(1H, m), 5.61(1H, brt, J=5.2 Hz), 5.96(2H, s),
6.79(1H, d, J=7.6 Hz), 6.84(1H, dd, J=7.6 Hz, 1.2 Hz), 6.87 (1H, d,
J=1.2 Hz), 7.39 (1H, d, J=8.8 Hz), 7.43.about.7.47(2H, m)
Example 69
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinoli-
ne
[0693] 107
a) 2-
(4-Ethoxycarbonylpiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-ch-
loroquinoline
[0694] A reaction of a mixture comprising 130 mg of
2,6-dichloro-4-(3,4-methylenedioxybenzyl)-aminoquinoline, 500 .mu.l
of ethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was
conducted on an oil bath at 150.degree. C. for 3 hours. The
reaction mixture was cooled, followed by the addition of water. The
resulting mixture was extracted with ethyl acetate and the ethyl
acetate layer was washed with water and a saturated aqueous
solution of sodium chloride, dried over anhydrous magnesium sulfate
and concentrated. The residue was purified by silica gel column
chromatography with 20 to 50% ethyl acetate/hexane to give 150 mg
of the title compound.
[0695] NMR .delta. (CDCl.sub.3);
[0696] 1.26(3H, t, J=7.1 Hz), 1.70.about.1.81(2H, m),
1.95.about.2.02 (2H, m), 2.54 (1H, tt, J=11.2 Hz, 3.8 Hz),
2.97.about.3.06 (2H, m), 4.14 (2H, q, J=7.1 Hz),
4.32.about.4.39(4H, m), 4.86 (1H, t, J=5.5 Hz), 5.98 (3H, s), 6.81
(1H, d, J=7.7 Hz), 6.84.about.6.89(2H, m), 7.39 (1H, dd, J=9.0 Hz,
2.4 Hz), 7.47 (1H, d, J=2.4 Hz), 7.55 (1H, d, J=9.0 Hz)
b)
2-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquin-
oline
[0697] A reaction of a mixture comprising 150 mg of the compound
prepared in the step (a), 1 ml of a 1N aqueous solution of sodium
hydroxide and 10 ml of ethanol was conducted on an oil bath at
60.degree. C. for 2 hours. The reaction mixture was concentrated,
followed by the addition of water. The resulting mixture was
neutralized by the addition of 1 ml of 1N hydrochloric acid to
precipitate crystals. The crystals were recovered by filtration,
washed with water, and dried to give 130 mg of the title
compound.
[0698] molecular formula; C.sub.23H.sub.22ClN.sub.3O.sub.4
[0699] yield (%); 92
[0700] m.p. (.degree. C.) ; 235.about.237
[0701] Mass m/e; 440 (M+1)
[0702] NMR .delta. (DMSO-d.sub.6);
[0703] 1.37.about.1.50 (2h, m), 1.77.about.1.86 (2H, m),
2.89.about.3.00 (2H, br, 3 peak), 4.20.about.4.28 (2H, br, 2 peak),
4.42 (2H, d, J=5.7 Hz), 5.96 (2H, s), 5.97 (1H, s), 6.85 (1H, d,
J=7.9 Hz), 6.92 (1H, dd, J=7.9 Hz, 1.5 Hz), 6.98 (1H, d, J=1.5 Hz),
7.42 (2H, brs), 7.58 (1H, brs), 8.15 (1H, brs)
Example 70
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-chloroquinoli-
ne
[0704] 108
[0705] The title compound was prepared in a similar manner to that
of Example 255.
[0706] molecular formula;
C.sub.23H.sub.23Cl.sub.2n.sub.3O.sub.3
[0707] m.p. (.degree. C.); 282.about.283
[0708] Mass m/e; 460 (M+1)
[0709] NMR .delta. (DMSO-d.sub.6) ;
[0710] 1.36.about.1.48 (2H, m), 1.76.about.1.84 (2H, m),
2.43.about.2.53 (1H, m), 2.91 (2H, t, J=11.2 Hz), 4.26 (2H, brd,
J=13.2 Hz), 4.44 (2H, d, J=5.9 Hz), 5.97 (1H, s), 7.10 (1H, d,
J=8.6 Hz), 7.36 (1H, dd, J=8.6 Hz, 2.2 Hz), 7.38 (2H, s), 7.50 (2H,
brs and d, J=2.2 Hz), 8.11 (1H, s)
Example 71
2- (3,4-Methylenedioxybenzylamino)-4-
(4-carboxypiperidino)-6-chloroquinol- ine
[0711] 109
[0712] 130 mg of the title compound was prepared from 140 mg of the
4,6-dichloro-2-(3,4-methylenedioxybenzyl)-aminoquinoline prepared
in the step (b) of Example 253 as a by-product in a similar manner
to that of Example 255.
[0713] molecular formula; C.sub.23H.sub.22ClN.sub.3O.sub.4
[0714] yield (%); 99
[0715] m.p. (.degree. C.); 270.about.272
[0716] Mass m/e; 440 (M+1)
[0717] NMR .delta. (DMSO-d.sub.6);
[0718] 1.78.about.1.89 (2H, m), 1.96.about.2.04 (2H, m),
2.70.about.2.79 (2H, m), 3.26.about.3.36 (2H, m), 4.49 (2H, d,
J=5.7 Hz), 5.96 (2H, s), 6.37 (1H, s), 6.85 (2H, s), 6.94 (1H, s),
7.37 (1H, t, J=5.7 Hz), 7.41 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.46 (1H,
d, J=8.8 Hz), 7.60 (1H, d, J=2.4 Hz)
Example 72
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-cyanoquinazol-
ine
[0719] 110
a)
2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyan-
oquinoline
[0720] A mixture comprising 750 mg of
2-chloro-4-(3-chloro-4-methoxybenzyl- )amino-6-cyanoquinoline, 1.6
ml of isonipecotic acid and 5 ml of N-methyl-2-pyrrolidone was
heated on an oil bath at 130.degree. C. for 3 hours and cooled,
followed by the addition of water. The resulting mixture was
extracted with ethyl acetate and the ethyl acetate layer was washed
with water and a saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate, and concentrated. The
residue was subjected to silica gel column chromatography (20 to
40% ethyl acetate/hexane) and thereafter recrystallized from ethyl
acetate/hexane to give 860 mg of the title compound.
[0721] NMR .delta. (CDCl.sub.3);
[0722] 1.26 (3H, t, J=7.1 Hz), 1.68.about.1.79 (2H, m),
1.95.about.2.03 (2H, m), 2.58 (1H, tt, J=11.0 Hz, 4.0 Hz),
3.03.about.3.12 (2H, m), 3.92 (3H, s), 4.15 (2H, q, J=7.1 Hz),
4.36.about.4.43 (4H, m), 5.08 (1H, t, J=5.1 Hz), 5.94 (1H, s), 6.95
(1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.42 (1H, d,
J=2.2 Hz), 7.55.about.7.61 (2H, m), 7.88 (1H, s)
b)
2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyanoquinol-
ine
[0723] A mixture comprising 500 mg of the compound prepared in the
step (a), 2 ml of a 1N aqueous solution of sodium hydroxide, 20 ml
of tetrahydrofuran and 25 ml of ethanol was reacted at 50.degree.
C. for 2 hours, followed by the addition of 2 ml of 1N hydrochloric
acid. About 20 ml of the solvents was distilled away to precipitate
crystals. The crystals were recovered by filtration, washed with
water and ethyl acetate, and dried to give 460 mg of the title
compound.
[0724] molecular formula; C.sub.24H.sub.23ClN.sub.4O.sub.3
[0725] yield (%); 98
[0726] m.p. (.degree. C.); 274.about.276 (dec.)
