The present invention relates to novel N-substituted azaheterocyclic compounds of the general formula ##STR1## wherein X, Y, Z, R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, p, r and s are as defined in the detailed part of the present description or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation as well as their use for treatment of indications caused by or related to secretion and circulation of insulin antagonising peptides.

FIELD OF INVENTION 
The present invention relates to novel N-substituted azaheterocyclic 
compounds in which a substituted alkyl chain forms part of the 
N-substituent or salts thereof, to methods for their preparation, to 
compositions containing them, to the use of the compounds for preparing 
compositions for the clinical treatment of painful, hyperalgesic and/or 
inflammatory conditions in which C-fibres play a pathophysiological role 
by eliciting neurogenic pain or inflammation, and to methods of treating 
said painful, hyperalgesic and/or inflammatory conditions. The invention 
also relates to the use of the present compounds for reducing blood 
glucose and/or inhibit the secretion, circulation or effect of insulin 
antagonising peptides like CGRP or amylin, the present compounds being 
known to interfere with neuropeptide containing C-fibres. Hence the 
present compounds can be used in the treatment of insulin resistance in 
non-insulin-dependent diabetes mellitus (NIDDM) in order to improve the 
glucose tolerance as well as ageing-associated obesity. 
BACKGROUND OF INVENTION 
The nervous system exerts a profound effect on the inflammatory response. 
Antidromic stimulation of sensory nerves results in localised vasodilation 
and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 
1967, 31, 138-151) and a similar response is observed following injection 
of peptides known to be present in sensory nerves. From this and other 
data it is postulated that peptides released from sensory nerve endings 
mediate many inflammatory responses in tissues like skin, joint, urinary 
tract, eye, meninges, gastrointestinal and respiratory tracts. Hence 
inhibition of sensory nerve peptide release and/or activity, may be useful 
in treatment of, for example arthritis, dermatitis, rhinitis, asthma, 
cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastrointestinal 
diseases or migraine. 
Further, the potent effects of CGRP on skeletal muscle glycogen synthase 
activity and muscle glucose metabolism, together with the notion that this 
peptide is released from the neuromuscular junction by nerve excitation, 
suggest that CGRP may play a physiological role in skeletal muscle glucose 
metabolism by directing the phosphorylated glucose away from glycogen 
storage and into the glycolytic and oxidative pathways (Rossetti et al. 
Am. J. Physiol. 264, E1-E10, 1993). This peptide may represent an 
important physiological modulator of intracellular glucose trafficking in 
physiological conditions, such as exercise, and may also contribute to the 
decreased insulin action and skeletal muscle glycogen synthase in 
pathophysiological conditions like NIDDM or ageing-associated obesity 
(Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma 
levels of CGRP are markedly increased. Hence inhibition of release and/or 
activity of the neuropeptide CGRP may be useful in the treatment of 
insulin resistance related to type 2 diabetes or ageing. 
In U.S. Pat. Nos. 4,383,999 and 4,514,414 and in EP 236342 as well as in EP 
231996 some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic 
carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 
and EP 374801, N-substituted azaheterocyclic carboxylic acids in which an 
oxime ether group and vinyl ether group forms part of the N-substituent 
respectively are claimed as inhibitors of GABA uptake. Further, in WO 
9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are 
claimed as GABA uptake inhibitors. EP 221572 claims that 
1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake. 
WO 9631472, WO 9631473 and WO 9631483, all of which are published on Oct. 
10 1996 discloses N-substituted azaheterocyclic compounds. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds of the general formula I, 
wherein X, Y, Z, M.sub.1, M.sub.2, R.sup.1 through R.sup.20, p, q, r, s, 
n, m and u are as defined in the detailed part of the present description. 
The present compounds are useful for the treatment, prevention, 
elimination, alleviation or amelioration of an indication related to all 
painful, hyperalgesic and/or inflammatory conditions in which C-fibres 
play a pathophysiological role, e.g. neurogenic pain, inflammation, 
migraine, neuropathy, itching and rheumatoid arthritis, as well as 
indications caused by or related to the secretion and circulation of 
insulin antagonising peptides, e.g. non-insulin-dependent diabetes 
mellitus (NIDDM) and ageing-associated obesity. 
In another aspect, the present invention includes within its scope 
pharmaceutical compositions comprising, as an active ingredient, at least 
one of the compounds of the general formula I or a pharmaceutically 
acceptable salt thereof together with a pharmaceutically acceptable 
carrier or diluent. 
In another aspect of the present invention there is provided a method of 
treating painful, hyperalgesic and/or inflammatory conditions in which 
C-fibres play a pathophysiological role, e.g. neurogenic pain, 
inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as 
well as a method of treating indications caused by or related to the 
secretion and circulation of insulin antagonising peptides like CGRP or 
amylin, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and 
ageing-associated obesity. The method of treating may be described as the 
treatment of one of the above indications in a subject in need thereof, 
which comprises the step of administering to the said subject a 
neurologically effective amount of a compound of the invention, or a 
pharmaceutically acceptable salt thereof. 
A further aspect of the invention relates to the use of a compound of the 
present invention for the preparation of a pharmaceutical composition for 
the treatment of all painful, hyperalgesic and/or inflammatory conditions 
in which C-fibres play a pathophysiological role, e.g. neurogenic pain, 
inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as 
well as for the treatment of indications caused by or related to the 
secretion and circulation of insulin antagonising peptides, e.g. 
non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated 
obesity. 
Further objects will become apparent from the following description. 
