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EP1768658A1 - Hydroxyalkylamides - Google Patents

Hydroxyalkylamides

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Publication number
EP1768658A1
EP1768658A1 EP04740859A EP04740859A EP1768658A1 EP 1768658 A1 EP1768658 A1 EP 1768658A1 EP 04740859 A EP04740859 A EP 04740859A EP 04740859 A EP04740859 A EP 04740859A EP 1768658 A1 EP1768658 A1 EP 1768658A1
Authority
EP
European Patent Office
Prior art keywords
methyl
trans
hydroxy
compounds according
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04740859A
Other languages
German (de)
English (en)
Inventor
Jean Ackermann
Johannes Aebi
Henrietta Dehmlow
Olivier Morand
Narendra Panday
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP1768658A1 publication Critical patent/EP1768658A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/56—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention is concerned with novel hydroxyalkylamide derivatives, their manufacture and their use as medicaments.
  • the invention relates to compounds of the formula (I)
  • R 1 is hydrogen or lower-alkyl
  • the compounds of the present invention inhibit 2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) which is required for the biosynthesis of cholesterol, ergosterol and other sterols.
  • Causal risk factors that directly promote the development of coronary and peripheral atherosclerosis include elevated low-density lipoprotein cholesterol (LDL-C), low high- density lipoprotein cholesterol (HDL-C), hypertension, cigarette smoking and diabetes mellitus.
  • Other synergistic risk factors include elevated concentrations of triglyceride (TG)- rich lipoproteins, small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)), and homocysteine.
  • Predisposing risk factors modify the causal or conditional risk factors and thus affect atherogenesis indirectly.
  • the predisposing risk factors are obesity, physical inactivity, family history of premature CVD, and male sex.
  • CHD coronary heart disease
  • LDL-C levels in plasma and the therapeutic advantage of lowering elevated LDL-C levels are now well established [Gotto et al., Circula- tion 81:1721-1733 (1990); Stein et al., Nutr. Metab. Cardiovasc. Dis. 2:113-156 (1992); Illingworth, Med. Clin. North. Am. 84:23-42 (2000)].
  • cholesterol lowering is greater for patients with pre-established CHD than for asymptomatic persons with hypercholesterolemia.
  • cholesterol lowering treatment is recommended for patients who had survived a myocardial infarct or patients suffering from angina pectoris or another atherosclerotic disease, with a target LDL-C level of 100 mg/dl.
  • statins i.e. HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin
  • statins i.e. HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin
  • statins i.e. HMG-Co-A reductase inhibitors such as simvastatin and atorvastatin
  • statins i.e. HMG-Co-A reductase inhibitors
  • simvastatin and atorvastatin i.e. HMG-Co-A reductase inhibitors
  • statins are well tolerated at standard dosage, but reductions in non-sterol inter- mediates in the cholesterol synthesis pathway, such as isoprenoids and coenzyme Q, may be associated with adverse clinical events at high doses [Davignon et al., Can. J. Cardiol. 8:843-864 (1992); Pederson and Tobert, Drug Safety 14:11-24 (1996)].
  • OSC 2,3-oxidosqualene:lanosterol cyclase
  • OSC inhibition does not trigger the overexpression of HMGR because of an indirect, nega- tive feed-back regulatory mechanism involving the production of 24(S),25-epoxychole- sterol [Peffley et al., Biochem. Pharmacol. 56:439-449 (1998); Nelson et al., J. Biol. Chem. 256:1067-1068 (1981); Spencer et al., J. Biol. Chem. 260:13391-13394 (1985); Panini et al., J. Lipid Res. 27:1190-1204 (1986); Ness et al., Arch. Biochem. Biophys. 308:420-425 (1994)].
  • This negative feed-back regulatory mechanism is fundamental to the concept of OSC inhibition because (i) it potentiates synergistieally the primary inhibitory effect/with. ... an indirect down-regulation of HMGR, and (ii) it prevents the massive accumulation of the precursor monooxidosqualene in the liver.
  • 24(S),25 ⁇ epoxycholesterol was found to be one of the most potent agonists of the nuclear receptor LXR [Janowski et al., Proc. Natl. Acad. Sci. USA 96:266-271 (1999)].