[0727] NMR .delta. (DMSO-d.sub.6);
[0728] 1.35.about.1.47 (2H, m), 1.78.about.1.87 (2H, m),
2.47.about.2.56 (1H, m), 2.95.about.3.04 (2H, m), 3.81 (3H, S),
4.30.about.4.39 (2H, m), 4.46 (2H, d, J=5.7 Hz), 6.01 (1H, s), 7.11
(1H, d, J=8.6 Hz), 7.37 (1H, dd, J=8.6 Hz, 2.2 Hz), 7.40 (1H, d,
J=8.8 Hz), 7.52 (1H, d, J=2.2 Hz), 7.65 (1H, dd, J=8.8 Hz, 1.6 Hz),
7.68 (1H, t, J=5.7 Hz), 8.55 (1H, d, =J=1.6 Hz), 12.20 (1H,
brs)
Example 73
2-(4-Carboxypiperidino)-8-(3,4-methylenedioxybenzyl)-aminopyrido[2,3-d]pyr-
imidine
[0729] 111
a) 2-(4-ethoxycarbonylpiperidino)-8-
(3,4-methylenedioxybenzylamino)pyrido- [2,3-d]pyrimidine
[0730] 41 mg of triethylamine and 190 mg of ethyl isonipecotate
were added to a solution of 127 mg of
2-chloro-8-(3,4-methylenedioxybenzyl)aminopyri- do[2,3-d]pyrimidine
in 8 ml of tetrahydrofuran. The obtained mixture was refluxed for 2
hours, followed by the addition of water. The resulting mixture was
extracted with chloroform twice. The organic layers were combined,
dried over magnesium sulfate, and distilled to remove the solvent.
The residue was purified by silica gel chromatography (with ethyl
acetate) to give 175 mg of the title compound (in a yield of
100%).
b)
2-(4-carboxypiperidino)-8-(3,4-methylene-dioxybenzyl)aminopyrido[2,3-d]-
pyrimidine
[0731] 1.56 ml of 1N sodium hydroxide was added to a solution of
170 mg of
2-(4-ethoxycarbonylpiperidino)-8-(3,4-methylenedioxybenzyl)aminopyrido[2,-
3-d]pyrimidine in 10 ml of ethanol. The obtained mixture was
stirred at room temperature for 6 hours and neutralized by the
addition of 1N hydrochloric acid and water. The crystals thus
precipitated were recovered by filtration, whereby 121 mg of the
title compound was obtained.
[0732] molecular formula; C.sub.21H.sub.21N.sub.5O.sub.4
[0733] yield (%); 76
[0734] m.p. (.degree. C.); 255.about.256
[0735] Mass m/e; 408 (M+1)
[0736] NMR .delta. (DMSO-d.sub.6);
[0737] 1.39 (2H, m), 1.80 (2H, m) , 2 51 (1H, m) 3.01 (2H, brt,
J=11.2 Hz), 4.56 (2H, d, J=5.6 Hz), 4.61 (2H, brd, J=12.8 Hz), 5.94
(2H, s), 6.82 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.93 (1H,
s), 7.03 (1H, dd, J=8.0 Hz, 4.4 Hz), 8.38 (1H, dd, J=8.0 Hz, 1.6
Hz), 8.61 (1H, dd, J=4.4 Hz, 1.6 Hz), 8.70 (1H, t, J=5.6 Hz), 12.16
(1H, brs)
Examples 74 to 82
[0738] The following compounds were prepared in a similar manner to
those of Examples 88 to 94.
Example 74
2-(4-Carboxypiperidino)-4-(3,5-dichloro-4-methoxybenzylamino)-6-cyanoquina-
zoline
[0739] 112
[0740] molecular formula;
C.sub.23H.sub.21Cl.sub.2N.sub.5O.sub.3
[0741] yield (%); 98
[0742] m.p. (.degree. C.); 255.about.256 (dec.)
[0743] Mass m/e; 486 (M+1).sup.+
[0744] NMR .delta. (DMSO-d.sub.6);
[0745] 1.36 (2H, brm), 1.80 (2H, brm), 2.52 (1H, m), 3.03 (2H, m),
3.78 (3H, s), 4.59 (2H, d, J=6.0 Hz), 4.59- (2H, brm), 7.29 (1H, d,
J=8.8 Hz), 7.50 (2H, s), 7.75 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.53 (1H,
d, J=1.6 Hz), 8.85 (1H, brt, J=6.0 Hz), 12.18 (1H, brs)
Example 75
2-[N-[2-(2-Pyridyl)ethyl]methylamino]-4-(3,4-methylene-dioxybenzyl)]amino--
6-chloroquinazoline dihydrochloride
[0746] 113
[0747] molecular formula; C.sub.24H.sub.22ClN.sub.5O.sub.2.2HCl
[0748] yield (%); 94
[0749] m.p. (.degree. C.); 234.about.236 (dec.)
[0750] Mass m/e; 448 (M+1).sup.+
[0751] NMR .delta. (DMSO- d.sub.6);
[0752] 3.2.about.3.3 (5H, br), 4.12 (2H, br), 4.61 (2H, br), 5.97
(2H, s), 6.82 (1H, brd), 6.88 (1H, brd), 7.00 (1H, s), 7.74 (2H,
br), 7.86 (1H, dd, J=9.2 Hz, 2.0 Hz), 8.01 (1H, br), 8.26 (1H, br),
8.57 (1H, d, J=2.0 Hz), 8.74 (1H, br), 10.16 (1H, brs), 12.12 (1H,
brs)
Example 76
2-
(4-Carboxypiperidino)-4-(3,4-dihydroxybenzyl)amino-6-chloroquinazoline
[0753] 114
[0754] molecular formula; C.sub.21H.sub.21ClN.sub.4O.sub.4
[0755] yield (%); 95
[0756] m.p. (.degree. C.); 216.about.218 (dec.)
[0757] Mass m/e; 429 (MH.sup.+)
[0758] NMR .delta. (DMSO-d.sub.6);
[0759] 1.38.about.1.47 (2H, m), 1.80.about.1.84 (2H, m),
2.44.about.2.49 (1H, m), 2.93.about.3.00 (2H, m), 4.48 (2H, d,
J=5.6 Hz), 4.57.about.4.61 (2H, m), 6.60.about.6.65 (2H, m), 6.74
(1H, d, J=1.6 Hz), 7.24 (1H, d, J=8.8 Hz), 7.46 (1H, dd, J=8.8 Hz,
2.0 Hz), 8.15 (1H, d, J=2.0 Hz), 8.48 (1H, brs), 8.675 (1H, s),
8.75 (1H, s), 12.14 (1H, brs)
Example 77
2-(4-Carboxypiperidino)-4-(5-nitroxypentyl)amino-6-chloroquinazoline
[0760] 115
[0761] molecular formula; C.sub.19H.sub.24ClN.sub.5O.sub.5
[0762] yield (%); 80
[0763] m.p. (.degree. C.); 176.about.179 (dec.)
