CN101001628A - Anti-HIV quinuclidine compounds - Google Patents
Anti-HIV quinuclidine compounds Download PDFInfo
- Publication number
- CN101001628A CN101001628A CN 200580018136 CN200580018136A CN101001628A CN 101001628 A CN101001628 A CN 101001628A CN 200580018136 CN200580018136 CN 200580018136 CN 200580018136 A CN200580018136 A CN 200580018136A CN 101001628 A CN101001628 A CN 101001628A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- chemical compound
- hiv
- cycloalkyl
- virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 230000036436 anti-hiv Effects 0.000 title description 2
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- 238000000034 method Methods 0.000 claims description 45
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Images
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Abstract
The invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the infectivity of a pathogen such as a retrovirus toward mammalian cells is implicated and inhibition of its infectivity is desired comprising administering to a mammal in need of such therapy, an effective amount of a benzoylquinuclidine derivative that inhibits pathogenic infectivity, including pharmaceutically acceptable salts thereof.
Description
Background of invention
2003, to die from HIV/AIDS popular for the whole world more than 300 ten thousand patients, and global range 500 ten thousand examples are new according to estimates infects human immunodeficiency viruses (HIV)-make the carrier reach 4,000 ten thousand.No matter the progress of antiviral therapy exploitation how, AIDS also there is not therapy in full force and effect.Present therapeutic strategy comprises that protease inhibitor, nucleoside analog reverse transcriptase inhibitor, non-nucleoside are like thing reverse transcriptase inhibitor, fusion inhibitor and high toxicity hydroxyurea (Yarchoan R et al.(1986)Lancet?1(8481)：575-580；Richards?AD?et?al.(1989)FEBS?Lett?247(1)：113-117；Gao?WY?et?al.(1995)Proc?NatlAcad?Sci?USA?92(18)：8333-8337；De?Clercq?E(1999)Farmaco?54(1-2)：26-45；Williams?IG(2003)MJ?CHn?Pract?57(10)：890-897)。Regrettably, resistance (Cavert W and Balfour HH (2003) the Clin Lab Med 23 (4): 915-928 that causes of viral genome sudden change; Gallant JE et al. (2003) Antivir Ther8 (6): 489-506; Olson WC and Maddon PJ (2003) Curr Drug TargetsInfect Disord 3 (4): 283-294) and serious toxic and side effects all seriously limited the effectiveness of treatment.
Need antiviral drugs at present, comprise anti--retrovirus retrovirus medicine.Also need pharmacological tool to infect relevant pharmacology's process with further research.
Summary of the invention
The present invention by blocking-up or suppress virus (, comprising HIV) as retrovirus retrovirus in vivo and in vitro the ability of mammalian cell-infecting prevent the method for virus replication.Therefore, the invention provides the mammal that treatment is exposed to infectious pathogen, comprise that infected sexually transmitted disease (STD) substance (as antibacterial or virus) threatens or the mammiferous Therapeutic Method of infringement, described method comprises the quinuclidine compounds of the formula I that gives described mammal treatment effective dose:
Wherein:
A) R
1, R
2, R
3And R
5Independent is H, OH, halogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl ((C
1-C
6) alkyl), (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkanoyl, halo (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxy carbonyl; (C
1-C
6) alkylthio group or (C
1-C
6) alkanoyl oxygen base; Or R
1And R
2Lump together expression methylene dioxy base;
B) X
1Be NO
2, CN ,-N=O, (C
1-C
6) alkyl C (O) NH-, azoles quinoline base or N (R
6) (R
7), R wherein
6And R
7Independent is H, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, ((C
1-C
6) alkyl), wherein cycloalkyl is chosen wantonly and is comprised 1-2 S, non-peroxide O or N (R
8), R wherein
8Be H, O, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, phenyl or benzyl; Aryl, aryl (C
1-C
6) alkyl, aryl (C
2-C
6) thiazolinyl, heteroaryl, heteroaryl (C
1-C
6) alkyl, or R
6And R
7Form 5-or former heterocycle of 6-or heteroaryl ring jointly with the nitrogen that is connected them, optional by R
1Replace and optional 1-2 S, non-peroxide O or the N (R of comprising
5);
C) Y and Z be=O ,-O (CH
2)
mO-or-(CH
2)
m-, wherein m is 2-4, or Y is H, Z is OR
9Or SR
9, R wherein
9Be H or (C
1-C
4) alkyl;
And pharmaceutically acceptable salt.
Preferably, R
1, R
2And R
3In 1,2 or 3 be H.
Preferably, R
6And R
7Independent is H, (C
1-C
4) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl or benzyl.
Preferably, X
1For-N (R
6) (R
7).
Preferably, R
1, R
2Or R
3In 1 or 2 be (C
1-C
6) alkoxyl.
Preferably, Z and Y lump together expression=O.
The present invention also provides for example Pharmaceutical composition of unit dosage form, it comprises described formula I chemical compound, or its pharmaceutically acceptable salt, and pharmacy can be accepted diluent or carrier, said composition can be chosen the inverase in the above-mentioned inverase that comprises one or more types wantonly, and can choose wantonly and comprise stabilizing agent, antiseptic and absorption controlling agent.
