CN1913881A - Preventive and/or therapeutic agent for chronic cerebral circulatory failure - Google Patents

Preventive and/or therapeutic agent for chronic cerebral circulatory failure Download PDF

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CN1913881A
CN1913881A CNA2005800039068A CN200580003906A CN1913881A CN 1913881 A CN1913881 A CN 1913881A CN A2005800039068 A CNA2005800039068 A CN A2005800039068A CN 200580003906 A CN200580003906 A CN 200580003906A CN 1913881 A CN1913881 A CN 1913881A
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岩隈裕明
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Tanabe Seiyaku Co Ltd
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Mitsubishi Pharma Corp
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Abstract

An ameliorant for cerebral circulatory metabolism or a preventive and/or therapeutic agent for chronic cerebral circulatory failures, characterized by containing any of an aminoalkoxybibenzil compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, and a hydrate or solvate of either.

Description

Chronic cerebral circulatory failure prevent and/or treat agent
Technical field
What the present invention relates to chronic cerebral circulatory failure prevents and/or treats agent and cerebral circulation metabolism improving agent.
Background technology
Chronic cerebral circulatory failure is the diagnosis name of being preced with in following disease: because subjective symptoms undulatory property growth and decline such as that the circulatory disturbance of brain causes is nose heave, dizzinesses, but clinical symptoms and imaging diagnosis all find no the organic disease of prompting vascular, nor belong to a kind of disease of the category of transient ischemic attack.Think that cerebral circulation improving agent (below, be also referred to as " cerebral circulation metabolism improving agent ") is to subjective symptomss such as nose heave, dizziness effectively (non-patent literature 1).
In addition,, just stay sequela mostly, therefore, think that the prevention of chronic cerebral circulatory failure is important (non-patent literature 1) as long as cause the outbreak of cerebrovascular disorders though there is not the long-term forecast of clear and definite chronic cerebral circulatory failure at present.
The cerebral circulation metabolism improving agent is the medicament that promotes the recovery of brain energy metabolism.Wherein also there is the character of improving blood by improve the erythrocyte deformability, suppress platelet aggregation, blood viscosity lowering etc. to bring into play the material of the effect that strengthens cerebral circulation.At present, as the cerebral circulation improving agent, use brain biological active substances such as citicoline, GABA or cerebral circulation improving agent such as nicergoline, dihydroergotoxine methanesulfonate etc.
In addition, common evaluation cerebral circulation metabolism improving agent such as observation according to clinical symptoms, but in recent years, also with good grounds mensuration E.E.G carries out the trial of objective evaluation.Past, carried out multiple research about the dependency relation between E.E.G and the cerebral circulation metabolism improving agent, for example clear and definite: if cerebral blood flow or brain metabolism reduce, then the α ripple reduces, and slow wave (δ ripple+θ ripple) increases (with reference to non-patent literature 2,3 and 4).
As the specific antagonists of 5-hydroxy tryptamine (5-HT) receptor, known useful following general formula
(in the formula, R 1Expression hydrogen atom, halogen atom, C 1～C 5Alkoxyl or C 2～C 6Dialkyl amido, R 2Expression hydrogen atom, halogen atom or C 1～C 5Alkoxyl, R 3Expression hydrogen atom, hydroxyl ,-O-(CH 2) n-COOH (in the formula, n represents 1～5 integer) or O-CO-(CH 2) 1-COOH (in the formula, the integer of 1 expression 1～3), R 4Expression-N (R 5) (R 6) (in the formula, R 5And R 6Represent hydrogen atom or C respectively independently 1～C 8Alkyl) or the expression
(in the formula, A represents to use the C of carboxyl substituted 3～C 5Alkylidene), m represents 0～5 integer) the amino propoxyl group bibenzyl of expression, this amino propoxyl group bibenzyl is to the improvement of the multiple microcirculation disturbance that causes because of thrombosis and vasoconstriction in the illness such as disturbance of cerebral circulation, ischemic heart illness, peripheral circulation disorders effectively (with reference to patent documentation 1).