DETAILED DESCRIPTION OF THE INVENTION 
Accordingly, the present invention relates to novel N-substituted 
azaheterocyclic compounds of formula I 
##STR2## 
wherein R.sup.1, R.sup.1a, R.sup.2 and R.sup.2a independently are 
hydrogen, halogen, trifluoromethyl, hydroxy, C.sub.1-6 -alkyl, C.sub.1-6 
-alkoxy or methylthio, --NR.sup.7 R.sup.8 or --SO.sub.2 NR.sup.7 R.sup.8 
wherein R.sup.7 and R.sup.8 independently are hydrogen or C.sub.1-6 
-alkyl; and 
X is completion of an optional bond, ortho-phenylene, --O--, --S--, 
--C(R.sup.9 R.sup.10)--, --(C.dbd.O)--, --N(R.sup.3)--, --(S.dbd.O)--, 
--CH.sub.2 --(C.dbd.O)--, --(C.dbd.O)--CH.sub.2 --, 
--N(R.sup.4)--(C.dbd.O)--, --(C.dbd.O)--N(R.sup.4)--, --O--CH.sub.2 --, 
--CH.sub.2 --O--, --S--CH.sub.2 --, --CH.sub.2 --S--, --CH.sub.2 CH.sub.2 
--, --CH.dbd.CH--, --O--CH.sub.2 --O--, --(CH.sub.2)N(R.sup.3)--, 
--N(R.sup.3)(CH.sub.2)--, --N(CH.sub.3)SO.sub.2 --, --SO.sub.2 
N(CH.sub.3)--, --CH(R.sup.10)CH.sub.2 --, --CH.sub.2 CH(R.sup.10)--, 
--CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CH.dbd.CH--, --CH.sub.2 CH.sub.2 
CH.sub.2 -- or --CH.sub.2 --O--CH.sub.2 -- wherein R.sup.9 is hydrogen or 
C.sub.1-6 -alkyl, and R.sup.10 is C.sub.1-6 -alkyl or phenyl optionally 
substituted with halogen, trifluoromethyl, hydroxy, C.sub.1-6 -alkyl or 
C.sub.1-6 -alkoxy, and R.sup.4 and R.sup.3 independently are hydrogen, 
C.sub.1-6 -alkyl or phenyl optionally substituted with halogen, 
trifluoromethyl, hydroxy, C.sub.1-6 -alkyl or C.sub.1-6 -alkoxy; and 
Y is --O--, --S(O).sub.q -- wherein q is 0, 1 or 2, or --N(R.sup.5)-- 
wherein R.sup.5 is hydrogen or C.sub.1-6 -alkyl; and 
s is 0 or 1 and p is 0 or 1 provided that s or p must not be 0 at the same 
time; and 
r is 1, 2, 3 or 4; and 
Z is selected from 
##STR3## 
wherein n is 0, 1 or 2; and R.sup.11 is hydrogen, C.sub.1-6 -alkyl, 
C.sub.1-6 -alkoxy or phenyl optionally substituted with halogen, 
triflouromethyl, hydroxy, C.sub.1-6 -alkyl or C.sub.1-6 -alkoxy; and 
R.sup.12 is --(CH.sub.2).sub.m OH or --(CH.sub.2).sub.u COR.sup.17 wherein 
m is 0, 1, 2, 3, 4, 5 or 6 and u is 0 or 1; 
and wherein R.sup.17 is --OH, --NHR.sup.20 or C.sub.16 -alkoxy, wherein 
R.sup.20 is hydrogen or C.sub.1-6 -alkyl; and 
R.sup.13 is hydrogen, halogen, trifluoromethyl, hydroxy, C.sub.1-6 -alkyl 
or C.sub.1-6 -alkoxy; and 
R.sup.14 is hydrogen or C.sub.1-6 -alkyl; and 
B is C.sub.1-6 -alkylene, C.sub.2-6 -alkenylene or C.sub.2-6 -alkynylene; 
and 
is optionally a single bond or a double bond; and 
R.sup.18 is selected from 
##STR4## 
wherein M.sub.1 and M.sub.2 independently are C or N; and R.sup.19 is 
hydrogen, C.sub.1-6 -alkyl, phenyl or benzyl; and 
R.sup.15 is hydrogen, halogen, trifluoromethyl, nitro or cyano; 
and R.sup.16 is hydrogen, halogen, trifluoromethyl, nitro, cyano, 
--(CH.sub.2).sub.m COR.sup.17, --(CH.sub.2).sub.m OH or --(CH.sub.2).sub.m 
SO.sub.2 R.sup.17, wherein m is 0, 1 or 2; 
or R.sup.16 is selected from 
##STR5## 
or a pharmaceutically acceptable salt thereof. 
Compounds of formula I wherein X is completion of an optional bond, 
--C(R.sup.9 R.sup.10)--, --(C.dbd.O)--, --N(R.sup.3)--, --CH.sub.2 
--(C.dbd.O)--, --(C.dbd.O)--CH.sub.2 --, --N(R.sup.4)--(C.dbd.O)--, 
--(C.dbd.O)--N(R.sup.4)--, --O--CH.sub.2 --, --CH.sub.2 --O--, 
--S--CH.sub.2 --, --CH.sub.2 --S--, --(CH.sub.2)N(R.sup.3)--, 
--N(R.sup.3)(CH.sub.2)--, --N(CH.sub.3)SO.sub.2 --, --SO.sub.2 
N(CH.sub.3)--, --CH(R.sup.10)CH.sub.2 --, --CH.sub.2 CH(R.sup.10)--, 
--CH.dbd.CH--CH.sub.2 --, --CH.sub.2 --CH.dbd.CH-- or --CH.sub.2 CH.sub.2 
CH.sub.2 -- wherein R.sup.9 is hydrogen or C.sub.1-6 -alkyl, and R.sup.10 
is C.sub.1-6 -alkyl or phenyl optionally substituted with halogen, 
trifluoromethyl, hydroxy, C.sub.1-6 -alkyl or C.sub.1-6 -alkoxy, and 
R.sup.4 and R.sup.3 independently are hydrogen or C.sub.1-6 -alkyl, and 
wherein R.sup.1, R.sup.2, Y, s, p, r and Z are as described above, are 
known from WO 9631472, WO 9631473 and WO 9631483. 
The compounds of formula I may exist as geometric and optical isomers and 
all isomers, as separated, pure or partially purified stereoisomers or 
racemic mixtures thereof are included in the scope of the invention. 
Isomers may be separated by means of standard methods such as 
chromatographic techniques or fractional crystallisation of suitable 
salts. 
Preferably, the compounds of formula I exist as the individual geometric or 
optical isomers. 
The compounds according to the invention may optionally exist as 
pharmaceutically acceptable acid addition salts or--when the carboxylic 
acid group is not esterified--as pharmaceutically acceptable metal salts 
or--optionally alkylated--ammonium salts. 
Examples of such salts include inorganic and organic acid addition salts 
such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, 
fumarate, maleate, citrate, lactate, tartrate, oxalate or similar 
pharmaceutically acceptable inorganic or organic acid addition salts, and 
include the pharmaceutically acceptable salts listed in Journal of 
Pharmaceutical Science, 66, 2 (1977) which are known to the skilled 
artisan. 
Also included are the hydrates of the above mentioned acid addition salts 
which the present compounds are able to form. 
The acid addition salts may be obtained as the direct products of compound 
synthesis. In the alternative, the free base may be dissolved in a 
suitable solvent containing the appropriate acid, and the salt isolated by 
evaporating the solvent or by precipitation or crystallisation. 
The compounds of formula I may be administered in a pharmaceutically 
acceptable acid addition salt form or where possible as a metal or a lower 
alkylammonium salt. Such salt forms exhibit approximately the same order 
of activity as the free base forms. 
In the above structural formula and throughout the present specification, 
the following terms have the indicated meaning: 
The term "C.sub.1-6 -alkyl" as used herein, alone or in combination, refers 
to a straight or branched, saturated hydrocarbon chain having 1 to 6 
carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, 
sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 
4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl 
and 1,2,2-trimethylpropyl. 
The term "C.sub.1-6 -alkoxy" as used herein, alone or in combination, 
refers to a straight or branched monovalent substituent comprising a 
C.sub.1-6 -alkyl group linked through an ether oxygen having its free 
valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy. 
The term "halogen" means fluorine, chlorine, bromine or iodine. 
In a preferred embodiment of the invention R.sup.1, R.sup.1a, R.sup.2 and 
R.sup.2a are independently selected from hydrogen halogen, 
trifluoromethyl, C.sub.1-6 -alkyl or methylthio, preferably R.sup.1, 
R.sup.1a, R.sup.2 and R.sup.2a are independently hydrogen, halogen, methyl 
or methylthio. 
In a another preferred embodiment of the invention X is selected from 
ortho-phenylene, --O--, --S--, --(S.dbd.O)--, --CH.sub.2 CH.sub.2 --, 
--CH.dbd.CH--, --O--CH.sub.2 --O-- or --CH.sub.2 --O--CH.sub.2 --, 
preferably X is --O-- or --S--. 
In another preferred embodiment of the invention Y is selected from Y is 
--O-- or --S(O).sub.q -- wherein q is 0. 
In another preferred embodiment of the invention r is 1 or 2. 
In another preferred embodiment of the invention Z is selected from 
##STR6## 
wherein R.sup.12 and R.sup.13 are as defined above. 
