MXPA00012238A - Compositions and methods for treatment of cough - Google Patents
Compositions and methods for treatment of coughInfo
- Publication number
- MXPA00012238A MXPA00012238A MXPA/A/2000/012238A MXPA00012238A MXPA00012238A MX PA00012238 A MXPA00012238 A MX PA00012238A MX PA00012238 A MXPA00012238 A MX PA00012238A MX PA00012238 A MXPA00012238 A MX PA00012238A
- Authority
- MX
- Mexico
- Prior art keywords
- cough
- compound
- warm
- methyl
- effective amount
- Prior art date
Links
- 206010011224 Cough Diseases 0.000 title claims description 80
- 239000000203 mixture Substances 0.000 title claims description 12
- 241001465754 Metazoa Species 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 11
- -1 hydroxy, hydroxymethyl Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000000460 chlorine Chemical group 0.000 claims description 5
- 238000007792 addition Methods 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 230000000954 anitussive Effects 0.000 abstract description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 102
- 235000015165 citric acid Nutrition 0.000 description 34
- 241000700198 Cavia Species 0.000 description 31
- 239000000443 aerosol Substances 0.000 description 30
- 239000003981 vehicle Substances 0.000 description 23
- NNJVILVZKWQKPM-UHFFFAOYSA-N Xylocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 19
- 229960004194 lidocaine Drugs 0.000 description 16
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002829 reduced Effects 0.000 description 6
- WFKXSWWTOZBDME-UHFFFAOYSA-N [2-(2,6-dimethylanilino)-2-oxoethyl]-trimethylazanium;chloride Chemical compound [Cl-].CC1=CC=CC(C)=C1NC(=O)C[N+](C)(C)C WFKXSWWTOZBDME-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VONWPEXRCLHKRJ-UHFFFAOYSA-N 2-chloro-N-phenylacetamide Chemical compound ClCC(=O)NC1=CC=CC=C1 VONWPEXRCLHKRJ-UHFFFAOYSA-N 0.000 description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N Codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LZDQPXAJNKGROO-UHFFFAOYSA-N 2-(dimethylamino)-N-phenylacetamide Chemical compound CN(C)CC(=O)NC1=CC=CC=C1 LZDQPXAJNKGROO-UHFFFAOYSA-N 0.000 description 3
- 240000000218 Cannabis sativa Species 0.000 description 3
- YKPUWZUDDOIDPM-SOFGYWHQSA-N Capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- LLPPOMUAOGMYQI-UHFFFAOYSA-N [2-(2,6-dimethylanilino)-2-oxoethyl]-triethylazanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C LLPPOMUAOGMYQI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 229960002504 capsaicin Drugs 0.000 description 3
- 229930003833 capsaicin Natural products 0.000 description 3
- 235000017663 capsaicin Nutrition 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000000977 initiatory Effects 0.000 description 3
- 239000006199 nebulizer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 206010041232 Sneezing Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 230000002051 biphasic Effects 0.000 description 2
- 230000003435 bronchoconstrictive Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 244000144993 groups of animals Species 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000002663 nebulization Methods 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
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- 230000001225 therapeutic Effects 0.000 description 2
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 description 1
- FPQQSNUTBWFFLB-UHFFFAOYSA-N 2-chloro-N-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CCl FPQQSNUTBWFFLB-UHFFFAOYSA-N 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
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- 101700067048 CDC13 Proteins 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 229940046978 Chlorpheniramine Maleate Drugs 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N Dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 229960000525 Diphenhydramine Hydrochloride Drugs 0.000 description 1
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 description 1
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
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- 230000036210 malignancy Effects 0.000 description 1
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N methoxyethyl Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000001613 neoplastic Effects 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 1
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- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
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- 231100000486 side effect Toxicity 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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Abstract
Pharmaceutical compositions possessing anti-tussive activity, and a method of administering the same to warm-blooded animals, including humans.
Description
COMPOSITIONS AND METHODS FOR THE TREATMENT OF T.A TOS
BACKGROUND OF THE INVENTION
Conventional cough preparations containing an effective antitussive agent, such as codeine, have been used for a long time for the symptomatic relief of coughs. However, codeine has several side effects which are undesirable.
Accordingly, the present invention relates to compositions of the art useful as pharmaceutical compositions having antitussive activity, and a method for treating warm-blooded animals affected by coughs or bronchoconstriction by administering an effective amount of the pharmaceutical compositions of the invention.
