CN1450995A - 5-hydroxy indazole derivatives for treating glaucoma - Google Patents

5-hydroxy indazole derivatives for treating glaucoma Download PDF

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CN1450995A
CN1450995A CN00819348A CN00819348A CN1450995A CN 1450995 A CN1450995 A CN 1450995A CN 00819348 A CN00819348 A CN 00819348A CN 00819348 A CN00819348 A CN 00819348A CN 1450995 A CN1450995 A CN 1450995A
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alkyl
hydrogen
indazole
aminopropyl
halogen
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J·A·梅
冯子侠
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Novartis AG
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Alcon Universal Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

3-(2-aminoethyl)-1H-indazol-5-ols useful for treating elevated intraocular pressure and glaucoma are disclosed.

Description

Be used for the treatment of glaucomatous 5-hydroxy indazole derivatives
The 3-that the present invention relates to replace (2-aminoethyl)-1H-indazole-5-phenols, the 3-of some replacement (2-aminoethyl)-1H-indazole-5-phenols is new, is used to reduce and control the intraocular pressure (IOP) and the treatment glaucoma of normal or rising.
Background of invention
Be called as glaucomatous disease and be characterised in that the sight function permanent loss that causes by the irreversible damage of optic nerve.On several morphology with function on different type of glaucoma generally all have the feature that IOP raises, it is relevant that it is considered on reason the pathologic process with disease.Intraocular pressure is too high to be the disease that tangible loss of visual function does not still take place in the intraocular pressure rising; It is very high to think that this type of patient finally develops into the risk of the relevant visual deprivation of glaucoma.Some patient who suffers from the glaucoma visual field loss has low relatively intraocular pressure.These so-called normal intraocular tensions or ocular hypotension glaucoma patient also can be benefited from the medicament that reduces or control IOP.If early detection is to glaucoma or intraocular pressure is too high and use the medicine that can effectively reduce intraocular pressure to treat immediately, loss of visual function or its gradual deterioration are improved.The verified pharmacotherapy that can effectively reduce intraocular pressure comprises the medicament that reduces the aqueous body fluids generation and promotes to flow out unobstructed medicament.This type of treatment is generally used by one of local (directly applying to eye) or oral these two kinds of possible approach.
When the glaucoma treatment method that has existed with certain was treated, some individuality did not produce sound response.Therefore, existence is to the demand of other topical therapeutic agent of control IOP.
Have now found that to have 5-HT 2The serotonin of receptor agonist activity can effectively reduce and control normal and elevated IOP by compound, and is used for the treatment of glaucoma, referring to the common pending application PCT/US99/19888 that owns together.As 5-HT 2The compound of receptor stimulant is well known and has shown multiple effectiveness, is mainly used in disease or the illness relevant with central nervous system (CNS).United States Patent (USP) (U.S Patent) 5,494,928 discloses some as 5-HT 2CThe 2-of agonist (indoles-1-yl)-1-ethanamine derivatives is used for mandatory pressure disease and other comes from the treatment of the personality disorder of CNS.United States Patent (USP) 5,571 discloses as 5-HT in 833 2The tryptamines derivative of agonist is used for a high pressure and migrainous treatment.United States Patent (USP) 5,874 discloses use 5-HT in 477 2A/2CThe method of agonist treatment malaria.United States Patent (USP) 5,902 discloses 5-HT in 815 2AThe purposes of agonist, the disadvantageous effect that is used to prevent nmda receptor hypofunction.5-HT is disclosed among the WO98/31354 A2 2BAgonist is used for dysthymia disorders and other CNS treatment of diseases.It is reported 5-HT 2AAcceptor is to cause to cause unreal active main activity to have some less 5-HT simultaneously to the reaction of agonist 2CAcceptor participates in [psychopharmacology (Psychopharmacology), 121 volumes: 357,1995].
