CA1341011C - Benzo-fused cycloalkane and oxa- and thia-, cycloalkane trans-1,2-diamine derivatives - Google Patents

Abstract

Benzo-fused cycloalkane and oxa- and thia-cycloalkane trans-1,2-diamine compounds of the formula:
(see formula I and II) wherein A, B, C, D, n, X, Y, R, R1, R2 and R3 are as defined in the specification, e.g., trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphth-1-yl)benzeneacetamide, and the pharmaceutically acceptable salts or N-oxides thereof, are useful as analgesics and/or diuretics.

Description

Title BENZO~-FUSED CYCLOALKANE AND OXA- AND THIA-, CYCLOALKANE TRAMS-1,2-DIAMINE DERIVATIVES
Field of the Invention The invention relates to benzo-fused cycloalkane compounds and their oxa- and this- derivatives, processes for their preparation, pharmaceutical composition, containing them, and their use as analgesics and/or diuretics.
Background of the Invention Studies of the binding properties of opioid drugs and peptides at specific sites in the brain and other organs have suggested the existence of several types of opioid receptors. In the central nervous system (CMS), good evidence has been demonstrated for at least three categories of opioid receptors: ~C (mu), k (kappa) and b (delta). Nalorphine, W.R. Martin, Pharmacol. Rev., 19, 463-521 (19157), and a series of benzomorphans, W.R.
Martin, et al., J. Pharmacol. Exp. Ther., 197, 517-532 (1976), were reported to display unusual pharmacological properties dissimilar to morphine, yet blocked by selective opioid antagonists. The existence of multiple subtypes of opioid receptors is of considerable interest as it suggests the possibility of separating the desirable (analgesic and psychothera~~eutic) and the undesirable (abuse potential ) ref fects of opioids .
Indeed, compounds that are agonists for k receptor have shown strong analgesia without opioid side effect, such as dependence liability, respiratory depression, .and constipation. The prototype of such compounds is U-50,488, trans-3,4-dichloro-N-methyl-N-[2-(pyrrolid.in-1-yl)cyclohexyl]benzeneacetamide, which is described in U.S. Patent 4,115,435, and reported by P.F. VonVoigitlander, et al., J. Pharmacol Exp. Ther., 224, 7 (1983). This compound is stated to exhibit analgesic aci:ions in a variety of assays, such as thermal, pre:sure .and irritant, in mice and rats.
Spiroc;tclic .analogs of U-50,488 are disclosed in U.S. Pat. Nos. 4,359,476, 4,360,531, and 4,438,130, as analgesic compounds having low physical dependence liability in humans. Examples of these derivatives are trans-3,4-dic:hloro-N-methyl-N-[7-(pyrrolidin-1-yl)-1,4-dioxaspiro[4"5]dec~-6-yl]benzeneacetamide; trans-3,4-dichloro-N-meahyl-N-[7-(pyrrolidin-1-yl)-1,4-dioxaspiro[4.,5]dec~-8-yl]benzeneacetamide; and (~)-(5-a-7-a-,9a)-3,4--dichloro-N-methyl-N-[7-(pyrrolidin-1-yl)-1-oxaspiro[4..5]dec~-8-yl]benzeneacetamide. Omega-(Hydroxy-, Et:her and Ester)-Alkyl-2-Amino-Cycloalkyl and Cycloalke:nyl Amides active as analgesics are disclosed in U.S. lPatent 4,632,935.
Substituted itrans-1,2-diaminocyclohexylamine compounds such as ~trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexylbenzo[b]thiophene-4-acetamide are disclosed in U.S. Patent 4,6.'i6,182. Napthaleneyloxy-1,2-diaminocyclohexyl amide compounds active as analgesics are disclosed in U.S. Patent 4,663,343.

Summary of the Invention According to the present invention there is provided a compound having the formula:
~X
/co.cH=
Y
I) ~R
C
I
13 (A)" R' (I) of R
~X
r~~. (A)" ''y NCOCHi -_ Y
g 1 ~N~RZ -(II) wherein for the enantiomers and racemic mixtures n is 1 A is - CH - or, -CH2CH2- provided that in Formula (I), A may also be -O-, or -S-;
B, C and D independently are selected from the group consisting of H, OH, OCORS, OCH2CH20R5, OFI6, R6, CH20R6, CH2COR~, C1, F, Br, I, NH2, NHRB, N1~8R9, SH, SR6, CH2SR6 and OC(S)N(CH3)2%
o z' two of B, C and D when on adjacent carbon atoms taken together form a fused benzo ring;

. 134101 1 X and Y independently are selected from the group consisting of H, OCH3, C1, F, Br, I, N02, CF3, CN, S02R10, and S02CF3; or X and 'Y taken together with the benzene ring f o nn ~J ;

R and lZl independently are selected from the group consisting of H, and alkyl of 1 to 3 carbon atoms;

R2 is H; alkyl of 1 to 6 carbon atoms; CH2CF3;

alkE:nylmethyl of 3 to 6 carbons atoms;

hydroxyalkylmethyl of 2 to 5 carbon atoms;

cyc7.oalky:l of 3 to 6 carbon atoms; cyclo-proF>ylmetlzyl; cyclobutylmethyl, or phenyl-alkyl of '7 to 9 carbon atoms; or R2 can be taken together with R1 and the nitrogen to which they are attached to be 1-azetidinyl;

pyrrolidinyl optionally substituted at the 3-posi.tion by OH, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkanoyloxy :20 of 1 to 3 carbon atoms; 1-piperazinyl optionally substituted at the-4-position by alkyl of 7. to 3 carbon atoms; 1-morpholino;

2,5-dihydro-iH-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl;

R3 is H, but if n is 1 and A is CH2, R3 may also be CH3, CH:20H, CHO, or COR11;

a0 3. 5 R4 is H, alkyl of 1 to 6 carbon atoms, -CH2oH-CHC~, or' (:OR12;
R5 is alkyl of 1 to 6 carbon atoms, phenyl, or mono-substituted phenyl;

5 R6, R8, R9, R10 and R13 are independently an alkyl group of 1 to 3 carbon atoms; and R~, R11 and R12 independently are selected from the group consisting of H, OH, OR13, NHR13, and NR213.; or a stable N-oxide o~r a pharmaceutically acceptable salt thereof.
Also provided is a pharmaceutical composition consisting essentially of a pharmaceutically suitable carrier and .an effective amount of at least one of the aforesaid compounds of Formula (I) or Formula (II).
Further provided is a method of treating pain in a mammal or .3 method of increasing the secretion of urine in a mammal comprising administering to the mammal an analgesic amount or a diuretic amount of at least one of the aforesaid compounds of Formula (I) or Formula (II).
Additionally provided is a process for preparing a compound o:E Formula (I) or Formula (II) comprising:
reacting a compound of the formula:

1 3 .41 0 1 1 a . NH
ID / N ~ Rz C----(~
a tv~~) i . ID~ ~A~w ....NHR .
C- ' l, ~ ~R~
~s ~~ "~ .
B P
R~
i (~I ) I
with (1) a carboxylic acid of the formula x i :Z 0 HC~OCCH2 .
Y
in the presence of dicyclohexylcarbodiimide;
(2) an acid chloride of the carboxylic acid in the presence of triethylamine, or aqueous 25 so~3ium bicarbonate; or (3) an acyl imidazole prepared by reacting the carboxylic acid with carbonyl diimidazole.
?t 0 3.5 Preferred Embodiments Preferred compounds are those of Formula (I), particularly those having the formula X
C4~CH=
Y
N
~Rt N~~Rz C
~ (A)n (Ia) wherein n is 1; or A is -C:H2-, ~-O-, or -S-; or B is OFt, OCORS, OCH2CH20R5, OR6, CH20R6, or CH2COR~ ,; or C is H, OH, or OR6; or ~ R1 and R2 independently are selected from H or alkyl o:E 1 to 3 carbon atoms or are taken together with the nitrogen to which they are ataached to form the group 1-azetidinyl, 1-pyrrolidinyl, 1-(2,5-dihydro-1H-pyrrolyl) or 2 5 1-~piper:idinyl .
More preferred are compounds of Formula (Ia) wherein A is -CH2-. .

13.41011 Specifically preferred compounds include:
(1) traps-3t,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphth-1-yl]ben-zeneaceaamide: hydrochloride or the methansulfonic acid salt;
(2) traps-3,4-dic;hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-t:etrahydronaphth-1-yl]benzeneaceaamide hydrochloride;

(3) traps-3,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-:LO yl)-6-m,ethoxy-1,2,3,4-tetrahydronaphth-1-yl]ben-zeneacetamide: hydrochloride;

(4) traps-3,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride;

:l5 (5) (+) traps-3,4~-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4.-tetrahydronaphth-1-yl]benzeneaceaamide hydrochloride;

(6) traps-3,4-dic:hloro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1.-yl)-1H-inden-1-20 yl]benzeneaceaamidehydrochloride;

(7) traps-3,4-dic:hloro-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1.-yl)-2H-benzopyran-4-yl]benzene-acetamide hydrochloride; .

(8) traps-3,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-25 yl)-5-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]-benzeneacetamide hydrochloride;

(9) traps-3,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-propionyloxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneaceaamide hydrochloride;

.60 a5 (10) trans-?c,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-benzoyloxy-1,2,3,4-tetrahydronaphth-1-yljbenz;eneacfaamide hydrochloride;

(11) trans-3,4-dic:hloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneaceaamide hydrochloride;

(12) trans-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl]benzeneacetamide hydrochloride:;

(13) trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-8-methoxy-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl]benzeneacetamide hydrochloride;

(14) trans-3,4-dichloro-N-methyl-N-[2-(pyrro.lidin-1-yl)-5-(;N,N-dimethylthiocarbamoyloxy)-1,2,3,4-7.5 tetrahydronaphth-1-yl]benzeneacetamide .

hydrochloride; and (15) trans-3,4-dichloro-N-methyl-N-[2-(2,5-dihydro-1H-pyrrol-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphth-1-yl)be;nzeneacetamide hydrochloride.

