CA1113937A - Substituted piperidinylpropanols - Google Patents
Substituted piperidinylpropanolsInfo
- Publication number
- CA1113937A CA1113937A CA299,457A CA299457A CA1113937A CA 1113937 A CA1113937 A CA 1113937A CA 299457 A CA299457 A CA 299457A CA 1113937 A CA1113937 A CA 1113937A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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- C—CHEMISTRY; METALLURGY
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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
- C07D217/04—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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- Heart & Thoracic Surgery (AREA)
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT Compounds having the formula and the pharmaceutically acceptable salts thereof, wherein R1 is alkanoyl; R2 is (i) (ii) (ii) (iv) (v)
Description
~ HA143/55/56 Cyclitol derivatives having the Eorrnula Cll -CH -CII -N~
2)n 0-~ O--Y
wherein Y is hydrogen or alkanoyl, t~le group -NXX' is a heterocyclic nitrogen con-taining yroup, and n is 0, 1 or 2 are encompassed by the disclosure of United Statcs patcnt
wherein Y is hydrogen or alkanoyl, t~le group -NXX' is a heterocyclic nitrogen con-taining yroup, and n is 0, 1 or 2 are encompassed by the disclosure of United Statcs patcnt
3,894,031, issued July 8, 1975. Among the heterocycli.c groups disclosed are pipera~ino, (lower alkyl)piperazino, di(lower alkyl)piperazino, (lower alko~y)piperazino, (hydroxy-lower alkyl)piperazino, (alkanoyloxy-lower alkyl)piperclzino, (hydroxy-lower alkoxy-lower alkyl)piperazino, an-l tcarbo-lower alkoxy)piperazino. The treatment of hypertension is one of the utilities for the compounds disclosod by t~,e patent.
~uryer, ~ledicinal Chemistry, third edition tpclrt II), John Wiley & Sons, Inc.! New York, 1970, chapter 39, "~nti-hypertensive Agents", pgs. 1019-1064 disclo~es various classcs of antihypertensive agents. ~,mong the classcs of compounds 20 disclosed are veratrum alkaloids, the hypotensive activity of which may be largely attribu-table to the acylation of sevcral hydroxyl functions of an alkamine. Other classes o~ anti.-hypertensive agents disclosed by Burger include pherlo~y-~i- propanolamines and phenethanolamines.
' Compounds having the formula Cl-'2-C~i--CE~2-R2 ORl OI~ll OR
~ ~ 6 ( ~ ~Cll - 1 $
.
and the pharmaceutically acceptable salts thereof, have hypotensive activity. In formula I, and throughout the specification, the symbols are as defined below.
n is 0, 1 or 2;
Rl is alkanoyl (acetyl is preferred);
R2 iS
(i) -N N-R7 ~
( i i ) ~.
(iii) ~ ' ' (iv) ~ CH=CH~) ; ~ , .. ;.
:;
.. . .
(v ) ~
.'., (vi) ~ , or , .~- ' (vii ) ~ N==
: ~ N~
~..
,~
. ~ -2-~;5 ~ 7 HA143/55/56 (viii) N ~ ~ R3 t (ix) ~4 -N
', (xi~ ~} (CE12)m-R5 (xii) O H or ,~ , (xiii.) i .,~ .
. .
R3 is alkyl of 1 to 4 carbon atoms;
~: R4 is cyano or hydroxy;
`:: R5 is hydroxy or alkanoyloxy (acetyloxy is pre~erred);
R6 is hydrogen or alkanoyl (acetyl is preferred) ~ ~ .
: ~' ,X
~33~,7 HA143/55/56 ~ is arylorpyridinyl;and m is 2, 3, or ~.
The terrns "alkanoyl" and "alkanoyloY~y'i, as used throur;~,ollt the .spec ~ication, refer to groups having the formu]a Y-C- and Y-C-O- respectively, wherein Y ls alkyl having 1 to 6 carbon ator.s (i.e., groups having 2 to 7 car~,on atoms).
The com~.ounds of this invention wherein R6 is hydro~en can be prepared by reacting an oxirane compound having the formula II O
~H2)n or~l ORl with a compound having the formula III
; R2 H-Reaction conditions are not critical, but the reaction proceeds more rapidly when carried out with heating in an organic solvent, or mixture of organic solvents, e.g., a lower alkanol such as ethanol, or an aromatic hydrocarbon such as benzene in combin-ation with a lower alkanol. Those compounds of ormula I wherein R6 is alkanoyl can },e prepared from the corresponding cornpound wherein R6 is hydrogen using conven-tional acylation techniclues.
The oxirane compounds of formula II are readily ohtained from a corresponding compound having the formula ~ 3~ Y HAl43/S5/56 IV
ORl CH2-CH2-CH2-~ (alkYl)2 ~, ~ (~H2)n ORl ORl ; Compounds of formula IV are known; see, for example, Unitcd ; States patent 3,894,031, issued July 8, 1915. Oxidation of a compound of formula IV yields the corxesponding N-oxide having the formula V
Cl~2-cH2-c~l2-N(alkyl)2 . ORl Rl¦
~ CH2)n ~ ORl 1 , Exemplary of oxidizing agents which may be used are the peracids, ?
e.~., m~chloroperbenzoic acid.
Vacuum pyrolysis of an N-oxide of formula V yields an .,! ~ ~ , olefin having the formula ~ "I
;~ 20 ; ~ CE~2-C~=C~2 ; 0~0~
CH2)n ORl ORl - ~:
~Oxidation of an olefin of formula VI yields the corresponding oxirane compound of formula II. Exemplary of oxidizin~ agen~s which may be used are the peracids, e.~., m-chloroperhenzoic acid.
The oxirane compounds o formula II and the olefins of formula ~I are novel intermediates which are useful in the preparation of the compounds of formula I, and as such, con 30 stitute an integral part of this invention.
v~7 The compounds of formula I can be converted to their pharmaceutically acceptable acid-addition salts with hoth organic and inorganic acids using methods well known in the art. ~xemplary salts are hydrohalides (e.g., hydrochloride and hydrobromide), nitrate, phosphate, borate, acetate, tar-trate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like.
Formula I includes all stereoisomers and mixtures thereof. Particular stereoisomers are prepared hy utilizing as the starting material the compound of formula IV ~!ith the correspondiny stereochemistry. The preferred stereG-isomers are those in which the ~1 groups are alI ai:ial.
Particularly preferred are those compounds havincJ the confiyuration VII
., CH2-1H-C~i2 2 " ~ ~6 2)n I
ORlC ORld ; 20 wherein the ORla and ORlC groups are in the trans configuration as are the Ol~lb and ORld groups.
The compounds of formula I show hypotensive propcrties in hypertensive rats and normotensive dogs. The compounds of this invention, and the pharmaceutically acceptahle salts thereof, are useful as hypotensive agents in mammals, ~
domestic animals such as dogs and cats. Daily doses of from 5 to 50 milligrams per kiloc~ram of animal body weicJllt, pref-erably about 5 to 25 milligrams peE kilocJram of animal body weight, can be administered orally or parenterally, in singlc or divided doses.
~$~37 HA143/55/56 The compounds of this invention includc indan derivatives having the formula VIII
CH2~ CH2 R2 0~0~ ~R6 ~ , .
ORl ORl naphthalen~ derivatives having the formula IX
CH CH-CH -R
~ . , ~ ~) .. . ~
ORl ORl ;, and benzocycloheptane derivatives haviny the formula .`i ,:, X
CH2-cH-CH2 -R
ORl ORll ¦. 2 ; ~ 6 ;~
' ~: . ORl ORl ;; 20 The naphthalene derivatives of formula IX are preferred.
: The fol.lo~ing examples are specific embodiments of this invention.
~` .
... . . .
.- :.
HA143/g~/56 ~i,xarrlple 1 3,4a,5~ -Decahydro~5-[2-hydroxy-3-[4 (2-methoxt~phenyl.)-1-piperazinyl]~ro~yl]-2,3;4a,3a-trans-naphthalenetetrol, tetraacetate ester -A) 3,4a,5_ is _ecahydro-5-(3-dirr~eth~l.aminoproPyl)-2,3;~a,8a-tr~ -naphthalenetetrol, tetraacetate ester, N-oxlcle A solution of 19.71g of 3,4a,5-cls-5-(3-dimethylarr.ino-propyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester and 9.25g of 85% m-chloroperbenzoic acid in 30 ml of chloro-form is prepared at 0C and warmed over 3 ho~lrs to room temperature. The solution is then partially evaporated ln vacuo and filtered through 520g of neutral ~lumina ~ lution with 1 liter each of chloroform and 20% methanolic chloroform aives 24.3g of oil. Crystallization from ethyl acetate gives 14.3g of the ~l-oxide as a hyclroscoI~ic solid, meltinc~ ~oint ; 160-161C. The filtrate is evaporated ln vacuo to clryness to give an additional 6.38c~ of solid (IR consistent ~itl cr~
for a total yield of 2Ø6nc3.
.) 3,4a,5~ -Decahydro-5-(2-propenyl)~2,3;4a,8a-trall.s-na~hthalcnetetrol, tetraacetate ~ster ..
~n amount of 20.2y of the above M-oxide is heated in a vacuum distillation set-up under 30 mm ~IcJ vacuum ~li.th nitrocl~n bleed until all the solid has melted and vi.gorous qas evoiution ceases. The vacuum is improvecl to 1 mm ~c~ ar~.d t}~e olefi.n product distillecl as a pale yellow liquid, 13. n g (boiling point 185-195 at 1 mm Hg), which solidifies on standing.
~ecrystallization frorn ether (75 - 1~0 rnl) gi.ves 8.6g cf a fine crystalline solid, melting point 151~155.5C.
C) 3~4a~5-~1~-D~cahydro-5-~o~x.iranylmethyl)-2,3;~a~na~
naphthalenetetrol, tetraacetate ester _ A solution of ~.09 of the ahovc tetra~ccta~e-olcfin ancl 3.12cJ of 85.~ m-ch].orol~c~rlc~n~oic .Ici(l ir, lnO nll Or c~lororor _ ~ _ is prepared at 0C and stirrecl at room tempera~ure for about 16 hours. I'he solutiorl is then suction filtered throuc3h a pad of 5nc~ of neutral Alumina III. The alumina is ~.lashed ~ith 100 ml of chloroform and the combined filtrates evapor-ated in vacuo to give 6.4g of a solid, melting point 135-159C.
D) 3,4a,5-ci.s-Decahydro-5-[2-hvdroxy-3-[4-(2-methoxy~henyl)-l-pipera~zinvl]propvl]-2,3;4a,8a-trans-naphthalcnetetrol, tetraacetate ester .
~ solution of 1.5g of 1-(2-methoxyphenyl)pil~crazine and 3.5g of the above epGxide in S0 ml of absolute ethanol and 2Q ml of benzene is stirred in a warm water batll (50-55C) for about 20 hours under a drying tube. The solvent is rcmoved n vacuo to give 5.lg of a foam, which is crystallizecl frGm ether to give 4.23g of the product as a crystalline ~olicl in two crops. Recrystallization of 3.58g of the solid from cthyl acetate (25-35 ml) gives 2.65g of the title compound, meltinc3 point 203-206C.
Anal. Calc'd. for C32H46N2O1o (618.7 (~/m):
C, 62.12; ~, 7.49; ~, ~.53 Found: C, 62.15; ~, 7.64; ~, 4.43 Example 2 3,4a,5-~L~-Decahydro-5-[2-hydroxy-3-[4-[3-(trifluorom ~ ~-phenyl]-l-piperazinyl]propyl]-2~3;4a~8a-~ ~-naphthalenetetrol, tetraacetate ester A solution of 2.75g of 3,4,5a-cls-decahydro-5-~oxir-anylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester and 1.3g of M-(a,cx,a-trifluoro-m-tolyl)piperazinc in 20:50 benzene-absolute ethanol is heated to 55-G0C or ]8 hours. The solution is evaporated 1n V~lCUO and the resiclue is crystallized from ~thyl acetate-heY.arl~ to give 2.7q o solid in three crops. Recrystalli~ation frorn e~lyl acet~tc-30 h~x~ne cJiVe~ ].. B5q of materi~l. q~he ].U5tl o~ n~ erilll is _ g ~
~ HA143/55/56 combined ~ith 0.75g from a previous run and recrystallizecl to~ive 2.ng of the title compound, meltinc~ point 150- n40c.
Anal- Calc d- for C32~3N2O9F3(h57-7 ~/m) C, 58.52; H, 6.60; M, 4.27i F, 8.68 Found: C, 58.30; H, 6.63; Il, 4.13i F, 8.56 xam le 3 P
:
3,4a,5-~is-5-[3-[4-[2-(Ethylthio)phenyll-l-p ~
h~droxypropyl]-decahydro-2,3;4a,8a-~xan~-naphthalenetetrol, tetraacetate ester A solution of 2.6g of 3,4,5a-cl~-decahydro~5-(oxiranyl-10 methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr and 1.4g of N-~(2-ethylthio)phenyl]piperazin~ in 20 ml of benzene-50ml of absolute ethanol is stirrc.~d at 57C for a~,out 16 hours. l'he solution ls evaporated in vacuo and th~ re~ lue crystallized from ether to give 3g of solid. T~o recrystal-lizations fror.l ethyl acetate-methanol give 2.2g of the title compound, melting point 230-232C.
Anal. Calc'd. for C33H48N2OgS (64~-82 g/m):
C, 61.09; ~-1, 7.46i N, 4.32; S, 4.94 Found: C, 61.27; ~, 7.74; N, 4.33; S, 5.00 Example 4 3,4a,5-cis-DecahYdro-5-[2-hydroxy-3-[4-(2-pyridinyl)-1~
piperazinyl]propyl]-2,3;4a,8a-~E~n~-naphthalenetetrol, te~ra-acetate ester 3,4,5a-cls-Decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, (2.10R~) is dissolved in 50 ml of absolute ethanol and 20 ml benzene.
Freshly distilled 1-~2-pyridyl)piperazine (.766~) is added and the resultin~ solution is heated to 50C+5, ~1ith stirring for 15 hours. Solvent i5 removed in vacuo, and the r~s~ulting foam is ta~.en up in 250 ml of ethanol from ~lhich it immediately 30 crystallizes to yield 2.3g of crystallille soli~. 'lhe solid 7 HAl 4 3/5 5/ 5 6 is recryctallized fro~ ethyl acetate to yield 1. 26~ crystal-line solid, melting point 225-229C.
E~a~.ples 5-13 Foll~winy the yroeedure of ~Y.ampl~ l, but au~stitutillg the piE~erazin~ derivative listed in eolumn I for l-(2-methoxy-phenyl)piperazine, yield the eompoun~. liste(7 in colu~,n I I .
Co].umn I Column II
5 l-phenylpiperazine 3,4a,5-cis-decahydro 5-~2--hydro~y-3-(4-phenyl-l-r,i~)er-azinyl)propvl]-2,3;4a,Ra-trans-naphthalenetotrol, tetraacetate ~ter 6 1-(2,6-dibromophenyl) 3,~a,5-ci.,-decahy~lro-5-[2-piperazine hy~ro~y-'-~4-(2,F.-dihrorro-~henyl)-l-ripera7.inyl]~rcpyl~-2,3;4a,8a-trans-naphthalerc--tetrol, tctraaeet;..Lc ester 7 l-(~-iGdephenyl)~iperaæin~ 3,~a,5-eic;-cleeahyclr~-5-r~-hyclr~;~.y~[4- (2-i~dor-hcnyl )-l-pi~r.lz.inyl]pro!~yl]-2,~;-9a,8a-~rnris-naE)hl;half-nc-t.~trol, tetraacetate e~tcr 8 l-(2-fluorophenyl)piper- 3,4a,5-ci.~-decahydro-5-[2-azine hydroxy~[4-(2-~luorolJhenyl)-l-piperazinyl~propyl]-2,3;4a,-~a-trans-naphthalenetetrol, tetraaeetate e.~ter 20 9 l-(3,4-dimethylphenyl) 3,4a,5-eis-deeahydro-5-~2-piperaæine hydroxy-3-[4-(3,4-dimethyl-henyl)-l-piperazinyl]~ropyl]-2,3;4a-,8a-trans-naphthalene-- tetrol, tetraaeetate ester l~ l-(2,6-dimethoxy~henyl) 3,~a,5-ei.s-deeahydro-5-[~-piperazine hydroY.y-3-[4-(2,6-dimetho~y-phenyl)-l-pipera7.inyl]propyl~-2,3;4a,8a-trans-naphthalene-tetrol, tetraaeetate ester ll l-(l-pyridyl)piperazine 3,4a,5-ei.s-~eeahydro-5-12-hydroxy-3-[4-(l-pyrldlnyl)-l-piperazinyl]propyl]-2,3;-~a,8a-tran~-naphthalelletetrol, tetraaeetate este~
~3~37 HA~43/55/56 . Colu3~ln I Colurr; JJ ;`
-- _.
121-(3 pyridyl)T?iperazine 3,4a,,~cis-decahy(lro-5~[2-hydroxy-3-~-(3-pyridinyl)- r ; l-~iperazinyl]propyl]-2,3;-4a,8a-trans-naphthalelletetrol, tetraact?tate e~tcr 131-(4-pyridyl)pipt?razine 3,4a,5-cis-decallydro-5-[2-h~ydro:cy-3-[4-(4-pyridinyl)-l-piperazinyl]propyl]-2,3;-~a,3a-trans-naj3~ht;halel~-tetrol, tetraacetate e.ster F.,ample 1~
3a,5-cis-3a,7a-5,6-trans-H-3exah clro-1-l2-h~clro~-3-,r4-(2-rrl-tho~-phenyl)-l_e~erazinyl; ~ l-intit_ne-3~J,5,-"7a-tetrt)l, t~tr(l-10 acetate ester, hydrochloridf.~
3a,5-fi~s-3a,7a;5,6-trc3n,-He~.ahy-lrc~-l-('-climethyl~mino-ropyl)-131-i~ren ~ a-tctrol, tetr-3.-3cct~3tc? ~citer, ~-oxide .~n amount of 2.ag of 85, m-chloro~erberzoic acid is ~3ddec~
to a solutiGn o 5.0g of 3a,5-cls-3a,7a;5,6-trans-hexahydro-1-(3-dlMethylaminopropyl) in 50 ml of ch1OroLorm .It - 0-5C. The cold bath is removed ancl thc mixturc- is sti3rcd for 3-1/2 hours under nitrosen. The solution i.5 partial ly evaporatecl in VaCUO and then chrornatoyraphe(1 on 98 c Gi r.cutral ~lumina III. ~lution with chloroform ar.d methanolic chlcrGforrn 20 yields, upon evaporation in vacuo, ~.6 y of thc ~!-o:~iclc as a - white solid.
