USH734H - Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor - Google Patents
Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor Download PDFInfo
- Publication number
- USH734H USH734H US07/164,689 US16468988A USH734H US H734 H USH734 H US H734H US 16468988 A US16468988 A US 16468988A US H734 H USH734 H US H734H
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- US
- United States
- Prior art keywords
- lower alkyl
- converting enzyme
- angiotensin converting
- enzyme inhibitor
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
Definitions
- the present invention relates to a method for inhibiting onset of or treating migraine headaches by administering an ACE inhibitor, such as captopril, zofenopril, fosinopril or enalapril, alone or in combination with a calcium channel blocker, such as diltiazem or nifedipine.
- an ACE inhibitor such as captopril, zofenopril, fosinopril or enalapril
- a calcium channel blocker such as diltiazem or nifedipine.
- R is hydroxy, NH 2 or lower alkoxy
- R 1 and R 4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl
- R 2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoyl-amidomethyl, ##STR2##
- R 3 is hydrogen, hydroxy or lower alkyl
- R 5 is lower alkyl, phenyl or phenyl-lower alkyl
- R 6 is lower alkyl, phenyl, substituted phenyl (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)lower alkyl;
- R 7 is ##STR3##
- M is O or S; m is 1 to 3; n and p each is 0 to 2.
- the asterisks indicate asymmetric carbon atoms.
- Each of the carbons bearing a substituent R 1 , R 3 and R 4 is asymmetric when that substituent is other than hydrogen.
- R 1 is lower alkyl, phenyl or phenyl-lower alkyl
- R 2 is hydrogen, phenyl-lower alkyl or a metal ion
- R 3 is hydrogen or lower alkyl
- R 4 is hydrogen, lower alkyl, phenyl-lower alkyl or a metal ion
- n 0 or 1.
- U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoyl substituted prolines having the formula ##STR5## or a salt thereof, wherein R 1 is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl; one of R 2 and R 4 is ##STR6## and the other is hydrogen, alkyl aryalkyl or ##STR7## wherein X is hydrogen, alkyl or phenyl and Y is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are --(CH 2 ) 2 --, --(CH 2 ) 3 --, --CH ⁇ CH--or ##STR8##
- R 3 is hydrogen or alkyl
- R 6 is hydrogen, hydroxy, alkyl, halogen, azido, amino, cycloalkyl, aryl, arylalkyl, carbamoyloxy, N,N-dialkylcarbamoyloxy, or --Z--R9;
- R 7 and R' 7 are the same and each is halogen or --Z--R 10 , or R 7 and R' 7 together are ⁇ O, --O--(CH 2 ) m --O--or --S--(CH 2 ) m --S--;
- R 8 is hydrogen and R' 8 is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl or R 8 and R' 8 together are ⁇ O;
- R 9 is alkyl, aryl, arylalkyl, 1-- or 2-naphthyl, or biphenyl;
- R 10 is alkyl, aryl or arylalkyl
- Z is oxygen or sulfur
- n 0 or 1
- n 1 or 2.
- R 7 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR13## azido, amino, ##STR14## a 1- or 2-naphthyl of the formula ##STR15## --(CH 2 ) m -cycloalkyl, ##STR16## --O-lower alkyl, ##STR17## a 1- or 2-naphthyloxy of the formula ##STR18## --S-lower alkyl, ##STR19## or a 1- or 2-naphthylthio of the formula ##STR20##
- R 8 is keto, halogen, ##STR21## --O-lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR22## --S-lower alkyl, ##STR23## or a 1- or 2-naphthylthio of the formula ##STR24##
- R 9 is keto or ##STR25##
- R 10 is halogen or --Y--R 16 ,
- R 11 , R' 11 , R 12 and R' 12 are independently selected from hydrogen and lower alkyl or R' 11 , R 12 and R' 12 are hydrogen and R 11 is ##STR26##
- R 13 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.
- R 14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy.
- n is zero, one, two or three.
