EP0000951B1 - Arzneimittel enthaltend 1-substituierte Imidazole, 1-substituierte Imidazole und 1-substituierte Imidazole zur Verwendung bei der Behandlung oder Prophylaxis von Thrombo-Embolien - Google Patents
Arzneimittel enthaltend 1-substituierte Imidazole, 1-substituierte Imidazole und 1-substituierte Imidazole zur Verwendung bei der Behandlung oder Prophylaxis von Thrombo-Embolien Download PDFInfo
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- EP0000951B1 EP0000951B1 EP78100754A EP78100754A EP0000951B1 EP 0000951 B1 EP0000951 B1 EP 0000951B1 EP 78100754 A EP78100754 A EP 78100754A EP 78100754 A EP78100754 A EP 78100754A EP 0000951 B1 EP0000951 B1 EP 0000951B1
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- imidazole
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
- A61K31/41—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
- A61K31/415—1,2-Diazoles
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- 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
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- 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
- A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
Definitions
- the present invention relates to imidazole derivatives and salts thereof, to their synthesis and intermediates therefor, to pharmaceutical formulations containing such compounds and to the use of these componds in medicine.
- Thromboxane A 2 (TXA,), a potent stimulator of blood platelet aggregation, is produced, in platelets, from the prostaglandin endoperoxides PGG 2 and PGH 2 .
- Prostacyclin (PGI 2 ) which has potent anti-aggregatory activity, is also produced (in blood vessel walls) from PGG 2 and PGH 2 and it has been suggested that a balance between the production of TXA 2 and PGI 2 is the controlling factor in thrombus formation. It would, in consequence, be desirable in the treatment and prophylaxis of thrombo-embolic disorders to be able to selectively inhibit TXA 2 synthetase, thereby favouring the production of the anti-aggregatory agent PGI 2 .
- Imidazole and 1-methylimidazole are known to provide some degree of inhibition of the enzymic conversion of the endoperoxides (PGG 2 and PGH 2 ) to thromboxane A 2 by platelet microsomes (Moncada et al., Prostaglandins, 13/4, 611-618, 1977).
- Certain 1-(C 10-19 )hydrocarbyl-imidazoles have been described as being capable of lowering serum cholesterol levels (U.K. Patent No. 1 364 312; Biochem. Pharmacol. 24, 1902-1903, 1975).
- German Auslegeschrift 1213413 describes a process for the preparation of a broad class of 1- alkenyl and 1-alkylimidazoles optionally substituted by alkyl groups in the 2,3- and/or 5-positions.
- the resulting imidazoles are described in the specification as being useful as intermediates for the preparation of pest control and textile treatment agents.
- the inhibitory potency of several derivatives of imidazole and 1-substituted imidazoles, such as 1-methylimidazole on thromboxane synthetase is known from Biochemical and Biophysical Research Communications, Vol. 80, No. 1 (1978), 236-242.
- the authors of this article report that the inhibitory potency of 1-substituted imidazoles is increased with increasing chain length, and state that 1-nonyl- imidazole and 1-(2-isopropylphenyl)imidazole were found to possess the highest potency.
- the best activities are obtained with compounds wherein the 1-substituent on the imidazole ring is a straight chain alkyl group.
- the reference gives no information as to the 1-substituted imidazoles carrying cycloalkyl or cycloalkenyl groups of 4 to 9 carbon atoms or alkyl radicals of from 4 to 7 carbon atoms or alkenyl or alkynyl radicals of from 4 to 9 carbon atoms.
- TXA 2 synthetase may be inhibited by 1-substituted imidazoles of formula (I) and pharmaceutically acceptable acid addition salts thereof.
- the compounds of formula (I) and their salts are hereinafter referred to as the "active compounds”.