3a,5-çl~-3a,7a;5,6-_ran ~ Ya~ly~lro-l-( indene-3a,5,6,7a-tetrol, tetraacetat~ ester The above N-oY~ide (4.6 5) is vacuurn pyrolyze~d at 16n-190CC
under 12 m~ Hc~T vacuum. The product is vacuurr~ disti]led to givc 2.1 g of crude olefin at 185-195C under 0.25 rrm lig vacuurn.
Further ~urification by chromatoyraphy on 35 cJ of ncutral Alumina III eluted with 15-2~ ethyl acetat-,-ie~anc Vie~-.'!-, ].O c~ oJ thc ol~fin as a whitc so]i(].
~ HA143/155/156 3a,5~cis-3a,7a~5,6-trans-Hexahydro-l-(oxiranylmethyl)--lH-indene-3a,5,6,7a-tetrol, tetraacetate ester -An amount of 0.52 g of 85~ m-chloroperbenzoic acid is added to a solution of 1.0 g of olefin in 25 ml of chloroform and the solution stirred for about 16 hours at room temperature.
The solution is partially evaporated in vacuo and then filtered through a column of 22 ~ of neutral Alumina III. Elution with 260 ml of 20-30% ethyl acetate-hexane yields 0.9 g of epoxide as a white solid.
3a,5-cis-3a,7a;5,6-trans-Hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-H-indene~3a,5,6,7a, tetrol, tetraacetate ester, hydrochloride (1:1) A solution of 0.9 g of epoxide and 0.43 g of _-methoxy-phenylpiperazine in 20:50 benzene-absolute ethanol is stirred for 18 hours in a 57C bath. The solvent is removed ln vacuo and the residue chromatographed on 25 g of neutral Alumina III.
Elution with 150 ml of 25-30% ethyl acetate-he~ane yields 0.53 g of forerun (mainly recovered epoxide). Elution with 200 ml of 35-40% ethyl acetate-hexane yields 0.57 g of the product as a free base. The free base is converted to the hydrochloride salt and recrystallized from ethyl acetate-ether to yield 0.5 g of the title compound, melting point 215-220C.
Anal. Calc'd. for C31H~4N2Olo. (641.16 g/m) C, 58.07; H, 7.08; N, 4.37; Cl, 5.53 Found: C, 57.89; H, 7.00; N, 4.31; Cl, S.67 Example 15 3,4a-cis-Hexahydro-5-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2,3;4a,9a-trans-benzocycloheptanetetrol, tetraacetate ester A~ 3,4a-cis-Hexahydro-5-(3-dimethylaminopropyl)-2,3;4a,9a-_ _ trans-benzocycloheptanetetrol, tetraacetate ester, N-oxide ___ A solution of 3,4a-cls-hexahydro-5-(3-dimethylaminopropyl)-~13~
~ t~ HA143/55/56 2,3;aa,9a-trans-benzocyclohep~ar.etetrol, tetraacetate e~;'cr (12.8 rr,mole) and rn-chloroperbenzoic acid (2.~ g) in chloro-form (100 ml) is prepared at 0C and gradually warmed to rooM temperature to yield the title ~-oxid(.
B) 3,4a-cis-llexahyclro 5-(2-propen~1)-2,3;4a,9a-trans-benY.
cyclo~eptanetetrol, t~traacetate ester The above N-oxi~e (10.8 mmole) is heated in a vacuum distillation set-up under 30 mm ~Ig vacuum Wit}l nitroqen hl.ee~
to yield the title olefin.
~ 10 C) 3,4a,5-~1~ exahydro- ~ .thyl.)-2,~;4~ L~Ul~-: benzocycloheptanetetrol, tetraacetate est~r A solution of the above tetraacetate-ole~in (5.9 r~nole) and 85~ m--chloroperbenzoic acid (1.3 c3) in chlorofor~, (50 ml) is prepared at 0C alld stirred at roorn temperat~rc for about 16 hours to yield the title epoxide.
` D) 3,4a~ lexahydrc-5-[2-hydroxy-3-[4-(2-n;etho~y~ nyl)-l-piperazinyl]propyl]-3,~; r,~ ~clo~.epi,ane-tetrol, tetraacetate ester A solution o~ 1-(2-methoxyphenyl)piperazinc (5.0 mrllole) and t~le above epoxide (5.0 mmole) in absolu~c eth.lrlol (50 ml) 20 and benzene (20 ml) is stirred in a ~.~arm :7atcr bath ~5n-r,5() for about 20 hours under a dryiny tuhe to yield the ti.tle compound.
~3~
Example 16 3,4a,S-~i~-5-~3-(3,6-Dihydro-4-pheIlyl-](2~)-pyridinyl)-2 ~ hydroxypropyl]~ecahydro-2~3;4a~8a-trans-naphth~llenetetr tetraacctate ~ster A solution of 2.5g of 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra acetate ester and 0.86g of 4-phenyl-1,2,3,6-tetrahydro-pyridine in 20 ml benzene-50 ml absolute ethanol is stirred at 55-57C for about 16 hours under a drying tube. The solution is evaporated in vacuo and the residue is crys-tallized from 30 ml of 1:2 ethyl acetate-ether to give 0.85g of solid. A second crop yields 0.35g of solid. Re-crystallization rom 2:1 ethyl acetate-ether yields l.ly of the title compound, melting point 133-199C.
: Example 17 Decahydro-5-[2-hyclro~ (]~4~5~o-tetrahydrohen~flic;oauinolin 3(2H)-yl)propy_]-3,4a,5-~ 2,3,4a,8a-tetraacetate ester -1,2,3,a,5,6-Hexahydrobenz[f]i.soquinolinc, mono-hydrochloride (l.Og) is dissolved in 20 ml of ~ater, layered over ~ith ether and neutralized with aqueous ammonia. The organic phase is removed and the aqueous phase is re-extracted with ether (two 20 ml portions). OrcJanics arc?
combined, dri.ed, filtered ancl strip~ed in vacuo to yield 0.75g of the free base, ~hich is dissolved in 20 ml of benzene and S0 ml of absolute ethanol. ',4a,5-c -Dccah!~rG-5-(oxiranylmethyl)-2,3;4a,8a-trans-nap}lthalcnctetrol, tetraacetate ester (1.~13g) is addcd to the solution, and the resultin~ solution is heated to 50C~S for 1~ hours.
Solvcnt is removed _ vacuo~ the residuc i.c taken up in ethcr and the rcsulting ~o~dcr is recrystal].izcd Irom c~thyl ~3~37 HA143/55/56 acetate to yield 1.17g of the title compounl.
Exam~le 18 .
3,4a,5~ -Decahydro-5-[2-hydrox~-3-~4-(2-phenvle~henyl)-3,6-dihydro-1(2H)-pyridinyl]propyl]-2,3,4a,8a-tran.s-naphthalenetetrol, tetraacetate ester A) 1,2,3,6-Tetrahydro-4-(2-phenylcthenyl)-1-(pheny]-methyl)pyrlc~lne, monohy rochlorlde W-Benzylstyrylpyridinium bromide (59.0g) is reduced by stirring in 750 ml of 50~ aqueous methanGl to which 30g of sodium borohydride is ac'ded portionwise.
Methanol is removed in vacuo, the resultinc3 slurry is filtered and the solids are partitioned bet~een water and chloroform. Thc aqueous layer is re-e~tractcd with chloroform. The chloroform extracts are combillccl, ~asllc?d with aqueous sodium chloride, dried and strippt-~d to vield 33.2g of the titlc compound. Four c;rams of this I)roduct is dissolved in absolute ethanol, acidified with arlhydrou hydrogen chloride in isopropanol, yielding 3.7y of sclid, ~hich is recrystallized frorn methanci-isoprcpanol to ~ielc 2.72g of crystals, melting point 235-240C.
B) 1~2~3~6-Tetrahydro-4-t2-JJhenylethenyl)pyridinc A solution of 46c3 1,2,3,6-tetrahydro-~-(2-phenethenylj-l-(phenylmethyl)~yridine in 150 ml of toluene is treated with 30.1~ of ~henyl chloroformatc and heated at reflux for 12 hours. Solvent is removed ln vacuo to yield 62.7g of a solid. The above solid is heated to 130C with the aid of an oil bath and 50g of po~der~d ~otassium hydro~ide is added, portionwise. Heating is continued for 90 minutcs, the mixture is cooled, taken up in 200 ml ~ater and e~.tracted with chloroform. Organics are comhined, washed with ac~ueou~
sot~ium chloride, dried, filtcred ancl strip!)ctl to yiel~l ~3(J
.. .. .. . .
- . , : . , . ~ .. . : , of an oil which is taken up in ether, filtered and s~rippcd to yield 33g of oil. Twenty-eight grams of the oil is reflu~ed in 1 liter of he~ane, the solvent is decanted from the oil, the oil is cooled to room temperature, filtered, then cooled in an ice box to yield a crystalline product.
~ue to the poor differential solubility, this process is repeated about eight times, yielding a total of 1.05c3 of the free base.
C) 3,4a,5-c s-Decahydro-5-[2-hydrox~-3-l~-(2-~henylr3thcnyl)-3!6-dihydro-1(2~)-pyridinyl]pro~yl]-2,3;4a,da-t_ans-naphthalenetetrol, t~traacetate ester 1,2,3,6-Tetrahvdro-4-(2-phc3nylethenyl)pyric'ine (1.04g) and 2.5q of 3,4a,5-cls-decahydro-5-(oxjranylrnelhyl)-2,3;4a,3a-trans-naphthalc3ne-tetrol, tetraacetate c~ster -Ire dissolved in 50 ml cf ~bsolutc eth~nol and 20 ml of bcn.~.en(?, and heated at 55OC~5r~ for 15 hours. Solvcnt is cv~poratcd in vacuo and the resulting gum cry.stallized from ether.
Solids are collected yielding 1.35g of browr~ solid WhiCIl is taken up in ethyl acetate, decolorizcd ~ith activatcd charcoal, filtered, hexane added and left standing. Resultin~
solids are collected and dried to yield l.Og of pow-ier, melting point 133-185C.
r,xample 19 -3,4a,5-~s-5-[3-[4-(2,3-Dihydro-2-he.nzoxazolyl)-3,6-dihy(lro-1(2_)-pyridinyl]-2-hydr~yprop~l]-decahy-lro-2,3;
naphthalenetetrol, tetraacetate ~3stcr A) 2-(4-Pyridinyl)benzoxa~ol~
A mixture of 2-aminophenol (10.9g), isonicotinic acid (12.3g) and polyphor~phoric acid (250g) is h~atc~ under a nitrogen atmo~ph~re at 210~C for 3 hours. rl~h~ mixture is then cooled to 160C and slow]y poured i.lltO 1 liter of water.
The mi~ture is cooled by ~ddinc~ ic~ an(l nelltr~lize~l with ~ . , 50'~ sodium hydroxid~ solutiorl yielding 16.2y of crude L)roduct.
Crvstallization from hexane yields 14.8g of the title compound, meltinc3 point 129-131C.
s) 4-(2-senzoxazolyl)-l-(phenylmethyl)pyridi~ium chloricle .
A solution of 117.0g of 2-(4-pyridinyl)benzoxazole and 95.0g of benzyl chloride in 1 1iter of a 9:1 rnixture of n-propanol and dimethylsulfoxide is heated at reflux for 72 hours. The solvent mixture is then removecl and the residue suspended in 100 ml of ~ater. Th~ crystalline product ~!hich separates is filtered, washed ~ith aCetOIIe, ar.d dried to give 76.6g of product. Concentration of the rr,othcr 1i.4uors gives an additional 27.~g of product, melting point 194-196C, dec. Recrystallization from water and drying in a vacuum at 100C for 5 hours raises ~o melting 1?0int to 216-217C, dec.
C) ?-(l-Benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzoxazolc~
To a stirred solution of 16.6g o 4-(2-benzoxazolyl)-l-(phenylmethyl)pyridinium chloride in 1 liter of a 1:1 mixture of alcohol and water is added a solution of 2.8~g of sodium borohydride at a rat~ that maintains the ternperaturc oL t11e mixture at 30-35ac. The reaction mixture is acidified ~lith hydrochloric acid, concentrated to one-half volu~e and t~e cryitals filtered to give 8.7g of the hydrochloride salt of the title cornPound, melting point 227-228C, dec.
The mother liquors are madc alkaline with solid sodium bicarbonate, extracted with chloroform and the extract concentrated to give a gummy residue. Recrystallization of this material from absolute alcohol gives 2.1g of ~he title compound, melting pOil.t 129-130C.
D) 4-(2-Penzoxazolyl)-3,~-d hyc1ro 1 _ 1) T~-~riclinec;lrbox~
acl(l, 2 2._2-trichloroc:thyl est(r ~ v~ ololl~,]y ~ r(~c~ ¢~]~ io~ r l()'3.
` ~143/55/56 a.3¢1~1~3!7 2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzo~azGle in 1 liter of dry toluene is added dropwise 96.4g of 2,2,2-trichloroethyl chloroformate during 2 hours and the mixture is heated at reflux for 1.5 hours. The reaction mixture is then cooled, extracted with 250 ml of cold 10% hydrochloric acid, with 250 ml of cold 10~ aqueous sodium hydroxide solution, and with an equal volume of ~ater, dried (anhydrous magnesium sulfate), and concentratcd. l'he oily re.sidue is then further concentrated from an oil bath maintaine~cl at 50C und~r a vacuum of 0.2 nm of Hg to removc tho ramainio~
benzyl chloride. ;
The viscous oil is dissolved in 500 ml of hoiling absolute ethanol and cooled to give, after filtration and drying, 56.9g~ of crystallinc product, meltlng point 13~-135GC.
The mother liquors give, after concentration to one-half volume and cooling an additional ll.Og of product identical with that above.
~) 2-(1,2,3,6-Tetrahydro-~-pyridinyl)henzoxazole ~To a solution of 52.6g of 4-(2-~enzoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloro~thyl ester in 1250 ml of glacial acetic acid is gradually addecl 92.5g of zinc dust and the reaction mixture~s~irred at room temperature under nitrogen for 6 hours. The reaction nlixture is filtered and concentrated on the rotary evaporator to givc a viscous gum. This r.naterial is suspended in 500 ml of ~ater, `~
the pH ~djusted to 2-3, and the suspension extracted with 500 ml of ether in two portions. These are combi;ned, drie~
and concentrated to give 11.32g of unreacted startirlg ~aterial.
The separated turbid, a~ueous phas,o is filtered, coolcd, madc strollgly alkaline~ and extractc(3 th~c ~inlo!;
with 250 ml portlons Gf chloroform. The com~ine~ e~.tracts are dried and concentrated to give 6.0g of crystal, melting point 136-138C.
F) 3,4a,5-cis-5-[3-[4-(2,3-~ihydro-2-henzoxazolyl)-3,6-dihydro-1(2~)-pyridinyl]~2-hydroxypropyl]-dec~hy~lro-2,3j4a~8a-tra~-naphthalenetetrol~ tetraacetate e~ter , Three grams of 3,aa,5-cis-decahydro 5-(o.Yiranyl-methyl)-2~3;aa~8a-trans-naphthalenetetrol~ tetraacetate ester is dissolved in 50 ml of absolute ethanol and 20 ml of benzene. To this is add~ 1.34g of 2-(1,2,3,6-tetra-hydro-4-p~ridinyl)~enzoxazole and t~.e resultiny solution is heated to 55C+5 for 16 hours. Solverlt is stripped in vacuo and the resulting gum is taken up in e~her. The ether solution is filtered, ailuted with he:cane an~i lcf~
standing. Solids are collectecl to yield 3~J of solid .~hich is recrystallized from ethyl acetate anc~ he~ane to yield 1.6g of the title compound, melting point 204-210C, dec.
Example 20 3,4a,5-~-~-Decahydro-5-[2-hyc`roxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)~ropyl~-2,3;4a,8a-~r~ns-na~hthalenetetrol, tetraacetate ester A solution of 3.0g of 3,4a,5-cis-decahy(lro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester and 0.94y of 1,2,3,4-tetrahy~roisoquinoline in ethanol-benzene (50:20) is warmed in a 55~C bath for about 16 hours. The solution is evaporated ln vacuo to giue 4g of solid. T~70 recrystallizations from ethyl acetate/ether/hexane yield l.9g of the title compound, melting point 185-195C~
' ' EY~ample 21 3 ! 4a,5-cis-Decahydro-5-[2-hydro~y-3-(4,5,6,?-tetrahydro-1~
imldazo[4, ~ )pro~yl]-2,3;4a,8a-trans-naphtha-lenetetrol To a solution of 0.55g of sodium hydro~ide in 30 ml of absolute ethallol is added 1.35y of 4,5,6,7-tetra-hydro-lH-imidazo[4,5-c]pyridine, hydrochloride. After stirring for about 5 minut~s a solution of 3.0g of 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-na~hthalcne-tetrol, tetraacetate ester in 3n:5~ etharlcl:~enzene is added and the solution is stirred fGr about 16 hours at 40-45C. -~
The mixture is filtered and 'he filtrate is eva~orat~ n vacuo to give 3.8y of foam. The foam is ciicsolve~l in 5~:2 ethanol:benzene and stirred for 24 hours at 55-58'C. 1~he solvent is removed ln vacuo and the residue i'3 di~solvecl in ethyl acetate, heated ~Jith activated charcoal and filtered.
