CA2141572C - Terfenadine metabolites and their optically pure isomers for treating allergic disorders - Google Patents
Terfenadine metabolites and their optically pure isomers for treating allergic disorders Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A pharmaceutical composition comprising a compound of formula (I): wherein Z
is COOH, COOCH3 or CH2OH, or a pharmaceutically acceptable salt thereof, for use in an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula (I) to a human patient.
is COOH, COOCH3 or CH2OH, or a pharmaceutically acceptable salt thereof, for use in an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula (I) to a human patient.
Description
TERFENADINE METABOLITIES AND THEIR OPTICALLY PURE IOSMERS FOR
TREATING ALLERGIC DISORDERS
DESCRIPTON
This invention relates to novel pharmaceutical compositions containing 4-[1-hydroxy-4-(4-1o hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetates and 1-[p-(2-hydroxymethylprop-2-yl)-phenyl]-4-[4-(oc-hydroxy-a-phenylbenzyl) piperidin-1-yl]butanol and their optically pure derivatives. These compositions possess potent antihistaminic activity and are useful in treating allergic rhinitis, asthma and other allergic disorders while avoiding adverse effects associated with the administration of other cc-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, including but not limited to cardiac 2o arrhythmias, drowsiness, nausea, fatigue, weakness and headache. Also, these compositions, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, are useful for the treatment of cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, pain, fever, and general malaise associated therewith. The aforementioned combinations may optionally include one or more other active components including a decongestant, cough suppressant/antitussive, or expectorant.
TREATING ALLERGIC DISORDERS
DESCRIPTON
This invention relates to novel pharmaceutical compositions containing 4-[1-hydroxy-4-(4-1o hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetates and 1-[p-(2-hydroxymethylprop-2-yl)-phenyl]-4-[4-(oc-hydroxy-a-phenylbenzyl) piperidin-1-yl]butanol and their optically pure derivatives. These compositions possess potent antihistaminic activity and are useful in treating allergic rhinitis, asthma and other allergic disorders while avoiding adverse effects associated with the administration of other cc-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, including but not limited to cardiac 2o arrhythmias, drowsiness, nausea, fatigue, weakness and headache. Also, these compositions, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, are useful for the treatment of cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, pain, fever, and general malaise associated therewith. The aforementioned combinations may optionally include one or more other active components including a decongestant, cough suppressant/antitussive, or expectorant.
2 ~ ~ ( ~ l 2 Additionally, these novel pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a,-dimethylbenzeneacetates and 1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(~-hydroxy-a,-phenylbenzyl)-1-piperidin-1-yl]butanol and their optically pure derivatives are useful in treating motion sickness, vertigo, diabetic retinopathy, small vessel complications due to diabetes and such other conditions as may be related to the activity of these 1o derivatives as antagonists of the H-1 histamine receptor while avoiding the adverse effects associated with the administration of other oc-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine.
Also disclosed are methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the administration of other oc-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, by administering the aforementioned pharmaceutical compositions containing 4-[1-2a hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,oc-dimethylbenzeneacetates and 1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(a-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol or their optically pure isomers to said human.
The active compounds of these compositions and methods are metabolic derivatives of terfenadine.
Chemically, these derivatives are methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a,-Y WO 94/03170 21415 7 2 p~/US93/07260 dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cc,a-dimethylbenzeneacetic acid, and 1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(a-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol and the optical isomers of the compounds. These compounds are described in Garteiz et al., Arzneimittel-Forschuna/Drua Research, 32: 1185-1190 (1982). Chemically, the optical isomers of the compounds are methyl R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-1o oc,a-dimethylbenzeneacetate,methyl S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,oc-dimethylbenzeneacetate, R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid, S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid, R-(+)-1-[p-(2-hydroxymethyl-2 prop-2-yl)phenyl]-4-[4-(oc-hydroxy-ac-phenylbenzyl)piperidin 1-yl]butanol and S-(-)-1-[p-(2-hydroxymethylprop-2 yl)phenyl]-4-[4-(oc-hydroxy-a-phenylbenzyl)piperidin-1 2o yl]butanol.
WO 94/03170 2141 5 l 2 p~-/US93/072oU
Also disclosed are methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the administration of other oc-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, by administering the aforementioned pharmaceutical compositions containing 4-[1-2a hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,oc-dimethylbenzeneacetates and 1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(a-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol or their optically pure isomers to said human.
The active compounds of these compositions and methods are metabolic derivatives of terfenadine.
Chemically, these derivatives are methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a,-Y WO 94/03170 21415 7 2 p~/US93/07260 dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cc,a-dimethylbenzeneacetic acid, and 1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(a-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol and the optical isomers of the compounds. These compounds are described in Garteiz et al., Arzneimittel-Forschuna/Drua Research, 32: 1185-1190 (1982). Chemically, the optical isomers of the compounds are methyl R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-1o oc,a-dimethylbenzeneacetate,methyl S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,oc-dimethylbenzeneacetate, R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid, S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid, R-(+)-1-[p-(2-hydroxymethyl-2 prop-2-yl)phenyl]-4-[4-(oc-hydroxy-ac-phenylbenzyl)piperidin 1-yl]butanol and S-(-)-1-[p-(2-hydroxymethylprop-2 yl)phenyl]-4-[4-(oc-hydroxy-a-phenylbenzyl)piperidin-1 2o yl]butanol.
WO 94/03170 2141 5 l 2 p~-/US93/072oU
l.l. Steric Relationship and Drug Action Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are 1o employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also b~ referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity can be of importance in the 2o field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the f3-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity can be important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that _ 2141572 WO 94/03170 _ 5 _ PCT/US93/07260 the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen.
The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetic acid are disclosed in Zamani et al., Chiralitv 3: 467-470 (1991). This reference states that the (R)-enantiomer of an orally administered racemic 1o terfenadine was preferentially oxidized in rats to form a carboxylic acid metabolite enriched in the (R)-enantiomer.
The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid are also disclosed in Chan et al., J. ChromatoQ. 571: 291-297 ( 1991 ) . This reference states that terfenadine does not undergo any stereoselective isomeric intercvnversion in man.
Terfenadine is an antagonist of the H-1 histamine receptor protein. Histamine receptor proteins occur in two 2o well-identified forms in tissues as H-1 and H-2 receptors.
The H-1 receptors are those that mediate the response antagonized by conventional antihistamines. H-1 receptors are present in the guinea pig ileum, the skin of Rhesus monkeys, and the bronchial smooth muscle of guinea pig.
Terfenadine antagonizes the effect of histamine in the guinea pig isolated ileum, suppresses histamine-induced whealing in the skin of Rhesus monkeys, and protects WO 94/03170 21415 l 2 P~./US93/07260 against histamine induced lethality in the guinea pig.
Through H-2 receptor-mediated responses, histamine stimulates gastric acid secretion in the guinea pig and the chronotropic effect in isolated guinea pig atria. Terfenadine has no effect on histamine-induced gastric acid secretion, nor does it alter the chronotropic effect of histamine on atria. Thus, terfenadine has no apparent effect on the H-2 histamine receptor. See Cheng et al., Drua Development Research, 2: 181-196 (1982).
1o Terfenadine is well absorbed but is extensively metabolized. See Okerholm et al., Biopharmaceutics and Drug Distribution, 2: 185-190 (1981). Two main metabolites have been identified and it has been suggested that one of the metabolites, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl-1-piperidinyl )butyl ~-oc,o~c-dimethylbenzeneacetic acid, may show antihistaminic activity, in vitro, but no actual data have been published. See Garteiz et al., Arzneimittel-ForschunQ/Drua Research, 32: 1185-1190 (1982).
On the basis of its antihistaminic activity, 2o researchers evaluated the effect of terfenadine in the treatment of allergic rhinitis. Clinical trials of efficacy indicated that terfenadine is slightly less effective than chlorpheniramine, another H-1 antagonist.
See Connell, Pharmacotherapy, 5: 201-208 (1985).
It has also been suggested that terfenadine would be useful for the treatment of asthma. In guinea pigs, the increase in airway resistance caused by LTD4 (leukotriene D4) was suppressed by terfenadine. See Akagi et al., ovo Yakuri, 35: 361-371 (1988).
Terfenadine may also be useful for the treatment of motion sickness and vertigo. Some antihistamines have been found to be effective for the prophylaxis and treatment of motion sickness. See Wood, Druas, 17: 471-479 (1979). Some antihistamines have also proven useful for treating vestibular disturbances, such as Meniere's disease, and in other types of vertigo. See Cohen et al., 1o Archives of NeuroloQV, 27: 129-135 (1972).
In addition, terfenadine may be useful in the treatment of diabetic retinopathy and other small vessel disorders associated with diabetes mellitus. In tests on rats with streptozocin-induced diabetes, treatment by antihistamines prevented the activation of retinal histamine receptors which have been implicated in the development of diabetic retinopathy. The use of antihistamines to treat retinopathy and small vessel disorders associated with diabetes mellitus is disclosed in 2o U.S. Patent No. 5,019,591.
It has also been suggested that terfenadine, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, would be useful for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever, and general malaise associated therewith. The use of pharmaceutical compositions containing terfenadine and non-narcotic WO 94/03170 PCT/US93/Oi..~O
_g_ analgesics or non-steroidal anti-inflammatory agents such as aspirin, acetaminophen, and ibuprofen are described in U.S. Patent Nos. 4,783,465 and 4,829,064. These compositions for the treatment of the above-described symptoms may optionally include one or more other active components including a decongestant (such as pseudoephedrine), a cough suppressant/antitussive (such as dextromethorphan) or an expectorant (such as guaifenesin).
