CN1338934A - Mono-acyloxy aralkyl neuronuscular relaxants - Google Patents
Mono-acyloxy aralkyl neuronuscular relaxants Download PDFInfo
- Publication number
- CN1338934A CN1338934A CN00803305A CN00803305A CN1338934A CN 1338934 A CN1338934 A CN 1338934A CN 00803305 A CN00803305 A CN 00803305A CN 00803305 A CN00803305 A CN 00803305A CN 1338934 A CN1338934 A CN 1338934A
- Authority
- CN
- China
- Prior art keywords
- dibromide
- benzyl
- dicarbapentaborane
- acetoxyl group
- tropine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
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- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
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- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- KOJGUMRURQVAIH-UHFFFAOYSA-N dodec-3-enedioic acid Chemical compound OC(=O)CCCCCCCC=CCC(O)=O KOJGUMRURQVAIH-UHFFFAOYSA-N 0.000 description 1
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 229960003054 gallamine Drugs 0.000 description 1
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- 231100000957 no side effect Toxicity 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
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- 230000001151 other effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- CYHOMWAPJJPNMW-RNLVFQAGSA-N pseudotropine Chemical compound C1[C@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-RNLVFQAGSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
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- 125000005504 styryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960003819 vecuronium Drugs 0.000 description 1
- BGSZAXLLHYERSY-XQIGCQGXSA-N vecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 BGSZAXLLHYERSY-XQIGCQGXSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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Abstract
Mono-acyloxy substituted aralkyl and aralkenyl bis-quaternary ammonium derivatives of cyclic alkanol diesters according to general Formula (a) or (b), where R1 and R1' are mono-acyloxy subst ituted aralkyl or aralkenyl; R2 and R2' are alkyl or alkenyl; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl or aromatic dicarbonyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R3 and R3' are H, CH3, or lower alkyl; R4 and R4' are H, CH3, or lower alkyl; R3 and R4 together can also be -CH=CH-, -(CH2)h-Y-(CH2)k-, or (1), where Y is CH2, O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; and R3' and R4' together can also be -CH=CH-, -(CH2)h-Y-(CH2)k-, or (1), where Y is CH2, O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein R1 and R1', R2 and R2', R3 and R3', and R4 and R4' can be the same or different; and X is a pharmaceutically acceptable anion; have advantageous neuromuscular relaxant properties.
Description
The present invention relates to chemical compound as neuromuscular (" NMB ") muscle relaxant.More particularly, the present invention relates to the aralkyl two-quaternary ammonium derivative of the ring-type chain triacontanol diester of a series of acyloxy-replacement.
Background of invention
In surgical operation and some non-operation process, particularly those need strengthen or the patient's of critical care breathing support and recovery process in, require patient's muscle fully lax usually.Though the anesthesia of general muscle can make the patient lose consciousness, this only can provide and inadequate skeletal muscle meat relaxes.In addition, the emergency treatment that need relax and intensive care patient often can not holonarcosis.
The all cpds that is referred to as neuromuscular blocking agents (NMB agent) generally is usually as muscle relaxant.Two the most useful features of NMB agent are that rapid onset and action time are short.Onset makes rapidly provided required relaxing before hypoxgia and the appearance of other complication.And recover rapidly to make the patient recover muscle strength, thereby can in operation latter stage or operation process, breathe.Even for the operation process that needs the long period, the NMB agent of part-time application remains and needs; Because, this reagent can continuous infusion satisfying the demand, and when stopping infusion, can recover rapidly.
The muscle relaxant that a kind of past often uses is a succinylcholine, and its onset is very fast, and acting duration is short.But succinylcholine can cause muscle film " depolarization ", and this often causes serious adverse, thereby and makes the described medicine can not be satisfactory or show mishandling.
Also known other several so-called " non depolarization " muscle relaxant, they are widely used in anesthesia and surgical operation.These different reagent chemically comprise: tubocurarine, Metocurine, handkerchief oolong, atracurium, suitable atracurium, Vecuronium, Mivacron and Luo Ku ammonium.Though can not make us satisfied fully, they are still acceptable clinically, and this is because people also have demand to them, and their side effect of producing are slight or have no side effect.But their onset is too slow and/or their continuous action time is oversize.As a result, need to adopt maneuver in many treatments with himself complication and side effect to compensate these defectives.Therefore, these reagent can't satisfy the requirement of " ideal " surgery muscle relaxant unlimitedly.
The conventional feature structure of NMB reagent is: introduce one or common two quaternary nitrogen atoms at the salt head.Though many " non depolarization " NMB reagent comprises alkoxyl at big salt head substituent group place, also there is not an a kind of part that comprises aralkyl that acyloxy replaces or aromatic yl alkenyl part as its molecular structure.Alkoxyl but not the introducing of acyloxy are based on traditional inveteracy understanding in the exploitation NMB Relaxant.For example, Metocurine is a kind of improvement to tubocurarine, because of it comprises additional methoxyl group substituent group.Modern NMB reagent atracurium (with suitable-atracurium), Mivacron and Duo Ku ammonium still comprise 4,5 or 6 methoxyl groups with a graded.Each additional methoxyl group all improves the effectiveness of these chemical compounds and reduces some side effect.Show that but there is no any hint under the prerequisite of not having additional group, the monoacylation on the aralkyl basic ring can produce excellent NMB reagent.
As having curaremimetic chemical compound, the quaternary ammonium derivative of the aliphatic series (as succinic acid) of tropine (bicyclic amino alkanol) and aromatics (as phthalic acid) dicarboxylic esters is stated in following document: Nador, K. and Gyermek, L. (Acta Chim.Acad.Sci.Hung.2,369-374,1952).All these chemical compounds are symmetrical replacement the at the nitrogen-atoms place all, and wherein some have not replacement or single benzyl (referring to hungarian patent 142,597, the mandate on the 15th of nineteen fifty-five JIUYUE) that replaces (methyl, bromine).
Also reported other some neuromuscular chemical compounds in the literature, they comprise the part of paired quaternary nitrogen as the tropane member ring systems.For example, Arch.Exper.Path.Pharmakol.215. 283-298, (1952) and Brit.J.Pharmacol.15,71. (1960).But, adopting these chemical compounds, tropane base (tropinyl) part can be connected by two quaternary nitrogens of bridging.US patent 2,746,964 (1953) disclose dicarboxylic ester and its quaternary ammonium alkyl derivant of piperidines-3-alcohol.These public publications all do not relate to the aralkyl two quaternary ammonium diester compounds that list-acyloxy replaces.
Finding that through the muscle relaxant of " ideal " being furtherd investigate the back that the mono-acyloxy of the aralkyl of cyclic amino chain triacontanol diester and aromatic yl alkenyl quaternary ammonium derivative turns into is high-effect with causing, onset is very fast, action time is very short and very little or do not have to the side effect of animal.Aralkyl that these mono-acyloxies replace and some in the aromatic yl alkenyl quaternary ammonium derivative are rapider and action time is shorter to the animal onset compared with known any muscular flaccidity chemical compound at present.
Therefore, consider other people and our some inveteracy theories, and former viewed concrete instance, the present invention is based on a kind of also not expectable new notion at present, promptly increase substituent quantity (usually on the benzyl quaternary ammonium group) and will improve NMB reagent.
Summary of the invention
The invention discloses aralkyl that the acyloxy of the cyclic amino chain triacontanol ester of a series of various dicarboxylic acids replaces and aromatic yl alkenyl two quaternary ammonium derivatives as neural muscle relaxant, its preparation method and using method are disclosed, and the pharmaceutical composition that comprises them.