The 3-that the present invention relates to replace (2-aminoethyl)-1H-indazole-5-phenols, the 3-of some replacement (2-aminoethyl)-1H-indazole-5-phenols is new.The 5-HT of these compounds and serotonin 2Acceptor has very high affinity and works as the latter's agonist, therefore to reducing and control intraocular pressure (IOP) and glaucomatous treatment normal or that raise are useful.When in this replacement, comprising the part of phenol, when for example on 5 of indazole ring, oh group being arranged, this compounds is to well-known especially responsive [the physical chemistry magazine (J.Phys.Chem.) of oxidizing reaction that usually occurs in the phenolic compound that comprises relevant hydroxyl color amine class, 103,8606 (1999), chemical research and toxicology (Chem.Res.Toxicol.), 11,639 (1998), organic chemistry magazine (J.Org.Chem.), 52,2817 (1987), pharmaceutical science magazine (J.Pharm.Sci), 77,911 (1988)], they are especially relevant with the application.It is not oxidized with the phenols of protecting this type of hydroxyl to replace to produce suitable ester (carbamate or carbonic ether) by the fragrant oh group of deriving.Although ester (carbamate or carbonic acid ester derivative) itself does not have the high-affinity with above-mentioned acceptor, they are useful to the treatment glaucoma really, because can or be organized the effect of esterase to decompose by chemical hydrolysis in vivo by the phenols of due care.This type of decomposition will discharge required therapeutical agent, required new 5-hydroxyl-indazole compound promptly disclosed by the invention.Using this type of deutero-phenolic compound is well-known [medicine and pharmacy science (Drugs Pharm.Sci.), 53,221 (1992), study of pharmacy (Pharm.Res.), 168 (1984)] in this area as the notion of chemical delivery agents.
The existing report of the chemosynthesis of 3-(2-dimethylamino-ethyl)-1H-indazole-5-phenol, but the effectiveness of this compound is not explained [Journal of the American Chemical Society (J.Amer.Chem.Soc.), 79,5242 (1957); Journal of the American Chemical Society, 80,965 (1958)].
1-(2-aminopropyl)-1H-indazole-6-phenol and other ring replace chemosynthesis existing report in disclosed International Patent Application WO 98/30548 (1998) of variant.The cited effectiveness of the compound of this application is to be used for the treatment of central nervous system disease, for example property disease, reproduction deficiency, appetite stimulator disorder, anxiety disorder, dysthymia disorders and sleep disease.The purposes in ophthalmology is not mentioned in this application.Disclose in the disclosed International Patent Application WO 00/12482 (2000) be used for central nervous system disease treatment some as 5-HT 2The 1-of agonist (indazole-3-yl)-2-propanamine derivatives.
Summary of the invention
The present invention relates to the derivative of 3-(2-aminoethyl)-1H-indazole-5-phenol, some derivative is new, and they are used in and reduce in the warm-blooded animal (comprising the people) and control and normal pressure glaucoma, intraocular pressure is too high and glaucoma is relevant IOP.These compounds are mixed with the pharmaceutical composition that is fit to the local use of eye. The description of embodiment preferred
The following structural formula I and the pharmacologically acceptable salt and the solvate of structural formula I compound are represented useful compound of the present invention.Structural formula I
Wherein G is selected from hydrogen, halogen or C 1-4Alkyl;
R is hydrogen, C 1-4Alkyl, C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3And R 4Be independently selected from hydrogen, C 1-4Alkyl, or R 3, R 4Form cyclopropyl rings with the carbon atom that they connected, or in addition, R 2And R 3Common formation (CH 2) mTo form saturated heterocycle;
Work as R 2And R 3During for a heterocyclic part, R 1Can be hydrogen or C 1-4Alkyl;
R 5Can be hydrogen or C 1-4Alkyl;
As R, R 1, R 2, R 5When all being hydrogen with G, R 3, R 4Can not be hydrogen simultaneously;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), OC 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2-4;
N is 1 or 2.
New and useful compound of the present invention can be defined as follows:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R be C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3, R 4Form cyclopropyl rings with the carbon atom that they connected, or in addition, R 2And R 3Common formation (CH 2) mTo form saturated heterocycle;
Work as R 2And R 3During for a heterocyclic part, R 1Can be hydrogen or C 1-4Alkyl;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), OC 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2-4;
N is 1 or 2.
Preferred compound is:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R be hydrogen, C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3And R 4Be independently selected from hydrogen, C 1-4Alkyl, or R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2 or 3;
N is 1 or 2.
Most preferred is:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R is hydrogen or C (=O) W;
R 1And R 2Be hydrogen;
R 3Be hydrogen, and R 4Be methyl, perhaps R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Be hydrogen;
W is C 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CON (C for alkyl 1-4Alkyl) 2, C (=NH) NH 2Replace).
The representative example of the preferred new compound of structural formula I is:
3-(2-aminopropyl)-1H-indazole-5-phenol;
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol;
2-(5-methoxyl group-1H-indazole-3-yl)-1-methyl-ethamine;
3-(2-aminopropyl)-6-fluoro-1H-indazole-5-phenol;
3-(2-aminopropyl)-7-methyl isophthalic acid H-indazole-5-phenol;
3-(2-aminopropyl)-6-fluoro-1-methyl isophthalic acid H-indazole-5-phenol;
2-methyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
2,2-dimethyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
Cyclopropane-carboxylic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
N, N-diethyl-succinamic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
Recognize that compound in structural formula I can contain one or more chiral centres.The present invention pays close attention to all enantiomorphs, diastereomer and their mixture.
