[go: up one dir, main page]

MXPA97005841A - No peptides as antagonists of the taquiquin - Google Patents

No peptides as antagonists of the taquiquin

Info

Publication number
MXPA97005841A
MXPA97005841A MXPA/A/1997/005841A MX9705841A MXPA97005841A MX PA97005841 A MXPA97005841 A MX PA97005841A MX 9705841 A MX9705841 A MX 9705841A MX PA97005841 A MXPA97005841 A MX PA97005841A
Authority
MX
Mexico
Prior art keywords
phenyl
methyl
ethyl
carbamic acid
hydrogen
Prior art date
Application number
MXPA/A/1997/005841A
Other languages
Spanish (es)
Other versions
MX9705841A (en
Inventor
Christopher Horwell David
Clive Pritchard Martin
Raphy Jennifer
Original Assignee
Horwell David C
Pritchard Martyn C
Raphy Jennifer
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
Priority claimed from US08/406,607 external-priority patent/US5554641A/en
Application filed by Horwell David C, Pritchard Martyn C, Raphy Jennifer filed Critical Horwell David C
Publication of MX9705841A publication Critical patent/MX9705841A/en
Publication of MXPA97005841A publication Critical patent/MXPA97005841A/en

Links

Abstract

The small non-peptides of the present invention are tachykinin antagonists. The compounds are highly selective and functional NK3 antagonists which are expected to be useful in the treatment of pain, depression, anxiety, panic schizophrenia, neuralgia, disorders by additions, inflammatory diseases, gastrointestinal disorders, vascular disorders and neuropathological disorders.

Description

NO PÉPTROOS AS TAQUIQUININ ANTAGONISTS BACKGROUND OF THE INVENTION During the past decade, important advances have been made in the understanding of the biology of mammalian tachykinin neuropeptides. It is now well established that the substance - P (1), neurokinin A (NKA) (2) and neurokinin B (NKB) (3), all of which share the terminal sequence - C Phe - X - Gly - Leu - Met-NH2, (Nakanishi S., Physiol. Rev., 67: 117 (1987)), are widely distributed throughout the periphery and the central nervous system (CNS) where it appears that they interact with at least three types of receptors referred to as NKi, NK2 and NK3, (Guard S., et al., Nueurosci. Int., 18: 149 (1991)). The P-substance displays the highest affinity for the NKi receptors, in that NKA and NKB bind preferentially to the NK2 and NK3 receptors, respectively. Recently, all three receptors have been cloned and sequenced and shown to members of the "super family" bound to the G protein of receptors (Nakanishi S., Annu, Rev. Neurosci., 14: 123 (1991)). A wealth of evidence supports the involvement of tachykinin neuropeptides in a variety of biological activities including pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, immune system activation (inflammatory pain) and neurogenic inflammation (Pernow B ., Pharmacol. Rev., 35:85 (1983)). However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been seriously injured due to a lack of metabolically stable, high affinity and selective tachykinin receptor antagonists possessing good viability at the same time and penetration in the CNS. Although several tachykinin receptor antagonists have been described (Tomczuk BE, et al., Current Reviews in Therapeutic Patents, 1: 197 (1991)), most have been developed through modification and / or elimination. of one or more of the amino acids comprising the endogenous mammalian tachykinins so that the resulting molecules are still peptides possessing poor pharmacokinetic faculties and limited in vivo activities.
However, since 1991, a number of high affinity non-peptide antagonists have been reported. Snider RM, et al., (Science, 251: 435 (1991)), and Garret C, et al., (Proc. Natil, Acad. Sci., 88: 10208 (1991)), described CP-96,345 and RP 67580, respectively as antagonists of the NKl5 receptor while Advenier C, et al., (Brit. J. Pharmacol., 105: 78 (1992)), presented data on SR 48968 showing their high affinity and selectivity for NK2 receptors. . More recently, McLeiod, et al., (J. Med. Chem., 36: 2044 (1993)) have published on a novel series of tryptophan derivatives as NKi receptor antagonists. It is of interest that most of the non-peptide tachykinin receptor antagonists described to date arose, either directly or indirectly, from the filtration of large collections of compounds using a robust radioligand binding assay as the primary filter. Recently, FK 888, a "dipeptide" with high affinity for the NKi receptor was described (Fujii J., et al., Neuropeptide, 22:24 (1992)). only a receptive ligand of the NK3 receptor, SR 142801, has been published to date (Edmonds.Alt, et al., Life Sciences, 56:27 (1995)).
The international publication numbers WO 93/01169, WO 93/01165 and WO 93/01160 cover certain non-peptide tachykinin receptor antagonists.
The NKB and also NK3 receptors are distributed throughout the periphery and the central nervous system (Maggi, et al., J. Auton Pharmacol., 13:23 (1993)). It is believed that NKB triggers a variety of biological actions through the NK3 receptor that include the secretion of gastric acids; appetite regulation; modulation of seretonergic, cholinergic and dopaminergic systems; contraction of smooth muscles and neuronal excitation. Recent descriptive publications of this technique include Polidor, et al., Neuroscience Letts., 103: 320 (1989); Massi, et al., Neuroscience Letts., 92: 341 (1988) and Improta, et al., Peptides, 12: 1433 (1991). due to their actions with the dopaminergic systems (Elliott, et al., Neuropeptides, 19: 119 (1991)), chlorinergics (Stoessl, et al., Psycho. Pharmacol., 95: 502 (1988) and serotonergic (Stoessl, et al. al., Neuroscience Letts., 80: 321 (1987), NKB may play a role in psychotic behavior, memory functions and depression.
Accordingly, compounds capable of antagonizing the effects of NKB receptors on NK will be useful in the treatment or prevention of a variety of disorders including pain, depression, anxiety, panic, schizophrenia, neuralgia, addictive disorders, diseases. inflammatory, gastrointestinal disorders that include colitis, Crohn's disease, inflammatory bowel disease and satiety; vascular disorders such as angina and migraine and neuropathological disorders such as Parkinson's disease and Alzheimer's.
Copending application serial number 08 / 346,052 filed on November 29, 1994, covers certain peptides of Formula I . n -R3 or a pharmaceutically acceptable salt thereof wherein: R1 is hydrogen, OR4, CO2R4, cyclo- or polycycloalkyl of from 4 to 10 carbon atoms with from 0 to 3 substitutes chosen from: alkyl, halogen, (CH2) mCO2R4, ( CH2) mOR4 wherein m is an integer from 1 to 6 and R4 is hydrogen or alkyl or phenyl unsubstituted or substituted by from 1 to 3 groups chosen from: alkyl, halogen, nitro, CF3, (CH2) pOR6, (CH2 pCO2R6, (CH2) PNR6R7 wherein p is an integer from 0 to 6 and R6 and R7 are each independently hydrogen or alkyl; A is - (CH2) q (C (CH3) 2) r (CH2) 8 - where q, r and s are integers from 0 to 6, 0 a 1 and 0 to 6, respectively; Ar1 and Ar2 are each independently phenyl unsubstituted or substituted with from 1 to 3 substituted substitutes of: alkyl, halogen, nitro, CF3, (CH2) tOR6, (CH2) tCO2R6 or (CH2) tNR6R7 where t is an integer of from 0 to 6 and R6 and R7 are each independently hydrogen or alkyl; X and Y are each independently - CONH -, - CONCH3 -, - COO -, - CH2NH -, - NHCO -, - CH2O - COCH2 - or - CH2CH -; n is an integer from 0 to 10; and R3 is hydrogen, straight or branched alkyl of from 3 to 10 carbon atoms with from 0 to 3 substitutes chosen from: (CH2) "OR8, CO2R8, - NHCOCH3, - NR8R9, - SO2Me, - SOMe, - SO2NH2, - CONR8R9, NHCONR8R9, - COR4 wherein n is an integer from 0 to 6, R4 is as above, R8 and R9 are each independently hydrogen or alkyl, - guanidine, - amidine; R3 is also wherein t is an integer from 0 to 5, V is an integer from 0 to 2, u is an integer from 0 to 4 and R10 is hydrogen, hydroxy, alkoxy, COOH, CO2alkyl, CONR8R9 guanidine or amidine; and • and - * • indicate all stereoisomers.
Co-pending application 08 / 344,046 covers certain tachykinin antagonists. It is incorporated herein by way of reference.
The compounds of the present invention provide small molecules that are not peptides; they are amino acids in contrast to the dipeptides of the co-pending application. The present compounds only have one bond and show higher binding affinities.
SUMMARY OF THE INVENTION The present invention is non-novel peptides that are capable of stimulating or blocking the effects of neurokinin B (NKB) on NK3 receptors.
The compounds of the present invention are those of the formula or a pharmaceutically salt thereof wherein Ar1, R1, n, A, Ar2, X, R2, R3, Y and R4 are as described below.
Pharmaceutical compositions of therapeutically effective amounts of one or more of the compounds of Formula I and a pharmaceutically acceptable carrier as useful in the treatment of central nervous system disorders such as, but not limited to, pain, anxiety, depression and schizophrenia, panic, addictive disorders.
The compounds are also expected to be useful in the treatment of gastrointestinal diseases including, but not limited to, colitis, Crohn's disease, inflammatory bowel disorder and satiety.
The compounds are also expected to be useful in the treatment of respiratory disorders without limitations, to asthma.
The compounds are also expected to be useful in the treatment of inflammation.
The compounds are also expected to be useful in the treatment of circulatory insufficiencies.
DETAILED DESCRIPTION The compounds of the present invention are those of Formula I above, wherein:, and Y indicate all stereoisomers in these carbon atoms; Ar 1 is phenyl unsubstituted or substituted by from 1 to 3 substituted substitutes of: alkyl, halogen, nitro, trifluoromethyl, cyano, hydroxy and alkoxy; Ar1 can also be pyridine; R1 is hydrogen or a straight or branched or cycloalkyl of from 1 to 7 atoms; or Ar1 and R1 form a chain of 5 to 8 atoms when they are attached to a bond; n is an integer from 0 to 2; A is OCONH, CONH, CO2, NHCONH, CH2NH and COCH2; Ar2 is phenyl as defined in Ar1 above; pyridine, thiophene, naphthyl, nature, benzofuran, benzothiofene or imidazole; X is - OCONH -, - CONH -, - CO2 -, - NHCONH -, - CH2NH -, - COCH2 -, - CONCH3 -, - CO2 -, - CH2O -, - CH2CH2 - or - CH = CH -; R2 is hydrogen, methyl, phenyl, benzyl, CH2C6H ?, or R3 is hydrogen or methyl; Y is - (CH2) m -, - (CH2) mO -, where is an integer from 1 to 5, - CONH -, - CH2NH., - CH = CH -; And R4 is hydrogen, straight or branched alkyl of from 1 to 8 atoms unsubstituted or substituted by stitute chosen from: hydrogen, OR5, NHCOCH3, NR5R6, SO2CH3, SO2NH2, NHSO2NH2, NHCONH2, CONR5R6, COR5, wherein R5 and R6 are each independently hydrogen or alkyl and R4 is "" "(CH:,? \> T_7 (0,« -: '(CH ^ "" R' - ~, (rCK? - > lF-Y? ~ / ° ^ -. (CH R - (CH2) N _yN- (CH2) aR7, - (OU, _CH 0 (CH :)? 0, CH2) qR-, "-. { CH.) - 0 (CH _R "where p is an integer from 0 to 5, q is an integer from 0 to 4 and R7 is hydrogen, hydroxy, alkoxy, CONR5R6 or NHCONR5R6 where R5 and R6 are as describes above.
Preferred compounds of the present invention are those of Formula I wherein: esSoR, FesRyYesS; Ar1 is phenyl unsubstituted or substituted with from 1 to 2 substituted substitutes of: alkyl, halogen, cyano and alkoxy; R1 is a straight, branched or cyclic alkyl of from 1 to 6 atoms; or Ar1 and R1 form a chain of 7 atoms; n is an integer from 0 to 1; A is OCONH, CONH, NHCONH or CH2NH; A2 is phenyl as defined in Ar1 above, pyridine, thiofene, naphthyl benzofuran; X is OCONH, CONH, NHCONH, CH2NH, CONCH3 or COCH2; R2 is hydrogen, phenyl, benzyl or R3 is hydrogen or methyl; Y is (CH2) m, CONH, CH2NH, or COCH2; R 4 is hydrogen, straight or branched alkyl of from 3 to 7 atoms with a substitute chosen from: OR 5, NHCOCH 3, SO 2 CH 3, NHCONH2, CONR5R6, COR5, wherein R5 and R6 are each independently hydrogen or alkyl and R4 is - ", R, or wherein p is an integer from 0 to 2, q is an integer from 0 to 3 and R7 is hydroxy, alkoxy, CONR5R6 or NHCONR5R6.
