| PATENT ASSIGNEE'S COUNTRY | UK |
| UPDATE | 06.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 06.06.00 |
| PATENT TITLE |
Carbazolypiperines as GABA uptake inhibitors |
| PATENT ABSTRACT |
A compound of formula (I). ##STR1## The present invention relates to thereutically active carbazole derivatives, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating a central nervous system ailment related to the inhibition of GABA uptake via the GAT-4 subtype carrier. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 21.10.97 |
| PATENT CT FILE DATE | 01.05.96 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | 07.11.96 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | Hagen et al. "Synthesis of 6-substituted beta-carbolines that behave as . . . " CA 106:196295, 1987. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of formula I ##STR7## wherein R.sup.1 and R.sup.2 independently are hydrogen, halogen, hydroxy, nitro, --(CH.sub.2).sub.n --(C.dbd.O)--(CH.sub.2).sub.m CH.sub.3, --NR.sup.9 R.sup.10, --SONR.sup.11 R.sup.12, --COOR.sup.13, --CONR.sup.14 R.sup.15, C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, trifluoromethyl or trifluoromethoxy wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl, and wherein n and m independently are 0, 1, 2, 3 or 4; and R.sup.3 is C.sub.1-5 -alkylene optionally substituted with one or two C.sub.1-6 -alkyl; and R.sup.4 is hydrogen or C.sub.1-6 -alkyl; and R.sup.5 and R.sup.6 independently are hydrogen, halogen, hydroxy, nitro, --NR.sup.16 R.sup.17, --COOR.sup.18, C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, trifluoromethyl or trifluoromethoxy wherein R.sup.16, R.sup.17 and R.sup.18 independently are hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl; and Z is --(CH.sub.2).sub.p --(C.dbd.O)--(CH.sub.2).sub.q CH.sub.3, --COOR.sup.19, ##STR8## wherein p and q independently are 0, 1, 2, 3 or 4; and R.sup.19 is hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl; and X is --NH--, oxygen or sulphur; and R.sup.7 is hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, phenyl, C.sub.3-7 -cycloalkyl, --OR.sup.8 or --SR.sup.8 wherein R.sup.8 is hydrogen or C.sub.1-6 -alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 which is 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(4-methoxyphenyl)piperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-phenylpiperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methoxyphenyl)piperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-3-methyl-4-(4-methoxyphenyl) piperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(4-chlorophenyl)piperidin-4-ol, (S)-1-((3-(9H-Carbazol-9-yl)-2-methyl)-1-propyl)-4-phenylpiperidin-4-ol, (R)-1-((3-(9H-Carbazol-9-yl)-2-methyl)-1-propyl)-4-phenylpiperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-tolyl)piperidin-4-ol, 1-(3-(3-Ethyl-9H-carbazol-9-yl)-1-propyl)-4-phenylpiperidin-4-ol, 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2,4-dimethoxyphenyl)piperidin-4-ol, 1-(3-(3-Nitro-9H-carbazol-9-yl)-1-propyl)-4-phenylpiperidin-4-ol, 1-(3-(3-Acetyl-9H-carbazol-9-yl)-1-propyl)-4-phenylpiperidin-4-ol, or a pharmaceutically acceptable salt thereof. 3. A method of preparing a compound according to claim 1, CHARACTERIZED IN a) reacting a compound of formula II ##STR9## wherein R.sup.1, R.sup.2 and Z are as defined above with a compound of formula III ##STR10## wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above and X is a leaving group; or b) reacting a compound of formula IV ##STR11## wherein R.sup.1, R.sup.2, R.sup.3, Z and X are as defined above with a compound of formula V ##STR12## wherein R.sup.4, R.sup.5 and R.sup.6 are as defined above; or c) reacting a compound of formula VI ##STR13## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Z are as defined above with a compound of formula VII ##STR14## wherein R.sup.5, R.sup.6 and Y are as defined above. 4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent. 5. A pharmaceutical composition suitable for treating a central nervous system ailment related to the inhibition of GABA uptake via the GAT-4 subtype carrier comprising an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent. 6. The pharmaceutical composition according to claim 4 or 5 comprising between 0.5 mg and 1000 mg of the compound according to claim 1 per unit dose. 7. A method of treating a central nervous system ailment related to the inhibition of GABA uptake via the GAT-4 subtype carrier in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1. 8. A method of treating a central nervous system ailment related to the inhibition of GABA uptake via the GAT-4 subtype carrier in a subject in need of such treatment comprising administering to said subject a pharmaceutical composition according to claim 5. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to novel substituted carbazole derivatives, to methods for their preparation, to pharmaceutical compositions containing them and to their use in the clinical treatment of abnormal functioning of the .gamma.-aminobutyric acid neurotransmission system. BACKGROUND OF THE INVENTION .gamma.-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS) (for review see Enna, 1983, Biochem. Pharmacol., 30, 907-15; Enna and Mohler, 1987, Raven Press, New York, 265-79; Lloyd and Morselli, 1987, Medical Biology, 65, (2-3), 159-65; Krogsgaard-Larsen, 1988, Medical Res. Reviews, 8, 1, 27-56; Schwartz, 1988, Biochem. Pharmacol. 27, 3369-76). GABA has been estimated to be present in 60-70% of all synapses within the CNS (Fahn, 1976, Raven Press, New York, 169-83). A reduction in GABA neurotransmission has been implicated in the etiology of a variety of neurological disorders including epilepsy Krogsgaard-Larsen et al., 1988, Medical Res. Reviews, 8, 1, 27-56; Loscher, 1985, Epilepsy and GABA Receptor Agonists: Basic and Therapeutic Research. L. E. R. S. Monograph. Vol. 3, G. Bartholoni, L. Bossi, K. G. Lloyd, P. L. Morselli (Eds.), Raven Press, New York, 109-18); Enna, 1981, Biochem. Pharmacol., 30, 907-14 and Neuropharmacology of Central Nervous System GABA and Behavioral Disorders, G. Palmer (Ed.). Academic Press, New York 1981, 507-25; Rebak et al., 1979, Science, 205, 211-13; Ross and Craig, 1981, J.Neurochem. 36, 1006). The GABA uptake system has traditionally been classified as either neuronal or glial GABA uptake carriers, on the basis of pharmacological selectivity for specific GABA uptake inhibitors (for review see: Krogsgaard-Larsen, 1988, Medical Res. Reviews, 8, 1, 27-56; Schousboe et al., 1991, GABA Mechanisms in Epilepsy, G. Tunnicliff, B. U. Raess (Eds.) Wiley-Liss, New York, 165-87). Several investigators (Gaustella et al., 1990, Science, 249, 1303-1306; Clark et al., 1992, Neuron 9, 337-348; Borden et al., 1992, J.Biol. Chem. 267, 21098-21104; Liu et al., 1993, J.Biol.Chem. 268, 2106-2112) have recently cloned, and sequenced, four subtypes of the rat and mouse GABA uptake carrier, whose pharmacology cannot be totally explained by the traditional neuronal and glial GABA uptake carriers. Gaustella et al., (1990, Science, 249, 1303-1306) and Nelson et al. (1990, FEBS Lett. 269, 181-184) reported on the cloning of GAT-1, which appears to be a neuronal GABA uptake carrier due to its high sensitivity to nipecotic acid (Gaustella et al., 1990, Science, 249, 1303-1306), and lipophilic nipecotic acid based compounds and distribution within the central nervous system (CNS) (Radian et al., 1990, J.Neurosci. 10, 1319-1330; Mabjeesh et al., 1992, J.Biol.Chem. 267, 2563-68). GAT-1 is not present outside the CNS (Nelson et al., 1990, FEBS Lett. 269, 181-184; Liu et al., 1992, FEBS. Lett. 305, 110-114). GAT-2 was initially cloned by Lopez-Corruera (1992, J.Biol.Chem. 267, 17491-17493) and is present in the CNS, kidney and liver, and has a pharmacology resembling the glial GABA uptake carrier characterized in primary cell culture. GAT-3 which was initially cloned by Liu et al., (1993, J.Biol.Chem. 267, 2106-2112), appears to be under developmental control, as GAT-3 mRNA is highly expressed in neonatal brain, but weakly expressed in adult brain. GAT-3 is also present in kidney and liver. GAT-4 (Liu et al., 1993, J.Biol.Chem. 268, 2106-2112; also termed GAT-B by Clark et al., (1992, Neuron 9, 337-348) and GAT-3 by Borden et al., (1992, J.Biol.Chem. 267, 21098-21104)), cDNA hybridized only in the CNS, and the mRNA for GAT-4 is highly enriched in the brain stem, but not present in the cerebellum or cerebral cortex. While GAT-4 has been shown to transport .beta.-alanine, it appears to have neuronal localization (Clarke et al., 1992, Neuron 9, 337-348). The distribution of GAT-1, closely resembles the previously reported distribution of .sup.3 H-Tiagabine receptor autoradiography (Suzdak et al., 1994, Brain Research, 647(2), 231-41), as would be expected due to the high affinity of lipophilic nipecotic acid based GABA uptake inhibitors for the GAT-1 transporter (Clarke et al., 1992, Neuron 9, 337-348). While in situ hybridization has revealed the presence of GAT-4 mRNA in the CNS, there has been no direct demonstration of a discretely localized neuronal GABA uptake carrier, which is not sensitive to lipophilic nipecotic acid based GABA uptake inhibitors. The inhibition of GABA uptake results in enhanced availability of this