a!-Annelated pyrrole derivatives and pharmaceutical use thereof

The present invention relates to heterocyclic compounds of the formula ##STR1## in which R.sup.1 -R.sup.7, B, a and X have the meanings recited in the specification. These compounds are usable in the treatment of diseases of the rheumatoid group and for the prevention of allergically induced diseases.

The invention relates to pyrroles which are anellated at bond a, and their 
use in pharmacology, as well as to pharmaceuticals that contain these 
compounds. 
It is known that arachidonic acid is metabolized by different routes. In 
the cyclooxygenase route, the arachidonic acid is metabolized into 
prostaglandins under the influence of the enzyme cyclooxygenase. In the 
lipoxygenase route, the arachidonic acid is metabolized into so-called 
leukotrienes under the influence of lipoxygenases. 
The prostaglandins are involved in the development of inflammation, fever 
and pain, while the leukotrienes play an important role in the development 
of asthma, inflammations, and allergies. To fight these symptoms, 
nonsteroidal anti- inflammatory drugs are used, such as arylethanoic acid 
derivatives, 2-arylpropionic acid derivatives, and anthranilic acid 
derivatives. These derivatives inhibit the cyclooxygenase and thus prevent 
the formation of the prostaglandins from arachidonic acid. Such 
derivatives are not used without reservations with regard to their side 
effects, however. Drugs that inhibit lipoxygenase are not available on the 
market. 
European Patent Disclosure EP-A-397 175 describes pyrrolizine compounds of 
the formula: 
##STR2## 
in which two of the radicals R.sup.3, R.sup.4 and R.sup.5 independently of 
one another stand for H, C.sub.5 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.12 
alkyl or aryl, which is optionally substituted by one or two radicals, 
which are selected from the group comprising halogen, NO.sub.2, C.sub.1 
-C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl or phenoxy, and the third of the 
radicals R.sup.3, R.sup.4 and R.sup.5 stands for CHO, CO.sub.2 HO, 
COSC.sub.1 -C.sub.4 alkyl or A--X, where A stands for a straight-chain or 
branched C.sub.1 -C.sub.8 alkylene group or a C.sub.2 -C.sub.8 alkenylene 
group, and X stands for CO.sub.2 H, SO.sub.3 H, CHO, OH, or SH. These 
compounds are cyclooxygenase- and/or lipoxygenase-inhibitors, and are 
therefore usable in the treatment of diseases of the rheumatoid variety 
and for the prevention of allergically induced diseases. 
Those compounds of the above formula in which A--X stands for CH.sub.2 
CO.sub.2 H are especially efficacious. However, they have a strong 
tendency to decarboxylate. For example, the half life in chloroform is ca. 
1-2 h, while a 1% alkaline, aqueous solution decarboxylates at a rate of 
ca. 2% per day. 
Surprisingly, it has now been found that certain heterocyclic compounds are 
chemically more stable, with a comparable effect. Moreover, the compounds 
also have novel effect qualities, such as lowering blood pressure, lipid 
reduction, and tracheal relaxation. 
The subject of the invention is therefore heterocyclic compounds of formula 
I: 
##STR3## 
in which two of the radicals R.sup.1, R.sup.2 and R.sup.3, which may be 
identical or different, stand for a hydrogen atom, an aryl radical, which 
optionally has one or two substituents which are selected from the group 
comprising halogen, pseudohalogen, CF.sub.3, NO.sub.2, OH, alkoxy, 
OCF.sub.3, alkyl and aryloxy, or a mono- or bicyclic aromatic heterocyclic 
radical which has at least one oxygen, nitrogen and/or sulfur atom and 
which is optionally condensed with a phenyl or napthyl radical and is 
optionally substituted by halogen, CF.sub.3, alkyl or alkoxy, and 
the third of the radicals R.sup.1, R.sup.2 and R.sup.3 stands for 
COCO.sub.2 H, COCO.sub.2 alkyl or A--Y, 
A stands for C.sub.1 -C.sub.8 alkylene or C.sub.2 -C.sub.8 alkenylene, 
Y stands for CONR.sup.8 R.sup.9, 
R.sup.8 and R.sup.9, which may be identical or different, stand for H, 
alkyl, OH, acyl, SO.sub.2 alkyl, or SO.sub.2 phenyl, and the alkyl radical 
of the sulfonyl group is optionally substituted by one or more halogen 
atoms and the aryl radical is optionally substituted by one or more 
halogen, C.sub.1 -C.sub.8 alkyl, or C.sub.1 -C.sub.8 alkoxy radicals, 
R.sup.4, R.sup.5, R.sup.6 and R.sup.7, which may be identical or different, 
stand for H or alkyl, or two of the vicinal radicals stand for a chemical 
bond between the two ring atoms to which they are bonded and the other two 
have the meanings stated, or two of the geminal radicals together with the 
carbon atom to which they are bonded stand for a carbonyl group, 
X stands for CH.sub.2, CO, O, S, SO, SO.sub.2, or NR.sup.10, where R.sup.10 
stands for H, alkyl or aryl, which is optionally substituted by halogen, 
C.sub.1 -C.sub.8 alkyl, or C.sub.1 -C.sub.8 alkoxy, 
B stands for CH.sub.2 or CH.sub.2 CH.sub.2, 
a stands for 0, 1 or 2, and 
their optical isomers, salts and esters.

The pharmaceutically compatible salts in the present case can be acid 
addition salts or base addition salts. Inorganic acids such as 
hydrochloric acid, sulfuric acid, or phosphoric acid, or organic acids 
such as tartaric acid, lactic acid, citric acid, malic acid, mandelic 
acid, ascorbic acid, maleic acid, fumaric acid, gluconic acid, and the 
like are used for acid addition salts. 
