AU670064B2 – Methods for using (2-imidazolin-2-ylamino) quinoxaline derivatives
– Google Patents
AU670064B2 – Methods for using (2-imidazolin-2-ylamino) quinoxaline derivatives
– Google Patents
Methods for using (2-imidazolin-2-ylamino) quinoxaline derivatives
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AU670064B2
AU670064B2
AU34700/93A
AU3470093A
AU670064B2
AU 670064 B2
AU670064 B2
AU 670064B2
AU 34700/93 A
AU34700/93 A
AU 34700/93A
AU 3470093 A
AU3470093 A
AU 3470093A
AU 670064 B2
AU670064 B2
AU 670064B2
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international
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1992-01-13
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James A Burke
Michael E. Garst
Charles Gluchowski
Larry A. Wheeler
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Allergan Inc
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Allergan Inc
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1993-01-12
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C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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
A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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
A61P27/02—Ophthalmic agents
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P7/00—Drugs for disorders of the blood or the extracellular fluid
A61P7/10—Antioedematous agents; Diuretics
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P9/00—Drugs for disorders of the cardiovascular system
A61P9/08—Vasodilators for multiple indications
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P9/00—Drugs for disorders of the cardiovascular system
A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
A method of treating a mammal comprises administering to a mammal an effective amount to provide a desired therapeutic effect in the mammal of a compound selected from the group consisting of those having the formula:
Description
AO
INTER
I DATE 03/08/93 APPLN. ID JP DATE 14/10/93 PCT NUMBER 34700/93 PCT/US93/00264 IIlll IIII ll lllllllI 1AU9334700 1 l AU9334700 NATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
I
i (51) International Patent Classification 5 International Publication Number: WO 93/13771 A61K 31/415, 31/495 Al (43) Inten.ational Publication Date: 22 July 1993 (22.07.93) (21) International Application Number: PCT/US93/00264 (74) Agents: VOET, Martin, A. et al.; Allergan, Inc., 2525 Dupont Drive, Post Office Box 19534, Irvine, CA (22) International Filing Date: 12 January 1993 (12.01.93) 92713-9534 (US).
Priority data: (81) Designated States: AT, AU, BB, BG, BR, CA, CH, DE, 07/820,329 13 January 1992 (13.01.92) US DK, ES, FI, GB, HU, JP, KP, KR, LK. LU, MG, MN, MW, NL, NO, NZ, PL, RO, RU, SD, SE, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, (71)Applicant: ALLERGAN, INC. [US/US]; 2525 Dupont LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, Drive, P.O. Box 19534, Irvine, CA 92713-9534 CI, CM, GA, GN, ML, MR, SN, TD, TG).
(72) Inventors: GLUCHOWSKI, Charles 20 Hines Avenue, Mahwah, NJ 07430 GARST, Michael, E. 2433 Published Vista Hogar, Newport Beach, CA 92660 BURKE, With international search report.
James, A. 670 West Third Street, Tustin, CA 92680 Before the expiration of the time limit for amending the WHEELER, Larry, A. 18 Valley View, Irvine, CA claims and to be republished in the event of the receipt of 92715 amendments.
6 7(54) Title: METHODS FOR USING (2-IMIDAZOLIN2- QUNOXALINE DERIVATIVES (54)Title: METHODS FOR USING (2-1MIDAZOLIN-2-YLAMINO) QUINOXALINE DERIVATIVES R4 H R 7 I R 2 (57) Abstract A method of treating a mammal comprises administering to a mammal an effective amount to provide a desired therapeutic effect in the mammal of a compound selected from the group consisting of those having formula pharmaceutically acceptable acid addition salts thereof and mixtures thereof, wherein R, and R 4 are independently selected from the group consisting of H and alkyl radicals having 1 to 4 carbon atoms; the R 2 s are independently selected from H or alkyl radicals having I to 4 carbon atoms or are, together, oxo; the R 3 s are independently selected from H or alkyl radicals having 1 to 4 carbon atoms or are, together, oxo; the 2-imidazolin-2-ylamino group may be in any of the 7- or 8-positions of the quinoxaline nucleus; and R 5
R
6 and R 7 each is located in one of the remaining 7- or 8-positions of the quinoxaline nucleus and is independently selected from the group consisting of Cl, Br, H and alkyl radicals having 1 to 3 carbon atoms. Such compounds, when administered to a mammal, provide desired therapeutic effects, such as reduction in peripheral pain, anesthetization of the central nervous system, constriction of one or more blood vessels, reduction in or prevention of at least one effect of ischemia, decongestion of one or more nasal passages, and reduction of at least one effect of an inflammatory disorder.
i d WO 93/13771 PCT/US93/00264 1 METHODS FOR USING (2-IMIDAZOLIN-2-YLAMINO) QUINOXALINE DERIVATIVES Related Application This application is a continuation-in-part of patent application Serial No. 758,696 filed September 12, 1991 which, in turn, is a division of patent application Serial No. 420,817 filed October 12, 1989; and a continuation-inpart of patent application Serial No. 560,776 filed July 31, 1990 which, in turn, is a continuation-in-part of application Serial No. 420,817 filed October 12, 1989. The disclosures of each of these prior applications is incorporated in its entirety herein by reference.
Background of the Invention The present invention relates to novel substituted derivatives of quinoxaline. More particularly, the invention relates to such derivatives which are useful as therapeutic agents, for example, to effect reduction in intraocular pressure, to increase renal fluid flow and to effect an alteration in the rate of fluid transport in the gastrointestinal tract.
Various quinoxaline derivatives have been suggested as therapeutic agents. For example, Danielewicz, et al U.S. Patent 3,890,319 discloses compounds as regulators of the cardiovascular system which have the following formula: H X N R N N l -R z where the 2-imidazolin-2-ylamino group may be in any of the 7- or 8- position of the quinoxaline nucleus; X, Y and Z may be in any of the remaining 7- or 8- positions and may be selected from hydrogen, halogen, lower alkyl, lower alkoxy or WO 93/13771 PCT/US93/00264 2 trifluoromethyl; and R is an optional substituent in either the 2- or 3- position of the quinoxaline nucleus and may be hydrogen, lower alkyl or lower alkoxy.
Summary of the Invention New methods for treating mammals, preferably human beings, to provide a desired therapeutic effect have been discovered. By administering an effective amount of one or more of certain compounds to a mammal, a desired therapeutic effect is provided in the mammal. Such desired therapeutic effects include reduction in peripheral pain, anesthetizaton of the central nervous system, constriction of one or more blood vessels, reduction in or prevention of at least one effect of ischemia, decongestion of one or more nasal passages, and reduction in at least one effect of an inflammatory disorder.
The compounds which are administered in the methods of the present invention are those having the formula:
R
4 H R 5
I
CN N R3 N i
R
7 I R 2
R
R,
and pharmaceutically acceptable acid addition salts thereof and mixtures thereof, wherein R i and R 4 are independently selected from the group consisting of H and alkyl radicals having 1 to 4 carbon atoms; the R 2 s are independently selected from H or alkyl radicals having 1 to 4 carbon atoms or are, together, oxo; the R 3 s are independently selected from H or alkyl radicals having 1 to 4 carbon atoms or are, together, oxo; the 2-imidazolin- 2-ylamino group may be in any of the 7- or 8positions of the quinoxaline nucleus; and R 5 R6 and R7 V^ j WO 93/13771 PCT/US93/00264 3 each is located in one of the remaining 7- or 8positions of the quinoxaline nucleus and is independently selected from the group consisting of Cl, Br, H and alkyl radicals having 1 to 3 carbon atoms.