In addition, the invention provides the Therapeutic Method of prevention or treatment mammal such as people's pathology symptom, wherein the infectivity of pathogen or microbial body such as virus or retrovirus retrovirus is a correlative factor, therefore need to suppress its infectivity, described method comprises formula I chemical compound or its pharmaceutically acceptable salt of the mammal treatment effective dose that needs this treatment.
The invention provides the described formula I chemical compound that is used for the treatment of purposes (as, be used for the treatment of and infect the mammal that retrovirus retrovirus such as HIV are arranged), and the purposes of described formula I chemical compound in the medicine that preparation treatment mammal such as people infect.
The invention provides described formula I chemical compound is incorporated into mammalian cell to change the method for cell membrane to the permeability of infector, be included in the inside and outside with the described formula I chemical compound exposing cell of effective dose to change the character of described cell membrane, the sterol that for example changes described cell membrane is formed.Comprising cell that described formula I chemical compound is incorporated into acceptor site as part can be used on the detection compound cell membrane or the selectivity of cell membrane internal specific receptor, or can be used as instrument and identify that treatment depends on the potential medicine of disease or disease of permeability of cell membrane, method contacts with described ligand receptor complex for making described medicine, and the displacement degree of detector ligand and/or the combination degree of medicine.
The present invention also provides novel formula I chemical compound disclosed herein, and to preparation formula (I) compound or its salt useful method and intermediate.This comprising C (Y) wherein (Z) group be incorporated into the analog of the ring-CH-group of quinuclidine, and wherein Y and R
2Analog by the key connection.Many formula I chemical compounds also are used as the intermediate of preparation I compound.
The accompanying drawing summary
Figure 1 shows that the structure of (4-aminophenyl) (1-aza-bicyclo [2,2,2] suffering-4-yl)-ketone or 4-(4-amino benzoyl)-1-aza-bicyclo [2,2,2]-octane (SP003).
Fig. 2 is the SP003 inhibition design sketch that strain is duplicated in the Hela cell to HIV-1 IIIB.Diluted chemical compound is in water or be dosage form (SP003 A), ddI be known anti--virus compound.
Fig. 3 gave SP003 the inhibition design sketch that strain is duplicated to HIV-1 IIIB for 24 hours in advance in the Hela cell.Experiment SP003 is dosage form (SP003A).
Fig. 4 gave SP003 the inhibition design sketch that strain is duplicated to HIV-1 IIIB for 48 hours in advance in the Hela cell.
Fig. 5 is the SP003 inhibition design sketch that strain is duplicated in the Hela cell to multidrug resistance HIV MDR-769.AZT is known antiviral compound.
Detailed Description Of The Invention
Unless otherwise indicated, its implication of definition used below is: halogen is fluorine, chlorine, bromine Or iodine. The expression straight chain such as alkyl, alkoxyl, thiazolinyl, alkynyl and branched group; But When referring to separate base, only comprise straight chain group such as " propyl group ", branched chain isomer is as " different Propyl group " to specifically note. Aryl represents containing of phenyl or ortho-condensed of about 9-10 annular atoms Wherein at least one the ring for aromatic ring two the ring carbon ring groups. Heteroaryl comprises by the monocycle virtue The ring carbon atom of ring connects contains 5-6 and is selected from separately non-peroxide by carbon atom and 1-4 Oxygen, sulphur and N (R8), R wherein8Do not exist or be H, O, (C1-C
4) alkyl, phenyl or benzyl The group of the annular atoms that the hetero atom of base forms, and the ortho-condensed of about 8-10 annular atoms The group of bicyclic heterocycles, particularly this annular atoms derive from benzo derivative or with propylidene, Trimethylene or tetramethylene two bases condense the group that forms.
The compound that it should be appreciated by those skilled in the art that tool chiral centre of the present invention can light Learn active and racemic form existence and separation and purification. These compounds can show polymorph The property. Be appreciated that any racemic of the present invention includes The compounds of this invention, optical activity, Polymorphic or its alloisomerism or form of mixtures, these compounds have and as herein describedly have With character, how to prepare as everyone knows in this area the optical activity form (for example by heavily the knot Crystal technique resolution of racemic form begins to synthesize from the optical activity raw material, or advances with chiral column Circumstances in which people get things ready for a trip spectrum is separated) and how to determine to resist with code test described herein or with other similar test Infection activity.
Concrete and preferred following groups, substituent value and scope are only for explanation; Do not arrange Except other value in other limit value or this group and the substituting group range of definition.
