GB1559987A

GB1559987A - 1,2,3,4-tetrahydronaphthalene derivatives

Info

Publication number: GB1559987A
Application number: GB4532276A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1975-11-06
Filing date: 1976-11-01
Publication date: 1980-01-30
Also published as: FR2330388A1; FR2330388B1; JPS5259144A; DE2650781A1

Description

(54) ,2,3,4-TETRAHYDRONAPHTHALENE DERIVATIVES (71) We, E. R. SQUIBB & SONS, INC., a corporation of Delaware, United States of America, residing at 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 particularly described in and by the following statement: This invention provides compounds having the formula

and such compounds in pharmaceutically acceptable salt form. In formula I, and throughout the specification, the symbols are as defined below.

R, can be hydrogen or acyl; R2 is acyl; R3 can be hydrogen, lower alkyl, aryl-lower alkyl, lower alkoxy, carboxy, or cycIoalkyl (preferably hydrogen); and R1 is lower alkyl e.g. isopropyl or t-butyl.

The term 'lower alkyl", as used throughout the specification, includes both straight and branched chain alkyl groups having 1 to 8 carbon atoms; lower alkyl groups having 1 to 4 carbon atoms are preferred.

The term "lower alkoxy", as used throughout the specification, refers to groups having the formula R wherein R is lower alkyl as defined above.

The term "aryl", as used throughout the specification, refers to phenyl and phenyl substituted with one or two lower alkyl, lower alkoxy, halogen, or nitro groups.

The term "aryl-lower alkyl", as used throughout the specification, refers to lower alkyl groups (as defined above) substituted with an aryl group (as defined above).

The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine.

The term "cycloalkyr', as used throughout the specification, refers to cycloalkyl groups having 3 to 6 carbon atoms.

The term "acyl", as used throughout the specification, refers to groups having the formula

wherein X can be a straight or branched chain alkyl group having 1 to 11 carbon atoms, an aryl group, or an aryl-lower alkyl group. Exemplary acyl groups are acetyl, propionyl, butyryl, isobutyryl, trimethylacetyl, hexanoyl, heptanoyl, decanoyl, dodecanoyl, benzoyl, Ftolyl, fnitrobenzoyl, phenylacetyl, 3-phenyipropionyl, and 3-(pchlorophenyl)butanoyl.

The compounds of formula I form acid addition salts with inorganic and organic acids. These acid addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble, and then neutralizing the salt with a base such as sodium hydroxide to obtain the free base. Any other salt may then be formed from the free base and the appropriate inorganic or organic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, borate, acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, salicyclate, methanesulfonate, bemenesulfonate and toluenesulfonate.

The compounds of formula I, and the pharmaceutically acceptable salts thereof, may be used in the treatment of coronary diseases, more specifically as antifibrillatory agents and to arrest cardiac arrhythmia in mammals by the inhibition of beta adrenergic receptors in the myocardium. For this purpose a compound of formula I, or a pharmaceutically acceptable salt thereof, may be incorporated in a pharmaceutical carrier in conventional dosage form such as a tablet, capsule, elixir or sterile injectable, e.g. with the inclusion of an excipient, lubricant or buffer. Daily doses of from about 5 to 100 milligrams per kilogram of body weight, preferably about 5 to 10 milligrams per kilogram of body weight can be administered in single or divided doses as described above.

The compounds of this invention, as represented by formula I, include both compounds wherein the RlS groups are in the cis and the trans configurations. They can be prepared from the corresponding cis or trans 1,2,3,4tetrahydr5- [2-hydroxy- 3alkylamino)propoxy] -2,3-naphthalenediol having the formula

In formula II, and throughout the specification, R, can be hydrogen or aryl-lower alkyL The compounds of formula II are known; see, for example, United States Patent 3,935,267 issued January 27, 1976.

A 2,3-trans (or cis) - 1,2,3,4 - tetrahydro - 5 - [2 - hydroxy - 3 - (alkylamino)- propoxy] - 2,3 - naphthalenediol of formula II can be prepared by first reducing a naphthol having the formula

with a metal such as sodium or lithium in liquid ammonia containing an alkanol such as ethanol, isopropanol, t-butanol or the like [e.g., by the procedure described in Organic Synthesis Coll. Vol. 4, page 887 (1963)] to obtain a 5,8-dihydronaphthol of the formula

A 5,8-dihvdronaphthol of formula IV can be converted to the corresponding acetate having the formula

by dissolving it in acetic anhydride and an organic base such as pyridine.