In addition, in non-patent literature 5, put down in writing, as (±)-1-(O-(2-(m-methoxyphenyl) ethyl) phenoxy group)-3-(the dimethylamino)-2-propyl group hydrogen succinate ester hydrochloride of one of preferred compound of above-mentioned amino propoxyl group bibenzyl, be that the effect of sarpogrelate hydrochloride is to the 5-HT in platelet and the vascular smooth muscle 2The specificity antagonism of receptor.
But, do not disclose this amino propoxyl group bibenzyl so far effectively or improve E.E.G and then cerebral blood flow increasing to chronic cerebral circulatory failure.
Patent documentation 1: the spy opens flat 2-304022 communique
Non-patent literature 1: vow that the rugged adopted ruler of great talent and bold vision compiles, the origin cause of formation of cerebrovascular disorders, cerebrovascular disorders series 1, the 197th page, modern medical service society, 1998
Non-patent literature 2: clinical E.E.G, No. 7 the 449th page (1991) of the 33rd volume
Non-patent literature 3: clinical E.E.G, No. 10 the 653rd page (1997) of the 39th volume
Non-patent literature 4: clinical E.E.G, No. 10 the 634th page (1994) of the 36th volume
Non-patent literature 5: 2003, the 937 pages in therapeutic agent handbook, medical science academy
Summary of the invention
Problem of the present invention provides a kind of medicine that has the effect that prevents and/or treats of chronic cerebral circulatory failure and have cerebral circulation metabolism improvement effect.
The present inventor furthers investigate in order to solve above-mentioned problem, found that as 5-HT 2The known amino propoxyl group bibenzyl of the antagonistic of receptor has above-mentioned effect, and has finished the present invention.
Promptly, main points of the present invention be a kind of chronic cerebral circulatory failure prevent and/or treat agent and cerebral circulation metabolism improving agent, it is characterized in that comprising aminoalkoxy bibenzyl or its pharmaceutically useful salt or these hydrate or solvate with following general formula (1) expression.
(in the formula, R 1Expression hydrogen atom, halogen atom, C 1～C 5Alkoxyl or C 2～C 6Dialkyl amido, R 2Expression hydrogen atom, halogen atom or C 1～C 5Alkoxyl, R 3Expression hydrogen atom, hydroxyl, C 2～C 5Acyloxy ,-O-(CH 2) n-COOH (in the formula, n represents 1～5 integer) or O-CO-(CH 2) l-COOH (in the formula, l represents 1～3 integer), R 4Expression-N (R 5) (R 6) (in the formula, R 5And R 6Represent hydrogen atom or C respectively independently 1～C 8Alkyl) or the expression
Figure A20058000390600072
(in the formula, A represents to use the C of carboxyl substituted 3～C 5Alkylidene), m represents 0～5 integer.〕
The effect of invention
Chronic cerebral circulatory failure involved in the present invention prevent and/or treat agent and cerebral circulation metabolism improving agent, reduce occipital slow wave in the mode that does not change mean blood pressure, increase the α ripple, have the effect of prevention or treatment chronic cerebral circulatory failure thus, and have the effect of improving cerebral circulation metabolism.
The specific embodiment
In this manual, as with the halogen atom in the chemical compound of general formula (1) expression, for example can enumerate chlorine atom and fluorine atom etc.
As C 1～C 5Alkoxyl, for example can list methoxyl group, ethyoxyl, propoxyl group, butoxy and amoxy etc.
As C 2～C 6Dialkyl amido, for example can list dimethylamino, diethylamino and Methylethyl amino etc.
As C 2～C 5Acyloxy, for example can list acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta acyloxy and isoamyl acyloxy etc.
As C 1～C 8Alkyl, for example can list methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, hexyl, isohesyl, heptyl and octyl group etc.
As R 1, preferably hydrogen atom, fluorine atom, chlorine atom, methoxyl group or dimethylamino particularly preferably are methoxyl group, are preferably 3 or 4 replacements, are preferably 3 replacements especially.
As R 2, preferably hydrogen atom, chlorine atom or methoxyl group particularly preferably are hydrogen atom, are preferably 3 replacements.
As R 3, preferably hydroxyl ,-O-(CH 2) n-COOH or O-CO-(CH 2) l-COOH is as n preferably 2, as l preferably 2.