Specific (C1-C
6) alkyl can be methyl, ethyl, propyl group, isopropyl, butyl, different Butyl, sec-butyl, amyl group, 3-amyl group or hexyl; (C3-C
6) cycloalkyl can be cyclopropyl, Cyclobutyl, cyclopenta or cyclohexyl; (C3-C
6) cycloalkyl (C1-C
6) alkyl can be the cyclopropyl first Base, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 2-cyclopropyl ethyl, 2-encircle fourth Base ethyl, 2-cyclopenta ethyl or 2-cyclohexyl ethyl; Heterocyclylalkyl and Heterocyclylalkyl alkyl Comprise above-mentioned cycloalkyl, wherein said ring is optional comprise 1-2 S, non-peroxide O or N (R8) and 2-5 carbon atom; For example morpholinyl, piperidyl, piperazinyl, indanyl, 1,3-dithiane-2-base etc.; (C1-C
6) alkoxyl can be methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, butoxy, different-butoxy, the second month in a season-butoxy, amoxy, 3-amoxy or oneself The oxygen base; (C2-C
6) thiazolinyl can be vinyl, pi-allyl, 1-acrylic, 2-acrylic, 1-fourth Thiazolinyl, 2-cyclobutenyl, 3-cyclobutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-penta Thiazolinyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; (C2-C
6) Alkynyl can be acetenyl, 1-propinyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-fourth Alkynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-oneself Alkynyl, 3-hexin base, 4-hexin base or 5-hexin base; (C1-C
6) alkanoyl can be formoxyl, Acetyl group, propiono or bytyry; Halo (C1-C
6) alkyl can be iodomethyl, bromomethyl, Chloromethyl, methyl fluoride, trifluoromethyl, 2-chloroethyl, 2-fluoro ethyl, 2,2, the 2-trifluoroethyl Or pentafluoroethyl group; Hydroxyl (C1-C
6) alkyl can be the alkyl that is replaced by 1 or 2 OH, as Hydroxymethyl, 1-hydroxyl ethyl, 2-hydroxyl ethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-Hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 3,4-dihydroxy butyl, 1-hydroxyl amyl group, 5-hydroxyl amyl group, 1-hydroxyl hexyl or 6-hydroxyl hexyl; (C1-C
6) alkoxy carbonyl can be first Oxygen base carbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, Pentyloxy carbonyl or hexyl oxygen base carbonyl; (C1-C
6) alkylthio group can be methyl mercapto, ethylmercapto group, Rosickyite base, isopropyl sulfenyl, butylthio, isobutyl sulfenyl, penta sulfenyl or own sulfenyl; (C2-C
6) Alkanoyl oxygen base can be acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, penta Acyloxy or hexylyloxy; Aryl can be phenyl, indenyl or naphthyl; Heteroaryl can be furans Base, imidazole radicals, triazolyl, triazine radical, azoles base, different azoles base, thiazolyl, different thiophene Azoles base, pyrazolyl, pyrrole radicals, pyrazinyl, tetrazole radical, pyridine radicals (or its N-oxide), Thienyl, pyrimidine radicals (or its N-oxide), 1H-indyl, isoquinolyl (or its N-oxygen Compound) or quinolyl (or its N-oxide).
Term " retroviruse " includes but not limited to, Retroviridae (family Retroviridae) member, comprise the α retroviruse (as, fowl hematopoiesis leucocyte tissue increases Sick poison), β retroviruse (such as, mouse mammary adenoma virus), Y retroviruse (as, Murine leukemia virus), δ retroviruse (such as, bovine leukemia virus), ε retroviruse (such as, Walley sarcoma cutis virus), slow virus (as, HIV-1, HIV-2) and foam Virus (as, the HFV).
Can be shown in option A, by with N-phenyl grignard reagent that replace or N-protected Or phenyl lithium and 4-cyano group-1-aza-bicyclo [2.2.2] octane (4) or 4-cyano group-quinuclidine reaction system Standby The compounds of this invention, wherein the example of phenyl grignard reagent has 4-(two (trimethyl silyl Base)) amino-1-phenyl-magnesium bromide.
Option A
With the radicals R on the phenyl of RMgBr or aryl lithium reaction1、R
2And/or R3, can be with removable protecting group such as ethoxyethyl group, THP, (C such as the group of hydroxyl1-C
4)
3The protections such as silicyl. Shielded HO and hydroxyl alkyl can be by the organic synthesis fields Known method carries out deprotection, and is converted into halogen, CN, alkoxy carbonyl, alkanoyl oxygen Base and alkanoyl. Shielded amino can take off by the known method in organic synthesis field Protection, and be converted into N (R6)(R
7). If need, the C=O group can advance in the conversion process Row protection and/or reduction, then deprotection and reoxidize and be C=O. See, for example, F.T. Harrison, Compendium of Organic Synthetic Reactions, Wiley-Interscience, N.Y. (1971); L.F.Fieser et al., Reagents for Organic Synthesis, John Wiley﹠Sons, Inc., N.Y. (1967), and U.S. Patent No. 5,411,965.
Therefore, the occurrence of R1 is H, (C among the following formula I2-C
4) alkyl, (C2-C
4) alkoxyl or (C3-C
6) Heterocyclylalkyl.
R
2Occurrence be H.
N(R
6)(R
7) occurrence be amino, diethylamino, dipropyl amino, cyclohexyl amino or propyl group amino, so R3Occurrence be NH2。
Another preferred compound is formula I compound, and it is 2,3 or 4-(4-substituted benzoyl Acyl group)-1-aza-bicyclo [2,2,2] octane.
