U.S. patent application number 13/574848 was filed with the patent office on 2013-02-21 for compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. The applicant listed for this patent is Naomi Kitamoto. Invention is credited to Naomi Kitamoto.
Application Number | 20130046000 13/574848 |
Document ID | / |
Family ID | 43770309 |
Filed Date | 2013-02-21 |
United States Patent
Application |
20130046000 |
Kind Code |
A1 |
Kitamoto; Naomi |
February 21, 2013 |
COMPOUNDS FOR SUPPRESSING A PERIPHERAL NERVE DISORDER INDUCED BY AN
ANTI-CANCER AGENT
Abstract
The present invention provides a medicament that suppresses (or
mitigates) various neurological symptoms caused by a peripheral
nerve disorder induced by an anti-cancer agent.
Inventors: |
Kitamoto; Naomi; (Kanagawa,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kitamoto; Naomi |
Kanagawa |
|
JP |
|
|
Assignee: |
Takeda Pharmaceutical Company
Limited
|
Family ID: |
43770309 |
Appl. No.: |
13/574848 |
Filed: |
January 26, 2011 |
PCT Filed: |
January 26, 2011 |
PCT NO: |
PCT/JP2011/052077 |
371 Date: |
October 15, 2012 |
Current U.S.
Class: |
514/373 ;
514/359; 514/381; 514/383; 514/460; 514/530; 514/533; 514/538 |
Current CPC
Class: |
A61K 31/4545 20130101;
A61K 31/4192 20130101; A61K 31/4196 20130101; C07C 311/28 20130101;
C07D 275/06 20130101; A61K 31/282 20130101; A61K 31/282 20130101;
A61P 25/02 20180101; A61K 31/337 20130101; A61K 31/4192 20130101;
A61K 31/428 20130101; A61K 31/235 20130101; A61K 31/216 20130101;
A61K 45/06 20130101; A61P 25/00 20180101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/69 20130101; A61P 43/00 20180101; C07D 249/06
20130101; A61K 31/216 20130101; A61K 2300/00 20130101; A61K 31/351
20130101; A61K 31/69 20130101; A61K 31/4196 20130101; A61K 31/428
20130101; A61K 31/4545 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
C07D 257/04 20130101; A61K 31/337 20130101; A61K 31/41 20130101;
A61K 31/41 20130101; C07D 309/28 20130101; A61P 39/00 20180101;
A61P 35/00 20180101 |
Class at
Publication: |
514/373 ;
514/538; 514/533; 514/359; 514/381; 514/383; 514/530; 514/460 |
International
Class: |
A61K 31/24 20060101
A61K031/24; A61K 31/41 20060101 A61K031/41; A61P 25/02 20060101
A61P025/02; A61K 31/428 20060101 A61K031/428; A61K 31/351 20060101
A61K031/351; A61K 31/4192 20060101 A61K031/4192; A61K 31/4196
20060101 A61K031/4196 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 27, 2010 |
JP |
2010-015935 |
Claims
1. A method for suppressing a peripheral nerve disorder induced by
an anti-cancer agent, which comprises administering a compound
represented by the formula ##STR00157## wherein R is (1) an
aliphatic hydrocarbon group optionally having substituent(s), (2)
an aromatic hydrocarbon group optionally having substituent(s), (3)
a heterocyclic group optionally having substituent(s), (4) a group
represented by the formula: --OR.sup.1 wherein R.sup.1 is a
hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), or (5) a group represented by the formula:
##STR00158## wherein R.sup.1b and R.sup.1c are the same or
different and each is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), R.sup.0 is a hydrogen atom
or an aliphatic hydrocarbon group, or R and R.sup.0 in combination
may form a bond, ring A.sup.1 is a cycloalkene optionally
substituted by 1 to 4 substituents selected from the group
consisting of (i) an aliphatic hydrocarbon group optionally having
substituent(s), (ii) an aromatic hydrocarbon group optionally
having substituent(s), (iii) a group represented by the formula:
--OR.sup.11 wherein R.sup.11 is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), and (iv) a
halogen atom, Ar is an aromatic hydrocarbon group optionally having
substituent(s), a group represented by the formula: ##STR00159## is
a group represented by the formula: ##STR00160## and n is an
integer of 1 to 4, or a salt thereof or a prodrug thereof, or a
compound represented by the formula (II): ##STR00161## wherein
R.sup.1' is (1) an aliphatic hydrocarbon group optionally having
substituent(s), (2) an aromatic hydrocarbon group optionally having
substituent(s), (3) a heterocyclic group optionally having
substituent(s), (4) a group represented by the formula:
--OR.sup.1a' wherein R.sup.1a' is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), or (5) a group
represented by the formula: ##STR00162## wherein R.sup.1b' and
R.sup.1c' are the same or different and each is a hydrogen atom or
an aliphatic hydrocarbon group optionally having substituent(s), X
is methylene, NH, a sulfur atom or an oxygen atom, Y is methylene
optionally having substituent(s) or NH optionally having
substituent(s), ring A' is a 5- to 8-membered ring optionally
having 1 to 4 substituents selected from the group consisting of
(i) an aliphatic hydrocarbon group optionally having
substituent(s), (ii) an aromatic hydrocarbon group optionally
having substituent(s), (iii) a group represented by the formula:
--OR.sup.2' wherein R.sup.2' is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), and (iv) a
halogen atom, Ar' is an aromatic hydrocarbon group optionally
having substituent(s), a group represented by the formula:
##STR00163## is a group represented by the formula: ##STR00164## s
is an integer of 0 to 2, t is an integer of 1 to 3, and the total
of s and t is 4 or less; provided that when X is methylene, then Y
should be methylene optionally having substituent(s), or a salt
thereof or a prodrug thereof, to a mammal in need thereof.
2. A method for suppressing a peripheral nerve disorder induced by
an anti-cancer agent, which comprises administering which comprises
administering a compound represented by the formula (III):
##STR00165## wherein R.sup.1aa is C.sub.1-6 alkyl, X.sup.aa is
methylene or an oxygen atom, and Ar.sup.aa is phenyl optionally
having 1 or 2 substituents selected from a halogen atom, C.sub.1-6
alkyl and C.sub.1-6 alkoxy, or a salt thereof or a prodrug thereof,
to a mammal in need thereof.
3. The agent method according to claim 1 wherein the compound is,
wherein the compound is ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
or a salt thereof or a prodrug thereof.
4. The agent method according to claim 1 wherein the compound is,
wherein the compound is ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate or a salt thereof or a prodrug thereof.
5. The agent method according to claim 1, wherein the anti-cancer
agent is selected from paclitaxel, docetaxel, vincristine,
cisplatin, carboplatin and bortezomib.
6. The method according to claim 5, wherein the anti-cancer agent
is paclitaxel.
7. The method according to claim 1, wherein the anti-cancer agent
is selected from paclitaxel, docetaxel, vincristine, vinblastine,
cisplatin, carboplatin, oxaliplatin and bortezomib.
8. The method according to claim 1, wherein the compound is ethyl
(-)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
or a salt thereof or a prodrug thereof.
9. The method according to claim 1, wherein the compound is ethyl
(t)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-2-carboxylate
or a salt thereof or a prodrug thereof.
10. The method according to claim 1, wherein the anti-cancer agent
is selected from taxane anti-cancer agents, vinca alkaloid
anti-cancer agents, platinum preparations and molecular targeted
drugs.
11. The method according to claim 10, wherein the taxane
anti-cancer agent is selected from paclitaxel and docetaxel.
12. The method according to claim 10, wherein the vinca alkaloid
anti-cancer agent is selected from vincristine and vinblastine.
13. The method according to claim 10, wherein the platinum
preparation is selected from cisplatin, carboplatin and
oxaliplatin.
14. The method according to claim 10, wherein the molecular
targeted drug is bortezomib.
15. The method according to claim 1, wherein the dosage form of the
compound is subcutaneous injection, intravenous injection,
intramuscular injection, intraperitoneal injection or drip
infusion.
16. The method according to claim 1, wherein the compound and the
anti-cancer agent are administered to the mammal simultaneously or
in a staggered manner.
17. The method according to claim 1, wherein the compound is used
in combination with other drugs that suppress side effects of the
anti-cancer agent.
18. The method according to claim 17, wherein the other drug is
selected from pregabalin, gabapentin and morphine.
19. The method according to claim 2, wherein the compound is ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
or a salt thereof or a prodrug thereof.
20. The method according to claim 2, wherein the compound is ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate or a salt thereof or a prodrug thereof.
21. The method according to claim 2, wherein the anti-cancer agent
is selected from paclitaxel, docetaxel, vincristine, cisplatin,
carboplatin and bortezomib.
22. The method according to claim 21, wherein the anti-cancer agent
is paclitaxel.
23. The method according to claim 2, wherein the anti-cancer agent
is selected from paclitaxel, docetaxel, vincristine, vinblastine,
cisplatin, carboplatin, oxaliplatin and bortezomib.
24. The method according to claim 2, wherein the anti-cancer agent
is selected from taxane anti-cancer agents, vinca alkaloid
anti-cancer agents, platinum preparations and molecular targeted
drugs.
25. The method according to claim 24, wherein the taxane
anti-cancer agent is selected from paclitaxel and docetaxel.
26. The method according to claim 24, wherein the vinca alkaloid
anti-cancer agent is selected from vincristine and vinblastine.
27. The method according to claim 24, wherein the platinum
preparation is selected from cisplatin, carboplatin and
oxaliplatin.
28. The method according to claim 24, wherein the molecular
targeted drug is bortezomib.
29. The method according to claim 2, wherein the dosage form of the
compound is subcutaneous injection, intravenous injection,
intramuscular injection, intraperitoneal injection or drip
infusion.
30. The method according to claim 2, wherein the compound and the
anti-cancer agent are administered to the mammal simultaneously or
in a staggered manner.
31. The method according to claim 2, wherein the compound is used
in combination with other drugs that suppress side effects of the
anti-cancer agent.
32. The method according to claim 31, wherein the other drug is
selected from pregabalin, gabapentin and morphine.
Description
TECHNICAL FIELD
[0001] The present invention relates to a medicament that
suppresses (or mitigates) various neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) due to peripheral
nerve disorders induced by anti-cancer agents.
BACKGROUND OF THE INVENTION
[0002] Neurological symptoms (e.g., dysesthesia such as numbness,
pain and the like) associated with the chemotherapy of cancer often
pose problems in cancer treatments. For example, a large variety of
side effects such as nausea (vomiting), hair loss, anorexia,
diarrhea, constipation, limb numbness, pain, stomatitis, leucopenia
and the like are known as the side effects of anti-cancer agents
such as paclitaxel (taxol) and the like. Among these side effects,
neurological symptoms (e.g., dysesthesia such as numbness, pain and
the like) caused by peripheral nerve disorders lack an effective
improving method.
[0003] Acute symptoms of such peripheral nerve disorders include
muscular pain and neuralgia, and these symptoms accompany numbness
and pain in the fingers and toes as the treatment proceeds. When
the symptoms become serious, the quality of life (QOL) of patients
is markedly degraded as evidenced by difficulty in using fingers
skillfully, increased risk of fall by difficulty in walking due to
numb toes and the like.
[0004] At present, a medicament clinically effective for these
neurological symptoms is not available, and therefore, when these
neurological symptoms are developed during treatment with
anti-cancer agents, either the dosage of the anti-cancer agents is
decreased, medication is discontinued, or medication is withdrawn.
Even when the treatment is stopped, sequelae of continued
neurological symptoms such as numbness and the like often
remain.
[0005] In view of the above, neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) by peripheral
nerve disorders caused by the administration of an anti-cancer
agent form a dose limiting factor of various anti-cancer agents,
and the development of a therapeutic drug for mitigating these
neurological symptoms associated with a treatment with an
anti-cancer agent has been desired (non-patent document 1 and
non-patent document 2).
[0006] While pain plays the most important role for biological
defense, it is also well known to bring an invasive severe pain
represented by a neuropathic pain, which exceeds the level of its
role and unnecessary for the body. The neuropathic pain is a severe
pain that continues even after a complete cure of an injured tissue
including peripheral and central nervous systems, which includes
hyperalgesia in which even a mild pain stimulation is felt as a
severe pain, spontaneous pain accompanying uncomfortable
dysesthesia, allodynia in which even a light contact stimulation
that does not develop a pain in itself causes a pain and the
like.
[0007] It has long been unclear in which site such neuropathic pain
is expressed by what mechanism. However, some neuropathic pain
animal models have been developed in recent years, and the
elucidation of the onset mechanism thereof is ongoing. The
representative models include the spinal cord nerve ligation model
by Kim and Chung (non-patent document 3), the sciatic nerve partial
ligation model by Seltzer et al. (non-patent document 4), the model
with gentle ligation of the sciatic nerve at several sites by
Bennett et al. (non-patent document 5), the model with ligation and
cleavage of tibial nerve and whole sural nerve, leaving the sural
nerve, by Decosterd and Woolf (non-patent document 6) and the like,
all of which creates pathology similar to human chronic neuropathic
pain by causing peripheral nerve disorders.
[0008] It has been clarified by the analysis of these animal models
that the development of neuropathic pain includes one caused by
changes in the peripheral nerve such as a sustained increase in the
sensitivity or spontaneous firing and the like of the peripheral
nerve starting from a peripheral nerve disorder (non-patent
document 7), and one caused by changes in the spinal cord or
highest center (non-patent document 8). The changes in the spinal
cord are caused by activation of microglia, and factors such as
cytokine and the like produced and liberated from the activated
microglia are considered to stimulate secondary neuron and enhance
pain sensitivity.
[0009] It has been reported, moreover, that incidents similar to
those in neuropathic pain model also occur in animal models of
neurological symptoms caused by the administration of an
anti-cancer agent. That is, by the administration of an anti-cancer
agent such as paclitaxel, vinblastine and the like, hyperalgesia
occurs along with a peripheral nerve disorder (non-patent document
9), and microglia is activated in the spinal cord (non-patent
document 10). From the above, it is considered that the expression
mechanism similar to that in neuropathic pain is also involved in
the expression of neurological symptoms in human, which is due to
peripheral nerve disorders caused by the administration of an
anti-cancer agent.
[0010] Patent document 1 describes that (i) a compound represented
by the formula:
##STR00001##
wherein R is an aliphatic hydrocarbon group optionally having
substituent(s), an aromatic hydrocarbon group optionally having
substituent(s), a heterocyclic group optionally having
substituent(s), a group represented by the formula: --OR.sup.1
wherein R.sup.1 is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), or a group represented by
the formula:
##STR00002##
wherein R.sup.1b is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), and R.sup.1c is the same as
or different from R.sup.1b, a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), R.sup.0 is a
hydrogen atom or an aliphatic hydrocarbon group, or R and R.sup.0
in combination form a bond, ring A is a cycloalkene substituted by
1 to 4 substituents selected from (1) an aliphatic hydrocarbon
group optionally having substituent(s), (2) an aromatic hydrocarbon
group optionally having substituent(s), (3) a group represented by
the formula: --OR.sup.11 wherein R.sup.11 is a hydrogen atom or an
aliphatic hydrocarbon group optionally having substituent(s), and
(4) a halogen atom, Ar is an aromatic hydrocarbon group optionally
having substituent(s), a group represented by the formula:
##STR00003##
is a group represented by the formula:
##STR00004##
and n is an integer of 1 to 4, and (ii) a compound represented by
the formula:
##STR00005##
wherein R.sup.a is an aliphatic hydrocarbon group optionally having
substituent(s), an aromatic hydrocarbon group optionally having
substituent(s), a heterocyclic group optionally having
substituent(s), a group represented by the formula: --OR.sup.1a
wherein R.sup.1a is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), or a group represented by
the formula:
##STR00006##
wherein R.sup.4a and R.sup.5a are the same or different and each is
a hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), R.sup.0a is a hydrogen atom or an aliphatic
hydrocarbon group, or R.sup.a and R.sup.0a in combination form a
bond, Ar.sup.a is an aromatic hydrocarbon group optionally having
substituent (s), a group represented by the formula:
##STR00007##
is a group represented by the formula:
##STR00008##
and n is an integer of 1 to 4, a salt thereof and a prodrug thereof
have a nitric oxide (NO) production-inhibiting effect and an
inhibitory effect on the production of inflammatory cytokines, such
as TNF-.alpha., IL-1, IL-6 and the like, and are useful as an agent
for the prophylaxis or treatment of diseases including cardiac
diseases, autoimmune diseases, inflammatory diseases, central
nervous system diseases, infectious diseases, sepsis, septic shock
and the like; and
[0011] Patent document 2 describes that a compound represented by
the formula:
##STR00009##
wherein R.sup.1 is an aliphatic hydrocarbon group optionally having
substituent(s), an aromatic hydrocarbon group optionally having
substituent(s), a heterocyclic group optionally having
substituent(s), a group represented by the formula: --OR.sup.1a
wherein
[0012] R.sup.1a is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), or a group represented by
the formula:
##STR00010##
wherein R.sup.1b and R.sup.1c are the same or different and each is
a hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), X is methylene, NH, a sulfur atom or an oxygen
atom, Y is methylene optionally having substituent(s) or NH
optionally having substituent(s), ring A is a 5- to 8-membered ring
optionally having 1 to 4 substituents selected from the group
consisting of (1) an aliphatic hydrocarbon group optionally having
substituent(s), (2) an aromatic hydrocarbon group optionally having
substituent(s), (3) a group represented by the formula: --OR.sup.2
wherein R.sup.2 is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), and (4) a halogen atom, Ar
is an aromatic hydrocarbon group optionally having substituent(s),
a group represented by the formula:
##STR00011##
is a group represented by the formula:
##STR00012##
m is an integer of 0 to 2, n is an integer of 1 to 3, and the total
of m and n is 4 or less; provided that when X is a methylene group,
then Y should be a methylene group optionally having
substituent(s), a salt thereof and a prodrug thereof have a nitric
oxide (NO) production-inhibiting effect and an inhibitory effect on
the production of inflammatory cytokines, such as TNF-.alpha.,
IL-1, IL-6 and the like, and are useful as an agent for the
prophylaxis or treatment of diseases including cardiac diseases,
autoimmune diseases, inflammatory diseases, central nervous system
diseases, infectious diseases, sepsis, septic shock and the
like.