As R 4For example can list amino, methylamino, ethylamino, fourth amino, oneself is amino, heptan is amino, dimethylamino, diethylamino and Methylethyl amino and trimethylene amino, 1,5-pentylidene amino, 3-carboxyl-1,5-pentylidene amino etc., preferably methylamino, dimethylamino, 1,5-pentylidene amino or 3-carboxyl-pentamethylene amino.
As m, preferably 0～4 integer particularly preferably is 1.
In addition, aminoalkoxy preferably is substituted on the optional position in 2～4, especially preferably is substituted on 4.
Table 1 has been listed with the several preferred chemical compound in the chemical compound of general formula (1) expression.
(table 1)
Table-1
Figure A20058000390600091
(table 2)
-1 (continuing) of table
Chemical compound R 1 R 2 Aminoalkoxy R 3 m R 4
No. The position
15 3-OCH 3 H 2 OH 1 N(CH 3) 2
16 3-OCH 3 H 2 O(CH 2) 2COOH 1 N(CH 3) 2
17 3-F H 2 OCO(CH 2) 2COOH 1 N(CH 3) 2
18 H H 2 OH 1 N(CH 3) 2
19 3-Cl H 2 H 2 N(CH 3) 2
20 H 5-Cl 2 H 2 N(CH 3) 2
21 H 3-OCH 3 2 H 2 N(CH 3) 2
In these chemical compounds, preferably use the No.14 of following formula (2) expression chemical compound,
Or with the chemical compound of the No.15 of following formula (3) expression.
As pharmaceutically useful salt, for example can list mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and nitric acid; Carboxylic acids such as acetic acid, propanoic acid, oxalic acid, succinic acid, adipic acid, maleic acid, tartaric acid, citric acid and benzoic acid; The salt of sulfonic acid such as toluenesulfonic acid and methanesulfonic acid etc.
As the chemical compound that prevents and/or treats agent and cerebral circulation metabolism improving agent that is used for chronic brain circulatory disturbance involved in the present invention, particularly preferably be (±)-1-(O-(2-(m-methoxyphenyl) ethyl) phenoxy group)-3-(dimethylamino)-2-propyl group hydrogen succinate ester hydrochloride, be sarpogrelate hydrochloride (Sarpogrelate Hydrochloride) with following formula (4) expression.
Figure A20058000390600111
Can utilize method that special public clear 63-13427 communique put down in writing or the method manufacturing that is consistent with it aminoalkoxy bibenzyl with general formula (1) expression.In addition, it is just passable to make the hydrate or the solvate of its pharmaceutically useful salt, aminoalkoxy bibenzyl or this salt according to method in common in this field.In addition, sarpogrelate hydrochloride is commercially available with Anplag (Anplag, registered trade mark) by Mitsubishi Pharmaceutical Corp as the medicine of effective ingredient, also can use Anplag in the present invention.
Chronic cerebral circulatory failure involved in the present invention prevent and/or treat agent and cerebral circulation metabolism improving agent, can use any means administration.As medication, for example can list the non-oral administration that subcutaneous injection, intravenous injection and intramuscular injection etc. utilize injection; Utilize the oral administration of tablet, capsule, powder, liquor and elixir etc.
The dosage that prevents and/or treats agent and cerebral circulation metabolism improving agent of chronic cerebral circulatory failure involved in the present invention can suitably determine according to patient's age, health status, body weight etc.Usually, with 0.5～50mg/kg body weight/day, be preferably 1～30mg/kg body weight/day, once or be divided into multiple dosing.
After suitable ratio mixed amino alkoxyl bibenzyl or its officinal salt or these hydrate or solvate and general preparations carrier, can modulate non-oral Preparation or oral Preparation by common method.
Embodiment
Below, specifically describe the present invention by embodiment, but only otherwise exceed its purport, the present invention is not subjected to the qualification of the following examples.
Embodiment 1
(method)
60 years old or 74 (40 of male, 34 of women) (tables-2) of the full patient of above tip circulation are divided into two groups, to ticlopidine group (43) administration ticlopidine hydrochloride 300mg/ day, to Sarpogrelate group (31) administration sarpogrelate hydrochloride 300mg/ day, continue 2 years.The mean age of ticlopidine group and Sarpogrelate group, men and women's ratio, mean blood pressure do not have significant difference.