BRIEF DESCRIPTION OF THE INVENTION
The problems of the prior art have been overcome by the present invention, which provides pharmaceutical compositions having antitussive activity, and a method for administering the same to warm-blooded animals;, including humans. The active antitussive agent according to the present invention is a quaternary ammonium compound
Ref. 0125722 represented by the following formula (I) and its pharmaceutically acceptable salts:
R le Y-N- £ An (I) R.
wherein Y and E are independently selected from -CH2-R2 or;
wherein R, Ri and R2 are independently selected from hydrogen, C? -C8 alkyl, C3-C8 alkoxyalkyl and C7-C? aralkyl; and wherein R3, R4 and R5 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, tri fluoromethyl, C2-C alkanoyloxy? , C C-C6 alkyl, C?-C6 alkoxy, C2-C7 alkoxycarbonyl, Cx-Ce thioalkyl, aryl and N (R6, R7), wherein R6 and R7 are independently selected from hydrogen, acetyl, methanesulfonyl and C alquilo alkyl; C6, An "is the acid addition salt of a pharmaceutically acceptable acid or the anion of a pharmaceutically acceptable salt, and enatiomeric, diastomeric and geometric isomers isolated therefrom, and mixtures thereof, with the proviso that Y and E do not they can be both -CH2-R2 in the same compound.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a flow diagram showing the schematic of the experimental apparatus used for the determination of cough;
Figures 2A and 2B are enlarged scale records of pressure changes derived from the differential pressure transducer during the characteristic responses presented by a guinea pig during exposure to a citric acid aerosol.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms have the following meaning:
The term "alkyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having a point of attachment. Examples include n-propyl (a C3 alkyl), isopropyl (also a C3 alkyl) and t-butyl (a C4 alkyl).
jjj? ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ? ^^ g ^^^ The term "alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group. For example, methoxyethyl (CH3OCH2CH2-) and ethoxymethyl (CH3CH2OCH2-) are cimbos C3 alkoxyalkyl groups.
The term "alkylene" refers to a divalent radicayl, which is a branched or unbranched hydrocarbon fragment that contains the specified number of carbon atoms and has two points of attachment. An example is propylene (-CH2CH2CH2-), a C3 alkylene.
The term "aralkyl" refers to an alkylene group, wherein one of the attachment points is to an aryl group. An example is the benzyl group (C6H5CH2-), a C7 aralkyl group.
The term "alkanoyloxy" refers to an ester substituent, wherein ether oxygen is the point of attachment to the molecule. Examples include propanoyloxy (CH3CH2C (O) 0-), a C3 alkanoyloxy and ethanoyloxy (CH3C (0) 0-), a C2 alkanoyloxy.
The term "alkoxy" refers to an O atom substituted by an alkyl group, for example methoxy (-OCH3), an alkoxy Ci.
The term "alkoxycarbonyl" refers to an ester substituent, wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl (CH3CH2OC = 0), a C3 alkoxycarbonyl, and methoxycarbonyl (CH3OC (0) -), a C2 alkoxycarbonyl.
The term "aryl" refers to aromatic groups, which have at least one ring having a pi conjugated electronic system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted . Carbocyclic aryl groups are generally preferred in the compounds of the present invention, wherein the phenyl and naphthyl groups are preferred carbocyclic aryl groups.
The term "cycloalkyl" refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic or tricyclic formed entirely from carbon atoms. An example is the cyclopentenyl group (C5H7-), which is an unsaturated cycloalkyl group of 5 carbons.
The term "carbocyclic" refers to a ring, which may be either an aryl ring or a cycloalkyl ring, both as defined above.
* * t The term "thioalkyl" refers to a sulfur atom substituted by an alkyl group, for example, thiomethyl (CH3S-), a thioalkyl Ci.
The origin of the cough that is treated by the present invention is not particularly limited, and can include virtually any respiratory disorder, such as chronic obstructive pulmonary disease, tuberculosis, bronchitis, respiratory malignancies, asthma, allergy, pulmonary fibrosis, inflammation of the respiratory tract , emphysema, pneumonia, lung cancer, presence of foreign bodies, sore throat, common cold, flu, respiratory tract infection, bronchoconstriction, inhalation of irritating substances, smoker's cough, chronic nonproductive cough, neoplastic cough, cough due to therapy with the angiotensin-converting enzyme (ACE) inhibitor, etc.
