Thiophenes useful for modulating the adenosine receptor

The present invention relates to compounds of formulas (IA), (IB), and (IC): ##STR1## the preparation thereof, pharmaceutical formulations thereof, and their use in medicine as allosteric adenosine receptor modulators for uses including protection against hypoxia and ischemia induced injury and treatment of adenosine-sensitive cardiac arrhythmias.

FIELD OF THE INVENTION 
The present invention relates to certain thiophene derivatives and their 
use in the practice of medicine as allosteric modulators of adenosine 
receptors. 
BACKGROUND OF THE INVENTION 
Adenosine (Ado) is an autocoid (or local hormone) that modulates numerous 
functions in the cardiovascular and other organ systems. The actions of 
Ado are mediated by at least four subtypes of cell surface receptors 
called A.sub.1, A.sub.2a, A.sub.2b, and A.sub.3. Because the ubiquity of 
adenosine receptors (AdoRs) throughout the body of a human, their 
indiscriminate activation may cause undesirable side effects. Therefore, 
new drug design approaches to achieve organ selectivity are needed. 
The overall function of Ado appears to be the regulation of the balance 
between oxygen (or energy) supply and consumption (or work). Ado increases 
oxygen supply by causing vasodilation and decreases oxygen consumption or 
work by inhibiting cellular functions, e.g., slowing of the heart rate. 
Consistent with this protective function, A.sub.1 AdoR agonists, Ado 
uptake blockers and Ado deaminase inhibitors have been shown to reduce 
cellular damage and dysfunction during hypoxia and ischemia. This 
protective role of Ado and A.sub.1 AdoR agonists has been shown in the 
heart, brain, liver, and intestines. This and other potentially beneficial 
actions of Ado have led to increased interest in the development of 
Ado-related drugs targeted to ameliorate conditions such as myocardial 
ischemia and stroke. 
However, the widespread expression of Ado receptors and the lack of 
sufficiently selective adenosine agonists have been a major impediment to 
the successful development of direct-acting AdoR agonists to exploit the 
cytoprotective properties of Ado. Therefore, other pharmacological 
approaches such as allosteric modulators of Ado may prove to be a valuable 
alternative to direct-acting Ado agonists and nucleoside uptake blockers. 
Such agents should selectively modulate the response to Ado in only those 
organs or localized areas of a given organ in which production of Ado is 
increased. Thus, allosteric modulators of Ado function should provide a 
more selective therapeutic effect than direct-acting AdoR agonists. Their 
action will be limited to times and locations at which significant release 
of Ado occurs so that systemic side effects would largely be avoided. 
Allosteric modulation of the actions of Ado on the A.sub.1 AdoR by several 
2-amino-3-benzoylthiophenes on cultured cells, cardiac and brain 
preparations have been reported. The specificity of these compounds for 
A.sub.1 AdoRs have also been demonstrated. 
A number of compounds known to modulate the action of neurotransmifters, 
hormones and peptides bind at sites distinct from, but functionally linked 
to, the primary recognition site of the respective receptors. This form of 
interaction between two different ligands at the same receptor protein, 
which may result in modulation in the form of enhancement or inhibition of 
each other's binding and function, is referred to as allosterism. Positive 
(enhancement) or negative (inhibition) allosterism are important 
mechanisms of action of drugs. For example, allosteric interactions 
between the GABA receptor and benzodiazepines, the atrial natriuretic 
factor (ANF) receptor and amiloride, the dextromethorphan binding site and 
ropizine, and the muscarinic receptor and gallamine have been described. 
SUMMARY OF THE INVENTION 
One aspect of the present invention is a compound selected from a group 
consisting of compounds of formulas IA, IB, and IC: 
##STR2## 
wherein: R.sub.1 is hydrogen, lower alkyl, or haloacetyl; 
R.sub.2, R.sub.3, and R.sub.4 are independently hydrogen, halogen, lower 
alkyl, phenyl, lower alkenyl, lower alkanoyl, amino, trifluoromethyl, 
amino lower alkyl, nitro, or cyano; 
t is 0, 1, 2, or3; 
Z is NH, N-(Gr).sub.m (Am).sub.n (Alk).sub.p (Ph).sub.q, or CH-(Gr).sub.m 
(Am).sub.n (Alk).sub.p (Ph).sub.q, 
wherein 
Gr is --SO.sub.2 --, --C(O)O--, or --C(O)--, 
Am is --CH(NH.sub.2)--, an amino acid residue, or an amino protected amino 
acid residue, 
Alk is hydrogen, lower alkylene or lower alkenylene, 
Ph is phenyl; phenyl substituted with one or more lower alkyl groups; or 
phenyl substituted with one or more nitro groups, 
m is 0 or 1 
n, p, and q are independently 0, 1, or 2, provided that at least one of m, 
n, p, and q is other than 0; 
R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, or taken 
together form a lower alkenyl ring of 5 or 6 members, 
provided that if R.sub.2, R.sub.3, and R.sub.4 are hydrogen, then, both 
R.sub.5 and R.sub.6 may be neither hydrogen nor methyl; further provided 
that if R.sub.2 and R.sub.3 are hydrogen while R.sub.4 is trifluoromethyl 
or if R.sub.2 and R.sub.4 are hydrogen while R.sub.3 is chloro, then both 
R.sub.5 and R.sub.6 may not be methyl; 
R.sub.7 is hydrogen or lower alkyl; 
Y is Nitrogen, CH or C(O)OR.sub.8 ; and 
Wherein R.sub.8 is hydrogen or lower alkyl. 
A second aspect of the present invention is a method of allosterically 
modulating adenosine receptors in a mammal, including a human, comprising 
the administration to the mammal of an effective amount of a compound of 
formula IA, IB, or IC sufficient to moderate adenosine receptors. 
A third aspect is a pharmaceutical formulation comprising a compound of 
formula IA, IB, or IC and one or more excipients. A fourth aspect are the 
novel chemical intermediates useful in the preparation of the compounds of 
formula IA, IB, or IC.