[0764] Mass m/e; 438 (MH.sup.+)
[0765] NMR .delta. (DMSO-d.sub.6);
[0766] 1.34.about.2.00 (10H, m), 2.57.about.2.64 (1H, m),
3.18.about.3.59 (4H, m), 4.44.about.4.58 (4H, m), 7.72.about.7.86
(2H, m), 8.39.about.8.41 (1H, m), 12.31 (2H, brs)
Example 78
2-(Carboxymethyl)methylamino-4-(3-pyridylmethyl)amino-6-chloroquinazoline
[0767] 116
[0768] molecular formula; C.sub.17H.sub.16ClN.sub.5O.sub.2
[0769] yield (%); 97
[0770] m.p. (.degree. C.) ; 222.about.223
[0771] Mass m/e; 358 (M+1)
[0772] NMR .delta. (DMSO-d.sub.6);
[0773] 3.10 (3H, s), 4.22 (2H, brs), 4.63 (2H, brs), 7.31 (2H, m),
7.48 (1H, m), 7.72 (1H, m), 8.14 (1H, d, J=2.4 Hz), 8.43 (1H, d,
J=4.8 Hz), 8.59 (1H, m), 8.66 (1H, brs)
Example 79
2-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-pyridylmethyl)amino-6-chloroqui-
nazoline
[0774] 117
[0775] molecular formula; C.sub.19H.sub.20ClN.sub.5O.sub.2
[0776] yield (%); 41
[0777] m.p. (.degree. C.); 110.about.112
[0778] Mass m/e; 386 (M+1)
[0779] NMR .delta. (DMSO-d.sub.6);
[0780] 1.67 (2H, brs), 2.09 (2H, m), 3.02 (3H, s), 3.53 (2H, t,
J=6.8 Hz), 4.67 (2H, d, J=5.6 Hz), 7.24 (2H, d, J=8.8 Hz), 7.31
(1H, dd, J=8.0 Hz, 4.8 Hz), 7.47 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.73
(1H, d, J=8.0 Hz), 8.13 (1H, d, J=2.0 Hz), 8.41 (1H, d, J=4.8 Hz),
8.58 (1H, s), 8.62 (1H, brs), 12.04 (1H, brs)
Example 80
2-(4-Carboxypiperidino)-4-(2-pyridylmethyl)amino-6-chloroquinazoline
[0781] 118
[0782] molecular formula; C.sub.20H.sub.20ClN.sub.5O.sub.2
[0783] yield (%); 92
[0784] m.p. (.degree. C.); 235.about.237
[0785] Mass m/e; 398 (M+1)
[0786] NMR .delta. (DMSO-d.sub.6);
[0787] 1.25.about.1.45 (2H, m), 1.71.about.1.83 (2H, m),
2.45.about.2.54 (1H, m), 2.93.about.3.10 (2H, m), 4.37.about.4.48
(2H, m), 4.77 (2H, d, J=5.5 Hz), 7.25 (1H, dd, J=7.7 Hz, 5.0 Hz),
7.37 (1H, d, J=7.7 Hz), 7.48 (1H, brs), 7.63 (1H, brs), 7.73 (1H,
td, J=7.7 Hz, 1.6 Hz), 8.34 (1H, brs), 8.51 (1H, brd, J=5.0 Hz),
12.23 (1H, brs)
Example 81
2-(4-Carboxypiperidino)-4-(3-pyridylmethyl)amino-6-chloroquinazoline
[0788] 119
[0789] molecular formula; C.sub.20H.sub.20ClN.sub.5O.sub.2
[0790] yield (%); 93
[0791] m.p. (.degree. C.); >250
[0792] Mass m/e; 398 (M+1)
[0793] NMR .delta. (DMSO-d.sub.6) ;
[0794] 1.45.about.1.60 (2H, m), 1.84.about.1.97 (2H, m),
2.58.about.2.68 (1H, m), 3.25.about.3.45 (2H, m), 4.45.about.4.54
(2H, m), 4.80 (2H, d, J=5.7 Hz), 7.41 (1H, dd, J=7.9 Hz, 4.8 Hz),
7.82 (1H, dd, J=9.0 Hz, 2.0 Hz), 7.86.about.7.96 (2H, m), 8.50 (1H,
d, J=4.8 Hz), 8.55 (1H, d, J=1.6 Hz), 8.69 (1H, s)
Example 82
2-(4-Carboxypiperidino)-4-(4-pyridylmethyl)amino-6-chloroquinazoline
[0795] 120
[0796] molecular formula; C.sub.20H.sub.20ClN.sub.5O.sub.2
[0797] yield (%); 89
[0798] m.p. (.degree. C.); 167.about.168
[0799] Mass m/e; 398 (M+1)
[0800] NMR .delta. (DMSO-d.sub.6);
[0801] 1.24.about.1.36 (2H, m) , 1.68.about.1.77 (2H, m),
2.40.about.2.49 (1H, m), 2.86.about.2.96 (2H, m), 4.42.about.4.50
(2H, m), 4.66 (2H, d, J=5.7 Hz), 7.28 (1H, d, J=9.0 Hz), 7.34 (2H,
d, J=6.0 Hz), 7.51 (1H, dd, J=9.0 Hz, 2.4 Hz), 8.18 (1H, d, J=2.4
Hz), 8.47 (2H, d, J=6.0 Hz), 8.74 (1H, t, J=5.7 Hz)
Example 83
2-
(4-Cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoli-
ne
[0802] 121
[0803] 75 ml of thionyl chloride and 150 ml of acetonitrile were
added to 3.8 g (0.0086 mol) of
2-(4-carbamoylpiperidino)-4-(3,4-methylenedioxybenz- yl)
amino-6-chloroquinazoline. The mixture thus obtained was heated
under reflux for one hour. The reaction mixture was distilled under
a reduced pressure to remove the solvent. A saturated aqueous
solution of sodium hydrogencarbonate and triethylamine were added
to the residue and the resultant mixture was extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous magnesium
sulfate, filtered and distilled under a reduced pressure to remove
the solvent. The obtained residue was purified by a silica gel
column chromatography (ethyl acetate-n-hexane) and recrystallized
from chloroform-n-hexane to give 3.1 g of the title compound.
[0804] molecular formula; C.sub.22H.sub.20ClN.sub.5O.sub.2
[0805] yield (%); 85
[0806] m.p. (.degree. C.); 169.about.170
[0807] NMR .delta. (CDCl.sub.3);
[0808] 1.88 (2H, m), 1.95 (2H, m), 2.87 (1H, m), 3.73 (2H, m), 4.25
(2H, m), 4.67 (2H, d, J=5.6 Hz), 5.65 (1H, t, J=5.6 Hz), 5.97 (2H,
s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.87
(1H, d, J=1.6 Hz), 7.39 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.4 Hz),
7.46 (1H, dd, J=8.8 Hz, 2.4 Hz)
Example 84
2-[4-(1H-tetrazol-5-yl)piperidinol-4-(3,4-methylenedioxybenzyl)amino-6-chl-
oroquinazoline hydrochloride
[0809] 122
[0810] 10 ml of toluene was added to a mixture comprising 0.50 g
(0.0012 mol) of
2-(4-cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroq-
uinazoline and 0.50 g (0.0024 mol) of trimethyl stannylazide. The
mixture thus obtained was heated under reflux for two days. The
reaction mixture was distilled under a reduced pressure to remove
the solvent. The residue was suspended in 10 ml of ethanol,
followed by the addition of 10 ml of 1N hydrochloric acid. The
mixture thus obtained was stirred at room temperature for several
hours. The mixture was filtered to recover the crystal. The crystal
was washed with water and air-dried to give 0.60 g of the title
compound.
[0811] molecular formula; C.sub.22H.sub.21ClN.sub.8O.sub.2.HCl
[0812] yield (%); quantitative
[0813] m.p. (.degree. C.); 212.about.214
[0814] Mass m/e; 465 (M+1).sup.+
[0815] NMR .delta. (DMSO-d.sub.6);
[0816] 1.80 (2H, m), 2.17 (2H, m), 3.45 (2H, m), 4.62 (2H, m), 4.69
(2H, d, J=5.6 Hz), 5.97 (2H, s), 6.86 (1H, d, J=7.6 Hz), 6.91 (1H,
dd, J=7.6 Hz, 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.84 (1H, dd, J=8.8
Hz, 1.6 Hz), 7.88 (1H, d, J=8.8 Hz), 8.51 (1H, d, J=1.6 Hz), 10.13
(1H, brs), 12.28 (1H, brs)
Example 85
4-Amino-6,7-dimethoxy-2-[4-(5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carb-
onyl)-piperazin-1-yl]-quinazoline Hydrochloride
[0817] A solution of
5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl chloride (5.17
g, 0.022 mole) in dioxane (35 ml. was added to a solution of
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (6.35 g., 0.022
mole) in diexane (190 ml.). The resultant mixture was stirred at
reflux for 1 hour, and then at 23.degree. C. for 18 hours.
Filtration gave the title compound; m.p. 281.degree.-284.degree. C.
(dec.) after crystallization from methanol.
[0818] Anal. Calcd. for C.sub.20H.sub.24N.sub.8O.sub.s.HCl: C,
45.76; H, 4.80; Cl, 6.75; N, 21.35. Found: C, 45.49; H, 4.65; Cl.,
7.10; N, 21.06.
