CN1450896A - Use of indole derivatives for intracular pressure for reducing - Google Patents

Use of indole derivatives for intracular pressure for reducing Download PDF

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CN1450896A
CN1450896A CN01815096A CN01815096A CN1450896A CN 1450896 A CN1450896 A CN 1450896A CN 01815096 A CN01815096 A CN 01815096A CN 01815096 A CN01815096 A CN 01815096A CN 1450896 A CN1450896 A CN 1450896A
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indole
unsubstituted
alkynyl
acetylaminohydroxyphenylarsonic acid
acid ethyl
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J·J·平特
M·A·佩拉尔
W·M·彼德森
R·小普罗德
E·G·布朗
B·R·耶扎
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Madrid Commscope Rutan Adams University
Inspire Pharmaceuticals Inc
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Madrid Commscope Rutan Adams University
Inspire Pharmaceuticals Inc
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention provides a method of reducing intraocular pressure by administering pharmaceutical compositions comprising indole derivatives. The pharmaceutical compositions useful in this invention comprise indole derivatives and melatonin analogs of Formulae I-IV. A preferred embodiment is a method of lowering intraocular pressure using 5-(methoxycarbonylamino)-N-acetyltryptamine (5-MCA-NAT), also known as GR 135531, which has a prolonged duration of action and greater efficacy in lowering intraocular pressure compared to melatonin. The present invention further provides a method of treating disorders associated with ocular hypertension, and a method of treating various forms of glaucoma; the method comprises administering an effective dose of a pharmacuetical composition comprising an indole derivative with or without agents commonly used to treat such disorders.

Description

Reduce the method for intraocular pressure with indole derivatives
The Spain that the application requires to be filed on July 28th, 2000 applies for P200001916 number priority.The application also requires to be filed in the priority of No. 60/276,885, the U.S. Provisional Application in March 16 calendar year 2001.
Technical field
The present invention relates to that a kind of indole analogs thing and pharmaceutical composition reduce intraocular pressure, the treatment intraocular pressure is too high and treat glaucomatous method by using.
Background of invention
Glaucoma is a kind of disease of the blinding of the slow development relevant with the chronic rising of intraocular pressure (IOP) usually.Very high and lasting intraocular pressure is considered to and can causes damage to papilla of optic nerve at optic nerve and amphiblestroid junction, causes amphiblestroid ganglion cells degeneration and causes the special visual deprivation of glaucoma.Yet IOP rising (being also referred to as ocular hypertension) causes the also clear understanding of glaucomatous mechanism.In addition, the patient of the typical visual field loss relevant of the part elevated IOP level (being called as ocular hypotension or normal tension glaucoma) that do not show abnormality with glaucoma.
Glaucoma mainly is divided into open-angle, angle-closure or congenital, also can be further divided into constitutional and Secondary cases.Glaucoma is treated with various pharmacologys and operation method.When glaucoma is relevant with ocular hypertension, pharmacological treatment comprises adrenergic agonist (epinephrine, dipevefrin, apraclonidine), cholinergic excitomotor (pilocarpine), Bextra (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide) or nearest prostaglandin analogue (latanoprost (latanoprost), Lumigan TM) and alpha-1 adrenergic excitomotor (brimonidine).These pharmacological method or produce aqueous humor by suppressing corpus ciliare, otherwise it is easier that girder or uvea sclera aqueous humor are flowed out, thus help to make IOP to recover normal pressure.Anticholinergic reduces the intraocular pressure of primary glaucoma, reduces the effusive resistance of aqueous humor.The anticholinergic inhibitor has been used to treat the secondary glaucoma of constitutional and some type, such as the aphakic glaucoma behind cataract extraction.Congenital glaucoma seldom respond to treatment, and it is normally by operative treatment.In NAG, at the sinus venous sclerae place inlet of trabecular space being freed from the retardance of iris to increase the outflow of aqueous humor, and this is the result of drug-induced iris sphincters contract.(Taylor, 123-125 page or leaf are seen The Pharmacological Basis of Therapeutics, the 7th edition, and A.G.Gilman, L.S.Goodman, T.W.Rall and R.Murad compile, MacMillan publishing company, New York (1985)).
In wide angle property or primary open angle glaucoma, the inlet of girder is not hindered by physics; The reticular tissue of this minor diameter hole of girder has lost their opening.The contraction of iris sphincter and ciliary muscle has increased the tonicity and the arrangement of trabecular reticulum, thereby promotes aqueous humor by absorption and outflow (Watson, the Br.J.Opthalmol.56:145-318 (1972) of this net to sinus venous sclerae; Schwartz, N.Engl.J.Med., 290:182-186 (1978); Kaufman etc., Handbook of Experimental Pharmacology69:149-192 (1984)).
The almost always medical emergency case of acute congestive (narrow angle) glaucoma, if the acute attack of drug main control at this moment, but control mainly is based on operation (periphery or total iridectomy) usually on a large scale.On the contrary, chronic simple (wide angle property) glaucoma be gradually, insidiousness outbreak, be difficult for usually improving with operation; Control of intraocular pressure depends on long periods of treatment.
Acute congestive glaucoma can allow the patient more than 40 years old use mydriatic because of unadvisable, or causes because of various meetings cause the factor of the platycoria or the ophthalmic congestion of blood vessel.Sign and symptom comprise tangible inflammatory eye, half-open big pupil, severe pain and feel sick.The purpose of treatment makes intraocular pressure be reduced to normal level when being outbreak.The compositions that anticholinergic inhibitor and parasympathomimetic agent constitute is splashed into conjunctival sac to bring into play maximum effect.Contain 5% physostigmine Salicylate solution and 4% pilocarpine nitrate solution in the normally used compositions.Auxiliary treatment comprises the secretion of intravenous administration carbonic anhydrase inhibitors (as acetazolamide (acetozolamide)) with the minimizing aqueous humor, or penetrating pharmaceutical (as mannitol or glycerol) is to induce the ophthalmic dehydration.Because the increase of the congestion of blood vessel and angle of anterior chamber retardance, long lasting organic phosphorus compound is not suitable for NAG.
Treatment to primary open angle glaucoma and secondary glaucoma comprises: (1) parasympathomimetic agent is (as pilocarpine nitrate, 0.5-0.6%); (2) fugitive (as, physostigmine Salicylate, 0.25-0.5%) or long-acting (demecarium bromide, 0.125-0.25%; The iodide of diethoxyphosphinylthiocholine, 0.03-0.25%; Isoflurophate, 0.025%) the anticholinergic inhibitor; (3) Beta-3 adrenergic antagonist, as timolol maleate, this is a kind of per depot drug product of using once in 12 hours, it does not directly influence pupil but can reduce generation (Boger etc., the Am.J.Opthalmol.86:8-18 (1978) of aqueous humor; Lotti etc., Handbook of ExperimentalPharmacology69:249-278 (1984)) and can avoid the part retardance of regulating action and the ill effect of long-acting anticholinesterase drug; And unusual, (4) sympathomimetic (as, epinephrine, 0.25-2%, phyenlephrinium, 10%), when being used in combination with anticholinergic inhibitor or cholinergic excitomotor, they are the most effective.Thereby they reduce intraocular pressure by the secretion that reduces aqueous humor, and prevent the hyperemia of little blood vessel.
Because cholinergic excitomotor and cholinesterase inhibitor have hindered adjusting, they make sees and occurs when far away of short duration fuzzyly that this takes place after using relative higher dosage at short notice usually.If chronic administration cholinergic excitomotor and cholinesterase inhibitor then can reduce owing to acetylcholinergic receptor quantity reduces this reaction.
Although long-acting anticholinesterase drug has not the convenience and the high efficiency of frequent medication, use long-acting anticholinesterase drug to be and crystalline lens huge risk muddy and occurs and link to each other the ill effect of autonomic nerve.Organic phosphates medicine DFP has the longest action time, and is effective especially when use the part; The solution made from Oleum Arachidis hypogaeae semen or Oleum sesami needs extremely use once weekly every day, and may control intraocular pressure in the serious case that other medicines is had resistance.Because Most patients is disliked oiliness carrier, DFP is replaced by diethoxyphosphinylthiocholine.
