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US 2005OO65094A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0065094A1 Davidai (43) Pub. Date: Mar. 24, 2005

(54) USE OF TELMISARTAN FOR THE Related U.S. Application Data PREVENTION AND TREATMENT OF WASCULAR HEADACHE (60) Provisional application No. 60/500.817, filed on Sep. 5, 2003. (75) Inventor: Giora Davidai, New Canaan, CT (US) Publication Classification Correspondence Address: (51) Int. Cl." ...... A61K 38/04; A61K 31/5513; MICHAEL P. MORRIS A61K 31/41.84 BOEHRINGER INGELHEM CORPORATION (52) U.S. Cl...... 514/19; 514/381; 514/221 900 RIDGEBURY ROAD P. O. BOX 368 (57) ABSTRACT RIDGEFIELD, CT 06877-0368 (US) The present invention relates to a method for the prophylaxis 9 of Vascular headaches which do not originate from hyper tension, especially , the method comprising admin (73) Assignee: Boehringer Ingelheim International istration of telmisartan to a Subject in need of Such a GmbH, Ingelheim (DE) treatment. The present invention relates also to a method for the prophylaxis of vascular headaches, comprising the co (21) Appl. No.: 10/925,788 administration of telmisartan in combination with other drugs Suitable for migraine prophylaxis and/or acute treat (22) Filed: Aug. 24, 2004 ment of migraine. US 2005/0065094A1 Mar. 24, 2005

USE OF TELMISARTAN FOR THE PREVENTION Standard of acute are the “', e.g. AND TREATMENT OF WASCULAR HEADACHE and . These triptans elicit their antimigraine effects due to their vasoconstrictive properties RELATED APPLICATIONS and presumably their inhibition of the release of the neu 0001. This application claims priority benefit of U.S. Ser. ropeptide calcitonin gene related peptide (CGRP). No. 60/500,817, filed Sep. 5, 2003, which is hereby incor 0007. A completely novel approach to treat migraine is porated by reference in its entirety. the use of CGRP antagonists (Doods, H. et al., Br. J. FIELD OF THE INVENTION Pharmacol., 129, 2000, pp. 420-423). Such CGRP antago nists have been disclosed, for example, in WO 98/11128. In 0002 The present invention relates to a method for the WO 03/015787 a CGRP antagonist has been disclosed, prophylaxis of vascular headaches which do not originate namely 1-N-3,5-Dibromo-N-(4-(3,4-dihydro-2(1H)- from hypertension, especially migraine, the method com oxochinazolin-3-yl)-1-piperidinylcarbonyl-D-tyrosyl-L- prising administration of 4-2-n-propyl-4-methyl-6-(1-me lysyl-4-(4-pyridinyl)-, which is, in combination thylbenzimidazol-2-yl)benzimidazol-1-ylmethylbiphenyl With a 5-HT1D or an ergot alkaloid, especially 2-carboxylic acid} (telmisartan) to a Subject in need of Such useful for the prevention and/or treatment of migraine. a treatment. The present invention relates also to a method for the prophylaxis of vascular headaches, comprising the 0008 Recently, in WO 01/97807 angiotensin II (AT II) co-administration of telmisartan in combination with other type I receptor antagonists have been disclosed for the drugs Suitable for migraine prophylaxis and/or acute treat prevention and/or therapeutic treatment of patients Suffering ment of migraine. from vascular headache conditions and more particularly migraine. These compounds are known to interfere with the 0003. The invention further relates to suitable pharma renin-angiotensin System (RAS) and have been used so long ceutical compositions comprising telmisartan and at least to treat common cardiovascular diseases, particularly arte one other drug used in migraine prophylaxis, as a combined rial hypertension and congestive heart failure. preparation for Simultaneous, Separate or Sequential use in the prophylaxis of Said disease. The invention relates further 0009 Tronvik et al. disclosed results of a randomized, to the use of telmisartan, optionally in combination with said double blind, placebo-controlled crossover study with an other antimigraine drugs for the manufacture of a pharma angiotensin II (AT II) type I receptor antagonist (cande ceutical composition for the prophylaxis of vascular head Sartan), of patients Suffering from migraine. The authors aches. concluded that candesartan provided effective migraine pro phylaxis with a good tolerability profile (JAMA, 1, 2003, pp. BACKGROUND OF THE INVENTION 65-69). 