EP0573581A1 - Compositions et methodes de traitement de douleurs sympathiques - Google Patents

Compositions et methodes de traitement de douleurs sympathiques

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Publication number
EP0573581A1
EP0573581A1 EP92907852A EP92907852A EP0573581A1 EP 0573581 A1 EP0573581 A1 EP 0573581A1 EP 92907852 A EP92907852 A EP 92907852A EP 92907852 A EP92907852 A EP 92907852A EP 0573581 A1 EP0573581 A1 EP 0573581A1
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alkyl
compound
acid
hydrido
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EP0573581A4 (en
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Inc. Arc 1
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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    • 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
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the invention relates to the diagnosis and treatment of sympathetically maintained pain using sympatholytic agents which are defined herein as compounds that interfere with sympathetic function in the peripheral tissue or interfere with the action of drugs associated with sympathetic function.
  • SMP sympathetically maintained pain
  • Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold and/or an increase in pain to suprathreshold stimuli is observed. The decrease in pain
  • SUBSTITUTESHEET threshold to mechanical stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.
  • IVRB intravenous regional blockage
  • LABSG is subject to false negative results if the local anesthetic fails to anesthetize adequately the sympathetic ganglia.
  • the anesthetic may reach the somatic afferents in the nearby nerve roots and produce pain relief because of concurrent somatic blockade, and certain afferents may in addition course with sympathetic efferents.
  • LABSG involves strategic localization of the needle prior to injection, and thus fluoroscopy is often needed.
  • IVRB the guanethidine may escape into the systemic circulation with resultant systemic untoward effects.
  • a series of complications have been reported with LABSG, including pneumothora , injury to the kidney, inadvertent systemic application, spinal anesthesia, hemorrhage, etc. It is difficult to evaluate placebo responses with both LABSG and IVRB.
  • peripheral adrenergic receptors are involved in SMP. Stimulation of the peripheral but not central cut end of the sympathetic chain reproduces pain in causalgia patients after sympathectomy.
  • Local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic blockade via intravenous administration of phentolamine rapidly abolishes sympathetically-maintained pain and hyperalgesia.
  • Depletion of peripheral catecholamines by regional intravenous guanethidine relieves pain and hyperalgesia.
  • Intradermal injection of norepinephrine rekindles the pain and hyperalgesia that had been relieved in patients by sympathectomy or sympathetic block but does not cause pain or hyperalgesia in normal subjects.
  • the non-specific ⁇ -adrenergic antagonist phenoxybenzamine and the specific ⁇ - j -adrenergic antagonist prazosin can be effective in relieving pain in patients with SMP.
  • the beta-adrenergic antagonist propranolol has little effect on SMP.
  • ⁇ -adrenergic blocking agent could be beneficial in the treatment of SMP patients.
  • Therapeutic uses of the ⁇ -adrenergic compounds are known in the art.
  • U.S. Patent No. 4,801,587 discloses the use of phentolamine as a vasodilator to treat impotence.
  • U.S. Patent No. 4,310,535 discloses the use of phentolamine in combination with other drugs for use in the control of immune reactions.
  • the use of phentolamine and clonidine for controlling hypertension is disclosed in U.S. Patent No. 4,250,191.
  • ⁇ -Adrenergic drugs have been found to be useful in the stabilization of intraocular lenses, as disclosed in U.S. Patent No. 4,443,441.
  • U.S. Patent No. 4,201,211 discloses the use of a clonidine patch for therapeutic use as a stimulant for the central nervous system.
  • Sympathetically maintained pain is treated topically by administering to the site where sympathetically maintained pain is present a sympatholytic agent, such as an ⁇ -adrenergic antagonist, ⁇ adrenergic antagonist, ⁇ 2 adrenergic agonist, or other drug that depletes or blocks synthesis of norepinephrine from the sympathetic terminals.
  • a sympatholytic agent such as an ⁇ -adrenergic antagonist, ⁇ adrenergic antagonist, ⁇ 2 adrenergic agonist, or other drug that depletes or blocks synthesis of norepinephrine from the sympathetic terminals.
  • Sympathetic efferent fibers release norepinephrine which in turn activates ⁇ -adrenergic receptors.
  • Activation of the ⁇ -adrenergic receptors by norepinephrine either directly or indirectly, excites nociceptors.
  • Activity in the nociceptors then evokes pain and further activity in the sympathetic efferent fibers. This, in turn, results in further discharge of the nociceptors.
  • the goal in therapy is to block the effects of norepinephrine on nociceptors.
  • Topical application to the site where sympathetically maintained pain is present of an ⁇ -adrenergic antagonist, ⁇ ⁇ - adrenergic antagonist, ⁇ , adrenergic agonist, a combination thereof, or other drug that depletes or blocks synthesis of norepinephrine at the sympathetic terminals (collectively referred to herein as "sympatholytic agents") relieves the pain.