Base addition salts include salts of the formula I compounds with inorganic 
bases such as sodium hydroxide or potassium hydroxide or with organic 
bases such as monoethanolamine, diethanolamine, or triethanolamine. 
The esters of the formula I compounds, in particular include esters that 
are physiologically easy to hydrolyze, for example alkyl ester, 
pivaloyloxymethyl ester, acetoxymethyl ester, phthalidyl ester, indanyl 
ester, and methoxymethyl ester. 
The term "alkyl, alkoxy, etc." includes straight-chain or branched alkyl 
groups such as methyl, ethyl, n-propyl and i-propyl, n-butyl, i-butyl, or 
t-butyl, n-pentyl, neopentyl, n-hexyl, etc. 
Unless otherwise indicated, "alkyl" preferably stands for C.sub.1 -C.sub.8 
alkyl, in particular for C.sub.1 -C.sub.6 alkyl, and in particular 
preferably, for C.sub.1 -C.sub.4 alkyl. 
"Aryl" preferably stands for naphthyl and in particular for phenyl. 
The term "halogen atom" includes a fluorine, chlorine, bromine, or iodine 
atom and in particular for a fluorine or chlorine atom. "Pseudohalogen" 
particularly stands for CN, OCN, SCN, or N.sub.3. 
"Alkylene" or "alkenylene" stands for straight-chain or branched alkylene 
or alkenylene groups with preferably 1 to 6 or 2 to 6 and in particular 1 
to 4 or 2 to 4 carbon atoms. The alkylene group and in particular the 
methylene group is preferable. 
"Acyl" stands for RCO, where R preferably has the meanings stated for 
"alkyl" and "aryl". Acetyl is particularly preferable. 
The "aromatic, heterocyclic radical" refers in particular to a 5- and 
6-member heterocyclic radical that can be substituted and anellated as 
indicated above. Examples are a thiophene, pyrrole, imidazole, thiazole, 
thiadiazole, furan, oxazole, isoxazole, pyridine, pyrimidine, benzofuran, 
or quinoline radical. If the heterocycle is substituted, 1, 2, or 3 
substituents are available, which are selected from the group comprising 
halogen, CF.sub.3, C.sub.1 -C.sub.8 alkyl, and C.sub.1 -C.sub.8 alkoxy. A 
thiophene- or halogen-substituted, in particular chlorine-substituted, 
thiophene radical, or a furan, pyridine, benzofuran or quinoline radical 
is preferable. 
If one of the radicals R.sub.1, R.sub.2, and R.sub.3 means a heterocyclic 
radical or a substituted aryl radical, then R.sub.2 preferably stands for 
such a radical. 
The substituents of the aryl group are preferably selected from the group 
comprising halogen, in particular fluorine or chlorine, CF.sub.3, 
NO.sub.2, and phenoxy. If the aryl group is a phenyl ring, the 
substituents are preferably situated in the m-position and/or the 
p-position. 
If Y stands for CONR.sup.8 R.sup.9, then R.sup.8 preferably stands for a 
hydrogen atom or an alkyl group and R.sup.9 stands for optionally halogen- 
substituted SO.sub.2 C.sub.1 -C.sub.8 alkyl or optionally C.sub.1 -C.sub.8 
alkyl- substituted SO.sub.2 phenyl, in particular SO.sub.2 CH.sub.3, 
SO.sub.2 CF.sub.3, SO.sub.2 phenyl or SO.sub.2 tolyl. 
Preferably the third of the radicals R.sup.1, R.sup.2, and R.sup.3 is 
situated in the 5-position of the pyrrolizidine structure. 
A preferred embodiment is the compounds of above formula I, in which two of 
the radicals R.sup.1, R.sup.2 and R.sup.3, independently of one another, 
stand for H, phenyl, halogen- or CF.sub.3 -substituted phenyl (one, two or 
three halogen atoms), or for a 5- or 6-member heterocyclic ring of the 
above-defined type, and the third of the radicals R.sup.1, R.sup.2, and 
R.sup.3 stands for A--Y, where A stands for C.sub.1 -C.sub.8 alkylene and 
Y stands for CONR.sup.8 R.sup.9, where R.sup.8 and R.sup.9 have the 
meanings indicated above. 
Another preferred embodiment is the compounds of the above-mentioned 
formula I, in which R.sup.1 stands for H or phenyl, R.sup.2 stands for 
phenyl, halogen-substituted phenyl, or a 5- or 6-member heterocyclic ring, 
and R.sup.3 stands for A--Y, where A and Y have the meanings stated. 
In a particularly preferable manner, A--Y stands for CH.sub.2 CONHSO.sub.2 
R, where R stands for CH.sub.3, CF.sub.3, phenyl, or tolyl. 
X preferably stands for CH.sub.2 ; B preferably stands for CH.sub.2 ; a 
preferably stands for 0. 
A particularly preferable set of embodiments is the compounds of the 
above-mentioned formula I, in which two of the radicals R.sup.4 and 
R.sup.6 or R.sup.5 and R.sup.7 together stand for a chemical bond or in 
which the radicals R.sup.4 -R.sup.7 stand for H or alkyl. These compounds 
have the formula: 
##STR4## 
The radicals R.sup.1 to R.sup.7 and X have the meanings stated. 
A further preferred embodiment is the compounds of formula I", in which if 
X stands for CH.sub.2, then R.sup.6 and R.sup.7 stand for alkyl and 
R.sup.4 and R.sup.5 stand for hydrogen, and if X stands for S, then 
R.sup.6 and R.sup.7 stand for H and R.sup.4 and/or R.sup.5 stand for 
alkyl. 
If the compounds according to the invention have asymmetry centers, 
racemates as well as optical isomers (enantiomers, diastereomers) are 
included. 
