FORMULES UTILES DE MEDICAMENTS COMPORTANT DES SELS D'ADDITION D'ACIDES

USEFUL FORMULATIONS OF ACID ADDITION SALT DRUGS

Abrégé français

L'invention porte sur des procédés et préparations servant à l'administration de sels d'addition d'acides de formule (A) ou (B) dans lesquelles: R¿1? consiste en un groupe aryle ou alkyle comportant un site accepteur à liaison hydrogène accessible à des interactions avec ledit azote tertiaire de formule (A) ou ledit ion ammonium quaternaire de formule (B); R¿2?, R¿3? et R¿4? sont des groupes aryle ou alkyle; et X?-¿ est un anion. Le procédé consiste à ajuster le pH d'une préparation injectable stérile comprenant un véhicule liquide contenant une solution de sel d'addition d'acides afin de diminuer le développement d'effets secondaires non souhaités de la substance, ou à amener ladite préparation à un pH compris environ entre 5,5 et 7,0, puis à administrer les sels d'addition d'acides par injection intramusculaire les contenant à une concentration d'au moins 50 mg/l, et dont le pH est compris environ entre 5,5 et 7,0.

Abrégé anglais

Methods of and formulations for administering acid addition salts of compounds
of Formula (A) or Formula (B), wherein R1 comprises an aryl or alkyl group
with a hydrogen bond acceptor site accessible to interaction with said
tertiary nitrogen of Formula (A) or said quaternary ammonium ion of Formula
(B), R2, R3 and R4 are alkyl or aryl groups, and X- is an anion. In the
methods, a sterile injectable formulation of a liquid vehicle containing the
acid addition salt in solution is adjusted in pH for reducing the development
of undesirable side effects of the material or provided at a pH within a range
of about 5.5 to 7.0, and administering these acid addition salts by
intramuscular injection contain the salt at a concentration of at least about
50 mg/ml and are at a pH within a range of about 5.5 to 7Ø

Revendications

CLAIMS
What is claimed is:
l. A method of administering to a human patient material selected from
the group consisting of acid addition salts of compounds that can form acid salts
of Formula (A) having a tertiary nitrogen present, acid addition salts of
compounds that can form acid salts of Formula (B) having a quaternary
ammonium ion present, and mixtures thereof, said Formula (A) and Formula (B)
being as follows:
<IMG>
<IMG>
wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site
accessible to interaction with said tertiary nitrogen of Formula (A) or said
quaternary ammonium ion of Formula (B), R2, R3 and R4 and alkyl or aryl
groups, and X is an anion, said method comprising the steps of
(a) providing a sterile injectable formulation comprising a liquid vehicle
containing the material in solution. at a pH within a range of about 5.5
to 7.0, and
61

(b) injecting the formulation into the patient in an amount for delivering to
the patient a dose of about one to 100 mg/kg of the material while the pH
of the formulation is within said range.
2. A method according to claim 1, wherein said hydrogen bond acceptor
site is a carbonyl or carboxylic oxygen atom.
3. A method according to claim 1, wherein X- is Cl-, F-, Br- or I :
4. A method according to claim 1, wherein said material is selected from
the group consisting of nicotinamides, benzamides, calcium antagonists,
antiemetics, antipsychotics and anaesthetics which are acid addition salts of
compounds that can form acid salts of Formula (A), acid addition salts of
compounds that can form acid salts of Formula (B), and mixtures thereof.
5. A method according to claim 1, wherein said formulation is provided
at a concentration of about 100 to 7000 mg/ml.
6. A method according to claim 1, wherein the injecting step comprises
injecting the formulation intramuscularly into the patient.
7. A sterile injectable formulation for intramuscular administration to a
human patient, comprising
(a) a material selected from the group consisting of acid addition salts of
compounds that can form acid salts of Formula (A) having a tertiary
nitrogen present, acid addition salts of compounds that can form acid
62

salts of Formula (B) having a quaternary ammonium ion present, and
mixtures thereof, said Formula (A) and Formula (B) being as follows:
<IMG>
<IMG>
wherein R1 comprises an aryl or alkyl group with a hydrogen bond
acceptor site accessible to interaction with said tertiary nitrogen of
Formula (A) or said quaternary ammonium ion of Formula (B), R2, R3
and R4 are alkyl or aryl groups, and X- is an anion;
(b) a liquid vehicle in which said material is in solution;
(c) said material being present in said formulation in a concentration of at
least about 50 mg/ml, and
(d) the formulation being at a pH within a range of about 5.5 to 7Ø
8. A formulation as defined in claim 7, wherein said material is selected
from the group consisting of nicotinamides, benzamides, calcium antagonists,
antiemetics, antipsychotics and anaesthetics which are acid addition salts of
compounds that can form acid salts of Formula (A), acid addition salts of
compounds that can form acid salts of Formula (B), and mixtures thereof.
63

9. A formulation as defined in claim 7, also including an amount of a
buffer or preservative effective to stabilize the pH of the formulation.
10. A formulation as defined in claim 9, including an amount of a
phosphate buffer effective to stabilize the pH of the formulation to a range of
less that 0.5 pH unit.
11. A formulation as defined in claim 9, including an amount of sodium
metabisulfite effective to stabilize the pH of the formulation to a range of less
than 0.5 pH unit.
12. A method of administering to a human patient material selected from
the group consisting of acid addition salts of compounds that can form acid salts
of Formula (A) having a tertiary nitrogen present, acid addition salts of
compounds that can form acid salts of Formula (B) having a quaternary
ammonium ion present, and mixtures thereof. said Formula (A) and Formula (B)
being as follows:
<IMG>
<IMG>
64

wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site
accessible to interaction with said tertiary nitrogen of Formula (A) or said
quaternary ammonium ion of Formula (B), R2, R3 and R4 are alkyl or aryl
groups, and X- is an anion, said method comprising the steps of
(a) providing a sterile formulation, comprising a liquid vehicle containing the
material in solution,
(b) adjusting the pH of said formulation for reducing the development of
undesirable side effects of the material, and
(c) administering the formulation having the adjusted pH to the patient.
13. A method according to claim 12, wherein said material is selected
from the group consisting of nicotinamides, benzamides, calcium antagonists,
antiemetics, antipsychotics and anaesthetics which are acid addition salts of
compounds that can form acid salts of Formula (A), acid addition salts of
compounds that can form acid salts of Formula (B), and mixtures thereof.
14. A method of administering to a human patient material selected from
the group consisting of acid addition salts of malphalan, amiloride, clomipramine,
chlorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline,
cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine,
chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine,
phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem,
clonidine, succinylcholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine,
ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin,
propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine,
doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin,

flupentixol, benoxinate. fluoxetin, gemcitabine, adrenaline, metformin,
chloropromazine, prenalterol, terazosine, oxymetazoline, loperamide,
propanolol, Iidocaine, apraclonidine. verapamil, pilocarpine, procyclidine,
ketamine, ketobemidon, yuinidine, granisetron, mefloquin, prommethazine,
remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide,
thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin,
pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium,
naloxone, xylometazoline, procarbazine. tropisetrone, phenyiephrine, thiamine,
tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin,
oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin,
cyproheptadine, prazosin, meperidine, meclizine, metoclopramide,
procainamide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine,
propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol,
buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol,
methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine
valaciklovir, vancomycin, amantadine, alfluzosine, idarubicin, ondansetron,
cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide,
nimorazole and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline
and mixtures thereof, said method comprising the steps of
(a) providing a sterile injectable formulation comprising a liquid vehicle
containing the material in solution, at a pH within a range of about 5.5 to
7.0, and
(b) injecting the formulation into the patient in an amount for delivering to
the patient a dose of about one to 100 mg/kg of the material while the pH
of the formulation is within said range.
66

15. A method according to claim 14, wherein the injecting step
comprises injecting the formulation intramuscularly into the patient.
16. A sterile injectable formulation for intramuscular administration to a
human patient, comprising
(a) a material selected from the group consisting of acid addition salts of
malphalan, amiloride, clomipramine, chlorcyclizine, hydralazine,
alprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin,
biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline,
bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine,
bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine,
succinylcholine. daunorubicin, ciprofloxacine, clopenthixol, prilocaine,
ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate,
clindamycin, propoxyphene, hydromorphone, orphenadrine,
dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine,
etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin,
gemcitabine, adrenaline, metformin, chloropromazine, prenalterol;
terazosine, oxymetazoline, loperamide, propanolol, lidocaine,
apraclonidine, verapamil, pilocarpine, procyclidine, ketamine,
ketobemidon, quinidine, granisetron, mefloquin, prommethazine,
remoxipride, lincomycin, levocabastin, amorolfine, maprotiline,
benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine,
mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol,
ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone,
phenyiephrine; thiamine, tramadol, hydrochlorotiazid, quinagolide,
noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine,

chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin,
meperidine, meclizine, metoclopramide, procainamide, pyridoxine,
alfentanil, naphazoline, methacycline, roxatidine, propafenone,
amitriptyline, nortriptyline, paroxetine, clohutinol, sotalol,
buprenorphin, tetracaine, ticlopidine. tocainide, obidoxime, imipramine,
labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene,
lefepramine, valaciklovir, vancomycin, amantadine, alfluzosine,
idarubicin, ondansetron, cetirizine, 3-chloro procainamide,
N-(2-diethylamino-ethyl) nicotinamide, nimorazole and
2.3-dimethyl-(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof.
(b) a liquid vehicle in which said material is in solution,
(c) said material being present in said formulation in a concentration of at
least about 50 mg/ml, and
(d) the formulation being at a pH within a range of about 5.5 to 7Ø
17. A method of administering to a human patient material selected from
the group consisting of acid addition salts of malphalan, amiloride, clomipramine.
chlorcyclizine, hydralazine, alprenolol, dopamine. quinapril, tetracycline,
cimetidine, doxoruhicin, biperiden, carteolol, ranitidine, hydroxyzine,
chlortetracycline. bambuterol, diphenhydramine, hetaxolol, bromhexine,
phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem,
clonidine. succinylcholine, daunoruhicin, ciprofloxacine, clopenthixol, prilocaine,
ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin,
propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine,
doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin,
flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin,
68

chloropromazine, prenalterol, terazosine, oxymetazoline, loperamide,
propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine,
ketamine, ketobemidon, quinidine, granisetron, mefloquin. prommethazine,
remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide,
thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin,
pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium,
naloxone, xylometazoline, procarbazine, tropisetrone, phenyiephrine, thi~mine,
tramadol, hydrochlorotiazid. quinagolide, noscapine, mitoxantrone, dipivefrin,
oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin,
cyproheptadine. prazosin, meperidine, meclizine, metoclopramide,
procain~mide, pyridoxine, alfentanil. naphazoline, methacycline, roxatidine,
propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol,
buprenorphin, tetracaine, ticlopidine. tocainide, obidoxime, imipramine, labetaloh
methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine,
valaciklovir, vancomycin, amantadine, alfluzosine. idarubicin, ondansetron,
cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide,
nimorazole and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline
and mixtures thereof
(a) providing a sterile formulation, comprising a liquid vehicle containing the
material in solution,
(b) adjusting the pH of said formulation for reducing the development of
undesirable side effects of the material, and
(c) administering the formulation having the adjusted pH to the patient.
69