(table 3)
Table-2
The Sarpogrelate group The ticlopidine group
Male/female (people) 17/14 23/20
Age (year) 71.6±6.4 72.6±5.6
Scope (60～83) (60～84)
60 years old or more than 12 people (38.7%) 11 people (25.6%)
70 years old or more than 16 people (51.6%) 27 people (62.8%)
80 years old or more than 3 people (9.7%) 5 people (11.6%)
Mean blood pressure (mmHg) 96.1±10.4 97.7±8.8
Scope (mmHg) (60～110) (76～113)
After measuring mean blood pressure, from 12 electrodes (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1, O2) according to international ten-twenty electrode system configuration, E.E.G when having measured quiet closing one's eyes 16 seconds with E.E.G meter (have EEG7314 type ATAMAP II, Japanese photoelectricity society make).Measure E.E.G at 2-8Hz (slow wave), 8-13Hz (α ripple), these 3 kinds of frequency bands of 13-30Hz (fast wave), represent the average % power (power) of slow wave (% slow wave), α ripple (% α ripple) and fast wave (% fast wave) with each frequency band for the ratio of full range band.
With on average ± standard deviation represents mean blood pressure, % slow wave, % α and % fast wave, compare in the front and back of test in 2 years.In addition, at region-wide (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1, O2), fore head (Fp1, Fp2, F3, F4, F7, F8, C3, C4) and the occiput (T5, T6, O1, O2) of brain, poor (the △ mean blood pressure) of mean blood pressure, poor (△ slow wave) and poor (the △ fast wave) of % fast wave of % slow wave have been compared.Use t-check (Student ' s t check or Wei Erkesong t-check) and pairing t-check, and p＜0.05 regarded as have significance
(result)
1) mean blood pressure
Mean blood pressure changes from 97.7 ± 8.8mmHg to 98.2 ± 10.5mmHg in the ticlopidine group, changes from 96.1 ± 10.4mmHg to 94.9 ± 12.6mmHg in the Sarpogrelate group.In addition, the △ mean blood pressure is 0.4 ± 9.6mmHg in the ticlopidine group, is-1.3 ± 9.2mmHg in the Sarpogrelate group.In ticlopidine group and Sarpogrelate group, mean blood pressure, △ mean blood pressure all do not have significant difference.
2) E.E.G
A) region-wide
The % slow wave of ticlopidine group, % α and % fast wave be from 46.1 ± 16.4% to 47.7 ± 16.5%, from 37.0 ± 14.3% to 36.5 ± 15.9%, from 16.9 ± 8.5% to 15.8 ± 7.3% variations respectively, but do not have significant difference.
The % slow wave of Sarpogrelate group shows the tendency of from 47.7 ± 13.5% to 43.1 ± 13.1% reduction.(p＝0.095)。In addition, % α and % fast wave from 38.2 ± 12.5% to 42.2 ± 12.3%, from 14.1 ± 5.2% to 14.7 ± 5.7% change, but do not have significant difference.
Compare △ slow wave descend significantly (1.5 ± 12.8% with respect to-4.5 ± 14.6%, p=0.062) in the Sarpogrelate group with the ticlopidine group.On the other hand, △ α and △ fast wave do not have significant difference (0.4 ± 12.4% with respect to 4.0 ± 14.2% ,-1.1 ± 6.1% with respect to 0.5 ± 6.0%).
B) fore head
In ticlopidine group and Sarpogrelate group, % slow wave, % α and % fast wave and △ slow wave, △ α and △ fast wave do not have significant difference.
C) occiput
In the ticlopidine group, % slow wave, % α and % fast wave and △ slow wave, △ α and △ fast wave do not have significant difference.
In the Sarpogrelate group, % slow wave from 14.0 ± 5.0% to 12.0 ± 4.6% reduces (p=0.024) significantly.In addition, % α from 14.6 ± 4.7% to 16.4 ± 4.4% increases (p=0.049) significantly.
Compare with the ticlopidine group, the △ slow wave reduces (0.7 ± 4.5% with respect to-2.0 ± 4.8%, p=0.013) significantly in the Sarpogrelate group, and △ α increases (0.5 ± 4.2% with respect to 1.8 ± 4.9%, p=0.034) significantly.