With the U.S. bromo-amine in effective long-acting anticholinergic medicated bag ground, diethoxyphosphinylthiocholine and isoflurophate) treatment glaucoma 6 months or longer time be relevant with cataractous excessive risk occurring.(Axelsson etc., ActaOpthalmol. (Kbh.) 44:421-429 (1966); De Roetth, J.A.M.A.195:664-666 (1966); Shaffer etc., Am.J.Opthalmol.62:613-618 (1966)).Although cataractous to appear in the untreated comparable age cohort be common, the generation of crystalline lens muddiness can reach 50% in this case, and its risk and solution strength, medicine frequency, treatment time and patient age increase pro rata.(Laties, Am.J.Opthalmol.68:848-857 (1969); Kaufman etc., the 149-192 page or leaf is seen Pharmacology of the Eye, Handbook of Experimental Pharmacology, 69 volumes, M.L.Sears compiles, Springer-Verlag, Berlin, (1984)).
In the time can glaucoma can being controlled, then do not recommend to use long-acting anticholinesterase drug with timolol, parasympathomimetic agent, physostigmine or other medicines.However, because inappropriate control, glaucoma can cause the irreversible blindness, and when other medicament was invalid, long-acting cholinesterase inhibitor still had their treatment importance.
It is found that, every day 1-5 time is single with pilocarpine (4%) or share physostigmine (0.2%) and treat, can not make the muddy occurrence rate of crystalline lens be higher than the spontaneous occurrence rate (Axelsson that in comparable age group, does not treat among the patient, Acta Opthalmol. (Kbh., Suppl.102,1-37 (1969)).Therefore, pilocarpine and other fugitive miotic can be used to control intraocular pressure.If invalid, before using effective long-acting anticholinesterase drug, must weigh the danger of cataract appearance and the danger of rising intraocular pressure.Yet, the patient must be at interval 6 months or shorter time the crystalline lens muddiness is checked.
Estimate other the glaucomatous new drug of treatment, comprised A 3Hypotype adenosine receptor antagonists, calmodulin, CaM antagonist and antiestrogen (WO00/03741); Oligonucleotide can replace its phosphate ester, sugar or base or modify, so that reduce intraocular pressure (United States Patent (USP) 5,545,626); One class is by non-armaticity azabicyclic system with arbitrarily by the derivant (United States Patent (USP) 5,219,849) of the pyrazine, pyrimidine and the pyridazine that replace of two substituent groups in addition at the most; And the analog latanoprost of prostacyclin (Higginbotham, Arch.Opthalmol.114:998-999 (1996)).The glaucomatous chemical compound of long-term control that is used for that four classes have clinical efficacy includes carbonic anhydrase inhibitors, selectivity alpha-2 adrenergic excitomotor, prostaglandins and the acidum ethacrynicum (Serle, Drugs Aging5:156-170 (1994)) of Topically active.
The side effect of contingent various eye has headache, metopodynia, the dimness of vision, crystalline lens thorn to open (phacodinesis), circumcorneal congestion, congested iritis, various allergy and rare detachment of retina behind the instillation anticholinergic inhibitor.When frequent instillation anticholinergic inhibitor in conjunctiva, thereby the effect that causes various generals can take place to absorb fully, this is owing to acetylcholine esterase and butyryl-degree of inhibition of AchE are caused.Therefore, cholinergic autonomic function can improve, and has the acting duration of the local anesthetic of ester bond to prolong, and the inductive neuromuscular blockade of succinylcholine strengthens and prolonged simultaneously.Suffer from vagotonia and allergic individual special hazard.
Latanoprost (Xalatan ) be a kind of prostaglandins excitomotor, thus it is believed that it reduces IOP by increasing uveoscleral aqueous humor outflow.Latanoprost is the prodrug of isopropyl ester, and it is become to have the acid of biologic activity by esterase hydrolyzed in cornea.Xalatan Prescription for dosage once a day and with every day two doses 0.5% timolol same effect is arranged.Xalatan Can change eye color gradually by the amount that increases iris toffee pigment.This long term to iris is unknown.The eyelid skin blackening also is in the news and Xalatan Use relevant.In addition, Xalatan Can increase length, thickness, color and the quantity of eyelashes gradually.Macular edema comprises that cystoid macular edema can be at Xalatan Take place during treatment.These phenomenons mainly occur in aphakic patient, in the intraocular lens patient that posterior lens capsule is torn, or in the known patient that the macular edema paathogenic factor arranged.((Ophthalmic?PDR，315-316(2001)。)
In a word, although exist various Drug therapys to reduce the method for IOP for glaucoma patient, these methods all are being restricted aspect the effect side effect.
Melatonin is a kind of mainly by the excretory neuro hormone of pinus, and retina is also secreted this hormone on a small quantity.The physiological period rhythm and pace of moving things is abideed by in the generation of melatonin, in level increase at night.Known melatonin can be regulated many aspects of the physiological period rhythm and pace of moving things, such as the processing of periodical information.Its mechanism of action comprises that the melatonin membrane receptor (is divided into three types, MT 1(be called as mel in the past 1a), MT 2(be called as mel in the past 1bOr ML 1) and MT 3(be called as ML in the past 2)) activation and remove active anti-oxidation protection effect of resisting oxidative damage by free radical.Be similar to M-ChR and purine energy (purinergic) receptor, MT 1And MT 2Receptor belongs to 7 kinds of membrane spaning domain g protein coupled receptor superfamilies of supposition.MT 1And MT 2Receptor has all been cloned and has been born coupling by pertussis toxin, PT sensing G-protein and adenyl cyclase.MT 3Also do not cloned, it seems and the phospholipase C coupling.(Mullins etc., Cell Signal9,169-173 (1997)).Studies show that MT 1The vasoconstriction of receptor-mediated rat arteria caudalis also suppresses neuron relatively with hypnosis (somnogenic) effect and causes (firing), and MT 2The stage of the vasodilation of receptor-mediated rat arteria caudalis and the physiological period rhythm and pace of moving things advances.(Marco etc., Current Medicinal Chemistry6,501-518 (1999)).Used high-affinity part 5-(methoxycarbonyl amino)-N-acetriptine (5-MCA-NAT) (being also referred to as GR135531) with MT 3Receptor is identified (Molinari etc., European J.Pharmacol.301,159-168 (1996)), although do not report any physiologically active.
The effect of melatonin in regulating intraocular pressure (IOP) is not clear, and former studies show that, according to the time of measuring IOP in the species and the physiological period rhythm and pace of moving things, melatonin can improve or reduce IOP.(Chiou and McLaughlin, Ophthalmic Res.16:302-306 (1984); Rohde etc., J.Ocul.Pharmacol.1:235-243 (1985); Chiou etc., Ophthalmic Res.17:373-8 (1985); Rohde etc., Ophthalmic Res.25:10-15 (1993); Meyer-Bothling etc., Invest.Ophthalmol.Vis.Sci 34:3035-3042 (1993); Osborne, ActaNeurobiol.Exp. (Warsz) 54Suppl:57-64 (1994); Aimoto etc., J.Ocul.Pharmacol.1:149-160 (1985); Wilsoet etc., Ophthalmic Physiol.Opt.13:357-165 (1993); Dkhissi etc., J.Neuroendocrimol.10:863-869 (1998); Ritch, Curr.Opin.Ophthalmol.11:78-84 (2000); Kiuchi etc., Curr.Eye Res.12:181-190 (1993); Dubocovich etc., FASEB J.12,1211-1220 (1998)).Great majority studies show that melatonin has improved IOP.Yet, United States Patent (USP) 4,654,361 have disclosed a kind of method that reduces intraocular pressure by the melatonin of using effective dose.Other the United States Patent (USP) of incorporating in full this patent here into and quoting here.
United States Patent (USP) 4,803,218 have disclosed a kind of pharmaceutical composition that contains [3-(aminoalkyl)-1H-indole-5-yl] urea compounds and pharmaceutically acceptable carrier by using treats hypertensive method in animal.This patent has also been mentioned manufacturing N-[3-(2-amino-ethyl)-1H-indole-5-yl] method of carbamide and relevant analog.United States Patent (USP) 5,633,276,6,040,451,5,948,804 and 6,159,998 have disclosed with 5-(2-imidazoline-2-base-amino) benzazolyl compounds that replaces to reduce intraocular pressure, presbyopia, treatment migraine, hypertension, alleviating alcohol addiction, drug dependence, rheumatoid arthritis, ischemic pain, spasticity, to suffer from diarrhoea, alleviate the method for nasal congestion and urinary incontinence.United States Patent (USP) 6,004,991,6,140,372,59,998,461 and 6,071,946 have disclosed the method for the disorderly relevant discomfort of treatment and melatonin.Here the method for having incorporated the synthetic substituted indole derivant of mentioning in the above-mentioned patent into, for your guidance.
PCT International Application No. WO 96/25397 has disclosed the activated indole derivatives of cannabinoid receptor and their application in reducing intraocular pressure and treatment glaucoma.PCT International Application No. WO 96/11685 has disclosed the indole derivatives that is used for treating glaucoma and other disease.The indole derivatives of mentioning in above-mentioned two PCT application is different with those materials of the present invention.
