CN1342169A - Oxocyclobutazone-one derivatives - Google Patents

Oxocyclobutazone-one derivatives Download PDF

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CN1342169A
CN1342169A CN00804391A CN00804391A CN1342169A CN 1342169 A CN1342169 A CN 1342169A CN 00804391 A CN00804391 A CN 00804391A CN 00804391 A CN00804391 A CN 00804391A CN 1342169 A CN1342169 A CN 1342169A
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alkyl
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约翰·贾森·金特里·穆林斯
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones

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  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Polysaccharides And Polysaccharide Derivatives (AREA)
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Abstract

The present invention relates to a novel oxetanone derivative and a process for producing the derivative useful as a lipase inhibitor. The invention also relates to salts and pharmaceutical compositions comprising at least one oxetanone derivative or salt thereof, and methods of using these compounds and compositions as lipase inhibitors.

Description

Oxetanone derivatives
Present patent application is 09/618,328 part continuation application on July 18th, 2000 application, wherein 09/618, the 328th, to 09/431 of application on October 29th, 1999,151 part continuation application, the latter is 60/165,960 part continuation application on November 17th, 1999 application.
Invention field
The present invention relates to a kind of novel oxetanone (oxetanone) derivative and this preparation method who is used as the derivative of lipase inhibitor.The preparation method who the invention still further relates to salt and comprise the medicinal compositions of at least a oxetanone derivatives or its salt, and these compounds and composition are as the using method of lipase inhibitor.Relate to lipase inhibitor in one aspect of the invention, it comprises oxetanone derivatives segment and covalently bound or the salifiable nonabsorbable segment of shape such as the polysaccharide that can suppress lipase on identical molecule.Of the present invention one preferred aspect in, the nonabsorbable segment is lipophilic and associates with oil or fat.By covalently bound nonabsorbable segment directly or indirectly and produce novel nonabsorbable lipase inhibitor thus, can make absorptivity oxetanone lipase inhibitor be transformed into non-absorbent.
The aspect background
Some suppress the oxetanone of lipase and prepare their intermediate well known.Referring to for example the 5th, 931,463,4,189,438 and 4,202, No. 824 United States Patent (USP)s.But existing still need follow-on oxetanone, their toxicity is lower and do not absorbed by the Digestive tract of Mammals such as dog, cat, inhuman primate and people primate substantially.
Lipase inhibitor such as esterastin are (referring to U.S.4,189,438), tetrahydroesterastin (3,5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-dihydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1,3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1,3-lactone etc. are well-known lipase inhibitor and pancreas cholesterol esterification enzyme inhibitors.Still be immunosuppressor (referring to U.S.4,189,438 and U.S.4,202,824) when but in addition these enzyme inhibitorss are oral, this may cause undesirable side reaction in normal or immunosuppressant human body.These lipase inhibitors are 3,5 dihydroxyl, 1,3 lactone derivatives, and wherein 5 hydroxyls can be esterified or be hydrolyzed into free hydroxyl group on 5.
Basic for non-absorbent popular lipase inhibitor be known Orlistat ((2S, 3S, 5S)-5-[(S)-2-formamido--4-methyl-penta acyloxy]-2-hexyl-3-hydroxy-hexadecanoic acid 1,3 lactone, referring to U.S.5,643,874).This compound is the steric isomer derivative of tetrahydroesterastin, and wherein 5 hydroxyls are by S-2-formamido--4-methyl-penta acyloxy esterification.Orlistat has been used to suppress intravital lipase, thereby has prevented the absorption of fat in the food.(perhaps eating meat after 1 hour in) takes in the Orlistat of 120mg dosage before eating fatty meat, takes in for ordinary person then that the fat up to 1/3 will not be absorbed and not be used as the dietary fat heat in the meat.These unabsorbed fat are directly eliminated from intestines by Digestive tract and with the form of indigested oil as oil.
Some polysaccharide is non-absorbent and some polysaccharide has the additional benefit that reduces the body fat absorption.The rice bud embryo polysaccharide of degreasing and sulfated polysaccharides are also as lipase inhibitor, they are not have the pulsating macromolecular cpd of lactone, its mechanism of action is different, their combining fats and it is discharged from Digestive tract after discharging from Digestive tract.Take off the acetyl polysaccharide as a kind of by Crustacean chitin deutero-, the chitosan of superfluorescent fiber shape has the effect that absorbs fat and cholesterol, during particularly with the vitamins C coupling.In fact the chitosan composition can absorb the fatty and oily of 6 to 8 times of its weight.Though the polyose from Crustacean is similar to the crude fibre vegetable fibre, compare with vegetable fibre that it has the ability of significant combining fat in Digestive tract.In addition, because polysaccharide, comprise that those are not better than the polysaccharide of the ability of combination water in conjunction with the ability of oil, in the Digestive tract of animal such as people, non-human primate, dog and cat, be not absorbed, these polysaccharide do not have calorific value, and they are not absorbed by Digestive tract the time and do not change basically.The example of nonabsorbable polysaccharide has the polysaccharide of molecular weight greater than 8kDa, for example dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan or the like.
Exist demand for nonabsorbable lipase inhibitor and improved Weight reducing compound in the art, simultaneously for for the absorption that reduces fat heat in the food but do not need the method for absolute lower fat food also to exist demand.
The invention summary
Relate to a kind of novel lipase inhibitor derivative in one aspect of the invention, it is a kind of nonabsorbable compound, and it comprises at least one lipase inhibitor segment and at least one nonabsorbable polymer fragments in a part or salt.With respect to the weight of polymer fragments, the pulsating weight ratio of lipase inhibitor is about 1: 10 to 1: 60 in the nonabsorbable compound, is preferably 1: 20 to 1: 40, more preferably 1: 25 to 1: 35.In aspect of invention, this lipase inhibitor comprises at least one lipase inhibitor segment that directly or indirectly links to each other with described polysaccharide segment.The present invention also comprises pharmaceutical composition, described lipase inhibitor and pharmaceutically acceptable carrier or thinner that it comprises significant quantity also comprise lipophilic, non-absorbent, biocompatibility, the acceptable oil-absorbing polymer of pharmacy of significant quantity in the said composition.
The salt and non-absorbent, biocompatibility, the acceptable oil-absorbing polymer of pharmacy that relate to a kind of novel nonabsorbable lipase inhibitor in another aspect of the present invention.The present invention also comprises pharmaceutical composition, described lipase inhibitor and pharmaceutically acceptable carrier or thinner that it comprises significant quantity also comprise lipophilic, non-absorbent, biocompatibility, the acceptable oil-absorbing polymer of pharmacy of significant quantity in the said composition.
Of the present invention one preferred aspect in relate to 1, the novel nonabsorbable derivative of 3 oxetanone lipase inhibitors, it comprises at least one and covalently or non-covalently is incorporated into 1 on non-absorbent, biocompatibility, the acceptable polymer fragments of pharmacy, 3 oxetanone lipase suppress segment, thereby form novel lipase inhibitor.Preferred compound has the dual function that suppresses lipase and absorb fat, wherein non-absorbent, biocompatibility, the acceptable polymer fragments of pharmacy in this novel lipase inhibitor is combining fat, with fat with himself taking Digestive tract out of and making unabsorbed fat from Digestive tract, eliminate with indigested form.By 1 of the direct or indirect derivatize of polymer fragments of the present invention, 3 oxetanone segments can be absorbability or non-absorbent when initial, it is derived by directly or indirectly being connected with polymer fragments, thereby form novel nonabsorbable lipase inhibitor, preferably on pulsating 5 hydroxyls of 1,3 oxetanone, derive.
One preferred aspect in, two segments described in the compound provided by the invention or take non-covalent connection, take the covalently bound mode of in Digestive tract hydrolysis or digestion, condition is that 1,3 oxetanone segment of the inhibition lipase that discharges in Digestive tract is non-absorbent substantially.
In aspect another is preferred, two segments described in the compound provided by the invention or take non-covalent connection, take the covalently bound mode of in Digestive tract not hydrolysis or digestion, make and suppress 1 of lipase, 3 oxetanone segments keep being connected by described non-covalent or covalently bound and polymer fragments, and are not released in the Digestive tract.
In one aspect of the invention, absorbability lipase suppresses segment such as esterastin segment, tetrahydroesterastin or similar segment, change into non-absorbently by directly or indirectly being connected, make lipase inhibitor in animal such as dog, cat, non-human primate and human digestive system, not be absorbed substantially with non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide.Preferably be converted to non-absorbent lipase inhibitor segment and comprise at least a esterastin of being selected from, tetrohydroesterastin (3 by this connection, 5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-dihydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1,3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1, the lipase inhibitor of 3-lactone etc.Preferably, described lipase inhibitor is connected with non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide, makes lipase inhibitor not be absorbed substantially in animal such as dog, cat, non-human primate and human digestive system.Particularly preferred polysaccharide comprises at least a polysaccharide that is selected from dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan, takes off acetyl polysaccharide methyl benzoic acid ester ether derivant etc.Particularly preferred combining fat enzyme inhibitors is by group on the deriveding group on the lipase inhibitor such as deutero-nitrogen, acid or alcohol groups and the polymer fragments such as deutero-alcohol, the lipase inhibitor that acid or amino group connect.Preferably, form the bis ether bridged bond between lipase inhibitor and polymer fragments, this bis ether bridged bond becomes the reaction of abutment group by the alcohol groups in the lipase inhibitor separately with alcohol groups in the polymkeric substance and forms with etherificate.Other preferred compounds are that wherein oxetanone sheet cracked ends is derived and had amino, then should amino be derived again and be the carbonyl amide group, after this carbonyl amide group is connected by bridged bond with acid or alcohol radical in the polymer fragments, wherein polymer fragments derivatize and having for the acid or the alcohol radical that connect.The example of these connections will be described in following preferred embodiment.
Relate to pharmaceutical composition in another aspect of this invention, it comprises at least a lipase inhibitor that is connected on the digestive tube nonabsorbable segment that lipase suppresses significant quantity.Preferred compositions comprises that being connected of significant quantity is non-absorbent, biocompatibility, the lipase inhibitor on the acceptable polymer fragments of pharmacy such as the polysaccharide, and wherein lipase inhibitor is not absorbed in animal such as dog, cat, non-human primate and human digestive system substantially.
In another aspect, the present invention relates to the method for treatment of obesity, wherein before taking in fatty meat or within one hour afterwards to a certain amount of at least a lipase inhibitor of patient's administration, this lipase inhibitor is combined on the nonabsorbable polymer fragments by the amount up to the absorption of 1/3 absorption fat in this meat of effective inhibition.Especially, preferable methods comprises at least a esterastin of being selected from of administration, tetrohydroesterastin (3,5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-dihydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1, the 3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1, the lipase inhibitor of 3-lactone etc., wherein said lipase inhibitor and non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide connect, and make lipase inhibitor animal such as dog, cat, substantially be not absorbed among non-human primate and the human digestive system.Particularly preferred polysaccharide is at least a polysaccharide that is selected from dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan etc.Particularly preferred combining fat enzyme inhibitors is the lipase inhibitor that is connected by the group on deutero-nitrogen, acid or alcohol groups and the polymer fragments such as deutero-alcohol, acid or amino group.