0004 Migraine is one of the most common neurological 0010 Hansson et al. published results from a double disorders, involving periodical attacks of headache and blind, placebo-controlled study with irbesartan of patients nausea as well as a plethora of other Symptoms. Approxi having mild/moderate hypertension. The use of an AT II type mately 240 million people worldwide have an estimated 1.4 I receptor antagonist Seems to be associated with a signifi billion attacks of migraine each year (Tronvik, E. et al., cant reduction in the incidence of headache commonly Seen JAMA, 1, 2003, pp. 65-69). Although considerable progress in hypertensive patients (Arch. Intern. Med. 160, 2000, pp. has been made, the pathophysiology of migraine is still not 1654-1658). understood. It is a disorder that exhibits a Spectrum of 0011 Etiminan et al. published data of a meta-analysis of treatment responses in afflicted individuals. Although Some 27 studies involving 12110 patients treated for hypertension. of the patients can be cured with life style modification The authors came to the conclusion that the risk of head (trigger elimination) and can be treated with over-the aches was about one third lower in patients taking an AT II counter or by acupuncture, hypnosis and the receptor antagonist than in those taking placebo (Am. J. like, the majority of the patients are in the need of prescrip tion drugs for relief from the migraine and prevention of Med. 112, 2002, pp. 642-646). further attacks. The Symptoms most in need of treatment are SUMMARY OF THE INVENTION the head pain and gastrointestinal Symptoms. But also pho tophobia and the aura have to be treated. The latter may also 0012. It has been found that a particular member of the be quite disturbing and require treatment although its dura group of AT II type I receptor antagonists, namely telmis tion is relatively brief. artan, provides unexpected advantages in the prophylaxis of vascular headaches, especially migraine, to a Subject in need 0005 The exact pathogenesis of migraine is still of Such treatment, with high efficacy, independently of its unknown. In recent years a consensus has been emerging known blood pressure reducing activity. INN Telmisartan, that in migraine both vascular and neural components are {4'-2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl relevant and most probably interrelated. )benzimidazol-1-ylmethylbiphenyl-2-carboxylic acid, has 0006 Common drugs, which at present are used for the been developed for the treatment of hypertension and other treatment of migraine and other forms of vascular head medical indications as disclosed in EPO 502 314 B1 and aches, are e.g. , aspirin and NSAIDS. The gold U.S. Pat. No. 5,591,762 and is already sold on the market US 2005/0065094A1 Mar. 24, 2005

under the trade name Micardis(R). It exists in two polymor vascular headache, usually temporal and unilateral in onset, phic forms as disclosed in WO 00/43370, U.S. Pat. No. commonly associated with irritability, nausea, vomiting, 6,358,986 and U.S. Pat. No. 6,410,742. Sodium salts of constipation or diarrhoea, and often with photophobia. Attacks are preceded by constriction of the cranial arteries, telmisartan and its Solvate, hydrate, and hemihydrate are usually with resultant prodromal sensory (especially ocular) disclosed in WO O3/037876. Symptoms called Aura, and commence with the vasodilata 0013 A first aspect of the present invention relates to a tion that follows. method for the prophylaxis of vascular headache conditions 0019 Migraine can be divided into various specific types not originating from hypertension, especially migraine, including abdominal, acephalic, acute confusional, basilar, comprising administering a therapeutically effective amount classic, common, complicated, fulgurating, Harris, of telmisartan, preferably alone, or in combination with a hemiplegic, ocular, ophthalmic and ophthalmoplegic. therapeutically effective amount of an other drug Suitable for the prophylaxis of migraine to a Subject in need of Such 0020. The term “cluster headache' is most typically treatment. defined as the temporal clustering of attacks during periods usually lasting between 2 weeks and 3 months, Separated by 0.014. The second aspect of the present invention relates intermissions of at least 14 days, but usually Several months. to a pharmaceutical composition for preventing a vascular This type of cluster headache is also known as “episodic headache condition not originating from hypertension com cluster headache'. The term "chronic cluster headache” is prising a therapeutically effective amount of telmisartan. characterized by the absence of intermissions of at least 14 Additionally it relates to a pharmaceutical composition of days for more than one year (Textbook of Pain, 3' ed., p. telmisartan in combination with a therapeutically effective amount of at least one other drug Suitable for migraine 504, 1994). prevention as a combined preparation for Simultaneous or 0021. The term “post-traumatic headache” is headache Sequential administration. caused by Some head trauma, whereas “tension headache” and "muscular headache' belong to the group of headaches 0.015. Another embodiment of the present invention is the formerly described as "muscle contraction”, “psychogenic', use of telmisartan, preferably alone, but also in combination with at least