[0819] The 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl
chloride starting material was obtained in the following
manner.
A
5-Ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylic Acid
[0820] A suspension of sodium thiocyanate (24.30 g, 0.30 mole) in
acetonitrile (120 ml), maintained at 19.degree. C., was treated
dropwise over 22 minutes with a solution of ethyl chloroformate
(28.7 ml, 0.30 mole) in acetonitrile (25 ml). The resultant mixture
was stirred for 25 minutes at 20.degree. C. and then ethyl
diazoacetate (31.5 ml, 0.30 mole) was added. After stirring for 24
hours, 6.0 N hydrochloric acid (300 ml) was added with cooling.
Acetonitrile solvent was removed in vacuo and the residual aqueous
suspension was extracted several times with ether. Combined ether
extracts were washed with water, dried (Na.sub.2SO.sub.4) and
evaporated to leave 51.0 g of ethyl
5-ethoxycarbonylamino-1,2,3-thiad- iazole-4-carboxylate. This ester
was hydrolyzed by refluxing for 6 hours in a mixture of ethanol (80
ml) and aqueous 6 N hydrochloric acid (400 ml) to yield the title
acid; m.p. 179.degree.-180.degree. dec. after crystallization from
nitromethane.
B
5-Ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl Chloride
[0821] Oxalyl chloride (8.76 g, 0.069 mole) was added slowly to a
stirred suspension of
5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylic acid (5.00 g,
0.023 mole) in dry ether (65 ml) containing three drops of
N,N-dimethylformamide. Tetrahydrofuran was added and the resultant
clear solution was stirred at 23.degree. C. for 2 hours. Filtration
and subsequent evaporation gave a residue which was triturated
under petroleum ether to yield the title acid chloride (5.17 g,
96%) m.p. 129.degree.-133.5.degree. C.
Example 86
4-Amino-6,7-dimethoxy-2-[4-(1,2,3-thiadiazole-4-carbonyl)piperazin-1-yl)qu-
inazoline Hydrochloride
[0822] The title compound was prepared by reacting
1,2,3-thiadiazole-4-car- bonyl chloride (D. L. Pain and R. Slack,
J. Chem. Soc., 5166 (1965)) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline according to the
procedure of Example 1. After crystallization from aqueous ethanol,
the title compound melted at 270.degree. C. (dec.).
[0823] Anal. Calcd for C.sub.17H.sub.19N.sub.7O.sub.3S.HCl: C,
46.62; H, 4.60; N, 22.39; S, 7.32. Found: C, 46.43; H, 4.39; N,
22.58; S, 7.14 (corrected for 6.08% water of hydration).
Example 87
4-Amino-6,7-dimethoxy-2-[4-(1,2,3-thiadiazole-5-carbonyl)piperazin-1-yl)qu-
inazoline Hydrochloride
[0824] A solution of potassium hydroxide (3.30 g.) in water (7 ml.)
was added to a solution of ethyl 1,2,3-thiadiazole-5-carboxylate
(8.00 g.) in ethanol (25 ml.). The mixture was stirred at
23.degree. C. for 2 hours, and then was worked up to yield
potassium 1,2,3-thiadiazole-5-carboxylate- . A suspension of this
salt (3.00 g.) in toluene (25 ml.) was treated at 0.degree. C. with
oxalyl chloride (1.6 ml.), stirred at 0.degree. C. for 1 hour, and
then was worked up to yield 1,2,3-thiadiazole-5-carbonyl
chloride.
[0825] Reaction of a 1, 2, 3-thiadiazole-5-carbonyl chloride and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline according to the
procedure of Example 1 provided the title compound having a melting
point of 295.degree.-297.degree. C. after crystallization from
aqueous ethanol.
[0826] Anal. Calcd. for C.sub.17H.sub.19N.sub.7O.sub.3S.HCl: C,
46.62; H, 4.60; N, 22.39; S, 7.32. Found: C, 46.91, H, 4.51; N,
21.91; S, 7.39 (corrected for 2.6% water of hydration).
Example 88
4-Amino-6,7-dimethoxy-2-[4-(5-methyl-1,2,3-thiadiazole-4-carbonyl)-piperaz-
in-1-yl)quinazoline Hydrochloride
[0827] Hydrolysis of ethyl 5-methyl-1,2,3-thiadiazole-4-carboxylate
(D. L. Pain and R. Sleck, J. Chem. Soc., 5166 (1965)) and
subsequent treatment of the acid with oxalyl chloride according to
the method of Example 3 provides
5-methyl-1,2,3-thiadiazole-4-carbonyl chloride.
[0828] Reaction of the carbonyl chloride and
4-amino-6,7-dimethoxy-2-(1-pi- perizinyl)-quinazoline according to
the procedure of Example 1 provides the title compound.
Example 89
4-Amino-6,7-dimethoxy-2-[4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-pipe-
razin-1-yl-quinazoline hydrochloride
[0829] A solution of 5-methylthio-1,3,4-oxadiazole-2-carbonyl
chloride (0.601 g., 3.36 mole) in dioxane (10 ml) was added to a
solution of 4-amino-6,7-dimethoxy-2-(1-piperizinyl)quinazoline
(0.972 g., 3.36 mmole) in dioxane (100 ml.). The resultant mixture
was stirred at room temperature for 65 hours, then was heated at
reflux for 30 minutes. Filtration gave the title compound (1.56
g.). Recrystallization from methanol gave a product having a M.P.
of 280.degree.-285.degree. C. with decomposition.
[0830] Anal. Calcd for C.sub.18H.sub.21N.sub.7O.sub.4S.HCl: C,
46.20, H, 4.74; Cl, 7.58; N, 20.96; S, 6.85. Found: C, 46.34, H,
4.89; Cl, 7.59; N, 20.38; S, 6.58.
Example 90
4-Amino-6,7-dimethoxy-2-[4-(5-ethylthio-1,3,4-oxadiazole-2-carbonyl)-piper-
azin-1-yl-quinazoline hydrochloride
[0831] The title compound was prepared from
5-ethylthio-1,3,4-oxadiazole-2- -carbonyl chloride (0.79 g., 4.1
mmole) and 4-amino-6,7-dimethoxy-2-(1-pip- erazinyl)-quinazoline
(1.19 g., 4.1 mmole) following the procedure described in Example
1. The product had a M.P. of 246.degree.-248.5.degre- e. C.
[0832] Anal. Calcd for C.sub.19H.sub.13N.sub.7O.sub.4S.HCl: C,
47.34, H, 5.02; N, 20.34; S, 6.65. Found: C, 47.37; H, 4.76; N,
20.15; S, 6.71 (corrected for 4.11% H.sub.2O).
Example 91
4-Amino-6,7-dimethoxy-2-[4-(5-isopropylthio-1,3,4-oxadiazole-2-carbonyl)-p-
iperazin-1-yl]-quinazoline hydrochloride
[0833] The title compound was prepared from
5-isopropylthio-1,3,4-oxadiazo- le-2-carbonyl chloride (1.54 g.,
7.5 mmole) and 4-amino-6,7-dimethoxy-2-(1- -piperazinyl)quinazoline
(2.1 g., 7.5 mmole) following the procedure of Example 1. The
product had a M.P. of 260.degree.-263.degree. C. with
decomposition.
[0834] Anal. Calcd for C_H.sub.23N.sub.7O.sub.4S.HCl: C, 48.43; H,
5.28; N, 19.77. Found: C, 48.05; H, 5.20; N, 19.61.
Example 92
4-Amino-6,7-dimethoxy-2-[4-(5-n-propylthio-1,3,4-oxadiazole-2-carbonyl)-pi-
perazin-1-yl]-quinazoline hydrochloride
[0835] The title compound was prepared from
5-n-propylthio-1,3,4-oxadiazol- e-2-carbonyl chloride (1.68 g.,
8.16 mmole) and 4-amino-6,7-dimethoxy-2-(1-
-piperazinyl)quinazoline (2.36 g., 8.16 mmole) following the
procedure of Example 1. The product had a M.P. of
230.degree.-245.degree. C. with decomposition.