Preferred The compounds of this invention is SP003 (Fig.1).
Alkalescence or acidity at compound are strong to the feelings that are enough to form stable non-toxic acid or alkali salt Under the condition, the compound that gives salt form is suitable. The example of the acceptable salt of pharmacy be with Physiology is learned the organic acid addition salt of the acid formation that can accept anion, for example toluenesulfonic acid Salt, mesylate, acetate, citrate, malonate, tartrate, butanedioic acid Salt, benzoate, ascorbate, alpha-ketoglutarate. Also can form suitable inorganic Salt comprises hydrochloride, sulfate, nitrate, bicarbonate and carbonate.
Pharmaceutically acceptable salt can with standard technique preparation known in this field, for example pass through alkalescence Enough strong compound such as amine and the suitable acid reaction that provides physiology can accept anion advance OK. Also can form alkali metal (for example sodium, potassium or lithium), alkaline-earth metal (such as calcium or magnesium) or zinc salt.
Embodiment of the present invention provide and have comprised formula I compound and zinc salt such as seven water sulphur The composition of acid zinc, wherein ascorbic acid preferably is not present in the composition, and reason is a kind of Or the brown stain effect that causes of the degraded of various ingredients. In one embodiment, described formula I The ratio that compound and zinc salt such as white vitriol exist in composition is about 27-107: 1.
Formula I chemical compound can be formulated as Pharmaceutical composition and give mammalian hosts such as patient with the various forms that are suitable for selected route of administration, promptly oral or parenteral, intravenous, intramuscular, part or subcutaneous route, or suck or be blown into administration.
The compounds of this invention can be through being administered systemically, as oral with pharmaceutical acceptable carrier such as inert diluent or absorbable edible carrier.This chemical compound can be used as powder, piller or suspendible body and is wrapped in hard or the Perle, maybe can suppress in flakes.For oral therapeutic administration, reactive compound can give with one or more excipient, but used form is absorbing sheet, buccal tablet, lozenge, capsule, elixir, suspensoid, syrup, wafer etc.This based composition and preparation should contain at least 0.1% reactive compound.Certainly, the percentage ratio of compositions and preparation can change to some extent, and can account for about 60% weight of about 2-of the unit dosage forms of giving as required.The amount of reactive compound is for reaching the amount of effective dose level in the compositions of this class therapeutic use.
But absorbing sheet, lozenge, pill, capsule etc. also can contain following composition: binding agent such as tragakanta, arabic gum, corn starch or gelatin; Excipient such as dicalcium phosphate; Disintegrating agent such as corn starch, potato starch, alginic acid etc.; Lubricant such as magnesium stearate; Sweeting agent such as sucrose, fructose, lactose or aspartame; Or correctives such as lavender, wintergreen oil or Fructus Pruni pseudocerasi correctives etc.When described dosage form was capsule, it can contain the above-mentioned type material and also contain outward just like vegetable oil or poly-ethanol.Can exist other material as coating, or be used for modifying the physical form of described solid unit dosage form.For example tablet, pill or capsule can be surrounded by gelatin, wax, Lac or sugar etc.Syrup or elixir can contain reactive compound, sucrose or fructose as sweeting agent, and methyl and propyl group Ni Baijin class be as antiseptic, dyestuff and correctives such as Fructus Pruni pseudocerasi or Fructus Citri tangerinae spice.Certainly, any material for preparing any unit dosage forms should be that pharmacy is acceptable and nontoxic when its dosage basically.In addition, reactive compound can be mixed in slow releasing preparation and the device, as patch, infusion pump or transplantation type durative action preparation.
Reactive compound also can give through vein or intraperitoneal infusion or injection.The solution of reactive compound or its salt can prepare in water, chooses wantonly and mixes with nontoxic surfactants.Dispersion also can prepare in glycerol, liquid macrogol, glyceryl triacetate and composition thereof and oil.Under normal storage and service condition, these preparations contain antiseptic in case growth of microorganism.
Be suitable for injecting, the medicament of infusion or suction can comprise aseptic aqueous solution or dispersion.Can prepare the sterilized powder that contains active component, it is suitable for facing of aseptic injection or infusion solution or dispersion using preparation, optional being coated in the liposome.In all cases, final preparation should be aseptic, liquid and stable under preparation and condition of storage.Liquid-carrier or solvent can be solvent or the liquid dispersion body medium that comprises following material: as water, ethanol, polyhydric alcohol (as glycerol, propylene glycol, liquid macrogol etc.), vegetable oil, nontoxic glyceryl ester, and stabilized mixture.Can be mobile by forming the liposome maintenance, under the dispersion situation, pass through to keep required particle diameter or keep flowability by the use surfactant.Can prevent microbial action by using various antibacterial and antifungal such as Ni Baijin class, methaform, phenol, ascorbic acid, thimerosal etc.In many cases, can preferably include isotonic agent such as saccharide, buffer agent or sodium chloride.The prolongation of injectable composition absorbs and can reach by use the delayed absorption agent in compositions, as using aluminum monostearate, cellulose ether and gelatin.After the filtration sterilization, as required, the reactive compound of aequum and above-mentioned other composition joined in the suitable solvent prepare aseptic injectable solution.When using sterilized powder, preferred manufacturing procedure is vacuum drying and freeze drying technology at the preparation aseptic injectable solution, uses this technology can obtain the active component in the aforementioned aseptic filtration solution and the powder of any required composition.