inhibitory neurotransmitter in the synaptic cleft and thus to increased GABA'ergic activity. Increased GABA'ergic activity can be useful in the treatment, for example of anxiety, pain and epilepsy, as well as muscular and movement disorders (see, for example, P. Krogsgaard-Larsen et al., Progress in Medicinal Chemistry, 1985, 22, 68-112). A well-known and potent inhibitor of GABA uptake from the synaptic cleft into presynaptic nerve terminals and glial cells is, for example, 3-piperidinecarboxylic acid (nipecotic acid). However, being a relatively polar compound and therefore unable to cross the blood-brain barrier, 3-piperidinecarboxylic acid itself has found no practical utility as a drug. In U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as inhibitors of GABA uptake. EP 221572 claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake. According to Yunger, L. M. et al., J.Pharm.Exp.Ther. 1984, 228, 109, N-(4,4-diphenyl-3-buten-1-yl)nipecotic acid (designated SK&F 89976A), N-(4,4-diphenyl-3-buten-1-yl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-3-buten-1-yl)-homo-.beta.-proline (designated SK&F 100561) and N-(4-phenyl-4-(2-thienyl)-3-buten-1-yl)nipecotic acid (designated SK&F 100604J) are orally active inhibitors of GABA uptake. These data are summarized in Krogsgaard-Larsen, P. et al., Epilepsy Res. 1987, 1, 77-93. The above cited references all disclose compounds inhibiting the uptake of GABA via the GAT-1 subtype carrier. U.S. Pat. No. 4,539,407 discloses .beta.-carboline-3-carboxylate ester derivatives having anticonvulsant activity. The present invention is directed to identifying novel compounds with affinity for the neuronal subtype of the GABA uptake carrier whose pharmacology resembles that of GAT-4. DESCRIPTION OF THE INVENTION The present invention relates to novel substituted carbazole derivatives of formula I ##STR2## wherein R.sup.1 and R.sup.2 independently are hydrogen, halogen, hydroxy, nitro, --(CH.sub.2).sub.n --(C.dbd.O)--(CH.sub.2).sub.m CH.sub.3, --NR.sup.9 R.sup.10, --SONR.sup.11 R.sup.12, --COOR.sup.13, --CONR.sup.14 R.sup.15, C.sub.1-6 -lalkyl, C.sub.1-6 -alkoxy, trifluoromethyl or trifluoromethoxy wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently are hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl, and wherein n and m independently are 0, 1, 2, 3 or 4; and R.sup.3 is C.sub.1-5 -alkylene optionally substituted with one or two C.sub.1-6 -alkyl; and R.sup.4 is hydrogen or C.sub.1-6 -alkyl; and R.sup.5 and R.sup.6 independently are hydrogen, halogen, hydroxy, nitro, --NR.sup.16 R.sup.17, --COOR.sup.18, C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, trifluoromethyl or trifluoromethoxy wherein R.sup.16, R.sup.17 and R.sup.18 independently are hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl; and Z is --(CH.sub.2).sub.p --(C.dbd.O)--(CH.sub.2).sub.q CH.sub.3, --COOR.sup.19, ##STR3## wherein p and q independently are 0, 1, 2, 3 or 4; and R.sup.19 is hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl or C.sub.2-6 -alkynyl; and X is --NH--, oxygen or sulphur; and R.sup.7 is hydrogen, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, phenyl, C.sub.3-7 -cycloalkyl, --OR.sup.8 or --SR.sup.8 wherein R.sup.8 is hydrogen or C.sub.1-6 -alkyl; or a pharmaceutically acceptable salt thereof. The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts. The compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts. Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, phthalate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference. Alkyl, alkenyl and alkynyl are intended to mean straight or branched alkyl, alkenyl or alkynyl chains. The compounds of formula I have a greater lipophilicity--and thus a greater availability to the brain--as well as a far higher affinity to the GABA uptake sites than the parent compounds without the carbazole moiety. It has been demonstrated that the novel compounds of formula I which selectively inhibit the uptake of GABA, via the GAT-4 subtype carrier, from the synaptic cleft possess useful pharmacological properties in the central nervous system, in that they cause a selective enhancement of GABA'ergic activity. Compounds of formula I may be used to treat for example, pain, anxiety, extrapyrimidinal dyskinesia, epilepsy and certain muscular and movement disorders. They are also useful as sedatives, hypnotics and antidepressants. The invention also relates to a method of preparing the above mentioned compounds of formula I. These methods comprise: Method A: ##STR4## A compound of formula II wherein R.sup.1, R.sup.2 and Z are as defined above, may be reacted with an azaheterocyclic compound of formula liI wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above and X is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate. This alkylation reaction may be carried out in a suitable solvent such as acetone, dibutylether, 2-butanone, tetrahydrofuran, methylisobutylketone, methylisopropylketone, toluene, benzene or DMF in the presence of a base e.g. potassium carbonate, sodium hydride or potassium tert.