Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them

This invention relates to a class of azacyclic compounds, which are useful 
as tachykinin antagonists. More particularly, the compounds of the 
invention comprise an azacyclic ring system substituted by an 
arylmethyloxy or arylmethylthio moiety. 
The tachykinins are a group of naturally-occurring peptides found widely 
distributed throughout mammalian tissues, both within the central nervous 
system and in the peripheral nervous and circulatory systems. The 
structures of three known mammalian tachykinins are as follows: 
Substance P: 
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 
Neurokinin A: 
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2 
Neurokinin B: 
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2 
For example, substance P is believed inter alia to be involved in the 
neurotransmission of pain sensations [Otsuka et al, "Role of Substance P 
as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 
Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 
(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as 
a Pain Transmitter?" TIPS (December 1987) 8 506-510], specifically in the 
transmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem, 
(1982) 25 1009) and in arthritis [Levine et al in Science (1984) 226 
547-549]. These peptides have also been implicated in gastrointestinal 
(GI) disorders and diseases of the GI tract such as inflammatory bowel 
disease [Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoli 
in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific 
Publishers, Amsterdam (1987) page 85)]. It is also hypothesised that there 
is a neurogenic mechanism for arthritis in which substance P may play a 
role [Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The 
Lancet, 11 Nov. 1989 and Gronblad et al "Neuropeptides in Synovium of 
Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. 
(1988) 15(12) 1807-10]. Therefore, substance P is believed to be involved 
in the inflammatory response in diseases such as rheumatoid arthritis and 
osteoarthritis [O'Byrne et al in Arthritis and Rheumatism (1990) 33 
1023-8]. Other disease areas where tachykinin antagonists are believed to 
be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. 
Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 
241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9] 
vasodilation, bronchospasm, reflex or neuronal control of the viscera 
[Mantyh et al, PNAS (1988) 85 3235-9] and, possibly by arresting or 
slowing .beta.-amyloid-mediated neurodegenerative changes [Yankner et al 
Science, (1990) 250, 279-82] in senile dementia of the Alzheimer type, 
Alzheimer's disease and Down's Syndrome. 
Substance P may also play a role in demyelinating diseases such as multiple 
sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., 
poster to be presented at C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul., 
1992, in press], and in disorders of bladder function such as bladder 
detrusor hyper-reflexia (Lancet, 16th May, 1992, 1239). 
It has furthermore been suggested that tachykinins have utility in the 
following disorders: depression, dysthymic disorders, chronic obstructive 
airways disease, hypersensitivity disorders such as poison ivy, 
vasospastic diseases such as angina and Reynauld's disease, fibrosing and 
collagen diseases such as scleroderma and eosinophillic fascioliasis, 
reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction 
disorders such as alcoholism, stress related somatic disorders, 
neuropathy, neuralgia, disorders related to immune enhancement or 
suppression such as systemic lupus erythmatosis (European patent 
application no. 0 436 334), opthalmic disease such as conjuctivitis, 
vernal conjunctivitis, and the like, and cutaneous diseases such as 
contact dermatitis, atropic dermatitis, urticaria, and other eczematoid 
dermatitis (European patent application no. 0 394 989). 
In view of their metabolic instability, peptide derivatives are likely to 
be of limited utility as therapeutic agents. It is for this reason that 
non-peptide tachykinin antagonists are sought. 
European patent application no. 0 436 334 discloses 4-to 7-membered 
azacyclic compounds substituted at the 3-position by a substituted amino 
moiety. The compounds are said to be tachykinin antagonists. 