The synthesis of the compounds according to the invention takes place 
analogous to the processes A to O described in FIGS. 1a-c, 2, 3a, 3b, 4, 
5a and 56. These methods are partially described in European Patent 
Disclosure EP-A-397 157; reference is hereby made to this publication and 
the literature references mentioned therein. 
Initial compounds for the production of the compounds according to the 
invention are the compounds of formula II: 
##STR5## 
where R.sup.1, R.sup.4 -R.sup.7, and X have the meanings stated. These 
compounds are known in the literature, or they can be produced analogously 
to known processes, for example by those described in EP-A-397 175 
(X.dbd.CH.sub.2, CO) through the reaction of aminothiols, diamines, and 
amino alcohols derived from D- and L-amino acids with the imide esters of 
correspondingly substituted carboxylic acids (FIG. 1b A1/A2). The formula 
II compounds are reacted with the corresponding compounds of formula III. 
##STR6## 
in which Z stands for Cl or Br and R.sup.2 and R.sup.3 have the desired 
meanings. The formula III compounds are likewise known from the literature 
or they can be produced analogously to known processes, for example those 
compounds in which R.sup.2 stands for an aromatic, heterocyclic radical 
are produced analogous to the processes described by J. J. Riehl in C. R. 
Hebd. Seance. Acad. Sci. Ser. C (1957), 245, pp. 1321-1322. The reaction 
takes place an inert solvent (such as ethanol, methylene chloride, diethyl 
ether, tetrahydrofuran) in the presence of a suitable base (such as 
NaHCO.sub.3, triethylamine). If X stands for 0, S or NR.sup.10, the 
reaction takes place preferably in an ether or aromatic hydrocarbon, such 
as diethyl ether, benzene or toluene; the quaternized intermediate product 
precipitates out. This product is isolated and dissolved in a chlorinated 
solvent, such as CH.sub.2 Cl.sub.2, and treated with a base, such as 
triethylamine. 
This reaction produces the formula Ia compounds: 
##STR7## 
If at least one of the radicals R.sup.1, R.sup.2, and R.sup.3 stands for a 
hydrogen atom, compounds of the following formulas IVa through IVc are 
obtained: 
##STR8## 
The compounds of series a, b, or c are derived from this depending on the 
position of the hydrogen atom. 
This reaction as well as the reactions mentioned below are outlined in 
FIGS. 1a-c, 2, 3a, 3b, 4, 5a, and 5b in the example of the compounds of 
series a. The same is true for the synthesis and derivative production of 
the compounds of series b and c. 
In addition to the process described in European Patent Disclosure EP-A-397 
175 (process A), another process (process B) is used for the composition 
of heterocycles IVa, IVb, and IVc, where X.dbd.O, S or NR.sup.10 (FIG. 2): 
the starting point of this process is correspondingly substituted 
2-(5H)furanones (VI), which are produced from carboxylic acid salts of 
structure V and the halogen aldehydes and halogen ketones of structure III 
(FIG. 2), analogous to the methods described in the literature (a: Rio, G. 
and Sekiz, B. Bull. Soc. Chim. Fr. 1976, 1491, 1495. b: Padwa, A., 
Brookhart, T., Dehm, D., and Wubbels, G., J. Am. Chem. Soc. 1978, 100, 
8247, 8259). Analogous to methods known from the literature, these are 
transformed into 1,5-dihydro-2-pyrrolones (VII or VIII) (c: Matsuda et al. 
Yakugaku Zasshi 95, 1975! 190, 194 (C.A. 83 1975! 42 780; d: Rio, G. and 
Sekiz, B., see above). 
Depending on the condensation reagent used and on the second functional 
group of the bifunctional amines NH.sub.2 -- CR.sup.4 R.sup.5 CR.sup.6 
R.sup.7 --B!.sub.a --OH or NH.sub.2 CH.sub.2 CH(OCH.sub.3).sub.2, the 
cyclization to the anellated heterocycle leads to partially hydrated forms 
(formula I", FIG. 2: B1/B2) or to dehydrated forms (formula I', FIG. 2: 
B3, B4, B5). 
To insert the substituent A--CONR.sup.8 R.sup.9, the radical A--CO.sub.2 H 
is first inserted, by methods known to one skilled in the art. These 
methods include, for example: 
a) Reaction of a formula Ia compound with a carboxylic acid halogenide 
HalOC--A'--COO alkyl, in which A' stands for a chemical bond, C.sub.1 
-C.sub.7 alkylene or C.sub.2 -C.sub.7 alkenylene and Hal stands for Cl or 
Br (FIG. 3a, process C/variant A). The formula Ia compound obtained, in 
which one of the radicals R.sup.1, R.sup.2, and R.sup.3 stands for 
CO--A'--CO.sub.2 alkyl, is then treated with a reagent which is suitable 
for the reduction of the carbonyl group to a CH.sub.2 group, for example 
hydrazine, NaCNBH.sub.3 or zinc amalgam. The reaction with the carboxylic 
acid halogenide is carried out in an inert solvent, e.g. diethyl ether or 
tetrahydrofuran, optionally in the presence of a catalyst. The reduction 
with hydrazine under the conditions of a Wolff-Kishner reduction, and 
especially the Huang-Minlon Variant of it, is preferred. The reduction 
with hydrazine is preferably carried out in a high-boiling alcohol, e.g. 
diethylene glycol. The formula XVI compound is obtained in this manner. 
b) There are a number of methods available for inserting the particularly 
preferable group CH.sub.2 CO.sub.2 H (see FIGS. 3a, 3b, and 4). The first 
possibility comprises reacting a formula IV compound with oxalyl chloride 
(FIG. 5b), wherein a formula I compound is obtained, in which one of the 
radicals R.sup.1, R.sup.2, and R.sup.3 stands for COCO.sub.2 H. This 
compound is then treated with a reagent which is suited to the reduction 
of the ketocarbonyl group, for example hydrazine, HaCNBH.sub.3, or zinc 
amalgam (also see point a) above). 