one other drug Suitable for migraine prevention, “stress” or “essential” (Textbook of Pain, 3" ed., p. 504, for the manufacture of a pharmaceutical composition for 1994). prophylaxis of vascular headache which do not originate 0022 With regard to the first aspect of the present inven from hypertension, preferably migraine. tion relating to a method for the prophylaxis of vascular headaches not originating from hypertension, especially DETAILED DESCRIPTION OF THE migraine, the method comprises the administration of an INVENTION effective amount of telmisartan to a Subject in need of Such 0016. Within the present invention the term “telmisartan” treatment. includes {4'-2-n-propyl-4-methyl-6-(1-methylbenzimida 0023 Telmisartan, may be administered orally, bucally, zol-2-yl)benzimidazol-1-ylmethylbiphenyl-2-carboxylic parenterally, nasally, rectally or topically, the oral adminis acid} in its neutral form as carboxylic acid as disclosed in EP tration being preferred. Parenteral administration may 0.502 314 B1 and U.S. Pat. No. 5,591,762, or in one of its polymorphic forms as disclosed in WO 00/43370, U.S. Pat. include Subcutaneous, intravenous, intramuscular and No. 6,358,986 and U.S. Pat. No. 6,410,742, or in the form intrasternal injections and infusion techniques. of a pharmaceutically acceptable Salt or the Solvate, hydrate, 0024 Telmisartan may be administered once, twice or or hemihydrate thereof as disclosed in WO 03/037876, thrice a day in a daily dosage of 10 mg (or 0.143 mg/kg body including but not limited to the Sodium, potassium or ammonium Salt. When a Salt of telmisartan is used, the weight, based on a person of 70 kg) to 500 mg (7.143 mg/kg Sodium Salt is preferred. In addition, according to the present body weight, based on a person of 70 kg) orally and of about invention the term “telmisartan” includes any prodrug, e.g. 20 mg (0.286 mg/kg body weight, based on a person of 70 an ester, which is hydrolyzed in Vivo to the pharmacologi kg) parenterally, preferably of 20 mg (0.286 mg/kg body cally active compound. weight, based on a person of 70 kg) to 100 mg (1.429 mg/kg body weight, based on a person of 70 kg) orally. Particularly 0.017. Within the present invention, the term “vascular preferred is an oral daily dosage of 40 mg (0.571 mg/kg headaches' includes any kind of vascular headaches, like migraine, cluster headache, post-traumatic headache, etc. body weight, based on a person of 70 kg) to 80 mg (1.143 not due to hypertension (i.e. not originated from hyperten mg/kg body weight, based on a perSon of 70 kg) or specifi sion). In a preferred embodiment of the invention the term cally of about 80 mg (1.143 mg/kg body weight, based on a is used for the prevention and/or treatment of migraine. person of 70 kg). 0.018. The term “migraine” is to be interpreted according 0025 Optionally, telmisartan can be administered in to: The Headache Classification Committee of the Interna combination with other drugs Suitable for migraine prophy tional Headache Society, Classification and Diagnostic Cri laxis. Such other drugs are, for example, CGRPantagonists teria for Headache Disorders, Cranial Neuralgias and like 1-N'-3,5-Dibromo-N-4-(3,4-dihydro-2(1H)-oxochi Facial Pain, Cephalalgia 1988, 8 SUPPL 7, pp. 1-96. It is nazolin-3-yl)-1-piperidinyl-carbonyl-D-tyrosyl-L-lysyll an often familial Symptom complex of periodic attacks of 4-(4-pyridinyl)-piperazine, US 2005/0065094A1 Mar. 24, 2005

Br

O N 1. \, ls ^ N ~, N1N N O

0026 and 1-4-Amino-3,5-dibrom-N-4-(2,3,4,5-tet 0028 Preferred compounds to be combined with telmis rahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl artan for the prophylaxis of vascular headaches are triptans carbonyl-D-phenylalanyl-4-(1-piperidinyl)-piperidin, like , avitriptan, , , naratrip tan, , Sumatriptan, Zolmitriptan, preferably Sumatriptan or Zolmitriptan, and CGRP antagonists, prefer ably 1-N-3,5-Dibromo-N-(4-(3,4-dihydro-2(1H)- oxochinazolin-3-yl)-1-piperidinylcarbonyl-D-tyrosyl-L- lysyl-4-(4-pyridinyl)-piperazine as disclosed in WO 98/11128 (page 80, No. 154) and 1-4-Amino-3,5-dibrom N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3- yl)-1-piperidinylcarbonyl-D-phenylalanyl)-4-(1-piperidi nyl)-piperidin (page 89, No. 231) or their pharmaceutically acceptable Salts. The Synthesis of these compounds has been disclosed in WO 98/11128 on page 332, example 6, No. 154 for 1-N'-3,5-Dibromo-N-4-(3,4-dihydro-2(1H)-oxochi O nazolin-3-yl)-1-piperidinylcarbonyl-D-tyrosyl-L-lysyl N 4-(4-pyridinyl)-piperazine and on page 323, example 4, No. 231 for 1-4-Amino-3,5-dibrom-N-4-(2,3,4,5-tetrahydro 2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinylcarbo 0027) which have been disclosed in WO98/11128, ACE nyl-D-phenylalanyl)-4-(1-piperidinyl)-piperidin. Inhibitors (e.g. quinapril, captopril, enalapril, ramipril, 