The most preferred compounds of the present invention are those of the Formula I wherein: • is S or R, is R and "is S, Ar1 is phenyl unsubstituted or substituted by halogen, cyano or alkyl, R1 is a branched or cyclic of from 3 to 6 atoms, or Ar1 and R1 form a chain of 7 atoms, n is O, A is OCONH, or NHCONH, A2 is phenyl unsubstituted or substituted by halogen, cyano or alkyl or Ar2 is thiophene, naphthyl or benzofuran, X is CONH, CH2NH or COCH2; R2 is hydrogen , phenyl R3 is hydrogen or methyl; And it's CH2 or CONH; R4 is hydrogen, alkyl which is a straight chain of from 4 to 6 atoms with a substitute chosen from: hydroxy, NHCOCH3, NHCONH2 The most preferred compounds of the present invention are those of the Formula 1 named: Carbamic acid, [2 - [(9-amino-9-oxononyl) amino] -1-methyl-2-oxo-1 - (phenylmethyl) ethyl] -, 2-methyl-1-phenylpropyl ester, [R - (R *, S *)] -; Carbamic acid, [2 - [(9-amino-9-oxononyl) amino] -1-methyl-2-oxo-1- (phenylmethyl) ethyl] -, 1- (4-chloro-phenyl) -2-methylpropyl ester; [1- (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid cyclopentyl-phenyl-methyl ester; [1 - (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 6,7,8,9-tetrahydro-5H-benzocycloethene-5-yl-ester; [1 - (8-carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 2,2-dimethyl-1-2,3,4-tetrahydro-naphthalen-1-yl-ester; Carbamic acid, [1-methyl-2-oxo-2 - [(1-phenylethyl) -amino] -1- (phenylmethyl) ethyl] -, (R) or (S) -2-methyl-1-phenylpropyl ester, [R - (R *, S *)] -; [1-methyl-1 - (1-methyl-1-phenyl-ethylcarbamoyl) -2-phenyl-ethyl] - carbamic acid 2 - . 2-methyl-1-phenyl-propyl ester; [1 - (2-hydroxy-1-phenyl-ethylcarbamoyl) -1-methyl-2-femyl-ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester; Carbamic acid, [2 - [(8-hydroxyoctyl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] -, 2-methyl-1-phenylpropyl ester; [2 - (2-fluoro-phenyl) -1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester; [2 - (2,3-difluoro-phenyl) -1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester; [1 - (8 - carbamoyl - octylcarbamoyl) - 1 - methyl - 2 - phenyl - ethyl] - carbamic acid 6,6 - dimethyl-6,7,8,9-tetrahydro-5H-benzocycloethene-5-yl ester; . { 1 - [1 - (6-hydroxy-hexylcarbamoyl) -2- (4-hydroxy-phenyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} - carbamic acid-2-methyl-1-phenyl-propyl ester; . { 1 - [1 - (7-hydroxy-heptylcarbamoyl) -2- (4-hydroxy-phenyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} - carbamic acid 2-methyl-1-phenyl-propyl ester; Y . { 1 - [2 - (4-hydroxy-phenyl) -1- (6-ureido-hexylcarbamoyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} Carbamic acid 2-methyl-1-phenyl-propyl ester.
The compounds of Formula I are further defined as follows: The term "alkyl" means a straight or branched hydrocarbon having from 1 to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-peptyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, undecyl, dodecyl and the like unless specifically indicated otherwise.
The term "cycloalkyl" means a saturated hydrocarbon chain containing from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except when specifically indicated to the contrary.
The term "alkoxy" means an alkyl as described above coupled by an oxygen.
The term "halogen" is chlorine, fluorine, bromine or iodine.
The chain formed by the bond of Ar1 and R1 is from 4 to 8 atoms in total and is unsubstituted or substituted by one or more selected substitutes of methyl, dimethyl or isopropyl.
The compounds of Formula I are capable of forming both pharmaceutically acceptable acid and / or base addition salts. All these forms are within the scope of the present invention.
The pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous and the like, as well as salts derived from acids non-toxic organic compounds, such as mono- and dicarboxylic aliphatic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Said salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, fanyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are amino acid salts such as areagenate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts" J. of Pharma, Sci., 66: 1 (1977)).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably, a compound of Formula I can be converted to an acid salt by treating it with an aqueous solution of the desired acid, so that the resulting pH is less than four. The solution can be passed through a C18 cartridge to absorb the peptide, washed with copious amounts of water, elute the peptide with a polar organic solvent such as, for example, methanol, acetonitrile, aqueous mixtures thereof and the like and Isolate by concentration under reduced pressure followed by lyophilization. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical characteristics such as solubility in polar solvents, but outside the salts are equivalent to their free bases for the purposes of the present invention.
The pharmaceutically acceptable basic addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, for example, Berge, S.M., et al., Supra.) The basic addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. Preferably, a peptide of Formula I can be converted to a basic salt by treating it with an aqueous solution of the desired base, so that the resulting pH is greater than 9, The solution can be passed through a cartridge of C18 to absorb the peptide, wash with copious amounts of water, the peptide is eluted with an organic polar solvent such as, for example, methanol, acetonitrile, aqueous mixtures thereof and the like and isolated by concentration under reduced pressure followed by lyophilization. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical characteristics such as solubility in polar solvents, but outside the salts are equivalent to their respective free acids for the purposes of the present invention.
Certain compounds of the present invention can exist in undissolved forms as well as dissolved forms, including hydrated forms. In general, the dissolved forms, including the hydrated forms, are equivalent to the undissolved forms and are intended to be understood within the scope of the present invention.
Certain compounds of the present invention possess one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all enantiomeric and epimeric forms as well as appropriate mixtures thereof.
The compounds of the present invention are highly selective and competitive antagonists of the NK3 receptor.
The compounds have been tested in the guinea pig medial habenula paradigm Central in vitro and the functional CHO cell assay of the human NK3 receptor.
TABLE I. NK3 Antagonist Activity Example: Human NK3 Receptor Hog Medial Habenula in Guinea (Ke, nM) CHO Cells (Ke, nM) 8 11 22 9 5.8 0.88 The protocols for these two in vitro assays are described below. For him Medial habenula assay of Guinea pigs, extracellular records of Medial habenula neurons of guinea pig in an in vitro brain slice preparation. The compounds were tested for the ability to block the increases induced by senktide in the rate of cauterization. The parallel changes to the right of the curve response to the dose of senktide without reduction at the maximum were taken as an indication of competitive antagonism. The constant equilibrium (Ke) values for antagonism were obtained from separate experiments and produced the actual Ke values illustrated in the final column. None of the compounds tested had any effect on the rhythms of Basal neuronal cauterization.
For the functional arrangement carried out on human NK3 receptors expressed in CHO cells, the protocol is as follows: CHO cells, up to passage 20, were harvested 1 to 2 days after the passage by means of trypsinization and centrifugation (2 minutes @ 100 m in a Beckman centrifuge) GPR), washed twice (1 minute @ 1.5 mark in a Beckman Microfuge) with Krebs-Hepes buffer without calcium (24.5 mm Hepes, 90 mm NaCl, 6 mm KCl, 2.5 mm NaH2PO4, 5 mm Pyruvate of Na, 5 mm of Na fumarate, 5 mm of glutamate of Na, 11.5 mm of glucose, 1 mm of MgCl2 and 2 mm of glutamine, pH 7.4) and resuspended in a final volume of 1 ml. The cells were loaded crude with 2.5 μm Fura-2AM for 1 hour at 37 ° C and washed by centrifugation (Beckman Microfuge as before) to remove excess dye. The loaded cells were then incubated at 21 ° C for 30 minutes before use to allow complete hydrolysis of Fura-2AM. The [CA2 +] levels were determined using a RF-5001-PC spectrofluorophotometer that measures fluorescence emission at 500 nm after excitation at 340/380 nm. The aliquots of the cells (~ 0.7 - 1 x 106 cells) were placed in a cuvette in total volume of 2 ml, the extracellular calcium was raised to 1.3 mm and a baseline was recorded before the addition of the agonists. When appropriate, the test compounds (2 μl) were added 5 minutes before the addition of the agonist. All compounds were dissolved in DMSO. Each run was calibrated by the addition of 20 μl of 10% SDS solution and 30 μl of 750 mm EGTA / Hepes (pH 8.0). The results were calculated as described by Grynkiewicz, et al., J. Biol. Chem., 260: 3440-3450 (1993).
The compounds of the invention were also evaluated in an NK3 receptor binding assay described below.
Ovarian cell membranes of Chinese hamsters were prepared on the day of use by thawing cells, diluting with culture medium and centrifuging at 1000 g for 4 minutes. The resulting pill was resuspended in assay buffer (50 mm of Tris, pH 7.4 containing 3 mm of MnCl2, 0.02% of BSA, 40 ug / 1 of bacitracin, 2 μg / ml of chymostatin, 2 μm of phosphoramidon and 4 μg. mL of leupeptin) and washed by centrifugation as above. The cells were then resuspended in assay buffer, they counted and adjusted the volume appropriately. The cell suspension was homogenized using a Brinkman polytron (mark 6, 3 x lOs) and the equivalent of 0.2-0.25 million cells were added per tube. For competition studies, the membranes are incubated with [I125] - [MePhe7] neurokinin B (40-100 pM) in the presence and absence of Test compounds for 90 minutes at 22 ° C. The tests were terminated by vacuum filtration using a Brandel harvester on pre-moistened GF / C filters with 0.1% PEI for at least 2 hours and the CPM link was determined using a counter range. In all cases, a specific bond was defined by 1 μm of senktide.
TABLE p. Link Data of the Human In Vitro NK3 Receptor Example Link IC5o of NK3 (nM) 1 52 2 258 3 40 4 102 5 18 6 61 7 43 8 16 9 7.8 10 91 11 30 12 15 13 12 14 74 15 114 16 94 17 982 The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, i.e., intravenous, intramuscular, intercutaneous, subcutaneous, intraduodenal or intraperitonally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be admixed transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active element, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, lozenges, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, bonds, preservatives, tablet disintegrating agents or an encapsulating material.
In the powders, the carrier is a finely divided solid that is in admixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in appropriate proportions and compacted in the desired shape and size.
The powders and tablets preferably contain from 5% or 10% up to about 70% of the active compound, the appropriate carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formula of the active compound with the encapsulating material as a carrier providing a capsule in which the active ingredient with or without other carriers is surrounded with the carrier, which is thus in relation thereto. Similarly, the pills are included. The tablets, powders, capsules, pills, pills and tablets can be used in solid dosage forms suitable for oral administration.
To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melts first and the active component disperses homogeneously therein, stirring. The homogenous melted mixture is then poured into molds of adequate size, allowed to cool and therefore solidify.
Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-glycol propylene solutions. Liquid preparations for parenteral injection can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e. natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, natural and artificial sweeteners, dispersants, thickeners, solubilizing agents and the like.
Preferably, the pharmaceutical preparation is in unit dosage form. In that form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The dosage form per unit can be a packaged preparation, the package contains discrete quantities of preparation, such as packed tablets, capsules and powders in vials or ampoules. Also, the dosage form per unit may also be a capsule, pill or tablet itself or it may have the appropriate number of any of these in packaged form.
The amount of the active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg conforms to the application and the particular potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use the highly selective and competitive receptor antagonists NK3, the compounds used in the pharmaceutical method of this invention are administered in the initial dose of about 0.01 mg to about 500 mg / kg daily. A daily dose ranging from about 0.01 mg to about 100 mg / kg is preferred. Doses, however, can be varied depending on the requirements of the patient, the severity of the condition being treated and the compound used. The determination of the appropriate dose for a particular situation is within the skills of the technique. Generally, treatment begins with doses smaller than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired. b Br (CH,) - CO "H Br (CH,), CO, CH, NC (CH,), CO-CH, H, N (CH,) 8CO, CH 3 + BOCNH (CH,)? CO, CH _.
BOCNH (CH,), CO, H - »• BOCNH (CH? 2) 'ft 8C * -O, NH BOCRaMePheNH (CH,) 8CONH a * RaMePheNH (CH:) ßCONH- Intermediary I Reagents and conditions: a) MeOH, TSOH b) NaCN, DMSO c) NH3: MeOH, Ra-Ni d) (BCO) 2O, DMAP, DMF e) i) LiOH H2O, THF, H2O; ii) 1NHC1 0 i) PFP, DCC, CH2C12; ii) NH3 (g) g) i) TFA, CH2CI; ii) BOC RaMePheCH, HBTU, DIPEA, DMF h) TFA, CH2CI SCHEME 2 Reagents and conditions: i) R = isopropyl, R * = H, = S, Et, N, THF, Intermediate II ii) R = isopropyl, R '= Cl, - =. iii) R = cyclopentyl, R '= H, - = SCHEME 3 1 Reagents and conditions: a) i) n = 1, NaH, CH3I, THF. -. il) n = 2, NaH, -CH3I, THF. b »i) n = 1, R = CH 3, 'NaBH 4, isopropanol. or n = 2, R = CH., NaBH 4, isopropanol. lii) n = 2, R =?, * NaBH < , isopropanol.
C) i) n, EtOAc - Intermediary v. íi) n, EtOAc - Intermediary vi ni) n 'EtOAc - Fel Intermediary, Schemes 1 to 3 above describe the synthesis of Intermediates required for the preparation of the final compounds as found in the Examples.
In Scheme 1, the Intermediate RaMePheNH (CH2) gCONH2 is prepared from readily available 8-bromooctanoic acid. The above is achieved by the conversion of the acid to the methyl ester followed by the displacement of the bromine by cyanide and the subsequent conversion to the amino using Raney nickel. The protection of the amino with a BOC group followed by the base hydrolysis of the ester produced the acid which was converted to the amide by coupling the active ester with ammonia. The lack of protection of the group BOC followed by coupling of the active ester with BOC RaMePheOH yielded the BOC-protected amide which in the deprotection produced Intermediate I, RaMePheNH (CH2) 8CONH2 Intermediary IVII.
Scheme 2 describes the synthesis of Intermediate II, III and IV carbonate prepared by the acylation of the substituted alcohols using rhenitrophenylchloroformate.
The synthesis of the conformationally restricted carbonates V, VI and VII are described in Scheme 3.
