GB1596357A - Propanolamine derivatives - Google Patents

Propanolamine derivatives Download PDF

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GB1596357A
GB1596357A GB12506/78A GB1250678A GB1596357A GB 1596357 A GB1596357 A GB 1596357A GB 12506/78 A GB12506/78 A GB 12506/78A GB 1250678 A GB1250678 A GB 1250678A GB 1596357 A GB1596357 A GB 1596357A
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compound
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cis
hydroxy
trans
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority claimed from US05/784,888 external-priority patent/US4101723A/en
Priority claimed from US05/824,378 external-priority patent/US4169200A/en
Priority claimed from US05/855,038 external-priority patent/US4127579A/en
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
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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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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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    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

(54) PROPANOLAMINE DERIVATIVES (71) We, E.R. SQUIBB & SONS, INC., a body corporate organised and existing under the laws of the State of Delaware, United States of America of Lawrenceville-Princeton Road, Princeton, New Jersey. United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularlv described in and by the following statement: Cyclitol derivatives having the formula
wherein Y is hydrogen or alkanoyl. the group -NXX' is a heterocyclic nitrogen containing group, and n is (). 1 or 2 are encompassed by the disclosure of the United States patent 3,894,031. issued July 8, 1975. Among the heterocyclic groups disclosed are piperazino, (lower alkyl)piperazino, di(lower alkyl )piperazino, (lower alkoxy )piperazino, (hydroxylower alkyl)piperazino, (alkanoyloxy-lower alkyl )piperazino, (hydroxy-lower al koxy-lower alkyl)piperazino, and (carbo-lower alkoxy)piperazino. The treatment of hypertension is one of the utilities for the compounds disclosed by the patent.
Burger, Medicinal ChemisQv third edition (part II), John Wiley & Sons, Inc., New York, 1970, chapter 39, "Anti-hypertensive Agents", pgs. 1019-1064 discloses various classes of antihypertensive agents. Among the classes of compounds disclosed are veratrum alkaloid, the hypotensive activity of which may be largely attributable to the acylation of several hydroxyl functions of an alkamine. Other classes of anti-hypertensive agents disclosed by Burger include phenoxy-propanolamines and phenethanolamines.
The present invention provides compounds having the formula
and such compounds in pharmaceutically acceptable salt form; these compounds have hypotensive activity. In formula 1, and throughout the specification, the symbols are as defined below. n is 0, 1 or 2; R1 is alkanoyl (acetyl is preferred); R2 is
R3 is alkyl of 1 to 4 carbon atoms; R4 is cyano or hydroxy; R5 is hydroxy or alkanoyloxy (acetyloxy is preferred); R6 is hydrogen or alkanoyl (acetyl is preferred) R7 is aryl or pyridinyl; and m is 2, 3, or 4.
The terms "alkanoyl" and "alkanoyloxy", as used throughout the specification, refer to groups having the formula
respectively, wherein Y is alkyl having 1 to 6 carbon atoms (i.e.. groups having 2 to 7 carbon atoms).
The compounds of this invention wherein R6 is hydrogen can be prepared by reacting an oxirane compound having the formula
with a compound having the formula III R2-H III 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 combination with a lower alkanol. Those compounds of formula I wherein R6 is alkanoyl can be prepared from the corresponding compound wherein R6 is hydrogen using conventional acylation techniques.
The oxirane compounds of formula II are readily obtained from a corresponding compound having the formula
Compounds of formula IV are known; see. for example, United States patent 3,894,031, issued July 8. 1975. Oxidation of a compound of formula IV yields the corresponding N-oxide having the formula
Exemplary of oxidizing agents which may be used are the peracids. e.g.. chloroperbenzoic acid.
Vacuum pyrolysis of an N-oxide of formula V yields an olefin having the formula
Oxidation of an olefin of formula VI yields the corresponding oxirane compound of formula II. Exemplary of oxidizing agents which may be usd are the peracids, e.g ., mchloroperbenzoic acid.
The compounds of formula I can be converted to their pharmaceutically acceptable acid-addition salts with both organic and inorganic acids using methods well known in the art. Exemplary salts are hydrohalides (e.g.. hvdrochloride and hydrobromide), nitrate. phosphate, borate. acetate, tartrate. methanesulfonate, benzenesulfonate, toluenesulton- ate and the like.
Formula I includes all stereoisomers and mixtures thereof. Particular stereoisomers ere prepared by utilizing as the starting material the compound of formula IV with the corresponding stereochemistry. The preferred stereoisomers are those in which the OR1 groups are all axial. Particularly preferred are those compounds having the configuration
wherein the OR1a and OR1c groups are in the trans configuration as are the OR1b and OR1d groups.
The compounds of formula I shown hypotensive properties in hypertensive rats and normotensive dogs. The compounds of this invention, including the pharmaceutically acceptable salts, may be used as hypotensive agents in mammals, e.g., domestic animals such as dogs and cats. Daily doses of from 5 to 50 milligrams per kilogram of animal body weight, preferably about 5 to 25 milligrams per kilogram of animal body weight, can be administered orally or parenterally, in single or divided doses.
The compounds of this invention include indan derivatives having the formula
naphthalene derivatives having the formula
and benzocycloheptane derivatives having the formula
The naphthalene derivatives of formula IX are preferred.
The following examples are specific embodiments of this invention.
EXAMPLE 1 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]2,3;4a,8a-trans-naphthalenetetrol,tetraacetate ester A) 3,4a,5-cis-Decahydro-5-(3-dimethylaminopropyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, N-oxide A solution of 19.71 g of 3,4a,5-cis-(3-dimethylaminopropyl)-2,3;4a,8a-trans- naphthalenetetrol. tetraacetate ester and 9.25g of 85% m-chloroperbenzoic acid in 3() ml ot chloroform is prepared at () C and warmed over 3 hours to room temperature. 'I he solution is then partially evaporated ill vacuo and filtered through 520g of neutral Alumina Ill.
Elution with 1 liter each of chloroform and 20% @ methanolic chloroform gives 24.3g of oil.
Crvstallization from ethyl acetate gives 14.3 of the N-oxide as a hydroscopic solid. melting point 160-161 C. The filtrate is evaporated is vacuo to drvness to give an additional 6.38u of solid (IR consistent with crop 1). for a total yield of 2().68g.
B) 3,4a,5-cis-Decahydro-5-(2-propenyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester An amount of 2().2g g of the above N-oxide is heated in a vacuum distillation set-up under 3() mm Hg vacuum with nitrogen bleed until all the solid has melted and vigorous gas evolution ceases. The vacuum is improved to I mm Hg and the olefin product distilled as a pale vellow liquid. 13.() g (boiling point 185-195 at I mm Hg). which solidifies on standing.