A trans-5,6,7,8-tetrahydro-l,6,7-naphthalenetriol can be prepared from an acetate of formula V by dissolving the acetate in acetic acid, and then treating the solution with from about 2 to about 4 equivalents of silver acetate and from about 1 to about 2 equivalents of iodine. The mixture is then heated at a temperature of from about 80 to about 1200C for a period of from about 1 to about 24 hours under nitrogen, to yield a trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol having the formula

after basic hydrolysis.

A compound of formula VI can be converted to a 2,3-trans-1,2,3,4-tetrahydro- 5- [2,3-(epoxy)propoxyj -2,3-naphthalenediol of the formula

by reacting a naphthalenetriol of formula VI with an alkali metal alkoxide (e.g., sodium methoxide) in an alcohol solvent boiling below about 100"C (e.g., methanol) under nitrogen, and then, after removal of the solvent, stirring the residue in a dipolar aprotic solvent such as dimethylsulfoxide, hexamethylphosphoramide or dimethyl formainide, with epichlorohydrin under nitrogen.

The 2,3 - trans - 1,2,3,4 - tetrahydro - 5 - [2,3 - (epoxy)propoxy] - 2,3 - naphthalenediol of formula VII is then reacted with an alkylamine having the formula VIII HN--%R, to form a 2,3 - trans - 1,2,3,4 - tetrahydro - 5 - [2 - hydroxy - 3 - (alkylanaino)- propoxy] - 2,3 - naphthalenediol of formula II.

The corresponding cis isomer of formula II can be prepared by dissolving a dihydronaphthalene acetate of formula V in acetic acid and water (from 92 to 98% acetic acid, preferably 96/ó acetic acid), and then treating the solution with silver acetate and iodine and heating under nitrogen (as described for the preparation of the trans isomer) to form the cis-5,S,7,8-tetrahydro-1,6,7-naphthalenetriol having the formual

after basic hydrolysis.A compound of formula IX can be converted to 2,3-cis-1,2,3,4- tetrahydr5- [2,3-(epoxy)propoxy] -2,3-naphthalenediol, which in turn can be converted to the 2,3 - cis - 1,2,3,4 - tetrahydro - 5 - [2 - hydroxy - 3 - (alkylamino)propoxy] 2,3 - naphthalenediol in the same manner as that described with respect to the preparation of the corresponding trans isomer.

Alternatively, the 2,3 - trans - 1,2,3,4 - tetrahydro - 5 - [2 - hydroxy - 3 (alkylamino)propoxy] - 2,3 - naphthalenediol of formula II can be prepared from a 5,8-dihydro-1-naphthol of formula IV by mixing a cooled solution (temperature less than about 30 C) of 5,8dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form a 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol having the formula

A solution of 5,6,7,8 - tetrahydro - 6,7 - epoxy - 1 - naphthol of formula X in tetrahydrofuran can be reacted with aqueous perchloric acid at a temperature within the range of from about 0 to about 60"C, to form a trans-5,6,7,8-tetrahydro-1,6,7-naph- thalenetriol of formula VI which can be converted to the corresponding 2,3-trans- 1,2,3,4-tetrahydro-5 [2,3-(epoxy)propoxy j -2,3-naphthanediol of formula VII, which in turn can be converted to the corresponding 2,3-trans-1,2,3,4-tetrahydrc-5- [2-hydroxy 3-(alkylamino)propoxy] -2,3-naphthalenediol of formula II using the procedures described above.

The compounds of this invention wherein Rl is hydrogen, i.e., compounds having the formula

can be prepared by first blocking the adjacent hydroxy groups of a compound of formula II, wherein R, is aryl-lower alkyl, as described in United States Patent Number 3,856,818, issued December 24, 1974, to obtain a compound having the formula

r e-s-et -7- 4 0N aljklThă A compound of formula XII can be acylated by reaction with an acylating agent such as an acid anhydride having the formula XIII (R2CO)2O or an acid chloride having the formula XIV R2COCl yielding a compound having the formula

her I is RJ OR2 RS A compound of formiula XV can be subjected to acid hydrolysis to obtain the corresponding compound having the formula

Reduction of a compound of formula XVI, e.g., with gaseous hydrogen over a catalyst such as palladium, yields the corresponding product of formula XI. The acylation reaction can be run using procedures well known in the art.The reaction can be run in an organic solvent in the presence of an organic base. In one embodiment of this procedure, the reaction can be run in pyridine which eliminates the need for additional base being present.

