Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
  • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
  • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4

Definitions

• the present invention relates to novel N-substituted azaheterocyclic compounds in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or infiammatory conditions in which C-fibres play a pathophysiological role, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions.
• the invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin, the present compounds being known to iterfere with neuropeptide containing C-fibres.
• NIDDM non-insulin-dependent diabetes mellitus
• the nervous system exerts a profound effect on the inflammatory response.
• Antidromic stimulation of sensory nerves results in localised vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151), and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro- intestinal and respiratory tracts.
• inhibition of sensory nerve peptide release and/or activity may be useful in treatment of for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine.
• CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993).
• This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or ageing-associated obesity (Melnyk et al.
• N- substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors.
• WO 9631498 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof.
• the present invention relates to compounds of the general formula I, wherein X, Y, R 1 , R 1a , R 2 , R 2a , R 12 , R 13 , A, r and s are as defined in the detailed part of the present description.
• the present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
• NIDDM non-insulin-dependent diabetes mellitus
• the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
• a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis
• C-fibres play a pathophysiological role
• a pathophysiological role e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis
• indications caused by or related to the secretion and circulation of insulin antagonising peptides e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
• NIDDM non-insulin-dependent diabetes mellitus
• the method of treatment may be described as the treatment, prevention, elimination, alleviation or amelioration of one of the above indications, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• a further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing- associated obesity.
• NIDDM non-insulin-dependent diabetes mellitus
• the present invention relates to novel N-substituted azaheterocyclic compounds of the general formula I
• R ⁇ R 1a , R 2 and R 2a independently are hydrogen, halogen, cyano, trifluoromethyl, methylthio, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy;
• R 12 is hydrogen, -(CH 2 ) n OH or -(CH 2 ) p COR 17 wherein n is 1 , 2, 3, 4, 5 or 6 and wherein p is 0 or 1 and wherein R 17 is -OH, -NHR 20 or C,. 6 -alkoxy wherein R 20 is hydrogen or C 1-6 -alkyl; and
• R 13 is cyano, -NR 5 R 7 , -NR 5 -Z or -(CHR 21 ) q -Z wherein R 5 and R 7 are as defined above and wherein q is 0, 1 , 2, 3, 4, 5 or 6, and wherein R 21 is hydrogen, halogen, cyano, trifluoromethyl, hydroxy, C 1-6 -alkyl, C ⁇ -alkoxy, -NR 5 R 7 or -COOH, and wherein Z is C M - cycloalkyl, aryl or heteroaryl, which rings may optionally be substituted with one or more of halogen, cyano, trifluoromethyl, hydroxy, methylthio, C 1-6 -alkyl or C L e-alkoxy; or a pharmaceutically acceptable salt thereof.
• the compounds of formula I may exist as geometric and optical isomers and all isomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
• the compounds of formula I exist as the individual geometric or optical isomers.
• the compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts, metal salts or, optionally alkylated, ammonium salts.
• salts include inorganic and organic acid addition salts such as hydrochlo- ride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartra- te, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
• inorganic and organic acid addition salts such as hydrochlo- ride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartra- te, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
• pharmaceutically acceptable inorganic or organic acid addition salts in- elude the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan.
• the acid addition salts may be obtained as the direct products of compound synthesis.
• the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by precipitation or crystallisation.
• the compounds of formula I may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
• C 1-6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms .
• groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4- methylpentyl, neopentyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 ,2,2-thmethylpropyl and the like.
• halogen means fluorine, chlorine, bromine or iodine.
• C ⁇ -alkoxy as used herein, alone or in combination is intended to include those C 1-6 - alkyl groups of the designated length in either a linear or branched or cyclic configuration linked thorugh an ether oxygen having its free valence bond from the ether oxygen.
• linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
• branched alkoxy are isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy.
• cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
• C ⁇ -cycloalkyl represents a carbocyclic group having from 3 to 8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycloheptyl and cyclooc- tyl and the like.
