WO2008029266A1 - Inhibiteurs de la stéaroyl coa désaturase - Google Patents

Inhibiteurs de la stéaroyl coa désaturase Download PDF

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Publication number
WO2008029266A1
WO2008029266A1 PCT/IB2007/002580 IB2007002580W WO2008029266A1 WO 2008029266 A1 WO2008029266 A1 WO 2008029266A1 IB 2007002580 W IB2007002580 W IB 2007002580W WO 2008029266 A1 WO2008029266 A1 WO 2008029266A1
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Prior art keywords
substituted
unsubstituted
oxazolan
pyridin
mmol
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PCT/IB2007/002580
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English (en)
Inventor
Abraham Thomas
V.S. Prasada Rao Lingam
Sachin S. Chaudhari
Neelima Khairatkar-Joshi
Daisy Manish Shah
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Glenmark Pharmaceuticals S.A.
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Publication of WO2008029266A1 publication Critical patent/WO2008029266A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel Stearoyl CoA desaturase inhibitors and uses thereof for treating diseases, conditions and/or disorders modulated by a Stearoyl CoA desaturase enzyme.
  • Metabolic energy balance is important for well being which is maintained by appropriate adjustment between energy intake and energy expenditure.
  • Primary defects in energy balance produce obesity. Over the past few years there has been a sharp increase in obesity in many countries. Obesity is a principal cause of morbidity and mortality mainly because it increases risk for other conditions that shorten life, including diabetes, insulin resistance, coronary artery disease, hypertension and non-alcoholic fatty liver disease collectively known as metabolic syndrome (J. Am. Med. Assoc. 288, (2002), 1723-1727). Obesity has been identified as an independent risk factor for the development of type 2 diabetes. Diabetes affects more than 230 million people worldwide and is expected to affect 350 million by 2025. More than 80% of type 2 diabetic patients are obese. Cardiovascular diseases caused by atherosclerosis (thickening of large blood vessels) account for approximately 25% of the deaths in diabetic patients.
  • liver fatty acids accumulate causing an increase in hepatic lipid content or get packaged into the very low density lipoprotein for export to other peripheral tissues.
  • Liver steatosis associated with obesity can also result from an enhanced rate of de novo fatty acid synthesis and/or dysregulation of intracellular lipid partitioning in which fatty acid oxidation is impaired and its esterification enhanced.
  • Lipid abnormalities in obese subjects are atherogenic.
  • the dyslipidemic state initiates a cascade of events including release of proinflammatory adipokines which induces a proinflammatory state that drives pathogenesis of atherosclerosis.
  • Increased release of proinflammatory adipokines also increases fibrinogen and plasminogen activator inhibitor levels thereby increasing risk for arterial thrombosis.
  • Several studies show that even modest wait gain can precipitate the onset of hypertension (Ann. Rev. Med. 56, (2005), 45-62). Hence obesity alone can drive all aspects of the metabolic syndrome. It is believed that effective treatment of obesity could lead to prevention and control of metabolic syndrome (Obesity Reviews 6, (2005), 169-174).
  • SCDl Stearoyl-CoA desaturase 1
  • SCDl has two preferred substrates palmitoyl and stearoyl CoA, which are desaturated to palmitoleoyl and oleoyl CoA respectively (J Biol Chem 251, (1976), 5095-5103).
  • Oleate is found to be the major monounsaturated fatty acid of membrane phospholipids, triglycerides, cholesterol esters, wax esters and alkyl-1, 2- diacylglycerol.
  • the ratio of stearate to oleate is one of the factors influencing membrane fluidity and its alteration is important in diseases like aging, cancer, diabetes, obesity, and neurological, vascular and heart diseases (Biochem. Biophys. Acta 431, (1976) 469-480, J. Biol. Chem.
  • CLA Conjugated linoleic acid
  • Sterculic acid (8-(2-octylcyclopropenyl) octanoic acid) and malvalic acid (7-(2- octylcyclopropenyl)heptanoic acid) are Cl 8 and Cl 6 derivatives of sterculoyl- and malvaloyl fatty acids, respectively and inhibit SCD enzymatic activity by direct interaction with the enzyme.
  • Sterculic acid (8-(2-octylcyclopropenyl) octanoic acid) and malvalic acid (7-(2- octylcyclopropenyl)heptanoic acid) are Cl 8 and Cl 6 derivatives of sterculoyl- and malvaloyl fatty acids, respectively and inhibit SCD enzymatic activity by direct interaction with the enzyme.
  • all these agents are weak and non specific inhibitors of SCDl.
  • SCDl antisense oligonucleotide inhibitors specifically reduce SCDl expression thereby reducing fatty acid synthesis and secretion, body adiposity, hapatomregaly, steatosis and prevent obesity in mice by improving energy balance (J Clinical Investigation, (2005), F 1-9).