After diluting with a small amount of ether and storing at -15C for 3 days, 1.3g of solid is obtained. Recrystallization from ethyl acetate (trace methanol) yields l.ny of th~ titlc 20 compound, melting point 214-216C.
..
~ 7 ~A143/S5/56 E~amples 22-23 Following the procedure of ~xample 16, kut substituting the compound listed in column I for 3,4a,5~c -decahydro-S-(oxiranylmethyl)-2,3;4a,~a-trans-naphthalenetetrol, tetra-acetate ester, yields the com~ound listed in column II.
Column I Column II
22 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trar.s-hexahydro-l-(oxiranylmethyl)~ he~ahydro~ 3-(3,~-dih~Zro-lH-indene-3a,5,6,7a-tetrOl, 4-phcny~-1(211)-pyridinyl)-tetraacetate ester (see 2-hydroxyprop~Jl]~ indene-United States patent No. 3a,5,6,7a-tetrol, tetra-
~uryer, ~ledicinal Chemistry, third edition tpclrt II), John Wiley & Sons, Inc.! New York, 1970, chapter 39, "~nti-hypertensive Agents", pgs. 1019-1064 disclo~es various classcs of antihypertensive agents. ~,mong the classcs of compounds 20 disclosed are veratrum alkaloids, the hypotensive activity of which may be largely attribu-table to the acylation of sevcral hydroxyl functions of an alkamine. Other classes o~ anti.-hypertensive agents disclosed by Burger include pherlo~y-~i- propanolamines and phenethanolamines.
' Compounds having the formula Cl-'2-C~i--CE~2-R2 ORl OI~ll OR
~ ~ 6 ( ~ ~Cll - 1 $
.
and the pharmaceutically acceptable salts thereof, have hypotensive activity. In formula I, and throughout the specification, the symbols are as defined below.
n is 0, 1 or 2;
Rl is alkanoyl (acetyl is preferred);
R2 iS
(i) -N N-R7 ~
( i i ) ~.
(iii) ~ ' ' (iv) ~ CH=CH~) ; ~ , .. ;.
:;
.. . .
(v ) ~
.'., (vi) ~ , or , .~- ' (vii ) ~ N==
: ~ N~
~..
,~
. ~ -2-~;5 ~ 7 HA143/55/56 (viii) N ~ ~ R3 t (ix) ~4 -N
', (xi~ ~} (CE12)m-R5 (xii) O H or ,~ , (xiii.) i .,~ .
. .
R3 is alkyl of 1 to 4 carbon atoms;
~: R4 is cyano or hydroxy;
`:: R5 is hydroxy or alkanoyloxy (acetyloxy is pre~erred);
R6 is hydrogen or alkanoyl (acetyl is preferred) ~ ~ .
: ~' ,X
~33~,7 HA143/55/56 ~ is arylorpyridinyl;and m is 2, 3, or ~.
The terrns "alkanoyl" and "alkanoyloY~y'i, as used throur;~,ollt the .spec ~ication, refer to groups having the formu]a Y-C- and Y-C-O- respectively, wherein Y ls alkyl having 1 to 6 carbon ator.s (i.e., groups having 2 to 7 car~,on atoms).
The com~.ounds of this invention wherein R6 is hydro~en can be prepared by reacting an oxirane compound having the formula II O
~H2)n or~l ORl with a compound having the formula III
; R2 H-Reaction conditions are not critical, but the reaction proceeds more rapidly when carried out with heating in an organic solvent, or mixture of organic solvents, e.g., a lower alkanol such as ethanol, or an aromatic hydrocarbon such as benzene in combin-ation with a lower alkanol. Those compounds of ormula I wherein R6 is alkanoyl can },e prepared from the corresponding cornpound wherein R6 is hydrogen using conven-tional acylation techniclues.
The oxirane compounds of formula II are readily ohtained from a corresponding compound having the formula ~ 3~ Y HAl43/S5/56 IV
ORl CH2-CH2-CH2-~ (alkYl)2 ~, ~ (~H2)n ORl ORl ; Compounds of formula IV are known; see, for example, Unitcd ; States patent 3,894,031, issued July 8, 1915. Oxidation of a compound of formula IV yields the corxesponding N-oxide having the formula V
Cl~2-cH2-c~l2-N(alkyl)2 . ORl Rl¦
~ CH2)n ~ ORl 1 , Exemplary of oxidizing agents which may be used are the peracids, ?
e.~., m~chloroperbenzoic acid.
Vacuum pyrolysis of an N-oxide of formula V yields an .,! ~ ~ , olefin having the formula ~ "I
;~ 20 ; ~ CE~2-C~=C~2 ; 0~0~
CH2)n ORl ORl - ~:
~Oxidation of an olefin of formula VI yields the corresponding oxirane compound of formula II. Exemplary of oxidizin~ agen~s which may be used are the peracids, e.~., m-chloroperhenzoic acid.
The oxirane compounds o formula II and the olefins of formula ~I are novel intermediates which are useful in the preparation of the compounds of formula I, and as such, con 30 stitute an integral part of this invention.
v~7 The compounds of formula I can be converted to their pharmaceutically acceptable acid-addition salts with hoth organic and inorganic acids using methods well known in the art. ~xemplary salts are hydrohalides (e.g., hydrochloride and hydrobromide), nitrate, phosphate, borate, acetate, tar-trate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like.
Formula I includes all stereoisomers and mixtures thereof. Particular stereoisomers are prepared hy utilizing as the starting material the compound of formula IV ~!ith the correspondiny stereochemistry. The preferred stereG-isomers are those in which the ~1 groups are alI ai:ial.
Particularly preferred are those compounds havincJ the confiyuration VII
., CH2-1H-C~i2 2 " ~ ~6 2)n I
ORlC ORld ; 20 wherein the ORla and ORlC groups are in the trans configuration as are the Ol~lb and ORld groups.
The compounds of formula I show hypotensive propcrties in hypertensive rats and normotensive dogs. The compounds of this invention, and the pharmaceutically acceptahle salts thereof, are useful as hypotensive agents in mammals, ~
domestic animals such as dogs and cats. Daily doses of from 5 to 50 milligrams per kiloc~ram of animal body weicJllt, pref-erably about 5 to 25 milligrams peE kilocJram of animal body weight, can be administered orally or parenterally, in singlc or divided doses.
~$~37 HA143/55/56 The compounds of this invention includc indan derivatives having the formula VIII
CH2~ CH2 R2 0~0~ ~R6 ~ , .
ORl ORl naphthalen~ derivatives having the formula IX
CH CH-CH -R
~ . , ~ ~) .. . ~
ORl ORl ;, and benzocycloheptane derivatives haviny the formula .`i ,:, X
CH2-cH-CH2 -R
ORl ORll ¦. 2 ; ~ 6 ;~
' ~: . ORl ORl ;; 20 The naphthalene derivatives of formula IX are preferred.
: The fol.lo~ing examples are specific embodiments of this invention.
~` .
... . . .
.- :.
HA143/g~/56 ~i,xarrlple 1 3,4a,5~ -Decahydro~5-[2-hydroxy-3-[4 (2-methoxt~phenyl.)-1-piperazinyl]~ro~yl]-2,3;4a,3a-trans-naphthalenetetrol, tetraacetate ester -A) 3,4a,5_ is _ecahydro-5-(3-dirr~eth~l.aminoproPyl)-2,3;~a,8a-tr~ -naphthalenetetrol, tetraacetate ester, N-oxlcle A solution of 19.71g of 3,4a,5-cls-5-(3-dimethylarr.ino-propyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester and 9.25g of 85% m-chloroperbenzoic acid in 30 ml of chloro-form is prepared at 0C and warmed over 3 ho~lrs to room temperature. The solution is then partially evaporated ln vacuo and filtered through 520g of neutral ~lumina ~ lution with 1 liter each of chloroform and 20% methanolic chloroform aives 24.3g of oil. Crystallization from ethyl acetate gives 14.3g of the ~l-oxide as a hyclroscoI~ic solid, meltinc~ ~oint ; 160-161C. The filtrate is evaporated ln vacuo to clryness to give an additional 6.38c~ of solid (IR consistent ~itl cr~
for a total yield of 2Ø6nc3.
.) 3,4a,5~ -Decahydro-5-(2-propenyl)~2,3;4a,8a-trall.s-na~hthalcnetetrol, tetraacetate ~ster ..
~n amount of 20.2y of the above M-oxide is heated in a vacuum distillation set-up under 30 mm ~IcJ vacuum ~li.th nitrocl~n bleed until all the solid has melted and vi.gorous qas evoiution ceases. The vacuum is improvecl to 1 mm ~c~ ar~.d t}~e olefi.n product distillecl as a pale yellow liquid, 13. n g (boiling point 185-195 at 1 mm Hg), which solidifies on standing.
~ecrystallization frorn ether (75 - 1~0 rnl) gi.ves 8.6g cf a fine crystalline solid, melting point 151~155.5C.
C) 3~4a~5-~1~-D~cahydro-5-~o~x.iranylmethyl)-2,3;~a~na~
naphthalenetetrol, tetraacetate ester _ A solution of ~.09 of the ahovc tetra~ccta~e-olcfin ancl 3.12cJ of 85.~ m-ch].orol~c~rlc~n~oic .Ici(l ir, lnO nll Or c~lororor _ ~ _ is prepared at 0C and stirrecl at room tempera~ure for about 16 hours. I'he solutiorl is then suction filtered throuc3h a pad of 5nc~ of neutral Alumina III. The alumina is ~.lashed ~ith 100 ml of chloroform and the combined filtrates evapor-ated in vacuo to give 6.4g of a solid, melting point 135-159C.
D) 3,4a,5-ci.s-Decahydro-5-[2-hvdroxy-3-[4-(2-methoxy~henyl)-l-pipera~zinvl]propvl]-2,3;4a,8a-trans-naphthalcnetetrol, tetraacetate ester .
~ solution of 1.5g of 1-(2-methoxyphenyl)pil~crazine and 3.5g of the above epGxide in S0 ml of absolute ethanol and 2Q ml of benzene is stirred in a warm water batll (50-55C) for about 20 hours under a drying tube. The solvent is rcmoved n vacuo to give 5.lg of a foam, which is crystallizecl frGm ether to give 4.23g of the product as a crystalline ~olicl in two crops. Recrystallization of 3.58g of the solid from cthyl acetate (25-35 ml) gives 2.65g of the title compound, meltinc3 point 203-206C.
Anal. Calc'd. for C32H46N2O1o (618.7 (~/m):
C, 62.12; ~, 7.49; ~, ~.53 Found: C, 62.15; ~, 7.64; ~, 4.43 Example 2 3,4a,5-~L~-Decahydro-5-[2-hydroxy-3-[4-[3-(trifluorom ~ ~-phenyl]-l-piperazinyl]propyl]-2~3;4a~8a-~ ~-naphthalenetetrol, tetraacetate ester A solution of 2.75g of 3,4,5a-cls-decahydro-5-~oxir-anylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester and 1.3g of M-(a,cx,a-trifluoro-m-tolyl)piperazinc in 20:50 benzene-absolute ethanol is heated to 55-G0C or ]8 hours. The solution is evaporated 1n V~lCUO and the resiclue is crystallized from ~thyl acetate-heY.arl~ to give 2.7q o solid in three crops. Recrystalli~ation frorn e~lyl acet~tc-30 h~x~ne cJiVe~ ].. B5q of materi~l. q~he ].U5tl o~ n~ erilll is _ g ~
~ HA143/55/56 combined ~ith 0.75g from a previous run and recrystallizecl to~ive 2.ng of the title compound, meltinc~ point 150- n40c.
Anal- Calc d- for C32~3N2O9F3(h57-7 ~/m) C, 58.52; H, 6.60; M, 4.27i F, 8.68 Found: C, 58.30; H, 6.63; Il, 4.13i F, 8.56 xam le 3 P
:
3,4a,5-~is-5-[3-[4-[2-(Ethylthio)phenyll-l-p ~
h~droxypropyl]-decahydro-2,3;4a,8a-~xan~-naphthalenetetrol, tetraacetate ester A solution of 2.6g of 3,4,5a-cl~-decahydro~5-(oxiranyl-10 methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr and 1.4g of N-~(2-ethylthio)phenyl]piperazin~ in 20 ml of benzene-50ml of absolute ethanol is stirrc.~d at 57C for a~,out 16 hours. l'he solution ls evaporated in vacuo and th~ re~ lue crystallized from ether to give 3g of solid. T~o recrystal-lizations fror.l ethyl acetate-methanol give 2.2g of the title compound, melting point 230-232C.
Anal. Calc'd. for C33H48N2OgS (64~-82 g/m):
C, 61.09; ~-1, 7.46i N, 4.32; S, 4.94 Found: C, 61.27; ~, 7.74; N, 4.33; S, 5.00 Example 4 3,4a,5-cis-DecahYdro-5-[2-hydroxy-3-[4-(2-pyridinyl)-1~
piperazinyl]propyl]-2,3;4a,8a-~E~n~-naphthalenetetrol, te~ra-acetate ester 3,4,5a-cls-Decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, (2.10R~) is dissolved in 50 ml of absolute ethanol and 20 ml benzene.
Freshly distilled 1-~2-pyridyl)piperazine (.766~) is added and the resultin~ solution is heated to 50C+5, ~1ith stirring for 15 hours. Solvent i5 removed in vacuo, and the r~s~ulting foam is ta~.en up in 250 ml of ethanol from ~lhich it immediately 30 crystallizes to yield 2.3g of crystallille soli~. 'lhe solid 7 HAl 4 3/5 5/ 5 6 is recryctallized fro~ ethyl acetate to yield 1. 26~ crystal-line solid, melting point 225-229C.
E~a~.ples 5-13 Foll~winy the yroeedure of ~Y.ampl~ l, but au~stitutillg the piE~erazin~ derivative listed in eolumn I for l-(2-methoxy-phenyl)piperazine, yield the eompoun~. liste(7 in colu~,n I I .
Co].umn I Column II
5 l-phenylpiperazine 3,4a,5-cis-decahydro 5-~2--hydro~y-3-(4-phenyl-l-r,i~)er-azinyl)propvl]-2,3;4a,Ra-trans-naphthalenetotrol, tetraacetate ~ter 6 1-(2,6-dibromophenyl) 3,~a,5-ci.,-decahy~lro-5-[2-piperazine hy~ro~y-'-~4-(2,F.-dihrorro-~henyl)-l-ripera7.inyl]~rcpyl~-2,3;4a,8a-trans-naphthalerc--tetrol, tctraaeet;..Lc ester 7 l-(~-iGdephenyl)~iperaæin~ 3,~a,5-eic;-cleeahyclr~-5-r~-hyclr~;~.y~[4- (2-i~dor-hcnyl )-l-pi~r.lz.inyl]pro!~yl]-2,~;-9a,8a-~rnris-naE)hl;half-nc-t.~trol, tetraacetate e~tcr 8 l-(2-fluorophenyl)piper- 3,4a,5-ci.~-decahydro-5-[2-azine hydroxy~[4-(2-~luorolJhenyl)-l-piperazinyl~propyl]-2,3;4a,-~a-trans-naphthalenetetrol, tetraaeetate e.~ter 20 9 l-(3,4-dimethylphenyl) 3,4a,5-eis-deeahydro-5-~2-piperaæine hydroxy-3-[4-(3,4-dimethyl-henyl)-l-piperazinyl]~ropyl]-2,3;4a-,8a-trans-naphthalene-- tetrol, tetraaeetate ester l~ l-(2,6-dimethoxy~henyl) 3,~a,5-ei.s-deeahydro-5-[~-piperazine hydroY.y-3-[4-(2,6-dimetho~y-phenyl)-l-pipera7.inyl]propyl~-2,3;4a,8a-trans-naphthalene-tetrol, tetraaeetate ester ll l-(l-pyridyl)piperazine 3,4a,5-ei.s-~eeahydro-5-12-hydroxy-3-[4-(l-pyrldlnyl)-l-piperazinyl]propyl]-2,3;-~a,8a-tran~-naphthalelletetrol, tetraaeetate este~
~3~37 HA~43/55/56 . Colu3~ln I Colurr; JJ ;`
-- _.
121-(3 pyridyl)T?iperazine 3,4a,,~cis-decahy(lro-5~[2-hydroxy-3-~-(3-pyridinyl)- r ; l-~iperazinyl]propyl]-2,3;-4a,8a-trans-naphthalelletetrol, tetraact?tate e~tcr 131-(4-pyridyl)pipt?razine 3,4a,5-cis-decallydro-5-[2-h~ydro:cy-3-[4-(4-pyridinyl)-l-piperazinyl]propyl]-2,3;-~a,3a-trans-naj3~ht;halel~-tetrol, tetraacetate e.ster F.,ample 1~
3a,5-cis-3a,7a-5,6-trans-H-3exah clro-1-l2-h~clro~-3-,r4-(2-rrl-tho~-phenyl)-l_e~erazinyl; ~ l-intit_ne-3~J,5,-"7a-tetrt)l, t~tr(l-10 acetate ester, hydrochloridf.~
3a,5-fi~s-3a,7a;5,6-trc3n,-He~.ahy-lrc~-l-('-climethyl~mino-ropyl)-131-i~ren ~ a-tctrol, tetr-3.-3cct~3tc? ~citer, ~-oxide .~n amount of 2.ag of 85, m-chloro~erberzoic acid is ~3ddec~
to a solutiGn o 5.0g of 3a,5-cls-3a,7a;5,6-trans-hexahydro-1-(3-dlMethylaminopropyl) in 50 ml of ch1OroLorm .It - 0-5C. The cold bath is removed ancl thc mixturc- is sti3rcd for 3-1/2 hours under nitrosen. The solution i.5 partial ly evaporatecl in VaCUO and then chrornatoyraphe(1 on 98 c Gi r.cutral ~lumina III. ~lution with chloroform ar.d methanolic chlcrGforrn 20 yields, upon evaporation in vacuo, ~.6 y of thc ~!-o:~iclc as a - white solid.