Another possibility comprises reacting a formula IVa compound with a 
diazoethanoic acid alkyl ester producing a formula I compound in which one 
of the radicals R.sup.1, R.sup.2, and R.sup.3 stands for CH.sub.2 COO 
alkyl. If so desired, this compound is then subjected to ester cleavage 
into the corresponding free carboxylic acid. (FIG. 3a, XVII). 
The reaction with the diazoethanoic acid is carried out in an inert 
solvent, for example toluene or xylene, in the presence of copper powder 
or complex copper(I) salts or copper(II) salts. The reaction is carried 
out at an increased temperature, suitably at the boiling temperature of 
the solvent used. 
A further possibility comprises the reaction of a formula IV compound with 
chloral producing a formula XIV compound and treatment of the activated 
compound with a dithionite, for example sodium dithionite or rongalite 
(hydroxymethane sulfinic acid sodium salt); see FIG. 3, process E. 
c) The insertion of a formyl group group into the pyrrole ring is carried 
out through the reaction of a formula IV compound with phosphorus 
oxychloride/dimethyl formamide (see FIG. 3b). The reaction is carried out 
in an inert solvent, for example benzene, toluene, or xylene, at an 
increased temperature, suitably at the boiling point of the solvent used. 
A formula IX compound is obtained, in which one of the radicals R.sup.1, 
R.sup.2, and R.sup.3 stands for CHO. The --CHO group can then be reduced 
in a usual way, for example with LiAlH.sub.4, in an inert solvent, for 
example tetrahydrofuran, forming the corresponding hydroxymethyl compound 
XIX (FIG. 3b). This can then be used for further reactions for the 
insertion of the desired groups (process K, J; FIG. 3b). 
The formyl group in a Wittig reaction carried out under normal conditions 
can be transformed into a corresponding alkenylene group producing the 
compound X (see compound X in FIG. 3b). If so desired, this can in turn be 
hydrated in a usual way, forming the corresponding alkylene compound 
(XXIII, FIG. 4). 
d) Reaction of a formula IV compound with an anhydride with the formula: 
##STR9## 
produces the corresponding formula I ketocarboxylic acids, in which one of 
the radicals R.sup.1, R.sup.2, and R.sup.3 stands for CO(CH.sub.2).sub.n 
CO.sub.2 H. With the reagent already mentioned, the ketocarbonyl group can 
be reduced to a CH.sub.2 group (see FIGS. 3, 3a, XI-XVI). 
The preparation of the formula I compounds, in which one of the radicals 
R.sup.1, R.sup.2, and R.sup.3 stands for A--CONR.sup.8 R.sup.9, is then 
done starting with the corresponding activated derivative of carboxylic 
acid of formula Ia, in which one of the radicals R.sup.1, R.sup.2, and 
R.sup.3 stands for ACO.sub.2 H, by reaction with the corresponding 
sulfonamide, amine, amide or hydroxylamine (see FIG. 2). Suitable 
activated carboxylic acid derivatives are known to one skilled in the art; 
the imidazole derivative is preferred. 
The reaction is performed in an inert solvent, for example an ether, such 
as diethyl ether or tetrahydrofuran, in the presence of a base, such as 
sodium hydride. The reaction temperature is in the range from room 
temperature to the boiling point of the solvent. Expediently, the reaction 
is performed at room temperature. 
The compounds according to the invention have proved to be potent 
cyclooxygenase and/or lipoxygenase inhibitors. They can therefore be used 
in the treatment of diseases which are associated with a change in 
arachidonic acid metabolism. In particular, this pertains to diseases of 
the rheumatoid variety and the prevention of allergically induced 
diseases. The compounds according to the invention consequently represent 
effective anti-inflammatory drugs, analgesics, antipyretics, 
antiallergics, and broncholytics or are effective against bronchial 
constriction and can therefore be used for thrombosis prophylaxis and for 
the prophylaxis of anaphylactic shock as well as for the treatment of 
dermatological diseases such as psoriasis, urticaria, acute and chronic 
exanthemas of allergic and non-allergic genesis. They are also usable for 
treating lipid exchange, in particular in order to lower cholesterol. 
The compounds according to the invention, as compared with the 
corresponding carboxylic acids, have considerably greater stability in 
solution. Thus 
6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl 
acetic acid in chloroform, with a half life of ca. 1 h and in aqueous 
solution (sodium salt) decarboxylates at a rate of ca. 2% per day. The 
analogous methane sulfonamide, conversely, is stable, with a largely 
unchanged profile of efficacy. 
The compounds according to the invention can be administered either as 
individual therapeutic agents or as mixtures with other therapeutic 
agents: They can be administered as is, but in general, they are 
administered in the form of pharmaceuticals, that is, as mixtures of 
agents with suitable pharmaceutical vehicles or diluents. The compounds or 
agents can be administered orally or parenterally, preferably, though, 
they are given in oral dosage forms. 
The type of pharmaceutical and the type of pharmaceutical vehicle or 
diluent depend on the desired type of administration. Oral agents can be 
in tablet or capsule form and can contain conventional excipients such as 
binders (e.g. syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinyl 
pyrrolidone), fillers (e.g. lactose, sugar, cornstarch, calcium phosphate, 
sorbitol, or glycine), lubricants (e.g. magnesium stearate, talcum, 
polyethylene glycol, or silicon dioxide), disintegrating agents (e.g. 
starch), or wetting agents (e.g. sodium lauryl sulfate). Oral fluid 
preparations can be in the form of aqueous or oleaginous suspensions, 
solutions, emulsions, syrups, elixirs, or sprays, etc. or can be in the 
form of dry powder for reconstitution in water or another suitable 
vehicle. 