[0013] Patent document 11 describes that the compounds described in
the above-mentioned patent document 1 and/or patent document 2 have
a TLR (particularly, TLR4) signal inhibitory action, and are useful
as an agent for suppressing production or expression of a factor
selected from IL-2 (Interleukin-2), IL-3, IL-8, IL-10, IL-12,
IL-17, MIP-2 (macrophage inflammatory protein-2), KC (keratinocyte
derived-chemokine), GM-CSF (granulocyte-macrophage
colony-stimulating factor), IFN (interferon)-.gamma. and
prostaglandin E2 and the like, and the like.
[0014] Patent documents 3-13 describe that the compounds described
in the above-mentioned patent document 1 and/or patent document 2
can be used for the treatment of pain.
[0015] However, patent documents 1-13 do not describe that the
compounds described in the above-mentioned patent document 1 and/or
patent document 2 can suppress peripheral nerve disorders induced
by anti-cancer agents.
DOCUMENT LIST
Patent Documents
[0016] patent document 1: WO99/46242 [0017] patent document 2:
WO01/10826 [0018] patent document 3: WO01/56562 [0019] patent
document 4: WO02/13816 [0020] patent document 5: WO02/32859 [0021]
patent document 6: WO03/013513 [0022] patent document 7: WO02/45750
[0023] patent document 8: WO03/084527 [0024] patent document 9:
WO2006/118329 [0025] patent document 10: WO2007/114296 [0026]
patent document 11: WO2007/123186 [0027] patent document 12:
WO2007/132825 [0028] patent document 13: WO2008/004673
Non-Patent Documents
[0028] [0029] non-patent document 1: Beinert T, Masuhr F, Mwela E,
Schweigert M, Flath B, Harder H, et al. Neuropathy under
chemotherapy. Eur J Med Res 2000; 5: 415-23. [0030] non-patent
document 2: Cavaliere R, Schiff D. Neurologic toxicities of cancer
therapies. Curr Neurol Neurosci Rep 2006; 6: 218-26. [0031]
non-patent document 3: Kim S H, Chung J M. An experimental model
for peripheral neuropathy produced by segmental spinal nerve
ligation in the rat. Pain 1992; 50: 355-363. [0032] non-patent
document 4: Seltzer Z, Dubner R, Shir Y. A novel behavioral model
of neuropathic pain disorders produced in rats by partial sciatic
nerve injury. Pain 1990; 43: 205-218. [0033] non-patent document 5:
Bennett G J, Xei Y- K. A peripheral mononeuropathy in rat that
produces disorders of pain sensation like those seen in man. Pain
1988; 33: 87-107. [0034] non-patent document 6: Decosterd I, Woolf
C J. Spared nerve injury: an animal model of persistent peripheral
neuropathic pain. Pain 2000; 87: 149-158. [0035] non-patent
document 7: Campbell, J. N. & Meyer, R. A. Mechanisms of
neuropathic pain. Neuron 2006; 52, 77-92. [0036] non-patent
document 8: Scholz, J. & Woolf, C. J. The neuropathic pain
triad: neurons, immunocytes, and glia. Nature Neurosci. 2007; 10:
1361-1368. [0037] non-patent document 9: Siau C, Xiao W H, Bennett
G J. Paclitaxel- and vincristine-evoked painful peripheral
neuropathies: loss of epidermal innervation and activation of
Langerhans cells. Exptl Neurol 2006; 201: 507-514. [0038]
non-patent document 10: Norikazu Kiguchi, Takehiko Maeda, Yuka
Kobayashi, Shiroh Kishioka. Up-regulation of tumor necrosis
factor-alpha in spinal cord contributes to vincristine-induced
mechanical allodynia in mice. Neuroscience Letters 2008; 445:
140-143.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0039] The present invention aims to provide a medicament for
suppressing (or mitigating) neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) due to peripheral
nerve disorders which are one of the side effects caused by the
administration of anti-cancer agents.
Means of Solving the Problems
[0040] The present inventors have conducted intensive studies in an
attempt to solve the aforementioned problems and found that the
compounds represented by the below-mentioned formula (I), formula
(II) and formula (III) unexpectedly suppress (or mitigate)
neurological symptoms of peripheral nerve disorders caused by
anti-cancer agents. Further studies made by the present inventors
based on these findings have resulted in the completion of the
present invention.
[0041] Accordingly, the present invention relates to
[1] An agent for suppressing a peripheral nerve disorder induced by
an anti-cancer agent, which comprises a compound represented by the
formula (I):
##STR00013##
wherein
R is
[0042] (1) an aliphatic hydrocarbon group optionally having
substituent(s), (2) an aromatic hydrocarbon group optionally having
substituent(s), (3) a heterocyclic group optionally having
substituent(s), (4) a group represented by the formula: --OR.sup.1
wherein R.sup.1 is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), or (5) a group represented
by the formula:
##STR00014##
wherein R.sup.1b and R.sup.1c are the same or different and each is
a hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), R.sup.0 is a hydrogen atom or an aliphatic
hydrocarbon group, or R and R.sup.0 in combination may form a bond,
ring A.sup.1 is a cycloalkene optionally substituted by 1 to 4
substituents selected from the group consisting of (i) an aliphatic
hydrocarbon group optionally having substituent(s), (ii) an
aromatic hydrocarbon group optionally having substituent(s), (iii)
a group represented by the formula: --OR.sup.11 wherein R.sup.11 is
a hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), and (iv) a halogen atom, Ar is an aromatic
hydrocarbon group optionally having substituent(s), a group
represented by the formula:
##STR00015##
is a group represented by the formula:
##STR00016##
and n is an integer of 1 to 4, or a salt thereof or a prodrug
thereof, or a compound represented by the formula (II):
##STR00017##
wherein
R.sup.1' is
[0043] (1) an aliphatic hydrocarbon group optionally having
substituent(s), (2) an aromatic hydrocarbon group optionally having
substituent(s), (3) a heterocyclic group optionally having
substituent(s), (4) a group represented by the formula:
--OR.sup.1a' wherein R.sup.1' is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), or (5) a group
represented by the formula:
##STR00018##
wherein R.sup.1b' and R.sup.1c' are the same or different and each
is a hydrogen atom or an aliphatic hydrocarbon group optionally
having substituent(s), X is methylene, NH, a sulfur atom or an
oxygen atom, Y is methylene optionally having substituent(s) or NH
optionally having substituent(s), ring A' is a 5- to 8-membered
ring optionally having 1 to 4 substituents selected from the group
consisting of (i) an aliphatic hydrocarbon group optionally having
substituent(s), (ii) an aromatic hydrocarbon group optionally
having substituent(s), (iii) a group represented by the formula:
--OR.sup.2' wherein R.sup.2' is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), and (iv) a
halogen atom, Ar' is an aromatic hydrocarbon group optionally
having substituent (s), a group represented by the formula:
##STR00019##
is a group represented by the formula:
##STR00020##
s is an integer of 0 to 2, t is an integer of 1 to 3, and the total
of s and t is 4 or less; provided that when X is methylene, then Y
should be methylene optionally having substituent(s), or a salt
thereof or a prodrug thereof; [2] an agent for suppressing a
peripheral nerve disorder induced by an anti-cancer agent,
comprising a compound represented by the formula (III):
##STR00021##
wherein R.sup.1aa is C.sub.1-6 alkyl, X.sup.aa is methylene or an
oxygen atom, and Ar.sup.aa is phenyl optionally having 1 or 2
substituents selected from a halogen atom, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy, or a salt thereof or a prodrug thereof; [3] the
agent of the above-mentioned [1] or [2], comprising ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
or a salt thereof or a prodrug thereof; [4] the agent of the
above-mentioned [1] or [2], comprising ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate or a salt thereof or a prodrug thereof; [5] the agent of
the above-mentioned [1] or [2], wherein the anti-cancer agent is
selected from paclitaxel, docetaxel, vincristine, cisplatin,
carboplatin and bortezomib; [5a] the agent of the above-mentioned
[1] or [2], wherein the anti-cancer agent is selected from
paclitaxel, vincristine, cisplatin, carboplatin and bortezomib; [6]
the agent of the above-mentioned [5], wherein the anti-cancer agent
is paclitaxel.
Effect of the Invention
[0044] According to the present invention, neurological symptoms
(e.g., dysesthesia such as numbness, pain and the like) due to
peripheral nerve disorders which are one of the side effects caused
by the administration of an anti-cancer agent can be suppressed (or
mitigated).
[0045] In addition, according to the present invention, a decrease
in the dosage due to the side effects of the administration of an
anti-cancer agent can be avoided.
[0046] According to the present invention, moreover, a treatment at
a high dose, which has been impossible heretofore, can be enabled
by controlling the side effects of the administration of an
anti-cancer agent.
[0047] According to the present invention, moreover, a long-term
treatment with an anti-cancer agent, while maintaining the QOL of
patients, can be enabled by controlling the side effects of the
administration of an anti-cancer agent.
DETAILED DESCRIPTION OF THE INVENTION
[0048] The compound represented by the formula (I) is
explained.
##STR00022##
(1) an aliphatic hydrocarbon group optionally having
substituent(s), (2) an aromatic hydrocarbon group optionally having
substituent(s), (3) a heterocyclic group optionally having
substituent(s), (4) a group represented by the formula: --OR.sup.1
wherein R.sup.1 is a hydrogen atom or an aliphatic hydrocarbon
group optionally having substituent(s), or (5) a group represented
by the formula:
##STR00023##
wherein R.sup.1b and R.sup.1c are the same or different and each is
a hydrogen atom or an aliphatic hydrocarbon group optionally having
substituent(s), or R and R.sup.0 in combination form a bond, with
particular preference given to the group represented by the
formula: --OR.sup.1 wherein R.sup.1 is as defined above.
[0049] R.sup.0 is a hydrogen atom or an aliphatic hydrocarbon
group.
[0050] When R and R.sup.0 in combination form a bond, the compound
represented by the formula (I) can be represented by the
formula:
##STR00024##
wherein each symbol is as defined above, and specifically can be
represented by the formula:
##STR00025##
wherein each symbol is as defined above, or
##STR00026##
wherein each symbol is as defined above.
[0051] When R is a group represented by the formula: --OR.sup.1
wherein R.sup.1 is as defined above, the compound represented by
the formula (I) can be represented by the formula:
##STR00027##
wherein R.sup.2 is a hydrogen atom or an aliphatic hydrocarbon
group, and other symbols are as defined above, and specifically can
be represented by the formula:
##STR00028##
wherein each symbol is as defined above, or
##STR00029##
wherein each symbol is as defined above.
[0052] As the compound represented by the formula (I), a compound
represented by the formula (Icc) or the formula (Inn) is
preferable.
[0053] As the "aliphatic hydrocarbon group" of the "aliphatic
hydrocarbon group optionally having substituent(s)" for R, R.sup.1,
R.sup.11, R.sup.1b or R.sup.1c and the "aliphatic hydrocarbon
group" for R.sup.0 or R.sup.2, for example, alkyl, cycloalkyl,
cycloalkylalkyl, alkenyl, alkynyl, etc. are preferable.
[0054] As alkyl, for example, linear or branched alkyl having 1 to
20 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl,
nonyl, decyl, dodecyl) and the like are preferable, and
particularly, for example, lower alkyl having 1 to 6 carbon atoms
(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl) and the like are preferable.
[0055] As cycloalkyl, for example, cycloalkyl having a carbon
number of 3 to 10 (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl) and the like are preferable
and, in particular, for example, cycloalkyl having a carbon number
of 3 to 6 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl)
and the like are preferable.
[0056] As cycloalkylalkyl, for example, cycloalkylalkyl having a
carbon number of 4 to 12 (e.g., cyclopropylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl) and the
like are preferable and, in particular, for example,
cycloalkylalkyl having a carbon number 4 to 8 (particularly 4 to 7)
(e.g., cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl) and
the like are preferable.
[0057] As alkenyl, for example, lower alkenyl having a carbon
number of 3 to 6 (e.g., propenyl, butenyl, pentenyl) and the like
are preferable and, in particular, for example, lower alkenyl
having a carbon number of 3 or 4 (e.g., propenyl, butenyl) and the
like are preferable.
[0058] As alkynyl, for example, lower alkynyl having a carbon
number of 3 to 6 (e.g., propynyl, butynyl, pentynyl) and the like
are preferable and, in particular, for example, lower alkynyl
having a carbon number of 3 or 4 (e.g., propynyl, butynyl) and the
like are preferable.
[0059] As the "substituent" of the aforementioned "aliphatic
hydrocarbon group optionally having substituent(s)", for
example,
(1) a heterocyclic group, (2) an oxo group, (3) hydroxy, (4)
C.sub.1-6 alkoxy, (5) C.sub.3-10 (particularly C.sub.3-6)
cycloalkyloxy, (6) C.sub.6-10 aryloxy, (7) C.sub.7-19 (particularly
C.sub.7-12) aralkyloxy, (8) heterocyclyloxy, (9) C.sub.1-6
alkylthio (the sulfur atom is optionally oxidized), (10) C.sub.3-10
(particularly C.sub.3-6) cycloalkylthio (the sulfur atom is
optionally oxidized), (11) C.sub.6-10 arylthio (the sulfur atom is
optionally oxidized), (12) C.sub.7-19 (particularly C.sub.7-12)
aralkylthio (the sulfur atom is optionally oxidized), (13)
heterocyclylthio, (14) heterocyclylsulfinyl, (15)
heterocyclylsulfonyl, (16) nitro, (17) a halogen atom, (18) cyano,
(19) carboxy, (20) C.sub.1-10 (particularly C.sub.1-6)
alkoxy-carbonyl, (21) C.sub.3-6 cycloalkyloxy-carbonyl, (22)
C.sub.6-10 aryloxy-carbonyl, (23) C.sub.7-19 (particularly
C.sub.7-12) aralkyloxy-carbonyl, (24) heterocyclyloxycarbonyl, (25)
C.sub.6-10 aryl-carbonyl, (26) C.sub.1-6 alkanoyl, (27) C.sub.3-5
alkenoyl, (28) C.sub.6-10 aryl-carbonyloxy, (29) C.sub.2-6
alkanoyloxy, (30) C.sub.3-5 alkenoyloxy, (31) carbamoyl optionally
having substituent(s), (32) thiocarbamoyl optionally having
substituent(s), (33) carbamoyloxy optionally having substituent(s),
(34) C.sub.1-6 alkanoylamino, (35) C.sub.6-10 aryl-carbonylamino,
(36) C.sub.1-10 (particularly C.sub.1-6) alkoxy-carboxamido, (37)
C.sub.6-10 aryloxy-carboxamido, (38) C.sub.7-19 (particularly
C.sub.7-12) aralkyloxy-carboxamido, (39) C.sub.1-10 (particularly
C.sub.1-6) alkoxy-carbonyloxy, (40) C.sub.6-10 aryloxy-carbonyloxy,
(41) C.sub.7-19 (particularly C.sub.7-12) aralkyloxy-carbonyloxy,
(42) C.sub.3-10 (particularly C.sub.3-6) cycloalkyloxy-carbonyloxy,
(43) ureido optionally having substituent(s), (44) C.sub.6-10 aryl
optionally having substituent(s) and the like are used.
[0060] These substituents are substituted at substitutable
positions of the aforementioned "aliphatic hydrocarbon group". They
are not limited to a single substituent, but may be the same or
different, and more than one substituent (preferably 2 to 4) may be
used.
[0061] As "C.sub.1-6 alkoxy", for example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy,
n-hexyloxy and the like are used.
[0062] As "C.sub.3-10 cycloalkyloxy", for example, cyclopropyloxy,
cyclohexyloxy and the like are used.
[0063] As "C.sub.6-10 aryloxy", for example, phenoxy, naphthyloxy
and the like are used.
[0064] As "C.sub.7-19 aralkyloxy", for example, benzyloxy,
1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy,
1-naphthylmethyloxy and the like are used.
[0065] As "C.sub.1-6 alkylthio (the sulfur atom is optionally
oxidized)", for example, methylthio, ethylthio, n-propylthio,
n-butylthio, methylsulfinyl, methylsulfonyl and the like are
used.
[0066] As "C.sub.3-10 cycloalkylthio (the sulfur atom is optionally
oxidized)", for example, cyclopropylthio, cyclohexylthio,
cyclopentylsulfinyl, cyclohexylsulfonyl and the like are used.