In above-mentioned definition, the total number of carbon atoms is expressed as C on the substituting group I-jPrefix, wherein digital i and j definition carbonatoms; This definition comprises straight chained alkyl, branched-chain alkyl and cycloalkyl or (cycloalkyl) alkyl group.
Recognize that importantly when substituting group was introduced specified structural unit, they can individually or a plurality ofly exist.For example, halogen (referring to fluorine, chlorine, bromine or iodine) replaces can represent that the unit that is attached thereto can be replaced by one or more halogen atoms, and these halogen atoms can be identical or different.
Synthetic
Can be by one of several synthetic methods preparation compound in structural formula I.For example, with the indazole-3-formaldehyde (1) that suitably replaces, it can make [journal of medicinal chemistry (J.Med.Chem.) from corresponding indazole by known method, 38,2331 (1995)], produce corresponding nitro alkene (2) with suitable nitro-paraffin condensation, products therefrom can be with for example LiAlH 4Reduction, and available if necessary for example boron tribromide dealkylation are to produce required compound in structural formula I 3.
Reaction process 1
Figure A0081934800131
The other method of preparation compound in structural formula I is summarized in schema 2.Buy or by currently known methods tetrahedron (Tetrahedron) for example, 50, the 2-fluoro-phenyl methyl ketone (4) of the suitable replacements of 1179 (1994) preparations is at highly basic for example in the presence of the LDA, produce aryl beta-hydroxy alkyl ketone (5) [synthesising communication (Synth.Commun.) with required aldehyde (as acetaldehyde) reaction, 10,851 (1980)], products therefrom produces the indazole 6[journal of medicinal chemistry that replaces by currently known methods and anhydrous hydrazine reaction, 37,2721 (1994)].By well-known order 6 secondary alcohol fractional conversion is become required primary amine; comprise by forming the sulfonated ester initial activation; next by replacing this ester, in the reduction trinitride, remove any phenol blocking group (as benzyl) at last, to produce required amine (3) with the sodium azide reaction.Perhaps, compound 4 produces the phenyl styryl ketone intermediate with aldehyde (as acetaldehyde) reaction under acidic conditions, 7[chemistry association's magazine (J.Chem.Soc.) for example, 2403 (1953)] (schema 3).Suitable protectiveness amine (as phenmethyl amine) is added to 7 two keys and produces required keto-amine 8[chemicals communication (Chem.Pharm.Bull.) 22,1348 (1974)], when handling 8, produced the indazole 9[journal of medicinal chemistry that replaces, 37,2721 (1994)] with hydrazine; Remove the protectiveness group by hydrogenolytic cleavage and produce required compound 3.
Reaction process 2
Figure A0081934800132
Reaction process 3
Figure A0081934800141
Also described the another kind of method of preparation compound in structural formula I in schema 4, it begins from (5-benzyloxy-1H-indazole-3-yl)-acetate (10) [Journal of the American Chemical Society, 79,5246 (1959)].[chemical association comment (Chem.Soc.Rev.), 17,91 (1988)] 10 produce intermediate 11 with acetic anhydride under the Dakin-West condition when suitable alkali exists, and next 11 produce oxime 12 with O-methyl-azanol reaction.To produce required compound in structural formula I 13[Europe journal of medicinal chemistry (Eur.J.Med.Chem.), 27,595 (1992), tetrahedron, 29,223 (1988) with for example borane reduction 12].
Reaction process 4
Figure A0081934800142
R be C (=O) compound in structural formula I of W can be prepared as follows: with suitable indazole 3; or, produce ester 15 preferably with suitable amino protected intermediates (as 14) (schema 5) and required activated acid derivatives (as acyl halide or Acibenzolar etc.) reaction.Remove the N-protected group from intermediate 15 and produce required compound in structural formula I 16.
Reaction process 5
Figure A0081934800151
Compound in structural formula I of the present invention can be sneaked into various types of be delivered to eye (for example through local, in the room or pass through implant) ophthalmic preparation.Preferably compound is sneaked into the topical ophthalmic formulations that is delivered to eye.Acceptable sanitas, tensio-active agent, tackifier, penetration enhancer, damping fluid, sodium-chlor and water on these compounds and the ophthalmology can be mixed and make aseptic moisture ophthalmic suspension or solution.Can ooze water-containing buffering liquid and prepare ophthalmic solution formulations by compound being dissolved in physiologically acceptable grade.In addition, this ophthalmic solution can comprise acceptable surfactant on the ophthalmology so that this compound of assist in dissolving.In addition, this ophthalmic solution can contain increase viscosity medicament to improve the stop of said preparation in conjunctival sac, the medicament of described increase viscosity is all if any Walocel MT 20.000PV, Natvosol, Vltra tears, methylcellulose gum, polyvinylpyrrolidone etc.Jelling agent be can also use, gellan gum and xanthan gum included but not limited to.In order to prepare the sterile ophthalmic ointment agent, in the suitable carrier such, activeconstituents is mixed with sanitas such as mineral oil, liquid lanolin or white vaseline.Can be according to the open compound method that is used for similar ophthalmic preparation, prepare aseptic gel for eye by activeconstituents being suspended in by the hydrophilic matrix that mixes for example Ka Baibo-974 preparations such as (carbopol-974); Can sneak into sanitas and tonicity agents.