Detailed Description of the Invention Methods for t:he synthesis of the compounds of the invention are illue~trated in Schemes 1 and 2.
The starting compounds of Formula III and IX can be prepared either according to literature procedures or by modifications. to these procedures which should be apparent to those familiar with the art of organic synthesis. A. convenient way to prepare the starting olefin III is by reduction of the corresponding ketone (e. g., 1-tetralone) to the corresponding alcohol (e. g., 1-tetralol) followed by dehydration of the alcohol (e.g., to 1,2-dihydronaphthalene). Dehydration of the alcohol can be done: by heating in the presence of acid (e.g., KHS04), pyrolysis of the alcohol acetate, or ;~5 often most conveniently by simply heating its solution in DMSO at 100-200°C, the preferred temperature depending on the nature of R3, (A)n, B, C, and D. Some references that describe the preparation of olefins III
or their precursor ketones or alcohols include: J.
:>.0 Chem. Soc., 4425 (1.961); J. Chem. Soc. Chem. Commun., 453 (1984); Chem. F~harm. Bull., 25(4), 632 (1977); J.
Chem. Soc., 3271 (1.949); ibid, 1894 (1953); Chem.
Pharm. Bull., 26, 3'.94, 1511 (1978); J. Med. Chem., 28, 1398 (1985); ibid 1.2, 487 (1969); U.S. Pat. 4,448,990 :?5 (1984); Chem. Pharm. Bull., 25 (11) 2988, 3066 (1977);
ibid 25(12) 3289 (1.977); ibid 31 (7) 2329 (1983); ibid 32(1) 130 (1984); E~ull Chem. Soc. Japan, 52, 251 (1979); J. Chem. Soc. Chem. Comm., 63 (1976); J. Indian Chem. Soc., LX, 1,16~3 (1983); J. Med. Chem., 15, 1306 :30, (1972); U.S. Pat. 3'.,379,731 (1968); J. OrcL Chem., 37(1), 13 (1972). This list is intended to be illustrative, not comprehensive.
:35 ~34101~ .

According to Scheme 1, a compound of Formula III
can be converted into an epoxide of Formula IV by a peracid such as 3-c:hloroperbenzoic acid in a halogenated solvent: such as methylene chloride at a temperature between 0° and 25°C. Alternatively, the epoxide of Formula IV can be prepared by converting a compound of Formula III into a bromohydrin of Formula V
with N-bromosuccinimide in a water-organic solvent mixture such as aqueous dimethylsulfoxide at room LO temperature followed by treating the compound of Formula V with a strong base such as sodium hydroxide in a solvent such ass aqueous dioxane at room temperature.
An epoxide of. Formula IV, on treatment with an :l5 amine, R1NHR2, preferably in the presence of a polar solvent such as ethanol or water at a temperature between 25° and 80°C, yields an amino alcohol of Formula VI.. .Alternatively, a compound of Formula VI
can also be obtained directly from a bromohydrin V by :!0 treating with an amine, R1NHR2. Route V~VI is sometimes preferred to route IV~VI when B, C, and D are electron-donating groups, such as OCH3.
An amin~oalcohol of Formula VI is converted to a diamine of Formula VII by first reacting with ~;5 methanesulfon;yl chloride in a chlorinated solvent such as methylene chloride in the presence of a base such as triethylamine at a temperature between 0° and 5°C.
Further treatment of the resulting sulfonate with an excess of an alcoholic solution of an amine, RNH2, such 3.0 as methylamin~:, ethylamine, or n-propylamine, at a 3. 5 w X34101 ~

temperature betweer.~ 70° and 80°C yields a compound of Formula VII. Alternatively, an aminoalcohol of Formula VI can be~treated with chlorosulfonic acid in a chlorinated solvent: such as methylene chloride at a temperature between 0° and 25°C to afford the sulfate salt of a compound of Fonaula VIII which on treatment with an amine RNH2 affords a diamine of Formula VII.
A diamine of Formula VII is converted to a compound of Formula. (I) by conventional methods, e.g., :10 treatment with a carboxylic acid (ArCH2COOH) either as its acid chloride in the presence of triethylamine, or aqueous sodium bicarbonate, or as its acyl imidazole prepared by reacting the acid with carbonyl diimidazole, ~or with the acid itself in the presence of :L5 dicyclohexylc~arbodiimide.
:~ 0 :! 5 a0 ~~ 5 i3 ~ 341 0.1 1 p p w C ~' / R' ~' (A'w . R' C

N-0romo. ~ R~NHR=
Hi0 O OH R~~ N ~R:
& O
r R~NHR= ~~ ~ .
,.
C
1 s v w~ R
v a ~ ~~~ R
R~ ~ / R
~ NO
R
2 0 p~~ ~,,~ p ~ ~ z r. , , ~ ~ NCR:
C . II ' l.~ _ c l /.
s ~ ~' vln 8 W ~R~
w :Z s X
R
\N,~ 1 ~Y

~.R:
c sA);, R~
:! 0 I

. - 1341011 '.

As shown in Scheme 2, the compounds of the invention can be prepared by converting a ketone of Formula IX to an oximino derivative of Formula X, using n-butyl nitrite and a strong base such as sodium methoxide, o:r sodium hydroxide, in a polar solvent such as ethanol at a temperature between 0° and 5°C. The oximino compound of Formula X is then reduced with hydrogen in the presence of a catalyst such as palladium on carbon in a polar solvent such as ethanol containing a stoic;hiometric amount of an inorganic acid such as hydrochloric acid to yield an amino ketone of Formula XI which can be further reduced to a trans-amino alcohol. of Formula XV with a borohydride reducing agent such a:. sodium borohydride in a polar solvent such as aqueous ethanol at a temperature between 0° and 25°C. The amino alcohol can be converted into a compound of Formula XVI via N-alkylation reactions that have been described in the literature, e.g., J. March, "Advanced Organic Chemistry", Wiley Interscience, New York, N.Y.
Transformation of a compound of Formula XVI to a diamine of Formula VII can be achieved in the same manner as converting an amino alcohol of Formula VI
into a diamine of Formula VII as shown in Scheme 1.
:25 Alternatively, an amino ketone of Formula XI can be converted to an amide of Formula XII by employing N-acylation reactions known to one skilled in the art such as using an acid chloride. The resulting amide can be reduced to a. cis-amino alcohol of Formula XIII
:30 a5 15 '~~41011 ' with a reducing agent such as lithium aluminum hydride (LAH) in-an .inert solvent such as tetrahydrofuran at a temperature between 25° and 80°C. An N-alkylation reaction is employed to convert an amino alcohol of Formula XIII to a compound of Formula XIV which is then treated with methanesulfonyl chloride in a chlorinated solvent such as me~thylene chloride at a temperature between 0° and 5°C followed by an alcoholic solution of amine RNH2 at: a temperature between 75° and 80'C to give a compound of Formula VII.
The dia~mines of Formula VII are converted to Formula (I) compounds of the invention by methods described in Scheme: 1.

:25 :30 :35 1341011 v SCHFME --D O D O
NOH
~..
c 1. ~.c. o c I~~ B~ (A)w R~
IX
hli lO
O
0 ~ NHG~R 0 NH, N.~~ C ~ Ha c 1. ~ ~~ ~ l~
:~ 5 »%' « ~ a ~ ~ ~ i jai weH, 1 ~, ;
0 INHR~ 0' HH~
r\-c 1. ~ c b.
c~" ~~ B~ ww ~ , XIII xv j ~~~~
R~
2; 5 ~ /R D N ~
0 N'~ , ~R=
R
~) cH,so,a ,~ cH,so,a ~,u" R, ~Nw ~R~ Z) ~~ '-VI~ B
XN

Schemes 1 and 2 leading to compounds of Formula (I) are equally applicable to the preparation of compounds of Formula (II). This analogous synthetic sequence is summarized in Scheme 3. Some of the intermediates in Scheme 3 may be accompanied by regioisomers. The undesirable isomers can be removed by conventional methods of separation, e.g., chromatography such. as high pressure liquid chromatography (HFLC), thin layer chromatography (TLC), :10 etc., distillation, or fractional crystallization.
:l5 :? 0 :! 5 ~t 0 a5 :30 :35 a (Nw a i fA?w 0 l I P~a~c4 ~~ ~,, , ,~~, o R' 8 XVti 7CV111 R~
R'NNR=
Bue 7.o p o R' (Nw ~~~,OH ~ (Nw NCR=
R'NNRr C
''~~oH
xlx p' a ~ R, ~so,a 1. 5 ~R, o L~.R: ~~ (A~, ,~,NHR
~c l N~R
B
t; O 7CCI1 ~ p~ R
X

~\ (Nw ',~~'HCOCf;t ~Y
C o.
w /. _ , l~ R
i. 5 B N ~
R~ R:

3. 0 134101 ~

Where several alternative routes are outlined in Scheme 1, 2, and 3,. sometimes one synthetic route can be preferred over another, depending on the particular compounds involved. One skilled in the art of organic synthesis can choose the best route.
In Schemes 1, 2, and 3, intermediates and products are written to show what is intended to be the stereochemical relationships (e. g. cis and trans relationships). However, these structures in most :10 cases are intended to represent d,l (racemic) forms, and not absolute stereochemical configurations. This ' is not to imply, however, that enantiomerically pure (resolved) compounds are not sometimes the preferred Compounds of the invention.
:l5 Whereas the Schemes 1, 2, and 3 outline the most general routes to the compounds of the invention, it will be understood by one skilled in the art of organic synthesis that these schemes do not include every possible appr~~ach to preparing compounds of Formula (I) or Formula (II). For example, for some definitions of groups B, C, ~3nd D, it may be preferable to start the reaction sequence from a starting material (a compound of Formula III, IX, or XVII) where the B, C, or D
groups are pr~:cursors to the eventually desired groups.
~~5 Thus, B may b~~ nitro or acetamido and later in the sequence it may be reduced to NHZ or NHC2H5. The sequence may also start from compounds of Formula III, IX, or XVII where B, C, or D are methoxy and are to be demethylated :later, e.g., at the end of the sequence, to ~ 341 ~1 ~
the correspor.~ding phenol. Often it is convenient to start with R3' being a carboxylic ester, e.g., a tertiary-butylcarboxylic ester, and then at the end of the synthesis, to hydrolyze and reduce the ester group 5 to CH20H or C;HO; oz- to hydrolyze and react the ester with an appropriate: organometallic reagent such as methyl lithium to afford COR11. Such ramifications of the basic schemes are common practice in analoging compounds of pharmaceutical interest.
Pharmaceutically acceptable acid addition salts of amines I or II c:an be prepared by reacting the free bases I or II with a stoichiometric amount of an appropriate acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid,'sulfuric acid, acetic acid, lactic acid, malefic acid, fumaric acid, succinic acid, citric acid, benzoic acid, salicylic acid, pamoic acid, methanesulfonic acid, naphthalenesulfonic: acid, p-toluenesulfonic acid and the like. The reaction can be carried out in water or in an organic solve:nt, or a mixture of the two; but nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or aceaonitrile are generally preferred.
Optically resolved enantiomers usually are conv~~iently :25 prepared from optically active acids such as (+) or (-) tartaric acid or di.benzoyltartaric acid, or citric acid, or the like. One enantiomer may be more active than the other.
:30 :35 21 ~ 1341 01 ~
Amine oxides of amines I or II can be prepared in the generally same manner as other amine oxides, for example, by reaction of the amines with hydrogen peroxide or pe:racet.ic acid in an aqueous medium, or by reaction with a peracid such as peracetic acid or m-chloroperbenzoic acid in a nonaqueous medium such as methylene chloride. The amine oxides are separated from acidic rE:action products by chromatography, e.g., on basic alumina, o:r by treatment with aqueous base such as sodium bicarbonate.
The invE:ntion can be further understood by the following exannples .in which parts and percentages are by weight unlE:ss otherwise indicated and all temperatures sire in degrees centigrade. The compounds were analyzed by proton nmr, TLC, mass spectroscopy, and by elemental analysis (C,H,N).
Example 1 trans-3,4-Dichloro-:N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3"4-tetrahydronaphth-1-yl]benzeneacetamide and its hydrochloride salt Step 1: 5-Methoxy-1-tetralol To a round bottom flask (1 liter) was added 5-methoxy-1-tetralone (100 g, 0.57 mole). Ethanol (400 ml) was added and the resultant suspension was stirred at room temperature. Sodium borohydride (17 g, 0.45 mole) was add~:d in portions over a period of about 20 minutes. Whem the reaction mixture became warm (about -40°C), it was cooled briefly in an ice/-H20 bath to 3. 0 ~t 5 1341 01 ~
bring the temperature to approximately room temperature. The resulting clear solution was stirred for 4-5 hours after the addition was completed, and then about 1/2 of the ethanol was evaporated under reduced pressure on a rotating evaporator. The remaining mixture was mixed with water (about 1.5 1) and extracted (3 times) with ethyl acetate. The ethyl acetate extra~~ts were combined and washed with water (2 times), washed with saturated NaCl, dried over MgS04, :l0 and evaporated, to give 5-methoxy-1-tetralol (about 100 g), m.p. 75°-76°; T'LC (2:1 EtOAc/hex) Rf = 0.6; 1 spot.
IR showed no 'C=O peak.
Step 2: B-Methox -1,2-dihydronaphthalene :l5 The above product (about 100 g) in dimethylsul-foxide (DMSO, 350 ml) was heated in an oil bath at 170°
with stirring for 12 hours. The mixture was cooled to room temperature an,d poured into H20 (3 1). The water/DMSO mixture was extracted with ether (3 times).

20 The ether layers were combined and washed with water (2 times), washed with saturated NaCl (1 time), and dried over anhyd. K2C03. The ether was evaporated and the remaining liquid wa~s_ distilled bulb to bulb to give e-methoxy-1,2-dihydronaphthalene (about 80 g), b.p. about 25 117-123°/4.5-5 mm; TLC: Rf = 0.8 (1:1 ether/hexane).
:30 ~~41011 Step 3: 1,2-E ox -5-methoxy-1,2,3,4-tetrahydro-naphthalene A solution of the above product (80 g, 0.5 mole) in CH2C12 (300 ml) was stirred in a 5 liter 3-neck round-bottom flask at 0-3° (ice/salt bath). A solution of 3-chloroperoxybenzoic acid (97 g, 0.50 mole of 85%
pure) in CH2C12 (2 1) was added dropwise with cooling over a 3 hour period (ca. 13 ml/min.) and then, with continued cooling, the mixture was stirred for 3 more :LO hours at 0°. To.th.e cold reaction mixture was then added with stirrings 10% Na2C03 aqueous solution (750 ml). The mixture was transferred to a separatory funnel, and the lower CH2C12 layer was drawn off. The CH2C12 layer was washed with 10% Na2C03 aqueous solution (2 x 75 ml.) and once with water. The CH2C12 solution was tested with moist starch/iodide test paper for the absence of peroxide. The solution was dried over MgS04 and evaporated at 45° to give 1,2-epoxy-5-methoxy-1,2,3,4-tet.rahydronaphthalene (95 g).
:20 Step 4: trans-1-(pY~rrolidin-1-yl)-2-hydroxy-5=methoxy-1,2,3,4-tetrah_ydroriaphthalene To a flask containing the above epoxide (17.6 g, 0.1 mole) was added dropwise, with stirring over a period of about 10 minutes, pyrrolidine (10 ml, 0.12 mole) in ethanol (_°. ml). The mixture was stirred at room temperature far about 18 hours and then warmed at 50° for about 1 hour. On cooling, the solid was collected by filtration and recrystallized from X34101 ~

absolute eth<inol. The crystalline product, traps-1-(pyrrolidin-.l-yl)-2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene, (14.5 g, ~59% yield) was collected by filtration, washed with cold ethanol, and air dried, m.p. 11:3-115°C; TLC Rf = 0.33 (2:1 EtOAc/hexane).
Step 5: transc-1-(Pyrrolidin-1-yl)-2-hydroxy-5-methoxy-1,2,3,4-tetrah dronaphthalene-O-sulfonic acid A solution of the above pyrrolidinyl alcohol (47 g, 0.19 mole) in CH2C12 (250 ml) was stirred under~N2 and cooled in. an ic:e-salt bath while chlorosulfonic acid (12.7 ml, 22.2 g, 0.19 mole) in CH2C12 (250 ml) was added dro~pwise., When addition was complete, the mixture was stirred at 0-5° for 2 hours and then at room temperature overnight. The solid was collected by filtration and air dried, giving traps-1-(pyrrolidin-1-yl)-2-hydroxy-5-met:hoxy-1,2,3,4-tetrahydronaph-thalene-0-sulfonic acid (62 g, 100%), m.p. 213-215°
a0 (dec.).
Step 6: traps-1-Met:hylamino-5-methoxy-2-(pyrrolidin-1-yl)-1,2, 3,4-tetrahydronaphthalene A Parr hydrogenation bottle was loaded with the above dry sulfonate: salt (62 g, 0.19 mole) and 33%
CH3NH2/EtOH (120 ml., 1 mole). The bottle was sealed with a rubber stopF~er held in place by a clamp and the contents were heated in an oil bath at 70° for 20 hours with stirring. The: mixture was cooled to room a0 _s 5 25 w temperature and evaporated on a rotating evaporator to remove most of the: ethanol. Ethyl acetate was added to the residual material followed by 5% NaOH aqueous solution (100 ml). The ethyl acetate layer was removed and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried over R2C03.
Evaporation of the. solvent gave crude diamine free base, trans-1-meth.ylamino-5-methoxy-2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalene (49 g).
This free base was dissolved in toluene and the solution was evaporated before the next step to remove traces of water or ethanol. This diamine can also be prepared by reacting trans-1-(pyrrolidin-1-yl)-2-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene with methanesulfonyl chloride in the presence of triethyl-amine followed by treatment of the methanesulfonate with methylamine using a procedure analogous to that used in Example 2, step 2.
Step 7: trans-3,4-Dichloro-N-methyl-N-[2-(pYrrolidin-1-yl)-5-methox -y 1,2L3,4-tetrahydronaphth-1-yl]benzene acetamide To a solution of 3,4-dichlorophenylacetic acid (51.6 g, 0.25 mole:) in dry tetrahydrofuran (THF) (300 ml) under N2 was added with stirring 1,1-carbonyldi-imidazole (40.8 g, 0.25 mole). The reaction mixture was stirred for 2 hours at room temperature and then a solution of diamine from Step 6 (54.6 g, 0.21 mole) in dry THF (110 ml) eras added dropwise. The mixture was 26 ~ 1341011 stirred overnight at room temperature under N2. The solvent was t',hen evaporated _in vacuo. The residue was dissolved in ether (1 1) and the solution washed with 5% NaOH aqueous solution (2 x 250 ml), then water, dried over Mg;504, and evaporated, giving traps-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetra:hydronaphth-1-yljbenzeneacetamide (89 g).
_Step 8: traps 3,4 Dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,.2,3,4-tetrahydronaphth-1-Yllbenzene-_acetamide hydrochloride The above crude amine amide (free base, 89 g), was dissolved in TH.F (400 ml) and this solution was added to ether (1 1) containing dissolved gaseous HC1 ;15 to precipitate a gummy HC1 salt. Ether (500 ml) was added to the mixture and the gum was triturated. The liquid was decanted and fresh ether (700 ml) was added to give a solid. Z'he ether was decanted and acetone (400 ml) was added to the solid. The acetone mixture 20 was boiled for 10-7.5 minutes, kept at room temperature for 1-1.5 hours, and filtered to collect the solid HC1 salt (32 g). Recrystallization from isopropanol/-methanol (1:1., 400 ml) using decolorizing charcoal, gave on standing overnight at room temperature, trans-25 3,4-dichloro-~N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphth-1-yljbenzeneacetamide hydrochloride: as white crystals (21.6 g), m.p. 230-232°
(dec) . The eiceton~e filtrate (from which 32 g of crude product had been isolated) was evaporated to give an .. 27 ~~ 1 3_ 41 0 1 1 oil (55 g). Boiling of the residual oil with fresh acetone and i~hen evaporation of the acetone on the rotating evaporator was repeated three times to remove traces of solvent .and then the product was crystallized from isopropanol and acetone giving a second crop (about 9 g), m.p. 225-227°. A smaller 3rd crop can sometimes be isolated.
Example 2 trans-3,4-Dic:hloro~-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydro:naphth-1-yl]benzeneacetamide hydrochloride.
Step 1: trans-1,2,:3,4-Tetrahydro-2-hydroxy-1-jpyrrolidin-'.l= yl)n,aphthalene A mixture of 1,2-epoxy-1,2,3,4-tetrahydro-naphthalene x;19.8 gig), pyrrolidine (15 ml) and ethanol (75 ml) was e~tirred at reflux for 2 hours and evaporated oj: the volatiles under reduced pressure.
The residue was dissolved in ether and the solution was extracted with 1N :hydrochloric acid (200 ml). The acid extract was washed with ether and basified with 1N
sodium hydroxide aqueous solution with cooling. The mixture was extracted with ether (2X) and the combined ether extractor were washed with water, dried over magnesium sulfate .and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-2-hydroxy-1-(p;rrrolidin-1-yl)naphthalene (16.5 g), b.p.
128-135°/0.2'i tOrr.