  • U.S. Patent Publication Nos. 2006-009459 and International Publication Nos. WO 2005/011653, WO 2005/01164, WO 2005/011655, WO 2005/011656, and WO 2005/011657 disclose certain pyridazine derivatives, pyidyl derivatives, and piperazine derivatives and their use for inhibiting human stearoyl-CoA desaturase (hSCD) activity.
  • U.S. Patent Publication No. 2004-072877 is directed to a method for increasing insulin sensitivity by reducing stearoyl-CoA desaturase 1 (SCDl) activity in a subject sufficiently to increase . insulin sensitivity.
  • the present invention relates to stearoyl CoA desaturase inhibitors of Formula I:
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
  • R 2 , R 3 and R 4 when present, are independently selected from hydrogen, nitro, cyano, formyl, acetyl, halogen, C(R 5 R 6 )OR', C(R 5 R 6 )R', OR', SR', oxo, thio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstitute
  • HET is selected from
  • X 1 to X 7 are independently N, S, O or CR a ;
  • A is a linker group
  • B, X, X' and Y are independently selected from C(R a ) or N; m and n are independently an integer from 0, 1 or 2.
  • Preferred compounds include those of formula I wherein R 1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted alkyl.
  • R 1 is selected from 2-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 2,5-dichloro ⁇ henyl, 2-ethylbutyl, 2,4-difluorophenyl, 2-fluorophenyl, 2-chlorophenyl and 2- cyanophenyl.
  • R and R independently are hydrogen, substituted or unsubstituted alkyl, C(R 5 R 6 )R' or C(R 5 R 6 )OR'.
  • R and R are independently hydrogen, CH 2 OH, CH 2 F, CH 2 OCH 3 , COOCH 2 CH 3 , C(CH 3 )(CH 3 )OH, CONHCH(CH 3 )(CH 3 ), (CH 2 ) 3 CH 3 or CH 3 .
  • R 3 and R 4 together form an optionally substituted 3 to 7 membered saturated, unsaturated or partially unsaturated monocyclic or bicyclic ring, which can optionally include at least two heteroatoms selected from O, NR' or S.
  • the SCDl inhibitor is represented by formula II:
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
  • R 2 , R 3 and R 4 when present, are independently selected from hydrogen, nitro, cyano, formyl, acetyl, halogen, C(R 5 R 6 )OR', C(R 5 R 6 )R', OR', SR', oxo, thio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstitute
  • X and Y are independently N or CR a ;
  • A, B, m and n have the same definition as above .
  • compositions comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • Yet another aspect of the invention is the method for preventing, ameliorating or treating disease, disorder or syndrome mediated by SCD-I in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present invention.
  • diseases, disorders, and syndromes include, but are not limited to, (1) obesity, such as obesity resulting from (i) genetics, (ii) diet, (iii) food intake volume, (iv) a metabolic disorder, (v) a hypothalmic disorder, (vi) age, (vii) abnormal adipose mass distribution, (viii) abnormal adipose compartment distribution, (ix) compulsive eating disorders, (x) motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value, and (xi) reduced activity, (2) overweight conditions, (3) anorexia, (4) bulimia, (5) cachexia, (6) dysregulated appetite, (7) obesity related diseases, disorders, and symptoms.
  • Other diseases, disorder, and syndromes mediated by SCD-I include, but are not limited to, (1) diabetes (including Type I and Type II diabetes), (2) diabetic complications, (3) glucose tolerance, (4) hyperinsulinemia, (5) insulin sensitivity or resistance, (6) hepatic steatosis, (7) increased abdominal girth, (8) metabolic syndrome, (9) cardiovascular diseases (such as (i) atherosclerosis, (ii) dyslipidemia, (iii) elevated blood pressure, (iv) microalbuminemia, (v) hyperuricaemia, (vi) hypercholesterolemia, (vii) hyperlipidemias, (viii) atherosclerosis, (ix) hypertriglyceridemias, (x) arteriosclerosis, and (xi) other cardiovascular diseases), (10) osteoarthritis, (11) dermatological diseases, (12) sleep disorders (e.g., disturbances of circadian rhythm, dysomnia, insomnia, sleep apnea and narcolepsy), (13) cholelithiasis, (14) he
  • Yet another aspect of the invention is the method of preparing a compound of formula
  • the method includes the steps of: (a) reacting a compound of formula (1) with a compound of formula (2) where R , R , A, B, X, Y and n are as defined above and L is a leaving group (includng halogen) to form a compound of formula (3)
  • Yet another embodiment is a method of preparing a compound of formula Ha and lib, where the variables are as defined above.