• C ⁇ -cycloalkylene represents a bisubstituted carbocyclic group having from 3 to 7 carbon atoms e.g. cyclopropylene, cyclobutylene, cyclopentylene, cyclo- hexylene and cycloheptylene and the like.
• aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), phenanthrenyl, fluorenyl, indenyl and the like.
• heteroaryl as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, py- ranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadiazinyl, indolyl, isoindolyl, ben- zofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinozolinyl, quinoli- nyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,
• Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above.
• Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazi- nyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydofuranyl.
• R 1 , R 1a , R 2 and R 2a are selected from hydrogen, halogen, trifluoromethyl or C 1-6 -alkyl.
• R 1 , R 1a , R 2 and R 2a are hydrogen.
• X is -CH 2 CH 2 -.
• Y is selected from >N- or wherein R 8 is hydrogen.
• R 8 is hydrogen.
• A is the completion of a bond or -(CR 9 R 10 )- wherein R 9 and R 10 are hydrogen.
• r is 0, 1 or 2.
• s is 0, 1 or 2.
• R 12 is hydrogen or -(CH 2 ) p COR 17 wherein p is 0 and wherein R 17 is -OH or -NH-, .
• R 13 is cyano, -N(CH 3 ) 2 , -NH-Z or -(CHR 21 ) q -Z wherein q is 0 or 1 , and wherein R 21 is hydrogen, cyano or -COOH, and wherein Z is cyclohexyl, phenyl, naphtyl or pyrrolidinyl, which rings may optionally be substituted with halogen or methyl.
• Preferred compounds of the present invention include:
• novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of histamine induced paw oedema Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995) in which the novel compounds of formula I exhibit a potent inhibitory effect.
• Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
• Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post- herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
• neuropathy diabetic, post-traumatic, toxic
• neuralgia rheumatoid arthritis
• spondylitis gout
• inflammatory bowel disease exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, g
• the compounds of general formula I lower the glucose levels in diabetic rodents (ob/ob mice and diabetic fat Zucker rats) as well as improve the glucose tolerance and that this may result from the reduced release of CGRP from peripheral nervous endings and other peptides derived from the sensory nervous system.
• the compounds of general formula I may be used in the treatment of NIDDM as well as ageing-associated obesity.
• this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I.
• the compounds of formula I may be prepared by the following method A:
• a compound of formula II wherein R 1 , R 2 , R 1a , R 2a , X, Y, A, r and s are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein R 12 and R 13 are as defined above to give the compound of formula I.
• This alkylation reaction may be carried out in a solvent such as acetone, N,N-dimethylformamide, acetonitrile, dibutylether, 2-butanone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride, potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
• a base e.g. sodium hydride, potassium carbonate
• a catalyst e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
• esters have been prepared in which R 17 is alkoxy
• compounds of formula I wherein R 17 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
• the compounds of formula I may be prepared by the following method B:
• a compound of formula II wherein R 1 , R 2 , R 1a , R 2a , X, Y, A, r and s are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an aza compound of formula IV to give a compound of formula V wherein R 1 , R 2 , R 1a , R 2a , X, Y, A, r and s are as defined above.
• This alkylation reaction may be carried out in a solvent such as acetone, N,N-dimethylformamide, acetonitrile, dibutylether, 2-butanone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride, potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
• a base e.g. sodium hydride, potassium carbonate
• a catalyst e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
• the compound of formula V may be transformed into a compound of formula VI wherein R 1 , R 2 , R 1a , R 2a , X, Y, A, r and s are as defined above and G is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate.
• the compound of formula VI may be reacted with an ⁇ -activated compound of formula VII wherein R 12 and R 13 are as defined above to give the compound of formula I.