Many antihistamines cause somewhat similar to adverse effects. These adverse effects include but are not limited to sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea. Terfenadine has been found to cause relatively less sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea, as compared with other antihistamines.
However, the administration of terfenadine to a human has been found to cause other adverse effects. These adverse effects include but are not limited to cardiac arrhythmias, including ventricular tachyarrhythmias, 2o torsades de pointes, and ventricular fibrillation.
Recently, clinical practitioners have noted an increase in the occurrence of these cardiac arrhythmias upon coadministration of terfenadine with other drugs such as ketoconazole and erythromycin or upon overdose of terfenadine. See Brian P. Monahan et. al. in JAMA, 5th Dec 1990, Vol. 264, No. 21, p-p 2788-90 and Sandra Knowles in the Canadian Journal of Hospital Pharmacy - Vol. 45, No. l, 1st Feb 1992, p. 33.
Thus, it would be particularly desirable to find a compound with the advantages of terfenadine which would not have the aforementioned disadvantages.
It has now been discovered that methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a.,oc-dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-lo dimethylbenzeneacetic acid, and 1-(p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(cc-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol and their optically pure isomers (hereinafter referred to as "the metabolic derivatives of terfenadine" and "optically pure isomers of the metabolic derivatives of terfenadine") are effective antihistamines. It has also been discovered that pharmaceutical compositions containing metabolic derivatives of terfenadine or their optically pure isomers are useful in treating allergic disorders and such other conditions as may be related to the composition's 2o activity as an antihistamine, including but not limited to allergic rhinitis, solar urticaria, and symptomatic dermographism.
Furthermore, it has now also been discovered that the metabolic derivatives of terfenadine or their optically pure isomers are useful in treating asthma. Also, these compounds are useful for the treatment of motion sickness and vertigo and in treating such disorders as retinopathy and WO 94/03170 PCT/US93/072oU
small vessel disorders associated with diabetes mellitus. The present invention also includes methods for treating the above-described conditions in a human, while avoiding the adverse effects that are associated with terfenadine, including but not limited to cardiac arrhythmias, sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea, by administering the metabolic derivatives of terfenadine or their optically pure isomers to said human.
It has also been discovered that the metabolic 1o derivatives of terfenadine and their optically pure isomers, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, are useful for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever, and general malaise associated therewith. The use of pharmaceutical compositions of the invention, containing (1) metabolic derivatives of terfenadine or their optically pure isomers and (2) non-narcotic analgesics or non-steroidal anti-inflammatory agents such aspirin, acetaminophen or ibuprofen, may optionally include 2o one or more other active components including a decongestant (such as pseudoephedrine), a cough suppressant/antitussive (such as dextromethorphan) or an expectorant (such as guaifenesin).
The present invention encompasses a method of treating a human afflicted by or susceptible to an allergic disorder while avoiding the concomitant liability of adverse effects associated with the administration of terfenadine, .
WO 94/03170 21415 7 ~ p~/US93/07260 which comprises administering to said human afflicted by or susceptible to an allergic disorder an amount of one or more compounds selected from the group of metabolic derivatives of terfenadine, optically pure isomers of metabolic derivatives s of terfenadine, and pharmaceutically acceptable salts thereof, said amount being sufficient to treat said allergic disorder, but insufficient to cause the adverse effects associated with terfenadine .
Accordingly and in a first aspect, the present to invention provides a pharmaceutical composition comprising a compound of formula I:
HO-C ~N-(CH2)3-CH O C-Z
wherein Z is COON, COOCH3 or CH20H, or a pharmaceutically acceptable salt thereof, for use in an anti-histaminic 2o treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula I to a human patient. The compounds of formula I include the metabolic derivatives of terfenadine and the optically pure isomers of 25 the metabolic derivatives of terfenadine as aforesaid.
Prior to the present invention, those skilled in the WO 94/03170 21415 7 2 p~-/US93/072a0 art would have expected compounds of formula I to have induced a form of cardiac arrhythmia known as Torsades de Pointes (as reported in Brian P. Monahan et. al., in JAMA, 5th Dec 1990, Vol. 264, No. 21, p-p 2788-90 and Sandra Knowles in The Canadian Journal of Hospital Pharmacy, Vol. 45, No. 1, 1 Feb 1992, p.33), since this potentially lethal arrhythmia was considered to be a "class effect" among non-sedating anti-histamines, in the sense that the arrhythmogenicity was considered to be coupled to the anti-histaminic potency of 1o such compounds. Accordingly, the fact that the compositions, in accordance with the present invention, do not induce any such cardiac arrhythmias is a new, highly useful and surprising technical effect, which enables the inventive compositions to be administered to individuals susceptible to cardiac arrhythmia , and in potentially larger doses than those non-sedating anti-histamines, such as terfenadine, in common use at the present time.
The anti-histaminic treatment can be a method of treating a human afflicted by or susceptible to: an allergic 2o disorder; motion sickness; vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. In embodiments, the invention can relate to any one, any combination, or all of the aforementioned methods of treatment.
r WO 94/03170 21415 l 2 PCT/US93/07260 Preferably, the invention relates to the treatment of an allergic disorder which, preferably, is asthma or allergic rhinitis.
In preferred embodiments, the anti-histaminic treatment comprises the administration of a compound of formula I, in an amount of 1-500mg/day and, preferably, in an amount of 20-200mg/day. When the inventive composition is for use in a method of treating asthma, or retinopathy or another small vessel disease associated with diabetes mellitus, io sufficient of the inventive composition should be administered such that the compound of formula I is provided to the patient in an amount of 0.01-500mg/day and, preferably, in an amount of 0.1-200mg/day.
In preferred embodiments, the inventive composition i5 further comprises a pharmaceutically acceptable carrier or excipient.
Particularly when the anti-histaminic treatment is that of cough, cold, cold-like or flu symptoms or the discomfort, pain, fever or general malaise associated 2o therewith, in a human, the composition can further comprise a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic, such as acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or naproxen, or a pharmaceutically acceptable salt thereof.
25 Alternatively, or additionally, a composition in accordance with the present invention can further comprise a WO 94/03170 21415 7 2 p~'/US93/07s.o0 therapeutically effective amount of a decongestant, such as pseudoephedrine, or a pharmaceutically acceptable salt thereof .
In a preferred embodiment, the inventive composition comprises from 20mg to 200mg of a compound of formula I and from 25mg to 600mg of an anti-inflammatory agent or an analgesic. When the inventive composition comprises a therapeutically effective amount of a decongestant, it, preferably, comprises from 20mg to 200mg of a compound of to formula I and from 5mg to 150mg of the decongestant.
In preferred embodiments of the present invention, the compound of formula I is in the form of a single optical isomer and the inventive composition is substantially free of the other such isomer. In such an embodiment, the compound of formula I, preferably, is selected from the group consisting of: methyl R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,oc-dimethylbenzeneacetate, R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,,oc-dimethylbenzeneacetic acid, and R-(+~-1-[p-(2-2o hydroxymethylprop-2-yl)phenyl]-4-[4-(ac-hydroxy-a,-phenylbenzyl)piperidin-1-yl]butanol and pharmaceutically acceptable salts thereof, and the composition is substantially free of the S stereoisomer of the selected compound; or, is selected from the group consisting of methyl S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-~,~-dimethylbenzeneacetate, S-(-)-4-[1-hydroxy-4-(4-r hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a,-dimethylbenzeneacetic acid, and S-(-)-1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-(~-hydroxy-~-phenylbenzyl)piperidin-1-yl]butanol and pharmaceutically acceptable salts thereof, and the composition is substantially free of the R stereoisomer of the selected compound.
Preferably, the compound of formula I comprises 90$
or more of the selected R- or S-stereoisomer.
In a most preferred embodiment Z, in formula I, is to COOH and the compound of formula I is terfenadine carboxylate.
In a second aspect, the invention relates to a method of providing an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, to a human patient, comprising administering a therapeutically effective amount of a pharmaceutical composition in accordance with the first aspect of the invention, preferably, in one of its preferred embodiments, to said human patient. Preferably, the inventive method is a method of treating a human afflicted by or susceptible to: an allergic disorder; motion sickness;
2o vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. Preferably, the method is a method for treating a human afflicated by or susceptible to an 25 allergic disorder and, more preferably, the allergic disorder is asthma or allergic rhinitis.
WO 94/03170 21415 7 2 p~/US93/072oU
In a third aspect, the invention relates to a use of a composition, in accordance with the first aspect of the invention, or any of its preferred embodiments, for the manufacture of a medicament for use in an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula I to a human patient. Preferably, said use is for the manufacture of a medicament for use in a method of treating a human afflicated 1o by or susceptible to: an allergic disorder; motion sickness;
vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. More preferably, said method is a method of treating a human afflicted by or susceptible to an allergic disorder which, preferably, is asthma or allergic rhinitis.
Terfenadine has antihistaminic activity and provides therapy and a reduction of symptoms for a variety of 2o conditions and disorders related to allergic disorders, diabetes mellitus and other conditions; however, this drug, while offering the expectation of efficacy, causes adverse effects. Utilizing the metabolic derivatives of terfenadine or their substantially optically pure isomers results in clearer dose-related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic r I
2115'72 index. It is, therefore, more desirable to use a metabolic derivative of terfenadine or an optically pure isomer thereof , than to use terfenadine itself.
The term "adverse effects" includes, but is not limited to cardiac arrhythmias, sedation, gastrointestinal distress, dry mouth, constipation, and diarrhea. The term "cardiac arrhythmias" includes, but is not limited to ventricular tachyarrhythmias, torsades de pointes, and ventricular fibrillation.