- the compounds of formula (1) are:- in which A is a straight or branched, saturated or unsaturated acyclic hydrocarbon radical of from 1 to 3 carbon atoms, n is 0 or 1, and R is a cycloalkyl or cycloalkenyl radical of from 4 to 9, preferably from 5 to 8, carbon atoms and optionally substituted by one, two, three or more alkyl radicals each containing from 1 to 4 carbon atoms, or, when n is 1, A and R together form a straight-chain alkyl radical of from 4 to 7 carbon atoms or an alkenyl or alkynyl group of from 4 to 9 carbon atoms.
- a novel class of compounds within the scope of formula (I) are those of formula (la): in which A is a straight or branched, saturated or unsaturated acyclic hydrocarbon radical of from 1 to 3 carbon atoms and R is a cycloalkyl or cycloalkenyl radical of from 4 to 9, preferably from 5 to 8, carbon atoms and optionally substituted by one or more alkyl radical each containing from 1 to 4 carbon atoms, with the proviso that when A is a methylene radical, R is not unsubstituted cyclohexyl.
- cycloalkyl radicals are cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; cycloalkenyl radicals include cyclohex-3-enyl, cyclopentyl, and 1,4-cyclohexadienyl; alkenyl radicals include pent-2-enyl and pent-4-enyl.
- a valuable class of compounds of formula (I) are those in which n is 1, R is cyclohexyl, cyclohexyl, cycloheptyl, cyclooctyl, or cycloalkenyl of 6 to 8 carbon atoms, and A is -cH 2 or ⁇ (CW 2 ) 2 ⁇ .
- Compounds of formula (I) or (la) may also be used pharmaceutically acceptable acid addition salts.
- Especially preferred compounds include:
- the compounds of formula (I) are more potent inhibitors of TXA 2 synthetase.
- the compounds of formula (I) also do not produce the side-effects found with imidazole upon in vivo administration.
- the compounds of formula (I) are further capable of inhibiting platelet aggregation in vivo and also are capable of disaggregating platelet clumps.
- Imidazoles of formula (I) and acid addition salts thereof may be made by any method known in the art for the synthesis of compounds of analogous structure. In general these methods comprise linking the imidazole ring to the remainder of the molecule; converting a precursor molecule by elimination of a functional group from the imidazole ring; and formation of the desired compound from a corresponding imidazoline, pyrazole or unsaturated analogue.
- a most convenient method of synthesis involves the reaction of imidazole (formula II) or a salt thereof with an alkylating agent of formula (III): wherein R and A are as defined in formula (I) and Z is a leaving group.
- This reacion is well established in the literature, and the leaving group may be chosen from a variety of substituents but especially halo, preferably chloro or bromo, or from p-toluenesulphonyloxy but other arylsulphonyloxy, alkane- sulphonyloxy or aralkylsulphonyloxy radicals may be used.
- the reaction is preferably performed in the presence of an acid acceptor, for example an alkali metal alkoxide such as sodium methoxide or potassium tertiary butoxide in the presence of a corresponding alkanol.
- an acid acceptor for example an alkali metal alkoxide such as sodium methoxide or potassium tertiary butoxide in the presence of a corresponding alkanol.
- a hydrohalogenic acid e.g. hydrochloric acid or a Lewis acid such as aluminium chloride: see Japanese Patent Kokai No. 131577/77
- an alkanol (Z OH) or
- a dehydrating agent such as phosphate acid, or a phosphate (see Japanese Patent Publication No. 5 1 105 060), sulphuric acid or sulphates (see Japanese Patent Publication No. 5 1 105 061 ).
- precursor molecules which may be converted to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof are substituted imidazole derivatives of formula (IV) or addition salts thereof wherein A and R are as defined in formula (I), and Q 1 , Q 2 and Q 3 are the same or different, at least one being selected from thio (-SH), alkylthio (-Salkyl wherein alkyl has 1 to 4 carbon atoms) and halo preferably chloro or bromo, the remaining radical or radicals being selected from a radical having the same function or from hydrogen.
- the reaction conditions are chosen according to the nature of the radicals Q 1 , Q 2 and Q 3.
- Desulphurisation may be performed by oxidative or reductive procedures using for example nitric acid or Raney nickel; and reductive dehalogenation by the use of zinc and acetic acid or Raney nickel or other reagents known in the literature.