Recrvstallization from ether (75 - 1()() ml) gives 8.6g of a fine crystalline solid. melting point 151-155.5 C.
C) 3,4a-5-cis-Decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraace tate ester A solution of 6.0g of the above tetraacetate-olefin and 3.12g of 85%m-chloroperbenzoic acid in 100ml of chloroform is prepared at 0 C and stirred at room temperature for about 16 hours. The solution is then suction filtered through a pad of 50g of neutral Alumina III. The alumina is washed with 100 ml of chloroform and the combined filtrates evaporated in vacuo to give 6.4g of a solid, melting point 135-159 C.
D) 3, 4a,5-cis-Decahydro-5-[2-hydroxy-3-[4- (2-methoxyphenyl) -1 -piperazinyl]propytj- 2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A solution of 1.5g of 1-(2-methoxyphenyl)piperazine and 3.5g of the above epoxide in 50 ml of absolute ethanol and 20 ml of benzene is stirred in a warm water bath (50-55 C) for about 20 hours under a drying tube. The solvent is removed in vacuo to give 5.1g of a foam, which is crystallized from ether to give 4.23g of the product as a crystalline solid in two crops. Recrystallization of 3.58g of the solid from ethyl acetate (25-35 ml) gives 2.65g of the title compound, melting point 203-206 C.
Anal. Calc'd. for C32H46N2O10 (618.7 g/m): C, 62.12; H, 7.49; N, 4.53 Found: C, 62.15: H, 7.64; N, 4.43 EXAMPLE 2 3 , 4 a , 5 - cis - D e c a h y d r o - 5 - [ 2 - h y d r o x y - 3 - [ 4 - [ 3 - ( t r i f l u o r o m e t h y l ) - p h e n y l ] - 1 piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A solution of 2.75g of 3,4,5a-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester and 1.3g of N-(α,α,α-trifluoro-m-tolyl)piperazine in 20:50 benzene-absolute ethanol is heated to 55-60 C for 18 hours. The solution is evaporated in vacuo and the residue is crystallized from ethyl acetate-hexane to give 2.7g of solid in three crops. Recrystallization from ethyl acetate-hexane gives 1.85g of material.
The 1.85g of material is combined with 0.75g from a previous run and recrystallized to give 2.0g of the title compound, melting point 150-204 C.
Anal. Calc'd. for C32H43N2O9F3(657.7 g/m): C, 58.52; H, 6.60: N, 4.27; F, 8.68 Found: C, 58.30; H, 6.63: N. 4.13: F, 8.56 EXAMPLE 3 3, 4a, 5-cis-5-[3-/4-J2- (Ethylthio)phenyU-1 -piperazinyl]-2-hydroxypropyl]-decahydro- 2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A solution of 2.6g of 3,4,5a-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol. tetraacetate ester and 1.4g of N-[(2-ethylthio)phenyl]piperazine in 20 ml of benzene-5()ml of absolute ethanol is stirred at 57 C for about 16 hours. The solution is evaporated in vacuo and the residue crystallized from ether to give 3g of solid. Two recrystallizations from ethyl acetate-methanol give 2.2g of the title compound, melting point 230-232 C.
Anal Calc'd, for C33H48N2O9S (648.82 g/m): C, 61.09; H, 7.46; N, 4.32: S, 4.94 Found: C, 61.27: H, 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,8atrans-naphthalenetetrol, tetraacetate ester 3,4,5a-cis-Decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, (2.1()8g) is dissolved in 50 ml of absolute ethanol and 2() ml benzene. Freshly distilled 1-(2-pyridyl)piperazine (.766g) is added and the resulting solution is heated to 50 C#5 , with stirring for 15 hours. Solvent is removed in vacuo, and the resulting foam is taken up in 250 ml of ethanol from which it immediately crystallizes to yield 2.3g of crvstalline solid.
The solid is recrystallized from ethyl acetate to yield 1.26g crystalline solid; melting point 225-229 C.
EXAMPLES 5-13 Following the procedure of Example 1, but substituting the piperazine derivative listed in column I for 1-(2-methoxyphenyl)piperazine, yields the compounds listed in column II.
Column I 5 1 -phenylpiperazine 6 1-(2,6-dibromophenyl) piperazine 7 1-(2-iodophenyl)piperazine 8 1-(2-fluorophenyl)piper azine 9 1-(3,4-dimethylphenyl) piperazine 10 1-(2,6-dimethoxyphenyl) piperazine 11 1-(1 -pyridyl)piperazine 12 l-(3-pyridyl)piperazine 13 1-(4-pyridyl)piperazine Column II 3,4a-5-cis-decahydro-5-[2-hydroxy-3-(4phenyl-1-piperazinyl)propyl]-2,3;4a-8atrans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4- ( 2 , 6 - d i b r o m o p h e n y l ) - 1 piperazinyl]propyl]-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester 3,4a-5-cis-decahydro-5-[2-hydroxy-3-[4- (2-iodophenyl)-1 -piperazinyl]propyl]- 2,3;-4a,8a-trans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4 (2-fluorophenyl)-1-piperazinyl]propyl] 2.3 ;4a,8a-trans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4- ( , 4 - d i n e t h ylp h e n yl )- 1- piperazinyl]propyl]-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4 ( 2 , 6 - d i m e t h o x y p h e n y l ) - 1 piperazinyl]propyl]-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester 3,4a.5-cis-decahydro-5-[2-hydroxy-3-[4- (1-pyridinyl)-1-piperazinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[4 (3-pyridinyl)-1-piperazinyl]propyl]2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-decahydro-5-[2-hydroxy-3-[-(4pyridinyl)-1-piperazinyl]propyl]2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester EXAMPLE 14 3a,5-cis-3a,7a;5,6-trans-Hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1piperazinyl]propyl]-1H-indene-3a,5,6,7a-tetrol, tetraacetate ester, hydrochloride (1:1) 3a,5-cis-3a,7a;5,6-trans-Hexahydro-1-(3-dimethylaminopropyl)-1H-indene-3a,5,6,7a tetrol, tetraacetate ester, N-oxide An amount of 2.4g of 85% m-chloroperbenzoic acid is added to a solution of 5.0g of 3a,5-cis-3a,7a;5,6-trans-hexahydro-1-(3-dimethylaminopropyl) in 50 ml of chloroform at 0-5 C. The cold bath is removed and the mixture is stirred for 31/2 hours under nitrogen. The solution is partially evaporated in vacuo and then chromatographed on 98 g of neutral Alumina III. Elution with chloroform and methanolic chloroform yields, upon evaporation in vacua, 4.6 g of the N-oxide as a white solid.