Alternatively, if R2 is a "bulky" acyl group, e.g., trimethylacetyl, the compounds of formula XI can be prepared by a single step procedure which comprises acylating a compound of formula II wherein Ri is hydrogen. One equivalent of acylating agent should be used to maximize the yield of monoester.

Those compounds of formula r wherein R1 and R2 are both acyl, and are both the same, are prepared by first converting an amine of formula II wherein R, is hydrogen into an acid-addition salt to prevent acylation of the amino group. The acid-addition salt is then acylated using conventional techniques as described above.

Those compounds of formula I wherein Rl and R, are both acyl, but are not the same, are prepared by first converting a monoester of formula XI into its acid-addition salt, and then acylating the salt as described above.

Many variations of the aboveaescribed procedures for preparing the compounds of this invention will be apparent to a person of ordinary skill in the chemical arts.

For example, a compound of formula XI can be prepared from a compound of formula II wherein R, is hydrogen instead of aryl-lower alkyl as described above. The amino should be protected by conversion to an acid-addition salt prior to the acylation step.

A compound of formula I wherein Rl and R2 are both acyl can be prepared from a compound of formula II wherein R5 is aryl-lower alkyl instead of hydrogen as des cribed above. This procedure requires the additional step of reducing the tertiary amine with gaseous hydrogen to obtain the secondary amine product.

The following examples are specific embodiments of this invention.

Example 1 CtS-S- [3- [(1, 1-Dimethyiethyl)amino j -2-(2,2-dimethyl-1-oxopropoxy)propoxy] 1,2,3,4-tetrahydro-2,3-naphthalenediol A solution of 6.0 g of trimethylacetic anhydride and 2.5 g of 2,3 - cis - 1,2,3,4 tetrahydro - 5 - [2 - hydroxy - 3 - [(1,1 - dimethylethyl) - amino]propoxy] - 2,3 naphthalenediol in 70 ml of dry pyridine is stirred for 18 hours at room temperature and for 4.5 hours at 5045 C under a drying tube. The solution is cooled to room temperature, diluted with 5 ml of methanol and stirred for 15 minutes.The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with saturated sodium bicarbonate and sodium chloride solutions, dried with magnesium sulfate, and evaporated n vocal to give 4.5 g of an oil-solid mixture. The mixture is suspended in ether and filtered. The solid is washed with ether, and dried in vacwo to give 1.6 g of white solid. A second crop of 0.15 g of solid is obtained from the filtrate to give a total of 1.75 g of material. Recrystallization from benzene yields 1.2 g of the title compound, melting point 145--149 C.

Example 2 5- [3- [(1,1-Dimethylethyl)amino] -2-(2,2 dimethyl-1-oxopropoxy)-propoxy] -1,2,3,4 tetrahydroris-2,3-naphthalenediol, diacetate ester, hydrochloride (1:1) A solution of 1.37 g of cis - 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 - (2,2 dimethyl - 1 - oxopropoxy)propoxyj - 1,2,3,4 - tetrahydro - 2,3 - naphthalenediol (prepared as described in Example 1) in 150 ml of benzene is acidified with a slight excess of anhydrous hydrogen chloride in isopropanol, and the resulting solution is evaporated in vxiw to give a white foam residue. The residue is dissolved in 25 ml of cold trifluoroacetic add, and this solution is cooled in a bath maintained at --10"C under a drying tube while 1.5 ml of acetyl chloride is added dropwise.The solution is stirred at - 100C for 30 minutes and at room temperature for 1 hour. The solvent is removed in vacuo, and the residue is dissolved in 200 ml of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and sodium chloride solutions, dried with magnesium sulfate and sodium sulfate, and evaporated in vacuo to give 1.7 g of oil. The oil is dissolved in 100 ml of hexane, the hexane solution is decanted from a small amount of insoluble residue, and then the hexane is removed in vxuo to give 1.55 g of crude product. The crude product is dissolved in etherhexane (100:20), the solution is acidified with anhydrous hydrogen chloride in isopropanol and the solvent is removed in vacuo to give 1.6 g of foam.Crystallization from ether-isopropyl ether yields 1.36 g of the title compound, melting point 177-183 0C.

