New geminally disubstituted indenes are of general formula I ##STR1## wherein each of R.sup.1 and R.sup.2 is hydrogen or R.sup.1 and R.sup.2 together form a direct bond or an alkylene group --(CH.sub.2).sub.n --, in which n is an integer from 1 to 4, R.sup.3 is hydrogen, C.sub.1-3 -alkoxy or halogen, and each of R.sup.4 and R.sup.5 is hydrogen or C.sub.1-4 -lower alkyl, or R.sup.4 and R.sup.5 together form an alkylene group --(CH.sub.2).sub.m --, in which m is an integer from 3 to 6; and the corresponding amine oxides, quaternary ammonium compounds and salts with physiologically acceptable acids. The indenes find use in treating incontinence, as a mucous membrane decongestant, as a blood pressure reducing agent, as vasocostrictor or as an anti-reserpine agent. The indenes may be prepared by processes known per se involving PA1 (a) synthesing the side chain --CH(OH)CH.sub.2 NR.sup.4 R.sup.5 by a method known per se in an indenyl precursor of a formula I compound in which the side chain is incomplete or PA1 (b) introducing the double bond into an indanyl precursor of a formula I compound in which the double bond is absent or PA1 (c) releasing the terminal amino group in a precursor of a formula I compound in which the terminal amino group is protected.

FIELD OF THE INVENTION 
This invention relates to new geminally disubstituted indenes, to methods 
for their preparation, to pharmaceutical compositions containing them and 
to their use in therapy. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides geminally disubstituted indenes 
characterised in that they are of the general formula (I) 
##STR2## 
wherein each of R.sup.1 and R.sup.2 is hydrogen or R.sup.1 and R.sup.2 
together form a direct bond or an alkylene group --(CH.sub.2).sub.n --, in 
which n is an integer from 1 to 4, R.sup.3 is hydrogen, C.sub.1-3 -alkoxy 
or halogen, and each of R.sup.4 and R.sup.5 is hydrogen or C.sub.1-4 
-lower alkyl, or R.sup.4 and R.sup.5 together form an alkylene group 
--(CH.sub.2).sub.m --, in which m is an integer from 3 to 6; and the 
corresponding amine oxides, quaternary ammonium compounds and salts with 
physiologically acceptable acids. 
The compounds of formula (I) contain an asymmetric carbon atom, and the 
invention includes racemic and other mixtures of the optical isomers as 
well as the optically active isomers themselves. The more active isomer 
can be separated in conventional manner e.g. by fractional crystallization 
of diastereoisomeric salts. 
In the compounds of the invention prepared compounds are those in which 
R.sup.1 and R.sup.2 are each H or those where R.sup.1 and R.sup.2 together 
represent --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, those where R.sup.3 
is H and those where R.sup.4 is H and R.sup.5 is H or CH.sub.3. 
When R.sup.3 is alkoxy or halogen, the substituent may be for example, 
methoxy or ethoxy or chloro or bromo, particularly at the 5-position on 
the indene ring. 
The compounds of the invention may be presented in free base form or as 
amino oxides, quaternary ammonium compounds or salts with pharmaceutically 
acceptable acids. The acid may be inorganic e.g. hydrochloric, sulphuric 
or phosphoric acid or organic e.g. acetic, oxalic, fumaric or tartaric 
acids. Quaternary ammonium compounds of interest include those which are 
triorgano ammonium halides or sulphates e.g. triethylammonium chlorides. 
Unless the context requires otherwise, references in this specification to 
the compounds of the invention includes a reference to their amine oxides, 
quaternary ammonium salts and salts with pharmaceutically acceptable 
acids. 
The new compounds according to the invention exhibit interesting 
pharmacodynamical properties, indicating their utility as drugs. In 
particular, the compounds present a pronounced sympatomimetic effect, 
illustrated by the effect on rat vas deferens, a screening test for 
noradrenaline like activity. Tests on isolated urethra strips of cat have 
shown that a representative example of the compounds of the invention is 
considerably more active on this organ than noradrenaline, while at the 
same time exhibiting a clearly reduced hypertensive effect on 
anaesthetized cat compared to noradrenaline. The selective effect on 
urethra has also been illustrated by similar tests on aortic strips of 
rabbit. 
These and other properties make the compounds of the invention useful as 
drugs against stress incontinence in women, and the compounds are also of 
interest as mucous membrane decongestants, as blood pressure reducing 
agents, and as vasoconstrictors (together with local anaesthetics). Some 
of the compounds also have anti-reserpine effect. 
Various methods are available for the preparation of the compounds of 
formula I and normally involve 
(a) synthesising the side chain --CH(OH)CH.sub.2 NR.sup.4 R.sup.5 by a 
method known per se in an indenyl precursor of a formula I compound in 
which the side chain is incomplete or 
(b) introducing the double bond into an indenyl precursor of a formula I 
compound in which the double bond is absent or 
(c) releasing the terminal amino group in a precursor of a formula I 
compound in which the terminal amino group is protected. 
More specifically, the formula I compounds can be prepared by one of the 
synthesis described below in which the symbol "Ring" denotes the ring 
system. 
##STR3## 
where R.sup.1, R.sup.2 and R.sup.3 are as defined above. 
(a) Reacting a compound of the general formula (II) 
##STR4## 
where X is a reactive leaving group, with an amine (III) 
##STR5## 
Preferred leaving groups are halogen or esterified hydroxyl groups such as 
arylsulphonic ester groups e.g. as tosyl and phosphonic ester groups. 
This reaction (a) can also be carried out using a protected amine instead 
of the amine (III), in which case the amino protecting group is removed 
after the reaction. Suitable protected amines are carbamic esters (such as 
HN(R.sup.6)COOAlkyl) and imides, such as succinimide, phthalimide, and the 
like. 