3a,5-cis-3a, 7a;5, 6-trans-Hhexahydro-I -(2-propenyl) -IH-indene-3a,S, 6-7a-tetrol, tet raacetate ester The above N-oxide (4.6 g) is vacuum pyrolyzed at 160-190 C under 12 mm Hg vacuum.
The product is vacuum distilles to give 2.1 g of crude olefin at 185-195 C under 0.25 mm Hg vacuum. Further purification by chromatography on 35 g of neutral Alumina III eluted with 15-20% ethyl acetate-hexane yields 1.0 g of the olefin as a white solid.
3a,5-cis 3a, 7a;5,6-trans-Hexahydro-1-(oxiranylmethyl)-1H-indene-3a,5,6,7a-tetrol, tet raacetate 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 g 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]-1H-indene-3a,5,6,7a-tetrol, tetraacetate ester, hydrochlorine (1:1) A solution of 0.9 g of epoxide and 0.43 g of o-methoxyphenylpiperazine in 20:50 benzene-absolute ethanol is stirred for 18 hours in a 57 C bath. The solvent is removed in vacuo and the residue chromatographed on 25 g of neutral Alumina III. Elution with 150 ml of 25-30% ethyl acetate-hexane yields 0.53 g of forerun (mainly recovered epoxide).
Elution with 200 ml of 35-40Wo 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 215-220 C.
Anal. Calc'd. for C31H44N2O19.HCl (641.16 g/m) C, 58.()7 H, 7.08; N, 4.37; Cl. 5.53 Found: C, 57.89; H, 7.00; N, 4.31; Cl. 5.67 EXAMPLE 15 3,4a-cis-Hexahydro-5-[2-hydroxy-3-[4-(2methoxyphenyl)-1-piperazinyl]propyl]-2,3;4a,9atrans-benzocycloptanetetrol, tatracetate ester A) 3,4a-cis-Hexahydro-5-(3-dimethylaminopropyl)-2,3;4a,9a-trans benzocycloptanetetrol, tetraacetate ester, N-oxide A solution of 3,4a-cis-hexahydro-5-(3-dimethylaminopropyl)-2.3:4as9a-trans- benzocycloheptanetetrol, tetraacetate ester (12.8 mmole) and m-chloroperbenzoic acid (2.5 g) in chloroform (100 ml) is prepared at 0 C and gradually warmed to room temperature to yield the title N-oxide.
B) 3,4a-cis-Hexahydro-5-(2-propenyl)-2,3;4a,9a-trans-benzocycloheptanetetrol, tetraace tate ester The above N-oxide (10.8 mmole) is heated in a vacuum distillation set-up under 3() mm Hg vacuum with nitrogen bleed to yield the title olefin.
C) 3,4a,5-cis-Hexahydro-5-(oxiranylmethyl)-2,3;4a-9a-trans-benzocycloheptanetetrol, tet raacetate ester A solution of the above tetraacetate-olefin (5.9 mmole) and 85'Xc m-chloroperbenzoic acid (1.3 g) in chloroform (51) ml) is prepared at O"C and stirred at room temperature for about 16 hours to yield the title epoxide.
D) 3,4a-cis-Hexahydro-5-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl] 3,3;4a,9a-trans-benzocycloheptanetetrol, tetraacetate ester A solution of 1-(2-methoxyphenyl)piperazine (5.0 mmole) and the above epoxide (5.() mmole) in absolute ethanol (50 ml) and benzene (20 ml) is stirred in a warm water bath (50-55 C) for about 20 hours under a drying tube to yield the title compound.
EXAMPLE 16 3,4a,5-cis-5-[3-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-2-hydroxypropyl]-decahydro2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A solution of 2.5g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)2-2,3;4a.8a-transnaphthalenetetrol, tetraacetate ester and 0.86g of 4-phenyl-1,2,3,6-tetrahydropyridine in 20 ml benzene-50 ml absolute ethanol is stirred at 55-57 C for about 16 hours under a drying tube. The solution is evaporated in vacuo and the residue is crystallized from 3() ml of 1:2 ethyl acetate-ether to give 0.85g of solid. A second crop yields 0.35g of solid.
Recrystallization from 2:1 ethyl acetate-ether yields 1.1g of the title compound, melting point 193-1990C.
EXAMPLE 17 Decahydro-5-[2-hydroxy-3-[1,4,5,6-tetrahydrobenz[f]isoquinolin-3-(2H-yl)propyl]-3,4a-5cis-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester 1,2,3,4,5,6-Hexahydrobenz[f]isoquinoline, monohydrochloride (1.0g) is dissolved in 20 ml of water, layered over with ether and neutralized with aqueous ammonia. The organic phase is removed and the aqueous phase is re-extracted with ether (two 20 ml portions).
Organics are combined, dried, filtered and stripped in vacuo to yield 0.75g of the free base, which is dissolved in 20 ml of benzene and 50 ml of absolute ethanol, 3,4a,5-cis-Decahydro5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester (1.813g) is added to the solution, and the resulting solution is heated to 50 C#5 for 18 hours. Solvent is removed in vacuo, the residue is taken up in ether and the resulting powder is recrystallized from ethyl acetate to yield 1.17g of the title compound.
EXAMPLE 18 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 A) 1,2,3,6-Tetrahydro-4-(2-phenylethenyl)-1-(phenylmethyl)pyridine, monohydrochloride N-Benzylstyrylpyridinium bromide (59.0g) is reduced by stirring in 750 ml of 50% aqueous methanol to which 3f)g of sodium borohydride is added portionwise. Methanol is removed in vacua the resulting slurry is filtered and the solids are partitioned between water and chloroform. The aqueous layer is rc-extracted with chloroform. The chloroform extracts are combined, washed with aqueous sodium chloride, dried and stripped to yield 33.2g of the title compound. Four grams of this product is dissolved in absolute ethanol, acidified with anhydrous hydrogen chloride in isopropanol, yielding 3.7g of solid, which is recrystallized from methanol-isopropanol to yield 2.72g of crystals, melting point 235-240 C.
B) 1,2,3,6-Tetrahydro-4-(2-phenylethenyl)pyridine A solution of 46 g 1,2,3,6-tetrahydro-4-(2-phenethenyl)-1-(phenylmethyl)pyridine in 150 ml of toluene is treated with 30.1g of phenyl chloroformate and heated reflux for 12 hours. Solvent is removed in vacuo to yield 62.7g of a solid. The above solid is heated to 130 C with the aid of an oil bath and 50g of powedered potassium hydroxide is added, portionwise. Heating is continued for 90 minutes, the mixture is cooled, taken up in 200 ml water and extracted with chloroform. Organics are combined, washed with aqueous sodium chloride, dried, filtered and stripped to yield 43g of an oil which is taken up in ether, filtered and stripped to yield 33g of oil. Twenty-eight grams of the oil is refluxed in l liter of hexane. 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. Due to the poor differential solubility, this process is repeated about eight times. yielding a total of l.()5g of the free base.