1o The term "substantially free of the S stereoisomer"
as used herein means that the metabolic derivative of terfenadine in a composition contains at least 90~ by weight of the R isomer of the metabolic derivative of terfenadine, and 10$ by weight or less of the S derivative. In a preferred embodiment, the term "substantially free of the S
stereoisomer" means that the metabolic derivative of terfenadine in a composition contains at least 99~ by weight of the R isomer of the metabolic derivative of terfenadine, and 1$ or less of the S isomer. In another preferred 2o embodiment, the term "substantially free of the S
stereoisomer" as used herein means that the metabolic derivative of terfenadine in a composition contains greater than 99$ by weight of the R isomer of the metabolic derivative of terfenadine and less than 1~ by weight of the S derivative.
The terms "substantially optically pure R isomers of the metabolic derivatives of terfenadine" and "optically pure R
WO 94/03170 21415 l 2 PCT/US93/07160 isomers of the metabolic derivatives of terfenadine" are also encompassed by the above-described definitions.
The term "substantially free of the R stereoisomer"
as used herein means that the composition contains at least 90~ by weight of the S isomer of the metabolic derivatives of terfenadine, and 10~ by weight or less of the R derivatives.
In a preferred embodiment, the term "substantially free of the R stereoisomer" means that the composition contains at least 99~ by weight of the S isomer of the metabolic derivatives of to terfenadine, and 1~ or less of the R isomer. In another preferred embodiment, the term "substantially free of the R
stereoisomer" as used herein means that the composition contains greater than 99$ by weight of the S isomer of the metabolic derivatives of terfenadine and less than 1~ by weight of the R derivatives. These percentages are based upon the total amount of metabolic derivatives of terfenadine in the composition. The terms "substantially optically pure S
isomers of the metabolic derivatives of terfenadine" and "optically pure S isomers of the metabolic derivatives of 2o terfenadine" are also encompassed by the above-described definitions.
The phrase "therapeutically effective amount" means that amount of one or more of the compounds of the invention which provides a therapeutic benefit in an anti-histaminic treatment, including the treatment or management of allergic disorders, asthma, retinopathy or other small vessel disorders WO 94/03170 21415 7 2 pOT/US93/07260 associated with diabetes mellitus, motion sickness, vertigo, or cough, cold, cold-like, and/or flu symptoms and the discomfort, pain, fever, and general malaise associated therewith. Examples of allergic disorders include, but are not limited to, allergic rhinitis, solar urticaria, and symptomatic dermographism. The symptoms associated with these allergic disorders and the cough, cold, cold-like, and/or flu symptoms include, but are not limited to, sneezing, rhinorrhea, lacrimation, and dermal irritation. The term to "asthma" is defined as a disorder characterized by increased responsiveness of the trachea and bronchi to various stimuli which results in symptoms which include wheezing, cough, and dyspnea. The term "vertigo" as used herein means the dizziness associated with, but not limited to motion, height, and changes in body position. The term "diabetic retinopathy"
or "retinopathy associated with diabetes mellitus" is that disorder caused by increased permeability of the capillaries in the eye which leads to hemorrhages and edema in the eye and can lead to blindness. The term "small vessel disorders 2o associated with diabetes mellitus" includes, but is not limited to diabetic retinopathy and peripheral vascular disease.
The separation of the optically pure isomers of the metabolic derivatives of terfenadine may be effected by resolution of the racemic mixture of enantiomers of the metabolic derivatives of terfenadine using conventional means ._ J
such as an optically active resolving acid. Furthermore, the optically pure isomers of the metabolic derivatives of terfenadine can be prepared from the racemic mixture by enzymatic biocatalytic resolution. See, for example, United States Patent Nos. 5,057,427 and 5,077,217, The magnitude of a prophylactic or therapeutic dose of a metabolic derivative of terfenadine, or an optically pure isomer thereof, in the acute or chronic management of disease 1o will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range, for the conditions described herein, is from about 0.01 mg to about 500 mg administered in single or divided doses orally, topically, transdermally, or locally by aerosol. For example, a preferred oral daily dose range should be from about 1 mg to about 500 mg, while most preferably an oral daily dose range should be between about 20 2o mg and about 200 mg. It is further recommended that children, patients aged over 65 years, and those with impaired renal or hepatic function initially receive low doses, and that they then be titrated based on individual responses) or blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating WO 94/03170 21415 l 2 PCT/US93/07260 physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The various terms "an amount sufficient to alleviate said allergic disorder but insufficient to cause said adverse effects," "an amount sufficient to alleviate said asthma but insufficient to cause said adverse effects," "an amount sufficient to alleviate said motion sickness but insufficient to cause said adverse effects," and "an amount sufficient to 1o alleviate said retinopathy or other small vessel diseases associated with diabetes mellitus but insufficient to cause said adverse effects" are encompassed by the above-described dosage amounts and dose frequency schedule. In addition, the terms "a pharmaceutical composition for use in the treatment is of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a human, said composition comprising (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine, or an optically pure isomer 2o thereof , with ( ii ) a therapeutically ef fective amount of at least one non-steroidal anti-inflammatory agent or non-narcotic analgesic," and "a pharmaceutical composition for use in the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated z5 therewith, in a human, said composition comprising (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine, or an optically pure isomer, with (ii) a therapeutically effective amount of a decongestant," as well as the term "therapeutically effective amount of at least one oc-aryl-4-substituted piperidinoalkanol derivative" are also encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of the inventive composition. For example, oral, rectal, parenteral, 1o transdermal, subcutaneous, intramuscular, and like forms of administration may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
The pharmaceutical compositions of the present invention comprise a metabolic derivative of terfenadine, or an optically pure isomer thereof as active ingredient, or a pharmaceutically acceptable salt thereof , and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
2o The term "pharmaceutically acceptable salts"
includes within its ambit salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids or bases or organic acids or bases. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic r I
WO 94/03170 21415 l 2 pL'f/US93/07260 and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucoronic, malefic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic. Examples of such inorganic bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
Appropriate organic bases may be selected, for example, from 1o N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine.
The compositions of the present invention include compositions such as suspensions, solutions and elixirs;
aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being 2o preferred over the oral liquid preparations. The most preferred oral solid preparations are tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out WO 94/03170 PCT/US93/Oi~oO
above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a to suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
2o For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 10 mg to about 150 mg of the active ingredient, and each cachet or capsule contains from about 10 mg to about 150 mg of the active ingredient, i.e., a metabolic derivative of terfenadine. Most preferably, the tablet, cachet or capsule contains either one of three dosages, 30 mg, 60 mg or 90 mg of the active ingredient.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced which are within the scope of this invention.
4. EXAMPLES
4.1. Example 1 A. Preparation of methyl R-4-fl-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyll-cc,oc-dimethvlbenzeneacetate.
4-(oc-hydroxy-cx-phenylbenzyl)piperidine (4.3 gm) was combined with methyl p-(4-chloro-1-oxobutyl)-a,oc-dimethylbenzeneacetate (4.5 gm), potassium bicarbonate (2.9 gm), potassium iodide (ca. 50 mg), and methyl isobutyl ketone (50 ml) and heated to reflux for 48 hours.
Additional 4-(oc-hydroxy-a-phenylbenzyl)piperidine (1.I gm) was added, and heating was continued for an additional 48 hours. Upon cooling the mixture to room temperature, water was added and the pH of the solution was adjusted to ca. 12 by addition of aqueous sodium hydroxide. The mixture was 2o extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The ethyl acetate was removed on a rotary evaporator and the residue was treated with 25$ ethyl acetate in hexane. The resulting precipitate was filtered and air dried to give methyl 4-[1-oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a,-dimethylbenzeneacetate. This intermediate precipitate (2.4 r I
-2~
gm) was combined with tetrahydrofuran (10 ml) and (+)-13-chlorodiisopinocamphenylborane (4.5 gm) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 gm) were added to the reaction solution, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate to give methyl R-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-ac,oc-dimethylbenzeneacetate.
B. R-(+~-4-fl-hvdroxy-4-(4-hydroxydiphenylmethvl 1 piperidinyllbutyll-cz,a-dimethylbenzeneacetic acid fR (+~
terfenadine carboxylate L
Methyl R-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,cx-dimethylbenzeneacetate -(1.2 gm) was combined with potassium hydroxide (0.4 gm) and ethanol (5 ml), and the mixture was heated to reflux for 7 hours.
The ethanol was removed on a rotary evaporator and the 2o residue was dissolved in water (2 ml). The aqueous solution was acidifed with glacial acetic acid to provide a solid which was recrystallized from 1:1 methanol/ethyl acetate to give R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetic acid (R-terfenadine carboxylate) (mp=213-215°C).
WO 94/03170 21415 l 2 p~/US93/07~00 _28_ C. Preparation of methyl S-4-fl-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyllbutyll-ac,~-dimethylbenzeneacetate.