DETAILED DESCRIPTION OF THE INVENTION 
As used herein the term "lower alkyl" means a monovalent radical, straight 
or branched chain, derived from the corresponding alkane having one to ten 
carbon atoms, i.e., methyl, ethyl, propyl, Isopropyl, n-butyl, sec-butyl, 
t-butyl, pentyl (all isomers), etc. Likewise, "lower alkylene" means a 
divalent radical of the corresponding alkane. Further, as used herein, 
other moieties having names derived from alkanes, such as alkoxyl, 
alkanoyl, alkenyl, cycloalkenyl, etc when modified by "lower," have carbon 
chains of ten or less carbon atoms. In those cases where the minimum 
number of carbons are greater than one, e.g., alkenyl (minimum of two 
carbons) and cycloalkyl, (minimum of three carbons), it is to be 
understood that "lower" means at least the minimum number of carbons. 
As used herein the term "amino acid" means an alpha amino acid selected 
from those amino acids which naturally occur in proteins but without 
regard for specific stereochemical properties. The term "protected amino 
acid" means an amino acid of which the alpha amino group has been 
converted to a less reactive moiety, but a moiety which can be converted 
back to the amino group with relative ease. The terms "amino acid residue" 
and "amino acid moiety" are use synonymously herein. 
Certain of the compounds of the present invention are sufficiently basic, 
(e.g., amino derivatives) or acidic (e.g., carboxylic acid derivatives) to 
form salts. Pharmaceutically acceptable salts of the compounds of formulas 
IA and IB are within the scope of the present invention. As will be 
understood by those skilled in the art, pharmaceutically acceptable salts 
include, but are not limited to, salts with inorganic acids such as 
hydrochloride, sulfate, phosphate, hydrobromide, and nitrate or salts with 
an organic acid such as malate, maleate, fumarate, tartrate, succinate, 
citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmoate, 
salicylate, and stearate. Other acids such as oxalic, while not in 
themselves pharmaceutically acceptable, may be useful as intermediates in 
obtaining the compounds of the invention and their pharmaceutical salts. 
Particular compounds of the present invention include compounds of formulas 
IA, IB, and IC wherein 
R.sub.1 is hydrogen, 
R.sub.2, R.sub.3, and R.sub.4 are independently hydrogen, halogen, or 
trifluoromethyl, 
t is 0, 1, 2, or3 
Z is NH, N-(CH.sub.2).sub.1-3 phenyl, N-(ethoxycarbonylmethyl), 
N-(2-t-butoxycarbonylamino-3-(4-hydroxyphenyl)-propion-1-yl), 
N-(3-methylbut-2-en-1-yl), N-(4-methylphenylsulphonyl), 
N-(4-nitro-(2-phenyleth-1-yl), or N-(benzyloxycarbonyl); 
R.sub.5 and R.sub.6 are both hydrogen or both methyl, or R.sub.5 and 
R.sub.6 together form a cyclopentyl or cyclohexyl ring; 
R.sub.7 is hydrogen or methyl; 
R.sub.8 is ethyl. 
Specific compounds of the present invention are: 
______________________________________ 
Com- 
pound/ 
Example 
Number Compound Name 
______________________________________ 
2 (2-amino-4,5-dimethyl-3-thienyl)-(3,5-dichloro-4-amino)- 
phenyl)!methanone, 
5 (2-amino-3-thienyl)-(4-chlorophenyl)methanone, 
7 2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
8 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 
9 2-amino-3-(4-chlorobenzoyl)-6-benzyloxycarbonyl-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
10 2-amino-3-(4-chloro-benzoyl)-4,5,6,7-tetrahydrothieno 
2,3-c!pyridine, 
11 2-amino-3-3-(trifluoromethyl)-benzoyl!-6-(3-phenylprop-1- 
yl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine, 
13 2-amino-3-3-(fluoromethyl)-benzoyl!-6-(phenylmethyl)- 
4,5,6,7,-tetrahydrothieno2,3-c!pyridine, 
14 2-amino-3-(4-chloro-benzoyl)-6-(2-phenyleth-1-yl)-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
15 2-amino-3-3-(fluoromethyl)-benzoyl!-6-(2-phenyleth-1-yl)- 
4,5,6,7-tetrahydrothieno2,3-c!pyridine, 
16 2-amino-3-(4-chloro-benzoyl)-6-(3-phenylprop-1-yl)-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
18 2-amino-3-(4-chloro-benzoyl)-6-(ethoxycarbonylmethyl)- 
4,5,6,7-tetrahydrothieno2,3-c!pyridine, 
20 2-amino-3-benzoyl-6-(3-methylbut-2-en-lyl)-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
21 2-amino-3-(4-chloro-benzoyl)-6-4-nitro-(2-phenyleth-1-yl)!- 
4,5,6,7-tetrahydrothieno2,3-c!pyridine, 
22 2-amino-3-benzoyl-6-4-nitro-(2-phenyleth-1-yl)!-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine, 
23 2-amino-3-benzoyl-6-2-t-butoxycarbonylamino-3-(4- 
hydroxyphenyl)-propion-1-yl!4,5,6,7-tetrahydrothieno 
2,3-c!pyridine, 
24 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzob!thiophene, 
25 4-phenyl-5,6,7,8-tetrahydro1!benzothieno2,3-d!pyrimidine 
26 2-methyl,3-ethoxycarbonyl-4-phenyl-5,6,7,8- 
tetrahydro1!benzothieno2,3-b!pyridine 
27 2-Amino-3-(4-bromobenzoyl)-cyclopentab!thiophene, and 
28 2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7- 
tetrahydrothieno2,3-c!pyridine. 
______________________________________ 
Those skilled in the art of organic chemistry will appreciate that reactive 
and fragile functional groups often must be protected prior to a 
particular reaction, or sequence of reactions, and then restored to their 
original forms after the last reaction is completed. Usually groups are 
protected by converting them to a relatively stable derivative. For 
example, a hydroxyl group may be converted to an ether group and an amino 
converted to an amide or carbamate. Methods of protecting and 
de-protecting, also known as "blocking" and "de-blocking," are well know 
and widely practiced in the art, e.g., see T. Green, Protective Groups in 
Organic Synthesis, John Wiley, New York (1981) or Protective Groups in 
Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, London (1973). 
Synthesis of Compounds 
Compounds of formula IB may be conveniently prepared according to Scheme 1. 
##STR3## 
In Step 1 a compound of formula (II) is reacted with a compound of formula 
(III) in the present of morpholine and molecular sulfur in a protic 
solvent, such as ethanol, at about 50.degree. to about 65.degree. C. for 
about an hour to yield a compound of formula IA wherein R1 is hydrogen. 