Example 3 2,3-cis-5- [2-(Acetyloxy)-3- [(1,1-dimethylethyl)amino] propoxy] - 1,2,3,4 tetrahydro2,3-naphthalenediol, diacetate ester, hydrochloride (1:1) 2,3 - cis - 1,2,3,4 - Tetrahydro - 5 - [2 - hydroxy - 3 - [(1,1- dimethylethyl) amino] propoxy] - 2,3 - naphthalenediol (3.09 g) is dissolved in a saturated solution of hydrogen chloride in isopropanol, and this solution is taken to dryness in vacuo. The salt is added to 50 ml of trifluoroacetic acid and the resulting solution is stirred at e5"C while adding 6.4 ml of acetyl chloride dropwise. After the addition is completed, the solution is allowed to stand at room temperature for 1 hour.The solution is then concentrated in vacuo, the residue diluted with aqueous sodium bicarbonate, and this is extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated aqueous sodium chloride, dried, and concentrated in vacuo. The residue is dissolved in dry ether, chilled, and treated with hydrogen chloride saturated iso propanol. The resulting precipitate is filtered and recrystallized from isopropanolther to yield 1.7 g of the title compound, melting point 151560C.

Example 4 cis-5- [2-(Acetyloxy)-3- [(1,1-dimethylethyl)amino] propoxy j - 1,2,3,4tetrahydro-2,3 -naphthalenediol A solution of 20 moles of 3a,9a - cis - 1 - [(1,1 - dimethylethyl) - (phenyl methyl)arnino] - 3 - [(3a,4,9,9a - tetrahydro - 2,2 - dimethyl - 2H - naphtho - [2,3-d]dioxol - 5 - yl)oxyj - 2 - propanol in 70 ml of pyridine and 30 ml of acetic anhydride is prepared and left at room temperature for about 16 hours.The pyridine and excess acetic anhydride are removed ;n vacua, the residue is taken up in a cold (0--5"C) mixture of 225 ml of Sot, hydrochloric acid and 25 ml of methanol, and the reaction mixture is stirred at 0--5 C for 2 hours. Most of the methanol is removed in vacuo and the solution is made basic with 5 % aqueous sodium bicarbonate and extracted with ether. The combined extracts are dried over magnesium sulfate and concentrated in vxuo.

The residue is taken up in 250 ml of glacial acetic acid, one equivalent of con centrated hydrochloric acid is added, and the resulting solution is hydrogenated in the presence of 5 g of 10% palladium/charcoal at 50 60 p.s.i. After uptake of one equivalent of hydrogen, the catalyst is filtered off and the filtrate is concentrated in vacuo to yield the title compound.

Examples 5-11 Following the procedure of Example 4, but substituting the compound listed in column I for acetic anhydride, yields the compound listed in column II.

Example Column I Column II 5 lauric anhydride cis - 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 (dodecanoyloxy)propoxy] - 1,2,3,4 - tetra hydro- 2,3 - naphthalenediol 6 benzoic anhydride cis - 5 - [2 - benzoyloxy) - 3 - [(1,1- dimethyl ethyl)anaino]propoxyj - 1,2,3,4 - tetrahydro 2,3 - naphthalenediol 7 Ftoluic anhydride cis - 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 (o - tolyloxy)propoxy] - 1,2,3,4 - tetrahydro 2,3 - naphthalenediol 8 p-nitrobenzoic cis - 5 - [3 - [(1,1 - dinaethylethyl)aminoj - 2 anhydride (p - nitrobenzoyloxy)propoxyj - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol 9 p-chlorobenzoic cis - 5 - [2 - (p - chlorobenzoyloxy) - 3 - [(1,1 anhydride dimethylethyl)amino]propoxy] - 1,2,3,4- tetra hydro - 2,3 - naphthalenediol 10 o-methoxybenzoic c.s - 5 - [2 - (o - methoxybenzoyloxy)- -3 - [(1,1 - anhydride dimethylethyl)aminojpropoxyj - 1,2,3,4- tetra hydro - 2,3 - naphthalenediol 11 phenylacetic cis - 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 acid (phenylacetyloxy)propoxyj - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol Examples 12-15 Following the procedure of Example 2, but substituting the compound listed in column I for acetyl chloride, yields the compound listed in column II.