Intermediates V and VI were prepared by dimethylation of the ketone followed by reduction of sodium borohydride to alcohol. The acylation of the alcohol with p-nitrophenylchloroformate in the presence of a base then produced the carbonates. Intermediary VII was prepared in a similar manner from the ketone by reduction followed by acylation of the alcohol.
The synthesis of Examples 1 through 6 are described in Scheme 4. These were each prepared by stirring a solution of the Amine Intermediate I in DMF with DMAP and the appropriate carbonate.
SCHEME 4 RccMePheNH (CH2) -CONH, e PheNH (CH,) PCONH- Example 5 a) Intermediary II, DMAP, DMF b) Intermediary III, DMAP, DMF c) Intermediary IV, DMAP, DMF d) Intermediary V, DMAP, DMF e) Intermediary VI, DMAP, DMF f) Intermediary VII, DMAP, DMF SCHEME 5 Intermediary vin Reagents and conditions: a) Ethyl chloroformate, THF, 4-methylmorpholine, 2 M LiBFL, in THF b) Trifenilfosfina, Br2, DMF SCHEME 6 Intermediary IX Intermediary x Reagents and conditions: a) Triethylamine, 4-chlorobenzaldeido, MgSO4, DCM b) i) LHMDS, THF, 2-fluorobenzilbromide; ii) HCl, H2O c) i) LHMDS, THF, 2,3-difluorobenzylbromide; ii) HCl, H2O d) i) LHMDS, THF, 2-bromomethylbenzofuran; ii) HCl, H2O H, N (CH,) 3X (CH2) 3NH:. PhCH, OCONH (CH,) 3X (CH2) 3NH; X = CH, or O , C »H2N. { CH2) 3X (CH2) 3NHCONH, X = CH2 Intermediate XII X = O Intermediate XIII Reagents and conditions: a) Benzylchloroformate, Na2CO3, 1,4-dioxane, H2O b) Trimethylsilyl isocyanate, THF c) EtOH, Pearlman catalyst SCHEME 8 ONH; Isomer II ~ Isomer Z1 Example R = CH2Ph X = CH2 8 R = (2-f) PhCH2 X = CH. 9 R = (2,3 d? -f) EhCH2 X = CH2 11 R = (2,3 d? -f) PhCH2 X = O Reagents and conditions: a) 4-nitrophenylchloroformate, triethylamine, THF b) a-Me-Phe-OCH3 substituted, DMF c) Chromatographic resolution, 10% ether : heptane d) 1 M LiOH, THF e) HBTU, DIPEA, DMF, H2N (CH2) 3 x (CH2) 3NHCONH2 Scheme 5 describes the synthesis of the HIV intermediary by reduction and subsequent bromination of berzofuran-2 acid -carboxylic In Scheme 6, the synthesis of the Intermediates from LX to XI is underlined. The SchifF base of the Middle Intermediate is prepared from alanine methyl ester by the addition of 4-chlorobenzaldehyde under basic and anhydrous conditions. Alkylation of the SchifF base with 2-fluorobenzylbromide followed by acidic hydrolysis yielded Intermediary IX. Similarly, Intermediates X and XI were isolated by alkylation of the SchifF base with 2,3-difluorobenzylbromide and 2-bromoethylbenzofuran, respectively, followed by acidic hydrolysis.
The synthesis of Intermediaries XII and XIII are described in Scheme 7. These two Intermediates were prepared by initial monoprotection of the initial material of diamine with benzylchloroformate followed by the preparation of the urea of the deprotected amine using the isocyanate TMS with the subsequent removal of the benzyl protecting group under reductive conditions.
Scheme 8 underlines the general scheme for the preparation of Examples 7 through 11. The reaction of (S) _l-phenyl-2-methylpropan-1-ol with chloroformate under basic conditions produced the reactive carbonate intermediate. The above was then reacted with the various moieties aMePheOMe substituted with aryl in DMF to produce, in all cases, the urethane as a mixture of diastereomers. The mixture was separated and in each case the slow fraction was taken through the synthesis. The hydrolysis catalyzed as the base of the methyl ester, followed by the coupling to either Intermediary XII or XIII, produced Examples 7 through 11.
SCHEME 9 RS (R) a-MePhe-OH eOCH.
OCH, XIV XV Reagents and conditions: a) 4-nitrophenylchloroformate, Py, DCM b) SOCl2, MeOH c) Et3N, DMF Scheme 9 describes the synthesis and chromatographic resolution of the Intermediaries XIV and XV. The racemic 2-methyl-1-phenyl-1-propanol was converted to a p-nitrophenylcarbonate. The coupling promoted as case to (R) aMePheOCH3 produced the desired carbamates. (R) aMePheOCH3 is synthesized from acid by the use of thionyl chloride and methanol. 0 SCHEME 10 Ph "s .0C II (R) a-MePhe0CH3 XIV Ph s OC (R) a-MePheOH BOCNH (CH -), CO-H Ph s 0C (R) a-MePhe (S) Tyr0CH, B? CNH (CH2), OH Ph s OC (R) a-MePhe (S) TyrOH TFA'H.N. { CH -) -. OH (crude) XVI d Ph s 0C (R) a-MePhe (S) TyrNH (CH2) 60H Ph s OC (R) a-MePhe (S) TyrNH (CH-), 0H Example 12 Example 13 Reagents and conditions. a) LiOH, THF: H2O b) HBTU, DIPEA, (S) -TyrOCH3, DMF c) LiOH, THF: H2O d) HBTU, DIPEA, H2O (CH2) 6OH, DMF e) i) EtOCOCl, NMM, THF; ii) LiBFL, 0 TFA g) i) HBTU, DIPEA, DMF; ii) K2CO3, H2O, DMF In Scheme 10, Intermediate XIV was hydrolyzed under basic conditions to the carboxylic acid. Coupling to (S) -TyrOCH3 using the active ester methodology followed by catalyzed hydrolysis as a base yields Intermediate XVI.
Example 12 is produced by coupling Intermediate XVI to 6-amino-1-hexanol.
Example 13 is produced by coupling the active ester of Intermediate XVI and the amino salt derived from BOC NH (CH2) 6CO2H by reducing the carboxylic acid to the alcohol and removing the acid catalyzed from the BOC group.
SCHEME 11 Ph '~ oc (R) a-MePheOCH3 XV (R) a-MePheOH R Intermediate XVII Ph 'R -0C (R) to ~ Me? HeNH-Ph Example 14 Reagents and conditions: a) LiOH, THF: H2O b) DCCI, HBOT, (s) -a-methylbenzylamine, EtOAc c) HBTU, DIPEA, cumilamine, DMF d) HBTU, DIPEA, (R) -2-phenylglycinol, DMF In Scheme 11, Intermediary XV is hydrolyzed under basic conditions for produce the carboxylic acid that is coupled using the active ester methodology with (S) -a-methylbenzylamine, cummylamine and (R) -2-phenylglycinol to produce Examples 14, 15 and 16, respectively.
SCHEME BOC (R) a-MePheOH.
Reagents and conditions: a) DCCI, HOBT, (S) -a-methylbenzylamine, EtOAc b) TFA, DCM c) Et2O d) 4-nitrophenylchloroformate, Py, DCM e) DMAP, DMF Scheme 12 describes the preparation of Example 17 BOC (R) -a-MePhe-OH is converted to (S) -a-methylbenzylamine by coupling the active ester. The catalyzed acid removal of the BOC group produces the amino salt. Coupling promoted as a base to the carbonate derived from the product of the Grignard reaction between 4-fluorobenzaldehyde and magnesium isopropyl chloride yields Example 17.
The following non-limiting examples illustrate the methods for preparing the compounds of the invention.
SYNTHESIS OF THE INTERMEDIATE I -CO, H ". CO.CH Step 1 p-Toluenesulfonic acid (0.20 g, 0.53 mmol) was added to a solution of 8-bromoactanoic acid (35.15 g, 156 mmol) in MeOH (100 mL) and the mixture was heated to reflux for 2.5 hours. After cooling, the solvent was removed in vacuo and the residue was dissolved in Et2O (2250 ml) and washed with saturated NaHCO3 (2 x 100 ml) and once with pitch (100 ml). The Et2O layer was separated and dried over MgSO4 and the solvent was removed in vacuo to give the product as a yellow mobile liquid (37 g, 100%). This product was used directly without any other purification. Br (CH2) 8CO2CH3? -NC (CH?) 8C02CH3 Step 2 Sodium cyanide (8.10 g, 165 mmol) was added to a solution of bromine ester (37.3 g, 157 mmol) in DMSO (100 mL) and the mixture was heated at 90 ° C for 2 hours. The mixture was allowed to cool and the solid was broken and poured into water (600 ml) containing saturated NaHCO3 (50 ml). The solution was extracted and the combined extracts were washed with water and pitch. The Et2O was dried over MgSO, filtered and the solvent removed in vacuo to give the product as a pale orange liquid (26.9 g, 93%). IR (film: 2936, 2860, 2246, 1739, 1437, 1363, 1199, 1101 and 1017 cm "1 .s MR (CDCl3): 1.30-1.68 (10H, m, 5CH2), 2.29-2.36 (4H, m, 2CÜ2) and 3.67 (3H, s, CCOCH).
NC (CH2) 8C02CH3 ?? 2N (CH2) 8C02CH3 Step 3 The cyano ester (14.56 g, 79.45 mmol) was dissolved in 5% NH3 MeOH (100 mL) and hydrogenated over Ra-Ni (25 mL) at 50 psi and 30 ° C for 6 hours. The catalyst was filtered and the solids washed well with methanol. The solvent was removed in vacuo to give the product as a solid as wax (13.80 g, 93%). This product was used without any other purification.
H2N (CH2) 8C02CH3-BOCNH (CH2) 8CO2CH3 Step 4 A solution of di-tert-butyldicarbonate (17.69 g, 81.1 mmol) in DMF (50 mL) was added dropwise over 10 minutes to a stirred solution of the amino ester (13.80 g, 73.7 mmol) and DMAP (0.53 g, 4.34 mmol) in DMF (100 ml). The mixture was stirred for 1 hour at room temperature and then the solvent was removed in vacuo. The residue was dissolved in Et2O and washed with water. The aqueous solution was extracted once more with Et2O and the extracts combined with Et2O were washed once with 10% citric acid, once with water and once with pitch. The Et 2 O solution was dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 33% EtOAc: 67% n-hexane as eluent gave the product as a gum (8.82 g, 42%). IR (Movie: 3378, 2976, 2931, 2857, 1740, 1716, 1520, 1366, 1250 and 1174 crn-1 .s MR (CDC13): 1.30-1.63 (21H, m, (CH ^ C, 6CH2), 2.30 (2H, t, J = 7.6Hz, CH2CO2CH, 3.07-3.13 (2H, m, NHCH2), 3.67 (3H, s, COzCH,) and 4.55 (1H, b, OCONH).
BOCNH (CH2) 8C02CH3- * BOCNH (CH2) 8C02H Step 5 LiOH "H 2 O (3.78 g, 90 mmol) was added to a stirred solution of the ester (7.14 g, 24.7 mmol) in THF: H 2 O (50 ml, mixture at 4 ° C). : 1) and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue in water and washed with Et2O. the aqueous layer was separated and brought to pH 2 with citric acid solution and extracted with EtOAc (x2). The combined extracts were washed with water and pitch, dried over MgSO 4, filtered and the solvent removed in vacuo. The above produced the product as an oil that crystallized to a solid such as wax upon cooling (6.72 g, 99%). s MR (DMSO-d6): 1.19-1.45 (21H, m, (CH ^ C, 6CH2), 2.14 (2H, t, J = 7.2 Hz, CH2COOH), 2.81-2.86 (2H, m, NHCH2), 6.69 (1H, b, OCONH) and 11.90 (1H, s, COOH).
BOCNH (CH2) 8C02H? > BOCNH (CH2) 8CONH2 Step 6 Pentafluorophenol (0.502 g, 2.73 mmol) and N, N1-dicyclohexylcarbodiimide (0.564 g, 2.74 mmol) were added to a stirred solution of the acid (0.789 g, 2.89 mmol) in CH2Cl2 (6 mL). The mixture was stirred for 2 hours at room temperature and the N, N'-dicyclohexyl urea was filtered. Ammonia gas was bubbled through the solution in CHC13. The CHCl3 solution was washed with K2CO3 and the aqueous layer was separated and re-extracted with CHC13. The combined extracts were washed once with K2CO3 solution and once with pitch, dried over MgSO4, filtered and the solvent removed in vacuo to give the product as a white solid (0.516 g, 69%). IR (film): 3363, 2924, 2850, 1684, 1651, 1633, 1525, 1471, 1411, 1365, 1318 and 1251 cm-1. s NMR (CDC13): 1.31-1.65 (12H,, or Cífc), 1.44 (9H, s, (C ^ C), 2.22 (2H, t, J = 7.6 Hz, CH2CONH2), 3.09-3.11 (2H, m, CH 4 NHCOO), 4.51 (1H, b, OCONH), 5.37 (1H, b, CONHH) and 5.48 (1H, b, CONHH).
BOCNH (CH2) 8CONH2? > TFA »H2N (CH2) 8CONH2 Step 7 The amide (5.63 g, 20.6 mmol) was dissolved in TFA: CH2C1 (40 mL, 1: 1 mixture) and stirred for 2 hours at room temperature. The solvent was removed in vacuo to give the product as a gum which was used without further purification.