-butoxide at a temperature up to reflux for the solvent used for e.g. 1 to 200 h. Method B: ##STR5## A compound of formula IV wherein R.sup.1, R.sup.2, R.sup.3, Z and X are as defined above may be reacted with an azaheterocyclic compound of formula V wherein R.sup.4, R.sup.5 and R.sup.6 are as defined above. This alkylation may be carried out in a suitable solvent as defined above in the presence of a base as defined above and a catalyst e.g. an alkali metal iodide at a temperature up to reflux for the solvent used for e.g. 1 to 200 h. Method C: ##STR6## An azaheterocyclic ketone of formula VI wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Z are as defined above may be reacted with a Grignard reagent of formula VII wherein R.sup.5 and R.sup.6 are as defined above and Y is chloro, bromo or iodo. This reaction may be carried out in a suitable solvent such as diethylether, THF, toluene or benzene at a suitable temperature up to reflux temperature for the solvent used for e.g. 1 to 5 h. Pharmacological Methods .sup.3 H-GABA uptake was measured by a modification of the method of Fjalland et al., (1978). A crude membrane preparation was prepared from selected brain areas by homogenization in 20 ml of ice-cold 0.32 M sucrose with a hand driven teflon/glass Potter-Elvehjem homogenizer. The homogenate was centrifuged at 4.degree. C. for 10 min. at 1.000.times.g, and the pellet was discarded. The supernatant was recentrifuged at 4.degree. C. for 20 min. at 20.000.times.g. The pellet was then homogenized in 50 volumes 0.32 M sucrose. To 300 .mu.l uptake-buffer (200 nM NaCl, 15.3 mM KCl, 6.67 mM MgSO.sub.4, 3.83 mM CaCl.sub.2, 16.67 mM glucose, 66.67 mM Tris, pH 7.5 at 30.degree. C.) was added 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridineca rboxylic acid (NNC 05-0711) (1 mM final concentration), 100 .mu.l test substance and 50 .mu.l tissue suspension. The samples were mixed and incubated at 30.degree. C. for 8 min. Then .sup.3 H-GABA (0.9 nM final concentration) and unlabelled GABA (25 nM final concentration) was added, and the incubation was continued for an additional 8 min. The reaction was terminated by rapid filtration through Whatman GF/F glass fiber filters under vacuum. The filters were then washed twice in 10 ml of ice-cold isotonic saline, and the tritium trapped on the filters was quantified by conventional scintillation spectroscopy. Non-GABA uptake carrier mediated uptake of .sup.3 H-GABA was determined in the presence of 500 .mu.l nipecotic acid. Values for non-GABA uptake carrier mediated uptake of .sup.3 H-GABA for some representative compounds are recorded in Table I. TABLE 1 ______________________________________ Non-GABA uptake carrier mediated uptake of .sup.3 H-GABA. Compound No. IC.sub.50 (nM) in vitro ______________________________________ 2 473 4 1128 5 1615 6 1632 7 592 11 1478 13 7858 14 3159 16 1703 18 2882 20 3857 23 3095 27 1729 28 3405 29 3910 ______________________________________ For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent. with a pharmaceutical carrier or diluent. The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. This invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contains a pharmaceutical carrier or diluent. The compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions. The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. Generally, the compounds of this invention are dispended in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage. The dosage of the compounds according to this invention is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug. A typical tablet, which may be prepared by conventional tabletting techniques contains: ______________________________________ Core: Active compound (as free compound 100 mg or salt thereof) Colloidal silicon dioxide (Aerosil,TM) 1.5 mg Cellulose, microcryst. (Avicel,TM) 70 mg Modified cellulose gum (Ac-Di-Sol,TM) 7.5 mg Magnesium stearate Coating: HPMC approx. 9 mg *Mywacett,TM 9-40 T approx. 0.9 mg ______________________________________ *Acylated monoglyceride used as plasticizer for film coating. The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred. |
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