In another preferred embodiment of the invention R.sup.12 is 
--(CH.sub.2).sub.p COR.sup.17 wherein p is 0 or 1 and R.sup.17 is --OH. 
In yet another preferred embodiment of the invention R.sup.13 is hydrogen. 
Illustrative examples of compounds encompassed by the present invention 
include: 
1-(2-( 
10,11-Dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-(3R)-piperidinecarboxyl 
ic acid; 
1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid; 
1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperi 
dinecarboxylic acid; 
1-(2-(2-Methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperi 
dinecarboxylic acid; 
1-(2-(2-Methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid; 
1-(2-(8-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid; 
1-(2-(8-Methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-pi 
peridinecarboxylic acid; 
(R)-1-(2-(10,11-Dihydrodibenzo[b,f]oxepin-10-yloxy)ethyl)-3-piperidinecarbo 
xylic acid; 
(R)-1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ylsulfanyl)ethyl)-3- 
piperidinecarboxylic acid; 
(R)-1-(11H-Dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic 
acid; 
(R)-1-(2-(2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl 
)-3-piperidinecarboxylic acid; 
(R)-1-(2-(2,4-Dichloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl)-3-p 
iperidinecarboxylic acid; 
or a pharmaceutically acceptable salt thereof. 
It has been demonstrated that the novel compounds of formula I inhibit 
neurogenic inflammation which involves the release of neuropeptides from 
peripheral and central endings of sensory C-fibres. Experimentally this 
can be demonstrated in animal models of histamine induced paw oedema 
(Amann et al, Europ. J. Pharmacol. 279, 227-231, 1995) in which the novel 
compounds of formula I exhibit a potent inhibitory effect. Compounds of 
formula I may be used to treat all painful, hyperalgesic and/or 
inflammatory conditions in which C-fibres play a pathophysiological role 
by eliciting neurogenic pain or inflammation, i.e.: 
Acutely painful conditions exemplified by migraine, postoperative pain, 
burns, bruises, post-herpetic pain (Zoster) and pain as it is generally 
associated with acute inflammation; chronic, painful and/or inflammatory 
conditions exemplified by various types of neuropathy (diabetic, 
post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, 
gout, inflammatory bowel disease, prostatitis, cancer pain, chronic 
headache, coughing, asthma, itching, chronic pancreatitis, inflammatory 
skin disease including psoriasis and autoimmune dermatoses, osteoporotic 
pain. 
Further, it has been demonstrated that the compounds of general formula I 
improve the glucose tolerance in diabetic ob/ob mice and that this may 
result from the reduced release of CGRP from peripheral nervous endings. 
Hence the compounds of general formula I may be used in the treatment of 
NIDDM as well as ageing-associated obesity. Experimentally this has been 
demonstrated by the subcutaneous administration of glucose into ob/ob mice 
with or without previous oral treatment with a compound of general formula 
I. 
The compounds of formula I may be prepared by the following method: 
##STR7## 
A compound of formula II wherein R.sup.1, R.sup.1a, R.sup.2, R.sup.2a, X, 
Y, r, p and s are as defined above and W is a suitable leaving group such 
as halogen, p-toluene sulphonate or mesylate may be reacted with an aza 
compound of formula Ill wherein Z is as defined above. This alkylation 
reaction may be carried out in a solvent such as acetone, dibutylether, 
2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or 
toluene in the presence of a base e.g. sodium hydride or potassium 
carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up 
to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters 
have been prepared in which R.sup.17 is alkoxy, compounds of formula I 
wherein R.sup.17 is OH may be prepared by hydrolysis of the ester group, 
preferably at room temperature in a mixture of an aqueous alkali metal 
hydroxide solution and an alcohol such as methanol or ethanol, for 
example, for about 0.5 to 6 h. 
Compounds of formula II and III may readily be prepared by methods familiar 
to those skilled in the art. 
Under certain circumstances it may be necessary to protect the 
intermediates used in the above methods e.g. a compound of formula III 
with suitable protecting groups. The carboxylic acid group can, for 
example, be esterified. Introduction and removal of such groups is 
described in "Protective Groups in Organic Chemistry" J. F. W. McOrnie ed. 
(New York, 1973). 
PHARMACOLOGICAL METHODS 
I. Histamine Induced Paw Oedema 
The rat histamine paw oedema test was performed essentially as described by 
Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995). In brief 250-300 g 
male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and 
placed on a 32 degree (Celsius) heated table. Ten minutes later histamine 
(50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes 
hereafter the paw swelling was determined by water plethysmography (Ugo 
Basile). Test compounds were administered intraperitoneally at 15 minutes 
before the anaesthetics. 
II. Reduced Release of CGRP 
ob/ob female mice, 16 weeks of age, where injected glucose (2 g/kg) 
subcutaneously. At times hereafter blood glucose was determined in tail 
venous blood by the glucose oxidase method. At the end of the study the 
animals were decapitated and trunk blood collected. Immunoreactive CGRP 
was determined in plasma by radio-immuno-assay. Two groups of animals were 
used. The one group was vehicle treated, whereas the other group received 
a compound of formula I via drinking water (100 mg/l) for five days before 
the test. 
Values for inhibition of histamine induced oedema response for some 
representative compounds are recorded in table 1. 
TABLE 1 
______________________________________ 
Inhibition of histamine induced pain response at 1.0 mg/kg 
Example no. 
% Oedema inhibition 
______________________________________ 
1 37 
5 49 
______________________________________ 
PHARMACEUTICAL COMPOSITIONS 
The present invention also relates to pharmaceutical compositions 
comprising a compound of formula I or a pharmaceutically acceptable salt 
thereof and, usually, such compositions also contain a pharmaceutical 
carrier or diluent. The compositions containing the compounds of this 
invention may be prepared by conventional techniques and appear in 
conventional forms, for example capsules, tablets, solutions or 
suspensions. 
The pharmaceutical carrier employed may be a conventional solid or liquid 
carrier. Examples of solid carriers are lactose, terra alba, sucrose, 
talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid. 
Examples of liquid carriers are syrup, peanut oil, olive oil and water. 
Similarly, the carrier or diluent may include any time delay material known 
to the art, such as glyceryl monostearate or glyceryl distearate, alone or 
mixed with a wax. The route of administration may be any route which 
effectively transports the active compound to the appropriate or desired 
site of action, such as oral, nasal, pulmonary or parenteral e.g. rectal, 
depot, transdermal, subcutaneous, intranasal, intramuscular, topical, 
intravenous, intraurethral, ophthalmic solution or an ointment, the oral 
route being preferred. 
If a solid carrier for oral administration is used, the preparation can be 
tabletted, placed in a hard gelatine capsule in powder or pellet form or 
it can be in the form of a troche or lozenge. The amount of solid carrier 
will vary widely but will usually be from about 25 mg to about 1 g. If a 
liquid carrier is used, the preparation may be in the form of a syrup, 
emulsion, soft gelatine capsule or sterile injectable liquid such as an 
aqueous or non-aqueous liquid suspension or solution. 
For nasal administration, the preparation may contain a compound of formula 
I dissolved or suspended in a liquid carrier, in particular an aqueous 
carrier, for aerosol application. The carrier may contain additives such 
as solubilising agents, e.g. propylene glycol, surfactants, absorption 
enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or 
preservatives such as parabenes. 