ONH (CH2) eCONH. HBTU (7.83 g, 20.65 mmol) was added to a stirred solution of the acid (5.77 g, . 60 mmol) in anhydrous DMF (30 ml) at 0 ° C. Diisopropylethylamine (7.17 ml, 41. 2 mmol) in drops and the mixture was stirred for 20 minutes at 0 ° C. The foregoing was followed by a solution of the salt TFA aminoamide (5.9 g, 20.6 mmol) and diisopropylethylamine (7.17 ml, 41.2 mmol) in DMF (30 ml) was added dropwise for 30 minutes and at 0 ° C. The cold mixture was stirred with slow reheating at room temperature for 2.5 hours and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with 10% citric acid solution (x2), saturated NaHCO3 solution (x2) and once with pitch. He EtOAc was dried over MgSO, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 5% MeOH: 95% CH2Cl2 as eluent gave the product as a white solid (4.11 g, 46%). IR (film): 3332, 3225, 2929, 2856, 1712, 1653, 1542, 1495, 1366, 1250, 1165 and 1077 cm "1 .s NMR (CDC13): 1.31-1.66 (15H, m, aCHj, 6CH2) , 1.47 (9H, s, 2.22 (2H, t, J = 7.2 Hz, CH2CONH2), 3.07 (1H, d, J = 13.6 Hz, PhCHH), 3.21-3.27 (2H, m, CONHCH2), 3.38 (1H, d, J = 13.6 Hz, PhCHH), 4.79 (1H, s, OCONH), 5.30 (1H, b, CONHH), 5.55 (1H, b, CONHH), 6.32 (1H, b, CONHCH2), 7.12-7.15 ( 2H, m, aromatic) and 7.23-7.31 (3H, m, aromatic).
(CH2) eCONH_ Step 9 Protected aminoamide (4.08 g, 9.41 mmol) was dissolved in a mixture of TFA (10 mL) and CH2Cl2 (10 mL) and stirred for 1 hour at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with K2CO3 solution (2 x 50 mL). The aqueous solution was re-extracted with EtOAc (2 x 50 mL) and the combined EtOAc extracts were washed with water 850 mL) and pitch (50 mL). The EtOAc was dried over MgSO, filtered and the solvent removed in vacuo to yield the product as a white solid (3.27 g, 100%), melting point 81-82 ° C. [a] 20D + 60.8 ° (C = 1.0, CHC13). IR (Film): 3352, 3195, 2928, 2855, 1652, 1524, 1454, 1406 and 1125 cm "1 .s NMR (CDCl3): 1.22-1.43 (10H, m, 5CH2), 1.62-1.65 (2H, m , CONHCH2CH2), 2.22 (2H, t, j = 8.0 Hz, CH2CONH2), 2.62 (1H, d, j = 13.2 Hz, PhCHH), 5.53 (1H, b, CONHH), 5.65 (1H, b, CONHH), 7.16-7.28 (5H, m, C6H5) and 7.47 (1H, b, CONHCH2) Analysis calculated for Ci9H3? N3? 2? «0.15 H2O: C, 67.88; H, 9.38; N, 12.50 Found: C, 67.86; H, 9.30; N, 12.41.
SYNTHESIS OF EXAMPLE 1 Carbamic acid. f 2 I and 9-amino-9-oxononyl-1-methyl-2-oxo-1 - (phenylmethyl) -. 2 - methyl - 1 - phenylpropyl ester TR - (R *. S *? 1 - Step 1 A solution of triethylamine (0.550 mL, 4.0 moles) in anhydrous THF (10 mL) is added dropwise for 10 minutes to a stirred solution of p-nitrophenyl-chloroformate. (0.671 g, 3.33 moles) and S - (-) - 2-methyl-1-phenyl-1-propanol (0.500 g, 3.33 moles) in Anhydrous THF (10 mL) is cooled to 5 ° C. The cooled solution is stirred with slow heating to room temperature for 48 hours and then Et2O (100 mL) is added.
The mixture is washed with a solution of 5% citric acid (2 x 25 mL) and once with saline (25 triL). The Et 2 O solution is dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using Et2Ü at % and 90% n - hexane as eluent, gives the product with a consistency like rubber. (0.335 g, 32%). IR (film): 3362, 1764, 1526, 1254 and 1218 crn "'. D NMR (CDC13): 0.85 (3H, D, J = 6.8 Hz, CHjCHCHs), 1.9 (3H, d, J = 6.8 Hz CHsCHCü, ), 2.22 - 2.27 (1H, m, CH3CHCH3), 5.38 (1H, d, J = 7.6 Hz, PhCH), 7.26 - 7.41 (7H, m, aromatic) and 8.24 (2H, d, J = 9.2 Hz, aromatic ) Analysis calculated for CpHpNOs: C, 64.75; H, 5.44; N, 4.44: Found: C, 64.89; H, 5.46; N, 4.39.
Step 2 CH, DMAP (0.010 g, 0.08 mole) is added to a solution of the amine salt (0.117 g, 0.262 mole) (Intermediate I), carbonate (0.091 g, 0.288 mole) (Intermediate II) and triethylamine (0.040 mL) , 0.288 moles) in anhydrous DMF (5 mL) at room temperature. The solution is stirred at room temperature for 30 hours and then diluted with EtOAc (50 mL). The EtOAc solution is washed with a 10% citric acid solution (2 x 25 mL), a 10% K2CO3 solution (4 x 25 mL), a 10% citric acid solution (25 mL) and a once with saline (25 mL). The EtOAc is dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using EtOAc as eluent gives the product as a foam (0.013 g, 10%). IR (film): 3338, 3211, 2929, 2855, 1712, 1655, 1495 and 1079 cm "\ d NMR (CDCI3): 0.80 (3H, d, J = 6.8 Hz, CH3CHCH), 0.98 (3H, d, J = 6.6 Hz, CH3CHCH3), 1.24 - 1.46 (10H, m, 5CH2), 1.42 (3H, s, CH3), 1.60 - 1.76 (2H, m, CH ^), 2.04 - 2.12 (1H, m, CH3CHCH3), 2.22 (2H, t, J = 7.3 Hz, CH2CONH2), 3.09 (1H, d, J = 13.7 Hz, PhCHH), 3.14 - 3.25 (2H, m, CONHCH2), 3.32 (1H, d, J = 13.9 Hz, PhCHH), 5.16 (1H, b, OCONH), 5.39 (1H, b, CONHH), 5.39 (lH, "d, J = 7.8 Hz, PhCH (0) CH), 5.55 (1H, b, CONHH), 6.22 (1H, b, CONHCH2), 6.94-6.95 (2H, m, Ph) and 7.14-7.38 (8H, m, Ph). HPLC: 93.3% pure.
SYNTHESIS OF EXAMPLE 2 Carbamic acid. \ 2 [(9-amino-9-oxononiDaminol-1-methyl-2-oxo-1 (phenylmethyl) ethyp -. 1 - (4-chlorophenyl) -2-methylpropyl ester.
Step 1 Isopropyl magnesium chloride (6.0 mL, 2.0 mL of Et2? Solution, 12 moles) is added dropwise over 5 minutes to a stirred solution of the aldehyde (1.24 g, 8.82 moles) in anhydrous Et? O (25 mL) and it is cooled to 5 ° C. The mixture is stirred for 20 minutes at 5 ° C. and then at room temperature for 40 minutes. INN HCl (25 mL) is added and the Et2 layer is separated? (2 x 25 mL) and the combined Et? O extracts are dried over MgSO, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 30% Et ?O: and 70% n-hexane as eluent to give the product as a gum (1.19 g, 73%). IR (film): 3384, 2961, 2873, 1490, 1090 and 1014 cm "1. d NMR (CDC13): 0.80 (3H, d, J = 6.8 Hz, CHsCHCH ^, 0.97 (3H, d, J = 6.4 Hz , CH3CHCH3), 1.86 (1H, s, OH), 1.88 - 1.96 (1H, m, CH3CHCH3), 4.35 - 4.37 (1H, m, PhCHOH) and 7.23 - 7.32 (4H, m, p_C¡C6H4). for doH 3 ClO: C, 65.04; H, 7.10 Found: C, 64.75; H, 7.11.
Step 2 A solution of triethylamine (0.83 mL, 5.95 moles) in anhydrous TFH is added dropwise over 20 minutes to a stirred solution of alcohol (1.Og, 5.41 moles) and p-nitrophenylchloroformate (1.09 g, 5.41 moles) in anhydrous THF. (20 mL) and cooled to 5 ° C. The mixture is stirred with slow reheating to room temperature for 48 hours and then Et2O (100 mL) is added. The solution is washed with 5% citric acid (2 x mL) and once with saline (25 mL). The Et 2 O solution is dried over MgSO, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 10% Et2O: 90% n-hexane as eluent gives the product as a gum (0.972 g, 51% IR (film): 3356, 2968, 1764, 1526, 1492, 1347, 1254 and 1218 cm "1. d NMR (CDC13): 0.85 (3H, d, J = 6.8 HCjCHCHj), 1.09 (3H, d, J = 6.4 HC3CHCH3), 2.18 - 2.24 (1H, m, CH3CHCH3, 5.33 (1H, d, J = 8.0 Hz, PhCHO), 7.26 - 7.38 (6H,, aromatic) and 8.25 (2H, d, J = 8.8 Hz, aromatic) Analysis calculated for CpHißCINOs: C, 58.38; H, 4.61; N, 4.01; Cl, 10.14 Found: C, 58.67; H, 4.70; N, Step 3 DMAP (0.010 g, 0.08 mole) to a stirred solution of the amine salt (0.156 g, 0.349 mole) (Intermediate I), carbonate (0.134 g, 0.384 mole) (Intermediate III), and triethylamine (0.054 mL) , 0.384 moles) in anhydrous DMF (5 mL) at room temperature. The solution is stirred for 24 hours and then diluted with EtOAc (50 mL). The EtOAc solution is washed with 5% citric acid (2 x 25 mL), K2CO3 (4 x 25 mL), 5% citric acid (25 mL) and once with saline (25 L). The EtOAc is dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using EtOAc as eluent gives the product as a foam (0.037g, 20%). IR (film): 3338, 3208, 2930, 2856, 1716, 1654, 1492, 1077 and 733 cm "1 .d NMR (CDC13): 0.79 - 0.81 (3H, m, CHCHCH3), 0.95 - 0.99 (3H, m , CHsCHCHj), 1.19 - 1.48 (12H, m, 6CH2), 1.44 and 1.48 (3H, 2s, CHj), 1.59 - 1.67 (2H, m, CH2), 2.00 - 2.08 (1H, m, CH3CHCH3), 2.21 ( 2H, t, J = 7.6 Hz, CH2CONH2), 3.10 - 3.31 (4H, m, CONHCH2, PhCHj), 5.32 - 5.36 (1H, m, pClCeHtCHO), 5.42 (1H, b, OCONH), 5.50 (1H, b, CONHH), . 59 (1H, b, CONHH), 6.08 and 6.19 (1H, 2bs, CONH), 6.95-6.99 (2H, m, aromatic) and 7. 16-7.34 (7H, m, aromatic). HPLC: 97.8%. Analysis calculated for C ^ H ^ CIN ^ • 0.25 H2O: C, 65.67; H, 7.81; N, 7.66; Cl, 6.46. Found: C, 65.46; H, 7.64; N, 7.52; Cl, 6.76.
SYNTHESIS OF EXAMPLE 3 [1- (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl-carbamic acid cyclopentyl-phenyl-methyl ester.
Step 1 A solution of triethylamine (1.67 mL, 12 moles) in anhydrous THF (10 mL) is d dropwise over 10 minutes to a stirred solution of alcohol (1.76 g, 10 moles) and p-nitrophenylchloroformate (2.02 g, 10 moles). in anhydrous THF (25 mL) is cooled to 5 ° C. The cooled mixture is stirred with slow heating for 24 hours and then Et? O is d. The mixture is washed with a solution of 5% citric acid (2 x 25 mL), saturated NaHCO3 (25 mL) and once with saline (25 mL). The Et2 solution? Dry over MgSO, filter and remove the solvent in vacuo. Purification of the residue by chromatography on silica using 10% Et2O: 90% n.hexane as eluent gives the product as a gum (2.03 g, 60%). IR (film): 2957, 2870, 1763, 1525 and 1215 cm "1. d NMR (CDC13): 1.12 - 1.25 (1H, m, cyclopentyl), 1.40 - 4.72 (6H, m, cyclopentyl), 1.91 - 1.99 ( 1H, m, cyclopentyl), 2.43-2.57 (1H, m, cyclopentyl) 5.44 (1H, d, J = 9.3 Hz, CHOCO), 7.30-7.41 (7H, m, aromatic) and 8.23 (1H, d, J = 9.2 Hz, aromatic) Analysis calculated for C19H19NO5: C, 66.85, H. 5.61; Found: C, 66.95; H, 5.61; Step 2 DMAP (0.055 g, 0.450 moles) to a stirred solution of aminoamide (0.50 g, 0.150 moles) (Intermediate I) and carbonate (0.154 g, 0.450 moles) in anhydrous DMF (1 mL) at room temperature . The solution is stirred at room temperature for 48 hours and then diluted with EtOAc (50 mL). The EtOAc solution is washed with a solution of citric acid (2 x 25 L) at 10%, a solution of 10% K2CO3 (4 x 25 mL) and once with saline (25 mL). The EtOAc is dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 50% EtOAc: and 50% n-hexane as eluent gives the product as a white solid (0.048 g, 60%), m.p. 45 - 50 ° C. IR (film): 339, 3209, 3063, 3031, 2932, 2858, 1711, 1655, 1488, 1078 and 733 cm "'.d NMR (CDC13): 1.10 - 1.83 (20H, m, 6CH2, cyclopentyl), 1.39 and 1.45 (3H, 2s, CHj), 2.21 (2H, t, J = 7.6 HZCH2CONH2), 2.32 - 2.37 (1H, m, cyclopentylCH), 3.06 - 3.35 (4H, m, PhCH2, CONHCH2J, 5.12 and 5.26 (1H, 2bs, OCONH), 5.42 - 5.46 (1H,, PhCHOCO), 5.52 (1H, b, CONHH), 6.11 and 6.27 (1H, 2bs, CONHCH2), 6.93 - 7.00 (2H, m, aromatic) and 7.14 - 7.38 (8H, m, aromatic). HPLC: 100% pure. Analysis calculated for C32H-j5N3O • 0.25 H2O: C, 71.14; H, 8.49; N, 7.78. Found: C, 70.78; H, 8.39; N, 7.53.