- Another class of examples include carboxyimidazoles or derivatives thereof of formula (VI): wherein A and R are as defined in formula (I), at least one of R 1 , R 2 and R 4 is carboxyl or a derivative thereof (for example an ester such as an alkyl ester, an acid halide such as the chloride, or the nitrile) and the other(s) is hydrogen or carboxyl or a derivative as described.
- the compounds of formula (VI) may be converted into the imidazoles of formula (I) by any suitable decarboxylation conditions which may simply comprise heating the compounds with or without a catalyst such as copper.
- the imidazoles of formula (I) may also be made a compound of formula (VII): is 1-imidazolidine, 1-imidazole or 1-pyrazole, A is a straight or branched saturated or unsaturated acyclic hydrocarbon radical, and R 3 is a cycloalkyl or cycloalkenyl radical of from 4 to 9 carbon atoms optionally substituted by alkyl as defined in formula (I), provided that at least one of A 1 and R 3 is other than 1-imidazole, a saturated acyclic hydrocarbon and an optionally substituted cycloalkyl group respectively as defined in formula (I).
- an imidazoline (VIII): wherein one of--- - represents an extra bond and A and R are defined in formula (I) may be dehydrogenated to the corresponding imidazole in the presence of a catalyst for example by heating to 250°C in the presence of palladium, nickel or platinum under pressure, or by heating with a dehydrogenating agent such as selenium or copper oxide.
- the 1-pyrazole compounds (VII) may be treated with ultra-violet irradiation, optionally under an inert atmosphere (e.g. argon) in for example 1,2-dimethoxyethane at room or elevated temperatures (see for example "Ring Transformations of Heterocycles" edited van der Plas, Academic Press, 1973 at page 261).
- the unsaturated imidazoles of formula (I) (in formula (VII), A and/or R 3 are unsaturated) may be reduced to the corresponding saturated compounds with a noble metal catalyst, for example platinum or palladium in alkanol.
- the intermediates for use in the above described reactions may also be made by conventional methods known in the art.
- the 1-pyrazole and 1-imidazoline intermediates (formula (VII) may be prepared by alkylation of pyrazole and imidazoline in an analogous manner to that described above for preparation of the corresponding imidazoles.
- the intermediates of formula (III) may be made in known manner preferably by halogenation of the corresponding alcohols (formula (III).
- Z -OH) where in such compounds R is cycloalkenyl; the alcohol is conveniently prepared by the Prins reaction from the cycloalkene and paraformaldehyde (Bull. Chem. Soc. Japan 46/8, 2512-5, 1973).
- substituted imidazole intermediates of formula (IV) may be made in known manner, for example see “Imidazole and its derivatives” Part I. Ed. K. Hofmann, Interscience Publishers In. New York, 1973.
- 2-thioimidazoles of formula (IV) may be made by cyciisation of an acetal of formula (IX): with thiocyanate, wherein R 5 is alkyl.
- the pharmaceutically acceptable addition salts of the compounds of formula (I) may be prepared by any method known in the art. In particular they may be prepared by treating the parent imidazole with the appropriate acid.
- Examples of the addition salts of the compounds of formula (I) include those salts derived from the following acids: oxalic, hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salycyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzene-sulphonic.
- the imidazoles of formula (I) may be used in conjunction with a phosphodiesterase inhibitor, which provides a further, synergistic increase in effect, as it acts against platelet aggregation by a different pathway.
- Suitable phosphodiesterase inhibitors for use in potentiating the anti-aggregatory effects of the active compounds include as such or as pharmaceutically acceptable salts:-
- the active compounds are particularly useful in the treatment and/or prophylaxis of thrombo-embolic disorders in mammals, including man. It is to be understood that the term "thrombo-embolic disorders" includes those disorders whose etiology is associated with platelet aggregation.
- the active compounds are useful wherever it is desired to inhibit platelet aggregation and/or to reduce the adhesive character of platelets, and consequently to treat or prevent the formation of thrombi in mammals, including man.