4-(cx-hydroxy-a-phenylbenzyl)piperidine (4.3 gm) was combined with methyl p-(4-chloro-1-oxobutyl)-oc,a,-dimethylbenzene-acetate (4.5 gm), potassium bicarbonate (2.9 gm), potassium iodide (ca. 50 mg), and methyl isobutyl ketone (50 ml) and heated to reflux for 48 hours. Additional 4-(oc-1o hydroxy-oc-phenylbenzyl)piperidine (1.1 gm) was added, and heating was continued for an additional 48 hours. Upon cooling the mixture to room temperature, water was added and the pH of the solution was adjusted to ca. 12 by addition of aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The ethyl acetate was removed on a rotary evaporator and the residue was treated with 25$ ethyl acetate in hexane. The resulting precipitate was filtered and air 2o dried to give methyl 4-[1-oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-c~c,cx-dimethylbenzeneacetate. This intermediate precipitate (2.4 gm) was combined with tetrahydrofuran (10 ml) and (-) chlorodiisopinocamphenylborane (4.5 gm) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 gm) were added to the reaction solution and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml) r 1 _29_ and washed with saturated aqueous sodium bicarbonate to give methyl S-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,a-dimethylbenzeneacetate. If the aforementioned intermediate precipitate were to be reacted with racemic j3-chlorodiisopinocamphenylborane, then a racemic mixture.of methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a~c-dimethylbenzeneacetate would be produced.
to D. S-l-)-4-fl-hvdroxv-4-(4-hydroxydiphenylmethyl 1 piperidinyl)butyll-a.a~c-dimethvlbenzeneacetic acid ~S ) terfenadine carboxvlatel Methyl S-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a-dimethylbenzeneacetate (1.2 gm) was combined with potassium hydroxide (0.4 gm) and ethanol (5 ml ) and the mixture was heated to ref lux for 7 hours . The ethanol was removed on a rotary evaporator and the residue was dissolved in water (2 ml). The aqueous solution was acidifed 2o with glacial acetic acid to provide a solid which was recrystallized from 1:1 methanol/ethyl acetate to give S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid (S-terfenadine carboxylate) (mp=215-218°C).
WO 94/03170 PCT/US93/07~00 4.2. Example 2 Activities of the compounds of the invention at the histamine H1-receptor were assessed using the [3H]pyrilamine binding assay as described in Chang et al., J. Neurochem. 32: 1653-1663 (1979). Briefly, membranes from bovine cerebellum were incubated with [3H]pyrilamine and varying concentrations of test compound. The reactions were carried out in 50 mM sodium phosphate buffer (pH 7.5) at 25°
to C for 30 minutes. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and compared to control values to acertain the interaction of the test compound with the H1-receptor. Results were as follows:
Compound Percent Inhibition (at various concentrations) 10-9 M 10-' M 10-5 M
R,S-terfenadine 11.0 28.7 86.9 R-(+)-terfenadine 11.4 19.4 90.3 R-(+)-terfenadine 12.4 45.2 87.3 carboxylate S-(-)-terfenadine 3.2 24.4 92.8 3o S-(-)-terfenadine 8.1 54.1 gg,7 carboxylate r I
4.3. Example 3 Single ventricular myocytes were obtained from isolated cat hearts by conventional techniques. The rod-shaped single cells were maintained in a HEPES buffer and they were "patch clamped" using suction pipettes. A Patch-Clamp L/M-PEC 7 amplifier was used to record current tracings and the recording electrodes were filled with a to solution of potassium aspartate. Voltage clamp pulses and data acquisition were controlled by a Sperry PC/IT Computer running P Clamp software. A minimum of 4 cells were studied at each test concentration of the following drugs: racemic terfenadine, racemic terfenadine carboxylate, and quinidine (as a reference compound). Results were as follows:
Conc (~M) Hlock of the delayed rectifier potassium current ($) Terfenadine 0.01 12 ~ 9.3 0.10 39.5 ~ 9.8 1.00 92.6 (92.5; 92.8) Terfenadine 0.01 0 ~ 0 carboxylate 0.10 0 ~ 0 1.00 0 ~ 0 3o These results show that terfenadine carboxylate, surprisingly, is not liable to cause cardiac arrhythmia, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself .
WO 94/03170 2 1415 l 2 p~/uS93/07~00 4.4. Example 4 Oral Formulation - Capsules:
Formula Quantity per capsule in mg.
A B C
Active ingredient (S)Terfenadine 30.0 60.0 90.0 carboxylate Starch 1500 69.0 39.0 9.0 Magnesium Stearate BP 1.0 1.0 1.0 Compression Weight 100.0 100.0 100.0 The active ingredient, which can instead be (R)terfenadine carboxylate or racemic terfenadine carboxylate, is sieved and blended with the excipients. The mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
r I
WO 94/03170 21415 l 2 _ 33_ . p~'/US93/07260 4.5. Example 5 Oral Formulation - Tablets:
Formula Quantity per Tablet in mg.
A B C
Active ingredient, (R)Terfenadine 30.0 60.0 90.0 Carboxylate Lactose BP 123.5 93.5 63.5 Starch BP 30.0 30.0 30.0 Pregelatinized Maize 15.0 15.0 15.0 Starch BP
2o Magnesium stearate 1.5 1.5 1.5 Compression Weight 200.0 200.0 200.0 The active ingredient, which can instead be (S)terfenadine carboxylate or racemic terfenadine carboxylate, is sieved through a suitable sieve and blended with the lactose until a uniform blend is formed. Suitable volumes of water are added and the powders are granulated.
3o After drying, the granules are then screened and blended with the magnesium stearate. The resulting granules are then compressed into tablets of desired shape. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipient(s) or the compression weight .
Stereochemical purity can be of importance in the 2o field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the f3-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity can be important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that _ 2141572 WO 94/03170 _ 5 _ PCT/US93/07260 the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen.
The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetic acid are disclosed in Zamani et al., Chiralitv 3: 467-470 (1991). This reference states that the (R)-enantiomer of an orally administered racemic 1o terfenadine was preferentially oxidized in rats to form a carboxylic acid metabolite enriched in the (R)-enantiomer.
The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid are also disclosed in Chan et al., J. ChromatoQ. 571: 291-297 ( 1991 ) . This reference states that terfenadine does not undergo any stereoselective isomeric intercvnversion in man.
Terfenadine is an antagonist of the H-1 histamine receptor protein. Histamine receptor proteins occur in two 2o well-identified forms in tissues as H-1 and H-2 receptors.
The H-1 receptors are those that mediate the response antagonized by conventional antihistamines. H-1 receptors are present in the guinea pig ileum, the skin of Rhesus monkeys, and the bronchial smooth muscle of guinea pig.
Terfenadine antagonizes the effect of histamine in the guinea pig isolated ileum, suppresses histamine-induced whealing in the skin of Rhesus monkeys, and protects WO 94/03170 21415 l 2 P~./US93/07260 against histamine induced lethality in the guinea pig.
Through H-2 receptor-mediated responses, histamine stimulates gastric acid secretion in the guinea pig and the chronotropic effect in isolated guinea pig atria. Terfenadine has no effect on histamine-induced gastric acid secretion, nor does it alter the chronotropic effect of histamine on atria. Thus, terfenadine has no apparent effect on the H-2 histamine receptor. See Cheng et al., Drua Development Research, 2: 181-196 (1982).
1o Terfenadine is well absorbed but is extensively metabolized. See Okerholm et al., Biopharmaceutics and Drug Distribution, 2: 185-190 (1981). Two main metabolites have been identified and it has been suggested that one of the metabolites, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl-1-piperidinyl )butyl ~-oc,o~c-dimethylbenzeneacetic acid, may show antihistaminic activity, in vitro, but no actual data have been published. See Garteiz et al., Arzneimittel-ForschunQ/Drua Research, 32: 1185-1190 (1982).
On the basis of its antihistaminic activity, 2o researchers evaluated the effect of terfenadine in the treatment of allergic rhinitis. Clinical trials of efficacy indicated that terfenadine is slightly less effective than chlorpheniramine, another H-1 antagonist.
See Connell, Pharmacotherapy, 5: 201-208 (1985).
It has also been suggested that terfenadine would be useful for the treatment of asthma. In guinea pigs, the increase in airway resistance caused by LTD4 (leukotriene D4) was suppressed by terfenadine. See Akagi et al., ovo Yakuri, 35: 361-371 (1988).
Terfenadine may also be useful for the treatment of motion sickness and vertigo. Some antihistamines have been found to be effective for the prophylaxis and treatment of motion sickness. See Wood, Druas, 17: 471-479 (1979). Some antihistamines have also proven useful for treating vestibular disturbances, such as Meniere's disease, and in other types of vertigo. See Cohen et al., 1o Archives of NeuroloQV, 27: 129-135 (1972).
In addition, terfenadine may be useful in the treatment of diabetic retinopathy and other small vessel disorders associated with diabetes mellitus. In tests on rats with streptozocin-induced diabetes, treatment by antihistamines prevented the activation of retinal histamine receptors which have been implicated in the development of diabetic retinopathy. The use of antihistamines to treat retinopathy and small vessel disorders associated with diabetes mellitus is disclosed in 2o U.S. Patent No. 5,019,591.
It has also been suggested that terfenadine, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, would be useful for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever, and general malaise associated therewith. The use of pharmaceutical compositions containing terfenadine and non-narcotic WO 94/03170 PCT/US93/Oi..~O
_g_ analgesics or non-steroidal anti-inflammatory agents such as aspirin, acetaminophen, and ibuprofen are described in U.S. Patent Nos. 4,783,465 and 4,829,064. These compositions for the treatment of the above-described symptoms may optionally include one or more other active components including a decongestant (such as pseudoephedrine), a cough suppressant/antitussive (such as dextromethorphan) or an expectorant (such as guaifenesin).
Many antihistamines cause somewhat similar to adverse effects. These adverse effects include but are not limited to sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea. Terfenadine has been found to cause relatively less sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea, as compared with other antihistamines.
However, the administration of terfenadine to a human has been found to cause other adverse effects. These adverse effects include but are not limited to cardiac arrhythmias, including ventricular tachyarrhythmias, 2o torsades de pointes, and ventricular fibrillation.