  • the method includes the steps of:
  • Yet another embodiment is a method of preparing a compound of formula Hc, where the variables are as defined above.
  • the method includes the steps of: (b) reducing the compound of formula (10)
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydro carbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are — OCH 3 and -OC 2 H 5 .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • niulticyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon- carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond (such as cyclopropenyl, cyclobutenyl, and cyclopentenyl) directly attached to an alkyl group.
  • the cycloalkenylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heterocyclic ring refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidiny
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • aryl refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.
  • treating or “treatment” of a state, disorder or condition includes:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” > means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the term “protecting group” refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • BOC t-butoxycarbonyl
  • CBz benzyloxycarbonyl
  • Fmoc 9-fluorenylmethylenoxycarbonyl
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • Phannaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with standard low molecular weight solvents by methods known in the art.
  • compositions of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound of the present invention may be associated with a phannaceutically acceptable excipient (such as 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.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, 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, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing methods known in the art.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that 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.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • 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, cornstarch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and prevention of diseases, conditions and disorders modulated by a stearoyl CoA desaturase, especially those modulated by the SCDl.
  • the present invention further provides a method of treating a disease, condition or disorder modulated by a stearoyl CoA desaturase, especially those modulated by SCDl, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • Diseases, conditions, and disorders that are modulated by a stearoyl CoA desaturase include, but are not limited to, diabetes, diabetes related syndromes, disorders or diseases obesity, obesity related diseases, conditions, and disorders, cardiovascular diseases (such as atherosclerosis), hepatic steatosis and other metabolic syndromes, metabolism related syndromes, disorders and diseases, and non-alcoholic fatty liver disease.
  • SCD can be regulated to treat obesity.
  • Obesity and overweight are defined as an excess of body fat relative to lean body mass.
  • An increase in caloric intake or a decrease in energy expenditure or both can bring about this imbalance leading to surplus energy being stored as fat.
  • anorexia and cachexia are characterized by an imbalance in energy intake versus energy expenditure leading to a negative energy balance and weight loss.
  • Agents that either increase energy expenditure and/or decrease energy intake, absorption or storage would be useful for treating obesity, overweight, and associated comorbidities.
  • Agents that either increase energy intake and/or decrease energy expenditure or increase the amount of lean tissue would be useful for treating cachexia, anorexia, and wasting disorders.
  • An SCD gene, translated proteins and agents which modulate the gene or portions of the gene or its products are useful for treating obesity, overweight, anorexia, cachexia, wasting disorders, appetite suppression, appetite enhancement, increases or decreases in satiety, modulation of body weight, and/or other eating disorders such as bulimia.
  • diseases, conditions, and disorders that are modulated by a stearoyl CoA desaturase include, but are not limited to, obesity, overweight, anorexia, cachexia, wasting disorders, appetite suppression, appetite enhancement, andr other eating disorders such as bulimia.
  • the compounds of the present invention increase or decrease in satiety and modulate body weight.
  • Obesity related syndromes, disorders and diseases include, but are not limited to, obesity as a result of (i) genetics, (ii) diet, (iii) food intake volume, (iv) a metabolic disorder, (v) a hypothalmic disorder, (vi) age, (vii) abnormal adipose mass distribution, (viii) abnormal adipose compartment distribution, (ix) compulsive eating disorders, and (x) motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value.
  • Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity. Obesity also increases the likelihood of sleep apnea, gallstones, osteoporosis and ceratin cancers.
  • Diabetes related syndromes, disorders and diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, and hyperglycemia.
  • Cardiovascular diseases include, but are not limited to, (i) coronary artery disease, (ii) atherosclerosis, (iii) heart disease, (iv) hypercholesterolemia, (v) hypertriglyceridemia, (vi) hypertriglyceridemia secondary to another disorder or disease (such as hyperlipoproteinemias), (vii) hyperlipidemia, (viii) disorders of serum levels of triglycerides, VLDL, HDL, and LDL, (ix) cholesterol disorders, (x) cerebrovascular disease (including but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA)), (xi) peripheral vascular disease, and (xii) ischemic retinopathy.
  • TIA ischemic stroke and transient ischemic attack
  • Metabolism related syndromes, disorders or diseases include, but are not limited to, (i) metabolic syndrome, (ii) dyslipidemia, (iii) elevated blood pressure, (iv) insulin sensitivity or resistance, (v) Type II diabetes, (vi) Type I diabetes, (vii) diabetic complications, (viii) increased abdominal girth, (ix) glucose tolerance, (x) microalbuminemia, (xi) hyperuricaemia, (xii) hyperinsulinemia, (xiii) hypercholesterolemia, (xiv) hyperlipidemias, (xv) atherosclerosis, (xvi) hypertriglyceridemias, (xvii) arteriosclerosis and other cardiovascular diseases, (xviii) osteoarthritis, (xix) dermatological diseases, (xx) sleep disorders (e.g., disturbances of circadian rhythm, dysomnia, insomnia, sleep apnea and narcolepsy), (xxi) cholelithiasis, (xxii) hepatomegaly,
  • Non-alcoholic fatty liver disease can manifest as hepatic steatosis (or fatty liver) and can progress to hepatitis, drug-induced hepatitis, hepatoma, fibrosis, hepatic cirrhosis, liver failure, non-alcoholic steatohepatitis, non-alcoholic hepatitis, acute fatty liver, and fatty liver of pregnancy.