The preferred compound of the present invention is a compound of the formula (I), wherein R and Rx are methyl and Y and E are each • This compound, wherein R3, R4 and R5 are each hydrogen ("Compound 1" ), was synthesized as described in Belgian Patent No. 614,154, which is derived from Swedish Patent 1779/61, the descriptions of which are incorporated herein by reference. A conventional route of synthesis comprises three steps and can be described (as in
^^^^^^^^^ * patent mentioned above; see also T. Takahashi, J. Okada, M. Hori, A. Kato, K. Kanematsu, and Y. Yamamoto, < J. Pharm. Soc. Japan 76, 1180-6 (1956)) as follows:
i) Chloroacetanilide
To a cooled solution of aniline (37.2 g, 0.40 mol) and potassium carbonate (66.4 g, 0.48 mol) in chloroform (200 ml) was added dropwise via a cannula a solution of chloroacetyl chloride (49.6 g, 0.44 mol) in chloroform (100 mL) and the reaction mixture was heated to 55 ° C for 90 minutes. Then water (300 ml) was added to the cooled reaction mixture, the organic layer was collected and the aqueous layer was extracted twice more with chloroform (2 x 100 ml). The combined organic layers were dried over sodium sulfate and evaporation of the solvent in vacuo gave the product without purification. The product was purified via extraction through a Soxhlet apparatus with diethyl ether to give 22.0 g of the desired chloroacetanilide, m.p. 133-135 ° C, 200 MHz) d: 8.3 (br.s, NH, 1H), 7.6-7.1 (m, Ar, 5H), 4.1 (s, CH2, 2H).
ii) Dimethylaminoacetanilide
A mixture of chloroacetanilide (10.0 g, 59 mmol) in dimethylamine, 40% by weight in water (100 ml) was refluxed
£ • • • • for 4 hours The cooled reaction mixture was partitioned between dichloromethane (100 ml) and aqueous 1M NaOH solution (100 ml) The aqueous layer was extracted twice with dichloromethane (2 x 100 ml). mi), the combined organic layers were concentrated in vacuo to a volume of about 100 ml and washed with water (2 x 100 ml) to remove the remaining dimethylamine.The organic layer was collected, dried over sodium sulfate and the solvent was added. evaporated in vacuo to give 10.2 g (97% yield) of the pure dimethylaminoacetanilide. ^? - NMR (CDC13, 200 MHz) d: 9.1 (br.s, NH, 1H), 7.6-7.0 (m, Ar, 5H ), 3.1 (s, CH2, 2H), 2.4 (s, CH3, 6H).
iii) N, N-bis- (phenylcarbamoylmethyl) dimethylammonium chloride
A mixture of chloroacetanilide (10.1 g, 59.5 mmol), dimethylaminoacetanilide (10.7 g, 60 mmol) and potassium iodide, 99 +% (0.1 g, 0.6 mmol) in dry xylene (30 mL) was refluxed for 1 hour and then it was allowed to stand overnight at room temperature. The solvent was decanted and the remaining gummy solid was triturated in diethyl ether to obtain a whitish powder. The resulting solid was collected and recrystallized from a mixture of ethanol and diethyl ether to give 9.3 g (45% yield) of the desired ammonium salt, m.p. 177-178 ° C, ^ -RMN (DMSO-d6, 300 MHz) d: 11.3 (s, NH, 2H), 7.7-7.1 (m, Ar, 10 H), 4.8 (s, CH2, 4H), 3.6 (s, CH3, 6H), I3C-NMR (DMSO-d6, 75 MHz) d: 162.1 (+), 137.8 (+), 128.8 (-), 124.3 (-), 119.7 (-), 63.0 (+) , 52.8 (-), LRMS (EI) m / z = 297 (0.95%, M + -CH3), elemental analysis calculated for C? 8H22N402Cl (347.84): C, 62.15; H, 6.37; N, 12.08; found: C, 61.75; H, 6.50; N, 12.04.
Reference: A.P. Truant and J.R. Dahlbom Belguim Patent No. 614154, Feb. 20, 1961.