To topical, when The compounds of this invention can pure form use during for liquid.But, need can accept carrier with liquid or solid skin with compositions or dosage form usually and give.
Used solid carrier comprises solid in small, broken bits such as Pulvis Talci, clay, microcrystalline Cellulose, silica gel, aluminium dioxide etc.Used liquid-carrier comprises water, alcohol or glycol or water-alcohol/glycol mixture, and wherein The compounds of this invention is can effect level optional dissolves or disperse with nontoxic surfactants.Can add adjuvant fluorine aromatic and additional antimicrobial to optimize the character of the purposes of being given.The gained fluid composition can be used self-absorption agent pad, is used for flooding binder and other dressing, or is sprayed onto the affected part with pump or aerosol spray device.
Thickening agent such as synthetic polymer, fatty acid, soap and ester, aliphatic alcohol, modified cellulose or modified mineral material also can use to form with liquid-carrier and disperse paste, gel, ointment, soap etc., directly are applied to patient skin.
The useful dermatological compositions that can be used to giving construction I chemical compound is known in the art; For example, referring to Jacquet et al. (U.S.Pat.No.4,608,392), Geria (U.S.Pat.No.4,992,478), Smith et al. (U.S.Pat.No.4,559,157) and Wortzman (U.S.Pat.No.4,820,508).
The useful dosage of formula I chemical compound can be determined by external in its animal model of contrast and activity in vivo.The method of effective dose extrapolation the pure man is known in the art in mice and other animal; For example, referring to U.S. Patent No. 4,938,949.
Generally speaking, fluid composition such as lotion Chinese style I compound concentrations scope are about 0.1-25wt-%, preferably about 0.5-10wt-%.Concentration in semisolid or solid composite such as gel or the powder is about 0.1-5wt-%, preferably about 0.5-2.5wt-%.
Need the amount of the chemical compound that uses or its active salt or derivant not only to regulate in the treatment according to selected specific salt, also regulate, and finally determine cautiously by attending doctor or internist according to route of administration, disease character, patient's age and condition to be treated.
But in general suitable dosage ranges is the about 100mg/kg of about 0.5-, as, be the about 75mg/kg body weight of about 10-every day, as the every experimenter of the about 50mg per kilogram of body weight of 3-every day, preferable range is about 6-90mg/kg/ days, most preferred range is 15-60mg/kg/ days.
Described chemical compound gives with unit dosage forms easily; As, contain 5mg extremely up to 1-3g, easily 10-1000mg, most preferably the active component per unit dosage form of 50-500mg.
Ideal, should give active component and make it reach the peak plasma concentration of reactive compound, this concentration is the about 75 μ M of about 0.5-, preferably about 1-50 μ M, the most preferably from about about 30 μ M of 2-.Can reach by the active ingredient solution of choosing wantonly in normal saline of intravenous injection 0.05-5%.For example, the described formula I chemical compound of about 0.5-3g dissolves in about 125-500ml parenteral solutions, this solution contain just like, 0.9%NaCl, about 5-10% glucose.This solution of infusion in time of 7 hours can reached, optional and couplings such as other antiviral drugs, antibiotic.Described active component also can be used as the bolus oral administration that contains about 1-100mg active component.Ideal blood levels keeps by the 0.01-5.0mg/kg/hr continuous infusion is provided approximately, or keeps by the active component of the about 0.4-15mg/kg of discontinuous infusion.
Required dosage can be according to circumstances with single dose or with proper spacing with the divided dose administration, for example every day two, three, four or more divided doses.Divided dose himself can be gone the administration that is subdivided into several discontinuous non-tight spacings again; As a plurality of inhalant, or a plurality of drops are applied to eyes from an insufflation.
The compounds of this invention can be determined with pharmacology model known in the art as the ability of antiviral drugs, or determine with following test.