Description

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USEFUL FORl\IULATIONS OF ACID ADDITION
SALT DRUGS
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of copending U.S. patent application
Serial No. 08/479,113 filed June 7, 1995, which is a division of copending U.S.
patent application Serial No. 08/218,072 filed March 25, 1994. The disclosures
of both of these patent applications are incorporated herein by this reference.
BACKGROUND OF THE INVENTION
This invention relates to acid addition salt drugs having utility in the treatment
of human patients. More particularly it relates to new and improved
formulations and methods of administration of such acid addition salt drugs.
Nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and
anaesthetics represent a wide range of diverse chemical and pharmacological
structures, but they share a common property of' modifying the tumor response
to radiation or chemotherapy. A variety of chemical structures including the
nitroimidazoles, phenothiazines, butyrophenones~ halopyrimidines, benzamides
and nicotinamides are known to possess radio- and chemosensitizing properties
(Horsman et al, Acta Oncologica 34:571-587, 1995: Brown et al, Cancer
Treatment Symposia 1, 85-101, 1984, Pu et al, Oncology 9(8):707-721, 1995,
George and Singh. Indian J. Expt. Biol. 22:305-307, 1984, Kennedy et al, Int. J.

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WO 98/OOlS9 PCTIUS97/10829
Radiat. Oncol. Biol. Phys. 12:1367-1370, 19~6). These various classes of agents
are believed to accomplish this mechanistic action either by altering tumor blood
supply to overcome hypoxia, inhibiting DNA repair, imbalancing calcium
homeostasis or combinations thereof (Horsman et al, Acta Oncologica 34:571-
5g7, 1995, Hirst et al, Br. J. Cancer 67: 1-6, 1993, Wood and Hirst. J. Radiat.
Oncol. Biol. Phys. 16: 1141-1144, 1989; Menke and Vaupel, Radiation Res.
114:64-76, 1988; Rosenthal and Hait, Yale J. Biol. Med. 61: 39-49, 1988, Lybak
and Pero, Carcinogenesis 12: 1613-1617, 1991, Olsson et al, Carcinogenesis 16:
1029-1035, 1995; Olsson, et al, Br. J. Cancer, In Press, 1996).
Regardless of the precise mechanism(s) the ultimate result is accumulation of
DNA damage and an increase in tumor cytntoxicity either by necrosis or
apoptosis (Kerr and Winterford, Cancer 73:2013-2026, 1993). As a result, these
agents are all potential cancer therapy drugs even though they may have other
well defined clinical uses. For example, metoclopramide, an N-substituted
benzamide, has been used as an antiemetic for over 30 years (Harrington et al,
Drugs 25: 451-494, 1983) but recently it has been shown to be an effective
radio- and chemo-sensitizer (Pero et al, Biochimie 77:385-391, 1995, Kjellén et
al, Eur. J. Cancer 31A(13/ 14):2196-2202, 1995). Furthermore, most drugs
having well established clinical uses are known to mediate their effects by
antagonizing high affinity receptors capable of initiating physiological responses
relating to many disease processes. Conformation and charge of these chemical
structures, in turn, determine their abilities to antagonize receptors and mediate
drug related efficacious responses.

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SUMMARY OF THE INVENTION
Reference is made hereinbelow to the following four papers, in all of which
~ applicant herein is a co-author: (1) R.W. Pero, M. Simanaitis, A. Olsson~ A.
Amiri and I. Andersen, "Pharmacokinetics, Toxicity, Side Effects, Receptor
Affinities and In Vitro Radiosensitizing Effects of the Novel Metoclopramide
- Formulations, Sensamide and Neu-Sensamide," unpublished typescript, 1996,
pp. 1-25 + 5 Figures (hereinafter "Pero et al unpublished 1996"), now published
as Pharmacolo~y & Toxicolo~y 80:231-239~ 1997 (2) A. Amiri, A.R. Olsson, J.
Hua and R.W. Pero, "Apoptosis in HL-60 Cells As A Model for Determining
Sensitization of Radio- And Chemotherapies By N-Substituted Benzamides."
unpublished typescript, 1996, 14 pp. (unpaginated) + 6 Figures (hereinafter
"Amiri et al unpublished 1996"),(3) H.H. Rotmensch, G.P. Mould~ J.A. Suttom
S. Kilminster, C. Moller, R.W. Pero, "Comparative Central Nervous System Effectsand Phannacokinetics of Neu-Sensamide and Metoclopramide in Healthy Volunteers,"unpublished typescript, 1996, pp. 1-19 + 2 Figures (hereinafter "Rotmensch et
al unpublished 1996"). now published as J. Clin Pharmacol 37:222-228 (1997),
(4) A. Schwartz and R.W. Pero, "Evidence for Conformational Mobility of
Me~oclopramide as a Function of pH: Implications for Drug Design,"
unpu'nlished typescript, 1996, 18 pp. (unpaginated) (hereinafter "Schwartz et alunpublished 1996") .
One of the most popular chemical functionalities (i.e. structures, substitutions)
used in drug design is a tertiary or a quarternary nitrogen usually introduced via
an alkylaminodialkyl sidè chain, so that drugs such as the nicotinamides,
ben~amides, calcium antagonists, antiemetics, antipsychotics and anaesthetics

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could be converted to more water soluble formulations for clinical
administration. However, drug formulation research with the N-substituted
benzamides (incident to the development of the present invention) has so far
shown that this structure can dramatically alter the pharmacological properties
of, for example, metoclopramide simply by changing the pH of the formulation.
Molecular modeling experiments support that Neu-Sensamide~ ("neutral"
metoclopramide) has been formulated without the presence of a hydrogen
mediated-bond between the tertiary ammonium ion and the carboxamide oxygen
atom, whereas this hydrogen mediated-bond is present in Sensamide~ ("acidic"
metoclopramide) (Schwartz et al unpublished 1996). Neu-Sensamiden' has a
reduced extrapyramidal side effect profiie in rats and humans but the
radiosensitizing properties remain unaltered compared to Sensamide~ at
equimolar doses (Amiri et al unpublished 1996; Hua et al, Anti-Cancer Drugs
6:451-4~3, 1995, Pero et al, Biochimie 77:385-393, 1995; Pero et al unpublished
1996; Rotmensch et al unpublished 1996). Therefore, it is logical to extrapolatethese data to other drugs containing acid addition salt structures in the following
way:
Compounds that can form acid salts of types A or B:
. H \X; X R2
R1-CH2)n-N~ R2 (A) R1-(CH2)n-N\ R3 (B)
R3 R4
R, 4=aLkyl or aryl groups; X = any anion, normally Cl~ or Br~ or I-

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Wherein:
(1) A tertiary nitrogen is present that can form an acid addition salt
(Type A) or a quarternary ammonium ion is present (Type B) and/or
(2) R, comprises an aryl or alkyl group with a hydrogen bond
acceptor site accessible to interaction with the tertiary/quarternary nitrogen, e.g.
a carbonyl or carboxylic oxygen atom.
Have the potential to become pharmacologically altered because:
(1) Most drugs express their biological activity by binding
receptors .
(2) Receptor affinities are determined l y conformation and charge-
distribution of the ligand drugs.
(3) Altering the pH of acid addition salt drugs can alter their
receptor affinity by either conformation or charge-distribution or both.
(4) Altering receptor affinity as has heen accomplished with
SensamideT"/Neu-Sensamiden' does not alter radiosensitizing potency (Hua et
al, Anti Cancer Drugs 6:451-453, 1995; Pero et al unpublished 1996).
There are at least 143 clinically available drugs (listed in Table 2 below) having
potential properties of radiosensitization, and altering their receptor affinities by
pH adjusting their formulations that in turn contain acid addition salt

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substitutions. could affect side effect profiles permitting higher doses to be used
for radiosensitization or other pharmacological indications. This point is a novel
discovery not obvious as previously known in the literature. Although the 143
clinically available drugs have been the subject of many patents and patent
applications, including recent patents and applications concerned with the radio-
chemo-sensitizing and antiemetic properties of N-substituted aryl compounds
such as the benzamides and nicotinamides (U.S. provisional Patent Application
No. 60/013,072, U.S. Patent No. 4,576,386, U.S. Patent No. 5,340,565, U.S.
Patent No. 5,215,738, U.S. Patent No. 5,032,617 and U.S. Patent No.
5,041,653), the latter citations do not disclose that the pH of acid addition salt
drugs could alter chemical structure, and in turn change the pharmacological
properties of the formulations. Examples of compounds that are not as yet
clinically available but that are capable of forming acid addition salts with a
potential for alteration of pharmacological properties by pH adjustment are 3-
chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and
2,3-dimethyl(dimethylaminoethyl)-5H-indolo-(2,3-b) guinoxline (procedures for
synthesizing 3-chloro procainamide and N-(2-diethylamino-ethyl) nicotinamide
are described in copending U.S. provisional patent application No. 60/013,072,
filed March 8, 1996, the disclosure of which is incorporated herein by this
reference). Hence in a hroad sense this invention is not confined to the 143
clinically available drugs listed in Table 2, but embraces the use of all compounds
formulated to possess water solubility by formation of a substituted amide acid
addition salt structure. The aforementioned U.S. Patent Application Serial No.
08/218,072 discloses that metoclopramide, a N-substituted benzamide, can
undergo pH-sensitive conformational changes. However, the claims of this
application and its division. Serial No. 08/479,113, are respectively directed to

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the N-substituted benzamides and phenothiazines and do not include claims
covering other acid addition salt drugs.
The present invention, in a first aspect, contemplates the provision of a methodof administering to a human patient material selected from the group consisting
of acid addition salts of chemical or pharmacological structures such as
nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, andanaesthetics as identified and listed in Table 2 below, comprising the s~eps of
providing a sterile injectable formulation comprising a liquid vehicle containing
the material in solution and injecting the formulation into the patient in an
amount for delivering to the patient a dose of about one to about 100 mg/kg of
the material. In important embodiments of this method, the injection is
intramuscular, also, conveniently or preferably, the material to be administered is
in the acid addition salt form, pH adjusted to 5.5 - 7Ø
Intramuscular injection, to achieve a dose of I - 100 mg/kg, requires a much more
concentrated formulation than i.v. injection of a like dose, owing to the limited
tolerance of muscle tissue for injected fluid. Whereas a solution at a 5 mg/ml
concentration of metoclopramide hydrochloride is suitable for i.v. injection of a
dose of 5 mg/kg, a concentration of at least about 50 mg/ml or even more
(preferably, in many cases, as much as 100 mg/ml) is needed to administer a likedose by intramuscular injection. At these high concentrations, present-day
commercial acid addition salt formulations tend to produce local tissue toxic
reactions at the injectable site if not pH adjusted to 5.5 - 7.0 (U.S. Patent
application No. 08/218,072, Pero et al unpublished 1996).