  • SCD disorders or diseases mediated by SCD include, but are not limited to, skin disorder, inflammation, respiratory diseases or disorders (e.g., sinusitis, asthma, and bronchitis), pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, pre-menstrual syndrome., cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas, neurological diseases, psychiatric disorders, multiple sclerosis, and viral diseases and infections.
  • respiratory diseases or disorders e.g., sinusitis, asthma, and bronchitis
  • pancreatitis e.g., osteoarthritis, rheumatoid arthritis
  • cystic fibrosis e.g., pre-menstrual syndrome.
  • cancer neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas,
  • compounds of the invention will, in a subject, increase HDL levels and/or decrease triglyceride levels and/or decrease LDL or non-HDL- cholesterol levels.
  • compounds of the invention will, in a subject, increase body lean mass and decrease obesity.
  • compounds of the invention will, in a subject, decrease hepatitic steatosis.
  • Suitable pharmaceutical agents include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, l l ⁇ -hydroxy steroid dehydrogenase- 1 (ll ⁇ -HSD type 1) inhibitors, peptide YY 3-36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor
  • anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, l l ⁇ -hydroxy steroid dehydrogenase- 1 (ll ⁇ -
  • anorectic agents such as a bombesin agonist
  • neuropeptide- Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analog thereof glucocorticoid receptor agonists or antagonists, orexin receptor antagonists
  • glucagon-like peptide-1 (GLP-I) receptor agonists GLP-I
  • DPP-IV dipeptidyl peptidase IV
  • ciliary neurotrophic factors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y.
  • anti-obesity agents including the preferred agents set forth herein below, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • anti-obesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY 3-36 or an analog thereof (including the complete peptide YY), and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • Anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874; and PYY 3-36 (including its analogs) can be prepared as described in U.S. Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All of the above recited references are incorporated herein by reference.
  • the compounds of the present invention may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.
  • a cyclic amine derivative of the general formula (3) can be prepared by a known approach as described in the literature (Hamlin K. et al., J. Am. Chem. Soc, 1949, 71, 2734; Willand, N. et al., Tetrahedron, 2002, 55, 5741).
  • the amine (1) is reacted with an intermediate of the general formula (2) (wherein L is a leaving group) in presence of a base in a suitable solvent to afford a compound (3) which is converted to an amino compound (4) by reduction of the nitro group.
  • the amino compound (4) is converted to a compound of formula I by two approaches as shown in Scheme 1.
  • the amine (4) is reacted with various epoxides of the general formula (6) under Lewis acid catalysis (Serrano, P. et al., J. Org. Chem., 2002, 67 (20), 7165) to give the amino alcohol (7).
  • the reaction of amino alcohol (7) with l,l'-carbonyldiimidazole (CDI) or a phosgene derivative gives a compound of general formula I.
  • the amine (4) is converted to a carbamate derivate such as benzyl carbamate and reacted with the epoxide (6) (preferably when R 3 or R 4 is H) in the presence of a strong base such as n-butyllithium (Brickner, S. J. et al., J. Med. Chem., 1996, 39, 673; Brickner, S. J. et al., J. Med. Chem., 1996, 39, 680) to give a compound of formula I.
  • a strong base such as n-butyllithium
  • suitable organic and inorganic bases include, but are not limited to, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, ammonium hydroxide, pyridine, n-butyllithium, sec-butyllithium, tert- butyllithium, methyllithium or lithium diisopropyl amine.
  • Suitable solvents include, but are not limited to, dimethylformamide, diethylformamide, dimethylsulfoxide, N- methylpyrrolidone, tetrahydrofuran, methanol, ethanol or isopropanol or ethylacetate.
  • Suitable reducing agents include, but are not limited to, hydrogen/palladium-carbon, hydrogen/Raney-Nickel, and hydrogen/Platinum-carbon, Zn/HCl, Sn/HCl or Raney- Ni/formic acid.
  • Suitable deprotecting agents include, but are not limited to, hydrochloric acid or trifluoroacetic acid.
  • the deprotecting agents include, but are not limited to, hydrochloric or trifluoroacetic acid.