(b) Reducing a compound of the general formula (IV) 
EQU Ring--CO--Z (IV) 
wherein Z is an aminomethyl group 
##STR6## 
or a group that can be reduced to this aminomethyl group under conditions 
under which the --CO--group is reduced to the 
##STR7## 
This reduction can also be carried out when the amino group is blocked by 
an amino protecting group, which is removed after the reduction. 
Preferred reducing agents are complex metal hydrides such as sodium 
borohydride and lithium aluminium hydride, and the reaction is preferably 
carried out in an inert solvent. 
Examples of suitable groups Z, which can be reduced to the aminomethyl 
group --CH.sub.2 NR.sup.4,R.sup.5 under the reduction conditions, are 
carbamic ester derivatives such as --CH.sub.2 NR.sup.6, COOAlkyl (which 
are reduced to amines --CH.sub.2 NR.sup.6, CH.sub.3), dicarboxylic 
acidamidomethyl derivatives 
##STR8## 
wherein l is an integer from 2 to 4 (which are reduced to tert.amines 
--CH.sub.2 --N(CH.sub.2).sub.1+2), amide groups such as --CO--NR.sup.4 
R.sup.5 (in which the --CO--group is reduced to --CH.sub.2 --), 
azidomethyl groups such as --CH.sub.2 --N.sub.3 (which are reduced to 
--CH.sub.2 --NH.sub.2), diazomethyl groups such as --CHN.sub.2 (which are 
reduced to --CH.sub.2 NH.sub.2), and nitromethyl groups --CH.sub.2 
NO.sub.2 (which are reduced to --CH.sub.2 NH.sub.2). 
(c) Reducing a compound of the formula (V) 
##STR9## 
wherein Y is a group which can be converted to the aminomethyl group 
--CH.sub.2 NR.sup.4,R.sup.5 by reduction. Examples of suitable groups Y 
are amide groups (--CO--NR.sup.4,R.sup.5), a cyano group (--CN), an 
azidomethyl group (--CH.sub.2 N.sub.3), iminomethyl groups 
(--CH.dbd.NR.sup.6), an oximinomethyl group (--CH.dbd.NOH), 
hydrazonomethyl groups (--CH.dbd.N--NH.sub.2, which may be substituted 
with e.g. alkyl), the nitromethyl group (--CH.sub.2 --NO.sub.2), and the 
like. 
This reaction can also be carried out by reducing a compound of formula 
(V), in which the hydroxyl group is protected e.g. by esterification or 
silylation. The hydroxy protecting group is removed either during the 
reduction or afterwards, e.g. by hydrolysis. 
The reductions according to syntheses (b) and (c) can be carried out by 
using a great variety of reducing agents and reaction conditions, it being 
well within the competence of chemists experienced in organic synthesis to 
choose suitable reducing agents and conditions depending on the nature of 
the groups to be reduced. The reduction can, for example, be carried out 
by using a complex metal hydride such as sodium borohydride or lithium 
aluminiumhydride in an inert solvent. Alternatively, catalytically 
activated hydrogen can be used, the reaction being carried out in an inert 
solvent and in the presence of a catalyst such as a platinum, a palladium 
or a nickel catalyst. 
(d) Oxidizing a compound of the formula (VI) 
##STR10## 
to form a compound of formula (VII) or (VIII) 
##STR11## 
which is then converted into a compound of formula (I) by dehydration or 
rearrangement (heating or treatment with a catalysing acid). 
This reaction can also be carried out using a compound corresponding to 
formula (VI), in which the amino group is protected, acyl groups being 
suitable amino protecting groups. In this case the amino protecting group 
is removed after the reaction. 
Preferred oxidizing agents are peroxy acids such as peracetic acid, 
perbenzoic acid or chloroperbenzoic acid, permanganates, osmium tetroxide, 
and the like. 
(e) Reacting an epoxide of formula (IX) 
##STR12## 
with an amine of formula (III) 
##STR13## 
(f) Removing the amino protecting group from a compound of formula (X) 
##STR14## 
wherein R.sup.4' and R.sup.5' have the same meaning as R.sup.4 and R.sup.5 
or signify an amino protecting group, at least one of R.sup.4' and 
R.sup.5' being such as amino protecting group. 
A great variety of amino protecting groups are available to chemists 
experienced in organic synthesis. These groups can, for example, be split 
off by hydrolysis (acid or alkaline), by hydrogenation, by hydrazinolysis, 
etc., depending on the nature of the group. 
Primary and secondary amines of formula (I) can be converted into the 
corresponding secondary or tertiary amines by alkylation, e.g. by 
treatment with an alkylating agent such as an alkyl halide. Tertiary 
amines can similarly be converted into the corresponding quaternary 
ammonium compounds, especially lower alkyl ammonium compounds. The 
alkylation can also be carried out by acylation of the primary or 
secondary amine, whereupon the acyl group is reduced to the corresponding 
alkyl group in analogy with method (b) above. 
The amines of formula (I) can, if desired, be converted into the 
corresponding salts with physiologically acceptable acids, and tertiary 
amines of formula (I) can be converted into the corresponding amine oxides 
by treatment with a suitable oxidation agent, for example a peroxide such 
as hydrogen peroxide. Tertiary amines of formula (I) can be dealkylated to 
the corresponding secondary amines, for example as described in the 
following Examples. 
Where the starting materials necessary for preparing the compounds 
according to the invention by the above described methods are not 
previously reported in the literature or described in the following 
Examples, they can be prepared by methods analogous to those used to 
prepare known starting materials and/or in analogy with the following 
Examples. 
The compounds of the invention can be formulated into pharmaceutical 
compositions together with pharmaceutically acceptable carriers, and the 
invention includes such compositions, which may be in the form of e.g. 
tablets or solutions, preferably in unit dose form. The invention also 
comprises the use of the compounds of the invention in treating stress 
incontinence, as mucous membrane decongestants, as blood pressure reducing 
agents, as vasoconstrictors and as anti-reserpine agents and methods of 
treating the above mentioned conditions by administering a therapeutically 
effective amount of a compound of formula (I) to a host in need of such 
treatment. The required dosage varies depending on the needs and 
requirements in the specific situation and on the specific substance used. 