First aspect of the present invention is one group of chemical compound 1/a, and it has the general formula shown in the following formula:
Formula a second aspect of the present invention is one group of chemical compound 1/b, and it has the general formula shown in the following formula:
Formula b wherein, R
1And R
1' be aralkyl or the aromatic yl alkenyl that list-acyloxy replaces; R
2And R
2' be alkyl, alkenyl or alkynyl; A is alkane dicarbapentaborane, alkene dicarbapentaborane, alkynes dicarbapentaborane, cycloalkanes dicarbapentaborane, cyclenes dicarbapentaborane, two cycloalkanes dicarbapentaborane, two cyclenes dicarbapentaborane, polynaphthene dicarbapentaborane, multi-ring alkene dicarbapentaborane or the aromatics dicarbapentaborane that does not replace or replace; N is 0,1 or 2; M is 0,1 or 2; P is 0,1 or 2; R
3And R
3' be H, CH
3Or low alkyl group; R
4And R
4' be H, CH
3Or low alkyl group; R
3And R
4Also can be altogether-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Or R
3' and R
4' also can be altogether-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Wherein, R
1And R
1', R
2And R
2', R
3And R
3' and R
4And R
4' can be identical or different; X is pharmaceutically acceptable anion.
The 3rd aspect of the present invention is the using method of the chemical compound of general formula 1/a-1/b as neural muscle relaxant.
The 4th aspect of the present invention is a kind of pharmaceutical composition, and it comprises chemical compound and the pharmaceutically acceptable excipient of general formula a and b.Detailed Description Of The Invention
Among the present invention, term " alkyl " is meant the alkyl with 1-20 carbon atom.In the present invention, alkyl can be and replaces or unsubstituted alkyl, for example, and methyl, butyl, octyl group and lauryl.Preferred alkyl is a methyl.
Among the present invention, term " alkenyl " is meant the alkyl that has 1-20 carbon atom and comprise a carbon-to-carbon double bond at least on any position.The example comprises vinyl, but-2-ene base, suffering-5-thiazolinyl and 12 carbon-2,10-dialkylene.
Among the present invention, term " alkynyl " is meant the alkyl that has 1-20 carbon atom and comprise carbon-to-carbon three key at least on any position.The example comprises acetenyl, 2-butyne base, 5-octyne base and 1,7-diynyl in the last of the ten Heavenly stems.
Among the present invention, term " aryl " is meant aromatic hydrocarbyl.The example comprises phenyl, naphthyl and anthryl.
Among the present invention, term " aralkyl " is meant the aryl alkyl that comprises as the moieties of preceding definition.The example comprises benzyl, phenethyl and 6-naphthyl hexyl.
Among the present invention, term " aromatic yl alkenyl " is meant and comprises as the alkenyl of preceding definition part and as the aryl moiety of the aryl moiety of preceding definition.The example comprise styryl, 3-(benzyl) third-2-thiazolinyl and 6-naphthyl oneself-the 2-thiazolinyl.
Among the present invention, term " cycloalkyl " is meant the alkyl with the carbon atom that is arranged in a ring.The example comprises cyclohexyl, cyclobutyl and cyclo-dodecyl.
Among the present invention, term " cycloalkenyl group " is meant the alkenyl with the carbon atom that is arranged in a ring.The example comprises cyclohexenyl group and 1, and 5-encircles 12 carbon dialkylenes.
Among the present invention, term " bicyclic alkyl " is meant the alkyl with the carbon atom that is arranged in two rings.The example comprises decahydronaphthalenes base, norborneol alkyl and bicyclo-[2.2.2] octyl group.
Among the present invention, term " bicycloenyl " is meant the alkenyl with the carbon atom that is arranged in two rings.The example comprises norbornene and 1,2,3,4,5,6,7,8-octahydro naphthyl.
Among the present invention, term " multi-ring alkyl " is meant the alkyl with the carbon atom that is arranged in three or more rings.
Among the present invention, term " multi-ring thiazolinyl " is meant the alkenyl with the carbon atom that is arranged in three or more rings.
Among the present invention, term " replacement " be meant be selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aromatic yl alkenyl, cycloalkyl, cycloalkenyl group, bicyclic alkyl, bicycloenyl, multi-ring alkyl, multi-ring alkenyl and just like the alkyl of predetermination justice, its one or more hydrogen are replaced by following radicals: alkyl, fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, alkoxyl, acyloxy, alkylthio group, arylthio, acetylamino, amino or nitro.Simultaneously, term " replacement " be meant be selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aromatic yl alkenyl, cycloalkyl, cycloalkenyl group, bicyclic alkyl, bicycloenyl, multi-ring alkyl, multi-ring thiazolinyl and just like the alkyl of predetermination justice, its one or more carbon are replaced by oxygen, sulfur, nitrogen or silicon atom.
Under the situation of quaternized aralkyl or aromatic yl alkenyl, " list-acyloxy replaces " is meant an acyloxy, and it has replaced a hydrogen atom of the aromatic group of aralkyl or aromatic yl alkenyl part.
Among the present invention, term " alkyl-cycloalkyl " is meant the alkyl that comprises alkyl and cycloalkyl.The example comprises 3-methylcyclohexyl and 4-hexyl suberyl.
Among the present invention, term " alkane dicarbapentaborane " is meant that comprises the group of alkyl and two carbonyls as previously mentioned.The example is succinyl group, glutaryl, sebacoyl, 9-methyl isophthalic acid, 11-dicarboxyl undecyl etc.
Among the present invention, term " alkene dicarbapentaborane " is meant the group that comprises at least one carbon-to-carbon double bond and two carbonyls.That the example comprises is fumaroyl, chloro is fumaroyl, 1,3-dicarboxyl acrylic, 1,6-dicarboxyl-3-hexenyl and dodecylene diacyl (1,10-dicarboxyl-2-decene base).
Among the present invention, term " alkynes dicarbapentaborane " is meant the group that comprises at least one carbon-to-carbon three key and two carbonyls.The example comprises 1,2-dicarboxyl propinyl, 1,6-dicarboxyl-2-hexin base etc.
Among the present invention, term " two cycloalkanes dicarbapentaborane " is meant the group that comprises foregoing bicyclic alkyl and two carbonyls.The example comprises 5-norbornane-2,3-dicarbapentaborane, dihydronaphthalene-1,5-dicarbapentaborane and 9,10-dihydro-9,10-ethano-anthracene-11,12-dicarbapentaborane.
Among the present invention, term " two cyclenes dicarbapentaborane " is meant the group that comprises foregoing bicycloenyl and two carbonyls.The example comprises 3, methylene-1,2,3 in the 6-, 6-tetrahydrochysene phthalyl and 1,2,3,4,5,6,7,8-octahydro naphthalene-1,5-dicarbapentaborane.
Among the present invention, term " aromatics dicarbapentaborane " is meant by the aromatic group of two carbonyl substituted.The example comprises phthalyl, terephthaloyl groups, 1,4-dicarboxyl naphthyl etc.
Among the present invention, term " acyloxy " is meant RC (O) O-, and wherein, R is hydrogen or replacement or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, bicyclic alkyl or bicycloenyl.The example comprises acetoxyl group, propionyloxy, 2,3-difluoro butyryl acyloxy, benzoyloxy, cyclopropyl acetoxyl group and chloro acetoxyl group.
Among the present invention, term " tropine " is meant tropine (8-methyl-8-azabicyclic [3.2.1] suffering-3 α-alcohol, also be referred to as α-or interior-tropine), and pseudotropine (8-methyl-8-azabicyclic [3.2.1] suffering-3 β-alcohol, also be referred to as β-or outer-tropine), this depends on the configuration of the hydroxyl that links to each other with the C3 atom of tropine.