- the compounds are useful in the treatment and prevention of myocardial infarcts cerebro-vascular thrombosis and ischaemic peripheral vascular disease; to treat and prevent post-operative thrombosis; and to promote patency of vascular grafts following surgery.
- the active compounds are also useful as an addition to blood, blood products, blood substitutes, and other fluids which are used in artificial extra-corporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. It may also be used in laboratory animals, e.g. cats, dogs, rabbits, monkey and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
- the active compounds also exhibit some vasodilatory action on blood vessels and therefore have a utility as anti-hypertensives for the treatment of high blood pressure in mammals, including man.
- the amount of active compound required for therapeutic or prophylactic effect will vary with the route of administration, and the nature of the condition under treatment.
- a suitable dose for a mammal, including man, of active compound will lie in the range of 0.1 to 300 mg per kg body weight, particularly from 0.5 to 10 mg per kg body weight, for example 2 mg per kg.
- a suitable single oral dose for an adult human lies within the range of 50 to 600 mg, for example 150 mg given say three times a day.
- the formulations both for veterinary and for human medical use, of the present invention comprise an active compound as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
- the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the references herein to pharmaceutical formulations do not include mere mixtures consisting of the active compound a non- sterile organic solvent or water.
- Unit doses of a formulation may contain between 60 mg and 1.5 g of an active compound.
- a tablet may contain 1-cyclooctylmethyl-imidazole or a pharmaceutically acceptable acid addition salt thereof in an amount of 50 to 500 mg based on the amount of imidazole base.
- the formulations include those suitable for oral, rectal, vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration.
- Preferred formulations include tablets, capsules and injectable suspensions or solutions.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound (in the form of the base or a pharmaceutically acceptable acid addition salt) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
- Imidazole (2.0 g, 0.03 mol) was added to a solution of sodium (0.7 g, 0.03 mol) in dry ethanol (50 ml). The mixture was stirred and heated to boiling when bromomethylcyclooctane (5.5 g, 0.027 mol) was added dropwise. Following the addition, the reaction mixture was stirred and boiled for 15 h.
- Imidazole (6.8 g, 0.1 mol) was added to a solution of sodium (2.3 g, 0.1 mol) in dry ethanol (100 ml). This solution was stirred and heated to reflux when bromomethylcyclopentane (16.3 g, 0.1 mol) was added dropwise. Following the addition, the mixture was stirred and heated under reflux for 1 6 h.
- Imidazole (1.0 g, 0.0147 mol) was added to a solution of sodium (0.34 g, 0.0148 mol) in dry ethanol (30 ml). This solution was stirred and heated to boiling when 3-bromopropylcyclopentane (2.94 g, 0.0154 mol) was added dropwise. Following the addition, the reaction mixture was stirred and boiled for 20 h.
- Bromomethylcycloheptane (5.3 g, 0.0278 mol) was added dropwise to a stirred solution of potassium t-butoxide (3.1 g, 0.0277 mol) and imidazole (1.9 g, 0.0279 mol) in dry n-butanol (50 ml) maintained at 100° and under dry nitrogen. After the additoin ( ⁇ 20 mins) the temperature of the reaction mixture was raised to boiling. The reaction mixture was then stirred and boiled for 7 h and then cooled.
- the reaction mixture was treated with water (50 ml) and the organic layer separated.
- the aqueous solution was extracted with petroleum ether (b.p. 40-60°,3 x 25 ml) and the organic layer and petroleum ether extracts combined, washed with 2M-sodium hydroxide solution (25 ml), and with water (25 ml), and then dried (MgS0 4 ). Concentration of the solution under reduced pressure gave an oil 2.3 g) which was distilled, b.p. 48 ⁇ 50°/0.25 mmHg (0,333 x 10- 8 Pa).