Compounds of formula (IA) wherein R.sub.1 is other than hydrogen may be 
prepared according to Step 2 by reacting a compound of formula (IB) from 
Step 1, wherein R.sub.1 is hydrogen, with R.sub.1 X (wherein R.sub.1 is 
other than hydrogen, and X is a leaving group). For a discussion of 
nucleophilic displacement reactions and leaving groups see standard 
organic chemistry texts such as J. March, Advanced Organic Chemistry, 
chap. 10, John Wiley & Sons, New York (1985). Compounds of formula (II) 
are commercially available or may be prepared by methods of the art. 
Compound of formula (III), benzophenone derivatives, may be prepared by 
methods of the art or conveniently according to Scheme 2. 
##STR4## 
In Scheme 2 a compound of formula (IV), a substituted acetophenone, is 
alpha brominated with molecular bromine in a protic, polar solvent, such 
as acetic acid to yield the corresponding alpha bromo compound of formula 
(V). The compound of formula (III) is produced by reacting the compound of 
formula (V) with a source of cyanide ions, such as sodium or potassium 
cyanide, in a polar solvent, such as water, ethanol, or a mixture thereof. 
##STR5## 
As shown in Scheme 3, a compound of formula (IA.sub.1) wherein Z is NH may 
be prepared by hydrolyzing the CO-N urethane linkage of a compound of 
formula (VI) under acidic conditions, e.g., hydrogen bromide in acetic 
acid. 
In turn, a compound of formula (VI) may be prepared in a similar manner as 
the reaction of Scheme 1 by substituting a compound of formula (II) with a 
corresponding amount of a compound of formula (VII). It may be necessary 
to 
##STR6## 
protect the carbonyl group of the piperidinone moiety during the synthesis 
of a precursor compound, e.g., by converting it to an ethylenedioxy 
derivative as seen in formula (VIII). The protecting or blocking group is 
removed after the synthesis of a compound of formula (VIII) to generate a 
compound of formula (VII). 
Compounds of formula (IA) wherein Z is a substituted nitrogen, i.e., 
N-(Gr).sub.m (Am).sub.n (Alk).sub.p (Ph).sub.q, may be prepared by 
nucleophilic displacement by reacting a compound of the formula 
X-(Gr).sub.m (Am).sub.n (Alk).sub.p (Ph).sub.q, wherein X is a leaving 
group (see March, supra), in a polar solvent in the presence of a weak 
base such as sodium or potassium carbonate or a tertiary amine. 
##STR7## 
According to Scheme 4, a compounds of formula (IC), can be prepared from 
the corresponding compound of formula (IB), wherein R.sub.1 is hydrogen, 
by reacting with a compound of formula (IX) in a protic, polar solvent, 
such as ethanol, in the presence of a strong base such as sodium ethylate 
to form the pyridine moiety. (If Y is nitrogen, then R.sub.8 ' is H.sub.2, 
and if Y is CH then R.sub.8 ' is C(O)OR.sub.8.) This reaction can 
conveniently be carried out by mixing the reactants, solvent and base at 
about 0.degree. C. followed by heating at reflux for about 10 hours. A 
compound of formula (IC) wherein Y is nitrogen, i.e., R.sub.8 is H.sub.2, 
can be prepared from the corresponding compound of formula (IB) by 
reaction with a R.sub.7 --COONH.sub.2, e.g., formamide, if R.sub.7 is 
hydrogen, at about 180.degree. C. for about 5 hours. 
Compounds of formula (IA) wherein Z is N-(Gr).sub.m (Am).sub.n (Alk).sub.p 
(Ph).sub.q, and Am is an amino acid or an amino acid with the amino group 
protected, and m, p, and q are 0, may be prepared by reacting the 
corresponding compound wherein Z is NH with a protected derivative of an 
amino acid. An example of a protected amino acid is BOC-tyrosine ( 
"BOC-Tyr-OH") wherein "BOC" is --COOC(CH.sub.3).sub.3. Preferably the 
reaction is run in a polar, aprotic solvent, such as dimethylformamide. 
Preparation of BOC derivative of amino acids are well known in the art of 
protein and peptide chemistry. If desired the BOC moiety may be removed by 
standard means of the art to restore the amino acid residue. 
Utility 
Compounds of this invention are useful for: 
Protection against hypoxia and/or ischemia induced injuries (e.g., stroke, 
infarction); 
Treatment of adenosine-sensitive cardiac arrhythmias; 
antinociception (i.e., analgesics); 
anticonvulsants; and 
Other indications for which A.sub.1 AdoR agonists are used. 
The amount of compound of the present invention required to be effective as 
an allosteric modulator of an adenosine receptor will, of course, vary 
with the individual mammal being treated and is ultimately at the 
discretion of the medical or veterinary practitioner. The factors to be 
considered include the condition being treated, the route of 
administration, the nature of the formulation, the mammal's body weight, 
surface area, age and general condition, and the particular compound to be 
administered. However, a suitable effective dose is in the range of about 
0.1 .mu.g/kg to about 10 mg/kg body weight per day, preferably in the 
range of about 1 mg/kg to about 3 mg/kg per day. 
The total daily dose may be given as a single dose, multiple doses, e.g., 
two to six times per day, or by intravenous infusion for a selected 
duration. Dosages above or below the range cited above are within the 
scope of the present invention and may be administered to the individual 
patient if desired and necessary. For example, for a 75 kg mammal, a dose 
range would be about 75 mg to about 220 mg per day, and a typical dose 
would be about 150 mg per day. If discrete multiple doses are indicated, 
treatment might typically be 50 mg of a compound of the present invention 
given 3 times per day. 
Binding Assays 
The prototypical allosteric enhancer PD 81,723, (prepared in Example 4; see 
Bruns, et al., Mole. Pharm., 38:939 (1990), Cao et al., Gen Pharmac. 
26:1545 (1995), and Amoah-Apraku et al., J. Pharm. Exper. Ther. 
266(No.2):611(1993)) has both enhancing and inhibitory activity at the 
A.sub.1,AdoR. Therefore, the affect of a novel series of benzoylthiophene 
derivatives were determined on both the agonist .sup.3 H!CCPA and the 
antagonist .sup.3 H!CPX binding to membranes prepared from CHO cells 
stably expressing the human A.sub.1 AdoR (CHO-huA.sub.1 AdoR). The 
enhancing activity was estimated by the magnitude of the increase in 
.sup.3 H!CCPA binding whereas the inhibitory and (or antagonistic) 
activity was evaluated by the potency of the benzoylthiophene derivatives 
to compete for the specific binding of .sup.3 H!CPX. The method used for 
the preparation of the membranes of CHO cells expressing huA.sub.1 AdoR, 
and the protocols for the radioligand binding assays are described by 
Kollias-Baker, et al., (JPET, 281, 761(1997) and Circ. Res., 75, 961 
(1994)). 