C) 3, 4a. 5-cis-Decahydro-5-[2-hydroxy-3-[4- (2-phenylethenyl] -3, -3,6-dil? ydro- 1(2 H) pyridinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester 1,2,3,6-Tetrahydro-4-(2-phenylethenyl)pyridine (1.04g) and 2.5g of 3,4a,5-cisdecahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester are dissolved in 50 ml of absolute ethanol and 20 ml of benzene, and heated at 55 C#5 for 15 hours. Solvent is evaporated in vacuo and the resulting gum crystallized from ether. Solids are collected yielding 1.35g of brown solid which is taken up in ethyl acetate, decolorized with activated charcoal, filtered, hexane added and left standing. Resulting solids are collected and dried to yield I.()g of powder, melting point 183-I850C.
EXAMPLE 19 3,4a-5-cis-[3-[4-(2,3-Dihydro-2-benzoxazolyl)-3,6-dihydro-1 (2H)-pyridinyl]-2hydroxypropyl]-decahydro-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A) 2- (4-Pyn'dinyl) henzoxazole A mixture of 2-aminophenol (10.9g), isonicotinic acid (12.3g) and polyphosphoric acid (250g) is heated under a nitrogen atmosphere at 210 C for 3 hours. The mixture is then cooled to 160 C and slowly poured into 1 liter of water. The mixture is cooled by adding ice and neutralized with 50% soldium hydroxide solution yielding 16.2g of crude product.
Crystallization from hexane yields 14.8g of the title compound, melting point 129-131 C.
B) 4-(-Benzoxazolyl)-1-(phenylmethyl)pyridinium chloride A solution. of 117.0g of 2-(4-pyridinyl)benzoxazole and 95.0g of benzyl chloride in 1 liter of a 9:1 mixture of n-propanol and dimethylsulfoxide is heated at reflux for 72 hours. The solvent mixture is then removed and the residue suspended in 100 ml of water. The crystalline product which separates is filtered, washed with acetone, and dried to give 76.6g of product. Concentration of the mother liquors gives an additional 27.8g of product, melting point 194-196 C, dec. Recrystallization from water and drying in a vacuum at 100 C for 5 hours raises to melting point to 216-217 C, dec.
C) 2- (1-Benzyl-1,2,3, 6-tetrahydro-4-pyr dinyl)benzoxazole To a stirred solution of 16.6g of 4-(2-benzoxazolyl)-1-(phenylmethyl)pyridinium chloride in 1 liter of a 1:1 mixture of alcohol and water is added a solution of 2.84g of sodium borohydride at a rate that maintains the temperature of the mixture at 30-350C. The reaction mixture is acidified with hydrochloric acid, concentrated to one-half volume and the crystals filtered to give 8.7g of the hydrochloride salt of the title compound, melting point 227-228 C, dec.
The mother liquors are made 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 the title compound, melting point 129-130 C.
D) 4-(2-Berizoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloroethyl ester To a vigorously stirred solution of 109.1g of 2-(1-benzyl-1,2,3,6-tetrahydro-4- pyridinyl)benzoxazole in 1 liter of dry toluene is added dropwise 96.4g of 2.2,2trichloroethyl 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 water, dried (anhydrous magnesium sulfate), and concentrated. The oily residue is then further concentrated from an oil bath maintained at 50 C under a vacuum of 0.2mm of Hg to remove the remaining benzyl chloride.
The viscous oil is dissolved in 500 ml of boiling absolute ethanol and cooled to give, after filtration and drying, 56.9g of crystalline product, melting point 134-135 C. The mother liquors give, after concentration to one-half volume and cooling an additional 11.0g of product identical with that above.
E) 2-(1,2,3,6-Tetrahydro-4-pyridinyl)benzoxazole To a solution of 52.6g of 4-(2-benzoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloroethyl ester in 1250 ml of glacial acetic is gradually added 92.5g of zinc dust and the reaction mixture stirred at room temperature under nitrogen for 6 hours. The reaction mixture is filtered and concentrated on the rotary evaporator to give a viscous gum. This material is suspended in 500 ml of water, the pH adjusted to 2-3, and the suspension extracted with 500 ml of ether in two portions. These are combined, dried and concentrated to give. 11.32g of unreacted starting material.
The separated turbid, aqueous phase is filtered. cooled, made stronglv alkaline. and extracted three with 250 ml portions of chloroform. The combined extracted are dried and concentrated to give 6.0g of crystals, melting point 136-138 C.
F) 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 Three grams of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester is dissolved in 50 ml of absolute ethanol and 20 ml of benzene. To this is added 1.34g of 2-(1,2,3,6-tetrahydro-4-pyridinyl)benzoxazole and the resulting solution is heated to 55 C#5 for 16 hours. Solvent is stripped in vacuo and the resulting gum is taken up in ether. The ether solution is filtered, diluted with hexane and left standing.Solids are collected to yield 3g of solid which is recrystallized from ethyl acetate and hexane to yield 1.6g of the title compound, melting point 204-210 C, dec.
EXAMPLE 20 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl]-2,3;4a,8atrans-naphthalenetetrol, tetraacetate ester A solution of 3.0g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetra-acetate ester and 0.94g of 1,2,3,4-tetrahydroisoquinoline in ethanol-benzene (50:20) is warmed in a 55 C bath for about 16 hours. The solution is evaporated in vacuo to give 4g of solid. Two recrytallizations from ethyl acetate/ether/ hexane yield 1.9g of the title compound, melting point 185-195 C.
EXAMPLE 21 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol To a solution of 0.55g of sodium hydroxide in 30 ml of absolute ethanol is added 1.35g of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, hydrochloride. After stirring for about 5 minutes a solution of 3.0g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester in 30:50 ethanol:benzene is added and the solution is stirred for about 16 hours at 40-450C. The mixture is filtered and the filtrate is evaporated in vacuo to give 3.8g of foam. The foam is dissolved in 50:20 ethanol:benzene and stirred for 24 hours at 55-58 C. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate, heated with activated charcoal and filtered. After diluting with a small amount of ether and storing at -15 C for 3 days, 1.3g of solid is obtained. Recrystallization from ethyl acetate (trace methanol) yields 1.0g of the title compound, melting point 214-216 C.