As mentioned above, be commonly used to treat glaucomatous medicament and may cause bad side effect, such as cataractous appearance.Therefore need treat glaucomatous medicine safely and effectively.
Summary of the invention
Here disclosed the method that chemical compound that new passing through use I, II, III and IV structure reduces intraocular pressure, these chemical compounds comprise the chemical constitution of indole nucleus or melatonin type.
The invention provides a kind of this compounds that uses to reduce the method for intraocular pressure, compare with melatonin, they have increased acting duration and/or intensity.Preferred chemical compound is 5-(methoxycarbonyl amino)-N-acetriptine (5-MCA-NAT), is also referred to as GR135531, (Molinari etc., Eur.J.Pharmacol.301,159-168 (1996)), and it is to MT 3Receptor has specific high-affinity part.
The invention provides the method for reduction intraocular pressure and the method for treatment and intraocular pressure diseases associated (as ocular hypertension and glaucoma).This method comprises that the experimenter who treats to needs uses the indole derivatives of effective dose to reduce intraocular pressure.Indole derivatives shown in structural formula I, II, III and IV has the action time and/or and the enhanced curative effect of prolongation when reducing intraocular pressure.
The accompanying drawing summary
Fig. 1 has shown that in 6 hours, melatonin is to the effect of New Zealand white rabbit IOP.
Fig. 2 showed in 10 hours, the effect of the 5-MCA-NAT of equivalent.
Fig. 3 has contrasted the dose-response of 5-MCA-NAT and melatonin reduction IOP.
Fig. 4 illustrates the reverse of falling IOP effect of melatonin receptors antagonist luzindole to 5-MCA-NAT and melatonin.
                             Detailed Description Of The Invention
The invention provides the method for a kind for the treatment of illness relevant with the intraocular pressure that raises. The method comprises and is common Be used for treating or control the curative of intraocular pressure of rising and adjuvant use together or not together effective dose such as knot The indole derivatives of structure formula I, II, III and IV. The applicant is unexpected to be found, adopts this compounds to make intraocular pressure Significantly also continue to reduce. Effective dose is to make intraocular pressure reduce the amount of necessary this compounds.
The present invention further provides the method for a kind of new reduction intraocular pressure relevant with the ocular hypertension illness, therefore can Be effective to prevention, control and treatment ocular hypertension.
Primary glaucoma can effectively be controlled and/or treat to method of the present invention, and it comprises two types: narrow angle Or acute congestive glaucoma and wide angle property or chronic simple glaucoma. But another embodiment of the present invention is control Secondary glaucoma processed.
Method of the present invention can effectively improve the effect that is used for treating and controlling dissimilar glaucomatous curatives and adjuvant.The curative that is used for treating narrow angle or acute congestive glaucoma comprises, for example, and physostigmine Salicylate and pilocarpine nitrate.The adjuvant that is used for controlling NAG comprises that for example, intravenous is used carbonic anhydrase inhibitors, reducing the secretion of aqueous humor, or uses penetrating pharmaceutical as acetazolamide, as mannitol or glycerol to induce the dehydration of ophthalmic.The curative that is used for controlling wide angle property or primary open angle glaucoma and secondary glaucoma comprises, for example, parasympathomimetic agent (such as pilocarpine nitrate), fugitive anticholinesterase drug (as the physostigmine Salicylate), long-acting anticholinesterase drug (as demecarium bromide, diethoxyphosphinylthiocholine iodide, isoflurophate), beta-adrenergic antagonist (as timolol maleate) and sympathomimetic (as epinephrine and phyenlephrinium).Recently, prostaglandin analogue (latanoprost (Xalatan), Lumigan TM), α adrenergic agonist (brimonidine) and Rescula (it may reduce intraocular pressure by a kind of mechanism of the unknown) be used to control the glaucoma relevant with ocular hypertension.
To some therapeutic agents, for reaching the level that realizes target effect, high dose needs, but this can bring the untoward reaction relevant with dosage of big frequency usually.Therefore, with chemical compound of the present invention be commonly used to treat glaucomatous medicine and be used in combination this type of medicine medicine that just can use relatively low dosage, so just can make the frequency reduction of the adverse side effect relevant with this type of curative of chronic administration.Therefore, another effect of The compounds of this invention is, reduces the adverse side effect that is used for treating glaucomatous medicine, such as with the relevant cataractous appearance of long-acting anticholinesterase drug (comprising the U.S. hypotyl in ground, diethoxyphosphinylthiocholine and isoflurophate).
The invention provides the method for indole derivatives of utilization structure formula I, II, III and the IV of a kind of persistent period that prolongation arranged and/or the effect of enhanced reduction intraocular pressure.The description of chemical compound
The invention provides a kind of utilization structure formula I-IV: The method of indole derivatives, wherein:
N=0,1,2,3,4 or 5;
M=0 or 1;
R 1And R 2Be the linearity that replaces of H independent of each other, (not)-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6(CO)-, F, OR 5R 1Or R 2Can also be R 6R 7N (CO)-;
Perhaps randomly, work as R 1And R 2When being brought together, can represent oxo; Or (not) 4,5,6 or 7 yuan of carbocyclic rings or heterocycle of replacing;
R 3And R 4Be the linearity that replaces of H independent of each other, (not)-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6(CO)-;
Perhaps at random, work as R 3And R 4When being brought together, can represent oxo; Or (not) 4,5,6 or 7 yuan of carbocyclic rings or heterocycle of replacing;
Perhaps at random, work as R 2And R 4When being brought together, 4,5,6 or 7 yuan of carbocyclic rings can representing that (not) replace or heterocycle;
R 5The linearity that=H, (not) replace-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8S (O)-, R 8OS (O) 2-, R 8OS (O)-, R 6R 7NP (O) (OR 9)-, R 8P (O) (OR 9)-, (R 8O) P (O) (OR 9)-, CF 3-;
R 6And R 7Be the linearity that replaces of H independent of each other, (not)-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl or heterocycle;
Or when at random putting together, NR 6 R 73,4,5,6 or 7 yuan of rings can representing (not) to replace;
R 8The linearity that=(not) replaces-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, heterocycle or CF 3-;
R 9The linearity that=H, (not) replace-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl; Or randomly when being brought together, R 6And R 9Can represent 5,6 or 7 yuan of rings;
R 10And R ' 10Be the linearity that replaces of H independent of each other, (not)-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, heterocycle, R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-, CF 3-;
R 11＝R 6R 7N(CO)-、R 6(CO)-、R 8O(CO)-、R 8S(O) 2-、R 8OS(O) 2-、R 6R 7NS(O) 2-，
X 1=O, S, NR 9,-CF 2-,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-or do not exist;
Z 1＝OR 5；NR 10R 11；
Z 2And Z 3Independently R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-;
A=halogen, NO 2, CN or R 5-X 1-;
B=halogen, NO 2, CN or R 5-X 1-;
Or randomly, if B is not halogen, NO 2, CN or H, and when B appears at 4 of indole, then B and R 1, or R 3, or Z 1When occurring together, 5,6 or 7 yuan of carbocyclic rings can representing that (not) replace or heterocycle;
D 1=halogen, NO 2, CN or R 5-X 1-;
D 2The linearity that=H, (not) replace-, branch-or ring-alkyl, halogen, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl;
The linearity that E=H, (not) replace-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 8O (CO)-, R 8S (O) 2-or OR 6
Or randomly, E=R 6(CO)-, as long as work as Z 1=NR 10R 11The time, R 10Be H;
Or randomly, E=R 6(CO)-, as long as work as Z 1=OR 5The time, R 5Not H, alkyl, aryl or aralkyl;
Or randomly, E=R 6R 7N (CO)-, as long as work as Z 1=NR 10R 11The time, R 10Be H;
Or randomly, E=R 6R 7N (CO)-, as long as work as Z 1=OR 5The time, R 5Not H, alkyl, aryl or aralkyl;
Or randomly, work as D 1=R 5-X 1-when being brought together with E, 4,5,6 or 7 yuan of heterocycles can representing (not) to replace;
Or randomly, work as D 1=R 5-X 1-and R 1When being brought together, 5,6 or 7 yuan carbocyclic ring or heterocycle can representing (not) to replace;
Or randomly, work as D 1=R 5-X 1-and R 3When being brought together, 5,6 or 7 yuan carbocyclic ring or heterocycle can representing (not) to replace;
Or randomly, work as D 1=R 5-X 1-and Z 1When being brought together, 5,6 or 7 yuan of heterocycles can representing (not) to replace;
Or randomly, work as Z 1And R 1When being brought together, 4,5,6 or 7 yuan of heterocycles can representing (not) to replace;
As long as work as n=1, m=O, R 5=CH 3, X 1=O, B=D 1=E=R 3=R 4During=H, Z is not-NHAc;
Also as long as work as D 2=H, R 5During=CH 3, R 6Not CH 3
Enantiomer, diastereomer, suitable/trans isomer, pharmaceutically effectively salt and their mixture all are included in the present invention.