SYNTHESIS OF EXAMPLE 4 [1- (8-carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl-carbamic acid 2. 2-dimethyl-1.2.3.4-tetrahydronaphthalen-1-yl ester.
Step 1 Add to - Tetralone (0.66 g, 5.0 moles) in anhydrous THF (2 mL) to a suspension of sodium hydride (0.40 g, &0% dispersion in mineral oil, 10 moles) in anhydrous THF (20 g). mL) under an atmosphere of N2 at room temperature. To this mixture is added methyl iodide (0.62, 10 moles) and the mixture is heated at reflux for 5 hours. After cooling, EtOAc (2 mL) is added carefully and then the solvent is removed in vacuo. The residue is taken up in EtOAc (60 mL) and washed with water (3 x 50 mL), the EtOAc extract is dried over MgSO, filtered and the solvent is removed in vacuo. Purification of the residue by chromatography on silica using n-hexane and then 2% EtOAc: 98% n-hexane as eluent gives the product as a colorless oil (0.57g, 65%). IR (film): 2963, 2927, 1684 and 1603 cm "'. D NMR (CDC13): 1.22 (6H, s, 20 !,), 1.99 (2H, t, J = 6.0 Hz, CH2), 2.99 (2H , t, J = 6.4 Hz, CH2) and 7.20 - 8.04 (4H, m, aromatic).
Step 2 Sodium borohydride (0.056 g, 1.50 mol) is added in portions to a stirred ketone solution (0.54 g, 3.1 mol) in anhydrous MeOH (12 mL) at 0 ° C. After stirring for 30 minutes an additional portion of sodium borohydride (0.050 g, 1.3 moles) is added and the mixture is stirred at room temperature. 2 N HCl (4 mL) is added dropwise and the solvent is removed in vacuo. 2 N HCl (30 mL) is added to the residue and the mixture is extracted with EtOAc (3 x 60 mL). The combined EtOAc extracts are dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 20% Et2 ?: 80% n-hexane as eluent gives the product as a colorless oil (0.26 g, 48%). d NMR (CDC13): 0.99 (3H, s, CHj), 1.01 (3H, s, CÜ), 1.50 - 1.60 (1H, m, CHH), 1.80 (1H, m, CHH), 2.72 - 2.90 (2H, m, CH2), 4.27 (1H, s, CHOH) and 7.08-7.50 (4H, m, aromatic). m + 159 (100%), 177 (m + 1). 0 Step 3 A solution of p-nitrophenylchloroformate (0.286 g, 1.42 mol) in EtOAc (3 mL) is added dropwise at room temperature over a stirred solution of alcohol (0.25 g, 1.42 mol) and pyridine (0.115 mL, 1.42 mol). moles) in EtOAc (12 mL). After stirring for 18 hours, the mixture is filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 10% Et 2 O: 90% n-hexane as eluent to give the product (Intermediate V) as a yellow oil (0.085 g, 18%). d NMR (CDC13): 0.99 (3H, s, C &), 1.15 (3H, s, CH3), 1.52 - 164 (1H, m, CÜ), 1.95 -2.04 (1H, .15 - 7.40 (6H, m , aromatic) Step 4 Add DMAP (0.027 g, 0.225 moles) to a stirred solution of the aminoamide (0.075g, 0.225 moles) (Intermediate I) and carbonate (0.073g, 0.225 moles) (Intermediary V) in anhydrous DMF (5 mL) at room temperature. The mixture is stirred at room temperature for 10 days and then diluted with EtOAc (50 mL). The EtOAc solution is washed with 2N HCl (2 x 30 mL) and a 10% solution of NaCO3 (4 x 50 mL), the EtOAc is dried over MgSO, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 40% EtOAc: 60% n-hexane, EtOAc and then 5% MeOH: 95% EtOAc as eluent gives the product as a white solid (0.015 g, 12%). IR (film): 3339, 2926, 1708, and 1653 cm "'. D NMR (CDC13): 0.94 - 1.94 (23H, m, 2CH3, aCiFc, or CHz, CHjC (CH3) 2), 2.22 (2H, t, J = 8Hz, CH2CONH2), 2.75 - 3.45 (6H, m, CH2Ph, CH ^ Ph, NHCü), 5.00 and 5.03 (1H, 2s, OCONH), 5.25 and 5.50 (1H, 2bs, CONHH), 5.60 (1H, s , CHOCO), 6.18 and 6.25 (1H, 2bs, CONHH) and 7.00-7.40 (10H, m, CONHCH2, aromatic) HPLC: 97% pure, m + 536 (m + 1), 447, 334.
SYNTHESIS OF EXAMPLE 5 [1- (8-carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 6.7.8.9-tetrahydro-5H-benzocyclohepten-5-yl ester.
Step 1 Sodium borohydride (0.594 g, 15.71 mol) is added in portions over 10 minutes to a stirred solution of 1-benzosuberone (1,007 g, 6.29 mol) in isopropanol (25 mL) and cooled to 5 ° C. The cooled mixture is stirred with slow heating at room temperature for 2.5 hours. The solution is again cooled to 5 ° C and IN of HCl (50 mL) is added dropwise for 1 hour. The isopropanol is evaporated and the residual mixture is extracted with EtOAc (3 x 50 mL). The combined extracts are dried over MgSO, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 75% n-hexane: 25% EtOAc as eluent, gives the product as a white solid (0.84 g, 82%), mp 98-100 ° C. IR (film): 3189, 2924, 2847, 1446, 1044, 759 and 733 cm "'. D NMR (CDC13): 1.44 - 2.09 (7H, m, 3CH2, OH), 2.68 - 2.75 (1H, m, PhCHHCH2 ), 2.93 (1H, dd, J = 14.2 Hz, 8.3 Hz, PhCHHCH2), 4.94 (1H, d, J = 7.6 Hz, CHOH), 7.08 - 7.23 (3H, m, aromatic) and 7.44 (1H, d, J = 7.3 Hz, aromatic) Analysis calculated for CpH? O: C, 81.44; H, 8.70.
Step 2 A solution of pyridine (0.299 mL, 3.70 mol) in EtOAc (10 mL) is added dropwise over 45 minutes to a stirred solution of the alcohol (0.50 g, 3.08 mol) and p-nitrophenylchloroformate (0.745 g, 3.70 mol) in EtOAc (10 mL) cooled to 5 ° C. The cooled mixture is stirred with slow heating to room temperature for two hours and then ed with 10% citric acid (2 x 20 mL) and once with saline. (20 mL). The EtOAc is dried over MgSO 4, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using 10% Et2O: 90% n -hexane as eluent to give the product (Intermediate VII) as a white solid (0.583 g, 58%), mp 78-82 ° C. IR (film): 3387, 2931, 2855, 1762, 1616, 1594, 1523, 1492, 1346, 1260, 1212 and 859 cm - i d NMR (CDC13): 1.68-174 (2H, m, CH2), 1.86-2.19 (4H, m, 2CH2), 2.73-2.80 (1H, m, PhCHH), 3.01-3.08 (1H, m, PhCHH), 5.90 (1H, d, J = 8.5 Hz, PhCHOCO), 7.14 - 7.26 (3H, m, aromatic), 7.32-7.40 (3H, m, aromatic) and 8.27 (2H, d, J = 9.0 Hz, aromatic). Analysis calculated for C, 66.05; H, 5.24; N, 4.28. It Ph CONH (CH.) FCONH.
Step 3 Add DMAP (0.028 g, 0.229 mol) to a stirred solution of carbonate (0.225 g, 0.687 mol) (Intermediate VII) and aminoamide (0.076 g, 0.229 mol) (Intermediate I) in anhydrous DMF (2 L) a temperature of the room. The solution is stirred at room temperature for 4 days and then diluted with EtOAc (50 mL). The EtOAc solution is ed with 10% citric acid (25 mL), 10% K2CO3 (6 x 25 mL) and once with saline (25 mL). The EtOAc is dried over MgSO 2, filtered and the solvent removed in vacuo. Purification of the residue by chromatography on silica using EtOAc as eluent gives the product as a white foam (0.073 g, 61%), mp 57-64 ° C. GO (film): 3338, 2928, 2855, 1708, 1655, 1489, 1453, 1262, 1078 and 733 cm "1. d NMR (CDC13): 1.25 - 2.05 (18H, m, 9CH2), 1.46 and 1.52 (3H, 2s, CHs), 2.21 (2H, t, J = 7. 3 Hz, CH2CONH2), 2.72 - 2.78 (1H.m. PhCHH), 2.91 - 2.96 (1H, m, PhCHH), 3.11 -3.38 (4H, m, CONHCH2, PhCHj), 5.22 (1H, b, OCONH =, 5.34 (1H, b, CONHH), 5.51 (1H, b, CONHH), 5.88 - 5.90 (1H, m, PhCHO), 6.14 and 6.22 (1H, 2bs, CONHCH2) and 7.01 - 7.32 (9H, m, aromatic). HPLC: 100% pure. Analysis calculated for C31H43N3O4 • 0.25 H2O: C, 70.76; H, 8.33; N, 7.99. Found: C, 70.55; H, 8.23; N, 7.84.
SYNTHESIS OF EXAMPLE 6 [1- (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethylcarbamic acid 6.6 -dimethyl-6.7.8.9-tetrahydro-5H-benzocyclohepten-5-yl ester Pyridine is added dropwise (0.203 mL, 2.52 mol) in ethyl acetate (25 mL) for 1.5 hours to a solution of alcohol (0.400 g, 2.10 mol) and p-nitrophenylchloroformate (0.509 g, 2.52 mol) in ethyl acetate (25 mL). ) cooled in a bath of ice water. The mixture is slowly heated to room temperature and stirred for 24 hours. Additional p-nitrophenylchloroformate (0.25 mg, 1.26 mol) is added and stirred continuously for 20 hours.
The reaction mixture is washed with IN of HCl (2 x 25 mL) and saline (25 mL). Dry (MgSO4) and further purification by chromatography on silica, elute with 10% diethyl ether: n.heptane separates the carbonate (0.310 g, 42%) as a white solid. IR (film): 2959, 2931, 2860, 1764, 1525, 1347 and 1554 cm "1. 1H NMR (CDC13): d 0.84 (3H, s, CH) 1.09 (3H, s, CH3), 1.55 - 1.80 (3H, m, CHz, CH2CH), 2.02 - 2.15 (1H, m, CH2CH), 2.63-2.70 (1H, m, ArCHH), 3.04 - 3.13 (1H, m, ArCHH), 5.45 (1H, s, PhCHOCO) ), 7.11 - 7.25 (4H, m, Ar), 7.34 (2H, d, J = 9.2 Hz, Ar) and 8.24 (2H, d, J = 9.2 Hz, Ar), m + 227, 185, 174, 173 and 117. Analysis calculated for C20H20NO5: C, 67.78; H, 5.69; N, 3.95, Found: C, 67.67; H, 5.96; N, 3.93.
Step 2 Add DMAP (0.026 g, 0.22 moles) to a stirred solution of aminoamide (0.072 g, 0.22 moles (Intermediate I) and carbonate (0.151 g, 0.43 moles) (Intermediate VI) in anhydrous DMF (2 mL) and stir at room temperature for 2 days.
The reaction mixture is diluted with ethyl acetate (50 mL) and washed with a solution of 10% potassium carbonate (5 x 25 mL) and saline (25 mL). It is dried (MgSO4) and a larger purification by column chromatography on silica, eluting with 50% ethyl acetate: 50% n-heptane and then ethyl acetate and separating the product (0.038 g, 31%). IR (film): 3326, 2929, 2856, 1712, 1652, 1487, 1261 and 1098 cm "1. • NMR (CDC13): d 0.81 (3H, s, CH3), 0.97 (3H, s, CH3), 1.24 - 1.67 (18H, m, 6CH2, CHHCH2, CH2CH2, CH3), 1.92-1.98 (1H m, CHHCH2) 2.22 (2H, t, J = 7.3 Hz, CH2CONH2), 2.62-2.65 (1H, m, PhCHH), 2.94-2.97 (1H, m, PhCHH ), 3.09 (1H, d, J = 13. 7 Hz, PhCHH), 3.18 - 3.25 (2H, m, CONHCHj), 3.34 (1H, d, J = 13.7 Hz, PhCHH), . 08 and 5.27 (1H, 2s, OCONH), 5.27 (1H, b, CONHH), 5.50 (1H, b, CONHH), 5.50 (1H, s, PhCHOCO), 6.01 and 6.23 (1H, 2s, CONHCH2), 6.88-6.96 (2H, m, Ar) and 7.06 - 7.28 (7H, m, Ar). HPLC: 100%. Analysis calculated for C33H 7N3O • 0.4 H2O: C, 71.16; H, 8.65; N, 7.55. Found: C, 71.32; H, 8.65; N, 7.47.