Fluid preparations of this kind can contain conventional additives, for 
example suspension agents, flavorings, diluents, or emulsifying agents. 
For parenteral administration, solutions or suspensions can be used with 
standard pharmaceutical vehicles. 
The compounds or agents according to the invention can be administered to a 
mammal (human and animal) in doses of approximately 0.5 mg to 
approximately 100 mg per kg of body weight per day. They can be 
administered in a single dose or in a number of doses. 
The spectrum of efficacy of the compounds was investigated using the 
following tests: 
1) Phenylquinone writhing test in the mouse p.o., S. Irwin, 
Psychopharmacologia, 13:222-257, 1968; 
2) Formalin analgesia test in the mouse p.o., B. Rubin et al., Endocrinol., 
49:429-439, 1951; 
3) Inhibition of arachidonic acid-induced platelet aggregation, V. Bertele 
et al., Science 220:517-519 (1983); 
4) Inhibiting inflammation in rat paw edema, C. A. Winter et al., Proc. 
Exper. Biol. Med., 111:544-547 (1962); 
5) Tracheal relaxation in the guinea pig, F. P. Luduena et al., Arch. Int. 
Pharmacodyn., 111:392-400, 1957; 
6) Cholesterol-reducing action in the mouse, C. E. Day et al., 
Atherosclerosis Drug Discovery, Ed. Charles E. Day, Plenum Publishing 
Corp., New York, 1976, 231-249. 
7) IC.sub.50 /LO/CO: Inhibition of the enzyme cyclooxygenase (CO) and 
5-lipoxygenase (LO), Dannhardt et al., J. Pharm. Pharmacol. 1992, 
44:419-424. 
The results are given in the following Table 1: 
______________________________________ 
Comp..sup.1/ 
1 2 3 4 5 6 7 
______________________________________ 
3 x x x 
x x 
4 x 
x x x 
2,3/1,5 .times. 10.sup.-7 
5 
x 
x 
6 
x 
7 
x x x 
8 
x 
x 
9 x x x x 
10 x 
x 
x 
11 x 
x 
12 
x x 
x 
13 
x x 
______________________________________ 
The following examples explain the invention. All temperature data is 
uncorrected. The IR spectra, unless otherwise indicated, were picked up 
from KBr compacts. Unless otherwise noted, the NMR spectra are 200 MHz 
spectra, picked up in CDCl.sub.3 with tetramethylsilane (TMS) as an 
internal standard. The IR spectra are indicated in cm.sup.-1 and the NMR 
spectra are indicated in .delta.(ppm). 
EXAMPLES 
General recipe for preparing aryl-substituted a!- or 1,2!-anellated 
pyrroles (pyrrolo1,2-a!pyrroles=pyrrolizines, 
pyrrolo1,2-a!pyridines=indolizines, pyrrolo1,2-a!azepines) 
To a solution of 20 mmol omega-bromacetyl compounds in 100 ml methylene 
chloride, 20 mmol of the corresponding cyclic imine derivative in 50 ml of 
methylene chloride is added quickly drop by drop and stirred for 4 h at 
room temperature with the exclusion of moisture. Next, 30 ml of 5% aqueous 
NaHCO.sub.3 solution is added, and the mixture is stirred intensively for 
another 4 h. After the addition of 200 ml of water, the organic phase is 
separated off, dried over Na.sub.2 SO.sub.4, and evaporated at reduced 
pressure. The residue is made to crystallize with methanol, and optionally 
recrystallized from methanol. 
General Recipe for Preparing Aryl-Substituted a!- or 1,2!-Anellated 
Pyrrol-5-yl-Oxoacetic Acids 
To a solution of 1.4 mmol oxalic acid ethyl ester chloride in 20 ml of dry 
methylene chloride, 1.3 mmol of correspondingly substituted anellated 
pyrrole, dissolved in 20 ml of dry methylene chloride, is added drop by 
drop while stirring, and stirring is continued for 20 min. After 40 ml of 
water is carefully added, the organic phase is separated out and dried 
over Na.sub.2 SO.sub.4. The residue remaining after the solvent has been 
extracted is suspended in 20 ml diisopropyl ether aspirated off, and 
rewashed two more times with 5 ml of diisopropyl ether each time. 
General Recipe for Preparing Aryl-Substituted a!- or 1,2!-Anellated 
Pyrrol-5-yl-Acetic Acids 
2 mmol of the corresponding oxoester derivative are mixed with 2 ml of 
diethylene glycol and 1.5 ml of 80% hydrazine derivative and stirred for 
30 min at 60.degree. C. Next, 2.1 g of potassium hydroxide are added, and 
the reaction mixture is heated while stirring for 2 h to 140.degree. C. 
The still-warm mixture is added to 20 ml of ice water and adjusted with 
dilute phosphoric acid to pH=3-4; the raw product settled out as a solid. 
This is aspirated, rewashed several times with water, dried in a vacuum, 
and then washed several times with a little diisopropyl ether. 
General Recipe for Preparing N-sulfonylated a!- or 1,2!-Anellated 
Arylpyrrolcarboxylic Acid Amides 
Mixture A: 
2.6 mmol of the applicable pyrrolcarboxylic acid are stirred with 5 mmol of 
carbonyl diimidazole in 25 ml dry tetrahydrofuran for 1 h at room 
temperature. 
Mixture B: 
3 mmol of the correspondingly substituted sulfonamide are dissolved in 20 
ml dry tetrahydrofuran in an argon atmosphere, mixed with 3.3 mmol sodium 
hydride (mineral oil suspension), and stirred for 1 h at room temperature. 