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Further in accordance with the invention, a concentrated acid addition salt
formulation (e.g. 100 - 7000 mg/ml) is advantageously provided at a pH of about
S.S to 7.0, for intramuscular injection. At pH values within this range (which is
substantially higher, i.e. Iess acidic, than the pH of currently available
formulations of equivalent concentration), local tissue toxic reactions are
satisfactorily minimized or avoided, yet without adversely affecting the
solubility of acid addition salt drugs or their therapeutic activity. A pH above7.0 would derogate from solubility, while values below about 5.5 are insufficient
to achieve the desired reduction in local tissue side effects. It has been shownthat this is the case because an acid addition salt formulation of metoclopramide
at pH 2.5 - 3.5 caused local tissue irritation but when neutralized to pH 6.5 - 7.0
a substantially reduced local tissue reaction was observed (U . S Patent
application No. 08/218,072, Pero et al unpublished 1996).
In a second aspect, the invention contemplates the provision of a sterile
injectable formulation for intramuscular administration ~o a human patient,
comprising a material selected from the group consisting of acid addition salts of
chemical or pharmacological structures such as nicotinamides, benzamides,
calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identifiedand listed in Table 2 below, a liquid vehicle in which the material is in solution
being present in the formulation in a concentration of at least about 50 mg/ml;
and the formulation being at a pH within a range of about 5.5 to 7 0. In these
formulations, the solution pH, once established, may be stabilized to a less
variable range (e.g. <0.5 pH unit) by the inclusion of a phosphate or other
buffer, or alternatively. by the inclusion of a preservative such as sodium
metabisulfite to prevent auto-oxidation

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Also surprisingly, it has been found that the administration of an acid additionsalt, metoclopramide hydrochloride, in otherwise conventional formulations
(which contain Na+ ions, present in the saline solution and/or introduced as
sodium metabisulfite) but at a pH of about 5.5 to 7.0 substantially prevents theextrapyramidal side effects of known metoclopramide treatments (Pero et al,
Biochimie 77:385-393, 1995, Pero et al unpublished 1996). In a third aspect,
which is not limited to intramuscular injection, the invention contemplates the
provision of a method of administering to a human patient material selected fromthe group consisting of acid addition salts of chemical or pharmacological
structures such as nicotinamides, benzamides, calcium antagonists, antiemetics,
antipsychotics, and anaesthetics as identified and listed in Table 2 below,
comprising a liquid vehicle containing the material in solution (and, in some
instances, also containing Na+ ions), adjusting the pH of the formulation for
reducing the development of undesirable side effects or improving
pharmacological indications of the material, and administering the formulation
having the adjusted pH to the patient. A preferred or effective range of
formulation pH for reduction or avoidance of extrapyramidal side effects is
between about 5.5 and 7Ø
Stated in some respects more broadly, the invention in each of the above
described aspects may be embodied in a method or formulation wherein the
aforementioned material is selected from the group consisting of acid addition
salts of compounds that can form acid salts of Formula (A) having a tertiary
nitrogen present, acid addition salts of compounds that can form acid salts of

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Forrnula (B) having a quaterrlary ammoniurn ion present, and mixtures thereof,
Formula (A) and Formula (B) being as fo}lows:
R2 X-
R1--(CH2)n--N~--R3 (A)
R4
~2 X-
R1--(CH2)n--N~--R3 (B)
R4
wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site
accessible to interaction with the tertiary nitrogen of Formula (A) or the
quaternary ammonium ion of Formula (B), R2 and R, and R4 are alkyl or aryi
groups, and X- is an anion. In specific embodiments, the hydrogen bond
acceptor site is a carbonyl or carboxy}ic oxygen atom, and X~ is Cl-, F-, Br- or I-.
Advantageously or preferably, the material is selected from the group consistingof nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics
and anaesthetics which are acid addition salts of compounds that can form acid
salts of Formula (A) or Formula (B), and mixtures thereof.
Further features and advantages of the invention will be apparent from the
detailed description herein below set forth, together with the accompanying
drawings .

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BRIEF DESCRIPI'ION OF DRAWINGS
Fig. 1 is a graph on which the UV absorption intensity is plotted against
wavelength of UV absorption between 195 nm and 215 nm for 100 ,uM
solutions of metoclopramide pH adjusted between 4.8 and 6.0 with I N HCI or
1 N NaOH.
Fig. 2A is a graph on which the UV absorption intensity of 100 ~M solutions of
aqueous (pH 5-6) and acidic (pH 2-3) 3-chloroprocainamide are plotted against
the wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2B is a graph on which the UV absorption intensity of 100 ~M solutions of
aqueous (pH 5-6) and acidic (pH 2-3) lidocaine are plotted against the
wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2C is a graph on which the UV absorption intensity of 100 ~IM solutions of
aqueous (pH 5-6) and acidic (pH 2-3) metoclopramide are plotted against the
wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2D is a graph on which the UV absorption intensity of 100 ~LM solutions of
aqueous (pH 5-6) and acidic (pH 2-3) remoxipride are plotted against the
wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2E is a graph on which the UV absorption intensity of 100 ~M solutions of
aqueous (pH 5-6) and acidic (pH 2-3) procainamide are plotted against the
wavelength of UV absorption between 195 nm and 380 nm.
.~ . , . ~ . .

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Fig. 2F is a graph on which the UV absorption intensity of 100 ~LM solutions of
aqueous (pH 5-6) chlorpromazine are plotted against the wavelength UV
absorption between 195 nm and 380 nm.
Fig. 2G is a graph on which the UV absorption intensity of 100 ~M solutions of
acidic (pH 2-3) chlorpromazine are plotted against the wavelength of UV
absorption between l9~ nm and 380 nm.
DETAILED DESCRIPIION
The invention is embodied in methods involving the use of pH adjustment of
acid addition salts of chemical or pharmacological structures such as
nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics~ andanaesthetics as identified and listed in Table 2 below, to reduce the development
of undesirahle side effects of the drug without affecting or enhancing the
pharmacological properties such as antiemetics, antiarrhythmics,
antidepressants, antipsychotics, antihypertensives. adrenergics. anaesthetics, or
the enhancement of radio- and chemotherapies of cancer.
In addition. the invention is embodied in methods involving the use of preparingaqueous sterile injectable formulations of acid addition salts of chemical or
pharmacological structures such as nicotinamides, benzamides, calcium
antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed
in Table 2 below, with pH adjustment, in order to avoid undesirable side effectsof the drug without affecting or improving the indicated clinically useful

CA 022~896~ 1998-12-22
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pharmacological properties (e.g. erlhancement of radio- and chemo-therapies of
cancer) .
In another aspect. the practice of this invention invol~es consideration of the pH
of acid addition salts of chemical or pharmacological structures such as
nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, andanaesthetics as identified and listed in Table 2 below. The 1993 Physicians'
Desk Reference lists over 145 hydrochloride salt formulations as available for
clinical use. Most of these hydrochloride salt formulations are acidic solutionsranging in pH from 2 to 6.5 depending on the initial drug concentration and
formulation ingredients (American Society of Hospital Pharmacists, 1993,
Sveriges Lakersmedels Information AB, FASS, 1993). In order to deliver doses
of 1-100 mg/kg by intramuscular injection to patients, the injectable formulations
would require initial drug concentrations of around 100 to 7000 mg/ml, which in
most cases is a concentration having a pH range of 1 to 4.5 depending on its
formulation (American Society of Hospital Phamacists, 1993, FASS, 1993).
Because commercial preparations of solutions of acid addition salt drugs
drastically vary in pH, and because they can be pH adjusted from 2 to 6.5
without regulatory restrictions, the prior art teaches that there is no difference in
biological activity associated with changes in pH between 2 and 6.5. However,
applicant herein has found that when acidic formulations of metoclopramide
hydrochloride solutions within a pH range of 2 to 3 . 7 are compared to a
neutralized formulation at around pH 7.0, the local tissue toxic reaction at thesite of intra-muscular injection and the extrapyramidal side effect of sedation, are
substantially reduced when the neutralized formulation is administered (Pero et
al, Biochimie 77:385-393, 1995; Peroetalunpublished 1996). Hence.this

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invention embraces the feature that high concentrations of metoclopramide
hydrochloride (e.g. 100 mg/m}), and by analogy other acid addition salt drugs
because the drug itsel~ is acidic, which would be required for intramuscular
administration of metoclopramide or other acid addition salt drugs as
pharmacological agents, have fewer toxic side effects in the near neutral pH range
than in the acidic form, which in turn are currently the cliniçally available forms
of these drugs.
Metoclopramide and the other acid addition salt drugs listed in Table 2 below are
known to bind to high affinity receptors such as both the dopamine2 (D2)
receptor and the 5-hydroxytryptamine3 (5-HT3) receptor (Pharmacokinetic
principles in the use drugs, in Medical Pharmacology, A. Goth ed., C.V. Mosby
Company, tenth edition, St. Louis, MO, pages 15-30, 1981; Harrington et al,
Drugs 25:451-494, 1983, Blower, Eur. J. Cancer 26 (Suppl . 1): S8-Sll, 1990).
The side effects of acid addition salt drugs are believed to be delivered from
receptor binding; for example, extrapyramidal side effects generated from D2
binding (King and Sanger, Drugs of the Future 14(9):875-889, 1989). These data
from the scientific literature support and are consistent with the altered systemic
biological effects of acidic metoclopramide hydrochloride salt formulations
described herein (Pero et al unpublished 1996). As already mentioned above,
acidic metoclopramide has a conformation altering pH sensitive hydrogen
mediated-bond which is lacking in neutralized metoclopramide (Pero et al,
Biochimie 77:385-393, 1995; Schwartz et al unpublished 1996). This finding is
supported by the data revealed in Examples 1-3 which establish that a wide
variety of drugs containing tertiary nitrogen substitutions that can convert drugs
to acid addition salts, have very similar UV spectra changes indicative of the pH