The terminal bis ether bridged bond that between lipase inhibitor segment and polymer fragments, forms or terminal ether bridged bond/ester bridged bond, be to be formed with becoming the bridge bond group reaction separately by the alcohol groups in the alcohol groups in the lipase inhibitor and the polymkeric substance, this is the preferred type of attachment between lipase inhibitor and polymer fragments.
The preferred bridged bond of between lipase inhibitor segment and polymer fragments other comprises ether bridge and at least one carbonyl amido linkage that at least one is formed by the alcohol radical in the polymer fragments.At least one amino acid derivative is arranged in bridged bond in other preferred compounds, and directly or indirectly is connected on pulsating 5 hydroxyls of 1,3 oxetanone by ester bond.
Preferred compound also comprises their pharmacy acceptable isomers, hydrate, solvate, salt and prodrug derivant.The detailed Description Of The Invention definition
Except as otherwise noted, according to the present invention, the following term of Shi Yonging is defined by following implication herein.
Term " alkenyl " refers to the undersaturated aliphatic group of trivalent straight or branched.Term " alkynyl group " refers to comprise at least two straight or branched aliphatic groups by the carbon atom of triple bond connection.If the carbon atom number to alkenyl and alkynyl group is stipulated, represent that then group contains 2-12 carbon atom.
Term " alkyl " refers to saturated aliphatic group, comprises the straight chain, side chain and the cyclic group that contain the defined amount carbon atom, if carbon atom number is stipulated, then expression contains up to 12 carbon atoms.Adopt term " cycloalkyl " to refer to contain 3 to 14 carbon atoms herein, be preferably single, two or three cycloaliphatic groups of 3 to 7 carbon atoms.
Term " one-tenth abutment " refers to difunctionality chain group or spacer groups, this group can with one and a plurality of functional group reactionses in the lipase inhibitor compound, and then with polymkeric substance in second identical or different radical reaction, thereby between two compounds, form syndeton or combination.Becoming the key that forms between abutment and two segments preferably to take to resist the cracked form of digestive environments, separating the lipase inhibitor that connects when taking place when bond cleavage and change absorbability into.In one aspect; becoming the molecular formula of abutment is X-R-X; wherein R is alkynyl group, monoacyl, two acyl groups of alkenyl, the straight or branched of the alkyl that is selected from straight or branched, straight or branched or the like; the R part of chain can comprise cycloalkyl or aryl, and X is for having reactive functional group such as halogen or acid groups under special reaction condition described below.Particularly preferred one-tenth abutment forms opposing digestive environments cracked bis ether, two acyl group or ether/acyl group bridge.In one aspect, discharging after becoming abutment by the digestive environments cracking also is preferred for the situation of non-absorbent lipase inhibitor substantially.It is methylene dichloride that formation alkylidene group dichloro becomes the examples for compounds of abutment, 1, and 2-ethylene dichloride, 1,2-and 1,3-propylene dichloride, 1,2-, 1,3-and 1,4-dichlorobutane or the like.It is oxalyl dichloro, malonyl-dichloro, succinyl-dichloro, glutaryl dichloro, adipyl chloride, pimeloyl dichloro, suberoyl dichloro, fumaryl dichloro, maloyl dichloro, glutamy dichloro, tere-phthaloyl dichloride, isophthaloyl dichloro, haloalkyl phenylformic acid or the like that the acyl group dichloro becomes the formed examples for compounds of abutment.Other become abutment reagent for example is Epicholorohydrin, phosphorus oxychloride, tetra-sodium four acyl chlorides or the like.
Adopt term " carbocyclic ring structure " and " C herein 3-16The carbocyclic ring list, two or tricyclic structure " or similar terms refer to only utilize carbon atom to make the stabilizing ring structure of annular atoms, wherein ring structure is replacement or the unsubstituted ring structure that is selected from following group: the stable aromaticity monocycle with 6 carbon atoms; Stable non-aromaticity monocycle with 3 to 7 carbon atoms; The stable dicyclo that has 7 to 12 carbon atoms altogether, wherein twin nuclei is selected from two rings dicyclo and two rings that to be the dicyclo of aromaticity, ring be aromaticity and is nonaromatic dicyclo; And the three stable rings that have 10 to 16 carbon atoms altogether, wherein tricyclic structure is selected from three rings to be three rings of aromaticity, two rings is that three rings and three rings of aromaticity are nonaromatic three rings.In each situation, be present in non-aromaticity ring in single, double or the tricyclic structure and can be respectively saturated, partially or completely saturated.Do not define herein, the example of these carbocyclic ring structures comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, ring octyl group, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] two cyclodecane (naphthane), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, 2,3-indanyl, adamantyl or tetralyl (tetraline).In addition, ring structure described herein can be connected to by the carbon atom of any formation rock steady structure on one or more specified side groups.The term " replacement " of uniting use with the carbocyclic ring structure refers to that the hydrogen atom that is connected carbon atom in the ring structure described herein is replaced by the substituting group of one or more specified structures, as long as this replacement can produce stable compound.
The term " aryl " that comprises in the term " carbocyclic ring structure " refers to aromatic nucleus unsubstituted or that replace, replaced by being selected from lower alkoxy, low alkyl group, low-grade alkane amino, hydroxyl, halogen, cyano group, hydroxyl, sulfydryl, nitro, thio alkoxy, aldehyde carbonyl, carboxyl, carbalkoxy and the amine acyl carbonyl one, two or three groups, do not define herein, also comprise isocyclic aryl, heterocyclic aryl and dibenzyl etc., they all can be optionally substituted.Preferred aryl groups comprises phenyl, halogenophenyl, low alkyl group phenyl, naphthyl, xenyl, phenanthryl and naphthyl.
The term " aralkyl " that comprises in the term " carbocyclic ring structure " refers to have one, two or three alkyl that have the aryl of the carbon atom that specifies number and have specified number carbon atom.Do not define, the aralkyl that is suitable for comprises benzyl, picolyl, menaphthyl, styroyl, benzyhydryl and trityl etc. herein, and they all can be optionally substituted.
Adopt term " heterocycle " or " heterocycle structure " to refer to be selected from the unsubstituted or heterocycle structure that replaces in following group herein: ring itself has the stable monocycle of 5 to 7 annular atomses, wherein has 1 to 4 heterocyclic atom that is selected from N, O and S; Have the stable twin nuclei of 7 to 12 atoms in two rings altogether, wherein at least one ring has 1 to 4 heterocyclic atom that is selected from N, O and S, comprises monocyclic heterocycles and the hexanaphthene and the benzene condensed twin nuclei of any aforementioned stable; And the stable tricyclic structure that has 10 to 16 atoms in three rings altogether, wherein at least one ring has 1 to 4 heterocyclic atom that is selected from N, O and S.Anyly be present in these heterocycle structure nuclear nitrogens and sulphur atom can be oxidized.Except as otherwise noted, otherwise term " heterocycle " or " heterocycle structure " comprise aromatic nucleus, and can be the non-aromaticity rings of saturated, fractional saturation or saturated fully non-aromaticity ring.In addition, except as otherwise noted, otherwise term " heterocyclic system " comprises comprising in all rings in the following ring of at least one heteroatomic ring structure and half and comprises at least one heteroatomic ring structure, and for example ring all contains at least one heteroatomic twin nuclei for another ring of phenyl ring has in one or more heteroatomic twin nucleis and two rings and all is included in the definition of term " heterocyclic system ".And ring structure described herein can be connected on one or more specified side groups by heteroatoms or the carbon atom that causes rock steady structure.In addition, term " replacement " refers to that the interior carbon atom of each ring or the one or more hydrogen atoms on the nitrogen-atoms of described ring structure can be by one or more specified substituting groups replacements, as long as this replacement can produce stable compound herein.Nitrogen-atoms in the ring structure can be by quaternized, but this compound will be specifically noted or be included in the term " pharmacologically acceptable salts " as a kind of particular compound.When the sum of O in the single heterocycle and S atom greater than 1 the time, preferred situation is that these atoms are not in the consecutive position.Preferably, be not more than in given heterocycle structure that O and S atom are in the same ring in 1 the ring.
The example of monocycle and bicyclic heterocycle system arranges in alphabetical order and is acridyl, the azocine base, benzimidazolyl-, benzofuryl, benzothienyl, benzothienyl, benzoxazolyl, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, the benzisoxa oxazolyl, the benzisothiazole base, the benzimidazoline base, carbazyl, the 4aH-carbazyl, carbolinyl, chromanyl, benzopyranyl, 1, the 2-phthalazinyl, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran also [2,3-b] tetrahydrofuran (THF), furyl, the furazan base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, indolinyl, the indolizine base, indyl, the 3H-indyl, isobenzofuran-base, the isochroman base, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl (benzimidazolyl-), isothiazolyl, isoxazolyl, morpholinyl, 1, the 5-phthalazinyl, the octahydro isoquinolyl, the oxadiazoles base, 1,2,3-oxadiazoles base, 1,2,4-oxadiazoles base, 1,2,5-oxadiazoles base, 1,3,4-oxadiazoles base, oxazolyl, oxazolidinyl, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, phenoxathiinyl, phenol oxazines base, 2, the 3-phthalazinyl, piperazinyl, piperidyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, the pyrido oxazole, pyridine-imidazole, the pyrido thiazole, pyridyl (pyridinyl), pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the 2H-pyrryl, pyrryl, quinazolyl, quinolyl, the 4H-quinolyl, quinoxalinyl, the peaceful cyclic group of quinoline, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, the thieno-thiazolyl, the thieno-oxazolyl, the Thienoimidazole base, thienyl, triazinyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3, the 4-triazolyl, and xanthenyl.Do not define, preferred heterocycle structure comprises pyridyl, furyl, thienyl, pyrryl, pyrazolyl, pyrrolidyl, imidazolyl, indyl, benzimidazolyl-, 1H-indyl, oxazoline group or isstinoyl herein.Also comprise fused ring and spirocyclic compound simultaneously, wherein comprise as above-mentioned heterocycle structure.
The term of Cai Yonging " aromaticity heterocyclic system " is basic identical with the definition of monocycle and bicyclic system herein, just at least one ring is for the aromaticity heterocycle or for dicyclo in the member ring systems, and one of them ring for another ring of aromaticity then is and the non-aromaticity heterocycle of aromaticity heterocycle structure condensed.
Adopt term " halo " or " halogen " to refer to Cl, Br, F and I substituting group herein.Term " alkylhalide group " or similar terms refer to the aliphatic group that at least one hydrogen atom is replaced by Cl, Br, F and I, comprising mixing situation about replacing.For example, three alkylhalide groups comprise preferred trifluoroalkyl or the like.
Term " methylene radical " refers to-CH 2-.
Term " pharmacologically acceptable salts " comprises compound and organic or inorganic acid deutero-salt.The free alkali of these compounds and salt all are useful.In fact use salt to be equivalent to use alkali; The bronsted lowry acids and bases bronsted lowry additive salt is all within the scope of the invention.
" the acceptable acid salt of pharmacy " refers to still keep free alkali biopotency and character and is not the undesirable salt of biology or other aspects, they and following acid form: mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid such as acetate, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulphonic acid, ethylsulfonic acid, tosic acid, Whitfield's ointment etc.