Mixture B is added in an argon atmosphere to mixture A and stirred for 40 
h. The suspension is poured onto 40 ml of ice water, adjusted with dilute 
phosphoric acid to pH=4, and extracted multiple times with diethyl ether. 
After drying of the organic phase over Na.sub.2 SO.sub.4 and extraction of 
the solvent, the remaining residue is recrystalized from isopropanol. 
The intermediate compounds and final compounds obtained, along with their 
physical data, are given in the following Tables 2-5. The intermediate 
compounds for Examples 1, 2 and 13 are described in EP-A 397 175, and 
those for Examples 3-6, 9 and 10 are prepared analogously. 
TABLE 2 
__________________________________________________________________________ 
Reference Examples 
1 #STR10## 
Reference 
Example X 
R.sup.1 
R.sup.2 R.sup.3 
R.sup.4 
R.sup.5 
R.sup.6 
R.sup.7 
X 
__________________________________________________________________________ 
1 Ph 
5-Cl-2-thienyl 
H H H CH.sub.3 
CH.sub.3 
CH.sub.2 
2 Ph 
5-Cl-2-thienyl 
COCO.sub.2 Et 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
3 Ph 
5-Cl-2-thienyl 
H H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
4 Ph 
5-Cl-2-thienyl 
COCO.sub.2 Et 
H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
5 Ph 
CO(CH.sub.2).sub.3 CO.sub.2 H 
5-Cl-2-thienyl 
H H H H CH.sub.2 
6.sup.1) 
Ph 
5-Cl-2-thienyl 
H CH.sub.3 
-- 
H -- S 
7.sup.1 
Ph 
5-Cl-2-thienyl 
CH.sub.2 CO.sub.2 Et 
CH.sub.3 
-- 
H -- S 
8 Ph 
4-CF.sub.3 -phenyl 
H H H CH.sub.3 
CH.sub.3 
CH.sub.2 
9 Ph 
4-CF.sub.3 -phenyl 
CH.sub.2 CO.sub.2 H 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
__________________________________________________________________________ 
.sup.1) Compound of Formula 1'- 
TABLE 3 
______________________________________ 
Compound of 
Reference 
Example # 
______________________________________ 
1 B.P.: Oil 
IR: 2950, 1656, 1596, 1444, 1414, 1382, 792, 759, 697 
NMR: 7,29-7,17(m, 5H,arom); 6,71(s,1H,N--CH--); 
6,70 (AB, J = 3,5, .dbd.CH--); 6,49 (AB,J = 
3,5. .dbd.CH--); 3,72(s,2H,--CH.sub.2 --N); 2,75(s,2H, 
--CH.sub.2 --); 1,27(s,6H,--CH.sub.3) 
2 B.P. 133.0 C 
IR; 2955, 1736, 1619, 1467, 1426, 1373, 1241, 1179, 
1049, 701 
NMR; 7,26-7,10(m, 5H, arom); 6,82 (AB, J = 3,7, 
--CH.dbd.); 6,77 (AB, J = 3,7, --CH.dbd.); 4,22 (s,2H, 
--CH.sub.2 N--); 3,87(q, 2H, J = 7,0, ethyl); 2,82(s,2H, 
--CH.sub.2 --); 7,31 (s,6H,--CH.sub.2); 1,19(t,3H,J = 7,0, 
ethyl) 
3 B.P. 80.3 C 
IR; 2995, 1550, 1447, 1380, 1157, 1062, 986, 786, 758, 
694 
NMR; 7,30-7,15(m,5H,arom); 6,68(d,AB,1H,J = 4,0, 
thienyl); 6,47 (d,AB,1H, thienyl) (6,67(s,1H,--N-- 
CH.dbd.); 3,74(s,2H,--CH.sub.2 --N); 2,73(s,2H, 
--CH.sub.2 pyr); 
4 B.P. 126.8 
IR; C.dbd.O; 1750, 1629 
NMR; 7,31-7,09 (m, 5H, arom); 6,81 + 6,76(AB,2H,J = 
3,7, --CH.dbd.CH--) 4,23(s,2H,--CH.sub.2 --N--); 3,87(q, 
2H,J = 7,2, ethylester); 2,79 (s,2H,CH.sub.2) 
5 B.P. 126.degree. C. 
IR; 1660, 1706, (C.dbd.O) 
NMR; 8,7-8,5(2H, Ar); 8,5-8,35(3H;Ar); 6,82(H.sub.A, 
J.sub.AB = 3,76Hz); 6,76 (H.sub.B, J.sub.AB = 3,75 Hz); 5,08 
(t,2H, 
CH.sub.2); 4,14(t,2H, CH.sub.2); 3,67(quint.. 2H, CH.sub.2); 
3,53(t,2H, CH.sub.2); 3,33 (t,2H, CH.sub.2); 2,95 (quint.. 2H, 
CH.sub.2). 
6 NMR; 7,24-7,06 (m, 5H, Ar); 7,16 (s, 1H); 6,80, 6,62 
(AB, J = 3,8 Hz, Thiophen-H); 6,31 (9,1H, J = 0.8 Hz); 
2,40 (d, 3H, J = 0.8 Hz) 
7 NMR; 7,26-7,03 (m, 5H, Ar); 6,80, 6,62 (AB, J = 3,8 
Hz, Thiophen-H); 6,30 (9, 1H, J = 0,8 Hz); 3,51 (s, 2H, 
CH.sub.2); 2,62 9,2H,6,8 Hz); 2,38 (d, 3H, 0,8 Hz); 1,12 
(t, 3H, J = 6,8 Hz) 
8 B.P. 104-105.degree. C. 
JR; 3435, 2960, 1608, 1315, 1158, 1121, 843, 762, 698 
NMR; 7,48-7,15 (m, 9H, Ar); 6,75 (s, 1H); 3,75 (s, 2H, 
CH.sub.2 --N); 2,79(s, 2H, --CH.sub.2 --); 1,28 (s,6H, 
CH.sub.3) 
9 B.P. 174-174.5.degree. C. 
IR; 3420, 2960, 1706, 1319, 1156, 1110, 846, 758, 695 
NMR; 7,5-7,04 (m, 9H, Ar); 3,77 (s, 2H, CH.sub.2 CO.sub.2 H); 
3,6 (s, 2H, CH.sub.2 --N); 2,86 (s, 2H, --CH.sub.2); 1,30 (s, 
6H, 
CH.sub.3) 
______________________________________ 
TABLE 4 
__________________________________________________________________________ 
EXAMPLES 
2 #STR11## 
Nr. 
