CN1098908A - The purposes of antioxidant hydroxy carbazole compounds neuroprotective and with the method for its treatment - Google Patents

The purposes of antioxidant hydroxy carbazole compounds neuroprotective and with the method for its treatment Download PDF

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CN1098908A
CN1098908A CN93120406A CN93120406A CN1098908A CN 1098908 A CN1098908 A CN 1098908A CN 93120406 A CN93120406 A CN 93120406A CN 93120406 A CN93120406 A CN 93120406A CN 1098908 A CN1098908 A CN 1098908A
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formula
carbon atoms
alkyl group
low alkyl
chemical compound
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CN1042795C (en
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F·C·巴龙尼
G·富尔斯坦
岳天立
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SmithKline Beecham Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Basically be selected from formula (I) chemical compound and pharmaceutically acceptable salt thereof as the new purposes of antioxidant neuroprotective and with the method for this compounds for treating, the new purposes of this antioxidant compound and can prevent to suffer from the oxidative tissue infringement that mammiferous organ, the particularly central nervous system of ischemic injury, particularly apoplexy due to the disease comprises brain with the method for this compounds for treating.R in the structural formula of described formula (I) chemical compound 7-R 13Reach being defined in the specification of A:
Figure 93120406.2_AB_0

Description

The purposes of antioxidant hydroxy carbazole compounds neuroprotective and with the method for its treatment
The present invention relates to formula I hydroxy carbazole compounds and pharmaceutically acceptable salt thereof is that antioxidant is used to protect vital organ, especially central nervous system to comprise that brain is avoided the new medical application of oxidative damage and with the method for this compounds for treating as oxygen free radical scavenger.Specifically; the invention provides the new purposes that this hydroxy carbazole compounds is used to prepare Pharmaceutical composition; described Pharmaceutical composition can be used for preventing organ to pour into (reperfusion) damage again; comprise relevant acute inflammation; neuroprotective particularly; promptly protect the central nervous system to avoid damage and the damage back damage (post-traumatic injury) relevant with apoplexy, for example prevention of stroke and nerve injury, and can reduce by the sickness rate due to the apoplexy sequela.The structure of described formula I hydroxy carbazole compounds is as follows:
In the formula
R 7-R 13Respectively do for oneself-H or-OH; And
A is respectively-H ,-OH or formula II part down:
Figure 931204062_IMG11
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
In developed country, with the ischemic injury of vital organ due to the disease as seen in apoplexy to the relevant M ﹠ M of situation be major health.
A large amount of biochemistry, physiology and pharmacology's evidence support such one to find and importance, promptly in cardiac ischemia/reperfusion injury, oxygen-derived free radicals causes lipid peroxidation (LPO) (Meerson, F.Z. etc., Basic Res.Cardiol. (1982) 77,465-485; Downey, J.M., Ann.Rev.Physiol. (1990) 52,487-504).It is believed that reoxidizing of ischemic myocardial can produce O in this tissue 2And H 2O 2, they can be transformed into highly active hydroxyl radical free radical (OH) in the presence of transition metal ions, and this free radical causes this radical chain reaction of LPO, thereby the change and tissue injury (McCord, J.M., the N.Engl.J.Med. (1985) that cause cell membrane integrity, 312,159-163; McCord, J.M., Fed.Proc., (1987) 46,2402; Kagan, V.E., Lipid Peroxidation in Biomembranes, (1988) CRC Press, Boca Raton Florida).Reoxidize after the remarkable activation of LPO and the temporary transient ischemia in the experimental myocardial infarction and be proved (Meerson etc., 1982; Rao etc., Adv.Exp.Med.Biol., (1983) 161,347-363).Myocyte or whole heart are exposed in the system that produces oxidant can produce serious damage, comprises the Ca of the dependency ATP of myocardium endoplasmic reticular structure 2+Complexation masking system (sequestering system) inactivation (Halliwell, B. and Gutteridge, J.M.C.Free Radicals in Biology and Medicine, second edition (1989), Clarendon Press, Oxford, England, 442-444).Also the someone reports recently, and blood plasma LPO level significantly increases in suffering from the patient of myocardial infarction, especially in postictal initial 48 hours (Loeper etc., Clinica Chimica Acta, (1991) 196,119-126).LPO further (is summarized at different ischemia models by following substances in the important function aspect the tissue injury relevant with ischemia with oxygen-derived free radicals; see Halliwell and Gutteridge; 1989) protective effect in is supported: natural or synthetic antioxidant is vitamin E and Lazaroid U-74500A(Levitt for example; M.A.; Clin.Res. (1991) 39,265A) or antioxidase for example superoxide dismutase (SOD) and catalase.