Particularly useful compounds are those in which R 1 and R4 are H, the 2-imidazolin-2-ylamino group is in the 6- position of the quinoxaline nucleus, Rg is selected from the group consisting of Cl, Br and alkyl radicals containing 1 to 3 carbon atoms, more preferably Br, and is in the 5- position of the quinoxaline nucleus, and R and R are H. Each of the R2s and each of the R3s is preferably independently selected from H and alkyl radicals having 1 to 4 carbon atoms, more preferably from H and methyl radical.
in one embodiment, at least one of the R 2 s and at least one of the R 3 s are H. At least one of the R2s or at least one of the R 3 s may be methyl radical. The R 2 s and the R 3 s that are not alkyl, methyl, radicals, are H, or together is oxo. At least one of the R 2 s may be different from at least one of the R 3 s.
Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate salts.
Detailed Description of the Invention The present invention involves methods for treating mammals to provide one or more desired therapeutic effects in the mammal. The present methods comprise administering an effective amount to provide the desired therapeutic WO 93/13771 PCr/US93/00264 4 effect or effects in a mammal of at least one compound, as described herein, to the mammal. Among the desired therapeutic effects are reduction in peripheral pain, anesthetization of the central nervous system, constriction of one or more blood vessels, reduction in or prevention of at least one effect of ischemia, decongestion of one or more nasal passages and reduction in at least one effect of an inflammatory disorder, for example, such disorders characterized by progressive joint and/or tissue deterioration. Thus, for example, the presently useful compounds may be effective as one or more of the following: a peripheral pain killing agent, a general anesthetic, a vaso-constricting agent, an agent for the treatment of ischemia, a nasal decongestant, and an anti- inflammatory agent. One important feature of many of the present methods is that the desired therapeutic effect is achieved with reduced side effects, in particular with reduced effects on the blood pressure of the mammal to which the presently useful compound or compounds are administered.
Any suitable method of administering the presently useful compound or compounds to the mammal to be treated may be used. The particular method of administration chosen is preferably one which allows the presently useful compound or compounds to have the des~.red therapeutic effect in an effective manner, low medication concentration and low incidence of side effects. In many applications, the presently useful compound or compounds are administered to a mammal in a manner substantially similar to that used to administer alpha agonists, in particular alpha 2 agonists, to obtain the same or similar therapeutic effect or effects.
Administration of the presently useful compounds for WO 93/13771 PCT/US93/00264 use in the methods of this invention can include, but are not limited to, oral, parenteral, topical, intra-articular and other modes of systemic administration. The compounds are administered in a therapeutically effective amount either alone or in combination with a suitable pharmaceutically acceptable carrier or excipient.
Depending on the intended mode of administration, the presently useful compound or compounds may be incorporated in any pharmaceutically acceptable dosage form, such as for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, emulsions, aerosols or the like, preferably in unit dosage forms suitable for single administration of precise dosages, or sustained release dosage forms for continuous controlled administration.
Preferably the dosage form will include a pharmaceutically acceptable excipient and the presently useful compound or compounds and, in addition, may contain other medicinal agents, pharmaceutical agents, carriers, adjutants, etc.
For solid dosage forms, non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate. An example of a solid dosage form for carrying out the invention is a suppository containing propylene glycol as the carrier.
Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic L-r~.-LL L-PI LIII~ WO 93/13771 PCT/US93/00264 6 auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of such auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleave, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 16th Edition, 1980. The composition of the formulation to be administered, in any event, contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, if desired, the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
The amount of the presently useful compound or compounds administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal’s condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgement of the prescribing physician. The therapeutically effective
C
WO 93/13771 PCT/US93/00264 7 dosage of the presently useful compound or compounds is preferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.
The presently useful compounds are as described above. All stereoisomers, tautomers and mixtures thereof which comply with the constraints of one or more formulae of the presently useful compounds are included within the scope of the present invention. For example, both tautomers SH R CNN N- H NI t 2
R,
are within the scope of the present invention.
The prer ‘ntly useful compounds may be prepared in a manner analogous to the procedures described in Danielewicz, et al U.S. Patent 3,890,319 for the production of the quinoxaline derivatives therein. This patent is hereby incorporated in its entirety by reference herein. Once a 2-imidazolin-2-ylamino quinoxaline intermediate corresponding to the compound described in Danielewicz, et al U.S. Patent 3,890,319 is obtained, this 2-imidazolin-2-ylamino quinoxaline intermediate is hydrogenated to saturate any unsaturation at the and 4- positions of the quinoxaline nucleus.
30 Briefly, the 2-imidazolin-2-ylamino quinoxaline intermediates may be prepared by reaction of the Bil t in q appropriate amino-quinoxaline with thiophosgene to form the corresponding isothiocyanate; and reacting this WO93/13771 PCT/US93/00264 8 isothiocyanate with excess ethylene diamine to form the corresponding beta-aminoethyl-thioureidoquinoxaline, which is then cyclized to the corresponding intermediate.
Alternately, such intermediates can be prepared by (1) reacting the corresponding aminoquinoxaline with benzoyl isothiocyanate to form the corresponding N-benzoyl tiioureido compound, followed by hydrolysis to the thioureido compound, or reaction of the aminoquinoxaline with ammonium thiocyanate to form the thioureido compound directly; methylation to form the S-methyl deviation of the thioureido compound; and reaction with ethylene diamine to form the intermediate.
The 2-imidazolin-2-ylamino quinoxaline intermediate is then reacted to saturate any unsaturation at the 2and 4- positions of the quinoxaline nucleus. For compounds in which R 1 the R 2s the R3 s and R4 are all to be H, the intermediate may be hydrogenated. This hydrogenation preferably occurs with the intermediate dissolved in a liquid, a lower alcohol such as methanol, ethanol or the like. A catalyst effective to promote the hydrogenation is preferably present. Examples of such catalysts include the platinum group metals, in particular platinum, platinum group metal compounds, such as platinum oxide, and mixtures thereof. Hydrogen, e.g., free molecular hydrogen, is present in an amount at least sufficient to provide the desired saturation, preferably in an amount in excess of that required to provide the desired saturation, of the intermediate. The temperature and pressure at which the hydrogenation occurs are preferably selected to maintain the intermediate and final c product substantially in the liquid phase. Temperatures in the range of about 100 C to about 100° C and pressures in the range of about 0.5 atmospheres to about n ZL -~iiL;-ii WO 93/13771 PCT/US93/00264 9 atmospheres often provide acceptable results. These conditions are maintained for a time sufficient to provide the desired hydrogenation reaction. This period of time is often in the range of about 1 minute to about 2 hours.
The final 2-imidazolin-2-ylamino tetrahydroquinoxaline is separated from the hydrogenation reaction mixture and recovered, using conventional techniques.
For compounds in which R1 the R2, s the R3 s and R 4 are all to be H and for compounds in which R1 and R 4 are to be H and at least one of the R 2 s and/or at least one of the R 3 s are to be alkyl, the intermediate may be re;crted with a suitable hydride reducing agent. This reaction preferably occurs with the intermediate and the hydride reducing agent dissolved in a liquid. Any suitable hydride reducing agent may be employed. Examples of useful hydride reducing agents include NaBH 4 NaCNBH 4 LiAlH4 and the like. The amount of hydride reducing agent used should be sufficient to saturate all the unsaturation present at the 3- and 4- positions of the intermediate. Excess hydride reducing agent may be employed provided that no deterioration of the final tetrahydroquinoxaline product results. The liquid employed should be such as to act as an effective solvent for the intermediate and the hydride reducing agent, and may also function to facilitate, activate, the reaction between the intermediate and hydride reducing agent. Examples of useful liquids include acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether and the like. The liquid employed is preferably selected so as to avoid excess hydride reducing agent reactivity. For example, where LiAlH 4 is used as the hydride reducing agent, the liquid is preferably tetrahydrofuran, diethyl ether and the like. One or more co-solvents, lower WO 93/13771 PCT/US93/00264 alcohols, may also be used. The temperature and pressures at which the reaction occurs are preferably selected to maintain the intermediate and final product in the liquid phase. Temperatures in the range of about 00 C to about 500 C and pressures in the range of about 0.5 atmospheres to about 2 atmospheres often provide acceptable results.