Among the present invention, term " Pericarpium Granati alcohol " is meant 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-3 α-alcohol or 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-3 β-alcohol, and term " granatanine " is meant 9-methyl-9-azabicyclic [3.3.1] nonane.Certainly, can recognize that the nitrogen-atoms of tropine and Pericarpium Granati alcohol is by methyl substituted.Therefore, when tropine or Pericarpium Granati alcohol nitrogen is called as when replacing,, be appreciated that nitrogen is quaternary nitrogen, and exist halogenide to be used for charge balance as in N-methyl tropine iodide.
Among the present invention, term " pharmaceutically acceptable anion " is meant that toxic and side effects is very little or do not have, and the anion that the drug effect of drug administration agent is not made significant difference.The example comprises chlorine, bromine, iodine, nitrate anion, sulfate radical, phosphate radical, sulfonate radical, methanesulfonate, benzenesulfonic acid root, tosylate etc.
For chemical compound lot, its various optical isomers, enantiomer and diastereomer are all within the scope of the present invention.All these chemical compounds all can be the mixture of optical isomer, enantiomer and the diastereomer of each structure mutation, comprise all pure compounds and racemic mixture.Comprise cis and trans geometric isomer and mixture.
Synthetic
Below, will the various synthetic routes of preparation The compounds of this invention be described.These routes describe as examples of materials with N-methyl-8-azabicyclic [3.2.1] suffering-3-alcohol (tropine).Equally, can adopt other suitable cyclic amino alkanol.
Synthetic route A
With reference to the reaction equation A of synthetic route A, this process is following carries out.In ice bath, in the 1 normal suitable cooling solution of acyl chlorides (II) in anhydrous methylene chloride, be added dropwise to 2 normal tropines in anhydrous methylene chloride, then, mixture is warming up to room temperature.After pouring into reactant mixture in the cooling water, water layer alkalizes to pH10-11 with the 2N sodium hydrate aqueous solution, uses chloroform extraction.Then, by chromatographic technique diester (III) is carried out purification.
In reaction equation B, the diester (III) behind the 1 normal purification is absorbed in the suitable polar aprotic solvent, as acetone or acetonitrile.Add aralkyl or aromatic yl alkenyl halogenide RX (IV) that 2.5 normal suitable list-acyloxy replace.The solution that forms was heated 6-12 hour down at 50-70 ℃, and this depends on reactant.The quaternary ammonium salt that forms is filtered, through recrystallization purifying.
Synthetic route B
Referring to the reaction equation C of synthetic route 2, in suitable polar non-solute such as acetone or acetonitrile, the 1 normal suitable tropine (I) and the aralkyl halide (IV) of the normal required list of 1-1.25-acyloxy replacement were heated 6-12 hour down at 60-70 ℃.The quaternary ammonium salt (V) that forms is filtered, through recrystallization purifying.
Then, shown in reaction equation D, with 2 normal quaternary ammonium salts (V) and 1 normal suitable two acid ihalides (II) at anhydrous methylene chloride and in hermetic container, react.Each composition is heated down in 80-100 ℃ in hermetic container.Except that after desolvating, residue through recrystallization purifying, is obtained the pure compound of formula a or b.
The chemical compound of formula a of the present invention and b also can be asymmetric diammonium ester.These chemical compounds can be by the preparation of following method: will be no more than aralkyl that 1 normal first kind of list-acyloxy replaces or aromatic yl alkenyl halogenide RX (IV) and 1 normal diester (III) and heat 12 hours down in 60 ℃ in acetone or acetonitrile.In reactant mixture, add aralkyl or the aromatic yl alkenyl halogenide RX (IV) that second kind of list-acyloxy replaces.Then, reactant mixture was heated 12 hours down at 90-100 ℃ again.The precipitate that forms is carried out purification through recrystallization.
The alternative scheme of another kind of synthetic route A is shown in synthetic route C.
Synthetic route C
Also can use other suitable cyclic amino alkanol hydrochloride such as tropine hydrochloride or Pericarpium Granati alcohol hydrochloride.
Practicality
The compound exhibits of formula a and b goes out the remarkable activity as neuromuscular blocking agents.This reagent passes through intravenous administration usually.Administering mode can be single injection, series injection or by venoclysis.The feature of The compounds of this invention is that onset in animal body is rapid and action time short, obviously is better than known and/or commercially available muscle relaxant now.With regard to side effect, chemical compound of the present invention does not in fact almost have tedious cardiovascular side effects, and these side effect are relevant with early stage clinical those succinylcholine, tubocurarine or gallamine as the muscle relaxant prototype.And then these side effect types also are can be comparable with the situation of the reagent of the clinical employing of present prior art.
When it used with other muscle relaxant, dense injecting amount was obvious at the individual patient differences, but usually, was that the basis estimates that dosage is generally the 0.1-1.0mg/kg body weight with the zoopery.Accurate dose should be considered concrete situation, comprises age, sex, weight and patient's health status and required muscular flaccidity degree.
Dosage form can be liquid solution, but direct injection or add in the Intervenous fluid perhaps also can be pressed powder or granule, before use it is dissolved in the solution.Liquid or solid can be prepared by conventional methods.
In clinical preparation, can comprise one or more pharmaceutically acceptable excipient or auxiliary agents, comprise pH regulator agent, stabilizing agent, antiseptic, the essential salt of physiology, sugar etc.
The activity of these chemical compounds can be by any test in the several method.
The practicality of formula a and b chemical compound can adopt rat, rabbit, monkey and/or the pig of anesthesia to test.The shank tendon is linked to each other with pick off.Stimulate suitable nervus motorius, as from bone nerve or common peroneal nerve.The muscle twitch that sensing and record cause.Neuromuscular of the present invention when the intravenously administrable, is reduced the muscle twitch response that stimulates.Measure this reduction relevant with dosage.Similarly, can measure the onset of this effect and continue, and compare with the reagent of known clinical employing.Electromyographic measurement method and mechanical flesh is moving to be traced measurement method and all can adopt.
Can understand the present invention better with reference to following embodiment, these embodiment only are used to illustrate the present invention, but not limiting the scope of the invention.
Following embodiment illustrates synthetic route A
Embodiment 1
Preparation two (granatane (granatan)-3-yl) glutarate
Under-20 ℃, (5.5g 32.6mmol) drips Pericarpium Granati-3-alcohol (10.1g, 65.3mmol) solution in the 20mL dichloromethane in the solution of 50mL dichloromethane to glutaryl chlorine.After stirring 1 hour under 0 ℃, mixture is poured in the 2N sodium hydrate aqueous solution of 100mL, extract with chloroform.Organic layer dried over mgso with after synthetic concentrates.The oil that forms is carried out purification (CHCl through column chromatography
3-MeOH: CHCl
3: NH
4OH=4: 5: 1), obtains two (granatane-3-yl) glutarate of 9.3g (70%), be a kind of toughening oil.
Similarly, adopt following chemical compound to replace glutaryl chlorine:
Malonyl chloride
Succinyl dichloride.