To the effectively preferred chemical compound of the present invention is 5-(methoxycarbonyl amino)-N-acetriptine (MCA-NAT), is also referred to as GR135531.
Embodiment preferred of the present invention includes the chemical compound of II structure, wherein:
Z 2And Z 3Be N R independently 6R 7(CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-;
Or randomly, each Z 2-N-R 10And Z 3-N-R 10Unit all is independently, represents 4-7 unit ring;
And the D among the structural formula I 1Be H now.
Another embodiment preferred of the present invention includes the chemical compound of III structure, wherein:
D 1Partly define as embodiment, or randomly, D 1Can and R 6Form ring, perhaps, D 1And R 6Can not exist, and in ring, connect this two positions with carbonyl; All other term all as preceding definition
One of the present invention more preferably embodiment relates to the following chemical compound of structural formula II I, wherein:
B, D 1And E=H
All terms such as preceding definition;
Another embodiment preferred of the present invention includes the chemical compound of IV structure, wherein;
Figure A0181509600173
D 2The linearity that=H, (not) replace-, branch-or ring-alkyl, halogen, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl;
Just work as R 5=R 6=CH 3The time, D 2Not H;
Another embodiment preferred of the present invention includes the chemical compound of IV structure, wherein:
R 5=C 1-C 4Alkyl, acetyl group, formoxyl or CF 3
R 6=H, C 1-C 4Alkyl or CF 3
Just work as R 5=CH 3, D 2During=H, R 6Not H;
Definition: (not) replaces this saying and relates to alkyl, thiazolinyl, alkynyl, aryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, it be meant described group can by or the base that is not selected from same group or is selected from halogen, nitrogen, oxygen, phosphorus or sulfur replace.Alkyl, thiazolinyl, these terms of alkynyl are meant this base that contains 1-9 carbon atom.Aralkyl, arylalkenyl, these terms of sweet-smelling alkynyl are meant and contain two groups of base formation thus defined.If do not further specify, encircle the 3-7 unit ring that this term is meant that (not) replaces.This term of heterocycle is meant and contains one or more non-carbon atoms and any degree of unsaturation is arranged or do not have the ring of degree of unsaturation.For example, arylalkenyl is meant the aryl that is connected on the thiazolinyl.
The method of the special example and the described chemical compound of manufacturing of The compounds of this invention is provided.The invention provides and be used to reduce intraocular pressure and treat glaucomatous use contain method just like the drug combination preparation of indole derivatives shown in the structural formula I-IV (can analog) and pharmaceutically acceptable carrier as melatonin.Chemical compound of the present invention also comprises the pharmaceutically acceptable salt class that they are nontoxic, such as (but being not limited to) chloride, sulfate and acetic acid salt, and sodium salt, ammonium salt and pyridiniujm.The pharmaceutically acceptable salt class is the salt that has kept the required biological activity of parent compound and do not had unwanted toxicological effect.The present invention also comprises the prodrug of chemical compound described here.Those technical staff that are proficient in this field will know various synthetic methods, and they can be used to make the salt and the prodrug of nontoxic pharmaceutically acceptable chemical compound.
Although chemical compound of the present invention mainly is used for treating human patients, they also can be used for veterinary's purpose, are used for treating other mammals patient, such as Canis familiaris L. class and cat class.
The drug effect of The compounds of this invention has been determined in the change of the IOP that the TONOPEN contact-type tonometer that provides according to usefulness Xomed (Jacksonville, Florida State, the U.S.) records.The effect of these chemical compounds is reflected in their activation melatonin receptors with on the ability that realizes target response.Target response is to reduce the intraocular pressure relevant with glaucoma.Effective dose will depend on activity, application method and the disease of each patient's feature, used special compound or the feature of disease, and can be proficient in personnel's decision in this field by those.
Required dosage and/or concentration level are from about 10 -12M is to about 10 -3M is preferably about 10 -11M is to about 10 -4In the scope of M, preferably from about 10 -10To about 10 -5M.Using of new compound
Can use chemical compound of the present invention with the treatment ophthalmic with the known method of the those of skill in the art in any this field.Indole derivatives is to use with the form of the sterile preparation that contains reactive compound or its pharmaceutically acceptable salt class and pharmaceutically acceptable excipient or carrier.
Can be administered to by the reactive compound that any suitable method will be narrated here in patient's the eye, but preferably make the liquid or the gel suspension of reactive compound, use with the form of eye drop, collyrium, spray, ointment or gel.Perhaps, can reactive compound be added in the eye by liposome or other carrier (as cyclodextrin).In addition, can reactive compound be infused into the tear film by pump-conduit system.Another embodiment of the invention relates to the reactive compound that is contained in continuous release or the selectivity releasing device, and these devices have film, is used in Ocusert such as (but being not limited to) TMThose films of system (Alza company, Palo Alto, California).In other embodiments, these reactive compounds can be contained in, be loaded into or attached to the recessive glasse that is placed on the eye.Another embodiment of the invention relates to the reactive compound in cotton swab or the sponge of being contained in that can apply on the eye surface.Another embodiment of the invention relates to the reactive compound in the liquid spray of being contained in that can be used for eye surface.Another embodiment of the invention relates to direct injection and enters lacrimal tissue or injection and be the eye surface, or the injection of the reactive compound of intravitreal injection.
The topical solutions that contains reactive compound can also contain the excipient of physical compatibility, and the personnel that are proficient in the ophthalmology technology can select with the standard of routine.The ophthalmology excipient that excipient can be selected oneself and be known includes, but is not limited to saline and aqueous electrolyte solution, aqueous polyethers (as Polyethylene Glycol), polyethylene kind (as polyvinyl alcohol and polypyrrole alkane ketone), cellulose derivative class (as methylcellulose and hydroxypropyl emthylcellulose), petroleum derivative class (as mineral oil and white vaseline), Animal fat (as lanoline), polymerizing acrylic acid thing (as carboxyl polymethylene gel), plant fat (as Oleum Arachidis hypogaeae semen) and polysaccharide (as glucosan) and glycosaminoglycan (as hyaluroni) and salt (as sodium chloride and potassium chloride).
Except the method for above-mentioned local application, also have many generals to use the method for reactive compound of the present invention, like this, chemical compound just can absorb and circulation arrival eye by whole body.One of these class methods relate to and are a kind ofly contained the particulate aerosol suspension liquid of sucking of reactive compound by what the experimenter sucked.Reactive compound will be absorbed into blood by lung, or contact with ocular tissue through nasolacrimal duct, subsequently again with medicine effective quantity and ophthalmic cells contacting.The granule that can suck can be a liquid or solid, particle diameter should be enough little when being inhaled into by oral cavity and larynx; Usually, particle diameter is at about 1-10 micron, but is preferably in the 1-5 micron, and the granule in this scope is considered to suck.
Another kind of method from reactive compound to experimenter's eye general that use comprises collyrium or collyrium or the collunarium liquid medicine form with liquid formulation, or uses liquid/liquid suspensions with the form that sucks particulate nasal spray of experimenter's suction.Can be with the method known to the skilled of being proficient in this field, with reactive compound and suitable excipient, mix as aseptic pyrogen-free water or Sterile Saline, be used for making the liquid medicine composition of the reactive compound of nasal spray or collunarium or eye drop with preparation.
The method that other general is used reactive compound comprises Orally administered, and the pharmaceutical composition that wherein contains I, II, III and IV structural compounds is the form of tablet, lozenge, aqueous or oily suspensions, dispersible powder or granule, Emulsion, hard or soft capsule or syrup or elixir.Can make for oral compositions according to the known any method that is used for making pharmaceutical composition in this field, and this compositions can contain one or more and is selected from: the material of sweeting agent, flavoring agent, coloring agent and antiseptic is to provide good-looking and delicious pharmaceutical preparation.Be suitable for making tablet with the tablet that contains active component of nontoxic pharmaceutically acceptable mixed with excipients.These excipient can be that for example, inert diluent is as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent are as corn starch or alginic acid; Binding agent, for example starch, gelatin or arabic gum; And lubricant, as magnesium stearate, stearic acid or Talcum.Tablet not coating or available known technology carries out coating postponing their disintegrate and absorptions in intestines and stomach, thereby provides lasting activity in the long time.For example, can use the slow-release material of glyceryl monostearate or distearin and so on.Form that can hard gelatin capsule for oral preparation provides, wherein active component and inert solid diluent (as, calcium carbonate, calcium phosphate or Kaolin) mix, or as the form of Perle, wherein active component and water or oil medium (as, Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil) mix.