Reaction time is chosen to allow the desired reaction to occur, and is often in the range of about one minute to about one hour. The final 2-imidazolin-2-ylamino tetraquinoxaline is separated from the reactive mixture and recovered, using conventional techniques, such as evaporation, deactivation of the excess hydride reducing agent, extraction and chromatographic separation.
For compounds in which R R 4 are to be alkyl, the intermediate (having no substituents corresponding to R1 and R 4 may be reacted with a suitable hydride reducing agent in the presence of a selected aldehyde or aldehydes. The aldehyde or aldehydes use’ are selected based on the specific R I and/or R 4 alkyl group or groups desired. For example, if R I and/or R 4 is to be methyl, formaldehyde is used, if R 1 and/or R 4 is to be ethyl, acetaldehyde is used, etc. The reaction etiditions used are similar to those described in tjai immediately preceding paragraph except that the reaction time is often in the range of about 1 hour to about 24 hours. The amount of aldehyde used may vary depending on the final compound desired. A mixture of final compounds, a compound in which both R 1 and R 4 are alkyl mixed with compounds in which only one of R 1 or R 4 is alkyl, may be produced by the reaction. One or more individual tetrahydroquinoxalines useful in the present invention can be separated and recovered from this mixture, using conventional techniques.
WO 93/13771 PCT/US93/00264 WO 93/13771 PCT/US93/00264 11 The presently useful compounds may be prepared from available starting materials. For example, 4-nitro-1,2phenylenediamine may be reacted with an appropriate halide substituted carbonyl halide, in particular, a bromide substituted carbonyl bromide. This reaction, which provides for substitution of one of the amine groups on the phenylene ring by the carbonyl halide, is preferably conducted in a solvent and preferably at a temperature in the range of about 10 0 C to about 50 0 C, in particular about room temperature. ‘Reaction pressure is preferably such that the solvent is maintained substantially in the liquid phase. The reaction preferably occurs over a period of time in the range of about 2 hours to about 24 hours.
Examples of useful solvents include methylene chloride (CHCi) chloroform (CHClg), tetrahydrofuran and the like.
A trialkyl amine, triethylamine, may be used as part of the solvent and/or to promote or facilitate the substitution reaction.
The resulting mixture of halo amide isomers are recovered preferably by conventional techniques, e.g., extraction, washing, drying, concentration, chromatography and the like, from the substitution reaction mixture. The isomers are then cyclized. This cyclization is preferably effected at a temperature in the range of about 10 0 C to about 50 0 C, in particular at room temperature, by contacting the isomers, preferably dissolved in a solvent such as methylene chloride, with a cyclizing agent, such as AgBF 4 AgNO 3 and the like. Reaction pressure is preferably such that the solvent is maintained substantially in the liquid phase. The reaction preferably occurs over a period of time in the range of about 1 hour to about 24 hours. Conventional techniques, such as noted above, can be used to recover the
F-
WO 93/13771 PCT/US93/00264 12 cyclized isomers. Chromography can be used to separate the isomers and provide them in substantially pure form.
The cyclized compound produced as described above, identified as a nitro-substituted quinoxalinone, is hydrogenated to convert the nitro group to an amino group.
This hydrogenation preferably occurs with the nitrosubstituted quinoxalinone dissolved in a liquid, a lower alcohol such as methanol, ethanol or the like. A catalyst effective to promote the hydrogenation is preferably present. Examples of such catalysts include the platinum group metals, in particular platinum or palladium, platinum group metal compounds, such as platinum oxide or palladium oxide, and mixtures thereof.
Hydrogen, free molecular hydrogen, is present in an amount at least sufficient to provide the desired hydrogenation, preferably in an amount in excess of that required to provide the desired hydrogenation. The temperature and pressure at which the hydrogenation occurs are preferably selected to maintain the nitro-substituted quinoxalinone and hydrogenated product substantially in the liquid phase. Temperatures in the range of about 100 C to about 1000 C and pressures in the range of about atmospheres to about 5 atmospheres often provide acceptable results. These conditions are maintained for a time sufficient to provide the desired hydrogenation reaction. This period of time is often in the range of about 1 hour to about 16 hours. The hydrogenated product is separated from the hydrogenation reaction mixture and recovered, using conventional techniques.
At this point, the hydrogenated product may be subjected to one or more reactions to include one or more groups in the compound, as desired. For example, in one embodiment, it is preferred that the final quinoxaline
I
2I x i WO 93/13771 PCT/US93/00264 13 derivative of the present invention includes at least one halide group, in particular a bromo group, on the aromatic ring structure. In order to provide such a bromo group, the above-noted hydrogenated product is brominated. Such bromination can occur by dissolving the hydrogenated product in a suitable solvent, glacial acetic acid, trifluoroacetic acid and the like, and contacting this solution with bromine. The mixture is preferably maintained at a suitably low temperature, in the range of about 10 0 C to about 50 0 C, so that the degree of bromination can be controlled. Cooling or removing heat from the reaction mixture may be desirable. Room temperature bromination provides satisfactory results.
Reaction pressure is preferably such that the solvent is maintained substantially in the liquid phase. The reaction preferably occurs over a period of time in the range of about 0.25 hours to about 6 hours. Conventional techniques, vacuum filtration, can be used to recover the brominated product, which may be a hydrobromide salt.
The above-noted hydrogenated product or substituted hydrogenated product is reacted with 2-imidazoline-2sulfonic acid to produce a 2-imidazolin-2-ylamino quinoxaline derivative useful in the present invention.
Such derivatives include an oxo group. This reaction can occur by dissolving the reactants in an appropriate solvent, an alcohol such as isobutanol, and heating this solution to reflux at atmospheric pressure.
Preferred reaction temperatures are in the range of about 70°C to about 1500 C. Reaction pressure is preferably such that the solvent is refluxed or maintained substantially in the liquid phase. The reaction preferably occurs over a period of time in the range of about 1 hour to about 24 I oms or are, togerner, oxo; me zl-milazoIln-L-yalmino group may oc In any i0 iu mt, i- UI o-pu IlluIa Vl tII, uinuAuuuaI, nucleus; and R 5
R
6 and R 7 each is located in one of the remaining 7- or 8-positions of the quinoxaline nucleus and is independently selected from the group consisting of CI, Br, H and alkyl radicals having I to 3 carbon atoms. Such compounds, when administered to a mammal, provide desired therapeutic effects, such as reduction in peripheral pain, anesthetization of the central nervous system, constriction of one or more blood vessels, reduction in or prevention of at least one effect of ischemia, decongestion of one or more nasal passages, and reduction of at least one effect of an inflammatory disorder.
.i- :i WO 93/13771 PCr/US93/00264 14 hours. Conventional techniques, concentration and chromatography, can be used to recover the desired quinoxaline derivative.
The present quinoxaline derivatives which do not include an oxo group can be obtained by reacting the above-described oxo-containing quinoxaline derivatives to remove the oxo group. This can be accomplished by dissolving the oxo-containing material in an appropriate solvent, tetrahydrofuran, acetic acid, trifluoroacetic acid, diethyl ether and the like, and subjecting this solution to a hydride reducing agent, such as LiAlH 4 NaBH 4 NaCNBH and the like. Reaction temperatures in the range of about 20 0 C to about 100 0 C can be used. Conventional techniques, cooling, concentration and chromatography, can be employed to provide the present quinoxaline derivative which do not include an oxo group.
Specific examples of compounds which are useful in the present invention include those which have the following formulas: HN NH HN NH ie
-L
‘1 WO 93/13771 III HN ,NH1 PCr/US93/00264
H
-N
HN ,NH1
IV
HN YNH CH3
VII
,pharmaceutically acceptable acid addition salts thereof WO 93/13771 PCT/US93/00264 16 and mixtures thereof. Compounds having formula pharmaceutically acceptable acid addition salts thereof and mixtures thereof are particular useful.