EXAMPLES 22-23 Following the procedure of Example 16, EXAMPLES 26-27 Following the procedure of Example 18, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)- ;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 11 3a,5-cis-3a,7a;5,6-trans hexahydro-l-(oxiranylmethyl)- 1H-indene-3a,5,6,7a-tetrol, tetraacetate ester 12 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a,9a- trans-benzocycloheptane tetrol,, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[2-hydroxy-3 [4-(1-phenylethenyl)-3 6- dihydro-1(2H)-pyridinyl]propyl]-1H-indene-3a,5 6,7a-tetrol, tetraacetate ester 3,4a-cis-hexahydro-5-[2hydroxy-3-[4-(1-phenylethenyl)-3,6-dihydro1 (2H)-pyridinyl]propyl]2,3;4a,9a-trans-benzocycloheptanetetrol, tetraacetate ester EXAMPLES 28-29 Following the procedure of Example 19, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 13 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranylmethyl) I H-indene-3a,5 ,6,7a-tetrol, tetraacetate ester 14 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a,9a trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[3-[4-(2,3dihydro-2-benzoxazolyl)3.6-dihydro-1(2H)-pyridinyl 2-hydroxypropyl]- lH-indene3a,5,6,7a-tetrol, tetraacetate ester 3,4a-cis-hexahydro-5-13-14- (2,3-dihydro-2-benzoxazolyl 3,6-dihydro-1(2H)-pyridinyl 2-hydroxypropyl]-2,3;4a,9a trans-benzocycloheptanetetrol, tetraacetate ester EXAMPLES 30-31 Following the procedure of Example 20, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 15 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranylmethyl) 1H-indene-3a,5,6,7a-tetrol, tetraacetate ester 16 3.4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3:4a.9a- trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[2-hydroxy-3 (1,2,3,4-tetrahydro-2 isoquinolinyl)propyl]- 1H- indene-3a,5 ,6,7a-tetrol, tetraacetate ester 3.4a-cis-hexahydro-5-[2hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl )propyl]-2,3;4a,9a-transbenzocycloheptanetetrol, tetraacetate ester EXAMPLE 32-33 Following the procedure of Example 21, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Cohiiizn I 17 3a,5-cis-3a,7a;5,7-trans hexahydro-1-(oxiranylmethyl) 1H-indene-3a,5,6,7a-tetrol, tetraacetate ester 18 3.4a,5-cis-hexahydro-5-(oxi ranylmethvl )2.3 :4a .9a-t) ans- benzocycloheptanetetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[2-hydroxy-3 (4,5,6,7-tetrahydro-1Himidazo[4,5-c]pyridin-5yl)propyl]-1H-indene-3a,5,6,7a-tetrol, tetraacetate ester 3,4-cis-hexahydro-5-[2hydroxy-3-(4,5,6,7-tetrahydro-1H-imidazo(4,5-c]pyridin-5-yl)propyl]-2,3;4a,9a-trans-benzocycloheptanetetrol. tetraacetate ester EXAMPLE 34 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-[4-[(1-oxopropyl)-phenylamino]-1piperidinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester 3,4a,5-cis-Decahydro-5-(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-4-piperidinylpropanamide and the resulting solution is heated to 55 C # 50 for 16 hours. The solvent is stripped off in 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 3.1g of powder, melting point 153-160 C.
EXAMPLE 35 1 - [2-Hydroxy-3-[cis-1,7,8a-4a,6,7,8a-tetrakis (acetyloxy)-decahydro-1naphthalenyl]propyl]-4-phenyl-4-piperidine-carbonitrile A solution of 1.0g of 4-cyano-4-phenylpiperidine and 2.5g of 3,4a,5-cis-decahydro-5 (oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester in 200ml benzene50ml ethanol is stirred at 55-57 C for about 16 hours under a drying tube. The solution is evaporated in vacuo to give 3.3g of oil. Chromatography on 80g of neutral alumina III gives 1.06 of epoxide eluted with 600 ml of 20-25% ethyl acetate in hexane, and 1.4g of the desired product eluted with 750ml of 40-45% ethyl acetate in hexane. Crystallization of this latter material from ethyl acetate hexane gives two crops of solid product. These are combined and dried in vacuo to yield 0.97g of the title compound, melting point 165-174 C.
EXAMPLE 36 3,4-cis-Decahydro-5-[2-hydroxy-3-(4-hydroxy-4-phenyl-1-piperidinyl)propyl]-2,3;4a,8atrans-naphthalenetetrol, tetraacetate ester A solution of 3.0g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester and 1.25g of 4-hydroxy-4-phenyl piperidine in 50 ml of absolute ethanol-20 ml benzene is stirred at 57 C for about 16 hours. Crystallization from 2:1 ethyl acetate-hexane gives 3.5g of solid. Recrystallization from ethyl acetate-hexane (20:5) gives 2.11g of the title compound. melting point 138-142 C.
EXAMPLE 37 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-(3,4-dihydrospiro[2H-1-benzopyran-2,4'-piperidin]1-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A) 3,4-Dihydro-1'-(phenylmethyl)spiro[2H-1-benzopyran-2,4'-piperidine], hydrochloride (1:1) 4-(o-Methoxyphenethyl)pyridine (40.5 g) and benzylbromide (36.0 g) are heated on a steam cone in 25() ml of acetonitrile for 6 hours. After cooling the reaction mixture is concentrated in vacua Addition of ethyl acetate causes crystallization. The product is filtered, washed with ether and dried over potassium hydroxide. The yield of a hydroscopic quaternary is 68.4 g. melting point 114-124 C.
The above quaternary (60.6 g) is dissolved in 600 ml of 1:1 methanol-water and 10 g of sodium borohydride is added portionwise at 35-40 C. After addition, the solution is allowed to stand for about 16 hours. It is then concentrated to about 400 ml and diluted with 300 ml of water. The product is extracted with two 300 ml portions of chloroform. The chloroform is dried, filtered and concentrated in vacua The hydrochloride salt is prepared in isopropanol-hydrogen chloride. After concentrating in vacuo, ethyl acetate is added to the residue. The hydrochloric salt crystalllizes over a 16-hpour period and is filtered to yield 54 g of product, melting point 122-128 C.
The above product (54.0 g) is dissolved im 250 ml of 48% hydrogen bromide. It is then heated at reflux for 6 hours and concentrated in vacuo. The residue is made strongly basic with 10% sodium hydroxide and the product is extracted with chloroform. The chloroform is dried, filtered and concentrated in vacuo. This free base is dissolved in ethyl acetate, and hydrogen chloride in isopropanol is added until strongly acidic. The product is filtered to yield 39.4 g. Two grams are recrystallized from acetonitrile to give the analytical sample, melting oint 243-245 C.