[0836] Anal. Calcd for C.sub.20H_N.sub.7O.sub.4S.HCl: C, 48.43; H,
5.25; N, 19.77. Found: C, 48.11; H, 5.35; N, 19.65.
Example 93
4-Amino-6,7-dimethoxy-2-
[4-(5-n-butylthio-1,3,4-oxadiazole-2-carbonyl)-pi-
perazin-1-yl]-quinazoline hydrochloride
[0837] The title compound was prepared from
5-n-butylthio-1,3,4-oxadiazole- -2-carbonyl chloride and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazolin- e following the
procedure of Example 89.
Example 94
4-Amino-6,7-dimethoxy-2-[4-(isoxazole-5-carbonyl)-piperazine-1-yl]quinazol-
ine Hydrochloride
[0838] A solution of isoxazole-5-carbonyl chloride (1.33 g., 0.01
mole) in dioxane was added to a solution at 30.degree. C. of
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.94 g., 0.01
mole) in dioxane. The mixture was stirred at reflux for three
minutes, then at room temperature for 16 hours. Filtration gave the
title compound (4.02 g., 94% yield). Recrystallization from aqueous
methanol gave a product having a m.p. of 270.degree. C. with
decomposition.
[0839] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.4S.HCl: C,
51.37; H, 5.03; Cl, 8.42; N, 19.97. Found: C, 50.86; H, 4.65; Cl,
8.52; N, 19.81 (corrected for 4.30% H.sub.2O).
Example 95
4-Amino-6,7-dimethoxy-2-[4-(isoxazole-3-carbonyl)-piperazin-1-yl]quinazoli-
ne Hydrochloride
[0840] A solution of isoxazole-3-carbonyl chloride (0.753 g.,
0.0057 mole) in dioxane (20 ml.) was added to a solution of
4-amino-6,7-dimethoxy-2-(1- -piperazinyl)quinazoline (1.66 g.,
0.0057 mole) in dioxane (60 ml.). The mixture was stirred at reflux
for 30 minutes, then at room temperature for 64 hours. Filtration
gave the title compound which was recrystallized from methanol
(1.81 g., 75% yield). The product had a m.p. of
268.degree.-273.degree. C. with decomposition.
[0841] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.4HCl: C,
51.37; H, 5.03; Cl, 8.42; N, 19.97. Found: C, 50.04; H, 4.86; Cl,
8.66; N, 19.57 (corrected for 3.11% H.sub.2O).
Example 96
4-Amino-6,7-dimethoxy-2-[4-(isoxazole-4-carbonyl)-piperazin-1-yl]quinazoli-
ne Hydrochloride
[0842] A solution of isoxazole-4-carbonyl chloride (1.06 g., 8.08
mmole) in dioxane (8 ml.) was added to a solution at of
4-amino-6,7-dimethoxy-2-- (1-piperazinyl)quinazoline (2.34 g., 8.08
mmole) in dioxane (200 ml.). The mixture was stirred at room
temperature for 20 hours. Filtration gave the title compound,
which, after recrystallization from methanol, had a m.p. of
225.degree.-260.degree. C. with decomposition.
[0843] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.4HCl: C,
51.37; H, 5.03; Cl, 8.42; N, 19.97. Found: C, 51.37; H, 4.95; Cl,
8.34; N, 19.95 (corrected for 1.63% H.sub.2O)
Example 97
4-Amino-6,7-dimethoxy-2-[4-(5-methylisoxazole-3-carbonyl)-piperazin-1-yl]q-
uinazoline Hydrochloride
[0844] A solution of 5-methylisoxazole-3-carbonyl chloride (0.41
g., 2.83 mmole) in dioxane was added to a solution of
4-amino-6,7-dimethoxy-2-(1-p- iperazinyl)quinazoline (0.82 g., 2.83
mmole) in dioxane. The mixture was treated as described in the
previous example to give the title compound having a m.p. of
271.degree.-273.degree. C. with decomposition.
[0845] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.4HCl H.sub.2O:
C, 50.38; H, 5.56; N, 18.56; H.sub.2O, 3.92. Found: C, 50.58; H,
5.40; N, 18.86; H.sub.2O, 3.72.
Example 98
4-Amino-6,7-dimethoxy-2-[4-(3-methylisoxazole-4-carbonyl)-piperazin-1-yl]q-
uinazoline Hydrochloride
[0846] A solution of 3-methylisoxazole-4-carbonyl chloride (1.01
g., 6.9 mmole) in dioxane and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00 g., 6.9
mmole) in dioxane was stirred under reflux for 15 hours, then
worked up as described in Example 1. The title compound after
recrystallization from methanol had a mp. of
300.degree.-301.degree. C. with decomposition.
[0847] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.4HCl: C,
52.47; H, 5.33; N, 19.33. Found: C, 52.62; H, 5.31; N, 19.12
(corrected for 1.13% H.sub.2O).
Example 99
4-Amino-6,7-dimethoxy-2-[4-(3-methylisoxazole-5-carbonyl)-piperazin-1-yl]q-
uinazoline Hydrochloride
[0848] A solution of 3-methylisoxazole-5-carbonyl chloride (0.73
g., 5.02 mmole) in dioxane was added to a solution of
4-amino-6,7-dimethoxy-2-(1-p- iperazinyl)quinazoline (1.45 g., 5.02
mmole) in dioxane. The mixture was heated briefly, then was stirred
at 20.degree. C. for 2.5 hours. Workup as in Example 1 gave the
title compound having a m.p. of 263.degree.-264.degree. C. with
decomposition.
[0849] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.4HCl: C,
52.47; H, 5.33; Cl, 8.15; N, 19.33. Found: C, 51.82; H, 5.04; Cl,
8.36; N, 19.46 (corrected for 4.82% H.sub.2O).
Example 100
4-Amino-6,7-dimethoxy-2-[4-(oxazole-4-carbonyl)-piperazin-1-yl]quinazoline
Hydrochloride
[0850] A solution of oxazole-4-carbonyl chloride (0.73 g., 5.53
mmole) in dioxane was added to a solution of
4-amino-6,7-dimethoxy-2-(1-piperazinyl- )quinazoline (1.60 g., 5.53
mmole) in dioxane. The mixture was heated at reflux for 0.5 hour,
then was stirred at 20.degree. C. for 64 hours. Filtration gave the
title compound having a m.p. of 291.degree.-294.degree. C. with
decomposition after recrystallization from aqueous ethanol.
[0851] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.4HCl H.sub.2O:
C, 49.26; H, 5.28; Cl, 8.08; N, 19.15. Found: C, 48.92; H, 4.83;
Cl, 8.33; N, 18.94.
Example 101
4-Amino-6,7-dimethoxy-2-[4-(2-methyloxazole-4-carbonyl)-piperazin-1-yl]qui-
nazoline Hydrochloride
[0852] A solution of 2-methyloxazole-4-carbonyl chloride (1.01 g.,
6.9 mmole) in dioxane was added to a solution of
4-amino-6,7-dimethoxy-2-(1-p- iperazinyl)quinazoline (2.00 g., 6.9
mmole) in dioxane. The mixture was heated at reflux for 2 hours.
Filtration gave the title compound having a m.p. of
278.degree.-280.degree. C. with decomposition after
recrystallization from methanol.
[0853] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.4HCl: C,
52.47; H, 5.33; N, 19.33. Found: C, 52.08; H, 5.43; N, 18.89
(corrected for moisture).
Example 102
4-Amino-6,7-dimethoxy-2-[4-(4-methyloxazole-5-carbonyl)-piperazin-1-yl]qui-
nazoline Hydrochloride
[0854] The title compound was prepared from
4-methyloxazole-5-carbonyl chloride (0.85 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.68 g.)
following the procedure of Example 1. The product had a m.p. of
283.5.degree.-288.degree. C. with decomposition.