Step 2: traps-1,2,f.,4-tetrahydro-1-methylamino-2-,(p)rrrolidin-1-yl)naphthalene A solution of: methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was added rapidly in drops to a stirred and cooled (0.5°C) solution of traps-1,2,3,4-tetra~hydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After the addition was complete, the mixture was stirred at room temperature :LO for 3 hours and them evaporated under reduced pressure.
The residue was treated carefully with a 33% solution of methylamine in eahanol (125 ml) and the mixture was stirred at reflux f:or 2 hours followed by evaporation of the solvent under reduced pressure. The residue was :15 treated with water and extracted twice with ether. The combined ether extracts were washed with 2N sodium hydroxide and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to :20 yield traps-1,2,3,4-tetrahydro-1-methylamino-2-(pyrrolidin-1.-yl)naphthalene (6.2 g), b.p. 126-134°/0.25 tOI'r.
Step 3: transc-3,4-Dichloro-N-methyl-N-[2-(pyrrolidin-25 1-yl)-1,2,3,4~-tetrahydronaphth-1-yllbenzeneacetamide hydrochloride:
A solution o:E dichlorophenylacetyl chloride (1.1 g) in methyle:ne chloride (25 ml) was added to a solution of t:he above diamine (1.1 g) in methylene 29 _. 1 3 4 1 0 1 1 chloride (50 ml) and the solution was stirred with aqueous sodium bicarbonate (75 ml) for 2 hours at room temperature. The organic layer was separated and washed with aqueou:a sodium carbonate and then with water, dried (MgSO,~) and evaporated, to yield an oil (1.5 g) of ttie crude title compound. This oil was dissolved in THF and added to a solution of HC1 in ether. The hydrochloride salt that precipitated was washed with Ether and air dried. The crude salt was crystallized from acetone. Recrystallization from isopropanol cave the pure hydrochloride salt of the title compound, m.p. 232-234° (dec).
This procedure exemplifies the use of an alternate synthetic: route to compounds of this invention. (:~cheme I, IV~VI~VIII~VII~I).
Example 3 trans-3,4-Dic:hloro--N-methyl-N-[2-(pyrrolidin-1-yl)-6-methoxy-1,2,3.,4-tet:rahydronaphth-1-yl]-benzeneacetamide and its hydrochloride salt Step 1: trans-2-Bromo-1-h~droxy-6-methoxy-1,2,3,4-tetrahydronaF~hthale:ne To a solution of 6-methoxy-1,2-dihydronaphthalene (44.8 g, 0.28 mole) dissolved in DMSO (450 ml) was added with st.irrinc~ H20 (16 ml). To the stirred a5 mixture was added in 5 portions, N-bromosuccinimide (99.7 g, 0.56 mole) while the exotherm was controlled by an ice bath. The mixture was stirred at room temperature for 3 hours. Water (ca. 1 1.) was added and the mixture wasc extracted with ether (3 times).
:30 :35 3~ 1 341 01 1 The combinedl extracts were washed with water twice, then with 5% NaHCO3, dried over K2C03, filtered, and evaporated to give: an oil. After all the solvent had been removed, the oil crystallized on being scratched.
It was recrystallized from hexane/ethyl acetate to yield traps-2-bromo-1-hydroxy-6-methoxy-1,2,3,4-tetra-hydronaphthalene, m.p. 80-82°, Rf = 0.85, silica gel, EtOAc; second crop from filtrate, 13 g, m.p. BO-81°.
Step 2: traps-2-Hydroxy-1-(pyrrolidin-1-yl)-6-methoxy-1,2,3,4-tetrahydronaphthalene To the above bromohydrin (30.8 g, 0.12 mole), cooled in a ~~rater bath, was added pyrrolidine (240 ml) and water (4'7 ml) all at once. The mixture was cooled for 10 minutes and then allowed to stand at room temperature :Eor 22 hours. The excess pyrrolidine was evaporated on a rotating evaporator. Aqueous 10%
Na2C03 was added a:nd the mixture was extracted with ethyl acetatE: (3x). The extract was dried over MgSO4 and evaporated, giving traps-2-hydroxy-1-(pyrrolidin-1-yl)-6-methoxy-1,2,:3,4-tetrahydro-naphthalene which was crystallized from :isopropanol. First crop, 17 g (m. p.
79-80°), second crop 7 g (m.p. 78-79°).
Step 3: trap=.-:-2Hyciroxy-1-(pyrrolidin-1-yl)-6-methoxy-1,2,3.,4-tet:rahydronaphthalene-O-sulfonic acid A solution oi° the above amino alcohol (7.4 g, 30 mmoles) in me~thylene chloride (30 ml) was cooled in ice while a solution of chlorosulfonic acid (2 ml) in :30 :f 5 ~ 3 ~t 1 0 1 1 ' methylene chloride (60 ml) was added dropwise. The mixture was stirred under nitrogen for 2 hours with cooling and then at room temperature overnight. The white precipitate was collected by filtration, washed twice with fresh methylene chloride, and dried to give traps-2-hydroxy-1-(pyrrolidin-1-yl)-6-methoxy-1,2,3,4-tetrahydronaphthalene O-sulfonic acid (8.7 g), m.p.
210-212 ° ( dec: ) .
Step 4: trams-1-mel~hylamino-2-(pyrrolidin-1-yl)-6-methoxy-1,2,3,4-tetrahydronaphthalene ' The above O-:~ulfonic acid salt (8.6 g) and 30%
methylamine i.n ethanol (20 ml) were heated in a sealed Parr bottle Eat 50° for 3-4 hours and then at 70° over-night. The mixture: was evaporated in vacuo and ethyl acetate was added to the residue. Aqueous 5% sodium hydroxide was. added, and the mixture was extracted quickly with ethyl acetate (3x). The ethyl acetate extract was dried over anhydrous potassium carbonate and then evaporated, giving traps-1-methylamino-2-(pyrrolidin-1.-yl)-f-methoxy-1,2,3,4-tetrahydronaph-thalene (3.5 g) as an oil. The aqueous layer was further extracted with methylene chloride, giving an additional amount of the product (0.5 g).
Step 5: transc-3,4-l~ichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-methoxy1,:1,:2,3,4-tetrahydro-1-y11-benzeneacetamide h~rLdrochloride The above diamine was converted into the corresponding 3,4-dichlorobenzeneacetamide by the 134101 ~