Sulfurous base diethyl acyl chlorides
2-ketone glutaryl chlorine
Adipyl chlorine
Sebacoyl chloride
4,4 '-dithio, two butyl chlorides
1,11-hendecane dicarbapentaborane dichloro
Fumaryl chloride
The chloro fumaryl chloride
Instead-wound healing acyl (traumatyl) chlorine
The acetylene diacid chloride
Instead-and Tetramethylene .-1,2-dicarbapentaborane dichloro
1,3-cyclohexane extraction dicarbapentaborane dichloro
1,1 '-Pentamethylene. diacetyl dichloro
O-phthaloyl chloride
4,5-dichloro o-phthaloyl chloride
Instead-3, methylene-1,2,3 in the 6-, 6-tetrahydrochysene o-phthaloyl chloride
Can obtain:
Two (granatane-3-yl) malonate
Two (granatane-3-yl) succinate
Two (granatane-3-yl) thiodiglycolic acid ester
Two (granatane-3-yl) 2-oxoglutaric acid ester
Two (granatane-3-yl) adipate ester
Two (granatane-3-yl) sebacate
Two (granatanes-3-yl) 4,4 '-dithio dibutyrate
Two (granatanes-3-yl) 1,11-hendecane dicarboxylic acid esters
Two (granatane-3-yl) fumarate
Two (granatane-3-yl) chlorofumaric acid ester
Two (granatanes-3-yl) are anti--the wound healing acid esters
Two (granatane-3-yl) acetylene two acid esters
Two (granatane-3-yl) Tetramethylene .-1, the 2-dicarboxylic ester
Two (granatane-3-yl) cyclohexane extraction-1, the 3-dicarboxylic ester
Two (granatane-3-yl) Pentamethylene .-1,1 '-diacetate esters
Two (granatane-3-yl) phthalic acid ester
Two (granatanes-3-yl) 4,5-dichloro phthalic acid ester
Two (granatanes-3-yl) are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester
Similarly, the cyclic amino alkanol of indicated other replaces Pericarpium Granati alcohol as raw material and listed acyl chlorides among formula a and the b by replacing, and can obtain corresponding dicarboxylic esters.
Embodiment 2 preparations two-[N-(4-acetoxyl group benzyl) granatanine (granatanium)-3-yl]
The glutarate dibromide
With two (granatane-3-yl) glutarate (4.0g; 9.85mmol) and 4-acetoxyl group benzyl bromide a-bromotoluene (5.0g; 21.7mmol; by the acetylization reaction of 4-hydroxy benzaldehyde through oh group; aldehyde is reduced into corresponding alcohol, and carries out bromination and obtain) solution in 100mL acetone is in 60 ℃ of heating 10 hours down.Filter collecting precipitation, with acetone and ether washing, vacuum drying; Obtain two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide of 7.5g (83%), be a kind of powder of white.
Similarly, replace 4-acetoxyl group benzyl bromide a-bromotoluene with following chemical compound:
2-acetoxyl group benzyl bromide a-bromotoluene
3-acetoxyl group benzyl bromide a-bromotoluene
4-propionyloxy benzyl bromide a-bromotoluene
2-butyryl acyloxy benzyl bromide a-bromotoluene
3-benzoyloxy benzyl bromide a-bromotoluene
4-acetoxyl group phenethyl bromide
3-(4-acetoxyl group phenyl) propylene-2-base bromine
4-acetoxyl group-1-naphthyl methyl bromine,
Can make:
Two [N-(2-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide
Two [N-(3-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide
Two [N-(4-propionyloxy benzyl) granatanine-3-yl] glutarate dibromide
Two [N-(2-butyryl acyloxy benzyl) granatanine-3-yl] glutarate dibromide
Two [N-(3-benzoyloxy benzyl) granatanine-3-yl] glutarate dibromide
Two [N-(4-acetoxyl group phenethyl) granatanine-3-yl] glutarate dibromide
Two [N-(3-(4-acetoxyl group phenyl) propylene-2-yl) granatanine-3-yl] glutarate dibromide
Two [N-(4-acetoxyl group-1-naphthyl methyl) granatanine-3-yl] glutarate dibromide.
Those skilled in the art will appreciate that two kinds of equal replaceables of raw material.For example, if 3-propionyloxy benzyl bromide a-bromotoluene replaces 4-acetoxyl group benzyl bromide a-bromotoluene, with two (tropine-3-yl) glutarate, two (tropine-3-yl) sebacate and two (tropine-3-yl) Tetramethylene .-1, the 2-dicarboxylic ester replaces two (granatane-3-yl) glutarate, then can obtain: two [N-(3-propionyloxy benzyl) tropine (tropanium)-3-yl] glutarate dibromide, two-[N-(3-propionyloxy benzyl) tropine-3-yl] sebacate dibromide and two [N-(3-propionyloxy benzyl) tropine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide.
Following embodiment illustrates synthetic route B.
Embodiment 3
Preparation N-(4-propionyloxy benzyl) tropine chloride
The tropine of 7.1g (50mmol) and the mixture of 4-propionyloxy benzyl chloride in 200mL acetone of 11.9g (60mmol) were heated 10 hours down in 60-70 ℃.Leach precipitation, washing, and recrystallization (ethanol-dichloromethane) obtains N-(4-propionyloxy benzyl) the tropine chloride of 14.4g (85%), is a kind of white powder.
Similarly, by replacing:
4-acetoxyl group benzyl chloride
2-butyryl acyloxy phenethyl chlorine
3-(3-acetoxyl group phenyl) propyl bromide
4-(diphenyl acetoxyl group) benzyl bromide a-bromotoluene
Can obtain:
N-(4-acetoxyl group benzyl) tropine chloride
N-(2-butyryl acyloxy benzyl) tropine chloride
N-(3-(3-acetoxyl group phenyl) propyl group) tropine bromide
N-(4-(diphenyl acetoxyl group) benzyl) tropine bromide
Chloride
With N-(4-propionyloxy benzyl) tropine chloride (13.0g, 38.3mmol) and the Tetramethylene .-1 of 3.17g (17.5mmol), 2-dicarbapentaborane dichloro in the 100mL anhydrous methylene chloride in sealed tube 100 ℃ of heating 12 hours down.After in refrigerative reactant mixture, adding 5mL methanol, solvent is removed through rotary evaporator.Product is carried out recrystallization purifying with methanol-dichloromethane; Obtain two [N-(4-propionyloxy benzyl) tropine-3-yl] Tetramethylene .-1 of 16.9g (50%), 2-dicarboxylic ester dichloride.
Similarly, by replacing:
N-(4-acetoxyl group benzyl) tropine chloride
N-(2-butyryl acyloxy benzyl) tropine chloride
N-(3-(3-acetoxyl group phenyl) propyl group) tropine bromide
N-(4-(diphenyl acetoxyl group) benzyl) tropine bromide
Can obtain:
Two [N-(4-acetoxyl group benzyl) tropine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dichloride
Two [N-(2-butyryl acyloxy benzyl) tropine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dichloride
Two [N-(3-(3-acetoxyl group phenyl) propyl group) tropine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide
Two [N-(4-(diphenyl acetoxyl group) tropine-3-yl) Tetramethylene .-1,2-dicarboxylic ester dibromide.
Following embodiment illustrates the preparation process of asymmetric diammonium ester.
Product-3-yl] the glutarate dibromide.
The 4-acetoxyl group benzyl bromide a-bromotoluene that in two (tropine-3-yl) the glutarate solution in the 500mL anhydrous propanone of the 18.9g (50mmol) in airtight bottle, adds 11.5g (50mmol).Mixture after 5 hours, is being added the 2-propionyloxy benzyl bromide a-bromotoluene of 12.1g (50mmol) in heating under 50 ℃ in refrigerative mixture.Then, with mixture 70-75 ℃ of following reheat 10 hours.Filter and collect the white precipitate that forms, carry out recrystallization purifying with methanol-dichloromethane, obtain 12.7g (30%) [N-(4-acetoxyl group benzyl) tropine-3-yl], [N-(2-propionyloxy benzyl) tropine-3-yl] glutarate dibromide is a kind of white powder.