0029. A formulation of 1-N'-3,5-Dibromo-N-4-(3,4- benazepril, foSinopril, or lisinopril), calcium channel dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinylcarbo antagonists (e.g. amlodipine, , diltiazepam, nimo nyl-D-tyrosyl-L-lysyl-4-(4-pyridinyl)-piperazine Suitable dipine, , , iomerizine HCl, and the like), for powder inhalation has been disclosed in the German beta blockers (e.g. atenolol, metropolol, nadolol, propanolol patent application DE 102 07026 A1 and salts thereof like or ), alpha2- (e.g. tizanidine), the hydrochloride, Sulphate, phosphate, hydrobromide, car antagonists (e.g. , or methylser bonate, methaneSulphonate, p-toluenesulphonate, nitrate, gide), (e.g. divalproex Sodium, gabapentin, citrate, malate, tartrate, lactate, Succinate, gluconate, acetate, , tiagabine, levetiracetam, Zonisamide, lamot formate, propionate, capronate, Oxalate, maleate, fumarate, rigine or ), anti-epileptics (e.g. topiramate), anti mandelate and hydroxySuccinate, also Suitable for powder depressants (e.g. like amitriptiline or , inhalation have been disclosed in the German patent appli Selective Serotonine reuptake inhibitors, monoamine oxidase cation DE 102 06 770 A1. inhibitors like pheneizine or other antipsychotics like quen 0030. In the acute phase of a migraine attack telmisartan tiapine), 5-HT1B-E-agonists (e.g. almotriptan, avitriptan, can also be administered in combination with drugs, which eletriptan, froVatriptan, , rizatriptan, Sumatriptan, are used for acute treatment of migraine as there are anti Zolmitriptan), or other AT II type I receptor antagonists (e.g. inflammatory agents such as NSAID's, cox-2 inhibitors, candesartan, candesartan cileXtil, eprosartan, irbesartan, agonists like lisurid, antiemetics like dimenhydri losartan, olmesartan, olmesartan medoxomil, and Valsartan) nate, B-blockers like timolol or propanolol, or the corresponding pharmaceutically acceptable Salts. like or dimenhydrinate, ergot alkaloids like ergota Other drugs Suitable for migraine prophylaxis are for mine and , analgesics like acetami example magnesium lycinate, riboflavin, botulinum toxin A, nophen, diclofenac propyphenazon, non-Steroidal antiphlo montelukast (an anti-inflammatory leukotriene inhibitor), gistics like acetylsalicylic acid, naproxen or ibuprofen. petasites (from petasites hybridus plant, a leukotriene bio Additional drugs which may be administrated in the acute Synthesis inhibitor), and naproxen. phase of a migraine attack include caffeine, iprazochrom, US 2005/0065094A1 Mar. 24, 2005 isometheptene, , pangamic acid or the phar N-4-(3,4-dihydro-2(1H)-oxochi nazolin-3-yl)-1-piperidi maceutically acceptable Salts thereof. nylcarbonyl-D-tyrosyl-L-lysyl-4-(4-pyridinyl)-pipera Zine the nasal or inhalative route is preferred and for 0.031 Telmisartan, administered alone or in combination 1-4-Amino-3,5-dibrom-N-4-(2, 3,4,5-tetrahydro-2(1H)- with one or more of the above mentioned drugs can be OXO-1,3-benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- administered orally, bucally, parenterally, nasally, rectally or phenylalanyl)-4-(1-piperidinyl)-piperidin oral administra topically, the oral administration being preferred. Parenteral tion is preferred. administration may include Subcutaneous, intravenous, intramuscular and intrasternal injections and infusion tech 0037. If telmisartan is used in combination with other niques. drugs Suitable for prophylaxis and/or acute treatment of migraine, the dosage for the combined migraine drug is 0032. In combination with one or more of the above mentioned drugs telmisartan may be administered once appropriately 1/100 of the lowest dose normally recom twice or thrice a day in a daily dosage of 10 mg (or 0.143 mended up to 1/1 of the normally recommended dosage, mg/kg body weight, based on a person of 70 kg) to 500 mg preferably 1/50 to 1/6 and more preferably 1/20 to 1/10, (7.143 mg/kg body weight, based on a person of 70 kg) orally, bucally, parenterally, nasally, rectally or topically orally and of about 20 mg (0.286 mg/kg body weight, based route. The normally recommended dose for the combined on a perSon of 70 kg) parenterally, preferably of 20 mg migraine drug should be understood to be the dose disclosed (0.286 mg/kg body weight, based on a person of 70 kg) to in Rote Liste(R) 2003, Editio Cantor Verlag, Aulendorf or 100 mg (1.429 mg/kg body weight, based on a person of 70 disclosed in Physicians’ Desk Reference 2003, 57. Ed. kg) orally. Particularly preferred is an oral daily dosage of 40 0038 If the method comprises co-administration of telm mg (0.571 mg/kg body weight, based on a person of 70 kg) isartan and another drug, it is possible to administer a to 80 mg (1.143 mg/kg body weight, based on a person of pharmaceutical composition comprising both telmisartan 70 kg) or specifically