  • Topical application of the sympatholytic agent is also used in the treatment of peripheral vascular diseases characterized by high alpha-adrenergic tone in cutaneous blood vessels, such as frostbite, Raynaud's disease, thrombophlebitis, and spastic peripheral vascular disorders.
  • peripheral vascular diseases characterized by high alpha-adrenergic tone in cutaneous blood vessels, such as frostbite, Raynaud's disease, thrombophlebitis, and spastic peripheral vascular disorders.
  • the compounds used in the present method are known to those skilled in the art.
  • the various classes of compounds and examples thereof are described in The Pharmacological Basis of Therapeutics. 8th Edition, Gill, A.G., T. W. Rail, A.S. Nies, P. Taylor, editors (Pergamon Press, Co., Inc., NY 1990), the teachings of which are incorporated herein.
  • Several different structural classes of sympatholytic agents have been developed, from which a compound can be selected for use as a topical therapy for sympathetically maintained pain.
  • a class of cyclic amidine compounds from which a suitable sympatholytic agent with alpha-l adrenoreceptor antagonist activity, alpha-2 adrenoreceptor agonist activity, or both activities combined can be represented by Formula I:
  • A is selected from aryl, aryloxy, anilino, arylamino, diarylamino, heteroaryl, heteroaryloxy, or heteroarylamino, which may be substituted with one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; B may be independently selected from linear alkylene containing from 1 to 4 methylene units, branched alkylene, i ino, or thio; and n is either 2 or 3; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of formula I consists of those compounds wherein A is phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, tetrahydronaphthyl, or diarylamino; wherein B is methylene or 1-ethylene; and n is 2.
  • An especially preferred class of compounds of Formula I consists of those compounds wherein A is substituted phenyl, in which positions 2 and 6 of the phenyl ring are substituted by radicals independently selected from hydrido, chloro, methyl, ethyl, cyclopropyl, or thiomethyl, and positions 3, 4, and 5 are substituted by radicals independently selected from hydrido, 2-propyl, tertbutyl, hydroxyl, trifluoromethyl, chloro, or fluoro; and B is methylene, or 1-ethylene when A is substituted phenoxy; and n is 2.
  • Another especially preferred class of compounds of formula I consists of those compounds wherein A is diarylamino, in which case each aryl group can be independently substituted by hydroxyl; and wherein B is methylene; and n is 2.
  • Yet another especially preferred class of compounds of Formula I consists of those compounds wherein A is 1- naphthyl or tetrahydronaphthyl; and B is either zero or one methylene unit; and n is 2.
  • a family of specifically preferred compounds which are included in Formula I consists of the compounds tetrahydrozoline, naphazoline, phentolamine, dexlofexidine, oxymetazoline, cirazoline, xylometazoline, and tolazidine.
  • Another class of compounds from which a suitable sympatholytic agent with sympathetic neurotransmitter depleting activity or alpha-1 adrenoreceptor antagonist activity may be selected is that of substituted ureas, represented by Formula II:
  • A is selected from alkyl, branched alkyl, aryl, aryloxy, heteroaryl, or heterocyclic moiety, which may bear one or more substituents selected from halogen.
  • SUBSTITUTESHEET lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein R 1 and R 2 may be independently selected from hydrido, lower alkyl, hydroxyl or cyano; wherein R 3 and R 4 may be independently selected from hydrido or lower alkyl, or together to form a carbonyl moiety; wherein R 5 is selected from hydrido or lower alkyl; and wherein n is any value between 0 and 4 inclusive; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula II consists of those compounds wherein A is selected from lower alkyl, phenyl, substituted phenyl, phenoxy, substituted phenoxy, anilino, substituted anilino, azacyclic, benzodioxan, and substituted dioxolane; wherein R 1 is selected from hydrido, methyl, or hydroxyl, and R 2 is selected from hydrido or cyano; wherein R 3 and R 3 are independently either hydrido or methyl, or together form a carbonyl; wherein R 5 is hydrogen; and n is any value from 0 to 3 inclusive.
  • An especially preferred class of compounds of Formula II consists of those compounds wherein A 2 is selected from lower alkyl, 2,6-dichlorophenyl, phenoxy, (2,6-dichloro)phenoxy, (2,6-dichloro)anilino, 4-phenyl- 1,2,3,6-tetrahydropyridinyl, octahydro-1-azocinyl, octahydro-2-azocinyl, benzodioxan-2-yl, or 1,4- dioxaspiro[4,5]dec-2-yl; wherein R 1 is selected from hydrido, methyl, or hydroxyl, and R 2 is selected from hydrido or cyano; wherein R 3 and R 3 are independently either hydrido or methyl, or together form a carbonyl; wherein R 5 is hydrogen; and n is any value from 0 to 3 inclusive.