[0067] As "C.sub.6-10 arylthio (the sulfur atom is optionally
oxidized)", for example, phenylthio, naphthylthio, phenylsulfinyl,
phenylsulfonyl and the like are used.
[0068] As "C.sub.7-19 aralkylthio (the sulfur atom is optionally
oxidized)", for example, benzylthio, phenylethylthio,
benzhydrylthio, benzylsulfinyl, benzylsulfonyl and the like are
used.
[0069] As the "halogen atom", for example, a fluorine atom, a
chlorine atom, a bromine atom and an iodine atom are used.
[0070] As "C.sub.1-10 alkoxy-carbonyl", for example,
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl and the like are used.
[0071] As "C.sub.3-6 cycloalkyloxy-carbonyl", for example,
cyclopropyloxycarbonyl, cyclopentyloxycarbonyl,
cyclohexyloxycarbonyl and the like are used.
[0072] As "C.sub.6-10 aryloxy-carbonyl", for example,
phenoxycarbonyl, naphthyloxycarbonyl and the like are used.
[0073] As "C.sub.7-19 aralkyloxy-carbonyl", for example,
benzyloxycarbonyl, benzhydryloxycarbonyl, 2-phenethyloxycarbonyl
and the like are used.
[0074] As "C.sub.6-10 aryl-carbonyl", for example, benzoyl group,
naphthoyl group and the like are used.
[0075] As "C.sub.1-6 alkanoyl", for example, formyl, acetyl,
propionyl, butyryl group, valeryl group, pivaloyl group and the
like are used.
[0076] As "C.sub.3-5 alkenoyl", for example, acryloyl, crotonoyl
and the like are used, as the "C.sub.6-10 aryl-carbonyloxy", for
example, benzoyloxy, naphthoyloxy and the like are used.
[0077] As "C.sub.2-6 alkanoyloxy", for example, acetoxy,
propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like are
used.
[0078] As "C.sub.3-5 alkenoyloxy", for example, acryloyloxy,
crotonoyloxy and the like are used.
[0079] As "carbamoyl optionally having substituent(s)", for
example, carbamoyl or cyclic amino (e.g., pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl)carbonyl or the like, which
is optionally substituted by one or the same or different two
substituents selected from
[0080] (i) C.sub.1-4 alkyl (e.g., methyl, ethyl),
[0081] (ii) phenyl,
[0082] (iii) C.sub.1-7 acyl (e.g., acetyl, propionyl, benzoyl),
[0083] (iv) C.sub.1-4 alkoxy-phenyl (e.g., methoxyphenyl), and the
like is used, and specifically, for example, carbamoyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl,
N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl,
1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl,
morpholinocarbonyl and the like are used.
[0084] As "thiocarbamoyl optionally having substituent(s)",
thiocarbamoyl optionally substituted by one or the same or
different two substituents selected from
[0085] (i) C.sub.1-4 alkyl (e.g., methyl, ethyl),
[0086] (ii) phenyl, and the like is used, and specifically, for
example, thiocarbamoyl, N-methylthiocarbamoyl,
N-phenylthiocarbamoyl and the like are used.
[0087] As "carbamoyloxy optionally having substituent(s)", for
example, carbamoyloxy optionally substituted by one or the same or
different two substituents selected from
[0088] (i) C.sub.1-4 alkyl (e.g., methyl, ethyl),
[0089] (ii) phenyl, and the like are used, and specifically, for
example, carbamoyloxy, N-methylcarbamoyloxy,
N,N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy
and the like are used.
[0090] As "C.sub.1-6 alkanoylamino", for example, an acetamido
group, a propionamido group, a butyramido group, a valeramido
group, a pivalamido group and the like are used.
[0091] As "C.sub.6-10 aryl-carbonylamino", for example, a benzamido
group, a naphthamido group, a phthalimido group and the like are
used.
[0092] As "C.sub.1-10 alkoxy-carboxamido", for example,
methoxycarboxamido (CH.sub.3OCONH--), ethoxycarboxamido,
tert-butoxycarboxamido and the like are used.
[0093] As "C.sub.6-10 aryloxy-carboxamido", for example,
phenoxycarboxamido (C.sub.6H.sub.5OCONH--) and the like are
used.
[0094] As "C.sub.7-19 aralkyloxy-carboxamido", for example,
benzyloxycarboxamido (C.sub.6H.sub.5CH.sub.2OCONH--),
benzhydryloxycarboxamido and the like are used.
[0095] As "C.sub.1-10 alkoxy-carbonyloxy", for example,
methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy,
isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy,
n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy and the like are
used.
[0096] As "C.sub.6-10 aryloxy-carbonyloxy", for example,
phenoxycarbonyloxy, naphthyloxycarbonyloxy and the like are
used.
[0097] As "C.sub.7-19 aralkyloxy-carbonyloxy", for example,
benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy,
2-phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy and the like
are used.
[0098] As "C.sub.3-10 cycloalkyloxy-carbonyloxy", for example,
cyclopropyloxycarbonyloxy, cyclohexyloxycarbonyloxy and the like
are used.
[0099] As "ureido optionally having substituent(s)", for example,
ureido optionally substituted by 1 to 3 (particularly 1 or 2)
substituents selected from
[0100] (i) C.sub.1-4 alkyl (e.g., methyl, ethyl),
[0101] (ii) phenyl, and the like is used and, for example, ureido,
1-methylureido, 3-methylureido, 3,3-dimethylureido,
1,3-dimethylureido, 3-phenylureido and the like are used. When two
or more substituents are present, they may be the same or
different.
[0102] When a heterocyclic group, heterocyclyloxy,
heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl or
heterocyclyloxycarbonyl is used as the "substituent" of the
"aliphatic hydrocarbon group optionally having substituent(s)", the
heterocyclic group is a group obtained by removing one hydrogen
atom bonded to the heterocycle, which is, for example, a 5- to
8-membered ring (particularly 5- or 6-membered ring) group
containing 1 to several, preferably 1 to 4, hetero atoms such as a
nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom
and the like, or a fused ring group thereof. As such heterocyclic
group, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, pyranyl,
thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl,
1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl,
thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl,
tetrahydropyranyl, dioxolanyl, dioxanyl and the like are used.
[0103] These heterocyclic groups may be substituted at
substitutable positions by 1 to 3 substituents selected from
(i) a C.sub.1-4 alkyl (e.g., methyl, ethyl), (ii) a hydroxy, (iii)
an oxo, (iv) a C.sub.1-4 alkoxy (e.g., methoxy, ethoxy, etc.), and
the like. When two or more substituents are present, they may be
the same or different.
[0104] As "C.sub.6-10 aryl" of the "C.sub.6-10 aryl optionally
having substituent(s)", for example, phenyl, naphthyl, etc. can be
used. The C.sub.6-10 aryl may be substituted at a substitutable
position by a substituent selected from those exemplified as the
"substituent" (except for C.sub.6-10 aryl optionally having
substituent(s)) of the "aliphatic hydrocarbon group optionally
having substituent(s)" described above. Such substituent is not
limited to a single substituent, but the same or different, more
than one (preferably 2 to 4) substituents may be used.
[0105] In the "aliphatic hydrocarbon group optionally having
substituent(s)", the substituent may form, together with the
aliphatic hydrocarbon group, an optionally substituted fused ring
group, and as such fused ring group, indanyl,
1,2,3,4-tetrahydronaphthyl, etc. can be used. This fused ring group
may be substituted at a substitutable position by a substituent
selected from those exemplified as the "substituent" of the
"aliphatic hydrocarbon group optionally having substituent(s)"
described above. Such substituent substitutes at a substitutable
position of the fused ring group, wherein the substituent is not
limited to a single substituent, but the same or different, more
than one (preferably 2 to 4) substituents may be used.
[0106] Among the above-mentioned "aliphatic hydrocarbon groups
optionally having substituent(s)", preferable examples of R,
R.sup.1, R.sup.11, R.sup.1b and R.sup.1c include lower alkyl having
a carbon number of 1 to 6 which may have substituent(s) (e.g.,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butoxycarbonylmethyl, hydroxyethyl, phenylmethyl,
carboxymethyl) and the like. Particularly, for example, C.sub.1-6
alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl
and the like are preferable, methyl, ethyl, n-propyl and the like
are more preferable, and ethyl and the like are particularly
preferable.
[0107] As the "aromatic hydrocarbon group" of the "aromatic
hydrocarbon group optionally having substituent(s)" for R, an
aromatic hydrocarbon group having a carbon number of 6 to 14 (e.g.,
phenyl, naphthyl, anthryl, indenyl) and the like are preferable. In
particular, for example, aryl having a carbon number of 6 to 10
(e.g., phenyl, naphthyl) and the like are preferable, and of these,
phenyl and the like are particularly preferable.
[0108] As the "substituent" of the "aromatic hydrocarbon group
optionally having substituent(s)" for R,
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom), (2) lower (C.sub.1-4) alkyl (e.g.,
methyl, ethyl, propyl, butyl), (3) lower (C.sub.1-4) alkoxy (e.g.,
methoxy, ethoxy, propoxy, butoxy), (4) lower (C.sub.1-4)
alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl), (5) carboxy, (6) nitro, (7)
cyano, (8) hydroxy, (9) acylamino (e.g., alkanoylamino having a
carbon number of 1 to 4 such as acetylamino, propionylamino,
butyrylamino and the like), (10) cycloalkyl having a carbon number
of 3 to 6 (e.g., cyclopropyl, cyclopentyl), (11) aryl having a
carbon number of 6 to 10 (e.g., phenyl, naphthyl, indenyl), (12)
halogeno lower (C.sub.1-4) alkyl (e.g., trifluoromethyl,
trifluoroethyl), (13) halogeno lower (C.sub.1-4) alkoxy (e.g.,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,
2,2,3,3,3-pentafluoropropoxy), (14) lower (C.sub.1-4) alkylthio
(e.g., methylthio, ethylthio, propylthio), (15) lower (C.sub.1-4)
alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl,
propanesulfonyl), (16) lower (C.sub.1-4) alkanoyl (e.g., formyl,
acetyl, propionyl), (17) a 5-membered aromatic heterocyclic group
(e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl, furyl),
(18) carbamoyl, lower (C.sub.1-4) alkyl-carbamoyl (e.g.,
methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl), (19) lower
(C.sub.1-4) alkoxy-carbonyl-lower (C.sub.1-4) alkyl-carbamoyl
(e.g., butoxycarbonylmethylcarbamoyl,
ethoxycarbonylmethylcarbamoyl), (20) 1,3-diacylguanidino-lower
(C.sub.1-4) alkyl (e.g., 1,3-diacetylguanidinomethyl,
1,3-bis-(tert-butoxycarbonyl)guanidinomethyl) and the like are
used. Preferably, a halogen atom (e.g., a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom), lower (C.sub.1-4) alkyl
(e.g., methyl, ethyl, propyl, butyl) and the like are used. More
preferably, a fluorine atom, a chlorine atom and methyl are
used.
[0109] These substituents substitute at substitutable positions of
the aromatic hydrocarbon group, and the number of the substituents
is preferably 1 to 5, more preferably 1 to 3, most preferably 1 or
2. When two or more of such substituents are present, they may be
the same or different.
[0110] The "heterocyclic group" of the "heterocyclic group
optionally having substituent(s)" for R is, for example, a 5 to
8-membered ring (particularly a 5 or 6-membered ring) group
containing 1 to several, preferably 1 to 4, hetero atoms such as
nitrogen atom (optionally oxidized), oxygen atom, sulfur atom and
the like, and a fused ring group thereof. As such heterocyclic
group, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, pyranyl,
thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl,
1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl,
thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl,
tetrahydropyranyl, dioxolanyl, dioxanyl and the like are used.
[0111] These heterocyclic groups are optionally substituted by 1 to
3 substituents selected from C.sub.1-4 alkyl (e.g., methyl, ethyl),
hydroxy, oxo, C.sub.1-4 alkoxy (e.g., methoxy, ethoxy) and the like
at substitutable positions. When two or more substituents are
present, they may be the same or different.
[0112] Preferable examples of the above-mentioned "aliphatic
hydrocarbon group" for R.sup.0 or R.sup.2 include lower alkyl
having a carbon number of 1 to 6 (e.g., methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl,
hydroxyethyl) and the like. Of these, for example, C.sub.1-6 alkyl
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
the like is preferable. For example, methyl, ethyl, n-propyl and
the like are more preferable, and methyl and the like are
particularly preferable.
[0113] As R.sup.0 or R.sup.2, in particular, a hydrogen atom and
methyl are preferable.
[0114] As the "aromatic hydrocarbon group" of the "aromatic
hydrocarbon group optionally having substituent(s)" for Ar, an
aromatic hydrocarbon group having a carbon number of 6 to 14 (e.g.,
phenyl, naphthyl, anthryl, indenyl) and the like are preferable. In
particular, for example, aryl having a carbon number of 6 to 10
(e.g., phenyl, naphthyl) and the like are preferable. Of these,
phenyl and the like are particularly preferable.
[0115] As the "substituent" of the "aromatic hydrocarbon group
optionally having substituent(s)" for Ar,
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom), (2) lower (C.sub.1-4) alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, butyl), (3) lower (C.sub.1-4)
alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), (4) lower
(C.sub.1-4) alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl), (5) carboxy, (6) nitro, (7)
cyano, (8) hydroxy, (9) acylamino (e.g., alkanoylamino having a
carbon number of 1 to 4 such as acetylamino, propionylamino,
butyrylamino and the like), (10) cycloalkyl having a carbon number
of 3 to 6 (e.g., cyclopropyl, cyclopentyl), (11) aryl having a
carbon number of 6-10 (e.g., phenyl, naphthyl, indenyl), (12)
halogeno lower (C.sub.1-4) alkyl (e.g., trifluoromethyl,
trifluoroethyl), (13) halogeno lower (C.sub.1-4) alkoxy (e.g.,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,
2,2,3,3,3-pentafluoropropoxy), (14) lower (C.sub.1-4) alkylthio
(e.g., methylthio, ethylthio, propylthio), (15) lower (C.sub.1-4)
alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl,
propanesulfonyl), (16) lower (C.sub.1-4) alkanoyl (e.g., formyl,
acetyl, propionyl), (17) a 5-membered aromatic heterocyclic group
(e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl, furyl),
(18) carbamoyl, (19) lower (C.sub.1-4) alkyl-carbamoyl (e.g.,
methylcarbamoyl, dimethylcarbamoyl, propionylcarbamoyl), (20) lower
(C.sub.1-4) alkoxy-carbonyl-lower (C.sub.1-4) alkyl-carbamoyl
(e.g., butoxycarbonylmethylcarbamoyl,
tert-butoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl),
(21) 1,3-diacylguanidino-lower (C.sub.1-4) alkyl (e.g.,
1,3-diacetylguanidinomethyl,
1,3-bis-(tert-butoxycarbonyl)guanidinomethyl) and the like are
used. Preferably, a halogen atom (e.g., a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom), lower (C.sub.1-4) alkyl
(e.g., methyl, ethyl, propyl, butyl) and the like are used. More
preferably, a fluorine atom, a chlorine atom and methyl are
used.
[0116] These substituents substitute at substitutable positions of
the aromatic hydrocarbon group, and the number of the substituents
is preferably 1 to 5, more preferably 1 to 3, most preferably 1 or
2. When two or more of such substituents are present, they may be
the same or different.
[0117] As Ar, specifically for example, phenyl, halogenophenyl,
lower (C.sub.1-4) alkylphenyl, lower (C.sub.1-4) alkoxyphenyl,
lower (C.sub.1-4) alkoxy-carbonylphenyl, carboxyphenyl,
nitrophenyl, cyanophenyl, halogeno lower (C.sub.1-4) alkylphenyl,
halogeno lower (C.sub.1-4) alkoxyphenyl, lower (C.sub.1-4)
alkanoylphenyl, phenyl substituted by a 5-membered aromatic
heterocyclic group, lower (C.sub.1-4) alkoxy-carbonyl-lower
(C.sub.1-4) alkyl-carbamoylphenyl, 1,3-diacylguanidino-lower
(C.sub.1-4) alkylphenyl, phenyl substituted by a halogen atom and
lower (C.sub.1-4) alkyl, phenyl substituted by a halogen atom and
lower (C.sub.1-4) alkoxy-carbonyl, phenyl substituted by a halogen
atom and cyano, phenyl substituted by a halogen atom and 5-membered
aromatic heterocycle, phenyl substituted by a halogen atom and
lower (C.sub.1-4) alkoxy-carbonyl-lower (C.sub.1-4) alkyl-carbamoyl
and the like are used.
[0118] As Ar, phenyl optionally having substituent(s) is
preferable. Particularly, halogenophenyl, lower (C.sub.1-4)
alkylphenyl, phenyl substituted by a halogen atom and lower
(C.sub.1-4) alkoxycarbonyl, phenyl substituted by a halogen atom
and lower (C.sub.1-4) alkyl and the like are preferably used.
[0119] As Ar, a group represented by the formula:
##STR00030##
wherein R.sup.4 and R.sup.5 are the same or different and each is a
halogen atom or lower (C.sub.1-4) alkyl, and n is an integer of 0
to 2, is more preferable, and one wherein at least one of R.sup.4
and R.sup.5 is a halogen atom is further preferable.
[0120] As the halogen atom for R.sup.4 or R.sup.5, a fluorine atom
or a chlorine atom is preferable.