3a,5-çl~-3a,7a;5,6-_ran ~ Ya~ly~lro-l-( indene-3a,5,6,7a-tetrol, tetraacetat~ ester The above N-oY~ide (4.6 5) is vacuurn pyrolyze~d at 16n-190CC
under 12 m~ Hc~T vacuum. The product is vacuurr~ disti]led to givc 2.1 g of crude olefin at 185-195C under 0.25 rrm lig vacuurn.
Further ~urification by chromatoyraphy on 35 cJ of ncutral Alumina III eluted with 15-2~ ethyl acetat-,-ie~anc Vie~-.'!-, ].O c~ oJ thc ol~fin as a whitc so]i(].
~ HA143/155/156 3a,5~cis-3a,7a~5,6-trans-Hexahydro-l-(oxiranylmethyl)--lH-indene-3a,5,6,7a-tetrol, tetraacetate ester -An amount of 0.52 g of 85~ m-chloroperbenzoic acid is added to a solution of 1.0 g of olefin in 25 ml of chloroform and the solution stirred for about 16 hours at room temperature.
The solution is partially evaporated in vacuo and then filtered through a column of 22 ~ of neutral Alumina III. Elution with 260 ml of 20-30% ethyl acetate-hexane yields 0.9 g of epoxide as a white solid.
3a,5-cis-3a,7a;5,6-trans-Hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-H-indene~3a,5,6,7a, tetrol, tetraacetate ester, hydrochloride (1:1) A solution of 0.9 g of epoxide and 0.43 g of _-methoxy-phenylpiperazine in 20:50 benzene-absolute ethanol is stirred for 18 hours in a 57C bath. The solvent is removed ln vacuo and the residue chromatographed on 25 g of neutral Alumina III.
Elution with 150 ml of 25-30% ethyl acetate-he~ane yields 0.53 g of forerun (mainly recovered epoxide). Elution with 200 ml of 35-40% ethyl acetate-hexane yields 0.57 g of the product as a free base. The free base is converted to the hydrochloride salt and recrystallized from ethyl acetate-ether to yield 0.5 g of the title compound, melting point 215-220C.
Anal. Calc'd. for C31H~4N2Olo. (641.16 g/m) C, 58.07; H, 7.08; N, 4.37; Cl, 5.53 Found: C, 57.89; H, 7.00; N, 4.31; Cl, S.67 Example 15 3,4a-cis-Hexahydro-5-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2,3;4a,9a-trans-benzocycloheptanetetrol, tetraacetate ester A~ 3,4a-cis-Hexahydro-5-(3-dimethylaminopropyl)-2,3;4a,9a-_ _ trans-benzocycloheptanetetrol, tetraacetate ester, N-oxide ___ A solution of 3,4a-cls-hexahydro-5-(3-dimethylaminopropyl)-~13~
~ t~ HA143/55/56 2,3;aa,9a-trans-benzocyclohep~ar.etetrol, tetraacetate e~;'cr (12.8 rr,mole) and rn-chloroperbenzoic acid (2.~ g) in chloro-form (100 ml) is prepared at 0C and gradually warmed to rooM temperature to yield the title ~-oxid(.
B) 3,4a-cis-llexahyclro 5-(2-propen~1)-2,3;4a,9a-trans-benY.
cyclo~eptanetetrol, t~traacetate ester The above N-oxi~e (10.8 mmole) is heated in a vacuum distillation set-up under 30 mm ~Ig vacuum Wit}l nitroqen hl.ee~
to yield the title olefin.
~ 10 C) 3,4a,5-~1~ exahydro- ~ .thyl.)-2,~;4~ L~Ul~-: benzocycloheptanetetrol, tetraacetate est~r A solution of the above tetraacetate-ole~in (5.9 r~nole) and 85~ m--chloroperbenzoic acid (1.3 c3) in chlorofor~, (50 ml) is prepared at 0C alld stirred at roorn temperat~rc for about 16 hours to yield the title epoxide.
` D) 3,4a~ lexahydrc-5-[2-hydroxy-3-[4-(2-n;etho~y~ nyl)-l-piperazinyl]propyl]-3,~; r,~ ~clo~.epi,ane-tetrol, tetraacetate ester A solution o~ 1-(2-methoxyphenyl)piperazinc (5.0 mrllole) and t~le above epoxide (5.0 mmole) in absolu~c eth.lrlol (50 ml) 20 and benzene (20 ml) is stirred in a ~.~arm :7atcr bath ~5n-r,5() for about 20 hours under a dryiny tuhe to yield the ti.tle compound.
~3~
Example 16 3,4a,S-~i~-5-~3-(3,6-Dihydro-4-pheIlyl-](2~)-pyridinyl)-2 ~ hydroxypropyl]~ecahydro-2~3;4a~8a-trans-naphth~llenetetr tetraacctate ~ster A solution of 2.5g of 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra acetate ester and 0.86g of 4-phenyl-1,2,3,6-tetrahydro-pyridine in 20 ml benzene-50 ml absolute ethanol is stirred at 55-57C for about 16 hours under a drying tube. The solution is evaporated in vacuo and the residue is crys-tallized from 30 ml of 1:2 ethyl acetate-ether to give 0.85g of solid. A second crop yields 0.35g of solid. Re-crystallization rom 2:1 ethyl acetate-ether yields l.ly of the title compound, melting point 133-199C.
: Example 17 Decahydro-5-[2-hyclro~ (]~4~5~o-tetrahydrohen~flic;oauinolin 3(2H)-yl)propy_]-3,4a,5-~ 2,3,4a,8a-tetraacetate ester -1,2,3,a,5,6-Hexahydrobenz[f]i.soquinolinc, mono-hydrochloride (l.Og) is dissolved in 20 ml of ~ater, layered over ~ith ether and neutralized with aqueous ammonia. The organic phase is removed and the aqueous phase is re-extracted with ether (two 20 ml portions). OrcJanics arc?
combined, dri.ed, filtered ancl strip~ed in vacuo to yield 0.75g of the free base, ~hich is dissolved in 20 ml of benzene and S0 ml of absolute ethanol. ',4a,5-c -Dccah!~rG-5-(oxiranylmethyl)-2,3;4a,8a-trans-nap}lthalcnctetrol, tetraacetate ester (1.~13g) is addcd to the solution, and the resultin~ solution is heated to 50C~S for 1~ hours.
Solvcnt is removed _ vacuo~ the residuc i.c taken up in ethcr and the rcsulting ~o~dcr is recrystal].izcd Irom c~thyl ~3~37 HA143/55/56 acetate to yield 1.17g of the title compounl.
Exam~le 18 .
3,4a,5~ -Decahydro-5-[2-hydrox~-3-~4-(2-phenvle~henyl)-3,6-dihydro-1(2H)-pyridinyl]propyl]-2,3,4a,8a-tran.s-naphthalenetetrol, tetraacetate ester A) 1,2,3,6-Tetrahydro-4-(2-phenylcthenyl)-1-(pheny]-methyl)pyrlc~lne, monohy rochlorlde W-Benzylstyrylpyridinium bromide (59.0g) is reduced by stirring in 750 ml of 50~ aqueous methanGl to which 30g of sodium borohydride is ac'ded portionwise.
Methanol is removed in vacuo, the resultinc3 slurry is filtered and the solids are partitioned bet~een water and chloroform. Thc aqueous layer is re-e~tractcd with chloroform. The chloroform extracts are combillccl, ~asllc?d with aqueous sodium chloride, dried and strippt-~d to vield 33.2g of the titlc compound. Four c;rams of this I)roduct is dissolved in absolute ethanol, acidified with arlhydrou hydrogen chloride in isopropanol, yielding 3.7y of sclid, ~hich is recrystallized frorn methanci-isoprcpanol to ~ielc 2.72g of crystals, melting point 235-240C.
B) 1~2~3~6-Tetrahydro-4-t2-JJhenylethenyl)pyridinc A solution of 46c3 1,2,3,6-tetrahydro-~-(2-phenethenylj-l-(phenylmethyl)~yridine in 150 ml of toluene is treated with 30.1~ of ~henyl chloroformatc and heated at reflux for 12 hours. Solvent is removed ln vacuo to yield 62.7g of a solid. The above solid is heated to 130C with the aid of an oil bath and 50g of po~der~d ~otassium hydro~ide is added, portionwise. Heating is continued for 90 minutcs, the mixture is cooled, taken up in 200 ml ~ater and e~.tracted with chloroform. Organics are comhined, washed with ac~ueou~
sot~ium chloride, dried, filtcred ancl strip!)ctl to yiel~l ~3(J
.. .. .. . .
- . , : . , . ~ .. . : , of an oil which is taken up in ether, filtered and s~rippcd to yield 33g of oil. Twenty-eight grams of the oil is reflu~ed in 1 liter of he~ane, the solvent is decanted from the oil, the oil is cooled to room temperature, filtered, then cooled in an ice box to yield a crystalline product.
~ue to the poor differential solubility, this process is repeated about eight times, yielding a total of 1.05c3 of the free base.
C) 3,4a,5-c s-Decahydro-5-[2-hydrox~-3-l~-(2-~henylr3thcnyl)-3!6-dihydro-1(2~)-pyridinyl]pro~yl]-2,3;4a,da-t_ans-naphthalenetetrol, t~traacetate ester 1,2,3,6-Tetrahvdro-4-(2-phc3nylethenyl)pyric'ine (1.04g) and 2.5q of 3,4a,5-cls-decahydro-5-(oxjranylrnelhyl)-2,3;4a,3a-trans-naphthalc3ne-tetrol, tetraacetate c~ster -Ire dissolved in 50 ml cf ~bsolutc eth~nol and 20 ml of bcn.~.en(?, and heated at 55OC~5r~ for 15 hours. Solvcnt is cv~poratcd in vacuo and the resulting gum cry.stallized from ether.
Solids are collected yielding 1.35g of browr~ solid WhiCIl is taken up in ethyl acetate, decolorizcd ~ith activatcd charcoal, filtered, hexane added and left standing. Resultin~
solids are collected and dried to yield l.Og of pow-ier, melting point 133-185C.
r,xample 19 -3,4a,5-~s-5-[3-[4-(2,3-Dihydro-2-he.nzoxazolyl)-3,6-dihy(lro-1(2_)-pyridinyl]-2-hydr~yprop~l]-decahy-lro-2,3;
naphthalenetetrol, tetraacetate ~3stcr A) 2-(4-Pyridinyl)benzoxa~ol~
A mixture of 2-aminophenol (10.9g), isonicotinic acid (12.3g) and polyphor~phoric acid (250g) is h~atc~ under a nitrogen atmo~ph~re at 210~C for 3 hours. rl~h~ mixture is then cooled to 160C and slow]y poured i.lltO 1 liter of water.
The mi~ture is cooled by ~ddinc~ ic~ an(l nelltr~lize~l with ~ . , 50'~ sodium hydroxid~ solutiorl yielding 16.2y of crude L)roduct.
Crvstallization from hexane yields 14.8g of the title compound, meltinc3 point 129-131C.
s) 4-(2-senzoxazolyl)-l-(phenylmethyl)pyridi~ium chloricle .
A solution of 117.0g of 2-(4-pyridinyl)benzoxazole and 95.0g of benzyl chloride in 1 1iter of a 9:1 rnixture of n-propanol and dimethylsulfoxide is heated at reflux for 72 hours. The solvent mixture is then removecl and the residue suspended in 100 ml of ~ater. Th~ crystalline product ~!hich separates is filtered, washed ~ith aCetOIIe, ar.d dried to give 76.6g of product. Concentration of the rr,othcr 1i.4uors gives an additional 27.~g of product, melting point 194-196C, dec. Recrystallization from water and drying in a vacuum at 100C for 5 hours raises ~o melting 1?0int to 216-217C, dec.
C) ?-(l-Benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzoxazolc~
To a stirred solution of 16.6g o 4-(2-benzoxazolyl)-l-(phenylmethyl)pyridinium chloride in 1 liter of a 1:1 mixture of alcohol and water is added a solution of 2.8~g of sodium borohydride at a rat~ that maintains the ternperaturc oL t11e mixture at 30-35ac. The reaction mixture is acidified ~lith hydrochloric acid, concentrated to one-half volu~e and t~e cryitals filtered to give 8.7g of the hydrochloride salt of the title cornPound, melting point 227-228C, dec.
The mother liquors are madc alkaline with solid sodium bicarbonate, extracted with chloroform and the extract concentrated to give a gummy residue. Recrystallization of this material from absolute alcohol gives 2.1g of ~he title compound, melting pOil.t 129-130C.
D) 4-(2-Penzoxazolyl)-3,~-d hyc1ro 1 _ 1) T~-~riclinec;lrbox~
acl(l, 2 2._2-trichloroc:thyl est(r ~ v~ ololl~,]y ~ r(~c~ ¢~]~ io~ r l()'3.
` ~143/55/56 a.3¢1~1~3!7 2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)benzo~azGle in 1 liter of dry toluene is added dropwise 96.4g of 2,2,2-trichloroethyl chloroformate during 2 hours and the mixture is heated at reflux for 1.5 hours. The reaction mixture is then cooled, extracted with 250 ml of cold 10% hydrochloric acid, with 250 ml of cold 10~ aqueous sodium hydroxide solution, and with an equal volume of ~ater, dried (anhydrous magnesium sulfate), and concentratcd. l'he oily re.sidue is then further concentrated from an oil bath maintaine~cl at 50C und~r a vacuum of 0.2 nm of Hg to removc tho ramainio~
benzyl chloride. ;
The viscous oil is dissolved in 500 ml of hoiling absolute ethanol and cooled to give, after filtration and drying, 56.9g~ of crystallinc product, meltlng point 13~-135GC.
The mother liquors give, after concentration to one-half volume and cooling an additional ll.Og of product identical with that above.
~) 2-(1,2,3,6-Tetrahydro-~-pyridinyl)henzoxazole ~To a solution of 52.6g of 4-(2-~enzoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloro~thyl ester in 1250 ml of glacial acetic acid is gradually addecl 92.5g of zinc dust and the reaction mixture~s~irred at room temperature under nitrogen for 6 hours. The reaction nlixture is filtered and concentrated on the rotary evaporator to givc a viscous gum. This r.naterial is suspended in 500 ml of ~ater, `~
the pH ~djusted to 2-3, and the suspension extracted with 500 ml of ether in two portions. These are combi;ned, drie~
and concentrated to give 11.32g of unreacted startirlg ~aterial.
The separated turbid, a~ueous phas,o is filtered, coolcd, madc strollgly alkaline~ and extractc(3 th~c ~inlo!;
with 250 ml portlons Gf chloroform. The com~ine~ e~.tracts are dried and concentrated to give 6.0g of crystal, melting point 136-138C.
F) 3,4a,5-cis-5-[3-[4-(2,3-~ihydro-2-henzoxazolyl)-3,6-dihydro-1(2~)-pyridinyl]~2-hydroxypropyl]-dec~hy~lro-2,3j4a~8a-tra~-naphthalenetetrol~ tetraacetate e~ter , Three grams of 3,aa,5-cis-decahydro 5-(o.Yiranyl-methyl)-2~3;aa~8a-trans-naphthalenetetrol~ tetraacetate ester is dissolved in 50 ml of absolute ethanol and 20 ml of benzene. To this is add~ 1.34g of 2-(1,2,3,6-tetra-hydro-4-p~ridinyl)~enzoxazole and t~.e resultiny solution is heated to 55C+5 for 16 hours. Solverlt is stripped in vacuo and the resulting gum is taken up in e~her. The ether solution is filtered, ailuted with he:cane an~i lcf~
standing. Solids are collectecl to yield 3~J of solid .~hich is recrystallized from ethyl acetate anc~ he~ane to yield 1.6g of the title compound, melting point 204-210C, dec.
Example 20 3,4a,5-~-~-Decahydro-5-[2-hyc`roxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)~ropyl~-2,3;4a,8a-~r~ns-na~hthalenetetrol, tetraacetate ester A solution of 3.0g of 3,4a,5-cis-decahy(lro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester and 0.94y of 1,2,3,4-tetrahy~roisoquinoline in ethanol-benzene (50:20) is warmed in a 55~C bath for about 16 hours. The solution is evaporated ln vacuo to giue 4g of solid. T~70 recrystallizations from ethyl acetate/ether/hexane yield l.9g of the title compound, melting point 185-195C~
' ' EY~ample 21 3 ! 4a,5-cis-Decahydro-5-[2-hydro~y-3-(4,5,6,?-tetrahydro-1~
imldazo[4, ~ )pro~yl]-2,3;4a,8a-trans-naphtha-lenetetrol To a solution of 0.55g of sodium hydro~ide in 30 ml of absolute ethallol is added 1.35y of 4,5,6,7-tetra-hydro-lH-imidazo[4,5-c]pyridine, hydrochloride. After stirring for about 5 minut~s a solution of 3.0g of 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-na~hthalcne-tetrol, tetraacetate ester in 3n:5~ etharlcl:~enzene is added and the solution is stirred fGr about 16 hours at 40-45C. -~
The mixture is filtered and 'he filtrate is eva~orat~ n vacuo to give 3.8y of foam. The foam is ciicsolve~l in 5~:2 ethanol:benzene and stirred for 24 hours at 55-58'C. 1~he solvent is removed ln vacuo and the residue i'3 di~solvecl in ethyl acetate, heated ~Jith activated charcoal and filtered.
After diluting with a small amount of ether and storing at -15C for 3 days, 1.3g of solid is obtained. Recrystallization from ethyl acetate (trace methanol) yields l.ny of th~ titlc 20 compound, melting point 214-216C.
..
~ 7 ~A143/S5/56 E~amples 22-23 Following the procedure of ~xample 16, kut substituting the compound listed in column I for 3,4a,5~c -decahydro-S-(oxiranylmethyl)-2,3;4a,~a-trans-naphthalenetetrol, tetra-acetate ester, yields the com~ound listed in column II.