- p is one, two or three provided that p is more than one only if R 13 or R 14 is hydrogen, methyl, methoxy, chloro or fluoro.
- R 15 is hydrogen or lower alkyl of 1 to 4 carbons.
- Y is oxygen or sulfur.
- R 16 is lower alkyl of 1 to 4 carbons, ##STR27## or the R 16 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
- R 4 is hydrogen, lower alkyl, cycloalkyl, or ##STR28##
- R 5 is hydrogen, lower alkyl, ##STR29##
- r is an integer from 1 to 4,
- R 1 is hydrogen, lower alkyl or cycloalkyl.
- R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR30##
- R 1 and R 2 taken together are --(CH 2 ) n -- wherein n is an integer from 2 or 4.
- R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, or ##STR31## wherein R 17 is hydrogen, lower alkyl, or phenyl, and R 18 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R 17 and R 18 taken together are --(CH 2 ) 2 --, --(CH 2 ) 3 --, --CH ⁇ CH--, or ##STR32##
- R 19 is lower alkyl, benzyl, or phenethyl.
- R 20 is hydrogen, lower alkyl, benzyl or phenethyl.
- R 21 is alkyl of 1 to 10 carbons, ##STR33## wherein q is zero or an integer from 1 to 7 and R 14 , p and m are as defined above.
- R 22 and R 23 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, ##STR34## wherein m, R 14 , and p are as defined above.
- U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula ##STR35## wherein R and R 6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy (dimethylaminoethoxy), acylamino lower alkoxy (acetylamino-ethoxy), acyloxy lower alkoxy (pivaloyloxymethoxy), aryloxy, such as phenoxy, arylloweralkoxy, such as benzyloxy, substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo, methoxy, amino, loweralkylamino, diloweralkylamino, hydroxyamino, arylloweralkylamino such as benzylamino;
- R 1 is hydrogen, alkyl of from 1 to 20 carbon atoms which include branched and cyclic and unsaturated (such as allyl) alkyl groups, substituted loweralkyl wherein the substituent can be halo, hydroxy, lower alkoxy, aryloxy such as phenoxy, amino, diloweralkylamino, acylamino, such as acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio such as phenylthio, carboxy or carboxamido, carboloweralkoxy, aryl such as phenyl or naphthyl, substituted aryl such as phenyl wherein the substituent is lower alkyl, lower alkoxy or halo, arylloweralkyl, arylloweralkenyl, heteroaryllower alkyl or heteroaryl
- R 2 and R 7 are the same or different and are hydrogen or lower alkyl
- R 3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (such as benzoylamino lower alkyl, acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkylthio lower alkyl;
- R 4 is hydrogen or lower alkyl
- R 5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkylthio lower alkyl;
- R 4 and R 5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above substituted with hydroxy, loweralkoxy, lower alkyl or dilower alkyl;
- Example 41 of U.S. Pat. No. 4,374,829 describes the preparation of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.
- R 4 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR38## azido, amino, ##STR39## a 1- or 2-naphthyl of the formula ##STR40## a 1- or 2-naphthyloxy of the formula ##STR41## or a 1- or 2-naphthylthio of the formula ##STR42##
- R 5 is keto, halogen, ##STR43## --O-lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR44## --S-lower alkyl, ##STR45## or a 1- or 2-naphthylthio of the formula ##STR46##
- R 7 is keto or ##STR47##
- Each R 8 is independently halogen or --Y--R 14 .
- R 9 , R 9 ', R 12 and R 10 ' are independently selected from hydrogen and lower alkyl or R 9 ', R 10 and R 10 ', are hydrogen and R 9 is ##STR48##
- R 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl.
- R 12 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy.
- n is zero, one, two or three.
- p is one, two or three provided that p is more than one only if R 11 or R 12 is hydrogen, methyl, methoxy, chloro or fluoro.
- R 13 is hydrogen or lower alkyl of 1 to 4 carbons.