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sensitive conformational changes observed for metoclopramide especially at
A200 (wavelength of 200 nm). In addition, it would have been an unexpected
observation for one skilled in the art to have been able to predict that
metoclopramide or other acid addition salt drugs could form a chemical
interaction (e g. a hydrogen bond) stable enough to be transported from the siteof intramuscular injection to receptors in the brain in order to mediate an
enhanced efficacy or side effect (e.g. sedation).
The UV spectra of the Examples below were run using a Beckman scanning UV-
visible spectrophotometer with a quartz cell having a l cm path length. The
spectra were produced by scanning the UVbsorption produced between lgS
nm and 380 nm (379 nm in Fig. 1) at a bandwidth of 5 nm. 100 ~M samples of
the drugs or model compounds were acidified to pH 2-3 and their UV spectra
were recorded. These UV spectra were compared with the UV spectra
determined at ambient (aqueous) pH which was normally between pH 5 and 6.
In some cases the ambient drug solutions were titrated with lN HCl and lN
NaOH to produce pH gradient solutions which were then subjected to scanning
of the UV spectrum between A,95 and A380. The UV spectra were corrected
for absorption from appropriate solvent blanks.
.. ..

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Example I
UV spectral evidence for the pH sensitive conformation change in
metoclopramide.
There is considerable analytical evidence supporting that a hydrogen bond is
formed in acidic aqueous solutions of metoclopramide between the tertiary
nitrogen of the N-ethylaminodiethyl substitution and the carbonyl of the
carboxamide group of substituted benzamide (Reviewed by Schwanz et al
unpublished 1996). The data in Fig. l report the result of a detailed UV spectral
analysis of metoclopramide solutions carefully adjusted in pH between 4.8 and
6Ø The UV absorption spectra recorded between 195 nm and 215 nm show a
very sharp change in maximal absorption in metoclopramide solutions around
pH 5Ø These UV spectra changes around 5.0 were taken as strong supportive
evidence for the shifting of equilibrium between the two conformational forms ofmetoclopramide, namely, one with the pH sensitive hydrogen bond present and
one without it. Because acidic metoclopramide induces extrapyramidal side
effects whereas neutral metoclopramide does not (Pero et al, Biochimie 77:385-
393, 1995, Pero et al unpublished 1996, Rotmensch et al unpublished 1996), Fig.
l also clarifies that unpredictable but detectable pH sensitive UV absorption
spectral changes reflect conformational structural changes in metoclopramide
altering the receptor mediated side effects of this drug.
16

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F,Y~mple 2
UV spectral evidence for pH sensitive changes of drugs having
alkylaminodialkyl substitutions that are capable of forming acid addition
salts .
First, the data in Figs. 2A-2G show that drugs that contain alkylaminodialkyl
substitutions can have very different UV absorption maxima in aqueous
solution, and several areas of each of these UV absorption maxima can be shiftedand varied in intensity due to acidic pH adjustment into the range pH 2. Second,the most striking change in UV absorption was associated with pH adjustment
at A20(, for all the drugs containing alkylaminodialkyl substitutions.

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Example 3
UV spectral evidence indicating alterations in A200 resulting from
proposed pH sensitive conformational changes in the structure of N-
alkylaminodialkyl substituted drugs.
The data in Table l show that aryl N-alkylaminodialkyl substitutions contribute
mainly to the pH adjusted UV spectra in the 200 nm range. This UV region has
been identified as being of interest by comparison to the UV spectral changes
associated with pH adjustment of metoclopramide a~ueous solutions (presented
in Example 1). Molecular modeling, analytical chemical analyses, extrapyramidal
biologic responses and the previous scientific literature have confirmed the
existence of a hydrogen mediated-bond between the carbonyl of the carboxamide
and the tertiary nitrogen present in the N-ethylaminodiethyl substituted
benzamide ring of metoclopramide (Schwartz et al unpublished 1996; Pero et al,
Biochimie 77: 385-393 l99~). Hence, acidic metoclopramide has the
conformational change imposed by the presence of this pH sensitive hydrogen
mediated-bond whereas neutral metoclopramide has an extended conformation
due to the lack of this hydrogen bond. The pH dependence of intramolecular
hydrogen bonding in metoclopramide is represented in Schwartz et al
unpublished 1996 as follows:
18
.. . . . , ... . ~

CA 02258965 1998-12-22
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WO 98100159 PCT/US97110829
"H~
C~'~ N, ~ N/~CI
H2N '~- H heat H2N o- H
H C energy
3 H3C
Metoclopramide HCI "extended hydrochloride conformation"
"highly structured, coplanar form" proton away from carbonyl
2 hydrogen bonds define structure 2nd hydrogen bond cannot form
d-2 receptor antagonist
base
H Cl
H2N~¢~N~
H3C
Neu-Sensamide~'
"extended side chain conforrnation"
1 hydrogen bond defines structure
poorer binding at d-2 receptor
g

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The formula in the upper left is metoclopramide HCI in the highly structured,
"coplanar" form in which two hydrogen bonds define the structure, this form~
dominant at lower (more acid) pH, is a D~ receptor antagonist. The formula at
the upper right represents the "extended hydrochloride conformation" wit}l the
proton away from the carbonyl such that the second hydrogen bond (between
the carbonyl oxygen and the proton of the side chain a~nmonium hydrogen)
cannot form. The formula at the lower right, representing "Neu-SensamideT~"', athigher (less acid, approaching neutral) pH, has an extended side chain
conformation, again with only one hydrogen bond (that between the oxygen of
the methoxy group and the amide hydrogen). and exhibits poorer binding at the
D. receptor. In a broader sense, Table 1 also shows that changes in UV
absorption at A20(, detects the conformational difference between acidic and
neutral metoclopramide formulations. and as a result, other aryl compounds
having N-alkylaminoalkyl substitutions capable of forming a quaternized
nitrogen and hydrogen mediating-bonding site, will display a pH sensitive changein their UV spectra at A20(,. For example. 3-amino benzarnide and procaine do
not contain either alkylaminodialkyl- or N- substitutions nor do they exhibit pHsensitive UV absorption changes at A20" (Table 1). On the other hand, 3-chloro
procainamide, procainamide, remoxipride, lidocaine and chlorpromazine all
contain N-alkylaminodialkyl substitutions, and they also display UV absorption
changes at A20n
~ . . . ~ . .

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Table 1. pH sensitive alterations in the UV spectra attributed tO proposed
conformational changes of the alkylaminodialkyl substructures of agents capable
of forming acid addition salts. 100 ~M samples of these agents were acidified topH 2 and their UV spectra were recorded. These spectra in turn were compared
with the UV spectra at ambient pH (i.e. pH 5-6).
Drl~p/A~ent A~ Comments
(1) 3 Amino benzamide No N-substitution of bem~ e-
Acidic 1.150 no pH change at A200
Aqueous l . 1 S0
(2) Procaine O-substituted alkylaminodialkyl
Acidic 1.500 benzoic acid-no pH change at A200
Aqueous 1 . 500
(3) Metoclopramide N-alkylaminodialkyl substituted
Acidic 0.200 benzamide-pH change at A200
Aqueous 1.400
(4) 3-Chloro proc~in~mide N-alkylaminodialkyl substituted
Acidic 0.200 benzamide-pH change at A20"
Aqueous 2.700
(5) Proc~in~mide N-alkylaminodialkyl substituted
Acidic 0.900 benzamide-pH change at A200
Aqueous 2 . 300
(6) Remoxipride N-alkylaminodialkyl substituted
Acidic 0.200 benzamide-pH change at A2W
Aqueous 2.800
(7) Lidocaine N-alkylaminodialkyl substituted
Acidic 0.180 benzamide-pH change at A200
Aqueous 2.700
(8) Chlorpro~n~7ine N-alkylaminodialkyl substituted
Acidic 0.200 phenothiazine-pH change at A20,
Aqueous 2.600

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Example 4
List of drugs capable of forming acid addition salts via the formation of a
quaternized nitrogen (e.g. alkylaminodialkyl substitutions), and thereb~
undergoing pH sensitive alteratioos, that may consequentially alter drug
efficacy or side effects.
The data for this example (obtained from literature, not actual experiment) are
presented in Table 2. It lists 143 drugs that are available for clinical use in
Sweden (FASS 1992-1996). The data show that the chemical structures and
clinical uses of the drugs listed in Table 2 are extremely diverse~ but they share a
common chemical substitution; namely all have been formulated as acid addition
salts (i.e. usually hydrochloride acid salts) because they contain a tertiary
nitrogen group (i. e . usually as alkylaminodialkyl substitutions) . Because
Examples 1-3 establish that compounds containing alkylaminodialky]
substitutions can undergo conformational changes due to pH adjustment,
together with the fact that conformation and charge can determine the degree of
drug mediated receptor binding antagonism, then Table 2 also show that all the
drugs listed are capable of pH modification leading to an altered receptor
mediated efficacy or side effect profile.

CA 02258965 1998-12-22
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Table 2. List of clinically available acid addition salt drugs including their
structures, chemical abstract numbers, trade marks, commercial suppliers and
clinical uses. This da~a has been compiled from the 1992-1996 Sveriges
Lakersmedels Information AB, (FASS) and the 1995 Merck Index.