The present invention provides a compound of formula (I), or a salt or 
prodrug thereof: 
##STR2## 
wherein n is 1, 2 or 3 and where any carbon atom of (CH.sub.2).sub.n may 
be substituted by R.sup.4 and/or R.sup.5 ; 
X represents O or S; 
R.sup.1 represents phenyl optionally substituted by 1, 2 or 3 groups 
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, 
cyano, nitro, trifluoromethyl, trimethylsilyl --OR.sup.a, SR.sup.a, 
SOR.sup.a, SO.sub.2 R.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a 
CO.sub.2 R.sup.b, --CO.sub.2 R.sup.a or --CONR.sup.a R.sup.b ; 
R.sup.2 represents aryl selected from phenyl and naphthyl; heteroaryl 
selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl 
and quinolyl: benzhydryl; or benzyl; wherein each aryl or heteroaryl 
moiety may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo or 
trifluoromethyl; 
R.sup.4 and R.sup.5 each independently represent H, halo, CH.sub.2 
OR.sup.9, C.sub.1-6 alkyl, oxo, CO.sub.2 R.sup.10 or CONR.sup.10 R.sup.11 
; 
R.sup.8 represents H, COR.sup.9, CO.sub.2 R.sup.10, COCONR.sup.10 R.sup.11, 
COCO.sub.2 R.sup.10 or C.sub.1-6 alkyl optionally substituted by a group 
selected from (CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, hydroxy, cyano 
COR.sup.9, NR.sup.10 R.sup.11, C(NOH)NR.sup.10 R.sup.11, 
CONHphenyl(C.sub.1-4 alkyl), COCO.sub.2 R.sup.10, COCONR.sup.10 R.sup.11 
and phenyl optionally substituted by one or more substituents selected 
from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo and trifluoromethyl); 
R.sup.a and R.sup.b each independently represent H, C.sub.1-6 alkyl, phenyl 
or trifluoromethyl; 
R.sup.9 represents H, C.sub.1-6 alkyl or phenyl; and 
R.sup.10 and R.sup.11 each independently represent H or C.sub.1-6 alkyl. 
One subgroup of compounds according to the invention is represented by 
compounds wherein n is 2 or 3; R.sup.4 and R.sup.5 each independently 
represent H, halo, C.sub.1-6 alkyl, CO.sub.2 R.sup.10 or CONR.sup.10 
R.sup.11 ; and R.sup.8 represents H, COR.sup.9 or C.sub.1-6 alkyl 
optionally substituted by a group selected from (CO.sub.2 
R.sup.10,CONR.sup.10 R.sup.11 and phenyl optionally substituted by 
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo or trifluoromethyl). 
A further subgroup of compounds according to the invention is represented 
by compounds wherein n is 2 or 3; R.sup.2 represents phenyl or benzhydryl 
wherein any of the phenyl rings of the phenyl or benzhydryl moieties may 
optionally be substituted by halo or trifluoromethyl; R.sup.4 and R.sup.5 
each independently represent H, C.sub.1-6 alkyl or CO.sub.2 (C.sub.1-6 
alkyl); and R.sup.8 represents H or C.sub.1-6 alkyl. 
Preferably n is 2 or 3, more preferably 3. 
Preferably X represents O. 
Preferably R.sup.1 represents substituted phenyl. When R.sup.1 is 
substituted phenyl suitable substituents include C.sub.1-6 alkyl 
especially C.sub.1-4 alkyl such as methyl and t-butyl, nitro, 
trifluoromethyl, trimethylsilyl, halo such as bromo, chloro and iodo, 
carboxy, cyano, C.sub.1-6 alkoxy such as methoxy and amino. Preferably 
R.sup.1 represents phenyl substituted by one or more groups selected from 
methyl, trifluoromethyl and halo, especially chloro. When monosubstituted, 
the substituent is suitably in the 3-position of the phenyl ring. More 
preferably R.sup.1 represents disubstituted phenyl. Particularly preferred 
are compounds of formula (I) wherein R.sup.1 represents 3,5-disubstituted 
phenyl, especially 3,5-bis(trifluoromethyl)phenyl. 
Suitable values for the group R.sup.2 include aryl such as substituted or 
unsubstituted phenyl, 5-membered heteroaryl such as thienyl, 6-membered 
heteroaryl such as pyridyl, and benzhydryl. 
Preferably R.sup.2 represents unsubstituted or substituted phenyl or 
thienyl, pyridyl or benzhydryl. When R.sup.2 is substituted phenyl, 
suitable phenyl substituents include C.sub.1-6 alkyl, such as methyl, and 
halo, such as chloro. Particularly preferred are compounds of formula (I) 
wherein R.sup.2 represents unsubstituted phenyl. 
Suitable values for R.sup.4 and R.sup.5 include H, C.sub.1-6 alkyl, 
especially methyl, CH.sub.2 OR.sup.9 such as hydroxymethyl and oxo. The 
substituents R.sup.4 and R.sup.5 may be located on any available ring 
carbon atom, including (except when they represent oxo) C-2 and C-3, but 
will preferably be located at the 6-position. Preferably at least one of 
R.sup.4 and R.sup.5 represents H. In one preferred group of compounds 
R.sup.4 and R.sup.5 both represent H. In a further preferred group of 
compounds one of R.sup.4 and R.sup.5 is H and the other is 
6-hydroxymethyl. 