In developed country; vital organ, particularly central nervous system comprise ischemic injury due to the disease of brain for example for example the rate known occurred frequently of apoplexy and sequela thereof are together with the patient's who is subjected to these damages high viability that the vital organ that all is sought after preventing such damage and the protection damage back patient in recovering avoids the medicament of organ ischemic damage and reperfusion damage.
It is that antioxidant is used to protect vital organ to avoid the new medical application of oxidative damage as oxygen free radical scavenger that first aspect of the present invention provides the formula I hydroxy carbazole compounds.Particularly, the invention provides preferably be selected from basically substituent group in the formula for as the formula I chemical compound or the new purposes of its pharmaceutically acceptable salt: the A that give a definition be the formula II part, R wherein 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH, and R 6Be-H, and R 7, R 9Or R 10One of be-OH; In the described formula I chemical compound, with substituent group in the formula for as the formula I chemical compound of giving a definition or its pharmaceutically acceptable salt for most preferably: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH, and R 6Be-H, and R 7Be-OH; Described chemical compound is used to prepare Pharmaceutical composition, and this Pharmaceutical composition can be used for preventing the organ reperfusion injury, generally comprises relevant acute inflammation, and especially for neuroprotective, promptly prevention of stroke and reduction are by the sickness rate due to the apoplexy sequela.
Second aspect of the present invention is that a kind of Therapeutic Method also is provided, this method is used for preventing the mammiferous oxidative tissue infringement of suffering from the organ of ischemic injury due to the disease, neuroprotective particularly, i.e. prevention of stroke and reducing by the sickness rate due to the apoplexy sequela; Described method comprises mammal to needs, preferably the people takes formula I chemical compound or its pharmaceutically acceptable salt of effective dose, in the described formula I chemical compound, basically in the preferred formula substituent group for as the formula I chemical compound or its pharmaceutically acceptable salt: the A that give a definition be the formula II part, R wherein 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH, and R 6Be-H, and R 7, R 9Or R 10One of be-OH; With substituent group in the formula is the most preferred as formula I chemical compound or its pharmaceutically acceptable salt of giving a definition: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH, and R 6Be-H, and R 7Be-OH.
United States Patent (USP) discloses time formula III carbazyl-(4)-oxidation Propanolamine chemical compound and pharmaceutically acceptable salt thereof for No. 4503067:
Figure 931204062_IMG12
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
This patent also discloses and has been called as your alcohol (carvedilol) (1-(carbazole-4-base oxygen base-3-[[2-(O-methoxy phenoxy group) ethyl of card dimension ground more] amino]-the 2-propanol) the formula III chemical compound, its structure is formula IV down:
These chemical compounds are medicines of the new multiple effect of tool, and your alcohol of card dimension ground is one of them example, and they can be used for slightly reducing hypertension and can be used for treating angina pectoris and congestive heart failure (CHF).Your alcohol of card dimension ground is known to be competitive β-adrenoreceptor antagonist and vasodilation, also is calcium-channel antagonists when higher concentration.You are pure when being used for the treatment of hypertension on card dimension ground, and its vasorelaxation action is mainly by α 1Due to the blocking-up of-adrenoreceptor, and the β of this medicine-adrenoreceptor blocking-up activity can be prevented reflex tachycardia.It is effective antihypertensive to mammal, particularly people that these various effects of your alcohol of card dimension ground make this medicine, and can be used for treating angina pectoris and CHF.