EXAMPLE 7 f 1-Methyl-2-phenyl-1 - (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester (CH.) -NHCONH, Pasp. H ?N (CH2) 7NH; ^ PhCH, OCONH (CH;), NH " The 1,7-heptanediamine (2.1 1 g, 16.2 moles) is dissolved in 1,4-dioxane (2L). Water (200 mL) and Na2CO3 • 10 H2O (6.96 g, 24.3 mol) are added to this solution. The solution is cooled in an ice bath and benzylchloroformate (2.3 mL, 16.1 moles) in 1,4-dioxane (100 mL) is added dropwise over 6.5 hours. The resulting cold mixture is stirred with slow heating at room temperature for 17 hours. The 1,4-dioxane is removed in vacuo and the residue is dissolved in EtOAc (200 mL). The organic part is washed with saline (3 x 50 mL), then dried over MgSO. Upon removal of the solvent in vacuo, a solid results (3.88 g, 91%). IR (film): 3347, 2928, 2855, 1687, 1652, 1532 and 1254 cm-1.
Step 2 PhCH2? CONH (CH2) 7NHCONH2 - PhCH2OCONH (CH2) 7NHCONH2 A solution of trimethylsilylisocyanate (2.2 mL, 16.2 moles) in anhydrous THF (50 mL) is added dropwise over an hour to a stirred solution of the amine (3.88 g). , 14.7 moles) in anhydrous THF (50 mL). The resulting mixture is stirred for 18 hours and the solvent is then removed in vacuo.
The residue is dissolved in EtOAc (100 mL) and washed with saline (2 x 50 mL), then dried over MgSO 4. The solvent is removed in vacuo and the residue recrystallized from EtOAc to give a white solid 350 mg (8%). IR (film): 3414, 3328, 2921, 2825, 1686, 1647, 1602, 1532, 1454, 1249 and 732 cm "l.
NMR (CDC13): 1.17 - 1.39 (10H, m, 5 x CH2), 2.90 - 3.00 (4H, m, 2 x CH2), 5.00 (2H, s, PhCüO), 5.32 (2H, s, CONH? 5.87 (1H, b, OCONH), 7.22 (lHn br, NHCONH2), and 7.29 - 7.38 (5H, m, C6H5).
Step 3 PhCH2OCONH (CH2) 7NHCONH2? H2N (CH2) 7NHCONH Urea (343 mg, 1.1 mol) is hydrogenated in EtOH (75 mL) on Pearlman catalyst (34 mg) at 45 psi H and 30 ° C. for 18 hours. The catalyst is removed by filtration and the solvent removed in vacuo to give a white solid (163 mg, 83%).
IR (film): 3339, 2930, 2857, 1649, 1567, 1489 and 1344 cm'1. NMR (CDC13): 1.25 - 1.39 (10H, m, CH2 x 5), 2.55 - 2.58 (2H, m, CH? NHA 2.90 - 2.95 (2H, m, CH2NHCONH2), 5.35 (2H, s, NHCONHA and 5.93 (1H, br, CH2NHCONH2).
The acid, (prepared from example 12, step 1) (50 mg, 0.14 moles), HBTU (53 mg, 0.14 moles) and DIPEA (68 μL, 0.28 moles) is dissolved in DMF (3 mL) and the solution is stirred for 20 minutes. The amine (25 mg, 0.14 mol) is added and stirred continuously for 4 hours. The solvent is removed in vacuo and the residue is taken up in EtOAc (40 mL). The solution is washed with 2M HCl (2 x 30 mL) 10% aqueous Na2CO3 (2 x 30 mL), saline (30 mL) and dried over MgSO4. The solvent is removed in vacuo and the residue is purified by column chromatography, 80% EtOAc: heptane followed by 10% MeOH: EtOAc. A white solid is obtained (30 mg, 43%), mp 54-57 ° C. IR: 3347, 2931, 1713, 1651 and 1538 cm '1. NMR (CDC13): 0.79 (3H, d, J = 6.8 Hz CH3CHCH3), 0.98 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.21 - 1.60 (13H, m, aCH3, CH2 x 5), 2.07 (1H, m, CH3CHCH3), 3.05 (1H, d, J = 13.6 Hz, PhCHH), 3.32 (1H, d, J = 13.6 Hz, PhCHH), 3.14 - 3.22 (4H, m, CONHCH, CH2NHCONH2), 4.42 (2H, brs, CONHA 4.85 (1H, br s, NHCONH? 5.09 (1H, s, NH urethane), 5.37 (1H, d, J = 7.6 Hz , PhCH), 6.28 (1H, br s, NH-amide) and 6.92-7.38 (10H, m, aromatics) Analysis calculated for C29Hi2N4O4 • 0.6 H2O: C, 66.79; H, 8.35; N, 10.74.
Found: C, 66.69; H, 8.09; N, 10.68.
EXAMPLE 8 [2 - (2-Fluoro-phenyl) -1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester ), NHCONH, Isomer II To a suspension of L-alanine methyl ester (5 g, 36 moles), MgSO 4 (2 g), and 4-chlorobenzaldehyde (51 g, 36 moles) in DCM (60 mL), triethylamine (5 mL, 36 moles) was added. ). The reaction mixture is stirred for 20 hours, filtered and concentrated in vacuo.
The resulting gum is triturated with ether and then the precipitate is removed by filtration. The filtrate is concentrated to separate the desired product as a colorless oil (7.90 g, 98%). IR (film): 2952 and 1743 cm "NMR (CDCI3): 1.52 (3H, d, J = 6.8 Hz, CH3), 3.75 (3H, s, OCH3), 4.16 (1H, q, aCH), 7.39 (2H, d, J = 8.8 Hz, H - aromatic), 7.72 (2H, d, J = 8.8 Hz, H - aromatic) and 8.27 (1H, s, CH = N).
To a solution of the base SchifF (2 g, 8.9 mol) in THF (20 mL) at -70 ° C, under N2, LHMDS (9.75 mL of 1 M THF, 9.7 mol) is added. The reaction mixture is stirred for 1.25 hours at -70 ° C. and then 2-fluorobenzylbromide (1.67 g, 8.9 mol) in THF (5 mL) is added dropwise. The reaction is allowed to warm to room temperature and is stirred continuously for 15 hours. Add 1 M HCl (10 mL) and stir continuously for an additional 24 hours. The solvent is removed in vacuo and the residue is partitioned between EtOAc (200 mL) and 1 M HCl (200 mL). The aqueous layer is made basic with Na2CO3 and extracted with EtOAc (3 x 100 mL). The combined extracts are dried over MgSO4 and the solvent is removed in vacuo to give an oil (1.54 g, 82%). IR (film): 2952 and 1735 cm "1. NMR (CDC13): 1.39 (3H, s, aCH3), 2.93 (1H, d, J = 13.6 Hz, ßCHH), 3.09 (1H, d, J = 13.6 Hz , ßCHH), 3.72 (3H, s, OCH3) and 7.00 - 7.25 (4H, m, aromatics).
Step 3 The 4-nitrophenol carbonate is prepared as described for Intermediary XIV, step 1, 0.56 g, (53%). IR (film): 31 19 and 1766 crn "'. NMR (CDC13): 0.85 (3H, d, J = 6.8 Hz, CJiCHCHs), 1.09 (3H, d, J = 6.8 Hz, CH3CHCH3) 2.24 (1H, , CH3CHCH3), 5.37 (1H, d, J = 8 Hz, PhCH), 7.31-7.41 (7H, m, aromatic) and 8.23 (2H, d, J = 9.2 Hz, aromatics).
I somer I I The carbonate (0.52 g, 1.7 moles) is dissolved in DMF (4 mL) and RS-alpha-methyl-2F-phenylalanine methyl ester (0.42 g, 2 moles) is added. The solution is stirred for 10 days and the solvent is removed in vacuo. The residue is dissolved in EtOAc (100 mL) and the solution is washed with 10% K2CO3 (5 x 75 mL) and saline (75 mL). The organic part is dried over MgSO 4 and the solvent is concentrated in vacuo. The residue is purified and the distereoisomers are separated by column chromatography, 10% etherheptane. Isomer I: 196 mg, 30%. Isomer II: 165 mg, 26%. Isomer III: IR (film): 3354, 2960, 1739 and 1717 crn '1. NMR (CDC13): 0.81 (3H, d, J = 6.8 Hz, CH3CHCH3), 0.97 (3H, d, J = 6.8 Hz, CHsCHCH) ), 1.54 (3H, s, aCH3), 2.08 (1H, m, CH3CHCH3), 3.25 (1H, d, J = 13.6 Hz, PhCHH), 3.40 (1H, d, J = 13.6 Hz, PhCHH), 3.73 ( 3H, s, OCH3), 5.39 (2H, m, PhCH, urethane NH) and 6.86-7.36 (9H, m, aromatics).
Isoiner II I somer I I The ester (0.13 g, 0.35 mol) is dissolved in THF (4 mL) and 1 M LiOH (1 mL) is added. The reaction mixture is stirred for 4 days and then the solvent is removed in vacuo.
The residue is dissolved in H 2 O (100 mL) and the pH of the solution is adjusted to 3 with 1 M HCl.
The solution is extracted with EtOAc (3 x 75 mL) and the combined extracts are washed with water (100 mL). The organic phase is dried over MgSO and the solvent is removed in vacuo to give a white foam (127 g, 97%). IR (film): 2964, 1714 and 1494 cm 'V NMR (CDC13): 0.81 (3H, d, J = 6.8 Hz, CH3CHCH3). 0.98 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.52 (3H, s, aCH3), 2.07 (1H, m, CH3CHCH3), 3.34 (2H, m, ßCH2), 5.22 (1H, s, urethane NH), 5.39 (1H, d, J = 7.2 Hz , PhCH) and 6.85-7.38 (9H, m, aromatics). ) 7NHCONH2 I somer I I I somer I I The acid (40 mg, 0.11 mol), HBTU (42 mg, 0.11 mol) and DIPEA (19 μL, 0.11 mol) are dissolved in DMF (1 mL). The solution is stirred for 10 minutes, then the amino urea (prepared from Example 7, step 3) (23 mg, 0.13 moles) and DIPEA (19 μL, 0.11 moles) are added. The reaction mixture is stirred for 15 hours and the solvent removed in vacuo. The residue is dissolved in EtOAc (100 mL) and the organic part is washed with 1M HCl (3 x 75 mL), saturated NaHCO3 (3 x 75 mL), H2O (75 mL) and saline (75 mL). The organic part is dried over MgSO and the solvent is removed in vacuo. The residue is purified by column chromatography with 5% MeOH in DCM to give a white foam (17 mg, 29%), mp 67-72 ° C.
IR (film): 3343, 2932, 2858, 1713, 1651 and 1539 c '1. NMR (CDC13): 0.81 (3H, d, J = 6.4 Hz, CH3CHCH3), 1.00 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.20 - 1.58 (13H, m, aCH3, CH2 x 5), 2.10 (1H, m, CH3CHCH3), 3.10 - 3.30 (6H, m, ßCH2, CONHCHj, CHMHCONH2), 4.48 (2H, br s, CONH?). 4.98 (1H, br, OCONH), 5.38 (2H, m, PhCH, NHCQNHA 6.22 (1H, br, NH-amide) and 6.82-7.36 (9H, m, aromatics) HPLC: 40-100% B for 20 minutes, A = H2O, B = CH3CN, 0.1% TFA K, = 13.21 minutes.
Analysis calculated for C29H4? N O4F • 0.3 H2O: C, 65.22; H, 7.85; N, 10.49. Found: C, 65.23; H, 7.77; N, 10.36.
EXAMPLE 9 2 - (2,3-Difluoro-phenyl) -1-methy1- (7-ureido-heptylcarbamoyl) -ethyl] - acid ), NHCONH The compound is prepared following the procedure described for Example 8, Step 2, using the Schiff base prepared in Example 8, Step 1 (0.5 g, 2.0 moles). The product is obtained as an oil (382 mg, 75%). IR (film): 3378, 2954, 1735, 1491 and 1206 cm '! NMR (CDC13): 1.40 (3H, s, aCH3), 2.96 (1H, d, J = 13 Hz, ßCHH), 3.12 (1H, d, J = 13 Hz, ßCHH), 3.72 (3H, s, OCH3) and 6.92 - 7.08 (3H, m, aromatics).
Isomer I I The desired product is prepared by the procedure described for Example 8, step 4, using the carbonate prepared in Example 8, Step 3 (250 mg, 0.79 moles). A resolution of analogs is carried out to give the desired isomer II as a white solid 11 mg (35%), mp 1 12 - 115 ° C. IR: 3343, 2957, 1735, 1713, 1492, 1268 and 1071 c, '1. NMR (CDC13): 0.81 (3H, d, J = 6.8 Hz, CH.CHCHA 0.98 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.54 (3H, s, aCH3), 2.07 (1H, m, CH3CHCH3), 3.29 (1H, d, J = 14 Hz, PhCHH), 3.46 (1H, d, J = 14 Hz, PhCHH), 3.76 (3H, s, OCH3), 5.38 (2H, m, PhCH, urethane NH), 6.65 (1H, m, aromatic), 6.85 (1H , m, aromatic), 7.02 (1H, m, aromatic) and 7. 26-7.36 (5H, m, aromatics). M / S (Cl): 406, 230 and 133. Analysis calculated for C 22 H 25 NO 4 F 2: C, 65.17; H, 6.21; N, 3.45. It was found: Isomer II Isomer I I The desired compound is prepared following the procedures described by Example 8 Step 5. The product is obtained as a white foam (94 mg, 92%). IR (film): 3418, 3035, 2965, 1715 and 1493 cm "NMR (CDC13): 0.80 (3H, d, J = 6.8 Hz, CHjCHCHa), 0.98 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.52 (1H, s, aCH3), 2.08 (1H, m, CH3CHCH3), 3.35 (1H, d, J = 13.6 Hz, ArCHH), 3.42 (1H, d, j 0 13.6 Hz, ArCHH), 5.21 (1H, br , urethane NH), 5.38 (1H, br d, PhCH), 6.57 (1H, br, aromatic), 6.82 (1H, br, aromatic), 7.02 (1H, br, aromatic), and 7.26 - 7.38 (5H, m , aromatic).