Synthetic scheme:
s Another preferred compound of the present invention, N- (2,6-dimethylphenylcarbamoylmethyl) trimethylammonium chloride (Compound 2) is a compound of Formula (I), wherein R and
Ri - they are methyl; E is -CH2-R2, where R2 is hydrogen; Y is -CHj-C-NH-ii wherein R3 is methyl at the C2 position of the phenyl ring, R5 is methyl at the C6 position of the phenyl ring, R4 is hydrogen and An "is the chloride anion. 2 can be synthesized according to the reaction scheme shown below (see, for example, T. Takahashi, J. Okada, M. Hori, A. Kato, K. Kanematsu and Y. Yamamoto, J. Pharm. Seo. , 7 £, 1180-6 (1956), incorporated herein by reference) from commercially available starting materials and reagents (e.g., Aldrich Chemical Company, Milwaukee, I and Sigma Chemical Company, St. Louis, MO):
HN (CHa) j,
Corrugated 2 Another preferred compound of the present invention, N- (2,6-dimethylphenylcarbamoylmethyl) triethylammonium chloride (Compound 3) is a compound of Formula I, wherein R and Ri are 'ethyl; E is -CH2-R2, where R2 is methyl; Y is where R3 is methyl at the C2 position of the phenyl ring, R5 is methyl at the C6 position of the phenyl ring, R4 is hydrogen and An "is the chloride anion Compound 3 can be synthesized by methods analogous to that described above for Compound 2. Alternatively, Compound 3 can be easily synthesized from a lidocaine base (commercially available from Sigma Chemical Company, St. Louis, MO) in a simple reaction as shown below (GK Ang et al., Anesthesiology, £ 3_, 1293-1301 (1995)):
fifteen
Lidocane Base Compound 3
Other compounds included by Formula I can be synthesized analogously and are within the skill in the art.
^^^ ¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ _ ^ _ ^ _ ^^ _ ^ _ ^ _ ^ _ ^^ _ ^^ _ ^ _ ^ í ^^^ _ ^ __ ^^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^^ _ ^ _ ^ ^^^ _- ^^ ggi ^ & £ _ß Acceptable pharmaceutically acceptable salts include acid addition salts of acids, such as hydrochloric acid, hydrobromic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, ethanesulfonic acid, acid fumaric, gluconic acid, glutamic acid, isethionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, succinic acid, para-toluenesulfonic acid, phosphoric acid, sulfuric acid, acid citric acid, tartaric acid, lactic acid and acetic acid, although the preferred acid addition salt is the hydrochloride salt.
The magnitude of the therapeutic and prophylactic dose of the compounds of the present invention in the treatment and / or prevention of cough will depend on the severity and nature of the condition being treated and the route of administration. Dosage and frequency of dosing will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range for the compounds of the present invention for the treatment and / or prevention of cough is from about 0.1 to about 800 mg in single or repeated doses.
Any suitable route of administration can be employed to provide an effective dosage of the compounds of the present invention, although administration by inhalation is preferred in a more "referable" manner in the form of an aerosol. Suitable forms of administration include, but are not limited to, inhalation (delivered by, for example, metered dose inhaler, jet nebulizer, ultrasonic nebulizer, dry powder inhaler, etc.), nasal sprays, nebulization, oral administration, such as via tablets, capsules, pills, syrups, sprays, suspensions, elixirs, gargle, and other liquid preparations, aerosol foams, parental administration, and sublingual administration.
The compounds of the present invention can include pharmaceutically acceptable carriers and other conventional additives, including water-based carriers, cosolvents, such as ethyl alcohol, propylene glycol and glycerin, fillers, lubricants, wetting agents, flavoring agents (seiborizers), coloring agents, emulsifying agents, suspension or dispersion agents, suspending agents, etc. For the aerosol delivery of the compounds of the present invention, pharmaceutically acceptable diluents, carriers, and / or propellants may be included in the formulations for use in suitable devices. These are prepared by methods well known to those skilled in the art (see, for example, Medication Teaching Manual, 5th Ed., Bethesda, MD, American Society of Hospital Pharmacists, 1991).
• The compositions of the present invention may optionally include other known therapeutic agents, including decongestants, such as pseudoephedrine HCl, phenylephrine HCl and ephedrine HCl, non-steroidal anti-inflammatory drugs, such as acetaminophen, aspirin, phenacetin, ibuprofen and ketoprofen, expectorants, such as glyceryl guayacolate, herpene hydrate and ammonium chloride, antihistamines, such as chlorpheniramine maleate, doxylamine succinate, brompheniramine maleate and diphenhydramine hydrochloride, and anesthetic compounds, such as phenol.