Suitable values for R.sup.8 include H, COR.sup.9 such as CHO and 
COCH.sub.3, CO.sub.2 R.sup.10, such as CO.sub.2 C.sub.1-6 alkyl e.g. 
CO.sub.2 C.sub.1-4 alkyl such as CO.sub.2 t-butyl, COCONR.sup.10 R.sup.11, 
such as COCONH.sub.2, COCO.sub.2 R.sup.10, such as COCO.sub.2 C.sub.1-4 
alkyl, for example, COCO.sub.2 CH.sub.3, C.sub.1-6 alkyl, such as methyl, 
and substituted C.sub.1-6 alkyl e.g. substituted C.sub.1-3 alkyl such as 
methyl, ethyl or n-propyl, such as C.sub.1-6 alkyl substituted by CO.sub.2 
R.sup.10, especially CO.sub.2 CH.sub.3 and CO.sub.2 H, CONR.sup.10 
R.sup.11 especially CONH.sub.2, CONHCH.sub.3, CONH(t-butyl), 
CONH(cyclopropyl) and CON(CH.sub.2 CH.sub.3).sub.2, cyano, C(NOH)NR.sup.10 
R.sup.11, especially C(NOH)NH.sub.2, CONHphenyl(C.sub.1-4 alkyl), 
especially CONHbenzyl, and optionally substituted phenyl, especially 
unsubstituted phenyl and phenyl substituted by one or more of C.sub.1-6 
alkoxy, such as methoxy or trifluoromethyl. 
In one preferred group of compounds of formula (I), R.sup.8 represents H. 
In a further preferred group of compounds of formula (I), R.sup.8 
represents C.sub.1-6 alkyl substituted by CO.sub.2 R.sup.10 or CONR.sup.10 
R.sup.11, more preferably R.sup.8 represents CH.sub.2 CO.sub.2 R.sup.10, 
CH(CH.sub.3)CO.sub.2 R.sup.10, CH.sub.2 CONR.sup.10 R.sup.11 or 
CH(CH.sub.3)CONR.sup.10 R.sup.11, especially CH.sub.2 CO.sub.2 CH.sub.3, 
CH(CH.sub.3)CO.sub.2 CH.sub.3, CH.sub.2 CONH.sub.2 or 
CH(CH.sub.3)CONH.sub.2. 
The alkyl, alkenyl and alkynyl groups referred to with respect to the 
formulae herein may represent straight, branched or cyclic groups or 
combinations thereof. Thus, for example, suitable alkyl groups include 
methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, 
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexy, and cycloalkyl-alkyl 
groups such as cyclopropylmethyl; suitable alkenyl groups include vinyl 
and allyl; and suitable alkynyl groups include propargyl. 
The term "halo" as used herein includes fluoro, chloro, bromo and iodo. 
For use in medicine, the salts of the compounds of formula (I) will be 
non-toxic pharmaceutically acceptable salts. Other salts may, however, be 
useful in the preparation of the compounds according to the invention 
(such as the dibenzoyltartrate salts) or of their non-toxic 
pharmaceutically acceptable salts. Suitable pharmaceutically acceptable 
salts of the compounds of this invention include acid addition salts which 
may, for example, be formed by mixing a solution of the compound according 
to the invention with a solution of a pharmaceutically acceptable 
non-toxic acid such as hydrochloric acid, oxalic acid, fumaric acid, 
maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, 
carbonic acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine 
groups may also comprise quaternary ammonium salts in which the amino 
nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, 
alkynyl or aralkyl moiety. Furthermore, where the compounds of the 
invention carry an acidic moiety, suitable pharmaceutically acceptable 
salts thereof may include metal salts such as alkali metal salts, e.g. 
sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or 
magnesium salts. 
Preferred salts of the compounds according to the invention include the 
hydrochloride, hydrobromide and p-toluenesulphonic acid salts, especially 
the hydrobromide salt. 