[0121] As halogenophenyl, for example, 2,3-difluorophenyl,
2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,
2,5-difluorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl,
2,6-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,
3,5-difluorophenyl, 3,5-dichlorophenyl, 2-fluorophenyl,
2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl,
4-chlorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl,
4-bromo-2-fluorophenyl, 2,3,4-trifluorophenyl,
2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl and the like are
used.
[0122] As lower (C.sub.1-4) alkylphenyl, for example,
2-ethylphenyl, 2,6-diisopropylphenyl and the like are preferably
used. As lower (C.sub.1-4) alkoxyphenyl, for example
4-methoxyphenyl and the like are preferably used.
[0123] As lower (C.sub.1-4) alkoxy-carbonylphenyl, for example,
2-ethoxycarbonylphenyl, 2-methoxycarbonylphenyl,
4-methoxycarbonylphenyl and the like are preferably used. As
halogeno lower (C.sub.1-4) alkylphenyl, for example,
2-trifluoromethylphenyl and the like are preferably used. As
halogeno lower (C.sub.1-4) alkoxyphenyl, for example,
2-trifluoromethoxyphenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl
and the like are preferably used.
[0124] As lower (C.sub.1-4) alkanoylphenyl, for example,
2-acetylphenyl and the like are preferably used. As phenyl
substituted by a 5-membered aromatic heterocyclic group, for
example, 4-(2H-1,2,3-triazol-2-yl)phenyl,
4-(2H-tetrazol-2-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl,
4-(1H-1,2,3-triazol-1-yl)phenyl and the like are preferably used.
As lower (C.sub.1-4) alkoxy-carbonyl-lower (C.sub.1-4)
alkyl-carbamoylphenyl, for example,
4-(N-ethoxycarbonylmethylcarbamoyl)phenyl and the like are
preferably used. As 1,3-diacylguanidino-lower (C.sub.1-4)
alkylphenyl, for example,
4-(1,3-bis-tert-butoxycarbonylguanidinomethyl)phenyl and the like
are preferably used.
[0125] As phenyl substituted by a halogen atom and lower
(C.sub.1-4) alkyl, for example, 2-fluoro-4-methylphenyl,
2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl and the like are
preferably used. As phenyl substituted by a halogen atom and lower
(C.sub.1-4) alkoxy-carbonyl, for example,
2-chloro-4-methoxycarbonylphenyl and the like are preferably used.
As phenyl substituted by a halogen atom and cyano,
2-chloro-4-cyanophenyl and the like are preferably used. As phenyl
substituted by a halogen atom and 5-membered aromatic heterocyclic
group, for example, 2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl and
the like are preferably used. As phenyl substituted by a halogen
atom and lower (C.sub.1-4) alkoxy-carbonyl-lower (C.sub.1-4)
alkyl-carbamoyl, for example,
2-chloro-4-(N-tert-butoxycarbonylmethylcarbamoyl)phenyl,
2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl and the like are
preferably used.
[0126] More specifically, as Ar in particular, phenyl, phenyl
substituted by 1 to 3 (particularly 1 or 2) halogen atoms (when
substituted by plural halogen atoms, these halogen atoms may be the
same or different; e.g., 2,3-difluorophenyl, 2,3-dichlorophenyl,
2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl,
2,5-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl,
3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl,
3,5-dichlorophenyl, 4-bromo-2-fluorophenyl, 2-fluorophenyl,
2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl,
4-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl,
2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl), phenyl substituted
by a halogen atom and lower (C.sub.1-4) alkyl (e.g.,
2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl) and the like are
preferable. Of these, phenyl substituted by 1 to 3 (particularly 1
or 2) halogen atoms (when substituted by plural halogen atoms,
these halogen atoms may be the same or different; e.g.,
2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,
2,6-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,
2-chloro-4-fluorophenyl, 2,4,5-trifluorophenyl), phenyl substituted
by a halogen atom and lower (C.sub.1-4) alkyl (e.g.,
2-chloro-4-methylphenyl, 4-fluoro-2-methylphenyl) and the like are
preferable. Particularly, 2,4-difluorophenyl, 2-chlorophenyl,
2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl and the like are
preferable, and 2,4-difluorophenyl, 2-chloro-4-fluorophenyl and the
like are preferable.
[0127] In the present specification, ring A.sup.1 is preferably
cycloalkene optionally substituted by 1 to 4 substituents selected
from
(i) an aliphatic hydrocarbon group optionally having
substituent(s), (ii) an aromatic hydrocarbon group optionally
having substituent(s), (iii) a group represented by the formula:
--OR.sup.11 wherein R.sup.11 is a hydrogen atom or an aliphatic
hydrocarbon group optionally having substituent(s), and (iv)
halogen atoms. Of these, cycloalkene optionally substituted by 1 to
4 substituents selected from (i) an aliphatic hydrocarbon group
optionally having substituent(s), (ii) an aromatic hydrocarbon
group optionally having substituent(s), and (iv) halogen atoms are
preferable.
[0128] These substituents (i) to (iv) substitute on substitutable
carbon atoms in the ring A.sup.1, and when the ring A.sup.1 is
substituted by two or more of such substituents, the substituents
may be the same or different. A single carbon atom may be
substituted by two substituents, and different carbon atoms may be
substituted by two or more substituents.
[0129] As the "aliphatic hydrocarbon group optionally having
substituent(s)" as the substituent on the ring A.sup.1, for
example, those similar to the "aliphatic hydrocarbon group
optionally having substituent(s)" for R and the like described
above may be used.
[0130] As the "aromatic hydrocarbon group optionally having
substituent(s)" as the substituent on the ring A.sup.1, for
example, those similar to the "aromatic hydrocarbon group
optionally having substituent(s)" for Ar described above may be
used.
[0131] As the substituents for the ring A.sup.1, 1 or 2 C.sub.1-6
alkyl groups (e.g., methyl, tert-butyl), phenyl, a halogen atom
(e.g., fluorine, chlorine, bromine, iodine atoms), etc. are
preferably used. When two substituents are present, they may be the
same or different.
[0132] As the integer of 1 to 4 for n, 1 to 3 is preferable, and 2
is particularly preferable.
[0133] As the compound represented by the formula (I), the compound
represented by the formula (Ibb') is preferable, and the compound
represented by the formula (Inn) is more preferable.
[0134] Furthermore, preferred as a compound represented by the
formula (Ibb') or the formula (Inn) is that wherein R.sup.1 is
lower alkyl optionally having substituent(s) (more preferably
R.sup.1 is C.sub.1-6 alkyl), R.sup.2 is a hydrogen atom or lower
(C.sub.1-6) alkyl, Ar is phenyl optionally having substituent(s)
(more preferably Ar is phenyl substituted by 1 or 2 halogen atoms),
and n is 1, 2 or 3 (more preferably n is 2).
[0135] A group represented by the formula:
##STR00031##
is a group represented by the formula:
##STR00032##
[0136] As the compound represented by the formula (I), for example,
the following compounds and the like are preferable.
(1) A compound represented by the formula (Ia):
##STR00033##
wherein R.sup.1a is C.sub.1-6 alkyl, R.sup.2a is a hydrogen atom or
C.sub.1-6 alkyl, Ara is phenyl substituted by 1 or 2 halogen atoms.
(2) compounds (1)-(85) described in Reference Example A mentioned
below. (3) the following compounds: [0137] d-ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 20), [0138] ethyl
6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 28), [0139] ethyl
6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 45), and [0140] ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 72).
[0141] The compound represented by the formula (II) is
explained.
##STR00034##
[0142] As the "aliphatic hydrocarbon group optionally having
substituent(s)", "aromatic hydrocarbon group optionally having
substituent(s)" and "heterocyclic group optionally having
substituent(s)" for R.sup.1', those similar to these substituents
for R can be used.
[0143] As the "aliphatic hydrocarbon group optionally having
substituent(s)" for R.sup.1b' and R.sup.1c', for example, those
similar to the aforementioned "aliphatic hydrocarbon group
optionally having substituent(s)" for R can be used. As R.sup.1b'
and R.sup.1c', for example, lower alkyl having 1 to 6 carbon atoms
optionally having substituent(s) (e.g., methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl,
hydroxyethyl) and the like are preferably used. Of these, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
the like are preferably used. Particularly, for example, methyl,
ethyl, n-propyl and the like are preferable, and ethyl and the like
are specifically preferable.
[0144] As R.sup.1', a group represented by the formula:
--OR.sup.1a' wherein R.sup.1' is as defined above is preferable. As
the "aliphatic hydrocarbon group optionally having substituent(s)"
for R.sup.1a', for example, those similar to the "aliphatic
hydrocarbon group optionally having substituent(s)" for the
aforementioned R can be used. Lower alkyl having a carbon number of
1 to 6 which may have substituent(s) (e.g., methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butoxycarbonylmethyl,
hydroxyethyl) and the like are preferably used. Of these, for
example, C.sub.1-6 alkyl such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl and the like are preferably used. In
particular, for example, methyl, ethyl, n-propyl and the like are
preferable, and ethyl and the like are preferable.
[0145] As the "substituent" of the "methylene optionally having
substituent(s)" for Y, for example, one or the same or different
two substituents selected from
(1) C.sub.1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl), (2) hydroxyl substituted-C.sub.1-6 alkyl (e.g.,
hydroxymethyl, hydroxyethyl), (3) C.sub.1-4
alkoxy-carbonyl-C.sub.1-4 alkyl (e.g., methoxycarbonylmethyl,
ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,
methoxycarbonylethyl, ethoxycarbonylethyl,
tert-butoxycarbonylethyl) and the like are used, and of these,
methyl is preferable. As Y, unsubstituted methylene is particularly
preferable.
[0146] As the "substituent" of the "NH optionally having
substituent(s)" for Y,
(1) C.sub.1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl), (2) hydroxyl substituted-C.sub.1-6 alkyl (e.g.,
hydroxymethyl, hydroxyethyl), (3) C.sub.1-4
alkoxy-carbonyl-C.sub.1-4 alkyl (e.g., methoxycarbonylmethyl,
ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,
methoxycarbonylethyl, ethoxycarbonylethyl,
tert-butoxycarbonylethyl) and the like are used, and of these,
methyl is preferable. As Y, unsubstituted NH is particularly
preferable.
[0147] In the "aromatic hydrocarbon group optionally having
substituent(s)" for Ar', those similar to the aforementioned
"aromatic hydrocarbon group optionally having substituent(s)" for
Ar can be used.
[0148] Particularly, as Ar', those similar to Ar are preferable.
Among others, a group represented by the formula (c):
##STR00035##
wherein R.sup.3' is a halogen atom or a lower alkyl group, and ring
B' is optionally further substituted by 1 or 2 halogen atoms is
preferable, and a group represented by the formula (c1):
##STR00036##
wherein R.sup.3a' and R.sup.3b' are the same or different and each
is a halogen atom is more preferable.
[0149] In the formula (c), a halogen atom for R.sup.3 and a halogen
atom which is a substituent of ring B' and a halogen atom for
R.sup.3a' and R.sup.3b' in the formula (c1), a fluorine atom or a
chlorine atom is preferable. As the lower alkyl for R.sup.3' in the
formula (c), for example, C.sub.1-4 alkyl such as methyl, ethyl,
propyl and the like can be mentioned. Among the groups represented
by the formula (c), 2,4-difluorophenyl, 2-chloro-4-fluorophenyl,
2-methyl-4-chlorophenyl and the like are preferable. Among the
groups represented by the formula (c1), 2,4-difluorophenyl,
2-chloro-4-fluorophenyl and the like are preferable.
[0150] X is methylene, NH, a sulfur atom or an oxygen atom, and
methylene or an oxygen atom is particularly preferable.
[0151] Ring A' is a 5- to 8-membered ring substituted by a group
represented by the formula: --CO--R.sup.1' wherein R.sup.1' is as
defined above and a group represented by the formula:
--SO.sub.2--Y--Ar' wherein Y and Ar' are as defined above, and
optionally further substituted by 1 to 4 substituents selected from
the group consisting of
(i) an aliphatic hydrocarbon group optionally having
substituent(s), (ii) an aromatic hydrocarbon group optionally
having substituent(s), (iii) a group represented by the formula:
--OR.sup.2' wherein R.sup.2' is as defined above and (iv) a halogen
atom. Of these, a 5- to 8-membered ring optionally substituted by 1
to 4 substituents selected from (i) an aliphatic hydrocarbon group
optionally having substituent(s), (ii) an aromatic hydrocarbon
group optionally having substituent(s) and (iv) a halogen atom are
preferable.
[0152] These substituents are present at substitutable positions on
the ring A'. When X constituting the ring is NH or methylene, they
can substitute the NH and methylene. When ring A' is substituted by
plural substituents, the kinds of such substituents may be the same
or different. In addition, two substituents may substitute on the
same carbon atom.
[0153] As the "aliphatic hydrocarbon group optionally having
substituent(s)" and "aromatic hydrocarbon group optionally having
substituent(s)", which are substituents of ring A', for example,
those similar to the aforementioned group for R can be
mentioned.
[0154] As the "aliphatic hydrocarbon group optionally having
substituent(s)" for R.sup.2', for example, those similar to the
aforementioned groups for R can be mentioned.
[0155] As the substituent for ring A', 1 or 2 C.sub.1-6 alkyl
(e.g., methyl, tert-butyl), phenyl, halogen atoms (e.g., fluorine,
chlorine, bromine, iodine) and the like are preferably used. When
two substituents are present, they may be the same or
different.
[0156] The "s" is an integer of 0 to 2, "t" is an integer of 1 to
3, and the total of "s" and "t" is 4 or less, with preference given
to "s" being 1 and "t" being 1.
[0157] A group represented by the formula:
##STR00037##
is a group represented by the formula:
##STR00038##
[0158] As the compound represented by the formula (II), for
example, the following compounds and the like are preferable. (1)
Compound (II) wherein
R.sup.1' is a group represented by the formula: --OR.sup.1a'
wherein R.sup.1a' is C.sub.1-6 alkyl, a group represented by the
formula:
##STR00039##
is a group represented by the formula:
##STR00040##
X is methylene or an oxygen atom, Y is methylene or --NH--, and Ar'
is phenyl optionally having 1 or 2 substituents selected from a
halogen atom and C.sub.1-4 alkoxy, that is, a compound represented
by the formula (IIa):
##STR00041##
wherein R.sup.1a'' is C.sub.1-6 alkyl, X.sup.a is methylene or an
oxygen atom, Y.sup.a is methylene or --NH--, Ar.sup.a' is phenyl
optionally having 1 or 2 substituents selected from a halogen atom
and C.sub.1-4 alkoxy, provided when X.sup.a is methylene, then
Y.sup.a is methylene optionally having substituent(s). (2) Compound
(II) wherein R.sup.1' is a group represented by the formula:
--OR.sup.1a' (R.sup.1a' is C.sub.1-6 alkyl), a group represented by
the formula:
##STR00042##
is a group represented by the formula:
##STR00043##
X and Y are both methylene, or X is an oxygen atom and Y is --NH--,
and Ar' is phenyl optionally having two halogen atoms (e.g.,
2-chloro-4-fluorophenyl). (3) Compounds (1')-(10') described in
Reference Example B mentioned below. (4) The following compounds:
[0159] ethyl
6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
(compound 4'), [0160] ethyl
(+)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
(compound 6'), [0161] ethyl
3-[(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate
(compound 8'), and [0162] ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9').
[0163] A compound represented by the formula (III) is
explained.
##STR00044##
[0164] R.sup.1aa is C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,
2-ethylbutyl etc.). Of these, ethyl is preferable.
[0165] X.sup.aa is methylene or an oxygen atom.
[0166] Ar.sup.aa is phenyl optionally having 1 or 2 substituents
selected from a halogen atom (e.g., fluorine atom, chlorine atom,
bromine atom, iodine atom etc.), C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,
2-ethylbutyl etc.) and C.sub.1-6 alkoxy (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
pentoxy, isopentoxy, hexoxy etc.). As Ar.sup.aa, phenyl optionally
having 1 or 2 substituents selected from a halogen atom
(particularly, a fluorine atom, a chlorine atom) and C.sub.1-6
alkyl (particularly, methyl, ethyl, isopropyl) is preferable. When
two substituents are present, they may be the same or
different.
[0167] As a compound represented by the formula (III), for example,
the following compounds and the like are preferable.
(1) A compound wherein R.sup.1aa is ethyl, X.sup.aa is methylene or
an oxygen atom, Ar.sup.aa is phenyl optionally having 1 or 2
substituents selected from a halogen atom (particularly, a fluorine
atom, a chlorine atom) and C.sub.1-6 alkyl (particularly, methyl,
ethyl, isopropyl). (2) Compounds 1, 3, 4, 6, 7, 10-17, 19, 20,
27-30, 34, 35, 37-39, 41, 45-47 and 71-74 of Reference Example A
and compounds 7'-9' of Reference Example B. (3) The following
compounds: [0168] d-ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 20), [0169] ethyl
6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 28), [0170] ethyl
6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 45), [0171] ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 72), [0172] ethyl
3-[(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate
(compound 8'), [0173] ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9'). (4) The following compounds: [0174] ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 72), and [0175] ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9'). (5) The following compound: [0176] ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 72). (6) The following compound: [0177] ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9').
[0178] When the compounds represented by the formulas (I), (II) and
(III) have stereoisomers, each stereoisomer and a mixture of these
stereoisomers are both encompassed in the present invention.