The following examples are presented by way of illustration, and not by way of limitation:
EXAMPLE 1
Guinea pigs of Dunkin-Hartley male albino breed (300-400 g of weight) were provided by Harlan UK Ltd., Bicester, Oxon, UK.
The method used was modified from that described by Adcock J.J., Schneider C. and Smith T., "Effects of Morphine and a
• i ^ s fei Novel Opioid Pentapeptide B 443C, on Cough, Nociception and Ventilation in the Unanaesthetized Guinea-pig ", Br. J. Pharmacol., 93, 93-100 (1988) The individual conscious guinea pigs were placed free in a sealed exposition perspex construction chamber (volume of 3,000 cm3) and allowed to acclimate prior to aerosol administration The schematic of the experimental apparatus used is shown in Figure 1.
0 The cylinder air was introduced into the exposure chamber at a flow rate of 1 liter / minute, maintained by a needle valve and verified by a rotameter. From the rotameter, the air stops through the suction cup of an ultrasonic nebulizer (DeVilbis UltraNeb 2000), which was used to generate drug aerosols or citric acid at 0.15 ml / minute. A Fleisch pneumotachograph, connected to a differential pressure transducer (Grass model PT5), joined the effluent of the exposure chamber and gave a measure of the air flow of the chamber. The differential pressure transducer was 0 connected to a Grass polygraph from which a printout record was produced. The polygraph output was directed to a computerized data acquisition system (Poh-Ne-Mah) for real-time data recording. A necktie-type microphone was placed in the exposure chamber and connected via a preamplifier to a speaker output to
Provide the observer with an audio monitor of answers.
. Cough responses were induced by exposure to a citric acid aerosol (1M) for 10 minutes. The animals were continuously monitored by an experienced observer, and the number of coughs was counted during a period of 15 minutes from the start of the citric acid aerosol administration. Three characteristic responses were produced by exposure to citric acid: cough, sneeze and chill of "wet dog".
The three types of response were mainly differentiated by sound and visual observation. "Confirmation of multiple cough numbers was determined by reference to the change in flow velocity presented by the Poh-Ne-Mah system monitor. which show the characteristic pressure changes of the different response to irritant substances are shown in Figures 2A and 2B.The data recorded for the individual guinea pigs in the Poh-Ne-Mah system were stored on an optical disk. it was marked on the paper trace of the Grass polygraph, and from these record numbers, the frequency and time of the attack of the coughs were determined.The cough response was defined by a characteristic sound and coughing behavior, associated with a change of marked biphasic pressure The biphasic pressure changes associated with a sneeze were not as great as those associated with a cough, the secondary increase in pressure is also much lower than during a cough (Figure 2B). The sound of a sneeze differs from that of a cough, and the sneezing was associated with the activity of rubbing the nose. The third response, a "wet dog" chill, produced a pressure increase only (Figure 2A) and lacked the definitive sound of a cough or sneeze.
The amounts of drugs were weighed and dissolved in a vehicle. Equal volumes were placed as aliquots in sample tubes before being passed, along with another sample tube containing the same volume of vehicle, to an independent observer for coding. The previous treatments were equalized by concentration together with a vehicle control group. Five guinea pigs were randomly distributed to caga treatment group. The animals were pretreated with either vehicle (0.9% sterile saline), lidocaine or test drugs for 5 minutes immediately prior to exposure to the citric acid aerosol. The test drugs and lidocaine were administered as aerosols at concentrations of 0.1, 1.0 and 10.0 mg / ml.
The sequence of the pretreatment administration was determined according to a 4x4 Latin Square design.
The data presented as the mean ± SEM number of the coughs produced by the individual guinea pigs within each group during the observation period of 15 minutes or mean latency ± SEM of cough were analyzed using a way of analysis of variance to compare the mean responses between the matched groups of animals (dose) and between the unequal groups (treatments) followed by the Tukey-Kramer multiple comparisons test where appropriate.
Results
Data from one animal (number 1) in group B (vehicle control for 10 mg / ml dose) were excluded because the animal was exposed to an insufficient citric acid aerosol.