" the acceptable base addition salt of pharmacy " includes mineral alkali deutero-salt, for example sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Particularly preferably be ammonium, potassium, sodium, lithium, calcium and magnesium salts.Comprise and the formed salt of following amine by the acceptable non-toxic organic alkali of pharmacy deutero-salt: one-level, secondary and tertiary amine, replace amine, comprise natural replacement amine, cyclic amine or deacidite are as Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, 2-diethylaminoethanol, Trimethylamine 99, dicyclohexylamine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, hydrabamine, choline, trimethyl-glycine, ethylene diamine, glycosamine, methylglucosamine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, versamid 900 etc.Particularly preferred non-toxic organic alkali is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and caffeine.
" biological property " refers to usually in the test in vivo by direct or indirect vivo effect device or antigenicity function or the activity that shows of The compounds of this invention herein.Effector functions comprises acceptor or aglucon combination, any enzymic activity or enzyme regulatory function, and any carrier is in conjunction with activity, any hormonal activity, any promotion or suppress the activity of cell adhesion on extracellular matrix or cell surface molecule, or any structure factor.Thereby the antigenicity function comprises and can make occupying of antigenic determinant that antibody resists with it or antigenicity position with antibody response.
In compound of the present invention, with the carbon atom of four different substituents bondings be asymmetrical.Therefore, compound may exist diastereomer, enantiomer or its mixture.Can adopt raceme, enantiomer or diastereomer as starting raw material or intermediate in described herein synthesizing.The diastereomer that is obtained by these synthetic methods can be separated by other currently known methodss in chromatogram or crystallization or this area.Similarly, the mixture of enantiomer can be separated by other currently known methodss in same procedure or this area.Each asymmetric c atom that is present in the The compounds of this invention can have two kinds of configurations (R or S), and the two is all at this
Within the invention scope.
Preferred embodiment
Relate to a kind of novel lipase inhibitor derivative in one aspect of the invention, it is non-absorbent, and comprises lipase inhibitor segment and polymer fragments in a part.The present invention also comprises pharmaceutical composition, described lipase inhibitor and pharmaceutically acceptable carrier or thinner that it comprises significant quantity also comprise lipophilic, non-absorbent, biocompatibility, the acceptable oil-absorbing polymer of pharmacy of significant quantity in the said composition.With respect to the weight of polymer fragments, the weight ratio of lipase inhibitor is about 1: 10 to 1: 60, is preferably 1: 20 to 1: 40, more preferably 1: 25 to 1: 35.In aspect of invention, this lipase inhibitor comprises at least one lipase inhibitor segment that directly or indirectly links to each other with polymer fragments.
Relate to nonabsorbable lipase inhibitor and new salts lipophilic, non-absorbent, biocompatibility, that the acceptable oil-absorbing polymer of pharmacy forms in another aspect of this invention.The present invention also comprises pharmaceutical composition, described lipase inhibitor and pharmaceutically acceptable carrier or thinner that it comprises significant quantity also comprise lipophilic, non-absorbent, biocompatibility, the acceptable oil-absorbing polymer of pharmacy of significant quantity in the said composition.
Of the present invention one preferred aspect in relate to 1, the novel nonabsorbable derivative of 3 oxetanone lipase inhibitors, it comprises at least one and covalently or non-covalently is incorporated into 1 on non-absorbent, biocompatibility, the acceptable polymer fragments of pharmacy, 3 oxetanone lipase suppress segment, thereby form a kind of novel lipase inhibitor.Preferred compound has the dual function that suppresses lipase and absorb fat, wherein non-absorbent, biocompatibility, the acceptable polymer fragments of pharmacy in this novel lipase inhibitor is combining fat, with fat with himself taking Digestive tract out of and making unabsorbed fat from Digestive tract, eliminate with indigested form.By 1 of the direct or indirect derivatize of polymer fragments of the present invention, 3 oxetanone segments can be absorbability or non-absorbent when initial, it is derived by directly or indirectly being connected with polymer fragments, thereby form a kind of novel nonabsorbable lipase inhibitor, preferably on pulsating 5 hydroxyls of 1,3 oxetanone, derive.
One preferred aspect in, two segments described in the compound provided by the invention or take non-covalent connection, take the covalently bound mode of in Digestive tract hydrolysis or digestion, 1, the 3 oxetanone segment that the lipase that only discharges in Digestive tract suppresses is non-absorbent getting final product substantially.
In aspect another is preferred, two segments or take non-covalent connection in the compound that the present invention proposes, take the covalently bound mode of in Digestive tract not hydrolysis or digestion, make and suppress 1 of lipase, 3 oxetanone segments keep being connected by described non-covalent or covalently bound and polymer fragments, and are not released in the Digestive tract.
In one aspect of the invention, absorbability lipase suppresses segment such as esterastin segment, tetrahydroesterastin or similar segment, change into non-absorbently by directly or indirectly being connected, make lipase inhibitor in animal such as dog, cat, non-human primate and human digestive system, not be absorbed substantially with non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide.Be converted to non-absorbent preferred absorptivity lipase inhibitor segment by this connection and comprise at least a esterastin of being selected from, tetrohydroesterastin (3,5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-dihydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1,3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1, the lipase inhibitor of 3-lactone etc.Preferably, described lipase inhibitor is connected with non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide, makes lipase inhibitor not be absorbed substantially in animal such as dog, cat, non-human primate and human digestive system.Particularly preferred polysaccharide comprises at least a polysaccharide that is selected from dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan, takes off acetyl polysaccharide methyl benzoic acid ester ether derivant etc.Particularly preferred combining fat enzyme inhibitors is the lipase inhibitor that is connected by the group on the deriveding group on the lipase inhibitor such as deutero-nitrogen, acid or alcohol groups and the polymer fragments such as deutero-alcohol, acid or amino group.Preferably, form the bis ether bridged bond between lipase inhibitor and polymer fragments, this bis ether bridged bond becomes the reaction of abutment group by the alcohol groups in the lipase inhibitor separately with alcohol groups in the polymkeric substance and forms with etherificate.Other preferred compounds are that wherein oxetanone sheet cracked ends is derived and had amino, then should amino be derived again and be the carbonyl amide group, after this carbonyl amide group is connected by bridged bond with acid or alcohol radical in the polymer fragments, wherein polymer fragments derivatize and having for the acid or the alcohol radical that connect.The example of these connections will be described in following preferred embodiment.
The terminal bis ether bridged bond that between lipase inhibitor segment and polymer fragments, forms or terminal ether bridged bond/ester bridged bond, be to be formed with becoming the bridge bond group reaction separately by the alcohol groups in the alcohol groups in the lipase inhibitor and the polymkeric substance, this is the preferred type of attachment between lipase inhibitor and segment.
The preferred bridged bond of between lipase inhibitor segment and polymer fragments other comprises ether bridge and at least one carbonyl amido linkage that at least one is formed by the alcohol radical in the polymer fragments.At least one amino acid derivative is arranged in bridged bond in other preferred compounds, and directly or indirectly is connected on pulsating 5 hydroxyls of 1,3 oxetanone by ester bond.
Preferred compound also comprises their pharmacy acceptable isomers, hydrate, solvate, salt and prodrug derivant.
A preferred aspect of the present invention relates to by with the represented novel oxetanone derivatives of following formula I and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivants: Wherein: t is that the integer X-O-Q between 0 to 1 is that a kind of ehter bond connects, wherein:
X during this ehter bond connects is for becoming abutment, and
Q during this ehter bond connects is a kind of polysaccharide, and it has enough molecular weight or function makes
Disappearing of Mammals such as dog, cat, non-human primate or human primate
Be not absorbed in the change system, below will be further described polysaccharide; R is the group that is selected from following group:
Saturated maybe can choose wantonly insertion up to 8 two keys or triple-linked straight or branched C 1-17Alkyl;
Saturated maybe can choose wantonly insert one or more be selected from Sauerstoffatom, sulphur atom, alkylsulfonyl or
The straight or branched C of the group in the sulfinyl 1-17Alkyl;
Saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more Sauerstoffatom, sulphur atom, sulphonyl of being selected from
The straight or branched C of the group in base or the sulfinyl 1-17Alkyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Phenyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Benzyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Xenyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The thiophenyl phenylene; And
Phenyl-C 1-6Alkyl-phenyl, wherein one or more benzyl rings and-C 1-6On the alkyl
0 to 6 hydrogen atom can be selected from independently-C 1-6Alkoxy-C 1-6Alkane
Base ,-C 1-6Alkylthio-C 1-6Alkyl ,-C 1-6Alkyl-OH and-C 1-6Alkane
Group among base-SH replaces; R 1Be the group that is selected from following group:
Hydrogen,
Ar，
Ar-C 1-5Alkyl, and
C 1-10Alkyl, it is inserted with 0-3 and is selected from group in following group: Sauerstoffatom, sulphur are former
Son, alkylsulfonyl, sulfinyl ,-N (R 4)-Ji ,-C (=O)-N (R 4)
-Ji and-N (R 4)-C (=O)-Ji, wherein C 1-10The 0-3 of alkyl
The group that carbon atom can be selected from respectively in following group replaces: hydroxyl, sulfydryl,
C 1-10Alkoxyl group, C 1-10Alkylthio ,-N (R 5,-R 6) base,
-C (=O)-N (R 7,-R 8) base and-N (R 9)-C (=O)-R 10Base; R 2Be the group that is selected from following group:
Hydrogen and C 1-6Alkyl, perhaps R 2With R 1Form 4-6 the member who contains 0-4 nitrogen-atoms together
Saturated rings, wherein said ring can be by 0-4 R 11Group replaces; R 3Be the group that is selected from following group:
Saturated maybe can choose wantonly insertion up to 8 two keys or triple-linked straight or branched C 1-17Alkyl;
Saturated maybe can choose wantonly insert one or more be selected from Sauerstoffatom, sulphur atom, alkylsulfonyl or
The straight or branched C of the group in the sulfinyl 1-17Alkyl;
Saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more Sauerstoffatom, sulphur atom, sulphonyl of being selected from
The straight or branched C of the group in base or the sulfinyl 1-17Alkyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Phenyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Benzyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Xenyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The thiophenyl phenylene; And
Phenyl-C 1-6Alkyl-phenyl, wherein one or more benzyl rings and-C 1-6On the alkyl
0 to 6 hydrogen atom can be selected from independently-C 1-6Alkoxy-C 1-6Alkane
Base ,-C 1-6Alkylthio-C 1-6Alkyl ,-C 1-6Alkyl-OH and-C 1-6Alkane
Group among base-SH replaces; R 4-R 10Be respectively a kind of group, be selected from hydrogen and C 1-6Alkyl; N is the integer between the 0-3.
The preferred compound of molecular formula I is following compound and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivants, and wherein X is the following formula group:
-(C (=O)) 0-1-Xa-is wherein: Xa is the group that is selected from following group:
Saturated two keys or the triple-linked straight or branched divalence C of insertion that maybe can choose wantonly up to 8 1-17
Alkylidene group;
Saturated maybe can choose wantonly insert one or more straight chains that are selected from the group in following group or
Chain divalence C 1-17Alkylidene group:
Sauerstoffatom,
Sulphur atom,
Alkylsulfonyl,
Sulfinyl,
Replace or unsubstituted 6-10 unit's monocycle or bicyclic aryl or have 1-4
Heteroatomic heterocyclic radical, wherein heteroatoms is selected from O, N, S,
-NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
-C (=O)-Ji,
-NH-C (=O)-and Ji, wherein hydrogen atom can be by C 1-10Alkyl replaces, and
-C (=O)-and the NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
Saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more straight chains that are selected from the group in following group
Or side chain divalence C 1-17Alkylidene group;
Sauerstoffatom,
Sulphur atom,
Alkylsulfonyl,
Sulfinyl,
Replace or unsubstituted 6-10 unit's monocycle or bicyclic aryl or have 1-4
Heteroatomic heterocyclic radical, wherein heteroatoms is selected from O, N, S,
-NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
-C (=O)-Ji,
-NH-C (=O)-and Ji, wherein hydrogen atom can be by C 1-10Alkyl replaces, and
-C (=O)-and the NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Divalence phenylene or divalence naphthylidene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The divalence biphenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Divalence thiophenyl phenylene.