Similarly, by replacing 4-acetoxyl group phenethyl bromide and 2-propionyloxy benzyl bromide a-bromotoluene with 3-acetoxyl group phenethyl bromide and 4-benzoyloxy benzyl bromide a-bromotoluene respectively, can obtain [N-(3-acetoxyl group phenethyl) tropine-3-yl], [N-(4-benzoyloxy benzyl) tropine-3-yl] glutarate dibromide.
Following embodiment illustrates synthetic route C.
Embodiment 6
Preparation two [quinuclidine-3-table] sebacate
In sealed tube, to sebacoyl chloride (4.78g.20.0mmol) in the solution of 40mL dichloromethane, add 3-quinuclidinol hydrochloride (7.85g, 48.0mmol).With multiphase mixture 80 ℃ of following heated overnight.After the cooling, mixture is poured in the 2N sodium hydrate aqueous solution of 100mL, extracted with chloroform.Organic layer dried over mgso after synthetic concentrates.With the oil silica gel chromatography (silica gel, the chloroformic solution of 10% methanol) that forms, obtain two [quinuclidine-3-yl] sebacate of 6.7g (80%), be a kind of toughening oil.
Embodiment 7
Preparation two " N-(4-propionyloxy benzyl) quinuclidine-3-yl] the sebacate dibromide
In sealed tube, (2.5g, 5.95mmol) (3.18g, 13.1mmol) solution in 50mL acetone heated 5 hours down in 60 ℃ with 4-propionyloxy benzyl bromide a-bromotoluene with two [quinuclidine-3-yl] sebacate.The white solid that collection leaches (4.5g, 84%), drying is 1 hour under vacuum.
Similarly,, can prepare other a few class symmetries and asymmetric bi-quaternary ammonium salt of formula 1/a and 1/b by suitably selecting raw material, for example:
[N-ethyl, N-(4-acetoxyl group benzyl) is nor--granatanine-the 3-yl], [N-ethyl, N-(3-benzoyloxy benzyl) is nor--granatanine-the 3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide, two [N-(2-propionyloxy benzyl) quinuclidine-3-yl] m benzene dicarboxylic acid ester dibromide, two [N-(4-propionyloxy phenethyl) 1,2,6-trimethyl-piperidine-4-yl] thioglycol acid esters dibromide.
Embodiment 8
The interior animal experiment of neuromuscular blocking agents biologic activity
Adopt neuromuscular activity (main pharmacotoxicological effect) and other effect (for example cardiovascular side effects) of different these reagent of Animal Experimental Study.The explanation of this research is based on the known fact, and there were significant differences for the drug effect of these reagent and pharmacokinetics character.Therefore, the onset of most important aspect such as neuromuscular effect, effect and continue and side effect can not or only adopt a kind of animal to determine in " external " preparation in the treatment practicality of these reagent.
At first, in the rat that is used for measuring the neuromuscular effect " screening " experiment, study new material of the present invention carefully, subsequently, the chemical compound of selecting is carried out concrete effect experiment, reach side effect other animal species such as rabbit and pig as onset, acting duration.
It below is the explanation that is used for the method for rat and pig; These methods also are used for other animal when needed.
A) make bull albinism rat anesthesia through the peritoneal injection pentobarbital.Conduit inserted in the trachea carry out artificial ventilation through the meiofauna respirator.Inserting conduit on the carotid artery through sensor record blood pressure and the cardiotachometer recorded heart rate on polygraph.In external jugular vein, insert conduit and carry out administration.Monitor neuromuscular function by electromyography, record is by the response of arousing that continues preceding tibia muscle that the list of 0.1-0.2 millisecond or super large nerve stimulation that " one group four (train-of-four) " rectangular pulse is formed cause every 10-12 second, and described pulse is sent to sciatic nerve or common peroneal nerve by the laboratory nerve stimulator.Another kind of stimulation mode is included in 0.1Hz or the 1Hz single stimulation of repetition of transmission down.Stimulate the neck vagus nerve and measure the possible blocking effect of bradycardia that vagus nerve is caused and evaluate cardiac vagal blocking-up by the periphery as the side effect of several muscle relaxants.Agent dissolves in normal saline, and is carried out intravenous injection at reasonable time at interval.Every kind of reagent is measured intensity, onset and lasting and the type of its neuromuscular.By several dosed administrations, measure dosage corresponding to 50%, 80% and/or 90% neuromuscular.All reagent and standard neuromuscular chemical compound compare, as succinylcholine, handkerchief oolong, Mivacron or Luo Ku ammonium.
B) mixture with the ethylurethan of the α chloralose of 70mg/kg and 0.5g/kg makes the heavy Duroc piglet anesthesia of 10-12kg through peritoneal injection.Adopt the probe electrode of shielding to stimulate sciatic nerve, the record muscle response.Through pressure transducer and cardiotachometer tremulous pulse recording blood pressure and changes in heart rate from suitable insertion conduit.
The result that a large amount of chemical compound of measuring respectively in rat, rabbit, pig and monkey of the present invention is obtained is shown in following table 1-4, wherein:
ED
50=cause the intravenous dosages of 50% neuromuscular, μ g/kg.
The onset time=time of 80-85% neuromuscular, minute.
The index of recovery of RI=25-75% neuromuscular response, minute, recover naturally.
Vagal nerve interruption during VB=80-85% neuromuscular blocking agents amount, %.
Arteriotony rate of change during BP=80-85% neuromuscular blocking agents amount, %.
Changes in heart rate rate during HR=80-85% neuromuscular blocking agents amount, %.
Number=laboratory animal number.
When all zooperies combine when considering, new muscle relaxant wants rapid-action 2-10 doubly with relatively comparing with chemical compound, continues short 2-10 doubly.Fig. 1 has illustrated the neuromuscular effect to rat of two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide and two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide and Luo Ku ammonium of the prior art, Mivacron and two [N-(4-methoxy-benzyl) tropine-3 α-yl] glutarate dibromide.Also shown in time and changed (minute) muscular flaccidity response and blood pressure response.
Those skilled in the art it will be understood that the particular form that can be embodied as other under spirit of the present invention or the essence not deviating from.In foregoing description of the present invention, the embodiment of illustrative is only disclosed, be appreciated that and in protection domain of the present invention, can consider various other variations.Therefore, the present invention is not subjected to the restriction of these specific embodiments, and they only are used to illustrate in greater detail the present invention.Protection scope of the present invention is that the claim by the application limits.