Functional Assays 
In previous studies (Amoah-Apraku, et al., J. Pharmacol Exp. Ther., 266, 
611 (1993) and Kollias-Baker, supra) the prototypical allosteric enhancer 
PD 81,723 was shown to selectively enhance A.sub.1 AdoR-mediated 
prolongation of the stimulus to His (S-H) bundle interval (negative 
dromotropic effect) but did not increase the A.sub.2a AdoR-mediated 
coronary vasodilation caused by Ado. Therefore, the effect of compound 20 
on the negative dromotropic action of Ado in guinea pig isolated perfused 
hearts was determined. The guinea pig isolated perfused heart preparation 
and the methods for recording His bundle electrograms and measuring the 
S-H intervals have been previously reported. 
Results 
Radioligand Binding Assays 
The effect of the benzoylthiophene derivative compound 20 on agonist and 
antagonist binding to CHO cells expressing the recombinant huA.sub.1 AdoR 
was investigated. Specifically, the effects of compound 20 on the binding 
of the agonist radioligand .sup.3 H!CCPA (2 nM) and the antagonist 
radioligand .sup.3 H!CPX (1 nM) to recombinant CHO-huA.sub.1,AdoR were 
determined. As shown in FIG. 1A, the effect of compound 20 on the specific 
binding of .sup.3 H!CCPA was biphasic, at concentrations up to 7 .mu.M it 
increased but thereafter it decreased the specific binding of .sup.3 
H!CCPA. In contrast, compound 20 did not enhance the binding of the 
antagonist radioligand .sup.3 H!CPX and at concentrations greater than 1 
.mu.M decreased the specific binding of .sup.3 H!CPX, see FIG. 1B. The 
values are mean .+-.SEM of 4 hearts. Each data point represents mean 
.+-.SEM specific binding with determinations from 2-3 experiments. FIGS. 2 
and 3 are similar to FIG. 1A but show the result of .sup.3 H!CCPA studies 
on other compounds of the present invention. 
Functional Studies 
Consistent with the results of the radioligand binding assays, compound 20 
enhanced the negative dromotropic effect (S-H interval prolongation) 
caused by Ado in a concentration-dependent manner (FIG. 4A). In pressure 
of 1 .mu.M compound 20, 3 .mu.M adenosine caused 2.degree. A-V block in 2 
of 4 hearts. The values are mean .+-.SEM of 4 guinea pigs. For instance, 
0.1, 0.5 and 1.0 .mu.M compound 20 enhanced the S-H prolongation induced 
by 3 .mu.M Ado by 32%, 77%, and 311%, respectively. At 1.0 .mu.M compound 
20, the negative dromotropic effect of Ado was maximal, eliciting 
2.degree. A-V block in 2 of 4 hearts. In contrast, in the absence of 
compound 20, the same concentration of Ado (3 .mu.M) prolonged the S-H 
interval by 11.-+.3 msec. To demonstrate that the enhancement of the 
dromotropic effect of Ado by compound 20 was mediated by activation of 
A.sub.1 AdoRs, prolongation of S-H interval caused by Ado in the presence 
of compound 20 was shown to be reversed by 10 .mu.M of the A.sub.1 AdoR 
antagonist CPX (FIG. 4B). The reversal of the effects of compound 20 by 
CPX establishes that the enhancement was mediated through the A.sub.1 
AdoR. 
Formulations 
Formulations of the present invention for medical use comprise an active 
compound, i.e., a compound of formula (IA), (IB) or (IC), together with a 
pharmaceutically acceptable carrier thereof and optionally other 
therapeutically active ingredients. The carrier must be pharmaceutically 
acceptable in the sense of being compatible with the other ingredients of 
the formulation and not deleterious to the recipient thereof. 
The present invention, therefore, further provides a pharmaceutical 
formulation comprising a compound of formula (IA), (IB) or (IC) together 
with a pharmaceutically acceptable carrier thereof. 
The formulations include, but are not limited to, those suitable for oral, 
rectal, topical or parenteral (including subcutaneous, intramuscular and 
intravenous) administration. Preferred are those suitable for oral or 
parenteral administration. 
The formulations may conveniently be presented in unit dosage form and may 
be prepared by any of the methods well known in the art of pharmacy. All 
methods include the step of bringing the active compound into association 
with a carrier which constitutes one or more accessory ingredients. In 
general, the formulations are prepared by uniformly and intimately 
bringing the active compound into association with a liquid carrier or a 
finely divided solid carrier and then, if necessary, shaping the product 
into desired unit dosage form. 
Formulations of the present invention suitable for oral administration may 
be presented as discrete units such as capsules, cachets, tablets or 
lozenges, each containing a predetermined amount of the active compound; 
as a powder or granules; or a suspension or solution in an aqueous liquid 
or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught. 
A tablet may be made by compression or molding, optionally with one or more 
accessory ingredients. Compressed tablets may be prepared by compressing 
in a suitable machine the active compound in a free-flowing form, e.g., a 
powder or granules, optionally mixed with accessory ingredients, e.g., 
binders, lubricants, inert diluents, surface active or dispersing agents. 
Molded tablets may be made by molding in a suitable machine, a mixture of 
the powdered active compound with any suitable carrier. 
A syrup or suspension may be made by adding the active compound to a 
concentrated, aqueous solution of a sugar, e.g., sucrose, to which may 
also be added any accessory ingredients. Such accessory ingredients may 
include flavoring, an agent to retard crystallization of the sugar or an 
agent to increase the solubility of any other ingredient, e.g., as a 
polyhydric alcohol, for example, glycerol or sorbitol. 
Formulations for rectal administration may be presented as a suppository 
with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark 
of Dynamite Nobel Chemical, Germany), for a suppository base. 
Formulations suitable for parenteral administration conveniently comprise 
sterile aqueous preparation of the active compound which is preferably 
isotonic with the blood of the recipient. Thus, such formulations may 
conveniently contain distilled water, 5% dextrose in distilled water or 
saline. Useful formulations also comprise concentrated solutions or solids 
containing the compound of formula (I) which upon dilution with an 
appropriate solvent give a solution suitable for parental administration 
above. 