- Y is oxygen or sulfur.
- R 14 is lower alkyl of 1 to 4 carbons, ##STR49## or the R 14 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
- R 21 is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR50##
- R 22 is hydrogen, lower alkyl, ##STR51##
- r is an integer from 1 to 4.
- R 1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR52## wherein q is zero or an integer from 1 to 7 and R 12 and p are as defined above.
- R 19 and R 20 are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, ##STR53## wherein m, R 11 , and p are as defined above.
- R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR54## wherein r is as defined above.
- R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, alkali metal such as Li, Na or K, benzhydryl, or ##STR55## wherein R 15 is hydrogen, lower alkyl, cycloalkyl or phenyl, and R 16 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R 15 and R 16 taken together are --(CH 2 ) 2 --, --(CH 2 ) 3 --, --CH ⁇ CH--, or ##STR56##
- R 17 is lower alkyl, benzyl, or phenethyl.
- R 18 is hydrogen, lower alkyl, benzyl or phenethyl.
- U.S. Pat. No. 4, 248,883 to Sawayame et al discloses 1-(3-mercapto-2-methylpropanoyl)-prolyl amino acid derivatives of the formula ##STR57## wherein R represents a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group or a substituted phenyl-lower alkyl group; R 1 represents a hydrogen atom, R 4 CO--, R 5 S-- or ##STR58##
- R 2 represents a hydrogen atom or a lower alkyl group
- R 3 represents a hydrogen atom, a phenyl group, a lower alkyl group, or a substituted lower alkyl group in which the substituent is hydroxy, phenyl-lower alkoxy, amino, guanidino, N-nitroguanidino, carboxyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, carbamoyl, mercapto, lower alkylthio, phenyl, hydroxyphenyl, indolyl or imidazolyl; or R 2 and R 3 form a heterocyclic ring together with the nitrogen and carbon atoms to which they are respectively bonded; R 4 represents a lower alkyl group, a lower alkoxy group, a phenyl group, a substituted phenyl group, a phenyl-lower alkyl group, a substituted phenyl-lower alkyl group, a phenyl-lower alkoxy group, a substituted
- the group X--R 1 is located at the 3- or 4-position in the ring;
- X is oxygen or sulfur
- R is hydrogen or lower alkyl
- R 1 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, 1- or 2-adamantyl, aryl, substituted aryl, phenyl-lower alkylene or substituted phenyl-lower alkylene.
- R 2 and R 3 are independently selected from hydrogen, lower alkyl, and trifluoromethyl
- R 4 is hydrogen, R 5 --CO-- or ##STR61##
- R 5 is lower alkyl, phenyl, phenyl-lower alkylene; substituted phenyl, or substituted phenyl-lower alkylene;
- n 0, 1 or 2; and salts thereof.
- a method for inhibiting onset of or treating migraine headaches wherein a therapeutically effective amount of an angiotensin converting enzyme inhibitor alone or in combination with a calcium channel blocker is systemically, such as orally or parenterally, administered over a prolonged period, whereby frequency and intensity of migraine headaches are significantly reduced.
- the ACE inhibitor will be employed in a weight ratio to the calcium channel blocker of within the range of from about 0.1:1 to about 10:1 and preferably from about 0.4:1 to about 2.5:1.
- the angiotensin converting enzyme inhibitor which may be employed herein includes substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,105,776 to Ondetti et al mentioned above, with captopril, that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, carboxyalkyl dipeptide derivatives, such as any of those disclosed in European Patent Application No. 0 012 401 mentioned above, with N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is, enalapril, being preferred.
- angiotensin converting enzyme inhibitors suitable for use herein include any of the phosphonate substituted amino or imino acids or salts disclosed in U.S. Pat. No. 4,452,790 with (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline being preferred, phosphinylalkanoyl prolines disclosed in U.S. Pat. No. 4,168,267 mentioned above with fosinopril being preferred, mercaptoacyl derivatives of substituted prolines, disclosed in U.S. Pat. No.