3) relation of △ slow wave and △ α and △ mean blood pressure
A) brain is region-wide
In the ticlopidine group, be-scope of 2mmHg～19mmHg (in the △ mean blood pressure-2～19mmHg) with good conditionsi, to observe between △ mean blood pressure and △ slow wave and have remarkable negative correlation (correlation coefficient in the △ mean blood pressure; R=0.37034, p value; P=0.0369).In addition, be in the scope of-6～19mmHg in the △ mean blood pressure, observe and between △ mean blood pressure and △ α, have significant positive correlation (r=0.39395, p=0.0211).
In the Sarpogrelate group,, observe and between △ mean blood pressure and △ α, have positive correlation (r=0.37572, p=0.0407) in the scope of-25～18mmHg.
In the scope of above-mentioned △ mean blood pressure, the △ mean blood pressure that the △ slow wave becomes positive number is 7.1mmHg in the ticlopidine group.In addition, in the scope of this △ mean blood pressure, the △ mean blood pressure that △ α becomes negative is 5.1mmHg in the ticlopidine group, in the Sarpogrelate group be-8.2mmHg.
B) fore head
In the ticlopidine group, in the △ mean blood pressure be-scope of 2mmHg～19mmHg in, observe and between △ mean blood pressure and △ α, have negative correlation (r=0.38991, p=0.0274).In addition, be in the scope of-12～19mmHg in the △ mean blood pressure, observe and between △ mean blood pressure and △ α, have positive correlation (r=0.33214, p=0.0446).
In the Sarpogrelate group, be in the scope of-25～13mmHg in the △ mean blood pressure, observe and between △ mean blood pressure and △ α, have positive correlation (r=0.39250, p=0.0352).
In the scope of above-mentioned △ mean blood pressure, the △ mean blood pressure that the △ slow wave becomes positive number is 5.9mmHg in the ticlopidine group.In addition, in the scope of this △ mean blood pressure, the △ mean blood pressure that △ α becomes negative is 12.9mmHg in the ticlopidine group, in the Sarpogrelate group be-10.2mmHg.
C) occiput
In the ticlopidine group, in △ mean blood pressure with good conditionsi is in the scope of 10～19mmHg, observes have negative correlation (r=0.89053, p=0.0173) between △ mean blood pressure and the △ slow wave, have positive correlation (r=0.85160, p=0.0314) between △ mean blood pressure and △ α.
In the Sarpogrelate group, be-25 in the △ mean blood pressure～-scope of 3mmHg in, observe and between △ mean blood pressure and △ slow wave, have negative correlation (r=0.65924, p=0.0381).In addition, be in the scope of-25～19mmHg in the △ mean blood pressure, observe and between △ mean blood pressure and △ α, have positive correlation (y=0.200x+2.0436, r=0.37873, p=0.0356).
In the scope of above-mentioned △ mean blood pressure, the △ mean blood pressure that the △ slow wave becomes positive number is 14.3mmHg in the ticlopidine group, in the ticlopidine group is-14.7mmHg.In addition, in the scope of this △ mean blood pressure, the △ mean blood pressure that △ α becomes negative is 12.9mmHg in the ticlopidine group, in the Sarpogrelate group be-10.2mmHg.
The effect that ticlopidine hydrochloride and sarpogrelate hydrochloride all have platelet aggregation inhibitor effect and improve the erythrocyte deformability, but ticlopidine hydrochloride does not change mean blood pressure and E.E.G, on the other hand, sarpogrelate hydrochloride reduces occipital slow wave, increase α ripple in the mode that does not change mean blood pressure.This expression, cerebral circulation metabolism improvement effect is not to have the effect that the medicine of antiplatelet effects all has, but the peculiar effect of aminoalkoxy bibenzyl.
According to above-mentioned test as can be known, the aminoalkoxy bibenzyl has the effect that activates cerebral circulation metabolism.Therefore, the aminoalkoxy bibenzyl can be used as the cerebral circulation metabolism improving agent, the disease that causes by brain circulatory disturbance prevent and/or treat agent.At this, the disease as being caused by brain circulatory disturbance can list coronary artery disease; Peripheral circulation disorderses such as chronic arteria occlusion disease, Arteriosclerosis obliterans; Ischemic cerebral vascular obstacles such as chronic cerebral circulatory failure, transient ischemic attack, vertebra arteria basilaris circulatory disturbance disease, cerebral thrombosis etc., wherein chronic cerebral circulatory failure preferably.