The preferred subgroup of The compounds of this invention is following compound, and wherein R is-(CH 2) 3-6-CH 3, R 3Be selected from-(CH 2) 8-14-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 2-8-CH 3R is-(CH in the more preferred compound 2) 5-CH 3, R 3Be selected from-(CH 2) 10-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 4-CH 3
In a preferred embodiment, the present invention relates to novel oxetanone derivatives and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivants, n promptly formed the compound of following formula at 0 o'clock in the wherein above-mentioned formula: Wherein: X, t, Q, R, R 1And R 2As mentioned above.Its preferred subgroup is following compound, and wherein R is-(CH 2) 3-6-CH 3, and R 3Be selected from-(CH 2) 8-14-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 2-8-CH 3R is-(CH in the more preferred compound 2) 5-CH 3, and R 3Be selected from-(CH 2) 10-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 4-CH 3T is 0 in the more preferred compound, and X for as defined above-C (=O)-Xa-.
T is 1 in the more preferred compound, and X is the group that is selected from following group:
Figure A0080439100312
R wherein 1aIndependently with R 1Define identical, R 2aIndependently with R 2Define identical, m is 0-10, be preferably 0-5, the integer between the 0-2 more preferably, z is 1-20, be preferably all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivant of 2-10, the integer between the 2-4 more preferably, and these compounds.
In a further preferred embodiment, the present invention relates to have the new I oxetanone derivatives of following structural formula and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivants:
Figure A0080439100321
Wherein: X, Q, R and R 3As defined above.Its preferred subgroup is following compound, and wherein R is-(CH 2) 3-6-CH 3, and R 3Be selected from-(CH 2) 8-14-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 2-8-CH 3R is-(CH in the more preferred compound 2) 5-CH 3, and R 3Be selected from-(CH 2) 10-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 4-CH 3
More preferred compound is that wherein X is the group that is selected from following group:
Figure A0080439100322
Wherein z is 0-10, is preferably 0-5, all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivants of the integer between the 0-2 more preferably, and these compounds.
T is 0 or 1 in other the preferred compound, and X is the group that is selected from following group: R wherein 1aIndependently with R 1Define identical, R 2aIndependently with R 2Define identical, m is 0-10, be preferably 0-5, the integer between the 0-2 more preferably, z is 1-20, be preferably all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivant of 2-10, the integer between the 2-4 more preferably, and these compounds.
Compound as claimed in claim 9, wherein X is the group that is selected from following group:
Figure A0080439100332
Wherein z is 0-10, is preferably 0-5, all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivants of the integer between the 0-2 more preferably, and these compounds.
More preferred compound is following compound, and wherein X is the group that is selected from following group:
Figure A0080439100333
Wherein z is the integer between the 0-18, and all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivants of these compounds.
Other preferred compound is following compound, and wherein X is the group that is selected from following group:
Figure A0080439100341
Wherein z is the integer between the 6-12, and all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivants of these compounds.
More preferred compound is following compound, and wherein X is the group that is selected from following group:
Figure A0080439100342
Wherein z is the integer between the 6-12, and all pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivants of these compounds.
Particularly preferred Q group is a kind of non-absorbent, biocompatibility, the acceptable polymkeric substance of pharmacy such as polysaccharide in the above-claimed cpd, it is preferably lipophilic and combining fat, is non-absorbent in animal such as dog, cat, non-human primate and the mankind's Digestive tract simultaneously.Particularly preferred polysaccharide comprises at least a polysaccharide that is selected from dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan etc.Particularly preferred Q group has hydroxyl, acyl group or amino, perhaps can be had hydroxyl, acyl group or amino by derivatize, and these groups can combine with R segment or X-R-X group.Preferably, form one or two ehter bond at least by the X-R-X bridge between lipase inhibitor segment and polymer fragments, wherein bridged bond is by hydroxyl or the hydroxyl in amino and the Q group, acyl group and amino formation of lipase inhibitor.More preferred Q group is a kind of chitosan of modification, and it is modified by the ether group that end has organic acid group.Organic acyl group is respectively the straight or branched alkyloyl in the more preferred modification chitosan Q group.The polarity that organic acyl group modification chitosan is caused in the highly preferred modification chitosan Q group makes the modification chitosan absorb lipid and water, and forms basic homogeneous gel with oil and water.
Highly preferred compound is above listed compound; wherein the Q group is a kind of chitosan compound; it is modified by the organic acyl group of capacity and makes the modification chitosan absorb or in conjunction with lipid and water, and forms basic homogeneous gel with oil and water.With respect to the mole number of the hydroxyl of esterification in the lipase inhibitor, the mole number of the organic acyl group that exists in the modification chitosan is 1 to 8 times, is preferably 2 to 5 times, more preferably 3 to 4 times.The preparation of compound
Lipase inhibitor of the present invention, polymer fragments and become abutment to synthesize to obtain or buy obtaining.Polymkeric substance becomes abutment, becomes bridge coupling method and compound purification process, particularly by bis ether bridge, ether/ester bridge, alcohol radical link coupled methods involving that ester/ketone bridge etc. carries out description is arranged in standard textbook, can be used as reference.The polymkeric substance textbook of standard typically refers to difunctionality and becomes abutment and coupling method.
The starting raw material that is adopted in these methods is that the commodity from chemical dealer such as Aldrich, Sigma, Nova Biochemicals, Bachem, Biosciences etc. maybe can obtain by currently known methods is synthetic.
Except as otherwise noted, adopt otherwise under the temperature and pressure of standard the laboratory glassware and the reactor of standard to react.
Between the synthesis phase of these compounds, can adopt protecting group functional group to be protected in case the cross reaction in the coupling process.Example of the protecting group that is suitable for and uses thereof is at " The Peptides:Analysis, Synthesis, Biology ", Academic Press, and the 3rd volume people such as (edit 1981) Gross and the 9th is rolled up has description in (1987), is incorporated herein by reference herein.
Lipase inhibitor segment such as tetrahydroesterastin (3 with free hydroxyl group, 5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-hydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1,3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1,3-lactone etc., easily and have the polymer fragments of free hydroxyl group such as Mierocrystalline cellulose, chitosan and other have the polysaccharide coupling of free hydroxyl group.Before reacting with another segment, lipase inhibitor can be formed part by derivatize with polymer fragments one or both of and be connected bridged bond.For example, shown in polysaccharide chemistry, the lipase inhibitor molecule can form ether or ester bond with two halogenizing compounds or end halogen end acyl compounds (acyl group can by an acidic group protection) condensation, and then with the polysaccharide coupling with free hydroxyl group.In a method, polymer fragments such as chitosan can with reactions such as a compound such as halogenated methyl benzoic ether, the ester hydrolysis produces the free carboxy that can form carbonyl, carbonyl amide structure with the lipase inhibitor reaction of derivatize then.Of the present invention one preferred aspect in, one of two segments become abutment such as alkylidene group dihalo-(as 1 with asymmetric pair of halogen, 2-bromo chloric ethane, 1,3-bromo chloro-propane etc.) reaction in 1: 1 in molar ratio, with the etherificate free hydroxyl group, a hydrogen atom in the substituted-amino, perhaps form carbonyl with carboxyl, the intermediate of gained can react with polymer fragments then, forms ehter bond with the free hydroxyl group reaction, hydrogen atom on displacement amino perhaps forms carbonyl with carboxyl.Particularly preferred polymer fragments is the polysaccharide with a plurality of free hydroxyl groups, can be made the lipase segment itself become lipase inhibitor by sulfonation at random after the coupling.The method of etherificate, amination and formation carbonyl structure is well-known and is within those skilled in the art's the limit of power in the art.In addition, other the one-tenth abutment and the method thereof that are used to make compound with reactive functional groups to be connected with polymer fragments also are well-known in the art.Preferred compound also comprises pharmacy acceptable isomers, salt, hydrate, solvate and the prodrug derivant that these compounds are all.
Become abutment to be meant a kind of bifunctional chain or spacer, it can with the one or more functional group reactionses in the lipase inhibitor, and then with polymkeric substance in second identical or different functional group reactions, make between two compounds to form syndeton or put together.Become the key that forms between abutment and each compound preferably can resist the key of digestive environments fracture.In one aspect; becoming the structural formula of abutment is X-R-X; wherein R is alkynyl group, monoacyl, two acyl groups of alkenyl, the straight or branched of the alkyl that is selected from straight or branched, straight or branched or the like, and X is for to have reactive functional group such as halogen under special reaction condition described below.Particularly preferred one-tenth abutment forms opposing digestive environments cracked bis ether or two acyl group bridge.
It is methylene dichloride that formation alkylidene group dichloro becomes the examples for compounds of abutment, 1, and 2-ethylene dichloride, 1,2-and 1,3-propylene dichloride, 1,2-, 1,3-and 1,4-dichlorobutane, glycol dibromide, 1,2-and 1,3-bromo chloro-propane or the like.
It is oxalyl dichloro, malonyl-dichloro, succinyl-dichloro, glutaryl dichloro, adipyl chloride, pimeloyl dichloro, suberoyl dichloro, fumaryl dichloro, maloyl dichloro, glutamy dichloro, tere-phthaloyl dichloride, isophthaloyl dichloro etc. that formation acyl group dichloro becomes the examples for compounds of abutment.
The halogen acyl group becomes the example of abutment to comprise chloro tolyl acid or its ester, 3-bromo-propionic acid, 2-Mono Chloro Acetic Acid, 6-bromocaproic acid or its ester, the acid of 12-bromo-dodecane or its ester, other n-haloalkyl acid or its ester or the like.
Other one-tenth abutment reagent such as Epicholorohydrin, phosphorus oxychloride, tetra-sodium four acyl chlorides or the like.
Preferred one-tenth abutment becomes abutment for terminal dihalo-with bromine and chlorine substituent, and perhaps end is the abutment that becomes of acyl group and halogenic substituent.More preferably becoming abutment is n-halo (being preferably the n-bromo)-C 4-C 18(be preferably C 6-C 14) alkyl acid or its ester.Bifunctional reagent such as diacyl dichloro compound, alkylidene group dichloro compound or bromo acyl ester compound are dissolved in a kind of basic and immiscible organic solvent of water, slowly are added in the alkaline aqueous solution of lipase inhibitor by the mol ratio that is 1: 1 substantially then and react.Carry out between the interface condensation reaction on the interface of two mutual immiscible solution and producing polysaccharide derivates or analogue.The one-level hydroxyl that has been found that the reaction pair polysaccharide that carries out on organic solution and aqueous solution interface has specificity.Should be realized that reactant of equal value such as diepoxides and haloalkyl oxyethane such as Epicholorohydrin also can react and produce new and useful ether bridge.
