CN1085214A - Tetrahydrochysene one and perhydro isoquinilone derivatives and the therapeutic composition that contains these compounds - Google Patents

Tetrahydrochysene one and perhydro isoquinilone derivatives and the therapeutic composition that contains these compounds Download PDF

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CN1085214A
CN1085214A CN93107318A CN93107318A CN1085214A CN 1085214 A CN1085214 A CN 1085214A CN 93107318 A CN93107318 A CN 93107318A CN 93107318 A CN93107318 A CN 93107318A CN 1085214 A CN1085214 A CN 1085214A
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B·海伦达尔
F·勒尔
M·拉沙克
R·施列克
M·齐普利斯
M·哈夫纳
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

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Abstract

A kind of oral pharmaceutical that contain the acid salt that on the compound of the racemize of the formula I of the every individually dosed 10～1000mg of being as active substance of medicinal adjuvant commonly used or II or isolating enantiomorph and their physiology, allows, active compound itself, they are new contents.
Wherein:
W is carbonyl or singly-bound;
R 1Be hydrogen or R 3CO, wherein R 3Be low alkyl group, lower alkoxy, single rudimentary-alkylamino or two-lower alkyl amino;
R 2Be that the alkyl of 3-20 carbon atoms is arranged and can be side chain or unbranched and therefore can contain 1-3 two keys or be connected in the ring of 3-7 carbon on the chain or substituting group or replaced or contain oxygen or sulphur atom by one or more aromatic rings.