R.sup.1 
R.sup.2 R.sup.3 R.sup.4 
R.sup.5 
R.sup.6 
R.sup.7 
X a 
__________________________________________________________________________ 
1 Ph 
Ph CH.sub.2 --CONHOH 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
2 Ph 
Ph CH.sub.2 --CON(CH.sub.3)OH 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
3 Ph 
4-Cl-ph CH.sub.2 --CONHSO.sub.2 CF.sub.3 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
4 Ph 
4-Cl-ph CH.sub.2 --CONHSO.sub.2 CH.sub.3 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
5 Ph 
4-Cl-ph CH.sub.2 --CONHSO.sub.2 Ph 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
6 Ph 
4-Cl-ph CH.sub.2 --CONHTosyl 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
7 Ph 
5-Cl-2-thienyl 
CH.sub.2 --CONHSO.sub.2 CH.sub.3 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
8 Ph 
5-Cl-2-thienyl 
CH.sub.2 --CONHTosyl 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
9 Ph 
4-Cl-ph CH.sub.2 --CONHSO.sub.2 CH.sub.3 
H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
0 
10 Ph 
4-Cl-ph CH.sub.2 --CONHTosyl 
H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
0 
11 Ph 
5-Cl-2-thienyl 
CH.sub.2 --CONHSO.sub.2 CH.sub.3 
H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
0 
12 Ph 
5-Cl-2-thienyl 
CH.sub.2 --CONHTosyl 
H H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
0 
13 Ph 
(CH.sub.2).sub.4 CONHTosyl 
Ph H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
14 Ph 
5-Cl-thienyl 
CH.sub.2 --CONHSO.sub.2 CH.sub.3 
CH.sub.3 
-- 
H -- S 0 
15 Ph 
4-CF.sub.3 --Ph 
CH.sub.2 --CONHSO.sub.2 CH.sub.3 
H H CH.sub.3 
CH.sub.3 
CH.sub.2 
0 
__________________________________________________________________________ 
TABLE 5 
______________________________________ 
Com- 
pound of 
Example # 
______________________________________ 
1 B.P. 77,1.degree. C. 
IR. 3255 (OH); 1651 (C.dbd.O) 
NMR; 7,12-6,67 (m, 1OH, Ar.); 3,53 (s, 2H, CH.sub.2 -3); 3,37 
(s, 2H, --CH.sub.2 --Py); 2,73 (s, 2H, CH.sub.2 -1); 1,38 (s, 6H, 
CH.sub.3) 
2 B.P. 160,1.degree. C. 
IR; 3450 (OH) 
1620(C.dbd.O) 
NMR; 7,30-6,90 (m, 1OH, Ar.); 3,81 (s, 2H, CH.sub.3 -3); 3,68 
(s, 2H, CH.sub.2 -Py); 2,93 (s, 3H, CH.sub.3 --N); 2,85 (s,2H, 
CH.sub.2 -1); 1,3 (s, 6H, CH.sub.3) 
3 B.P. 178-179.degree. C. 
IR; 3415 (--NH--), 1689 (--C.dbd.O), 1531, 1010 (SO.sub.2) 
NMR; .delta. = 7,4-7,0 (m, 9H, 2 Ar); 5,42 (b; 1H, --NH); 3,72 
(s, 2H, CH.sub.2), 3,67 (s; 2H, --CH.sub.2 --); 2,87 (s, 2H, 
CH.sub.2), 
1,30 (s, 6H, 2CH.sub.3) 
4 B.P. 187-188.degree. C. 
IR; 3240, 2955, 1729, 1480, 1449, 1397, 1325, 1180, 1102, 
695, 3190, 2955, 1717, 1450, 1400, 1341, 1321, 1170, 1115, 
974, 693, 500 
NMR; .delta.(ppm); 7,91 (s, 1H, --NH--); 7,32-7,01 (m, 9H, 
arom); 3,69 (s, 2H, --CH.sub.2 --N--); 3,67 (s, 2H, 
CH.sub.2 --C.dbd.O); 3,10 (s, 3H, CH.sub.3 -s); 2,87 (s, 2H, 
--CH.sub.2 --); 1,31 (s, 6H, --CH.sub.3) 
5 B.P. 196-197.degree. C. 
IR; 3480 (--NH--) 1716 (--C.dbd.O), 1447 (--SO.sub.2 --) 
cm.sup.-1 
1175, 1131, 1084 (SO.sub.2) 
NMR; .delta. = 8,3 (s, b NH), 7,9-6,9 (m, 14 H, 3M); 3,55 (s, 
4H, 2--CH.sub.2 --); 2,83 (s, 2H, CH.sub.2), 1,26 (s, 6H, 2 
CH.sub.3) 
6 B.P. 207-209.degree. C. 
IR; 3295 (--NH--), 1721 (--C.dbd.N), 1413, 1183, 1084 
(--SO.sub.2) 
NMR; 7,8-7,7 (m, 2H, AA'), 7,35-6,95 (m, 11H, 2 Ar 
+ BB'); 3,55 (5,2H, CH.sub.2); 3,54 (s; 2H, CH.sub.2); 2,84 (s, 
2H; 
CH.sub.2); 2,45 (s, 3H, Ar--CH.sub.3); 1,26 (s; 6H; 2--CH.sub.3) 
7 B.P. 163.degree. C. 
IR; 3220, 2950, 1721, 1432, 1395, 1341, 1176, 1113, 971, 
878 
NMR; 7,31-7,14 (m, 5H, arom,); 6,83 + 6,56(AB,2H,J = 
3,7Hz--CHCH--); 3,72(s,2H,); 3,69(s, 2H); 3,44(s,3H, 
--SO.sub.2 CH.sub.3); 2,84(s,2H,--CH.sub.2 --); 1,30(s,6H,--CH.sub. 