- Horse platelets were prepared from whole horse blood by differential centrifugation. Approximately 10 6 platelets were homogenised in 1 ml 100 mM Tris buffer pH 7.4. Various concentrations of active compound were added and the reaction sets incubated for 5 minutes at ambient temperature. To each tube was added 20 nM of arachidonic acid containing 10 6 DPM of labelled arachidonic acid and the tubes incubated for 3 minutes at 37°C in a shaking water bath. After incubation the radioactive products were extracted from the acidified aqueous phase wieth ethyl acetate and after concentration resolved by thin layer chromotography on silica gel with chloroform/methanol/acetic acid/water (90:8:1:0.8) as a developing solvent. The amount of thromboxane produced was measured by scraping the radioactive zone corresponding to thromboxane B 2 and estimating the radioactivity in a liquid scintillation counter.
- the selectivity of the active compounds was measured in a similar manner to that described above and the amount of PGE, PGF and PGD produced was determined. The greater the selectivity, the more of the prostaglandins are produced indicating lower inhibition of cyclo-oxygenase.
- the imidazole salt is ground to a fine powder, blended with the starch and then the mixture granulated with an aqueous solution of the polyvinylpyrrolidone.
- the granules are sieved 1000 ⁇ , dried, sieved again and the magnesium stearate added. The mixture is then compressed into tablets.
- the lactose is blended with the starch.
- Tablets (150 mg) of the imidazoles of Example 8 are prepared in the same manner from the following ingredients, except that the starch, pregelled starch and imidazole compound are all blended together prior to granulation:
- Each 1 ml ampoule supplies 150 mg of the imidazole compound: 1-cyclooctylmethylimidazole fumarate.
- Each 1 ml of solution provides 150 mg of the compound: 1-cyclooctylmethylimidazole fumarate.
- Bromocycloheptane (10.0 g, 0.0565 mol) was added dropwise to a stirred, boiling mixture of imidazole (3.85 g, 0.0566 mol) and sodium bicarbonate (4.75 g, 0.0565 mol) in methanol. Following the addition, the reaction mixture was stirred and boiled for 24 h.
- tablets were prepared of:
- Injectable formulations were prepared by the method of the Injectable formulation in Example 12 above using the imidazoles mentioned in the immediately preceding Example.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (26)
Applications Claiming Priority (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB3591277 | 1977-08-26 | ||
GB3591377 | 1977-08-26 | ||
GB3591277 | 1977-08-26 | ||
GB3591377 | 1977-08-26 | ||
GB398478 | 1978-02-01 | ||
GB398378 | 1978-02-01 | ||
GB398478 | 1978-02-01 | ||
GB398378 | 1978-02-01 | ||
GB7832536 | 1978-08-08 | ||
GB7832526 | 1978-08-08 | ||
GB3252678 | 1978-08-08 | ||
GB3253678 | 1978-08-08 | ||
GB7834106A GB2006752B (en) | 1977-08-26 | 1978-08-22 | Imidazole derivatives and salts thereof their synthesis and intermediates and pharmaceutical formulations |
GB3410678 | 1978-08-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000951A1 EP0000951A1 (de) | 1979-03-07 |
EP0000951B1 true EP0000951B1 (de) | 1984-05-23 |
Family
ID=27562526
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100754A Expired EP0000951B1 (de) | 1977-08-26 | 1978-08-25 | Arzneimittel enthaltend 1-substituierte Imidazole, 1-substituierte Imidazole und 1-substituierte Imidazole zur Verwendung bei der Behandlung oder Prophylaxis von Thrombo-Embolien |