Description

Tetrahydrochysene one and perhydro isoquinilone derivatives and the therapeutic composition that contains these compounds
The present invention is relevant medicinal preparation for oral administration and the tetrahydrochysene one and the perhydro isoquinilone derivatives that contain as the formula I and the II of active substance, and active compound itself is new contents with them.
In formula I and II
Figure 931073189_IMG3
W is carbonyl or singly-bound
R 1Be hydrogen or R 3CO, wherein R 3Be a single rudimentary alkylamino or two-rudimentary-alkylamino, be preferably low alkyl group or lower alkoxy; For active compound itself, the R in the formula II 1Cannot be hydrogen.
R 2Be to have 3-20, be preferably 5-18, be preferably the alkyl of 7-18 carbon atom and they and can be side chain or unbranched and can contain 1-3 two keys or 3-7 in addition, preferably 5-6 carbon atom is connected in saturated rings on the chain, or as replacing composition, or by 1～3, best 1 aromatic nucleus replaces or contains oxygen or sulphur atom.With the pharmaceutical composition that produces by them.
The meaning of " low alkyl group " is C 1-C 5, be preferably C 1-C 3Alkyl.
The formula I comprises the Stereoisomeric compounds I aAnd I bRacemoid and the enantiomorph of purifying, wherein R 1, R 2Identical with in the implication of W and the formula I, enantiomorph can be by on optically-active matrix
Figure 931073189_IMG4
Chromatography obtains from racemoid with the mode that purifies; or by other usual method preparation; for example by with optically-active acid for example dibenzoyl tartaric acid, dimethylbenzene acyl group tartrate or camphor-10-sulfonic acid change into diastereo-isomerism salt; separate them with the crystalline method then, thereafter salt decomposition.
Narrated the inhibitor of the derivative of some 3-hydroxyl naphthalanes and 3-hydroxyl-8-Azadecalin in the literature as oxygen squalene cyclase.（WO89/8450;JACS100（1978）4900，Biochem.Pharmac.37（1988）1955;US5084461）。
Stated for restraining effect that at this methyl on 4 is necessary.Now, we are surprised to find, do not contain the 4-methyl substituents according to the compound of formula I of the present invention or II, suppress oxygen squalene cyclase equally and oral back is more effective than methyl substituted analogue.
Transform by compound of the present invention, make it to become their additive salt with the acid that allows on the physiology.Organic and example mineral acid that the physiology that is suitable for allows is a hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, oxalic acid, toxilic acid, fumaric acid, lactic acid, tartrate, hexanodioic acid, phenylformic acid.Other be described in Fortschritte der Arzneimittelforschung, 10(1966) 224 et seq., Birkhauser Verlag is among the Basel and Stuttgart.
Usually the acid salt that obtains is with the general method preparation, by free alkali or their solution and the acid that is suitable for or their solution in organic solvent, lower alcohol for example, as methyl alcohol, ethanol or propyl alcohol, ether is as methyl tertiary butyl ether (MTB); Ketone mixes as the solution in acetone or butanone or ester such as the vinyl acetic monomer.Using the mixture of above-mentioned solvent also is possible to improve crystallization, and it is possible therefore being dissolved in the aqueous solution for preparing the acid salt of the acceptable The compounds of this invention I of medicine in the aqueous acid by free alkali.
We have found that the compound of the present invention control disease that suits, treat cardiovascular disorder and fungi infestation especially.They can be taken with common oral or non-enteron aisle (subcutaneous, vein, muscle, endoperitoneal) mode; Also can take by nasopharynx with steam or spraying.
The dosage that uses depends on patient's age, condition and body weight and take mode.The per daily dose of general active substance is 10～1000mg for everyone every day is oral.Intestines use outward and are about 1-500mg everyone every day.
The compound of formula I and II can use with common solid or liquid preparation form, tablet, capsule, powder, particle, suppository, solution or aerosol that for example uncoated or (film) applies.These pharmaceutical preparations are to prepare with usual method.For this purpose, working substance mass-energy is processed with general medicine auxiliary, for example the tablet binding agent, filler, sanitas, tablet disintegrating agent, flowing regulator, plastic agent, wetting agent, dispersion agent, emulsifying agent, Lip river agent, slow dose, oxidation inhibitor and/or propellant gas (cf.H.Sucker et.al.:Pharmazelltische Technologie, Thieme-Verlag, St-uttgart, 1978).The amount that the various medicine types that obtain with these methods contain active substance usually is 1～99%(weight)
The compound of formula I can be pressed, the method preparation shown in for example following reaction formula.PG is in this reaction formula, for example at Houben-weyl, and Methoden der organi-schen chemie Vol.6/1b, the protecting group described in the 735-784.R 1With 2With the same meaning in formula I and the II.