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1. MELPHALAN [148-82-3]
TRADE NAME: ALKERAN (GLAXO,
H WELLcoME)
CICH2CH2 t=\ CLINICAL USE: CYTOSTATIC
N~ /~cH2~c~cooH ALKYLATING AGENT
CICH2CH2 '~Y
NH2
2. AMILORIDE [260946-3]
TRADE NAME: AMILOFERM (NORDIC)
AMILORID (NM PHARMA)
Cl NCONHCNHNH2 MIDAMOR (MSD)
MODURETIC (MSD)
NORMORIX (NYCMED)
~ ~ ~ ~ SPARKAL (SELENA)
H2N N NH2 CLINICAL USE: POTASSIUM-SPARING
DIURETIC
3 CLOMIPRAMINE [36349-1l
TRADE NAME: ANAFRANIL (CIBA)
/ KLOMIPRAMIN
\~ (NM PHARMA)
N Cl CLINICAL USE ANTIDEPRESSANT
, CH3
CH2CH2CH2N ~ CH
4. CHLORCYCLIZINE l82-93-9]
,~ TRADE NAME: ANERVAN (RECIP)
Dl-PARALENE (ABBOTT)
EXOLYT (ABIGO)
CH--N N--CH3 CLINICAL USE: ANTIHISTAMINE
24

CA 02258965 1998-12-22
WO 981001S9 PCTIUS97110829
5. HYDRALAZINE [86-544]
TRADE NAME: APRESOLIN (CIBA)
NHNH2 CLINICAL USE: ANTIHYPERTENSIVE
~N
~N
6. ALPRENOLOL [13655-52-2]
O - CH2CHOHCH2NHCH(CH3)2
CH2CH=CH2 TRADE NAME: APTIN (HAssLE)
CLINICAL USE: ANTIHYPERTENSIVE
ANTIARRHYT~IMIC
7 DOPAMINE [51-61-6]
OH TRADE NAME: ABBODOP (ABBOTT)
\'-- GILUDOP (MEDA)
HO ~\~CH2CH2NH2 INTROPIN (HAssLE)
CLINICAL USE: ADRENERGIC
8. QUINAPRIL [85441-61-8]
COOH
COOCH2CH3 CH3 H
~3CH2CH2--C--NI I C CO-N
H H
TRADE NAME: ACCUPRO (PARKE DAVIS)
CLINICAL USE: ANTIHYPERTENSIVE

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9. TETRACYCLINE ~60-54-8l -
OH O OH O TRADE NAME: ACHROMYCIN (LEDERLE)
OH I ACTISITE (MEDA)
\/ \~ CONH2 TETRACYKLIN
r T¦ ll (NM PHARMA)
~CR3 CLINICAL USE ANTIBACTERIAL
CH3
10. CIMETIDINE ~51481-61-9l
TRADE NAME: ACILOC (ORION)
ACINIL (SELENA)
CIMETIDIN (SELENA)
TAGAMET (SMITH KLINE BEECHA)
CLINICAL USE: HISTAMINE 2 RECEPTOR
ANTIAGONIST, ESPECIALLY IN
THE TREATMENT OF DUODENAL
AND GASTRIC ULCERS
H
~CH3 N-CN
CH2SCH2CH2NHCNHCH3
11. DOXORUBICIN [23214-92-8]
~ OH
Il I COCH20H
~OH TRADE NAME: ADRIAMYCIN
(PHARMACIABl UPJOHN)
o DOXORUBICI N ~NYCOMED)
OCH3 O OH H
CLINICAL USE: ANTINEOPLASTIC
~r~~
I\CH3/
HO ~ H
NH2
12. BIPERIDEN [514-65-8]
TRADE NAME: AKINETON (MEDA)
~CH2~ CLINICAL USE: ANTICHOLINERGIC
4 ANTIPARKINSON
r~
COHCH2CH2--N~ ~
26

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13. CARTEOLOL [51781-06-7]
TRADE NAME: ARTEOPTIC (CIBA VISION)
N ~ CLINICAL USE: 13-RECEPTOR BLOCKER
OCH2CHOHCH2NHC(CH3)3
14. RANITIDINE 166357-35-5]
CHN02
H3C ll
~NCH2~ ~ ~CH2SCH2CH2NHCNHCH3
TRADE NAME: ARTONIL (SELENA)
ZANTAC (GLAXO WELLCOME)
CLINICAL USE: ANTIULCERATIVE
15. HYDROXYZINE 168-88-2]
Cl TRADE NAME: ATARAX(UCB)
HISTILOS (UCB)
~=\ VISTARIL (ROERIG)
CLINICAL USE: TRANQUILIZER
CH--N N--CH2CH20CH2cH20H
/=< --/
16. CHLORTETRACYCLINE 157-62-5]
TRADE NAME: AUREOMYCIN
~"CONH2 CLINICAL USE: ANTIBIOTIC
~OH
cr CH31 1H INCH3
CH3

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17. BAMBUTEROL
TRADE NAME: BAMBEC (DRACO)
H3CNCOO
CH3 CLINICAL USE: BRONCHODIALATOR
CH3 ~CHOHCH2NHCCH3
CH3
H 3CNCOO
CH3
18. DIPHENHYDRAMINE [482-05-31
TRADE NAME: BENYLAN (PARK-DAVIS)
DESENTOL
CH3 ~PHARMACIA~ UPJOHN)
CHOCH2CHlNCH3 ANTI-MOTIONSICKNESS
19. BETAXOLOL [63659-18-7]
~=~ CH3
~CH20CH2CH2~0CH2CHOHCH2NH-CHCH3
TRADE NAME: BETOPTIC (ALCON)
KERLON (SEARLE)
CLINICAL USE: ANTI-GLAUCOMA
ANTlH'~tK I tNSlVE
20. BROMHEXINE 1357243-8l
TRADE NAME: BISOLVON (BOEHRINGER)
Br BROMHEXIN (ACO)
MOLLIPECT (TIKA)
\~cH2NcH3 CLINICAL USE: MUCOLYTIC
~=( ,J~ EXPECTORANT
Br NH2 ~J

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21. PHENYLEPHRINE HYDROCHLORIDE [61-76-71
TRADE NAME: BLEFCON (ALLERGAN)
HO METAOXEDRIN (MEDA)
OH NEOSYNEPHRINE
- (SANOFI WINTHROP)
CH2NH--CH3 ZINCFRIN (ALCON)
H CLINICAL USE: ADRENERGIC
22. BUPIVACAINE 12180-92-9]
TRADE NAME: BUPIVAKAIN (NORCOX)
MARCAIN (ASTRA)
CH2CH2CH2CH3
CH3 I CLINICAL USE: LOCAL ANAESTHETIC
~=< N
~NHCO~
CH3
23. MELPERONE l3575-80-2
/=\ r~
F ~COCH2CH2CH2--N~CH3
TRADE NAME: BURONIL (LUNDBECK)
CLINICAL USE: NEUROLEPTIC
24. BUSPIRONE [36505-84-7]
o
(~N N-cH2cH2cH2cH2--N~:X
TRADE NAME: BUSPAR
(BRISTOL-MEYERS SQUIBB)
CLINICAL USE: ANXIOLYTIC
29

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25. MEPIVACAINE [96-88-8]
TRADE NAME: CARBOCAIN (ASTRA)
c~3 CH3 CLINICAL USE LOCALANAESTHETIC
N
~NHCO~
CH3
26. DILTIAZEM [4239941-7]
TRADE NAME: CARDIZEM
H3CNCH2cH2 tPHARMAClA & UPJOHN)
~,~ ENTRYDIL (ORION)
N--S_OCOCH3 TILDIEM (TIKA)
l~ ,1 ~ CLINICAL USE: CALCIUM ANTAGONIST
~v S ~ VASODILATOR
H ¢~
~<
OCH3
27. CLONIDINE [4205-90-7]
H Cl TRADE NAME: CATAPRESAN
~=~ (BOEHRINGER INGELHEIM)
CLINICAL USE: ANTIHYPERTENSIVE
H Cl
28. SUCCINYLCHOLINE CHLORIDE [71-27-2]
CH3 TRADE NAME: CELOCURIN
~ (PHARMACIA ~ UPJOHN)
COOCH2CH2N+CH3
CLINICAL USE: SKELETAL MUSCLE RELAXANT
CH2 CH3 (SHORT DURATION)
ICH2 CH3
COOCH2CH2N+CH3
CH3

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29. DAUNORUBICIN ~20830-81-3l -
O OH TRADE NAME CERUBIDIN (RHONE-POULENC
OH DAUNOXOME (SWEDISH
CLINICAL USE: CYTOSTATIC
OCH3 O OH H ~
~r~~
f~CH3 ~
HO ~--H
NH2
30. CIPROFLOXACINE [85721-33-1, 86393-32-0(HCI)]
TRADE NAME- CILOXAN (ALCON)
V CIPROXIN (BAYER)
A I CLIN1CAL USE: ANTIBACTERIAL
H N N ~ N ~
F I'~COOH
31. CLOPENTHIXOL 1982-24-1]
S TRADE NAME: CISORDINOL
(LUNDBECK)
CI CLINICAL USE: ANTIPSYCHOTIC
/ \ /--\
H CH2CH2--N~N--CH2CH2~H
32. PRILOCAINE l721-50-6l
TRADE NAME: CITANEST (ASTRA)
EMLA (ASTRA)
~/ ,\)--NtlCOCHNHCH2CH2CH3 CLINICAL USE: LOCAL ANAESTHETIC
'=<~ CH3
CH3
31
. , ,

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33. ETHYLMORPHINE [76-58~3
CH3CH2~ TRADE NAME: COCILLANA - ETYFIN
(PHARMACIA & UPJOHN)
¦ ¦ COSYLA (PARKE-DAVIS)
l LEPHETON
G<' ~ (PHARMACIA & UPJOIlN)
H ~ N--CH3 CLINICAL USE: ANTITUSSIVE
HO
34. TACRINE [321-64-2]
TRADE NAME: COGNEX (PARKE-DAVIS)
NH2 CLINICAL USE: CHOLINERGIC
35. PROTRIPTYLINE [43B-60-8]
TRADE NAME: CONCORDIN (MSD)
CLINICAL USE: ANTIDEPRESSANT
CH2CH2CH2NHCH3
36. AMIODARONE t1951-25-3]
o CH2cH2cH2cH3
~1' CH2CH3
--\CO ~ OCH2CH2NCH2CH3
TRADE NAME: CORDARONE
(SANOFI WINTHROP)
CLINICAL USE: ANTIARRYHYTHMIC
32
, ................ .