By suitably being chosen to the type of abutment, different structure group with different chemical character can be introduced in the gained bridged bond and polytype lipase inhibitor can be connected on the non-absorbent polymer fragments, for example polysaccharide is preferably chitosan.The control of temperature of reaction and other reaction conditionss and reactant ratio is within those skilled in the art's the limit of power.From what has been discussed above, for persons skilled in the art, other groups and improvement are conspicuous.
The functional of lipase inhibitor can adopt well-known test to measure in the relevant link coupled lipase inhibitor.To patient can the drug treatment significant quantity the combining fat enzyme inhibitors.Other fat-binding polymers can be added in the composition arbitrarily.
At the preparation of The compounds of this invention, below do not work the effect of defining reaction scheme I, II, III and IV the preferred embodiments of the invention have been described.
Synthetic line I
Figure A0080439100391
Synthetic line II
Figure A0080439100401
Synthetic line III
Synthetic line IV
Figure A0080439100421
Therefore, of the present invention one preferred aspect in a kind of method for preparing compound as claimed in claim 1 is provided, comprising the compound that makes with following formula
Figure A0080439100431
With the following formula: compound reaction,
Figure A0080439100432
Wherein t is 0 or 1, and Y is the leavings group that carries out etherificate or esterification with hydroxyl, forms the compound or its salt with following formula: Pharmaceutical composition and edible composition
In one aspect, the invention provides a kind of sports beverages, pot foods, nutritional supplement, food or powder, be furnished with the lipase inhibitor composition of the present invention that suppresses lipase treatment significant quantity therein.
In one aspect of the method, the present invention relates to pharmaceutical composition, it contains the non-absorbent segment link coupled of at least a and digestive tube lipase inhibitor of lipase treatment significant quantity.Preferred pharmaceutical composition contain significant quantity with non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide link coupled lipase inhibitor, wherein lipase inhibitor is not absorbed in animal such as dog, cat, non-human primate and human Digestive tract substantially.Before or after taking in fatty meat within one hour to patient's administration medicine composition, can suppress in the meat absorption up to 1/3 absorption fat.
In another aspect, the present invention relates to the method for treatment of obesity, wherein before taking in fatty meat or within one hour afterwards to a certain amount of at least a lipase inhibitor of patient's administration, this lipase inhibitor is combined on the nonabsorbable polymer fragments by the amount up to the absorption of 1/3 absorption fat in this meat of effective inhibition.Especially, preferable methods comprises at least a esterastin of being selected from of administration, tetrohydroesterastin (3,5-hydroxyl-2-16 carbon-7,10-diolefinic acid 1, the 3-lactone), 3,5-dihydroxyl-2-hexyl 16 carbon-7,10-diolefinic acid 1, the 3-lactone, 3,5-dihydroxyl-2-hexyl hexadecanoic acid 1, the lipase inhibitor of 3-lactone etc., wherein said lipase inhibitor and non-absorbent, biocompatibility, acceptable polymer fragments of pharmacy such as polysaccharide connect, and make lipase inhibitor animal such as dog, cat, in the non-human primate and the mankind's the Digestive tract is non-absorbent.Particularly preferred polysaccharide is at least a polysaccharide that is selected from dextran, molecule Microcrystalline Cellulose, wheat bran, oat bran, degreasing Rice plumule, alginic acid, pectin, amylopectin, chitin, crude fibre, agar, chitosan etc. that is selected from.Particularly preferred combining fat enzyme inhibitors is the lipase inhibitor that is connected by the group on deutero-nitrogen, acid or alcohol groups and the polymer fragments such as deutero-alcohol, acid or amino group.Reacting formation bis ether bridged bond with becoming abutment by the alcohol groups in the lipase inhibitor separately with the alcohol groups in the polymkeric substance between lipase inhibitor and polymer fragments, is the preferred mode of connection between lipase inhibitor and polymer fragments.
Compound of the present invention can free acid or the form of free alkali be able to purifying or adopt multiple inorganic or organic bronsted lowry acids and bases bronsted lowry to transform salify.These salt are also within the scope of the invention.Separate and purge process in nontoxic and salt physiological compatibility be useful especially, though other are not that very ideal salt also can use.
Can adopt above-mentioned and well known by persons skilled in the art several different methods to prepare above-mentioned salt.For example, in insoluble solvent of salt or mixed solvent, react with a kind of free acid of compound or free alkali and monovalent or greater than the required acid or the alkali of monovalent, reaction also can be carried out in solvent such as water, after this removes by evaporation, distillation or freeze-drying and desolvates.
In addition, the free acid of product or free alkali can be transformed into the form of required salt by ion exchange resin, perhaps adopt same procedure that a kind of salt of product is changed into another kind of salt.The prodrug derivant of compound
The present invention also comprises the prodrug derivant of compound.Term " prodrug " is meant the no drug effect derivative of parent drug, needs in vivo to discharge active medicine by bio-transformation, spontaneous acid/alkali reaction or enzyme reaction.Prodrug is the variant or the derivative of The compounds of this invention, and it has the group that can rupture in the Digestive tract environment.When carrying out solvolysis or enzyme liberating under physiological condition, prodrug changes into the The compounds of this invention that has pharmaceutical activity in vivo.What of the required biotransformation step of active medicine are foundation discharge in vivo, and prodrug of the present invention can be called as one-level prodrug, secondary prodrug, three grades of prodrugs etc., and is used for the number that indication is present in the functional group of prodrug.In mammalian body prodrug usually have advantages such as solvability, digestive tube consistency or slowly-releasing (referring to, Bundgard, Design of Drugs, pp.7-9,21-24, Elsevier, Amsterdam 1985 andSilverman, The Organic Chemistry of Drug Design and Drug Action, pp.352-401, Academic Press, San Diego, CA, 1992).Prodrug well-known in the art comprises acid derivative well-known to those skilled in the art, the acid amides of for example ester of parent acid and suitable alcohol reaction gained, or parent acid compound and amine reaction gained, or with the alkali derivant of basic group reaction generation acidylate.In addition, for improving bioavailability, prodrug of the present invention can be the comprehensive of above-mentioned advantage.
Compound, the physiology of required purity can be accepted carrier, vehicle, stablizer etc. be mixed with the preparation of the present invention that supplies storage and administration, and can make the preparation that continues release or timing release.Medicinal acceptable carrier or thinner are well-known in pharmaceutical field, and for example, they are described in Remington ' s Pharmaceutical Sciences, among the Mack Publishing Co. (A.R.Gennaro edits, 1985).These materials are nontoxic under dosage that is adopted and concentration, and comprise buffer reagent such as phosphoric acid salt, Citrate trianion and other organic acid salts, oxidation inhibitor comprises xitix, lower molecular weight (less than 10 residues) peptide such as poly arginine, albumen such as serum albumin, gelatin or immunoglobulin (Ig), hydrophilic polymer such as polyvinylpyrrolidone, amino acid such as glycine, L-glutamic acid, aspartic acid or arginine, monose, disaccharides, and other sugar, comprise Mierocrystalline cellulose and derivative thereof, glucose, seminose or dextrin, sequestrant such as EDTA, sugar alcohol such as N.F,USP MANNITOL or sorbyl alcohol, counter ion such as sodium and/or nonionogenic tenside such as Tween, Pluronics or polyoxyethylene glycol.
The preparation of the present invention of being used for the treatment of property administration must be aseptic.As filtering in the 0.2 μ m film or passing through other ordinary methods, can easily accomplish aseptic by no mycoderm.Typically, preparation stores with the form of freeze-dried or the aqueous solution.The typical pH of preparation of the present invention is 3-11, is preferably 5-9, most preferably is 7-8.Should be realized that the formation of using some above-mentioned vehicle, carrier or stablizer can cause ring type polypeptide salt.
Can determine the treatment effective dose by method in external or the body.For each particular compound of the present invention, need definite one by one optimal dose separately.The scope of treatment effective dose will be subjected to the influence of factors such as route of administration, therapeutic goal and patient.Therefore, for obtaining optimum therapeuticing effect, the clinician need measure dosage and improve administering mode.To those skilled in the art, effective dose, promptly obtain required result of treatment the required dosage level determine it is easy.Typically, begin to drug compound, increase dosage gradually till obtaining required curative effect from low dosage.
The The compounds of this invention Orally-administrable comprises the meat of fat in every kg in treatment plan, the effective dosage ranges of every day is about 10 to 400mg/kg, is preferably about 50 to 300mg/kg, and more preferably about 100 to 200mg/kg, divides and takes for 1 time or 2 to 4 times.It is similar to oral Orlistat 120mg (about 1-2mg/kg dosage) that the lipase of preferred dose (100 to 200mg/kg according to appointment) suppresses effect.Can adopt in vitro tests, in vivo test or adopt two kinds of tests simultaneously by well-known lipase inhibition test, determine that lipase of equal value suppresses effect.By patient who contrasts the lipase inhibitor of the present invention of taking in lipase inhibition equivalent and the anus fat excretion of only taking in patient Orlistat, the fat absorption properties that can observe lipotropy lipase inhibitor of the present invention.Adopt anus fat index in contrast, contrast Orlistat or actual comparing animals and people's anus excretion is raised mouse and is shown reduced the fatty excretion of anus when administration lipotropy lipase inhibitor of the present invention.
Typically,, for the drug treating method that the people accepted the The compounds of this invention of 500mg to 2g or the mixture of compound are mixed with the acceptable media of physiology, carrier, vehicle, tackiness agent, sanitas, stablizer, dyestuff, spices etc. with the form of free acid or free alkali or the form of pharmaceutically acceptable salt by so-called.The feasible suitable dosage that can obtain how of absorption of active ingredient in the composition.
The typical auxiliary material that can be added in tablet, the capsule etc. is tackiness agent such as Sudan Gum-arabic, W-Gum or gelatin, and vehicle such as Microcrystalline Cellulose, disintegrating agent such as W-Gum or alginic acid, lubricant such as Magnesium Stearate, sweeting agent such as sucrose or lactose, perhaps spices.When formulation is capsule, except that above-mentioned materials, can also comprise liquid vehicle such as water, physiological saline or fatty oil.Other numerous types of materials can be used as dressing or as the modifying agent of formulation physical properties.Can prepare the aseptic composite of injection according to the conventional pharmaceutical method.For example can prepare solution or the suspension of active compound in carrier, wherein carrier for example is oil or synthetic fat carrier such as ethyl oleate or is formulated in the liposome.Can be by the drug treating method of accepting by the people with addings such as buffer reagent, sanitas, oxidation inhibitor.
Of the present invention aspect some in, the compound that is provided can be used as the diagnostic reagent of determining lipase activity.In another aspect, the present invention includes pharmaceutical composition, it comprises the The compounds of this invention and the pharmaceutically acceptable carrier of pharmacy effective dose.In another aspect, the present invention includes and use above-claimed cpd and pharmaceutical composition to prevent or treat the method for disease, thereby perhaps by in fatty prod that is stored or sample, suppressing the method for lipase effect stabilised fat, wherein disease is characterised in that and has unwished-for lipid or fat absorbing, for example the ateioscherosis disease in obesity, hyperlipidemia, arteriosclerosis and the mammalian process of setting.Randomly, method of the present invention comprises Combined Preparation such as pharmaceutical composition and other treatment agent such as anti-cholesterol agent, appetite-inhibiting agent, metabolic improver.
Preferred compound also comprises their pharmacy acceptable isomers, hydrate, solvate, salt and prodrug derivant.