Table 1
| Rat | ??ED50 | Onset | ???RI | ??VB | ??ΔBP | ??ΔHR | Number |
| Noval chemical compound: | |||||||
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ??355 | ??0.9 | ??1.2 | ??16 | ???-5 | ???+2 | ???5 |
| Two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ??217 | ??0.9 | ??2.2 | ??78 | ???0 | ???+4 | ???5 |
| Two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ??313 | ??1.3 | ??2.3 | ??60 | ???-3 | ????0 | ???5 |
| Two [N-(4-propionyloxy benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ??412 | ??0.9 | ??1.0 | ??27 | ???-5 | ????0 | ???4 |
| Two [N-(4-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ??143 | ??1.2 | ??1.5 | ??16 | ???-5 | ????0 | ???4 |
| Two [N-(3-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ??168 | ??1.2 | ??1.8 | ??50 | ????0 | ????0 | ???3 |
| Two [N-(2-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ??258 | ??1.2 | ??2.0 | ??77 | ????0 | ???+4 | ???4 |
| Two [N-(4-propionyloxy benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ??169 | ??1.3 | ??1.2 | ??36 | ???-5 | ????0 | ???4 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide | ??300 | ??0.95 | ??1.1 | ??15 | ????0 | ????0 | ???3 |
| Two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide | ??400 | ??1.1 | ??1.6 | ??75 | ???-3 | ???-1 | ???3 |
| Two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide | ??485 | ??1.0 | ??1.4 | ??70 | ???-12 | ???-5 | ???3 |
| Two [N-(4-propionyloxy benzyl) tropine-3 α-yl] glutarate dibromide | ??510 | ??1.0 | ??1.0 | ??56 | ???-2 | ???+2 | ???3 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide | ??188 | ??0.9 | ??1.1 | ??41 | ???-4 | ????0 | ???4 |
| Two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide | ??190 | ??1.1 | ??1.6 | ??77 | ???-3 | ????4 | ???4 |
| Two (the adipate ester dibromide of N-(2-acetoxyl group benzyl) tropine-3 α-yl) | ??325 | ??0.9 | ??1.0 | ??64 | ???-10 | ????0 | ???4 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] fumarate dibromide | ??904 | ??1.4 | ??1.7 | ??45 | ???-3 | ????0 | ???4 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] succinate dibromide | ??67 | ??0.55 | ??0.45 | ??30 | ????0 | ????0 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide | ??115 | ??0.63 | ??0.45 | ??0 | ????0 | ????0 | ???5 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] glutarate dibromide | ??94 | ??0.66 | ??0.45 | ??8 | ????0 | ???+2 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ????98 | ???0.65 | ???0.45 | ??6 | ???0 | ???0 | ???5 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ????241 | ???0.73 | ???0.60 | ??15 | ???0 | ??+2.5 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] adipate ester dibromide | ????111 | ???0.8 | ???0.5 | ??25 | ???0 | ????0 | ???6 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] thiodiglycolic acid ester dibromide | ????311 | ???0.7 | ???0.5 | ??48 | ???+2 | ????0 | ???5 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] thiodiglycolic acid ester dibromide | ????240 | ???0.75 | ???0.6 | ??55 | ???-2 | ???+2 | ???6 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] fumarate dibromide | ????195 | ???1.0 | ???0.75 | ??0 | ???0 | ????0 | ???4 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] fumarate dibromide | ????353 | ???1.0 | ???0.6 | ??0 | ???0 | ????0 | ???3 |
| Two [N-(4-propionyloxy benzyl) quinuclidine-3-yl] sebacate dibromide | ????800 | ???1.1 | ???1.4 | ??80 | ???-10 | ???+3 | ???3 |
| Two [N-(4-acetoxyl group benzyl) quinuclidines-3-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ????1200 | ???1.4 | ???2.5 | ??100 | ???0 | ????0 | ???4 |
| Two [N-(4-propionyloxy benzyl) quinuclidines-3-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ????1050 | ???1.7 | ???2.3 | ??100 | ???0 | ????0 | ???4 |
| Comparative compound: | |||||||
| The Luo Ku ammonium | ????450 | ???1.0 | ???1.3 | ??60 | ???0 | ????0 | ???7 |
| Mivacron | ????140 | ???1.8 | ???3.9 | ??0 | ???0 | ????0 | ???8 |
| Atracurium | ????320 | ???1.5 | ???2.9 | ??0 | ???0 | ????0 | ???5 |
| Two [N-methyl tropine-3 α-yl] glutarate diiodide | ????2000 | ???1.2 | ???4.2 | ??100 | ???0 | ????0 | ???4 |
| Two [N-benzyl tropine-3 α-yl] glutarate dibromide | ????5500 | ???2.5 | ???3.7 | ??100 | ???-10 | ????0 | ???4 |
| Two [N-(2-bromobenzyl) tropine-3 α-yl] glutarate dibromide | ????1400 | ???2.3 | ???3.6 | ??100 | ???-9 | ????0 | ???5 |
| Two [N-(4-methoxy-benzyl) tropine-3 α-yl] glutarate dibromide | ????1200 | ???1.1 | ???1.6 | ??85 | ???-4 | ???-3 | ???3 |
| Two [N-(4-methyl-benzyl) tropine-3 α-yl] glutarate dibromide | ????1000 | ???1.0 | ???1.6 | ??85 | ???-8 | ???-4 | ???3 |
| Two [N-(3-benzyl chloride base) tropine-3 α-yl] glutarate dibromide | ????900 | ???1.1 | ???1.8 | ??100 | ???-11 | ????0 | ???3 |
(continuous table 1)
Table 2
| Rabbit | ??ED50 | Onset | ????RI | ??ΔBP | ??ΔHR | Number |
| Noval chemical compound: | ||||||
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???57 | ???1.6 | ????1.6 | ????0 | ???-3 | ???5 |
| Two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???38 | ???2.4 | ????4.6 | ????0 | ???-3 | ???4 |
| Two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???67 | ???2.1 | ????3.8 | ???+4 | ???-15 | ???4 |
| Two [N-(4-propionyloxy benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???79 | ???1.7 | ????1.7 | ???+3 | ???-8 | ???4 |
| Two [N-(4-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???95 | ???1.4 | ????1.4 | ???+5 | ???-24 | ???4 |
| Two [N-(3-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???63 | ???2.1 | ????3.8 | ???+2 | ???-20 | ???4 |
| Two [N-(2-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???95 | ???2.1 | ????3.3 | ???+2 | ???-12 | ???4 |
| Two [N-(4-propionyloxy benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???53 | ???1.3 | ????1.2 | ???+5 | ???-6 | ???4 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide | ???30 | ???1.7 | ????2.2 | ??+10 | ???-15 | ???2 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide | ???30 | ???1.7 | ????2.1 | ????0 | ???-4 | ???3 |
| Two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide | ???60 | ???2.2 | ????3.7 | ????0 | ????0 | ???2 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide | ???75 | ???1.0 | ????0.9 | ???+7 | ????0 | ???4 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] glutarate dibromide | ???107 | ???1.0 | ????0.9 | ????0 | ???-5 | ???4 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???70 | ???1.0 | ????1.2 | ????0 | ????0 | ???4 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???95 | ???0.9 | ????0.8 | ???+1 | ???-9 | ???4 |
| Two [N-(4-propionyloxy benzyl) quinuclidine-3-yl] sebacate dibromide | ???180 | ???2.5 | ????4.2 | ????0 | ????0 | ???2 |
| Comparative compound: | ||||||
| The Luo Ku ammonium | ???30 | ???1.1 | ????2.4 | ????0 | ????0 | ???7 |
| Mivacron | ???20 | ???2.8 | ????3.9 | ????0 | ????0 | ???4 |
| Atracurium | ???30 | ???2.7 | ????5.7 | ????0 | ????0 | ???7 |
| Two [N-benzyl tropine-3 α-yl] sebacate dibromide | ???75 | ???2.3 | ????6.0 | ????0 | ????0 | ???2 |
| Two [N-ethyl tropine-3 α-yl] adipate ester diiodide | ???150 | ???2.2 | ????9.0 | ????0 | ????0 | ???2 |
Table 3
| Pig | ??ED50 | Onset | ???RI | ???VB | ?ΔBP | ??ΔHR | Number |
| Noval chemical compound: | |||||||
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???380 | ???1.1 | ??1.5 | ???28 | ???0 | ???+7 | ????3 |
| Two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???261 | ??1.35 | ??4.5 | ???89 | ???0 | ???+9 | ????3 |