Below describe representative medicaments in detail, its contain the treatment or prophylactic use in mammal such as people's formula I chemical compound
(I) tablet 1
The mg/ sheet
SP003 100.0
Lactose 77.5
Polyvidone 15.0
Cross-linking sodium carboxymethyl cellulose 12.0
Microcrystalline Cellulose 92.5
Magnesium stearate 3.0
300.0
(ii) tablet 2
The mg/ sheet
SP003 20.0
Microcrystalline Cellulose 410.0
Starch 50.0
Primojel 15.0
500.0
(iii) capsule
The mg/ capsule
SP003 10.0
Silica sol 1.5
Lactose 465.5
Pregelatinized starch 120.0
Magnesium stearate 3.0
600.0
(iv) injection 1 (1mg/ml)
Mg/ml
SP003 (free alkali form) 1.0
Sodium hydrogen phosphate 12.0
Sodium dihydrogen phosphate 0.7
Sodium chloride 4.5
1.0 (pH transfers in right amount the N sodium hydroxide solution
7.0-7.5)
Water for injection adds to 1mL in right amount
(v) injection 2 (10me/ml)
Mg/ml
SP003 (free alkali form) 10.0
Sodium dihydrogen phosphate 0.3
Sodium hydrogen phosphate 1.1
PEG400 200.0
(pH transfers in right amount 01 N sodium hydroxide solution
7.0-7.5)
Water for injection adds to 1mL in right amount
(vi) aerosol
The mg/ jar
SP003 20.0
Oleic acid 10.0
Isceon 5,000.0
Dichlorodifluoromethane 10,000.0
Dichlorotetra-fluoroethane 5,000.0
Above preparation can be according to the method preparation of pharmaceutical field routine.The present invention is further elaborated in conjunction with following detailed embodiment.
The synthetic method of chemical compound 4 is seen T.Kanai, heterocycles (1992) Vol.34, and No.11,213, as described in above-mentioned option A, N, N-pair-(trimethyl silyl)-4-bromaniline is available from Sigma-Aldrich.Solvent is by the standard method purification.EI-Mass mass spectrum VG Tribid, Varian CH7 instrument record.Thin layer chromatography (TLC) is analyzed at silica gel 60 F
254Carry out on the aluminium sheet (Merck).NMR-spectrogrph: Bruker AMX300.Chemical shift is recorded as ppm.
Under argon, N, N-two-(trimethyl silyl)-4-bromaniline (2.5ml, 8.86mmol) be added drop-wise to Mg rotation suspension in anhydrous THF (2ml) (250mg, 10.3mmol) in, keep speed that the consumes considerable of Mg is examined.With the five equilibrium Grignard reagent of 1.1ml be added drop-wise to be dissolved in anhydrous THF (2ml) 4 (200mg, 1.47mmol) in.After the stirring, reflux solution 2 hours, add ice-cold HCl (20%, 4ml) aqueous solution.After the stirred overnight at room temperature, use saturated NaHCO
3Aqueous solution this mixture that neutralizes is used dichloromethane extraction.Separate organic layer, through MgSO
4Drying, vacuum concentration.Residue obtains SP003 (44mg, 0.19mmol, 13%) with the PTLC purification on silica gel.
1H NMR (d-methanol) δ 7.66 (d, 2H, 9Hz), 6.51 (d, 2H, 9Hz), 2.86 (m, 6H), 1.86 (m, 6H) MS (EI) m/z 230 (M
+), 174,135,110,96.
Embodiment 2.SP003 suppresses the research that HIV-1 IIIB duplicates in the Hela cell
A. method
For studying viral replication in vitro, adopt GenPhar AV-Finder
TMThe test of-HIV drug development, this is a kind of new technique, is made up of two parts: (1) a kind of clone's continuous passage HeLa cell line contains activatory molecular switch of HIV-1 tat-and green fluorescence protein gene; (2) recombinant adenovirus (rAd) carrier, it contains HIV-1 receptor/co-receptor (CD4, CXCR4 and CCR5) gene that the HeLa cell is gone in all three kinds of transductions, and they are converted into hypersensitivity HIV-1 indicator for experiment usefulness.Indicator cells is crossed expression HIV-1 acceptor gene and is subject to the HIV-1 strain or the chorista infection.All HIV-1 strains to be measured, no matter co-receptor preferably whether, and the hypotype of all HIV-1 or class will infect this indicator cells.The fluorescence of infected cell is bright, therefore is easy to read plate technique with standard laboratory and detects and the inhibition of quantitative potential antiviral thing to virus replication.
Detector plates was set up at first day, and method is for to be added into HeLa cell (3000/ hole) in the DMEM culture medium in 96 orifice plates that contains CCS and adenovirus AD-3R, and in 37 ℃, 95% humidity and 5%CO
2Under cultivated two days.Under the situation that does not have medication in advance, added SP003 or control compound (AZT, ddI, 3TC) and overnight incubation that HIV-1 IIIB (200IP/ hole) and concentration raise gradually at the 3rd day.The 4th day, culture medium is changed into the fresh culture of the target compound that contains respective concentration.The 7th day by detecting the fluorescence assessment infectivity (λ in each hole
Emis=485nm; λ
Exc=520nm).Under the situation of medication in 24 hours in advance, added SP003 or control compound (AZT, ddI, 3TC) and the overnight incubation that concentration raises gradually at the 3rd day.Added SP003 or control compound (AZT, ddI, 3TC) and overnight incubation that HIV-1 IIIB (200IP/ hole) and concentration raise gradually at the 4th day.The 5th day, culture medium is changed into the fresh culture of the target compound that contains respective concentration.The 8th day by detecting the fluorescence assessment infectivity in each hole.The result suppresses the percentage ratio formal representation with virus replication.
After the above-mentioned cell processing scheme, measure the 3-(4,5-dimethylthiazole-2-yl)-2 of cell, 5-diphenyl bromination tetrazolium (MTT) reduced level, and measure the mitochondrion integrity, to check whether testing compound has cytotoxicity.