The Azadecalin derivative of formula I be known (J.Med.chem.30, (1987), 1204-1210).Alcohol 2 can be used complex metal hydride, for example LiAlH 4Or NaBH 4Synthetic with general technology reduction.
Benzyl in the alcohol 2 can be removed by general method catalytic hydrogenation, to produce compound 3.
The compound of 3 clear key and aldehydes or ketones production 4.The reduction amination method of aldehydes or ketones is normally known, and, Houben-Weyl for example, Methoden der organischen chemie, Vol.4/ld, 335-364 and Vol.4/lc narrated among the 427-457.Be used for reduction complexing metal hydride, for example NaBH 4Or NaCNBH 3Or catalytic hydrogenation is possible.Add catalytic amount or etc. the lewis acid of gram molecular weight, zinc chloride or add a kind of acid for example, for example acetate can activate suitable carboxyl composition.
The compound of formula 5 can be with suitable chloride of acid or anhydride acylation, or with suitable chloro-formic ester, the general technology preparation (Houben-Weyl of chloromethane acid amides or isocyanate reaction; Methoden der organischen chemie, Vol.E4,64-97; 154-155,181-189.
2.）
Figure 931073189_IMG6
For the acid amides of preparation formula 9 and 10, with the hydroxyl in the general method protection compound 2, remove benzyl also the acid amides of 7 conversion accepted way of doing sth 8 with hydrogenolysis then, be feasible for example with the chloride of acid reaction that is suitable for.The removal of protecting group produces the compound of form 9, then 9 can be by 1.) in the such further reaction pointed out obtain the compound of reaction formula 10.
The compound of formula II can by, for example descend the prepared in reaction that shows in the reaction formula:
3.）
Figure 931073189_IMG8
(J.Am.Chem.Soc 56(1934), is known in 1769-1771) to 6-hydroxy tetrahydro isoquinoline 99.9 11 at document.For 3 change into 4 usefulness as shown in the reaction formula I 11 clear key and the aldehydes or ketones reaction to produce compound 12.As reaction formula 1,12 to 13 acylation reaction takes place in shown method, can change into 5 to 4.
4.）
Figure 931073189_IMG9
For the acid amides for preparing acid amides 9 and 10,17 and 18 can be by reaction formula 2.) shown in the method preparation.
Embodiment 1
N-decyl-8-azepine-anti--3 β-naphthanol
A) N-benzyl-8-azepine-anti--3 β-naphthanol
Be dissolved in the 31.6g(0.13 mole of 600ml anhydrous diethyl ether) N-benzyl-8-azepine-anti--3-decalone solution under-20 ℃, in 1.25 hours, be added drop-wise to the 5.33g(0.14 mole LiAlH that is dissolved in the anhydrous Anaesthetie Ether of 1350ml 4Outstanding solution in add finish after, mixture stirred 1 hour down at-20 ℃, Dropwise 5 .3g is dissolved in the water of 20 milliliters of THF, the water of strong sodium hydroxide solution of 5.3g10% and 16g continuously then.Warm after room temperature, filter out solid with suction, and use methanol wash.Mix ether and methyl alcohol mutually, at Na 2SO 4Last dry and concentrated.The oily residue is dissolved in again in the ether, filters out residual solid.Filtrate is once more at Na 2SO 4Last dry, concentrate thereafter, obtain 26.9gN-benzyl-8-azepine-anti--3 β-naphthanol (productive rate 84%)
B) 8-azepine-anti--3 β-naphthanol
The palladium that 1.9g is invested on the activated carbon (10%) is added to the 19g(0.077 mole) N-benzyl-8-azepine-anti--3 β-naphthanol and 20ml be dissolved in the Glacial acetic acid in the 500ml ethanol and in 2 hours, 45 ℃ of following 21 hydrogen be pressed into by, after reaction is finished, use the filtered through silica gel mixture, use washing with alcohol, the thickening filtration thing is also dry on oil pump, residue 16.2g8-azepine-anti--3 β-naphthanol acetic ester (productive rate: 97%)
C) N-decyl-8-azepine-anti--3 β-naphthanol
2g(0.0093 8-azepine-anti--3 β-naphthanol (acetic ester) mole), 2g(0.013 mole) capraldehyde, 1.9g(0.014 mole) zinc chloride and 1 spoon of molecular sieve (3A) at room temperature stirred in the 90ml anhydrous methanol 1 hour.Slowly be added dropwise to the 0.9g(0.014 mole then) NaCNBH 3Be dissolved in the 30ml absolute methanol solution, mixture at room temperature stirred 2 days.Leach molecular sieve with the suction method, concentrate the methyl alcohol phase then, add ammoniacal liquor and MTB, isolate organic phase, with MTB aqueous phase extracted twice, the blended organic phase is at MgSO 4Last dry and concentrated.On silica gel, use chromatography purification residue (mobile phase: methylene chloride=95/5).Obtain 1.3g colorless oil product (yield: 47%)
IR data [cm -1]: 3344,2923,2853,1466,1377,1096,1055.
Being listed in and implementing 2-6 in the table, is to prepare with similar approach.
Embodiment 7
N-10-undecenyl-3 β-acetoxyl group-8-azepine-anti--naphthalane