Recently, clinical practitioners have noted an increase in the occurrence of these cardiac arrhythmias upon coadministration of terfenadine with other drugs such as ketoconazole and erythromycin or upon overdose of terfenadine. See Brian P. Monahan et. al. in JAMA, 5th Dec 1990, Vol. 264, No. 21, p-p 2788-90 and Sandra Knowles in the Canadian Journal of Hospital Pharmacy - Vol. 45, No. l, 1st Feb 1992, p. 33.
Thus, it would be particularly desirable to find a compound with the advantages of terfenadine which would not have the aforementioned disadvantages.
It has now been discovered that methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a.,oc-dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-lo dimethylbenzeneacetic acid, and 1-(p-(2-hydroxymethylprop-2-yl)phenyl]-4-[4-(cc-hydroxy-a-phenylbenzyl)piperidin-1-yl]butanol and their optically pure isomers (hereinafter referred to as "the metabolic derivatives of terfenadine" and "optically pure isomers of the metabolic derivatives of terfenadine") are effective antihistamines. It has also been discovered that pharmaceutical compositions containing metabolic derivatives of terfenadine or their optically pure isomers are useful in treating allergic disorders and such other conditions as may be related to the composition's 2o activity as an antihistamine, including but not limited to allergic rhinitis, solar urticaria, and symptomatic dermographism.
Furthermore, it has now also been discovered that the metabolic derivatives of terfenadine or their optically pure isomers are useful in treating asthma. Also, these compounds are useful for the treatment of motion sickness and vertigo and in treating such disorders as retinopathy and WO 94/03170 PCT/US93/072oU
small vessel disorders associated with diabetes mellitus. The present invention also includes methods for treating the above-described conditions in a human, while avoiding the adverse effects that are associated with terfenadine, including but not limited to cardiac arrhythmias, sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea, by administering the metabolic derivatives of terfenadine or their optically pure isomers to said human.
It has also been discovered that the metabolic 1o derivatives of terfenadine and their optically pure isomers, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, are useful for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever, and general malaise associated therewith. The use of pharmaceutical compositions of the invention, containing (1) metabolic derivatives of terfenadine or their optically pure isomers and (2) non-narcotic analgesics or non-steroidal anti-inflammatory agents such aspirin, acetaminophen or ibuprofen, may optionally include 2o one or more other active components including a decongestant (such as pseudoephedrine), a cough suppressant/antitussive (such as dextromethorphan) or an expectorant (such as guaifenesin).
The present invention encompasses a method of treating a human afflicted by or susceptible to an allergic disorder while avoiding the concomitant liability of adverse effects associated with the administration of terfenadine, .
WO 94/03170 21415 7 ~ p~/US93/07260 which comprises administering to said human afflicted by or susceptible to an allergic disorder an amount of one or more compounds selected from the group of metabolic derivatives of terfenadine, optically pure isomers of metabolic derivatives s of terfenadine, and pharmaceutically acceptable salts thereof, said amount being sufficient to treat said allergic disorder, but insufficient to cause the adverse effects associated with terfenadine .
Accordingly and in a first aspect, the present to invention provides a pharmaceutical composition comprising a compound of formula I:
HO-C ~N-(CH2)3-CH O C-Z
wherein Z is COON, COOCH3 or CH20H, or a pharmaceutically acceptable salt thereof, for use in an anti-histaminic 2o treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula I to a human patient. The compounds of formula I include the metabolic derivatives of terfenadine and the optically pure isomers of 25 the metabolic derivatives of terfenadine as aforesaid.
Prior to the present invention, those skilled in the WO 94/03170 21415 7 2 p~-/US93/072a0 art would have expected compounds of formula I to have induced a form of cardiac arrhythmia known as Torsades de Pointes (as reported in Brian P. Monahan et. al., in JAMA, 5th Dec 1990, Vol. 264, No. 21, p-p 2788-90 and Sandra Knowles in The Canadian Journal of Hospital Pharmacy, Vol. 45, No. 1, 1 Feb 1992, p.33), since this potentially lethal arrhythmia was considered to be a "class effect" among non-sedating anti-histamines, in the sense that the arrhythmogenicity was considered to be coupled to the anti-histaminic potency of 1o such compounds. Accordingly, the fact that the compositions, in accordance with the present invention, do not induce any such cardiac arrhythmias is a new, highly useful and surprising technical effect, which enables the inventive compositions to be administered to individuals susceptible to cardiac arrhythmia , and in potentially larger doses than those non-sedating anti-histamines, such as terfenadine, in common use at the present time.
The anti-histaminic treatment can be a method of treating a human afflicted by or susceptible to: an allergic 2o disorder; motion sickness; vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. In embodiments, the invention can relate to any one, any combination, or all of the aforementioned methods of treatment.
r WO 94/03170 21415 l 2 PCT/US93/07260 Preferably, the invention relates to the treatment of an allergic disorder which, preferably, is asthma or allergic rhinitis.
In preferred embodiments, the anti-histaminic treatment comprises the administration of a compound of formula I, in an amount of 1-500mg/day and, preferably, in an amount of 20-200mg/day. When the inventive composition is for use in a method of treating asthma, or retinopathy or another small vessel disease associated with diabetes mellitus, io sufficient of the inventive composition should be administered such that the compound of formula I is provided to the patient in an amount of 0.01-500mg/day and, preferably, in an amount of 0.1-200mg/day.
In preferred embodiments, the inventive composition i5 further comprises a pharmaceutically acceptable carrier or excipient.
Particularly when the anti-histaminic treatment is that of cough, cold, cold-like or flu symptoms or the discomfort, pain, fever or general malaise associated 2o therewith, in a human, the composition can further comprise a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic, such as acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or naproxen, or a pharmaceutically acceptable salt thereof.
25 Alternatively, or additionally, a composition in accordance with the present invention can further comprise a WO 94/03170 21415 7 2 p~'/US93/07s.o0 therapeutically effective amount of a decongestant, such as pseudoephedrine, or a pharmaceutically acceptable salt thereof .
In a preferred embodiment, the inventive composition comprises from 20mg to 200mg of a compound of formula I and from 25mg to 600mg of an anti-inflammatory agent or an analgesic. When the inventive composition comprises a therapeutically effective amount of a decongestant, it, preferably, comprises from 20mg to 200mg of a compound of to formula I and from 5mg to 150mg of the decongestant.
In preferred embodiments of the present invention, the compound of formula I is in the form of a single optical isomer and the inventive composition is substantially free of the other such isomer. In such an embodiment, the compound of formula I, preferably, is selected from the group consisting of: methyl R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,oc-dimethylbenzeneacetate, R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,,oc-dimethylbenzeneacetic acid, and R-(+~-1-[p-(2-2o hydroxymethylprop-2-yl)phenyl]-4-[4-(ac-hydroxy-a,-phenylbenzyl)piperidin-1-yl]butanol and pharmaceutically acceptable salts thereof, and the composition is substantially free of the S stereoisomer of the selected compound; or, is selected from the group consisting of methyl S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-~,~-dimethylbenzeneacetate, S-(-)-4-[1-hydroxy-4-(4-r hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a,-dimethylbenzeneacetic acid, and S-(-)-1-[p-(2-hydroxymethylprop-2-yl)phenyl]-4-(~-hydroxy-~-phenylbenzyl)piperidin-1-yl]butanol and pharmaceutically acceptable salts thereof, and the composition is substantially free of the R stereoisomer of the selected compound.
Preferably, the compound of formula I comprises 90$
or more of the selected R- or S-stereoisomer.
In a most preferred embodiment Z, in formula I, is to COOH and the compound of formula I is terfenadine carboxylate.
In a second aspect, the invention relates to a method of providing an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, to a human patient, comprising administering a therapeutically effective amount of a pharmaceutical composition in accordance with the first aspect of the invention, preferably, in one of its preferred embodiments, to said human patient. Preferably, the inventive method is a method of treating a human afflicted by or susceptible to: an allergic disorder; motion sickness;
2o vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. Preferably, the method is a method for treating a human afflicated by or susceptible to an 25 allergic disorder and, more preferably, the allergic disorder is asthma or allergic rhinitis.
WO 94/03170 21415 7 2 p~/US93/072oU
In a third aspect, the invention relates to a use of a composition, in accordance with the first aspect of the invention, or any of its preferred embodiments, for the manufacture of a medicament for use in an anti-histaminic treatment which does not induce any significant cardiac arrhythmia, comprising administering a therapeutically effective amount of a compound of formula I to a human patient. Preferably, said use is for the manufacture of a medicament for use in a method of treating a human afflicated 1o by or susceptible to: an allergic disorder; motion sickness;
vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith. More preferably, said method is a method of treating a human afflicted by or susceptible to an allergic disorder which, preferably, is asthma or allergic rhinitis.
Terfenadine has antihistaminic activity and provides therapy and a reduction of symptoms for a variety of 2o conditions and disorders related to allergic disorders, diabetes mellitus and other conditions; however, this drug, while offering the expectation of efficacy, causes adverse effects. Utilizing the metabolic derivatives of terfenadine or their substantially optically pure isomers results in clearer dose-related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic r I
2115'72 index. It is, therefore, more desirable to use a metabolic derivative of terfenadine or an optically pure isomer thereof , than to use terfenadine itself.
The term "adverse effects" includes, but is not limited to cardiac arrhythmias, sedation, gastrointestinal distress, dry mouth, constipation, and diarrhea. The term "cardiac arrhythmias" includes, but is not limited to ventricular tachyarrhythmias, torsades de pointes, and ventricular fibrillation.
