# Patent

## Title
Treatment or prevention of hypotension and shock

## Abstract

The present invention relates to a method for the prevention and treatment of hypotension and shock due to low peripheral resistance, comprising administering to a mammal in need thereof an effective amount of a certain imidazole derivative or pharmaceutically acceptable ester or salt thereof. In addition, the present invention relates to a method for the treatment of cardiopulmonary resuscitation, comprising administering to a mammal in need thereof an effective amount of a certain imidazole derivative or pharmaceutically acceptable ester or salt thereof.

## Background
BACKGROUND OF THE INVENTION
The present invention relates to a method for the prevention or treatment of hypotension and shock due to low peripheral resistance. Further, the present invention relates to a method for the treatment of cardiopulmonary resuscitation. Accordingly, the present invention relates to a method for the prevention or treatment of hypotension and shock due to low peripheral resistance by administering an imidazole derivative of the formula I:




wherein R is hydrogen or methyl, or a pharmaceutically acceptable ester or salt thereof.

Further, the present invention relates to a method for the treatment of cardiopulmonary resuscitation by administering an imidazole derivative of formula I or a pharmaceutically acceptable ester or salt thereof.
The present invention also relates to the use of an imidazole derivative of formula I, or a pharmaceutically acceptable ester or salt thereof, in the manufacture of a medicament for the prevention or treatment of hypotension and shock due to low peripheral resistance. Further, the present invention also relates to the use of an imidazole derivative of formula I, or a pharmaceutically acceptable ester or salt thereof, in the manufacture of a medicament for the treatment of cardiopulmonary resuscitation.
Additional objects and advantages of the invention will he set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The preparation of the imidazole derivatives of formula I in general has been described in WO 97/12874. Enteral, topical, and parenteral routes of administration and their use as α2-adrenoceptor agonists useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety, and different neurological, musculosketal, psychiatric and cognition disorders as well as a sedative and an analgesic agent, nasal decongestant, and as an adjunct to anaesthesia are discussed in WO 97/12874.
α2-Adrenoceptor agonists, such as dexmedetomidine, are known to induce a characteristic pattern of cardiovascular responses including e.g., bradycardia and hypotension and therefore they are typically considered as potential candidates for the treatment of hypertension.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the time-course of mean arterial pressure (MAP) (upper) and heart rate (HR) (lower) in anaesthetized rats after slow intravenous administration (during 5 minutes) of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol at the doses of 1 and 3 μg/kg. Means±SEM of percent changes from the baseline value are shown, n=6 in each group.
FIG. 2 shows the time-course of mean arterial pressure (MAP) (upper) and heart rate (HR) (lower) in anaesthetized rats after slow intravenous administration (during 5 minutes) of dexmedetomidine (DMD) at the doses of 3 and 10 μg/kg. Means±SEM of percent changes from baseline value are shown, n=6 in each group.