  • the OSC inhibitors of the present invention could also indirectly activate LXR-dependent pathways such as (i) cholester- ol-7alpha-hydroxylase to increase the consumption of cholesterol via the bile acid route, (ii) expression of ABC proteins with the potential to stimulate reverse cholesterol transport and increase plasma HDL-C levels [Venkateswaran et al., J. Biol. Chem. 275:14700-14707 (2000); Wang et al., J. Biol. Chem.
  • the present compounds of formula I inhibit OSC and therefore also inhibit the biosynthesis of cholesterol, ergosterol and other sterols, and reduce the plasma cholesterol levels. They can therefore be used in the therapy and prophylaxis of hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular diseases in general. Furthermore, they can be used in the therapy and/ or prevention of neurodegenerative diseases, mycoses, parasite infections, gallstones, cholestatic liver disorders, tumors and hyperproliferative disorders, e.g. hyper- proliferative skin and vascular disorders. In addition, it has unexpectedly been found that the compounds of the present invention can also be of therapeutic use to improve glucose tolerance in order to treat and/ or prevent related diseases such as diabetes. The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
  • lower is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
  • halogen refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
  • alkyl alone or in combination with other groups, refers to a branched or ⁇ straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups.
  • lower-alkyl refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n- propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • cycloalkyl refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • alkoxy refers to the group R'-O-, wherein R' is an alkyl.
  • lower-alk- oxy refers to the group R'-O-, wherein R' is a lower-alkyl.
  • thio-alkoxy refers to the group R'-S-, wherein R' is an alkyl.
  • thio-lower-alkoxy refers to the group R'-S-, wherein R' is a lower-alkyl.
  • alkenyl stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and 2 to 20, preferably 2 to 16 carbon atoms, more preferrably 2 to 10 carbon atoms. Lower- alkenyl groups as described below also are preferred alkenyl groups.
  • lower-alkenyl refers to a straight-chain or branched hydrocarbon residue comprising an olefinic bond and 2 to 7, preferably 2 to 4 carbon atoms, such as e.g. 2-propenyl.
  • alkynyl stands for a straight- chain or branched hydrocarbon residue comprising a triple bond and 2 to 20, preferably 2 to 16 carbon atoms, more preferably 2 to 10 carbon atoms. Lower-alkynyl groups as described below also are preferred alkynyl groups.
  • lower-alkynyl refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and 2 to 7, preferably 2 to 4 carbon atoms, such as e.g. 2-propinyl.
  • alkylene refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower- alkylene groups as described below also are preferred alkylene groups.
  • lower-alkylene refers to a straight chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 7, preferably 1 to 6 or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylene groups are preferred.
  • aryl relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be substituted by 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower- alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g.
  • abenzodioxyl group halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower- alkyl) 2 , aminocarbonyl, carboxy, NO 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbon- yl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl.
  • Preferred substituents are halogen, CF 3 , CN, lower-alkyl and/or lower-alkoxy.
  • R 1 is hydrogen or lower-alkyl
  • R 2 is hydroxy-lower-alkyl, hydroxy-cycloalkyl, or carbamoyl-lower-alkyl which is optionally substituted with lower-alkyl; or
  • R 1 and R 2 are bonded to each other to form a ring together with the nitrogen atom to which they are attached and -R ⁇ R 2 - is lower-alkylene which is substituted with hydroxy, hydroxy-lower-alky or carbamoyl;
  • R 3 is hydrogen or lower-alkyl;
  • R 4 is aryl;
  • W is a CO, COO, CONR 5 , CSO, CSNR 5 , SO 2 , or SO 2 NR 5 ;
  • R 5 is hydrogen or lower- alkyl
  • m is 0, 1 or 2, more preferably m is O or 2.
  • O or 2 are also individually preferred.
  • Compounds of formula (I), in which n is 0, 1 or 2 are also preferred, with those compounds wherein n is O or 2 being more preferred.
  • O or 2 are also individually preferred.
  • Compounds as decsribed above, in which W is COO or SO 2 are also preferred, with COO and SO 2 individually being particularly preferred.
  • R 1 represents lower-alkyl, preferably those in which R 1 is methyl.
  • R 2 represents hydroxy-lower-alkyl or carbamoyl-lower-alkyl optionally substituted with lower-alkyl, with those compounds wherein R 2 represents 3-hydroxy-propyl, 2-carbamoyl-ethyl or 2-methylcarbamoyl-ethyl being especially preferred.
  • R 2 represents 3 -hydroxy-propyl.