Column I Column II
22 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trar.s-hexahydro-l-(oxiranylmethyl)~ he~ahydro~ 3-(3,~-dih~Zro-lH-indene-3a,5,6,7a-tetrOl, 4-phcny~-1(211)-pyridinyl)-tetraacetate ester (see 2-hydroxyprop~Jl]~ indene-United States patent No. 3a,5,6,7a-tetrol, tetra-
4,101,723 issued July 18, a~etat~ ~stcr 23 3,4a,5-cis-hexahydro-5- 3~4a-ci.s-hcY.a}lydro-5-[3-toxiranylmethyl)-2,3;4a,9a- (3,6-~ihyclro-4-phenyl 1(2~
trans-benzocyclohe~tanetetrol- pyridinyl)-~-hydrox~propyl]-tetraacetate ester (see 2,3;4a,9a-trans-benzocyclo-United States patent No. heptanetetrol, tetraacctate 4,101,723 issued July 18, ester ~xamples 24-25 Follo~ing the procedur~ of r:~ample 17, but substituting the compound li.sted in.column I for 3,qa,5-cis-decahydro-5-(o~iranylmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetraacetate ester, yields the compound listed in column II.
Column I C~].umn II
24 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-tr~ns- ' hexah ~ o-l-(oxiranylmethvl)- hexahydro-l-[2-hyclroxy-3-l~l-indene-3a,5,6,7a-tetroi, (1,4,5,~-tetrahyclrohenz[f]-tetraacetate ester isoquinolin-3(2}1)-yl)propyl~-indene-3a,5,6,7a-tetrol, tetraacetate estcr 3,4a,5-cis-hexahydro-S- 3,4a-cis-hexahyclro-5-~2-(oxiranylmethyl)-2,3;4a,9a- hydro~v-3-(1,4,~6-tctra-trans-benzocycloheptane- hydrobenz[~]isoq~inolin-tetrol, tetraacetate ester 3(2H)-y3.)propyl]-~,3;4a,9a-trans-benzocyclohc~tanetetrol, tetraacct~te ester B
~3~'7 HA143/55/56 Examples 26-27 ~ollowing the procedure of Ex~mple 18, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-~oxiranyl~.ethyl)-2,3;4a,8a-tr~ns-naphthalenetetrol, ~etra-acetate ester, yields the compound listed in colun~n II.
Column I Colu~.n II
26 3a,5-cis-3a,7a;5,~-trans- 3a,5-cis-3a,7a;5,~-trans-hexahydro-l-(oxiranylmcthyl)- he~ah ~ c-l- ! 2-~ydr ~ -l~l-indene-3a,5,6,7a-tetrol, [4-(1-ph~.:nyleth~nyl)-~,6-tetraacetate ester dihydro-1(2~ yridinyl]-r~ropy~ nd~nr~-3~5/6 7a-tetrol, tetraLlcet~tc ~ster ' 27 3,4a,5-cis-heY.ahydro-5- 3,~a-cis-~c~ally~ro-5-[2-(oxiran~lrn2thyl)-2,3;4a,9a- hydro~y-3-[4-(1-phenyl-tràns-henzocycloheptane- ~thcnyl)-3,5-dihydro-tetrol, tetraacetate ester 1(2l~)-pyri~inyl]propyl]-2,3,4a,9a-trans-benzocyclo-hcptanetctrol, tctra-acetate ester r;Y~amples 28-29 Following the procedure of Examnle 19, but substituting the compound listed in columrl I for 3,4a,5-cl~-decahydro-5-(Gxiran~l-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacet~te ester, yieid~
the compound listed in column II.
Column I Column II
28 3a,5-cis-3a,7a;5,6-trans- 3~,5-cis-3a,7a;5,6-trans-hexahydro-l-(oxiranylrnethyl)- heY~ahydro-1-[3-[4-(2,3-l~l-indene-3a,5,6,7a-tetrol, clihyclro-2-hen~ovazolyl)-tetraacetate ester 3,6-dihy~ro-1(2~1)-pyridiny3 2-hvdroxypro~yl~-lH-indenc~-- 3a,~,6,7a-tetrol, tetra-. acetate ester 29 3,4a,5-cis-hexahydro-5- 3,4a-cis-he~:ahydro-5-[3-[4-(oxiranylmethyl)-2,3;4a,9a- (~,3-(lihydro-2-henzoxa~oly trans-benzocycloheptane- 3,6-dihyro-1(2~)~pyridir.;
tetrol, t2traacetate ester ~-hydro~.ypropyl~-2,3;4~, 9a trar,s-benzocycloher)t~ne-tetrol, tetraacetate ester .
23 ~
E~ `
i.3'~ HA19 3/5 5/ 5 6 ~am~lc~ 30-31 ~ ollo~-~ing the procedure or ~:ample 20, but substituting the compound listed in column I for 3,4a,5-cls-decahydro-S-~oxiranyl-methyl)-2,3;4a,8a-tra~.~-naphthalenete~rol, tetraacetate ester, yieldc Lhe co~ound listed ir. column II.
Column I Column II
-3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trans-hexahydro-l-(oxiranylmethyl)- hcxah~-o-1-[2-hy~lro~y-3-lH~indene-3a,5,6,7a-tetrol, (1,2,3,4-tetrahydro-2-t~traacetate ~ster icoquinolinyl)nro~yl]-lll-indcne-3a,5,h,ia-te~rol, tetraacet,ate estcr 31 3,4a,5 cis-~.exahydro-5- 3,4a-cis-hexahydxo-5-[2-(oxiranylmethyl)-~,3;4a,9a- hydroxy-3-(1,2,3,4-tetra-trans-benzocvcloheptar:e.- hy~ro-2-isoquinolinyl)-tetrol, tetraacetate ester propvl]-~ 7 3;4a,9a-trans-benzocycloheptan~tetrol, tetraacctatc ester Exam?les 32-33 Follo~Jing the procedurc of ~xample 21, but substituting the compound listed in column I for 3,4a,5-cis-dccahydro-S-(oxiranylmethyl)-2,3i4a,8a-trans-naphthalenc-tetrol, tctra-acetate.ester, yields the compound liste~ ir. colulr!r. II.
Column I . Co].umn JI
32 3a,5-cis-3a,7a;5,7-trans- 3a,5-,ci.s-3a,7a;5,6-trans-hexahydro-l-(oxiranylmethyl)- hexahydro-l-[2 hydroxy-3- .
l~l-indene--3a,5,6,7a-t~krol, ~4,5,6,7-tetrahydro-lJI-tetraacetate ester imidazo[4,5-c]pyridin-5-yl)propyl]-lll-inden~-3
trans-benzocyclohe~tanetetrol- pyridinyl)-~-hydrox~propyl]-tetraacetate ester (see 2,3;4a,9a-trans-benzocyclo-United States patent No. heptanetetrol, tetraacctate 4,101,723 issued July 18, ester ~xamples 24-25 Follo~ing the procedur~ of r:~ample 17, but substituting the compound li.sted in.column I for 3,qa,5-cis-decahydro-5-(o~iranylmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetraacetate ester, yields the compound listed in column II.
Column I C~].umn II
24 3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-tr~ns- ' hexah ~ o-l-(oxiranylmethvl)- hexahydro-l-[2-hyclroxy-3-l~l-indene-3a,5,6,7a-tetroi, (1,4,5,~-tetrahyclrohenz[f]-tetraacetate ester isoquinolin-3(2}1)-yl)propyl~-indene-3a,5,6,7a-tetrol, tetraacetate estcr 3,4a,5-cis-hexahydro-S- 3,4a-cis-hexahyclro-5-~2-(oxiranylmethyl)-2,3;4a,9a- hydro~v-3-(1,4,~6-tctra-trans-benzocycloheptane- hydrobenz[~]isoq~inolin-tetrol, tetraacetate ester 3(2H)-y3.)propyl]-~,3;4a,9a-trans-benzocyclohc~tanetetrol, tetraacct~te ester B
~3~'7 HA143/55/56 Examples 26-27 ~ollowing the procedure of Ex~mple 18, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-~oxiranyl~.ethyl)-2,3;4a,8a-tr~ns-naphthalenetetrol, ~etra-acetate ester, yields the compound listed in colun~n II.
Column I Colu~.n II
26 3a,5-cis-3a,7a;5,~-trans- 3a,5-cis-3a,7a;5,~-trans-hexahydro-l-(oxiranylmcthyl)- he~ah ~ c-l- ! 2-~ydr ~ -l~l-indene-3a,5,6,7a-tetrol, [4-(1-ph~.:nyleth~nyl)-~,6-tetraacetate ester dihydro-1(2~ yridinyl]-r~ropy~ nd~nr~-3~5/6 7a-tetrol, tetraLlcet~tc ~ster ' 27 3,4a,5-cis-heY.ahydro-5- 3,~a-cis-~c~ally~ro-5-[2-(oxiran~lrn2thyl)-2,3;4a,9a- hydro~y-3-[4-(1-phenyl-tràns-henzocycloheptane- ~thcnyl)-3,5-dihydro-tetrol, tetraacetate ester 1(2l~)-pyri~inyl]propyl]-2,3,4a,9a-trans-benzocyclo-hcptanetctrol, tctra-acetate ester r;Y~amples 28-29 Following the procedure of Examnle 19, but substituting the compound listed in columrl I for 3,4a,5-cl~-decahydro-5-(Gxiran~l-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacet~te ester, yieid~
the compound listed in column II.
Column I Column II
28 3a,5-cis-3a,7a;5,6-trans- 3~,5-cis-3a,7a;5,6-trans-hexahydro-l-(oxiranylrnethyl)- heY~ahydro-1-[3-[4-(2,3-l~l-indene-3a,5,6,7a-tetrol, clihyclro-2-hen~ovazolyl)-tetraacetate ester 3,6-dihy~ro-1(2~1)-pyridiny3 2-hvdroxypro~yl~-lH-indenc~-- 3a,~,6,7a-tetrol, tetra-. acetate ester 29 3,4a,5-cis-hexahydro-5- 3,4a-cis-he~:ahydro-5-[3-[4-(oxiranylmethyl)-2,3;4a,9a- (~,3-(lihydro-2-henzoxa~oly trans-benzocycloheptane- 3,6-dihyro-1(2~)~pyridir.;
tetrol, t2traacetate ester ~-hydro~.ypropyl~-2,3;4~, 9a trar,s-benzocycloher)t~ne-tetrol, tetraacetate ester .
23 ~
E~ `
i.3'~ HA19 3/5 5/ 5 6 ~am~lc~ 30-31 ~ ollo~-~ing the procedure or ~:ample 20, but substituting the compound listed in column I for 3,4a,5-cls-decahydro-S-~oxiranyl-methyl)-2,3;4a,8a-tra~.~-naphthalenete~rol, tetraacetate ester, yieldc Lhe co~ound listed ir. column II.
Column I Column II
-3a,5-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7a;5,6-trans-hexahydro-l-(oxiranylmethyl)- hcxah~-o-1-[2-hy~lro~y-3-lH~indene-3a,5,6,7a-tetrol, (1,2,3,4-tetrahydro-2-t~traacetate ~ster icoquinolinyl)nro~yl]-lll-indcne-3a,5,h,ia-te~rol, tetraacet,ate estcr 31 3,4a,5 cis-~.exahydro-5- 3,4a-cis-hexahydxo-5-[2-(oxiranylmethyl)-~,3;4a,9a- hydroxy-3-(1,2,3,4-tetra-trans-benzocvcloheptar:e.- hy~ro-2-isoquinolinyl)-tetrol, tetraacetate ester propvl]-~ 7 3;4a,9a-trans-benzocycloheptan~tetrol, tetraacctatc ester Exam?les 32-33 Follo~Jing the procedurc of ~xample 21, but substituting the compound listed in column I for 3,4a,5-cis-dccahydro-S-(oxiranylmethyl)-2,3i4a,8a-trans-naphthalenc-tetrol, tctra-acetate.ester, yields the compound liste~ ir. colulr!r. II.
Column I . Co].umn JI
32 3a,5-cis-3a,7a;5,7-trans- 3a,5-,ci.s-3a,7a;5,6-trans-hexahydro-l-(oxiranylmethyl)- hexahydro-l-[2 hydroxy-3- .
l~l-indene--3a,5,6,7a-t~krol, ~4,5,6,7-tetrahydro-lJI-tetraacetate ester imidazo[4,5-c]pyridin-5-yl)propyl]-lll-inden~-3
5,G,7a-tetrol, tetra-` . . acetate cster.
33 3,4a,5-cis-hexahydro-5-(oxi- 3,4a-cis-hexahydro-5-[2-ranylmethyl)-2,3i4a,9a-trans- hydroxy-3-(4,5,6,7-tetra-henzocycloheptanete~rol, ~ hydro-1ll-imidaYo[4,5-c]-tetraacetate ester pyridin-5-yl)propyl]-2,3;-. . . 4a,9a-trans-benzocyclo--. - . hrptanetc~L-ol, te.tra-. acetar~ c~;t-r .
~ r~7 HA1~3/55/56 E~ample 34 3,4a,5-~iLc-!jer.ih~-.l o=5-[2-1~dro~y-3-[4-[(l-oxopropyl)-phenylarnino]~ c~ridin~ir~ ~ 3 ,~a-tran.s-na~hthalenetetrol, tetraacc~.ate ester 3,4a,5-cis-Decahydro~S~(oxiranylmethyl)--2,3;4a, 8a-trans-naphthalenetetrol, tetraacetate ester 3.37g is -dissolved in 50 ml of absolute ethanol and 20 ml of benzene.
To this solution is added 1.75g of N-phenyl-N-~piperi dinylpropanamide and the resulting solution is heated to 55C + 50 for 16 hours. The solvent is stripped off ln vacuo and the resulting gum is taken up in ether and left for about 16 hours to crystallize, yielding ~after drying) 3.9g of powder. Crystallization of the powder from ethyl acetate-hexane yielding 3.lg of powder, melting point 153-160C.
Example_35 1-[2-~i~droxy-3-[~l~-1,7,8a-4a,6,7,8a-1etra)is(acet~1Oxy)-decah~ydro-1-naphthalenyl]propyl]-4-phenyl-4-pi~ dine-carbonitrile A soIution of l.ng of 4-cyano-4-phen~lpiperidine and 2.5g of 3,4a,5-cis-decah~ydro-5-(oY~irclnylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tctraacetate estcr in 20ml henzene-50ml ethanol is stirred at 55-57C for about lG hours under a drying tu~e. The solution is eva~orcltcd ln va~uo to give 3.3c3 of oil. Chromatoyraphy on 80g of nelltral alun:ina llI
gives 1.06 of epoxide eluted with 60n rnl or. 20-25~ ethyl acetate in hexane, and 1.4g of the desired product eluted ith 750ml of 40-45~ ethyl acetate in hcxane. Cryctallization of this latter matexial from ethyl ac~tate hexane gives t~o crops of solid product. These are cornbined and dried ~n vacuo to yield 0.97(1 of the title compound, rnelting ~)oint 165-174C.
~ HA143/55/56 r`xarr!3jlc 36 3,4a,5- Q -Decahydro-5~[2-hy~roxy-3-(~-hydroxy-~-J)henyl-l-piperidinyl)propyl]-2 3;4a,3a-trans-naphthaleretetl~ol tetra-acetate ester A solution of 3.0g of 3,4a,5-cls-decahydro-5-(oxiranyl-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr and 1.25~ of 4-hydroxy-4-phenyl piperidine in 50ml of al~solute ethanol-20ml benzene is stir-ed at 57C for about 16 hours.
Crystallization from 2:1 cthyl acetat~-hexane cliv-s 3.5-~ o~
solid. Recrystallization from ethyl acctate-hcx-lnc (?0:5) gives 2.11g of the title comr.ound, melting l~oint 13P-142C.
Example 37 3,4a,5-c s-Decahydro-5-[2-hydroxy-3-(3,4~dillydrosl~iro~2~
benzopyran-2,4'-plperidin]-1-yl)propyl]-2,3;4a,8a-tr~n.s-na~hthalenetetrol, tetraacetate ester A) 3,4-Dih~dro-1'-(phenylmethyl)spiro[~ }-~en~o~rarl-2 4'-Eiperidine], hydrochloride (1:1) 4-(o-Methoxyphenethy])py~idine (40.5 y) and henzyl-bromide (36.0 g) are heated on a steam cone iri 250 ml of acetonitrilc for 6 hours. A~ter coolinc3 the rcaction mi~turc is concentratcd in vacuo. Addition of ethyl acetatc CclUS~S
crystallization. The product is filtered, washed with etllcr and dried over potassium hydroxide. rhe yield of a hydro-scopic quaternar~ is 68.4 g, melting point il4-124C.
rhe above quaternary (60.6 g) is dissolved in 600 ml of 1:1 methanol-water and 10 g of sodium 3~orohydride is added portionwise at 35~40C. After addition, the solution is allowed to stand for about 16 hours. It is then conccntrated to about 400 ml and diluted with 3no ml of water. The product is extracted with two 300 ml portions o~ c~.loroform. ~J33~.c chloroform i5 dried, filtered and concentrated ln ~cuo.
The hydrochlori(1c salt is prepare(3 in isor~roE~anol-hydro-len - 2~ -~3~3~ HA143/55/56 ehloride. ~fter eoneentrating in vaeuo, eth~ aeetate is added to the residue. The hydrochloride salt erystallizes over a 16-hour period and ~s filtered to yie~d 5a cJ of product, melting point 122-12soc.
The above product (54.0 y) is dissolved in 2sn ml of 48% hydrogen bromicle. It is then heated at r~flux for
33 3,4a,5-cis-hexahydro-5-(oxi- 3,4a-cis-hexahydro-5-[2-ranylmethyl)-2,3i4a,9a-trans- hydroxy-3-(4,5,6,7-tetra-henzocycloheptanete~rol, ~ hydro-1ll-imidaYo[4,5-c]-tetraacetate ester pyridin-5-yl)propyl]-2,3;-. . . 4a,9a-trans-benzocyclo--. - . hrptanetc~L-ol, te.tra-. acetar~ c~;t-r .