1o The term "substantially free of the S stereoisomer"
as used herein means that the metabolic derivative of terfenadine in a composition contains at least 90~ by weight of the R isomer of the metabolic derivative of terfenadine, and 10$ by weight or less of the S derivative. In a preferred embodiment, the term "substantially free of the S
stereoisomer" means that the metabolic derivative of terfenadine in a composition contains at least 99~ by weight of the R isomer of the metabolic derivative of terfenadine, and 1$ or less of the S isomer. In another preferred 2o embodiment, the term "substantially free of the S
stereoisomer" as used herein means that the metabolic derivative of terfenadine in a composition contains greater than 99$ by weight of the R isomer of the metabolic derivative of terfenadine and less than 1~ by weight of the S derivative.
The terms "substantially optically pure R isomers of the metabolic derivatives of terfenadine" and "optically pure R
WO 94/03170 21415 l 2 PCT/US93/07160 isomers of the metabolic derivatives of terfenadine" are also encompassed by the above-described definitions.
The term "substantially free of the R stereoisomer"
as used herein means that the composition contains at least 90~ by weight of the S isomer of the metabolic derivatives of terfenadine, and 10~ by weight or less of the R derivatives.
In a preferred embodiment, the term "substantially free of the R stereoisomer" means that the composition contains at least 99~ by weight of the S isomer of the metabolic derivatives of to terfenadine, and 1~ or less of the R isomer. In another preferred embodiment, the term "substantially free of the R
stereoisomer" as used herein means that the composition contains greater than 99$ by weight of the S isomer of the metabolic derivatives of terfenadine and less than 1~ by weight of the R derivatives. These percentages are based upon the total amount of metabolic derivatives of terfenadine in the composition. The terms "substantially optically pure S
isomers of the metabolic derivatives of terfenadine" and "optically pure S isomers of the metabolic derivatives of 2o terfenadine" are also encompassed by the above-described definitions.
The phrase "therapeutically effective amount" means that amount of one or more of the compounds of the invention which provides a therapeutic benefit in an anti-histaminic treatment, including the treatment or management of allergic disorders, asthma, retinopathy or other small vessel disorders WO 94/03170 21415 7 2 pOT/US93/07260 associated with diabetes mellitus, motion sickness, vertigo, or cough, cold, cold-like, and/or flu symptoms and the discomfort, pain, fever, and general malaise associated therewith. Examples of allergic disorders include, but are not limited to, allergic rhinitis, solar urticaria, and symptomatic dermographism. The symptoms associated with these allergic disorders and the cough, cold, cold-like, and/or flu symptoms include, but are not limited to, sneezing, rhinorrhea, lacrimation, and dermal irritation. The term to "asthma" is defined as a disorder characterized by increased responsiveness of the trachea and bronchi to various stimuli which results in symptoms which include wheezing, cough, and dyspnea. The term "vertigo" as used herein means the dizziness associated with, but not limited to motion, height, and changes in body position. The term "diabetic retinopathy"
or "retinopathy associated with diabetes mellitus" is that disorder caused by increased permeability of the capillaries in the eye which leads to hemorrhages and edema in the eye and can lead to blindness. The term "small vessel disorders 2o associated with diabetes mellitus" includes, but is not limited to diabetic retinopathy and peripheral vascular disease.
The separation of the optically pure isomers of the metabolic derivatives of terfenadine may be effected by resolution of the racemic mixture of enantiomers of the metabolic derivatives of terfenadine using conventional means ._ J
such as an optically active resolving acid. Furthermore, the optically pure isomers of the metabolic derivatives of terfenadine can be prepared from the racemic mixture by enzymatic biocatalytic resolution. See, for example, United States Patent Nos. 5,057,427 and 5,077,217, The magnitude of a prophylactic or therapeutic dose of a metabolic derivative of terfenadine, or an optically pure isomer thereof, in the acute or chronic management of disease 1o will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range, for the conditions described herein, is from about 0.01 mg to about 500 mg administered in single or divided doses orally, topically, transdermally, or locally by aerosol. For example, a preferred oral daily dose range should be from about 1 mg to about 500 mg, while most preferably an oral daily dose range should be between about 20 2o mg and about 200 mg. It is further recommended that children, patients aged over 65 years, and those with impaired renal or hepatic function initially receive low doses, and that they then be titrated based on individual responses) or blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating WO 94/03170 21415 l 2 PCT/US93/07260 physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The various terms "an amount sufficient to alleviate said allergic disorder but insufficient to cause said adverse effects," "an amount sufficient to alleviate said asthma but insufficient to cause said adverse effects," "an amount sufficient to alleviate said motion sickness but insufficient to cause said adverse effects," and "an amount sufficient to 1o alleviate said retinopathy or other small vessel diseases associated with diabetes mellitus but insufficient to cause said adverse effects" are encompassed by the above-described dosage amounts and dose frequency schedule. In addition, the terms "a pharmaceutical composition for use in the treatment is of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith, in a human, said composition comprising (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine, or an optically pure isomer 2o thereof , with ( ii ) a therapeutically ef fective amount of at least one non-steroidal anti-inflammatory agent or non-narcotic analgesic," and "a pharmaceutical composition for use in the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated z5 therewith, in a human, said composition comprising (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine, or an optically pure isomer, with (ii) a therapeutically effective amount of a decongestant," as well as the term "therapeutically effective amount of at least one oc-aryl-4-substituted piperidinoalkanol derivative" are also encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of the inventive composition. For example, oral, rectal, parenteral, 1o transdermal, subcutaneous, intramuscular, and like forms of administration may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
The pharmaceutical compositions of the present invention comprise a metabolic derivative of terfenadine, or an optically pure isomer thereof as active ingredient, or a pharmaceutically acceptable salt thereof , and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
2o The term "pharmaceutically acceptable salts"
includes within its ambit salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids or bases or organic acids or bases. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic r I
WO 94/03170 21415 l 2 pL'f/US93/07260 and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucoronic, malefic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic. Examples of such inorganic bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
Appropriate organic bases may be selected, for example, from 1o N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine.
The compositions of the present invention include compositions such as suspensions, solutions and elixirs;
aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being 2o preferred over the oral liquid preparations. The most preferred oral solid preparations are tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out WO 94/03170 PCT/US93/Oi~oO
above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a to suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
2o For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 10 mg to about 150 mg of the active ingredient, and each cachet or capsule contains from about 10 mg to about 150 mg of the active ingredient, i.e., a metabolic derivative of terfenadine. Most preferably, the tablet, cachet or capsule contains either one of three dosages, 30 mg, 60 mg or 90 mg of the active ingredient.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced which are within the scope of this invention.
4. EXAMPLES
4.1. Example 1 A. Preparation of methyl R-4-fl-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyll-cc,oc-dimethvlbenzeneacetate.
4-(oc-hydroxy-cx-phenylbenzyl)piperidine (4.3 gm) was combined with methyl p-(4-chloro-1-oxobutyl)-a,oc-dimethylbenzeneacetate (4.5 gm), potassium bicarbonate (2.9 gm), potassium iodide (ca. 50 mg), and methyl isobutyl ketone (50 ml) and heated to reflux for 48 hours.
Additional 4-(oc-hydroxy-a-phenylbenzyl)piperidine (1.I gm) was added, and heating was continued for an additional 48 hours. Upon cooling the mixture to room temperature, water was added and the pH of the solution was adjusted to ca. 12 by addition of aqueous sodium hydroxide. The mixture was 2o extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The ethyl acetate was removed on a rotary evaporator and the residue was treated with 25$ ethyl acetate in hexane. The resulting precipitate was filtered and air dried to give methyl 4-[1-oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a,-dimethylbenzeneacetate. This intermediate precipitate (2.4 r I
-2~
gm) was combined with tetrahydrofuran (10 ml) and (+)-13-chlorodiisopinocamphenylborane (4.5 gm) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 gm) were added to the reaction solution, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate to give methyl R-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-ac,oc-dimethylbenzeneacetate.
B. R-(+~-4-fl-hvdroxy-4-(4-hydroxydiphenylmethvl 1 piperidinyllbutyll-cz,a-dimethylbenzeneacetic acid fR (+~
terfenadine carboxylate L
Methyl R-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,cx-dimethylbenzeneacetate -(1.2 gm) was combined with potassium hydroxide (0.4 gm) and ethanol (5 ml), and the mixture was heated to reflux for 7 hours.
The ethanol was removed on a rotary evaporator and the 2o residue was dissolved in water (2 ml). The aqueous solution was acidifed with glacial acetic acid to provide a solid which was recrystallized from 1:1 methanol/ethyl acetate to give R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,oc-dimethylbenzeneacetic acid (R-terfenadine carboxylate) (mp=213-215°C).
WO 94/03170 21415 l 2 p~/US93/07~00 _28_ C. Preparation of methyl S-4-fl-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyllbutyll-ac,~-dimethylbenzeneacetate.