  • SUBSTITUTESHEET A family of specifically preferred compounds of Formula II consists of bethanidine, guanfacine, guanclofine, guanoxan, guanethidine, guanazodine, guanoxyfen, guanocline, guanoctine, and guanadrel.
  • Another class of compounds from which a suitable sympatholytic agent may be selected with sympathetic neurotransmitter depleting activity, alpha-1 adrenoreceptor antagonist activity, alpha-2 adrenoreceptor agonist activity, or a combination of these actions, is represented by Formula III:
  • A is selected from alkyl, branched alkyl, aryl, aryloxy, heteroaryl, or heterocyclic moiety, which may bear one or more substituents selected from halogen, lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; B 2 is either carbon, wherein it forms an unsaturated imino linkage with the adjacent nitrogen, or linear or branched chain alkylene moiety of 1-4 methylene units in length; R 1 and R 2 are as defined for Formula II; and R 6 is selected from hydrogen or lower alkyl, when the attached nitrogen is not incorporated into an unsaturated imino bond; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula III consists of those compounds wherein A is selected from phenyl or substituted phenyl; wherein B 2 is a carbon attached by a double bond to the adjacent nitrogen to form an imino moiety, or where B 2 is a saturated linear
  • An especially preferred class of compounds of Formula III consists those compounds wherein is a 2,6- disubstituted phenyl moiety, wherein the substituents are selected from chloro or methyl.
  • a group of specifically preferred compounds of Formula III consists of guanabenz, guanoxabenz, and guanoclor.
  • Another class of compounds from which a suitable sympatholytic agent with alpha-2 adrenoreceptor agonist activity may be selected is represented by Formula IV:
  • a 4 may be selected from aryl, and heteroaryl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxy1, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein X is selected from thio, imino, or methylene; wherein R 7 is selected from hydrogen, lower alkyl, or oxygen-containing heterocycle; and wherein n is either 2 or 3; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula IV consists of those compounds wherein A 4 is phenyl; wherein A 4 is substituted phenyl, on which positions 2 and 6 of the phenyl ring may be independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl, and positions 3, 4, and 5 may be
  • SUBSTITUTE SHEET independently substituted by a radical selected from hydrogen, methyl, trifluoromethyl, fluoro, or cyano; wherein A 4 is 3-thienyl, on which positions 2 and 4 are independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl; wherein A 4 is 1-naphthyl, 5,6,7,8-tetrahydronaphth-l-yl, pyrrolyl, oxazolyl, isoxazolyl, indol-3-yl, indazol-3- yl, quinolinyl, quinazolinyl, quinoxazolinyl, benzoxazolyl, and benzothiophen-3-yl; wherein A 4 is pyrimidin-4-yl, on which positions 3 and 5 are independently substituted by hydrogen, chloro, methyl, ethyl, cycloalkyl, or ethoxy; wherein R
  • An especially preferred class of compounds of Formula IV consists of compounds wherein A 4 is selected from phenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6- diethylphenyl, 3,4- dihydroxyphenyl, 3-fluoro-6- methylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-chloro- 4-methylphenyl, 3-chloro-4-methylthien-3-yl, 5,6,7,8- tetrahydronaphth-l-yl, and 4-chloro-5-methoxy-2- methylpyrimidin-4-yl; wherein R 7 is hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2.
  • a specifically preferred class of compounds of Formula IV consists of xylazine, flutonidine, moxonidine, tramazoline, tolonidine, piclonidine, tiamenidine, and clonidine.
  • Another class of compounds from which a suitable sympatholytic agent with sympathetic neurotransmitter depleting activity alone or in combination with alpha-2 adrenoreceptor agonist activity may be selected is represented by Formula V:
  • Y represents the remainder of a cyclic structure selected from 1,2,3,4-tetrahydroisoquinoline or 2,3- dihydroisoindole, which may be substituted by one or more radicals selected from halogen, lower alkyl, alkoxy, hydroxyl, oxo, amino, dialkylamino, aryl, aryloxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, alkylsulfonyl, alkanoyl, or alkylthio; and wherein R 1 and R 2 are defined as in Formula II; or a pharmaceutically acceptable salt thereof.
  • An especially preferred class of compounds of Formula V consists of those compounds wherein Y is substituted tetrahydroisoquinoline, and wherein the preferred substituents are wither hydrogen or halogen, preferably on position 7 of the tetrahydroisoquinoline nucleus, and wherein R 1 and R 2 are both hydrogen.
  • a specifically preferred class of compounds of Formula V consists of debrisoquin and guanisoquin.
