Title of Invention	SERUM CHOLESTEROL LOWERING AGENT OR PREVENTIVE OR THERAPEUTIC AGENT FOR ATHEROSCLEROSIS.
Abstract	A serum cholesterol lowering agent or a preventive or therapeutic agent for atherosclerosis, which each comprises a combination of a compound represented by the following general formula (I) or a pharmaccutically acceptable sail thereof with a cholesterol biosynthesis inhibitor and/or a fibrate type cholesterol lowering agent. (I) (b) (a) [In the Ibrmula. A,. A,. and A, each is hydrogen, a group reprcscnlcd by the formula (b). or a group represented by the Ibrmula (a), provided that at least one of these is a group represented by the formula (a); A2: is C1-8 alkyl. etc.: and n. p. q. and r each is an integer of O.1.or 2.]

Title of Invention

SERUM CHOLESTEROL LOWERING AGENT OR PREVENTIVE OR THERAPEUTIC AGENT FOR ATHEROSCLEROSIS.

Abstract

A serum cholesterol lowering agent or a preventive or therapeutic agent for atherosclerosis, which each comprises a combination of a compound represented by the following general formula (I) or a pharmaccutically acceptable sail thereof with a cholesterol biosynthesis inhibitor and/or a fibrate type cholesterol lowering agent. (I) (b) (a) [In the Ibrmula. A,. A,. and A, each is hydrogen, a group reprcscnlcd by the formula (b). or a group represented by the Ibrmula (a), provided that at least one of these is a group represented by the formula (a); A2: is C1-8 alkyl. etc.: and n. p. q. and r each is an integer of O.1.or 2.]