  • Suitable solvents include, but are not limited to, methanol, ethanol, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide or ethylacetate.
  • Suitable reducing agents include, but are not limited, hydrogen/palladium-carbon, hydrogen/raney-nickel, hydrogen/platinum-carbon, zinc/hydrochoride, tin/hydrochloride or raney-Ni/formic acid.
  • Suitable cyclizing agents but are not limited to, N 5 N'- carbonyldiimidazole or carbonyl chloride.
  • the intermediate of formula (10) is prepared in two steps using a known approach (Salvatore Lepore, et al., J. Org. Chem., 2003, 68 (21), 8261) from an appropriate phenol, a cyclic amino alcohol and a nitro aryl derivative having a suitable leaving group such as a halogen atom.
  • Reduction of nitro compound (10) using a suitable reducing agent such as H 2 ZPd-C in an alcoholic solvent gives the amine (11).
  • Amine (11) on reaction with epoxides under Lewis acid catalysis gives amino alcohol, which on reaction with a l,l'-carbonyldiimidazole (CDI) gives a compound of Hc.
  • Step 1 fert-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate: To a stirred solution of 2-chloro-5-nitropyridine (20.00 g, 126.151 mmol) in DMF (200 ml) was added JV- BOC-piperazine (25.81 g, ' 138.766 mmol) and KHCO 3 (18.94 g, 189.226 mmol) and the mixture was stirred at 70 °C for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate (300 ml) and water (3 x 200 ml). The layers were separated.
  • Step 2 4-(5-Nitropyridin-2-yl)piperazine: To a stirred solution of Step 1 intermediate (32 g, 103.896 mmol) in dichloromethane (200 ml) was added trifiuoroacetic acid (96 ml) at 0 °C over 5 min. The reaction mixture was stirred for another 1 h at the same temperature. The residue obtained after evaporation of the solvent was dissolved in ethyl acetate (180 ml) and washed with saturated NaHCO 3 (2 x 100 ml) and dried over anhydrous Na 2 SO 4 . The solvent was evaporated under reduced pressure to afford 19.5 g of the desired salt as a yellow solid.
  • Step 3 l-(5-Nitropyridin-2-yl)-4-[2-(trifluoromethyl)benzoyl]piperazine: To a stirred solution of 2-(trifluoromethyl)benzoic acid (16.45 g, 86.538 mmol) in dry dichloromethane (150 ml) was added l-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (14.61 g, 108.172 mmol), 1-hydroxybenzotriazole (11.04 g, 72.115 mmol) and triethylamine (35.113 ml, 252.40 mmol) at 0 "C.
  • Step 2 intermediate (15.00 g, 72.115 mmol) was added and the mixture was slowly allowed to warm to room temperature. The mixture was further stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and washed with water (2 x 100 ml) and dried over anhydrous Na 2 SO 4 .
  • Step 4 6- ⁇ 4-[2-(Trifluoromethyl)benzoyl]piperazin-l-yl ⁇ pyridin-3-yl-amine: Dry ethanol (50 ml) was added to a stirred solution of Intermediate 1 (16 g, 42.105 mmol) over 15 min at room temperature. Then 10 % Pd/C (1.6 g) was added to it and stirred overnight at the same temperature. The reaction mixture was filtered through a celite bed, washed with toluene and concentrated under reduced pressure to afford 13.39 g of the desired amine as an off-white solid which was used as such for the next step without purification.
  • Step 5 5-(Benzyloxycarbonyl)aminopyridin-2-ylpiperazino-2-trifluoromethylphenyl- methanone: To a stirred solution of Step 4 Intermediate (10 g, 28.571 mmol) in dry THF (100 ml) was added triethylamine (5.959 ml, 42.857 mmol) and benzyl chloroformate (5.34 g, 31.428 mmol) at 0 °C over 5 min. The reaction mixture was allowed to warm to room temperature and left overnight at the same temperature.
  • Step 1 tert-Butyl 4-(5-aminopyridin-2-yl)piperazine-l-carboxylate: To a stirred solution of tert-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (20 g, 64.935 mmol) in EtOAc (200 ml) was added 5 % Pd/C (4 g) and the mixture was maintained under hydrogen pressure (45 psi) for 3 h at room temperature. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to afford 16.24 g of the amine as a light brown solid which was used as such for the next step.
  • Step 2 tert-Bxxtyl 4-(5- ⁇ [(benzyloxy)carbonyl]amino ⁇ pyridin-2-yl)piperazine-l- carboxylate: To a stirred solution of step 1 intermediate (10 g, 35.971 mmol) in dry THF (100 ml) was added triethylamine (7.506 ml, 53.956 mmol) and the mixture was stirred at 0 0 C and benzyl chloroformate (6.75 g, 39.568 mmol) was added over 5 min. The reaction mixture was allowed to warm to room temperature and stirred overnight.