  • R 8 is hydrogen, alkyl, or cycloalkyl; wherein R and R 10 are independently selected from hydrogen, alkyl, alkoxy, acyloxy, dialkylamino, or alkylthio; wherein R is selected from hydrogen, alkyl, or alkoxy; wherein R 1 and R 13 are independently selected from hydrogen or alkyl; wherein n' and n" independently represent values from 2 to 4 inclusive; and wherein Z may abe selected from alkyl, alkoxy, alkylaryl, alkenylaryl, alkoxyalkyl, hydroxyalkyl, aryl, heteroaryl, and heteroalkyl; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula VI consists of those compounds wherein R 8 is hydrogen, R 9 and R 10 are both alkoxy; wherein R 11 is selected from hydrogen or alkoxy; and wherein R 12 is selected from hydrogen or alkyl.
  • a preferred class of compounds of Formula VII consists of those compounds wherein R 8 is hydrogen, R 9 and R 10 are both alkoxy; wherein R 11 is selected from hydrogen or alkoxy; and wherein n' and n" are independently either 2 or 3.
  • Formula VI consists of those wherein R and R are both methoxy; wherein an R is selected from hydrogen or methoxy; wherein R is selected from hydrogen or methyl; wherein R 13 is hydrogen; and wherein Z is selected from ethyl, propyl, butyl, 2-methylpropyl, 1-methoxyethyl, 2- (2-furoyl)-ethenyl, 2-tetrahydrofuranoyl, 2-furoyl, 2- hydroxy-2-methylpropyloxy, 2-hydroxypropyl, and 2- thiomethyl-1 , 3 ,4-oxadiozol-4-yl.
  • An especially preferred class of compounds of Formula VII consists of those compounds wherein R 9 and R are both methoxy; wherein an R 11 is selected from hydrogen or methoxy; wherein Z is selected from ethyl, propyl, butyl, 2-methylpropyl, 1-methoxyethyl, 2-(2- furoyl)-ethenyl, 2-tetrahydrofuranoyl, 2-furoyl, 2- hydroxy-2-methylpropyloxy, 2-hydroxypropyl, and 2- thiomethyl-l,3,4-oxadiazol-4-yl; and wherein n' is 2 and n H is 2 or 3.
  • a specifically preferred class of compounds of Formulas VI and VII consists of alfuzosin, bunazosin, doxazosin, metazosin, neldazosin, prazosin, terazosin, trimazosin, tiodazosin, and MY-5561.
  • N may be selected from aryl or heteroaryl, which may be substituted with one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; and M can be further defined as:
  • R 14 and R 15 are independently selected from hydrogen, alkyl, alkoxy, or hydroxy; wherein P is selected from heteroaromatic or polycyclic heteroaromatic, which may be substituted by one or more radicals selected from halogen, alkyl, alkoxy, oxo, cyano, alkoxycarbonyl, arylalkyl, trifluromethyl, or aryloxyalkyl; and wherein Q is selected from oxygen or imino; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula VIII consists of those compounds wherein N is phenyl, pyridyl, thienopyridinyl, indolyl, or pyrimidin-2-yl; wherein, if N is phenyl, then the phenyl ring may be substituted by one or more of the following preferred radicals: chloro, methoxy, cyano, thiomethyl, trifluoromethyl; wherein R 14 is hydroxy, ethoxy, or methoxy; wherein R 15 is hydrogen; and wherein P is selected from 3-pyridyl, 1-naphthyl, 2- quinazolin-l,3-dione, 6,7-methylenedioxyindol-2-yl, 1,3- pyrimidin-2,4-dion-6-yl; 3H-1,2,4-triazol-3-on-2-yl; 1,2,4-triazolo[4,3-a]pyridin-3(2H)-on-2-
  • An especially preferred class of compounds of Formula VIII consists of those compounds wherein N is selected from phenyl, 3-chlorophenyl, 2-methoxyphenyl, 3- methoxyphenyl, 3-trifluoromethylphenyl, or 3-indolyl.
  • a specifically preferred class of compounds of Formula VIII consists of urapidil, solypertine, naftopidil, saterinone, trazodone, nefazodone, tiospirone, SGB-1534, and IP-66.
  • Another class of compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity may be selected is represented by
  • a 5 is selected from aryl, aryloxy, arylalkyloxy, arylamino, cycloalkyl, cycloalkyloxy, arylcarbonyl. arylsulfonyl, heteroaryl, heteroarylcarbonyl , heteroaryloxy, heteroarylamino, and heteroarylsulfonyl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxy1, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, heterocyclic, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, or arylsulfonyl; wherein K is
  • a preferred class of compounds of Formula IX consists of those compounds wherein A 5 is selected from substituted phenyl, heteroaromatic, or heterocyclic structures; wherein K is a linear alkylene chain of 1 to 4 methylene units in length; wherein R16 is selected from hydrogen, phenyl, substituted phenyl, heteroaromatic, arylcarbonyl, or arylcarbonylamino; wherein R 17 is selected from hydrogen or methyl; or wherein R 16 and R together represent a double bond attached to a substituted carbon, preferably a diary1 substituted carbon; wherein R 16 and R 17 taken together represent attachment points for a spirocyclic ring moiety, preferably selected from 1,3-dioxalane, or 5,5'- oxazolidin-3-one; and wherein R18 may be selected from hydrogen or arylcarbonylamino.