When ischemic organ injury such as apoplexy, the cell of a high proportion of ischemia organ is subjected to irreversibly damaging and becoming non-viable non-apoptotic cell, and degree of injury depends on the length of damaging the time of keeping as arterial occlusion.This infringement and necrosis during the obturation that produces when pouring into again after protecting central nervous system neurons to avoid apoplexy and damage are essential to the therapeutic purposes that reach recovery function of nervous system; This character is to represent with " neuroprotective " and its synonym in this article.
Although traditional β-adrenoreceptor antagonist such as propranolol have significant protection action of the heart, they also often have bad side effect such as heartbeat low, diastolic pressure raises and total peripheral resistance increases with heart and suppresses.But it is effective heart protective agent when resisting hypertension dosage that formula III carbazyl-(4)-oxidation Propanolamine chemical compound, particularly card are tieed up your alcohol of ground, and they unexpectedly make these influences reduce to minimum.When resisting hypertension dosage, during just can providing acute myocardial infarction, the β-adrenoreceptor blocking-up of your alcohol of card dimension ground and the combination of vasodilation characteristic reach Cardioprotective afterwards.It is believed that, thus β-adrenoreceptor antagonist the protection action of the heart under this dosage condition be since by reduce that cardiac muscle load has improved that myocardial oxygen is given and damage between balance due to, this produces insecondary heart rate and contractility reduces.
Some formula I chemical compounds are known to be that card dimension ground that alcohol is at human and the intravital metabolite of other mammal (as pallasiomy).Preferred chemical compound of the present invention promptly is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7, R 9Or R 10One of be-OH; These chemical compounds are known to be the metabolite of your alcohol of card dimension ground.
By studying with electron paramagnetic resonance (EPR), our recent findings: the formula I hydroxy carbazole compounds is an oxygen free radical scavenger.We also find: above-claimed cpd has inhibitory action as oxygen scavenger to LPO; in addition; surprisingly, the formula I hydroxy carbazole compounds behind ischemic injury common prevention with because the LPO oxidative tissue damages aspect the relevant morbid state widely of organ is effective protective agent.Particularly, The compounds of this invention especially can be used for neuroprotective, that is: prevention of stroke and reduction are because the sickness rate due to the sequela of apoplexy.
As following further specifying, the formula I compound exhibits goes out the effect of neuroprotective, the oxidative tissue infringement that especially can be used for protecting cerebral tissue to avoid apoplexy and nerve injury and be used to prevent ischemia patient cerebral tissue after ischemia situation such as apoplexy or brain injury take place; In the described formula I chemical compound, substituent group is the chemical compound as giving a definition in the preferred formula basically: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7, R 9Or R 10One of be-OH, with substituent group in the formula for as the formula I chemical compound of giving a definition the most preferred: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7Be-OH.Therefore, take these chemical compounds for a long time and both can reduce the danger that dangerous individual cerebral ischaemia or apoplexy take place, also can after the cerebral ischaemia situation takes place, provide auxiliary treatment by the degree that alleviates the oxidative tissue infringement.Because the danger that the hypertension individuality suffers stroke increases, the purposes of The compounds of this invention neuroprotective matches with antihypertensive treatment under suitable administering mode, can significantly reduce the danger of this patient's apoplexy and apoplexy sequela.
According to the present invention, the formula I chemical compound can be used for human neuroprotective, and dosage is in the quiet notes of about 1-3mg/kg(, twice of every day) and 3-30mg/kg(oral, twice of every day) scope in; In the described formula I chemical compound, substituent group is the formula I chemical compound as giving a definition in the preferred formula basically: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7, R 9Or R 10One of be-OH, with substituent group in the formula for as the formula I chemical compound of giving a definition the most preferred: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7Be-OH.