  • Another group of compounds are those wherein R 2 is hydroxy-lower-alkyl which is optionally substituted with lower-alkyl.
  • R 2 is hydroxy-cycloalkyl which is optionally substituted with lower-alkyl.
  • a further preferred embodiment of the present invention relates to compounds of formula (I), wherein R 3 represents lower-alkyl, particularly methyl.
  • Preferred compounds of general formula (I) are those selected from the group consisting of trans-N- ⁇ 4-[3-(4-Hydrox7-piperidin-l-yl)-3-oxo-propoxy]-cyclohexyl ⁇ -N-methyl-4-tri- fluoromethyl-benzenesulfonamide, trans-N- ⁇ 4-[3-(4-Hydroxymethyl-piperidin-l-yl)-3-oxo-propoxy]-cyclohexyl ⁇ -N-methyl-
  • Particularly preferred compounds of general formula (I) are those selected from the group consisting of trans-N- ⁇ 4-[3-(4-Hydroxy-piperidin-l-yl)-3-oxo-propox7]-cyclohex7l ⁇ -N-methyl-4-tri- fluoromethyl-benzenesulfonamide, trans-N- ⁇ 4-[3-(4-Hydroxymethyl-piperidin-l-yl)-3-oxo-propox7]-cyclohex7l ⁇ -N-methyl-
  • Compounds of formula (I) can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or as racemats. They can exist as cis- or trans- isomers. The invention embraces all of these forms. Compounds of formula (I) which are trans-isomers (with reference to the cyclohexyl ring) are preferred.
  • the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
  • the present invention also relates to a process for the manufacture of compounds as described above, which process comprises (a) reacting a compound of formula (II)
  • Reactions of a compound of formula (II) with a compound NHR 1 R 2 can be carried out by procedures known in the art, as described in the examples and as described in scheme 3 (step f) with EDCI, HOBT or BOP and a base such as Huenig's base, NEt 3 or NMM in CH 2 Cl 2 , DMF, DMA or dioxane.
  • a base such as Huenig's base, NEt 3 or NMM in CH 2 Cl 2 , DMF, DMA or dioxane.
  • the invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
  • the compounds of formula (I) of the present invention can be used for the treatment and/or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infec- tions and gallstones, and/ or treatment and/or prophylaxis of impaired glucose tolerance, diabetes, tumors and/ or hyperproliferative disorders, preferably for the treatment and/ or prophylaxis of hypercholesterolemia and/or hyperlipemia.
  • Hyperproliferative skin and vascular disorders particularly come into consideration as hyperproliferative disorders.
  • the invention therefore also relates to pharmaceutical compositions comprising a com- pound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
  • the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/ or prophylaxis of of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/ or hyperlipemia.
  • diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/ or hyperlipemia.
  • the invention relates to a method for the treatment and/ or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyper- lipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/ or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/ or prophylaxis of hypercholesterolemia and/ or hyperlipemia, which method comprises administering a compound as defined above to a human being or animal.
  • diseases which are associated with OSC such as hypercholesterolemia, hyper- lipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/ or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/ or prophylaxis of hypercholesterolemia and/ or hyperlipemia, which method comprises administering a compound as defined above to a human being or
  • the invention further relates to the use of compounds as defined above for the treatment and/ or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/ or hyperlipemia.
  • diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/ or treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/ or hyperlipemia.
  • the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/ or prophylaxis of diseases which are associated with OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/ or hyperproliferative disorders, and/or treatment and/ or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/ or prophylaxis of hypercholesterolemia and/or hyperlipemia.
  • diseases which are associated with OSC
  • Such medicaments comprise a compound as defined above.
  • the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the examples or by methods known in the art.
  • Lithium aluminum hydride reduction yields trans-4-methylaminocyclohexanol 3 which is either BOC-protected to yield compound 4 (step c) or is directly transferred (step d) into the desired R 4 W- derivative 5 using one of the methods described later for compound 4 in scheme 2.
  • the aminocyclohexanol derivative can be treated with hexamethyldi- silazane at reflux, prior to the introduction of the R 4 W-moiety.
  • the residue R 3 can be introduced via alkylation.
  • compound 2 can be first O-protected and then N- alkylated at the protected amino function with an alkyl derivative in the presence of a base like sodium hydride in a solvent like N,N-dimethylformamide, THF or acetonitrile at temperatures between room temperature (hereinafter: RT) and 8O 0 C; after O-deprotec- tion the compound 3 is .obtained (step e).