  • Step 3 5-(Benzyloxycarbonyl)aminopyridin-2-ylpiperazine hydrochloride: Deprotection of Step 2 intermediate (8.0 g, 0.529 mmol) carried out as described in Step 2 of method A by treatment with 15 % HCl in EtOAc (24 ml) in dichloromethane (10 ml) afforded 5.74 g of the product as a white solid, which was used as such for the next step.
  • Step 4 5-(Benzyloxycarbonyl)aminopyridm-2-ylpiperazino-2-trifluoromethylphenyl- methanone: To a stirred mixture of Step 3 intermediate (4.0 g, 12.82 mmol), 2- (trifluoromethyl)benzoic acid (2.92 g, 15.358 mmol), EDCI (2.59 g, 19.23 mmol) and HOBT (1.96 g, 12.82 mmol) in dry dichloromethane (40 ml) was added triethylamine (6.24 ml, 44.87 mmol) and the mixture was stirred overnight at room temperature under nitrogen atmosphere.
  • reaction mixture was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (3 x 150 ml) and dried over anhydrous Na 2 SO 4 .
  • the mixture was diluted with water (150 ml) and the layers were separated.
  • the aqueous layer was extracted with dichloromethane (200 ml).
  • the combined organic extracts were washed with water (2 x 150 ml) and dried over anhydrous Na 2 SO 4 .
  • Step 1 (3i?)-l-(5-Nitropyridin-2-yl)pyrrolidin-3-ol: To a stirred solution of 2-chloro- 5-nitro ⁇ yridine (18.19 g, 114.784 mmol) in dry DMF (180 ml) was added (3 ⁇ )-pyrrolidin-3- ol (10.01 g, 114.784 mmol) and KHCO 3 (11.473 g, 172.004 mmol) at 70 °C and the reaction mixture was stirred at the same temperature for 3 h. The reaction mixture was allowed to cool to room temperature.
  • Step 2 2 ⁇ [(3>S)-3-(2-Fluorophenoxy) ⁇ yrrolidin-l-yl]-5-nitropyridine: To a stirred solution of step 1 Intermediate (9.0 g, 43.062 mmol) in dry THF (100 ml) was added 2- fluorophenol (4.82 g, 43. ,062 mmol), triphenylphosphine (16.92 g, 64.593 mmol) followed by addition of diethyl azodicarboxylate (9.74 g, 55.98 mmol) over 10 min at room temperature. The reaction was exothermic. The reaction was allowed to cool to room temperature and the reaction mixture was stirred at this temperature for 3 h.
  • Step 3 6-[(36)-3-(2-Fluorophenoxy)pyrrolidin-l-yl]pyridin-3-amine: To a stirred solution of step 2 intermediate (7 g, 23.102 mmol) in 30 % aqueous ethanol (70 ml) was added ammonium chloride (12.35 g, 231.02 mmol) at 85 °C. To this, iron powder (3.87 g, 69.306 g atom) was added in lots over 15 min. The reaction mixture was stirred at the same temperature for 1 h. The catalyst was then filtered off and the filtrate was washed with ethyl acetate and concentrated under reduced pressure.
  • Step 4 Benzyl ⁇ 6-[(35)-3-(2-fluorophenoxy)pyrrolidin-l-yl]pyridin-3-yl ⁇ carbamate: To a stirred solution of step 3 intermediate (4 g, 14.638 mmol) in dry THF (50 ml) was added triethylamine (3.93 ml, 29.251 mmol) and benzyl chloroformate (2.99 g, 17.565 mmol) at 0 0 C over 5 min. The reaction mixture was allowed to warm to room temperature and left overnight at the same temperature.
  • reaction mixture was quenched with saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water (3 x 150 ml) and dried over anhydrous Na 2 SO 4 .
  • Step 1 (5i?)-5-Hydroxymethyl-3 -(6-piperazin- 1 -ylpyridin-3 -yl)- 1 ,3-oxazolan-2-one hydrochloride: tert-But ⁇ 4- ⁇ 5-[(5i?)-5-hydroxymethyl-2-oxo-l,3-oxazolan-3-yl] pyridin-3- yl ⁇ piperazin-l-carboxylate, Intermediate 2 (600 mg, 1.587 mmol) was treated with 15 % HCl in EtOAc (10 ml) at 0-5 0 C and stirred at the same temperature for 2 h. Ethyl acetate was evaporated under reduced pressure to give 440 mg of the amine hydrochloride as a white solid, which was used as such for the next step.