The 1.4g(7.1 mmole) 3 β-acetoxyl group-8-azepine-anti--naphthalane (can be by acetic anhydride esterification N-benzyl-8-azepine-anti--3 β-naphthanol, thereafter cleaning benzyl with hydrogen obtains) and the 1.4g(14.2 mmole) triethylamine is dissolved in the 40ml methylene dichloride, dropping is dissolved in the 2.1g(10.6 mmole of 20ml methylene dichloride then) the 10-undecene acyl chloride.At room temperature stirred the mixture 3 hours, and washed with water then, at MgSO 4Last dry and concentrated, with silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=3: 1) purifying resistates.Obtain the above-mentioned colorless oil product of mentioning of 2g (77% yield),
IR data [cm -1]: 2926,2853,1736,1645,1439,1247,1030.
Embodiment 8
6-hydroxyl-2-(6,10-dimethyl undecyl) tetrahydroisoquinoline
The 0.9g(14.5 mmole) the cyano group sodium borohydride be dissolved in the 15ml absolute methanol solution and slowly be added drop-wise to the 3g(13.9 mmole) 6-hydroxyl tetrahydroisoquinoline hydrobromide, 1.14g(13.9 sodium-acetate mmole), the 4g(20 mmole) 6,10-dimethyl 2-11 carbon ketone, one spoonful of molecular sieve (3
Figure 931073189_IMG11
) and be dissolved in the zinc chloride of a spatula point of 45ml anhydrous methanol.Mixture at room temperature stirred 2 days.Leach molecular sieve thickening filtration thing, residue mixes with ammoniacal liquor and vinyl acetic monomer.Thereafter the organic phase of removing is carried out secondary or more times extraction with vinyl acetic monomer.The organic phase that merges is at MgSO 4Last dry concentrating.With silica gel chromatography (mobile phase: purifying resistates hexanaphthene/Methane Carboxylic Acid=3: 1).Obtain 3.8g oily product (82% yield).
IR data [cm -1]: 3300,2954,2925,2867,1504,1465,1380,1366,1284,1245,1157
Embodiment 9
6-acetoxyl group-2-(6,10-dimethyl undecyl) tetrahydroisoquinoline
The 3.8g(11.5 mmole) compound that obtains of embodiment 8 is dissolved among the 70mlMTB, adds 3ml acetic anhydride and 4ml triethylamine then.Solution at room temperature stirred four hours, washed with water then, at MgSO 4Last dry and concentrated, with silica gel chromatography (mobile phase: purifying resistates hexanaphthene/Methane Carboxylic Acid=4: 1).Obtain the light yellow oily product of 2.6g.(yield 61%).
IR data [cm -1]: 2954,2926,2868,1767,1501,1464,1367,1215,1201,1144.
Embodiment 10
6-acetoxyl group-N-(10-undecylene acyl group) tetrahydroisoquinoline
This compound is to be used and embodiment 7 similar methods preparations by 6-acetyl oxygen tetrahydroisoquinoline hydrobromide (for example can obtain from 6-hydroxy tetrahydro isoquinoline 99.9 hydrobromide and acetic anhydride) and 10-undecylene chloride of acid.
IR data [cm -1]: 2926,2854,1758,1650,1500,1438,1226,1209,1148.
Embodiment 11
N-[5-(3-methyl butyl sulfydryl, pentanoyl fourth-8-azepine-anti--3 β-naphthanol
A) N-benzyl-3 β-tert-butyl dimethylsilane oxygen base-8-azepine-anti--naphthalane
9.3g(37.9 N-benzyl-8-azepine-anti--naphthalane-3 β alcohol mmole), 5.5g(80.9 mmole) imidazoles and 5.9g(39.3 mmole) t-butyl dimethylsilane muriate stirred 2 hours down at 50 ℃ in 50mlDMF.Add saturated NH thereafter 4Cl solution is with MTB extraction mixture twice, at MgSO 4Go up dry organic phase and concentrated.Stay the 13.6g crude product.
B) 3 β-t-butyl dimethylsilane oxygen base-8-azepine-anti--naphthalane
With do not add acid with embodiment I b) similarly method in ethanol hydrogenation at 11a) in the 13.6g(37.9 mmole that obtains) product, separate 7.0g(69%) product.
C) 3 β-t-butyl dimethylsilane oxygen base-N-(5-bromo pentanoyl)-8-azepine-anti--naphthalane
The 4g(14.0 mmole) at 11b) in the product and the 2.25(22.3 mmole that obtain) triethylamine is dissolved in the 50ml methylene dichloride, and cools off in frozen water simultaneously.Slowly drip the 2.6g(14.9 mmole that is dissolved in the 30ml methylene dichloride) 5-bromo valeryl chloride.After having reacted, wash mixture with water, at MgSO 4Last dry and concentrated.Obtain 6.2g(96%) product.
D) pentanoyl 3 β-t-butyl dimethylsilane oxygen base-N-[5-(3-methyl butyl sulfydryl)]-8-azepine-anti--naphthalane
Be dissolved in the 2g(4.63 mmole of 30ml acetone) product that in 11c, obtains, the 0.96g(6.94 mmole) K 2CO 3With the 0.48g(4.63 mmole) 3-methyl isophthalic acid-butane mercaptan refluxed 2 hours.Use suction method filtering mixt then, the thickening filtration thing is with silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=4/1), the purifying resistates obtains 1.0g(46%) product.
E) pentanoyl N-[5-(3-methyl butyl sulfydryl)]-8-azepine-anti--3 β-naphthanol
The 0.45g(1 mmole) at 11d) in the product that obtains be dissolved in the 5ml methyl alcohol, add several 10% strength hydrochloric acid, mixture at room temperature stirs and spends the night.Second day dilute with water solution is used NaHCO with etherophosphoric acid extraction three times 3Solution washing is at MgSO 4Last dry, concentrate and with silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=1/1) purifying.Isolate 0.3g(89%) the colorless oil product.
IR data [cm -1]: 3411,2924,2862,1626,1450,1366,1108,1054.
Figure 931073189_IMG12