For adults, a daily dosage of 0.1 mg to 100 mg is usually sufficient.

The invention is further illustrated in the following Examples. 
EXAMPLE 1 
3-Bromo-1,1-dialkylindenes (starting materials) 
The 1,1-dialkylindene (1 mole) in dichloromethane (100 ml) is treated 
dropwise with stirring at 5.degree. C. with a solution of bromine (1 mole) 
in dichloromethane (500 ml). After stirring for an additional 30 minutes, 
the solvent is evaporated under reduced pressure and the crude 
2,3-dibromo-1,1-dialkylindene is dissolved in tetrahydrofuran (1100 ml) 
and treated at -20.degree. C. with potassium tert.-butoxide (112 g). After 
completed addition, the mixture is allowed to come to about 20.degree. C., 
diluted with water (3 liters) and extracted with diethyl ether 
(3.times.400 ml). The ether solution is washed with water and dried with 
sodium sulphate. Evaporation of the ether and distillation of the 
remaining oil gives the desired 3-bromo-1,1-dialkylindene as an oil of 
fairly low stability which are immediately used for the subsequent steps. 
The following compounds were prepared: 
3'-Bromospiro(cyclopentane-1,1'-indene), b.p. 120.degree. C./0.5 torr. 
3'-Bromo-5'-methoxyspiro(cyclopentane-1,1'-indene), b.p. 
130.degree.-132.degree. C./0.1 torr. 
3-Bromo-1,1-dimethylindene, unstable oil which is used without 
distillation. 
3'-Bromospiro(cyclohexane-1,1'-indene), unstable oil which is used without 
distillation. 
3'Bromospiro(cyclopropane-1,1'-indene), b.p. 127.degree.-128.degree. C./0.5 
torr. 
EXAMPLE 2 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
(a) 1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
3'-Bromospiro(cyclopentane-1,1'-indene) (23 g) is dissolved in 
tetrahydrofuran (200 ml) and cooled to -70.degree. C. While stirring under 
nitrogen, n-butyllithium (75 ml of a 2 M solution in hexane) is added 
followed after 30 minutes by acetaldehyde (14 g) in one portion. Stirring 
and cooling is maintained for 30 minutes whereupon the mixture is allowed 
to come to about 20.degree. C. and is kept there for 2 hours. Water (600 
ml) is then added and the solution is extracted three times with diethyl 
ether. The ether extracts are washed, dried over sodium sulphate and the 
ether is distilled off. Distillation of the residual oil gives the title 
alcohol, b.p. 139.degree. C./0.4 torr. 
(b) 3'-Acetylspiro(cyclopentane-1,1'-indene) 
The alcohol from step (a) (14.3 g) is stirred for 2 days at about 
20.degree. C. with manganese dioxide (150 g) in light petroleum ether 
(b.p. 40.degree.-60.degree. C.; 450 ml). Solid material is filtered off 
and the filtrate concentrated. Distillation of the residual oil gives the 
title ketone, b.p. 148.degree.-150.degree. C./0.5 torr. 
(c) 3'-(.alpha.-Bromoacetyl)spiro(cyclopentane-1,1'-indene) 
Pyrrolidone hydrotribromide [(pyrrolidone).sub.3 HBr.sub.3 ] is added at 
about 20.degree. C. to the ketone from step (b) (12 g) in tetrahydrofuran 
(1500 ml) containing 10 drops of concentrated sulphuric acid. The mixture 
is stirred for 24 hours. Precipitated salts are removed by filtration and 
the filtrate is concentrated to a small volume. Water (200 ml) is added 
and the mixture is extracted three times with diethyl ether. After drying 
the solvent is evaporated, yielding a semi-crystalline residue. 
Crystallization from methanol gives the pure bromoacetyl title compound, 
m.p. 75.degree.-77.degree. C. 
(d) N,N-dimethyl-2-oxo-2-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethylamine 
The bromoacetyl compound from step (c) (7.0 g) is added to a solution of 
dimethylamine (19 g) in methanol (100 ml) and kept for 2 hours. After 
concentration of the solution, the residual oily material is treated with 
water and diethyl ether. The ether extract is washed and dried. 
Evaporation of the solvent gives the title ketoamine as a colourless oil. 
A sample in diethyl ether is treated with oxalic acid, giving the 
crystalline hydrogen oxalate, m.p. 215.degree. C. 
(e) 2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
The crude amino ketone from step (d) (2.0 g) in ethanol (50 ml) is treated 
for 2 hours at about 20.degree. C. with sodium borohydride (2.0 g). Water 
is added and the amine is extracted into diethyl ether. The ether solution 
is dried, concentrated to about 100 ml, and then added to a solution of 
oxalic acid (1.5 g) in ether (500 ml). The precipitated salt is collected 
and crystallized from acetonitrile. M.p. 133.degree.-134.degree. C. 
The following compounds were prepared by the procedure described in steps 
(d) and (e) above, using the corresponding amines: 
2-tert.-Butylamino-1-[spirocyclopentane-1,1'-indene)-3'-yl]-ethanol (the 
reaction between tert.-butylamine and bromo-ketone is carried out at 
120.degree. C. for 2 days). 
Hydrochloride, m.p. 292.degree. C. 
2-Pyrrolidino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen 
oxalate, m.p. 167.degree. C. 
2-Piperidino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen 
oxalate, m.p. 179.5.degree. C. 