  • Step 2 Coupling reaction of the above amine hydrochloride (200 mg, 0.635 mmol) with 2-(trifmoromethyl)benzoic acid (145 mg, 0.763 mmol) in the presence of EDCI (128 mg, 0.952 mmol), HOBT (97 mg, 0.635 mmol) and triethylamine (0.4 ml, 2.875 mmol) in dry dichloromethane (10 ml) afforded 248 mg of the desired compound as an off-white solid.
  • IR, 1 H NMR and Mass spectra of the product were identical in all respects with the compound obtained from Method A.
  • Example 1 To a stirred and cooled (-40 °C) solution of Example 1 (200 mg, 0.44 mmol) in dry DCM (30 ml) was added (diethylamino)sulfur trifluoride (179 mg, 1.11 mmol) over 5 min under a nitrogen atmosphere. The reaction mixture was stirred for another 45 min at the same temperature. The mixture was gradually allowed to warm to room temperature and left overnight at this temperature. The reaction mixture was quenched with saturated solution of sodium bicarbonate (50 ml) and extracted with chloroform (2 x 50 ml). The combined organic layer was washed with water (2 x 50 ml) and dried over anhydrous Na 2 SO 4 .
  • Example 1 To a stirred solution of Example 1 (200 mg, 0.444 mmol) and methyliodide (94 mg, 0.666 mmol) in dry THF (10 ml) was added silver oxide (155 mg, 0.666 mmol) at room temperature under nitrogen atmosphere and further stirred for 72 h. The mixture was filtered through a celite bed and the filtrate was evaporated under reduced pressure.
  • Example 12 To a stirred solution of Example 12 (150 mg, 0.304 mmol) in dry THF (10 ml) was added 3.0 M methylmagnesium bromide (0.249 ml, 0.761 mmol) at 18 °C. The reaction mixture was allowed to cool to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was quenched by saturated solution of ammonium chloride (50 ml), extracted with ethyl acetate (2 x 50 ml), washed with water (3 x 100 ml), brine (50 ml) and dried over anhydrous Na 2 SO 4 . The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using
  • Example 12 To a stirred solution of Example 12 (50 mg, 0.101 mmol) in dry MeOH (1 ml) and dry THF (1 ml) was added isopropylamine (60 mg, 1.015 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. The residue obtained after evaporation of the solvent was dissolved in EtOAc, washed with brine (50 ml) and dried (Na 2 SO 4 ).
  • Step 1 tert-Butyl 4-[5-(5-Butyl-2-oxo-l,3-oxazolan-3-yl)pyridine-2-yl]piperazine-l- carboxylate: To a stirred solution of Intermediate 5 (600 mg, 1.587 mmol) in dry THF (30 ml) was added CDI (511 mg, 3.173 mmol) and 4-dimethylaminopyridine (DMAP) (20 mg, 0.158 mmol) over 5 min under nitrogen atmosphere and the mixture was stirred at room temperature for 5 days. The excess solvent was removed under reduced pressure. The residue was treated with water and EtOAc.
  • CDI 511 mg, 3.173 mmol
  • DMAP 4-dimethylaminopyridine
  • Step 2 4-[5-(5-Butyl-2-oxo-l ,3-oxazolan-3-yl)pyridme-2-yl]piperazme hydrochloride:
  • the Step 1 intermediate 500 mg, 1.237 mmol
  • EtOAc 10 ml
  • Method B give 375 mg of the product as a white solid, which was used as such for the next step.
  • Step 3 Coupling reaction of Step 2 intermediate (300 mg, 0.881 mmol) with 2- (trifluoromethyl)benzoic acid (169 mg, 0.889 mmol) in the presence of EDCI (150 mg, 1.113 mmol), HOBT (113 mg, 0.742 mmol) and triethylamine (0.428 ml, 3.083 mmol) in dry DCM (20 ml) afforded 260 mg of the desired compound as an off-white solid; IR (KBr) 3482, 2958, 2861, 1747, 1496, 1243, 1127, 771 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.62-1.00 (m, 3H), 1.25 (br s, IH), 1.40 (br s, 3H), 1.85 (br s, 2H), 3.29 (br s, 2H), 3.45 (br s, 2H), 3.60 (s, 3H), 3.85-4.00 (m, 2
  • Step 2 4-[5-(5,5-dimethyl-2-oxo-l ,3-oxazolan-3-yl)-2-pyridyl]-l -piperazine hydrochloride:
  • the Step 1 intermediate (600 mg, 1.595 mmol) was deprotected with 15 % HCl in EtOAc (10 ml) as described in Example 1, Method B gave 440 mg of the product as a white solid, which was used as such for the next step.
  • Step 2 4-[5-(2-oxo-l-oxa-3-azaspiro[4.5]dec-3-yl)pyridin-2-yl]piperazine hydrochloride: Deprotection of Step 1 intermediate (650 mg, 1.081 mmol) using 15 % HCl in EtOAc (10 ml) as described in Example 15, Step 3 gave 495 mg of the product as a white solid, which was used as such for the next step.