| Two [N-(4-propionyloxy benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???478 | ???1.1 | ??1.4 | ???50 | ???0 | ???+8 | ????3 |
| Two [N-(4-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???220 | ???1.3 | ??1.4 | ???48 | ???0 | ???+5 | ????3 |
| Two [N-(4-propionyloxy benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide | ???290 | ???1.2 | ??1.3 | ???57 | ???0 | ???+7 | ????3 |
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide | ???400 | ???1.5 | ??2.1 | ???80 | ???0 | ???+10 | ????2 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide | ???158 | ??0.85 | ??0.8 | ???37 | ???0 | ???+3 | ????3 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] glutarate dibromide | ???142 | ??0.85 | ??0.85 | ???37 | ???0 | ???+6 | ????3 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???113 | ???1.0 | ??1.0 | ???34 | ???0 | ???+3 | ????3 |
| Two [N-(4-propionyloxy benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide | ???128 | ??0.95 | ??0.7 | ???37 | ???0 | ???+8 | ????3 |
| Comparative compound: | |||||||
| The Luo Ku ammonium | ???350 | ???1.5 | ??3.2 | ???47 | ???0 | ????0 | ????7 |
| Atracurium | ???135 | ???1.5 | ??3.6 | ???17 | ???0 | ????0 | ????10 |
| Two [N-(amyl group) tropine-3 α-yl] sebacate dibromide | ???300 | ???2.0 | ??6.9 | ???50 | ???0 | ????0 | ????4 |
| Two [N-(3-(phenyl) third-2-thiazolinyl) tropines-3 α-yl] 1,10-decane dicarboxylic acid esters dibromide | ???170 | ???1.6 | ??6.4 | ???27 | ???0 | ???-10 | ????4 |
Table 4
| Monkey | ??ED50 | Onset | ????RI | ?ΔBP | ?ΔHR | Number |
| Noval chemical compound | ||||||
| Two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide | ???61 | ????1.2 | ????1.6 | ???0 | ???0 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] succinate dibromide | ???44 | ???0.85 | ????0.6 | ???0 | ???0 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide | ???54 | ????0.9 | ????0.6 | ???0 | ???0 | ???5 |
| Two [N-(4-acetoxyl group benzyl) granatanine-3-yl] adipate ester dibromide | ???46 | ????0.9 | ????0.6 | ???0 | ???0 | ???5 |
| Comparative compound: | ||||||
| The Luo Ku ammonium | ???34 | ????1.9 | ????2.4 | ???0 | ???0 | ???3 |
| Mivacron | ???13 | ????3.5 | ????5.6 | ???0 | ???0 | ???6 |
| Atracurium | ??186 | ????3.0 | ????7.5 | ???0 | ???0 | ???6 |
Claims (15)
1. the chemical compound of a following formula
Wherein, R
1And R
1' be aralkyl or the aromatic yl alkenyl that list-acyloxy replaces; R
2And R
2' be alkyl, alkenyl or alkynyl; A is alkane dicarbapentaborane, alkene dicarbapentaborane, alkynes dicarbapentaborane, cycloalkanes dicarbapentaborane, cyclenes dicarbapentaborane, two cycloalkanes dicarbapentaborane, two cyclenes dicarbapentaborane, polynaphthene dicarbapentaborane, multi-ring alkene dicarbapentaborane or the aromatics dicarbapentaborane that does not replace or replace; N is 0,1 or 2; M is 0,1 or 2; P is 0,1 or 2; R
3And R
3' be H, CH
3Or low alkyl group; R
4And R
4' be H, CH
3Or low alkyl group; R
3And R
4Also can be altogether-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Or R
3' and R
4' also can be altogether-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Wherein, R
1And R
1', R
2And R
2', R
3And R
3' and R
4And R
4' can be identical or different; X is pharmaceutically acceptable anion.
2. according to the chemical compound of claim 1, wherein, R
3And R
4Together formation-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; And R
3' and R
4' together formation-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3.
3. according to the chemical compound of claim 2, wherein, R
1With R
1' identical, R
2With R
2' identical, R
3With R
3' identical, R
4With R
4' identical.
4. according to the chemical compound of claim 3; wherein A be selected from oxalyl group, malonyl, succinyl group, glutaryl, adipyl, heptanedioyl group, octanedioyl, nonanedioyl, sebacoyl, fumaroyl, chloro is fumaroyl, anti--3; methylene-1 in the 6-; 2; 3,6-tetrahydrochysene phthalyl, 1,9-nonane dicarbapentaborane, Tetramethylene .-1; 2-dicarbapentaborane and cyclohexane extraction-1, the 3-dicarbapentaborane.
5. according to the chemical compound of claim 4, wherein, A is selected from Tetramethylene .-1,2-dicarbapentaborane, anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrochysene phthalyl, glutaryl, adipyl and fumaroyl; R
1With R
1' identical, be the aralkyl of acyloxy replacement; R
2With R
2' identical, be methyl; N and m=1; R
3And R
4Be together-(CH
2)
2-; R
3' and R
4' be together-(CH
2)
2-.
6. according to the chemical compound of claim 5, it is selected from:
-two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide;
-two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide;
-two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide;
-two [N-(4-propionyloxy benzyl) tropine-3 α-yl] Tetramethylene .-1,2-dicarboxylic ester dibromide;
-two [N-(4-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide;
-two [N-(3-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide;
-two [N-(2-acetoxyl group benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide;
-two [N-(4-propionyloxy benzyl) tropines-3 α-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide;
-two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide;
-two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide;
-two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] glutarate dibromide;
-two [N-(4-propionyloxy benzyl) tropine-3 α-yl] glutarate dibromide;
-two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide;
-two [N-(3-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide;
-two [N-(2-acetoxyl group benzyl) tropine-3 α-yl] adipate ester dibromide;
-two [N-(4-propionyloxy benzyl) tropine-3 α-yl] adipate ester dibromide; With
-two [N-(4-acetoxyl group benzyl) tropine-3 α-yl] fumarate dibromide.
7. according to the chemical compound of claim 4, wherein A is selected from succinyl group, glutaryl, Tetramethylene .-1,2-dicarbapentaborane, adipyl, thiodiglycol and fumaroyl; Wherein, R
1With R
1' identical, be the aralkyl of acyloxy replacement; R
2With R
2' identical, be methyl; N and m=1; R
3And R
4Be together-(CH
2)
3-; R
3' and R
4'-rise is-(CH
2)
3-.
8. according to the chemical compound of claim 7, it is selected from:
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] succinate dibromide;
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] glutarate dibromide;
-two [N-(4-propionyloxy benzyl) granatanine-3-yl] glutarate dibromide;
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic acid esters dibromide;
-two [N-(4-propionyloxy benzyl) granatanine-3-yl] Tetramethylene .-1,2-dicarboxylic acid esters dibromide;
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] adipate ester dibromide;
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] thiodiglycolic acid ester dibromide;
-two [N-(4-propionyloxy benzyl) granatanine-3-yl] thiodiglycolic acid ester dibromide;
-two [N-(4-acetoxyl group benzyl) granatanine-3-yl] fumarate dibromide; With
-two [N-(4-propionyloxy benzyl) granatanine-3-yl] fumarate dibromide.
9. according to the chemical compound of claim 13, wherein, R
1With R
1' identical, be the aralkyl of acyloxy replacement; A is selected from malonyl, succinyl group, glutaryl, 1,1 '-cyclohexyl diacetyl, sebacoyl, fumaroyl or anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrochysene phthalyl; N=1, and p=2, m=0; R
3And R
4Be together-(CH
2)
2-; And R
3' and R
4' be together-(CH
2)
2-.