EXAMPLE 3 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
3'-Bromoacetylspiro(cyclopentane-1,1'-indene) (7.5 g) in ethanol (150 ml) 
is stirred at about 20.degree. C. with sodium borohydride (3.0 g) for 15 
minutes. The solution is diluted with water and extracted three times with 
diethyl ether. The extracts are dried and the solvent removed, giving 
crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol. This 
bromohydrine is dissolved in dioxane (75 ml) and dimethylamine (10 g) is 
added. The solution is heated in an autoclave at 90.degree. C. for 2 
hours. Evaporation of excess of dimethylamine and solvent gives an oily 
residue, which is treated with 2 N sodium hydroxide solution. Extraction 
with dichloromethane, drying of the extract and evaporation of the solvent 
gives the title amine as a colourless oil, which on treatment with oxalic 
acid in acetonitrile solution is converted to the crystalline hydrogen 
oxalate; m.p. 133.degree.-134.degree. C. after crystallization from 
acetonitrile. 
The following compounds were prepared in an analogous manner, using the 
corresponding amines: 
2-Pyrrolidino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen 
oxalate, m.p. 167.degree. C. 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, free base, 
m.p. 134.degree. C. 
2-Piperidino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen 
oxalate, m.p. 179.5.degree. C. 
2-Ethylamino-1-[spiro(cyclopentane-1,1'-indene-3'-yl]ethanol, 
hydrochloride, m.p. 227.degree. C. 
EXAMPLE 4 
2-Amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
Crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (7.3 g; 
prepared as described in Example 3) in dimethylformamide (100 g) is 
stirred at 40.degree. C. for 4 hours with potassium phthalimide (5.0 g), 
then diluted with water and extracted three times with chloroform. The 
combined extracts are dried and evaporated to dryness. The crude 
2-phthalimido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is added to 
ethanol (100 ml) containing hydrazine hydrate (1.5 g). The reaction 
mixture is stirred under reflux for 4 hours, concentrated hydrochloric 
acid (2 ml) is added, and the mixture is heated for 15 minutes. The 
solution is cooled, filtered from the solid precipitate and concentrated 
to a small volume. The concentrate is made alkaline with 2 N sodium 
hydroxide solution and repeatedly extracted with diethyl ether. 
Evaporation of the ether and crystallization of the residual product from 
cyclohexane gives 
2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 
76.degree.-78.degree. C. 
EXAMPLE 5 
2-Pyrrolidino-1-[spiro)cyclopentane-1,1'-indene)-3'-yl]-ethanol 
3'-Bromoacetylspiro(cyclopentane-1,1'-indene) (5.8 g) in dimethylformamide 
(50 ml) is stirred at 40.degree. C. for 4 hours with potassium succinimide 
(3.0 g). Water (300 ml) is added and the crude 
N-[2-oxo-2-spiro(cyclopentane-1,1'-indene)-3'-ylethyl]-imide is extracted 
with diethyl ether. The extract is carefully dried with sodium sulphate, 
concentrated to about 100 ml and added dropwise to a boiling solution of 
lithium aluminium hydride (5.0 g) in diethyl ether (250 ml) under 
nitrogen. The mixture is refluxed overnight and the excess of hydride is 
decomposed with a slight excess of saturated sodium sulphate solution. The 
inorganic salts are filtered off and washed with ether and the filtrate is 
dried. The solution is concentrated to about 200 ml and added to oxalic 
acid (2.0 g) in diethyl ether. The hydrogen oxalate precipitates and is 
recrystallized from a mixture of isopropyl alcohol/diisopropyl ether; m.p. 
167.degree. C. 
EXAMPLE 6 
3'-Spiro(cyclopentane-1,1'-indene)carbaldehyde 
To 3'-bromospiro(cyclopentane-1,1'-indene) (7.5 g) in tetrahydrofuran, (500 
ml) is added at -70.degree. C. a solution of n-butyllithium in hexane (200 
ml of a 1.8 M solution) in two portions. The temperature is kept at 
-70.degree. C. for a further 30 minutes. Dimethylformamide (73 g) is then 
added and the mixture is allowed to come to about 20.degree. C. After 3 
hours sulphuric acid (400 ml; 1 M) and diethyl ether (200 ml) are added. 
The ether phase is separated, washed with saturated sodium chloride 
solution and dried over sodium sulphate. Evaporation of the ether and 
distillation gives the title aldehyde; b.p. 130.degree.-135.degree. C./0.1 
torr. 
In the same manner, the following compounds are prepared from the 
corresponding bromoindenes: 
Spiro(cyclohexane-1,1'-indene)-3'-carbaldehyde; b.p. 
125.degree.-130.degree. C./0.1 torr. 
1,1-Dimethylindene-3-carbaldehyde; b.p. 82.degree.-87.degree. C./0.1 torr. 
5'-Methoxyspiro(cyclopentane-1,1'-indene)-3'-carbaldehyde; b.p. 
148.degree.-150.degree. C./0.1 torr. 
Spiro(cyclopropane-1,1'-indene)-3'-carbaldehyde; solidifies after 
evaporation of the ether and is crystallized from cyclohexane without 
distillation; m.p. 112.5.degree. C. 
EXAMPLE 7 
2-Amino-1-[5'-methoxyspiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol 
5'-Methoxyspiro(cyclopentane-1,1'-indene)-3'-carbaldehyde (4.4 g) is added 
to anhydrous aluminium chloride (0.1 g) in dichloromethane (25 ml). 
Trimethylsilyl cyanide (2.1 g) is added dropwise to the stirred mixture at 
about 20.degree. C. and the mixture is stirred for 2 hours. The solvent is 
then removed under reduced pressure at about 25.degree. C. bath 
temperature. The remaining oil is dissolved in anhydrous diethyl ether (50 
ml) and slowly added to lithium aluminium hydride (3.5 g) in diethyl ether 
(200 ml). The mixture is stirred overnight and decomposed by careful 
addition of saturated, aqueous sodium sulphate solution (30 ml). The solid 
precipitate is removed by filtration and washed with diethyl ether. The 
combined filtrate and washings are concentrated to dryness and the solid 
is crystallized from diisopropyl ether; m.p. 118.degree. C. The hydrogen 
fumarate is obtained from the base and an excess of fumaric acid in 
ethanol; m.p. 182.degree. C. 