[0855] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.4HCl: C,
52.48; H, 5.33; Cl, 8.15; N, 19.33. Found: C, 52.19; H, 4.94; Cl,
8.13; N, 19.05 (corrected for 1.59% H.sub.2O).
Example 103
4-Amino-6,7-dimethoxy-2-[4-(isothiazole-4-carbonyl)-piperazin-1-yl]quinazo-
line Hydrochloride
[0856] The title compound was prepared from isothiazole-4-carbonyl
chloride (1.01 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.99 g.)
following previously described procedures. The product had a mp. of
286.degree.-287.degree. C. with decomposition.
[0857] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.3S HCl: C,
49.48; H, 4.84; Cl, 8.11; N, 19.23; S, 7.34. Found: C, 49.29; H,
4.81; Cl, 8.19; N, 19.27; S, 7.23 (corrected for 0.93%
H.sub.2O)
Example 104
4-Amino-6,7-dimethoxy-2-[4-(thiazole-2-carbonyl)-piperazin-1-yl]quinazolin-
e Hydrochloride
[0858] The title compound was prepared from thiazole-2-carbonyl
chloride (0.79 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.54 g.)
following previously described procedures. The product had a m.p.
of 273.degree.-276.degree. C. with decomposition.
[0859] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.3S HCl: C,
49.48; H, 4.84; N, 19.23. Found: C, 48.68; H, 4.62; N, 18.87
(corrected for 4.19% H.sub.2O).
Example 105
4-Amino-6,7-dimethoxy-2-[4-(thiazole-4-carbonyl)-piperazin-1-yl]quinazolin-
e Hydrochloride
[0860] The title compound was prepared from thiazole-4-carbonyl
chloride (1.02 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00 g.)
following previously described procedures. The product had a m.p.
of 274.degree.-277.degree. C. with decomposition.
[0861] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.3S HCl: C,
49.48; H, 4.48; N, 19.24. Found: C, 49.11; H, 4.69; N, 19.31
(corrected for 4.47% H.sub.2O).
Example 106
4-Amino-6,7-dimethoxy-2-[4-(2-methylthiazole-4-carbonyl)-piperazin-1-yl]qu-
inazoline Hydrochloride
[0862] The title compound was prepared from
2-methylthiazole-4-carbonyl chloride (0.49 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.87 g.)
following previously described procedures. The product had a m.p.
of 260.degree.-263.degree. C. with decomposition.
[0863] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.3S HCl: C,
50.60; H, 5.14; N, 18.64. Found: C, 50.88; H, 4.96; N, 18.67
(corrected for 2.88% H.sub.2O).
Example 107
4-Amino-6,7-dimethoxy-2-[4-(thiazole-5-carbonyl)-piperazin-1-yl]quinazolin-
e Hydrochloride
[0864] The title compound was prepared from thiazole-5-carbonyl
chloride (0.77 g.) and
4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.51 g.)
following previously described procedures. The product had a m.p.
of 280.degree.-281.degree. C. with decomposition.
[0865] Anal. Calcd. for C.sub.18H.sub.20N.sub.6O.sub.3S HCl: C,
49.48; H, 4.84; Cl, 8.11; N, 19.23; S, 7.34. Found: C, 49.22; H,
5.19; Cl, 8.31; N, 19.49; S, 6.79 (corrected for 2.63%
H.sub.2O).
Example 108
4-Amino-6,7-dimethyoxy-2-[4-(2-methylthiazole-5-carbonyl)-piperazin-1-yl]q-
uinazoline Hydrochloride
[0866] The title compound was prepared from
2-methylthiazole-5-carbonyl chloride (0.42 g.) and
4-amino-6,7-dimethyoxy-2-(1-piperazinyl)-quinazoli- ne (0.75 g.)
following previously described procedures. The product had a m.p.
of 294.degree.-297.degree. C. with decomposition.
[0867] Anal. Calcd. for C.sub.19H.sub.22N.sub.6O.sub.3S HCl: C,
50.60; H, 5.14; N, 18.64. Found: C, 50.60; H, 4.95; N, 18.50
(corrected for 1.96% H.sub.2O).
Example 109
4-Amino-6,7-dimethoxy-2-[4-(4-methylthiazole-5-carbonyl)-piperazin-1-yl]qu-
inazoline Hydrochloride
[0868] The title compound was prepared from
4-methylthiazole-5-carbonyl chloride (1.1 g.) and
4-amino-6,7-dimethyoxy-2-(1-piperazinyl)quinazoline (2.0 g.)
following previously described procedures. The product had a m.p.
of 293.degree.-295.degree. C. with decomposition.
Example 110
Synthesis of 2-[N.sup.4- (2-furoyl) -homopiperazinol
-4-amino-6,7-dimethoxy-quinazoline:
a. Synthesis of
2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline:
[0869] 17 Grams of 2-chloro-4-amino-6,7-dimethoxy-quinazoline and
18.2 g of N-formylhomopiperazine are added to 170 ml of butanol and
the whole is refluxed with stirring for three hours. After
completion of the reaction, the mixture is cooled, and the crystals
thus precipitated are filtered out, washed with a small quantity of
ethanol and air-dried. 25 Grams of crude crystal are obtained. 13
Grams of the crystal thus obtained are taken and added with 80 ml
of 9% hydrochloric acid. The mixture is refluxed under stirring for
60 minutes. After completion of the reaction, the mixture is
allowed to cool. The crystal thus precipitated are filtered out and
then recrystallized from a mixture of methanol and ethanol.
[0870] Yield: 10.7 g (80.4%)
[0871] Melting point: 246-247.degree. C.:
[0872] Elementary analysis (as C.sub.18H.sub.21n.sub.5O.sub.2-2HCl
1/2 H.sub.2O):
1 C H N Theoretical (%) 46.74 6.29 18.17 Found (%) 46.44 6.40
17.90
b. Synthesis of
2-[N.sup.4-(2-furoyl)-homopiperazino]-4-amino-6,7-dimethox-
y-quinazoline:
[0873] A solution of 3 g of
2-homopiperazino-4-amino-6,7-dimethoxy-quinazo- line in 60 ml of
acetone is added dropwise to a solution of 1.3 g of
2-furancarboxylic acid chloride in 30 ml of acetone under stirring
and ice-cooling. After completion of the addition, the stirring is
continued for additional one hour to complete the reaction. The
crystals thus precipitated are filtered out and recrystallized from
a mixture of methanol and ethanol.
[0874] Yield: 3.1 g (70.4%)
[0875] Melting point: 278-280.degree. C.
[0876] Elementary analysis (as C.sub.20H.sub.23N.sub.3O.sub.4
HCl):
2 C H N Theoretical (%) 55.36 5.59 16.15 Found (%) 55.30 5.45
16.18
Example 111
Synthesis of
2-(N.sup.4-homopiperazino)-4-amino-6,7-dimethoxy-quinazoline:
[0877] 2 Grams of triethylamine are added to a solution of 1.5 g of
2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline and 1.5 g of
.alpha.-butyl chloride in 20 ml of n-butanol and the mixture is
refluxed under stirring for 24 hours. After completion of the
reaction, the solvent is distilled off and then the thus obtained
residue is made alkaline by addition of 10% aqueous caustic soda
solution. The oily substance thus separated out is extracted with
chloroform. The extract is washed with water, dried with potassium
carbonate and filtered. The filtrate is concentrated. The residue
thus obtained is dissolved in 30 ml of isopropanol. The solution is
added with 3 ml of saturated isopropanol/ hydrochloric acid and the
resulting crystals are filtered out and recrystallized from a
mixture of methanol/ethanol. The aimed compound is obtained as
dihydrochloride.
[0878] Yield: 0.9 g (50.6%)
[0879] Elementary analysis (as
C.sub.10H.sub.23N.sub.2O.sub.4-2HCl-1/2 H.sub.2O)
3 C H N Theoretical (%) 51.68 7.32 15.86 Found (%) 51.74 7.13
16.42
Examples 112 to 126
[0880] Various compounds shown in Table 1 were obtained by the
methods similar to those used in Examples 110 and 111.