of about 80 mg (1.143 mg/kg body and the other , or to administer two phar weight, based on a person of 70 kg). maceutical compositions, one comprising telmisartan as 0033. If telmisartan is administered in combination with active ingredient and the other comprising the other antimi triptans or a physiologically acceptable Salt thereof, the graine drug as active ingredient jointly or timely shifted. By triptans, can be administered by intravenous or Subcutane the expression “jointly or timely shifted” administration of ous route in a dosage of 0.0001 to 1.0 mg/kg of body weight the telmisartan containing and the other antimigraine drug or by oral, rectal, nasal or inhalative route in a dosage of containing pharmaceutical composition for the purpose of 0.0005 to 10 mg/kg of body weight once, twice or thrice a the present invention it is understood that both pharmaceu day. tical compositions are administered to a patient in need thereof Simultaneously or in a time interval within one day, 0034). If telmisartan is administered with Sumatriptan or a however, in Some cases it may also be possible to have a physiologically acceptable Salt thereof Sumatriptan may be better effect, if the telmisartan containing pharmaceutical administered by oral route in a dosage of 0.03 to 1.43 mg/kg composition and the antimigraine containing pharmaceutical of body weight once, twice or thrice a day or by intravenous composition are administered in an interval of more than 24 or subcutaneous route in a dosage of 0.002 to 0.09 mg/kg of hours. If the compositions are administered in a time inter body weight once or twice a day or by rectal route in a val, the composition comprising telmisartan can be admin dosage of 0.007 to 0.36 mg/kg of body weight once or twice istered before or after administration of the other antimi a day or by nasal route in a dosage of 0.006 to 0.29 mg/kg graine drug. of body weight once or twice a day. 0039. With regard to the second object of the present 0035) If telmisartan is co-administered with Zolmitriptan invention, pharmaceutical compositions are provided for the or a physiologically acceptable Salt thereof the latter may be prophylaxis of vascular headaches which do not originate administered by oral route in a dosage of 0.0007 to 0.036 from hypertension, in particular migraine. These composi mg/kg of body weight once or twice a day. tions comprise a therapeutically effective amount of telm isartan, optionally in combination with at least one other 0036). If telmisartan is administered in combination with CGRP antagonists like 1-N'-3,5-Dibromo-N-4-(3,4-di drug Suitable for the prophylaxis of , preferably, hydro-2(1H)-oxochinazolin-3-yl)-1-piperidinylcarbonyl triptans or CGRP antagonists or pharmaceutically accept D-tyrosyl-L-lysyl-4-(4-pyridinyl)-piperazine or 1-4- able Salts thereof as a combined preparation for Simulta Amino-3,5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1, neous or Sequential administration. 3-benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- 0040 Telmisartan and the other active compounds can be phenylalanyl)-4-(1-piperidinyl)-piperidin O orally administered in a wide variety of different dosage physiologically acceptable Salt thereof, the CGRP antago forms, i.e., they may be formulated with various pharma nists, preferably 1-N-3,5-Dibromo-N-4-(3,4-dihydro ceutically acceptable inert carriers in the form of tablets, 2(1H)-oxochi nazolin-3-yl)-1-piperidinylcarbonyl-D-ty capsules, lozenges, troches, hard candies, powders, SprayS, rosyl-L-lysyl-4-(4-pyridinyl)-piperazine and 1-4-Amino aqueous Suspensions, elixirs, Syrups, and the like. Such 3,5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3- carriers include Solid diluents or fillers, Sterile aqueous benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- media and various non-toxic organic Solvents. Moreover, phenylalanyl)-4-(1-piperidinyl)-piperidin, may be Such oral pharmaceutical formulations can be Suitably administered by intravenous or Subcutaneous route in a Sweetened and/or flavoured by means of various agents of dosage of 0.0001 to 3 mg/kg of body weight or by oral, nasal the type commonly employed for Such purposes. In general, or inhalative route in a dosage of 0.1 to 20 mg/kg of body the compounds of this invention are present in Such oral weight once, twice or trice a day. For 1-N-3,5-Dibromo dosage forms at concentration levels ranging from about US 2005/0065094A1 Mar. 24, 2005