The present invention includes within its scope prodrugs of the compounds 
of formula (I) above. In general, such prodrugs will be functional 
derivatives of the compounds of formula I which are readily convertible in 
vivo into the required compound of formula (I). Conventional procedures 
for the selection and preparation of suitable prodrug derivatives are 
described, for example, in "Design of Prodrugs", ed. H. Bundgaard, 
Elsevier, 1985. 
The compounds according to the invention may exist both as enantiomers and 
as diastereomers. It is to be understood that all such isomers and 
mixtures thereof are encompassed within the scope of the present 
invention. 
A particular sub-class of compounds according to the invention is 
represented by compounds of formula (Ia), and salts and prodrugs thereof: 
##STR3## 
wherein R.sup.2, R.sup.8 and X are as defined for formula (I); 
R.sup.20 and R.sup.21 independently represent H, C.sub.1-6 alkyl, C.sub.2-6 
alkenyl, C.sub.2-6 alkynyl, halo, cyano, nitro, trifluoromethyl, 
trimethylsilyl, OR.sup.a, SR.sup.a SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a 
R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, CO.sub.2 R.sup.a 
or CONR.sup.a R.sup.b, where R.sup.a and R.sup.b are as previously 
defined; and 
R.sup.22 represents H, C.sub.1-6 alkyl, CH.sub.2 OR.sup.9 or oxo, 
preferably H. 
Particular values of R.sup.20 and R.sup.21 include H, methyl, butyl, halo, 
trimethylsilyl, trifluoromethyl, nitro, carboxy, cyano and amino. 
Preferably R.sup.20 and R.sup.21 are both other than H and are located at 
the 3-and 5-positions of the phenyl ring. More preferably R.sup.20 and 
R.sup.21 each represent trifluoromethyl. 
R.sup.22 may be located on any available carbon atom of the piperidine 
ring. In particular when R.sup.22 is C.sub.1-6 alkyl or CH.sub.2 OR.sup.9, 
it may be located at the 2-, 3-, or 6-position of the piperidine ring, 
preferably the 6-position. When R.sup.22 is oxo, it is preferably located 
at the 6-position. 
The invention also provides pharmaceutical compositions comprising one or 
more compounds of this invention in association with a pharmaceutically 
acceptable carrier. Preferably these compositions are in unit dosage forms 
such as tablets, pills, capsules, powders, granules, sterile parenteral 
solutions or suspensions, or suppositories, for oral, parenteral or rectal 
administration. For preparing solid compositions such as tablets, the 
principal active ingredient is mixed with a pharmaceutical carrier, e.g. 
conventional tableting ingredients such as corn starch, lactose, sucrose, 
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or 
gums, and other pharmaceutical diluents, e.g. water, to form a solid 
preformulation composition containing a homogeneous mixture of a compound 
of the present invention, or a non-toxic pharmaceutically acceptable salt 
thereof. When referring to these preformulation compositions as 
homogeneous, it is meant that the active ingredient is dispersed evenly 
throughout .the composition so that the composition may be readily 
subdivided into equally effective unit dosage forms such as tablets, pills 
and capsules. This solid preformulation composition is then subdivided 
into unit dosage forms of the type described above containing from 0.1 to 
about 500 mg of the active ingredient of the present invention. The 
tablets or pills of the novel composition can be coated or otherwise 
compounded to provide a dosage form affording the advantage of prolonged 
action. For example, the tablet or pill can comprise an inner dosage and 
an outer dosage component, the latter being in the form of an envelope 
over the former. The two components can be separated by an enteric layer 
which serves to resist disintegration in the stomach and permits the inner 
component to pass intact into the duodenum or to be delayed in release. A 
variety of materials can be used for such enteric layers or coatings, such 
materials including a number of polymeric acids and mixtures of polymeric 
acids with such materials as shellac, cetyl alcohol and cellulose acetate. 
The liquid forms in which the novel compositions of the present invention 
may be incorporated for administration orally or by injection include 
aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, 
and flavoured emulsions with edible oils such as cottonseed oil, sesame 
oil, coconut oil or peanut oil, as well as elixirs and similar 
pharmaceutical vehicles. Suitable dispersing or suspending agents for 
aqueous suspensions include synthetic and natural gums such as tragacanth, 
acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, 
polyvinylpyrrolidone or gelatin. 
The present invention futher provides a process for the preparation of a 
pharmaceutical composition comprising a compound of formula (I), which 
process comprises bringing a compound of formula (I) into association with 
a pharmaceutically acceptable carrier or excipient. 