Full Text	DESCRIPTION SERUM CHOLESTEROL LOWERING AGENT OR PREVENTIVE OR THERAPEUTIC AGENT FOR ATHEROSCLEROSIS FIELD OF THE INVENTION The present invention relates to medicinal compositions that are useful as serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis, in more detail, relates to medicinal compositions of /?-lactam cholesterol absorption inhibitors containing C-glycoside in those molecules combined with cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents. BACKGROUND OF THE INVENTION Conventionally, cholesterol biosynthesis inhibitors or fibrate-type cholesterol lowering agents have been widely used for serum cholesterol reduction and prevention or therapy of atherosclerosis, and proposing the combination of /? -lactam cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors (JP 8-505141). The present applicant has previously published that (3 -lactam cholesterol absorption inhibitors containing C-glycoside in those molecules have an lixcelTent cholesterol lowering actioiL. and are useful as serum cholesterol lowering agents (WO-02/066464 A1). The purpose of the present invention is supply of more excellent serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis. DISCLOSURE OF THE INVENTION The present invention is serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis consist of the combination of a compound represented by the following general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents. [wherein • A1, A3 and A4 are hydrogen atom, halogen atom, alkyl group having one to five carbon atoms, alkoxy group having one to five carbon atoms, -COORi, a following formula : [wherein "• R2 is -CH2OH group, -CH2OC(O)-Ri group or -CO2-R1 group ; R3 is -OH group or -OC(O)-Ri group ", R4 is -(CH2)kR5(CH2)r (k and 1 are 0 or 1 more integer ; k +1 is 10 or fewer integer) and binds to tetrahydropyran ring by OC bond. R5 means single bond (-), -CH=CH-, -OCH2-, carbonyl group or -CH(OH)-.] More than one of A1, A3 and AUn formula (I) must be the group in above-mentioned formula (a). A2 is alkyl chain having one to five carbon atoms, alkoxy chain having one to five carbon atoms, alkenyl chain having one to five carbon atoms, hydroxyl alkyl chain having one to five carbon atoms or carbonyl alkyl chain having one to five carbon atoms, n, p, q or r are 0, 1 or 2. ] Also, the present invention is serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis consist of the mixture of a compound represented by the above general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents. Also, the present invention is serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis formed a kit by single packaging a container containing a compound represented by the above general formula (I) or pharmaceutical acceptable salts and a container containing cholesterol biosynthesis inhibitor and/or fibrate-type cholesterol lowering agents. Also, it is able to administer a compound represented by the above general formulaCO or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents simultaneously or consecutively. PREFERRED EMBODIMENT OF THE INVENTION The present invention is serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis consisting of the combination of a compound represented by the following general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents. Concretely, this combined medicine means - CD the medicine combined a compound represented by the general formula (I) or pharmaceutical acceptable s salts with cholesterol biosynthesis inhibitors, 2 the medicine combined a compound represented by the general formula (I) or pharmaceutical acceptable salts with fibrate-type cholesterol lowering agents, 3 the medicine combined a compound represented by the general formula (I) or pharmaceutical acceptable salts with cholesterol biosynthesis inhibitors and fibrate-type cholesterol lowering agents. This combined usage means combined administration, and is able to administer simultaneously or consecutively. A compound represented by the above general formula (I) or pharmaceutical acceptable salts in the present invention have serum cholesterol lowering actions. These compounds are shown in WO02/066464 Al. These b-lactam compounds, which show cholesterol lowering actions and has Oglycoside in those molecules, show synergistic effects by using in combination with cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents for serum cholesterol lowering effect or preventive or therapeutic effect for atherosclerosis. A compound represented by the above general formula (I) or pharmaceutical acceptable salts using in the present invention are , for example, the compounds shown in Table 1~ 12. Also, cholesterol biosynthesis inhibitors using in the present invention is at least one sort chosen from the group consisit of HMG-CoAreductase inhibitors, squalene synthase inhibitors and squalene epoxydase inhibitors. HMG-CoA reductase inhibitors include, for example, pravastatin, lovastatin, fluvastatin, simvastatin, itavastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin and carvastatin (TF802); squalene synthase inhibitors include, for example, squalestatin l; squalen epoxydase inhibitors include, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-heptyn-4-ynyl)-3-[(3,3'-bithiophen-5-yl) methoxylbenzenemethanamine hydrochloride). One or over two agents chosen from those are used in the present invention. Also, fibrate-type cholesterol lowering agents using in the present invention is at least one sort chosen from the group consisting of clofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl and AHL-157. The medicine in the present invention is administered in oral dosage or non-oral dosage form. And, combined usage of a compound represented by the general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents can be carried out in various forms. For example, a compound represented by the general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents are mixtured at the predetermined ratio, furthermore, it is able to form a combination agent which blended additives and excipients according to the request (a powder agent, a tablet, a granule agent, a capsule agent, a liquid agent, a suspended agent, a suppository, an ointment agent, an inhalation agent and others). Additives and excipients are lubricants, binders, collapses, fillers, buffers, emulsifiers, preservatives, anti-oxidants, coloring agents, coating agents, suspending agents and others. 