In the same manner, the following compounds were prepared from the 
corresponding aldehydes: 
2-Amino-1-[spiro(cyclohexane-1,1'-indene)-3'-yl]ethanol; m.p. 117.degree. 
C. Hydrogen fumarate, m.p. 174.degree. C. 
2-Amino-1-(1,1-dimethylindene-3-yl)ethanol; m.p. 93.degree. C. Neutral 
fumarate, m.p. 196.degree. C. 
2-Amino-1-[spiro(cyclopropane-1,1'-indene)-3'-yl]ethanol; m.p. 
133.degree.-134.degree. C. Hydrochloride, m.p. 229.degree. C. 
2-Amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol; m.p. 
76.degree.-78.degree. C. Hydrochloride, m.p. 169.degree.-172.degree. C. 
EXAMPLE 8 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
N-Methyl-[spiro(cyclopentane-1,1'-indan)-3'-yliden]acetamide (9.6 g; 
Swedish Pat. No. 7203905-0) is dissolved in dichloromethane (200 ml) and 
added to sodium bicarbonate solution (30 ml; 0.5 M). The solution is 
treated with m-chloroperbenzoic acid (13.76 g of a 50% product) in small 
portions with stirring at about 20.degree. C. After stirring for an 
additional 2 hours, the solution is washed with saturated sodium carbonate 
solution and water and dried with sodium sulphate. The solvent is 
evaporated and the remaining oil is dissolved in tetrahydrofuran (100 ml). 
Perchloric acid (70%, 10 drops) is added and the mixture is kept at about 
20.degree. C. for 1.5 hour. Evaporation of the solvent in vacuo gives the 
crude 
.alpha.-hydroxy-N-methyl-[spiro(cyclopentane-1,1'-indene)-3'-yl]acetamide 
as a viscous oil. A sample is triturated with diisopropyl ether and the 
crystalline product obtained is recrystallized from this solvent. A 
colourless product is obtained, melting at 136.degree.-138.degree. C. The 
crude hydroxyamide is dissolved in anhydrous diethyl ether (200 ml) and 
added dropwise to a suspension of lithium aluminium hydride (30 g) in 
anhydrous ether (500 ml). The mixture is stirred at room temperature for 5 
days and the excess of hydride is destroyed with ethyl acetate, followed 
by saturated aqueous sodium sulphate solution. The ether phase is washed 
with water and dried. Evaporation of the solvent gives the crude title 
compound, which after crystallization from diisopropyl ether melts at 
134.degree. C. 
In an analogous manner, the following compounds are prepared from the 
corresponding acetamide derivatives: 
2-Amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol; m.p. 
76.degree.-78.degree. C. (from cyclohexane). 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, oil. The 
hydrogen oxalate is prepared by adding an excess of oxalic acid, dissolved 
in acetonitrile, to the amine in acetonitrile, m.p. 
133.degree.-134.degree. C. 
2-Methylamino-1-[5'-chlorospiro(cyclopentane-1,1'-indene)-3'-yl]ethanol; 
m.p. 120.degree. C. 
2-Amino-1-(1,1-dimethylindene-3-yl)ethanol, oil. The fumarate, m.p. 
196.degree. C., is obtained from the base and fumaric acid in 
acetonitrile. 
2-Amino-1-[spiro(cyclohexane-1,1'-indene)-3'-yl]ethanol, oil. The hydrogen 
fumarate is obtained from the amine and fumaric acid in ethanol; m.p. 
174.degree. C. 
EXAMPLE 9 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
N-Methyl-2-[spiro(cyclopentane-1,1'-indene)-3'-yliden]ethylamine (8.1 g; 
Swedish Pat. No. 7203905-0) in diethyl ether (100 ml) is treated with 
trifluoroacetic anhydride (8 ml) while being stirred with powdered 
anhydrous sodium carbonate (6 g). The solid is filtered off and the 
solvent is evaporated from the filtrate. The crude 
N-trifluoroacetyl-N-methylspiro(cyclopentane-1,1'-indan)-3'-ylideneethylam 
ine is dissolved in dichloromethane (100 ml), added to sodium bicarbonate 
solution (40 ml; 0.5 M) and treated in portions with m-chloroperbenzoic 
acid (50%; 3.4 g) with stirring at about 20.degree. C. After stirring for 
2 hours, the solution is washed with saturated sodium carbonate solution 
and water, and dried with sodium sulphate. After filtration, the solvent 
is evaporated. The crude epoxy compound is dissolved in tetrahydrofuran 
(100 ml), and treated with perchloric acid (10 drops) at room temperature 
for 2 hours. After evaporation of the solvent the remaining crude 
2-(N-methyltrifluoroacetamido)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-e 
thanol is dissolved in a mixture of methanol (20 ml), water (50 ml) and 
potassium carbonate (10 g) and stirred overnight. The methanol is 
evaporated under reduced pressure and the free amine is extracted into 
dichloromethane. After drying with sodium sulphate the solvent is 
evaporated. The title compound is crystallized from diisopropyl ether; 
m.p. 134.degree. C. 
In an analogous manner, the following compounds are prepared from the 
corresponding indanylidenethylamines: 
2-Dimethylamino-1-[5'-chlorospiro(cyclopentane-1,1'-indene)-3'-yl]ethanol; 
m.p. 75.degree. C. 
2-Methylamino-1-(1,1-dimethylindene-3'-yl)ethanol; m.p. 120.degree. C. 