[0179] Furthermore, when the compound represented by the formula
(I) is a compound represented by the formula (Icc) or (Inn), and
the formula (b) of the compound represented by the formula (II) is
the formula (b1), s and t are 1 and the compound represented by the
formula (III), each has an optical isomer based on the asymmetric
carbon in cycloalkene or cyclohexene ring. Such optical isomer and
a mixture of such optical isomers are both encompassed in the
present invention.
[0180] The compounds represented by the formulas (I), (II) and
(III) may be converted into a salt with an inorganic base, organic
base, inorganic acid, organic acid, basic or acidic amino acid, and
the like. As the salt with an inorganic base, for example, an
alkali metal salt such as sodium and potassium salts, etc.; an
alkaline earth metal salt such as calcium and magnesium salts,
etc.; aluminum salt; ammonium salt; and the like are used. As the
salt with an organic base, for example, a salt with trimethylamine,
triethylamine, pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine,
etc can be used. As the salt with an inorganic acid, for example, a
salt with hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid, etc can be used. As the salt with
an organic acid, for example, a salt with formic acid, acetic acid,
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,
maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
and the like can be used. As the salt with a basic amino acid, for
example, a salt with arginine, lysine, ornithine, etc can be used.
As the salt with acidic amino acid, for example, a salt with
aspartic acid, glutamic acid, and the like can be used.
[0181] A prodrug of the compound represented by the formula (I),
(II) or (III) or a salt thereof is a compound which is converted
into a parent compound (that is, the compound represented by the
formula (I), (II) or (III)) as a result of a reaction with an
enzyme, gastric acid etc. under physiological conditions in vivo.
Thus, the compound is converted into a parent compound by
enzymatical oxidation, reduction, hydrolysis etc., by hydrolysis
due to gastric acid etc. A prodrug of a parent compound may be a
compound obtained by subjecting an amino group of a parent compound
to an acylation, alkylation or phosphorylation (e.g., a compound
obtained by subjecting an amino group of a parent compound to an
eicosanoylation, alanylation, pentylaminocarbonylation,
2-hydroxypropionylation, 2-acetoxypropionylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation, tert-butylation, etc.); a compound obtained
by subjecting a hydroxy group of a parent compound to an acylation,
alkylation, phosphorylation or boration (e.g., a compound obtained
by subjecting a hydroxy group of a parent compound to an
acetylation, palmitoylation, propanoylation, pivaloylation,
succinylation, fumarylation, alanylation,
dimethylaminomethylcarbonylation, etc.); a compound obtained by
subjecting a carboxyl group of a parent compound to an
esterification or amidation (e.g., a compound obtained by
subjecting a carboxyl group of a parent compound to an
ethyl-esterification, phenyl-esterification,
carboxymethyl-esterification, dimethylaminomethyl-esterification,
pivaloyloxymethyl-esterification,
ethoxycarbonyloxyethyl-esterification, phthalidyl-esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterification,
cyclohexyloxycarbonylethyl-esterification and methylamidation,
etc.) and the like. Any of these compounds can be produced from a
parent compound by a method known per se.
[0182] A prodrug of the compound represented by the formula (I),
(II) or (III) may also be one which is converted into a parent
compound (that is, the compound represented by the formula (I),
(II) or (III)) under a physiological condition, such as those
described in "IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198,
Published by HIROKAWA SHOTEN (1990).
[0183] The compound represented by the formula (I), a salt thereof
or a prodrug thereof can be produced according to a method known
per se, for example, a production method described in WO99/46242
and WO02/32859 or a method analogous thereto.
[0184] The compound represented by the formula (II), a salt thereof
or a prodrug thereof can be produced according to a method known
per se, for example, a production method described in WO01/10826 or
a method analogous thereto.
[0185] A compound represented by the formula (III) or a salt
thereof or a prodrug thereof can be produced according to a method
known per se. For example, when X.sup.aa in the formula (III) is
methylene, it can be produced by the production methods described
in WO99/46242 and WO02/32859 or the method analogous thereto, and
when X.sup.aa is an oxygen atom, it can be produced by the
production methods described in WO01/10826, the below-mentioned
Reference Example 1 and Reference Example 2 or a method analogous
thereto.
[0186] When the optically active compound or a salt thereof
contains an enantiomer, general separation means may be applied
such as diastereomeric salt methods wherein a salt with an
optically active acid (e.g., camphor sulfonic acid) or optically
active base (e.g., 1-methylbenzylamine) is formed, inclusion
compound methods using an optically active host molecule (e.g.,
1,6-bis(2-chlorophenyl)-1,6-diphenylhexa-2,4-diyn-1,6-diol),
various chromatographies (e.g., liquid chromatography using an
optically active column), fractional recrystallization and the
like, whereby an optically pure compound can be obtained.
[0187] A compound represented by the formula (I), (II) or (III), or
a salt thereof or a prodrug thereof (hereinafter to be
comprehensively referred to as "compound A") may be any of hydrate,
non-hydrate, solvate and non-solvate.
[0188] In addition, compound A may be labeled with an isotope
(e.g., .sup.3H, .sup.14C, .sup.3S, .sup.125I) and the like.
[0189] Furthermore, compound A may be a deuterated compound wherein
.sup.1H is converted to .sup.2H(D).
[0190] Compound A is useful for suppressing (or mitigating) various
neurological symptoms (e.g., dysesthesia such as numbness, pain
(e.g., muscular pain, neuralgia), anesthesia, ache and the like)
caused by peripheral nerve disorders that may be developed as the
side effects of the administration of chemotherapeutic agents such
as anti-cancer agent and the like.
[0191] Compound A is useful for the suppression (or mitigation) of
numbness from among the above-mentioned neurological symptoms.
[0192] Compound A is also useful for the suppression (or
mitigation) of pain from among the above-mentioned neurological
symptoms.
[0193] Examples of the anti-cancer agent in the present
specification include prophylactic agents and therapeutic agents
for lung cancer (e.g., non-small cell lung cancer, small cell lung
cancer, malignant mesothelioma), mesothelioma, pancreatic cancer
(e.g., pancreatic duct cancer, pancreatic endocrine tumor),
pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric
cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma,
adenosquamous carcinoma), duodenal cancer, small intestinal cancer,
colorectal cancer (e.g., colorectal cancer, rectal cancer, anal
cancer, familial colorectal cancer, hereditary nonpolyposis
colorectal cancer, gastrointestinal stromal tumor), breast cancer
(e.g., invasive ductal carcinoma, ductal carcinoma in situ,
inflammatory breast cancer), ovarian cancer (e.g., ovarian
epithelial carcinoma, extragonadal germ cell tumor, ovarian germ
cell tumor, ovarian low malignant potential tumor), testis tumor,
prostate cancer (e.g., hormone-dependent prostate cancer,
non-hormone dependent prostate cancer), liver cancer (e.g.,
hepatocyte cancer, primary liver cancer, extrahepatic bile duct
cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney
cancer (e.g., renal cell carcinoma, transitional cell carcinoma of
renal pelvis and ureter), uterine cancer (e.g., uterine cervical
cancer, cancer of uterine body, uterus sarcoma), brain tumor (e.g.,
medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma,
diffuse astrocytoma, anaplastic astrocytoma, hypophysial adenoma),
retina blastoma, skin cancer (e.g., basalioma, malignant melanoma),
sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue
sarcoma), malignant bone tumor, urinary bladder cancer, hematologic
cancer (e.g., multiple myeloma, leukemia, malignant lymphoma,
Hodgkin's disease, chronic bone marrow proliferative disease),
cancer of unknown primary and the like, which cause peripheral
nerve disorders as side effects.
[0194] Examples of such anti-cancer agent include taxane
anti-cancer agents (e.g., paclitaxel (taxol), docetaxel), vinca
alkaloid anti-cancer agents (e.g., vincristine, vinblastine),
platinum preparations (e.g., cisplatin, carboplatin, oxaliplatin),
molecular targeted drugs (e.g., bortezomib) and the like.
[0195] Among the above-mentioned anti-cancer agents, paclitaxel,
vincristine, cisplatin, carboplatin and bortezomib are known as the
agents having numbness and/or pain (e.g., muscular pain, neuralgia)
as remarkable side effects (J. Clin Oncol. 24:1633-1642, 2006;
Neurotoxicology, 27:992-1002, 2006; British Journal of Haematology,
127, 165-172, 2004).
[0196] Therefore, compound A is particularly useful for suppressing
(or mitigating) dysesthesia such as numbness and/or pain (e.g.,
muscular pain, neuralgia) and the like caused by paclitaxel,
vincristine, cisplatin, carboplatin and/or bortezomib.
Particularly, compound A is useful for suppressing (or mitigating)
dysesthesia such as numbness and/or pain (e.g., muscular pain,
neuralgia) and the like caused by paclitaxel.
[0197] The dose of the aforementioned anti-cancer agents can be
appropriately determined based on the clinical dose of each of the
agents. As long as compound A can suppress the side effects, a dose
higher than the conventional dose can also be administered.
[0198] In the case of paclitaxel as a representative example, the
dose is administered by drip infusion according to the schedule of
an administration at 60-70 mg/m.sup.2 every 3 weeks, or at 210
mg/m.sup.2 once a week for 3 weeks and one week cessation of the
drug.
[0199] Such preparation can be produced by the method
conventionally used in the technical field of preparations, for
example, the method described in the Japanese Pharmacopoeia and the
like.
[0200] The dose of compound A can be appropriately determined in
consideration of the dose and dosing period of the above-mentioned
anti-cancer agents, age, body weight and symptom of the subject of
administration, dosage form, administration method and the
like.
[0201] Representatively, the dose of compound A is, for example,
generally 0.1-10 mg/kg/day, preferably 0.6-2.4 mg/kg/day, of
compound A in a free form for an adult patient (body weight 60 kg).
This mount is orally or parenterally administered in one to several
portions (e.g., 1-3 portions) a day. It is needless to say that an
amount smaller than the aforementioned dose may be sufficient or an
administration beyond the above level may be necessary, since the
dose changes under various conditions as mentioned above.
[0202] Compound A can be safely administered to mammals (e.g.,
human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey)
orally or parenterally.
[0203] Examples of the dosage form of compound A include oral
preparations such as tablet (including sugar-coated tablet,
film-coated tablet, sublingual tablet, orally disintegrating
tablet), capsule (including soft capsule, microcapsule), granule,
powder, troche, syrup, emulsion, suspension, films (e.g., orally
disintegrable films) and the like; and parenteral agents such as
injection (e.g., subcutaneous injection, intravenous injection,
intramuscular injection, intraperitoneal injection, drip infusion),
external preparation (e.g., dermal preparation, ointment),
suppository (e.g., rectal suppository, vaginal suppository),
pellet, nasal preparations, pulmonary preparation (inhalant), eye
drop and the like. In addition, these preparations may be release
control preparations (e.g., sustained-release microcapsule) such as
immediate-release preparations, sustained-release preparations and
the like. Such preparation can be produced by the method
conventionally used in the technical field of preparations, for
example, the method described in the Japanese Pharmacopoeia and the
like.
[0204] Compound A is used in combination with the aforementioned
anti-cancer agents to suppress (or mitigate) various neurological
symptoms caused by peripheral nerve disorders that may be developed
as the side effects of the administration of the aforementioned
anti-cancer agents.
[0205] In one embodiment, the present invention relates to kit of
parts for suppressing a peripheral nerve disorder induced by an
anti-cancer agent comprising compound A and the anti-cancer
agent.
[0206] In another embodiment, the present invention relates to a
medicament comprising compound A and the anti-cancer agent.
[0207] Here, one or more kinds of the aforementioned anti-cancer
agents may be combined. For example, in the case of paclitaxel, it
may be combined with cisplatin and/or carboplatin and
administered.
[0208] For combined use of compound A and the aforementioned
anti-cancer agents, the timing of the administration of compound A
and an anti-cancer agent is not particularly limited. Compound A
(or a pharmaceutical composition thereof) and an anti-cancer agent
(or a pharmaceutical composition thereof) may be administered to an
administration subject simultaneously or in a staggered manner.
[0209] When one or more kinds of anti-cancer agents are
administered, similarly, each of compound A (or a pharmaceutical
composition thereof) and one or more kinds of anti-cancer agents
(or a pharmaceutical composition thereof) may be administered to an
administration subject simultaneously or in a staggered manner.
[0210] The mode of administration of compound A and an anti-cancer
agent is not particularly limited as long as compound A and an
anti-cancer agent are combined.
[0211] Examples of such administration mode include the
following
(1) administration of a single preparation obtained by
simultaneously processing compound A (or a pharmaceutical
composition thereof) and one or more kinds of anti-cancer agents
(or a pharmaceutical composition thereof) (to be sometimes
abbreviated as "the combination drug of the present invention"),
(2) simultaneous administration of two or more kinds of
preparations of compound A (or a pharmaceutical composition
thereof) and one or more kinds of anti-cancer agents (or a
pharmaceutical composition thereof), which preparations are
separately produced, by the same administration route, (3)
administration of two or more kinds of preparations of compound A
(or a pharmaceutical composition thereof) and one or more kinds of
anti-cancer agents (or a pharmaceutical composition thereof), which
preparations are separately produced, by the same administration
route in a staggered manner, (4) simultaneous administration of two
or more kinds of preparations of compound A (or a pharmaceutical
composition thereof) and one or more kinds of anti-cancer agents
(or a pharmaceutical composition thereof), which preparations are
separately produced, by different administration routes, (5)
administration of two or more kinds of preparations of compound A
(or a pharmaceutical composition thereof) and one or more kinds of
anti-cancer agents (or a pharmaceutical composition thereof), which
preparations are separately produced, by different administration
routes in a staggered manner (e.g., administration in the order of
compound A (or a pharmaceutical composition thereof) and an
anti-cancer agent (or a pharmaceutical composition thereof), or in
the reverse order) and the like.
[0212] The mixing ratio of compound A and the aforementioned
anti-cancer agent in the combination drug of the present invention
can be appropriately determined according to the subject of
administration, administration route, disease and the like.
[0213] For example, the content of compound A in the combination
agent of the present invention differs depending on the form of a
preparation, and is usually from about 0.01 to 99.8% by weight,
preferably from about 0.1 to 50% by weight, further preferably from
about 0.5 to 20% by weight, based on total of the preparation.
[0214] The content of the anti-cancer agent in the combination
agent of the present invention varies depending on the form of the
preparation, and is usually from about 0.01 to 99.8% by weight,
preferably from about 0.1 to 50% by weight, further preferably from
about 0.5 to 20% by weight, based on the total of the
preparation.
[0215] When one or more kinds of anti-cancer agents are
administered, the content of each anti-cancer agent can be
determined within the range of the above-mentioned content. Here,
the mixing rate of the respective anti-cancer agents can be
appropriately determined according to the administration subject,
administration route, disease and the like.
[0216] The content of additives such as carrier in the combination
agent of the present invention differs depending on the form of a
preparation, and is usually from about 1 to 99.98% by weight,
preferably from about 10 to 90% by weight, based on total of the
preparation.
[0217] When compound A and an anti-cancer agent are independently
prepared, the contents thereof may be the same as those mentioned
above.
[0218] When compound A is administered to a human, it can be safely
administered orally or parenterally as it is or in a mixture with
an appropriate pharmacologically acceptable carrier, excipient and
diluent, in a pharmaceutical composition such as an oral
administration formulation (e.g., powder, granule, tablet, capsule
etc.), a parenteral administration formulation (e.g., injection,
external formulation (e.g., nasal administration formulation,
percutaneous administration formulation etc.) and suppository
(e.g., rectal suppository and vaginal suppository etc.).
[0219] Any of these formulations may be produced by any method
known per se which is employed ordinarily for producing a
pharmaceutical formulation. The amount of compound A to be
incorporated into a formulation may vary depending on the dosage
forms, and is preferably about 10 to 95% by weight in an oral
administration formulation described above and about 0.001 to about
95% by weight in a parenteral administration formulation described
above.
[0220] For example, compound A can be prepared into an aqueous
injection together with a solubilizer (e.g., .beta.-cyclodextrins
etc.), a dispersant (e.g., Tween 80 (manufactured by ATLASPOWDER
USA), HCO 60 (manufactured by NIKKO CHEMICALS),
carboxymethylcellulose, sodium arginate etc.), a preservative
(e.g., methyl paraben, propyl paraben, benzyl alcohol,
chlorobutanol etc.), an isotonic agent (e.g., sodium chloride,
glycerine, sorbitol, glucose etc.) and the like according to a
conventional method, or into an oil-based injection by
appropriately dissolving, suspending or emulsifying using a
vegetable oil (e.g., olive oil, sesame oil, peanut oil, cottonseed
oil, corn oil etc.) and propylene glycol and the like.
[0221] An oral administration formulation can be produced by, for
example, compressing compound A together with an excipient (e.g.,
lactose, sucrose, starch etc.), a disintegrant (e.g., starch,
calcium carbonate etc.), a binder (e.g., starch, gum arabic,
carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl
cellulose etc.), a lubricant (e.g., talc, magnesium stearate,
polyethylene glycol 6000 etc.), and the like, followed by, where
necessary, a coating process known per se for the purpose of
masking a taste, forming an enteric coat, or achieving a sustained
release.