  • a base like sodium hydride
  • a solvent like N,N-dimethylformamide, THF or acetonitrile
  • RT room temperature
  • 8O 0 C acetonitrile
  • the aminocyclohexanol derivatives maybe derived from the corresponding aminophenol, 4-hydroxybenzylamine, tyramine or 3-(4-hydroxyphenyl)propyl- amine by hydrogenation. These derivatives may be converted to the compounds of formula 10 as described for 5.
  • ether derivatives of formula (I) is depicted in scheme 2.
  • the amino-cyclo- hexanol derivative 1 can be treated under phase transfer conditions with e.g. ⁇ -halo-alkyl- carbonic acid tert butlyl esters, NaOH, nBu4NHSO4 to yield ester 2.
  • the preparation via the in situ generated triflate is possible. From the corresponding ⁇ -hydroxy- alkylcarbonic acid alkyl esters the triflates may be formed with trifluoromethane sulfonic anhydride/2,6-di-tert-butylpyridine in CH 2 Cl 2 at 0°C.
  • Saponification of the ester 2 using standard conditions e.g. LiOH or NaOH in EtOH, MeOH or THF for the alkyl esters or TFA or HCl in THF, ether or CH 2 Cl 2 for tert butyl esters give the acid 3 (step b).
  • Treatment of the acid 3 with NHR 1 R 2 , EDCI, HOBT or NHR 1 R 2 , BOP and a base such as Huenig's base, NEt 3 or NMM in CH 2 Cl 2 , DMF, DMA or dioxane gives amide 4 (step c).
  • a two-step procedure might be used: treatment of the acid 2 with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with the corresponding amine NHR 1 R 2 .
  • the amino-cyclohexanol derivative 1 can be treated under phase transfer conditions with the appropriate ⁇ -halo-alkylcarbonic acid amide, NaOH, nBu 4 NHSO 4 to yield ester 4 directly (step d).
  • the preparation via the in situ generated triflate is possible.
  • the triflates maybe formed with trifluoromethane sulfonic anhydride/2,6-di-tert-butylpyridine in CH 2 Cl 2 at O 0 C.
  • step d • In the case that the reaction was performed with an amine NHR 1 R 2 in which R 2 contains an ester . rnoiety this can be reduced by e.g. NaBH ⁇ in solvents like THF or MeOQ to the corresponding hydroxyalkyl derivatives.
  • ester moiety may be saponified as described above and the acid maybe transferred into the carbamoyl lower alkyl derivative by treatment of the acid with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with alkylamine or ammonia.
  • R 4 W in 4 is a protecting moiety this can be cleaved using TFA in CH 2 Cl 2 for BOC-groups or by hydrogenation in methanol/HCl with Pd/C for Z-groups.
  • the resulting ammonium salt maybe treated according to one of the procedures described to derive the appropriate R 4 W derivative 4. If needed, the aminocyclohexane derivative can be treated with hexa- methyldisilazane at reflux, prior to the introduction of the R 4 W-moiety.
  • Sulfonamides Sulfonylation of the amines is done in dioxane or CH 2 Cl 2 with Huenig's base and a sulfonyl chloride over night at RT to yield the sulfonamide 4.
  • the amines may be reacted with R 4 OCOCl/Huenig's base in dioxane or CH 2 Cl 2 .
  • the chloroformates may be prepared in situ by treatment of R 4 OH with Cl 3 COCl in the presence of quinoline followed by reaction with the amines in the presence of Huenig's base.
  • Ureas The amines may be reacted with isocyanate in dioxane at RT.
  • the amines maybe reacted with isothiocyanate in dioxane at RT.
  • Amides The amines may be reacted with R 4 COCl/Huenig's base in CH 2 Cl 2 , R 4 COOH/- EDCI/DMAP (via formation of the symmetrical anhydride, and subsequent addition of the starting amine at - 10 0 C to RT) or alternatively with R 4 COOH/EDCI/DMAP or R 4 COOH/- Huenig's base or NMM/EDCI/HOBT in DMF, dioxane or CH 2 Cl 2 at RT.
  • Sulfamides The amines may be reacted with sulfamoyl chlorides in dioxane in the presence of an excess of triethylamine to yield sulfamide 3 or 5.
  • the sulfamoyl chlorides can be prepared from R NH 2 and chlorosulfonic acid in CH 2 Cl 2 at 0 0 C to RT followed by reaction with PCI 5 in toluene at 75°C.