1 f Also, it is able to form a kit by single packaging a container containing a compound represented by the general formula (I) or pharmaceutical acceptable salts and a container containing cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents. Also, it is able to administer a compound represented by the general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents simultaneously or consecutively. > The daily dose of the medicine in the present invention is determined by the potency of the compound administered, the weight, age, and condition of the patient and others. Also, the medicine is administered in a single dose or 2~5 divided doses depending oral dosage or non-oral dosage forms. A compound represented by the general formula (I) or pharmaceutical acceptable salts are administered the amount of 0.1~100mg/kg (mammalian weight) per day in division. Cholesterol biosynthesis inhibitors are administered the amount of Img ~3g/kg (mammalian weight) per day in division, and for HMG-CoA reductase inhibitors are administered the amount of 5~l00mg/kg (mammalian weight) per day in division. For fibrate-type cholesterol lowering agents are administered the amount of l~l000mg/kg (mammalian weight) per day in division. EXAMPLE In the pharmacological experiments of this example, the compound of compound No. 56 (called compound 56 as following) and the compound of compound No. 37 . (called compound 37 as following) in the above Table were used as a compound represented by the general formula (I) or pharmaceutical acceptable salts. ! Pharmacological experiment 1 The pharmacological experiment of serum cholesterol lowering action by the combination of compound 56 and atorvastatin or fenofibrate in cholesterol-fed rat. Male Splague-Dawley rats weighing 300~500g (Nihon SLC Co. Ltd.) were fed MF-2 chow (Nihon Crea Co. Ltd.) until study onset. At the study onset, the chow was changed to MF-2 chow containing 1% cholesterol and 0.5% cholic acid. Compound 56 at 0.3mg/kg, atorvastatin at lmg/kg or fenofibrate at lOmg/kg dissolved in polyethylene glycol 400 were simultaneously administered once a day for 7 days. Twenty hours after the last administration, blood was collected from the abdominal aorta under ether anaesthesia, and serum was separated. The cholesterol value was measured using Cholesterol E Test Wako (Wako Pure Chemical Co. Ltd.). Furthermore, the effect of combined dosage of compound 56 at 0.3mg/kg and atorvastatin at lmg/kg or fenofibrate at lOmg/kg were examined similarly. The results were shown in Table 13. The experimental No. of 1~3, 4 and 5 indicates the case of compound 56 alone, atrovastatin alone and fenofibrate alone, respectively. The experimental 5 and 6 indicates the combined dosage examples in the present invention. Each reduction percent is shown as the value to control. From Table 13, in the case of combined dosage compound 56 at 0.3mg/kg/day and atrovastatin lmg/kg/day (Experimental No. 6), and compound 56 at 0.3mg/kg/day and fenofibrate at l0mg/kg/day (Experimental No. 7), each reduction % of serum cholesterol value was over the sum of reduction % when each agent was administered alone (Experimental No. 2, 4 and 5), indicating synergistic effect. Pharmacological experiment 2 Except of the use of compound 37 instead of compound 56, quietly same experiment to pharmacological experiment 1 was carried out. The results were shown in Table 14. Each reduction % is shown as the value to control. From Table 14, in the case of combined dosage compound 37 at 0.3mg/kg/day and atrovastatin lmg/kg/day (Experimental No. 16), and compound 37 at 0.3mg/kg/day and fenofibrate at l0mg/kg/day (Experimental No. 17), the reduction % of serum cholesterol values were over the sum of reduction % when each agent was administered alone (Experimental No. 12, 14 and 15), indicating synergistic effect. INDUSTRIAL APPLICABILITY The medicine consist of the combination of a compound represented by the following general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents show the synergistic effect and an excellent serum cholesterol lowering effect or preventive or therapeutic effect for atherosclerosis. Therefore, it is useful for serum cholesterolol lowering or preventive or therapy for atherosclerosis. WE CLAIM; 1. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis consist of the combination of a p lactam compound represented by the following general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents, wherein, A1 and A4 are hydrogen atom, halogen or alkyl group of C1C5. A2 is an alkyl chain of C1-C5, hydroxyalkyl chain of C1-C5, or carbonylalkyl chain of C1-Cs. R2 is-CH2OH group or-CO2-H group. R5 indicates a bond, and is single bond (-) or -CH=CH- or -OCH2- k and 1 is an integer of 0 or 1 or more, k+1 is an integer of 10 or less. 2. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed claim 1, wherein it consists of the mixture of a compound represented by the above general formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents, 3. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in claim 1, wherein a kit is formed by single packaging a container containing a compound represented by the above general formula (I) or pharmaceutical acceptable salts and a container containing cholesterol biosynthesis inhibitor and/or fibrate-type cholesterol lowering agents. 4. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis-as claimed in any one of claims 1, 2 and 3, wherein it consists of a compound which the above-mentioned general formula (I) is the following formula. 5. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in any one of claims 1, 2 and 3, consist of a compound which the above-mentioned general formula (I) is the following formula. 6. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in any one of claims 1-5 wherein the cholesterol biosynthesis inhibitors selected from the group consisting of HMG-CoA reductase inhibitors, squalene synthase inhibitors and squalene epoxydase inhibitors. 7. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in any one of claims 1.- 5 wherein the fibrate-type cholesterol lowering agents is selected from the group consisting of clofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl and 2-[3-[l-(4- fluorobenzoyl)-piperidin-4yl] phenoxyl-2-methylpropanoic acid A serum cholesterol lowering agent or a preventive or therapeutic agent for atherosclerosis, which each comprises a combination of a compound represented by the following general formula (I) or a pharmaccutically acceptable sail thereof with a cholesterol biosynthesis inhibitor and/or a fibrate type cholesterol lowering agent. (I) (b) (a) [In the Ibrmula. A,. A,. and A, each is hydrogen, a group reprcscnlcd by the formula (b). or a group represented by the Ibrmula (a), provided that at least one of these is a group represented by the formula (a); A2: is C1-8 alkyl. etc.: and n. p. q. and r each is an integer of O.1.or 2.]