0.5% to about 90% by weight of the total composition, in the pharmaceutical composition according to the present amounts which are Sufficient to provide the desired unit invention may comprise a Single dosage unit of 1/300 of the dosages. Other Suitable dosage forms for the compounds of lowest dose normally recommended up to 1/1 of the nor this invention include controlled release formulations and mally recommended dosage, preferably 1/150 to 1/6 and devices well known to those who practice in the art. more preferably 1/60 to 1/10 of the combined migraine drug 0041. For purposes of oral administration, tablets con for oral, bucal, parenteral, nasal, rectal or topical adminis taining various excipients Such as Sodium citrate, calcium tration. The normally recommended dose for the combined carbonate and calcium phosphate may be employed along migraine drug should be understood to be the dose disclosed with various disintegrants Such as Starch and preferably in Rote Liste(R) 2003, Editio Cantor Verlag, Aulendorf or potato or tapioca Starch, alginic acid and certain complex disclosed in Physicians’ Desk Reference 2003, 57. Ed. Silicate, together with binding agents Such as polyvinylpyr 0046 For example, a pharmaceutical composition rolidone, Sucrose, gelatine and acacia. Additionally, lubri according to the invention may comprise a single dosage cating agents Such as magnesium Stearate, Sodium lauryl unit of 40 or 80 mg telmisartan and Sulfate and talc or compositions of a similar type may also be employed as fillers in Soft and hard-filled gelatine cap 0047 a single dosage unit of 0.1 to 10 mg of 1-IN Sules, included lactose or milk Sugar as well as high molecu 3,5-Dibromo-N-4-(3,4-dihydro-2(1H)-oxochinazo lar weight polyethylene glycols. When aqueous Suspensions lin-3-yl)-1-piperidinylcarbonyl-D-tyrosyl-L-lysyl and/or elixirs are desired for oral administration, the essen 4-(4-pyridinyl)-piperazine or tial active ingredient therein may be combined with various 0048 a single dosage unit of 0.1 to 10 mg of 1-4- Sweetening or flavouring agents, colouring matter or dyes Amino-3,5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)- and, if So desired, emulsifying agents and/or water, ethanol, OXO-1,3-benzodiazepin-3-yl)-1-piperidinylcarbonyl propylene glycol, glycerine and various like combinations D-phenylalanyl-4-(1-piperidinyl)-piperidin or thereof. 0.042 For purposes of parenteral administration, solu 0049) a single dosage unit of 1 to 100 mg of Sumatrip tions of the compounds in Sesame or peanut oil or in aqueous tan Or propylene glycol may be employed, as well as Sterile aque 0050 a single dosage unit of 0.1 to 2.5 mg of Zolmi ous Solutions of the corresponding pharmaceutically accept . able salts. Such acqueous solutions should be suitably buff ered if necessary, and the liquid diluent rendered isotonic 0051 All doses or dosage units of a physiologically with Sufficient Saline or glucose. These particular aqueous acceptable Salt of an active compound mentioned hereinbe Solutions are especially Suitable for intravenous, intramus fore and below should be understood as the dose or dosage cular and Subcutaneous injection purposes. In this connec of the active compound itself. tion, the Sterile aqueous media employed are readily 0052 Furthermore, if telmisartan is used in combination obtained by standard techniques well known to those skilled with another drug used for the treatment and/or prevention in the art. For instance, distilled water is ordinarily used as of migraine or a physiologically acceptable Salt thereof, the the liquid diluent and the final preparation is passed through pharmaceutical composition according to the invention may a Suitable bacterial filter Such as a Sintered glass filter or a be a kit of parts which kit comprises diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, the Chamberland 0053 (a) a first containment containing a pharma and the Asbestos Disk-Metal Seitz filter, wherein the fluid is ceutical composition comprising a therapeutically Sucked into a Sterile container with the aid of a Suction effective amount of telmisartan or a physiologically pump. The necessary Steps should be taken throughout the acceptable Salt thereof and one or more pharmaceu preparation of these injectable Solutions to insure that the tically acceptable diluents and/or carriers, and final products are obtained in a Sterile condition. 0054 (b) a second containment containing another 0.043 For purposes of transdermal administration, the drug used for the prophylaxis of migraine or a dosage form of the particular compound or compounds may physiologically acceptable Salt thereof and one or include, by way of example, Solutions, lotions, ointments, more pharmaceutically acceptable diluents and/or creams, gels, Suppositories, rate-limiting Sustained release carriers. formulations and devices therefore. Such dosage forms comprise the particular compound or compounds and may 0055. A preferred kit of parts comprises a triptan like include ethanol, water, penetration enhancer and inert car almotriptan, avitriptan, eletriptan, froVatriptan, naratriptan, rierS Such as gel-producing materials, mineral oil, emulsi rizatriptan, Sumatriptan, Zolmitriptan, or a CGRP antago fying agents, benzyl and the like. nists in the Second containment. 