  • the sulfamoyl chlorides can be synthesized in acetonitrile with R 4 NH 2 and sulfuryl chloride at 0 0 C to 65°C.
  • the ester 3 is BOC deprotected (TFA, CH 2 Cl 2 , step c), transferred into the desired R 4 W-derivative using one of the methods described previously for compound 4 in scheme 2 (step d), and saponified using standard conditions e.g. LiOH or NaOH in EtOH, MeOH or THF for the alkyl esters or TFA or HCl in THF, ether or CH 2 Cl 2 for tert butyl esters to give the acid 4 (step e).
  • a two-step procedure might be used: treatment of the acid 4 with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with the corresponding amine NHR 1 R 2 .
  • this can be reduced by e.g. NaBH 4 in solvents like THF, MeOH to the corresponding hydroxyalkyl derivatives.
  • ester moiety may be saponified as described above and the acid maybe transferred into the carbamoyl lower alkyl derivative by treatment of the acid with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with alkylamine or ammonia.
  • the BOC protected ester 3 can be transferred into the desired amide before introducing the appropriate residue R 4 W.
  • the conversion of acid 8 to the final product 5 may be achieved as described previously for compound 4 (step f).
  • the introduction of the appropriate WR 4 residue maybe accomplished via the procedures described in c and d either at the nitrile stage (compound 7) or after amide formation.
  • the aldehyde 9 maybe prepared via the Weinreb-amide starting from ester 3 (saponification of the ester using LiOH or NaOH in EtOH, MeOH or THF, followed by treatment with N,O-dimethyl-hydroxyl-amine-hydrochloride with EDCI and HOBT in CH 2 Cl 2 at RT and reduction by lithium aluminum hydride, step 1).
  • ester 10 (step m).
  • Acid 8 can then be converted to the final product 5 as described above (step f).
  • the introduction of the appropriate WR 4 residue maybe accomplished via the procedures described in c and d either at the ester stage (compound 10) or after amide formation.
  • the aldehyde 9 can be treated with triphenylphosphine, tetrabromomethane and triethylamine in CH 2 Cl 2 at 0 0 C to RT to yield 2,2-dibromo-vinyl derivative 11 (step p) .
  • Rearrangement with n-BuLi (ca 1.6 M in hexane) in THF at -78°C, followed by reaction with formaldehyde (- 78°C to RT) gives the propargyl alcohol 12 (m 0) [step q, following conditions described in Marshall et al., J. Org. Chem. 61:5729-5735 (1996); and Baker et al., J. Chem. Soc. Perkin Trans. 1:1415-1421 (1990)].
  • Acid 8 can then be converted to the final product 5 as described above (step f).
  • step q e.g. 1-bromo-n-tetrahydropyaranyloxyalkane
  • step q e.g. 1-bromo-n-tetrahydropyaranyloxyalkane
  • step f Oxidation of the primary alco- hol using e.g. Jones' reagent gives the acid 13.
  • Compound 1 can also be first O-protected and then N-alkylated at the tert-butoxycarbonyl protected amino group with an alkyl halide in the presence of a base like sodium hydride in a solvent like N,N-dimethylformamide, THF or acetonitrile at temperatures between RT and 80°C to introduce substituents R 3 ; after O-deprotection the compound 3 is obtained (step c).
  • Compound 3 is subsequently oxidized to the corresponding aldehyde 4 by using e.g. Swern conditions: oxalyl chloride/ di- methylsulfoxide/triethylamine in dichloromethane, -78 0 C to RT (step d).
  • This aldehyde 4 can be oxidized to the desired carboxylic acid 5 using e.g. ruthenium (III) chloride*hydrate, sodium metaperiodate in a mixture of CCU, water and acetonitrile.
  • the oxidation of compound 3 can be accomplished in one step using ruthenium (III) chloride*hy- drate, sodium metaperiodate in a mixture of CCI 4 , water and acetonitrile to give acid 5 (step e).
  • step d Treatment of the amino-alcohol 4 first with di-tert-butyl-dicarbonate in dichloromethane in the presence of triethylamine followed by acetic anhydride and pyridine in dichloromethane gives the di-protected compound 5 (step d).