[0222] For such coating agent, for example, hydroxypropylmethyl
cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl
cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,
cellulose acetate phthalate, hydroxypropylmethyl cellulose
phthalate, hydroxymethyl cellulose acetate succinate, Eudragit
(manufactured by ROHM, Germany, a copolymer of methacrylic acid and
acrylic acid), a dye (e.g., titanium oxide, colcothar etc.) and the
like may appropriately be used.
[0223] Compound A can also be employed as an external formulation
in the form of a solid or semi-solid or a liquid.
[0224] For example, a solid external formulation may be compound A
as it is or can be produced by mixing compound A with an excipient
(e.g., glycol, mannitol, starch, microcrystalline cellulose etc.),
a thickening agent (e.g., natural gums, cellulose derivatives,
acrylic acid polymers etc.) which is then converted into a powder
composition. A semi-solid external formulation may be produced by a
standard method and preferably used in the form of an aqueous or
oil-based gel or ointment. A liquid external formulation may be
produced by a method employed for producing an injection
formulation or an analogous method in the form of an oil-based or
aqueous suspension.
[0225] The solid, semi-solid or liquid external formulation may be
supplemented also with a pH modifier (e.g., carbonic acid,
phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide
etc.), an antiseptic (e.g., p-oxybenzoate esters, chlorobutanol,
benzalkonium chloride etc.) and the like, as appropriate.
Typically, an ointment usually containing about 0.1 to about 100 mg
of compound A per 1 g a vaseline or a lanolin etc. as a formulation
base, can be used.
[0226] Compound A may be also formulated as an oil or aqueous,
solid or semi-solid or liquid suppository. As an oil base in
preparing suppository, for example, a higher fatty acid glyceride
(e.g., cocoa butter, WITEPSOL (manufactured by DYNAMIT NOBEL)
etc.), a middle fatty acid (e.g., MYGLYOL (manufactured by DYNAMIT
NOBEL) etc.), a vegetable oil (e.g., sesame oil, soybean oil,
cottonseed oil etc.) and the like are used as appropriate. An
aqueous base may be, for example, polyethylene glycol or propylene
glycol, and an aqueous gel base may be, for example, a natural
gums, a cellulose derivative, a vinyl polymer, an acrylic polymer
and the like.
[0227] In the present invention, compound A (particularly, ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(compound 72), and ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9')) may be used as an emulsion composition
(adjusted to pH about 3.7-about 5.5) containing the compound and a
buffer (hereinafter to be abbreviated as emulsion composition
A).
[0228] According to emulsion composition A, compound A can be
effectively used as a component of a composition comprising an
emulsifier.
[0229] Compound A may be in a liquid form or a solid form in an oil
phase, and emulsion composition A is formed as an oil-in-water type
(O/W type) or S/O/W type emulsion composition.
[0230] Emulsion composition A can be produced by, for example,
using emulsifier.
[0231] Emulsion composition A is a composition comprising
dispersion phase particles comprising an oil component, an
emulsifier, and compound A, and water containing buffer wherein
dispersion phase particles are dispersed. The dispersion phase
particles mean a dispersion phase wherein one of two liquids
immiscible in each other is present as fine particles in the
other.
[0232] As the oil component, any pharmaceutically acceptable fats
and oils generally used for the preparation of fat emulsions in the
pharmaceutical technical field can be used. Examples of fats and
oils include vegetable oil, partially hydrogenated vegetable oil,
fats and oils obtained by transesterification reaction (single acid
group glyceride (simple glyceride) or mixed acid group glyceride
(mixed glyceride)), and middle chain fatty acid glycerol ester and
the like.
[0233] The aforementioned fats and oils include fatty acid glycerol
ester having a carbon number of about 6 to 30 (preferably about 6
to 22). Examples of the aforementioned fatty acid include saturated
fatty acid such as caproic acid, caprylic acid, capric acid, lauric
acid, myristic acid, palmitic acid, stearic acid, behenic acid and
the like, unsaturated fatty acid such as palmitoleic acid, oleic
acid, linoleic acid, arachidonic acid, eicosapentanoic acid,
docosahexaenoic acid and the like.
[0234] Among vegetable oils, a preferable oil component contains,
for example, vegetable oil such as soybean oil, cottonseed oil,
rape seed oil, peanut oil, safflower oil, sesame oil, rice bran
oil, corn germ oil, sunflower oil, poppy oil, olive oil and the
like, and the like. Among these vegetable oils, soybean oil and the
like are preferably used.
[0235] As fats and oils, a middle chain fatty acid triglyceride
having a carbon number of about 6 to 14 (preferably about 8 to 12)
can also be used. Preferable middle chain fatty acid glycerol ester
includes, for example, caprylic/capric triglycerides such as
"miglyol 810", "miglyol 812" (both manufactured by Huls, available
from Mitsuba Trading Co., Ltd.) and the like, caprylic acid
triglycerides (glycerol tricaprylic acid ester) such as "Panacete
800" (manufactured by NOF Corporation) and the like, and the
like.
[0236] The amount of the oil component in emulsion composition A to
be used is, for example, about 1 to about 30 wt %, preferably about
2 to about 25 wt %, more preferably about 2.5 to about 22.5 wt %,
of the whole composition.
[0237] As the aforementioned emulsifier, any pharmaceutically
acceptable emulsifier can be used. Particularly, pharmaceutically
acceptable phospholipids and non-ionic surfactants are preferable.
The emulsifier can be used alone or as a mixture of two or more
kinds thereof.
[0238] Phospholipid includes, for example, naturally occurring
phospholipids (e.g., egg-yolk lecithin, soybean lecithin etc.),
hydrogenated products thereof, or synthetically obtained
phospholipids (e.g., phosphatidylcholine,
phosphatidylethanolamines, phosphatidic acid, phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol etc.) and the like.
Among these phospholipids, egg-yolk lecithin, soybean lecithin, and
phosphatidyl choline derived from egg-yolk and soybean are
preferable. A particularly preferable phospholipid is lecithin.
Among synthetic phospholipids, anionic phospholipid is preferable.
As the anionic synthetic phospholipid, anionic synthetic
phospholipids such as dimyristoylphosphatidylglycerol,
dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol,
dioleoylphosphatidylglycerol, oleoylpalmitoylphosphatidylglycerol,
dioctanoylphosphatidic acid, didecanoylphosphatidic acid,
dilauroylphosphatidic acid, dimyristoylphosphatidic acid,
dipalmitoylphosphatidic acid, diheptadecanoylphosphatidic acid,
distearoylphosphatidic acid, dioleoylphosphatidic acid,
arachidonylstearoylphosphatidic acid,
dipalmitoylphosphatidylserine, dioleoylphosphatidylserine,
dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol,
distearoylphosphatidylinositol, dioleoylphosphatidylinositol,
dimyristoylphosphatidylserine, distearoylphosphatidylserine and the
like are specifically used, and dimyristoylphosphatidylglycerol is
particularly preferable.
[0239] These anionic synthetic phospholipids can be chemically
synthesized by a method known per se, or can also be obtained by
purification.
[0240] As the non-ionic surfactant, a polymer surfactant having a
molecular weight of about 800 to 20000, for example,
polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl
ether, polyoxyethylene alkyl aryl ether, hydrogenated castor oil
polyoxyethylene derivative, sorbitan polyoxyethylene derivative,
polyoxyethylene sorbitol derivative, polyoxyethylene alkyl ether
sulfate and the like can be mentioned.
[0241] The emulsifiers of phospholipid and non-ionic surfactants
can be used alone or as a mixture of two or more kinds thereof.
Alternatively, commercially available phospholipids may be
used.
[0242] The total amount of the emulsifier in emulsion composition A
to be used is generally about 0.1 to about 10% (W/V), preferably
about 0.2 to about 7% (W/V), more preferably about 0.5 to about 5%
(W/V), relative to the whole composition. The anionic synthetic
phospholipid is in a proportion of about 0.0001 to about 5% (W/V)
relative to the whole composition.
[0243] In emulsion composition A, the proportion of the emulsifier
relative to the oil component is, for example, about 0.1 to about
150 wt %, preferably about 0.5 to about 125 wt %, more preferably
about 1 to about 100 wt %. The emulsifier is often used in a
proportion of generally about 1 to about 15 wt %, particularly
about 1 to about 10 wt %, relative to the oil component.
[0244] Water to be used in emulsion composition A is not
particularly limited as long as it is acceptable as a
pharmaceutical product and, for example, purified water, water for
injection (distilled water for injection) and the like can be
mentioned. For production of a product other than pharmaceutical
products, water is not particularly limited.
[0245] The amount of water in emulsion composition A to be used is
generally about 40 to about 99% (W/V), preferably about 55 to about
98.8% (W/V), relative to the whole composition.
[0246] Emulsion composition A can be prepared by mixing a
dispersion phase component comprising compound A (main drug), an
oil component and an emulsifier with water and emulsifying the
mixture and a buffer may be added to an aqueous phase before
emulsification, or may be added to the emulsion composition after
emulsification. Where necessary, additives such as a stabilizer to
improve the stability of the aforementioned main drug, an
isotonicity agent to control the osmotic pressure, an emulsion aid
to improve the emulsifying power, an emulsion stabilizer to improve
stability of emulsifier and the like may be added.
[0247] Examples of the stabilizer include antioxidants (e.g.,
ascorbic acid, tocopherol, sorbic acid, retinol etc.), chelating
agents (e.g., edetic acid, citric acid, tartaric acid etc., and
salts thereof) and the like. The amount of the stabilizer to be
used is generally about 0.00001 to about 10% (W/V), preferably
about 0.0001 to about 5% (W/V), relative to the whole emulsion
composition A.
[0248] An isotonicity agent contains, for example, glycerol, sugar
alcohol, monosaccharides, disaccharides, amino acid, dextran,
albumin and the like. These isotonicity agents can be used alone or
in a mixture of two or more kinds thereof.
[0249] Examples of the emulsion aid include fatty acid having a
carbon number of about 6 to 30, salts of such fatty acid,
monoglycerides of the aforementioned fatty acid and the like. The
aforementioned fatty acid includes, for example, caproic acid,
capric acid, caprylic acid, lauric acid, myristic acid, palmitic
acid, stearic acid, behenic acid, palmitoleic acid, oleic acid,
linoleic acid, arachidonic acid, eicosapentanoic acid,
docosahexaenoic acid and the like, and salts of fatty acid include,
for example, alkali metal salts such as sodium salt, potassium salt
and the like, calcium salt and the like.
[0250] As the emulsion stabilizer, for example, cholesterol,
cholesteryl ester, tocopherol, albumin, fatty acid amide
derivative, polysaccharides, fatty acid ester derivative of
polysaccharides and the like can be used.
[0251] While the concentration of compound A in emulsion
composition A varies depending on the pharmacological activity or
blood kinetics of the compound, it is generally about 0.001 to
about 5% (W/V), preferably about 0.01 to about 2% (W/V), more
preferably about 0.1 to about 1.5% (W/V). In addition, the content
of compound A in emulsion composition A can also be set to about 1
to about 5000 mg, preferably about 10 to about 2000 mg, more
preferably about 100 to about 1500 mg, in 100 ml of the
composition. In addition, the content of compound A can also be
adjusted to about 0.001 to about 95 wt %, preferably about 0.01 to
about 30 wt %, more preferably about 0.1 to about 3 wt %, relative
to the whole composition.
[0252] The proportion (wt %) of compound A relative to the
dispersion phase consisting of an oil component and an emulsifier
is generally about 0.0047 to about 24%, preferably about 0.047 to
about 9.4%.
[0253] Emulsion composition A is adjusted to pH about 3.7 to about
5.5, preferably about 3.7 to about 5.0, more preferably about 4.0
to about 5.0.
[0254] As a pH adjuster, for example, phosphoric acid, carbonic
acid, citric acid, hydrochloric acid, sodium hydroxide and the like
are used and hydrochloric acid, sodium hydroxide and the like are
particularly preferable.
[0255] As the aforementioned buffer, any pharmaceutically
acceptable buffer can be used. For example, a buffer containing
acetic acid, glacial acetic acid, lactic acid, citric acid,
phosphoric acid, carbonic acid, histidine, glycine, barbital,
phthalic acid, adipic acid, ascorbic acid, maleic acid, succinic
acid, tartaric acid, glutamic acid, benzoic acid, aspartic acid and
a salt thereof (e.g., potassium, sodium etc.), specifically sodium
acetate, sodium lactate, sodium citrate, disodium hydrogen
phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium
hydrogen carbonate, hydrochloric acid, sodium hydroxide and the
like as a constituent component is preferable. Moreover, respective
buffers may be used in combination. Particularly, one or more
buffers selected from acetate buffer, glacial acetate buffer,
lactate buffer, citrate buffer and phosphate buffer are
preferable.
[0256] As the buffer, (i) a combination of acetic acid or glacial
acetic acid and sodium acetate (acetate buffer or glacial acetate
buffer), or (ii) a combination of lactic acid and sodium lactate
(lactate buffer), and the like are preferable.
[0257] The concentration of the buffer is generally not more than
about 100 mM, specifically about 0.1 mM to about 100 mM, preferably
about 0.2 mM to about 50 mM, more preferably about 5 mM to about 40
mM.
[0258] The pH adjuster is an acidic or alkaline compound to be
added to adjust the pH of a solution to a desired pH.
[0259] The amount of the pH adjuster to be generally added to an
injection is trace. The amount of sodium hydroxide as a pH adjuster
in a fatty emulsion commercially available in Japan is often not
more than about 0.5 mM. While the pH can be adjusted to a desired
pH during preparing the solution, the pH of the solution easily
changes by the addition of an acid or alkali, and maintenance of pH
is difficult.
[0260] The buffer is a compound having an action to reduce changes
in pH on addition of acid or alkali, namely, a bufferizing action.
In many cases, it is a mixed solution of a weak acid and a salt
thereof, or a weak base and a salt thereof.
[0261] By addition of a buffer, emulsion composition A is not
influenced by the development of free fatty acid, and can maintain
a constant pH of an emulsion composition during high-pressure vapor
sterilization and long-term preservation.
[0262] The amount of the buffer to be used for general injections
is the aim of bufferizing action. For example, the amount of an
acetate buffer in a solution injection commercially available in
Japan is about 0.2 mM to about 100 mM.
[0263] Emulsion composition A is preferably used, for example, as a
composition for injection.
[0264] Emulsion composition A can be basically produced by a known
method or a method according thereto. Particularly, while a
conventionally used emulsion technique can be utilized for the
emulsion, compound A is preferably dissolved or dispersed in
advance in an oil component. To be precise, a composition
containing an O/W type or S/O/W type emulsion can be produced by
dispersing a mixture of dispersion phase (1) containing an oil
component and an emulsifier, and compound A (2) in water. The
buffer may be added to an aqueous phase before emulsification, or
added to an emulsion after emulsification during production.
[0265] The more preferable method includes, for example, a method
of preparing an oil-in-water type composition comprising
homogenizing an unhomogeneous mixture of a mixture of the main
drug, an oil component, an emulsifier and, where necessary, an
additive such as isotonicity agent and the like, and water
containing a buffer using an emulsifying machine to give a crude
emulsion, adding water as necessary, further homogenizing the
emulsion using the above-mentioned emulsifying machine, and
removing large particles by a filtration means such as a filter and
the like. The aforementioned mixture is often warmed to a
temperature of, for example, about 30 to about 90.degree. C.,
preferably about 40 to about 80.degree. C., to dissolve or disperse
the main drug. As the emulsifying machine to emulsify an
unhomogeneous mixture of the aforementioned mixture and water,
conventionally used apparatuses, for example, homogenizers such as
a pressurization injection type homogenizer, ultrasonication
homogenizer and the like, homomixers such as high-speed rotation
type mixer and the like, and the like can be used. To remove large
particles having a particle size of not less than about 5 .mu.m,
homogenized emulsion is often subjected to a filtration means such
as a filter and the like.
[0266] In emulsion composition A, the particle size distribution of
a dispersion phase, wherein compound A is dissolved, is, for
example, often about 0.01 to about 7 .mu.m, preferably about 0.02
to about 5 .mu.m. From the aspects of the stability of the emulsion
and distribution in the body after administration, the mean
particle size of the dispersion phase particles, wherein compound A
is dissolved, is for example, about 0.025 to about 0.7 .mu.m, more
preferably about 0.05 to about 0.4 .mu.m.
[0267] The mean particle size used in the present specification
means a mean particle size based on the volume distribution and
measured by a laser diffraction particle size distribution
measurement apparatus, with the laser diffraction.cndot.scattering
method as a measurement principle.
[0268] Pyrogen can be removed from emulsion composition A by a
method known per se.
[0269] Where necessary, after nitrogen gas substitution, emulsion
composition A is sterilized and tightly sealed.
[0270] Since pH of emulsion composition A is adjusted to about 3.7
to about 5.5 by adding a buffer, pH of the composition and mean
particle size of the dispersion phase particles hardly change even
after sterilization by an autoclave etc. or after long-term
preservation, and the composition is stable. Therefore, the
stability of compound A and emulsion composition A is superior.
Moreover, emulsion composition A is free of a visibly observed free
oil drop even after sterilization by an autoclave etc. or after
long-term preservation, and therefore, phase separation of
dispersion phase particles and water wherein the dispersion phase
particles are dispersed does not occur, and the composition is
stable.