The acid (50 mg, 0.13 mol) is bound to the amino urea (prepared in Example 7, Step 3) (28 mg, 0.16 mol) following the procedure described for Example 8, step 6, separates 39 mg (55%) ), mp 59-64 ° C. IR (film): 3363, 2932, 2864, 1709, 1651 and 1539 cm - 1 m / e (APCI): 1050, 547 and 504. NMR (CDCb): 0.80 (3H, d, J = 6.8 Hz, CüCHCHj), 0.99 (3H, d, J = 6.8 Hz CH3CHCH, 1.26 - 1.57 (13H, m, aCH3, CH2x 5), 2.09 (1H, m, CH3CHCH3), 3.19 (4H, m, CONHCH ?. CHzNHCONHz), 3.26 (1H, d, J = 14 Hz, PhCHH), 3.36 (1H, d, J = 14 Hz, PhCHH), 4.40 (2H, br, NHCONH2), 4.80 (1H, br, NHCONHA 5.28 (1H, br, urethane NH), 5.37 (1H, br d, PhCH). 6.25 (1H, br, amide NH), 6.55 (1H, br, aromatic), 6.76 (1H, br, aromatic), 7.00 (1H, m, aromatic) and 7.26 - 7.38 (5H, m, Ph). Analysis calculated for C 9H40N4O4F • 0.75 H2O: C, 62.18; H, 7.47; N, 10.00, found: C, 61.17; H, 7.20; N, 9.80.
EXAMPLE 10 \ 2 - Benzofuran-3-yl-1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] - acid Step 1 Isomer II To a solution of 4-methylformoline (1.5 mL, 13.6 moles) in anhydrous THF (25 mL) is added drop wise over one hour to a stirred solution of benzo [b] furan-2-carboxylic acid (2.0 g, 12.3 moles) and ethyl chloroformate (1.30 mL, 13.6 moles in THF (50 mL) is cooled in a salt-cold bath, the mixture is stirred for 1 hour and then the precipitate is filtered off, the filtrate is cooled again and added dropwise. a solution of 2 M LiBHt in THF (18.5 mL, 37 moles) for 20 minutes The reaction mixture is stirred for 2 hours and then slowly added with IN HCl (25 mL) The THF is removed in vacuo and the aqueous part is then extracted with EtOAc (2 x 50 mL) The combined extracts are washed with saline (25 mL) and then dried over MgSO.The residue is purified by column chromatography, 75% n-hexane, % EtOAc, they separate 1.53 g (84%). IR (film): 3346, 2922, 2862, 1606, 1454, 1255, 1012 and 752 cm "1. NMR (CDC13): 1.98 (1H, t, J = 6.0 Hz, CH2OH), 4.77 (2H, d, J = 6.0 Hz, CH2OH) .6.66 (1H, s, H3 - aromatic), 7.20 - 7.30 (2H, m, H5, He-aromatic), 7.46 (1H, d, J = 8 Hz, H7 - aromatic) and 7.55 (1H, d, J = 7.6 Hz, H - aromatic).
A solution of bromide (0.42 mL, 8.2 moles) in DMF is added dropwise for 5 minutes to a cold stirred solution of the alcohol (1.16 g, 7.8 moles) and triphenylphosphine (2.15 g, 8.2 moles) in anhydrous DMF (10 mL) under an atmosphere of N2. The reaction mixture is stirred overnight and then diluted with water (150 mL). The solution is extracted with EtOAc (3 x 100 mL) and the combined extracts are then washed with saline (50 mL) and dried over MgSO: The solvent is reduced in vacuo and the residue is precipitated with heptane. The solid is removed by filtration and the filtrate is concentrated in vacuo. The product is purified by column chromatography, 10% DCM in heptane to give the desired bromide 587 mg (36%). IR (film): 1584, 1452, 1475, 1422, 1282, 1254, 1208, 1189 and 953 cm "\ NMR (CDC13): 4.60 (2H, s, CH2Br), 6.75 (1H, s, aromatic), 7.21 - 7.34 (2H, m, aromatics) and 7.47-7.56 (2H, m, aromatics).
The amino acid is prepared following the procedure described for Example 8, Step 2 using the SchifF base (prepared in Example 8, Step 1) (547 mg, 2.4 moles). The desired product is obtained as an oil 326 mg (58%). IR (film): 3376, 2951, 1733, 1586, 1455, 1253, 1212, 1106, 816 and 751 cm '1. NRM (CDC13): 1.45 (3H, s, CH3), 1.70 (2H, b, NH2) , 3.02 (1H, d, J = 14.4 Hz, ArCHH), 3.29 (1H, d, J = 14.4 Hz, ArCHH), 3.75 (3H, s, OCH3), 6.49 (1H, s, aromatic), 7.16 - 7.25 (2H, m, aromatics), 7.39-7.41 (1H, m, aromatic) and 7.48-7.51 (1H, m, aromatic). Analysis calculated for C? HuNO3 • 0.25 H2O: C, 65.67; , H »» ,, 6 - .. 5-7.;, N »- .., 5.89. Found: C, 65.71; H, 6.45; N, 5.80.
Isomer I I The desired product is prepared by the procedure described by Example 8, step 4, using the carbonate prepared in Example 8 Step 3 (250 mg, 0.8 moles). The resulting mixture is resolved by column chromatography, 10% ether in heptane followed by % ether in heptane. Isomer II is obtained as a white solid 80 mg (25%), mp. 101 -. 101 - 107 ° C. IR (film): 3420, 3356, 2958, 2932, 2873, 1740, 1721, 1497, 1455, 1253, 1122, 1056 and 751 cm "1.
NMR (CDC): 0.80 (3H, d, J = 6.8 Hz, CH3CHCH3), 0.95 (3H, d, J = 6.8 Hz, CH.CHCHQ 1.60 (3H, s, aCH3), 2.07 (1H, m, CH3CHCH3 ), 3.43 (1H, d, J = 14.8 Hz, ArCHH), 3.61 (1H, d, J = 14.0 Hz, ArCHH), 3.80 (3H, s, OCH3), 5.40 (1H, d, J = 6.8 Hz, PhCH), 5.53 (1H, br, urethane NH), 6.27 (1H, s, aromatic), 7.16-7.36 (8H, m, aromatic) and 7.43-46 (1H, m, aromatic).
Isomer II The desired compound is prepared following the procedure described by Example Step 5. The product is obtained as a solid, 43 mg (60%), mp 69-73 ° C. IR (film): 3409, 2962, 1716, 1507, 1455, 1253, 1057 and 752 cm * 1. NMR (DMSO-d6): 0.78 (3H, d, J = 6.4 Hz, CH3CHCH3). 0.89 (3H, d, J = 6.4 Hz, CH3CHCH3), 1.34 (3H, s, aCH3), 1.99 - 2.05 (1H, m, CH3CHCH3), 3.08 (1H, d, J = 14.8 Hz, ArCHH), 3.49 ( 1H, d, J = 14.8 Hz, ArCHH), 5.33 (1H, d, J = 6.4 Hz, PhCH), 6.16 (1H, s, aromatic) and 7.18-7.50 (10H, m, aromatics, NHCO). [a] 20D = + 68.4 (C = 0.25, acetone).
The acid (35 mg, 0.09 mol) is bound to the amino urea (prepared from Example 7, Step 3) (16 mg, 0.09 mol) following the procedure described for Example 8, Step 6, separates 25 mg (51%) .
IR (film): 3494, 3350, 2931, 2857, 1709, 1651, 1602, 1543, 1455, 1383, 1335, 1254, 1054, 910 and 735 cm 'V [a] 20D = + 68.7 ° (C = 0.31, acetone). NMR (CDC13): 0.80 (3H, d, J = 6.8 Hz, CH.CHCHA 0.97 (3H, d, J = 6.6 Hz, CH.CHCH,), 1.26 - 1.51 (10H, m, 5 x CH2), 1.51 (3H, s, aCH3), 2.02 - 2.17 (1H, m, CH3CHCH3), 3.08 - 3.19 (4H, m, CONHCH2, CH2NHCONH2), 3.30 (1H, d, J = 14.8 Hz, ArCHH), 3.54 (1H, d, J = 14.8 Hz, ArCHH), 4.60 (2H, s, NHCONH 5.17 (1H, b, urethane NH), 5.39 (1H, d, J = 7.6 Hz, PhCH), 5.48 (1H, s, aromatic), 6.19 (1H, br, NHCONH2), 6.47 (1H, b, NH-amide) and 7.15-7.42 (9H, m, aromatics). Analysis calculated for C3? H42N4Os • 0.25 H2O: C, 67.06; H, 7.72; N, 10.09. Found: C, 67.12; H, 7.64; N, 9.95.
EXAMPLE 11 (2 - (2,3-Difluoro-phenyl.) - 1-methyl-1 - [3 - (3-ureido-propoxy) -propylcarbamoyl] - , 0 (CHJ .NHCONH Step 1 I somer II H2N (CH2) 3O (CH2) 3? PhCH2? CONH (CH2) 3O (CH2) 3NH2 Dissolve bis- (3-aminopropyl) ether (4.89 g, 37 moles) in 1.4 - dioxane (1.5 L) and add Na2CO3 (3.16 g, 11 moles) in H2O (150 mL) The solution is cooled in a bath of ice water with salt and benzylchloroformate (1.5 mL, 7.4 moles) is added in 1 , 4 - dioxane (100 mL) for 2.5 hours. The reaction mixture is stirred for 15 hours, after which the solvent is removed in vacuo. The residue is dissolved in EtOAc (100 mL) and the solution is washed with saline (3 x 75 mL), then dried over MgSO. Upon removing the solvent, a white solid remains 2.01 g. IR (film): 3333, 2943, 2868, 1704, 1538 and 1260 cm "1.
Step 2 PhCH2OCONH (CH2) 3O (CH2) 3NH3? PhCH2OCONH (CH2) 3O (CH2) 3NHCONH2 The amine (2.03 g, 7.4 moles) is dissolved in THF (20 mL) and trimethylsilylisocyanate (935 μL, 7.4 moles) is added by Drip for 15 minutes under a nitrogen atmosphere. The reaction mixture is stirred for 3.5 hours, after which an additional aliquot of trimethylsilylisocyanate (500μL, 3.7 moles) is added. It is stirred continuously for an additional 15 hours and then the solvent is removed in vacuo. The residue is dissolved in EtOAc (50 mL) and washed with saline (2 x 25 mL), then dried over MgSO4. The solvent is removed in vacuo and the residue recrystallized from EtOAc to give a white solid 0.31 g (13%). IR (film): 3339, 2943, 2869, 1703, 1657, 1607, 1548, 1261 and 1113 cm '\ NMR (CDC13): 1.75 (4H, m, CH? CH? CH, x 2), 3.34 (4H, m, CONHCH, CH2NHCO), 3.49 (4H, m, CH2O x 2), 4.59 (2H, br s, CONHA 5.08 (3H, m, PhCH ,. CHzNHCO), 5.65 (1H, br, NH urethane) and 7.26 - 7.52 (5H, m, aromatics).
Step 3 PhCH2OCONH (CH2) 3O (CH2) 3NHCONH2 - ** H2N (CH2) 3O (CH2) 3 NHCONH2 Urea (294 mg, 0.95 mol) is dissolved in ethanol (60 mL) and Pearlman catalyst (30 mg) is added. The reaction mixture is hydrogenated at 47 psi, H2, at 30 ° C. for 3 hours and then the catalyst is removed by filtration through Kieselguhr. The solvent is removed in vacuo to give an elongated solid (152 mg, 92%). IR (film): 3350, 2940, 2871, 1652, 1574, 1346 and 1109 cm "1. NMR (CDC13): 1.73 (4H, m, CH? CH7CH7 x 2), 2.80 (2H, t, j 0 6.8 Hz , CH, NHA 3.18 (2H, t, J = 6.8 Hz, CH2NHCONH2) and 3.51 (4H, m, CH, O x 2). , 0 (CHJ, NHCONH, Isomer II Isomer II The acid (prepared from Example 9, Step 3) (40 mg, 0.1 mole), HBTU (39 mG, 0.1 mole) and DIPEA (18 μL, 0.1 mole) are dissolved in DMF (2 mL). The solution is stirred for 2 minutes and then the amino urea (19 mg, 0.11 mol) and DIPEA (18 μL, 0.1 mol) are added: The reaction mixture is stirred for 8 hours, and the solvent is removed in vacuo. The residue is dissolved in EtOAc (50 mL) and the solution is washed with 1M HCl (2 x 30 mL), saturated NaHCO3 (2 x 30 mL) and saline (30 mL). The organic part is dried over MgSO4 and the solvent is removed in vacuo. The product is purified by column chromatography 5% MeOH in DCM to give a white solid, 38 mg (69%), mp 58-62 ° C. IR (film): 3341, 2937, 2872, 1714, 1652, 1607 and 1539 cm '1. NMR (CDCI3): 0.80 (3H, d, J = 6.6 Hz, CH3CHCH3), 0.99 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.43 (3H, 3, aCH3), 1.58 - 1.74 (4H, m, CH? CH? CH? X 2), 2.08 (1H, m, CH3CHCH3), 3.29 - 3.45 (10H, m, ArCH2 , CH? NHCONH? CH2O x 2, CONHCHA 4.65 (2H, s, CONH,), 5.31 (1H, s, urethane NH), 5.37 (! H, d, J = 7.3 Hz, PhCH). br, aromatic), 6.78 (1H, br, aromatic), 7.01 (lH, m, aromatic) and 7.26 - 7.38 (5H, m, Ph).