The present compound or compounds may be included in a medication composition together with one or more other components to provide a medication composition which can be effectively administered. Such other components, e.g., carriers, anti-oxidants, bulking agents and the like, may be chosen from those materials which are conventional and well known in the art, as being included in medication compositions with alpha 2 agonists.
The following non-limiting examples illustrate certain aspects of the present invention.
EXAMPLE 1 Preparation of 5-Bromo-6-(2-imidazolin-2-ylamino)- 1,2,3,4-tetrahydroquinoxaline 1,2,4-Triaminobenzene dihydrochloride To a suspension of 4-nitrophenylenediamine (Aldrich, g, 65.3 mmol) in absolute ethanol (240 ml) was added 600 mg of 10% by weight palladium on charcoal catalyst.
The container including the suspension was evacuated and filled with hydrogen three times and the suspension was hydrogenated at 18 psi until hydrogen uptake ceased. The reaction was slightly exothermic and one refill of hydrogen was required. The resulting light yellow solution, which darkens rapidly on contact with air, was filtered and concentrated to about 150 ml. Concentrated hydrochloric acid (12 ml) was added and the solid formed was filtered off. After drying in vacuo overnight, 12 g (a yield of 93%) of purple solid was obtained, m.p. 224-50 C. Using various analytical procedures, this solid was determined to be 1,2,4-triaminobenzene dihydrochloride.
6-Aminoquinoxaline Il Glyoxal sodium bisulfite adduct (Aldrich, 14.3g, mmol) was added in small portions to a solution of 1,2,4triaminobenzene dihydrochloride (9.8 g, 50 mmol) in 200 ml of 10% by weight sodium carbonate in water. The reaction mixture was heated to 1000 C for two hours and then cooled to 00 C. The crystals formed were filtered off and dried in vacuo to give a crude yield of 7.06 g (a yield of 97%) of brown crystals. Recrystallization from benzene gave 6.32 g (a yield of 87%) yellow crystals, m.p. 157-80 C.
Using various analytical procedures, these yellow crystals were determined to be 6-aminoquinoxaline.
hydrobromide 6-Aminoquinoxaline (2.08 g, 14.4 mmol) was dissolved in 11.5 ml glacial acetic acid. The solution was cooled in water while a solution of bromine (0.74 ml, 2.3g, 14.4 mmol) in 1.5 ml glacial acetic acid was added slowly over min. After stirring for an additional 30 min, the orange red solid formed was filtered off and washed thoroughly with dry ether. The solid was dried in vacuo overnight to yield 4.44 g crude product (a yield of 100%).
The compound, 6-amino-5-bromoquinoxaline hydrobromide, had no definite melting point. A phase change (from fine powder to red crystals) was noticed at about 2200 C.
Decomposition was observed at about 2450 C. It was used directly for the next step.
The crude 6-amino-5-bromoquinoxaline from above was dissolved in water and saturated sodium bisulfite solution was added until the resulting solution tested negative 1 30 with starch-iodide paper. The solution was then basified with 2N sodium hydroxide and extracted thoroughly with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated under reduced’pressure Lii 1 d n _r -I ul.u LI~ WO 93/13771 PCT/US93/00264 18 to give the free base. The crude product was recrystallized from boiling benzene to give yellow crystals, m.p. 1 5 5 C. Using various analytical procedures, the yellow crystals were determined to be 6amino-5-bromoquinoxaline. The yield was 82%.
5-Bromo-6-isothiocyanatoquinoxaline The crude hydrobromide product previously noted (4.27g, 14.0 mmol) was dissolved in 60 ml of water and thiophosgene (Aldrich, 1.28 ml, 16.8 mmol) was added in small portions with vigorous stirring. After 2 hours, the red color of the solution was discharged. The solid formed was filtered off and washed thoroughly with water.
After drying in vacuo at 250 C, 3.38 g (a yield of 90%) of brick red crystals was obtained, m.p. 157-80 C. A portion of this material was further purified by column chromatography to give white crystals, m.p. 157-80 C.
Using various analytical procedures, these crystals were determined to be 5-bromo-6-isothiocyanatoquinoxaline.
5-Bromo-6(-N -(2-aminoethyl)thioureido)quinoxaline A solution of the isothiocyanate (3.25 g, 12.2 mmol) in 145 ml benzene was added to a solution of ethylenediamine (Aldrich, 5.43 g, 90.0 mmol) in 18 ml benzene at 250 C over 2 hours. After stirring for a further 30 min., the supernatant was poured off. The oil which remained was washed by swirling with dry ether three times and used directly for the next step.
A portion of this product was further purified by column chromatography (Si02 CHC13 for characterization. A white solid was recovered which decomposed at 1750 C with gas evolution (puffing). This white solid was determined to be 5-bromo-6(-N-2- (aminoethyl)thioureido) quinoxaline.
i i a WO 93/13771 PCT/US93/00264 19 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline The crude product from above was dissolved in 100 ml dry methanol and the brown solution was refluxed for 19 hours until hydrogen sulfide gas was no longer evolved.
The mixture was cooled to room temperature and concentrated to about 50 ml. The yellow solid was filtered off and dried in vacuo; weight 2.52 g (a yield of mp 242-40 C.
As the crude product was insoluble in most common organic solvents, initial purification was achieved by an acid-base extraction procedure. 23 g of the crude product was dissolved in 100 ml 0.5N hydrochloric acid. The turbid yellow solution was filtered to give a clear orange yellow solution which was extracted twice with ‘ethyl acetate (2 X 10 ml). The aqueous phase was cooled to 0° C and basified with 6N sodium hydroxide, keeping the temperature of the solution below 150 C at all times. The yellow solid which precipitated was filtered off and washed thoroughly with water until the washings were neutral to pH paper. The solid was dried overnight in vacuo to give 1.97 g yellow solid, m.p. 249-500 C. The recovery was about 88%.
Further purification was achieved by recrystallization as described below. The partially purified product from above was dissolved in N, Ndimethylformamide (about 17 ml/g) at 1000 C with vigorous -stirring. The solution was filtered hot and set aside to cool overnight. The bright yellow crystals were collected by filtration, m.p. 2 5 2 -30 C. Recovery was from 65-77%.
Using various analytical procedures, the bright yellow solid was determined to be 5-bromo-6-(2-imidazolin-2ylamino) quinoxaline.
WO 93/13771 PCT/US93/00264 5-Bromo-6-(2-imidazolin-2-ylamino)- 1,2,3,4-tetrahydroquinoxaline A thick-walled Parr hydrogenation flask was charged with 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (950 mg, 3.23 mmol), platinum oxide (95 mg) and 20 ml of methanol. The contents of the flask were contacted with hydrogen at 15 psi for 15 minutes. The resulting solution was filtered through acid washed silicon dioxide, followed by evaporation of solvent. The resulting tan solid was chromatographed.(SiO 2 80/20 CHCl 3 /CH OH saturated with NH to yield 820 mg (a yield of 86%) of an off white solid, mp 218-2200 C. Using various analytical procedures, this off white solid was determined to be bromo-6- 2-imidazolin-2-ylamino)-1,2,3,4tetrahydroquinoxaline.
EXAMPLE 2 Preparation of (±)2-Methyl-5-bromo-6-(2-imidazolin-2ylamino)-1,2,3,4-tetrahydroquinoxaline 2-Methyl-6-nitroquinoxaline A solution of pyruvic aldehyde (Aldrich, 40% solution in H0, 11.8 g, 65.3 mmol) was added dropwise to a solution of 4-nitro-1,2-phenylenediamine (Aldrich, log, 65.3 mmol) in 150 ml of 20. The reaction mixture was heated to 800 C for four hours. The reaction was cooled to room temperature, diluted with H 2 0 and extracted with CHC 1 3 The organic extracts were dried over MgSO 4 and evaporated to yield 10.7 g (a yield of 87%) of as a brick red solid. Using various analytical procedures, this solid was determined to be 2-methyl-6 nitroquinoxaline.