- ACE inhibitors include Beecham's BRL 36,378 as disclosed in European patent Nos. 80822 and 60668; Chugai's MC-838 disclosed in CA. 102:72588v and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824 (3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]-amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1 acetic acid HCl) disclosed in U.K. Pat. No.
- the calcium antagonist which will be used herein may be diltiazem which is disclosed in U.S. Pat. No. 3,562,257 and which has the chemical name 3-(acetyloxy)-5-[2-(dimethylamino)ethyl-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and the structure ##STR63##
- 4-Phenyl-1,4-dihydropyridine calcium antagonists may be employed which will have the structure ##STR64## wherein R 1 and R 2 may be the same or different and are lower alkyl or lower alkoxy (lower alkyl) where lower alkyl and lower alkoxy contain 1 to 4 carbons.
- the dihydropyridine calcium antagonist present in the composition of the invention will preferably by nifedipine, that is, the compound of formula C wherein R 1 CH 3 , R 2 is CH 3 and NO 2 is at the 2-position, namely, ##STR65## which is disclosed in U.S. Pat. Nos. 3,644,627 and 3,485,847.
- niludipine that is, the compound of formula C wherein R 1 is --(CH 2 ) 2 OC 3 H 7 , R 2 is --(CH 2 ) 2 OC 3 H 7 and NO 2 is at the 3-position
- nimedipine that is the compound of formula C wherein R 1 is --(CH 2 ) 2 OCH 3 , R 2 is --CH(CH 3 ) 2 and NO 2 is at the 3-position
- nitrendipine that is, the compound of formula C wherein R 1 is --CH 2 CH 3 , R 2 is --CH 3 and NO 2 is at the 3-position
- nisoldipine that is, the compound of formula C wherein R 1 is --CH 3 , R 2 is -- CH 2 CH(CH 3 ) 2 and NO 2 is at the 2-position (disclosed in U.S. Pat. Nos. 3,799,934, 3,932,645 and 4,154,839).
- Verapamil may also be employed.
- the angiotensin converting enzyme inhibitor alone or in combination with the calcium channel blocker may be administered to mammalian species, such as monkeys, dogs, cats, rats and humans, and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable.
- a conventional systemic dosage form such as a tablet, capsule, elixir or injectable.
- the above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid of sodium bisulfite) or the like.
- Oral dosage forms are preferred, although parenteral forms such as intramuscular, intraperitoneal, or intravenous are quite satisfactory as well.
- the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
- ACE inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 25 mg/kg alone or in combination with the calcium channel blocker in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 25 mg/kg with the ACE inhibitor and calcium channel blocker being employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
- a preferred oral dosage form such as tablets or capsules, will contain the ACE inhibitor in an amount of from about 0.1 to about 500 mg, preferably from about 125 to about 200 mg, and more preferably from about 25 to about 150 mg, alone or with the calcium channel blocker in an amount of from about 1 to about 350 mg, preferably from about 2 to about 200 mg, and more preferably from about 30 to about 150 mg.
- the ACE inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.01 mg/kg to about 1 mg/kg, alone or with the calcium channel blocker in an amount within the range of from about 0.005 mg/kg to about 20 mg/kg and preferably from about 0.01 mg/kg to about 2 mg/kg.
- composition described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
- Tablets of various sizes can be prepared, e.g., of about 50 to 700 mg in total weight, containing one or both of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses. Gelatin capsules can be similarly formulated.
- Liquid formulations can also be prepared by dissolving or suspending one or the combination of active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonsful.
- Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
- the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances.
- the respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above.
- ACE inhibitor and calcium channel blocker are more convenient and are preferred, especially in tablet or capsule form for oral administration.
- the active substances in the amounts described above, are compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form.
- Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as orange, peppermint, oil of wintergreen or cherry.