The time course of cough responses to the citric acid aerosol in guinea pigs treated with vehicle was recorded. A latent period of approximately 60 seconds passed between the start of exposure to the citric acid aerosol and the first cough (Table 1). Then, the frequency of the coughs increased, reaching a peak between 2-3 minutes before gradually decreasing during the subsequent 7-8 minutes. After 10 minutes, exposure to the citric acid aerosol was stopped and t the number of coughs observed decreased to zero between 14-15 minutes. There was no difference in the average number of coughs produced by the three groups of animals pretreated with vehicle in the 15 minutes after exposure to the citric acid aerosol (Table 2).
TABLE 1
Average Cough Latency
Time (seconds) to the attack of the first cough after the initiation of the exposure to the citric acid spray
Concentration Solution Lidocaine Salt aerosol compound 1 0.1 mg / ml 58 + 14 88 ± 20 88 ± 6 * 1.0 mg / ml 94 ± 19 92 ± 25 103 ± 11 * 10 mg / ml a56 ± 18 136121 7781137 **
The values are the mean ± SEM for n = 5 or n = 4 guinea pigs per group. * P < 0.001 compared to 10 mg / ml; ** P < 0.001 compared to saline and lidocaine (ANOVA followed by the multiple comparisons test of Tukey-Kramer).
** É »* uJ?. ~ -», «-..-,. tt.t ^ -, .- ^ ". . -,. ,, ^ ^ - - '^^^ TABLE 2
Total Coughs
Number of coughs produced by a 1M citric acid spray administered for 10 minutes. Coughs were counted during the 15-minute period after the initiation of exposure to the citric acid aerosol. The percent reduction in the cough response compared to the matched vehicle control groups is shown by the values in the parentheses.
Concentration Solution Lidocaine Salt aerosol compound 1 0.1 mg / ml 30,016.9 27,215.3 22,416.0 * (9.3%) (25.3%) 1.0 mg / ml 28.216.0 19.014.3 16.814.0 ** (32.6%) ( 40.4%) 10 mg / ml "28,816.5 24,412.9 0.610.6 ** (40.9%) (97.6%)
The values are the medial SEM for n = 5 or n = 4 guinea pigs per group. * P < 0.05 and * P < 0.01 compared to 10 mg / tnl; ** P < 0.05 compared to lidocaine and P < 0.001 compared to the solution
saline (ANOVA followed by the Tukey-Kramer multiple comparisons test).
• Pretreatment with lidocaine did not have a significant effect over time on cough responses at any of the concentrations used, but it seems to delay the attack of the first cough at 10 mg / ml (Table 1) and reduce the frequency of cough both at 1.0 and 10 mg / ml.
Compound 1 extended the cough attack latency to 10 mg / ml (Table 1). The pretreatment of the guinea pigs with Compound 1 produced a reduction related to the concentration of the total number of coughs induced by the citric acid during the observation period of 15 minutes (Table 2), which was highly significant compared to both group treated with equalized vehicle and the group treated with lidocaine equaled to 10 mg / ml. The reduction percentage compared to the guinea pigs treated with vehicle equalized is shown in Table 2. The frequency of the coughs was reduced to 1 mg / ml. At a concentration higher than 10 mg / ml, cough responses were completely inhibited in 4 of the 5 guinea pigs in the group, producing a significant prolongation of cough latency (Table 1).
With the Compound 1 at 10 mg / ml, in those animals that did not cough (4 out of 5) there was an absence of marked sneezing.
EXAMPLE 2 In another experiment similar to that described above in Example 1, the antitussive activity of N- (2,6-dimethylphenylcarbamoylmethyl) trimethylammonium chloride (Compound 2) and N- (2,6-dimethylphenylcarbamoylmethyl chloride) were tested. Rietilamonium 0 (Compound 3). The results showed that both Compound 2 and Compound 3 are effective.
The pretreatment of guinea pigs with the aerosols of Compound 2 immediately prior to exposure to citric acid inhibited cough responses above 80% compared to guinea pigs pretreated with vehicle matched.
The pretreatment of guinea pigs with the aerosols of Compound 3 immediately prior to exposure to citric acid inhibited cough responses above 70% compared to guinea pigs pretreated with vehicle matched.