Claims (7)

1, a kind of contain except that medicinal adjuvant commonly used as active substance every individually dosed for the formula I of 10-1000mg or II racemoid and isolating enantiomorph and physiology on the oral pharmaceutical of additive salt of the acid that allows
Wherein,
W is carbonyl or singly-bound;
R 1Be hydrogen or R 3CO, wherein R 3Be low alkyl group, lower alkoxy, single rudimentary-alkylamino or two-lower alkyl amino
R 2Be that the alkyl of 3-20 carbon is arranged and can be side chain or unbranched and can contain the two keys of 1-3 or be connected in the saturated rings of 3-7 carbon on the key or as substituting group or by one or more aromatic nucleus replacements or contain oxygen or sulphur atom.
2, a kind of non-intestines are taken medicine, its contain every individually dosed for 1-500mg except that medicinal adjuvant commonly used as active substance by the formula I in the claim 1 or the compound of II.
3, a kind of medicine for the treatment of cardiovascular disorder, its contain significant quantity except that medicinal adjuvant commonly used as active substance by the formula I of claim 1 or the compound of II.
4, a kind of antifungal medicine, its contain significant quantity except that medicinal adjuvant commonly used as active substance according to the formula I of claim 1 or the compound of II.
5, be used for the production for treating cardiovascular disease medicine according to the formula I of claim 1 or the application of compound of II.
6, be used for production for treating mycosis medicine according to the formula I of claim 1 or the application of compound of II.
7, according to the tetrahydrochysene of the formula I or the II of claim 1-or perhydro isoquinilone derivatives, wherein R 1Can have following meaning:
R 3CO, wherein R 3Be low alkyl group, lower alkoxy, a single rudimentary alkylamino or two-lower alkyl amino; In the formula I, can be hydrogen also, or the additive salt of the acid that allows on the physiology.
CN93107318A 1992-05-22 1993-05-22 Tetrahydrochysene one and perhydro isoquinilone derivatives and the therapeutic composition that contains these compounds Pending CN1085214A (en)

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Publication number Priority date Publication date Assignee Title
CN100386319C (en) * 2005-12-05 2008-05-07 中国人民解放军第二军医大学 Tetra hydro iso quinoline compounds possessing anti breed and anti fungus activity and its salt

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CA2190708A1 (en) * 1995-12-08 1997-06-09 Johannes Aebi Aminoalkyl substituted benzo-heterocyclic compounds

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FR1489903A (en) * 1965-07-16 1967-07-28 Marion Laboratories Inc Isoquinoline derivatives and their preparation
DE2620179A1 (en) * 1975-10-28 1977-05-12 Knoll Ag Beta:adrenergic-blocking, amino-hydroxy-propoxy isoquinoline derivs. - prepd. by reacting epoxy-propoxy-(2)-acyl-isoquinolines with amines
DE3308554A1 (en) * 1983-03-10 1984-09-13 Hoechst Ag, 6230 Frankfurt 1- / 1,3-DIOXOLAN-2-YLMETHYL) -AZOLE, THEIR SALTS, METHOD FOR THE PRODUCTION AND THEIR USE
US4963563A (en) * 1989-10-13 1990-10-16 Abbott Laboratories 6-substituted-1,2,3,4-tetrahydroisoquinolines

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CN100386319C (en) * 2005-12-05 2008-05-07 中国人民解放军第二军医大学 Tetra hydro iso quinoline compounds possessing anti breed and anti fungus activity and its salt

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