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37. CYCLOPENTOLATE [512-15-2]
TRADE NAME CYCLOGYL (ALCON)
CYCLOPENTOLAT (MEDA)
fH3 CLINICAL USE~ ANTICHOLINERGIC
CHCOOCH2CH2NCH3
OH
38 CLINDAMYCIN 11 832344-9l
C~3 CH3 TRADE NAME: DALACIN
N H CH -Cl (PHARMACIA & UPJOHN)
H~CONHCH CLINICAL USE~ ANTIBIOTIC
CH3CH2C 2 1~
SCH3
OH
39. PROPOXYPHENE l469-62-5]
TRADE NAME DEXODON (TIKA)
DEXOFEN (ASTRA)
Cl H3 ICH3 DISTALQESIC (LILLY)
\--/ CHCH NCH DOLERON (ASTRA)
2 3 DOLOTARD (NYCOMED)
C DOLOXENE (LILLY)
~CH2 OOccH2CH3 PARAFLEX (ASTRA)
\=/ CLINICAL USE: ANALGESIC
40 HYDROMORPHONE [466-99-9]
TRADE NAME: DILAUDID (MEDA)
CLINICAL USE: ANALGESIC
,~'
H H
H_~ ~N--CH3
0~

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41. ORPHENADRINE 183-98-7]
TRADE NAME: DISIPAL (YAMANOUCHI)
CH3 NORFLEX (3M)
\=~ CH3 NORGESIC (3M)
CH NCH CLINICAL USE: MUSCLE RELAXANT
CHO--CH2 2 3 (SCELETETAL)
ANTIPARKINSON
42. DOBUTAMINE [30468-04-2]
HOCH3
HO ~ CH2CH2NHCHCH2cH2 ~OH
TRADE NAME: DOBUJECT (LEIRAS)
DOBUTREX (LILLY)
CLlNiCAL USE: CARDIOTONIC
43. DOPEXAMINE [86494-91-5(HYDROCHLORIDE)]
HO
HO ~CH2CH2NH(CH2)6NHCH2cH2 ~
TRADE NAME: DOPACARD
(FISONS)
CLINICAL USE: CARDIOTONIC
44. DOXYCYCLINE [564-25-0]
OH O 10 TRADE NAME: DORYX (SCAND PHARM)
CONH2 DOXYCYKLIN (ENAPHARM)
/ DOXYFERM (NORDIC)
1 IDOCYKLIN (ROERIG)
~= ~ OH VIBRAMYCIN (PFIZER)
H \ H H\H H NCH3 CLINICAL USE: ANTIBACTERIAL
CH3 OH CH3

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45. NEOMYCIN [1404-04-2 FOR THE MIXTURE]
CH2NH2
~0
~OH \
Ho\Ll/ TRADE NAME: ECOMYTRIN (LUNDBECK)
CELESTON (SCHERING-PLOUGH)
H2N DECARDRON (MSD)
O ISOPTO- BIOTIC (ALCON)
/~ NEBACETIN (LUNDBECK)
H2 N~ CLINICAL USE: ANTIBACTERIAL
o o
R~ NEOMYCIN B R = H, R = CH2NH2
~ ~/ NEOMYCIN C R = CH2NH2, R' = H
HO O OH
NH2
46. EPHEDRINE l50-98-61
HO NHCH TRADE NAME EFEDRIN (NM PHARMA)
~\ 3 LEPHETON (PHARMACIA& UPJOHN)
// \--C C--CH3 LERGIQAN (RECIP)
H H MOLLIPECT (TIKA)
CLINICAL USE: ADRENERGIC
47. VENLAFAXINE []
N(CH3)2 TRADE NAME: EFEXOR (WYETH)
CH30~3 CH~ CLINICAL USE: ANTIDEPRESSANT
48 ETILEFRIN [709-55-7]
o TRADE NAME: EFFORTIL
H (BOEHRINGER INGELHEIM)
CLINICAL USE: ADRENERGIC
CHCH2NHCH2CH3 DOPAMINERGIC
OH ANTIHYPERTENSIVE

CA 02258965 1998-12-22
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49. DEPRENYL l2323-36-6]
TRADE NAME: ELDEPRYL (ORION)
,~ CH3 SELEGILIN (NM PHARMA)
~CH2--C~--NCH2C--CH CLINICAL USE: ANTIPARKINSON
H CH3
50. EPIRUBICIN [56390-09-1(HCI), 56420-45-2(BAS)~
O OH
Il I COCH20H
/~ ~ /~,/\~ TRADE NAME: FARMORUBICIN
'OH (PHARMACIA~ UPJOHN)
\~ CLINICAL USE: ANTINEOPLASTIC
Jl ANTIBIOTIC
OCH3 O OH o
HO O
~,
NH2
51. FLUPENTIXOL [2709-56-0l
TRADE NAME: FLUANXOL
~CF3 (LUNDBECK)
CLINICAL USE; ANTIPSYCHOTIC
CHCH2CH2--N hl -CH2CH20H
52. BENOXINATE [99-43 1]
TRADE NAME: FLURESS (ABIGO)
OXIBUPROKAIN (MEDA)
CLINICAL USE: ANAESTHETIC (TOPICAL)
CH3CH2CH2cH20\
H2N ~ CoocH2cH2N(cH2cH3)2
36

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53. FLUOXETIN [54910-89-3]
TRADE NAME: FONTEX (LILLY)
F3C~OCHCH2CH2NHCH3 CLINICAL USE. ANTIDEPRESSANT
~3
54. GEMCITABINE []
NH2 TRADE NAME: GEMZAR (LILLY~
CLINICAL USE: ANTINEOPLASTIC
l~N~o
HO~H2
~o~
;~
HO F
55. ADRENALINE/EPINEPHRINE l~
TRADE NAME: CITANEST ADRENALIN
OH (ASTRA)
~_ OH EPPY (ABIGO)
// \\ GLAUFRIN (ALLERGAN)
HO~/ '~C--CH2NHCH3 MARCAiN ADRENALIN
\=/ H (ASTRA)
XYLOCAIN ADRENALIN
(ASTRA)
CLINICAL USE: ADRENERGIC
56. METFORMIN [657-24-g]
NH TRADE NAME: GLUCOPHAGE (MEDA)
NH ll CLINICAL USE: ANTIDIABETIC
(CH3)2N - C - NHCN~2

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57. CHLORPROMAZINE [50-53-3]
S TRADE NAME. HIBERNAL
~/ ~ (RHONE-POULENE RORER)
/~ CLINICAL USE: ANTI-EMETIC
N Cl TRANQUILIZER
CH2CH2CH2N(CH3)2 SEDATIVE
58. PRENALTEROL [57526-81-5]
OH
HO ~30CH2--C-CH2NHCH(cH3)2
H
TRADE NAME: HYPRENAN (HASSLE)
CLINICAL U SE: ADRENERGIC
59. TERAZOSINE~63590-64-7, 70024-40-7(HYDROCHLORIDE)]
CH30~ N / \ 11
\
NH2
TRADE NAME: HYTRINEX (ASTRA)
SINALFA (SINALFA ABBOTT)
CLINICAL USE: ANTIHYPERTENSIVE
60. OXYMETAZOLINE 11491-594]
CH3 OH TRADE NAME: LLIADIN (MEDA)
H ~ NASIN (TIKA)
N CH2~/ \~C(CH3)3 NEZERIL (DRACO)
~=/ ZOLIN (ACO)
N CH3 CLINICAL USE: ADRENERGIC
38
. ,. ~ .

CA 02258965 1998-12-22
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WO 98~00159 PCTIUS97110829
61. LOPERAMIDE t53179~ 6]
Cl TRADE NAME: IMODIUM
~1 ~ (JENSSEN-CILAG)
// \\ LOPERAMID
~/ ~ ~ (SCAND PHARM)
/--\ >=' PRIMODIUM
(CH3)2NCO--C--CH2CH2--N~OH TRAVELLO
,~ ( PHARMACIA ~ U PJ OH N )
IJ CLINICAL USE: ANTIDIARETIC
62. PROPRANOLOL ~25-66-6l
~, TRADE NAME: INDERAL (ZEN ECA)
PROPRANOLOL
~\~ (NM PHARMA)
T CLINICAL USE: 13-ADRENERGIC BLOCKER
ocJ-l2fHcH2NHcH(cH3)2 ANTIARRHYTHMIC
OH
63. LIDOCAINE [137-58-6~
TRADE NAME: DEPO - MEDROL
(PHARMACIA & UPJOHN
CH3 EMLA ~ASTRA)
_~ INSTILLAGEL (ELLEM)
// \\ LEDERSPAN (LEDERLE)
~/ \~NHCOCH2N(CH2cH3)2 XYLOCAIN (ASTRA)
\=~ XYLOCARD (ASTRA)
\CH3 XYLOPROCT (ASTRA)
CLINICAL USE: LOCAL ANAESTHETIC
64 APRACLONIDINE [66711-21-5]
H ~ TRADE NAME: LOPIDINE (ALCON)
N N~/ \\) NH2 CLINICAL USE: TREATMENT OF POSTSURGICAL
~=/ ELEVATED INTRAOCULAR PRESSURE
N--H C
39

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65. VERAPAMIL 152-53-9l
TRADE NAME: ISOPTIN (MEDA)
VERALOC (ORION)
VERAPAMIL (NM PHARMA)
CLINICAL US~: ANTlARRHYTtlMlC
VASODILATOR
CH30 OCH3
CH30 ~3CCH2CH2CH2NCH2CH2~ocH3
66. PILOCARPINE 192-13-7l
TRADE NAME: FOTIL (LEIRAS)
O o ISOPTO - PILOKARPIN (ALCON)
~ ~. H LICARPIN (ALLERGAN)
CH3CH2 1 ¦ -H Cl 3 PILOKARPIN (MEDA)
J N SPERSACARPINE (CIBA)
H CH2~ 1 TIMPILO (MSD)
N CLINICAL USE: ANTIGLAUCOMA
CHOLINERGIC
67. PROCYCLIDINE [77-37-2]
TRADE NAME: KEMADRIN
(GLAXO WELLCOME)
CLINICALUSE: ANTIPARKINSON
HO -~ CH2cH2--N
68. KETAMINE [6740-88-1]
TRADE NAME: KETALAR (PARKE-DAVIS)
¢~ CLINICAL USE: GENERAL ANAESTHETIC
r~cl
\~ NHCH3

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69. KETOBEMIDON 1]
TRADE NAME: KETOGAN
(NOVUM-LUNDBECK)
CLINICAL USE: ANAL(~ETIC
~/ \~OH SPASMOLYTIC
CH3N~ COCH2CH3
70. QUINIDINE [130-95-0, 60-93-5(~1YDROCHLORIDE)]
~N TRADE NAME: KININ (NM PHARMA)
~,~ CLINICAL USE: ANTIMALARIAL
CH30 H
HO I C y N~,
H ~H
CH=CH2
71. GRANISETRONE [109889-09-0, 107007-99-8(HYDROCHLORIDE)]
~CH3 TRADE NAME: KYTRIL
N (SMITH KLINE BEECHAM)
CLINICAL USE: ANTIEMETIC
l\ HCO
72. MEFLOQUIN [51773-92-3(HYDROCHLORIDE)
CF3
l~yN~CF3 TRADE NAME: LARIAM (ROCHE)
b~ CLINICAL USE: ANTIMALARIAL
HC--OH
~H
41