[0881] The results are summarized in Table 1.
4TABLE 1 Elementary analyais (%) Molecular formula Theoretical
Example A M.P. (.degree. C.) Found 112
C.sub.17H.sub.19N.sub.3O.sub.3--HCl--H.sub.2O 51.05 6.57 17.52
235-240 51.16 6.34 17.8 113
C.sub.19H.sub.17N.sub.3O.sub.3--HCl--1/2H.sub.2O 54.46 6.99 16.71
240-250 54.20 6.97 17.18 114 C.sub.19H.sub.17N.sub.3O.sub.3--HCl
55.66 6.90 17.09 280-282 55.40 6.89 16.79 115
C.sub.23H.sub.24ClN.sub.3O.sub.3--HCl--H.sub.2O 53.22 5.49 14.11
235-240 53.18 5.79 13.61 116 C.sub.23H.sub.27N.sub.3O.sub.4--HCl
58.27 5.97 14.78 225-235 57.78 6.09 14.32 117
C.sub.23H.sub.27N.sub.2O.sub.1S--HCl 52.91 5.42 13.42 270-272 52.98
5.44 13.45 118 C.sub.24H.sub.28N.sub.2O.sub.3--HCl--1/2H.sub- .2O
56.18 6.10 13.65 220-225 56.06 6.29 13.46 119
C.sub.94H.sub.97N.sub.3O.sub.3--HCl--H.sub.2O 59.06 6.21 14.35
210-215 58.65 5.82 14.20 120 C.sub.24H.sub.22N.sub.3O.sub.3--HCl---
H.sub.2O 55.17 5.61 13.41 245-250 55.62 5.46 13.83 121
C.sub.23H.sub.29N.sub.3O.sub.3--HCl--1/2H.sub.2O 57.51 5.42 13.42
235-240 57.80 5.62 13.52 122 C.sub.27H.sub.31N.sub.2O.sub.2--HCl---
1/2H.sub.2O 57.18 5.88 12.35 292-294 57.52 6.06 12.41 123
C.sub.10H.sub.22N.sub.2O.sub.2 60.54 7.32 22.07 208-210 60.37 7.22
22.07 124 C.sub.22H.sub.22Cl.sub.2N.sub.2O.sub.2--2HCl 49.35 5.09
13.08 240-245 49.44 5.56 12.52 125
C.sub.22H.sub.22N.sub.2O.sub.2--2HCl 55.63 6.31 14.11 280-285 55.59
6.36 14.34 126 C.sub.22H.sub.22N.sub.2O.sub.2--3HCl 51.01 6.04
16.23 250-260 50.52 6.30 15.90
Example 127
4-Amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline
[0882] a. A mixture of N-(cyclopentylcarbonyl) piperazine (3.6 g.,
0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.79 g.,
0.02 mole) in 50 ml. of absolute ethanol is heated in an enclosed
reactor at 170.degree. C. for a period of 16 hours. The reaction
mixture is cooled, filtered and insolubles triturated with 100 ml.
of concentrated ammonium hydroxide to provide the free base. The
insoluble product is collected and crystallized from methanol to
afford analytically pure
4-amino-2-[4-cy-clopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquina-zoli-
ne, m.p. 256.0.degree. C. (corr.).
[0883] Analysis. Calcd. for C.sub.20H.sub.27N.sub.5O.sub.3
(percent): C, 62.32; H, 7.06; N, 18.17. Found (percent): C, 62.06;
H, 7.24; N, 17.99.
[0884] Example 127(a) illustrates the procedure of Equation 1 of
U.S. Pat. No. 4,060,615 to Matier et al., which is incorporated
herein by reference, while the following Examples 127(b-e)
illustrate procedures of Equations 2-5 of U.S. Pat. No. 4,060,615,
respectively, for the preparation of
4-amino-2-[4-(cyclopentyl-carbonyl)-1-piperazinyl]-6,7-dim-
ethoxyquinazoline.
[0885] b. Cyclopentylcarbonyl chloride (0.1 mole) is added to 0.1
mole of 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline in 300
ml. of methanol with vigorous stirring at room temperature.
Stirring is continued for a period of 2 to 6 hours and the product
is isolated according to the procedure of Example 127(a) to provide
4-amino-2-[4-(cyclopentylcarbonyl)-
-1-piperazinyl]-6,7-dimethoxyquinazoline. If the hydrochloride salt
is desired, the base treatment is omitted and evaporation of the
solvent provides
4-amino-2-[4-(cyclopentylcarbonyl)-piperazinyl]-6,7-dimethoxyqui-
nazoline hydrochloride, m.p. 279.degree.-280.degree. C. (dec.)
(corr.) crystallized from methanol-isopropanol.
[0886] Analysis. Calcd. for C.sub.20H.sub.27N.sub.5O.sub.3.HCl
(percent): C, 56.93; H. 6.69; N, 16.60. Found (percent): C, 56.65;
H. 6.89; N. 16.44.
[0887] c. A mixture of anhydrous ammonia and
4-chloro-2-[4-(cyclopentylcar-
bonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline in 100 ml. of
tetrahydrofuran is heated at 100.degree. C. for a period of 16 to
24 hours and the product isolated according to the procedure of
Example 127(a) to provide
4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-d-
imethoxyquinazoline.
[0888] d. A mixture of
4-amino-2-methylmercapto-6,7-dimethoxyquinazoline (0.1 mole) and
from 0.1 to 0.15 mole of N-(cyclopentylcarbonyl)piperazine in 150
ml. of isoamyl alcohol is refluxed for a period of 8 to 24 hours.
The solvent is evaporated and residual material, treated according
to procedure of Example 127(a), provides
4-amino-2-[4-(cyclopentylcarbonyl)--
1-piperazinyl]-6,7-dimethoxyquinazoline.
[0889] e. Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-for-mamidate
hydrochloride (0.01 mole) is added to a solution of
4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of
N,N-dimethylformamide. Sodium hydride (0.02 mole of a 56%
suspension in mineral oil) is added and the mixture stirred 0.5 hr.
at room temperature and then at 100.degree. C. for a period of 12
hr. When the reaction period is complete, water is added providing
4-amino-2-[4-cyclopentylcarb-
onyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Example 128
4-Amino-2-[4-(cyclopropylcarbonyl)-1-pinerazinyl]-6,7-dimethoxyquinazoline
[0890] N-(Cyclopropylcarbonyl)piperazine (3.08 g., 0.02 mole) and
2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are
reacted according to the procedure of Example 127(a). The crude
product crystallized from ethanol affords analytically pure
4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolin-
e, m.p. 283.5.degree. C. (corr.).
[0891] Analysis, Calcd. for C.sub.18H.sub.23N.sub.5O.sub.3
(percent): C, 60.49; H, 6.49; N, 19.59. Found (percent): C, 60.56;
H, 6.46; N, 19.41.
Example 129
4-Amino-2-[4-(cyclohexylcarbonyl)-1-piperazinyll-6,7-dimethoxyquinazoline
[0892] N-(Cyclohexylcarbonyl)piperazine (5.9 g., 0.03 mole) and
2-chloro-4-amino-6,7-dimethoxyquinazoline (7.2 g., 0.03 mole) are
reacted according to the procedure of Example 127(a). The crude
product crystallized from methanol affords analytically pure
4-amino-2-
[4-(cyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,
m.p. 223.degree.-225.degree. C., resolidifying and remelting at
248.0.degree.-250.0.degree. C. (corr.)
[0893] Analysis. Calcd. for C.sub.21H.sub.29N.sub.5O.sub.3
(percent): C, 63.14; H, 7.32; N, 17.53. Found (percent): C, 63.07;
H, 7.43; N, 17.63.