4-(cx-hydroxy-a-phenylbenzyl)piperidine (4.3 gm) was combined with methyl p-(4-chloro-1-oxobutyl)-oc,a,-dimethylbenzene-acetate (4.5 gm), potassium bicarbonate (2.9 gm), potassium iodide (ca. 50 mg), and methyl isobutyl ketone (50 ml) and heated to reflux for 48 hours. Additional 4-(oc-1o hydroxy-oc-phenylbenzyl)piperidine (1.1 gm) was added, and heating was continued for an additional 48 hours. Upon cooling the mixture to room temperature, water was added and the pH of the solution was adjusted to ca. 12 by addition of aqueous sodium hydroxide. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The ethyl acetate was removed on a rotary evaporator and the residue was treated with 25$ ethyl acetate in hexane. The resulting precipitate was filtered and air 2o dried to give methyl 4-[1-oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-c~c,cx-dimethylbenzeneacetate. This intermediate precipitate (2.4 gm) was combined with tetrahydrofuran (10 ml) and (-) chlorodiisopinocamphenylborane (4.5 gm) and stirred for 48 hours. Methanol (10 ml) and sodium bicarbonate (1.5 gm) were added to the reaction solution and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate (200 ml) r 1 _29_ and washed with saturated aqueous sodium bicarbonate to give methyl S-4-(1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-a,a-dimethylbenzeneacetate. If the aforementioned intermediate precipitate were to be reacted with racemic j3-chlorodiisopinocamphenylborane, then a racemic mixture.of methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a~c-dimethylbenzeneacetate would be produced.
to D. S-l-)-4-fl-hvdroxv-4-(4-hydroxydiphenylmethyl 1 piperidinyl)butyll-a.a~c-dimethvlbenzeneacetic acid ~S ) terfenadine carboxvlatel Methyl S-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-cx,a-dimethylbenzeneacetate (1.2 gm) was combined with potassium hydroxide (0.4 gm) and ethanol (5 ml ) and the mixture was heated to ref lux for 7 hours . The ethanol was removed on a rotary evaporator and the residue was dissolved in water (2 ml). The aqueous solution was acidifed 2o with glacial acetic acid to provide a solid which was recrystallized from 1:1 methanol/ethyl acetate to give S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-oc,a-dimethylbenzeneacetic acid (S-terfenadine carboxylate) (mp=215-218°C).
WO 94/03170 PCT/US93/07~00 4.2. Example 2 Activities of the compounds of the invention at the histamine H1-receptor were assessed using the [3H]pyrilamine binding assay as described in Chang et al., J. Neurochem. 32: 1653-1663 (1979). Briefly, membranes from bovine cerebellum were incubated with [3H]pyrilamine and varying concentrations of test compound. The reactions were carried out in 50 mM sodium phosphate buffer (pH 7.5) at 25°
to C for 30 minutes. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped on the filters was determined and compared to control values to acertain the interaction of the test compound with the H1-receptor. Results were as follows:
Compound Percent Inhibition (at various concentrations) 10-9 M 10-' M 10-5 M
R,S-terfenadine 11.0 28.7 86.9 R-(+)-terfenadine 11.4 19.4 90.3 R-(+)-terfenadine 12.4 45.2 87.3 carboxylate S-(-)-terfenadine 3.2 24.4 92.8 3o S-(-)-terfenadine 8.1 54.1 gg,7 carboxylate r I
4.3. Example 3 Single ventricular myocytes were obtained from isolated cat hearts by conventional techniques. The rod-shaped single cells were maintained in a HEPES buffer and they were "patch clamped" using suction pipettes. A Patch-Clamp L/M-PEC 7 amplifier was used to record current tracings and the recording electrodes were filled with a to solution of potassium aspartate. Voltage clamp pulses and data acquisition were controlled by a Sperry PC/IT Computer running P Clamp software. A minimum of 4 cells were studied at each test concentration of the following drugs: racemic terfenadine, racemic terfenadine carboxylate, and quinidine (as a reference compound). Results were as follows:
Conc (~M) Hlock of the delayed rectifier potassium current ($) Terfenadine 0.01 12 ~ 9.3 0.10 39.5 ~ 9.8 1.00 92.6 (92.5; 92.8) Terfenadine 0.01 0 ~ 0 carboxylate 0.10 0 ~ 0 1.00 0 ~ 0 3o These results show that terfenadine carboxylate, surprisingly, is not liable to cause cardiac arrhythmia, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself .
WO 94/03170 2 1415 l 2 p~/uS93/07~00 4.4. Example 4 Oral Formulation - Capsules:
Formula Quantity per capsule in mg.
A B C
Active ingredient (S)Terfenadine 30.0 60.0 90.0 carboxylate Starch 1500 69.0 39.0 9.0 Magnesium Stearate BP 1.0 1.0 1.0 Compression Weight 100.0 100.0 100.0 The active ingredient, which can instead be (R)terfenadine carboxylate or racemic terfenadine carboxylate, is sieved and blended with the excipients. The mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
r I
WO 94/03170 21415 l 2 _ 33_ . p~'/US93/07260 4.5. Example 5 Oral Formulation - Tablets:
Formula Quantity per Tablet in mg.
A B C
Active ingredient, (R)Terfenadine 30.0 60.0 90.0 Carboxylate Lactose BP 123.5 93.5 63.5 Starch BP 30.0 30.0 30.0 Pregelatinized Maize 15.0 15.0 15.0 Starch BP
2o Magnesium stearate 1.5 1.5 1.5 Compression Weight 200.0 200.0 200.0 The active ingredient, which can instead be (S)terfenadine carboxylate or racemic terfenadine carboxylate, is sieved through a suitable sieve and blended with the lactose until a uniform blend is formed. Suitable volumes of water are added and the powders are granulated.
3o After drying, the granules are then screened and blended with the magnesium stearate. The resulting granules are then compressed into tablets of desired shape. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipient(s) or the compression weight .
Claims (48)
1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I:
wherein Z is COOH or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for use in an anti-histaminic treatment of a disorder or condition in a human patient wherein said treatment does not induce any significant cardiac arrhythmia.
wherein Z is COOH or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for use in an anti-histaminic treatment of a disorder or condition in a human patient wherein said treatment does not induce any significant cardiac arrhythmia.
2. A pharmaceutical composition, as claimed in claim 1, wherein the human patient is afflicted by or susceptible to: an allergic disorder; asthma; motion sickness;
vertigo; retinopathy;
or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
vertigo; retinopathy;
or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
3. A pharmaceutical composition, as claimed in claim 2, wherein the allergic disorder is allergic rhinitis, solar urticaria, or symptomatic dermographism.
4. A pharmaceutical composition, as claimed in any of the preceding claims, wherein a therapeutically effective amount of the compound of formula I is 1-500mg.
5. A pharmaceutical composition, as claimed in claim, 1, 2 or 3 wherein the therapeutically effective amount of the compound of formula I is 20-200mg.
6. A pharmaceutical composition, as claimed in claim 2, wherein the human patient is afflicted by or susceptible to asthma, or retinopathy or another small vessel disease associated with diabetes mellitus, and the therapeutically effective amount of the compound of formula I is 0.01-500mg.
7. A pharmaceutical composition as claimed in claim 2, wherein the human patient is afflicted by or susceptible to asthma, retinopathy or another small vessel disease associated with diabetes mellitus, and the therapeutically effective amount of the compound of formula I is 0.01-200mg.
8. A pharmaceutical composition, as claimed in any of the preceding claims, further comprising a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic.
9. A pharmaceutical composition, as claimed in claim 8, comprising from 20mg to 200mg of a compound of formula I and from 25mg to 600mg of the anti-inflammatory agent or analgesic.
10. A pharmaceutical composition, as claimed in any of the preceding claims, further comprising a therapeutically effective amount of a decongestant.
11. A pharmaceutical composition, as claimed in claim 10, comprising from 20mg to 200mg of a compound of formula I and from 5mg to 150mg of a decongestant.
12. A pharmaceutical composition, as claimed in any of the preceding claims, wherein the compound of formula I is in the form of a single optical isomer and the composition is substantially free of the other such isomer.
13. A pharmaceutical composition, as claimed in claim 12, wherein the compound of formula I is R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid, or a pharmaceutically acceptable salt thereof, and the composition is substantially free of the S-(-) stereoisomer.
14. A pharmaceutical composition, as claimed in claim 12, wherein the compound of formula I is S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alpha.-dimethylbenzeneacetic acid, or pharmaceutically acceptable salt thereof, and the composition is substantially free of the R-(+) stereoisomer.
15. A pharmaceutical composition, as claimed in claim 13, wherein the compound of formula I comprises 90% or more, by weight, R-(+) stereoisomer.
16. A pharmaceutical composition, as claimed in claim 14, wherein the compound of formula I comprises 90% or more, by weight, S-(-) stereoisomer.
17. A pharmaceutical composition, as claimed in any of the preceding claims, wherein the compound of formula I is terfenadine carboxylate.
18. A use of a therapeutically effective amount of a pharmaceutical composition as claimed in any of claims 1-17 for an anti-histaminic treatment which does not induce any significant cardiac arrhythmia in a human patient in need thereof.
19. A use as claimed in claim 18 wherein said human patient is afflicted by or susceptible to:
an allergic disorder: motion sickness; asthma; vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
an allergic disorder: motion sickness; asthma; vertigo; retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
20. A use, as claimed in claim 19, wherein the allergic disorder is allergic rhinitis, solar urticaria, or symptomatic dermographism.
21. Use of a therapeutically effective amount of a pharmaceutical composition, as claimed in any of claims 1-17, for the manufacture of a medicament for use in an antihistaminic treatment which does not induce any significant cardiac arrhythmia in a human patient.
22. A use, as claimed in claim 21, wherein the antihistaminic treatment is the treatment of a human afflicted by or susceptible to: an allergic disorder; asthma; motion sickness; vertigo;
retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
retinopathy, or another small vessel disease associated with diabetes mellitus; cough, cold, cold-like or flu symptoms; or the discomfort, pain, fever or general malaise associated therewith.
23. A use, as claimed in claim 21, wherein the allergic disorder is allergic rhinitis, solar urticaria, or symptomatic dermographism.
24. Use of a therapeutically effective amount of a composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for the preparation of a medicament for use in a treatment of allergic rhinitis in which the induction of cardiac arrhythmia is avoided, in a human patient whose hepatic function is not impaired.
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for the preparation of a medicament for use in a treatment of allergic rhinitis in which the induction of cardiac arrhythmia is avoided, in a human patient whose hepatic function is not impaired.