Preferably described compound is mixed with topical ophthalmic that pH is about 5-8 with suspension or solution.The amount of compound generally accounts for 0.01% to 5% weight in these preparations, and preferable amount is to account for 0.25% to 2% weight.Therefore, with regard to topical preparation, according to experienced clinicist's judgement, every day, 1-4 the 1-2 with these preparations dripped to the eye surface.
Can also and be used for the treatment of glaucomatous other medicament coupling with these compounds, described other medicament is such as, but not limited to beta blocker (for example timolol, betaxolol, levobetaxolol, carteolol, levobunolol, Proprasylyte), carbonic anhydrase inhibitor (for example brinzolamide and dorzolamide), α 1Antagonist (for example nipradolol), α 2Stimulant (for example iopidine and brimonidine); myotic (for example pilocarpine and suprarenin); prostaglandin analogue (latanoprost for example; travaprost; Unoprostone and U.S. Pat 5; 889; 052; 5; 296; 504; 5; 422; 368 and 5; 151; listed compound in 444); " low pressure lipid " (lumigan and 5 for example; 352; listed compound in 708) and neuroprotective (for example from U.S. Pat 4,690,931 compound; listed Eliprodil and R-Eliprodil and from the suitable compound of WO94/13275 among the application particularly co-pending U.S.S.N.06/203350 comprise memantine).
The preferred compound of structural formula I is described in embodiment 1 and 2.The compound of embodiment 1 most preferably.The embodiment that is fit to this compound is delivered to the preparation of eyes of expection is provided.
Embodiment 1
3-(2-aminopropyl)-1H-indazole-5-phenates hydrochlorate
Steps A: 1-[5-benzyloxy-3-(2-oxo-propyl group)-indazole-1-yl]-ethyl ketone
(5-benzyloxy-1H-indazole 3-yl)-acetate (2g, 7.08mmol) and sodium acetate (0.99g, 12mmol) mixture in diacetyl oxide (6ml) stirred 3 hours in 130 ℃.After the cooling, in reaction mixture, add entry (15ml) and ethyl acetate (15ml).Water phase separated is also used ethyl acetate extraction (2 * 15ml).Extract is merged the back use saturated NaHCO 3The aqueous solution (2 * 20ml) and the saturated NaCl aqueous solution (20ml) washing, dry (MgSO 4) and be evaporated to and obtain residue, residue with chromatography (silicon-dioxide, the hexane solution of 15% ethyl acetate) purifying, is obtained yellow solid (0.48g): 1H NMR (CD 3OD) δ 8.35-8.30 (m, 1H), 7.48-7.23 (m, 6H), 7.04-7.02 (m, 2H), 5.11 (s, 2H), 4.02 (s, 2H), 2.77 (s, 3H); 13C NMR (CDCl 3) δ 203.64 (C), 170.47 (C), 156.20 (C), 145.04 (C), 136.52 (C), 128.64 (CH), 128.31 (CH), 127.60 (CH), 120.51 (CH), 116.74 (CH), 102.26 (CH), 70.68 (CH 2), 42.76 (CH 2), 29.59 (CH 3), 22.77 (CH 3), MS (APCl) m/z 323 (M+H) +
Step B:1-[5-benzyloxy-3-(2-hydroxypropyl)-indazole-1-yl]-ethyl ketone
Product (0.13g, 0.4mmol) adding of the solution in methyl alcohol (8ml) NaBH to steps A 4(0.016g, 0.4mmol), mixture was stirring at room 20 minutes.In reaction mixture, add saturated NH then 4The Cl aqueous solution (20ml) and ethyl acetate (20ml).Water phase separated is also used ethyl acetate extraction (3 * 15ml).Extract is merged the back use the saturated NaCl aqueous solution (2 * 15ml) washings, dry (MgSO 4) and be evaporated to and obtain oily matter (0.12g).MS(APCl)?m/z?325(M+H) +。
Step C:1-[3-(2-azido--propyl group)-5-benzyloxy-indazole-1-yl]-ethyl ketone