Use the independent aqueous solution form (SP003) or the aqueous compositions form (SP003A) of (4-amino-phenyl)-(1-aza-bicyclo [2.2.2] suffering-4-yl)-ketone (Fig.1), medicament in the said preparation: zinc sulfate: the ratio of ascorbic acid is that 26.6/1/1.6 (for example, has 7.5mg zinc sulfate heptahydrate and 12.5mg ascorbic acid among the 200mg SP003; Xu, J.et al., J.Pharmacol.Exper.Ther., (2003) 307:1148-1157.
B. result
1. to the influence of HIV-1 IIB virus replication.There is not administration in advance (Fig.2)
The structure of chemical compound (4-amino-phenyl)-(1-aza-bicyclo [2,2,2] suffering-4-yl)-ketone (SP003) is shown in Fig.1.Chemical compound is water-soluble, or be dissolved in the preparation (SP003A) that contains zinc sulphate heptahydrate, ascorbic acid and sodium benzoate.When administration concentration reached 1 μ M, the effectiveness that SP003 suppresses HIV-1 IIIB virus replication was higher than classical antiviral drugs ddI (Fig.2).SP01A also suppresses virus replication (Fig.2) under low-down concentration.Interesting is, SP003 and SP003A until 100 μ M, do not detect cytotoxicity with the analysis of MTT cell toxicity test in all test concentrations, and on the contrary, classical antiviral agents ddI, AZT and 3TC demonstrate toxicity, its IC
50Concentration value is respectively 89,161 and 71 μ M.Therefore, for experiment from now on, and, estimate the concentration range of pM to 10 μ M in order accurately to contrast the antiviral properties of testing compound and classical antiviral drugs.
2. to the influence of HIV-1 IIB virus replication.Effect (the Fig. of administration in 24 hours in advance
3)
In this research, use SP003A.After giving SP003 A in 24 hours in advance, its effectiveness to the virus replication influence is better than AZT (Fig.3).
3. to the influence of HIV-1 IIB virus replication.Effect (the Fig. of administration in 48 hours in advance
4)
Gave SP003 in 48 hours in advance, 50%HIV duplicates the IC of inhibition
50Value is 0.03nM (Fig.4).Use the AZT of same scheme to suppress HIV and duplicate IC in the dose dependent mode
50Value is 30nM.
4. to the influence of HIV MDR 769 virus replications.Effect (the Fig. that does not have administration in advance
5)
As expected, AZT can not effectively suppress HIV MDR 769 strains and duplicates (Fig.5).SP003 suppresses 60% HIV MDR 769 virus replications, and the IC50 value is 0.01nM (Fig.5).
These embodiment show, quinuclidine compounds (4-amino-phenyl)-) 1-aza-bicyclo [2,2,2] suffering-4-yl)-ketone (SP003) reduces the ability that HIV-1 IIB duplicates in people's cell and is higher than AZT or ddI.In a testing program that does not have an administration in advance, observe this chemical compound and suppress concentration that the HIV-1 MB more than 50% duplicates in the nanomole scope, and the compound water solution form and be dissolved in zinc sulphate heptahydrate and the form of ascorbic acid solution (SP003A) between do not have significant difference.
In order to determine whether directly targeting virus of this chemical compound, or there is not other mechanism to mediate this compound effects, the Hela cell was anticipated 24 hours with the form that contains zinc sulphate heptahydrate and ascorbic acid with SP003 before adding virus in virus replication.Interesting is, the gained effect far is better than does not have pretreated situation and the concentration situation in the picomole scope.The curve flat-top of SP003 A be positioned at 60% suppress more than, and AZT about 40%.Also demonstrated significant effect in 48 hours with the testing compound preincubate.Administration in advance and the effectiveness difference that do not show between administration in advance hint formula I chemical compound may be direct targeting virus, more may change the sensitivity that cell enters virus, thereby make its more infection.Compare with ddI with classical antiviral drugs AZT, thereby SP003 should be able to effectively block HIV MDR 769 virus replications owing to reduced the infectivity of cell.In fact, though AZT can not effectively block HIV MDR 769 virus replications, the effective blocking virus of SP003 duplicates/infectivity of cell.
In a word, the digital proof of this paper (4-amino-phenyl)-(1-aza-bicyclo [2.2.2] suffering-4-yl)-ketone (SP003) novel anti retrovirus retrovirus therapy is provided, this therapy is used separately or is all effective with HAART and the coupling of mega HAART therapy.These results show that these chemical compounds most possibly play a role to the resistance that virus enters by improving cell, rather than directly act on virus itself.Though its mechanism of action is not fully aware of, it acts on host cell rather than acts on the effectiveness that viral expectation can reduce the incidence rate of resistant strain and therefore improve the anti-retroviral therapy.
All publications, patent and patent document are bonded to herein by reference, as separately by reference and combination.In conjunction with various specific and embodiment preferred and technical descriptions the present invention.But, should be appreciated that many changes of invention and change still within the spirit and scope of the present invention.