The compounds of formula (I) are of value in the treatment of a wide 
variety of clinical conditions which are characterised by the presence of 
an excess of tachykinin, in particular substance P, activity. These may 
include disorders of the central nervous system such as anxiety, 
depression, psychosis and schizophrenia; neurodegenerative disorders such 
as dementia, including senile dementia of the Alzheimer type, Alzheimer's 
disease and Down's syndrome; demyelinating diseases such as MS and ALS and 
other neuropathological disorders such as peripheral neuropathy, for 
example, diabetic and chemotherapy-induced neuropathy, and postherpetic 
and other neuralgias; respiratory diseases such as chronic obstrucutive 
airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory 
diseases such as inflammatory bowel disease, psoriasis, fibrositis, 
osteoarthritis and rheumatoid arthritis; allergies such as eczema and 
rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic 
diseases such as conjunctivitis, vernal conjunctivitis, and the like; 
cutaneous diseases such as contact dermatitis, atropic dermatitis, 
urticaria, and other eczematoid dermatitis; addiction disorders such as 
alcoholism; stress related somatic disorders; reflex sympathetic dystrophy 
such as shoulder/hand syndrome; dysthymic disorders; adverse immunological 
reactions such as rejection of transplanted tissues and disorders related 
to immune enhancement or suppression such as systemic lupus erythematosis; 
gastrointestinal (GI) disorders and diseases of the GI tract such as 
disorders associated with the neuronal control of viscera such as 
ulcerative colitis, Crohn's disease and incontinence; disorders of bladder 
function such as bladder detrusor hyper-reflexia; fibrosing and collagen 
diseases such as scleroderma and eosinophilic fascioliasis; disorders of 
blood flow caused by vasodilation and vasospastic diseases such as angina, 
migraine and Reynaud's disease; and pain or nociception, for example, that 
attributable to or associated with any of the foregoing conditions, 
especially the transmission of pain in migraine. For example, the 
compounds of formula (I) may suitably be used in the treatment of 
disorders of the central nervous system such as anxiety, psychosis and 
schizophrenia; neurodegenerative disorders such as senile dementia of the 
Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory 
diseases such as bronchospasm and asthma; inflammatory diseases such as 
inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; 
adverse immunological reactions such as rejection of transplanted tissues; 
gastrointestinal (GI) disorders and diseases of the GI tract such as 
disorders associated with the neuronal control of viscera such as 
ulcerative colitis, Crohn's disease and incontinence; disorders of blood 
flow caused by vasodilation; and pain or nociception, for example, that 
attributable to or associated with any of the foregoing conditions or the 
transmission of pain in migraine. 
The compounds of formula (I) are particularly useful in the treatment of 
pain or nociception and/or inflammation and disorders associated therewith 
such as, for example, neuropathy, such as diabetic or peripheral 
neuropathy and chemotherapy-induced neuropathy, postherpetic and other 
neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially 
migraine. 
The present invention further provides a compound of formula (I) for use in 
therapy. According to a further or alternative aspect, the present 
invention provides a compound of formula (I) for use in the manufacture of 
a medicament for the treatment of physiological disorders associated with 
an excess of tachykinins, especially substance P. The present invention 
also provides a method for the the treatment or prevention of 
physiological disorders associated with an excess of tachykinins, 
especially substance P, which method comprises administration to a patient 
in need thereof of a tachykinin reducing amount of a compound of formula 
(I) or a composition comprising a compound of formula (I). 
In the treatment of the conditions associated with an excess of 
tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, 
in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to 
about 10 mg/kg per day. For example, in the treatment of conditions 
involving the neurotransmission of pain sensations, a suitable dosage 
level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 
mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The 
compounds may be administered on a regimen of 1 to 4 times per day, 
preferably once or twice per day. 
The compounds according to the invention may be prepared by a process which 
comprises reacting a compound of formula (III) with a compound of formula 
(IV): 
##STR4## 
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5 and n are as defined for 
formula (I), R.sup.8 is as defined for formula (I) except that, when 
R.sup.8 is H it is replaced by a suitable protecting group, such as 
CO.sub.2 (C.sub.1-6 alkyl); and one of R.sup.30 and R.sup.31 represents a 
leaving group and the other of R.sup.30 and R.sup.31 represents XH, where 
X is as defined for formula (I); in the presence of a base, followed by 
deprotection, if required. 