Topical formulations include ointments, creams, gels and lotions which may 
be prepared by conventional methods known in the art of pharmacy. In 
addition to the ointment, cream gel, or lotion base and the active 
ingredient, such topical formulation may also contain preservatives, 
perfumes, and additional active pharmaceutical agents. 
In addition to the aforementioned ingredients, the formulations of this 
invention may further include one or more optional accessory ingredient(s) 
utilized in the art of pharmaceutical formulations, e.g., diluents, 
buffers, flavoring agents, binders, surface active agents, thickeners, 
lubricants, suspending agents, preservatives (including antioxidants) and 
the like. 
EXAMPLES 
The following examples illustrate aspects of this invention but should not 
be construed as limitations. The symbols and conventions used in these 
examples are intended to be consistent with those used in the 
contemporary, international, chemical literature, for example, the Journal 
of the American Chemical Society and Tetrahedron. 
Example 1 
(2-Amino-4,5-dimethyl-3-thienyl)-(phenyl)methanone 
Compound 1 
A. General Procedure for the Preparation of Phenacyl-bromides, the 
Compounds of Formula (V). 
A solution of bromine (55 mmol) in acetic acid (50 mL) is added dropwise to 
an acetophenone (50 mmol), which is a compound of formula (IV), in glacial 
acetic (100 ml) in half an hour, with stirring. The resulting suspension 
is heated at 50.degree. C. for an hour, and then poured into ice water 
(500 mL). The precipitated phenacyl bromide, a compound of fomula (V), is 
filtered and washed with cold water three times, and finally crystallized 
from ethanol. (See Rather and Reid, J.Am.Chem.Soc. 41, 77 (1919)). 
B. General Procedure for the Preparation of Substituted Benzoyl 
Acetonitriles, the Compounds of Formula (III) 
A phenacyl bromide as prepared in Step A, above, in ethanol is reacted with 
an aqueous solution of potassium cyanide dissolved in distilled water. The 
reaction is monitored by TLC control and during this time the solution 
changes color from yellow-orange to yellow-red. When the reaction is 
complete, crushed ice is added in a large amount and the solution is 
acidified with acetic acid. The precipitated corresponding benzoyl 
acetonitriles is filtered and washed with cold water then air dried. 
C. (2-amino-4,5-dimethyl-3-thienyl)-(phenyl)methanone 
A mixture of equimolar amounts of methylethyl ketone (0.01 mol), which is a 
compound of formula (II) wherein R.sub.5 and R.sub.6 are methyl, benzoyl 
acetonitrile (0.01 mol), which is a compound of formula (III) wherein 
R.sub.2, R.sub.3, and R.sub.4 are hydrogen, sulfur (0.01 mol) and 
morpholine (0.01 mol) in ethanol (4 mL) was stirred and heated at 
60.degree. C. for an hour (TLC control). After this time, the suspension 
was left standing overnight, the mixture was poured into water and the 
precipitated solid was extracted with ethyl acetate (3.times.50 mL). The 
organic layers are dried on magnesium sulfate and evaporated under vacuum. 
The crude product was chromatographed on silica gel column using mixtures 
of ethyl acetate and petroleum ether. 
(m.p. 140-141.degree. C., 80% yield). 1H-NMR: (CDCl.sub.3):1.53 (s, 3H), 
2.13 (s, 3H); 6.44 (sb, 2H); 7.43-7.54 (m, 5H). 
Examples 2-6 
Compounds 2-6 
The following compounds of formula (IB) are prepared by the procedure of 
Scheme 1 taught herein above, and in an analogous manner to Example 1 
using appropriate precursor compounds of formula (II) and formula (III). 
If the desired compounds of formulas (II) and (III) are not commercially 
available, they may be prepared according to Example 1, sections A and B. 
2: 
(2-amino-4,5-dimethyl-3-thienyl)-(3,5-dichloro-4-amino)-phenyl)!methanone 
(m.p. 155-157.degree. C., 88% yield). 1H-NMR: (CDCl.sub.3):1.71 (s, 3H), 
2.16 (s, 3H); 4.79 (sb, 2H); 6.03 (sb, 2H); 7.48 (s,2H). 
3: (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-phenyl)methanone 
(m.p. 128-130.degree. C., 89% yield). 1H NMR: (CDCl.sub.3):1.54 (s, 3H), 
2.13 (s, 3H); 6.47 (sb, 2H); 7.35-7.48 (m, 4H). 
4: (2-amino-4,5-dimethyl-3-thienyl)-3-(trifluoromethyl)-phenyl!methanone 
(m.p. 103-105.degree. C., 78% yield); 1H NMR: (CDCl.sub.3):1.48 (s, 3H), 
2.13 (s, 3H); 6.67 (sb, 2H); 7.54-7.75 (m, 4H). 
5: (2-amino-3-thienyl)-(4-chlorophenyl)methanone 
(m.p. 178-180.degree. C., 81% yield). 1H NMR: (DMSO-d6) 6.27 (d, 1 H), 
6.72 (d, 1 H); 7.52-7.63 (m, 4H); 8.39 (sb, 2H). 
6: (2-amino-3-thienyl)-phenylmethanone 
(m.p.150-152.degree. C., 75% yield). 1H NMR: (CDCl.sub.3): 6.11 (d, 1H), 
6.87 (d,IH); 7.05 (sb, 2H); 7.3-7.7 (m, 5H). 
Example 7 
2-Amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno2,3-c!pyridi 
ne 
Compound 7 
A. Preparation of 8-benzyloxycarbonyl 1,4-dioxa -8-azaspiro4,5!decane 
To a well-stirred and ice-cooled solution of 
1,4-dioxa-8-azaspiro4,5!decane (34.9 mmol, 5 g) in dichloromethane (200 
mL) under an argon atmosphere, was added triethylamine (52.4 mmol, 7.3 mL) 
and then benzyloxycarbonyl chloride (42 mmol, 5.93 mL) dropwise. The 
suspension was stirred at room temperature for 24 hours and the 
precipitated solid was filtered. The organic solution was evaporated under 
vacuum to give an oily residue which was chromatographed on silica gel 
eluting with ethyl ether and petroleum ether mixture to afford 
8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro 4,5!decane in quantitative 
yield. 
1H-NMR (CDCl.sub.3): 1.63 (m, 4H); 3.56 (m,4H); 3.89 (s, 4H); 5.09 (s, 2H); 
7.28 (s, 5H). 