Example Column I Column II 12 butyryl chloride 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 - (2,2 dimethyl- 1- oxopropoxy)propoxy} - 1,2,3,4 - tetrahydro - cis - 2,3 - naphthalenediol, di butyrate, hydrochloride 13 benzoyl chloride 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 - (2,2 dimethyl- 1- oxopropoxy)propoxy] - 1,2,3,4 - tetrahydro - cis - 2,3 - naphthalenediol, di benzoate, hydrochloride 14 p-toluyl chloride 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 - (2,2 dimethyl - 1 - oxopropoxy)propoxyj - 1,2,3,4 - tetrahydro - cis - 2,3 - napthalenediol, di-(p toluate), hydrochloride 15 3-phenylpropionyl 5 - [3 - [(1,1 - dimethylethyl)amino] - 2 - (2,2 chloride dimethyl- 1- oxopropoxy)propoxyj - 1,2,3,4 - tetrahydro - cis - 2,3 - naphthalenediol, di - (3 phenylpropionate), hydrochloride Examples 1918 Following the procedure of Example 3, but substituting the compound listed in column I for acetyl chloride, yields the compound listed in column II.

Example Column I Column II 16 caproyl chloride 2,3 - cis - 5 - [2 - (hexanoyloxy) - 3 - [(1,1 - dimethylethyl)amino]propoxy] - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol, dihexanoate ester, hydrochloride 17 benzoyl chloride 2,3 - cis - 5 - [2 - (benzoyloxy) - 3 - [(1,1 - di methylethyl)amino]propoxy] - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol, dibenzoate ester, hydrochloride 18 pchlorobenzoyl 2,3 - cfs- 5 - [2 - (p - chlorobenzoyloxy) chloride 3 - [(1,1 - dimethylethyl)amino]propoxy] 1,2,3,4 - tetrahydro - 2,3 - naphthalenediol, di - (p- chlorobenzoate), hydrochloride Example 19 trans-5- [3- [(l,l-Dimethylethyl)amino] -2-(2,2-dimethyl-1-oxo-propoxy)propoxy3 1,2,3,4-tetralaydro-2,3-naphthalenediol Following the procedure of Example 1, but substituting 2,3 - trans - 1,2,3,4 tetrahydro - 5 - [2 - hydroxy - 3 [(1,1 - dimethylethyl)amino] - propoxy] - 2,3 naphthalenediol for its cis isomer yields the title compound.

WHAT WE CLAIM IS:- 1. A compound having the formula

or such a compound in pharmaceutically acceptable salt form, wherein R1 is hydrogen or acyl; R2 is acyl; R3 is hydrogen, lower alkyl, aryl-lower alkyl, lower alkoxy, carboxy, or cycloalkyl; and Rr is lower alkyl; wherein acyl is a group having the formula

wherein X is alkyl having 1 to 11 carbon atoms, aryl, or aryl-lower alkyl; wherein aryl is phenyl or phenyl substituted with 1 or 2 lower alkyl, lower alkoxy, halogen or nitro groups; and wherein lower alkyl and lower alkoxy are groups having 1 to 8 carbon atoms.

2. A compound in accordance with claim 1 wherein R3 is hydrogen.

3. A compound in accordance with claim 2 wherein R1 is hydrogen.

4. A compound in accordance with claim 2 wherein R1 is acyl.

5. A compound in accordance with claim 4 wherein R1 and R2 are the same.

6. A compound in accordance with claim 4 wherein R1 and R2 are different.

7. A compound in accordance with claim 2 wherein R, is isopropyl or t-butyl.

8. The compound in accordance with claim 1 having the name cis - 5 - [3 - [(1,1 dimethylethyl)amino] - 2 - (2,2 - dimethyl - 1 - oxopropoxy)propoxy] - 1,2,3,4 - tetrahydro - 2,3 - naphthalenediol.

9. The compound in accordance with claim 1 having the name 5 - [3 - [(1,1 dimethylethyl)amino] - 2 - (2,2 - dimethyl - 1 - oxopropoxy)propoxyj - 1,2,3,4 tetrahydro - cis - 2,3 - naphthalenediol, diacetate ester, hydrochloride (1:1).