CA 02258965 1998-12-22
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73. PROIAETHAZINE ~7440-12-12]
TRADE NAME: LERGIGAN (RECIP)
CLINICAL USE: ANTIHISTAMINE
CH2CHN(Ctl3)2
CH3
74. REMOXIPRIDE 11
Br CH3 TRADE NAME: ROXIAM (ASTRA)
CH3 --~2CH3 CLINICAL USE: NEUROLEPTIC
75. LINCOMYCIN 1154-21-2]
ICH3 TRADE NAME: LINCOCIN
N H HO~CHCH3 (UPJOHN)
H ~CO--NH--CH CLINICAL USE: ANTIBIOTIC
CH3CH2CH2 HO~o
~&~SCH3
OH
76. LEVOCABASTIN l]
TRADE NAME: LIVOSTIN
H CH3 (JENSSEN-CILAG)
CN~O,N~COOH CLINICAL USE: H,-ANTAGONIST
H ~
42

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WO 98/OOlS9 PCTIUS97/10829
77. AMOROLFINE ~78613-35-1, 78613-38-4(HYDROCHLORIDE)]
H3C H CH3
C~N--Ctl2CHCH2 ~ C(CH3)2CH2CH3
H3C H
TRADE NAME: LOCERYL (ROCHE)
CLINICAL USE: ANTIMYCOTIC
78. MAPROTILINE [10260~9-8]
TRADE NAME: LUDIOMIL tC113A)
~ ~ r\ ,~ MAPROTILIN
'' 'I ' 1l ~NM PHARMA)
~/ ~/) CLINICAL USE: ANTIDEPRESSANT
CH2CH2CH2NHCH3
79. BENSERAZIDE l322-35-0]
TRADE NAME: MADOPARK (ROCHE)
OH OH CLINICAL USE: ANTIPARKINSON
DOPAMINERGIC
HO ~ CH2NHNHCOCHCH2OH
NH2
80. THIORIDAZINE [50-52-21
TRADE NAME: MALLOROL (SANDOZ)
~¢ ~3~ CLINICAL USE. NEUROLEPTIC
N SCH3
CH
CH
N
CH3
43
, _ .. ..

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81. CYCLIZINE [82-92-8]
TRADE NAME: MARZINE
~9 (GLAXO WELLCOME)
\=( A CLINICAL USE: ANITHISTAMINE
CH--N N--CH3 ANTIEMETIC
82. CEPHEPIME []
TRADE NAME: MAXIPIME
(BRISTOL-MEYERS SQUIBB~
CLINICAL USE: ANTIBIOTIC
H2N S
NOCH3 H H, S
COO CH3
83. METHADONE [1095-90-53
TRADE NAME: METADON
J (PHARMACIA & UPJOHN)
~ CH3 CLINICAL USE: NARCOTIC ANALGETIC
CH3CH2CO- lC--CH2CHN(CH3)2
84. MEXILETINE 131828-71-4]
TRADE NAME: MEXITIL
CH3 (BOEHRINGER INGELHEIM)
/=~ CLINICAL USE: ANTIARRHYTHMIC
~OCH2CH-NH2
CH3
44

CA 02258965 1998-12-22
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85. MIANSERIN [24219-974]
TRADE NAME: MIANSERIN ~NM PHARMA)
/~ TOLVON (ORGANON)
N ~d CLINICAL USE ANTIDEPRESSANT
<~N
~ CH3
86. PIVMECILLINAM []
TRADE NAME: MIRAXID (LOVENS)
CLINICAL USE: ANTIBACTERIAL
~ H COOCH20COC(CH3)3
87. PHENYLPROPANOLAMINE [154-41-61]
TRADE NAME: LUNERIN (TIKA)
/=\ MONYDRIN (TIKA)
(~ ~CHCHNH2 RINEXIN (RECIP)
'~b I I RINOMAR (RECIP)
HO I H CLINICAL USE: VASOCONSTRICTOR
3 ADRENERGIC
88. MORPHINE [52-27-2]
TRADE NAME: DOLCONTIN
HO (PHARMACIA & UPJOHN)
LOCEPTIN (NYCOMED)
MAXIDON (ASTRA)
~ ~\ MORFIN
o _, H (PHARMACIA ~ UPJOHN)
H _~ SPASMOFEN (ABIGO)
N--CH3 CLINICAL USE: NARCOTIC
HO, \~ ANALGESIC

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89. ETHAMBUTOL [304-84-7]
CH3CH2CHNHCH2--CH2NHCHCH2CH TRADE NAME: MYAMBUTOL
CLINICAL USE: TUBERCULOSTATIC
HOH2C CH20H
90. AMBENONIUM CHLORIDE [115-79-7]
Cl TRADE NAME: MYTELASE
CH2CH3 \~ (SANOFI WINTHROP)
CONHCH2CH~N CH2~ ~ CLINICAL USE: CHOLINESTERASE
~ INHIBITOR
CH2CH3
CH2CH3
CONHCH2CH2N I C~2 ~3
CH2CH3
91. NALOXONE [465-65-6]
HO TRADE NAME: NARCANTI (MEDA)
~ ~ CLINICAL USE: ANTAGONIST
C~/ ~ (TO NARCOTICS)
H--~N--CH2CH=CH2
~ 0~--
92. XYLOMETAZOLINE [526-36-33
TRADE NAME: NASOFERM (NORDIC)
H CH3 OTRIVIN (CIBA)
\ ~ CLINICAL USE: ADRENERGIC
H2C ~ ~ C(H3)3 VASOCONSTRICTOR
CH3
46
._ ... , . .. .~.. ..

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93. PROCARBAZINE [671-16-9]
CH3NHNHCH2 ~ coNHcH(cH3)2
TRADE NAME. NATULANAR (ROCHE)
CLINICAL USE: ANTI N EOPALSTIC
94. TROPISETRONE []
TRADE NAME: NAVOBAN (SANDOZ)
H3 H CLINICAL USE ANTIEMETIC
~" H ¦
O-CO
95. PHENYLEPHRINE [61-76-7(HYDROCHLORIDE)l
TRADE NAME: BLEFCON (ALLERGAN)
ISOPTO-BIOTIC (ALCON)
OH OH METAOXEDRIN (MEDA)
'~=, NEOSYNEPHRINE
(SANOFI WINTHROP)
C--CH2NHCH3 ZINCFRIN (ALCON)
H CLINICAL USE: ADRENERGIC
96. THIAMINE [67-03-8~
TRADE NAME: ASTRATONIL FORTE (ASTRA)
H3C N~ NH S ,CH2CH2OH BETABION (MEDA)
\~ / 2~ ~ CLINICAL USE: ENZYME
N~ ~C~N ~CH3 CO-FACTOR-VITAMIN B1
47

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97. TRAMADOL 127203-92-5, 22204-88-2(HYDFi OCHLORIDE)]
H CH2N(CH3)2 TRADE NAME: NOBLIGAN (SEARLE)
~3Hoh CLINICAL USE: ANALGESIC
CH30
- 98. HYDROCHLOROTIAZID [5~-93-5]
TRADE NAME: SPARKAL (SELENA)
~~ ,~ TRIATEC COMP (HOECHST)
H2N--SO2 S AMILOFERM (NORDIC)
C~NH~J H CLINICAL USE: DIURETIC
99. QUINAGOLIDE [
OH
H
\ NH - S~2--N(CH2CH3)2
--N TRADE NAME: NORPROLAC (SANDOZ)
H I
CH2CH2CH3 CLINICAL USE: PROLACTIN ANTAGONIST
100. NOSCAPINE [128-62-1. 912-60-7(HYDROCHLORIDE)]
TRADE NAM~: NIPAXON (PHARMACIA &
O ~ ~ UPJOHN)
/ ~r rl H 1 NOSKAPIN (ACO)
\o ~ N ~ CH SPAMOFEN (AE~IGO)
CLINICAL USE: ANTITUSSIVE
CH30
H O
0
r OCH3
OCH3
48
... . , ~

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101. MITOXANTRONE ~65271-80-90, 76476-82-3(HYDROCHLORIDE)]
OH O NHcH2cH2NHcH2cH2oH TRADE NAME: NOVANTRONE
(LEDERLE)
CLINICAL USE: ANTINEOPALSTIC
OH O NHcH2cH2NHcH2cH2oH
102. DIPIVEFRIN l52365-63-6, 64019-93-8(HYDROCHLORIDE)I
TRADE NAME: OFTAPINEX (LEIRAS)
PROPINE ~ALLERGAN)
(CH3)3CCOo
CLINICAL USE: ANTI-GLAUCOMA
(CH3)3CCOO~/ \~CHCH2NHCH3 ADRENERGIC
OH
103. OXYTETRACYCLINE [79-57-2, 2058-46-0(HYDROCHLORIDE)]
O OH O TRADE NAME: OXYTETRAL (DUMEX)
ll I OHII TERRACORTRIL (PFIZER)
,~J~"r- CONH2 TERRAMYCIN (PFIZER)
CLINICAL USE: ANTIBIOTIC
~/ ~ --OH
HO ' ~ H NCH3
t04. FLUPHENAZINE [69-23-8, 146-56-5(HYDROCHLORIDE)]
TRADE NAME: PACINOL (SCHERING-
PLOUGH)
SIQUALONE (BRISTOL
S ~ MEYER S-SQU IBB)
CLINICAL USE: ANTIPSYCHOTIC
~/ ~N~ ~/ ~CF3~
CH2CH2CH2--N N - CH2CH2OH
49

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105. CHLORGUANIDE [500-92-5]
TRADE NAME: PALUDRINE
NH NH (ZENECA)
ClgNHCNHCNHCH(CH3)2 CLINICAL USE: ANTIMALARIAL
106. TRIHEXYPHENIDYL [52-49-31
TRADE NAME: PARGITAN (ABIGO)
CLINICAL USE: ANTIPARKINSON
HO - C - CH2CH2--N~
107. BACAMPICILLIN [50972-17-3, 37661-08-8(HYDROCHLORIDE)l
TRADE NAME: PENGLOBE (ASTRA)
CLINICAL USE ANTI8ACTERIAL
C - CONH ~ CH3
H CoocHocoocH2cH3
108. CYPROHEPTADINE [129-03-3, 41354-29-4(HYDROCHLORIDE)I
,~ ~ TRADE NAME: PERIACTIN (MSD)
CLINICAL USE H1 ANTAGONIST
ANTIHISTAMINE
~N~
CH3