  • the in-vitro activity of the compounds of the present invention against stearoyl coenzyme desaturase was determined by following conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using human SCDl enzyme using a previously published assay procedure with some modifications (Talamo, B. R. and Bloch, K. Analytical Biochemistry, 1969, 29, 300- 304). This assay protocol is only illustrative and is not meant to limit to the scope of the present invention.
  • the microsomal SCDl enzyme desaturates its substrate, Stearoyl CoA (purchased from American Radiochemicals Ltd.) which is tritiated at C9 and ClO positions.
  • Test compounds were dissolved in dimethylsulfoxide and tested at 10 ⁇ M final concentration. Before substrate addition, the test compound or standard reference compound (conjugated linoleic acid at 100 ⁇ M final concentration) were pre-incubated in reaction buffer with the enzyme for 10 minutes at 30 °C with shaking. Reaction buffer was prepared as described in literature (Obukowicz M. G. et al.

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Abstract

La présente invention concerne de nouveaux inhibiteurs de la Stéaroyl CoA désaturase (SCD) et leurs utilisations pour traiter des maladies, états et/ou troubles modulés par une enzyme Stéaroyl CoA désaturase. Les inhibiteurs de la SCD ont une certaine formule ou un sel pharmaceutiquement acceptable de celle-ci, un ester pharmaceutiquement acceptable de celle-ci, un tautomère de celle-ci, un régioisomère de celle-ci, un stéréoisomère de celle-ci, un énantiomère de celle-ci, un diastéréomère de celle-ci, un polymorphe de celle-ci ou un solvate pharmaceutiquement acceptable de celle-ci, les variables étant telles que décrites présentement.
PCT/IB2007/002580 2006-09-08 2007-09-07 Inhibiteurs de la stéaroyl coa désaturase WO2008029266A1 (fr)

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WO2009012573A1 (fr) * 2007-07-20 2009-01-29 Merck Frosst Canada Ltd. Composés hétéroaromatiques bicycliques en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2010073011A2 (fr) 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
US7842696B2 (en) 2007-06-21 2010-11-30 Forest Laboratories Holdings Limited Piperazine derivatives as inhibitors of stearoyl-CoA desaturase
US8383643B2 (en) 2009-07-28 2013-02-26 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
WO2013056148A2 (fr) 2011-10-15 2013-04-18 Genentech, Inc. Procédés d'utilisation d'antagonistes de scd1
WO2013108026A1 (fr) 2012-01-17 2013-07-25 Baltic Bio Ab Dérivés de thiadiazolone utiles dans le traitement du diabète
WO2013175474A2 (fr) 2012-05-22 2013-11-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs sélectifs de cellules indifférenciées
US9168248B2 (en) 2009-02-17 2015-10-27 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
WO2018129403A1 (fr) 2017-01-06 2018-07-12 Yumanity Therapeutics Méthodes de traitement de troubles neurologiques
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US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7842696B2 (en) 2007-06-21 2010-11-30 Forest Laboratories Holdings Limited Piperazine derivatives as inhibitors of stearoyl-CoA desaturase
WO2009012573A1 (fr) * 2007-07-20 2009-01-29 Merck Frosst Canada Ltd. Composés hétéroaromatiques bicycliques en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2010073011A2 (fr) 2008-12-23 2010-07-01 Betagenon Ab Composés utiles comme médicaments
US9168248B2 (en) 2009-02-17 2015-10-27 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
US8383643B2 (en) 2009-07-28 2013-02-26 Merck Canada Inc. Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase
US9358250B2 (en) 2011-10-15 2016-06-07 Genentech, Inc. Methods of using SCD1 antagonists
WO2013056148A2 (fr) 2011-10-15 2013-04-18 Genentech, Inc. Procédés d'utilisation d'antagonistes de scd1
WO2013108026A1 (fr) 2012-01-17 2013-07-25 Baltic Bio Ab Dérivés de thiadiazolone utiles dans le traitement du diabète
WO2013175474A2 (fr) 2012-05-22 2013-11-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Inhibiteurs sélectifs de cellules indifférenciées
US9456998B2 (en) 2012-05-22 2016-10-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Selective inhibitors of undifferentiated cells
JP2019533022A (ja) * 2016-10-24 2019-11-14 ユマニティ セラピューティクス，インコーポレーテッド 化合物及びその使用
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2018129403A1 (fr) 2017-01-06 2018-07-12 Yumanity Therapeutics Méthodes de traitement de troubles neurologiques
US10973810B2 (en) 2017-01-06 2021-04-13 Yumanity Therapeutics, Inc. Methods for the treatment of neurological disorders
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof

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