In one embodiment, the invention provides a kind of pharmaceutical composition that is used to limit or prevent some absorption fat absorbing, it comprises the compound of at least a the invention described above of at least a pharmaceutically acceptable carrier vehicle and treatment significant quantity.In a preferred embodiment, pharmaceutical composition comprises a kind of microorganism of significant quantity or slowly-releasing lipoprotein lipase of plant origin for the treatment of, the terminal triglycerin ester group of alternative hydrolysis when the polysaccharide of this lipase and oil suction significant quantity such as chitosan coupling, wherein with respect to the weight of oil suction polysaccharide, the ratio of described lipoprotein lipase is less than 25%.
In another embodiment, the invention provides a kind of pharmaceutical composition that is used to limit or prevent some absorption fat absorbing, it comprises at least a pharmaceutically acceptable carrier vehicle and the compound of at least a the invention described above of treatment significant quantity and the polysaccharide of oil suction significant quantity, wherein the lipase inhibitor selectivity suppresses the lipase of the terminal triglycerin ester group of non-hydrolysis, this lipase inhibitor does not suppress vitamin A, the absorption of D and E substantially.
In another embodiment, the invention provides a kind of method that adopts described compound and pharmaceutical composition as therapeutical agent, be used for the treatment of in the Mammals at least a because of taking in the disease that unnecessary absorption caused of fat, perhaps be used for effectively reducing the mammiferous absorption heat of taking in fat, this method can be used for treating unnecessary weight increase and obesity.
Compound of the present invention also can be used as the intermediate that is used to prepare therapeutical agent, perhaps is used for the treatment of in the Mammals because of taking in the treatment of diseases agent that unnecessary absorption caused of fat.The method for preparing starting raw material can be the 4th, 931, finds in No. 463 United States Patent (USP)s, is incorporated herein by reference herein.The preferred oxetanone of the present invention is following compound, and wherein R is methyl, ethyl, propyl group, hexyl, decyl, hexadecyl, allyl group and benzyl, wherein most preferably is hexyl; R 1For hydrogen, methyl, ethyl, propyl group, 2-butyl, isobutyl-, benzyl and methylthio group hexyl, most preferably be hydrogen or isobutyl-; R 2For hydrogen, methyl or ethyl, most preferably be hydrogen; N is 0 or 1, and when t was 1, X preferably was connected on the N by amino acid, and described amino acid for example is Xie Ansuan, L-Ala, is preferably L-Ala; R 3Be preferably saturated maybe can choose wantonly insertion up to 8 two keys or triple-linked straight or branched C 1-17Alkyl, perhaps R 3Be that one or more straight or branched C that are selected from the group in Sauerstoffatom, sulphur atom, alkylsulfonyl or the sulfinyl are inserted in saturated maybe can choosing wantonly 1-17Alkyl, perhaps R 3Be saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, on the non alpha position of unsaturated carbon atom, can choose wantonly simultaneously and insert one or more straight or branched C that are selected from the group in Sauerstoffatom, sulphur atom, alkylsulfonyl or the sulfinyl 1-17Alkyl.
Also can be used as intermediate according to the prepared compound of the present invention and be used to form the compound that to unite use with other treatment or diagnostic reagent.In certain preferred aspects, the typical compound co-administered that can be used for the treatment of these diseases by the compound of intermediate preparation of the present invention with other, these typical compounds that use in usually for the medical practice that the people accepted are medicines of some other control meals, are used for the treatment of because of taking in the disease that fat absorbing caused or caused.Compound by intermediate preparation of the present invention can form synergy with other medicines, and these compounds also make other the dosage of cholesterol inhibitor, appetite-inhibiting agent and metabolic improver etc. reduce.These compounds can use in Mammals such as primate (non-human and the mankind), sheep, horse, ox, pig, dog, cat, rat and mouse in vivo usually, or in external use.
The starting raw material that is adopted in these methods is that the commodity from chemical dealer such as Aldrich, Sigma, Lancaster, TCI etc. maybe can obtain by currently known methods is synthetic.
Except as otherwise noted, otherwise adopt the laboratory glassware and the reactor of standard to react under the temperature and pressure of standard, these are reflected in the document of this area well known.In addition, above-mentioned method of the present invention of declaring can be undertaken by commercial size, has wherein adopted in this area under state of trade to preparing reactor and the standard that a large amount of compounds use to enlarge equipment.For the those skilled in the art in the commodity compound preparation field, these devices and expansion method are well-known.
In the building-up process of these compounds, can adopt protecting group that amino or carboxyl are protected to prevent amino or the unnecessary reaction of carboxyl generation in some reaction process.The protection of protecting group and the method for deprotection are routinely in the art, are well-known for the those skilled in the art in this area.
More than shown three kinds of exemplary building-up reactions routes that do not work the effect of defining, they are the preferred embodiments of the invention.In the generalized treatment step of above institute, also can further comprise initial step, as J.Med.Chem., the initial step of describing among the Vol.15, No.8 (1972), perhaps to the required functional group of amido modified feasible generation, as described group treatment step in the fat suppression field.The amino coupled reaction is well-known in the art.In addition, in the reaction scheme of above-mentioned preferred embodiment, listed concrete step.By ordinary method, be typically and adopt the compatible solvent extraction, carry out the separation and the purifying of reaction product.Preferred solvent is low-molecular-weight alkyl oxide and alkyl alcohol; For solvent extraction or recrystallization operation, ether and Virahol are preferred.Can form the ester of carboxylic acid side chain base, making can selective separation R and S type enantiomer by solvent extraction or recrystallization.D-alaninol is preferred enantiomer resolution reagent, but other resolution reagent or similarly method also can adopt, as tartaric acid derivatives etc.Product can be further purified by column chromatography or other appropriate means.The formation of optical isomer fractionation and hydrochlorate
Can be clear that from the said structure formula with discussing, adopt above-mentioned reaction can obtain the chroman acetate of racemization, it can randomly be split to obtain being rich in the racemic mixture of R or S enantiomer, perhaps can split into a kind of pure enantiomer that is almost fully.The example that splits the ordinary method of enantiomer has been discussed in the document of this area.The linked reaction of hydrochloride midbody compound
According to the above-claimed cpd that the invention described above the produced single step reaction of separatedly to go forward side by side, thereby, utilize this required group and free hydroxyl group or free acyl group to carry out linked reaction with the one or more hydrogen atoms on the required group substituted-amino.Composition and preparation
Compound of the present invention can free acid or the form of free alkali be able to purifying or adopt multiple inorganic or organic bronsted lowry acids and bases bronsted lowry to transform salify.These salt are also within the scope of the invention.Separate and purge process in nontoxic and salt physiological compatibility be useful especially, though other are not that very ideal salt also can use.
Can adopt above-mentioned and well known by persons skilled in the art several different methods to prepare above-mentioned salt.For example, in insoluble solvent of salt or mixed solvent, to have the free acid of compound of said structure or free alkali and monovalent or react greater than the required acid or the alkali of monovalent, reaction also can be carried out in solvent such as water, after this removes by evaporation, distillation or freeze-drying and desolvates.In addition, the free acid of product or free alkali can be transformed into the form of required salt by ion exchange resin, perhaps adopt same procedure that a kind of salt of product is changed into another kind of salt.
The preparation that the The compounds of this invention typical case adopts in diagnostic use is solution or suspension.Compound of the present invention can use being used for liquid preparations for oral administration when the unnecessary fat absorbing of reply, and for example tablet, capsule or tincture perhaps in aseptic solution or suspension etc., or are added among the article of moulding.The object (being typically Mammals) that needs the employing The compounds of this invention to treat can adopt the dosage of optimum curative effect.Dosage and method are different because of object, are dependent on some other factor known to the concrete using method of the medical conditions of carrying out the mammiferous type for the treatment of, sex, body weight, diet, the same period, whole clinical setting, the particular compound that is adopted, compound and the medical field technician and decide.
The compound of required purity and physiology acceptable carrier, vehicle, stablizer etc. are mixed with for storing and the preparation of the present invention of administration, and can make and continue the preparation that discharges or regularly discharge.Acceptable carrier or thinner medicinal in pharmaceutical field are well-known, and for example, they are described in Remington ' s Pharmaceutical Sciences, among the Mack Publishing Co. (A.R.Gennaro edits, 1985).These materials are nontoxic under dosage that is adopted and concentration, and comprise buffer reagent such as phosphoric acid salt, Citrate trianion and other organic acid salts, oxidation inhibitor comprises xitix, lower molecular weight (less than 10 residues) peptide such as poly arginine, albumen such as serum albumin, gelatin or immunoglobulin (Ig), hydrophilic polymer such as polyvinylpyrrolidone, amino acid such as glycine, L-glutamic acid, aspartic acid or arginine, monose, disaccharides, and other sugar, comprise Mierocrystalline cellulose and derivative thereof, glucose, seminose or dextrin, sequestrant such as EDTA, sugar alcohol such as N.F,USP MANNITOL or sorbyl alcohol, counter ion such as sodium and/or nonionogenic tenside such as Tween, Pluronics or polyoxyethylene glycol.
The preparation of the present invention of being used for the treatment of property administration must be aseptic.As filtering in the 0.2 μ m film or passing through other ordinary methods, can easily accomplish aseptic by no mycoderm.Typically, preparation stores with the form of freeze-dried or the aqueous solution.The typical pH of preparation of the present invention is 3-11, is preferably 5-9, most preferably is 7-8.Should be realized that the formation of using some above-mentioned vehicle, carrier or stablizer can cause ring type polypeptide salt.Though preferred route of administration is oral tablet, capsule or other administering mode such as liquid agent, also can estimate other medication, for example fits in the food with multiple dosage form.Compound of the present invention is preferably fitted in the food that may contain fat, is used to prevent the absorption of fat.
Compound of the present invention also can use to improve its result of treatment with suitable combination with polymers.These polymkeric substance can comprise lipophilic polymer, for example polysaccharide etc.
Can determine the treatment effective dose by method in external or the body.For each particular compound of the present invention, need definite one by one optimal dose separately.The scope of treatment effective dose will be subjected to the influence of factors such as route of administration, therapeutic goal and patient.For route of administration,, must measure the inhibition activity of each lipase inhibitor with known method in the pharmacy in view of the intake of fat.Therefore, for obtaining optimum therapeuticing effect, the clinician need measure dosage and improve administering mode.Effective dose to those skilled in the art, promptly obtain required result of treatment the required dosage level determine it is easy.Typically, begin to drug compound, increase dosage then gradually till obtaining required curative effect from low dosage.
Typically,, for the drug treating method that the people accepted the lipase inhibitor compound of the present invention of 500mg to 3g or the mixture of lipase inhibitor compound are mixed with the acceptable media of physiology, carrier, vehicle, tackiness agent, sanitas, stablizer, dyestuff, spices etc. with the form of free acid or free alkali or the form of pharmaceutically acceptable salt by so-called.The feasible suitable dosage that can obtain stated limit of absorption of active ingredient in the composition.Other one or more therapeutic components for example absorb the agent of going on a diet of the polysaccharide of fat and fiber, fatty specific lipase inhibitor or lipase and other routines, can treat significant quantity and use.