Suitably R.sup.30 represents XH and R.sup.31 represents a leaving group. 
Suitable leaving groups include halo, e.g. chloro, bromo or iodo, or 
sulphonate derivatives such as tosylate or mesylate. 
The reaction is conveniently carried out in a suitable organic solvent, 
such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in the region 
of 0.degree. C. Favoured bases of use in the reaction include alkali metal 
amides and hydrides, such as potassium bis(trimethylsilyl)amide or 
potassium hydride. Suitably, potassium bis(trimethylsilyl)amide is used. 
Compounds of formula (I) may also be prepared from different compounds of 
formula (I) by interconversion processes. In particular, interconversion 
processes may be used to vary the group R.sup.8. For example, compounds of 
formula (I) wherein R.sup.8 is other than H may be prepared from the 
corresponding compounds of formula (I) wherein R.sup.8 is H by 
conventional methods, such as reaction with a compound R.sup.8 -Hal, where 
Hal represents halo, in the presence of a base. Suitable reagents and 
conditions will be readily apparent to those skilled in the art and are 
illustrated by the accompanying Examples. Suitable bases include organic 
bases, such as tertiary amines, e.g. triethylamine, and inorganic bases, 
such as alkali metal carbonates, e.g. sodium carbonate. Compounds of 
formula (I) wherein R.sup.8 is COR.sup.9 may also be prepared from 
compounds of formula (I) wherein R.sup.8 is H by, for example, reaction 
with an appropriate acid anhydride. Compounds of formula (I) wherein 
R.sup.8 is C.sub.1-6 alkyl may be prepared from corresponding compounds of 
formula (I) wherein R.sup.8 is COR.sup.9 by reduction using, for example, 
borane or a borohydride such as sodium cyanoborohydride. Suitable 
procedures are described in the accompanying examples. Compounds of 
formula (I) wherein R.sup.8 is C.sub.1-6 alkyl substituted by CONR.sup.10 
R.sup.11 may be prepared from corresponding compounds of formula (I) 
wherein R.sup.8 is C.sub.1-6 alkyl substituted by CO.sub.2 R.sup.10 by 
treatment with ammonia or an amine of formula NR.sup.10 R.sup.11. 
The intermediates of formula (III) above wherein R.sup.30 is SH may be 
prepared from the corresponding intermediates of formula (III) wherein 
R.sup.30 represents OH by treating the latter compound with Lawesson's 
reagent or phosphorus pentasulphide in a suitable solvent, e.g. pyridine, 
at ambient or elevated temperatures, suitably at reflux temperature. 
Intermediates of formula (III) above wherein R.sup.30 is OH may be prepared 
from corresponding compounds of formula (V): 
##STR5## 
wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.8 are as defined for formula 
III above, q is 1 or 2 and R.sup.50 is an optional carbonyl group, by 
reduction. Suitable reducing agents will be readily apparent to one 
skilled in the art and include, for example, metallic hydrides, such as 
lithium aluminium hydride or, preferably, sodium borohydride. 
Intermediates of formula (III) wherein R.sup.30 is a leaving group may be 
prepared from compounds of formula (III) wherein R.sup.30 is OH, for 
example, by reaction with a thionyl halide, a mesyl halide or a tosyl 
halide. 
Where they are not commercially available, the intermediates of formula 
(IV) above may be prepared by the procedures described in the accompanying 
Examples or by alternative procedures which will be readily apparent to 
one skilled in the art. 
Compounds of formula (V) wherein q is 1, the carbonyl group R.sup.50 is 
absent, and R.sup.5 represents CO.sub.2 (C.sub.1-6 alkyl), may be prepared 
by reaction of compounds of formula (VI) with compounds of formula (VII): 
##STR6## 
wherein R.sup.2 is as above defined, R.sup.d represents C.sub.1-6 alkyl 
and CO.sub.2 R.sup.e is R.sup.5 ; in the presence of a base. 
Suitable bases include alkali metal hydrides, such as sodium hydride, and 
alkali metal alkoxides, such as sodium butoxide. The reaction is 
conveniently effected in a suitable organic solvent, such as a 
hydrocarbon, for example, benzene or toluene, or an ether, for example 
tetrahydrofuran. 