~ r~7 HA1~3/55/56 E~ample 34 3,4a,5-~iLc-!jer.ih~-.l o=5-[2-1~dro~y-3-[4-[(l-oxopropyl)-phenylarnino]~ c~ridin~ir~ ~ 3 ,~a-tran.s-na~hthalenetetrol, tetraacc~.ate ester 3,4a,5-cis-Decahydro~S~(oxiranylmethyl)--2,3;4a, 8a-trans-naphthalenetetrol, tetraacetate ester 3.37g is -dissolved in 50 ml of absolute ethanol and 20 ml of benzene.
To this solution is added 1.75g of N-phenyl-N-~piperi dinylpropanamide and the resulting solution is heated to 55C + 50 for 16 hours. The solvent is stripped off ln vacuo and the resulting gum is taken up in ether and left for about 16 hours to crystallize, yielding ~after drying) 3.9g of powder. Crystallization of the powder from ethyl acetate-hexane yielding 3.lg of powder, melting point 153-160C.
Example_35 1-[2-~i~droxy-3-[~l~-1,7,8a-4a,6,7,8a-1etra)is(acet~1Oxy)-decah~ydro-1-naphthalenyl]propyl]-4-phenyl-4-pi~ dine-carbonitrile A soIution of l.ng of 4-cyano-4-phen~lpiperidine and 2.5g of 3,4a,5-cis-decah~ydro-5-(oY~irclnylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tctraacetate estcr in 20ml henzene-50ml ethanol is stirred at 55-57C for about lG hours under a drying tu~e. The solution is eva~orcltcd ln va~uo to give 3.3c3 of oil. Chromatoyraphy on 80g of nelltral alun:ina llI
gives 1.06 of epoxide eluted with 60n rnl or. 20-25~ ethyl acetate in hexane, and 1.4g of the desired product eluted ith 750ml of 40-45~ ethyl acetate in hcxane. Cryctallization of this latter matexial from ethyl ac~tate hexane gives t~o crops of solid product. These are cornbined and dried ~n vacuo to yield 0.97(1 of the title compound, rnelting ~)oint 165-174C.
~ HA143/55/56 r`xarr!3jlc 36 3,4a,5- Q -Decahydro-5~[2-hy~roxy-3-(~-hydroxy-~-J)henyl-l-piperidinyl)propyl]-2 3;4a,3a-trans-naphthaleretetl~ol tetra-acetate ester A solution of 3.0g of 3,4a,5-cls-decahydro-5-(oxiranyl-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate estcr and 1.25~ of 4-hydroxy-4-phenyl piperidine in 50ml of al~solute ethanol-20ml benzene is stir-ed at 57C for about 16 hours.
Crystallization from 2:1 cthyl acetat~-hexane cliv-s 3.5-~ o~
solid. Recrystallization from ethyl acctate-hcx-lnc (?0:5) gives 2.11g of the title comr.ound, melting l~oint 13P-142C.
Example 37 3,4a,5-c s-Decahydro-5-[2-hydroxy-3-(3,4~dillydrosl~iro~2~
benzopyran-2,4'-plperidin]-1-yl)propyl]-2,3;4a,8a-tr~n.s-na~hthalenetetrol, tetraacetate ester A) 3,4-Dih~dro-1'-(phenylmethyl)spiro[~ }-~en~o~rarl-2 4'-Eiperidine], hydrochloride (1:1) 4-(o-Methoxyphenethy])py~idine (40.5 y) and henzyl-bromide (36.0 g) are heated on a steam cone iri 250 ml of acetonitrilc for 6 hours. A~ter coolinc3 the rcaction mi~turc is concentratcd in vacuo. Addition of ethyl acetatc CclUS~S
crystallization. The product is filtered, washed with etllcr and dried over potassium hydroxide. rhe yield of a hydro-scopic quaternar~ is 68.4 g, melting point il4-124C.
rhe above quaternary (60.6 g) is dissolved in 600 ml of 1:1 methanol-water and 10 g of sodium 3~orohydride is added portionwise at 35~40C. After addition, the solution is allowed to stand for about 16 hours. It is then conccntrated to about 400 ml and diluted with 3no ml of water. The product is extracted with two 300 ml portions o~ c~.loroform. ~J33~.c chloroform i5 dried, filtered and concentrated ln ~cuo.
The hydrochlori(1c salt is prepare(3 in isor~roE~anol-hydro-len - 2~ -~3~3~ HA143/55/56 ehloride. ~fter eoneentrating in vaeuo, eth~ aeetate is added to the residue. The hydrochloride salt erystallizes over a 16-hour period and ~s filtered to yie~d 5a cJ of product, melting point 122-12soc.
The above product (54.0 y) is dissolved in 2sn ml of 48% hydrogen bromicle. It is then heated at r~flux for
6 hours and coneentrated in vacuo. The resiclue is made strongly basie with 10% sodium hydroxide and the prod-1ct is extraeted with ehloroform. The ehloroform is dried, filtered and concentrated in vacuo. This frec hase is dissolve(1 in ethyl aeetate,and hydrogen chloride in isoproparol is added until strongly acidic. The product is filter(d to yield 39.4 g~ Two grams are recrystallized frorn aeetonitrilc to give the analytical sample, meltincJ point 243-245C.
B) 3,4-Dihydrospiro[2~ c-~n7.opyran-2,a -pir)cri(lirl(?
-3,4-Dihydro-l -(phenylmethyl)spiro[21~ h,ellzo[~r~
2,4 -piperidine] (25.? g) is dissolved in 250 ml of anh~!drous toluene. The reaetion mixture is eooled to 5C ard trichloro-ethyl ehloroformate is added dropt~ise. The solution is refluxed for 5 l1ourc and al1c~ed to stand at room tc~ )erature for about 16 hours. It is then washed sec~u~ntially with 100 ml of 10~ sodium hydroxide, 100 ml of ~ater, 100 ml o~
10~ hydroehlorie aeid ~nd fir!ally ~ith 200 ml of ~,ater. Tne toluene is dried, filtered and eoneentratcd in vacuo to yield 32.0 g of product.
The above material is dissolved in 300 ml of glacial acetic acid. Zine dust (30 g) is added portion~ise over a 30-minute period at 20C. The reaetion mixture i5 ~3tirred at roorn temperature for about 16 llours, filtcrcd arld concen-tr~ted in vacuo. Ihe r ;id~3c is h(e~ () Oll a 'i~(!aln (,Orl~ 30r ~3~3~7 HA143/55/56 15 minutes in 200 ml of 10~c sodium hydroxide. Product is extracted with chloroform. The chloroform is dried, filtered and concentrated in vacuo to yield 17.8 g of crude secondary amine. Its h~drochloride salt was prepared in isopropar.ol-hydrogen chloride. ~.fter crystallizing for about 16 hours, the product is filtered to ~ield 11.1 g of the hydrochloride salt of the title compound, melti.ng point 238-240C.
C) 3,4a,5-~L~-~ecahydro-5-[2-hydrox~-3-(3,4-dihyclrospiro-[2H-l-henzopyran-2,4-piperidin]-1-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacctate ester An amount of 1.7 y of 3,4-dihydrosplro[21l-1-bclllzopyran-2,4'-piperidine] is added to a solution of 3.55 ~I o~ 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalcnc-tetrol, tetraacetate ester in 50:20 ml of ethanol-bcni~enc.
rrhe solution is stirrcd for about 16 hours at 55C and th~n evaporated in vacuo. The residue is crystallizecl ovrr 3 days from 2:1 ether-hexane to give 3.6 g of ~solid. r~ec~ys~al-lization from ethyl acetate-hexane gives 2.3 (1 oE thc tit]e compound (thin-layer chromatoc3raph~ on alumina in ethyl acet:ate developed in iodine indicatc:s thc ti-tle cornpound to bc thc main isomer of two isomers), melting point 135-152C~
~xamPle 38 3,4a,5-c s-Decahydro-5-[2-hydroxy-3-[4-(2-h~dro~:yt-th~
piperidinyl]propyl]-2~3i4a~8a-~rn~-naphthalcnetetrol~ tetr,-~-acetate estcr ~ solution of 2.5 g of-3,4a,5-cis-decahydro-5-(o~.ir~r.~i-methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tctraacctatc e.stcr and 0.75 g of 4-ethanolpiperidine in 50 ml of abxGlutc eth,-lnol and 20 ml of benzene is stirred at 55C ior 18 hour.-;. '~'hc solvents are removed n vacuo and the reiidue i.s concen-tl^ated in _ several times with bcnzene to livc a ~o,lrn-like pro(luct.
Crystnllization f-roM et~(~r (3ivc<s 2. 55 ~3 ;.lrld t~,c~r").5 ~3 (,f HA14~/55/56 ~3~
solid product. Recrystallization of the 3 g ~f solid from 2:1 ethyl acetate-hexane gives 2.0 g of the title compound, melting point 112-120C.
Example 39 3,4a,5-L~-5-[2-(Ace~~loY~y)-3-[4-[2-(acetyloY~y)eth-l]-l-~iperidlnyl]~ropyl]-decahydro-2,3;4a,8a-trans-naphthalenc-tetrol, tetraacetate ester A mi~turc of 5 ml of acetic anh~dride and 1.25 g of 3,4a,5-c -decahydro-5-[2-hydroxy-3-[4-(2-hydroY.yethyl)-l-piperidinyl]propyl]-2,3;4a,8a-trans-naphthalcr.etc~trol, tetraacetate ester (see Exam~le 5) in 25 ml of dry pyridine is stirred at room temperature for about 16 hours. The solution is evaporated in vacuo. The residue i5 partitioncd between ether and a saturated aqueous sodiuln ~ic~rhonate solution. The aqueous layer i5 re-extracted witn ether, and the ether extracts are comhincd, dried and c~/aIjoratcc' in vacuo yieldlng 1.3 g of product~ r~ecryc~tallizatiorl rron, 1:9 ethyl acetate-hexane yields 1.22 q of the title compound, melting point 125-144C.
~xample 40 3,4a,5~ -5-[3-(2,3-Dihydro-2-oxo-l~-henæimidazol-l-yl)-l-pi~eridinyl~-2-hydroxypropyl]decahyclro-2,3;4a,8a-trans-na~hthalenetetrol, tetraacetate ester An amoun-t of 1.5 g of 3,4a,5-c -decahydro-5-(c)~iranyl-methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tetraacetatc cs~cr is dissolved in 20 m] of benzene and 50 ml of a},,olute e~}larlol and maintained at 50C~5 with a water ~ath. To this is added 0.73 q of 4-(2-keto-1-~enzimidazolinyl)pipcri~ine and stirrinq is continued for 36 hours. Solvent is strippcd in vacuo, and the product is cry~tallized from cthyl acetate-hexane to yicld 1.67 g of material, nlelting point 137-144GCo ~ 29 -~xa~le 41 3,4a,5~ 5-[3-[4-(2-Benzoxazolyl)-l=piperidinyl]-2-hydroxypropyl]-decahydro-2,3;4a,8a-naphthalenetetrol, tetraacetate ester A) 2-(4-Piperidinyl)~enzoxazole A solution of 1.71 g of benæyl bromide in 10 rnl of acetonitrile is added to a solution of 1.96 g c,f 2-(4-pyridinyl)benzoxazole in 25 ml of hot acetonitrile. ~fter 10 minutes the product be~ins to crvstallize out of solution.
The mixture is heated on the steam hath for 2 hours and then diluted with ether and filtered. The crude solid is dissolved in 50 ml of 1:1 methanol-water and treated portion~ise with 2 g of sodium borohydridc. The mixture is diluted with water and 2.4 g of the solid product is collected. The 2.4 y of solid is dissolved ir. 150 ml of ethanol, 2 g of 5% paladium on car~on is added, and the mixture is placed on the Parr hydrogenatGr under 50 psi hydrogen. I'he mixture is filtered, and the filtr 2t~
evaporated in vacuo to give 1.4 g of the title compound.
B) 3,4a,5-~i~5-~3-[4-t2-Ben_o azolv~l)-l-pi~eridinyl]-2 hydroxypropyl]decahydro-2,3,4a,8a-~ -naphthalene~
tetrol, tetraacetate ester A solution of 3.6 g of 3,4a,5-cis-decahydro-5-(oxiranyl-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate est~r and 1.4 g of the 2-(4-piperidinyl)benzoxazole in 20 ml of benzene and 50 ml of absolute ethanol is stirred for 7.5 hours at 55C and then for a~out 16 hours at room tenlperature under nitro~en. The solution is evapora~ed in V2CUO and the residue dissolved in hot ethyl acetate (30-90 ml), diluted with hexane (30 ml) and crystallized on standin~ lo yivc 3.14 y OL ~olid. q'he solid is disso]vec] in }lOt ethyl acctatc (50 ~ ), treated with l)arco, fi~erec'f aIcl ~ 3~ HA143/55/56 dilut~d ~ith h~Y.ane (20 ml). The solution c-ystallizes to give 2.02 9 of the t tle compound, meltinq point 195-205~C.
Examples 42-43 Following the procedure of ~xample 34, but substituting the compound listed in column I for 3,9a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in column II.
Column I Column II
42) 3a,5-cis-3a,7a;5,6-trans~ 3a,5-ci.s-3a,7~;5,fi-trans-hexahydro-l-(oxiranyl'-''''~~ hexahydro-1~[2-hydro~y-3-meth~-l)-lH-indene-3a,5,6,- [4-[(1-oxopropyl)phenyl-7a-tetrol, tetraacetate aminoJ-l-pip~ridinyl~-ester (see United St~tes pro~yl]~ indene-3a,5,6~-patent No. 4,101,723 7a-tctrol, tet~aacet~te issued July 18, 1978 ~.cter 43) 3,4a,5-cis-hexahydro-5- 3,4a,5-cis-hexahydro-5-(oxiranylmethyl~-2,3;4a,- [2-hydroxy-3-[~-[(1-o~o-9a-trans-~enzocycloheptane- propyl)phenylarnino~-l-tetrol, tetraacetate ester piperidinyl]propyl]-2,3;-(sec United States patent ~a,9a-trans-bellzocyclo-No. 4,101,723 issued July heptanetetrol, tetr~-18, 1978 acetate ester .
~:
~xa~ples 44-45 .
Follol,Jing the procedure of ~xample 35, but substituting the compound listed in colu~.n I for 3,4a,5-cis-deca~.ldro-S- .
(oxiranvlmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetra- .
acetate ester yields the co~.pound listed in column II.
Column I Column 'LI
44) 3a,5-cis-3a,7a;5,6-trans- 1-[2-hydroxy-3-[cis-- hexah~ro-l-(o~iranyl- 3a,5-3a,5,6,7a-tetra- ' methyl)-l~-indene-3a,5,6,- kis(acetyloxy)hcY.ah~ro- ' 7a-tetrol, tetraacetate lH-inden-l-yl~propy]~-4~ .
ester . ph~nyl-4-piperidinecar~on-itrile. ' .
.
1~ ' ' - - .
~ HAl~3/5S/56 45) 3,4a,'-cis~ ahydro-5- l-[2-hydrox~-3-[cis-(oxiranylmethyl)-2,3;4a,- 1,8,9a-2,3,~a,9a~tetra-~a-trans-benzocycloheptane- kis(acetyloxy)hexahydro-tetrol, tetraacetate ester l-benzocycloheptanyl]-Dropyl]-4-phenyl-4-piperidinecarbor.itrilc xamples 46-47 Follo~ing the proceaure of Example 36, but substituting the co~pound listed in column I for 3,~a,5-~is-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in column II.
Column I Column II
46) 3a,5-cis-3a,7a;5,6-trans- 3a,5-ci.s-3a,73;5,6-trans~
he~ah~dro-l-(oxiranyl- hexahydro-l-[2-hydro~y-3-methyl)~ indene-3a,5,6,- (4-hydroYy-4-1~henyl-l-7a-tetrol, tetraacetate ~iT~eridinyl)yropyl]-l~l-estcr in~ene-3a,5,6,7a~tetrol, tetraacetatc e.~tcr 47) 3,4a,5-cis-hexahydro-5- 3,4a,5~cis-hexahydro-5-(oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(4-hydroxy-9a-trans-benzocycloheptane- 4-phenyl-l-piperidinvl)-tetrol, tetraacetate e~.ter propyl]-2,3;4a,9a-trans~
benzocycloheptan~tetrol, .j tetraacetate cster Examples 48-49 Followir.g the procedure of ~:~ample 37, but substitùting the compoun~ listecl in column I for 3,9a,5-cis-decahydro-5- .
(oxiranylmethyI)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in colu.~n II.
Column I Columr, ~I
.
48) 'a,5-cis-3a,7a;5,6-trans- 3a,5-cls-3a,7a;5,6-trans-hexahydro-l-(oxiranyl- hexahydro-l-[2-hydroxy-3-.
methyl)~ -indene-3a,5,6,- (3,4-di~.y~rospiro[211-l-7a-tetrol, tetraacetate benzopyran-2,4'-piperidin]~
ester l-yl)propyl]-ll1-ind~r.e-3a,5,6,7a-tetrol, tetra-acetate ester 49) 3,4a,5-cis-hexahydro-5- 3,~.a,5-ci.s-hexah~dro-5-~oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(3,4-dihydro-~a-trans-benzocycloheptane- spiro[21~-henzopyran-2,4'-tetrol, tetraacetate ester ~,iperidln]-l yl)propyl]~
~,3;4a,ga-trans-~enzocyclo-heutanetetrol, t~traacetate ester : 32 .. ~ .
.
~ ,, . .
~ y ~ 3 7 HAl43/55/56 ~xa~plcs 50~51 Followir,s the procedure of i;:a~plr 38, but substituting the compound list~d in column I for 3,~a,5-cis-d~cahydro-5-(oxiran~ylmethyl)-2,3;4a,82-trans-naphthaleneietr~l, tc';rc7-acet~te ~stcr, yields the compoul1d listcd in colu~.n TI.