The present invention also provides Therapeutic Method, and it is used to prevent the mammiferous oxidative tissue infringement of suffering from the organ of ischemic injury due to the disease; Described method comprises mammal to needs, preferably the people takes formula I chemical compound or its pharmaceutically acceptable salt of effective dose, in the described formula I chemical compound, basically in the preferred formula substituent group for as the formula I chemical compound or its pharmaceutically acceptable salt: the A that give a definition be the formula II part, R wherein 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H, and R 7, R 9Or R 10One of be-OH, with substituent group in the formula for as formula I chemical compound or its pharmaceutically acceptable salt of giving a definition the most preferred: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H and R 7Be-OH.
The formula I chemical compound can prepare with the method described in the embodiment 1 easily.
The Pharmaceutical composition that is used for the formula I chemical compound of neuroprotective according to the present invention can be mixed with solution or the freeze dried powder that is used for parenteral administration.Powder can with preceding by add suitable diluent or other pharmaceutically acceptable carrier is prepared temporarily.Liquid preparation generally is buffered, isoosmotic aqueous solution.The example of suitable diluent is the normal isotonic saline solution of standard, 5% D/W or the buffered sodium acetate or the ammonium acetate solution of standard.Such preparation especially is suitable for parenteral administration, but also can be used for orally, and perhaps metered dosage is packed into and used the insufflation administration in inhaler or the aerosol apparatus.Preferably add excipient for example ethanol, polyvinylpyrrolidone, gelatin, hydroxylated cellulose, arabic gum, Polyethylene Glycol, mannitol, sodium chloride or sodium citrate.
Perhaps, these chemical compounds can be made into capsule, tablet or make Emulsion or syrup is used for oral administration.Can add pharmaceutically acceptable solid or liquid-carrier to strengthen or stable said composition, perhaps be convenient to prepare said composition.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, glycerol, saline, second alcohol and water.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, Gypsum Fibrosum powder, magnesium stearate or stearic acid, Pulvis Talci, pectin, arabic gum, agar or gelatin.Carrier also can comprise monostearin or the glycerol distearate that slow-release material is for example independent, or the mixture of they and wax.The amount of solid carrier is indefinite, but preferably between the about 20mg to 1g of every dosage unit.Pharmaceutical formulation comprises pulverizing, mixing, granulates and be pressed into tablet form when needs by following pharmacy routine techniques preparation; Perhaps pulverize, mix and the hard capsule of packing into is made capsule form.When using liquid-carrier, preparation will be syrup, elixir, Emulsion or aqueous or non-aqueous form of suspension.Such liquid preparation can be directly oral or be loaded into soft capsule.
The following example is used as purely and illustrates, and the preparation method of The compounds of this invention is provided, and the scope that does not limit the present invention in any way.
In an embodiment, all temperature be Celsius temperature (℃).
Embodiment 1
Substituent group is for synthesizing and synthesize as the formula I chemical compound example a: R of approach as follows in the formula as the formula I chemical compound of giving a definition 7Be-OH and R 8-R 13All be-H, and A is formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH, and R 6Be-H.
3-benzyloxy-4-hydroxycarbazole
(881mg 2.73mmol) once adds to 4-hydroxycarbazole (500mg, ChCl 2.73mmol) in 25 ℃ with benzoyl peroxide 3(20ml) in the suspension.Mixture was stirred 2 hours, wash with water then.Organic layer also concentrates with dried over sodium sulfate.Residue gets 15mg3-benzyloxy-4-hydroxycarbazole after dodging chromatography (silica gel, dichloromethane).
MS（DCI/NH 3）∶304.2（M+H） +。
The step of generation product subsequently is well-known: with the reaction of 3-chloro-1,2 epoxy prapane, and then with the reaction of 2-methoxybenzene ethamine, and the saponification of last benzoate.
How above description produces and uses the present invention if fully disclosing.But the present invention is not subjected to the restriction of above-mentioned specific embodiment, and comprises the improvement within the scope of the following claims that they are all.