30 2-Methyl-6-Aminoquinoxaline A thick-walled Parr hydrogenation flask was charged with 2-methyl-6-nitroquinoxaline (10.Og, 52.9) and CH 3
OH
(200 ml). The flask was flushed with a stream of N 2 and by weight palladium on charcoal (500 mg) was added.
WO 93/13771 PCT/US93/00264 21 The flask was pressurized with H 2 to 50 psi and maintained at this pressure for three hours. The reaction mixture was filtered tnrough acid washed silicon dioxide and concentrated in vacuo to yield a tan solid. The crude material was chromatogrnphed (SiO 2 95/5 CHCl 3
/CH
3
OH
saturated with NH 3 and recrystallized from benzene to yield 7.4 g (a yield of 88%) of a tan solid. Using various analytical procedures, this tan solid was determined to be 2-methyl-6-aminoquinoxaline.
2-Methyl-5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline By a series of reaction steps analogous to the reaction steps described above in Example 1, the title compound (mp. 2600 C) was prepared starting with 2-methyl- 6-aminoquinoxaline in place of 6-aminoquinoxaline.
(+)2-methyl-5-Bromo-6-(2-imidazolin-2ylamino-A, 2, 3, 4-tetrahydroquinoxaline A solution of 2-methyl-5-bromo-6-(2-imidazolin-2ylamino) quinoxaline (40.5 mg, 0.132 mmol) in acetic acid was cooled to 100 C and carefully treated with NaBH 4 mg, 0.132 mmol). The reaction mixture was stirred for minutes before the .solvent was removed in vacuo. The residue was dissolved in H0, treated with solid NaOH to pH 13 and extracted with CHC1 3 The combined organic extracts were dried over MgSO 4 and concentrated in vacuo to yield a yellow oil. The crude material was chromatographed (SiO 2 80/20 CHC1 3 /COH saturated with
NH
3 to yield 21.8 mg (a yield of 53%) of a tan solid, mp 203-205 C. Using various analytical procedures, this tan solid was determined to be 2-methyl-5-bromo-(2imidazolin-2-ylamino)-1,2,3,4-tetrahydroquinoxaline.
EXAMPLE 3 SPreparation of 3-Methyl-5-bromo-6-(2-imidazolin-2 ylamino)-1, 2, 3, 4-tetrahydroquinoxaline i- V. WO 93/13771 PCT/US93/00264 22 3-Methyl-6-aminocuinoxaline Pyruvic aldehyde (Aldrich, 892 mg, 4.95 mmol, solution H 2 0) was added dropwise to a stirred solution of 1, 2, 4-triaminobenzene hydrochloride (1.0 c, 4.95 mmol) dissolved in 10% aqueous Na 2
CO
3 (15 ml). The mixture was heated at 1000 C for two hours before cooling to room temperature. The mixture was extracted with CHC1l. The combined organic extracts were dried over MgSO 4 and concentrated in vacuo to yield a brown solid. The crude product was chromatographed (SiO 2 95/5 CHCL /CH 3
OH
saturated with NH to yield 616 mg (a yield of of a yellow crystalline solid. An analytical sample was prepared by recrystallization from benzene, mp 170-173 C.
Using various analytical procedures, the solid was determined to be 3-methyl-6-aminoquinoxaline.
(+)3-Methyl-5-bromo-6-(2-imidazolin-2-ylamino)-1, 2,3,4tetrahydroquinoxaline By a series of reaction steps analogous to the reaction steps described above in Example 2, the title compound (mp 250-2510 C) was prepared starting with 3methyl-6-aminoquinoxaline in place of 2-methyl-6aminoquinoxaline.
EXAMPLE 4 Preparation of 5-Bromo-6-(2-imidazoline-2-ylamino)- 1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline,5-Bromo-6-(2- I imidazolin-2-ylamino)-1-methyl-1,2,3,4tetrahydroquinoxaline and 5-Bromo-6-(2-imidazolin-2ylamino)-4-methyl-1,2,3,4-tetrahydroquinxoaline.
5-Bromo-6-(2-imidazolin-2-ylamino) quinoxaline (291 mg, I mmol) is suspended in CH3OH (2 ml) and treated with glacial acetic acid (1 ml). The reaction mixture is treated with NaCNBH 3 (252mg, 4 mmol) and paraformaldehyde (450 mg, 5 mmol) and stirred at room temperature for 4-8 C WO 93/13771 PCT/US93/00264 23 hours. The reaction mixture is quenched with H 2 0 (5 ml), basified with solid NaOH (3g) to pH 12 and extracted with CHC1 3 The CHC1 3 extracts are dried over MgS 0 4 concentrated invacuo and chromatrgraphed (Si0 2 80/20 CHC13/CH30H saturated with NH 3 to yield the individual title compounds. Each of these title compounds is tested and is found to have one or more useful therapeutic effects which known alpha 2 agonists exhibit.
EXAMPLE Preparation of 5-Bromo-6-(2-imidazolin-2-ylamino)- 1,4-diethyl-1,2,3,4-tetrahydroquinoxaline, 5-Bromo-6-(2imidazolin-2-ylamino) -1-ethyl-1, 2, 3, 4tetrahydroquinoxaline and 5-Bromo-6-(2-imidazolin-2ylamino)-4-ethyl-1,2,3,4-tetrahydroquinoxaline The individual title compounds are prepared using the method illustrated in Example 5 except that acetaldehyde (220 mg, 5 mmol) is substituted for paraformaldehyde and the reaction time is 6-12 hours instead of 4-8 hours.
Each of these title compounds is tested and is found to have one or more useful therapeutic effects which known alpha 2 agonists exhibit.
EXAMPLE 6 Preparation of 1,2-dihydro-2,2-dimethyl-6-nitro-3-(4H)cuinoxalinone and 3,4-dihydro-3 ,3-dimethyl-6-nitro-2-(1H)quinoxalinone To a stirred solution of 4-nitro-1,2-phenylen’diamine (Aldrich, 5.0 g, 32.6 mmol) and triethylamine (5.05 g, mmol) in CHC± 2 (50 ml) is added 2-bromo-2-methyl propionyl bromide (Aldrich 7.49 g, 32.6 mmol) dropwise.
The mixture is stirred at room temperature until the starting material (4-nitro-1,2-phenylenediamine) is consumed. The reaction is quenched with aqueous NH 4 C1 and the organic material is extracted with CH3C1 2 The organic extract is washed with H0 (20 ml), dried over -i v v -II20 WO 93/13771 PCT/US93/00264 24 MgSO 4 and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes: ethyl acetate elution to yield a mixture of bromo amide isomers. This mixture is dissolved in CHC 2 Cl (30 ml) and treated with AgBF 4 (Aldrich, 6.36 g, 32.6 mmol) at room temperature to effect cyclization. After the starting bromo amide isomers are consumed, the reaction is quenched with aqueous NH4C1 and the organic material is extracted with
CH
2 Cl 2 The organic extract is washed with H 2 0 (10 ml), dried over MgSO 4 and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes: ethyl acetate elution to yield the title compounds in pure form.
This chromatographing separates the title compounds and allows recovery of each of them individually.
EXAMPLE 7 Synthesis of 6-amino-1,2-dihydro-2,2-dimethyl-6-(2imidazolin-2-ylamino)-3-(4H)-quinoxalinone A solution of 1,2-dihydro-2,2-dimethyl-6-nitro-3- (4H)-quinoxalinone(663 mg, 3 mmol) in CH30H (10 ml) is hydrogenated with 50 psi H 2 at room temperature in the presence of a catalyst of 10% by weight palladium on charcoal (50 mg). After the starting material is consumed, the solution is filtered and concentrated in vacuo to yield 6-amino-l,2-dihydro-2,2-dimethyl-3-(4H)quinoxalinone.