Other eye general to the experimenter uses the method for active component to comprise the suppository form of active component, makes the chemical compound of treatment effective dose arrive eye to absorb by general and to circulate.
The chemical compound of direct instillation gel, emulsifiable paste, powder, foam, crystal, liposome, spraying or liquid suspension form when the method that further general is used reactive compound is included in surgical operation, the reactive compound for the treatment of effective dose so just contacts with described experimenter's ocular tissue with circulation by the general absorption.Further set forth the present invention by following examples, these embodiment can not be interpreted as in the scope that limits the present invention to their described particular step.
Embodiment 1
5-nitro-tryptamines
This method is according to Macor etc., and Synth.Comm.23:65-72 (1993) is method improvement similarly.In ether (30mL) suspension of 5-nitroindoline (6.2mmol) and phthalimide (0.4g), dropwise add oxalyl chloride (19.2mmol), reactant mixture was stirred 48 hours down at 24 ℃.Then reaction vessel is connected with the Dewar condenser, is cooled to 0 ℃, and in mixture, blasted anhydrous ammonia 1.5 hours.Under vacuum, remove gas and solvent.Grind gained yellow solid, filtration together, and use the toluene wash residue with water.Solid is dried, and obtains 2-amino-1-(5-nitro-1H-indol-3-yl)-second-1, the 2-diketone.A part of chemical compound (0.59mmol) is added among the THF (15mL) and handled 16 hours down at 28 ℃ with borine-THF (solution of 2.4mL1M).With the sodium bicarbonate neutralization reactant and use ethyl acetate extraction.The extract of dry ethyl acetate under vacuum is dissolved in the ethanol (10mL) again and refluxes when existing at cesium fluoride (360mg) and sodium carbonate (312mg).By the diatomite filtration mixture, evaporation is carried out chromatography and is obtained title compound (20mg) with chloroform-methanol-ammonia (8: 2: 0.2) as eluant residue on silica gel.
Embodiment 2
N-[2-(5-nitro-1H-indol-3-yl)-ethyl]-acetamide
5-nitro tryptamines (6mmol) is dissolved in pyridine (15ml), and handled 20 minutes down at 27 ℃ with acetic anhydride (7mmol).Under vacuum, remove and desolvate, residue is dissolved in small amount of methanol and by short silica gel plug to contain 5% methanol-chloroform eluant eluting.The fraction of the product that collection contains, evaporation and in＜0.1mm Hg finish-drying.
Embodiment 3
N-[2-(5-amino-1H-indol-3-yl)-ethyl]-acetamide
The product (0.05mmol) of embodiment 2 is dissolved in ethanol (3mL), and at 3 atmospheric H 2Hydrogenation 6 hours on the 10%Pd/C of catalytic amount under the pressure.Remove catalyst and under vacuum, solvent is removed by diatomite filtration, obtained title compound.This product is responsive slightly to air, should be used for later reaction immediately.
Embodiment 4
3-[2-(2-hydroxyl-benzylamino)-ethyl]-1H-indole-5-yl }-methyl carbamate
5-nitro tryptamines (6mmol) and salicylide (7mmol) are dissolved in in the buffered ethanol of potassium hydroxide (0.15g) (35mL), and handled 8 hours down at 24 ℃ with sodium borohydride (18mmol).Under vacuum, remove ethanol and residue is distributed between ether and water, ether is dry mutually, evaporation, and oil is carried out chromatography obtain 2-{[2-(5-nitro-1H-indol-3-yl)-ethylamino with ethyl acetate-hexane eluting on silica gel]-methyl }-phenol.The same on Pd/C after the hydrogenation, residue is dissolved in the pyridine (12mL) and with methylchloroformate (9mmol) handles.Formed brownish precipitation immediately after adding chloro-formate, it dissolved again in 20 minutes.Carry out silica gel tlc (5% methanol-chloroform eluting) back after short time and judge finishing of reaction.Mixture is evaporated to dry doubling to be kept 2 hours under the vacuum of＜0.1mmHg at least.Then it is dissolved in the small amount of methanol, and carries out purification with the water-methanol gradient by reversed-phase HPLC.
Embodiment 5
[3-(2-propionamido-ethyl)-1H-indole-5-yl]-methyl carbamate
5-nitro tryptamines (6mmol) is dissolved in the pyridine (15ml) and handled 20 minutes down at 27 ℃ with propionic andydride (7mmol).Under vacuum, remove and desolvate, with the pressure finish-drying of residue in＜0.1mm Hg.Then residue hydrogenation also is converted into methyl carbamate as the embodiment of front.By short silica gel plug filter and with 5% methanol-chloroform as eluant with the title compound purification.
Embodiment 6
N-[2-(5-dimethylamino-1H-indol-3-yl)-ethyl]-acetamide
With N-[2-(5-nitro-1H-indol-3-yl)-ethyl] acetamide (0.6mmol) be dissolved in the acetonitrile (1mL) and and the DMAP and the coke acid-two-tert-butyl ester (0.7mmol) of catalytic amount stirred together 1 hour.Under vacuum, remove desolvate and to residual oil carry out chromatography with ethyl acetate-hexane as eluant.Product is dissolved in ethanol (10ml) and carries out hydrogenation as above-mentioned method.Residue is dissolved in DMF (2mL), adds diisopropylethylamine (1.4mmol) and then add methyl iodide (1.4mmol).Mixture was stirred 3 hours down at 25 ℃, filter then, be evaporated to driedly, be dissolved in the ethanol and use activated carbon decolorizing.Residue is dissolved in trifluoroacetic acid and 1 normal phenylmercaptan., and stirred 1 hour down at 20 ℃.Remove and desolvate, compound dissolution is also handled with the Dowex AG1-X8 ion exchange resin of 2 equivalents (w/w) hydroxide form in isopropyl alcohol-water (5: 1).Solvent evaporated, crystallization then obtains title compound.
Embodiment 7
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-phenyl-1H-indole-5-yl)-methyl carbamate
With 2-[2-(5-nitro-1H-indol-3-yl)-ethyl]-iso-indoles-1,3-diketone (1mmol) is dissolved in THF/ chloroform (1: 1), and handles 90 minutes down at 0 ℃ with pyridine hydrobromide perbromide, then from silicagel column chloroform-methanol eluting.Product is dissolved in toluene-ethanol (1: 1) also with phenylboric acid (1.5 equivalent), sodium carbonate (2.5 equivalent), lithium chloride (3 equivalent) and four (triphenyl phasphine) palladium (5mol%) processing.Mixture was refluxed 4 hours, under vacuum, concentrates, and on silica gel, oil is carried out chromatography, obtain 2-[2-(5-nitro-2-phenyl-1H-indol-3-yl)-ethyl with ethyl acetate-hexane eluting]-iso-indoles-1, the 3-diketone.With this compound dissolution in ethanol (6mL), and and ethylenediamine (3 equivalent) refluxed together 18 hours.Under vacuum, remove and desolvate, and with pyridine-acetic anhydride (1: 1,6mL) with this material acetylation.Under vacuum, remove and desolvate, with residue chromatography on the silicon brain, and with ethyl acetate-hexane eluting.Be transformed into methyl carbamate with product hydrogenation and as above embodiment.Isolate pure product by reversed-phase HPLC.
Embodiment 8
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-Methyl-1H-indole-5-yl)-methyl carbamate
In ether (10mL) suspension of 2-methyl-5-nitro indole (1.4mmol) and phthalimide (0.1g), dropwise add oxalyl chloride (4.4mmol), reactant mixture was stirred 48 hours down at 24 ℃.Then reaction vessel is connected with the Dewar condenser, is cooled to 0 ℃, and in mixture, fed anhydrous ammonia 1.5 hours.Under vacuum, remove gas and solvent.Grind gained brown solid, filtration together, and use the toluene wash residue with water.Solid is dried, and obtains 2-amino-1-(5-nitro-1H-indol-3-yl)-second-1, the 2-diketone.A part of chemical compound (0.59mmol) is dissolved among the THF (15mL) and handled 16 hours down at 28 ℃ with borine-THF (solution of 2.4mL1M).With the sodium bicarbonate neutralization reactant and use ethyl acetate extraction.The extract of dry ethyl acetate under vacuum is dissolved in the ethanol (10mL) again and refluxes when existing at cesium fluoride (360mg) and sodium carbonate (312mg).By the diatomite filtration chemical compound, evaporation is carried out chromatography and is obtained 2-(2-methyl-5-nitro-1H-indol-3-yl)-ethamine with chloroform-methanol-ammonia (8: 2: 0.2) eluting residue on silica gel.This chemical compound is acetylation, hydrogenation and be converted to aforesaid methyl carbamate.