The product of step B (0.12g, 0.37mmol) and methylsulfonyl chloride (0.04ml is 0.48mmol) at CH 2Cl 2Solution (5ml) is cooled to 0 ℃ in the presence of nitrogen, add again triethylamine (0.07ml, 0.48mmol).The mixture of gained was stirred 10 minutes down at 0 ℃, add saturated NH again 4The Cl aqueous solution (20ml) and ethyl acetate (20ml).Water phase separated is also used ethyl acetate extraction (2 * 5ml).Extract is merged the back use the saturated NaCl aqueous solution (2 * 15ml) washings, dry (MgSO 4) and be evaporated to and obtain residue, residue is dissolved in DMF (3ml).(0.08g, 1.2mmol), this mixture stirred 18 hours down at 70 ℃ then to add sodiumazide.After the cooling, add entry (20ml) and ether (20ml), water phase separated also further extracts (3 * 20ml) with ether.Extract is merged the back use the saturated NaCl aqueous solution (3 * 15ml) washings, dry (MgSO 4) and be evaporated to and obtain residue, residue with chromatography (silicon-dioxide, the hexane solution of 10% ethyl acetate) purifying, is obtained yellow oil (0.12g).MS(ES)m/z?350(M+H) +。
Step D:3-(2-aminopropyl)-1H-indazole-5-phenates hydrochlorate
(0.12g, 0.34mmol) solution in methyl alcohol (20ml) carried in the presence of the palladium (0.12g) jolting 18 hours at (35psi) under the hydrogen environment in 10% carbon to the product of step C.Filter and remove catalyzer, filtrate being evaporated to obtained residue, residue is obtained oily matter with purification by chromatography.Use the solution-treated oily matter of HCl in ethanol of 1N to obtain colourless semisolid hydrochloride (0.013g): 1H NMR (CD 3OD) δ 7.34-7.30 (m, 1H), 7.05-6.98 (m, 2H), 7.04-7.02 (m, 2H), 3.68-3.58 (m, 1H), 3.19-3.05 (m, 2H), 1.19-1.16 (d, J=6Hz, 3H), MS (ES) m/z 192 (M+H) +Handle the fumarate of the oily matter acquisition gray solid shape of this step generation with fumaric acid; Fusing point 227-230 ℃.Analyze: calculate C 10H 13N 3OC 4H 4O 40.3H 2O:C, 53.77; H, 5.63; N, 13.43.Result: C, 53.83; H, 5.85; N, 13.34.
Embodiment 2
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol fumarate
Steps A .1-(5-benzyloxy-1H-indazole-3-yl)-third-2-ketone
With the product of embodiment step 1 (2.0g, 6.2mmol) and sodium hydroxide (0.3g 7.5mmol) stirred 18 hours under the solution room temperature in the mixture of methyl alcohol (15ml) and water (15ml).The reaction mixture ethyl acetate extraction (4 * 30ml), extract is merged back salt water washing, drying (MgSO 4) and be evaporated to and obtain residue, residue with chromatography (silicon-dioxide, ethyl acetate/hexane, 1: 1) purifying, is obtained syrup (1.5g): ESI/MSm/z 281 (M+H) +
Step is (5-benzyloxy-1-methyl isophthalic acid H-indazole-3-yl)-third-2-ketone B.1-
To the product of steps A (1.2g, 4.28mmol) add in the solution in DMF (10ml) methyl iodide (0.53ml, 8.6mmol) and salt of wormwood (1.2g, 8.6mmol); This mixture stirred 16 hours down at 70 ℃.Add entry (15ml) and ethyl acetate (15ml) in reaction mixture after, water phase separated is also utilized ethyl acetate extraction (3 * 20ml).Extract is merged the back use salt water washing, drying (MgSO 4) and be evaporated to and obtain residue, residue with chromatography (silicon-dioxide, ethyl acetate/hexane, 1: 1) purifying, is obtained viscosity oily matter (0.6g): APCl/LCMSm/z 295 (M+H) +
Step is (2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol fumarate C.3-
(0.3g 0.1mmol), obtains oily matter to product by the similar fashion treatment step B that describes to the step D with the step B of embodiment 1, converts thereof into fumarate (0.071g): fusing point 136-139 ℃; LCMS m/z 206 (M+H) +Analyze: calculate C 11H 15N 3OC 4H 4O 40.1H 2O: C, 55.76; H, 5.98; N, 13.00.The result: C, 55.53; H, 6.11; N, 13.22.