action of 3,~4-dichlorophenylacetic acid (3.37 g) that had been treated with N,N'-carbonyldiimidazole (2.6 g) in THF by a procedure similar to that used in Example 1, step 7.
This gave an amino amide that was converted to its hydrochloride aalt (by the procedure described in Example 1, step 8) which was recrystallized from isopropanol/rnethanol. The salt was washed with acetone and recrystaJllized from isopropanol/methanol again for an analyticaJ~. sample of traps-3,4-dichloro-N-methyl N-[2-(pyrrolid~:n-1-y:1)-6-methoxy-1,2,3,4-tetrahydro-1-yl]benzeneaceaamide hydrochloride, m.p. 245-247° (dec).
Example 4 traps-3,4-Dic:hloro--N-methyl-N-[2-(pyrrolidin-1-yl)-6-hydroxy-1,2,3,4-tetrahydro-1-yl]benzeneacetamide hydrochloride:
traps-a,4-Dic:hloro-N-methyl-N-[2-pyrrolidin-1-yl)-6-methoxy-1,2,:3,4-tetrahydro-1-yl]benzeneacetamide was treated with 6 molar equivalents of boron tribromide in CH2C:l2 at -78°. The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for 2 hrs. The reaction mixture was then treated with methanol and then aqueous 5%
NaHC03. Extraction with CH2C12 gave the free base form of the desired product. The free base was dissolved in tetrahydrofuran and treated with HC1/ether, giving the title compound, m.p. 238-240°.
' Example 5 A. (+) trans.-3,4-L~ichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide and its hydrochloride salt The compound (d,l) 3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1.,2,3,4-tetrahydronaphth-1-yl]ben-zeneacetamide hydrochloride prepared as in Example 2 was converted to it.s free. base with aqueous potassium carbonate.
A solution of this free base'(1.10 g, 2.64 mmole) in hot acetonitrile; (5 ml) was added to a solution of (-) dibenzoyltartaric acid~H2o (0.90 g, 2.4 mmole, prepared from natural tartaric acid) in hot acetonitrile (5 ml). The resulting solution was warmed :15 to dissolve an oil that formed and then allowed to cool slowly with seeding~from material obtained earlier in a similar experiment. The next day, crystalline solid was collected, washed with fresh acetonitrile (5 ml) and dried at 55° under vacuum, giving the resolved salt ;ZO (0.92 g), m.p. 157-158°. The resolved salt prepared from (-) dibenzoyl-tartaric acid was converted back to free base and then into the HC1 salt of the title compound, m.p~. 222-223°; [a]D5 + 63.0° + 0.8°
(c=1.0, EtOH).
:? 5 :30 :35 B. (-) traps-3,4-lDichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide and its hydrochloride salt The mother liquors from the crystallization described in A were treated with excess aqueous K2C03, and the free base ithus obtained was treated with (+) dibenzoyltart:aric acid~H2o (made from unnatural tartaric acict) giving the enantiomeric salt (0.616 g), m.p. 157-158°'. This salt was converted to free base and then into the HC1 salt of the title compound, m.p.
221-222°, [a]D5 -6:3.6° (C=1.0, EtOH).
Example 6 traps-3,4-Dichloro--N-methyl-N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1-yl]benzeneacetamide hydrochloride:
Step 1: traps-2,3-I>ihydro-2-hydroxy-1-(pyrrolidin-1-yl)-1H-inde~ne 1,2-Epoxy-2,a-dihydro-1-H indene, prepared from indene (34.2 g) according to the procedure of M. Imuta and H. Ziffer, J. Orq. Chem., 44, 1351 (1979), was treated immediately with pyrrolidine (50 ml). The exothermic reaction mixture was set aside for 15 minutes and then evaporated to remove the excess pyrrolidine under reduced pressure. The residue was distilled under vacuum to yield traps-2,3-dihydro-2-hydroxy-1-(pyrrolidin-1-yl)-iH-indene (10.2 g), b.p.
148-150°/0.25 torn, Step 2: traps-2,3-I>ihydro-1-methylamino-2-(pyrrolidin-1-yl)-iH-inde~ne i ___ A solution o1: methanesulfonyl chloride (6 g) in methylene chloride (50 ml) was added dropwise rapidly 35 1 3 .41 0 1 1 to a stirred and cooled (0-5°) solution of trans-2,3-dihydro-2-hy<iroxy-(pyrrolidin-1-yl)-1H-indene (5.5 g) and triethylamine (6 ml) in methylene chloride (200 ml). After t:he addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated with a 33% solution of methylamine in ethanol (100 ml) and the mixture was stirred at reflux for 3 hours and evaporated under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed successively with a N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure to yield a liquid which was distilled under vacuum to give trans-2,3-dihydro-1-methylamino-:!-(pyrrolidin-1-yl)-1H-indene (6.3 g) b.p.
118-120°/0.2.i tOrr.
Step 3: tran:>-3,4-l~ichloro-N-methyl-N-f2,3-dihydro-2-~pyrrolidin-7_ yl)-:LH-inden-1-yl~benzeneacetamide hydrochloride:
A solut:ion o:E the above product (5.4 g) in anhydrous tet:rahydrofuran (25 mlj was added in one lot to a stirred mixture of 3,4-dichlorophenylacetic acid (5.2 g), dicyclohexylcarbodiimide (5.2 g) and a few milligrams of: 4-dirnethylaminopyridine in anhydrous tetrahydrofuran (50 ml). The mixture was stirred at room temperature overnight and filtered. The solid was washed with a smal:L quantity of anhydrous _~ ~ ~ 3~1 01 1 tetrahydrofuran and the combined filtrates were evaporated under reduced pressure. The residue was dissolved in anhydrous ether (50 ml) and the solution was filtered to rernove a small quantity of insoluble material. The clear filtrate was added to an excess of an etheral solution of gaseous hydrogen chloride. The sticky hydrochloride that separated was removed by decantation a.nd crushed under anhydrous ether to a fine powder which was boiled with acetonitrile (50 ml) briefly and cooled to yield a colorless crystalline material which was filtered, washed with ether, and air-dried to give t:he title compound (6.1 g), m.p. 233-235°.
Example 7 trans-3,4-Dichloro-~N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl]benzeneacetamide and its hydrochloride salt Step 1: Benzo ran :?0 A mixture of 4-chromanol (30 g; 0.02 mole), benzene (200 :ml) and 4-toluenesulfonic acid (200 mg) was refluxed, with a Dean-Stark trap, until separation of water ceased (ca. 3 hrs.). It was then washed successively 'with saturated NaHC03 aqueous solution and water, dried ~wer anhydrous MgS04 and evaporated under reduced pressvure to yield an almost colorless liquid which was di stilled under vacuum to give benzopyran (20.2 g, 76.4'0 b.p. 73-78°/3 tOrr.
a0 3.5 134 p~ 1 Step 2: 3,4-I))ihydro-4-methylamino-3-(1-pyrrolidino)-2H-1-benzopyran 3-Chloroperoacybenzoic acid (MCPBA, 19.0 g of 80-85%; ca. O.OS~ mole) was added in small portions to a vigorously stirred mixture of a solution of 11.4 g (0.087 mole) of the above product in CH2C12 (300 ml) and saturated aqueous NaHC03 (300 ml) at 0-5°. After the addition was complete, the mixture was stirred for 3 hours at 0--5° and additional MCPBA (5 g) was added in small portions. Tlae mixture was then stirred for 1 hour at 0-5° and tile methylene chloride layer separated, was washed successively with cold saturated aqueous NaHC03, cold 10% aqueous sodium sulfite and water, dried over anhydrous MgS04 and filtered. The filtrate was treated with pyrrolidine (25 ml) and the mixture was evaporated under reduced pressure. The residue was treated with an additional amount of pyrrolidine (10 ml), warmed briefly to ca. 80° and evaporated under rE:duced pressure. The residue was dissolved in ether and extracted with 1 N HC1 (200 ml).
The acid fraction was extracted once with ether and the ether extract..was discarded. The aqueous layer was cooled and ba.sified carefully with 20% aqueous NaOH.
The mixture was them extracted with ether (2X) and the combined ether extracts were washed with water, dried over MgS04 and evaporated under reduced pressure to yield a reddish brown liquid (9.3 g, 48.9%) which was used as such in thE: next reaction.
:30 :35 38 ~ 1341011 A solution o1: methanesulfonyl chloride (5.2 g;
0.045 mole) i.n methylene chloride (25 ml) was added dropwise to a. stirred and cooled solution of the above product (9.3 g; 0.042 mole) and triethylamine (9 g;
0.09 mole) in. methylene chloride (200 ml). After the addition was compleae, the mixture was stirred at room temperature for 3 hours and then evaporated at reduced pressure. The residue was treated with a 33% solution of methylamine in eahanol (100 ml) and the mixture was stirred at reflux f:or 3 hours and evaporated under reduced pressure. The residue was treated with water and extracted with ether (2 X). The ether extract was washed successively with 2 N NaOH and water,~dried over anhyd. MgS04 and evaporated under reduced pressure to :15 yield a viscous, reddish brown liquid, 3,4-dihydro-4-methylamino-3-(1-pyrrolidino)-2H-1-benzopyran (8.2 g;
84%) which was usedL as such in the following step.
Step 3: Trans-3,4-~iichloro-N-methyl-N-[3,4-dihydro-3-a0 ~pyrrolidin-1-yl)-2H-benzopyran-4-yllbenzeneacetamide and its hydrochloride salt A solution of the above benzopyran (8.1 g) and triethylamine (6 g) in methylene chloride (200 ml) was stirred and treated, with a solution of 3,4-dichloro-;~5 phenylacetyl chloride (8.5 g) in methylene chloride (10 ml). After the addition was complete, the mixture was stirred at room temperature for 2 hours and then treated with a 2% aqueous solution of sodium hydroxide (150 ml). The mixture was transferred to a separatory :30 :35 .39.. ~ 341 01 1 funnel, shaken vigorously and the methylene chloride layer was separated, washed successively with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sul:Eate and evaporated under reduced pressure. The residual viscous liquid was dissolved in anhydrous ether and the solution was added to an excess of an etheraT. solution of gaseous hydrogen chloride.
The lumpy hydrochloride that separated was removed by decantation, crushed to a fine powder under anhydrous ether and fil.tered., The product was boiled with.
acetonitrile (100 rnl) and filtered to remove slight coloration. The colorless solid thus obtained was recrystallize:d fronn a mixture of methanol and ether to yield the title compound, m.p. 260-261° (dec.).
Example 8 trans-3,4-Dichloro-N-methyl-N-[(3-(pyrrolidin-1-yl)-1,2,3,4-tetrahydror~aphthalen-2-yl)]benzamide The starting diamine prepared in Example 2, step 2 (1.0 g) was suspended in dry methylene chloride (20 ml) and cooled in an ice-water bath. While stirring, a solution of 3,4-dic:hlorobenzoyl chloride (1.35 g) in methylene chloride (10 ml) was added dropwise. The resulting mixture was allowed to warm to room .25 temperature, stirred overnight, quenched with half-saturated aqueous rfa2CO3, and extracted with methylene chloride. The combined extracts were washed with brine, dried and evaporated to give a brownish oil.
The crude oil was chromatographed by flash column :30 :35 chromatography (si.lica gel; methylene chloride:
methanol= 30:.1) to give the desired amide (1.1 g), m.p.
126-129° from acetone-hexane.
Example 9 traps-3,4-Dic:hloro.-N-methyl-N-[3-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzeneacetamide 2-naphthalenesulfonic: acid salt Step 1: 2,3-E: op xy=_1,2,3,4-tetrahydronaphthalene 1,4-Dihydronaphthalene (5 g) was dissolved in methylene chloride (250 ml) and saturated aqueous NaHC03 (280 ml). 9~he mixture was stirred vigorously at room temperature while meta-chloroperbenzoic acid (70%, 10.0 g) was added in portions. After 1 hour, an aqueous solution oi: Na2S203 (1M, 100 ml) and methylene chloride were: added. The methylene chloride layer was separated, washed with water and brine, dried (MgS04) and evaporated to dive a brownish crude mixture, which was chromatog~raphed on a flash column (silica gel;
ether: hexane = 1:E>) to give 2,3-epoxy-1,2,3,4-tetrahydronap~hthale:ne (3.45 g) .
Step 2: traps--2Hyciroxy-3-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronap~hthale:ne :25 The above product (3.45 g), pyrrolidine (2.8 g), and dioxane (15 ml) were sealed under vacuum in a glass tube. The sealed tube was heated at 100° for 15 hours.
The content was evaporated under reduced pressure and the residue was partitioned between ether (50 ml) and 1 :30 :35 41-~ 1341011 N HC1 (50 ml). The aqueous layer was separated, basified to pH9, and extracted with methylene chloride.
The combined extracts were washed with brine, dried, and evaporate=d to .give trans-2-hydroxy-3-(pyrrolidin-1-yl)-1,2,3,4-l:etrah:ydro-naphthalene (4.5 g).
Step 3: trap:~-2-Methylamino-3-(pyrrolidin-1-yl)-1,2, 3, 4-tetrahydi.-onaph~thalene The above product (4.5 g) and triethylamine (3.5 ml) were dis:>olyed in methylene chloride (80 ml) and stirred at 0", whi:le a solution of methanesulfonyl chloride (l.Et3 ml) in CH2C12 (40 ml) was added dropwise. Alter the addition, the mixture was placed in the refric(erator overnight. Water (50 ml) was added, and the organic layer was separated, washed with brine, dried (MgSO,~) and evaporated to give a brownish residue. The: residue was dissolved in 33%
CH3NH2/ethanol (20 ml) and stirred at reflux under N2 for 2 hours. The Excess CH3NH2 and ethanol were evaporated. The residue was dissolved in methylene chloride (lOC~ ml) and washed with Water and brine.
Evaporation cave mans-2-methylamino-3-pyrrolidin-1-yl)-1,2,3,4-t.etrah3rdronaphthalene (4.2 g).
Step 4: Trans-3,4-I)ichloro-N-methyl-N-[3-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzeneacet-amide 3,4-Dichlorophenylacetic acid (1.05 g) and carbonyldiimidazole~ (856 mg) were dissolved in dry THF