For parenteral application, particularly suitable are injectable solutions 
or suspensions, preferably aqueous solutions with the active compound 
dissolved in polyhydroxylated castor oil. Tablets, dragees, or capsules 
having talc and/or a carbohydrate carrier or binder or the like are 
particularly suitable for oral application. Preferable carriers for 
tablets, dragees, or capsules include lactose, corn starch, and/or potato 
starch. A syrup or elixir can be used in cases where a sweetened vehicle 
can be employed. 
A typical tablet which may be prepared by conventional tabletting 
techniques contains 
______________________________________ 
Core: 
Active compound (as free compound 100 mg 
or salt thereof) 
Colloidal silicon dioxide (Areosil 
.RTM.) 1.5 mg 
Cellulose, microcryst. (Avicel .RTM.) 70 mg 
Modified cellulose gum (Ac-Di-Sol .RTM.) 7.5 mg 
Magnesium stearate 
Coating: 
HPMC approx. 9 mg 
*Mywacett .RTM. 9-40 T approx. 0.9 mg 
______________________________________ 
*Acylated monoglyceride used as plasticizer for film coating. 
The compounds of the invention may be administered to a mammal, especially 
a human, in need of such treatment, prevention, elimination, alleviation, 
or amelioration of an indication related to all painful, hyperalgesic 
and/or inflammatory conditions in which C-fibres play a pathophysiological 
role such as e.g. neurogenic pain, inflammation, migraine, neuropathy, 
itching and rheumatoid arthritis, as well as indications caused by or 
related to the secretion and circulation of insulin antagonising peptides, 
such as non-insulin-dependent diabetes mellitus (NIDDM) or 
ageing-associated obesity. Such mammals include also animals, both 
domestic animals, e.g. household pets, and non-domestic animals such as 
wildlife. 
The compounds of the invention may be administered in the form of an alkali 
metal or earth alkali metal salt thereof, concurrently, simultaneously, or 
together with a pharmaceutically acceptable carrier or diluent, especially 
and preferably in the form of a pharmaceutical composition thereof, 
whether by oral, rectal, or parenteral (including subcutaneous) route, in 
an effective amount. 
For the above indications the dosage will vary depending on the compound of 
formula I employed, on the mode of administration and on the therapy 
desired. However, in general, satisfactory results are obtained with a 
dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg 
to about 500 mg of compounds of formula I, conveniently given from 1 to 5 
times daily, optionally in sustained release form. Usually, dosage forms 
suitable for oral administration comprise from about 0.5 mg to about 1000 
mg, preferably from about 1 mg to about 500 mg of the compounds of formula 
I admixed with a pharmaceutical carrier or diluent. 
Suitable dosage ranges varies as indicated above depending as usual upon 
the exact mode of administration, form in which administered, the 
indication towards which the administration is directed, the subject 
involved and the body weight of the subject involved, and the preference 
and experience of the physician or veterinarian in charge. 
Generally, the compounds of this invention are dispensed in unit dosage 
form comprising 50-200 mg of active ingredient in or together with a 
pharmaceutically acceptable carrier per unit dosage. 
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal 
administration comprise from about 0.5 mg to about 1000 mg, preferably 
from about 1 mg to about 500 mg of the compounds of formula I admixed with 
a pharmaceutically acceptable carrier or diluent. 
Any novel feature or combination of features described herein is considered 
essential to this invention.

EXAMPLES 
The process for preparing compounds of formula I and preparations 
containing them is further illustrated in the following examples, which, 
however, are not to be construed as limiting. 
Hereinafter, TLC is thin layer chromatography and wherever it is stated 
that chloroform is used as eluent or part of an eluent mixture in TLC, the 
eluent that has been used is chloroform saturated with ammonia. CDCl.sub.3 
is deutero chloroform and DMSO-d.sub.6 is hexadeutero dimethylsulfoxide. 
The structures of the compounds are confirmed by either elemental analysis 
or NMR, where peaks assigned to characteristic protons in the title 
compounds are presented where appropriate. .sup.1 H NMR shifts 
(.delta..sub.H) are given in parts per million (ppm). M.p. is melting 
point and is given in .degree. C. and is not corrected. Column 
chromatography was carried out using the technique described by W. C. 
Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 
(Art. 9385). Compounds used as starting materials are either known 
compounds or compounds which can readily be prepared by methods known per 
se. 
Example 1 
1-(2-(10,11-Dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-(3R)-piperidineca 
rboxylic acid acetate 
##STR8## 
10-Chloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 0.041 mol, prepared as 
described in Monatshefte 96, 182, 1965) was slowly added to a mixture of 
2-bromoethanol (44 g, 0.35 mol) and powdered potassium carbonate (10 g, 
0.072 mol) at room temperature. After stirring for 6 h, dichloromethane 
(15 ml) was added, and the reaction mixture was heated at 50.degree. C. 
for 3 h. After cooling, dichloromethane (35 ml) was added and the mixture 
was filtered. The dichloromethane was evaporated and excess of 
2-bromoethanol was distilled off in vacuo. The oily residue was dissolved 
in benzene (100 ml), washed with water (3.times.70 ml), dried (K.sub.2 
CO.sub.3) and the solvent was evaporated to give 13.8 g of crude 
10-(2-bromoethoxy)-10,11-dihydrodibenzo[b,f]thiepine as an oil. 
A mixture of the above crude bromide (6.1 g, 0.018 mol), 
(R)-3-piperidinecarboxylic acid ethyl ester tartrate (6.0 g, 0.02 mol), 
potassium carbonate (8.2 g, 0.06 mol) and acetone (100 ml) was heated at 
reflux temperature under stirring for 20 h. The mixture was filtered and 
the solvent evaporated in vacuo. The oily residue was purified by 
chromatography on silica gel using benzene as eluent to give 5.3 g of 
1-(2-(10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-(3R)-piperidinec 
arboxylic acid ethyl ester as an oil. 
TLC: R.sub.f =0.45 (SiO.sub.2 : chloroform) 
The above ester (4.9 g, 0.0119 mol) was dissolved in ethanol (30 ml) and 5 
N sodium hydroxide (5 ml) was added. The mixture was stirred at room 
temperature for 20 h, and ethanol was evaporated in vacuo. Water (50 ml) 
followed by acetic acid (7 ml) were added, and the mixture was extracted 
with dichloromethane (100 ml). The organic phase was dried (MgSO.sub.4) 
and the solvent was evaporated in vacuo. The residue was triturated with 
diethyl ether and the solid was isolated by filtration and dried to give 
4.0 g (76%) of the title compound as an amorphous solid. 
M.p. 82-89.degree. C. 
Calculated for C.sub.22 H.sub.25 NO.sub.3 S, CH.sub.3 COOH: 
C, 64.99%; H, 6.59%; N, 3,16%; S, 7.23%; Found: C, 65.13%; H, 6.49%; N, 
2.99%, S, 7.48%. 
Example 2 
1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid hydrogen oxalate 
##STR9## 
To a mixture of 2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ol (10 g, 38 
mmol, prepared similarly as described in Coll. Czech. Chem. Commun. 33, 
1852, 1968), 2-bromoethanol (7.5 g, 60 mmol) and potassium carbonate (5 g, 
38 mmol) in absolute benzene (100 ml), boron trifluoride etherate (5.7 g, 
40 mmol) was dropwise added at 10-14.degree. C., and stirring was 
continued at 10-14.degree. C. for 1.5 h. The mixture was cooled to 
10.degree. C., and cold water (50 ml) was added dropwise. The organic 
layer was separated, washed with water (3.times.50 ml) and dried (Na.sub.2 
SO.sub.4). The solvent was evaporated in vacuo, and the residual oil (12.9 
g, 92%) was used without further purification in the next step. 