Full Text

DESCRIPTION
SERUM CHOLESTEROL LOWERING AGENT OR PREVENTIVE
OR THERAPEUTIC AGENT FOR ATHEROSCLEROSIS
FIELD OF THE INVENTION
The present invention relates to medicinal compositions that are useful as serum
cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis, in
more detail, relates to medicinal compositions of /?-lactam cholesterol absorption
inhibitors containing C-glycoside in those molecules combined with cholesterol
biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents.
BACKGROUND OF THE INVENTION
Conventionally, cholesterol biosynthesis inhibitors or fibrate-type cholesterol
lowering agents have been widely used for serum cholesterol reduction and
prevention or therapy of atherosclerosis, and proposing the combination of /?
-lactam cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors (JP
8-505141). The present applicant has previously published that (3 -lactam
cholesterol absorption inhibitors containing C-glycoside in those molecules have an
lixcelTent cholesterol lowering actioiL. and are useful as serum cholesterol lowering
agents (WO-02/066464 A1).
The purpose of the present invention is supply of more excellent serum
cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis.
DISCLOSURE OF THE INVENTION
The present invention is serum cholesterol lowering agent or preventive or
therapeutic agent for atherosclerosis consist of the combination of a compound
represented by the following general formula (I) or pharmaceutical acceptable salts
and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering
agents.
[wherein • A1, A3 and A4 are hydrogen atom, halogen atom, alkyl group having one
to five carbon atoms, alkoxy group having one to five carbon atoms, -COORi, a
following formula :
[wherein "• R2 is -CH2OH group, -CH2OC(O)-Ri group or -CO2-R1 group ; R3 is -OH
group or -OC(O)-Ri group ", R4 is -(CH2)kR5(CH2)r (k and 1 are 0 or 1 more integer ; k
+1 is 10 or fewer integer) and binds to tetrahydropyran ring by OC bond. R5 means
single bond (-), -CH=CH-, -OCH2-, carbonyl group or -CH(OH)-.] More than one
of A1, A3 and AUn formula (I) must be the group in above-mentioned formula (a).
A2 is alkyl chain having one to five carbon atoms, alkoxy chain having one to five
carbon atoms, alkenyl chain having one to five carbon atoms, hydroxyl alkyl chain
having one to five carbon atoms or carbonyl alkyl chain having one to five carbon
atoms, n, p, q or r are 0, 1 or 2. ]
Also, the present invention is serum cholesterol lowering agent or preventive or
therapeutic agent for atherosclerosis consist of the mixture of a compound
represented by the above general formula (I) or pharmaceutical acceptable salts
and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering
agents. Also, the present invention is serum cholesterol lowering agent or
preventive or therapeutic agent for atherosclerosis formed a kit by single packaging
a container containing a compound represented by the above general formula (I) or
pharmaceutical acceptable salts and a container containing cholesterol biosynthesis
inhibitor and/or fibrate-type cholesterol lowering agents. Also, it is able to
administer a compound represented by the above general formulaCO or
pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or
fibrate-type cholesterol lowering agents simultaneously or consecutively.
PREFERRED EMBODIMENT OF THE INVENTION
The present invention is serum cholesterol lowering agent or preventive or
therapeutic agent for atherosclerosis consisting of the combination of a compound
represented by the following general formula (I) or pharmaceutical acceptable salts
and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol lowering
agents. Concretely, this combined medicine means - CD the medicine combined a
compound represented by the general formula (I) or pharmaceutical acceptable
s
salts with cholesterol biosynthesis inhibitors, 2 the medicine combined a
compound represented by the general formula (I) or pharmaceutical acceptable
salts with fibrate-type cholesterol lowering agents, 3 the medicine combined a
compound represented by the general formula (I) or pharmaceutical acceptable
salts with cholesterol biosynthesis inhibitors and fibrate-type cholesterol lowering
agents. This combined usage means combined administration, and is able to
administer simultaneously or consecutively.
A compound represented by the above general formula (I) or pharmaceutical
acceptable salts in the present invention have serum cholesterol lowering actions.
These compounds are shown in WO02/066464 Al. These b-lactam compounds,
which show cholesterol lowering actions and has Oglycoside in those molecules,