  • a specifically preferred class of compounds of Formula IX consists of piperoxan, proroxan, fenspiride, indoramin, and lidanserin.
  • Another class of compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity is represented by Formula X:
  • a 6 may be selected from aryl, aryloxy, heteroaryl, heteroaryloxy, arylthio, heteroarylthio, arylalkyl, and heteroarylalkyl, which may be substituted by one or more radicals selected from chloro, hydroxyl, alkoxy, alkyl, amino, aminoalkyl, arylsulfonamino, alkylsulfonamino, aminocarbonyl, aminosulfonyl, thiol, aryl, heteroaryl, or alkylthio; wherein R 19 , R 22 , and R 23 may be independently selected from hydrogen or alkyl; wherein R 20 may be selected from hydrogen or alkyl; wherein R 21 may be further described as:
  • R 24 and R 25 may be independently selected from hydrogen or alkyl; wherein A 7 is aryl, preferably phenyl or substituted phenyl; and n"" represents a value of 0 to 4 methylene units.
  • Formula X describes compounds wherein R 20 and R21 taken together represent contact points which form a ring, such as pyrrolidine or piperidine, which may be further substituted; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula X consists of those compounds wherein A 6 is selected from phenyl, substituted phenyl, carbostyril, 2,3- dihydrobenzo[b]thiophen-5-yl, and thiazolyl-2-thio; wherein R 19 is hydrogen; wherein R 23 is hydrogen or methyl; wherein R 20 is hydrogen; wherein R 24 and R 25 are independently hydrogen or methyl; and wherein A is phenyl.
  • Another preferred class of compounds of Formula X consists of those compounds wherein R 20 and R 21 together form a piperidine moiety, which is further substituted by a phenylmethyl substituent.
  • a specifically preferred class of compounds of Formula X consists of labetalol, amosulalol, arotinolol, brefanolol, ifenprodil and tibalosin.
  • Another class of compounds from which a suitable sympatholytic agent may be selected as an irreversible alpha-1 adrenoreceptor antagonist is represented by Formula XI:
  • R 26 and R 27 are independently selected from alkyl, arylalkyl, aryloxyalkyl, or heteroalkyl; or wherein R 26 and R 7 taken together represent a ring
  • G represents a suitable leaving group substituent selected from halogen, alkylsulfonyloxy, or arylsulfonyloxy; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula XI consists of those compounds wherein R 26 and R 27 are independently taken from phenylalkyl or phenyloxyalkyl, and G is chloro.
  • a specifically preferred class of compounds of Formula XI consists of phenoxybenzamine and dibenzamine.
  • Another class of compounds from which a suitable sympatholytic agent may be selected as an alpha-2 adrenoreceptor agonist is represented by Formula XII:
  • a 8 is selected from aryl or heteroaryl, which may be substituted by one or more radicals independently selected from alkyl, halogen, alkoxy, alkylthio, hydroxyl, amino, arylsulfonylammo, of carboxamido; and wherein R 28 is selected from hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds of Formula XII consists of those compounds wherein A 8 is phenyl or substi •tuted phenyl, and R28 i•s hydrogen or methyl.
  • a specifically preferred class of compounds of Formula XII consists of detomidine and medetomidine.
  • a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity or sympathetic neurotransmitter depleting activity may also be selected from the structural class of compounds known generically as the Rauwolfia alkaloids. As described in Burger ' s Medicinal Chemistry, 4th Edition, Part III, pages 302- 305 and 932-933 (M. E. Wolff, editor, Wiley-Interscience,
  • compounds in this class are well known sympatholytic agents. Specifically preferred compounds of this class are reserpine, mediodespidine, deserpidine, rauwulscine, and extracts of Rauwolfia serpentina; or a pharmaceutically acceptable salt thereof.
  • a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity may also be selected from the class of compounds known generally as the ergot alkaloids.
  • compounds of this class are well known sympatholytic agents.
  • Specifically preferred compounds from this class are nicergoline, dihydroergocornine, dihydroergocryptine , dihydroergocristine, amsulosin, BAM-1125, and the mixture of hydrogenated derivatives of the ergotoxine alkaloids.
  • Another class of compounds from which a suitable sympatholytic agent may be selected as an inhibitor of dopamine beta-hydroxylase is represented by Formula XIII:
  • a more preferred class of compounds within Formula XIV consists of those compounds wherein each of R 36 , R 37 and R 40 through R 43 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through four, inclusive; wherein each of R 38 and R 39 is independently selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl.