EXAMPLE 8 Synthesis of 6-amino-5-bromo-l,2-dihydro-2,2-dimethyl-3- (4H)-quinoinoxalinone hydrobrmide A solution of 6-amino-l,2-dihydro-2,2-dimethyl-3- (4H)-quinoxalinone (250 mg, 1.31 mmol) in glacial acetic acid (4 ml) is cooled using a water bath. Bromine (210 mg, 1.31 mmol) in acetic acid (0.25 ml) is added dropwise over a 5 minute period. The mixture is stirred at room temperature for 4 hours and the resulting precipitate is L. i ,n 1 1 WO 93/13771 PCT/US93/00264 collected by vacuum filtration. The title compound is obtained in pure form after drying in vacuo.
EXAMPLE 9 Synthesis of 2-imidazoline-2-sulfonic acid 2-Imidazolidinethione (66.3 g, 650 mmol), Na 2 MoO 4 g, 227 mmol) and NaCl (15 g. 256 mmol) were added to 300 ml H 2 0. Although some dissolution occurred, a solid residue remained in the liquid of the mixture. The mixture was cooled to -100 C using an immersion cooler.
500 ml of a 30% aqueous H 2 0 2 solution was placed in a jacketed controlled drip rate addition funnel .and cooled to OOC using an ice/H 2 0 bath. The aqueous H 2 0 2 solution was added to the mixture at a rate of drops/minute. The mixture was stirred for 16 hours at 100 C. During this time, the mixture changed from a white suspension to a dark blue solution to a light blue suspension. At the end of 16 hours, a solid was filtered from the suspension and dried in vacuo. No further purification was needed. 57.8 g (a yield of 52.3%) of the title compound as a white solid, which was characterized spectroscopically, was recovered. This solid was stable when stored in the dark at 00 C for at least 6 months.
EXAMPLE Synthesis of 5-bromo-1,2 dihydro-2,2-dimethyl-6-(2imidazolin-2-ylamino)-3-(4H)-quinoxaline A mixture of 6-amino-5-bromo-1,2-dihydro-2,2dimethyl-3-(4H) quinoxalinone hydrobromide (479 mg, 1 mmol) and 2-imidazoline-2-sulfonic acid (224 mg, 1.5 mmol) in isobutanol (5 ml) is heated at reflux until the starting hydrobromide material is consumed. The solvent is removed in vacuo and the residue chromatographed on silica gel with CHC1 3 CH OH saturated with NH(g) elution to yield the title compound.
L ,F 1. i: 1 n~ Yr~r~ WO 93/13771 PCr/US93/00264 26 EXAMPLE 11 Preparation of 5-brorno-2 ,2-dimethvl-6-(C2-imidazolin-2ylamino) -1 ,2 ,3 ,4-tetrahydroa~uinoxaline A suspension of 5-bromo-1 ,2-dihydro-2 ,2-dimethyl-6- (2-imidazolin-2-ylamino)-3–(4H)-quinoxalinone (150 mg, 0.45 Minol) and LiAL- 4 (17 mg, 0.45 mmol) in tetrahydrofuran (3 ml) is heated and maintained at a temperature of 50-80 0 C until the starting material is consumed. The mixture is cooled to 00 C, 2-3 drops of is added and the mixture is filtered. The solution is concentrated in vacuo to yield a residue which is chromatographed on silica gel with CI{C1 3
CH
3 OH saturated with NH 3 elution to produce the title compound.
EXAMPLE 12 Preparation of 5-bromo-3,4-dihydro-3,3-dimethyl-6-(2imidazolin-2-ylamino) -auinoxalinone By a series of reaction steps analogous to the steps described above in Examples 7 to 10, the title compound is prepared starting with 3, ,4-d ihydro-3, ,3-dimethyl-6 -nitro-2 (1H) -quinoxalinone in place of 1, 2 dihydro-2,2-dimethyl-6nitro-3- (4H) -quinoxalinone.
EXAMPLE 13 Preparation of 5-bromo-3,4-dihydro-3,3-dimethyl-6-(2imidazolin-2-yiamino)-1,2 ,3,4-tetrahydro-quinoxaline 1.25 Using the procedure illustrated in Example 11, the dihydro-3 ,3-dimethyl-6- (2-imidazolin-2-ylamino) (1H)quinoxalinone in place of 5boo12dhdo22 The quinoxaline derivatives produced in Examples to 13 are tested for activity using the following in vitro methods.
WO 93/13771 PCT/US93/00264 27 Rabbit Vas Deferens: Alpha 2 Adrenergic Receptors New Zealand white rabbits (2-3 kg) are killed by CO 2 inhalation and the vasa deferentia is removed. The prostatic ends of the vasa deferentia (2-3 cm lengths) are mounted between platinum ring electrodes in 9 ml organ baths and bathed in Krebs bicarbonate solution of the following composition (millimolar): NaCl 118.0; KC1 4.7; CaCI 2.5; MgS04 1.2; KH 2
P
4 1.2; glucose 11.0; NaHC03 25.0; which solution is maintained at 350 C and bubbled with 95% 02 and 5% CO2. The initial tension of the vas deferens is 0.5 g. The tissues are left to equilibrate for 30 minutes before stimulation is started. Vasa are then field stimulated (0.1 Hz, 2 ms pulse width at 90 mA) using a square wave stimulator (WPI A310 Accupulser with A385 stimulus). The contractions of the tissue are recorded isometrically using Grass FTO3 force-displacement transducers and displayed on a Grass Model 7D polygraph.
A cumulative concentration-response relationship is obtained for the quinoxaline derivative being tested with a 4 minute contact time at each concentration. Each of the quinoxaline derivatives of Examples 10 to 13 is effective to reduce the response height. Therefore, such compounds may be properly classified as Alpha 2 agonists since they are also inhibited pharmacologically by treatment with rauwolscine.
EXAMPLES 18 to 21 Each of the quinoxaline derivatives produced in Examples 10 to 13 is tested for renal and blood pressure effects using the following method.
Young male (20-24 weeks old) Sprague-Dawley rats are used. Under ketamine (60 mg/kg b.wt. and pentobarbital to effect) anesthesia, medical grade plastic tubes are implanted into the abdominal aorta and abl’ MII’ WO 93/13771 PCT/US93/00264 28 vena cava via the femoral vessels. In addition, a Silastic-covered stainless steel cannula is sewn in the urinary bladder. After the surgery, the rats are housed individually and are allowed free access to food and water until the day of the-experiment.
For about 7 to 10 days before surgery and during recovery, the rats are accustomed to a restraining cage by placement in the cage for 2 to 3 hours every 2nd and 3rd day. The cage is designed for renal clearance studies (a model G Restrainer sold by Braintree Scientific, Inc., Braintree, Massachusetts). The animals’ adjustment to the cage is judged by the stability of blood pressure and heart rate.
For an experiment, a rat is placed in the restraining cage, and the arterial line is connected to a Statham pressure transducer and a Beckman Dynograph R61 to monitor the mean arterial blood pressure, hereinafter referred to as MAP. The venous line is connected to an infusion pump system for infusion of replacement fluid. The quinoxaline derivative is administered intraduodenally by cannula.
The bladder cannula was extended with a silastic tube to facilitate collection of urine in preweighed tubes. The volume of urine is measured gravimetrically. Body weight is recorded before and after the experiment.
Throughout the experiments, 0.9% NaCI containing polyfructosan (Inutest) and 1% sodium PAH is infused at a rate of 20 microliters/min. An equilibration period of minutes is followed by two consecutive 30 minute control K clearance periods. Then, the quinoxaline derivative is administered for 90 minutes. Urine collection is resumed minutes after the start of quinoxaline derivative administration. By this time the washout of the bladder cannula dead space (approximately 200 microliters) is WO 93/13771 PCT/US93/00254 29 completed. Three additional clearance measurements are made. Blood samples (150 microliters) are collected at the midpoint of urine collections. Plasma is separated and saved for analyses, and the cells are resuspended in saline and returned to the animals. Water and sodium loss is carefully replaced i.v. by a variable speed infusion pump.