- a binder such as gum tragacanth, acacia, corn starch or gelatin
- an excipient such as dicalcium phosphate or cellulose
- a disintegrating agent such as corn starch, potato starch, alginic acid or the like
- a lubricant such as stearic acid or magnesium stearate
- a sweetening agent such as sucrose, lactose or sac
- tablets or capsules may be coated with shellac, sugar or both.
- a syrup of elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.
- formulations as described above will be administered for a prolonged period, that is, for as long as the potential for onset of a migraine headache remains or the symptoms of a migraine headache continue.
- Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed.
- a dosing period of at least two weeks and preferably at least 4 to 6 weeks are required to achieve minimal benefit.
- a captopril formulation suitable for oral administration in inhibiting onset of or treating a migraine headache is set out below.
- the captopril and corn starch are admixed with an aqueous solution of the gelatin.
- the mixture is dried and ground to a fine powder.
- the Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 25 mg of active ingredient which is used for inhibiting onset of or treating migraine headache.
- the captopril, lactose and Avicel are admixed, then blended with the corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 1205 mg tablets each containing 600 mg of active ingredients. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6. The resulting tablets are useful in treating or inhibiting onset of migraine headache.
- Two piece #1 gelatin capsules each containing 25 mg of captopril and 100 mg of carbamazepine are filled with a mixture of the following ingredients:
- the resulting capsules are useful in treating or inhibiting onset of migraine headache.
- An injectable solution for use in treating or inhibiting onset of migraine headache trigeminal neuralgia is produced as follows:
- the captopril, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters.
- the solution is filtered through a sterile filter and aseptically filled into presterilized vials which are then closed with presterilized rubber closures.
- Each vial contains 5 ml of solution in a concentration of 100 mg of active ingredient per ml of solution for injection for treating or inhibiting onset of migraine headache.
- Tablets for use in treating or inhibiting onset of migraine headache are prepared as described in Example 1 except that N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) is used in place of captopril.
- An injectable for use in treating or inhibiting onset of migraine headache is prepared as described in Example 5 except that N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) is employed in place of captopril.
- a zofenopril formulation suitable for oral administration in treating or inhibiting onset of migraine headache is set out below.
- the zofenopril and corn starch are admixed with an aqueous solution of the gelatin.
- the mixture is dried and ground to a fine powder.
- the Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 100 mg of active ingredient which is used for treating or inhibiting onset of migraine headache.
- the fosinopril, carbamazepine, lactose and Avicel are admixed, then blended with the corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 705 mg tablets each containing 300 mg of active ingredients. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6. The resulting tablets are useful in treating or inhibiting onset of migraine headache.
- Tablets for use in treating or inhibiting onset of migraine headache are prepared as described in Example 1 except that 1-[N-[hydroxy-(4-phenylbutyl)phosphinyl]-L-alanyl-L-proline, disodium salt (prepared as described in U.S. Pat. No. 4,432,971) is used in place of captopril.
- An injectable for use in treating or inhibiting onset of migraine headache is prepared as described in Example 5 except that 1-[N-[hydroxy(4-phenylbutyl)phosphinyl]-L-alanyl]-L-proline, disodium salt (prepared as described in U.S. Pat. No. 4,432,971) is used in place of captopril.
- a captopril-diltiazem formulation suitable for oral administration in the treatment of migraine headache is set out below.
- the captopril, diltiazem and corn starch are admixed with an aqueous solution of the gelatin.
- the mixture is dried and ground to a fine powder.
- the Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 200 mg of active ingredients which is used for preventing or treating migraine headache.
- Example 13 By substituting 100 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline for the captopril in Example 13, 1000 tablets each containing 100 mg of the 1-(3-mercapto-2-D-methylpropanoyl)-L-proline and 100 mg diltiazem are produced which is useful in preventing or treating migraine headache.
- the captopril, diltiazem, lactose and Avicel are admixed, then blended with the corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg tablets each containing 200 mg of each active ingredient. The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6. The resulting tablets are useful in preventing or treating migraine headache.