Country Status (4)
Country | Link |
---|---|
US (1) | US4284641A (de) |
EP (1) | EP0000951B1 (de) |
JP (1) | JPS5455568A (de) |
DE (1) | DE2862409D1 (de) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2862340D1 (en) * | 1978-02-01 | 1983-11-24 | Wellcome Found | Imidazole derivatives and salts thereof, their synthesis, and pharmaceutical formulations thereof |
EP0055991A3 (de) * | 1978-10-02 | 1982-08-11 | Merck & Co. Inc. | Lysosomotropische therapeutische Detergentia, diese enthaltende Mischungen und ihre Anwendung |
GB2044754B (en) * | 1978-11-14 | 1983-05-05 | Eisai Co Ltd | Imidazoles |
US4430445A (en) | 1979-07-19 | 1984-02-07 | Asahi Kasei Kogyo Kabushiki Kaisha | Novel basic imidazolylmethylstyrene compound, its polymer, a process for the preparation thereof and a use as ion exchange resin |
DE2944663A1 (de) * | 1979-11-06 | 1981-05-14 | Bayer Ag, 5090 Leverkusen | Imidazolderivate, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
DE2944662A1 (de) * | 1979-11-06 | 1981-05-14 | Bayer Ag, 5090 Leverkusen | Cycloheptatrienylimidazolderivate, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
JPS5681566A (en) * | 1979-12-05 | 1981-07-03 | Yoshitomi Pharmaceut Ind Ltd | Imidazole derivative |
US4731363A (en) * | 1979-12-26 | 1988-03-15 | Hoffmann-La Roche Inc. | Thromboxane synthase inhibitors as insulin lowering agents and antiobesity agents |
US4522948A (en) * | 1981-04-24 | 1985-06-11 | Syntex (U.S.A.) Inc. | Spermicidal substituted 1-(cycloalkyl)alkylimidazoles |
ES8503669A1 (es) * | 1982-07-05 | 1985-03-01 | Erba Farmitalia | Procedimiento para preparar derivados n-imidazolilicos de compuestos biciclicos. |
DE3484023D1 (de) * | 1983-03-03 | 1991-03-07 | Basf Ag | Azolylmethylcycloalkane, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel. |
US4992459A (en) * | 1983-04-12 | 1991-02-12 | Smithkline Beecham Corporation | Dopamine-β-hydroxylase inhibitors |
CA1249832A (en) * | 1984-02-03 | 1989-02-07 | Shionogi & Co., Ltd. | Azolyl cycloalkanol derivatives and agricultural fungicides |
US4659730A (en) * | 1984-06-18 | 1987-04-21 | Eli Lilly And Company | Aromatase inhibiting imidazole derivatives |
US4634711A (en) * | 1985-08-02 | 1987-01-06 | Smithkline Beckman Corporation | Pyridylalkyl imidazole-2-thiols |
US4719223A (en) * | 1985-10-31 | 1988-01-12 | Smithkline Beckman Corporation | Imidazolethiol dopamine-beta-hydroxylase inhibitors |
US4743613A (en) * | 1986-04-08 | 1988-05-10 | Smithkline Beckman Corporation | Ester prodrugs of dopamine-β-hydroxylase, inhibitors, composition containing them, and method of using them to inhibit dopamine-β-hydroxylase activity |
US4837333A (en) * | 1987-05-14 | 1989-06-06 | G. D. Searle & Co. | Substituted alkylidene imidazoles |
US4876266A (en) * | 1987-12-31 | 1989-10-24 | Smithkline Beckman Corporation | 1-aralkyl-2-mercaptoimidazolines as DBH inhibitors |
US5091454A (en) * | 1988-08-03 | 1992-02-25 | Velsicol Chemical Corporation | Hot melt adhesive composition |
IL91542A0 (en) * | 1988-10-06 | 1990-04-29 | Erba Carlo Spa | N-imidazolyl-and n-imidazolyl-methyl derivatives of substituted bicyclic compounds,their preparation and pharmaceutical compositions containing them |
US4968713A (en) * | 1989-07-31 | 1990-11-06 | Merck & Co., Inc. | Certain imidazole compounds as transglutaminase inhibitors |