3) 
8 B.P. 188.degree. C. 
IR; 3235 (--NH--), 1725 (--C.dbd.O), 1442, 1166, 1083 
(SO.sub.2 --) 
NMR; 8,1 (b, 1H,--NH), 7,9-7,8(m,2H,AA',Ar), 7,4- 
7,1 (m,7H,Ar + BB') 6,74, 2,82(s,2H, CH.sub.2); 2,29-2,41 
(m,2H,CH.sub.2 --COOH) (6,45(AB,JAB = 3,75Hz); 3,58 
(s,2H,CH.sub.2); 3,56(s,2H,CH.sub.2) 2,80(s,2H,CH.sub.2), 
2,45(s,3H,Ar--CH.sub.3); 1,25(5,6H;2CH.sub.3) 
9 B.P. 191.degree. C. 
IR; 3435, 3225, 1721, 1598, 1447, 1400, 1340, 1320, 1111, 
971 
NMR; 7,32-7,01 (m, 9H, arom); 3,71 (s, 2H, 
--CH.sub.2 --CO-7); 3,68 (s, 2H, ); 3,11 (s, 3H, 
--SO.sub.2 --CH.sub.3); 2,85 (s, 2H, --CH.sub.2 --); 1,64 (q, 4H, 
J = 7,5, ethyl), 0,91 (t, 6H, J = 7,5, ethyl) 
10 IR; 3225 (--NH--), 1721 (--C.dbd.O), 1439 (--SO.sub.2 --) 
cm.sup.-1 1184 ((SO.sub.2), 1081 (SO.sub.2) 
NMR; 7,79-6,95 (m, 13H, arom), 3,57 (s, 2H, 
--CH.sub.2 --C.dbd.O), 3,54 (s, 2H, --CH.sub.2 --N--), 2,8 
(s, 2H,--CH.sub.2 --), 2,44 (s, 3H, Ph--CH.sub.3) 
11 B.P. 140-142.degree. C. 
IR; 3260 (--NH--), 1722(--C.dbd.O), 1437 
(--SO.sub.2 --) 1327, 1113 
NMR; 7,4-7,1 (m, 5H, Ar); 6,82/6,55 (AB-System, 
J.sub.AB = 3,8 Hz 3,72 (s,2H, CH.sub.2); 3,71(s,2H, CH.sub.2); 
3,21 (s; 3H, SO.sub.2 CH.sub.3), 2,82(s,2H,CH.sub.2), 1,619 
(q,4H, 
2--CH.sub.2, J = 7,4Hz; 0,899 (t, 6H, J = 7,4Hz, 2CH.sub.3 --) 
12 B.P. 158-160.degree. C. 
IR; 3225 (--NH--), 1721 (--C.dbd.O); 1432, 1184, 1084 
(--SO.sub.2) 
NMR; 8,02 (b,1H; NH--); 7,9-7,8 (m,2H; AA') 7,4-7,1 
(m.dbd.,7H, Ar + BB'); 6,740/6,446(AB,2H, JAB = 3,7HZ); 
3,58(s,4H, 2--CH.sub.2); 2,79 (s,2H,CH.sub.2), 2,45(s,3H, 
Ar--CH.sub.3); 1,57 (q,4H;2CH.sub.2); 0,861 (t,6H,2CH.sub.3) 
13 B.P. 210.degree. C. unter Zersetzung 
IR; 3300 (NH); 1720 (C.dbd.O) 
NMR; 1,20-1,58 (m, 4H, --CH.sub.2 --CH.sub.2 --); 1,26 (s, 6H, 
CH.sub.3); 1,99-2,20 (m, 2H, CH.sub.2 --CO); 2,42 (s, 3H, 
Ar--CH.sub.3); 
2,83 (s, 2H, CH3); 2,28-2,39 (m, 2H, CH.sub.2 --Py); 
3,75 (s, 2H, CH.sub.2), 6,94-7,71 (m, 14H, Ar.) 
14 B.P. 203-204.degree. C. 
IR; 3430, 3175, 3161, 1678, 1596, 1466, 1438, 1341, 1133. 
NMR; 8,2-7,7 (b, 1H, NH), 7,4-7,1 (m, 5H, Ar,); 6,90 
(d, 1H, J = 4,0Hz, thien.), 6,69 (d, 1H, J = 4,0 Hz, thien.); 
6,38 (q, 1H, J = 0,8Hz, thiaz,);4,07 (s, 2H, CH.sub.2); 3,271 
(s, 3H, SO.sub.2 CH.sub.3); 2,554 (d, 3H, J = 0,8Hz). 
15 B.P. &gt;190.degree. C. u.Z. 
IR; 3480 (CNH); 1722 (C.dbd.O) 
NMR; 7,51-7,08 (m, 9H, Ar); 3,67 (s, 2H, CH.sub.2 --C); 3,58 
(s, 2H, CH.sub.2 --), 3,07 (s, 3H, CH.sub.3); 2,86 (s, 2H, 
CH.sub.2); 
1,28 (s, 6H, CH.sub.2) 
______________________________________