[0271] Furthermore, emulsion composition A can increase the
concentration of compound A, and control the particle size of the
dispersion phase particles. Thus, it can enhance retentivity in
blood, blood vessel permeability and transitivity into inflammation
site. Therefore, in vivo kinetics or distribution in the body of
compound A can be improved and targeting becomes possible, as a
result of which administration of an effective drug with suppressed
side effects becomes possible. Accordingly, emulsion composition A
is particularly useful for the treatment of a target disease by an
intravenous administration.
[0272] Compound A can also be used in combination with other drugs
that suppress side effects of the anti-cancer agents, such as
antidepressants (e.g., amitriptyline, imipramine, clomipramine,
desipramine, doxepin, nortriptyline, duloxetine, milnacipran,
fluoxetine, paroxetine, sertraline, citalopram), anticonvulsants
(e.g., carbamazepine, pregabalin, gabapentin, lamotrigine,
phenyloin, valproic acid), antiphlogistic analgesics (e.g.,
loxoprofen sodium, naproxen, indomethacin, ketoprofen, ibuprofen,
diclofenac, celecoxib, acetaminophen, acetylsalicylic acid),
adrenal cortex hormones (e.g., dexamethasone, prednisone),
narcotics (e.g., morphine, oxycodone, fentanyl, methadone, codeine,
tramadol), local anesthetics (Mexiletine, tocamide, lidocaine),
alpha-2-adrenergic agonist (clonidine), herbal medicines (e.g.,
goshajinkigan, kanzoto), vitamins and the like.
[0273] The administration period, dose and administration mode of
compound A and other drugs that suppress side effects of the
anti-cancer agents are not limited, and can be appropriately
determined in consideration of the age, body weight and symptom of
the administration subject, dosage form, administration method,
kind of side effect, combination of drugs and the like.
EXAMPLES
[0274] The present invention is explained in detail in the
following by referring to Reference Examples and Experimental
Examples, which are not to be construed as limitative.
[0275] The .sup.1H-NMR spectrum was measured using
tetramethylsilane as the internal standard and a Varian Mercury 300
(300 MHz) or Varian Gemini 200 (200 MHz) spectrometer, and total 6
value was shown in ppm. In mixed solvents, the numerical values
shown in parentheses are volume mixing ratio of each solvent.
Unless particularly specified, % means weight percent. The ratio of
solvents in silica gel chromatography is a volume ratio of the
solvents to be mixed.
[0276] High polar diastereomer means a diastereomer having a
smaller Rf value when Rf values of normal phase thin layer
chromatography under the same conditions (e.g., ethyl
acetate/hexane and the like can be used as the solvent) are
compared, and low polar diastereomer means a diastereomer having a
larger Rf value.
[0277] The following compounds of Reference Example A can be
produced according to the Examples of WO99/46242. In Reference
Example A, an optically active compound can be produced according
to the Examples of WO02/32859. For example, compound 72 can be
produced according to Examples 1 and 2 or Examples 3 and 4 of
WO02/32859.
Reference Example A
[0278] (compound 1) ethyl
6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0279] (compound 2) ethyl
6-[N-(4-chloro-2-fluorophenyl)-N-methylsulfamoyl]-1-cyclohexene-1-carboxy-
late [0280] (compound 3) ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0281] (compound 4) ethyl
6-[N-(2,6-diisopropylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0282] (compound 5) ethyl
6-[N-(4-nitrophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0283]
(compound 6) ethyl
6-(N-phenylsulfamoyl)-1-cyclohexene-1-carboxylate [0284] (compound
7) ethyl 2-(N-phenylsulfamoyl)-1-cyclohexene-1-carboxylate [0285]
(compound 8) ethyl
2-[N-(4-methoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0286]
(compound 9) ethyl
2-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0287] (compound 10) ethyl
6-[N-(2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0288]
(compound 11) ethyl
6-[N-(3-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0289]
(compound 12) ethyl
6-[N-(4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0290]
(compound 13) ethyl
6-[N-(2,6-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0291] (compound 14) ethyl
6-[N-(2,3-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0292] (compound 15) ethyl
6-[N-(2,5-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0293] (compound 16) ethyl
6-[N-(3,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0294] (compound 17) ethyl
6-[N-(3,5-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0295] (compound 18) ethyl
2-[N-(4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0296]
(compound 19) 1-ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0297] (compound 20) d-ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0298] (compound 21) ethyl
6-[N-(2-ethoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0299] (compound 22) methyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0300] (compound 23) propyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0301] (compound 24) methyl
6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0302] (compound 25) isopropyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0303] (compound 26) ethyl
6-[N-(2-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0304] (compound 27) ethyl
6-[N-(2-fluoro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0305] (compound 28) ethyl
6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0306]
(compound 29) ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0307] (compound 30) ethyl
6-[N-(4-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0308]
(compound 31) ethyl
6-[N-(2,3,4-trifluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0309] (compound 32) isobutyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0310] (compound 33) butyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0311] (compound 34) ethyl
6-[N-(4-bromo-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0312] (compound 35) ethyl
6-[N-(2,4-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0313] (compound 36) ethyl
6-[N-(2-acetoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0314]
(compound 37) ethyl
6-[N-(3-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0315]
(compound 38) ethyl
6-[N-(2,3-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0316] (compound 39) ethyl
6-[N-(2-ethylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate [0317]
(compound 40) ethyl
6-[N-[4-(2H-1,2,3-triazol-2-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxyl-
ate [0318] (compound 41) ethyl
6-[N-(2,5-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0319] (compound 42) ethyl
6-[N-(2-trifluoromethoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0320] (compound 43) ethyl
6-[N-(2,4,5-trifluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0321] (compound 44) ethyl
6-[N-[4-(2H-tetrazol-2-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate
[0322] (compound 45) ethyl
6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0323] (compound 46) ethyl
6-[N-(4-fluoro-2-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0324] (compound 47) ethyl
6-[N-(2,6-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0325] (compound 48) ethyl
6-[N-[4-(1H-tetrazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate
[0326] (compound 49) ethyl
6-[N-(4-(1H-1,2,3-triazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxyl-
ate [0327] (compound 50) ethyl
6-[N-(2-trifluoromethylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0328] (compound 51) ethyl
6-[N-(4-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0329] (compound 52) benzyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0330] (compound 53) ethyl
6-[N-[4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl]sulfamoyl]-1--
cyclohexene-1-carboxylate [0331] (compound 54) ethyl
6-[N-(2-chloro-4-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxy-
late [0332] (compound 55) ethyl
6-[N-(2-chloro-4-cyanophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0333] (compound 56) 2-hydroxyethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0334] (compound 57) ethyl
6-[N-[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-
-carboxylate [0335] (compound 58) ethyl
5-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate
[0336] (compound 59) tert-butyl
[6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetate
[0337] (compound 60)
[6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetic
acid [0338] (compound 61) ethyl
7-[N-(2,4-difluorophenyl)sulfamoyl]-1-cycloheptene-1-carboxylate
[0339] (compound 62) ethyl
6-[N-[2-chloro-4-(N-tert-butoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]--
1-cyclohexene-1-carboxylate [0340] (compound 63) ethyl
6-[N-[2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]-1-cyc-
lohexene-1-carboxylate [0341] (compound 64) ethyl
5-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate
[0342] (compound 65) ethyl
7-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cycloheptene-1-carboxylate
[0343] (compound 66) ethyl
2-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate
[0344] (compound 67)
2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1,2-benzoisothiazol-3(2H)-one
1,1-dioxide [0345] (compound 68)
2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-one
1,1-dioxide [0346] (compound 69)
2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-4,5,6,7-tetrahydro-1,2-benziso-
thiazol-3(2H)-one 1,1-dioxide [0347] (compound 70)
2-(2,4-difluorophenyl)-5,6,7,7a-tetrahydro-1,2-benzoisothiazol-3(2H)-one
1,1-dioxide [0348] (compound 71) ethyl
(6S)-6-[(2-chloro-4-fluoroanilino)sulfonyl]-1-cyclohexene-1-carboxylate
(also referred to as "1-ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate")
[0349] (compound 72) ethyl
(6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
(also referred to as "ethyl
(6R)-6-[(2-chloro-4-fluoroanilino)sulfonyl]-1-cyclohexene-1-carboxylate")
[0350] (compound 73) ethyl
6-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0351] (compound 74) ethyl
6-[N-(4-bromo-2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0352] (compound 75) high polar diastereomer of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxylate
high polar diastereomer [0353] (compound 76) low polar diastereomer
of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carbox-
ylate [0354] (compound 75) high polar diastereomer of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxylate
[0355] (compound 76) low polar diastereomer of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxylate
[0356] (compound 77) high polar diastereomer of ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxy-
late [0357] (compound 78) low polar diastereomer of ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxy-
late [0358] (compound 79) high polar diastereomer of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-carboxyl-
ate [0359] (compound 80) low polar diastereomer of ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-carboxyl-
ate [0360] (compound 81) high polar diastereomer of ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-car-
boxylate [0361] (compound 82) low polar diastereomer of ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-car-
boxylate [0362] (compound 83) ethyl
6-[N-(2,4-difluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxyl-
ate [0363] (compound 84) ethyl
6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-car-
boxylate [0364] (compound 85) ethyl
3-bromo-6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate
[0365] The chemical structural formulas of compounds 1-85 are shown
in Table 1-Table 12.
TABLE-US-00001 TABLE 1 ##STR00045## Compound No. R.sup.1 R.sup.2 Ar
n 1 C.sub.2H.sub.5 H ##STR00046## 2 2 C.sub.2H.sub.5 CH.sub.3
##STR00047## 2 3 C.sub.2H.sub.5 H ##STR00048## 2 4 C.sub.2H.sub.5 H
##STR00049## 2 5 C.sub.2H.sub.5 H ##STR00050## 2 6 C.sub.2H.sub.5 H
##STR00051## 2 10 C.sub.2H.sub.5 H ##STR00052## 2
TABLE-US-00002 TABLE 2 11 C.sub.2H.sub.5 H ##STR00053## 2 12
C.sub.2H.sub.5 H ##STR00054## 2 13 C.sub.2H.sub.5 H ##STR00055## 2
14 C.sub.2H.sub.5 H ##STR00056## 2 15 C.sub.2H.sub.5 H ##STR00057##
2 16 C.sub.2H.sub.5 H ##STR00058## 2 17 C.sub.2H.sub.5 H
##STR00059## 2 19 (1-form) C.sub.2H.sub.5 H ##STR00060## 2 20
(d-form) C.sub.2H.sub.5 H ##STR00061## 2
TABLE-US-00003 TABLE 3 21 C.sub.2H.sub.5 H ##STR00062## 2 22
CH.sub.3 H ##STR00063## 2 23 (CH.sub.2).sub.2CH.sub.3 H
##STR00064## 2 24 CH.sub.3 H ##STR00065## 2 25 CH(CH.sub.3).sub.2 H
##STR00066## 2 26 C.sub.2H.sub.5 H ##STR00067## 2 27 C.sub.2H.sub.5
H ##STR00068## 2 28 C.sub.2H.sub.5 H ##STR00069## 2 29
C.sub.2H.sub.5 H ##STR00070## 2 30 C.sub.2H.sub.5 H ##STR00071##
2
TABLE-US-00004 TABLE 4 31 C.sub.2H.sub.5 H ##STR00072## 2 32
CH.sub.2CH(CH.sub.3).sub.2 H ##STR00073## 2 33
(CH.sub.2).sub.3CH.sub.3 H ##STR00074## 2 34 C.sub.2H.sub.5 H
##STR00075## 2 35 C.sub.2H.sub.5 H ##STR00076## 2 36 C.sub.2H.sub.5
H ##STR00077## 2 37 C.sub.2H.sub.5 H ##STR00078## 2 38
C.sub.2H.sub.5 H ##STR00079## 2 39 C.sub.2H.sub.5 H ##STR00080## 2
40 C.sub.2H.sub.5 H ##STR00081## 2
TABLE-US-00005 TABLE 5 41 C.sub.2H.sub.5 H ##STR00082## 2 42
C.sub.2H.sub.5 H ##STR00083## 2 43 C.sub.2H.sub.5 H ##STR00084## 2
44 C.sub.2H.sub.5 H ##STR00085## 2 45 C.sub.2H.sub.5 H ##STR00086##
2 46 C.sub.2H.sub.5 H ##STR00087## 2 47 C.sub.2H.sub.5 H
##STR00088## 2 48 C.sub.2H.sub.5 H ##STR00089## 2 49 C.sub.2H.sub.5
H ##STR00090## 2 50 C.sub.2H.sub.5 H ##STR00091## 2
TABLE-US-00006 TABLE 6 51 C.sub.2H.sub.5 H ##STR00092## 2 52
##STR00093## H ##STR00094## 2 53 C.sub.2H.sub.5 H ##STR00095## 2 54
C.sub.2H.sub.5 H ##STR00096## 2 55 C.sub.2H.sub.5 H ##STR00097## 2
56 (CH.sub.2).sub.2OH H ##STR00098## 2 57 C.sub.2H.sub.5 H
##STR00099## 2 58 C.sub.2H.sub.5 H ##STR00100## 1 59
CH.sub.2COOC(CH.sub.3).sub.3 H ##STR00101## 2 60 CH.sub.2COOH H
##STR00102## 2
TABLE-US-00007 TABLE 7 61 C.sub.2H.sub.5 H ##STR00103## 3 62
C.sub.2H.sub.5 H ##STR00104## 2 63 C.sub.2H.sub.5 H ##STR00105## 2
64 C.sub.2H.sub.5 H ##STR00106## 1 65 C.sub.2H.sub.5 H ##STR00107##
3 71 (S-form) C.sub.2H.sub.5 H ##STR00108## 2 72 (R-form)
C.sub.2H.sub.5 H ##STR00109## 2 73 C.sub.2H.sub.5 H ##STR00110## 2
74 C.sub.2H.sub.5 H ##STR00111## 2
TABLE-US-00008 TABLE 8 ##STR00112## Compound No. R.sup.1 Ar n 7
C.sub.2H.sub.5 ##STR00113## 2 8 C.sub.2H.sub.5 ##STR00114## 2 9
C.sub.2H.sub.5 ##STR00115## 2 18 C.sub.2H.sub.5 ##STR00116## 2 66
C.sub.2H.sub.5 ##STR00117## 1
TABLE-US-00009 TABLE 9 ##STR00118## Compound No. ##STR00119## Ar 67
##STR00120## ##STR00121## 68 ##STR00122## ##STR00123## 69
##STR00124## ##STR00125## 70 ##STR00126## ##STR00127##
TABLE-US-00010 TABLE 10 ##STR00128## Compound No. R.sup.1 R.sup.2
R* Ar 75 high polar diastereomer C.sub.2H.sub.5 H ##STR00129##
##STR00130## 76 low polar diastereomer C.sub.2H.sub.5 H
##STR00131## ##STR00132## 77 high polar diastereomer C.sub.2H.sub.5
H ##STR00133## ##STR00134## 78 low polar diastereomer
C.sub.2H.sub.5 H ##STR00135## ##STR00136## 79 high polar
diastereomer C.sub.2H.sub.5 H C(CH.sub.3).sub.3 ##STR00137## 80 low
polar diastereomer C.sub.2H.sub.5 H C(CH.sub.3).sub.3 ##STR00138##
81 high polar diastereomer C.sub.2H.sub.5 H C(CH.sub.3).sub.3
##STR00139##
TABLE-US-00011 TABLE 11 82 low polar diastereomer C.sub.2H.sub.5 H
C(CH.sub.3).sub.3 ##STR00140## 85 C.sub.2H.sub.5 H Br
##STR00141##
TABLE-US-00012 TABLE 12 ##STR00142## Compound No . Ar 83
##STR00143## 84 ##STR00144##
[0366] Compounds 1'-8' of the following Reference Example B can be
produced according to the Examples of WO01/10826. Compound 9' can
be produced according to the following Reference Example 1 or
Reference Example 2. Compound 10' can be produced according to the
following Reference Example 1.
Reference Example B
[0367] (compound 1') ethyl
6-(benzylsulfonyl)-1-cyclohexene-1-carboxylate [0368] (compound 2')
ethyl 6-[(4-methoxybenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
[0369] (compound 3') ethyl
6-[(2,4-difluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate [0370]
(compound 4') ethyl
6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
[0371] (compound 5') ethyl
(-)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
[0372] (compound 6') ethyl
(+)-6-[(2-chloro-4-fluorobenzyl)sulfonyl]-1-cyclohexene-1-carboxylate
[0373] (compound 7') ethyl
3-[(2,4-difluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate
[0374] (compound 8') ethyl
3-[(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxylate
[0375] (compound 9') ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate [0376] (compound 10') ethyl
(3R)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate
[0377] The chemical structural formulas of compounds 1'-10' are
shown in Table 13 and Table 14.
TABLE-US-00013 TABLE 13 ##STR00145## Compound No. Ar.sup.a 1'
##STR00146## 2' ##STR00147## 3' ##STR00148## 4' ##STR00149## 5'
(-)-form ##STR00150## 6' (+)-form ##STR00151##
TABLE-US-00014 TABLE 14 ##STR00152## Compound No. Ar.sup.a 7'
##STR00153## 8' ##STR00154## 9' (S-form) ##STR00155## 10' (R-form)
##STR00156##
Reference Example 1
production of ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (Reference Example B; compound 9') and ethyl
(3R)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (Reference Example B; compound 10')
[0378] Ethyl
3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carboxyla-
te (Reference Example B; compound 8', 11.4 g) obtained according to
Example 7 of WO01/10826 was resolved into two kinds of optical
isomers by high performance liquid chromatography (CHIRALCEL OD;
eluate: hexane/ethanol/trifluoroacetic acid=80/20/0.01) to give
ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9', 5.53 g) and ethyl
(3R)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 10', 5.59 g) each as an oil.