Industrial applicibility
The aminoalkoxy bibenzyl is owing to have the effect that activates cerebral circulation metabolism, thus can be used as the cerebral circulation metabolism improver, by the agent that prevents and/or treats of the disease of brain circulatory disturbance initiation. In addition, the application number that the application requires to propose in Japan is the priority of 2004-25285, and its full content is all incorporated in this specification.

Claims (8)

  1. A chronic cerebral circulatory failure prevent and/or treat agent, it is characterized in that, comprise aminoalkoxy bibenzyl or its pharmaceutically useful salt or these hydrate or solvate with following general formula (1) expression,
    Figure A2005800039060002C1
    (in the formula, R 1Expression hydrogen atom, halogen atom, C 1～C 5Alkoxyl or C 2～C 6Dialkyl amido, R 2Expression hydrogen atom, halogen atom or C 1～C 5Alkoxyl, R 3Expression hydrogen atom, hydroxyl, C 2～C 5Acyloxy ,-O-(CH 2) n-COOH (in the formula, n represents 1～5 integer) or O-CO-(CH 2) l-COOH (in the formula, l represents 1～3 integer), R 4Expression-N (R 5) (R 6) (in the formula, R 5And R 6Represent hydrogen atom or C respectively independently 1～C 8Alkyl) or the expression
    Figure A2005800039060002C2
    (in the formula, A represents to use the C of carboxyl substituted 3～C 5Alkylidene), m represents 0～5 integer.〕
  2. Chronic cerebral circulatory failure according to claim 1 prevent and/or treat agent, it is characterized in that the chemical compound of aminoalkoxy bibenzyl for representing with following formula (2)
  3. Chronic cerebral circulatory failure according to claim 1 prevent and/or treat agent, it is characterized in that the aminoalkoxy bibenzyl is the chemical compound with following formula (3) expression
  4. 4. according to the agent that prevents and/or treats of each described chronic cerebral circulatory failure in the claim 1 to 3, wherein, pharmaceutically useful salt is hydrochlorate.
  5. 5. a cerebral circulation metabolism improving agent is characterized in that, comprises aminoalkoxy bibenzyl or its pharmaceutically useful salt or these hydrate or solvate with following general formula (1) expression,
    Figure A2005800039060003C3
    (in the formula, R 1Expression hydrogen atom, halogen atom, C 1～C 5Alkoxyl or C 2～C 6Dialkyl amido, R 2Expression hydrogen atom, halogen atom or C 1～C 5Alkoxyl, R 3Expression hydrogen atom, hydroxyl, C 2～C 5Acyloxy ,-O-(CH 2) n-COOH (in the formula, n represents 1～5 integer) or O-CO-(CH 2) l-COOH (in the formula, l represents 1～3 integer), R 4Expression-N (R 5) (R 6) (in the formula, R 5And R 6Represent hydrogen atom or C respectively independently 1～C 8Alkyl) or the expression
    Figure A2005800039060004C1
    (in the formula, A represents to use the C of carboxyl substituted 3～C 5Alkylidene), m represents 0～5 integer.〕
  6. 6. cerebral circulation metabolism improving agent according to claim 5 is characterized in that, the aminoalkoxy bibenzyl is the chemical compound with following formula (2) expression
  7. 7. cerebral circulation metabolism improving agent according to claim 5 is characterized in that, the aminoalkoxy bibenzyl is the chemical compound with following formula (3) expression
    Figure A2005800039060004C3
  8. 8. according to each described cerebral circulation metabolism improving agent in the claim 5 to 7, wherein, pharmaceutically useful salt is hydrochlorate.
CNA2005800039068A 2004-02-02 2005-02-02 Preventive and/or therapeutic agent for chronic cerebral circulatory failure Pending CN1913881A (en)

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JP025285/2004 2004-02-02
JP2004025285 2004-02-02

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CN1913881A true CN1913881A (en) 2007-02-14

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