10. The compound in accordance with claim 1 having the name 2,3 - cis - 5 [2 - (acetyloxy) - 3 - [(1,1- dimethylethyl)amino] - propoxy] - 1,2,3,4 - tetrahydro 2,3 - naphthalenediol, diacetate ester, hydrochloride (1:1).

11. A compound in accordance with claim 1 as named in any of the Examples.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Example Column I Column II

16 caproyl chloride 2,3 - cis - 5 - [2 - (hexanoyloxy) - 3 - [(1,1 - dimethylethyl)amino]propoxy] - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol, dihexanoate ester, hydrochloride

17 benzoyl chloride 2,3 - cis - 5 - [2 - (benzoyloxy) - 3 - [(1,1 - di methylethyl)amino]propoxy] - 1,2,3,4 - tetra hydro - 2,3 - naphthalenediol, dibenzoate ester, hydrochloride

18 pchlorobenzoyl 2,3 - cfs- 5 - [2 - (p - chlorobenzoyloxy) chloride 3 - [(1,1 - dimethylethyl)amino]propoxy] 1,2,3,4 - tetrahydro - 2,3 - naphthalenediol, di - (p- chlorobenzoate), hydrochloride Example 19 trans-5- [3- [(l,l-Dimethylethyl)amino] -2-(2,2-dimethyl-1-oxo-propoxy)propoxy3 1,2,3,4-tetralaydro-2,3-naphthalenediol Following the procedure of Example 1, but substituting 2,3 - trans - 1,2,3,4 tetrahydro - 5 - [2 - hydroxy - 3 [(1,1 - dimethylethyl)amino] - propoxy] - 2,3 naphthalenediol for its cis isomer yields the title compound.

WHAT WE CLAIM IS:- 1. A compound having the formula

or such a compound in pharmaceutically acceptable salt form, wherein R1 is hydrogen or acyl; R2 is acyl; R3 is hydrogen, lower alkyl, aryl-lower alkyl, lower alkoxy, carboxy, or cycloalkyl; and Rr is lower alkyl; wherein acyl is a group having the formula

wherein X is alkyl having 1 to 11 carbon atoms, aryl, or aryl-lower alkyl; wherein aryl is phenyl or phenyl substituted with 1 or 2 lower alkyl, lower alkoxy, halogen or nitro groups; and wherein lower alkyl and lower alkoxy are groups having 1 to 8 carbon atoms.
2. A compound in accordance with claim 1 wherein R3 is hydrogen.
3. A compound in accordance with claim 2 wherein R1 is hydrogen.
4. A compound in accordance with claim 2 wherein R1 is acyl.
5. A compound in accordance with claim 4 wherein R1 and R2 are the same.
6. A compound in accordance with claim 4 wherein R1 and R2 are different.
7. A compound in accordance with claim 2 wherein R, is isopropyl or t-butyl.
8. The compound in accordance with claim 1 having the name cis - 5 - [3 - [(1,1 dimethylethyl)amino] - 2 - (2,2 - dimethyl - 1 - oxopropoxy)propoxy] - 1,2,3,4 - tetrahydro - 2,3 - naphthalenediol.
9. The compound in accordance with claim 1 having the name 5 - [3 - [(1,1 dimethylethyl)amino] - 2 - (2,2 - dimethyl - 1 - oxopropoxy)propoxyj - 1,2,3,4 tetrahydro - cis - 2,3 - naphthalenediol, diacetate ester, hydrochloride (1:1).
10. The compound in accordance with claim 1 having the name 2,3 - cis - 5 [2 - (acetyloxy) - 3 - [(1,1- dimethylethyl)amino] - propoxy] - 1,2,3,4 - tetrahydro 2,3 - naphthalenediol, diacetate ester, hydrochloride (1:1).
11. A compound in accordance with claim 1 as named in any of the Examples.
12. A pharmaceutical composition comprising a compound in accordance with any

preceding claim and a pharmaceutical carrier.
13. A composition in accordance with claim 12 in the form of a tablet, capsule, elixir or sterik injectable preparation.
14. A composition in accordance with claim 12 or 13 including an excipient, lubricant or buffer.