EXAMPLE 10 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol 
(a) N,N-Dimethyl-2-oxo-2-[spiro(cyclopentane-1,1'-indene)-3'-yl]acetamide 
Butyllithium in hexane (13 ml of a 2 M solution) is added to 
3'-bromospiro(cyclopentane-1,1'-indene) (5.0 g) in tetrahydrofuran at 
-70.degree. C. After 10 minutes a solution of tetramethyloxyamide (5.8 g) 
in tetrahydrofuran (50 ml) is rapidly added. The mixture is stirred and 
allowed to come to about 20.degree. C. After 2 hours, it is poured into a 
mixture of 50 ml 1 M hydrochloric acid and diethyl ether (100 ml) and the 
ether layer is separated. The aqueous phase is extracted twice with 
diethyl ether and the combined ether solutions are washed and dried. 
Evaporation of the solvent and crystallization from diisopropylether of 
the crude product obtained gives the colourless title compound; m.p. 
119.degree.-121.degree. C. 
(b) 2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol 
The oxoamide from step (a) (2.69) in anhydrous diethyl ether (200 ml) is 
stirred for 24 hours at about 20.degree. C. with lithium aluminium hydride 
(2 g) in diethyl ether (100 ml). The excess of hydride is destroyed with 
saturated aqueous sodium sulphate solution. The ether phase is separated, 
washed, dried and concentrated to an oil which contains 
2-dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
contaminated by much of the corresponding indanyl analogue. The two 
compounds are separated by chromatography on aluminium oxide with diethyl 
ether/methanol as eluent. The product so obtained is converted into the 
hydrogen oxalate of the title compound in acetonitrile solution. M.p. 
133.degree.-134.degree. C. 
EXAMPLE 11 
2-tert.-Butylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
A solution of n-butyllithium in hexane (6 ml of a 2 M solution) is added 
dropwise under nitrogen to a stirred suspension of powdered 
trimethylsulphonium iodide in anhydrous tetrahydrofuran (30 ml) at 
0.degree. C. After stirring for 5 minutes, a solution of 
spiro(cyclopentane-1,1'-indene)-3'-carbaldehyde (2.0 g) in tetrahydrofuran 
(25 ml) is added. Stirring is continued at 0.degree. C. for 1 hour, 
whereupon tert.-butylamine (1.0 g) is added and the mixture is allowed to 
come to about 20.degree. C. After 24 hours, water (200 ml) is added and 
the solution is extracted three times with diethyl ether. The combined 
extracts are washed, dried and concentrated to about 50 ml. An excess of 
hydrogen chloride is added and the precipitated salt is collected and 
crystallized from ethanol; m.p. 292.degree. C. 
In an analogous manner, the following compounds are prepared from the 
corresponding aldehydes, amines and acids. 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol, 
hydrochloride; m.p. 217.degree. C. 
2-Amino-1-[spiro(cyclopropane-1,1'-indene)-3'-yl]ethanol, free base; m.p. 
133.degree.-134.degree. C. 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen 
oxalate; m.p. 134.degree. C. 
2-Amino-1-[spiro(cyclohexane-1,1'-indene)-3'-yl]ethanol, hydrogen fumarate; 
m.p. 117.degree. C. 
EXAMPLE 12 
2-Isopropylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
2-Amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (5.0 g) is 
refluxed with acetone (50 ml) for 12 hours and the excess of acetone is 
removed under reduced pressure. The crude N-isopropylidene derivative thus 
obtained is dissolved in diethyl ether (50 ml) and slowly added to a 
stirred mixture of lithium aluminium hydride (2.0 g) and diethyl ether 
(200 ml). After stirring for about 12 hours, the excess of hydride is 
decomposed with aqueous sodium sulphate solution. The ether phase is 
separated, dried with sodium sulphate and concentrated to give a viscous 
yellowish oil. This oil is dissolved in acetonitrile (100 ml) and added to 
a hot solution of oxalic acid (2.10 g) in 500 ml of acetonitrile. On 
cooling the solution forms colourless crystals of the hydrogen oxalate of 
the title compound. The crystals are collected and recrystallized from 
acetonitrile; m.p. 180.degree. C. 
EXAMPLE 13 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl-ethanol 
Ethyl chloroformate (2.06 g) is added dropwise at about 7.degree. C. to a 
stirred mixture of 
2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (3.35 g) in 
chloroform (50 ml) and sodium hydroxide (0.9 g) in water (20 ml). After 2 
hours, the chloroform phase is separated and the aqueous phase is 
extracted twice with chloroform. The combined chloroform solutions are 
dried and concentrated under reduced pressure. The crude 
2-ethoxycarbonylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
thus obtained is dissolved in tetrahydrofuran (50 ml) and added dropwise 
to lithium aluminium hydride (1.8 g) in tetrahydrofuran (150 ml). After 
refluxing for 3 hours, the mixture is cooled and decomposed with a slight 
excess of saturated sodium sulphate solution. The solid precipitate is 
filtered off and washed with tetrahydrofuran. The combined filtrate and 
washings are dried and the solvent is removed, finally under reduced 
pressure. The residual oil crystallizes on scratching. Crystallization 
from diisopropyl ether gives the title compound; m.p. 134.degree. C. 
2-Ethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is similarly 
obtained when using acetic anhydride instead of ethyl chloroformate and 
reduction of the crude N-acetyl derivative. The free base is obtained as 
an oil, which is converted to the hydrochloride by treatment with hydrogen 
chloride in diethyl ether, m.p. 227.degree. C. after crystallization from 
isopropyl alcohol. An identical product is obtained by reduction of crude 
2-acetamido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol acetate 
obtained by the treatment of 
2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol with 
acetylchloride in diethyl ether containing an excess of triethylamine, 
removal of the precipitated triethylamine hydrochloride by filtration and 
evaporation of the filtrate. 