Embodiment 9
[3-(3-acetylaminohydroxyphenylarsonic acid third-1-yl)-1H-indole-5-yl]-methyl carbamate
In THF-HMPA (9: 3, cyano group methanephosphonic acid diethylester (7mmol) was handled 10 minutes down at 0 ℃ in 11mL) with sodium hydride (7mmol).Add 1-acetyl-5-nitroindoline-3-formaldehyde (6mmol) then, and at room temperature with solution stirring 3 hours.Mixture poured in the frozen water and with pH transfer to 5.Evaporation desolvate and and methanol grinding residues together, obtain solid-state 3-(1-acetyl-5-nitro-1H-indol-3-yl)-acrylonitrile.It is dissolved in by the saturated ethanol of ammonia (75mL), and at 3 atmospheric H 2Hydrogenation 16 hours on Raney nickel under the pressure.Remove catalyst, acetylation as stated above then makes N-[3-(5-nitro-1H-indol-3-yl)-third-1-yl] acetamide, with said method its hydrogenation, carbamylization are also used the reversed-phase HPLC purification.
Embodiment 10
[3-(3-benzenesulfonamido--ethyl)-1H-indole-5-yl]-methyl carbamate
5-nitro tryptamines (6mmol) is dissolved in pyridine (15ml) and under 25 ℃, handled 4 hours with benzene sulfonyl chloride.Mixture is poured in the frozen water also with ether (3 * 50mL) extractions.(2 * 50mL) washing ether extracts, (2 * 50mL) washings are with dried over mgso and vapourisation under reduced pressure to use saturated sodium bicarbonate then with 1M HCl.As the embodiment of front, with the gained solid hydride and change into methyl carbamate.
Embodiment 11
N-[2-(5-urea groups-1H-indole-3-ethyl]-acetamide
With the product of embodiment 3 be dissolved in acetic acid-water (1: 2,3mL) and add Sodium cyanate (NaOCN) (2mmol).Stirring is until there being browny jelly to be settled out.(3 * 30mL) extract mixture, and with saturated sodium bicarbonate washing organic extract liquid, desolvate with dried over mgso and vaporising under vacuum with chloroform.As stated above, with reversed-phase HPLC purification products obtained therefrom.
Embodiment 12
N-[2-(5-methoxycarbonyl group amino-1H-indol-3-yl)-ethyl]-succinamic acid
In dichloromethane (25mL) solution of 5-nitro tryptamines (6mmol), add triethylamine (12mmol), DMAP (0.6mmol) and succinic anhydrides (9mmol).Mixture was stirred 4 hours, under vacuum, remove and desolvate, residue is carried out chromatography on silica gel, with containing the 10% methanol-chloroform of 1% acetic acid as eluant.Then as the embodiment of front, with product hydrogenation and be transformed into methyl carbamate.As stated above, use the reversed-phase HPLC purified product.
Embodiment 13
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-allyl carbamate
Use allyl chlorocarbonate then, with the product (5mmol) of top same method Processing Example 3, and with silica gel purification, with the chloroformic solution of 5% methanol as eluant.
Embodiment 14
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 3-hydroxyl-third-1-base ester
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-allyl carbamate (1mmol) is dissolved in THF (27mL), and splashes into borine-THF (2mmol).After 2 hours, add sodium hydroxide (4mL, 3M) and hydrogen peroxide (4mL, 30%) and solution continued stirring 1 hour.Solution concentration to half volume, is added 10mL water and uses ethyl acetate (4 * 25mL) extractions.With the extract that the salt water washing merges, drying, under vacuum, remove and desolvate, at silica gel upper strata division thing, and with the chloroformic solution of 5% methanol as eluant.
Embodiment 15
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 2,3-dihydroxy-allyl ester
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-allyl carbamate (1mmol) is dissolved in pyridine (7mL) and uses Osmic acid. (0.01mmol) and H down at 25 ℃ 2O 2(1mL, 30% aqueous solution) handled 15 hours.Under vacuum, remove and desolvate and at silica gel upper strata division thing, with the chloroformic solution of 10% methanol as eluant.
Embodiment 16
N-[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-acetamide
The product (0.05mmol) of embodiment 1 is dissolved in the ethanol (3mL), and at 3 atmospheric H 2Depressing on the 10%Pd/C of catalytic amount hydrogenation spends the night.Remove catalyst and under vacuum, solvent is removed by diatomite filtration.As mentioned above, carry out acetylation with pyridine/acetic anhydride and make title compound.
Embodiment 17
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-bromo-1H-indole-5-yl]-methyl carbamate
Under 25 ℃, acetic acid (0.5mL) solution of usefulness N-bromine butanimide (0.05mmol) processing 5-methoxycarbonyl group amino-N-acetriptine (0.05mmol) 3.5 hours.Then with neutralize this solution and use ethyl acetate extraction of 50% sodium hydroxide solution.With organic collection liquid evaporation, on silica gel, carry out chromatography, the methane-chloroform with 2% obtains the product of purification as eluant.
Embodiment 18
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1-benzyl-1H-indole-5-yl]-methyl carbamate
In the DMF of embodiment 2 products (0.04mmol) (0..7mL) solution, add sodium hydride (0.1mmol).Mixture becomes redness by yellow immediately.Stir after 20 minutes, add benzyl bromide a-bromotoluene (0.1mmol) and mixture restir 2 hours.Between water and ethyl acetate, reactant is distributed then, separates each layer, the vaporising under vacuum ethyl acetate mutually and under fine vacuum with the product drying.Then residue is dissolved in a spot of methanol, the gradient of employing water-methanol is carried out reversed-phase HPLC product is separated.With the method among the former embodiment, by hydrogenation and change into methyl carbamate, product is changed into title compound.
Embodiment 19
(1-oxo-2,3,4,9-tetrahydrochysene-1H-B-carboline-6-yl)-methyl carbamate
With the method for using among the former embodiment, by hydrogenation and change into methyl carbamate, with 6-nitro-2,3,4,9-tetrahydrochysene-B-carboline-1-ketone (0.05mmol) changes into title compound.
Embodiment 20
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1-Methyl-1H-indole-5-yl]-methyl-methyl carbamate
In the DMF (0.7mL) of 5-(methoxycarbonyl group amino)-N-acetriptine (0.03mmol) solution, add sodium hydride (0.1mmol), and at room temperature mixture was stirred 20 minutes.Add iodomethane (0.1mmol) then and mixture is continued stirring 2 hours.Between water and ethyl acetate, reactant mixture is distributed, the vaporising under vacuum ethyl acetate mutually and under fine vacuum with the product drying.Then residue is dissolved in a spot of methanol, the gradient of employing water-methanol is carried out reversed-phase HPLC product is separated.With the method among the former embodiment, by hydrogenation and change into methyl carbamate, product is changed into title compound.
Embodiment 21
[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole-5-yl]-methyl carbamate
In DMF (7mL) solution of 1-(1H-indole-4-yl)-ethanol (4mmol), add sodium hydride (10mmol).Stir after 20 minutes, add iodomethane (10mmol) and mixture is continued stirring 2 hours.Between water and ethyl acetate, reactant is distributed then, separates each layer, the vaporising under vacuum ethyl acetate mutually and under fine vacuum with the product drying.Then residue is dissolved in a spot of methanol, on silica gel, carries out chromatography, as eluant 4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole is separated with chloroform-methanol.Product (2mmol) is dissolved in ether (40mL), dropwise adds oxalyl chloride (8mmol), and mixture was stirred 8 hours down at 24 ℃.Then reaction vessel is connected with the Dewar condenser, is cooled to 0 ℃, and in mixture, fed anhydrous ammonia 1.5 hours.Under vacuum, remove gas and solvent.The gained solid is dissolved in the ethyl acetate, with the saline extraction, and with dried over mgso ethyl acetate phase and with its evaporation.This substance dissolves was handled 16 hours with borine-THF (3mL, the solution of 1M) down in THF (15mL) and at 25 ℃.With the sodium bicarbonate neutralization reactant and use ethyl acetate extraction.Dry ethyl acetate extract under vacuum is dissolved in (10mL) and backflow in the presence of cesium fluoride (380mg) and sodium carbonate (350mg) in the ethanol again then.By the diatomite filtration chemical compound, evaporation is carried out chromatography and is obtained 2-[4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole-3-yl with chloroform-methanol-ammonia (9: 1: 0.1) as eluant residue on silica gel]-ethylamine.This substance dissolves is handled to obtain N-{2-[4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole-3-yl in pyridine (6mL) and with acetic anhydride (3mL)]-ethyl }-acetamide.Under＜0.1mmHg, after dry 24 hours, chemical compound (1mmol) is dissolved in dichloromethane (2mL).Add ammonium nitrate (1.7mmol), add trifluoroacetic anhydride (TFAA) (3mmol) then.The mixture stirring is spent the night, then it is distributed between cold saturated sodium bicarbonate and chloroform.Wash organic facies with water, with dried over mgso and be evaporated to dried.Chromatography on silica gel, isolate N-{2-[4-(1-methoxyl group-ethyl)-1-methyl-5-nitro-1H-indol-3-yl with ethyl acetate-hexane as eluant]-ethyl }-acetamide, with the method among the former embodiment, the formation by hydrogenation and methyl carbamate is finally converted into title compound with it.