Example 130
4-Amino-2-[4-(cyclopenten-1-ylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazol-
ine
[0894] N-(1-cyclopenten-1-ylcarbonyl)piperazine (1.8 g., 0.01 mole)
and 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g., 0.01 mole)
are reacted according to the procedure of Example 127(a). The
isolated product crystallized from methanol affords analytically
pure
4-amino-2-[4-(1-cyclopenten-1-ylcarbonyl)piperazinyl]-6,7-dimethoxyquinaz-
oline, m.p. 256.5.degree.-258.0.degree. C. (corr.).
[0895] Analysis. Calcd. for C.sub.20H.sub.25N.sub.5O.sub.3
(percent): C, 62.65; H, 6.57; N, 18.26. Found (percent): C, 65.23;
H, 6.56; N, 18.42.
Example 131
4-Amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl-6,7-dimethoxyquinazol-
ine
[0896] N-(3-cyclopentenylcarbonyl)piperazine (2.7 g., 0.015 mole)
and 2-chloro-4-amino-6,7-dimethoxyquin-azoline (3.6 g., 0.015 mole)
are reacted according to the procedure of Example 127(a). The crude
product crystallized from methanol affords analytically pure
4-amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinaz-
oline, m.p. 215.5.degree.-217.5.degree. C. (corr.).
[0897] Analysis. Calcd. for C.sub.20H.sub.25N.sub.5O.sub.3
(percent): C, 62.65; H, 6.57; N, 18.26. Found (percent): C, 62.35;
H, 6.72; N, 18.21.
Example 132
4-Amino-2-[4-(3-cyclohexenylcarbonyl)-1-piperazinyl]-
6,7-dimethoxyquinazoline
[0898] N-(3-cyclohexenylcarbonyl)piperazine (7.65 g., 0.04 mole)
and 2-chloro-4-amino-6,7-dimethoxyquinazoline (9.6 g., 0.04 mole)
are reacted according to the procedure of Example 127(a). The crude
product crystallized from methanol affords analytically pure
4-amino-2-[4-(3-cyclohexenlcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazol-
ine, m.p. 211.degree.-213.degree. C. resolidifying and melting at
234.0.degree.-236.0.degree. C. (corr.).
[0899] Analysis. Calcd. for C.sub.21H.sub.27N.sub.5O.sub.3
(percent): C, 63.46; H, 6.85; N, 17.62. Found (percent): C, 63.18;
H, 6.80; N, 17.63.
Example 133
4-Amino-2-[4-(cyclobutylcarbonyl)-1-piperazinyl]-6,7-dimethyxyquinazoline
Hydrochloride
[0900] N-(Cyclobutylcarbonyl)piperazine (0.02 mole) and
2-chloro-4-amino-6,7-dimethoxyquinazoline (0.02 mole) are reacted
according to the procedure of Example 127(a). When reaction is
complete, the solvent is removed and the residue crystallized from
methanolisopropanol to provide analytically pure
4-amino-2-[4-(cyclobutyl-
carbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride
hydrate, m.p. 267.degree.-268.degree. C. (dec.) (corr.).
[0901] Analysis. Calcd. for
C.sub.19H.sub.25N.sub.5O.sub.3.HCl.1/4H.sub.2O (percent): C, 55.33;
H, 6.48; N, 16.98. Found (percent): C, 55.49; H, 6.75; N.
16.62.
Example 134
4-Amino-2-[4-(cycloheptylcarbonyl)-1-piperazinyl]-6,7-dimethoxyqinazoline
Hydrochloride
[0902] N-(Cycloheptylcarbonyl)piperazine (0.02 mole) and
2-chloro-4-amino-6,7-dimethoxyquinazoline (0.02 mole) are reacted
according to the procedure of Example 133. Crystallization of the
product from methanol-isopropanol provides analytically pure
4-amino-2-[4-(cycloheptylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolin-
e hydrochloride, m.p. 278.degree.-279.degree. C. (corr.).
[0903] Analysis. Calcd. for C.sub.22H.sub.31N.sub.5O.sub.3.HCl
(percent): C, 58.72; H, 7.17; N, 15.56. Found (percent): C, 58.73;
H, 7.39; N, 15.44.
Example 135
[0904] Following the procedure of Example 127 but employing an
equimolar amount of: N-(2-cyclopentenylcarbonyl)piperazine,
N-(1-cyclohexen-1-ylcar- bonyl)piperazine,
(1-cyclohexen-1-ylcarbonyl)piperazine,
N-(cyclooctylcarbonyl)piperazine,
N-(2-methylcyclopentylcarbonyl)piperazi- ne,
N-(1-methylcyclopentylcarbonyl)piperazine,
N-(1-methylcyclohexylcarbon- yl)piperazine, in place of
N-(cyclopentylcarbonyl)piperazine, there is produced:
[0905] a.
4-amino-2-[4-(2-cyclopentenylcarbonyl)1-pipera-zinyl]-6,7-dimeth-
oxyquinazoline.
[0906] b.
4-amino-2-[4-(1-cyclohexen-1-ylcarbonyl)-1-piperazinyl]-6,7-dime-
thoxyquinazoline,
[0907] c.
4-amino-2-[4-(cyclooctylcarbonyl)-1-piperazinyl]-6,7-dimethoxyqu-
inazoline,
[0908] d.
4-amino-2-[4-(2-methylcyclopentylcarbonyl)-1-piperazinyl]-6,7-di-
methoxyquinazoline.
[0909] e.
4-amino-2-[4-(1-methylcyclopentylcarbonyl)-1-piperazinyl3-6,7-di-
methoxyquinazoline,
[0910] f.
4-amino-2-[4-(1-methylcyclohexylcarbonyl)-1-piperazinyl]-6,7-dim-
ethoxyquinazoline.
Example 136
4-Hydrazino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazo-
line Hydrochloride
[0911] N-(Cyclopentylcarbonyl)piperazine (0.02 mole) and
2-chloro-4-hydrazino-6,7-dimethoxyquinazoline (0.02 mole) reacted
according to the procedure of Example 133 provides
4-hydrazino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinaz-
olinehydrochloride, m.p. 282.degree.-284.degree. C.
Example 137
[0912] Suspensions
[0913] A suspension of
4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6-
,7-dimethoxyquinazoline or a pharmaceutically acceptable salt
thereof is prepared with the following ingredients:
[0914] Active ingredient: 20 g.
[0915] Sucrose, U.S.P.: 400 g.
[0916] Sorbitol, U.S.P.: 100 g.
[0917] Bentonite: 20 g.
[0918] Flavors, q.s.
[0919] Water, distilled to make 1 liter
[0920] Each milliliter of the suspension contains approximately 20
mg. of the active ingredient.
Example 138
[0921] Tablets
[0922] The following ingredients are blended in the proportion by
weight indicated according to conventional pharmaceutical
techniques to provide a tablet base:
[0923] Lactose: 79
[0924] Corn Starch: 10
[0925] Talcum: 6
[0926] Tragancanth: 4
[0927] Magnesium Stearate: 1
[0928] This tablet base is blended with sufficient
4-amino-2-[4-(cyclopent-
ylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a
pharmaceutically acceptable salt thereof to provide tablets
containing 0.1, 0.25, 0.5, 1, 2.5, 5, 7.5, 10, 25, and 50 mg. of
active ingredient; formed in a tablet of the desired size in a
conventional tablet press.
Example 139
[0929] Dry Filled Capsules
[0930] The following ingredients are blended in a conventional
manner in the proportion by weight indicated.
[0931] Lactose, U.S.P.: 50
[0932] Starch: 5
[0933] Magnesium Stearate: 2
[0934] Sufficient
4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-di-
methoxyquinazoline or a pharmaceutically acceptable salt thereof is
added to the blend to provide capsules containing 0.1, 0.25, 0.5,
1, 2.5, 5, 7.5, 10, 25, and 50 mg. of active ingredient, and filled
into hard gelatin capsules of a suitable size.
[0935] It will be understood that various changes and modifications
can be made in the details of procedure, formulation and use
without departing from the spirit of the invention, especially as
defined in the following claims.
* * * * *