show synergistic effects by using in combination with cholesterol biosynthesis
inhibitors and/or fibrate-type cholesterol lowering agents for serum cholesterol
lowering effect or preventive or therapeutic effect for atherosclerosis.
A compound represented by the above general formula (I) or pharmaceutical
acceptable salts using in the present invention are , for example, the compounds
shown in Table 1~ 12.
Also, cholesterol biosynthesis inhibitors using in the present invention is at least
one sort chosen from the group consisit of HMG-CoAreductase inhibitors, squalene
synthase inhibitors and squalene epoxydase inhibitors. HMG-CoA reductase
inhibitors include, for example, pravastatin, lovastatin, fluvastatin, simvastatin,
itavastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin and carvastatin
(TF802); squalene synthase inhibitors include, for example, squalestatin l; squalen
epoxydase inhibitors include, for example, NB-598
((E)-N-ethyl-N-(6,6-dimethyl-2-heptyn-4-ynyl)-3-[(3,3'-bithiophen-5-yl)
methoxylbenzenemethanamine hydrochloride). One or over two agents chosen
from those are used in the present invention.
Also, fibrate-type cholesterol lowering agents using in the present invention is at
least one sort chosen from the group consisting of clofibrate, bezafibrate, cinfibrate,
fenofibrate, gemfibrogyl and AHL-157.
The medicine in the present invention is administered in oral dosage or non-oral
dosage form. And, combined usage of a compound represented by the general
formula (I) or pharmaceutical acceptable salts and cholesterol biosynthesis
inhibitors and/or fibrate-type cholesterol lowering agents can be carried out in
various forms. For example, a compound represented by the general formula (I)
or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or
fibrate-type cholesterol lowering agents are mixtured at the predetermined ratio,
furthermore, it is able to form a combination agent which blended additives and
excipients according to the request (a powder agent, a tablet, a granule agent, a
capsule agent, a liquid agent, a suspended agent, a suppository, an ointment agent,
an inhalation agent and others). Additives and excipients are lubricants, binders,
collapses, fillers, buffers, emulsifiers, preservatives, anti-oxidants, coloring agents,
coating agents, suspending agents and others.
1 f
Also, it is able to form a kit by single packaging a container containing a
compound represented by the general formula (I) or pharmaceutical acceptable
salts and a container containing cholesterol biosynthesis inhibitors and/or
fibrate-type cholesterol lowering agents. Also, it is able to administer a
compound represented by the general formula (I) or pharmaceutical acceptable
salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol
lowering agents simultaneously or consecutively. > The daily dose of the medicine in the present invention is determined by the
potency of the compound administered, the weight, age, and condition of the
patient and others. Also, the medicine is administered in a single dose or 2~5
divided doses depending oral dosage or non-oral dosage forms. A compound
represented by the general formula (I) or pharmaceutical acceptable salts are
administered the amount of 0.1~100mg/kg (mammalian weight) per day in
division. Cholesterol biosynthesis inhibitors are administered the amount of Img
~3g/kg (mammalian weight) per day in division, and for HMG-CoA reductase
inhibitors are administered the amount of 5~l00mg/kg (mammalian weight) per
day in division. For fibrate-type cholesterol lowering agents are administered the
amount of l~l000mg/kg (mammalian weight) per day in division.
EXAMPLE
In the pharmacological experiments of this example, the compound of compound
No. 56 (called compound 56 as following) and the compound of compound No. 37
. (called compound 37 as following) in the above Table were used as a compound
represented by the general formula (I) or pharmaceutical acceptable salts. !
Pharmacological experiment 1
The pharmacological experiment of serum cholesterol lowering action by the
combination of compound 56 and atorvastatin or fenofibrate in cholesterol-fed rat.
Male Splague-Dawley rats weighing 300~500g (Nihon SLC Co. Ltd.) were fed
MF-2 chow (Nihon Crea Co. Ltd.) until study onset. At the study onset, the chow
was changed to MF-2 chow containing 1% cholesterol and 0.5% cholic acid.
Compound 56 at 0.3mg/kg, atorvastatin at lmg/kg or fenofibrate at lOmg/kg
dissolved in polyethylene glycol 400 were simultaneously administered once a day
for 7 days. Twenty hours after the last administration, blood was collected from the