B) 3,4-Dihydrospiro[2H-1-benzopyran-2,4'-piperidine 3,4-Dihydro-1'-(phenylmethyl)spiro[2H-1-benzopyran-2,4'-piperidine] (25.7 g) is dissolved in 250 ml of anhydrous toluene. The reaction mixture is cooled to 59C and trichloroethyl chloroformate is added dropwise. The solution is refluxed for 5 hours and allowed to stand at room temperature for about 16 hours. It is then washed sequentially with 100 ml of 10% sodium hydroxide, 1()0 ml of water, 100 ml of 1OC/c hydrochloric acid and finally with 200 ml of water. The toluene is dried, filtered and concentrated in l'aC'UO to yield 32.0 g of product.
The above material is dissolved in 300 ml of glacial acetic acid. Zinc dust (30 g) is added portionwise over a 30-minute period at 200C. The reaction mixture is stirred at room temperature for about 16 hours. filtered and concentrated in vacua. The residue is heated on a steam cone for 15 minutes in 200 ml of 10 sodium hydroxide. Product is extracted with chloroform. The chloroform is dried, filtered and concentrated in vacua to yield 17.8 g of crude secondary amine. Its hydrochloride salt was prepared in isopropanol-hydrogen chloride. After crystallizing for about 16 hours. the product is filtered to yield 11. l ig of the hydrochloride salt of the title compound. melting point 238-240 C.
C) 3,4a,5-cis-Decahydro-5-[2-hydroxy-3-(3,4-dihydrospiro-[2H-1]-benzopyran-2,4 piperidin-1-yl)propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester An amount of 1.7 g of 3,4-dihydrospiro[2H-1-benzoDyran-2,4'-piperidine] is added to a solution of 3.55 g of 3 ,4a,5-cis-decahydro-5-oxiranylmethyl)2,3 ;4a ,8a-trans- naphthalenetetrol, tetraacetate ester in 50:20 ml of ethanol-benzene. The solution is stirred for about 16 hours at 55 C and then evaporated in vacuo. The residue is crystallized over 3 days from 2.1 ether-hexane to give 3.6 of solid. Recrystallzation from ethyl acetate-hexane gives 2.3 g of the title compound (thin-layer chromatography on alumina in ethyl acetate in iodine indicates the title to be the main isomer of two isomers), melting point 135-152 C.
EXAMPLES 38 3,4,5-cis-Decahydro-5-[2-hydroxy-3-[4-(2-hydroxyethyl)-1-piperidinyl]propyl]-2,3;4a,8atrans-naphthalenetetrol tetraacetate ester A solution of 2.5 g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3,4a,8a-transnaphthalenetetrol, tetraacetate ester and 0.75 g of 4-ethanolpiperidine in 50 ml of absolute ethanol and 20 ml of benzene is stirred at 55 C for 18 hours. The solvents are removed in vacuo and the residue is concentrated in vacuo several times with benzene to give a foam-like product. Crystallization from ether gives 2.55 g and then 0.5 g of solid product.
Recrystallisation of the 3 g of solid from 2:1 ethyl acetate-hexane gives 2.0 of the title compound, melting point 112-120 C.
EXAMPLE 39 3, 4a, 5-cis-5-J2- (A cetvloxy) -3-/4-[2- (acetyloxy) etlzyl]-l -piperidinylipropylj-decahydro- 2,3:4a, 8a-trans-naphthalenetetrol, tetraacetate ester A mixture of 5 ml of acetic anhydride and 1.25 g of 3,4a,5-cis-decahydro-5-[2-hydroxy-3 [4-(2-hydroxyethyl)-1-piperidinyl]propyl]-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester (see Example 5) in 25 ml of dry pyridine is stirred at room temperature for about 16 hours. The solution is evaporated in vacuo. The residue is partitioned between ether and a saturated aqueous sodium bicarbonate solution. The aqueous layer is re-extracted with ether, and the ether extracts are combined, dried and evaporated in vacuo yielding 1.3 g of product, Recrystallization from 1:9 ethyl acetate-hexane yields 1.22 g of the title compound, melting point 125-144 C.
EXAMPLE 40 3,4a,5-cis-[3-[2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-2hydroxypropyl]decahydro-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester An amount of 1.5 g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3,4a,8a-transnaphthalenetetrol, tetraacetate ester is dissolved in 20 ml of benzene and 50 ml of absolute ethanol and maintained at 500C+50 with a water bath. To this is added 0.73 g of 4-(2-keto-1-benzimidasolinyl)piperidine and stirring is continued for 36 hours. Solvent is stripped in vacuo, and the product is crystallized from ethyl acetate-hexane to yield 1.67 g of material, melting point 137-144 C.
EXAMPLE 41 3,4a,5-cis-[3-[4-(2-Benzoxazolyl)-1-piperidinyl]-2-hydroxypropyl]-decahydro-2,3,4a,8anaphthalenetetrol, tetraacetate ester A) 2- (4-Piperidinyl) bestzoxazole A solution of 1.71 g of benzyl bromide in 10 ml of acetonitrile is added to a solution of 1.96 g of 2-(4-pyridinyl)benzoxazole in 25 ml of hot acetonitrile. After 10 minutes the product begins to crystallize out of solution. The mixture is heated on the steam bath for 2 hours and then diluted with ether and filtered. The crude solid is dissolved in 5() ml of 1:1 methanol-water and treated portionwise with 2 g of sodium borohydride. The mixture is diluted with water and 2.4 g of the solid product is collected. The 2.4 g of solid is dissolved in 150 ml of ethanol, 2 g of 5% paladium on carbon is added, and the mixture is placed on the Parr hydrogenator under 50 psi hydrogen. The mixture is filtered, and the filtrate evaporated in vacuo to give 1.4 g of the title compound.
B) 3,4a,5-cis-[3-[4-(2-Benzoxazolyl)-1-piperidinyl]-2-hydroxypropyl]decahydro 2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester A solution of 3.6 g of 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester and 1.4 g of the 2-(4-piperidinyl)benzoxazole in 20 ml of benzene and 50 ml ethanol is stirred for 7.5 hours at 55 C and then for about 16 hours at room temperature under nitrogen. The solution is evaporated in vacuo and the residue dissolved in hot ethyl acetate (30-40 ml), diluted with hexane (30 ml) and crystallized on standing to give 3.14 g of solid. The solid is dissolved in hot ethyl acetate (50 ml), treated with Darco (Trade Mark) filtered, and diluted with hexane (20 ml). The solution crystallizes to give 2.02 g of the title compound, melting point 195-205 C.