42 ~ 1341011 (20 ml). This solution was cannulated into a stirred suspension of~ the above product (1.0 g) in methylene chloride (20 ml) at: 0°. The mixture was allowed to warm to room temperature and stirred overnight. Water (50 ml) and methylene chloride (100 ml) were added and the organic layer was separated, washed with brine, dried, and ev~aporat:ed to give a crude product which was chromatograph.ed (si:lica gel; CH2C12 : CH30H = 40:1) to yield the pure free: base of the title compound (1.2 g).
Its naphthalenesulf:onate Was recrystallized from ethyl acetate: 2-propanol.; m.p. 161-164°.
The compounds; prepared in Examples 1-9 and other compounds which were prepared or can be prepared by the methods described i.n the specification are listed in Tables I and II.
:20 :30 :35 ~

4 3 1 3 4 '1 0 1 ~
Tubl~ I
X
p CaCH=~~
,vN~ r 0 N.~p~
gyp:
c_ :10 a ~ cAn Ex.
~~P~
No. A 8 C 0 n R R1 R2 R3 X if salt °C
7l51 CH26-OCH3H H 1 CH3-(CH2)4-H 3-CI4-CINCI 238-2 lA 6-OCH3H H 1 CH3-(CH12)4-H 3-C14-CIHCI 283-6 (.) i sonr 2 CH2H H H 1 CH3-(CH2)4-H 3-CI4-CIHCI 232-4 3 CH26-OCH3H H 1 CH3-(CH2)4-H 3-CI4-CIHCI 246-7 (d~c) 4 CH2a-OH H N 1 CH3-(CH2)4-H 3-CI4-CIHCI 23H-40 6A CH2H H H 1 CH3-(CH2)4-H 3-CI4-CIHCI 222-3 () 2 i aon,r 68 CH2H H H 1 CH3-(CH;Z)4-H 3-CI4-CINCI 221-2 (-) iaomr d - H H H 0 CH3-(CH.~)4-H 3-Ci4-CIHCI 233-6 3 7 0 H H H 1 CH3- (CH.t)H 3-C 4-C HC 260-1 (d~c) 18 CH2H H H 1 ~CH3- (CH~t)H H 4-8rHC 1a8-78 l CH2H H H 1 CH3- (CHt)H H H HC 17B-80 l 4- I

35 12 CH2H H H 1 ~:H3-(CH~,)4-H H 4-CF3HCI 178-2 44 1 3 41 0 1 '~
T°bl° I (continwd) Ex. m.p.
No. A B C ~ n R' R1 R2 R3 X 1f avlt °C
13 CH26-OCH3 H H 1 -(CH2)I-H 3-CI4-CICH3S03H183-6 11 CH26-OH H H 1 -(CH2)I-H 3-CII-CIHCI 2T3-6 (dc) 16 CH26-OCOC2H6 H H 1 -(CH2)I-H 3-CII-CIHC1 228-38 16 CH26-OCOCeH6 H H 1 -(CH2)I-H 3-CI4-CIHCI 2ts0-2 17 CH2a-OCH3 T-OCH3H 1 -(CH2)I-H 3-CI4-CINCI 128-30 CIi3 (d~c) 18 CH2a-OH T-OH H 1 -(CH2)I-H 3-CI4-CIHCI 213-6 18 0 H H H 1 -(CH2)I-H H H HCI 2a8-1 (d~c) 20 0 6-OCH3 H H 1 -(CH2)I-H 3-CII-CIHCI 206-7 21 CH26-OCH2-CH20CH3H H 1 -(CH2)I-H 3-CI4-CIHCI 232-I
Chl3 22 CH26-OCH3 Q-OCIi3H 1 -(CH2)I-H 3-CIs-CIHCI 281-4 23 CH26-CH20CH3 a-OCH3H 1 -(CH2)I-H 3-CI4-CIHCI

21 CH26-OCH3 8-OCH3H 1 -(CH2)I-H 3-CI1-CI 138-111 26 CH26-CH20CH3 d-OH H 1 -(CH2)I-H 3-CI4-CIHCI 203-T

(dc) 26 CH26-OCH3 7-OCH3H 1 -(CH2)I-H 3-CII-CIHCI ' 2T CH36-SCH3 8-OCH3H l -(CH2)I-H 3-CI4-CIHCI
CH'3 28 CH26-C02ET s-OChl3H 1 -(CH2)I-H 3-CI4-CIHCI

28 CH2H H H 1 -(CH2)I-CH20H3-CII-CIHCI

44' ~45 134101' T°bl~ I (continwd) Ex. m.p.
No. A B C D n R R1 R2 R3 X Y salt °C
30CHCH20H6-NHZ 1!-OCH3 1 -(CH2)4- H 3-CI 4-CI HCI

31CHCH20Hd-OCH3 H H 1 -(CH2)4- H 3-CI 4-CI HCI

32CH2 6-CH2C02C3H7 H 1 -(CH2)4- H 3-CI 4-CI HCI
1!-OH CH3 33CH2 6-N(CH3)21!-OHH 1 -(CH2)4- H 3-CI 4-CI HCI

34CHCON- 6-OCH3 H H 1 -(CH2)4- H 3-CI 4-CI HCI

(Et) 3SS 6-OCH3 1!-OCH37-~ 1 -(CH2)3- H H 4-CF3 NSA~
C2Hb OC;H3 8Q0 4-N(C3HT)CH3 H 1 CH3 CH2CdH6 H 3-N02 4- HCI
li C3HT

3TCH2 6-OC3HT I~ H 1 (CH2)2CH(OH)CH2-H 3-F 4-F HCI

38- 4-NH2 IS-F a-~Fd -(CH2)20(CH2)2-H H 4- H8r 39- 4-OCH3 H H a -(CH2)4- H 3-CI 4-CI HCI

40- 4-CH2SC2H6li-OHH d CH3 CH2- ~ H 3-CI 4-N02 HCI

41CH2 6-OC3HT I!-OHH 1 CH3 CH2- H 3-F 4- HBr CH3 .