The typical auxiliary material that can be added in tablet, the capsule etc. is tackiness agent such as Sudan Gum-arabic, W-Gum or gelatin, and vehicle such as Microcrystalline Cellulose, disintegrating agent such as W-Gum or alginic acid, lubricant such as Magnesium Stearate, sweeting agent such as sucrose or lactose, perhaps spices.When formulation is capsule, except that above-mentioned materials, can comprise liquid vehicle such as water, physiological saline or fatty oil.Other numerous types of materials can be used as dressing or as the modifying agent of formulation physical properties.Can prepare the aseptic composite of injection according to the conventional pharmaceutical method.By being the drug treating method that the people accepted, can be with addings such as buffer reagent, sanitas, oxidation inhibitor.
When implementing method of the present invention, compound of the present invention can use or unite use separately, or unites use with other treatment or diagnostic reagent.In some preferred embodiment, The compounds of this invention can be used to treat the typical compound co-administered of these diseases with other in usually for the medical practice that the people accepted, for example
The compounds of this invention can use in Mammals such as primate (non-human and the mankind), sheep, horse, ox, pig, dog, cat, rat and mouse in vivo usually, or in external use.
Below can not adopt the embodiment of the effect of defining to further describe the present invention.
Embodiment 1
Be equipped with in the flask of agitator, thermometer and electric heater at a 500ml, under 50 ℃, the low viscous chitosan of 10g be dissolved in the mixture of 190g dimethyl sulfoxide (DMSO) and 10g Paraformaldehyde 96.After adding 0.1g sodium hydroxide fine powder, under this temperature, add 400mg right-solution of chloromethyl benzoic acid methyl esters and 10g dimethyl sulfoxide (DMSO), about 30 minutes consuming time.Mixture stirred 4 hours down at 50 ℃.After reaction mixture is cooled to room temperature, under vigorous stirring, pour in the ethanol.The solid suction filtration also is suspended in the ethanol repeatedly, is removed until all soluble substances, thereby obtains thick product.Thick product stirs in aqueous 1N sodium hydroxide ethanolic soln, then with hcl acidifying to the neutral pH scope of chitosan.Solid obtains solid drying the functionalized chitosan of about 10g ether then with cold ethanol and cold wash 2 times.Analytical results shows that about free hydroxyl group of 1% to 3% is by right-tolyl acid group etherificate on the chitosan polymer backbone.
Embodiment 2
With 3,5-dihydroxyl-2-hexyl-hexadecanoic acid 1,3-lactone colourless powder (6g, press United States Patent (USP) 4,202, the preparation of method described in the 11st and 12 page in 824) be dissolved among the 500ml THF, add Boc-(L) 2-amino-4-methylpent acyl chlorides (3g, Boc-(L)-leucine).Stirred reaction mixture and reflux are till HPLC shows esterification fully.With the organic phase evaporate to dryness, residue adopts toluene-ethyl acetate chromatogram purification on silica gel, obtains 5-[Boc-(L) 2-amide group-4-methylpent acyloxy]-2-hexyl-hexadecanoic acid 1,3 lactone (6g).
Embodiment 3
In 120ml THF, in the presence of 10%Pd/C, the Boc group of the product (6mg) that makes among the embodiment 2 is removed by hydrogenation under the room temperature.After the hydrogenation fully, filtration catalizer obtains having the crude product of free amine group with the filtrate evaporate to dryness, and it is added among the 100ml THF.Be added among the 200ml THF the functionalized chitosan that makes among the embodiment 1 and stirring, at room temperature slowly drip crude product simultaneously with free amine group.In stirring down mixture is heated to 40 ℃ gradually, till HPLC shows that the product of carbonyl acid amides connection forms.Products obtained therefrom is 5-[2-{ (4-chitosan methyl ether) benzoylamino }-4-methylpent acyloxy]-2-hexyl-hexadecanoic acid 1,3 lactone (about 15g).
Embodiment 4
In 1 liter flask, add 20g and be dissolved in chitosan among the 350ml DMF (N, dinethylformamide), stir and temperature is risen to 50 ℃.Stir the 6-bromocaproic acid of the NaOH, the 1g that slowly add 0.2g down and the mixture of 20ml DMF, about 30 minutes consuming time.Mixture stirred 4 hours down at 50 ℃.Reaction mixture is poured in the 500ml ethanol after being cooled to room temperature.Give a baby a bath on the third day after its birth time with the solid suction filtration and with cold ethanol.Slightly be deposited in the 1N sodium hydroxide ethanolic soln and handled 3 hours, add the hydrochloric acid neutralization then.Solid is washed 3 times with cold second alcohol and water (4: 1) and is dry, obtains the functionalized chitosan of about 19.7g.
Embodiment 6
The functionalized chitosan that adding 9.3g makes in embodiment 5 in 200ml THF (tetrahydrofuran (THF)) also stirs.In this mixture, add the 10mmol HBTU be dissolved among the 10ml DMF (1H-benzotriazole-1-[is two, (dimethylamino) methylene radical]-hexafluorophosphate (1-)-3-oxide compound).Stir and drip the tetrahydrostatin L-leucine ester (about 525mg) that is dissolved among the 100ml THF down.PH is adjusted to about 8.5 by adding DIEA (diisopropyl ethyl amine) then, mixture at room temperature stirs and spends the night.Boiling off about 50% volume under vacuum reduces the volume of reaction mixture and adds the 500ml hexane.Mixture filtered and solid filter cake is given a baby a bath on the third day after its birth time with cold hexane, after this use cold ethanol/water (3: 1) to give a baby a bath on the third day after its birth time.Filter cake is at the dry 9.3g finished product 2S that gets of Freeze Drying Equipment, 3S, 4S[2-{ (the chitosan 6-hexanoyl amido that caproic acid is modified)-4-methylpent acyloxy }-2-hexyl-hexadecanoic acid 1,3 lactone (compd A).
Embodiment 7
The functionalized chitosan that adding 9.65g makes in embodiment 5 in 200ml THF also stirs.Add 2mmol HBTU then.Mixture stirred 15 minutes, added the 3.50mg 2S that is dissolved among the 30ml THF (tetrahydrofuran (THF)), 3S, 4S2-hexyl-4-hydroxyl-hexadecanoic acid 1,3 lactone then.PH is adjusted to about 8.5 by adding DIEA then, mixture at room temperature stirs and spends the night.Reaction mixture filters and solid is given a baby a bath on the third day after its birth time with cold hexane, after this uses cold ethanol/water (3: 1) to give a baby a bath on the third day after its birth time.Filter cake is in the dry chitosan 6-hexylyloxy that gets the modification of 11.1g finished product 4-[(caproic acid of Freeze Drying Equipment)-2-hexyl-hexadecanoic acid 1,3 lactone (compd B).The embodiment of biology and other tests
Embodiment 8
Adopt compd A and B to carry out the lipase inhibition test substantially by the following method.
Prepare 1L 1N NaOH mother liquor and prepare 500mL 0.025N NaOH mother liquor by diluting this mother liquor.Prepare 0.2N HCl mother liquor simultaneously.(from Aldrich lipase assay kit, catalog number (Cat.No.): 800B) dilution of usefulness 100ml Denatured alcohol and 300ml water forms 500ml TEW solution with 100ml TRIZMA.Compd A among the embodiment 6 (100mg) is added in a 0.2NHCl mother liquor and is diluted to final volume with identical HCl mother liquor is 300ml, forms the compd A mother liquor.Compd B among the embodiment 7 is added in a 0.2N HCl mother liquor and is diluted to final volume with identical HCl mother liquor is 80ml, forms the compd B mother liquor.With Aldrich lipase PS standard (people's lipase 3ml * 3, Aldrich production number: 8054) ooze the volume (lipase 1# solution) that physiological saline is diluted to 25ml with waiting.Similarly, with Aldrich porcine pancreatic lipase (EC3.1.1.3, production number: 32313) ooze the volume (lipase 2# solution) that physiological saline is diluted to 25ml with waiting.Aldrich Sigma lipase substrate standard (3 * 100,300ml, catalog number: 62314) be used as fat source.
(the sample contrast is a 20ml 0.2N HCl mother liquor to add 100ml distilled water, 10ml TEW solution, 10ml Sigma lipase substrate and 20ml sample in a 500ml beaker that is equipped with thermal source and magnetic stirring apparatus, sample A is a 20ml compd A mother liquor, and sample B is a 20ml compd B mother liquor).Use pH meter pH is adjusted to is about 8, the reading of record pH meter and with its baseline value of adjusting as pH by adding 1N NaOH.Temperature is adjusted to 37.5 ℃ also adds 1ml lipase 1# solution and lipase 2# solution respectively, carry out 30 minutes timing with timing register.Stir the mixture and with temperature maintenance between 35 ℃ to 37 ℃.When reaction finishes, stir the mixture and carry out titration with 0.025N NaOH.The interpolation volume of NaOH solution makes pH get back to the baseline value of record.Employing makes the pH of sample A or sample B get back to the required NaOH volume of baseline value and deducts and make the percent inhibition (parallel 3 times test) of pH in the same old way being got back to the required average N aOH volume calculation of baseline value sample A or sample B, difference is removed so that the pH of contrast sample gets back to the required average N aOH volume of baseline value, then the gained result be multiply by 100%, obtain the percent inhibition of sample A or sample B.
Compared with the control, sample A or sample B are respectively about 50% to the percent inhibition of lipase 1# solution and lipase 2# solution.
Embodiment 9
Adopt compd A and B to carry out grease substantially by the following method in conjunction with test.
To 4 or the sample bottle of 7ml in add Star board sweet oil (sweet oil that color is very shallow) and make 6 contrasts, on 10 inches distance, adopt IZONE POLAROID photographic camera to take pictures in the following manner.Contrast 1 is to add the contrast that the 3ml sweet oil makes in the sample bottle of 7ml, and it shows transparency but reflective oil.Contrast 2 is to add the 3ml sweet oil and add the contrast that 10 McCormick Schilling edible haematochromes (RFC) make in the sample bottle of 7ml, and it is presented at the bottle bottom non-oil-soluble pigment, the reflective sweet oil of 3ml adrift on haematochrome.Contrast 3 is to add the 3ml sweet oil and add 3ml water and 5 contrasts that RFC makes in the sample bottle of 7ml, and its red water and floating thereon reflective sweet oil that is presented at the bottle bottom has interface clearly.Contrast 4 is that the 1.5g sweet oil is added 1g chitosan (Natural Max board, chitosan greater than 90%) in and with mixing tank the two is stirred, add 4ml water and 5 contrasts that RFC makes then, it is presented at the chitosan that oily mortise is arranged at bottle bottom, edible haematochrome water layer (not observing the meniscus of floating oil clearly substantially) adrift on it.Contrast 5 is the 1.5g sweet oil to be added in the 1g Mierocrystalline cellulose (Avicel) and with mixing tank the two is stirred, add 4ml water and 5 contrasts that RFC makes then, it is presented at the bottle bottom some oily cellulose-bindings, edible haematochrome water layer adrift on it, upwards be the clear oil reservoir of buoyant again, about 3/4ml (can observe the meniscus of floating oil clearly, show that Mierocrystalline cellulose can not mortise surpasses the oil of its weight).Contrast 6 is the 8g sweet oil to be added in the 1g chitosan and with mixing tank the two is stirred, add 1ml water and 5 contrasts that RFC makes then, its demonstration is centered around the chitosan institute bonded hourglass shape oil at bottle middle part, has the edible haematochrome aqueous solution (chitosan is in conjunction with oil and basically all water are got rid of outside binding mixture) at the narrowest place.