- Two piece #1 gelatin capsules each containing 250 mg of enalapril and 150 mg of nitrendipine are filled with a mixture of the following ingredients:
- the resulting capsules are useful in preventing or treating migraine headache.
- An injectable solution for use in treating or preventing migraine headache is produced as follows:
- captopril, diltiazem, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters.
- the solution is filtered through a sterile filter and aseptically filled into presterilized vials which are then closed with presterilized rubber closures.
- Each vial contains 5 ml of solution in a concentration of 100 mg of active ingredient per ml of solution for injection.
- Tablets for use in preventing or treating migraine headache are prepared as described in Example 13 except that N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (enalapril) is used in place of captopril and nifedipine is used in place of diltiazem.
- Tablets for use in treating or preventing migrane headache are prepared following the procedure of Example 13 except that zofenopril is employed in place of captopril and nisoldipine is used in place of diltiazem.
- Tablets for use in treating or preventing migraine headache are prepared following the procedure of Example 13 except that fosinopril is employed in place of captopril.
- Tablets for use in treating or preventing migraine headache are prepared following the procedure of Example 13 except that alacepril is employed in place of captopril.
- Tablets for use in treating or preventing migraine headache are prepared following the procedure of Example 13 except that (S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline or lisinopril is employed in place of captopril.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/164,689 USH734H (en) | 1988-03-07 | 1988-03-07 | Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor |
JP63283527A JPH01157919A (ja) | 1987-11-09 | 1988-11-09 | 片頭痛の抑制治療剤 |
EP88120133A EP0331803A3 (de) | 1988-03-07 | 1988-12-02 | Medicament zum Verhindern oder zur Behandlung von Migräne durch Verwendung eines Ace-Inhibitors |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/164,689 USH734H (en) | 1988-03-07 | 1988-03-07 | Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11813187A Continuation-In-Part | 1987-11-09 | 1987-11-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
USH734H true USH734H (en) | 1990-02-06 |
Family
ID=22595633
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/164,689 Abandoned USH734H (en) | 1987-11-09 | 1988-03-07 | Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor |
Country Status (2)
Country | Link |
---|---|
US (1) | USH734H (de) |
EP (1) | EP0331803A3 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992021340A1 (en) * | 1991-06-05 | 1992-12-10 | United States Of America, As Represented By The Secretary Of The Army | A method of treating infectious encephalitis of viral or bacterial, or parasitic pathogenesis |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5444042A (en) * | 1990-12-28 | 1995-08-22 | Cortex Pharmaceuticals | Method of treatment of neurodegeneration with calpain inhibitors |
US6162802A (en) * | 1992-03-10 | 2000-12-19 | Papa; Joseph | Synergistic combination therapy using benazepril and amlodipine for the treatment of cardiovascular disorders and compositions therefor |
ES2125198B1 (es) * | 1997-05-13 | 1999-11-16 | Vita Invest Sa | Asociacion a dosis fija de un inhibidor de la enzima convertidora de angiotensina y de un antagonista de los canales de calcio, procedimiento para su preparacion y su utilizacion para el tratamiento de enfermees cardiovasculares. |
Citations (10)
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US4374829A (en) | 1978-12-11 | 1983-02-22 | Merck & Co., Inc. | Aminoacid derivatives as antihypertensives |
US4432971A (en) | 1981-08-03 | 1984-02-21 | E. R. Squibb & Sons, Inc. | Phosphonamidate compounds |