Embodiment 22
Melatonin and 5-(methoxycarbonyl amino)-N-acetriptine (5-MCA-NAT) effect intrinsic pressure to lagophthalmos
In New Zealand white rabbit, studied melatonin and 5-(methoxycarbonyl amino)-N-acetriptine (5-MCA-NAT), be also referred to as the effect of GR135531 intraocular pressure (IOP)
The measurement of intraocular pressure: IOP records with the TONOPEN contact-type tonometer that Xomed (Jacksonville, Florida State, the U.S.) provides.To a side angle film local application 10 microlitre medicines, and use the saline solution of same volume to the eyes of offside.With corneal anesthesia with avoid any with use the relevant discomfort of tonometer.Before drug administration, carry out twice measurement.
Pharmaceutical research: in DMSO, melatonin (Sigma, St. Louis) and 5-MCA-NAT (Tocris, Bristol, Britain) made 10-100 doubly high concentration and dilute with saline.Adopted the 10pg/10 μ L-1mg/10 μ L dosage of (melatonin is equivalent to 43fmol-43 μ mol, and 5-MCA-NAT is equivalent to 34fmol-34 μ mol), the 0.5th, 1,2,3,4,5 and 6 hour measurement intraocular pressure after medication.Every day is to dosage of an animal experiment.Before with melatonin or 5-MCA-NAT 30 minutes, add nonspecific melatonin antagonist luzindole with the dosage of 100 μ g/10 μ L or 342nM.
Melatonin and 5-MCA-NAT are to the effect of rabbit IOP: melatonin and 5-MCA-NAT (10pg/10 μ L-1mg/10 μ L) have caused the reduction of IOP dose dependent, and this value maximum when 10 μ g/10 μ L has reduced by 24 ± 4.4% (n=8).After 1 hour, observed maximum efficiency and kept 3 hours (Fig. 1).5-MCA-NAT (10pg/10 μ L-1mg/10 μ L) has also caused the reduction of IOP dose dependent, and it is maximum when 100 μ g/10 μ L, has reduced by 43.1 ± 3.65% (n=8).After 2 hours, observed maximum efficiency and kept 10 hours (Fig. 2).The peak response of 5-MCA-NAT is significantly higher than response to melatonin statistically.The IC of melatonin and 5-MCA-NAT 50Value is respectively 363 ± 23.0ng/10 μ L and 423 ± 30ng/10 μ L, and this is equivalent to the dosage (Fig. 3) of 1.6 ± 0.1nmol and 1.8 ± 0.1nmol respectively.These values do not have significant difference each other.
Anticipate the effect (Fig. 4) that to eliminate melatonin and 5-MCA-NAT with nonspecific melatonin receptors antagonist luzindole (100 μ g/10 μ L), but when using separately, after 6 hours, just do not acted on.
These results show, melatonin and MT optionally 3Receptor stimulating agent 5-MCA-NAT causes the reduction of dose dependent to IOP, and the peak response that 5-MCA-NAT causes is about the twice of the response that melatonin causes.These presentation of results suppose there is one group of melatonin receptors as if then melatonin just becomes partial agonist, and 5-MCA-NAT then becomes full agonist.Nonspecific melatonin receptors antagonist luzindole eliminates the ability explanation of melatonin and 5-MCA-NAT effect, and the effect of melatonin and 5-MCA-NAT mediates by melatonin receptors.
Used now complete, clear, succinctly and accurately term description the present invention and manufacturing and its mode of use and method, this just makes any technical staff who is proficient in this field to make and uses it.Described the preferred embodiment of the invention above it should be understood that, and can under the situation that does not deviate from the scope of the invention listed, make improvements it as claim.For particularly pointing out and explicitly call for theme of the present invention, finish this description with following claim.

Claims (24)

1. method that in this experimenter who needs is arranged, reduces intraocular pressure, described method comprises:
Amount with effective reduction intraocular pressure is used a kind of indole derivatives to described experimenter, and wherein said indole derivatives is structural formula I:
Figure A0181509600021
Chemical compound, wherein
N=0,1,2,3,4 or 5;
M=0 or 1;
R 1And R 2Be H independent of each other, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6(CO)-, F, OR 5, perhaps R 1Or R 2Be R 6R 7N (CO)-; Perhaps work as R 1And R 2When being brought together, be oxo; Or replacement or unsubstituted 4,5,6 or 7 yuan of carbocyclic rings or heterocycle;
R 3And R 4Be H independent of each other, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6(CO)-,
Perhaps work as R 3And R 4When being brought together, be oxo; Or replacement or unsubstituted 4,5,6 or 7 yuan of carbocyclic rings or heterocycle;
Perhaps work as R 2And R 4When being brought together, representative replaces or unsubstituted 4,5,6 or 7 yuan of carbocyclic rings or heterocycle;
A=halogen, NO 2, CN or R 5-X 1-;
B=halogen, NO 2, CN or R 5-X 1-;
When B appears at 4 of indole and B is not halogen, NO 2, when CN or H, then B and R 1, or R 3, or Z 1Representative replaces or unsubstituted 5,6 or 7 yuan of carbocyclic rings or heterocycle together;
When B is not halogen, NO 2, when CN or H and B appear at 7 of indole, then B and E can represent together and replace or unsubstituted 5,6 or 7 yuan of carbocyclic rings or heterocycle;
X 1=O, S, NR 9,-CF 2-,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-or do not exist;
R 5=H, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8S (O)-, R 8OS (O) 2-, R 8OS (O)-, R 6R 7NS (O) 2, R 6R 7NP (O) (OR 9)-, R 8P (O) (OR 9)-, (R 8O) P (O) (OR 9)-, CF 3-;
R 6And R 7Be H independent of each other, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl or heterocycle; Maybe when being brought together, NR 6R 7Representative replaces or unsubstituted 3,4,5,6 or 7 yuan of rings;
R 8=replace or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, heterocycle or CF 3-;
R 9=H, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl;
When being brought together, R 6And R 9Represent 5,6 or 7 yuan of rings;
E=H, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, R 8O (CO)-, R 8S (O) 2-or OR 6
Or E=R 6(CO)-, as long as Z 1=NR 10R 11The time, R 10Be H;
Or E=R 6(CO)-, as long as Z 1=OR 5The time, R 5Not H, alkyl, aryl or aralkyl;
Or E=R 6R 7N (CO)-, as long as Z 1=NR 10R 11The time, R 10Be H;
Or E=R 6R 7N (CO)-, as long as Z 1=OR 5The time, R 5Not H, alkyl, aryl or aralkyl;
D 1=halogen, NO 2, CN or R 5-X 1-;
Work as D 1=R 5-X 1-when being brought together with E, representative replaces or unsubstituted 4,5,6 or 7 yuan of heterocycles;
Work as D 1=R 5-X 1-and R 1When being brought together, representative replaces or unsubstituted 5,6 or 7 yuan carbocyclic ring or heterocycle;
Work as D 1=R 5-X 1-and R 3When being brought together, representative replaces or unsubstituted 5,6 or 7 yuan carbocyclic ring or heterocycle;
Work as D 1=R 5-X 1-and Z 1When being brought together, representative replaces or unsubstituted 5,6 or 7 yuan of heterocycles;
Z 1=OR 5Or NR 10R 11
Work as Z 1And R 1When being brought together, representative replaces or unsubstituted 4,5,6 or 7 yuan of heterocycles; R 10=H, replacement or unsubstituted linearity-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, heterocycle, R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-, CF 3-; And
R 11=NR 6R 7(CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-; If n=1, m=O, R 5=CH 3, X 1=O, B=D 1=E=R 3=R 4During=H, Z is not-NHAc.