Column I Col~r JI
3a,~-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7.~;5,6-traJ~s-hexahydro-l-(oxiranyl- hexahydro-l-[2-11ydroYy-3-meth~ indcn2-3a,5,~ -h~ydro~ct.h~l)-]-7a-tetrol, tetraacetatc pip~.ri-7.inyl]~rc~p~
estcr indenc-3a,~ ,7;--~cttol, t~txaac~tat~ cr 51 3,4a,5-cis-h~xahy~ro-5- 3,~a,5-cis-he~ hvclro-5-loxiral1vlmethvl)-2,3;4a,9a- [2-hyrlro~-3-[4~
trans-benzocvcloher~tane- hydro:Jcth~l)-]-ripcr-- tetxol, tetraacetatc cstex i~3ir;yl]!JroTjvll-2~3;4;2, .-t-~rans-~enzoc~r-l(,h(-r~i:. e-tetrJl, tctr~ cctate est:er ,-~aTnnles 52-53 Follo~ing the procrc7.ur~ o$ Pxanlp]es 38 and 39, but s~bstituting ~hr co-.~.pound listed in column I for 3,4a,5-cis-dcca'1vt~r~-r)-- (oY.irar.ylmethyl)-2,3;4a,8a-trans-nal?ht}-alrnc!tctr(~l, tc~tnnl-acetate ester, yields the compound listc~d in colllmn II.
Colu~n I ^ Col~lmn ~1 -- - -- .
52 3a,5-cis-3a,7a;5,6-trans- -3~.,5-ci.s-3a, 7~!~; 5, ~-t.raJ`5-heY.ah~ldro-l~(oxiranyl- hcxah~dro-l~[~-(acctylo:.y)-methyl)-l~ ndene-3a,5,~,- 3-[4-[2-(~lce~ylr,~ etb~l]-7a-te~rol, tctraace~ate l-nipcric7ir.yll!~rpyl!-ll.-estcx indenc-3;,5,~,7ci-t-~trol, . tc~raace.ate e tcr -53 3,4a,5-cis-hexahydro-5- 3,-1a,~-cis-~,exilhydro-5-(o~:iranvlmethyl)-2,3;4a,9a- l2-(ac~tylo.~)-3-[4-[~-trans-benzocvcloheptane- !acet,~lo:~y)ct!.yl]-l-pil,er-tctrol, tetraacetate ester idinyl]propyl7,-2,3;4a,9a-trans-b~n.~ocyclohcptanc-tctrol, t~trailcct~c cs-cr ~ ~ i ~r i i - 33 - ;
,~, ' "' . i ~143/55/56 E:~aJ,r,ies 54 55 Following the pl-ocedure of Exa~.ple 40, but substituting he compound l~st~d in column I for 3,4a,5-cis-decahy~ro-S-(oxiranvl~eth~ ;4a,8a~trans-r.aphtha,(!netctrol, ';~
acetate ester, yields the cor:.?o~r,d li~;t~d in col-rfi TI.
Col~.n I Cclur^.n I.
54 3a,5-cis-3a,7a;5,6-~rilr~ 3a,'-ci.s-3a,7.~;5,6-~raJls-heYahyclro-l-(o~ir2nyl~ ~le:~a}ly(lro-1-[3-(2,~ lro-methvl)-l~l-indene-3a,5,6,- ~-oY.o-].l~-henzilnidil7.Gl-l-vl)-7a-tctrol, te~traacetatc 1-l)iperidirl~].~-2-hy~]ro~:v ester ........................ I~ro5~yl]-lH-in(lene-3a,5~h~7a-te~trol, tetraacetate estcr 55 3,4a,5-cis-h~i:ahydro-5- 3,~a,5-c~-hc~ y(lro-5-~3-(cxiranylm~thvl)-2,~;4~,9a- (2,3-dihy~ro~ r~
trans-benzocycloheptane- benziJnidazol-l-y~)-l-tetrol, tetl-aiioetate ester ~i~criclirly].]-2-h~-.lro~
p~ol)vl~- ,3;~, 9~ L~a~
benzoc~cloheptanc~ tro~l, tetlaacotl!tc ester ~arn~le.c 56-57 - Follo~in~ the procedure cF ~xam!~lc- 41, but substituting the_compound listed in column I for 3,4a,5-cls-decahy(lro-5-(ox~lranylmethyl)-2,3;4a,8a-lrans-na~iht!lL-IleJletetrol, tet:ra-acetate cstcr, yiel~ the corl!po~nd liste~ in colulnn Il C`olu~ I Coll~ln I_ 56 3a,5-cis-3a,7a;5,~-trans- 3a,5-ci.~-3a,7a;5,fi- ' Lan.r;-he.Yahvdro-l-(oxiranvl- hexahv~ro-1-13-~ d- (2-metny;)-l~l-indene-3L-l,5,6/- ~,enzo:ca701~ er-7a-tetrol, tc-traac~tate idinyl]-2-hy~rG~v~rol~yl]-este. lll-in~lcne-3a,5, r ~ 7a-tetrol, tctLaacetate e~ter 57 3,4a,5-cis-he~ahydro-5- 3,4a,5-cis-hex~h~lro-~-(o~iran~lmethyl)-2,3;4a,9a- 13-[~.-(2-benzox~oly~
trans-benzocyclohe~Jtane~ iperidinyl]-2-hydroXy- -tetrol, tetraacetate eLter r~r~ yl]-2~3;4a~ trans-~nzocyclollel)taJletet~ol~
tetraacetate ~ er ~ .
B) 3,4-Dihydrospiro[2~ c-~n7.opyran-2,a -pir)cri(lirl(?
-3,4-Dihydro-l -(phenylmethyl)spiro[21~ h,ellzo[~r~
2,4 -piperidine] (25.? g) is dissolved in 250 ml of anh~!drous toluene. The reaetion mixture is eooled to 5C ard trichloro-ethyl ehloroformate is added dropt~ise. The solution is refluxed for 5 l1ourc and al1c~ed to stand at room tc~ )erature for about 16 hours. It is then washed sec~u~ntially with 100 ml of 10~ sodium hydroxide, 100 ml of ~ater, 100 ml o~
10~ hydroehlorie aeid ~nd fir!ally ~ith 200 ml of ~,ater. Tne toluene is dried, filtered and eoneentratcd in vacuo to yield 32.0 g of product.
The above material is dissolved in 300 ml of glacial acetic acid. Zine dust (30 g) is added portion~ise over a 30-minute period at 20C. The reaetion mixture i5 ~3tirred at roorn temperature for about 16 llours, filtcrcd arld concen-tr~ted in vacuo. Ihe r ;id~3c is h(e~ () Oll a 'i~(!aln (,Orl~ 30r ~3~3~7 HA143/55/56 15 minutes in 200 ml of 10~c sodium hydroxide. Product is extracted with chloroform. The chloroform is dried, filtered and concentrated in vacuo to yield 17.8 g of crude secondary amine. Its h~drochloride salt was prepared in isopropar.ol-hydrogen chloride. ~.fter crystallizing for about 16 hours, the product is filtered to ~ield 11.1 g of the hydrochloride salt of the title compound, melti.ng point 238-240C.
C) 3,4a,5-~L~-~ecahydro-5-[2-hydrox~-3-(3,4-dihyclrospiro-[2H-l-henzopyran-2,4-piperidin]-1-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacctate ester An amount of 1.7 y of 3,4-dihydrosplro[21l-1-bclllzopyran-2,4'-piperidine] is added to a solution of 3.55 ~I o~ 3,4a,5-cls-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalcnc-tetrol, tetraacetate ester in 50:20 ml of ethanol-bcni~enc.
rrhe solution is stirrcd for about 16 hours at 55C and th~n evaporated in vacuo. The residue is crystallizecl ovrr 3 days from 2:1 ether-hexane to give 3.6 g of ~solid. r~ec~ys~al-lization from ethyl acetate-hexane gives 2.3 (1 oE thc tit]e compound (thin-layer chromatoc3raph~ on alumina in ethyl acet:ate developed in iodine indicatc:s thc ti-tle cornpound to bc thc main isomer of two isomers), melting point 135-152C~
~xamPle 38 3,4a,5-c s-Decahydro-5-[2-hydroxy-3-[4-(2-h~dro~:yt-th~
piperidinyl]propyl]-2~3i4a~8a-~rn~-naphthalcnetetrol~ tetr,-~-acetate estcr ~ solution of 2.5 g of-3,4a,5-cis-decahydro-5-(o~.ir~r.~i-methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tctraacctatc e.stcr and 0.75 g of 4-ethanolpiperidine in 50 ml of abxGlutc eth,-lnol and 20 ml of benzene is stirred at 55C ior 18 hour.-;. '~'hc solvents are removed n vacuo and the reiidue i.s concen-tl^ated in _ several times with bcnzene to livc a ~o,lrn-like pro(luct.
Crystnllization f-roM et~(~r (3ivc<s 2. 55 ~3 ;.lrld t~,c~r").5 ~3 (,f HA14~/55/56 ~3~
solid product. Recrystallization of the 3 g ~f solid from 2:1 ethyl acetate-hexane gives 2.0 g of the title compound, melting point 112-120C.
Example 39 3,4a,5-L~-5-[2-(Ace~~loY~y)-3-[4-[2-(acetyloY~y)eth-l]-l-~iperidlnyl]~ropyl]-decahydro-2,3;4a,8a-trans-naphthalenc-tetrol, tetraacetate ester A mi~turc of 5 ml of acetic anh~dride and 1.25 g of 3,4a,5-c -decahydro-5-[2-hydroxy-3-[4-(2-hydroY.yethyl)-l-piperidinyl]propyl]-2,3;4a,8a-trans-naphthalcr.etc~trol, tetraacetate ester (see Exam~le 5) in 25 ml of dry pyridine is stirred at room temperature for about 16 hours. The solution is evaporated in vacuo. The residue i5 partitioncd between ether and a saturated aqueous sodiuln ~ic~rhonate solution. The aqueous layer i5 re-extracted witn ether, and the ether extracts are comhincd, dried and c~/aIjoratcc' in vacuo yieldlng 1.3 g of product~ r~ecryc~tallizatiorl rron, 1:9 ethyl acetate-hexane yields 1.22 q of the title compound, melting point 125-144C.
~xample 40 3,4a,5~ -5-[3-(2,3-Dihydro-2-oxo-l~-henæimidazol-l-yl)-l-pi~eridinyl~-2-hydroxypropyl]decahyclro-2,3;4a,8a-trans-na~hthalenetetrol, tetraacetate ester An amoun-t of 1.5 g of 3,4a,5-c -decahydro-5-(c)~iranyl-methyl)-2,3;4a,8a-tran~-naphthalenetetrol, tetraacetatc cs~cr is dissolved in 20 m] of benzene and 50 ml of a},,olute e~}larlol and maintained at 50C~5 with a water ~ath. To this is added 0.73 q of 4-(2-keto-1-~enzimidazolinyl)pipcri~ine and stirrinq is continued for 36 hours. Solvent is strippcd in vacuo, and the product is cry~tallized from cthyl acetate-hexane to yicld 1.67 g of material, nlelting point 137-144GCo ~ 29 -~xa~le 41 3,4a,5~ 5-[3-[4-(2-Benzoxazolyl)-l=piperidinyl]-2-hydroxypropyl]-decahydro-2,3;4a,8a-naphthalenetetrol, tetraacetate ester A) 2-(4-Piperidinyl)~enzoxazole A solution of 1.71 g of benæyl bromide in 10 rnl of acetonitrile is added to a solution of 1.96 g c,f 2-(4-pyridinyl)benzoxazole in 25 ml of hot acetonitrile. ~fter 10 minutes the product be~ins to crvstallize out of solution.
The mixture is heated on the steam hath for 2 hours and then diluted with ether and filtered. The crude solid is dissolved in 50 ml of 1:1 methanol-water and treated portion~ise with 2 g of sodium borohydridc. The mixture is diluted with water and 2.4 g of the solid product is collected. The 2.4 y of solid is dissolved ir. 150 ml of ethanol, 2 g of 5% paladium on car~on is added, and the mixture is placed on the Parr hydrogenatGr under 50 psi hydrogen. I'he mixture is filtered, and the filtr 2t~
evaporated in vacuo to give 1.4 g of the title compound.
B) 3,4a,5-~i~5-~3-[4-t2-Ben_o azolv~l)-l-pi~eridinyl]-2 hydroxypropyl]decahydro-2,3,4a,8a-~ -naphthalene~
tetrol, tetraacetate ester A solution of 3.6 g of 3,4a,5-cis-decahydro-5-(oxiranyl-methyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate est~r and 1.4 g of the 2-(4-piperidinyl)benzoxazole in 20 ml of benzene and 50 ml of absolute ethanol is stirred for 7.5 hours at 55C and then for a~out 16 hours at room tenlperature under nitro~en. The solution is evapora~ed in V2CUO and the residue dissolved in hot ethyl acetate (30-90 ml), diluted with hexane (30 ml) and crystallized on standin~ lo yivc 3.14 y OL ~olid. q'he solid is disso]vec] in }lOt ethyl acctatc (50 ~ ), treated with l)arco, fi~erec'f aIcl ~ 3~ HA143/55/56 dilut~d ~ith h~Y.ane (20 ml). The solution c-ystallizes to give 2.02 9 of the t tle compound, meltinq point 195-205~C.
Examples 42-43 Following the procedure of ~xample 34, but substituting the compound listed in column I for 3,9a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in column II.
Column I Column II
42) 3a,5-cis-3a,7a;5,6-trans~ 3a,5-ci.s-3a,7~;5,fi-trans-hexahydro-l-(oxiranyl'-''''~~ hexahydro-1~[2-hydro~y-3-meth~-l)-lH-indene-3a,5,6,- [4-[(1-oxopropyl)phenyl-7a-tetrol, tetraacetate aminoJ-l-pip~ridinyl~-ester (see United St~tes pro~yl]~ indene-3a,5,6~-patent No. 4,101,723 7a-tctrol, tet~aacet~te issued July 18, 1978 ~.cter 43) 3,4a,5-cis-hexahydro-5- 3,4a,5-cis-hexahydro-5-(oxiranylmethyl~-2,3;4a,- [2-hydroxy-3-[~-[(1-o~o-9a-trans-~enzocycloheptane- propyl)phenylarnino~-l-tetrol, tetraacetate ester piperidinyl]propyl]-2,3;-(sec United States patent ~a,9a-trans-bellzocyclo-No. 4,101,723 issued July heptanetetrol, tetr~-18, 1978 acetate ester .
~:
~xa~ples 44-45 .
Follol,Jing the procedure of ~xample 35, but substituting the compound listed in colu~.n I for 3,4a,5-cis-deca~.ldro-S- .
(oxiranvlmethyl)-2,3;4a,8a-trans-naphthalenctetrol, tetra- .
acetate ester yields the co~.pound listed in column II.
Column I Column 'LI
44) 3a,5-cis-3a,7a;5,6-trans- 1-[2-hydroxy-3-[cis-- hexah~ro-l-(o~iranyl- 3a,5-3a,5,6,7a-tetra- ' methyl)-l~-indene-3a,5,6,- kis(acetyloxy)hcY.ah~ro- ' 7a-tetrol, tetraacetate lH-inden-l-yl~propy]~-4~ .
ester . ph~nyl-4-piperidinecar~on-itrile. ' .
.
1~ ' ' - - .
~ HAl~3/5S/56 45) 3,4a,'-cis~ ahydro-5- l-[2-hydrox~-3-[cis-(oxiranylmethyl)-2,3;4a,- 1,8,9a-2,3,~a,9a~tetra-~a-trans-benzocycloheptane- kis(acetyloxy)hexahydro-tetrol, tetraacetate ester l-benzocycloheptanyl]-Dropyl]-4-phenyl-4-piperidinecarbor.itrilc xamples 46-47 Follo~ing the proceaure of Example 36, but substituting the co~pound listed in column I for 3,~a,5-~is-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in column II.
Column I Column II
46) 3a,5-cis-3a,7a;5,6-trans- 3a,5-ci.s-3a,73;5,6-trans~
he~ah~dro-l-(oxiranyl- hexahydro-l-[2-hydro~y-3-methyl)~ indene-3a,5,6,- (4-hydroYy-4-1~henyl-l-7a-tetrol, tetraacetate ~iT~eridinyl)yropyl]-l~l-estcr in~ene-3a,5,6,7a~tetrol, tetraacetatc e.~tcr 47) 3,4a,5-cis-hexahydro-5- 3,4a,5~cis-hexahydro-5-(oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(4-hydroxy-9a-trans-benzocycloheptane- 4-phenyl-l-piperidinvl)-tetrol, tetraacetate e~.ter propyl]-2,3;4a,9a-trans~
benzocycloheptan~tetrol, .j tetraacetate cster Examples 48-49 Followir.g the procedure of ~:~ample 37, but substitùting the compoun~ listecl in column I for 3,9a,5-cis-decahydro-5- .
(oxiranylmethyI)-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester, yields the compound listed in colu.~n II.
Column I Columr, ~I
.
48) 'a,5-cis-3a,7a;5,6-trans- 3a,5-cls-3a,7a;5,6-trans-hexahydro-l-(oxiranyl- hexahydro-l-[2-hydroxy-3-.
methyl)~ -indene-3a,5,6,- (3,4-di~.y~rospiro[211-l-7a-tetrol, tetraacetate benzopyran-2,4'-piperidin]~
ester l-yl)propyl]-ll1-ind~r.e-3a,5,6,7a-tetrol, tetra-acetate ester 49) 3,4a,5-cis-hexahydro-5- 3,~.a,5-ci.s-hexah~dro-5-~oxiranylmethyl)-2,3;4a,- [2-hydroxy-3-(3,4-dihydro-~a-trans-benzocycloheptane- spiro[21~-henzopyran-2,4'-tetrol, tetraacetate ester ~,iperidln]-l yl)propyl]~
~,3;4a,ga-trans-~enzocyclo-heutanetetrol, t~traacetate ester : 32 .. ~ .
.
~ ,, . .