US4548941A (en) | 1984-07-30 | 1985-10-22 | Merck & Co., Inc. | 1,5-Methano-1H-4-benzazonine dicarboxylates, process for preparing and use as calcium blockers |
US4579851A (en) | 1984-05-29 | 1986-04-01 | Merck & Co., Inc. | Substituted and bridged tetrahydropyridines useful as calcium entry blockers |
US4587253A (en) | 1984-07-30 | 1986-05-06 | Merck & Co., Inc. | Bridged pyridine compounds useful as calcium channel blockers and analgesics |
US4591587A (en) | 1984-10-01 | 1986-05-27 | Merck & Co., Inc. | Cyclopropyl pyridine compounds useful as calcium channel blockers |
US4599341A (en) | 1984-10-01 | 1986-07-08 | Merck & Co., Inc. | Substituted and bridged pyridines useful as calcium channel blockers |
US4634716A (en) | 1982-09-30 | 1987-01-06 | Merck & Co., Inc. | Substituted N-carboxymethyl-aminoacylaminoalkanoic acids useful as antihypertensive agents |
US4675321A (en) | 1986-02-07 | 1987-06-23 | Merck & Co., Inc. | Substituted pyrimidines useful as calcium channel blockers |
US4711893A (en) | 1984-05-28 | 1987-12-08 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Use of hydroxyindole derivatives in lowering blood pressure |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3437917A1 (de) * | 1984-10-17 | 1986-04-17 | Bayer Ag, 5090 Leverkusen | Kombination von dihydropyridinen mit ace-hemmern sowie ihre verwendung in arzneimitteln |
DE3629060A1 (de) * | 1986-08-27 | 1988-03-03 | Bayer Ag | Kombination von positiv inotrop wirkenden dihydropyridinen mit ace-hemmern, sowie ihre verwendung in arzneimitteln |
DE3633496A1 (de) * | 1986-10-02 | 1988-04-14 | Hoechst Ag | Kombination von angiotensin-converting-enzyme-hemmern mit calciumantagonisten sowie deren verwendung in arzneimitteln |
-
1988
- 1988-03-07 US US07/164,689 patent/USH734H/en not_active Abandoned
- 1988-12-02 EP EP88120133A patent/EP0331803A3/de not_active Withdrawn
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4374829A (en) | 1978-12-11 | 1983-02-22 | Merck & Co., Inc. | Aminoacid derivatives as antihypertensives |
US4472380A (en) | 1978-12-11 | 1984-09-18 | Merck & Co., Inc. | Amino acid derivatives as antihypertensives |
US4432971A (en) | 1981-08-03 | 1984-02-21 | E. R. Squibb & Sons, Inc. | Phosphonamidate compounds |
US4634716A (en) | 1982-09-30 | 1987-01-06 | Merck & Co., Inc. | Substituted N-carboxymethyl-aminoacylaminoalkanoic acids useful as antihypertensive agents |
US4711893A (en) | 1984-05-28 | 1987-12-08 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Use of hydroxyindole derivatives in lowering blood pressure |
US4579851A (en) | 1984-05-29 | 1986-04-01 | Merck & Co., Inc. | Substituted and bridged tetrahydropyridines useful as calcium entry blockers |
US4548941A (en) | 1984-07-30 | 1985-10-22 | Merck & Co., Inc. | 1,5-Methano-1H-4-benzazonine dicarboxylates, process for preparing and use as calcium blockers |
US4587253A (en) | 1984-07-30 | 1986-05-06 | Merck & Co., Inc. | Bridged pyridine compounds useful as calcium channel blockers and analgesics |
US4591587A (en) | 1984-10-01 | 1986-05-27 | Merck & Co., Inc. | Cyclopropyl pyridine compounds useful as calcium channel blockers |
US4599341A (en) | 1984-10-01 | 1986-07-08 | Merck & Co., Inc. | Substituted and bridged pyridines useful as calcium channel blockers |
US4675321A (en) | 1986-02-07 | 1987-06-23 | Merck & Co., Inc. | Substituted pyrimidines useful as calcium channel blockers |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992021340A1 (en) * | 1991-06-05 | 1992-12-10 | United States Of America, As Represented By The Secretary Of The Army | A method of treating infectious encephalitis of viral or bacterial, or parasitic pathogenesis |
Also Published As
Publication number | Publication date |
---|---|
EP0331803A2 (de) | 1989-09-13 |
EP0331803A3 (de) | 1990-05-09 |
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