EXAMPLE 3
The duration of the antitussive effects of Compound 1 and lidocaine against cough responses induced by citric acid were investigated in conscious guinea pigs. The test agents or vehicle were administered as pretreatments in areosol (10 mg / ml, duration of 5 minutes) at 5 minutes, 30 minutes, 1 hour, 2 hours and 4 hours before the induction of cough responses by the aerosol of citric acid.
Pretreatment of guinea pigs with aerosols of Compound 1 immediately prior to exposure to citric acid inhibited cough responses by 84.9% compared to 15 guinea pigs pretreated with vehicle matched.
Compound 1 dispersed in a gas maintained effective antitussive pretreatment when administered between 30 minutes and 2 hours before the induction of cough 20 responses with citric acid, significantly inhibiting responses by 63% after 30 minutes, 60.7% after 60 minutes and 44.0% after 2 hours.
Increasing the time period between pretreatment 25 with Compound 1 and exposure with citric acid up to 4
^^^^^^^^^^^^^^^^^^^^ M ^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^. ^. ^^^ - ^ - ^ - M - ^. ^. ^. ^ .- ^ .- ^ .- ^^ * > -. - • f «yf- hours resulted in a modest reduction of 15% in the average number of cough responses induced by citric acid.
The time for the first recorded response of cough produced by citric acid was prolonged by pretreatment with Compound 1 immediately before exposure with citric acid, when the latency of the cough attack increased 3.3 times. 10 The pretreatment of guinea pigs with lidocaine sprays did not result in a significant inhibition of the cough responses purchased with the guinea pigs pretreated with vehicle equaled in
any of the time points. None of the pretreatments with lidocaine affected the latency of the cough attack.
EXAMPLE 4 The antitussive effects of a 5 minute pretreatment with Compound 1 dispersed in a gas and lidocaine in the cough induced by the capsaicin aerosol were investigated in guinea pigs in conscious guinea pigs. 25
-... & - &tat-8 ¡¡s Pretreatment of guinea pigs with lidocaine sprays at 10 and 30 mg / ml reduced the number of cough responses induced by capsaicin by 42.2% and 10.3% respectively compared to the guinea pigs pretreated with vehicle equaled, but this effect was not significant (P> 0.05).
The pretreatment of guinea pigs with the aerosols of Compound 1 to 10 and 30 mg / ml reduced the number of cough responses induced by capsaicin by 25% (P> 0.05) and
76. 9% (P <0.01) respectively, compared to the guinea pigs
Indians treated with vehicles matched.
Lidocaine had little effect on the mean latency of the cough attack at either 10 and 30 mg / ml, producing only changes of 1.2 and 0.8 times, respectively.
At a concentration of 10 mg / ml, Compound 1 did not have a significant effect on the latency of the cough attack. However, pretreatment with a higher dose of Compound 1
(30 mg / ml) prolonged the mean latency of the cough attack by 2.1 times (P <0.05).
EXAMPLE 5
The antitussive effects of Compound 1 and lidocaine administered after the induction of cough 5 responses by exposure to the citric acid aerosol were investigated in guinea pigs. The vehicle or test agents were administered as aerosols (10 mg / ml, duration of 5 minutes) 2 minutes after exposure to citric acid began. Cough responses were recorded during a 15 minute observation period (t = 0 to t = 15 minutes) from the initiation of exposure to citric acid.
The therapeutic treatment of guinea pigs with the aerosols of Compound 1 during exposure to citric acid dispersed in a gas inhibited the total number of cough responses recorded during the 15 minute observation period by 63.8% (P <0.001). ) compared to guinea pigs treated with vehicle matched.
In contrast, total cough responses in guinea pigs therapeutically treated with lidocaine aerosols were reduced by only 32.4% (n.s.) of that recorded for guinea pigs treated with matched vehicles.
An additional analysis of the number of cough responses revealed that between t = 2 and t = 10 minutes, Compound 1 and lidocaine significantly reduced the number of cough responses, inhibiting coughs by 70.8% (P < 0.001) and 39.1%
(P <0.05), respectively.
EXAMPLE ß
Investigation of the antitussive activity of Compound 1 10 dispersed in a gas on cough responses induced by citric acid in conscious rabbits
Protocol
Twenty-two New Zealand white rabbits were randomly distributed to either group of 11 rabbits.
The pairs of rabbits (control against test) were placed in individual exposure chambers with an air flow of 5 liters / minute through the chambers.