EXAMPLE 14 
2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
Phosgene (1 g) is added to 
dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (2.9 g) in 
benzene (25 ml). The mixture is stirred at room temperature for 30 minutes 
and then under reflux for 2 hours. Evaporation of the solvent under 
reduced pressure gives an oil which crystallizes. Recrystallization from 
diisopropyl ether gives a pure product, m.p. 75.degree.-77.degree. C. This 
compound, 5-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (2 g), is 
refluxed for 2 hours with a solution of potassium hydroxide (5 g) in 
ethanol (50 ml) and water (10 ml). Most of the solvent is evaporated under 
reduced pressure, water (25 ml) is added and the amine is extracted into 
chloroform. Drying and evaporation of the solvent gives the crystalline 
title compound, which after recrystallization from diisopropyl ether melts 
at 133.degree.-134.degree. C. 
EXAMPLE 15 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
Ethyl chloroformate (0.7 g) and sodium hydroxide (0.3 g) dissolved in water 
(10 ml) are added to 
2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol (1.3 g) in 
chloroform (25 ml). The mixture is stirred vigorously for 2 hours at about 
10.degree. C. The chloroform layer is separated, washed with water and 
dried. The solvent is removed in vacuo and the residual crude 
2-(N-ethoxycarbonyl-N-methylamino)-1-[spiro(cyclopentane-1,1'-indene)-3'-y 
l]ethanol is dissolved in tetrahydrofuran (75 ml) and added to lithium 
aluminium hydride (2.0 g) in tetrahydrofuran (25 ml). The mixture is 
refluxed for 3 hours, and the excess of hydride is destroyed with a slight 
excess of saturated aqueous sodium sulphate solution. The inorganic salt 
precipitate is filtered off and washed with tetrahydrofuran. The combined 
filtrate and washings are dried over sodium sulphate and the solvent is 
removed under reduced pressure. The crude title compound is dissolved in 
acetonitrile and treated with a slight excess of oxalic acid dissolved in 
acetonitrile. The slowly depositing hydrogen oxalate is collected by 
filtration and recrystallization from acetonitrile; m.p. 
133.degree.-134.degree. C. 
EXAMPLE 16 
2-Trimethylammonio-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
Methyl iodide (8 g) is added to 
2-dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (1.3 g) 
in diethyl ether (100 ml). The mixture is kept for 24 hours and the 
precipitated methiodide is collected by filtration; m.p. 
115.degree.-120.degree. C. (decomposition). 
EXAMPLE 17 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol-N-oxide 
2-Dimethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (5.4 g), 
hydrogen peroxide (2.3 g, 30%) and methanol (10 ml) are mixed and kept for 
2 days at about 20.degree. C. The solution is evaporated to dryness and 
the solid is dried in vacuo over phosphorous pentoxide to remove water. 
After crystallization from anhydrous acetone/diisopropyl ether the 
crystals of the title compound melted at 151.degree. C. 
EXAMPLE 18 
Resolution of 
2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
(.+-.)-2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (12 
g) is dissolved in ethanol (75 ml) and added to a solution of 
D(-)-tartaric acid (15 g) in water (300 ml) at about 20.degree. C. The 
mixture is concentrated at reduced pressure to 200 ml and kept overnight 
at 4.degree. C. The crystalline precipitate is collected and 
recrystallised from water until constant specific rotation is obtained, 
which requires 3 to 5 recrystallizations. The 
(-)-2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol 
(-)-hydrogen tartrate melts at 79.degree.-83.degree. C.; 
[.alpha.].sub.546.sup.20 =-32.6.degree. (c=1 in water). 
The original mother liquor and the liquors from the first two 
recrystallizations are combined and made alkaline with 2 N sodium 
hydroxide solution. The free base is extracted into dichloromethane, and 
the extract is washed and dried. After evaporation of the solvent the 
crude base in ethanol (300 ml) is treated with L(+)-tartaric acid (5.6 g) 
in water (300 ml) as described above for the preparation of the (-)salt. 
The (+)-2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'yl]ethanol 
(+)-hydrogen tartrate melts at 85.degree.-90.degree. C.; 
[.alpha.].sub.546.sup.20 =+34.4.degree. (c=1 in water). 
The pharmacological properties of the various compounds of the invention 
were demonstrated by the following test procedure. 
Effect on Rat Isolated Vas Deferens 
Male albino rats weighing 250-350 g were anaesthetized with diethyl ether 
and then decapitated. The vas deferens was removed, freed from mesenteric 
attachments and then suspended in Kreb's bicarbonate solution (Hukovic, 
1961). Threads were attached to both ends of the organ. The distal part 
was tied to a fixed pin in the organ bath and the proximal part to a force 
displacement transducer connected to a recording system. The organ bath 
had a volume of 10 ml and was surrounded by a waterjacket of 31.degree. 
C., and the bath was gassed with 93.5% O.sub.2 and 6.5% CO.sub.2. The load 
on the organ was adjusted to 0.5 g. The vas deferens was allowed to 
stabilize for 15 minutes before dose-response curves were obtained. 
The technique for making cumulative dose-response curves in accordance with 
van Rossum (1963) was employed. The stimulating drug, noradrenaline (NA), 
was added to the bath in a manner to achieve geometrically increasing 
concentrations in the organ bath without washings in between. After each 
injection of NA the organ was allowed to contract until a state of 
equilibrium had been reached, and then the next dose of NA was added. This 
procedure was repeated until no further increase in contraction was 
obtained. The dosage of NA was adapted to give a concentration step in the 
bath of 1/2 log 10. The tested concentration interval was 10.sup.-8 
-10.sup.-4 M, 3.10.sup.-4 M plus maximum effect at 3 10.sup.-5 and 
10.sup.-4 M. Compounds of formula I, identified as 2-12, and comparison 
compounds 13-15, were tested by the same technique. The compounds conform 
to the formula below except where indicated for other values of R.sup.1, 
R.sup.2 and R.sup.3. The test results are given in Table 1 below. 