42CH2 a-CI '1-CIH 1 -(CH2)2NCH3(CH2)2-CO- 2-0CH34-N02 1/2 43CH2 6-NIA2 I!-CH3H 1 H 3-ABHX CHO 3-C 4-CN 112504 44CH2 6-SC2H6 I!-C18-~CI1 CH3 3-ABHP~ CH3 3-CI 4-OCH3HCI

46CH(CH3)H H H 1 -(CH2)4- H 2-CI 3-CI HCI
C3HT ' 47CH(C3HT)H I~ H 1 -(CH2?3-- 2-CI 4-CI HCI

48CH2 6-OCH20CH3H H 1 -(CH2)4- H 3-CI 4-CI HCI

.46 . ~1~41011 .
Table I (continued) Ex. m.p.
No. A B C D n R Ri R2 R3 X Y salt °C
48CH2 7-OH H H i CH3-(CH2)4- H >1-CI4-CI HCI 193-a (dee) 60CH2 6-OCH3 H H i CH3-CH2CH=CHCH2-H i-CI4-CI HCI

61CHC02H H H H 1 CH3-(CH2)4- H 3-N024-OCH3HCI

62CHC02CH3H H H i CH3-(CH2)4- H 2-CN6-N02HCI

63CHCON- H H H i CH3-(CH2)4- H 3-CI4-CI NCI

(C3H7)2 64CH2CH2 H H H i H CH3 H H 3-CI4-CI NCI

6dCHC02CH3H H H i H H CH2C2H60H H 3-CI4-CI HCI

67CHCON- H H H 1 H H -(CH2)6- H 3-CI4-CI HCI

(CH3) 68CH2 6-OCH3 H H 1 CH3-CH2CH=CHCH2-H 3-CI4-CI HCI

69CH2 4-CH20C3HT6-CI H 1 H -(CH2)4- CH33-I 4-Br HCI

Q8CH2 6-CH2CONHCH3H H 1 H -(CH2)4- H H E-CI HCI

61CH2 d-CH2C02H 7-CH3 H 1 CH3-(CH2)3- H H 3-CI HCI

62CH2 4-CH2COC2H6H H 1 H -(CH2)3- H 3-CI4-Br HCI

Q3CH2 6-CH2CH0 a-C2H6 H 1 CH3-(CH2)3- H 3-N024-Ol~teHCI

Q4CH2 4-Br 6-I H 1 H -(CH2)6- H 2-CI3-Br HCI

d6CH2 6-SC3HT Q-NH2 H 1 H -(CH2)4- CH33-CI4-06teHCI

Q6CH2 4-SCH3 6-N(CZHh)2H 1 H -(CH2)4- H 3-CI4-CI HCI

6TCH2 6-Br a-CI T-Ii H -(CH2)4- H i-CI4-CI HCI

Q8CH2 6-OC(S)N(CH3)2H H 1 CH3-(CN2)4--- H a-CI4-C HCI 266-7 ~34~01~~, Tabl° I (contin wd) Ex. m.p.
No. A B C D n R R1 R2 R3 X 1f i°It °C
d8CH2H 7,B-(-CH=CH-CH=CH-)1 CH3 -(CH2)4- H 3-CI 4-CI HCI 288-2 (d~c) 78CH2H 6,7-(-CH=CH-CH=CH-)1 CH3 -(CH2)4- H 3-CI 4-CI HCI
.

71CH2N 6,a-(-CH=CH-CH_-CH-)1 CH3 -(CH2)4- H 3-CI 4-CI HCI

72CH26-OCH3 H H 1 CH3 -(CH2)4- H 2,3-(-CH=CH-S-) HCI 242-6 (d~c) T3- H H H ~ a CH3 4-N02 HCI
-(CH2)2CH(CH3)(CH2)2-H

74CH26-OH H H a CH3 H 3-CI 4-CI HCI
-(CH2)2CH(OH)CH2-7bCH26-OCH3 8-OCH3 1 C2H6 -(CH2)4- H 3-CI 4-CI HCI
H

7aCH26-CH3 Q-OH 7-Ohl 1 CH3 -(CH2)3- H H 4-S02C3H7NCI

77CH2H b,6-(-CH=CH-Chl=CH-)1 CH3 -(CH2),~- H 3-CI 4-CI HCI

78CH2H 0,7-(-CH=CH-CFI=CH-)1 CH3 -(CH2)4- H 3-CI 4-CI HCI

79CH2H 7,8-(-CH=CH-CFI=CH-)1 CH3 -(CH2)4- H 3-CI 4-CI HCI

Tabl° II (eontin wd) CI ~ ~I
(N° ~w ~9 Ex. . m.p.
No. A B C D n R R1 R2 R3 X if a°It °C
8 CH2N N H 1 CH3 -(CH2)4- H E-CI.4-CI (bs) 12a-a !iCH2H H H 1 CIH3-(CH2) 4- H a-C 4-C ItSA~ lesl-4 88- H H H d CIH3-(CH2)2CH(CH3)(CH2)2- 4-N02 NCI

81CH26-OH H H d CIH3-(CH2)2CH(OH)CH2-H 3-CI 4-C) HCI

82CH26-OCH3 8-OCH3H 1 C;ZH6-(CH2)4- H 3-CI -CI HCI

83CH26-CH3 a-OH 7-OH CIH3-(CH2)3- H H 4-S02C3H7 1 HC) I~ISA 2-nphthalnsultonie = cid Analgesia Testing Procedure The standard procedure for detecting and comparing the analgesic activity of compounds is the phenylquinone: writlhing test (PQW) modified from E.
Seigmund, et al.; Proc. Soc. Exp. Biol. Med., 95, 729 (1957).
Test: compounds were dissolved in saline or distilled wager using dilute lactic acid as needed, or suspended in an aqueous vehicle containing 2% by volume . of Tween 80~, a pharmacological dispersant manufactured by Fisher-Scientific Company and containing 100%
polysorbate 8.0, and 0.25% by weight of Methocel~ A15C
powder, a suspending agent manufactured by Dow Chemical company and containing 100% methylcellulose. Test compounds were given orally or subcutaneously to fasted (17-21 hrs) male write mice (CF1), 5-15 animals per graded dose, in a volume of 10 ml/kg body weight.
After 5-25 minutes, aqueous 0.01% phenyl-p-benzoquinone, 0.125 mg/kg, was injected :ZO intraperitoneally. After an additional 5 minutes, mice were observed 10 minutes for the characteristic stretching or writhing syndrome which is indicative of pain produced by phenylquinone. The effective analgesic dose in 50% of the mice (ED50) was calculated :?5 by the moving average method of W.R. Thompson, Bac.
Rev., 11, 115-145 (1947).
The ;mouse analgesic data are summarized in Table III.
a0 a5 50 ~~ 1 3 41 0 '~ ~
Analgesic Activity In Mice Ex. ED50 (mg/kg) _No. s.c. p.o.

1 0.46 6.5 1A 0.15 5.2 2 2.7 13.

3 1.5 6.5 4 0.032 4.2 5A 0.90 3.4 58 X81. X81.

6 1.5 30.

7 1.7 36 8 16. 47.

9 47. X81.

10 8.1 54. ' 11 30. X81.

12 19. 54.

13 0.33 7.4 14 0.72 13.

15 0.24 10.

16 0.71 10.

18 0.19 3.3 19 1.7 36.

1.2 30.

22 8.1 16.

20 24 47. 24.

0.19 54.

48 4.5 13.

49 0.46 16.

50 0.24 3.4 68 1.7 18.

69 3.0 16.

25 72 0.46 16.

U-50,488H 1.2 13.

Morphine 1.0 3.8 As shown in '.table III, mpounds of the invention co produce potent analgesic effects in warm-blooded animals. This ana:Lgesia is the same range of potency in as morphine and of the standard kappa agonist analgesic U-50,488H [P.,F. VonVoigt lander,et al.; J. Pharmacol.

Exp. Ther., :!24, 7 (1983 )].

51 _1 341 0 1 1 Strong sedation, occurring at 23x the analgesic ED50 dose, was an additional property observed with all compounds of the invention when tested in mice. This sedation is characteristic of kappa agonist compounds such as U-50,488H [P.F. VonVoigtlander, et al.; J.
Pharmacol. Exp. Ther., 224, 7 (1983)]. Morphine and other mu agonist compounds do not produce sedation in mice. All compounds of the invention which produced analgesia in mice (Table III) also produced strong sedation within their analgesicalljr-effective range of doses, suggesting that they have selective kappa agonist activity.
A standard procedure useful for confirming kappa receptor opioid activity is the production of diuresis in the rat. Known kappa agonists such as U-50,488H
produce significant. increases in urine flow [P. F.
VonVoigtlander, et al.; J. Pharmacol. Exp. Ther., 224, 7 (1983)]. Mu agonist analgesics, such as morphine, are largely devoid of this property. Thus, kappa agonist :20 induced urine formation is the basis of a test in rats for distinguishing kappa and mu agonist activity.
Testing for diuretic activity was conducted in male Sprague Dawley rats, weight approximately 200-300 g. Rats were not fasted prior to use, but no food or water was available: for the duration of the study.
Animals were allowed to acclimate for approximately 30 minutes in individual metabolism cages, then administered test compound doses subcutaneously in a volume of 1 ml/kg body weight. Spontaneously voided :30 urine was collected for the next five hours. Test compounds were prepared in either distilled water (solutions) or Methocel~/Tween 80~ suspensions, according to the meahods indicated above.
The rat diureaic data are summarized in Table IV.

._ ~ . . 1341011 KAPPA AGONIST-INDUCED DIURESIS RATS
IN

(N = 5 RATS/DOSE) MEAN CUMULATIVE

EX. DOSE URINE OUTPUT % INCREASE

NO. (mg/kg s.c.) AT 5 HOURS (ml) OVER CONTROL

1 0.0 0.80 ---0.063 1.20 (NS) 50%

0.25 3.44 * 330%

1. 8.76 * 995%

~4. 10.9 * 1263%

16. 8.64 * ~ 980%

2 ~D.O 1.40 ---iD.33 0.96 (NS) -31%

:1. 2.24 (NS) 60%

:3. 3.08 * 120%

!9. 6.36 * 354%

2~~ 8.56 * 511%

U-50,4E38H 1).0 2.44 ---0.063 3.48 (NS) 43%

0.25 2.84 * 16%

:~ 5 . 44 * 123%

4. 10.5 * 330%

lli. 13.6 * 457%

MORPH IDtE 0 . 0 0 . 9 3 ---~)1 1.38 (NS) 48%

7l. 2.41 * 159%

20. Toxic (2/8 dead) ---(NS) - not significant * - P<0.0_. significant vehicle compared to control X34'1011 As shown in Table IV, compounds of the invention produced large increases in urine flow similar to that observed with the standard kappa agonist analgesic U-50,488H. Mu agonist analgesics (morphine) produce minimal or no diuresis in rats. These data confirm that compounds of the invention are kappa agonist analgesics.
Dosage Forms Dosage forms (compositions) suitable for administration contain from about 0.1 milligram to about 500 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily b~e present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or .in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medica-tion over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect ~~he ta:blet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. - _--Liquid dosage forms for oral administration can contain colo~:ing and flavoring to increase patient acceptance. .