2. the method for claim 1, wherein said indole is the chemical compound of II structure:
Figure A0181509600041
R wherein 10And R ' 10Be the linearity that replaces of H independent of each other, (not)-, branch-or ring-alkyl ,-thiazolinyl ,-alkynyl ,-aryl ,-aralkyl ,-arylalkenyl ,-sweet-smelling alkynyl, heterocycle, R 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-, CF 3-;
Z wherein 2And Z 3Be R independently 6R 7N (CO)-, R 6(CO)-, R 8O (CO)-, R 8S (O) 2-, R 8OS (O) 2-, R 6R 7NS (O) 2-;
Perhaps each Z 2-N-R 10And Z 3-N-R 10Unit independently represents 4-7 unit ring.
3. the method for claim 1, wherein said indole is the chemical compound of III structure:
D wherein 1Be halogen, NO 2, CN or R 5-X 1, perhaps D 1Can and R 6Form ring, or D 1And R 6Can not exist, and in ring, connect this two positions with carbonyl.
4. method as claimed in claim 3, wherein B=D 1=E=H.
5. the method for claim 1, wherein said indole is the chemical compound of IV structure:
D 2=H, replacement or unsubstituted linearity-, branch-or ring-alkyl, halogen, replacement or unsubstituted phenyl or replacement or unsubstituted aralkyl; As long as R 5=R 6=CH 3The time, D 2Not H.
6. method as claimed in claim 5, wherein R 5=C 1-C 4Alkyl, acetyl group, formoxyl or CF 3R 6=H, C 1-C 4Alkyl or CF 3As long as R 5=CH 3The time, R 6Not CH 3
7. the method for claim 1, wherein said chemical compound is reaching about 10 on described experimenter's eye surface -12M-10 -3The effective dose of M concentration is used.
8. the method for claim 1, wherein said chemical compound is 5-(methoxycarbonyl amino)-N-acetriptine.
9. the method for claim 1; wherein said indole is selected from N-[2-(5-dimethylamino-1H-indol-3-yl)-ethyl]-acetamide; 3-[2-(2-hydroxyl-benzylamino)-ethyl]-1H-indole-5-yl }-methyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-phenyl-1H-indole-5-yl)-methyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1-Methyl-1H-indole-5-yl)-methyl carbamate; [3-(3-acetylaminohydroxyphenylarsonic acid propyl group)-1H-indole-5-yl]-methyl carbamate; [3-(3-benzenesulfonyl amino-propyl group)-1H-indole-5-yl]-methyl carbamate; N-[2-(5-urea groups-1H-indol-3-yl)-ethyl]-acetamide; [3-(2-propionamido-ethyl)-1H-indole-5-yl]-methyl carbamate; N-[2-(5-methoxycarbonyl group amino-1H-indol-3-yl)-ethyl]-succinamic acid; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-allyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 3-hydroxyl-propyl ester; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 2; 3-dihydroxy-allyl ester; and N-[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-acetamide; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-bromo-1H-indole-5-yl]-methyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-Methyl-1H-indole-5-yl]-methyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1-benzyl-1H-indole-5-yl]-methyl carbamate; (1-oxo-2; 3; 4,9-tetrahydrochysene-1H-B-carboline-6-yl)-methyl carbamate and [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole-5-yl]-methyl carbamate.
10. the method for claim 1, the indole derivatives of the wherein said I of having structure are applied to the experimenter who needs treatment, are selected from ocular hypertension and glaucomatous symptom with treatment, and used amount can effectively be treated described symptom.
11. method as claimed in claim 10, wherein said glaucoma is a primary glaucoma.
12. method as claimed in claim 11, wherein said primary glaucoma is selected from narrow angle, acute congestive glaucoma; Wide angle property, primary open angle glaucoma; And secondary glaucoma.
13. method as claimed in claim 12, wherein said indole derivatives are to use together with the treatment that is selected from anticholinergic inhibitor, carbonic anhydrase inhibitors, prostaglandin analogue that is used for controlling narrow angle, acute congestive glaucoma and ancillary drug and penetrating pharmaceutical.
14. method as claimed in claim 13, wherein said anticholinergic inhibitor are Salicylate or pilocarpine nitrate; Described carbonic anhydrase inhibitors is an acetazolamide; Described prostaglandin analogue is Xalatan or Lumigan; Described penetrating pharmaceutical is mannitol or glycerol.
15. the method for claim 1, wherein said indole are to use together with the curative that is selected from parasympathomimetic agent, fugitive anticholinesterase drug, long-acting anticholinesterase drug, alpha-adrenergic agonist, beta-adrenergic antagonist, sympathomimetic and prostaglandin analogue that is used for controlling wide angle property, primary open angle glaucoma.
16. method as claimed in claim 15, wherein said parasympathomimetic agent are pilocarpine nitrate; Described fugitive anticholinesterase drug is the physostigmine Salicylate; Described long-acting anticholinesterase drug is demecarium bromide, diethoxyphosphinylthiocholine iodide or isoflurophate; Described beta-adrenergic antagonist is a timolol maleate; Described sympathomimetic is epinephrine or phyenlephrinium; Described prostaglandin analogue is latanoprost or Lumigan.
17. method as claimed in claim 12, wherein said indole derivatives are to use together with the curative that is selected from parasympathomimetic agent, fugitive anticholinesterase drug, long-acting anticholinesterase drug, beta-adrenergic antagonist, sympathomimetic and prostaglandin analogue that is used for controlling secondary glaucoma.
18. method as claimed in claim 17, wherein said parasympathomimetic agent are pilocarpine nitrate; Described fugitive anticholinesterase drug is the physostigmine Salicylate; Described long-acting anticholinesterase drug is as demecarium bromide, diethoxyphosphinylthiocholine iodide or isoflurophate; Described beta-adrenergic antagonist is a timolol maleate; Described sympathomimetic is epinephrine or phyenlephrinium; Described prostaglandin analogue is latanoprost or Lumigan.
19. the method for claim 1, wherein said indole derivatives are to use with the sterile preparation that contains described chemical compound or their pharmaceutically acceptable salt and pharmaceutically acceptable excipient or carrier.
20. method as claimed in claim 19, wherein said pharmaceutically acceptable carrier is the excipient of the aqueous electrolyte solution of being selected from of physical compatibility, polyethers, polyethylene kind, polymerizing acrylic acid thing, lanoline and glucosaminoglycan, has reduced intraocular pressure thereby wherein said preparation has improved liquid from the eye outflow.
21. the method for claim 1, the wherein said method of using described chemical compound is selected from: a) by being selected from the vehicle excipients local application of eye drop, collyrium, gel, ointment, spray or liposome; B) by be selected from pump-conduit system, continuously or the device of selectivity releasing device and contact lens be infused into described eye surface; And c) general is used.
22. method as claimed in claim 22, the described indole of wherein said systemic administration is to realize that by the chemical compound of instillation gel, emulsifiable paste, powder, foam, crystal, liposome, spraying or liquid suspension form when the surgical operation the described chemical compound for the treatment of effective dose so just contacts with described experimenter's ocular tissue with circulation by the whole body absorption.
23. the method for claim 1, wherein said indole derivatives are used to reduce the disadvantageous side effect that is used for treating glaucomatous medicine, may further comprise the steps:
Use described indole derivatives together with the medicine that is selected from demecarium bromide, diethoxyphosphinylthiocholine and isoflurophate.
24. one kind is selected from: [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-Methyl-1H-indole-5-yl)-methyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-2-phenyl-1H-indole-5-yl)-methyl carbamate; [3-(3-acetylaminohydroxyphenylarsonic acid third-1-yl)-1H-indole-5-yl]-methyl carbamate; N-[2-(5-methoxycarbonyl group amino-1H-indol-3-yl)-ethyl]-succinamic acid; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-allyl carbamate; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 3-hydroxyl-third-1-base ester; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-carbamic acid 2,3-dihydroxy-allyl ester; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-4-(1-methoxyl group-ethyl)-1-Methyl-1H-indole-5-yl]-methyl carbamate; N-[3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1H-indole-5-yl]-acetamide; [3-(2-acetylaminohydroxyphenylarsonic acid ethyl)-1-benzyl-1H-indole-5-yl]-methyl carbamate; The compositions of the material of (1-oxo-2,3,4,9-tetrahydrochysene-1H-B-carboline-6-yl)-methyl carbamate.
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