Claims (18)

1, be used for preventing the mammiferous Therapeutic Method of suffering from the oxidative tissue infringement of the organ of ischemic injury due to the disease, it comprises chemical compound that is selected from down formula I basically and the pharmaceutically acceptable salt thereof of taking effective dose to the mammal of needs:
Figure 931204062_IMG2
In the formula
R 7-R 13Respectively do for oneself-H or-OH, and
A is respectively-H ,-OH or formula II part down:
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
2, according to the Therapeutic Method of claim 1, wherein said mammal is the people.
3, according to the Therapeutic Method of claim 1, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is 0, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7, R 9Or R 10One of be-OH.
4, the Therapeutic Method that is used for mammiferous neuroprotective, it comprises to the mammal of needs takes chemical compound or its pharmaceutically acceptable salt that effective dose is selected from down formula I basically:
Figure 931204062_IMG4
In the formula
R 7-R 13Respectively do for oneself-H or-OH, and
A is respectively-H ,-OH or formula II part down:
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
5, according to the Therapeutic Method of claim 4, wherein said mammal is the people.
6, according to the Therapeutic Method of claim 4, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is 0, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7, R 9Or R 10One of be-OH.
7, according to the Therapeutic Method of claim 6, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is 0, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7Be-OH.
8, be used to protect the Therapeutic Method of apoplexy survival patient's nerve, it comprises that patient to needs takes the Pharmaceutical composition according to the chemical compound of claim 1 of containing of effective dose, and described treatment can be lowered the danger of oxidative damage cerebral tissue.
9, according to the Therapeutic Method of claim 1, wherein said chemical compound is used to prepare the Pharmaceutical composition that is suitable for parenteral administration.
10, be selected from down the chemical compound of formula I and pharmaceutically acceptable salt thereof basically and suffer from purposes aspect the mammiferous organ of ischemic injury due to the disease in the infringement of prevention oxidative tissue:
Figure 931204062_IMG6
In the formula
R 7-R 13Respectively do for oneself-H or-OH, and
A is respectively-H ,-OH or formula II part down:
Figure 931204062_IMG7
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
11, according to the purposes of claim 10, wherein said mammal is the people.
12, according to the purposes of claim 10, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7, R 9Or R 10One of be-OH.
13, be selected from down the chemical compound or the purposes of its pharmaceutically acceptable salt aspect the protection mammalian nervous of formula I basically:
Figure 931204062_IMG8
In the formula
R 7-R 13Respectively do for oneself-H or-OH, and
A is respectively-H ,-OH or formula II part down:
Figure 931204062_IMG9
In the formula
R 1Be hydrogen, be no more than the lower alkane acyl group of 6 carbon atoms or be selected from benzoyl or the aroyl of naphthoyl,
R 2Be hydrogen, be no more than the low alkyl group of 6 carbon atoms or be selected from the aryl alkyl of benzyl, phenylethyl and phenyl propyl,
R 3Be hydrogen or the low alkyl group that is no more than 6 carbon atoms,
R 4Be hydrogen or the low alkyl group that is no more than 6 carbon atoms, perhaps when X is oxygen, R 4And R 5Can represent together-CH 2-O-,
X be valence bond ,-CH 2-, oxygen or sulfur,
Ar is selected from phenyl, naphthyl, 2,3-indanyl and tetralyl,
R 5And R 6Be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl separately, be no more than 6 carbon atoms low alkyl group ,-CONH 2-group, the lower alkoxy that is no more than 6 carbon atoms, benzyloxy, be no more than 6 carbon atoms lower alkylthio, be no more than the low alkyl group sulfinyl of 6 carbon atoms and be no more than the low alkyl group sulfonyl of 6 carbon atoms, perhaps R 5And R 6Represent methylene-dioxy together.
14, according to the purposes of claim 13, wherein said mammal is the people.
15, according to the purposes of claim 13, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7, R 9Or R 10One of be-OH.
16, according to the purposes of claim 15, wherein said chemical compound is that substituent group is the formula I chemical compound as giving a definition in the formula: A is the formula II part, wherein R 1Be-H R 2Be-H R 3Be-H R 4Be-H, X is O, and Ar is a phenyl, R 5Be neighbour-OH and R 6Be-H; And R 7Be-OH.
17, according to the purposes of the chemical compound of claim 13, it is used to protect apoplexy survival patient's nerve, and described purposes can lower the danger of oxidative damage cerebral tissue.
18, according to the purposes of claim 13, wherein said Pharmaceutical composition is suitable for parenteral administration.
CN93120406A 1992-12-01 1993-12-01 Antioxidant neuroprotective use of, and method of treatment using hydroxycarbazole compounds Expired - Fee Related CN1042795C (en)

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WO1997040680A1 (en) * 1996-04-29 1997-11-06 Smithkline Beecham Corporation Antioxidant compound
AU3542697A (en) * 1996-07-13 1998-02-09 Boehringer Mannheim Gmbh Pharmaceutical formulations for topical application containing as an active ingredient carbazolyl-(4)-oxy-propanol amine derivate
US6369106B1 (en) * 1996-12-26 2002-04-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Treatment of ischemic brain injuries with brain targeted anti oxidant compounds
JPH10251147A (en) * 1997-03-06 1998-09-22 Akira Matsumori Preventing and/or treating agent for inflammatory disease
AR035455A1 (en) * 2001-04-23 2004-05-26 Hoffmann La Roche TRICYCLE DERIVATIVES OF ALQUILHIDROXAMATO, PROCESSES FOR THEIR DEVELOPMENT, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THE USE OF SUCH COMPOUNDS IN THE PREPARATION OF MEDICINES

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KR950703950A (en) 1995-11-17
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AU5732394A (en) 1994-06-22
JPH08503711A (en) 1996-04-23
CA2150695A1 (en) 1994-06-09
EP0671914A4 (en) 1995-10-25
ZA938897B (en) 1994-08-01
CN1042795C (en) 1999-04-07

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