EXAMPLES 42-43 Following the procedure of Examples 34, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 9) 3a,5-cis-3a,7a;5,6-trans hexahydro-l(oxiranyl methyl)-1H-indene-3a,5,6,- 7a-tetrol, tetraacetate ester (see United States patent application serial no. 784,888, filed April 5. 1977) 10) 3.4a,5-cis-hexahydro-5 oxiranylmethyl)-2,3;4a 9a-trans-benzocycloheptane tetrol, tetraacetate ester (see United States patent application serial no.
784,888, filed April 5.
1977) Column II 3a,5-cis-3a,7a;5,6-trans hexahydro-1-[2-hydroxy-3- (4-[( 1-oxopropyl)phenyl- amino]-1-piperidinyl]propyl]-1H-indene-3a,5,6,7a-tetrol, tetraacetate ester 3,4a,5-cis-hexahydro-5 [2-hydroxy-3-[4-(1-oxopropyl)phenylamino]- 1piperidinyl]propyl]-2,3;4a,9a-trans-benzocyclo heptanetetrol, tetraacetate ester EXAMPLES 44-45 Following the procedure of Example 35, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester yields the compound listed in column II.
Column I 11) 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranyl methyl)-1H-indene-3a,5,6 7a-tetrol tetraacetate ester 12) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a, 9a-trans-benzocycloheptane tetrol, tetraacetate ester Column II 1-[2-hydroxy-3-[cis3a,5-3a,5,6,7a-tetra kis(acetyloxy)hexahydro1H-inden-1-ly]propyl]-4phenyl-4-piperidinecarbon ltrile.
1-[2-hydroxy-3-[cis1,8,9a-2,3,4a,9a-tetra kis(acetyloxy)hexahydro 1-beazocycloheptanyl propyl]-4-phenyl-4piperidinecarbonitrile EXAMPLES 46-47 Following the procedure of Example 36, but substituting the compound listed in column I for 3 ,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3 ;4a,8a-trans-naphthalenetetrol, - tetraacetate ester, yields the compound listed in column II.
Column I 13) 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranyl methyl)-1H-indene-3a,5,6, 7a-tetrol, tetraacetate ester 14) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a, 9a-trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-trans- hexahydro-1-[2-hydroxy-3 (4-hydroxy-4-phenyl-1 piperidinyl)propyl -1H- indene-3a,5 ,6,7a-tetrol, tetraacetate ester 3,4a,5-cis-hexahydro-5 [2-hydroxy-3-(4-hydroxy4-phenyl-1-piperidinyl)propyl]-2,3;4a,9a-transbenzocycloheptanetetrol, tetraacetate ester EXAMPLES 48-49 Following the procedure of Example 37 but sustituting the compound listed in column I for 3 ,4a ,5-cis-decahydro-5-(oxiranylmethyl)-2,3 ;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 15) 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranyl methyl)-1H-indene-3a,5,6 7a-tetrol, tetraacetate ester 16) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a, 9a-trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-trans hexahydro-1-[2-hydroxy-3- (3,4-dihydrospiro[2H-1benzopyran-2,4'-piperidin] 1-yl)propyl]-lH-indene- 3a,5,6,7a-tetrol, tetraacetate ester 3 ,4a,5-cis-hexahydro-5- [2-hydroxy-3-(3,4-dihydrospiro[2H-benzopyran-2,4'piperidin]-1-yl)propyl]2,3;4a,9a-trans-benzocycloheptanetetrol, tetraacetate ester EXAMPLES 5S51 Following the procedure of Example 38, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphtalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 17) 3a,5-cis-3a,7a;6-trans hexahydro-1-(oxiranyl methyl)-1H-indene-3a,5,6, 7a-tetrol, tetraacetate ester 18) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3 ;4a ,9a- trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[2-hydroxy-3 [4-(2-hydroxyethyl)-1piperidinyl]propyl]-1Hindene-3a,5,6,7a-tetrol, tetraacetate ester 3 ,4a,5-cis-hexahydro-5- [2-hydroxy-3-[4-(2hydroxyethyl)-1-piperidinyl]propyl]-2,3;4a,9atrans-benzocycloheptanetetrol, tetraacetate ester EXAMPLES 52-53 Following the procedure of Examples 38 and 39, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxiranylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 19) 3a,5-cis-3a,7a;5,6-trans hexahydro-1-(oxiranyl methyl)-1H-indene-3a,5,6,- 7a-tetrol, tetraacetate ester 20) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a,9a trans-benzocycloheptane tetrol. tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[2-(acetyloxy)3-[4-[2-(acetyloxy)ethyl]1-piperidinyl]propyl]-1Hindene-3a,5,6,7a-tetrol, tetraacetate ester 3,4a,5-cis-hexahydro-5 [2-(aetyloxy)-3-[4-[2 (acetyloxy)ethyl]-1-piperidinyl]propyl]-2,3;4a,9atrans-benzocycloheptanetetrol, tetraacetate ester EXAMPLES 54-55 Following the procedure of Example 40, but substituting the compound listed in column I for 3,4a ,5-cis-decahydro-5-(oxiranylmethyl)-2 ,3;4a, 8a-trans-naphthalenetetrol , tetraacetate ester, yields the compound listed in column II.
Column I 21) 3a,5-cis-3a,7a;5,6-trans hexahydro- I -(oxiranyl- methyl)-1H-indene-3a,5,6, 7-tetrol, tetraacetate ester 22) 3,4a,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a,9a trans-benzocycloheptane tetrol, tetraacetate ester Column II 3a,5-cis-3a,7a;5,6-transhexahydro-1-[3-(2,3-dihydro 2-oxo-1H-benzimidazole- 1-yl)- 1-piperidinyl]-2-hydroxypropyl]-1H-indene-3a,5,6,7atetrol, tetraacetate ester 3 ,4a,5-cis-hexahydro-5-[3- (2,3-dihydro-2-oxo-lHbenzimidazol-l-yl)-lpiperidinyl]-2-hydroxypropyl]-2,3;4a,9a-transbenzocycloheptanetetrol, tetraacetate ester EXAMPLES 56-57 Following the procedure of Example 41, but substituting the compound listed in column I for 3,4a,5-cis-decahydro-5-(oxinylmethyl)-2,3;4a,8a-trans-naphthalenetetrol, tetraacetate ester, yields the compound listed in column II.