B. Preparation of the 1-benzyloxycarbonyl piperidin-4-one 
To a stirred solution 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro4,5!decane 
(0.037 mol, 10 g) in tetrahydrofuran (150 mL) was added a solution of 
hydrochloric acid 5% (20 mL) dropwise a room temperature. The solution was 
stirred for 18 h (TLC control) and then evaporated under vacuum to small 
volume (20 mL) and neutralized with saturated sodium bicarbonate solution. 
The aqueous solution was extracted with ethyl acetate (3.times.100 mL) and 
the organic layers were dried on sodium sulfate and finally evaporated 
under vacuum to give 1-benzyloxycarbonyl piperidin-4-one practically pure 
which was then used in the next step without any further purification (92% 
yield). 
1H-NMR (CDCl.sub.3): 1.63 (m, 4H); 3.56 (m,4H); 5.09 (s, 2H); 7.28 (s, 5H). 
C. 
2-Amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno2,3-c!pyrid 
ine 
A mixture of equimolar amounts of 1-benzyloxycarbonyl piperidine (0.01 
mol), benzoyl acetonitrile (0.01 mol), sulfur (0.01 mol) and morpholine 
(0.01 mol) in ethanol (4 mL) was stirred and heated at 60.degree. C. for 1 
h (TLC control). After this time, the suspension was standing overnight 
and the mixture is poured into water and the precipitated solid is 
extracted with ethyl acetate (3.times.50 mL). The organic layers were 
dried on magnesium sulfate and evaporated under vacuum. The crude product 
was chromatographed on silica gel column using mixtures of ethyl acetate 
and petroleum ether. 
(m.p. 138-140.degree. C., 80% yield). 1H-NMR(CDCl.sub.3):1.92 (m, 2H), 3.42 
(t, 2H); 4.43 (s, 2H); 5.14 (s, 2H); 6.87 (sb, 2H); 7.35-7.46 (m, 5H). 
Example 8 
2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine 
Compound 8 
To a cooled and stirred suspension of protected 
2-amino-3-benzoyl-6-benzyloxycarbonyl4,5,6,7-tetrahydrothieno2,3-c!pyridi 
ne (0.01 mol) in acetic acid (2 mL), as prepared in Example 7, was added a 
solution of HBr (33%) in acetic acid (10 mL). After stirring at room 
temperature for 4 h (TLC control), n-hexane was added and the resulting 
suspension was evaporated under vacuum to give a solid which was dissolved 
in water (10 mL) and neutralized with NaOH (5% solution). The precipitated 
solid was chromatographed on a silica gel column eluting with an ethyl 
acetate and petroleum ether mixture to give 
2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine. 
(m.p.160-162.degree. C., 92% yield). 1H-NMR (CDCl.sub.3): 1.86 (m, 1 H); 
1.95 (m, 2H); 2.79 (t, 2H); 3.79 (s, 2H). 
Example 9 
2-Amino-3-(4-chloro-benzoyl)-6-benzyloxycaronyl-4,5,6,7-tetrahydrothieno2, 
3-c!pyridine 
Compound 9 
The procedure of Example 7 was followed except that a corresponding amount 
of the 4-chloro-derivative of benzoyl acetonitrile was used in place of 
benzoyl acetonitrile to yield 
2-amino-3-(4-chloro-benzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno 
2,3-c!pyridine. 
(m.p. 60-62.degree. C., 88% yield). 1H-NMR (CDCl.sub.3):1.94 (m, 2H), 3.45 
(t, 2H); 4.44 (s, 2H); 5.16 (s, 2H); 6.85 (sb, 2H); 7.36-7.45 (m, 4H). 
Example 10 
2-Amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno2,3-c!pyridine 
Compound 10 
The procedure of Example 8 was followed except that a corresponding amount 
of 
2-amino-3-(4-chloro-benzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno 
2,3-c!pyridine, prepared as in Example 9, was used in place of 
2-amino-3-benzoyl-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno2,3-c!pyrid 
ine. 
(m.p. 164-166.degree. C., 90% yield). 1 H-NMR (CDCl.sub.3): 1.74 (m, 1 H); 
1.89 (m, 2H); 2.84 (t, 2H); 3.82 (s, 2H); 6.85(sb, 2H), 7.29-7.48 (m, 5H). 
Example 11 
2-Amino-3-3-(trifluoromethyl)-benzoyl!-6-(3-phenylprop-1-yl)-4,5,6,7-tetra 
hydrothieno2,3-c!pyridine 
Compound 11 
A mixture of equimolar amounts of 3-phenylpropylpiperidin-4-one (0.01 mol) 
(prepared by a procedure corresponding to that of Example 7, Steps A and 
B), 3-trifluoromethyl benzoyl acetonitrile (0.01 mol), sulfur (0.01 mol) 
and morpholine (0.01 mol) in ethanol (4 mL) was stirred and heated at 
60.degree. C. for 1 hour (TLC control). After this time, the suspension 
was allowed to stand overnight and the mixture was poured into water and 
the precipitated solid was extracted with ethyl acetate (3.times.50 mL). 
The organic layers were dried on magnesium sulfate and evaporated under 
vacuum. The crude product was chromatographed on silica gel column using 
mixtures of ethyl acetate and petroleum ether. 
(m.p.176-178.degree. C.; 78% yield). 1H-NMR (CDCl.sub.3): 1.88-2.00 (m, 
4H); 2.45-2.71 (m, 6H); 3.44 (s, 2H);6.83(sb, 2H); 7.17-7.48 (m, 9H). 
Example 12 
2-Amino-3-(4-chloro-benzoyl)-6-(phenylmethyl)-4,5,6,7-tetrahydrothieno2,3- 
c!pyridine 
Compound 12 
The same procedure as Example 11 was used except that a corresponding 
amount of benzylpiperidin-4-one was used in place of 
3-phenylpropylpiperidin-4-one and a corresponding amount of 
4-chlorobenzoyl acetonitrile was used in place of 3-trifluoromethyl 
benzoyl acetonitrile. 
(m.p.155-157.degree. C.; 78% yield). 
Example 13 
2-Amino-3-3-(fluoromethyl)-benzoyl!-6-(phenylmethyl)-4,5,6,7-tetrahydrothi 
eno2,3-c!pyridine 
Compound 13 
The same procedure as Example 11 was used except that a corresponding 
amount of benzylpiperidin-4-one is used in place of 
3-phenylpropylpiperidin-4-one. 