A mixture of the above bromide (11.2 g, 29 mmol), 3-piperidinecarboxylic 
acid ethyl ester (4.7 g, 30 mmol) and potassium carbonate (8.3 g, 60 mol) 
in N,N-dimetyl-formamide (50 ml) was heated for 6 h at 60.degree. C. After 
cooling, water (150 ml) and toluene (150 ml) were added, the phases were 
separated, and the aqueous phase was extracted with toluene (100 ml). The 
combined organic phases were dried (K.sub.2 CO.sub.3 and Na.sub.2 
SO.sub.4), and the solvent was evaporated in vacuo. The oily residue (13.6 
g) was purified by column chromatography on silica gel, using benzene as 
eluent. This afforded 9.05 g (68%) of 
1-(2-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piper 
idinecarboxylic acid ethyl ester. 
TLC: R.sub.f =0.5 (SiO.sub.2 : chloroform) 
To the above ester (2.63 g, 6 mmol) in ethanol (10 ml), a solution of 
potassium hydroxide (0.85 g, 15 mmol) in water (5 ml) was added, and the 
resulting mixture was heated at reflux temperature for 3.5 h. Ethanol was 
evaporated in vacuo, and water (20 ml) and acetic acid (1 ml), were added. 
The mixture was extracted with chloroform (2.times.15 ml), the organic 
extracts were dried (Na.sub.2 SO.sub.4) and evaporated in vacuo. The 
residue (2.7 g) was transformed into the corresponding hydrogen oxalate. 
M.p. 95-99.degree. C. 
Calculated for C.sub.22 H.sub.24 ClNO.sub.3 S, (COOH).sub.2 : 
C, 56.74%; H, 5.16%; Cl, 6.98%; N, 2.76%; S, 6.31%; Found: C, 56.88%; H, 
5.19%; Cl, 7.00%; N, 2.72%; S, 6.60%. 
Example 3 
1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperi 
dinecarboxylic acid hydrogen oxalate 
##STR10## 
A mixture of 10-(2-bromoethoxy)-2-chloro-10,11-dihydrodibenzo[b,f]thiepine 
(5.19 g, 14 mmol, prepared similarly as described in example 2), 
4-piperidinecarboxylic acid ethyl ester (2.20 g, 14 mmol) and anhydrous 
potassium carbonate (4.70 g, 34 mmol) in dry N,N-dimethylformamide (25 ml) 
was stirred at 60-66.degree. C. for 6 h. After standing overnight at room 
temperature, benzene (50 ml) and water (50 ml) were added, and the phases 
were separated. The organic layer was washed with water (2.times.50 ml), 
dried (K.sub.2 CO.sub.3) and evaporated in vacuo. The oily residue was 
purified by column chromatography on silica gel using benzene as eluent, 
affording 4.28 g (68%) of oily 
1-(2-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piper 
idinecarboxylic acid ethyl ester. The oil was dissolved in dry acetone (40 
ml), oxalic acid dihydrate (1.76 g, 14 mmol) and ether were added, and the 
formed hydrogen oxalate was crystallised from a mixture of acetone and 
ether. 
TLC: R.sub.f =0.4 (SiO.sub.2 : chloroform/methanol=150:1) 
To a solution of the above ethyl ester hydrogen oxalate (2.0 g, 3.73 mmol) 
in ethanol (15 ml), potassium hydroxide (13%, 7 ml) was added and the 
mixture was heated at reflux temperature for 3.5 h. Ethanol was 
evaporated, the residue dissolved in water (20 ml), and pH was adjusted 
with acetic acid to 5.5. The mixture was extracted with chloroform (45 
ml), the organic layer was dried (Na.sub.2 SO.sub.4) and evaporated in 
vacuo. The oily residue was dissolved in acetone (15 ml) and afforded 
after treatment with oxalic acid (0.50 g, 4 mmol) 1.55 g (81%) of the 
title compound. 
M.p. 114-117.degree. C. 
Calculated for C.sub.22 H.sub.24 ClNO.sub.3 S, 0.5 H.sub.2 O, (COOH).sub.2 
: 
C, 55.75%; H, 5.26%; Cl, 6.86%; N, 2.71%; S, 6.20%; Found: C, 55.57%; H, 
5.18%; Cl, 6.86%; N, 2.76%; S, 6.14%. 
Example 4 
1-(2-(2-Methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperi 
dinecarboxylic acid hydrogen oxalate 
##STR11## 
To a solution of 2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol (3.63 g, 
15 mmol, prepared as described in Ger. Offen. 2,336,130, 1974) and 
2-bromoethanol (2.5 g, 20 mmol) in absolute benzene (25 ml), a solution of 
boron trifluoride etherate (2.25 g. 15.8 mmol) in absolute benzene (10 ml) 
was dropwise added at 10-15.degree. C. over 15 minutes. The reaction 
mixture was stirred at 10-15.degree. C. for 2 h and water (18 ml) was 
added. The organic layer was separated, washed with water (2.times.25 ml), 
dried (Na.sub.2 SO.sub.4) and evaporated in vacuo to give 3.83 g (73%) 
crude 10-(2-bromoethoxy)-2-methyl-10,11-dihydrodibenzo[b,f]thiepine, which 
was used without further purification in the next step. 
The above bromide (3.83 g, 11 mmol), 4-piperidinecarboxylic acid ethyl 
ester (1.71 g, 11 mmol) and potassium carbonate (3.04 g, 22 mmol) in dry 
N,N-dimethylformamide (16 ml) were stirred for 1 h at room temperature, 
and then for 4 h at 40.degree. C. The reaction mixture was diluted with 
benzene (100 ml), washed with water (2.times.50 ml), and the organic layer 
was dried (K.sub.2 CO.sub.3). After evaporation in vacuo, the oily residue 
was purified by column chromatography on silica gel using benzene as 
eluent. This afforded 4.28 g (68%) of 
1-(2-(2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piper 
idinecarboxylic acid ethyl ester as an oil. The ethyl ester (4.28 g, 9.3 
mmol) was dissolved in acetone (9 ml) and oxalic acid dihydrate (0.26 g) 
was added. The mixture was heated shortly at reflux temperature. After 
cooling, the precipitate was filtered off and recrystallised from a 
mixture of acetone and diethyl ether, to give 2.38 g (40%) of the hydrogen 
oxalate. 
TLC: R.sub.f =0.6 (SiO.sub.2 : chloroform/methanol=150:1) 
A mixture of the above ester hydrogen oxalate (1.03 g, 2 mmol) in ethanol 
(9 ml) and a 16% solution of potassium hydroxide (3.6 ml) was heated at 
reflux temperature for 4 h. Ethanol was evaporated in vacuo and the 
residue was dissolved in water (15 ml). pH was adjusted to 5.5 with acetic 
acid (1 ml) and the mixture was extracted with chloroform (30 ml). The 
organic layer was washed with water (4.times.10 ml), dried (Na.sub.2 
SO.sub.4) and evaporated in vacuo. The residual amorphous solid (0.79 g, 
99%) was dissolved in acetone (7.5 ml), oxalic acid dihydrate (0.26 g) was 
added at 40.degree. C. and the mixture was left to stay overnight. The 
precipitate was filtered off and recrystallised from acetone to give the 
title compound. 