10. according to the chemical compound of claim 9, it is selected from:
-two [N-(4-propionyloxy benzyl) quinuclidine-3-yl] sebacate dibromide;
-two [N-(4-acetoxyl group benzyl) quinuclidines-3-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide; With
-two [N-(4-propionyloxy benzyl) quinuclidines-3-yl] are anti--3, methylene-1,2,3 in the 6-, 6-tetrahydrophthalic acid ester dibromide.
11. one kind makes patient's method of flaccid muscles, comprises the chemical compound of the claim 1 of effective dosage.
12. a pharmaceutical composition, it comprises chemical compound and pharmaceutically suitable carrier of the claim 1 of effective dose.
13. the chemical compound of a following formula
Wherein, R
1And R
1' be aralkyl or the aromatic yl alkenyl that list-acyloxy replaces; R
2And R
2' be alkyl, alkenyl or alkynyl; A is alkane dicarbapentaborane, alkene dicarbapentaborane, alkynes dicarbapentaborane, cycloalkanes dicarbapentaborane, cyclenes dicarbapentaborane, two cycloalkanes dicarbapentaborane, two cyclenes dicarbapentaborane, polynaphthene dicarbapentaborane, multi-ring alkene dicarbapentaborane or the aromatics dicarbapentaborane that does not replace or replace; N is 0,1 or 2; M is 0,1 or 2; P is 0,1 or 2; R
3And R
3' be H, CH
3Or low alkyl group; R
4And R
4' be H, CH
3Or low alkyl group; Perhaps R
3And R
4Together formation-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
, wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Or R
3' and R
4' together formation-CH=CH-,-(CH
2)
h-Y-(CH
2)
k-or
Wherein, Y is CH
2, O or S, h is 0,1,2 or 3, k is 0,1,2 or 3; Wherein, R
1And R
1', R
2And R
2', R
3And R
3' and R
4And R
4' can be identical or different; X is pharmaceutically acceptable anion.
14. a pharmaceutical composition, it comprises chemical compound and pharmaceutically suitable carrier of the claim 13 of effective dose.
15. one kind makes patient's method of flaccid muscles, comprises the chemical compound of the claim 13 of effective dosage.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11839299P | 1999-02-01 | 1999-02-01 | |
| US60/118,392 | 1999-02-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1338934A true CN1338934A (en) | 2002-03-06 |
Family
ID=22378296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00803305A Pending CN1338934A (en) | 1999-02-01 | 2000-01-31 | Mono-acyloxy aralkyl neuronuscular relaxants |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1150673A4 (en) |
| JP (1) | JP2002535366A (en) |
| KR (1) | KR20010108125A (en) |
| CN (1) | CN1338934A (en) |
| AR (1) | AR022472A1 (en) |
| AU (1) | AU2634900A (en) |
| BR (1) | BR0007863A (en) |
| CA (1) | CA2360790A1 (en) |
| CO (1) | CO5170470A1 (en) |
| CZ (1) | CZ20012780A3 (en) |
| HK (1) | HK1039455A1 (en) |
| HU (1) | HUP0200413A3 (en) |
| IL (1) | IL144249A0 (en) |
| MX (1) | MXPA01007783A (en) |
| NO (1) | NO20013741L (en) |
| NZ (1) | NZ513064A (en) |
| PE (1) | PE20001593A1 (en) |
| PL (1) | PL349099A1 (en) |
| TR (1) | TR200102196T2 (en) |
| WO (1) | WO2000044377A1 (en) |
| ZA (1) | ZA200105882B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0204087D0 (en) * | 2002-02-21 | 2002-04-10 | Legislator 1563 Ltd | Di-ester derivatives as short acting neuromuscular blockers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2746964A (en) * | 1953-11-02 | 1956-05-22 | Lakeside Lab Inc | Dicarboxylic acid esters of nu-alkyl-3-hydroxypiperidine and salts thereof |
| AT292702B (en) * | 1968-12-29 | 1971-09-10 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of new N-methyl-piperidine derivatives and the acid addition salts and the onium derivatives of these compounds |
| US5494898A (en) * | 1991-02-13 | 1996-02-27 | Ohmeda Pharmaceutical Products Division Inc. | Peptide skeletal muscle relaxants |
| US5990124A (en) * | 1997-10-24 | 1999-11-23 | Gyermek; Laszlo | Neuromuscular relaxants |
-
2000
- 2000-01-31 MX MXPA01007783A patent/MXPA01007783A/en unknown
- 2000-01-31 AU AU26349/00A patent/AU2634900A/en not_active Abandoned
- 2000-01-31 CZ CZ20012780A patent/CZ20012780A3/en unknown
- 2000-01-31 EP EP00904621A patent/EP1150673A4/en not_active Withdrawn
- 2000-01-31 IL IL14424900A patent/IL144249A0/en unknown
- 2000-01-31 CA CA002360790A patent/CA2360790A1/en not_active Abandoned
- 2000-01-31 JP JP2000595680A patent/JP2002535366A/en not_active Withdrawn
- 2000-01-31 KR KR1020017009305A patent/KR20010108125A/en not_active Application Discontinuation
- 2000-01-31 CN CN00803305A patent/CN1338934A/en active Pending
- 2000-01-31 TR TR2001/02196T patent/TR200102196T2/en unknown
- 2000-01-31 WO PCT/US2000/002228 patent/WO2000044377A1/en active Search and Examination
- 2000-01-31 HU HU0200413A patent/HUP0200413A3/en unknown
- 2000-01-31 PL PL00349099A patent/PL349099A1/en not_active Application Discontinuation
- 2000-01-31 PE PE2000000069A patent/PE20001593A1/en not_active Application Discontinuation
- 2000-01-31 NZ NZ513064A patent/NZ513064A/en unknown
- 2000-01-31 BR BR0007863-8A patent/BR0007863A/en not_active IP Right Cessation
- 2000-02-01 CO CO00005913A patent/CO5170470A1/en not_active Application Discontinuation
- 2000-02-01 AR ARP000100432A patent/AR022472A1/en not_active Application Discontinuation
-
2001
- 2001-07-17 ZA ZA200105882A patent/ZA200105882B/en unknown
- 2001-07-31 NO NO20013741A patent/NO20013741L/en not_active Application Discontinuation
-
2002
- 2002-02-08 HK HK02100995.3A patent/HK1039455A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002535366A (en) | 2002-10-22 |
| KR20010108125A (en) | 2001-12-07 |
| EP1150673A1 (en) | 2001-11-07 |
| WO2000044377A1 (en) | 2000-08-03 |
| PL349099A1 (en) | 2002-07-01 |
| HUP0200413A3 (en) | 2002-11-28 |
| HK1039455A1 (en) | 2002-04-26 |
| AR022472A1 (en) | 2002-09-04 |
| ZA200105882B (en) | 2003-02-18 |
| PE20001593A1 (en) | 2001-01-16 |
| EP1150673A4 (en) | 2002-04-24 |
| NO20013741L (en) | 2001-09-19 |
| TR200102196T2 (en) | 2002-01-21 |
| MXPA01007783A (en) | 2002-08-20 |
| NZ513064A (en) | 2003-08-29 |
| AU2634900A (en) | 2000-08-18 |
| BR0007863A (en) | 2001-11-06 |
| CO5170470A1 (en) | 2002-06-27 |
| NO20013741D0 (en) | 2001-07-31 |
| CZ20012780A3 (en) | 2002-01-16 |
| HUP0200413A2 (en) | 2002-06-29 |
| IL144249A0 (en) | 2002-05-23 |
| CA2360790A1 (en) | 2000-08-03 |
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