~ y ~ 3 7 HAl43/55/56 ~xa~plcs 50~51 Followir,s the procedure of i;:a~plr 38, but substituting the compound list~d in column I for 3,~a,5-cis-d~cahydro-5-(oxiran~ylmethyl)-2,3;4a,82-trans-naphthaleneietr~l, tc';rc7-acet~te ~stcr, yields the compoul1d listcd in colu~.n TI.
Column I Col~r JI
3a,~-cis-3a,7a;5,6-trans- 3a,5-cis-3a,7.~;5,6-traJ~s-hexahydro-l-(oxiranyl- hexahydro-l-[2-11ydroYy-3-meth~ indcn2-3a,5,~ -h~ydro~ct.h~l)-]-7a-tetrol, tetraacetatc pip~.ri-7.inyl]~rc~p~
estcr indenc-3a,~ ,7;--~cttol, t~txaac~tat~ cr 51 3,4a,5-cis-h~xahy~ro-5- 3,~a,5-cis-he~ hvclro-5-loxiral1vlmethvl)-2,3;4a,9a- [2-hyrlro~-3-[4~
trans-benzocvcloher~tane- hydro:Jcth~l)-]-ripcr-- tetxol, tetraacetatc cstex i~3ir;yl]!JroTjvll-2~3;4;2, .-t-~rans-~enzoc~r-l(,h(-r~i:. e-tetrJl, tctr~ cctate est:er ,-~aTnnles 52-53 Follo~ing the procrc7.ur~ o$ Pxanlp]es 38 and 39, but s~bstituting ~hr co-.~.pound listed in column I for 3,4a,5-cis-dcca'1vt~r~-r)-- (oY.irar.ylmethyl)-2,3;4a,8a-trans-nal?ht}-alrnc!tctr(~l, tc~tnnl-acetate ester, yields the compound listc~d in colllmn II.
Colu~n I ^ Col~lmn ~1 -- - -- .
52 3a,5-cis-3a,7a;5,6-trans- -3~.,5-ci.s-3a, 7~!~; 5, ~-t.raJ`5-heY.ah~ldro-l~(oxiranyl- hcxah~dro-l~[~-(acctylo:.y)-methyl)-l~ ndene-3a,5,~,- 3-[4-[2-(~lce~ylr,~ etb~l]-7a-te~rol, tctraace~ate l-nipcric7ir.yll!~rpyl!-ll.-estcx indenc-3;,5,~,7ci-t-~trol, . tc~raace.ate e tcr -53 3,4a,5-cis-hexahydro-5- 3,-1a,~-cis-~,exilhydro-5-(o~:iranvlmethyl)-2,3;4a,9a- l2-(ac~tylo.~)-3-[4-[~-trans-benzocvcloheptane- !acet,~lo:~y)ct!.yl]-l-pil,er-tctrol, tetraacetate ester idinyl]propyl7,-2,3;4a,9a-trans-b~n.~ocyclohcptanc-tctrol, t~trailcct~c cs-cr ~ ~ i ~r i i - 33 - ;
,~, ' "' . i ~143/55/56 E:~aJ,r,ies 54 55 Following the pl-ocedure of Exa~.ple 40, but substituting he compound l~st~d in column I for 3,4a,5-cis-decahy~ro-S-(oxiranvl~eth~ ;4a,8a~trans-r.aphtha,(!netctrol, ';~
acetate ester, yields the cor:.?o~r,d li~;t~d in col-rfi TI.
Col~.n I Cclur^.n I.
54 3a,5-cis-3a,7a;5,6-~rilr~ 3a,'-ci.s-3a,7.~;5,6-~raJls-heYahyclro-l-(o~ir2nyl~ ~le:~a}ly(lro-1-[3-(2,~ lro-methvl)-l~l-indene-3a,5,6,- ~-oY.o-].l~-henzilnidil7.Gl-l-vl)-7a-tctrol, te~traacetatc 1-l)iperidirl~].~-2-hy~]ro~:v ester ........................ I~ro5~yl]-lH-in(lene-3a,5~h~7a-te~trol, tetraacetate estcr 55 3,4a,5-cis-h~i:ahydro-5- 3,~a,5-c~-hc~ y(lro-5-~3-(cxiranylm~thvl)-2,~;4~,9a- (2,3-dihy~ro~ r~
trans-benzocycloheptane- benziJnidazol-l-y~)-l-tetrol, tetl-aiioetate ester ~i~criclirly].]-2-h~-.lro~
p~ol)vl~- ,3;~, 9~ L~a~
benzoc~cloheptanc~ tro~l, tetlaacotl!tc ester ~arn~le.c 56-57 - Follo~in~ the procedure cF ~xam!~lc- 41, but substituting the_compound listed in column I for 3,4a,5-cls-decahy(lro-5-(ox~lranylmethyl)-2,3;4a,8a-lrans-na~iht!lL-IleJletetrol, tet:ra-acetate cstcr, yiel~ the corl!po~nd liste~ in colulnn Il C`olu~ I Coll~ln I_ 56 3a,5-cis-3a,7a;5,~-trans- 3a,5-ci.~-3a,7a;5,fi- ' Lan.r;-he.Yahvdro-l-(oxiranvl- hexahv~ro-1-13-~ d- (2-metny;)-l~l-indene-3L-l,5,6/- ~,enzo:ca701~ er-7a-tetrol, tc-traac~tate idinyl]-2-hy~rG~v~rol~yl]-este. lll-in~lcne-3a,5, r ~ 7a-tetrol, tctLaacetate e~ter 57 3,4a,5-cis-he~ahydro-5- 3,4a,5-cis-hex~h~lro-~-(o~iran~lmethyl)-2,3;4a,9a- 13-[~.-(2-benzox~oly~
trans-benzocyclohe~Jtane~ iperidinyl]-2-hydroXy- -tetrol, tetraacetate eLter r~r~ yl]-2~3;4a~ trans-~nzocyclollel)taJletet~ol~
tetraacetate ~ er ~ .
Claims (72)
1. A process for preparing compounds of the formula or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; R1 is alkanoyl having 2 to 7 carbon atoms;
R2 is (i) (ii) (iii) (iv) (V) (vi) , (Vii) , (viii) , (ix) , , (X) (xi) , or (Xii) (xiii) ;
R3 is alkyl of 1 to 4 carbon atoms; R4 is cyano or hydroxy;
R5 is hydroxy or alkanoyloxy of 2 to 7 carbon atoms; R6 is hydrogen or alkanoyl of 2 to 7 carbon atoms; R7 is phenyl, substituted phenyl or pyridinyl and m is 2, 3 or 4, which comprises reacting a compound of the formula II
with a compound having the formula wherein R2 is defined as above, and where R6 is to be alkanoyl, acylating the corresponding compound wherein R6 is hydrogen.
R2 is (i) (ii) (iii) (iv) (V) (vi) , (Vii) , (viii) , (ix) , , (X) (xi) , or (Xii) (xiii) ;
R3 is alkyl of 1 to 4 carbon atoms; R4 is cyano or hydroxy;
R5 is hydroxy or alkanoyloxy of 2 to 7 carbon atoms; R6 is hydrogen or alkanoyl of 2 to 7 carbon atoms; R7 is phenyl, substituted phenyl or pyridinyl and m is 2, 3 or 4, which comprises reacting a compound of the formula II
with a compound having the formula wherein R2 is defined as above, and where R6 is to be alkanoyl, acylating the corresponding compound wherein R6 is hydrogen.
2. A process in accordance with claim 1 wherein R7 is phenyl or phenyl substituted with 1 or 2 halogen, alkyl, trifluoromethyl, alkoxy or alkylthio groups.
3. A process in accordance with claim 1 wherein n is 0.
4. A process in accordance with claim 1 wherein n is 1.
5. A process in accordance with claim 1 wherein n is 2.
6. A process in accordance with claim 1 wherein n is 1 and R1 is acetyl.
7. A process in accordance with claim 1 wherein n is 1 and R6 is hydrogen.
8. A process in accordance with claim 1 wherein n is 1, R1 is acetyl and R7 is pyridinyl.
9. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R7 is 2-pyridinyl,
10. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R7 is phenyl.
11. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R7 is phenyl substituted with 1 or 2 halogen, alkyl, trifluoromethyl, alkoxy or alkylthio groups.
12. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is (ii)
13. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is
14. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is
15. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is
16. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is
17. A process in accordance with claim 1 wherein n is one, R1 is acetyl and R2 is
18. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R2 is
19. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R3 is
20. A process in accordance with claim 1 wherein n is one, R6 is hydrogen, R3 is and R4 is cyano.
21. A process in accordance with claim 1 wherein n is one, R6 is hydrogen, R3 is and R4 is hydroxy.
22. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R2 is
23. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R2 is
24. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R2 is
25. A process in accordance with claim 1 wherein n is one, R6 is hydrogen and R2 is
26. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]propyl]-2,3;4a,8-trans-naphthalene-tetrol, tetraacetate ester.
27. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-[3-(tri-fluoromethyl)phenyl]-1-piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
28. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-5-[3-[4-[2-(ethylthio)-phenyl]-l-piperazinyl]-2-hydroxypropyl]decahydro-2,3;4a,8a-trans-naphthalene tetrol, tetraacetate ester.
29. The process in accordance with claim 1 wherein the process prepared is 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-(2-pyridinyl)-1-piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
30. The process in accordance with claim 1 wherein the compound prepared is 3a,5-cis-3a,7a;5,6-trans-hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-1H-indene-3a,5,6,7a-tetrol, tetraacetate ester, monohydro-chloride.
31. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-5-[3-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-2-hydroxypropyl]decahydro-2,3;4a, 8a-trans-naphthalenetetrol, tetraacetate ester.
32. The process in accordance with claim 1 wherein the compound prepared is decahydro-5-[2-hydroxy-3-(1,4,5,6-tetrahydrobenz[f]-isoquinolin-3(2H)-yl)propyl]-3,4a,5,cis-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
33. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-decahydro-5 [2-hydroxy-3-[4-(2-phenylethenyl)-3,6-dihydro-1(2H)pyridinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
34. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-5-[3-[4-(2,3-dihydro-2-benzoxazolyl)-3,6-dihydro-1(2H)pyridinyl]-2-hydroxypropyl]-decahydro-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
35. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5,-cis-decahydro-5-[2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
36. The process in accordance with claim 1 wherein the compound prepared is 3,4a,5-cis-decahydro-5-[2-hydroxy-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
37. A compound having the formula or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; R1 is alkanoyl having 2 to 7 carbon atoms;
R2 is (i) (ii) (iii) (iv) (v) (vi) , (vii) , (viii) , (ix) , (x) , (xi) , (xii) or (xiii) R3 is alkyl of 1 to 4 carbon atoms; R4 is cyano or hydroxy;
R5 is hydroxy or alkanoyloxy of 2 to 7 carbon atoms; R6 is hydrogen or alkanoyl of 2 to 7 carbon atoms; R7 is phenyl, substituted phenyl or pyridinyl and m is 2, 3 or 4 when prepared by the process of claim 1.
R2 is (i) (ii) (iii) (iv) (v) (vi) , (vii) , (viii) , (ix) , (x) , (xi) , (xii) or (xiii) R3 is alkyl of 1 to 4 carbon atoms; R4 is cyano or hydroxy;
R5 is hydroxy or alkanoyloxy of 2 to 7 carbon atoms; R6 is hydrogen or alkanoyl of 2 to 7 carbon atoms; R7 is phenyl, substituted phenyl or pyridinyl and m is 2, 3 or 4 when prepared by the process of claim 1.
38. A compound in accordance with claim 37 wherein R7 is phenyl or phenyl substituted with 1 or 2 halogen, alkyl, trifluoromethyl, alkoxy or alkylthio groups when prepared by the process of claim 2.
39. A compound in accordance with claim 37 wherein n is 0 when prepared by the process of claim 3.
40. A compound in accordance with claim 37 wherein n is 1 when prepared by the process of claim 4.
41. A compound in accordance with claim 37 wherein n is 2 when prepared by the porcess of claim 5.
42. A compound in accordance with claim 37 wherein n is one and R1 is acetyl when prepared by the process of claim 6.
43. A compound in accordance with claim 37 wherein n is one and R6 is hydrogen when prepared by the process of claim 7.
44. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R7 is pyridinyl when prepared by the process of claim 8.
45. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R7 is 2-pyridinyl when prepared by the process of claim 9.
46. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R7 is phenyl when prepared by the process of claim 10.
47. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R7 is phenyl substituted with 1 or 2 halogen, alkyl, trifluoromethyl, alkoxy or alkylthio groups when prepared by the process of claim 11.
48. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is (ii) when prepared by the process of claim 12.
49. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is when prepared by the process of claim 13.
50. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is when prepared by the process of claim 14.
51. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is hen prepared by the process of claim 15.
52. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is when prepared by the process of claim 16.
53. A compound in accordance with claim 37 wherein n is one, R1 is acetyl and R2 is when prepared by the process of claim 17.
54. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen and R2 is when prepared by the process of claim 18.
55. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen and R3 is when prepared by the process of claim 19.
56. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen, R3 is and R4 is cyano when prepared by the process of claim 20.
57. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen, R3 is and R4 is hydroxy when prepared by the process of claim 21.
58. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen and R2 is when prepared by the process of claim 22.
59. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen and R2 is when prepared by the process of claim 23.
60. A compound in accordance with claim 37 wherein n is one, R is hydrogen and R2 is when prepared by the process of claim 24.
61. A compound in accordance with claim 37 wherein n is one, R6 is hydrogen and R2 is when prepared by the process of claim 25.
62. The compound in accordance with claim 37 having the name 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]propyl]-2,3;4a,8-trans-naphthalene-tetrol, tetraacetate ester when prepared by the process of claim 26.
63. The compound in accordance with claim 37 having the name 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-[3-(tri-fluoromethyl)phenyl]-1-piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 27.
64. The compound in accordance with claim 37 having the name 3,4a,5-cis-5-[3-[4-[2-(ethylthio)phenyl]-1-pipera-zinyl]-2-hydroxypropyl]decahydro-2,3;4a,8a-trans-naphthalene-tetrol, tetraacetate ester when prepared by the process of claim 28.
65. The compound in accordance with claim 37 having the name 3,4a-5-cis-decahydro-5-[2-hydroxy-3-[4-(2-pyridinyl)-1-piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetra-acetate ester when prepared by the process of claim 29.
66. The compound in accordance with claim 37 having the name 3a,5-cis-3a,7a;5,6-trans-hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-1H-indene-3a,5,6,-7a-tetrol, tetraacetate ester, monohydrochloride when prepared by the process of claim 30.
67. The compound in accordance with claim 37 having the name 3,4a,5-cis-5-[3-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-2-hydroxypropyl]decahydro-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 31.
68. The compound in accordance with claim 37 having the name decahydro-5-[2-hydroxy-3-(1,4,5,6-tetrahydrobenz-[f]-isoquinolin-3(2H)-yl)propyl]-3,4a, 5-cis-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 32.
69. The compound in accordance with claim 37 having the name 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4-(2-phenyl-ethenyl)-3,6-dihydro-1(2H)pyridinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 33.
70. The compound in accordance with claim 37 having the name 3,4a,5-cis-5-[3-[4-(2,3-dihydro-2-benzoxazolyl)-3,6-dihydro-1(2H)pyridinyl]-2-hydroxypropyl]decahydro-2,3;
4a,8a trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 34.
4a,8a trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 34.
71. The compound in accordance with claim 37 having the name 3,4a,5-cis-decahydro-5-[2-hydroxy-3-(1,2,3,4-tetra-hydro-2-isoquinolinyl)propyl]-2,3;4a,8a-trans-naphthalene-tetrol, tetraacetate ester when prepared by the process of claim 35.
72. The compound in accordance with claim 37 having the name, 3,4a,5-cis-decahydro-5-[2-hydroxy-3-(4,5,6,7-tetra-hydro-1H-imidazo[4,5-c]pyridin-5-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester when prepared by the process of claim 36.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US784,888 | 1977-04-05 | ||
| US05/784,888 US4101723A (en) | 1977-04-05 | 1977-04-05 | Substituted piperazinopropanols |
| US05/824,378 US4169200A (en) | 1977-08-15 | 1977-08-15 | Substituted 3,6-dihydro-1(2H)-pyridinylpropanols |
| US855,038 | 1977-11-25 | ||
| US05/855,038 US4127579A (en) | 1977-11-25 | 1977-11-25 | Substituted piperidinylpropanols |
| US824,378 | 1992-01-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113937A true CA1113937A (en) | 1981-12-08 |
Family
ID=27419822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA299,457A Expired CA1113937A (en) | 1977-04-05 | 1978-03-21 | Substituted piperidinylpropanols |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS53130670A (en) |
| CA (1) | CA1113937A (en) |
| DE (1) | DE2814799A1 (en) |
| FR (1) | FR2386528B1 (en) |
| GB (1) | GB1596357A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4103094A (en) * | 1977-05-10 | 1978-07-25 | E. R. Squibb & Sons, Inc. | Cyclohexanetetrol alkanoates |
| US4127717A (en) * | 1978-03-20 | 1978-11-28 | E. R. Squibb & Sons, Inc. | Benzo-cyclitolamines |
| US4255575A (en) * | 1979-05-04 | 1981-03-10 | Richardson-Merrell Inc. | 2-Hydroxy-5-(1-hydroxy-2-piperazinylethyl)-benzoic acid derivatives |
-
1978
- 1978-03-21 CA CA299,457A patent/CA1113937A/en not_active Expired
- 1978-03-30 GB GB12506/78A patent/GB1596357A/en not_active Expired
- 1978-03-31 FR FR7809535A patent/FR2386528B1/fr not_active Expired
- 1978-04-05 JP JP4079378A patent/JPS53130670A/en active Pending
- 1978-04-05 DE DE19782814799 patent/DE2814799A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2386528B1 (en) | 1981-07-24 |
| GB1596357A (en) | 1981-08-26 |
| JPS53130670A (en) | 1978-11-14 |
| FR2386528A1 (en) | 1978-11-03 |
| DE2814799A1 (en) | 1978-10-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry | ||
| MKEX | Expiry |
Effective date: 19981208 |