Table 1 
______________________________________ 
##STR15## 
______________________________________ 
threshold 
Substance, R conc., M EC.sub.50,M 
______________________________________ 
1. noradrenaline 10.sup.-6 3 .multidot. 10.sup.-5 
2. CH(OH)CH.sub.2 NH.sub.2 
10.sup.-7 4 .multidot. 10.sup.-5 
3. CH(OH)CH.sub.2 NHCH.sub.3 
3 .multidot. 10.sup.-8 
1.5 .multidot. 10.sup.-7 
4. CH(OH)CH.sub.2 NHC.sub.2 H.sub.5 
5 .multidot. 10.sup.-7 
1.5 .multidot. 10.sup.-6 
5. CH(OH)CH.sub.2 N(CH.sub.3).sub.2 
10.sup.-5 - 10.sup.-4 
-- 
______________________________________ 
threshold 
Substance, R cont., M EC.sub.50,M 
______________________________________ 
##STR16## 10.sup.-6 3 .multidot. 10.sup.-6 
4 .multidot. 10.sup.-6 
7. CH(OH)CH.sub.2 NH.sub.2 ; 
10.sup.-6 1.5 .multidot. 10.sup.-5 
R.sup.1,R.sup.2 = CH.sub.2 
3 .multidot. 10.sup.-6 
8. CH(OH)CH.sub.2 NH.sub.2 ; 
3 .multidot. 10.sup.-7 
2 .multidot. 10.sup.-6 
R.sup.1 = R.sup.2 = H 
9. CH(OH)CH.sub. 2 NH.sub.2 ; 
3 .multidot. 10.sup.-6 
1.5 .multidot. 10.sup.-5 
R.sup.1,R.sup.2 = (CH.sub.2).sub.3 
10. CH(OH)CH.sub.2 NH.sub.2 ; 
5 .multidot. 10.sup.-6 
5 .multidot. 10.sup.-5 
R.sup.3 = CH.sub.3 Oin 
position 5 
11. (-)-form of No. 3 
3 .multidot. 10.sup.-8 
7 .multidot. 10.sup.-8 
12. (+)-form of No. 3 
5 .multidot. 10.sup.-6 
-- 
##STR17## -- -- 
14. No. 3 without -- -- 
double bond 
15. CH.sub.2 CH.sub.2 NH(CH.sub.3) 
-- -- 
______________________________________ 
max. effect, 
Substance, R % of NA max. 
n 
______________________________________ 
1. noradrenaline 100 10 
2. CH(OH)CH.sub.2 NH.sub.2 
100 7 
3. CH(OH)CH.sub.2 NHCH.sub.3 
100 10 
4. CH(OH)CH.sub.2 NHC.sub.2 H.sub.5 
85 2 
5. CH(OH)CH.sub.2 N(CH.sub.3).sub.2 
50 2 
##STR18## 90 2 
7. CH(OH)CH.sub. 2 NH.sub.2 ; 
120 2 
R.sup.1,R.sup.2 = CH.sub.2 
8. CH(OH)CH.sub.2 NH.sub.2 ; 
100 2 
R.sup.1 = R.sup.2 = H 
9. CH(OH)CH.sub.2 NH.sub.2 ; 
70 2 
R.sup.1,R.sup.2 = (CH.sub.2).sub.3 
10. CH(OH)CH.sub.2 NH.sub.2 ; 
65 2 
R.sup.3 = CH.sub.3 O in 
position 5 
11. (-)-form of No. 3 
90 2 
12. (+)-form of No. 3 
35 2 
##STR19## 0 2 
14. No. 3 without 0 3 
double bond 
15. CH.sub.2 CH.sub.2 NH(CH.sub.3) 
0 
______________________________________ 
As appears from the above test results, the effect is highly 
structure-specific. Thus, the corresponding ketone is inactive; see 
comparison compound No. 13. Furthermore, the effect disappears when the 
indene double bond is hydrogenated (see comparison compound No. 14) or 
when the hydroxyl group is removed (see comparison compound No. 15). 
Effect on urethra strip of cat and aortic strip of rabbit 
Adult male and female cats weighing 2-5 kg were used. The animals were 
anaesthetized with pentobarbital, 30-50 mg/kg intraperitoneally. An 
abdominal incision was made and the bladder and urethra were dissected 
free and cut. The bladder and urethra were placed in Tyrode solution of 
room temperature. Care was taken to keep the tissue moist during the 
preparation. The bladder was cut away and the urethra was cut 
longitudinally. Segments of 2-3 mm width were mounted in an organ-bath 
with Tyrode solution at 37.degree. C. and connected to a strain gauge 
transducer so that the isometric tension could be recorded. The 
preparation was maintained at pH 7.5 by bubbling a mixture of 93.5 
volume-% O.sub.2 and 6.5 volume-% CO.sub.2 through the solution. This 
experimental set up thus allowed the recording of circular muscle activity 
as isometric tension changes. The initial tension was set at approximately 
0.5 g. After mounting, the preparation was allowed 1 hour for 
acclimatization before starting the experiment. All recordings were made 
from the base line. The drugs were added directly to the organ-baths and 
cumulative dose-response curves were recorded. Noradrenaline has 
consistently been used as a reference drug for agonistic action. The 
substances tested as agonists were noradrenaline bitartrate (NA) and the 
above compound No. 3. The test results are reported in Table 2 below, 
which also indicates the results of corresponding tests on aortic strips 
of rabbit in order to illustrate the selective effect on urethra of the 
compound according to the invention. 
Table 2 
______________________________________ 
EC.sub.50 -values 
index 
compound No. 3 NA No. 3/NA 
______________________________________ 
Urethra 
(6.9.+-.3.6) . 10.sup.-7 M 
(2.7.+-.0.4) . 10.sup.-5 M 
.about.40 
strip 
(cat) 
Aortic (4.5.+-.1.4) . 10.sup.-8 M 
(1.8.+-.0.8) . 10.sup.-7 M 
.about.4 
strip 
(rabbit) 
______________________________________