0044) A pharmaceutical composition according to the 0056 More preferably a kit of parts comprises Sumatrip invention may comprise a single dosage unit of 3 to 500 mg, tan, Zolmitriptan, 1-N'-3,5-Dibromo-N-4-(3,4-dihydro preferably 6 to 100 mg, more preferably 10 to 80 mg 2(1H)-oxochinazolin-3-yl)-1-piperidinylcarbonyl-D-ty telmisartan if orally administered. Particularly preferred is a rosyl-L-lysyl-4-(4-pyridinyl)-piperazine or 1-4-Amino-3, Single dosage unit of 40 or 80 mg of telmisartan for oral 5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3- administration. For parenteral administration the pharma benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- ceutical composition may comprise a single dosage unit of phenylalanyl)-4-(1-piperidinyl)-piperidin in the Second 6 to 20 mg. containment. 0.045. If telmisartan is used in combination with other 0057 With regard to the third object, the present inven drugs used for the treatment and/or prevention of migraine, tion provides the use of telmisartan for the manufacture of US 2005/0065094A1 Mar. 24, 2005

a pharmaceutical composition for the prophylaxis of vascu 3. The method according to claim 2, wherein the other lar headaches which do not originate from hypertension, in drug is a calcitonin gene related peptide (CGRP) antagonist particular migraine. or a physiologically acceptable Salt thereof. 0.058 As already mentioned, telmisartan can be used in 4. The method according to claim 3, wherein the CGRP its neutral form as carboxylic acid, or in one of its poly antagonist or a physiologically acceptable Salt thereof is morphic forms, or in the form of a pharmaceutically accept administered by intravenous or Subcutaneous route in a able Salt or the Solvate, hydrate, or hemihydrate thereof, dosage of 0.0001 to 3 mg/kg of body weight or by oral, nasal including but not limited to the Sodium, potassium or or inhalative route in a dosage of 0.1 to 20 mg/kg of body ammonium Salt. Additionally, telmisartan can be adminis weight once, twice or thrice a day. tered as a prodrug, e.g. an ester, which is hydrolyzed in vivo 5. The method according to claim 3, wherein the CGRP to the pharmacologically active compound. antagonist is 1-N'-3,5-Dibromo-N-4-(3,4-dihydro 2(1H)-oxochinazolin-3-yl)-1-piperidi nylcarbonyl-D-ty 0059 Telmisartan can be administered using for instance rosyl-L-lysyl-4-(4-pyridinyl)-piperazine or 1-4-Amino-3, pharmaceutical formulations Sold under the trade name 5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3- Micardis(R or a formulation as disclosed, for example in EP benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- 0502314 B1, or WO 03/037876 or using, for example, one phenylalanyl)-4-(1-piperidinyl)-piperidin O of the following pharmaceutical formulations: physiologically acceptable Salt thereof. 0060 tablets containing 20, 40 or 80 mg of active 6. The method according to claim 2, wherein the other Substance, drug is a triptan Selected from the group consisting of 0061 capsules containing 20, 40 or 80 mg of active almotriptan, avitriptan, eletriptan, froVatriptan, naratriptan, Substance, rizatriptan, Sumatriptan, Zolmitriptan or a physiologically acceptable Salt thereof. 0.062 Furthermore, telmisartan may be used in combina tion with another drug used for the prophylaxis of migraine, 7. The method according to claim 6, wherein the triptan preferably a triptan or a CGRP antagonist or a physiologi is administered by intravenous or Subcutaneous route in a cally acceptable Salt thereof for the manufacture of a phar dosage of 0.0001 to 1.0 mg/kg of body weight or by oral, maceutical composition for the prophylaxis of Vascular rectal, nasal or inhalative route in a dosage of 0.0005 to 10 headaches which do not originate from hypertension, in mg/kg of body weight once, twice or trice a day. particular migraine. These drugs and preferred embodiments 8. The method according to claim 1, wherein the telmis thereof as well as pharmaceutical compositions are men artan is administered by oral route in a dosage of 0.143 to tioned hereinbefore under the first and Second aspect of the 7.143 mg/kg of body weight preferably in a dosage of 0.286 invention. Most preferred with respect to all aspects of the to 1.429 mg/kg body weight once, twice or thrice a day. invention is the combination of telmisartan with more pref 9. The method according to claim 1, wherein the telmis erably Sumatriptan, Zolmitriptan, 1-N'-3,5-Dibromo-N- artan is administered by oral route in a dosage of 0.571 to 4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl 1.142 mg/kg body weight once, twice or thrice a day. carbonyl-D-tyrosyl-L-lysyl-4-(4-pyridinyl)-piperazine or 10. The method according to claim 1, wherein the telm 1-4-Amino-3,5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)- isartan is administered by parenteral route in a dosage of OXO-1,3-benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- about 0.286 mg/kg of body weight once, twice or thrice a phenylalanyl)-4-(1-piperidinyl)-piperidin or of physiologi day. cally acceptable Salts thereof. 