US5359073A (en) * | 1992-11-24 | 1994-10-25 | G. D. Searle & Co. | Substituted-phenyl (N,N'-cycloalkyl/alkyl carboxamide)-1H/3H-imidazo[4,5-b]pyridine compounds as PAF antagonists |
US5262426A (en) * | 1993-01-22 | 1993-11-16 | G. D. Searle & Co. | N,N'-cycloalkyl/alkyl carboxamide 4H-imidazo-[4,5-b]pyridine compounds as PAF antagonists |
US5360907A (en) * | 1993-06-14 | 1994-11-01 | G.D. Searle & Co. | Pyrrolo[3,2-B]pyridinylalkyl benzamide derivatives |
US5652363A (en) * | 1995-10-05 | 1997-07-29 | C.D. Searle & Co. | Pyrido-1,4-oxazinylalkyl-benzamide derivatives |
EP2630136A1 (de) * | 2010-10-21 | 2013-08-28 | Universität des Saarlandes | Selektive cyp11b1-inhibitoren zur behandlung von cortisolbedingten erkrankungen |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1213413B (de) | 1963-12-05 | 1966-03-31 | Basf Ag | Verfahren zur Herstellung von N-Alkylimidazolen |
DE1620362A1 (de) * | 1966-05-04 | 1970-04-02 | Shell Int Research | Verfahren zur Herstellung von N-Alkyl- bzw.N-Alkenylimidazolen |
GB1164564A (en) * | 1967-08-21 | 1969-09-17 | Shell Int Research | Novel Cyclobexylpentadienone Acid Derivatives, the preparation thereof and Compositions containing the same |
ES348533A2 (es) * | 1967-12-22 | 1969-05-01 | Trossinger Metallstimmenfab H | Aparato reproductor de senales. |
US3541109A (en) * | 1968-06-25 | 1970-11-17 | Du Pont | 1-substituted imidazoles useful in acth reserve assay |
US3637731A (en) * | 1968-07-18 | 1972-01-25 | Du Pont | 1-(alkylsubstituted phenyl)imidazoles useful in acth reserve assay |
FR1603793A (en) | 1968-12-17 | 1971-05-24 | Substd imidazoles intermediates for insecticides | |
CH548398A (de) * | 1971-02-13 | 1974-04-30 | Basf Ag | Verfahren zur herstellung von substituierten imidazolen. |
GB1364312A (en) | 1972-01-25 | 1974-08-21 | Beecham Group Ltd | Biologically active imidazoles |
IE40911B1 (en) * | 1974-04-11 | 1979-09-12 | Schering Ag | Imidazole derivatives and process for their manufacture |
US3927017A (en) * | 1974-06-27 | 1975-12-16 | Janssen Pharmaceutica Nv | 1-({62 -Aryl-{62 -R-ethyl)imidazoles |
US3991201A (en) * | 1974-06-27 | 1976-11-09 | Janssen Pharmaceutica N.V. | 1-(β-Aryl-β-R-ethyl)imidazoles as antimicrobial agents |
DE2533211A1 (de) | 1975-07-24 | 1977-02-10 | Heumann Ludwig & Co Gmbh | Verfahren zur herstellung von imidazolderivaten |
US4036975A (en) * | 1975-07-28 | 1977-07-19 | Xyntex (U.S.A) Inc. | 1-[2-(1-Adamantyl)-2-(R-thio)ethyl]imidazoles and 1-[2-(1-adamantyl)-2-(R-oxy)ethyl]imidazoles |
US4115578A (en) * | 1975-12-18 | 1978-09-19 | Rohm And Haas Company | 1-Substituted aralkyl imidazoles |
-
1978
- 1978-08-24 US US05/936,406 patent/US4284641A/en not_active Expired - Lifetime
- 1978-08-25 DE DE7878100754T patent/DE2862409D1/de not_active Expired
- 1978-08-25 EP EP78100754A patent/EP0000951B1/de not_active Expired
- 1978-08-25 JP JP10374878A patent/JPS5455568A/ja active Pending
Non-Patent Citations (2)
Title |
---|
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, VOL. 80, No. 1, 1978, pp. 236-242 * |
BIOCHEMICAL PHARMACOLOGY, 23, 2377-2386 (1974) * |
Also Published As
Publication number | Publication date |
---|---|
EP0000951A1 (de) | 1979-03-07 |
US4284641A (en) | 1981-08-18 |
JPS5455568A (en) | 1979-05-02 |
DE2862409D1 (en) | 1984-06-28 |
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