  • Compound 5 can be N-alkylated at the tert-butoxycarbonyl protected amino group with an alkyl halide in the presence of a base like sodium hydride in a solvent like N,N-dimethylformamide or acetonitrile at temperatures between RT and 8O 0 C to introduce substituents R 3 and gives, after basic cleavage of the acetate function, the primary hydroxy compound 6 (step e).
  • the primary hydroxy compound 6 can be oxidized subsequently to the corresponding aldehyde 7 by using e.g. Swern conditions: oxalyl chloride/ dimethylsulfoxide/triethylamine in dichloromethane, -78 0 C to RT (step f).
  • This aldehyde 7 can be oxidized to the desired carboxylic acid 8 using e.g. ruthenium (III) chloride'hydrate, sodium metaperiodate in a mixture of CCl ⁇ water and acetonitrile (step g).
  • the oxidation of compound 6 can be accomplished in one step using ruthenium (III) chloride'hydrate, sodium metaperiodate in a mixture of CCU, water and acetonitrile to give acid 8 (step g).
  • Scheme 6 depicts an alternative route to aminocyclohexane derivatives 6 and 7.
  • Compounds 2 maybe derived from the corresponding 4-(aminomethyl)benzyl alcohol, 4-(2- aminoethyl)benzyl alcohol, 4-(3-aminopropyl)benzyl alcohol by hydrogenation (step a).
  • step a Treatment of the amino-alcohol 2 first with di-tert-butyl-dicarbonate in dichloromethane in the presence of triethylamine (step b) followed by acetic anhydride and pyridine in dichloromethane gives the di-protected compound 4 (step c).
  • Compound 4 can be N-alkylated at the tert-butoxycarbonyl protected amino group with an alkyl halide in the presence of a base like sodium hydride in a solvent like N,N-dimethylformamide or acetonitrile at temperatures between RT and 80°C to introduce substituents R 3 and gives, after basic cleavage of the acetate function, the primary hydroxy compound 5 (step d).
  • the primary hydroxy compound 5 can be oxidized subsequently to the corresponding aldehyde 6 by using e.g. Swern conditions: oxalyl chloride/ dimethylsulfoxide/triethylamine in dichloromethane, -78 0 C to RT (step e).
  • This aldehyde 6 can be oxidized to the desired carboxylic acid 7 using e.g. ruthenium (III) chloride'hydrate, sodium metaperiodate in a mixture of CCI 4 , water and acetonitrile (step f).
  • ruthenium (III) chloride'hydrate sodium metaperiodate in a mixture of CCI 4 , water and acetonitrile
  • the oxidation of compound 5 can be accomplished in one step using ruthenium (III) chloride'hydrate, sodium metaperiodate in a mixture of CCI 4 , water and acetonitrile to give acid 7 (step f).
  • Scheme 7 describes the synthesis of pure trans-aldehyde building block 8.
  • R 3 substituted cyclohexanol 1 is synthesized by hydrogenation of the corresponding 4-at ⁇ ino- phenol, 4-hydroxybenzylamine, tyramine or 3-(4-hydroxyphenyl)propylamine (see also scheme 1).
  • Amine 1 is converted to the N-protected-derivative 2 (e.g. ZCl, Na 2 CCVTHF/- H 2 O) (step a).
  • Oxidation with TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl, radical) and sodium hypochlorite gives ketone 3 (step b).
  • a two-step procedure might be used: treatment of the acid 1 with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with the corresponding amine NHR 1 R 2 .
  • the reaction was performed with an amine NHR 1 R 2 in which R 2 contains an ester moiety this can be reduced by e.g. NaBH 4 in solvents like THF, MeOH to the corresponding hydroxy- alkyl derivatives.
  • the ester moiety may be saponified as described above and the acid may be transferred into the carbamoyl lower alkyl derivative by treatment of the acid with oxalyl chloride in CH 2 Cl 2 in the presence of DMF, followed by reaction with alkylamine or ammonia (step a).
  • the amine moiety of the amide 2 is deprotected (for BOC: TFA, CH 2 Cl 2 , for Z: hydrogenation), and the amine transferred into the desired R 4 W-derivative using one of the methods described previously for compound 4 in scheme 2 (step b,c).
  • the sequence of steps can be inverted, introduction of the desired R 4 W- residue prior to amide formation.
  • the acid moiety can be treated with hexamethyl- disilazane at reflux prior to the introduction of the R 4 W-moiety.
  • the aldehyde 7 (see scheme 4-6 for preparation) maybe subjected to Horner-Emmons reaction with triethyl phosphono acetate, sodium methanolatejji ethanol to give the unsaturated ester 8 (step f).