(m.p. 58-60.degree. C.; 88% yield). 1 H-NMR (CHCl.sub.3): 1.78-1.87 (m, 
2H); 2.48 (t, 2H); 3.42 (s, 2H); 3.63 (s,2H);7.01 (sb, 2H); 7.28-7.74 (m, 
9H). 
Example 14 
2-Amino-3-(4-chloro-benzoyl)-6-(2-phenyleth-1-yl)-4,5,6,7-tetrahydrothieno 
2,3-c!pyridine 
Compound 14 
The same procedure as Example 11 was used except that a corresponding 
amount of phenylethylpiperidin-4-one was used in place of 
3-phenylpropylpiperidin-4-one and a corresponding amount of 
4-chlorobenzoyl acetonitrile was used in place of 3-trifluoromethyl 
benzoyl acetonitrile. 
(m.p. 148-150.degree. C.; 62% yield). 
Example 15 
2-amino-3-3-(trifluoromethyl)-benzoyl!-6-(2-phenyleth-1-yl)-4,5,6,7-tetrah 
ydrothieno2,3-c!pyridine 
Compound 15 
The same procedure as Example 11 was used except that a corresponding 
amount of benzylpiperidin-4-one was used in place of 
3-phenylpropylpiperidin-4-one. 
(m.p. 137-138.degree. C.; 81 % yield). 1H-NMR (CHCl.sub.3): 1.89 (m, 2H); 
2.54 (t, 2H); 2.67-2.87 (m, 4H); 3.51 (s, 2H); 6.99 (sb, 2H); 7.17-7.33 
(m, 5H); 7.53-7.74 (m, 4H). 
Example 16 
2-Amino-3-(4-chloro-benzoyl)-6-(3-phenylprop-1-yl)-4,5,6,7-tetrahydrothieno 
2,3-c!pyridine 
Compound 16 
The same procedure as Example 11 was used except that a corresponding 
amount of 4-chlorobenzoyl acetonitrile was used in place of 
3-trifluoromethyl benzoyl acetonitrile. 
(m.p. 98-100.degree. C.; 65% yield). 
Example 17 
2-Amino-3-benzoyl-6-methyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine 
Compound 17 
2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine (2 mmol), as 
prepared in Example 8, and methyl iodide (3 mmol) were dissolved in dry 
dimethyformamide (20 mL). Finely ground anhydrous potassium carbonate (1.9 
g) and sodium iodide (0.2 g) were added to the solution and the resulting 
mixture was warmed to 65.degree. C. overnight under nitrogen. After this 
period (TLC control), the reaction mixture was cooled, diluted with water, 
extracted with diethyl ether (3-50 mL), and dried on sodium sulfate. The 
crude product was isolated and then purified by column chromatography 
eluting with ethyl acetate and petroleum ether solutions to give the 
desired compound. 
(m.p. 164-165.degree. C.; 77% yield). 
Example 18 
2-Amino-3-(4-chloro-benzoyl)-6-(ethoxycarbonylmethyl)-4,5,6,7-tetrahydrothi 
eno2,3-c!pyridine 
Compound 18 
The same procedure as in Example 17 was used except an equivalent amount of 
2-amino-3-(4-chloro-benzoyl)-4,5,6,7-tetrahydrothieno2,3-c!pyridine was 
used in place of 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine 
(2 mmol), and an equivalent amount of ethoxycarbonylmethyl iodide was used 
in place of methyl iodide (3 mmol). 
(m.p. 105-106.degree. C.; 70% yield). 
Example 19 
2-Amino-3-benzoyl-6-(ethoxycarbonylmethyl)-4,5,6,7-tetrahydrothieno2,3-c!p 
yridine 
Compound 19 
The same procedure as in Example 17 was used except an equivalent amount of 
ethoxycarbonylmethyl iodide was used in place of methyl iodide (3 mmol). 
(m.p. 115-117.degree. C.; 83% yield). 
Example 20 
2-Amino-3-benzoyl-6-(3-methylbut-2-en-lyl)-4,5,6,7-tetrahydrothieno2,3-c!p 
yridine 
Compound 20 
The same procedure as in Example 17 was used except an equivalent amount of 
dimethylallyl iodine was used in place of methyl iodide (3 mmol). 
(m.p. 76-78.degree. C. 90% yield). 1H-NMR (CDCl.sub.3): 1.63 (s, 3H); 1.73 
(s, 3H); 1.94 (m, 2H)); 2.44 (t, 2H); 3.06 (d, 2H); 3.42 (s, 2H); 5.26 (t, 
1 H); 6.80 (sb, 2H); 7.35-7.50 (m, 5H). 
Example 21 
2-Amino-3-(4-chloro-benzoyl)-6-4-nitro-(2-phenyleth-1-yl)!-4,5,6,7-tetrahy 
drothieno2,3-c!pyridine 
Compound 21 
The same procedure as in Example 17 was used except an equivalent amount of 
2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno2,3-c!pyridine was 
used in place of 2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine 
(2 mmol), and an equivalent amount of p-nitrophenylethyl iodide was used 
in place of methyl iodide (3 mmol). 
(m.p. 150-152.degree. C.; 72% yield). 
Example 22 
2-Amino-3-benzoyl-6-4-nitro-(2-phenyleth-1-yl)!-4,5,6,7-tetrahydrothieno2 
,3-c!pyridine 
Compound 22 
The same procedure as in Example 17 was used except an equivalent amount of 
p-nitrophenylethyl iodide was used in place of methyl iodide (3 mmol). 
(m.p. 89-91.degree. C.; 70% yield). 
Example 23 
2-Amino-3-benzoyl-6-2-t-butoxycarbonylamino-3-(4-hydroxyphenyl)-propion-1- 
yl!4,5,6,7-tetrahydrothieno2,3-c!pyridine 
Compound 23 
To an ice-cooled and stirred solution of 
2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine (0.775 mmol) in 
dry DMF (11 mL), was added BOC-Tyr-OH (0.08 mmol) and EDCl (0.08, 0.445 g) 
under an argon atmosphere. After stirring overnight, the mixture was 
evaporated under vacuum to give a solid residue, which was dissolved in a 
saturated sodium bicarbonate solution and is extracted with ethyl acetate 
(3.times.20 mL), then dried on magnesium sulfate. The organic layers were 
evaporated under vacuum to give a solid which is chromatographed on silica 
gel column eluting with ethyl acetate and petroleum ether to afford 
2-amino-3-benzoyl-6-2-t-butoxycarbonylamino-3-(4-hydroxyphenyl)-propion-1 
-yl!-4,5,6,7-tetrahydrothieno2,3-c!pyridine as a yellow solid. 