Compare with contrast 4 (oil/chitosan is 1.5: 1), compd A and B mixed with the oil of same ratio respectively (oil/compound is 1.5: 1, aqueous phase at the compd A sample bottle adds edible marennin, at the edible blue pigment of aqueous phase adding of compd B sample bottle).Compare with the chitosan of contrast in 4, compd A has also shown identical result with B, and wherein in the bottom of sample and there is not buoyant oil substantially, and each meniscus is green clearly and meniscus blue look to oil by mortise.Wherein compd B is more more firm than chitosan or compd A with the combination degree of oil.
Compare with contrast 6 (oil/chitosan is 8: 1 and adds the aqueous solution of 1ml food dye), in compd B, add the oil of 8 times of weight and stir.Add 1ml water and 5 edible haematochromes.Oil and compd B expand to form the granulous gelling material in stirring, and it evenly absorbs the aqueous solution of 1ml food dye, form the homogeneous gel composition, this gelatinous composition even remain uniform substantially after 24 hours in placement.This shows that compd B has in conjunction with the ability of oil and with the water that post-absorption equals itself weight at least and forms the uniform mixture of granulated gel sample that it is still securely in conjunction with oil when water carries out hydration.
Can believe that by above-mentioned description those skilled in the art just can realize the present invention.The above embodiments right and wrong circle under the condition that does not deviate from main concept of the present invention, can easily envision other change or variation with reference to above description those skilled in the art qualitatively.These changes or variation are also within the scope of the invention.

Claims (20)

1, the novel oxetanone derivatives of following structural formula: Wherein: t is that the integer X-O-Q between 0 to 1 is that a kind of ehter bond connects, wherein:
X during this ehter bond connects is for becoming abutment, and
Q during this ehter bond connects is a kind of polysaccharide, and it has enough molecular weight or function makes
Disappearing of Mammals such as dog, cat, non-human primate or human primate
Be not absorbed in the change system, described polysaccharide will be further described following; R is the group that is selected from following group:
Saturated maybe can choose wantonly insertion up to 8 two keys or triple-linked straight or branched C 1-17Alkyl;
Saturated maybe can choose wantonly insert one or more be selected from Sauerstoffatom, sulphur atom, alkylsulfonyl or
The straight or branched C of the group in the sulfinyl 1-17Alkyl;
Saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more Sauerstoffatom, sulphur atom, sulphonyl of being selected from
The straight or branched C of the group in base or the sulfinyl 1-17Alkyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Phenyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Benzyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Xenyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The thiophenyl phenylene; And
Phenyl-C 1-6Alkyl-phenyl, wherein one or more benzyl rings and-C 1-6On the alkyl
0 to 6 hydrogen atom can be selected from independently-C 1-6Alkoxy-C 1-6Alkane
Base ,-C 1-6Alkylthio-C 1-6Alkyl ,-C 1-6Alkyl-OH and-C 1-6Alkane
Group among base-SH replaces; R 1Be the group that is selected from following group:
Hydrogen,
Ar，
Ar-C 1-5Alkyl, and
C 1-10Alkyl, it is inserted with 0-3 and is selected from group in following group: Sauerstoffatom, sulphur are former
Son, alkylsulfonyl, sulfinyl ,-N (R 4)-Ji ,-C (=O)-N (R 4)
-Ji and-N (R 4)-C (=O)-Ji, wherein C 1-10The 0-3 of alkyl
The group that carbon atom can be selected from respectively in following group replaces: hydroxyl, sulfydryl,
C 1-10Alkoxyl group, C 1-10Alkylthio ,-N (R 5,-R 6) base,
-C (=O)-N (R 7,-R 8) base and-N (R 9)-C (=O)-R 10Base; R 2Be the group that is selected from following group:
Hydrogen and C 1-6Alkyl, perhaps R 2With R 1Form 4-6 the member who contains 0-4 nitrogen-atoms together
Saturated rings, wherein said ring can be by 0-4 R 11Group replaces; R 3Be the group that is selected from following group:
Saturated maybe can choose wantonly insertion up to 8 two keys or triple-linked straight or branched C 1-17Alkyl;
Saturated maybe can choose wantonly insert one or more be selected from Sauerstoffatom, sulphur atom, alkylsulfonyl or
The straight or branched C of the group in the sulfinyl 1-17Alkyl;
Saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more Sauerstoffatom, sulphur atom, sulphonyl of being selected from
The straight or branched C of the group in base or the sulfinyl 1-17Alkyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Phenyl;
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Benzyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Xenyl;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The thiophenyl phenylene; And
Phenyl-C 1-6Alkyl-phenyl, wherein one or more benzyl rings and-C 1-6On the alkyl
0 to 6 hydrogen atom can be selected from independently-C 1-6Alkoxy-C 1-6Alkane
Base ,-C 1-6Alkylthio-C 1-6Alkyl ,-C 1-6Alkyl-OH and-C 1-6Alkane
Group among base-SH replaces; R 4-R 10Be respectively and be selected from hydrogen and C 1-6Group in the alkyl; N is the integer between the 0-3, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
2, compound as claimed in claim 1, wherein X is following group:
-(C (=O)) 0-1-Xa-wherein Xa is the group that is selected from following group:
Saturated two keys or the triple-linked straight or branched divalence C of insertion that maybe can choose wantonly up to 8 1-17
Alkylidene group;
Saturated maybe can choose wantonly insert one or more straight chains that are selected from the group in following group or
Chain divalence C 1-17Alkylidene group:
Sauerstoffatom,
Sulphur atom,
Alkylsulfonyl,
Sulfinyl,
Replace or unsubstituted 6-10 unit's monocycle or bicyclic aryl or have 1-4
Heteroatomic heterocyclic radical, wherein heteroatoms is selected from O, N, S,
-NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
-C (=O)-Ji,
-NH-C (=O)-and Ji, wherein hydrogen atom can be by C 1-10Alkyl replaces, and
-C (=O)-and the NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces, saturated maybe can choose wantonly insertion up to 8 two keys or triple bond, simultaneously at unsaturated carbon atom
Can choose wantonly on the non alpha position and insert one or more straight chains that are selected from the group in following group
Or side chain divalence C 1-17Alkylidene group;
Sauerstoffatom,
Sulphur atom,
Alkylsulfonyl,
Sulfinyl,
Replace or unsubstituted 6-10 unit's monocycle or bicyclic aryl or have 1-4
Heteroatomic heterocyclic radical, wherein heteroatoms is selected from O, N, S,
-NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
-C (=O)-Ji,
-NH-C (=O)-and Ji, wherein hydrogen atom can be by C 1-10Alkyl replaces, and
-C (=O)-and the NH-base, wherein hydrogen atom can be by C 1-10Alkyl replaces,
Be selected from-C by 0 to 4 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Divalence phenylene or divalence naphthylidene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The divalence biphenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
The phenoxy group phenylene;
Be selected from-C by 0 to 6 1-6Alkoxy-C 1-6Alkyl ,-C 1-6Alkylthio-C 1-6
Alkyl ,-C 1-6Alkyl-OH and-C 1-6Group among alkyl-SH replaces
Divalence thiophenyl phenylene, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
3, compound as claimed in claim 2, wherein R is-(CH 2) 3-6-CH 3, and R 3Be selected from-(CH 2) 8-14-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 2-8-CH 3, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
4, compound as claimed in claim 2, wherein R is-(CH 2) 5-CH 3, and R 3Be selected from-(CH 2) 10-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 4-CH 3, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
5, compound as claimed in claim 2, wherein n is the compound of 0 formation following formula: Wherein: X, t, Q, R, R 1And R 2As described in claim 2, and isomer, salt, hydrate, solvate and prodrug derivant.
6, require 5 described compounds as profit, wherein R is-(CH 2) 3-6-CH 3, and R 3Be selected from-(CH 2) 8-14-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 2-8-CH 3, and isomer, salt, hydrate, solvate and prodrug derivant.
7, compound as claimed in claim 5, wherein R is-(CH 2) 5-CH 3, and R 3Be selected from-(CH 2) 10-CH 3With-CH 2-CH=CH-CH 2-CH=CH-(CH 2) 4-CH 3, and isomer, salt, hydrate, solvate and prodrug derivant.
8, compound as claimed in claim 5, wherein t is 0, and isomer, salt, hydrate, solvate and prodrug derivant.
9, compound as claimed in claim 2, wherein t is 0 or 1, and X is the group that is selected from following group:
Figure A0080439100081
R wherein 1aIndependently with R 1Define identical, R 2aIndependently with R 2Define identically, m is 0-10, be preferably 0-5, the integer between the 0-2 more preferably, and z is 1-20, be preferably 2-10, the integer between the 2-4 more preferably, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
10, compound as claimed in claim 9, wherein X is the group that is selected from following group:
Figure A0080439100082
Wherein z is 0-10, is preferably 0-5, the integer between the 0-2 more preferably, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
11, compound as claimed in claim 9, wherein X is the group that is selected from following group:
Figure A0080439100091
Wherein z is the integer between the 0-18, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
12, compound as claimed in claim 9, wherein X is the group that is selected from following group: Wherein z is the integer between the 6-12, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
13, compound as claimed in claim 9, wherein X is the group that is selected from following group:
Figure A0080439100093
Wherein z is the integer between the 6-12, and all pharmacy acceptable isomers, salt, hydrate, solvate and prodrug derivant.
14, compound as claimed in claim 13, wherein the Q group is a kind of chitosan compound, it is modified by organic acyl group of capacity and makes the modification chitosan absorb or in conjunction with lipid and water, and forms basic homogeneous gel with oil and water.
15, a kind of method for preparing compound as claimed in claim 1 is comprising the compound that makes with following formula
Figure A0080439100101
With the following formula: compound reaction,
Figure A0080439100102
Wherein t is 0 or 1, and Y is the leavings group that carries out etherificate or esterification with hydroxyl, forms the compound or its salt with following formula:
Figure A0080439100103
16, a kind of pharmaceutical composition, it comprises at least a pharmaceutically acceptable carrier and vehicle and for restriction or prevent that some from taking at least a as claimed in claim 1 compound of fat absorbing for the treatment significant quantity.
17, pharmaceutical composition as claimed in claim 16, it also comprises the polysaccharide of the oil suction significant quantity for the treatment of significant quantity, as chitosan.
18, a kind ofly use compound as claimed in claim 1 to be used for the treatment of in the Mammals at least a because of the disease that unnecessary absorption caused of taking in fat or the method that is used for effectively reducing the mammiferous absorption heat of taking in fat as therapeutical agent.
19, method as claimed in claim 18, it can be used as a part that is used for the treatment of or controls the method for unnecessary weight increase and obesity.
20, a kind ofly use pharmaceutical composition as claimed in claim 16 to be used for the treatment of in the Mammals at least a because of the disease that unnecessary absorption caused of taking in fat or the method that is used for effectively reducing the mammiferous absorption heat of taking in fat as therapeutical agent.
CN00804391A 1999-10-29 2000-10-27 Oxocyclobutazone-one derivatives Pending CN1342169A (en)

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US7074822B2 (en) 2004-02-23 2006-07-11 Solvay Pharmaceuticals Gmbh Alkyl carbamate-substituted β-lactones, process for their preparation, and pharmaceutical compositions containing them
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US5246960A (en) * 1984-12-21 1993-09-21 Hoffmann-La Roche Inc. Oxetanones
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