DETAILED DESCRIPTION OF THE INVENTION
Applicants have surprisingly discovered that unlike other pure α2-adrenoceptor agonists, the imidazole derivatives of formula I do not decrease the blood pressure after intravenous, intramuscular or subcutaneous administration in a mammal. Accordingly, they cause an increase in the blood pressure with a reflector decrease in heart rate after the administration. Thus, the imidazole derivatives of formula I, or a pharmaceutically acceptable ester or salt thereof, can be used in situations where returning the blood from peripheral circulation to the central circulation is needed, like in circulatory shock due to low resistance of peripheral circulation and cardiac arrest. Further, the advantage of the compounds of the present invention compared to adrenalin which is commonly used in these situations, is the lack of direct stimulation of the heart i.e., the heart rate does not raise and cause further ischemia of the heart. Accordingly, an object of the invention is to provide a method for the prevention or treatment of hypotension and shock due to low peripheral resistance by administering an imidazole derivative of formula I, or a pharmaceutically acceptable ester or salt thereof to a mammal. Further, an object of the invention is to provide a method for the treatment of cardiopulmonary resuscitation by administering an imidazole derivative of formula I, or a pharmaceutically acceptable ester or salt thereof to a mammal.
The preferred compound of the present invention is 3-(1H-imidazol-4-ylmethyl)-indan-5-ol.
It should be noted that the method for the treatment of hypotension and shock due to low peripheral resistance encompasses all of the potential conditions that require the treatment of hypotension and shock, e.g., hypotension due to vasodilatation, anaphylactic shock, septic shock and post heart surgery shock.
The precise amount of the drug to be administered to a mammal for the prevention and treatment of hypotension and shock due to low peripheral resistance and for the treatment of cardiopulmonary resuscitation is dependent on numerous factors known to one skilled in the art, such as, the compound to be administered, the general condition of the patient, the condition to be treated, the desired duration of use, the type of mammal, the method of administration etc. The desired dose can be administered intravenously, using a bolus dose or by a steady infusion, intramuscularly or subcutaneously. For example, the dose of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol administered intravenously to a human can be from about 10 to 500 μg/patient, preferably about 30-200 μg/patient.
One skilled in the art would recognize the dosage forms suitable in the method of the present invention. The injections or infusions may contain one or more diluents or carriers.
The invention will be further clarified by the following example, which is intended to be purely exemplary of the invention.
EXAMPLE 1
The effects of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol on blood pressure and heart rate after slow intravenous administration were studied in anaesthetized rats. Dexmedetomidine (Orion Corporation Orion Pharma, Finland), a specific α2-adrenoceptor agonist was studied as a reference compound.
Male Spraque-Dawley rats (B&K, Sweden), weighing 290-400 g, were anaesthetized with sodium pentobarbital (Mebunat® 60 mg/ml) 75 mg/kg i.p. The left femoral vein was cannulated (PE-50) for slow drug injections. The left femoral artery was cannulated (PE-60) and the mean arterial blood pressure (MAP) and heart rate (HR) were recorded continuously via a Micro MP-15 transducer connected to a Grass Model 7D Polygraph. Arterial pressure was sampled at a rate 150 samples/second and recorded on a Pinus PC computer using the software program AcqKnowledge version 3.5.3 and a MP100A data acquisition unit for analog/digital conversion (BIOPAC Systems, Inc.). Pulse waves of the blood pressure were used for displaying heart rate continuously. The body temperature (rectal) was kept constant at 37±0.5° C. by warming with a lamp above the animal's chest. Only rats with MAP of 73 mmHg or higher were used for the tests. After a stabilizing period of 10-20 min, 3-(1H-imidazol-4-ylmethyl)-indan-5-ol (1 and 3 μg/kg, as hydrochloride) or dexmedetomidine (3 and 10 μg/kg, as hydrochlorides) dose was given as slow intravenous injection (during 5 min) by an infusion pump (Perfusor® ED 2, B. Braun). The total injection volume was adjusted to 1 ml in each experimental group.
3-(1H-imidazol-4-ylmethyl)-indan-5-ol induced an immediate and dose-dependent increase in MAP (maximally+31%) and long-lasting decrease in HR (maximally−19%) after slow (during 5 minutes) i.v. dosing of 1 and 3 μg/kg (see FIG. 1 and Table 1). Instead, the reference compound dexmedetomidine (3 and 10 μg/kg) decreased both MAP and HR (maximally−37% and −21%, respectively) immediately and dose-dependently (see FIG. 2 and Table 1) after slow intravenous administration at the tested doses.







TABLE 1







The effects of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol and dexmedetomidine on mean arterial


pressure (MAP) and heart rate (HR) after slow (during 5 minutes) intravenous administration


in anaesthetized rats. The values are means ± SEM, n = 6 in each group.












Dose
Time
MPV-2426 AI
Dose
Time
Dexmedetomidine














(μg/kg)
(min)
MAP(mmHg)
HR (beats/min)
(μg/kg)
(min)
MAP (mmHg)
HR (beats/min)

















1
0
97 ± 4
373 ± 8
3
0
89 ± 5
 348 ± 12



3
114 ± 3 
324 ± 9

3
86 ± 5
310 ± 6



5
112 ± 3 
321 ± 9

5
79 ± 7
310 ± 5



10
83 ± 4
327 ± 7

10
61 ± 4
308 ± 4



20
84 ± 4
319 ± 9

20
65 ± 2
309 ± 5



30
80 ± 3
317 ± 9

30
67 ± 2
309 ± 5


3
0
94 ± 5
 366 ± 11
10
0
92 ± 2
 383 ± 11



3
123 ± 9 
309 ± 7

2
94 ± 4
308 ± 5



5
117 ± 12
311 ± 4

5
75 ± 6
309 ± 3



10
88 ± 4
321 ± 4

10
59 ± 3
303 ± 3



20
83 ± 5
321 ± 6

20
68 ± 2
296 ± 7



30
77 ± 3
305 ± 6

30
73 ± 2
297 ± 6









Immediate and dose-dependent initial hypertensive action was seen after administration of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol at all tested doses. In addition, immediate, and long-lasting bradycardic action was noted after administration 3-(1H-imidazol-4-ylmethyl)-indan-5-ol at all tested doses. Instead, the reference compound dexmedetomidine (3 and 10 μg/kg) decreased both MAP and HR after slow intravenous administration. After slow intravenous administration 3-(1H-imidazol-4-ylmethyl)-indan-5-ol produces both hypertensive and bradycardic actions, unlike dexmedetomidine, which in turn has typical cardiovascular effects of an alpha-2-adrenoceptor agonist.
Those skilled in the art will recognize that while specific embodiments have been illustrated and described, various modifications and changes may be made without departing from the spirit and scope of the invention.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
The references discussed herein are specifically incorporated by reference in their entirety.

## Claims

1. A method for the treatment of hypotension and shock due to low peripheral resistance, comprising intravenously administering to a human in need thereof about 10-500 μg/patient of an imidazole derivative of formula I:




wherein R is hydrogen or methyl, or hydrochloride salt thereof.

2. The method according to claim 1, wherein 3-(1H-imidazol-4-ylmethyl)-indan-5-ol is administered.

3. The method according to claim 1, wherein the effective amount administered is about 30-200 μg/patient.