(m.p. 143-145.degree. C., 84% yield). 
Example 24 
2-Amino-3-benzoyl-4,5,6,7-tetrahydrobenzob!thiophene 
Compound 24 
The same procedure as in Example 1 was used except a corresponding amount 
of cyclohexanone was used in place of methylethyl ketone. 
(m.p.150-152.degree. C., 75% yield). 1H-NMR (CDCl.sub.3):1.46-1.49 (m,2H), 
1.69-1.80 (m,4H); 2.47-2.54 (m, 2H); 6.71 (sb, 2H); 7.37-7.50 (m, 5H). 
Example 25 
4-Phenyl-5,6,7,8-tetrahydro1!benzothieno2,3-d!pyrimidine 
Compound 25 
A suspension of 2-amino-3-thienyl)-phenylmethanone (5 mmol) in formamide 
(7mL) was heated at 180.degree. C. for 5 hours in an open vessel. The 
residue was diluted with dimethylformamide (5 mL), treated with charcoal, 
and filtered over a small pad of Celite 503 (brand of filter aid). The 
cyclized compound was precipitated by addition of water (30 mL) to the 
filtrate and recrystallized from the same solvents. 
(m.p. 135-137.degree. C.). 
Example 26 
2-Methyl,3-ethoxycarbonyl-4-phenyl-5,6,7,8-tetrahydro1!benzothieno2,3-b!p 
yridine 
Compound 26 
To an ice-cooled and stirred solution of 2-amino-3-thienyl)-phenylmethanone 
in absolute ethanol (20 mL), ethyl acetoacetate (0.055 mol) was added. To 
the mixture sodium ethylate (100 mg) was added at 0.degree. C. and the 
solution was refluxed for about 10 hours. After completion of the reaction 
(TLC control), the solution was evaporated under vacuum and the residue 
was taken up with water (50 mL) and the aqueous solution was extracted 
with ethyl acetate (3.times.100 mL). The combined organic layers were 
dried and evaporated under vacuum to give a yellow residue which was 
crystallized from tetrahydrofuran/hexane. 
(m.p. 118-120.degree. C.). 
Example 27 
2-Amino-3-(4-bromobenzoyl)-cyclopentab!thiophene 
Compound 27 
The same procedure as in Example 1 was used except a corresponding amount 
of cyclopentanone was used in place of methylethyl ketone and an 
equivalent amount of 4-bromo-benzoyl acetonitrile was used in place of 
benzoyl acetonitrile. (m.p. 205-206.degree. C., 87% yield). 
(CDCl.sub.3):2.1-2.13 (m, 4H), 2.63-2.68 (m, 2H); 6.99 (sb, 2H); 7.34 
(d,2H);7.53 (d, 2H). 
Example 28 
2-Amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7-tetrahydrothieno2,3- 
c!pyridine 
Compound 28 
To a well-stirred and ice-cooled solution of 
2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno2,3-c!pyridine (0.78 mmol, 0.2 
g) in dichloromethane (20 ml) under an argon atmosphere, was added 
triethylamine (0.162 ml) and then p-toluenesulphonyl chloride (0.93 mmol, 
177 mg) portionwise. The suspension was stirred a room temperature for 24 
h and the precipitated solid was filtered. The organic solution was 
evaporated under vacuum to give a solid residue which was chromatographed 
on silica gel eluting with an ethyl ether and petroleum ether mixture to 
afford 
2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7-tetrahydrothieno2,3 
-c!pyridine. 
(m.p.165-167.degree. C., 85 yield). 1 H-NMR (CDCl.sub.3): 1.95 (m, 2H); 
2.43 (s, 3H); 3.07 (t, 2H); 3.51 (s, 2H); 6.76 (sb, 2H); 7.3-7.67 (m, 9H). 
Example 29 
4-Phenyl-thieno2,3-d!pyrimidine 
Compound 29 
The same procedure as in Example 25 was used except a corresponding amount 
of 2-amino-3-benzoyl-cyclopentab!thiophene was used in place of 
2-amino-3-thienyl-phenylmethanone (5 mmol). In turn, 
2-amino-3-benzoyl-cyclopentab!thiophene can be prepared by the procedure 
of Example 1. 
Example 30 
Pharmaceutical Formulations 
(A) Transdermal System--for 1000 patches 
______________________________________ 
Ingredients Amount 
______________________________________ 
Active compound 100 g 
Silicone fluid 450 g 
Colloidal silicon dioxide 
2 g 
______________________________________ 
The silicone fluid and active compound are mixed together and the colloidal 
silicone dioxide is added to increase viscosity. The material is then 
dosed into a subsequent heat sealed polymeric laminate comprised of the 
following: polyester release liner, skin contact adhesive composed of 
silicone or acrylic polymers, a control membrane which is a polyolefin, 
and an impermeable backing membrane made of a polyester multilaminate. The 
resulting laminated sheet is then cut into 10 sq. cm patches 
(B) Oral Tablet--For 1000 Tablets 
______________________________________ 
Ingredients Amount 
______________________________________ 
Active compound 50 g 
Starch 50 g 
Magnesium Stearate 
5 g 
______________________________________ 
The active compound and the starch are granulated with water and dried. 
Magnesium stearate is added to the dried granules and the mixture is 
thoroughly blended. The blended mixture is compressed into tablets. 
(C) Injection--for 1000, 1 mL Ampules 
______________________________________ 
Ingredients Amount 
______________________________________ 
Active compound 10 g 
Buffering Agents q.s. 
Propylene glycol 400 mg 
Water for injection q.s. 1000 mL 
______________________________________ 
The active compound and buffering agents are dissolved in the propylene 
glycol at about 50.degree. C. The water for injection is then added with 
stirring and the resulting solution is filtered, filled into ampules, 
sealed and sterilized by autoclaving. 
(D) Continuous Injection--for 1000 mL 
______________________________________ 
Ingredients Amount 
______________________________________ 
Active compound 10 g 
Buffering agents q.s. 
Water for injection q.s. 1000 mL 
______________________________________