Embodiment 3
2-methyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester
Steps A: 3-(2-(9-fluorenyl methoxy carbon acylamino) propyl group)-1H-indazole-5-phenol
Xiang the mixture of diox and water (4: 1, add in 10mL) 3-(2-aminopropyl)-1H-indazole-5-phenol (0.10g, 0.36mmol), 9-fluorenyl methoxy carbonyl chloride (0.13g, 0.54mmol) and sodium bicarbonate (0.9g, 0.54mmol).Reaction mixture is poured in the dilute sodium bicarbonate, and the mixture of gained uses ether extraction.Organic extraction is merged after drying (MgSO 4) and concentrate the residue purification by chromatography of gained.
Step B:2-methyl-propionic acid 3-(2-(9-fluorenyl methoxy carbon acylamino) propyl group)-1H-indazole-5-base ester
To 3-(2-(9-fluorenyl methoxy carbon acylamino) the propyl group)-1H-indazole-5-phenol (0.17g that is cooled to 0 ℃, 0.41mmol) and diisopropylethylamine (0.06g, 0.50mmol) solution in methylene dichloride (10mL) adds 2-methyl-prop acyl chlorides (0.05g, 0.5mmol) after, add again 4-dimethylaminopyridine (0.05g, 0.4mmol).Reaction can be warming up to room temperature and in stirring at room.Reaction mixture is added in the dilute aqueous solution of sodium bicarbonate and use ether extraction.Ether extract is merged after scouring, drying (MgSO 4) and concentrate.The residue purification by chromatography.
Step C:2-methyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester
With 2-methyl-propionic acid 3-(2-(9-fluorenyl methoxy carbon acylamino) propyl group)-1H-indazole-(0.16g, 0.33mmol) solution in 1: 4 mixture of piperidines and dimethyl formamide (2.5mL) stirs 5-base ester at ambient temperature.Reaction mixture is poured in the sodium bicarbonate aqueous solution of dilution, the mixture of gained is at first with ethyl acetate extraction, and then with dichloromethane extraction.Organic extraction is merged after drying (MgSO 4) and concentrate.The residue purification by chromatography.
Can use following method to measure according to acceptor of the present invention with in conjunction with agonist activity.
Method 1
5-HT 2The receptors bind test
For measuring serotonin energy compound to 5-HT 2The avidity of acceptor, they and agonist radioactive ligand [ 125I] DOI competes in conjunction with brain 5-HT 2The ability of acceptor is measured [neuropharmacology (Neuropharmacology), 26,1803 (1987)] by the following method that literature method is done after the improvement slightly.The aliquots containig (400 μ l) that is dispersed in rat after death in the 50mM TrisHCl damping fluid (pH 7.4) or people's brain cortex homogenate methiothepin (final concentration 10 μ M) exist or not in the presence of, with [ 125I] DOI (final concentration 80pM) incubation to be determining total respectively and non-specific binding, reaction cumulative volume 0.5ml.The test mixing thing is at polypropylene 23 ℃ of incubations 1 hour in vitro, filters by WhatmanGF/B glass fiber filter fast vacuum and stops test, and wherein said glass fiber filter is immersed in 0.3% polymine of ice-cold damping fluid preparation in advance.Replace the methyl methyllanthionine with test compounds (with different concns).On the beta counting instrument, measure filter membrane bonded radioactive activity by scintillation spectrometry.Use nonlinear iteration fitting of a curve computer program [pharmacology science trend (TrendsPharmacol.Sci.), 16,413 (1995)] analytical data, to determine the affinity parameter of compound.Suppress 50%[ 125I] DOI is defined as IC in conjunction with required maximization compound concentration 50Or K iValue.
Method 2
5-HT 2Function test: phosphoinositide (PI) conversion test
Can external use compound [ 3H] the inositol mark A7r5 rat smooth muscle cells moderate stimulation [ 3H] ability (activating the ability of Phospholipase C) that produces of inositol monophosphate by it measure serotonin can compound to 5-HT 2The relative agonist activity of acceptor.These cells are grown on the culture plate, and culture plate maintains 5%CO 2With add the improved Eagle substratum of Dulbecco (DMEM) that once contains 4.5g/l glucose and replenished 2mM glutamine, 10 μ g/ml gentamicins and 10% foetal calf serum in the wet environment of 95% air and every half cycle.In order to reach the purpose of carrying out phosphoinositide (PI) transformation experiment, [pharmacology and experimental therapeutic magazine (J.Pharmacol.Expt.Ther.), 286,411 (1998)] cultivate the A7r5 cell on 24 hole flat boards as mentioned previously.Make the cell that converges in the substratum of 0.5ml serum-free with 1.5 μ Ci[ 3H]-inositol (18.3Ci/mmol) contact 24-30 hour.Then with the cell flushing once with the DMEM/F-12 that contains 10mM LiCl, then in the 1.0ml same medium, be incubated 1 hour under 37 ℃ with test agent (or solvent in contrast), after this this substratum of sucking-off, and add the cold 0.1M formic acid of 1ml with termination reaction.As mentioned previously [pharmacology and experimental therapeutic magazine 286,411 (1998)] on the AG-1-X8 post to [ 3H]-inositol monophosphate ([ 3H]-IPs) carry out chromatographic separation, wherein use H 2O and 50mM ammonium formiate wash successively, subsequently with the 1.2M ammonium formiate wash-out that contains 0.1M formic acid total [ 3H]-the IPs fraction.Collect elutriant (4ml), mixes with the 15ml scintillation solution and always measure by counting at the enterprising line flicker of beta counting instrument [ 3H]-IPs.(Microcal Software, Northampton, sigmoid curve fitting function MA) come analytical concentration-response data and render a service (EC so that measure agonist by Origin Scientific Graphics software 50Be worth) and effect (E Max).Serotonin (5-HT) is used as positive control (standard substance) agonist compound, and the effect of test compounds and the effect of 5-HT (being set at 100%) are compared.To stimulate 50%[ 3H]-IPs produces required maximization compound concentration and is called EC 50Value.