25. A use as claimed in claim 24, wherein the therapeutically effective amount of the compound of formula I is 1-500mg.
26. A use as claimed in claim 24 or 25, wherein the therapeutically effective amount of the compound of formula I is 20-200mg.
27. A use as claimed in any one of claims 24 to 26, wherein the composition further comprises a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic.
28. A use as claimed in claim 27, wherein the composition comprises from 20mg to 200mg of a compound of formula I and from 25mg to 600mg of the anti-inflammatory agent or analgesic.
29. A use as claimed in any one of claims 24 to 28, wherein the composition further comprises a therapeutically effective amount of a decongestant.
30. A use as claimed in claim 29, wherein the composition comprises from 20mg to 200mg of a compound of formula I and from 5mg to 150mg of a decongestant.
31. A use as claimed in any one of claims 24 to 30, wherein the compound of formula I is in the form of a single optical isomer and the composition is substantially free of the other such isomer.
32. A use as claimed in claim 31, wherein the compound of formula I comprises 90% or more, by weight, R-(+) stereoisomer.
33. A use as claimed in claim 31, wherein the compound of formula I comprises 90% or more, by weight, S-(-) stereoisomer.
34. A use as claimed in any one of claims 24 to 33, wherein the compound of formula I is terfenadine carboxylate.
35. A pharmaceutical composition in the form of an oral solid preparation comprising 60mg of a compound of formula I:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for use in a treatment of allergic rhinitis in which the induction of cardiac arrhythmia is avoided.
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, for use in a treatment of allergic rhinitis in which the induction of cardiac arrhythmia is avoided.
36. A pharmaceutical composition, as claimed in claim 35, further comprising a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic.
37. A pharmaceutical composition, as claimed in claim 36, comprising from 25mg to 600mg of the anti-inflammatory agent or analgesic.
38. A pharmaceutical composition as claimed in any one of claims 35 to 37, further comprising a therapeutically effective amount of a decongestant.
39. A pharmaceutical composition, as claimed in claim 38, comprising from 5mg to 150mg of a decongestant.
40. A pharmaceutical composition, as claimed in any one of claims 35 to 39, wherein the compound of formula I is in the form of a single optical isomer and the composition is substantially free of the other such isomer.
41. A pharmaceutical composition, as claimed in claim 40, wherein the compound of formula I comprises 90% or more, by weight, R-(+) stereoisomer.
42. A pharmaceutical composition, as claimed in claim 40, wherein the compound of formula I comprises 90% or more, by weight, S-(-) stereoisomer.
43. A pharmaceutical composition, as claimed in any of claims 35 to 42, wherein the compound of formula I is terfenadine carboxylate.
44. A pharmaceutical composition for use in treating allergic rhinitis in a human while avoiding the concomitant liability of cardiac arrhythmias associated with the administration of terfenadine, comprising a therapeutically effective amount of racemic terfenadine carboxylate, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier thereof.
45. A composition of claim 44 wherein the amount of racemic terfenadine carboxylate is from about 1mg to about 500mg.
46. A composition of claim 45 wherein the amount of racemic terfenadine carboxylate is about 20mg to about 200mg.
47. A pharmaceutical composition for use in treating allergic rhinitis in a human while avoiding the concomitant liability of cardiac arrhythmias associated with the administration of terfenadine, comprising (i) a therapeutically effective amount of racemic terfenadine carboxylate or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a nonsteroidal anti-inflammatory agent or non-narcotic analgesic.
48. A pharmaceutical composition for use in treating allergic rhinitis in a human while avoiding the concomitant liability of cardiac arrhythmias associated with the administration of terfenadine, comprising (i) a therapeutically effective amount of racemic terfenadine carboxylate or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a decongestant.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92415692A | 1992-08-03 | 1992-08-03 | |
| US92418292A | 1992-08-03 | 1992-08-03 | |
| US07/924,156 | 1992-08-03 | ||
| US07/924,182 | 1992-08-03 | ||
| PCT/US1993/007260 WO1994003170A1 (en) | 1992-08-03 | 1993-08-03 | Terfenadine metabolites and their optically pure isomers for treating allergic disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2141572A1 CA2141572A1 (en) | 1994-02-17 |
| CA2141572C true CA2141572C (en) | 2001-02-06 |
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|---|---|---|---|
| CA002141572A Expired - Lifetime CA2141572C (en) | 1992-08-03 | 1993-08-03 | Terfenadine metabolites and their optically pure isomers for treating allergic disorders |
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|---|---|
| US (1) | US5375693A (en) |
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| JP (6) | JP3041954B2 (en) |
| KR (1) | KR950702420A (en) |
| AT (3) | ATE322899T1 (en) |
| AU (3) | AU675240B2 (en) |
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| CA (1) | CA2141572C (en) |
| CZ (1) | CZ27495A3 (en) |
| DE (5) | DE9320925U1 (en) |
| DK (3) | DK0701443T4 (en) |
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| FI (1) | FI950467A (en) |
| GB (1) | GB2284351B (en) |
| GR (3) | GR960300024T1 (en) |
| HK (1) | HK1045806B (en) |
| HU (1) | HU226242B1 (en) |
| NO (1) | NO310644B1 (en) |
| PL (1) | PL174373B1 (en) |
| PT (2) | PT1214937E (en) |
| RO (1) | RO116043B1 (en) |
| RU (1) | RU2167657C2 (en) |
| SK (1) | SK12495A3 (en) |
| WO (1) | WO1994003170A1 (en) |
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-
1993
- 1993-08-03 HU HU9500313A patent/HU226242B1/en unknown
- 1993-08-03 DE DE9320925U patent/DE9320925U1/en not_active Expired - Lifetime
- 1993-08-03 GB GB9502183A patent/GB2284351B/en not_active Revoked
- 1993-08-03 WO PCT/US1993/007260 patent/WO1994003170A1/en active IP Right Grant
- 1993-08-03 AT AT97104837T patent/ATE322899T1/en active
- 1993-08-03 AT AT02006356T patent/ATE363283T1/en active
- 1993-08-03 ES ES97104837T patent/ES2257757T3/en not_active Expired - Lifetime
- 1993-08-03 DK DK93918584T patent/DK0701443T4/en active
- 1993-08-03 EP EP97104837A patent/EP0815860B1/en not_active Revoked
- 1993-08-03 BR BR9306841A patent/BR9306841A/en not_active Application Discontinuation
- 1993-08-03 AT AT93918584T patent/ATE162399T1/en active
- 1993-08-03 RO RO95-00160A patent/RO116043B1/en unknown
- 1993-08-03 AU AU47986/93A patent/AU675240B2/en not_active Expired
- 1993-08-03 DK DK02006356T patent/DK1214937T3/en active
- 1993-08-03 ES ES02006356T patent/ES2284740T3/en not_active Expired - Lifetime
- 1993-08-03 KR KR1019950700382A patent/KR950702420A/en not_active Application Discontinuation
- 1993-08-03 DE DE0701443T patent/DE701443T1/en active Pending
- 1993-08-03 CA CA002141572A patent/CA2141572C/en not_active Expired - Lifetime
- 1993-08-03 ES ES93918584T patent/ES2086270T5/en not_active Expired - Lifetime
- 1993-08-03 EP EP93918584A patent/EP0701443B2/en not_active Expired - Lifetime
- 1993-08-03 EP EP06114048A patent/EP1688142A1/en not_active Withdrawn
- 1993-08-03 JP JP6505499A patent/JP3041954B2/en not_active Expired - Lifetime
- 1993-08-03 PL PL93307339A patent/PL174373B1/en unknown
- 1993-08-03 RU RU95107881/14A patent/RU2167657C2/en active
- 1993-08-03 DK DK97104837T patent/DK0815860T3/en active
- 1993-08-03 SK SK124-95A patent/SK12495A3/en unknown
- 1993-08-03 DE DE69334008T patent/DE69334008T2/en not_active Expired - Lifetime
- 1993-08-03 DE DE69334145T patent/DE69334145T2/en not_active Expired - Lifetime
- 1993-08-03 PT PT02006356T patent/PT1214937E/en unknown
- 1993-08-03 PT PT97104837T patent/PT815860E/en unknown
- 1993-08-03 DE DE69316660T patent/DE69316660T3/en not_active Expired - Lifetime
- 1993-08-03 EP EP02006356A patent/EP1214937B1/en not_active Revoked
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1994
- 1994-02-02 US US08/191,061 patent/US5375693A/en not_active Expired - Lifetime
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1995
- 1995-02-01 NO NO19950374A patent/NO310644B1/en not_active IP Right Cessation
- 1995-02-02 FI FI950467A patent/FI950467A/en unknown
- 1995-02-03 CZ CZ95274A patent/CZ27495A3/en unknown
-
1996
- 1996-05-31 GR GR960300024T patent/GR960300024T1/en unknown
- 1996-11-19 AU AU71822/96A patent/AU7182296A/en not_active Abandoned
-
1998
- 1998-04-03 GR GR980400714T patent/GR3026530T3/en unknown
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1999
- 1999-02-25 AU AU18429/99A patent/AU1842999A/en not_active Abandoned
- 1999-10-13 JP JP11291230A patent/JP3037697B2/en not_active Expired - Lifetime
- 1999-10-13 JP JP29122399A patent/JP3288661B2/en not_active Expired - Lifetime
- 1999-10-13 JP JP29122899A patent/JP3288662B2/en not_active Expired - Lifetime
- 1999-10-13 JP JP11291216A patent/JP2000086512A/en active Pending
- 1999-10-13 JP JP29122099A patent/JP3288660B2/en not_active Expired - Lifetime
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2001
- 2001-02-14 GR GR20010400247T patent/GR3035417T3/en unknown
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2002
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