  • Acid 6 maybe converted to compound 3 as described above (steps a,b,c).
  • the aldehyde 7 can be treated with triphenylphosphine, tetrabromomethane and triethylamine in CH 2 Cl 2 at 0 0 C to RT to yield 2,2-dibromo-vinyl derivative 9 (step i).
  • n-BuLi ca 1.6 M in hexane
  • formaldehyde -78 0 C to RT
  • step q e.g. 1-bromo-n-tetrahydropyaranyloxyalkane
  • step q e.g. 1-bromo-n-tetrahydropyaranyloxyalkane
  • step q e.g. 1-bromo-n-tetrahydropyaranyloxyalkane
  • step q Oxidation of the primary alcohol using e.g. Jones' reagent gives the acid 11.
  • the acid 11 maybe directly converted to the corresponding final products 3 using the procedures described above (step a,b,c).
  • Liver microsomes from a healthy volunteer were prepared in sodium phosphate buffer (pH 7.4).
  • the OSC activity was measured in the same buffer, which also contained ImM EDTA and 1 mM dithiothreitol.
  • the microsomes were diluted to 0.8 mg/ml protein in cold phos- phate buffer.
  • Dry [ 14 C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20 nCi/ ⁇ l with ethanol and mixed with phosphate buffer-1% BSA (bovine serum albumin).
  • BSA bovine serum albumin
  • microsomes 40 ⁇ l of microsomes were mixed with 20 ⁇ l of the solution of the test substance and the reaction was subsequently started with 20 ⁇ l of the [ 14 C]R 5 S- MOS solution.
  • the final conditions were: 0.4mg/ml of microsomal proteins and 30 ⁇ l of [ 14 C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5% albumin, DMSO ⁇ 0.1% and ethanol ⁇ 2%, in a total volume of 80 ⁇ l.
  • the entire extract was evaporated to dryness with nitrogen, the residue was suspended in 50 ⁇ l of hexane: ether and applied to a silica gel plate. Chromatographic separation was effected in hexane:ether (1:1, v/v) as the eluent.
  • the Rf values for the MOS substrate and the lanosterol product were 0.91 and 0.54, respectively. After drying, radioactive MOS and lanosterol were observed on the silica gel plate. The ratio of MOS to lanosterol was determined from the radioactive bands in order to determine the yield of the reaction and OSC inhibition.
  • the test was carried out on the one hand with a constant test substance concentration of 100 nM and the percentage OSC inhibition against controls was calculated. The more preferred compounds of the present invention exhibit inhibitions larger than 50%.
  • the test was carried out with different test substance concentrations and subsequently the IC50 value was calculated, i.e. the concentration required to reduce the conversion of MOS into lanosterol to 50% of the control value.
  • the preferred compounds of the present invention exhibit IC 60 values of 1 nM to 10 ⁇ M, preferrably of 1 - 500 nM.
  • the compounds of formula I and/ or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of in- jection solutions or infusion solutions, or topically, e.g. in . the form of ointments, creams or oils. Oral administration is preferred.
  • the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other • therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
  • the pharmaceutical preparations conveniently contain about 1 to 500 mg, preferably 1 to 100 mg, of a compound of formula I.
  • BOC t-butyloxycarbonyl
  • BOP benzotriazol-l-yloxytris(dimethyl- amino)phosphonium hexafluorophosphate
  • CH 2 Cl 2 dichloromethane
  • CH 3 I methyl iodide
  • CCI 4 tetrachloromethane
  • DIBAH di-z ' -butylaluminium hydride
  • DMA di- methylacetamide
  • DMF dimethylformamide
  • EDCI N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • EtOAc ethylacetate
  • EtOH ethanol
  • Et 2 O diethyl- ether
  • Et 3 N triethylamine
  • eq equivalents
  • HOBT 1-hydroxybenzo-triazole
  • trans-4- ⁇ 2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-eth- yl ⁇ -cyclohexanecarboxylic acid and 2-(methylamino)ethanol were converted to trans-(2- ⁇ 4- [ (2-hyd ⁇ oxy-ethyl)-methyl-carbamoyl] -cyclohexyl ⁇ -ethyl)-methyl-carbamic acid 4- chloro-phenyl ester, MS: 397 (MH + , ICl).