Column I 23) 3a,5-cis-3a,7a;5 6-trnns- hexahydro- 1 -(oxiranyl methyl)-1 H-indene-3a,5,6- 7a-tetrol, tetraacetate ester 24) 3,4,5-cis-hexahydro-5 (oxiranylmethyl)-2,3;4a,9a trans-benzocycloheptane tetrol. tetraacetate ester Column II 3a,5-cis-3a,7a;5 ,6-trans hexahydro-1-[3-[4-(2- benzoxazolyl)-1-piper- idinyl]-2-hydroxypropyl j- lH-indene-3a,5,6,7a-tetrol, tetraacetate ester 3,4a,5-cis-hexahydro-5 [3-[4-(2-benzoxazolyl) l-piperidinyll-2-hydroxy- propyl ]-2.3 ;4a,9a-transbenzocycloheptanetetrol, tetraacetate ester

Claims (40)

  1. WHAT WE CLAIM IS: I. A compound having the formula
    or such a compound in pharmaceutically acceptable salt form, wherein n is 0, 1 or 2; R1 is alkanoyl having 2 to 7 carbon atoms; R2 is
    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 aryl or pyridinyl and m is 2, 3 or 4.
  2. 2. A compound in accordance with claim 1 wherein R7 is phenyl or phenyl substituted with 1 or 2 halogen, alkyl trifluoromethyl -alkoxy or alkylthio radicals.
  3. 3. A compound in accordance with claim 1 wherein n is 0.
  4. 4. A compound in accordance with claim 1 wherein n is 1.
  5. 5. A compound in accordance with claim 1 wherein n is 2.
  6. 6. A compound in accordance with claim 4 wherein Rl is acetyl.
  7. 7. A compound in accordance with claim 4 wherein R,, is hydrogen.
  8. 8. A compound in accordance with claim 6 wherein R7 is pyridinyl.
  9. 9. A compound in accordance with claim 8 wherein R7 is 2-pyridinyl.
  10. 10. A compound in accordance with claim 6 wherein R7 is phenyl.
  11. 11. A compound in accordance with claim 6 wherein R7 is phenyl substituted with l or 2 halogen, alkyl. trifluoro-methyl, alkoxy or alkvlthio radicals.
  12. 12. A compound in accordance with claim 6 wherein R2 is
  13. 13. A compound in accordance with claim 6 wherein R2 is
  14. 14. A compound in accordance with claim 6 wherein R2 is
  15. 15. A compound in accordance with claim 6 wherein R2 is
  16. 16. A compound in accordance with claim 6 wherein R2 is
  17. 17. A compound in accordance with claim 6 wherein R2 is
  18. 18. A compound in accordance with claim 7 wherein R2 is
  19. 19. A compound in accordance with claim 7 wherein R2 is
  20. 20. A compound in accordance with claim 19 wherein R4 is cyano.
  21. 21. A compound in accordance with claim 19 wherein R4 is hydroxy.
  22. 22. A compound in accordance with claim 7 wherein R2 is
  23. 23. A compound in accordance with claim 7 wherein R2 is
  24. 24. A compound in accordance with claim 7 wherein R2 is
  25. 25. A compound in accordance with claim 7 wherein R2 is
  26. 26. The compound in accordance with claim 1, having the name 3,4a,5-cis-decahydro-5 [2-hydroxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]propyl]-2,3 ;4a,8-trans- naphthalenetetrol, tetraacetate ester.
  27. 27. The compound in accordance with claim 1, having the name 3,4a,5,cis-decahydro-5 [2-hydroxy-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]propyl]-2,3 ;4a ,8a-transnaphthalenetetrol, tetraacetate ester.
  28. 28. The compound in accordance with claim 1, having the name 3,4a,5-cis-5-[3-[4-[2 (ethylthio)phenyl]-1-piperazinyl]-2-hydroxypropyl]decahydro-2,34a,8a-transnaphthalenetetrol, tetraacetate ester.
  29. 29. The compound in accordance with claim 1, having the name 3,4a,5-cis-decahydro-5 [2-hydroxy-3-[4-(2-pyridinyl)- 1-piperazinyljpropylj2 3 ;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
  30. 30. The compound in accordance with claim 1, having the name 3a,5-cis-3a,7a;5,6trans-hexahydro-1-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-1H-indene3a,5,6,-7a-tetrol, tetraacetate ester, monohydrochloride.
  31. 31. The compound in accordance with claim 12 having the name 3,4a,5-cis-5-[3-[3,6dihydro-4-phenyl-1(2H)-pyridinyl)-2-hydroxypropyl]decahydro-2,3;4a,8a-transnaphtalenetetrol, tetraacetate ester.
  32. 32. The compound in accordance with claim 13 having the name decahydro-5-[2 hydroxy-3-( 14,5 6-tetrahydrobenz-[f]-isoquinolin-3(2H)-yl )propyl]-3 ,4a,5-cis-2,3 ;4a ,8a- trans-naphthalenetetrol, tetraacetate ester.
  33. 33. The compound in accordance with claim 14 having the name 3,4a,5-cis-decahydro5-[2-hydroxy-3-[4-(2-phenyl-ethenyl)-3,6-dihydro-1(2H)pyridinyl]propyl]-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester.
  34. 34. The compound in accordance with claim 15 having the name 3,4a,5-cis-5-[3-[4-(2,3dihydro-2-benzoxazolyl)-3,6-dihydro-1(2H)pyridinyl]-2-hydroxypropyl]decahydro2,;4a,8a-trans-naphthalenetetrol, tetraacetate ester.
  35. 35. The compound in accordance with claim 16 having the name 3,4a,5-cis-decahydro5-[2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl]-2,3;4a,8a-transnaphthalenetetrol, tetraacetate ester.
  36. 36. The compound in accordance with claim 17 having the name 3,4a,5-cis-decahydro 5-[2-hydroxy-3-(4,5 .6,7-tetrahydro-l H-imidazo[4,5-c]pyridin-5-yl]propyl]2,3 ;4a,8a-transnaphthalenetetrol, tetraacetate ester.
  37. 37. A compound in accordance with claim 1 as named in any of the Examples.
  38. 38. A compound in accordance with claim 1, wherein R, is of formula (i) and R7 is pyridinyl, phenyl or phenyl substituted with one or two halogen. alkyl, trifluoromethyl, alkoxy or alkylthio radicals, and R, is hydrogen.
  39. 39. A compound in accordance with claim 1, wherein R2 is of one of formulae (ii) to (vii) and R6 is hydrogen.
  40. 40. A compound in accordance with claim l, wherein R2 is of one of formulae (viii) to (xiii) and R6 is hydrogen.
GB12506/78A 1977-04-05 1978-03-30 Propanolamine derivatives Expired GB1596357A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
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
US05/855,038 US4127579A (en) 1977-11-25 1977-11-25 Substituted piperidinylpropanols

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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

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FR2386528A1 (en) 1978-11-03

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