Results of these tests indicate that the present quinoxaline derivatives produce renal effects, e.g., increased renal fluid flow. The effect on blood pressure of such derivatives is limited relative to such renal effects.
EXAMPLES 22 TO Each of the quinoxaline derivative produced in Examples 10 to 13 is tested for anti-diarrheal effects and blood pressure effects using the following method.
Cecectomies are performed in unfasted rats in a conventional manner. The cecectomized rats are put into individual wire-bottomed cages placed over sheets of clean paper, and deprived of food and water for the duration of the assay. The MAP is monitored, as described in Examples 17 to 20, throughout the assay. Rats are given a 2 hour acclimatization period prior to the start of the assay in order to eliminate sporadic episodes of anxiety-induced defecation. During this period they are observed also for consistent occurrences of pelleted feces; an animal producing other than a pelleted stool is disqualified from the study.
Diarrhea is induced with oral administration of 16,16-dimethyl prostaglandin E 2 (dmPGE 2 in 3.5% EtOH.
The quinoxaline derivative is administered by gavage after the onset of diarrheal episodes. The cage papers are removed and examined at 30 minute intervals for dmPGE 2 2- WO 93/13771 PCT/US93/00264 induced diarrhea. Fecal output is recorded at each interval and fecal consistency is assigned a numerical score in each experimental group as follows: 1= normal pelleted stool; 2= soft-formed stools; 3= water stool and/or diarrhea. The fecal output index (FOI) is defined as the summation of the number of defecation episodes and their ranked consistency score within an observation period.
Results of these tests indicate that the quinoxaline derivatives produced in Examples 10 to 13 provide substantial anti-diarrheal effects. Further, such antidiarrheal effects are produced with no or relatively limited effects on blood pressure.
While this invention has been described with respect to various specific examples and embodiments, it is to be understood that the invention is not limited thereto and that it can be variously practiced within the scope of the following claims.
3~ LL~- i i-
Claims (4)
1736.KD -9/5/96 -31- The Claims defining the invention are as follows: 1. A method of treating a mammal in need of such treatment to provide a desired therapeutic effect from the group comprising reduction in peripheral pain, anaesthetisation of the central nervous system, constriction of one or more blood vessels, reduction in or prevention of at least one effect of ischaemia, decongestion of one or more nasal passages and reduction of at least one effect of a inflammatory disorder which comprises administering to said mammal an effective amount 41 of the compound selected from the group consisting of those a C having the formula R4 R H I 3 N R3 R N N R 2 H R 7 I 20 R pharmaceutically acceptable acid addition salts thereof and mixtures thereof, wherein R, and R4 are independently selected from the group consisting of H and alkyl radicals having 1 to 4 carbon atoms; the R 2 s are independently selected from H or alkyl radicals having 1 to 4 carbon atoms or are, together, oxo; the R 3 s are independently selected from H or alkyl radicals having 1 to 4 carbon atoms or are, together, oxo; the 2-imidazolin-2- e 30 ylamino group may be in any of the or 8- positions of the quinoxaline nucleus; and R 5 RG and R 7 each is located in one of the remaining 7- or 8- positions of the quinoxaline nucleus and is independently selected from the group consisting of Cl, Br, H and alkyl radicals having 1 to 3 carbon atoms. «I -W WO 93/13771 PCT/US93/00264 32 2. The method of claim 1 wherein said desired therapeutic effect is a reduction in peripheral pain. 3. The method of claim 1 wherein said desired therapeutic effect is anesthetization of the central nervous system. 4. The method of claim 1 wherein said desired therapeutic effect is constriction of one or more blood vessels. The method of claim 1 wherein said desired therapeutic effect is reduction in or prevention of at least one effect of ischemia. 6. The method of claim 1 wherein said therapeutic effect is decongestion of one or more nasal passages. 7. The method of claim 1 wherein said desired therapeutic effect is reduction in at least one effect of an inflammatory disorder. 8. The method of claim 1 at least one of the Rs and at least one of the R 3 s is H. 9. The method of claim 1 wherein the 2-imidazolin-2- ylamino group is in the 6- position of the quinoxaline nucleus, R 5 is in the 5- position of the quinoxaline 4 nucleus and is selected from the group consisting of Cl, Br and alkyl radicals containing 1 to 3 atoms,.and Rg and R 7 are both H. P WO 93/13771 PCT/US93/00264 33 The method of claim 1 wherein each of R 1 and R, is H. 11. The method of claim 1 wherein each of the R 2 s and each of the R s is independently selected from the group consisting of H and alkyl radicals having 1 to 4 carbon atoms. 12. The method of claim 1 wherein at least .one of the R 2 s is different from at least one of the R.s. 13. The method of claim 11 wherein at least one of the R 2 s is different from at least one of the R 3 s. 14. The method of claim 8 wherein one of the R 2 s and one of the Rs are independently selected from the group consisting of H and methyl radical. The method of claim 14 wherein at least one of the R 2 s is different from at least one of the R s. 16. The method of claim 1 wherein R S is Br. 17. The method of claim 1 wherein said formula is: HN NH Br H N N N pk I *6I ii; WO 93/13771 PCT/US93/00264 34 18. The method of claim 1 wherein said formula HN NH N. 19. The method of claim 1 wherein said formula is: I- HN NHB Y Br H N N CH3 Iy N H The method of claim 1 wherein said formula is: HN NH I-N NH S Br Y, f 4 W 21. The method of claim 1 wherein said formula HN yNH r _i 1 I x WO 93/13771 PCTr/US93/00264 22. The method of claim 1 wherein said formula is: HN NH Y, Br H N N CH 3 NA0 23. The method of claim 1 wherein said formula is: HN NI-I Y, r H N N 0 *N C11 3 H~ I~ j INTERNATIONAL SEARCH REPORT PCT/US 93/00264 IntisnationaJ Application No 1. CLASSIFICATION OF SUBJECT M1ATTER (if several Ciassification Symbols apply, indicate u11)6 According to International Patent Classification (IPC) or to both National Classification auif IPC Int.Cl. 5 A61K31/415; A61K31/495 HI. FIELDS SEARCHED Minimum Documentation Searched 7 Classification system Classification Symbols Documentation Searched other than Minimum Documentation to the Extent that such Documents ae Included in the Fields Searche’ I!H. DOCUMENTS CONSIDERED TO BE RELEVANT9 Category 0 Citation of Document, 11 with indication, where appropriate, of the revat passages 12 kEevant to Claim No.L3 Y US,A,3 890 319 (PFIZER INC.) 1-273 17 June 1975 cited in the application see column 1, line 6 column 1, line 13; claims 1-9 Y CHEMICAL ABSTRACTS, vol. 105, no. 1, 1-23 7 July 1986, Columbus, Ohio, US; abstract no. 481u, C.F. COLPAERT ‘Maximal magnitude of effect and potency of putative alpha-adrenoceptor agonists in causing CNS depression, in relaxing muscle, and in lowering body temperature in rat’ page see abstract Drug. Rev. Res. 7 209-220 (1986) 0 Special categories of cited documents 10 IT’ later document published after the international filing date A’ ocuentdefnin th geerl sateof he n wichis otor pr* -ity date and not in conflict with the appication but »dcnside n te nersi of th rahc sntcted .u understand the principle or theory underlying the consdere tobe o paticuar elevnceinvention I’ earlier document but published on or after the international Xr document of patilatr relevane; the claimed invention filing date cannot be considered novel or canot be considered to LV document which my throw doubts on priority dais(s) or involve an inventive seop which is cited to estakilsh the publication date of another IY document of particular relevance; the clalmed Invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is comblned with one or more other such docu- other means meents, such combination beiag obvious to a person skilled ‘1P document publishei iprior to the international filing date but in the an. later than the priority dale claimed W& document mmber of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Smjds Date of Mailing of this International Search Resport 19 APRIL 1993 1 International Searching Authority Signatue of Authorize Officer EUROPEAN PATENT OFFICE HERZ C .P. Feorm KCTISAZI imum andsh 4Jerenr 1185 PCT/US 93/00264 Intanational Application No m. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) Category I CitatiDo of Document, with indication, where appmprinae, of the relevant passages Relevant o Claim No. Y CHEMICAL ABSTRACTS, vol. 99, no. 15, 1-23 October 1983, Columbus, Ohio, US; abstract no. 116644m, A. PHILIPPU ET AL. ‘Changes in the arterial blood pressure increase the release of endogeneous histamine in the hypothalamus of anesthetized cats’ page 137 see abstract Nauyn-Schmiedeberg’s Arch. Pharmacol. 323 162-167 (1983) Y CHEMICAL ABSTRACTS, vol. 98, no. 25, 1-23 June 1983, Columbus, Ohio, US; abstract no. 210440t, R.D. EKAS ET AL. ‘Presynaptic alpha- and beta-adrenoceptor stimulation and norepinephrine release in the spontaneously hypertensive rat’ page 109 see abstract Hypertension (Dallas) 5 198-204 (1983) Y CHEMICAL ABSTRACTS, vol. 98, no. 1, 1-23 3 January 1983, Columbus, Ohio, US; abstract no. 921, R.D. EKAS ET AL. ‘Increased presynaptic alpha-adrenoceptor-mediated regulation of spontaneously hypertensive rats’ page 918 see abstract Clin; Sci., Suppl. 63 309-311 (1982) Y CHEMICAL ABSTRACTS, vol. 93, no. 13, 1-23 29 September 1980, Columbus, Ohio, US; abstract no. 126080q, J.G. DE MEY ET AL. ‘Differences in pharmacological properties of postjunctional alpha-adrenergic receptors among arteries and veins’ page 96 see abstract Arch. Int. Pharmacodyn. Ther. 244 (2) 328-329 (1980) Fau PCT/ISAJO210 (rtn ht (Jmmy J.G. -AIL- MEY ET L D f n i International Application No PCT/US 93/00264 I. DOCUMENTS CONSIDERED TO HE RELEVANT (CONTINUED FROM THE SECOND SHEET) Itewory Citation of Document, with Indication, where app.yopriateg of the eant passaw» Relevanit to Claim No. YCHEMICAL ABSTRACTS, vol. 91, no. 21, 1-23 19 November 1979, Columbus, Ohio, US; abstract no. 168403m, A. STEPPLER ET AL. ‘Pre- and postsynaptic effects of phenylephrine and tramazoline on blood vessels in vivo’ page 43; i see abstract &Adv. Biosci. 99-104 (1979) V CHEMICAL ABSTRACTS, vol. 90, no. 5, 1-23 29 January 1979, Columbus, Ohio, US; I abstract no. 33949c, A. STEPPELER ET AL. ‘A comparison of pre- and postsynaptic alpha-adrenergic effects of phenylephrine and tramazoline on blood vessels of the rabbit in vivo’ page 37 see abstract Naunyn-Schmiedeberg’s Ar-1h. Pharmacol. 304 223-230 (1978) V CHEMICAL ABSTRACTS, vol. 89, no. 1, 1-23 3 July 1978, Columbus, Ohio, US; abstract no. 474v, P.B.M.W.M. TIMMERMANS ET AL. ‘Hypotensive and bradycardic effects of classical alpha-sympathomimetic drugs upon intraveneous administration to pentobarbi tone-anesthetized ratd’ page 49 see abstract Arch. Int. Pharmacodyn. Ther. 231 (1) 98-103 (1978) Y CHEMICAL ABSTRACTS, vol. 88, no. 23, 1-23 June 1978, Columbus, Ohio, US; abstract no. 164291p, A. WALLAND ‘Inhibition of a. somato-sympathetic reflex via peripheral presynapti c al1pha-adrenoceptors’ page see abstract Eur. J. Pharmacol. 47 211-221 (1978) Fes PLTAISA/210 tinfte sld (Jam UI I PCT/US 93/00264 International Application No Ill. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) Catewory 0 1Citation of Document, with indication, where appropriate, of the reievant passages -7 Reevant to Claim No. CHEMICAL ABSTRACTS, vol. 82, no. 17, 28 April 1975, Columbus, Ohio, US; abstract no. 106180s, H.A.J. STRUYKER BOUDIER ET AL. ‘Central and peripheral alpha adrenergic activity of imidazoline derivatives’ page 13; see abstract Life Sci. 15 887-8939 (1974) EP,A,0 422 878 (ALLERGAN, INC.) -7 April 1991 see page 4, line 30 line 38; claims 1-12 EP,A,O 426 390 (ALLERGAN, INC.) 8 May 1991 see claims 1-13 WO,A,9 202 515 (ALLERGAN, INC.) February 1992 see page 8, line 9 page 9; claims 1-43 1-23 1-23 1-23 1-23 Az FoampCTjt2A1IO(wMire 190(Jn IS -a- INTERNATIONAL SEARCH REPORT l…rnational application No. PCT/US 93/00264 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. O Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Pls. see rule 39.1(IV) PCT! Although claims 1-23 are directed to a method o of treatment of the human/animal body the search has been carried out and b ased on the alleged effects of the compound/composition.
2. O Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment Sof any additional fee.
3. As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:
4. D No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: i Remark on Protest The additional search fees were accompanied by the applicant’s protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISA;210 (continuation of first sheet (July 1992) 2** ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. 9300264 69336 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members ame as contained in die European Patent Office EDP file on The European Patent Office is in no way liable for these particuiars which are merely given for the purpose of inforination. 19/04/93 Patent document Pubication Patent family Publication cited in search report date mber(s) T date US-A-3890319 17-06-75 GB-A- 1381979 29-01-75 AU-B- 471598 29-04-76 AU-A- 5198573 08-08-74 BE-A- 795970 27-08-73 CA-A- 981678 13-01-76 CH-A- 577500 15-07-76 CH-A- 576975 30-06-76 DE-A- 2309160 27-09-73 FR-A,B 2181776 07-12-73 JP-C- 1170985 17-10-83 JP-A- 48097878 13-12-73 JP-B- 57054516 18-11-82 JP-C- 1156372 15-07-83 JP-A- 56025176 10-03-81 JP-B- 57045439 28-09-82 NL-A- 7302799 31-08-73 SE-B- 417204 02-03-81 US-A- 4029792 14-06-77 EP-A-0422878 17-04-91 US-A- 5077292 31-12-91 AU-B- 628666 17-09-92 AU-A- 6390090 18-04-91 CA-A- 2025212 13-04-91 JP-A- 3145490 20-06-91 WO-A- 9213855 20-08-92 US-A- 5112822 12-05-92 EP-A-0426390 08-05-91 US-A- 5021416 04-06-91 AU-B- 627626 27-08-92 AU-A- 6396690 09-05-91 CA-A- 2025189 01-05-91 JP-A- 3153626 01-07-91 WO-A-9202515 20-02-92 US-A- 5112822 12-05-92 AU-A- 8289491 02-03-92 &W For more details about this an x mm Offieial Journal of the European Patent Office, No. 12/82 L
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1992-01-13
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2006-05-02
James A. Burke
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2001-11-27
Allergan
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The Procter & Gamble Company
6-(2-imidazolinylamino)quinoline compounds useful as alpha-2 adrenoceptor agonists
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1996-11-19
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7-(2-imidazolnylamino) quinoline compounds useful as alpha-2 adrenoceptor agonists
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COMPOUNDS 6- (2-IMIDAZOLINYLAMINO) QUINOLINE UTEIS AS ALPHA-2 ADRENOCEPTOR AGONISTS
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1993-12-17
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5-(2-imidazolinylamino) benzimidazole compounds useful as alpha-2 adrenoceptor agonists
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5-(2-imidazolinylamino)-benzimidazole derivatives, their preparation and their use as .alpha.-adrenoceptor agonists with improved metabolic stability
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