Aforesaid method is used for the data shown in the generation table 1.
Table 1. 5-HT 2Receptors bind and performance data
Compound IC50，nM ?EC50，nM Effect (E max％)
3-(2-aminopropyl)-1H-indazole-5-phenates acid ????2.5 ??1,210 ????97
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol fumarate ????- ??778 ????98
Embodiment 4
Composition Content (wt%)
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol fumarate ???0.01-2％
Vltra tears ???0.5％
Sodium phosphate dibasic (anhydrous) ???0.2％
Sodium-chlor ???0.5％
EDTA disodium (disodium ethylene diamine tetraacetate) ???0.01％
Polysorbate80 ???0.05％
Geramine ???0.01％
Sodium hydroxide/hydrochloric acid Be used for adjust pH
Purify waste water Capacity to 100%
Embodiment 5
Composition Content (wt%)
3-(2-aminopropyl)-1H-indazole-5-phenol ???0.01-2％
Methylcellulose gum ???4.0％
Sodium phosphate dibasic (anhydrous) ???0.2％
Sodium-chlor ???0.5％
EDTA disodium (disodium ethylene diamine tetraacetate) ???0.01％
Polysorbate80 ???0.05％
Geramine ???0.01％
Sodium hydroxide/hydrochloric acid Be used for adjust pH
Pure water Capacity to 100%
Embodiment 6
Composition Content (wt%)
3-(2-aminopropyl)-1H-indazole-5-phenol ????0.01-2％
Guar gum ????0.4-6.0％
Sodium phosphate dibasic (anhydrous) ????0.2％
Sodium-chlor ????0.5％
EDTA disodium (disodium ethylene diamine tetraacetate) ????0.01％
Polysorbate80 ????0.05％
Geramine ????0.01％
Sodium hydroxide/hydrochloric acid Be used for adjust pH
Pure water Capacity to 100%
Embodiment 7
Composition Content (wt%)
2-methyl-propionic acid-3-(2-aminopropyl)-1H-indazole-5-phenolic ester ????0.01-2％
White vaseline and mineral oil and lanolin The ointment denseness
Sodium phosphate dibasic (anhydrous) ????0.2％
Sodium-chlor ????0.5％
EDTA disodium (disodium ethylene diamine tetraacetate) ????0.01％
Polysorbate80 ????0.05％
Geramine ????0.01％
Sodium hydroxide/hydrochloric acid Be used for adjust pH

Claims (9)

1. be used to reduce and control the method for normal or the intraocular pressure that raise, this method comprises compound and the pharmaceutically useful salt of this compounds and the solvate of the following structural formula of using pharmacy effective dose: structural formula I
Wherein G is selected from hydrogen, halogen or C 1-4Alkyl;
R is hydrogen, C 1-4Alkyl, C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3And R 4Be independently selected from hydrogen, C 1-4Alkyl, or R 3, R 4Form cyclopropyl rings with the carbon atom that they connected, or in addition, R 2And R 3Common formation (CH 2) mTo form saturated heterocycle;
Work as R 2And R 3During for a heterocyclic part, R 1Can be hydrogen or C 1-4Alkyl;
R 5Can be hydrogen or C 1-4Alkyl;
As R, R 1, R 2, R 5When all being hydrogen with G, R 3, R 4Can not be hydrogen simultaneously;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), OC 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2-4;
N is 1 or 2.
2. the process of claim 1 wherein that compound is defined as follows:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R be C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3, R 4Form cyclopropyl rings with the carbon atom that they connected, or in addition, R 2And R 3Common formation (CH 2) mTo form saturated heterocycle;
Work as R 2And R 3During for a heterocyclic part, R 1Can be hydrogen or C 1-4Alkyl;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), OC 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2-4;
N is 1 or 2.