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109. PRAZOSIN [19216-56-9,19237-84-4(HYDROCHLORIDE)]
A o
CH30~N~N N--CO~
CH30 ~ N
NH2
TRADE NAME: PERIPRESS (PFIZER)
CLINICAL USE: o~ 1 -ADRENERGIC E~LOCKER
ANTIHYPERTENSIVE
110. MEPERIDINE [57~2-1, 50-13-5(HYDROCHLORIDE)]
TRADE NAME: PETIDIN
,~ (PHARMACIA & UPJOHN)
/--\ / \=/ CLINICAL USE~ NARCOTIC
CH3--N ~)~ ANALGETIC
COOCH2CH3
111. MECLIZINE [569-65-3, 31884-77-2(HYDROCHLORIDE)]
Cl TRADE NAME: HISTILOS (UCB)
POSTAFEN (UCB)
CLINICAL USE: ANTIEMETIC
C H--N N--CH2 ~9
CH3
112. METOCLOPRAMIDE [364-62-5, 54143-57-6(HYDROCHLORIDE)
CONHCH2CH2N(CH2cH3)2 TRADE NAME: PRIMPERAN
~,OCH3 CLINICAL USE: ANTIEMETIC
Cl~
NH2

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113 PROCAINAMIDE [614-39-1]
H2N ~CONHCH2CH2N(CH2CH3)2
TRADE NAME: PROKAINAMID
(HASSLE)
CLINICAL USE: ANTIARRYTHMIC
114. PYRIDOXINE 158-56-0]
TRADE NAME: ASTRANOI L FORTE
N CH3 (ASTRA)
~ CLINICAL USE: VITAMIN B6
HOCH2 ~r OH
CH20H
1 15. ALFENTANIL [71 195-28-6. 70879-28-6(HYDROCHLORIDE)]
N N 2 2 ~ ~N--COCH.2CH3
N=N
3 TRADE NAME. RAPIFEN
(JENSSEN-CILAG)
CLINICAL USE: NARCOTIC
ANALGESIC
1 16 NAPHAZOLINE [835-31-4, 550-29-2(HYDROCHLORIDE)]
~ TRADE NAME: ANTASTEN-PRIVIN (CIBAVISION)
IH ~ RIMIDOL (UCB)
N CH2 CLINICAL USE: ADRENERGIC (VASOCONSTRICTOR
~y DECONGESTANT
N
~ . .

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117 METHACYCLINE [914-00-1 3963-95-9(HYDROCHLORIDE)]
~ ~ CONH2
~OH TRADE NAME RONDOMYCIN
~ \ ~ ~ (ROERIG)
- H OH CH CLINICAL USE ANTIBACTERIAL
118 ROXATIDINE [1
OCH2CH2CH2NHCOCH20H
CN CH2~
TRADE NAME ROXIT (HOECHST)
CLINICAL U SE ANTI-U LC ERATIVE
119 PROPAFENONE ~54063-53-5 34183-22-7(HYDROCHLORIDE)]
CH2CH2--CO
OCH2CHCH2NHCH2CH2CH3
TRADE NAME RYTMONORM (MEDA)
CLINICAL USE ANTIARRHYTHMIC
120 AMITRIPTYLINE [50-48-6 549-18-8(HYDROCHLORIDE)]
TRADE NAME
SAROTEN (LUNDBECK)
/ ~ TRYPTIZOL (MSD)
CLINICAL USE
ANTIDEPRESSANT
CHCH2CH2N~CH3)2

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121. NORTRIPTYLINE [72-69-5 894-71 -3(HYDROCHLORIDE)]
TRADE NAME: SENSAVAL (LUNDBECK)
~, ~ CLINICAL USE. ANTIDEPRESANT
CHCH2CH2NHCH3
122. PAROXETINE [61869-08-7~
TRADE NAME: SEROXAT
(NOVO NORDISK)
O~O--CH2 H CLINICAL USE. ANTIDEPRESSANT
O F ~f \NH
H
123. CLOBUTINOL [14860-4g-23
TRADE NAME: SILOMAT
CI ~ CH2COHCHCH2N(cH3)2 (BOEHRINGER INGELHEIM)
CLINICAL USE: ANTITUSSIVE
H3C CH3
124. SOTALOL [3930-20-9, 959-24-0(HYDROCHLORIDE)]
CH3S~2NH' ~3CHCH2NHCH(CH3)2
TRADE NAME: SOTACOR
(BRISTOL-MEYERS SQUIBB)
SOTALOL (NM PHARMA)
CLINICAL USE: ANTIANGINAL
ANTIARRHYTHMIC
ANTIHYPERTENSIVE
54

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125. BUPRENORPHINE [52485-79-7, 53152-21-9(HYDROCHLORIDE)]
Il 1
~ I TRADE NAME: TEMGESIC
H ~ N--CH2 ~ (MEDA)
~ ~J CLINICAL USE: ANALGESIC
CH30 H ~
HO - C--C(CH3)3
CH3
126. TETRACAINE [136-47-0]
CH3CH2CH2CH2NH ~COOCH2CH2N(CH3)2
TRADE NAME: TETRACAIN (ALCON)
CLINICAL USE: ANAESTHETIC (TOPICAL)
127. TICLOPIDINE [55142-a5-3, 53885-31-1(HYDROCHLORIDE)I
TRADE NAME: TICLID (SANOFI WINTHROP)
~/ S CLINICAL USE: PLATELETAGGREGATION
H2C ~L3 INHIBITOR
128 TOCAINIDE 141708-72-9]
CH3 TRADE NAME: TONOCARD (HASSLE~
CLINICAL USE: ANTIARRHYTHMIC
NHC ICHNH2
CH
CH3 3
_ . ... .

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129. OBIDOXIME CHLORIDE [114-90-9]
TRADE NAME: TOXOGONIN (MEDA)
HON=CH~N+--CH2 CLINICAL USE: CHOLINESTERASE
,=, b REACTIVATOR
~ +
HON--CH~=~N --CH2
130. IMIPRAMINE [5049-7, 113-52-0(HYDROCHLORIDE)]
TRADE NAME: TOFRANAL (CIBA)
CLINICAL USE: ANTIDEPRESSANT
CH2CH2CH2N(CH3)2
131. LABETALOL [36894-69-6, 32780-64-6(HYDROCHLORIDE)~
H2NCO OH CH3
HO ~CHCH2NHCHCH2cH2 ~
TRADE NAME: TRANDATE
(GLAXO WELLCOME)
CLINICAL USE: ANTIHYPERTENSIVE
132. METHIZENE[4969-02-2, 70814-5(HYDROCHLORIDE)l
S TRADE NAME: TREMOQUIL (ASTRA)
CLINICAL USE: ANTICHOLINERGIC
ANTIPARKINSON
I r\
H2C ~
N
CH3
56

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133. SPECTINOMYCIN [1695-77-8. 22189-32-3(HYDROCHLORIDE)~
HO
H3C--HN ~ ~--~ ~ CH3
TRADE NAME: TROBICIN
~10 ~o ~ (PHARMACIA & UPJOHN)
tl HO o CLINICAL USE: ANTIBIOTIC
CH3
134. DOR20LAMIDE []
o o TRADE NAME: TRUSOPT (MSD)
H3C ~'S~ S S02NH2 CLINICAL USE~ ANTIGLAUCOMA
~ ~ / ~ ~ CARBONIC ANHYDRASE
H i~ _ ANTAGONIST
H NHcH2cH3
135 C H LOR PROTH IXE N E l 113-59-7]
,~,S~ TRADE NAME: TRUXAL (LUNDBECK)
~ CLINICAL USE ANTIPSYCHOTIC
H ' ' CH2CH2N(CH3)2
136. LOFEPRAMINE [23047-25-8 26786-32-3(HYDROCHLORIDE)]
~ ~ TRADE NAME: TYMELYT (LUNDE3ECK)
bJ~ ~ CLINICAL USE: ANTIDEPRESSANT
CH2CH2CH2 INCH2C~~CI

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137. VALACIKLOVIR []
O TRADE NAME: VALTREX
(GLAXO WELLCOME)
HN ~ N H NH2 CLINICAL USE: ANTIVIRAL AGENT
H2N N 'CH20CH20C0CcH(cH3)2
138. VANCOMYCIN 11404-90-6, 1404-93-09(HYDROCHLORIDE)]
NH2
HOAL ~ TRADE NAME: VANCOCIN (LILLY)
H3 ~ VANCOMYCIN (DUMEX)
~3 'I VANCOMYCIN (NORCOX)
o CLINICAL USE: ANTIBACTERIAL
H~Vr~
\OH 'I
~~1
ClHO~H2 ~ Cl
HQ~ 1~ ~ 3 "G1H
~~ N ~ N ~ N J~ ~ NH
H~ H2NCO-CH2 C~O
139. AMANTADINE [768-94-5, 665-66-7(HYDROCHLORIDE)]
NH2 TRADE NAME: VIROFRAL (FERROSAN)
CLINICAL USE: ANTIVIRAL (INFLUENZA A)
140. ALFLUZOSINE [] CH30~q, NCH2CH2CH2NHCO~
TRADE NAME: XATRAL (ASTRA)
CLINICAL USE~ RECEPTOR ANTAGONIST
58

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141. IDARUBICIN []
TRADE NAME: ZAVEDOS
~ OH (PHARMACIA ~ UPJOHN)
COCH3 CLINICAL USE: CYTOSTATIC
O OH O
- ~r~
~CH3
HO~--
NH2
142 ONDANSETRON ~99614-02-5, 99614-01-4(HYDROCHLORIDE)]
o TRADE NAME ZOFRAN
Il /= (GLAXO WELLCOME)
~,H2C--N ~ CLINICAL USE ANTIEMETIC
CH3
143. CETIRIZINE [83881-51-0, 83881-52-1 (HYDROCHLORIDE)l
TRADE NAME: ZYRLEX (UCB)
Cl CLINICAL USE: ANTIHISTAMINE
/-\
CH--N N--CH3
59
... _ .. ....

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It is to he understood that the invention is not limited to the features and
embodiments hereinabove specifically set forth. but may be carried out in other
ways without departure from its spirit.

Dessin représentatif