[0379] The above-mentioned compound 9' (4.07 g) was crystallized
from a mixed solution of ethanol and hexane to give colorless
powder crystals of compound 9' (3.78 g).
[0380] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.2 Hz),
3.70 (1H, dd, J=13, 3.0 Hz), 4.21-4.50 (5H, m), 4.65 (1H, d, J=13
Hz), 6.92-7.15 (4H, m), 7.72 (1H, dd, J=9.3, 5.4 Hz).
[0381] elemental analysis value: C.sub.14H.sub.15ClFNO.sub.5S
[0382] Calculated (%): C, 46.22; H, 4.16; N, 3.85
[0383] Found (%): C, 46.18; H, 4.02; N, 3.87.
[0384] specific optical rotation: +94.30 (c=1.0, in methanol;
20.degree. C.).
[0385] The above-mentioned compound 10' (5.59 g) was crystallized
from a mixed solution of ethanol and hexane to give colorless
powder crystals of compound 10' (5.34 g).
[0386] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.0 Hz),
3.70 (1H, dd, J=13, 2.8 Hz), 4.19-4.48 (5H, m), 4.65 (1H, d, J=13
Hz), 6.92-7.16 (4H, m), 7.72 (1H, dd, J=9.2, 5.6 Hz).
[0387] elemental analysis value: C.sub.14H.sub.15ClFNO.sub.5S
[0388] Calculated (%): C, 46.22; H, 4.16; N, 3.85
[0389] Found (%): C, 46.19; H, 3.95; N, 3.84.
[0390] specific optical rotation: -96.0.degree. (c=1.0, in
methanol; 20.degree. C.).
Reference Example 2
production of ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (Reference Example B; compound 9')
Production of ethyl
3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate
[0391] To an aqueous solution (400 mL) of
(3R,4S)-tetrahydrofuran-3,4-diol (100 g) was added sodium periodate
(225 g) at 0.degree. C., and the mixture was stirred at room
temperature for 1 hr. An aqueous solution (50 mL) of potassium
carbonate (13.2 g) was added at room temperature, and an aqueous
solution (100 mL) of ethyl diethylphosphonoacetate (322 g) was
added dropwise over 2 hr. Then, an aqueous solution (800 mL) of
potassium carbonate (384 g) was added dropwise over 2 hr. The
reaction mixture was stirred at room temperature for 24 hr, and
extracted with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate and the solvent was evaporated under reduced
pressure. The residue was distilled under reduced pressure
(110-130.degree. C./3-4 mmHg) The obtained crude product was
subjected to silica gel column chromatography (hexane/ethyl
acetate=1:1) to give the title compound (66.5 g, 40%) as a
colorless liquid.
[0392] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.0 Hz),
2.85 (1H, J=5.0 Hz), 3.67-3.75 (1H, m), 3.91-3.98 (1H, m),
4.10-4.45 (5H, m), 7.07 (1H, d, J=2.6 Hz).
Production of ethyl
(3R)-3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate
[0393] To a solution (380 mL) of ethyl
3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (91.2 g) in
diisopropyl ether were added vinyl hexanoate (150 mL) and Lipozyme
IM (4.8 g). The reaction mixture was stirred at 35.degree. C. for
24 hr and the insoluble material was filtered off. The obtained
filtrate was concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (hexane/ethyl
acetate=6:1.fwdarw.1:1) to give the title compound (45.9 g,
50%).
[0394] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.0 Hz),
2.85 (1H, J=5.0 Hz), 3.67-3.75 (1H, m), 3.91-3.98 (1H, m),
4.10-4.45 (5H, m), 7.07 (1H, d, J=2.6 Hz).
[0395] enantiomeric excess: >99% ee [column: CHIRALCEL OD
(manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase:
hexane/2-propanol=95/5].
Production of ethyl
(3S)-3-(acetylsulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate
[0396] Under a nitrogen atmosphere, to a solution (500 mL) of ethyl
(3R)-3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (23.5 g) in
tetrahydrofuran was added dropwise N,N-diisopropylethylamine (35.7
mL) at -70.degree. C. Then, methanesulfonyl chloride (13.7 mL) was
added dropwise, and the mixture was stirred at -45.degree. C. for 2
hr. The mixture was again cooled to -70.degree. C.,
N,N-diisopropylethylamine (14.6 mL) and thioacetic acid (35.7 mL)
were respectively added, and the mixture was stirred at -45.degree.
C. for 2 hr. The reaction mixture was treated with 1N hydrochloric
acid (300 mL) and extracted with diisopropyl ether (300
mL.times.2). The extract was washed with saturated aqueous sodium
hydrogen carbonate solution (300 mL) and water (300 mL), dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography (hexane/ethyl acetate=6:1.fwdarw.4:1) to give the
title compound (19.5 g, 62%).
[0397] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (3H, t, J=7.0 Hz),
2.34 (3H, s), 3.81-4.03 (2H, m), 4.10-4.52 (5H, m), 7.05-7.08 (1H,
m).
[0398] enantiomeric excess: 98.0% ee [column: CHIRALCEL OD-H
(manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase:
hexane/2-propanol=90/10].
Production of ethyl
(3S)-3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate
[0399] To a solution (100 mL) of ethyl
(3S)-3-(acetylsulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate (19.5 g)
in ethanol was added dropwise hydrochloric acid-ethanol solution
(24% w/w, 100 mL) at 0.degree. C. The reaction mixture was stirred
at room temperature for 40 hr, and cooled to 0.degree. C. Saturated
aqueous sodium hydrogen carbonate solution (750 mL) was added
dropwise. The reaction mixture was maintained at 10.degree. C. or
lower, and the final pH was adjusted to 7 to 8. After extraction
with ethyl acetate (500 mL.times.2), the extract was washed with
water (300 mL.times.2), dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (hexane/ethyl acetate=5:1) to give
the title compound (14.5 g, 91%).
[0400] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, t, J=7.2 Hz),
2.23 (1H, d, J=9.6 Hz), 3.64-4.48 (7H, m), 6.83-6.86 (1H, m).
[0401] enantiomeric excess: 97.2% ee [column: CHIRALPAK AD
(manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase:
hexane/2-propanol=98/2].
Production of ethyl
(3S)-3-{[(2-chloro-4-fluorophenyl)amino]sulfanyl}-3,6-dihydro-2H-pyran-4--
carboxylate
[0402] To a solution (400 mL) of ethyl
(3S)-3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (14.5 g) in
dichloromethane was added dropwise tert-butyl hypochlorite (10 mL)
at -78.degree. C. After stirring for 30 min,
2-chloro-4-fluoroaniline (23 mL) was added dropwise at -78.degree.
C. The reaction mixture was stirred for 1 hr, and the reaction was
discontinued with 5% aqueous sodium sulfite solution (300 mL).
After extraction with dichloromethane (300 mL), the extract was
washed with water, and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was
subjected to silica gel column chromatography (hexane/ethyl
acetate=15:1.fwdarw.5:1) to give the title compound as a crude
product (20.0 g, 96.3% ee). This product was crystallized from
diisopropyl ether/hexane (120 mL, 1:5) to give the title compound
(12.3 g, 62%) as white crystals.
[0403] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, t, J=7.2 Hz),
3.72-3.79 (2H, m), 4.20-4.46 (5H, m), 5.53 (1H, br s), 6.90-7.03
(3H, m), 7.54-7.59 (1H, m).
[0404] enantiomeric excess: >99% ee [column: CHIRALPAK AD
(manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase:
hexane/2-propanol=97.5/2.5].
Production of ethyl
(3S)-3-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,6-dihydro-2H-pyran-4-carb-
oxylate (compound 9')
[0405] To a solution (200 mL) of ethyl
(3S)-3-{[(2-chloro-4-fluorophenyl)amino]sulfanyl}-3,6-dihydro-2H-pyran-4--
carboxylate (12.3 g) in ethyl acetate was added
meta-chloroperbenzoic acid (24.5 g) at 0.degree. C. After stirring
at room temperature for 2 hr, the mixture was again cooled to
0.degree. C., and 5% aqueous sodium sulfite solution (200 mL) and
saturated aqueous sodium hydrogen carbonate solution (200 mL) were
added dropwise. After extraction with ethyl acetate (200
mL.times.2), the extract was washed with saturated aqueous sodium
hydrogen carbonate solution (200 mL) and water (200 mL), and dried
over anhydrous magnesium sulfate. After concentration under reduced
pressure, the residue was subjected to silica gel column
chromatography (hexane/ethyl acetate=2:1) to give the title
compound as a crude product (13.8 g). This product was crystallized
from ethyl acetate/diisopropyl ether/hexane (115 mL, 5:100:10) to
give the title compound (12.0 g, 90%).
[0406] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, t, J=7.4 Hz),
3.66-3.74 (1H, m), 4.19-4.48 (5H, m), 4.65 (1H, d, J=12.8 Hz),
6.92-7.16 (4H, m), 7.68-7.75 (1H, m).
[0407] enantiomeric excess: >99% ee [column: CHIRALCEL OD
(manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase:
hexane/ethanol/trifluoroacetic acid=80/20/0.1, flow rate: 0.5
mL/min, detection: UV 254 nm, temperature: 30.degree. C.].
Experimental Example 1
[0408] Mice (C57BL/6N, male, 7-week-old) were divided into Group A
(6 mice), Group B (6 mice), and Group C (6 mice). Group B and Group
C were intraperitoneally administered with paclitaxel (dissolved in
ethanol:Cremophor EL:saline=0.5:0.5:9; 4 mg/kg body weight). As
Group A, non-treated animals were used. Group C was intravenously
administered with compound 72 (10 mg/kg body weight) of Reference
Example A dissolved in an emulsion containing soybean oil, egg-yolk
lecithin, glycerol and the like immediately before and 1 and 2
weeks after intraperitoneal administration of paclitaxel (total 3
times). Pain threshold of each group was measured 3 weeks after
paclitaxel administration to Group B and Group C. Pain threshold is
a weighed value (gram) at the time when a false escape response is
observed by pressurizing the plantar part of the right hindlimb
using a balance type pressing device (Ugo Basile). The results are
shown in the following Table 15. The values in the Table show
mean.+-.standard error of the weighed values.
TABLE-US-00015 TABLE 15 Pain threshold (g) Group A 443.3 .+-. 32.8
Group B 185.0 .+-. 19.3 Group C 441.7 .+-. 28.6
[0409] From the above results, compound A has been shown to have a
suppressing (or mitigating) action on neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) of peripheral
nerve disorders induced by paclitaxel.
Experimental Example 2
[0410] Mice (C57BL/6N, male, 8-week-old) were divided into Group A,
Group B, and Group C. As Group A, non-treated animals were used. To
Group B and Group C, any one of various anti-cancer agents
(docetaxel, vincristine, cisplatin, carboplatin, bortezomib) is
diluted with saline to a given concentration, and intraperitoneal
administered (docetaxel at 3 mg/kg body weight, vincristine at 0.1
mg/kg body weight, cisplatin at 3 mg/kg body weight, carboplatin at
40 mg/kg body weight, bortezomib at 0.4 mg/kg body weight). Group C
was intravenously administered with compound 72 (3 mg/kg body
weight) of Reference Example A dissolved in an emulsion containing
soybean oil, egg-yolk lecithin, glycerol and the like immediately
before intraperitoneal administration of various anti-cancer
agents. Pain threshold of each group was measured 1 week after the
administration of the anti-cancer agent. Pain threshold is a
weighed value (gram) at the time when a false escape response is
observed by pressurizing the plantar part of the right hindlimb
using a balance type pressing device (Ugo Basile). The results are
shown in the following Table 16. The values in the Table show
mean.+-.standard error of the weighed values, and n is the number
of the mice in each group.
TABLE-US-00016 TABLE 16 Pain threshold (g) non-treatment group
Group A (n = 6) 365.0 .+-. 17.8 Docetaxel administration group
Group B (n = 6) 123.3 .+-. 8.0 Group C (n = 6) 276.7 .+-. 17.4**
Vincristine administration group Group B (n = 12) 160.8 .+-. 16.0
Group C (n = 12) 289.2 .+-. 44.6** Cisplatin administration group
Group B (n = 12) 118.3 .+-. 6.7 Group C (n = 12) 166.7 .+-. 18.5*
Carboplatin administration group Group B (n = 6) 110.0 .+-. 6.8
Group C (n = 6) 213.3 .+-. 13.3** Bortezomib administration group
Group B (n = 6) 126.7 .+-. 17.6 Group C (n = 6) 306.7 .+-. 24.0**
*p < 0.025, **p < 0.001; t-test
[0411] From the above results, compound A has been shown to have a
suppressing (or mitigating) action on neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) of peripheral
nerve disorders induced by various anti-cancer agents.
Experimental Example 3
[0412] Rat (Wistar, male, 5-week-old) were divided into Group A,
Group B, and Group C. As Group A, non-treated animals were used. To
Group B and Group C, paclitaxel is diluted with saline to a given
concentration, and intraperitoneally administered at 6 mg/kg body
weight for a total of 3 times at intervals of 1 to 2 days. Group C
was intravenously administered with compound 72 (10 mg/kg body
weight) of Reference Example A dissolved in an emulsion containing
soybean oil, egg-yolk lecithin, glycerol and the like immediately
before intraperitoneal administration of paclitaxel (total 3
times). Pain threshold of each group was measured 2 weeks after
first paclitaxel administration. Pain threshold is a weighed value
(gram) at the time when an avoidance response is observed by
pressurizing the plantar part of the right hindlimb using an
Electronic von Frey (IITC Life Science). The results are shown in
the following Table 17. The values in the Table show
mean.+-.standard error of the weighed values, and n is the number
of the rats in each group.
TABLE-US-00017 TABLE 17 Pain threshold (g) Group A (n = 8) 25.8
.+-. 0.7 Group B (n = 9) 15.4 .+-. 2.6 Group C (n = 8) 24.9 .+-.
0.9** **p < 0.001; t-test
[0413] From the above results, compound A has been shown to have a
suppressing (or mitigating) action on neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) of peripheral
nerve disorders induced by paclitaxel.
Experimental Example 4
[0414] Mice (C57BL/6N, male, 8-week-old) were divided into Group B
and Group D. To Group B and Group D, any one of various anti-cancer
agents (paclitaxel, docetaxel, vincristine, cisplatin, carboplatin,
bortezomib) is diluted with saline to a given concentration, and
intraperitoneally administered (paclitaxel at mg/kg body weight,
docetaxel at 3 mg/kg body weight, vincristine at 0.1 mg/kg body
weight, cisplatin at 3 mg/kg body weight, carboplatin at 40 mg/kg
body weight, bortezomib at 0.4 mg/kg body weight). Group D was
intravenously administered with compound 9' (1 mg/kg body weight)
of Reference Example B dissolved in solution of N
methyl-D(-)-glucamine (0.01 mol/L) immediately before
intraperitoneal administration of various anti-cancer agents. Pain
threshold of each group was measured 3 week after the
administration for paclitaxel and 1 week after the administration
for the anti-cancer agents other than paclitaxel. Pain threshold is
a weighed value (gram) at the time when a false escape response is
observed by pressurizing the plantar part of the right hindlimb
using a balance type pressing device (Ugo Basile). The results are
shown in the following Table 18. The values in the Table show
mean.+-.standard error of the weighed values, and n is the number
of the mice in each group.
TABLE-US-00018 TABLE 18 Pain threshold (g) Paclitaxel
administration group Group B (n = 6) 130.0 .+-. 13.4 Group D (n =
6) 406.7 .+-. 61.2** Docetaxel administration group Group B (n = 6)
123.3 .+-. 8.0 Group D (n = 6) 276.7 .+-. 38.1** Vincristine
administration group Group B (n = 6) 140.0 .+-. 18.6 Group D (n =
6) 306.7 .+-. 73.5** Cisplatin administration group Group B (n = 6)
113.3 .+-. 9.9 Group D (n = 6) 193.3 .+-. 26.2* Carboplatin
administration group Group B (n = 6) 110.0 .+-. 6.8 Group D (n = 6)
176.7 .+-. 16.7** Bortezomib administration group Group B (n = 6)
133.3 .+-. 12.3 Group D (n = 6) 256.7 .+-. 26.5** *p < 0.025,
**p < 0.001; t-test
[0415] From the above results, compound A has been shown to have a
suppressing (or mitigating) action on neurological symptoms (e.g.,
dysesthesia such as numbness, pain and the like) of peripheral
nerve disorders induced by various anti-cancer agents.
INDUSTRIAL APPLICABILITY
[0416] The present invention is useful for suppressing (or
mitigating) neurological symptoms (e.g., dysesthesia such as
numbness, pain and the like) of peripheral nerve disorders which
are one of the side effects caused by the administration of an
anti-cancer agent. In addition, the present invention is useful for
avoiding a decrease in the dosage due to the side effects of the
administration of an anti-cancer agent.
[0417] This application is based on patent application No.
2010-015935 filed in Japan, the contents of which are encompassed
in full herein.
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