  • Formula XIV consists of those compounds where in each of
  • R 36 , R 37 and R 40 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through three, inclusive; and wherein each of
  • R 38 and R 39 is selected from hydrido, alkyl, amino and monoalkylamino. Most preferred are compounds wherein each of R 40 through R 43 is independently selected from hydrido and alkyl; wherein each of R 36 and R 37 is hydrido; wherein r is selected from zero, one and two; wherein R 38 is selected from hydrido, alkyl and amino; and wherein R 39 is selected from hydrido and alkyl.
  • Another class of compounds from which a suitable sympatholytic agent with dopa ine beta-hydroxylase inhibitor activity may be selected to provide the conjugate first residue is represented by Formula XV:
  • each of R 44 through R 48 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aryloxy, alkoxy, alkylthio, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl.
  • A' is -CO-R 49 or -NR 51 R 52 wherein R 49 is selected from hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy, -OR 50 and -NR 53 R 54 , wherein R 50 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; wherein each of R through R 54 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, ary
  • each of R 49 through R52 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, phenyl, benzyl, alkoxy, phenoxy, benzyloxy, alkoxyalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxya ino, carboxyl, carboxyalkyl.
  • a class of specifically-preferred compounds of Formula XVI consists of:
  • 5-n-butyl-4-aminopicolinic acid 5-n-butyl-4-hydroxyaminopicolinic acid; and 5-n-butyl-4-methylpicolinic acid.
  • Especially preferred of the foregoing class of compounds of Formula XVI is the compound 5-n- butylpicolinic acid (fusaric acid) .
  • SUBSTITUTESHEET Another class of compounds from which a suitable sympatholytic agent with dopamine beta-hydroxylase inhibiting activity is represented by Formula XVII:
  • R 55 is hydrido, hydroxy, alkyl, amino and alkoxy; wherein R 56 is selected from hydrido, hydroxy and alkyl; wherein each of R 57 and R 58 is independently selected from hydrido, alkyl and phenalkyl; wherein R 59 is selected from hydrido and R 60 C- with R 60 selected from alkyl, phenyl and phenalkyl; wherein u is a number from one to three, inclusive; and wherein v is a number from zero to two, inclusive; or a pharmaceutically-acceptable salt thereof.
  • a preferred class of compounds within Formula XVII consists of those compounds wherein R 55 is selected from hydroxy and lower alkoxy; wherein R 56 is hydrido; wherein R 57 is selected from hydrido and lower alkyl; wherein R 58 is hydrido; wherein R 59 is selected from hydrido and R 60 C- with R 60 selected from lower alkyl and phenyl; wherein u is two; and wherein v is a number from zero to two, inclusive.
  • a more preferred class of compounds within Formula XVII consists of those compounds of Formula XVIII
  • R 61 is selected from hydroxy and lower alkyl; wherein R 57 is selected from hydrido and lower alkyl; wherein R 59 is selected from hydrido and R 60 C- with R 60 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive.
  • XVIII consists of those compounds wherein R 61 is hydroxy; wherein R 57 is hydrido or methyl; wherein R 59 is hydrido or acetyl; and wherein n is a number from zero to two, inclusive.
  • Formula XVIII are the compounds l-(3-mercapto-2-methyl- l-oxopropyl)-L-proline and l-(2-mercaptacetyl)-L-proline
  • Suitable sympatholytic compounds which are not encompassed in Formulas I through XVIII from which a suitable agent may be selected include the sympathetic neurotransmitter depleting agents bretylium and M -10459, and the alpha-1 adrenergic antagonist methylapogalanthamine.
  • ⁇ -Adrenergic blocking agents bind selectively to the ⁇ class of adrenergic receptors and thereby interfere with the capacity of sympathomimetic amines to initiate actions at these sites.
  • ⁇ -Adrenergic blockade is due to the direct action of these drugs on ⁇ receptors and is independent of any effects on adrenergic neurons or on the basic response mechanisms of effector cells, ⁇ - Adrenergic receptors are not affected by conventional doses of any ⁇ -blocking agent currently in use.
  • ⁇ -adrenergic antagonists examples include phenoxybenzamine, dibenzamine, phentolamine, tolazoline, and prazosin. Phenoxybenzamine and dibenzamine bind covalently to the ⁇ receptor and produce an irreversible type of blockade. Phentolamine, tolazoline, and prazosin bind reversibly and antagonize the actions of sympathomimetic amines competitively. There are differences in the relative abilities of ⁇ -adrenergic blocking agents to antagonize the effects of sympathomimetic amines at the two subtypes of ⁇ receptors, ⁇ ⁇ and ⁇ 2 receptors.