Each rabbit was exposed to ozone (3 ppm) for 1 hour.
ITID-lill-f ^^ - ^ < ~ * '»^ I • .-». -*".faith-"..
The rabbits were then exposed immediately to aerosols from either vehicle (chamber 1) or Compound 1 (10 mg / ml, chamber 2) at a nebulization rate of 0.9 ml / min.
Cough responses were induced with citric acid aerosol (1.6M).
Coughs were counted during the 10 minute exposure to citric acid. 10 Results
All rabbits were exposed to ozone before pretreatment with vehicle or test drug. The number
medialSEM of cough responses induced by citric acid recorded in rabbits pretreated with vehicle was 22.015.1. This level of response was significantly reduced to 2,710.9 coughs in rabbits pretreated with Compound 1 (P = 0.004, unpaired t test). 20 All publications and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if individual publication or patent application were incorporated.
specifically and individually by reference.
«-! ---- at? * I .i From the foregoing, it will be appreciated that, although the specific embodiments of the invention have been described herein for purposes of illustration, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited, except for the amended claims
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
£ W # sík?, *
Claims (12)
1. A pharmaceutical composition for the treatment and / or prevention of cough, characterized in that it comprises an effective amount of a compound of the following formula: wherein R and Rx are independently selected from C 1 -C 8 alkyl, C 3 -C 8 alkoxyalkyl and C 7 -C 12 aralkyl; Y and E are independently selected from -CH2-R2 or: wherein R2 is independently selected from hydrogen, C? -C8 alkyl, C3-C8 alkoxyalkyl and C7-C? aralkyl; and wherein R3, R4 and R5 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7 alkanoyloxy, C6-C6 alkyl, C6-C6 alkoxy , alkoxycarbonyl C2-C7, C? -C6 thioalkyl, aryl and N (R6, R7), wherein R6 and R7 are independently selected from hydrogen, acetyl, methanesulfonyl and C? -C6 alkyl; An "is an anion of an acid addition salt of a pharmaceutically acceptable acid or an anion of a pharmaceutically acceptable salt, and enatiomeric, diastomeric and geometric isomers isolated therefrom, and mixtures thereof, together with one or more acceptable carriers pharmaceutically, with the proviso that Y and E can not be both -CH2-R.2 in the same compound.
2. The pharmaceutical composition according to claim 1, characterized in that R and Rx are methyl, Y and E are each -CH, -C-NH-? , and An "is Cl
3. The pharmaceutical composition according to claim 1, characterized in that R and R? they are methyl, E is -CH2-R2, where R2 is hydrogen; and Y is: where R3 is methyl at the C2 position of the phenyl ring, R5 is methyl at the C6 position of the phenyl ring, R4 is hydrogen and An "is Cl".
4. The pharmaceutical composition according to claim 1, characterized in that R and Rx are ethyl, E is -CH2-R2, wherein R2 is methyl; and Y is: where R3 is methyl at the C2 position of the phenyl ring, R5 is methyl at the C6 position of the phenyl ring, R4 is hydrogen and An "is Cl".
5. A method for the treatment and / or prevention of cough in warm-blooded animals including humans, characterized in that the method comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of a compound of formula I as it is stated in claim 1.
6. A method for the treatment and / or prevention of cough in warm-blooded animals including humans, characterized in that it comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of a compound as set forth in claim 2 .
7. A method for the treatment and / or prevention of cough in warm-blooded animals including humans, characterized in that it comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of a compound as set forth in claim 3 .
8. A method for the treatment and / or prevention of cough in warm-blooded animals including humans, characterized in that it comprises administering to a warm-blooded animal in need thereof a therapeutically effective amount of a compound as set forth in claim 4 .
9. The method according to claim 5, characterized in that the effective amount of the compound of formula (I) comprises 1 to less than 2 mg per kg of human weight.
10. The method according to claim 5, characterized in that the composition is administered by inhalation.
11. The pharmaceutical composition according to claim 1, characterized in that the effective amount of the compound of formula (I) comprises 1 to less than 2 mg per kg of human weight.
12. The pharmaceutical composition according to claim 1, characterized comprises a composition that can be inhaled. ? S a < * > 3 S * && + £ ^ í ¡j¿
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/088,597 | 1998-06-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00012238A true MXPA00012238A (en) | 2002-07-25 |
Family
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