3. the process of claim 1 wherein that compound is defined as follows:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R be hydrogen, C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3And R 4Be independently selected from hydrogen, C 1-4Alkyl, or R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2 or 3;
N is 1 or 2.
4. the process of claim 1 wherein that compound is defined as follows:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R is hydrogen or C (=O) W;
R 1And R 2Be hydrogen;
R 3Be hydrogen, and R 4Be methyl, perhaps R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Be hydrogen;
W is C 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CON (C for alkyl 1-4Alkyl) 2, C (=NH) NH 2Replace).
5. the process of claim 1 wherein that compound is selected from:
3-(2-aminopropyl)-1H-indazole-5-phenol;
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol;
2-(5-methoxyl group-1H-indazole-3-yl)-1-methyl-ethamine;
3-(2-aminopropyl)-6-fluoro-1H-indazole-5-phenol;
3-(2-aminopropyl)-7-methyl isophthalic acid H-indazole-5-phenol;
3-(2-aminopropyl)-6-fluoro-1-methyl isophthalic acid H-indazole-5-phenol;
2-methyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
2,2-dimethyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
Cyclopropane-carboxylic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
N, N-diethyl-succinamic acid 3-(2-aminopropyl)-1H-indazole-5-base ester.
6. the compound of following structural formula:
Figure A0081934800041
Wherein G is selected from hydrogen, halogen or C 1-4Alkyl;
R be C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3, R 4Form cyclopropyl rings with the carbon atom that they connected, or in addition, R 2And R 3Common formation (CH 2) mTo form saturated heterocycle;
Work as R 2And R 3During for a heterocyclic part, R 1Can be hydrogen or C 1-4Alkyl;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), OC 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2-4;
N is 1 or 2.
7. the compound of claim 6, wherein:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R be hydrogen, C (=O) W or P (=O) (OX) (OY),
R 1And R 2Be hydrogen;
R 3And R 4Be independently selected from hydrogen, C 1-4Alkyl, or R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Can be hydrogen or C 1-4Alkyl;
W is C 1-6Alkyl, NR 6R 7, N (R 6) CH 2(CH 2) nC (=O) N (R 7) (R 8), C 1-6(it can be by halogen, hydroxyl, CO for alkyl 2C 1-4Alkyl, CON (C 1-4Alkyl) 2, C (=NH) NH 2, HC (=NH) NH 2, NH 2Replacement), C 2-4Alkenyl (replaced by phenyl, not by or by C 1-4Alkyl, C 1-4One or more replacements in the alkoxy or halogen);
R 6, R 7And R 8Be independently selected from hydrogen or C 1-4Alkyl;
X and Y are independently selected from hydrogen, C 1-10Alkyl, or X and Y can form rudimentary (CH jointly 2) mAlkyl chain;
M is 2 or 3;
N is 1 or 2.
8. the compound of claim 6, wherein:
G is selected from hydrogen, halogen or C 1-4Alkyl;
R is hydrogen or C (=O) W;
R 1And R 2Be hydrogen;
R 3Be hydrogen, and R 4Be methyl, perhaps R 3, R 4Form cyclopropyl rings with the carbon atom that they connected;
R 5Be hydrogen;
W is C 1-6Alkyl, C 1-6(it can be by halogen, hydroxyl, CON (C for alkyl 1-4Alkyl) 2, C (=NH) NH 2Replace).
9. the compound of claim 6, wherein compound is selected from:
3-(2-aminopropyl)-1H-indazole-5-phenol;
3-(2-aminopropyl)-1-methyl isophthalic acid H-indazole-5-phenol;
2-(5-methoxyl group-1H-indazole-3-yl)-1-methyl-ethamine;
3-(2-aminopropyl)-6-fluoro-1H-indazole-5-phenol;
3-(2-aminopropyl)-7-methyl isophthalic acid H-indazole-5-phenol;
3-(2-aminopropyl)-6-fluoro-1-methyl isophthalic acid H-indazole-5-phenol;
2-methyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
2,2-dimethyl-propionic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
Cyclopropane-carboxylic acid 3-(2-aminopropyl)-1H-indazole-5-base ester;
N, N-diethyl-succinamic acid 3-(2-aminopropyl)-1H-indazole-5-base ester.
CN00819348A 2000-03-17 2000-11-14 5-hydroxy indazole derivatives for treating glaucoma Pending CN1450995A (en)

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US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
EP1392292B1 (en) 2001-06-01 2006-03-01 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
US7196082B2 (en) 2002-11-08 2007-03-27 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
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US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
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