In gen~sral, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
Solutions for pare;nteral administration preferably contain a wal:er soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antio:Kidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
Also used arE: citric acid and its salts and sodium EDTA.
In addition, pareni:eral solutions can contain preservativefo, such as benzalkonium chloride, methyl- or propyl-parabe:n, and chlorobutanol.
Suitable pharmaceutical carriers are described in Reminqton's F~harmac:eutical Sciences, A. Osol, a standard reference texa in this field.
Useful pharmaceutical dosage forms for administration of t:he compounds of this invention can be illustrated as follows:
Capsules A large number of unit capsules are prepared by filling standard twa-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 :?5 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is a0 prepared and injected by means of a positive displacement ;pump into gelatin to ~orin~-soft gelatin capsules containing 100 milligrams of the active ingredient. 'The capsules are washed and dried.
.c 5 55 ~ - 1341011 Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams o:E the .active ingredient, 3 milligrams of magnesium stearate, 75 milligrams of microcrystalline cellulose, 10 milligrams of starch and 112 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
In7ectable Composition A parenteral composition suitable for administration by :injection is prepared by stirring 1.5%
by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
Suspension An aquE:ous suspension is prepared for oral administration so ithat each 5 milliliters contain 100 milligrams o!: fine:Ly divided active ingredient, 100 milligrams o!: sodium cairboxymethyl cellulose, 5 milligrams o!: sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
The term 'consisting essentially of as used in the present ctisclosure is intended to have its customary meaning, namely, that all specified material and conditions ax-e ver~,r important in practicing the invention but; that unspecified materials and condi-tions are not: excluded so long as they do not prevent the benefits of the invention from being realized.
This application is a division of Canadian Applicatior..~lo. 54G 3~4, filed September 8, 1987.

Claims (70)

1. A compound having the formula:
wherein for the enantiomers and racemic mixtures n is 1;
A is -CH2CH2- provided that in Formula (I) A may also be -O-, or -S-;
B, C and D independently are selected from the group consisting of H, OH, OCOR5, OCH2CH2OR5, OR6, R6, CH2OR6, CH2COR7, Cl, F, Br, I, NH2, NHR~, NR8R9, SH, SR6, CH2SR6 and OC(S)N(CH3)2;
or two of B, C and D when on adjacent carbon atoms taken together form a fused benzo ring;

X and Y independently are selected from the group consisting of H, OCH3, Cl, F, Br, I, NO2, CF3, CN, SO2R10, and SO2CF3 or;
X and Y taken together with the benzene ring form ~
R and R1 independently are selected from the group consisting of H, and alkyl of 1 to 3 carbon atoms;
R2 is H; alkyl or 1 to 6 carbon atoms; CH2CF3;
alkenylmethyl of 3 to 6 carbon atoms;
hydroxyalkyl methyl of 2 to 5 carbon atoms;
cycloalkyl of 3 to 6 carbon atoms;
cyclopropylmethyl; cyclobutylmethyl, or phenyl- alkyl of 7 to 9 carbon atoms; or R2 can be taken together with R1 and the nitrogen to which they are attached to be 1-azetidinyl; 1- pyrrolidinyl optionally substituted at the 3-position by OH, alkyl of 1 to 3 carbon atoms, alkyoxy of 1 to 3 carbon atoms or alkanoyloxy of 1 to 3 carbon atoms; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms;
1-morpholino; 2,5-dihydro-1H-pyrrol-1-yl;
3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo [3.2.0] heptan-3-yl;
R3 is H, but if A is CH2, R3 is CHO, or COR11;
R4 is H, alkyl of 1 to 3 carbon atoms, -CH2OH, -OCH, COR12;
R5 is alkyl of 1 to 6 carbon atoms, phenyl, or mono-substituted phenyl;

R6, R8, R9, R10 and R13, are independently an alkyl group of 1 to 3 carbon atoms; and R7, R11 and R12 independently are selected from the group consisting of H, OH, OR13, NHR13, and NR2 13; or a stable N-oxide or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 wherein the compound has the formula:
and the definitions of A, B, C, n, X, Y, R, R1, R2, and R3 are as in Claim 1.

3. The compound of Claim 2 wherein A is -CH2-, -O-, or -S-.

4. The compound of Claim 2 wherein B is OH, OCOR5, OCH2CH2OR5, OR6, CH2OR6, or CH2COR7.

5. The compound of Claim 2 wherein C is H, OH, or OR6.

6. The compound of Claim 2 wherein R1 and R2 independently sire selected from H and alkyl of 1 to 3 carbon atoms, or are taken together with the nitrogen to which they are attached to form the group 1-azetidinyl, 1-pyrrolidinyl, or 1-piperidinyl.

7. The compound of Claim 2 wherein n is 1;
A is -CH2-, -O-, or -S-;
B i s OH , OCOR5, OR6, CH2OR6, CH2COR7;
C is H, OH, or OR6; and R1 and R2 independently are selected from H and alkyl of 1 to 3 carbon atoms, or are taken together with the nitrogen to which they are attached to form the group 1-azetidinyl, 1-pyrrolidinyl, or 1-piperidinyl.

8. The compound of Claim 7 wherein A is -CH2-.

9. The compound of Claim 1 which is traps-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride or its methansulfonic acid salt.

10. The compound of Claim 1 which is traps-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4-tetra-hydronaphth-1-yl]benzeneacetamide hydrochloride.

11. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-methyoxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

12. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-6-hydroxy-1,2,3,4-tetrahydonaphth-1-yl]benzeneacetamide hydrochloride.

13. The compound of Claim 1 which is (+) trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4,-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

14. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl]benzeneacetamide hydrochloride.

15. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

16. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-propionyloxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

17. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-benzoyloxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

18. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidine-1-yl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

19. The compound of Claim 1 which is trans-N-methyl-N-[3,4-dihydro-3-(pyrrolidine-1-yl)-2H-benzopyran-4-yl]benzeneacetamide hydrochloride.

20. The compound of Claim 1 which is trans-3-4-dichloro-N-methyl-N-[3,4-dihydro-8-methoxy-3-(pyrrolidin-1-yl)-2H-benzopyran-4-yl]benzeneacetamide hydrochloride.

21. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-5-(NN-dimethylthiocarbamoyloxy)-1,2,3,4-tetrahydronaphth-1-yl]benzeneacetamide hydrochloride.

22. The compound of Claim 1 which is trans-3,4-dichloro-N-methyl-N[2-(2,5-dihydro-1H-pyrrol-1-yl)-5-methyoxy-1,2,3,4-tetrahydronaphth-1-yl)benzeneacetamide hydrochloride.

23. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 1.

24. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 2.

25. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 3.

26. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 4.

27. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 5.

28. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 6.

29. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 7.

30. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 8.

31. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 9.

32. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 10.

33. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 11.

34. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 12.

35. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 13.

36. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 14.

37. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 15.

38. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 16.

39. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 17.

40. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 18.

41. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 19.

42. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 20.

43. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 21.

44. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 22.

45. The use of analgesically effective amount of a compound of Claim 1 to treat pain in a mammal.

46. The use of analgesically effective amount of a compound of Claim 2 to treat pain in a mammal.

47. The use of analgesically effective amount of a compound of Claim 3 to treat pain in a mammal.

48. The use of analgesically effective amount of a compound of Claim 4 to treat pain in a mammal.

49. The use of analgesically effective amount of a compound of Claim 5 to treat pain in a mammal.

50. The use of analgesically effective amount of a compound of Claim 6 to treat pain in a mammal.

64~

51. The use of analgesically effective amount of a compound of Claim 7 to treat pain in a mammal.

52. The use of analgesically effective amount of a compound of Claim 8 to treat pain in a mammal.

53. The use of analgesically effective amount of a compound of Claim 9 to treat pain in a mammal.

54. The use of analgesically effective amount of a compound of Claim 10 to treat pain in a mammal.

55. The use of analgesically effective amount of a compound of Claim 11 to treat pain in a mammal.

56. The use of analgesically effective amount of a compound of Claim 12 to treat pain in a mammal.

57. The use of analgesically effective amount of a compound of Claim 13 to treat pain in a mammal.

58. The use of analgesically effective amount of a compound of Claim 14 to treat pain in a mammal.

59. The use of analgesically effective amount of a compound of Claim 15 to treat pain in a mammal.

60. The use of analgesically effective amount of a compound of Claim 16 to treat pain in to a mammal.

61. The use of analgesically effective amount of compound of Claim 17 to treat pain in a mammal.

62. The use of analgesically effective amount of compound of Claim 18 to treat pain in a mammal.

63. The use of analgesically effective amount of compound of Claim 19 to treat pain in a mammal.

64. The use of analgesically effective amount of compound of Claim 20 to treat pain in a mammal.

65. The use of analgesically effective amount of compound of Claim 21 to treat pain in a mammal.

66. The use of analgesically effective amount of compound of Claim 22 to treat pain in a mammal.

67. The use of a diuretic amount of a compound of Claim 1 to increase the secretion of urine in a mammal.

68. The use of a diuretic amount of a compound of Claim 2 to increase the secretion of urine in a mammal.

69. The use of a diuretic amount of a compound of Claim 7 to increase the secretion of urine in a mammal.

70. A process fro preparing a compound of Claim 1 comprising:

66~

reacting a compound of the formula:
with (1) a carboxylic acid of the formula in the presence of dicyclohexylcarbodiimide;
(2) an acid chloride of the carboxylic acid in the presence of triethylamine, or aqueous sodium bicarbonate; or (3) an acyl imidazole prepared by reacting the carboxylic acid with carbonyl diimidazole.