M.p. 112-116.degree. C. 
Calculated for C.sub.23 H.sub.27 NO.sub.3 S, (COOH).sub.2 : 
C, 61.58%; H, 5.99%; N, 2.87%; S, 6.58%; Found: C, 61.11%; H, 5.96%; N, 
2.74%; S, 6.48%. 
Example 5 
1-(2-(2-Methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid hydrogen oxalate 
##STR12## 
A mixture of 10-(2-bromoethoxy)-2-methyl-10,11-dihydrodibenzo[b,f]thiepine 
(3.41 g, 9 mmol, prepared as described in example 4), 
3-piperidinecarboxylic acid ethyl ester (1.41 g, 9 mmol) and anhydrous 
potassium carbonate (2.5 g, 18 mmol) in N,N-dimethylformamide (14 ml) was 
stirred at 50.degree. C. for 8 h, and left to stay overnight. After 
cooling, benzene (40 ml) and water (90 ml) were added, and the phases were 
separated. The organic phase was treated with charcoal, dried (Na.sub.2 
SO.sub.4) and evaporated in vacuo. The oily residue (3.85 g) was purified 
by column chromatography on silica gel using benzene as eluent. This 
afforded 2.6 g (68%) of 
1-(2-(2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piper 
idinecarboxylic acid ethyl ester as an oil. The ethyl ester (2.6 g, 6.1 
mmol) was dissolved in acetone (9 ml), oxalic acid dihydrate (0.77 g, 6.1 
mmol) was added, and the mixture was heated to 40.degree. C. After 
cooling, the resulting precipitate was filtered off and recrystallised 
from a mixture of acetone (50 ml) and ethanol (20 ml) to give 1.28 g (33%) 
of the hydrogen oxalate. 
TLC: R.sub.f =0.45 (SiO.sub.2 : chloroform/methanol=150:1) 
A mixture of the above ester hydrogen oxalate (1.03 g, 2 mmol) in ethanol 
(9 ml) and a 14% solution of potassium hydroxide (4.6 ml) was stirred at 
reflux temperature for 6.5 h. Ethanol was evaporated, the residue was 
dissolved in water (15 ml) and acidified with acetic acid (1.5 ml) to pH 
5.5. The solution was extracted with chloroform (80 ml), washed with water 
(15 ml), dried (Na.sub.2 SO.sub.4) and evaporated in vacuo. The oily 
residue was dissolved in hot acetone (20 ml) and oxalic acid dihydrate 
(0.265 g, 2.1 mmol) was added. After cooling, ether (20 ml) was added. The 
precipitate was filtered off and crystallised from a mixture of 2-propanol 
and ether. Yield 0.82 g (84%) of the title compound. 
M.p. 102-104.degree. C. 
Calculated for C.sub.23 H.sub.27 NO.sub.3 S, 0.5 H.sub.2 O, (COOH).sub.2 : 
C, 60.46%; H, 6.09%; N, 2.82%; S, 6.46%; Found: C, 60.50%; H, 6.05%; N, 
2.69%; S, 6.85%. 
Example 6 
1-(2-(8-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-piperi 
dinecarboxylic acid hydrogen oxalate 
##STR13## 
8, 10-Dichloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 35.6 mmol, prepared 
as described in Coll. Czech. Chem. Commun. 33,183, 1968) was slowly added 
to a mixture of 2-bromoethanol (44 g, 0.352 mol) and powdered potassium 
carbonate (10 g, 0.072 mol) at 20.degree. C. under stirring. After 6 h, 
dichloromethane (15 ml) was added and the reaction mixture was heated at 
50.degree. C. for 3 h. After cooling, dichloromethane (35 ml) was added 
and the mixture was filtered. Dichloromethane was evaporated and excess of 
2-bromoethanol was distilled off in vacuo. The oily residue was dissolved 
in benzene (100 ml), washed with water (3.times.70 ml), dried (K.sub.2 
CO.sub.3) and the solvent evaporated to give 13.0 g of crude 
8-chloro-10-(2-bromoethoxy)-10,11-dihydrodibenzo[b,f]thiepine as an oil. 
A mixture of the above crude bromide (12.1 g, 32.7 mmol), 
3-piperidinecarboxylic acid ethyl ester (5.0 g, 31.8 mmol), potassium 
carbonate (5.0 g, 36.2 mmol), potassium iodide (0.5 g) and acetone (100 
ml) was heated at reflux temperature under stirring for 20 h. The mixture 
was filtered and the solvent evaporated in vacuo. The oily residue was 
purified by column chromatography on silica gel (100 g) using ethyl 
acetate as eluent to give 9.7 g of 
1-(2-(8-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-pipe 
ridinecarboxylic acid ethyl ester as an oil. 
TLC: R.sub.f =0.50 (SiO.sub.2 : chloroform/methanol=150:1) 
The above ester (5.4 g, 12.1 mmol) was dissolved in ethanol (50 ml), 5 N 
sodium hydroxide (5 ml) was added, and the mixture was stirred at room 
temperature for 20 h. Ethanol was evaporated in vacuo, water (50 ml) and 
acetic acid (7 ml) were added, and the mixture was extracted with 
dichloromethane (100 ml). The organic phase was dried (MgSO.sub.4) and the 
solvent was evaporated in vacuo. The residue was dissolved in acetone and 
treated with oxalic acid to give 3.8 g (62%) of the title compound. 
M.p. 190-192.degree. C. 
Calculated for C.sub.22 H.sub.24 ClNO.sub.3 S, (COOH).sub.2 : 
C, 56.74%; H, 5.16%; N, 2.76%; Cl, 6.98%; S, 6.31%; Found: C, 56.86%; H, 
5.33%; N, 2.59%; Cl, 6.87%; S, 6.31%. 
Example 7 
1-(2-(8-Methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-3-pi 
peridinecarboxylic acid hydrogen oxalate 
##STR14## 
The title compound was prepared analogously as described for the title 
compound in example 6, using 
8-methylthio-10-chloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 34.1 mmol, 
prepared as described in Coll. Czech. Chem. Commun. 33, 1895, 1968) as 
starting material. 
M.p. 166-169.degree. C. 
Calculated for C.sub.23 H.sub.27 NO.sub.3 S.sub.2, (COOH).sub.2 : 
C, 57.78%; H, 5.63%; N, 2.70%; S, 12.34%; Found: C, 57.55%; H, 5.62%; N, 
2.44%; S, 12.00%. 
Example 8 
(R)-1-(2-(10,11-Dihydrodibenzo[b,f]oxepin-10-yloxy)ethyl)-3-piperidinecarbo 
xylic acid hydrochloride 
##STR15## 
At 10-15.degree. C., and over 15 minutes, a solution of boron trifluoride 
ethyl etherate (1.66 g, 11.6 mmol) in dry benzene (5 ml) was added 
dropwise to a stirred solution of 10,11-dihydrodibenz[b,f]oxepin-10-ol 
(2.29 g, 10.8 mmol, prepared as described in Coll. Czech. Chem. Commun.34, 
2258 (1969) ) and 2-bromoethanol (2.13 g, 17 mmol) in dry benzene (20 ml). 
Stirring was continued at 10-15.degree. C. for 1.5 h. The reaction mixture 
was quenched with cold water (15.degree. C., 15 ml), the organic phase was 
washed with water (3.times.30 ml), dried (sodium sulfate) and evaporated 
in vacuo. The residual oily raw product (2.77 g), 
10-(2-bromoethoxy)-10,11-dihydrodibenz[b,f]oxepine was used without 
further purification in the next reaction step. 