abdominal aorta under ether anaesthesia, and serum was separated. The
cholesterol value was measured using Cholesterol E Test Wako (Wako Pure
Chemical Co. Ltd.). Furthermore, the effect of combined dosage of compound 56
at 0.3mg/kg and atorvastatin at lmg/kg or fenofibrate at lOmg/kg were examined
similarly. The results were shown in Table 13. The experimental No. of 1~3, 4
and 5 indicates the case of compound 56 alone, atrovastatin alone and fenofibrate
alone, respectively. The experimental 5 and 6 indicates the combined dosage
examples in the present invention. Each reduction percent is shown as the value
to control.
From Table 13, in the case of combined dosage compound 56 at 0.3mg/kg/day and
atrovastatin lmg/kg/day (Experimental No. 6), and compound 56 at 0.3mg/kg/day
and fenofibrate at l0mg/kg/day (Experimental No. 7), each reduction % of serum
cholesterol value was over the sum of reduction % when each agent was
administered alone (Experimental No. 2, 4 and 5), indicating synergistic effect.
Pharmacological experiment 2
Except of the use of compound 37 instead of compound 56, quietly same
experiment to pharmacological experiment 1 was carried out. The results were
shown in Table 14. Each reduction % is shown as the value to control.
From Table 14, in the case of combined dosage compound 37 at 0.3mg/kg/day and
atrovastatin lmg/kg/day (Experimental No. 16), and compound 37 at 0.3mg/kg/day
and fenofibrate at l0mg/kg/day (Experimental No. 17), the reduction % of serum
cholesterol values were over the sum of reduction % when each agent was
administered alone (Experimental No. 12, 14 and 15), indicating synergistic effect.
INDUSTRIAL APPLICABILITY
The medicine consist of the combination of a compound represented by the
following general formula (I) or pharmaceutical acceptable salts and cholesterol
biosynthesis inhibitors and/or fibrate-type cholesterol lowering agents show the
synergistic effect and an excellent serum cholesterol lowering effect or preventive
or therapeutic effect for atherosclerosis. Therefore, it is useful for serum
cholesterolol lowering or preventive or therapy for atherosclerosis.
WE CLAIM;
1. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis consist of the
combination of a p lactam compound represented by the following general formula (I) or
pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type cholesterol
lowering agents,
wherein, A1 and A4 are hydrogen atom, halogen or alkyl group of C1C5.
A2 is an alkyl chain of C1-C5, hydroxyalkyl chain of C1-C5, or carbonylalkyl chain of C1-Cs.
R2 is-CH2OH group or-CO2-H group.
R5 indicates a bond, and is single bond (-) or -CH=CH- or -OCH2-
k and 1 is an integer of 0 or 1 or more, k+1 is an integer of 10 or less.
2. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed
claim 1, wherein it consists of the mixture of a compound represented by the above general formula (I)
or pharmaceutical acceptable salts and cholesterol biosynthesis inhibitors and/or fibrate-type
cholesterol lowering agents,
3. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in
claim 1, wherein a kit is formed by single packaging a container containing a compound represented by
the above general formula (I) or pharmaceutical acceptable salts and a container containing cholesterol
biosynthesis inhibitor and/or fibrate-type cholesterol lowering agents.
4. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis-as claimed in
any one of claims 1, 2 and 3, wherein it consists of a compound which the above-mentioned general
formula (I) is the following formula.
5. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in
any one of claims 1, 2 and 3, consist of a compound which the above-mentioned general formula (I) is
the following formula.
6. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in
any one of claims 1-5 wherein the cholesterol biosynthesis inhibitors selected from the group
consisting of HMG-CoA reductase inhibitors, squalene synthase inhibitors and squalene epoxydase
inhibitors.
7. Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis as claimed in
any one of claims 1.- 5 wherein the fibrate-type cholesterol lowering agents is selected from the
group consisting of clofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl and 2-[3-[l-(4-
fluorobenzoyl)-piperidin-4yl] phenoxyl-2-methylpropanoic acid
A serum cholesterol lowering agent or a preventive or therapeutic agent for atherosclerosis, which each comprises
a combination of a compound represented by the following general formula (I) or a pharmaccutically acceptable sail thereof with a
cholesterol biosynthesis inhibitor and/or a fibrate type cholesterol lowering agent. (I) (b) (a) [In the Ibrmula. A,. A,. and A, each is
hydrogen, a group reprcscnlcd by the formula (b). or a group represented by the Ibrmula (a), provided that at least one of these is a
group represented by the formula (a); A2: is C1-8 alkyl. etc.: and n. p. q. and r each is an integer of O.1.or 2.]

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Patent Number

223815

Indian Patent Application Number

02584/KOLNP/2005

PG Journal Number

39/2008

Publication Date

26-Sep-2008

Grant Date

23-Sep-2008

Date of Filing

13-Dec-2005

Name of Patentee

KOTOBUKI PHARMACEUTICAL CO.,LTD.

Applicant Address

6351,OAZASAKAKI, SAKAKI-MACHI, HANISHINA-GUN, NAGANO

Inventors:

#	Inventor's Name	Inventor's Address
1	TOMIYAMA, HIROSHI	1113,OAZA-SAKAKI, SAKAKI-MACHI, HANISHINA-GUN, NAGANO, 389-0601
2	YOKOTA, MASAYUKI	2671-10, YAWATA, CHIKUMA-SHI, NAGANO, 387-0023
3	KOSAKAI, KAZUHIRO	1054-7, OAZA-HOYA, UEDA-SHI, NAGANO, 386-1321

PCT International Classification Number

A61K 45/00

PCT International Application Number

PCT/JP2004/008678

PCT International Filing date

2004-06-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2003-185171	2003-06-27	Japan