11. The method according to one or more of the claims 1 0.063. Several of the drugs used for the treatment or to 8, characterized in that the vascular headache is migraine. prevention of migraine mentioned hereinbefore are already 12. A pharmaceutical composition for the prophylaxis of on the market, e.g. acetylsalicylic acid is Sold under the trade vascular headache, comprising a therapeutically effective name Aspirine), Sumatriptan is Sold under the trade name amount of telmisartan and at least one other drug used for imigrane, Zolmitriptan is Sold under the trade name asc the treatment or prevention of migraine as a combined otop6), irbesartan under the trade name Aprovel E), cande preparation for Simultaneous or Sequential administration. Sartan cileXetil under trade name Atacand(R), Valsartan under 13. The pharmaceutical composition according to claim the trade name Diovan(R), Iprazochrom under the trade name 12, wherein the other drug is a calcitonin gene related Divascan E), topiramate under the trade name TopamaXCE) and peptide (CGRP) antagonist or a physiologically acceptable dihydroergotamin and the pharmaceutically acceptable Salts Salt thereof. thereof under the trade name Dihytamin(R). A combination of 14. The pharmaceutical composition according to claim acetylisalicylic acid, acetamionophen and caffeine is Sold 13, wherein the CGRP antagonist is 1-N'-3,5-Dibromo under the trade name Thomapyrin(R). N-4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidi What is claimed is: nylcarbonyl-D-tyrosyl-L-lysyl-4-(4-pyridinyl)-pipera 1. A method for the prophylaxis of vascular headache zine or 1-4-Amino-3,5-dibrom-N-4-(2, 3,4,5-tetrahydro which does not originate from hypertension, the method 2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl comprising administering a therapeutically effective amount carbonyl-D-phenylalanyl-4-(1-piperidinyl)-piperidin or a of telmisartan to a Subject in need of Such a treatment. physiologically acceptable Salt thereof. 2. The method according to claim 1, comprising co 15. The pharmaceutical composition according to claim administering a therapeutically effective amount of telmis 12, wherein the other drug is a triptan Selected from the artan and a therapeutically effective amount of at least one group consisting of almotriptan, avitriptan, eletriptan, fro other drug Suitable for the prophylaxis of migraine to a Vatriptan, naratriptan, rizatriptan, Sumatriptan, Zolmitriptan perSon in need of Such treatment. or a physiologically acceptable Salt thereof. US 2005/0065094A1 Mar. 24, 2005

16. The pharmaceutical composition according claim 12, 20. The kit of parts according to claim 19, wherein the comprising an oral Single dosage unit of 10 to 500 mg of drug comprised in the Second containment is a calcitonin telmisartan. gene related peptide (CGRP) antagonist or a physiologically 17. The pharmaceutical composition according claim 12, acceptable Salt thereof. comprising an oral Single dosage unit of 20 to 100 mg of telmisartan. 21. The kit of parts according to claim 20, wherein the 18. The pharmaceutical composition according claim 12, CGRP antagonist is 1-N-3,5-Dibromo-N-4-(3,4-dihy comprising an oral Single dosage unit of 40 to 80 mg of dro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl-carbonyl-D- telmisartan. tyrosyl-L-lysyl-4-(4-pyridinyl)-piperazine or 1-4-Amino 19. Akit of parts for the prophlaxis of vascular headache, 3,5-dibrom-N-4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3- comprising: benzodiazepin-3-yl)-1-piperidinylcarbonyl-D- (a) a first containment containing a pharmaceutical com phenylalanyl)-4-(1-piperidinyl)-piperidin O position comprising a therapeutically effective amount physiologically acceptable Salt thereof. of telmisartan and one or more pharmaceutically 22. The kit of parts according to claim 19, wherein the acceptable diluents or carriers, and drug comprised in the Second containment is a triptan (b) a Second containment containing a pharmaceutical Selected from the group consisting of almotriptan, avitriptan, composition comprising at least one other drug used for eletriptan, froVatriptan, naratriptan, rizatriptan, Sumatriptan, the treatment and/or prevention of migraine or a physi Zolmitriptan or a physiologically acceptable Salt thereof. ologically acceptable Salt thereof and one or more pharmaceutically acceptable diluents or carriers.