A mixture of the above bromide (2.77 g, 8.7 mmol), 
(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.42 g, 9 mmol) and 
powdered potassium carbonate (1.56 g, 10 mmol) in dry 
N,N-dimethylformamide (15 ml) was stirred, first at 40-48.degree. C. for 7 
h and then at room temperature overnight. The mixture was diluted with 
benzene (80 ml) and washed with water (3.times.30 ml). The organic layer 
was dried (potassium carbonate) and evaporated in vacuo. The oily residue 
(3.31 g) was purified by column chromatography on silica gel (70 g), using 
first benzene and then chloroform as eluents. The chloroform fraction 
contained 1.75 g (54%) of 
(R)-1-(2-(10,11-dihydrodibenzo[b,f]oxepin-10-yloxy)ethyl)-3-piperidinecarb 
oxylic acid ethyl ester. 
TLC: R.sub.f =0.3 (SiO.sub.2 : chloroform saturated with 
ammonia/methanol=100:1). 
Under stirring at room temperature, a solution of the above ethyl ester 
(1.7 g, 4.3 mmol) in ethanol (17 ml) was treated with 4 N sodium hydroxide 
(11 ml, 43 mmol) for 20 h. Ethanol was evaporated and the oily residue was 
dissolved in water (80 ml). The solution was extracted with ether 
(3.times.50 ml), and the aqueous layer was filtered first with charcoal 
(0.5 g) and then on silica gel (2 g). Dichloromethane (350 ml) was added 
and the mixture was acidified to pH 1 using 6 N hydrochloric acid (7.5 
ml). The organic layer was dried (MgSO.sub.4), evaporated in vacuo and 
stripped with dry acetone (2.times.20 ml) twice. The crude product (1.3 g) 
was dissolved in dry acetone (20 ml) and dropwise added very slowly into 
vigorously stirred dry ether (150 ml). The mixture was stirred for 1 h at 
room temperature. The precipitate was filtered off, washed with dry ether 
(4.times.25 ml) and dried to give 1.27 g (73%) of the title compound. 
M.p. 106-112.degree. C. 
Calculated for C.sub.22 H.sub.25 NO.sub.4, HCl, 0.5 H.sub.2 O: 
C, 63.99%; H, 6.59%; N, 3.39%; Cl, 8.59%, Found: C, 63.93%; H, 6.57%; N, 
3.17%; Cl, 8.29%. 
Example 9 
(R)-1-(2-(2-Chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ylsulfanyl)ethyl)-3- 
piperidinecarboxylic acid hydrochloride 
##STR16## 
To a solution of sodium ethoxide (prepared by dissolving sodium (0.3 g, 13 
mmol) in dry ethanol (20 ml) ), 
2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-ylthiol (3.6 g, 13 mmol, 
prepared as described in Coll. Czech. Chem. Commun. 54, 1403, 1989) was 
added and the mixture was stirred for 30 minutes at 60.degree. C. 
2-Bromoethanol (2.0 g,16 mmol) was added and the mixture was heated at 
reflux temperature for 2 h. Ethanol was evaporated and benzene (60 ml) and 
water (25 ml) were added. The organic phase was separated and washed with 
1 M potassium carbonate (3.times.20 ml) and water (3.times.30 ml) to pH 
6.5, dried (potassium carbonate) and evaporated in vacuo. The residual oil 
(4.5 g) was purified by column chromatography on silica gel (100 g) using 
benzene as eluent, affording 
2-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yl-sulfanyl)ethanol in 
quantitative yield. 
TLC: R.sub.f =0.46 (SiO.sub.2 : chloroform). 
A solution of methanesulfonyl chloride (2.02 g, 20 mmol) in dry toluene (20 
ml) was added dropwise to a solution of the above alcohol (4.16 g, 12.9 
mmol) in dry toluene (100 ml) and triethylamine (4.05 g, 40 mmol) at 
8-15.degree. C., over 0.5 h. Stirring was continued for 0.5 h at 
8-15.degree. C. and then at room temperature for 6 h. The mixture was 
washed with water (4.times.100 ml), dried (sodium sulfate) and evaporated 
in vacuo, to give the corresponding mesylate in quantitative yield as an 
oil. 
To a solution of the above mesylate (5.16 g, 12.8 mmol) in dry acetone (100 
ml), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.26 g, 14.4 
mmol) and potassium carbonate (2.1 g, 15 mmol) were added. The reaction 
mixture was stirred at room temperature overnight and then at reflux 
temperature for 5 h. After cooling, the precipitate was filtered off and 
the filtrate was evaporated in vacuo. The residue (6.45 g) was purified by 
column chromatography on silica gel (150 g), using first benzene and then 
chloroform as eluents, affording 4.24 g (71%) of 
(R)-1-(2-(dibenzo[b,f]thiepin-10-ylsulfanyl)ethyl)-3-piperidinecarboxylic 
acid ethyl ester. 
TLC: R.sub.f =0.18 (SiO.sub.2 : chloroform). 
The free base was treated with oxalic acid dihydrate (1.26 g, 10 mmol) in 
dry acetone (25 ml), affording, after recrystallisation from 2-propanol, 
3.9 g (69%) of the ethyl ester hydrogen oxalate. 
A mixture of the above ethyl ester hydrogen oxalate (3.3 g, 6 mmol) in 
ethanol (35 ml) and 4 N sodium hydroxide (15 ml, 60 mmol) was stirred 
overnight at room temperature and then for 0.5 h at reflux temperature. 
After cooling to 15.degree. C., dichloromethane was added and the mixture 
was acidified using 6 N hydrochloric acid (12 ml) to pH 1. The organic 
layer was separated, dried (MgSO.sub.4) and evaporated in vacuo. The solid 
residue was triturated with a 1:1 mixture of acetone and ether (50 ml), 
filtered off and washed with dry ether (2.times.25 ml), to give 2.44 g 
(94%) of the title compound. 
M.p. 220-224.degree. C. (ethanol/diethyl ether). 
Calculated for C.sub.22 H.sub.24 ClNO.sub.2 S.sub.2, HCl: 
C, 56.16%; H, 5.36%; Cl, 15.07%; N, 2.98%; S, 13.63%; Found: C, 56.35%; H, 
5.65%; Cl, 15.04%; N, 2.68%; S, 13.31%. 
Example 10 
(R)-1-(11H-Dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic 
acid hemimaleate 
##STR17## 
A mixture of 11-bromomethyl-11H-dibenz[b,f][1,4]oxathiepine (6.15 g, 20 
mmol, prepared similarly as described in Coll. Czech. Chem. Commun. 50, 
1484, 1985), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.7 g, 
30 mmol) and chloroform (10 ml) was warmed to achieve dissolution. The 
solution was then allowed to stand for 1 week at room temperature, and was 
subsequently heated at reflux temperature for 7 h. After cooling, the 
mixture was diluted with benzene and washed with 5% ammonia. The organic 
phase was dried (potassium carbonate) and evaporated. The residue was 
purified by column chromatography on silica gel (55 g) using first benzene 
and then diethyl ether as eluents to give 4.1 g (53%) of 
(R)-1-(11H-dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic 
acid ethyl ester as an oil. 
TLC: R.sub.f =0.50 (SiO.sub.2 : chloroform/ethanol/ammonium 
hydroxide=20:1:0.005). 