Compounds of formula (V) wherein R.sup.50 is absent and R.sup.5 represents 
CO.sub.2 (C.sub.1-6 alkyl) (VB), may be prepared by reaction of a compound 
of formula (VI) with a compound of formula (VIIA) 
##STR7## 
wherein q is 1 or 2 and Hal represents halo, such as chloro, bromo or 
iodo, and CO.sub.2 R.sup.e is as above defined, in the presence of a base, 
as above described. 
Further procedures for the preparation of compounds of formula (V) using 
the Dieckmann reaction will be apparent to those skilled in the art and 
are described in the accompanying examples. 
Compounds of formula (V) wherein R.sup.5 is other than CO.sub.2 (C.sub.1-6 
alkyl) may be prepared from compounds of formula (V) wherein R.sup.5 
represents CO.sub.2 (C.sub.1-6 alkyl) by decarboxylation using, for 
example, oxalic acid. 
Alternatively, compounds of formula (V) wherein q is 2 may be prepared from 
enamines of formula (VIII): 
##STR8## 
according to the method of Cervinka et al, Collect. Czech. Chem. Commun., 
1988, 53, 308-10. 
Compounds of formula (V) wherein q is 2 and the carbonyl group R.sup.50 is 
present may be prepared from intermediates of formula (IX): 
##STR9## 
by ozonolysis, or by means of the Nef reaction. Suitable reagents and 
conditions are described in Organic Reactions, 38, 655. 
Compounds of formula (V) wherein one or both of R.sup.4 and R.sup.5 
represents halo, C.sub.1-6 alkyl, CONR.sup.10R11 or CO.sub.2 R.sup.10 may 
be prepared from appropriately substituted analogues of the compounds of 
formulae (VI), (VII) and (VIIA), or by appropriate interconversion 
procedures which will be readily apparent to those skilled in the art. 
Intermediates of formula (VI) wherein R.sup.d is C.sub.1-6 alkyl (VIA) may 
be prepared from the corresponding compounds of formula (VI) wherein 
R.sup.d is hydrogen (VIB), by conventional methods. 
Intermediates of formula (VIB) may be prepared from the compound of formula 
(X): 
##STR10## 
by reaction with a compound R.sup.2 -Hal, wherein R.sup.2 is as above 
defined and Hal is halo, such as bromo, chloro or iodo, in the presence of 
a base, followed by hydrolysis and suitable modification of the nitrogen 
substituent using conventional methods. 
Suitable bases of use in the reaction include metal hydroxides, for 
example, sodium hydroxide. The reaction is conveniently effected in a 
mixture of water and a suitable organic solvent, such as a hydrocarbon, 
for example, toluene, in the presence of a phase transfer catalyst, such 
as benzyltrimethylammonium chloride. 
Hydrolysis is conveniently effected by heating a solution of the product of 
reaction between the compound of formula (IX) and R.sup.2 -Hal in 
concentrated hydrochloric acid, at reflux. 
The compound of formula (X) is commercially available. 
Intermediates of formula (IX) are prepared as described in European Patent 
Application No. 0 436 334. 
Compounds of formula R.sup.2 -Hal may be prepared according to the 
procedure described by E. J. Corey, Tetrahedron Lett., 1972, 4339. 
Intermediates of formula (III) wherein n is 1 or 2 are novel compounds and 
constitute a further aspect of the present invention. 
Where the above-described process for the preparation of the compounds 
according to the invention gives rise to mixtures of stereoisomers these 
isomers may, if desired, be separated, suitably by conventional techniques 
such as preparative chromatography. 
The novel compounds may be prepared in racemic form, or individual 
enantiomers may be prepared either by enantiospecific synthesis or by 
resolution. For example, intermediate alcohols of formula (III), wherein 
R.sup.30 is OH, may be resolved into their component enantiomers by 
standard techniques, such as the formation of diastereomeric esters or 
amides, followed by chromatographic separation or separation by fractional 
crystallization and removal of the chiral auxiliary. The diastereomeric 
alcohols can then be used to prepare optically pure compounds of formula 
(I). 
During any of the above synthetic sequences it may be necessary and/or 
desirable to protect sensitive or reactive groups on any of the molecules 
concerned. This may be achieved by means of conventional protecting 
groups, such as those described in Protective Groups in Organic Chemistry, 
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. 
Wutts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. 
The protecting groups may be removed at a convenient subsequent stage 
using methods known from the art.