  • Phenoxybenzamine is approximately 100-fold more potent in blocking ⁇ ⁇ (postsynaptic) receptors than ⁇ 2 receptors (that modulate neural release of transmitter) .
  • Prazosin is also a highly selective ⁇ 1 -blocking agent, while phentolamine is only three to five times more potent in inhibiting ⁇ than ⁇ ,-adrenergic receptors.
  • yohimbine is a selective ⁇ 2 blocker and has been shown to prevent the antihypertensive effect of systemic clonidine. Phentolamine is the preferred ⁇ -adrenergic antagonist at this time.
  • Topical administration also includes iontophoresis wherein an electric current drives the drug, in the form of an ion such as a pharmaceutically acceptable salt, into the skin.
  • the topical application allows the drug to reach high concentration at the desired target without appreciable systemic dosing.
  • ⁇ 2 -agonists an an ihyper ensive agent stimulating both central and peripheral ⁇ ⁇ - and ⁇ ,- adrenergic receptors
  • ⁇ 2 -agonists an an ihyper ensive agent stimulating both central and peripheral ⁇ ⁇ - and ⁇ ,- adrenergic receptors
  • a third class of effective drugs are those that deplete norepinephrine from the sympathetic terminals.
  • the prototype drug in this class is guanethidine.
  • Other examples are bretylium, bethanidine, debrisoquin, and reserpine.
  • Additional compounds are specific inhibitors of catecholamine synthesis and monoamine oxidase inhibitors.
  • These compounds are normally administered systemically (orally or by intravenous injection) , although as described herein they are administered in a pharmaceutically acceptable topical carrier or by iontophoresis, as described above.
  • the effective dosage of these compounds is determined by applying dosages of the compound to the affected site and observing local vasodilatation.
  • Vasodilatation can be determined by laser Doppler flow measurements or by measuring local increases in skin temperature.
  • Example l Demonstration of effectiveness of intravenous administration of blocking agent. If peripheral ⁇ -adrenergic receptors are blocked completely, skin temperature would approach core temperature. Such a blockage would produce profound hypotension and a reflex tachycardia. Therefore, a
  • SUBSTITUTESHEET cumulative dose of phentolamine was selected such that the heart rate did not exceed 150 beats per minute and the effects on blood pressure were mild. This dose ranged from 35 mg to 45 mg over a 30 minute period. Preliminary studies suggested that this amount of phentolamine effectively relieved pain in patients with SMP.
  • the heart rate, systolic and diastolic blood pressure changes produced by phentolamine in a typical patient were relatively mild. In the first seven patients phentolamine alone was administered. The heart rate increased moderately. In subsequent sessions, patients pretreated with propranolol 1-2 mg showed minimal increase in pulse rate. Blood pressure was little effected regardless of whether propranolol was given as patients were maintained in a supine position.
  • the patient was diagnosed as having SMP and then underwent local LABSG, and the administration of phentolamine systemically by intravenous injection.
  • the LABSG procedure failed to afford long-term relief and the patient subsequently underwent a surgical lumbar sympathectomy. The patient had complete pain relief from this procedure and continues to be pain free as of 15 months post operatively.
  • SUBSTITUTESHEET Exa ple 2 Topical Administration of Clonidine for relief of SMP.
  • a patient with a sciatic nerve injury was diagnosed as having SMP, based on lumbar sympathetic blockage. The patient had ongoing pain and intense hyperalgesia to both mechanical and cold stimuli in the painful zone.
  • Clonidine was applied to the hyperalgesic zone transdermally via a 7.0 or 10.5 cm 2 patch (Catapres-TTS; Boehringer) . These patches deliver 0.2 mg or 0.3 mg of clonidine/day for 7 days. A series of 6 patches were applied consecutively to different sites and each left in place for 2-10 days. Prior to, during, and post drug application, the heart rate and blood pressure were taken and sensory testing performed. Pain evoked by mechanical and cold stimuli was rated on a scale from 0-10.
  • Topical Clonidine Clonidine was administered to the hyperalgesic skin via a 7.0 or 10.5 cm 2 patch (Catapres-TTS R -2 and TTS R -3, Boehringer Ingelheim) . These patches deliver a systemic does of 0.2 mg and 0.3 mg respectively of clonidine/day (i.e., 30 ⁇ g/cm 2 /day)
  • SUBSTITUTESHEET for a maximum of 7 days.
  • a series of 2-7 patches were applied consecutively to different sites within the hyperalgesic zone. Each patch was left in place for 2- 10 days within this affected zone.
  • the following parameters Prior to, during and immediately after drug application, the following parameters were monitored: heart rate, blood pressure, ongoing pain and pain to mechanical and cold stimuli.
  • the mechanical stimuli included innocuous brushing with a camel's hair brush and innocuous pressure from the 206 g weight of a 13 mm diameter (i.e., 2N) brass probe. Pain thresholds to mechanical stimuli were determined in the area within and surrounding the patch sites using calibrated von Frey filaments.