The above ester (4.1 g, 10.7 mmol) was dissolved in ethanol (70 ml) and 5 N 
sodium hydroxide (5 ml) was added. The mixture was allowed to stand for 3 
days at room temperature, and then ethanol was evaporated in vacuo and 
water (50 ml) was added. The mixture was extracted with diethyl ether and 
the phases were separated. Acetic acid (4 ml) was added and the mixture 
was extracted with dichloromethane (5.times.50 ml). The combined organic 
extracts were dried (MgSO.sub.4) and the solvent was evaporated in vacuo. 
The residue was dissolved in diethyl ether and neutralised with maleic 
acid in diethyl ether. The amorphous precipitate was filtered off and 
dried. This afforded 3.95 g (77%) of the title compound. 
Calculated for C.sub.20 H.sub.21 NO.sub.3 S, 0.5 C.sub.4 H.sub.4 O.sub.4, 
0.5 H.sub.2 O: 
C, 59.99%; H, 5.45%; N, 2.91%; S, 6.67%; Found: C, 60.19%; H, 5.64%; N, 
2.67%; S, 6.54%. 
Example 11 
(R)-1-(2-(2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl 
)-3-piperidinecarboxylic acid hydrochloride 
##STR18## 
To a solution of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine 
(4.14 g, 13.8 mmol, prepared as described in Coll. Czech. Chem. Commun. 
40, 2887, 1975) in dichloromethane (24 ml), 2-bromoethanol (17.0 g, 136 
mmol) was added, followed by dry potassium carbonate (6.25 g, 45 mmol). 
The reaction mixture was stirred at 40.degree. C. for 11 h, additional 
dichloromethane (30 ml) was added, the inorganic salts were filtered off 
and the filtrate was evaporated in vacuo. This afforded 5.35 g (100%) of 
10-(2-bromoethoxy)-2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine as 
an oil. 
A mixture of the above bromide (5.35 g, 13.8 mmol), 
(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.5 g, 16 mmol) and 
potassium carbonate (3.0 g, 22 mmol) in N,N-dimethylformamide (25 ml) was 
stirred at 65-72.degree. C. for 12 h and left to stand at room temperature 
overnight. The reaction mixture was diluted with benzene (150 ml) and 
washed with water (4.times.30 ml). The organic layer was dried (sodium 
sulfate) and evaporated in vacuo to give an oily residue (5.72 g), which 
was further purified by column chromatography on silica gel (100 g) using 
benzene and chloroform as eluents. The main fraction afforded 4.0 g (61%) 
of 
(R)-1-(2-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethy 
l)-3-piperidinecarboxylic acid ethyl ester as an oil. 
TLC: R.sub.f =0.52 (SiO.sub.2 : chloroform saturated with 
ammonia/chloroform/methanol=5:1:0.02) 
The free base (4.0 g, 8.6 mmol) was transformed to the corresponding 
hydrogen oxalate using oxalic acid dihydrate. (1.2 g, 9.3 mmol) in 
2-propanol (10 ml) and ether (20 ml). Yield: 4.1 g (88%) 
A mixture of the above ethyl ester hydrogen oxalate (2.2 g, 3.97 mmol) in 
96% ethanol (22 ml) and 5 N sodium hydroxide (6 ml) was stirred at room 
temperature for 21 h. Ethanol was evaporated in vacuo, and the residue was 
dissolved in water (65 ml) and washed with diethyl ether (2.times.50 ml). 
Dichloromethane (250 ml) was added to the alkaline aqueous phase and the 
mixture was acidified with 5 N hydrochloric acid to pH 1. After stirring 
for 15 minutes, the organic layer was separated, dried (MgSO.sub.4) and 
evaporated in vacuo. The residue was triturated with a mixture of acetone 
and ether (1:1) (3.times.25 ml). The solid product was filtered off and 
washed with ether (2.times.10 ml), affording 1.24 g (53%) of the title 
compound. 
M.p. 130-134.degree. C. 
Calculated for C.sub.22 H.sub.23 ClFNO.sub.3 S, HCl, 0.5 H.sub.2 O: 
C, 54.89%; H, 5.23%; N, 2.91%; Cl, 14.73%; F, 3.95%; S, 6.66%; Found: C, 
55.17%; H, 5.29%; N, 2.74%; Cl, 14.43%; F, 4.05%; S, 6.72%. 
Example 12 
(R)-1-(2-(2,4-Dichloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl)-3-p 
iperidinecarboxylic acid hydrochloride 
##STR19## 
A mixture of 2,4,10-trichloro-10,11-dihydrodibenzo[b,f]thiepine (2.5 g, 8.6 
mmol, prepared as described in Coll. Czech. Chem. Commun. 46, 781, 1981), 
2-bromoethanol (12.5 g, 100 mmol) and potassium carbonate (4.0 g, 30 mmol) 
in dichloromethane (20 ml) was stirred at 40.degree. C. for 11 h. The 
solid was filtered off and the filtrate was evaporated in vacuo. The 
residue (3.4 g) was dissolved in a mixture of diethyl ether and light 
petroleum (1:1) (40 ml) and left to stand in a refrigerator for a week, 
affording after isolation 2.6 g (80%) of 
10-(2-bromoethoxy)-2,4-dichloro-10,11-dihydrodibenzo[b,f]thiepine. 
A mixture of the above bromide (2.5 g, 6.2 mmol), 
(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.7 g, 11 mmol) and 
dry potassium carbonate (2.8 g, 20 mmol) in N,N-dimethylformamide (15 ml) 
was stirred at 50.degree. C. for 18 h, diluted with benzene (60 ml), 
washed with water (5.times.30 ml), dried (sodium sulfate) and evaporated 
in vacuo. The oily residue (3.68 g) was purified by column chromatography 
on silica (70 g) using benzene and chloroform as eluents. This afforded 
2.63 g (89%) of 
(R)-1-(2-(2,4-dichloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)ethyl)-3- 
piperidinecarboxylic acid ethyl ester as an oil. 
TLC: R.sub.f =0.64 (SiO.sub.2 : chloroform saturated with 
ammonia/methanol=300:1). 
The free base was transformed to the corresponding hydrogen oxalate by 
treatment with oxalic acid dihydrate (0.76 g, 6 mmol) in 2-propanol (3 ml) 
and ether (14 ml). This afforded 1.7 g (48%) of the hydrogen oxalate. 
A mixture of the above ethyl ester hydrogen oxalate (1.58 g, 2.77 mmol), 
96% ethanol (16 ml) and 5 N sodium hydroxide (4 ml) was stirred at 
40.degree. C. for 4 h and then overnight at room temperature. 
Dichloromethane (250 ml) was added, followed by 5 N hydrochloric acid (4 
ml) to pH 1. After stirring for 15 minutes, the organic layer was 
separated, dried (MgSO.sub.4) and evaporated in vacuo. The solid residue 
was triturated with a mixture of acetone and ether (1:1) (3.times.30 ml), 
filtered off and washed with dry ether (2.times.10 ml), affording 1.1 g 
(81%) of the title compound. 
M.p. 168-172.degree. C. 
Calculated for C.sub.22 H.sub.23 Cl.sub.2 NO.sub.3 S, HCl, 0.25 H.sub.2 O: 
C, 53.56%; H, 5.01%; N, 2.64%; Cl, 21.56%, S, 6.50%; Found: C, 53.66%; H, 
5.02%; N, 2.73%; Cl, 21.14%, S, 6.61%.