• This alkylation reaction may be carried out in a solvent such as N,N-dimethylfor ⁇ mamide, tetrahydrofuran, ethanol, toluene, N- methylpyrrolidone or hexamethylphosphoramide in the presence of a base e.g. potassium tertbutoxide, sodium ethanolate, sodium hydride, potassium carbonate or triethyl amine at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
• a base e.g. potassium tertbutoxide, sodium ethanolate, sodium hydride, potassium carbonate or triethyl amine
• esters have been prepared in which R 17 is alkoxy
• compounds of formula I wherein R 17 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
• the carboxylic acid group can, for example, be esterified. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry” J.F.W. McOrnie ed. (New York, 1973).
• the rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995). In brief 250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and placed on a 32 degree Celsius heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes hereafter the paw swelling was determined by water plethysmography (Ugo Basile). Test compounds were administered intraperitoneally at 15 minutes before the anaesthetics. II. Reduced release of CGRP
• mice 16 weeks of age, where injected glucose (2g/kg) subcutaneously.
• blood glucose was determined in tail venous blood by the glucose oxidase method.
• glucose oxidase method was determined in tail venous blood by the glucose oxidase method.
• the animals were decapitated and tunk blood collected.
• Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
• the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutically acceptable carrier or diluent.
• compositions comprising a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed.. 1995.
• the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
• Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
• conventional techniques for the preparation of pharmaceutical compositions may be used.
• the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
• a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
• the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
• the active compound can be adsorbed on a granular solid container for example in a sachet.
• suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium ' stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
• the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
• the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
• compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
• the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transder- mal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
• the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
• the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
• a liquid carrier in particular an aqueous carrier
• the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
• Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
• a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
• a typical tablet which may be prepared by conventional tabletting techniques may contain:
• Active compound (as free compound or salt thereof) 100 mg
• the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role such as e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, such as non-insulin-dependent diabetes mellitus (NIDDM) or ageing-associated obesity.
• NIDDM non-insulin-dependent diabetes mellitus
• Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
• the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, in an effective amount.
• the compounds of the invention are effective over a wide dosage range.
• dosages from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily.
• a most preferable dosage is from about 50 to about 200 mg per dose when administered to e.g. a human.
• the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
• the compounds of the present invention are dispensed in unit dosage form comprising from about 50 to about 200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
• dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
• the method of treating may be described as the treatment of an indication caused by or related to the secretion and circulation of insulin antagonising peptides like CGRP or amylin in a subject in need thereof, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• TLC thin layer chromatography
• CDCI 3 deuterio chloroform
• DMSO-d 6 hexadeuterio dimethylsulfoxide.
• the structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate.
• 1 H NMR shifts ( ⁇ H ) are given in parts per million (ppm).
• M.p. is melting point and is given in °C and is not corrected.
• Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385).
• Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
• ester was isolated as p-toluenesulfonate), 5-(3-bromo-1-propyiidene)- 10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.0 g, 0.0064 mol), anhydrous potassium car- bonate (3.00 g, 0.021 mol) and potassium iodide (2.0 g, 0.012 mol) in 2-butanone (60 ml) was stirred at 60 - 70 °C for 7.5 h. The mixture was diluted with ether (90 ml) and water (60 ml), and the phases were separated.
• the aqueous phase was extracted with additional ether (60 ml) and the combined organic extracts were washed with water (60 ml) and dried (MgSO 4 ). The solvent was removed in vacuo and the oily residue (3.47 g) was purified by gradient column chromatography on silica gel using mixtures of benzene and ethyl acetate as eluents.
• the mixture was diluted with ether (150 ml) and water (150 ml) and the layers were separated.
• the aqueous phase was extracted with additional ether (80 ml) and the combined organic extracts were washed with water (100 ml) and dried (MgSO 4 ).
• the solvent was removed in vacuo and the oily residue (6.60 g) was purified by gradient column chromatography on silica gel using mixtures of benzene and ethyl acetate as eluents.
• HPLC retention time 21.32 minutes (5mm C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 30 minutes at room temperature).

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