Claims (32)
1. treat the mammiferous method that infected sexually transmitted disease (STD) substance threatens or encroaches on for one kind, described method comprises quinuclidine compounds and the pharmaceutically acceptable salt thereof of the formula I that gives described mammal effective dose:
Wherein:
A) R
1, R
2, R
3And R
5Independent is H, OH, halogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl ((C
1-C
6) alkyl), (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkanoyl, halo (C
1-C
6) alkyl, hydroxyl (C
1-C
6) alkyl, (C
1-C
6) alkoxy carbonyl; (C
1-C
6) alkylthio group or (C
1-C
6) alkanoyl oxygen base; Or R
1And R
2Lump together expression methylene dioxy base;
B) X
1Be NO
2, CN ,-N=O, (C
1-C
6) alkyl C (O) NH-, azoles quinoline base or N (R
6) (R
7), R wherein
6And R
7Independent is H, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, ((C
1-C
6) alkyl), wherein cycloalkyl is chosen wantonly and is comprised 1-2 S, non-peroxide O or N (R
8), R wherein
8Be H, O, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, (C
3-C
6) cycloalkyl (C
1-C
6) alkyl, phenyl or benzyl; Aryl, aryl (C
1-C
6) alkyl, aryl (C
2-C
6) thiazolinyl, heteroaryl, heteroaryl (C
1-C
6) alkyl, or R
6And R
7Form 5-or 6-unit's heterocycle or heteroaryl ring jointly with the nitrogen that is connected them, it is optional by R
1Replace and optional 1-2 S, non-peroxide O or the N (R of comprising
5);
C) Y and Z lump together expression=O ,-O (CH
2)
mO-or-(CH
2)
m-, wherein m is 2-4, or Y is that H and Z are OR
9Or SR
9, R wherein
9Be H or (C
1-C
4) alkyl.
2. the process of claim 1 wherein that described pathogen is antibacterial or virus.
3. the process of claim 1 wherein that described effective dose can effectively suppress pathogen or its subunit enters mammalian cell.
4. the method for claim 1-3, wherein said pathogen are virus.
5. the method for claim 1-4, wherein said pathogen is a retrovirus retrovirus.
6. the method for claim 1-5, wherein said pathogen is HIV.
7. the method for claim 3, wherein said cell is in external contact.
8. the method for claim 3, wherein said cell contacts in vivo.
9. the method for claim 1-8, the administration object of its Chinese style I chemical compound is behaved.
10. the method for claim 9, wherein the people has been exposed to virus.
11. the method for claim 9-10, wherein the people has been exposed to retrovirus retrovirus.
12. the method for claim 9-11, wherein the people is the HIV-positive.
13. the method for claim 9-12, wherein the people is AIDS patient.
14. the method for claim 1-13, wherein X
1Be N (R
6) (R
7).
15. the method for claim 1-14, wherein X
1Be NH
2
16. the method for claim 1-15, wherein R
1, R
2Or R
3In 1 or 2 be H or (C
1-C
6) alkoxyl, preferred (C
1-C
3) alkoxyl.
17. the method for claim 1-16, wherein Y and Z lump together expression=O.
18. the method for claim 1-16, wherein Y is OH, and Z is H.
19. the method for claim 1-18, wherein R
1, R
2And R
3Be H.
20. the method for claim 1-6 and 8-19, its Chinese style I chemical compound passes through oral administration.
21. the method for claim 1-6 and 8-19, its Chinese style I chemical compound passes through parenteral.
22. the method for claim 1-6,8-19 and 21, its Chinese style I chemical compound by injection, infusion, suck or be blown into administration.
23. the method for claim 1-22, its Chinese style I chemical compound is with the pharmaceutical acceptable carrier administration.
24. the method for claim 23, wherein said carrier are liquid, as solution, suspension or gel.
25. the method for claim 23, wherein said carrier are solid.
26. the method for claim 22-25, wherein said carrier comprises zinc sulphate heptahydrate.
27. the method for claim 1-26, its Chinese style I chemical compound are (4-amino-phenyl)-(1-aza-bicyclo [2.2.2] suffering-4-yl) ketone.
28. a compositions, described compositions comprise the chemical compound and the pharmaceutical acceptable carrier of formula (I).
29. the compositions of claim 28, wherein said compositions are dosage form.
30. the purposes of formula I chemical compound in the mammiferous medicine of infected sexually transmitted disease (STD) substance threat of preparation treatment or infringement.
31. the purposes of claim 30, wherein said infectious pathogen are virus or antibacterial.
32. the purposes of claim 30, wherein said medicine comprise that the physiology can accept carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55955004P | 2004-04-05 | 2004-04-05 | |
| US60/559,550 | 2004-04-05 | ||
| US60/590,209 | 2004-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101001628A true CN101001628A (en) | 2007-07-18 |
Family
ID=38693300
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580018136 Pending CN101001628A (en) | 2004-04-05 | 2005-04-01 | Anti-HIV quinuclidine compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101001628A (en) |
-
2005
- 2005-04-01 CN CN 200580018136 patent/CN101001628A/en active Pending
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