  • the cooling stimulus consisted of small drops of acetone lightly placed onto the patient's skin. Patients with SMP typically find that the 1-2°C decrease in temperature induced by such a stimulus is painful.
  • Tactile sensibility To rule out local anesthetic effects, the detection (touch) thresholds were determined in the area within the surrounding selected patch sites using calibrated von Frey filaments. In addition, the patient's ability to distinguish the blunt from the sharp ends of a pin was also assessed. The patients were instructed to close their eyes during the hyperalgesia and von Frey threshold testing procedures.
  • SMP sympathetically maintained pain
  • the patient was a 30 year old, normotensive, white female who sustained an injury to the sciatic nerve from hip replacement surgery three years prior to entering the study. Subsequently, the patient developed continuous pain and hyperalgesia in the antero-lateral aspect of her left leg from the knee to the foot. Thermography revealed that most of this area was 1-2°C colder than corresponding parts of the contralateral leg. Within the affected region, the patient experienced intense ongoing pain and was extraordinarly sensitive to mechanical stimuli.
  • SUBSTITUTESHEET Mild mechanical stimuli (e.g., light brushing or pressure) evoked severe pain. Cooling stimuli (e.g., acetone) were not detected when applied to some parts of the affected area and were painful when applied to other parts. The results of local anesthetic sympathetic ganglion blocks and i.v. phentolamine blocks confirmed that her ongoing pain and hyperalgesia were sympathetically maintained.
  • Cooling stimuli e.g., acetone
  • the patch was applied for 36 hours to an area of skin which had previously been hyperalgesic to brushing, pressure and cooling stimuli.
  • mechanical (brush, pressure) and cooling (a drop of acetone) stimuli applied to this region were detected but were not painful, although these stimuli still elicited pain when applied to the adjacent skin.
  • the mechanical detection thresholds inside and outside the patch site were identical and were similar to the contralateral leg. Within the patch site, the pain threshold to von Frey filaments approximated the patient's 'normal' pain threshold at a corresponding contralateral site and far exceeded the mechanical detection threshold. The ability to distinguish sharp from blunt stimuli were not affected at this site after the patch was removed. Outside the patch site, the pain threshold was low and approached the detection threshold. The patient's ratings of her stimulus-independent pain were not affected by the patch.
  • FIG. 2 A summary of the effect of four of the clonidine patches in which quantitative sensory testing was performed for case #1 is shown in Fig. 2.
  • Each clonidine patch greatly reduced and, in many cases, completely eliminated the patient's hyperalgesia to mechanical stimuli.
  • a confounding local anesthetic effect did not occur since detection thresholds were unchanged.
  • the time course of the effect of each patch was not evaluated quantitatively.
  • the patient did note a reduction of her mechanical hyperalgesia within 36-48 hours after the patch was applied to the skin. After removing a patch, hyperalgesia was still absent for at least 12 hours. Typically, the patient's hyperalgesia returned within less than a week of the patch application.
  • clonidine patch was applied to the top of a normal subject's foot and sensory testing was performed
  • norepinephrine acts peripherally via reduction of norepinephrine release
  • an intradermal injection of norepinephrine (5 ⁇ g in 10 ⁇ l saline) was made at a previously hyperalgesic site that had been treated effectively with clonidine (case 1) .
  • lightly brushing the skin at this site was only mildly hyperalgesic (rated 1 out of 10) whereas brushing the untreated skin evoked a pain sensation rated as 4 out of 10.
  • the norepinephrine injection evoked an intense, burning pain sensation that subsided after four minutes.
  • any ⁇ -adrenergic antagonist, ⁇ -1-adrenergic antagonist, ⁇ 2 adrenergic agonist, or other drug that depletes sympathetic norepinephrine, for example, bretylium, reserpine, phenoxybenzamine, or guanethidine, will relieve SMP using the method according to the present invention. Further, due to the number of side-effects and short effective half-lives associated with these compounds, topical administration of these compounds is preferred.

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Abstract

La douleur sympathique est traitée localement par administration sur le site de manifestations de la douleur sympathique un antagoniste alpha-1-adrénergique, un agoniste alpha-2-adrénergique ou une autre substance médicamenteuse qui affaiblit ou inhibe la synthèse de la norépinéphrine sympathique. Ces substances étant désignées collectivement agents sympatholytiques. Les formules chimiques de plusieurs agents sympatholitiques sont données.
EP19920907852 1991-02-26 1992-02-26 Compositions and methods of treatment of sympathetically maintained pain Withdrawn EP0573581A4 (en)

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CA2104873A1 (fr) 1992-09-03
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EP0573581A4 (en) 1994-06-29
CA2104873C (fr) 2000-05-23

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