  • trans-4- ⁇ 2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-eth- yl ⁇ -cyclohexanecarboxylic acid and 4-hydroxypiperidine were converted to trans- ⁇ 2-[4-(4- Hydroxy-piperidine-1-carbonyl) -cyclohexyl] -ethylj-methyl-carbamic acid 4-chloro-phen- yl ester, MS: 423 (MH + , ICl).
  • this solution was added tp a solution of 0.20 g (1.56 mmol, 1.3 eq) of 3-methylamino-propionic acid ethyl ester and 0.84 mL (6.00 mmol, 5 eq) OfEt 3 N in 4 mL OfCH 2 Cl 2 .
  • the reaction mixture was kept at RT for 1.5h, then the substance was partitioned between Et 2 O (x3)/ aqueous 10% KHSO 4 .
  • trans-3-[(4- ⁇ 2-[(4-chloro-phenoxycarbonyl)-methyl-amino]- ethyl ⁇ -cyclohexanecarbonyl)-methyl-arnino] -propionic acid and ammonia (2M in EtOH) gave trans-(2- ⁇ 4- [(2-carbamoyl-ethyl)-methyl-carbamoyl] -cydohexyl ⁇ -ethyl)-methyl- carbamic acid 4-chloro-phenyl ester, MS: 424 (MH + , ICl).
  • trans-4- ⁇ 2-[(4-chloro-phenoxycarbonyl)-methyl-amin ⁇ ]-- " ethyl ⁇ -cyclohexanecarboxylic acid and 3 eq sarcosinamide ⁇ Cl/16 eq Et 3 N gave trans- ⁇ 2- [4-(carbamoylmethyl-methyl-carbamoyl)-cyclohexyl] -ethyl ⁇ -methyl-carbamic acid 4- chloro-phenyl ester, MS: 409 (MH + , ICl).
  • trans-4- ⁇ 2-[(4-chloro-phenoxycarbonyl)-methyl-amino]- ethyl ⁇ -cyclohexanecarboxylic acid and 3 eq isonipecotamide/5 eq Et 3 N gave trans- ⁇ 2-[4-(4- carbamoyl-piperidine- 1 -carbonyl) -cyclohexyl] -ethyl ⁇ -methyl-carbamic acid 4-chloro- phenyl ester, MS: 450 (MH + , ICl), MP: 162-165°C, dec.
  • Film coated tablets containing the following ingredients can be manufactured in a conven- tional manner:
  • the active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water.
  • the granulate is mixed with sodium starch glycolate and magnesiumstearate and compressed to yield kernels of 120 or 350 mg respectively.
  • the kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
  • Capsules containing the following ingredients can be manufactured in a conventional manner:
  • the components are sieved and mixed and filled into capsules of size 2.
  • Injection solutions can have the following composition:
  • the active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part).
  • the pH is adjusted to 5.0 by Acetic Acid.
  • the volume is adjusted to 1.0 ml by addition of the residual amount of water.
  • the solution is filtered, filled into vials using an appropriate overage and sterilized.
  • Soft gelatine capsules containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is dissolved in a warm melting of the other ingredients and the mix- ture is filled into soft gelatine capsules of appropriate size.
  • the filled soft gelatin capsules are treated according to the usual procedures.
  • Sachets containing the following ingredients can be manufactured in a conventional manner:
  • the active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxy- methyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water.
  • the granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

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Abstract

L'invention concerne des composés représentés par la formule (I) dans laquelle R1, R2, R3, R4, X, W, m et n sont tels que définis dans le descriptif et les revendications. Lesdits composés sont utilisés pour traiter et/ou prévenir les maladies associées à la 2,3-oxidosqualène-lanostérol cyclase, telles que l'hypercholestérolémie, l'hyperlipémie, l'artériosclérose, les maladies vasculaires, les mycoses, les infections parasitaires, les calcules biliaires, les tumeurs et/ou les troubles hyperprolifératifs, ainsi que pour traiter et/ou prévenir l'intolérance au glucose et le diabète.
EP04740859A 2004-07-09 2004-07-09 Hydroxyalkylamides Withdrawn EP1768658A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO1990005723A1 (fr) * 1988-11-24 1990-05-31 Yoshitomi Pharmaceutical Industries, Ltd. Composes de trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane et leur utilisation en medecine
WO2002014267A1 (fr) * 2000-08-16 2002-02-21 F. Hoffmann-La Roche Ag Nouveaux derives d'aminocyclohexane

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