Analysis calculated for C28H38N4OsF2: C, 61.30; H, 6.98; N, 10.21. Found: C, 61.05; H, 7.11; N, 10.06.
SYNTHESIS OF XIV AND XV INTERMEDIARIES 4 - . 4-Nitrophenylchloroformate (8.05 g, 39.9 moles) in dichloromethane (40 mL) is added dropwise to a solution of (RS) -2-methyl-1-phenyl-1-propanol (6.00 g, 39.9 moles) and pyridine ( 3.23 mL, 39.9 moles) in dichloromethane (100 mL) at 0 ° C. The solution is allowed to warm to room temperature and stirred for two days. The reaction mixture is washed with water and 2 M HCl and dried (MgSO). With further purification by column chromatography using 20% diethyl ether: hexane, gives the carbonate as a white solid (7.50 g, 60%). IR (film): 2967, 1762, 1525, 1346, and 1216 c "1. H1 NMR (CDC13): d 0.85 (3H, d, J = 7 Hz, - CH3), 1.09 (3H, d, J = 6 Hz, -CH3), 2.24 (1H, m, (CH3) 2CH), 5.37 (1H, d, J = 7 Hz, PhCH, 7.36 (7H, m, Ar), and 8.24 (2H, m, Ar).
Step 2 (R) a - MePHE - OH - (R) a - MePheOCH3 Cool methanol (120 mL) at -5 ° C and add thionyl chloride (14 mL, 195 moles) for 5 minutes, followed by the addition of (R) - aMEPhe-OH (7.00 g, 39 moles).
The resulting suspension is allowed to warm to room temperature, stirred by 16 hours and heat to reflux for 1.5 hours. Upon cooling, the mixture is evaporated on a white solid which is deposited in ethyl acetate (200 mL) and washed with saturated NaHCO3 (2 x 100 mL). Dry (MgSO4) and evaporate to give a pale yellow liquid (4.08 g, 64%). IR (film): 3030, 2951, 1733, 1603 and 1453 cm '1. 1 H NMR (CDC13): d 1.60 (3H, s, dMe), 2.80 (1H, d, J = 13.2 Hz, PhCHH), 3.13 ( 1H, d, J = 13. 2 Hz), 3.70 (3H, s, OCH3) and 7.12-7.31 (5H, m, Ar).
(R) a-MePhe? The carbonate (3.00 g, 9.5 mol), (r) - aMePheOMe (1.84 g, 9.5 mol) and triethylamine (1.33 mL, 9.5 mol) are dissolved in DMF (20 mL) and stirred at room temperature for 3 days . When the solvent is removed, the residue is placed in ethyl acetate (100 mL) and washed with 2 M HCl (2 x 70 mL) and saline (70 mL). Dry (MgSO) and evaporation give a colorless oil which is purified by column chromatography on silica using 6% diethyl ether: hexane, yielding: y) a colorless oil (l .Og) (R, R isomer); Intermediary XV. IR (film): 3423, 2960, 1740, 1721, 1496 and 1451 cm * 1. 1H NMR (CDC13): d 0.81 (3H, d, J = 6.8 Hz, - CH3), 0.98 (3H, d, J = 6.4 Hz, - CH3), 1.66 (3H, s, aCH3), 2.03 - 2.10 (1H, m, (CH3) 2 CH), 3.05 (1H, d, J = 13.6 Hz, PhCHH), 3.40 (1H, m , d, J = 13.2 Hz, PhCHH), 3.72 (3H, s, CO2CH3), 5.35 (1H, D, J = 6.8 Hz, PhCHOCO), 5.55 (1H, bs, urethane), 6.76-6.77 (2H, m , Ph) and 7.08-7.40 (8H, m, Ph).
M *: 133, 194, 238 and 370. [a] 20D = + 21.4 ° (C = 0.25, acetone). ii) a white solid 80.68 g (S, R-isomer); Intermediary XIV, mp = 118.5 - 120 ° C. IR (film): 3353, 2959, 1732, 1497 and 1451 cm "1. 1H NMR (CDC13): d 0.83 (3H, d, J = 6.8 Hz, - CH3), 0.99 (3H, d, J = 6.6 Hz , - CH3), 1.55 (3H, s, aCH3), 2.06 - 2.11 (1H, m, (CH3) 2 CH, 3.19 (1H, d, J = 13.4 Hz, PhCHH), 3.39 (1H, d, J = 13.4 Hz, PhCHH), 3.75 (3H, s, CO2CH3), 5.41 (2H, m, urethane, PhCHOCO), 6.96 - 6.98 (2H, m, Ph), and 7.18 - 7.37 (8H, m, Ph). : 91, 133, 194, 238 and 370. [a] 20D = + 45.6 ° (C = 0.475, acetone).
SYNTHESIS OF EXAMPLE 12 f 1 - f 1 - (6-Hydroxy-hexylcarbamoyl) -2- (4-hydroxy-phenyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl I - carbamic acid-2-methyl-1 - phenyl-propyl ester.
(R) a-MePhe-OH The methyl ester (0.74 g, 2 moles) (Intermediate XIV) is dissolved in THF (20 mL). Monohydrate lithium hydroxide (0.16 g, 4 moles) in water (4 mL) is added and the mixture is heated at reflux for 48 hours. When removing the solvents, the residue is divided between 2M HCl and ethyl acetate. The aqueous layer is back extracted with ethyl acetate and the combined organics are dried (MgSO 4) and evaporated until a colorless oil remains. (0.61 g, 86%). IR (film): 3409, 2969, 1713, 1497, 1452 and 1052 cm "1 1 H NMR (CDC13): d 0.82 (3H, d, J = 6.8 Hz, - CH3), 0.99 (3H, d, J = 6.4 Hz, - CH3), 1.55 (3H, s, aCH3), 2.10 (1H, m, (CH3) 2CH), 3.29 (2H, m, PhCHa), 5.27 (1H, bs, urethane), 5.42 (1H, d, J = 7.2 Hz, PhCHOCO), 6.99 (2H, m, Ar), and 7.17 - 7.38 (8H, m, Ar).
M / e (Cl): 356, 302, 266, 180, 133 and 91.
(R) a-MePhe-OH Ph '"OC (R) a-MePhe (S) TvrOCH.
The acid (0.60 g, 1.7 moles), HBTU (0.64 g, 1.7 moles) and DIPEA (0.81 mL, 3.4 moles) are stirred in DMF (10 mL) for 20 minutes. Add (S) - TyrOMe (0.33 g, 1.7 moles) and the mixture is stirred at room temperature for 16 hours. When removing the DMF, the residue is deposited in ethyl acetate (70 mL) and washed with 2M HCl (2 x 70 mL), % NA2CO3 (2 x 70 mL). Dry (MgSO) and by column chromatography on silica using 50% EtOAc: hexane, gives a colorless oil (0.74 g, 82%).
IR (film): 3353, 2962, 1728, 1661, 1516 and 1230 cm'1. 1H NMR (CDC13): d 0.78 (3H, d, J = 6.4 Hz, -CH3), 0.95 (3H, d, J = 6.4 Hz, -CH3), 1.33 (3H, s, aCH3), 2.00 (1H, m, (CH3) 2CH), 2.85 - 3.08 (3H, m, - CH ^ Ph - OH, Ph - CHH), 3. 29 (1H, d, J = 12 Hz, PhCHH), 3.69 (3H, s, CO2Me), 4.76 (1H, m, aH)), 4.98 (1H, s, Ar - OH), 5.35 - 5.40 (2H, m, urethane, Ph-CHOCO) and 6.64 - 7.40 (15H, m, Ar, amide). m / e (CI): 133, 357 and 533.
Step 3 Pn S OC (R) a-MePhe (S) TyrOCH- Ph S OC (R'a ~ MePhe (S) Tyr-OH XVI The methyl ester (0.73 g, 1.37 mol) is dissolved in THF (20 mL) and add a solution of monohydrate lithium hydroxide (0.086 g, 2.05 mole) in water (5 mL) The resulting solution is stirred vigorously for 60 hours.When removing the solvents, the residue is divided between 2M HCl (50 mL) and Ethyl acetate (70 mL) The aqueous layer is back extracted with ethyl acetate (70 mL) and the combined organics are dried (MgSO) Further purification by column chromatography on silica using 50% ethyl acetate: hexane gives a solid white (0.49 g, 69%) (Intermediary XVI). IR (film): 3391, 2965, 1706, 1695, 1652, 1515 and 1237 cm "1. 1 H NMR (DMSO - di): 0.70 (3H, d, J = 6.8 Hz, - CH3), 0.82 (3H, d, J = 6.4 Hz, - CH3), 1.09 (3H, s, aCH3), 2.82 - 3.30 (4H, m, PhCH2 -, ArCH ^ -), 1.86 - 2.00 (1H, m, (CH3) 2CH), 4.10 (1H, m, aH), 5.22 (1H, d, PHCHOCO), 6.50-7.50 (16H, m, Ar, amide, urethane) and 9.10 (1H, bs , ArOH).
(R) a-MePhe (S) Tyr-OH -? Ph "S" OC () a-MePhe. { S) TyrNH (CH2) 6OH XVI Example 12 The acid (0.080 g, 0.15 mol) (Intermediate XVI), HBTU (0.057 g, 0.15 mol) HOBT (catalytic amount) and 6-amino hexanol (0.018 g, 0.15 mol) are dissolved in DMF (7 mL) and cooled at -10 ° C. DIPEA (0.072 mL, 0.30 mol) is added and the solution is stirred at -10 ° C. for 2 hours. Upon removal of the DMF, the residue is taken up in ethyl acetate (70 mL) and washed with 2 M HCl (2 x 50 mL), 10% Na2CO3 (2 x 50 mL) and saline (50 mL). Dry (MgSO4) and further purification by column chromatography on silica using 5% methanol: dichloromethane, give a white solid (57 mg, 61%), mp = 73-78 ° C.
IR (film): 3332, 2934, 1698 and 1652 cm "\ 1H NMR (CDC13): d 0.73 (3H, d, J = 6.8 Hz, - CH3), 0.89 (3H, d, J = 6.4 Hz, - CH3 ), 1.20 - 1.65 (11H, m, aCH3, - (CH2) 4 -), 2.03 (1H, m, (CH3) 2CH), 2.81 (1H, dd, CHHAr), 3.04 - 3.88. (5H, m, CH ^ Ph, CHHAr, -NHCH2 -), 3.68 (2H, t, J = 6.0 Hz, CH2-OH), 4.62 (1H, m, aH), 4.85 (1H, s, urethane), 5.21 (1H, d , J = 8.0 Hz, PhCHOCO), 6.38 (1H, d, amide) and 6.70-7.43 (16H, m, Ar, amide, ArOH), m / e (FAB), 281, 618, 550 and 355. [a ] 21 -5 = + 48.86 (C = 0.745, MeOH) HPLC Column: C? 8 Ultrasphere, 5?, 4.6 x 250 mm Solvent 40-100% CH3CN: H2O + 0.1% TFA for 30 minutes Rt = 14.6 minutes Purity = 98.9% (+ 1% S, R, R isomer) Analysis calculated for C36H 8N3? 6 • 0.3 H2O: C, 69.27; H, 7.85; N, 6.73 It was found: C, 69.26; H, 7.58; N, 6.71.
SYNTHESIS OF EXAMPLE 13. { 1 - [1 - (7-Hydroxy-heptylcarbamoyl) -2- (4-hydroxy-phenyD-ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} - carbamic acid 2-methyl-1-phenyl-propyl ester BOCNH (CH2) 6CO2H? BOCNH (CH2) 7OH Step 1 Ethyl chloroformate (192 μ mL, 2 moles) in dry THF (10 mL) is added dropwise over 20 minutes to a stirred solution of BOC NH (CH2) 6CO2H (450 mg, 1.8 moles) and N-methylmorpholine (221 μL, 2 moles) in THF (15 mL) cooled in an ice bath The mixture is stirred for one hour and filtered, 2.0 M lithium borohydride in THF is added dropwise. (3 mL, 6 moles) to the filtrate that is cooled in an ice bath and allowed to warm to room temperature for 3 hours.The solvent is removed in vacuo and the residue is deposited in ethyl acetate (50 mL) and washed with water (3 x 40 mL) and dried (MgSO). evaporation gives a colorless oil (395 mg, 95%).
IR (film): 3344, 2931, 2858, 1689 and 1531. 1H NMR (CDC13): d 1.28-1.60 (19H, m, BOC CH3 x 3, CH2 x 5), 3.10 (2H,, CONHCHj), 3.64 (2H, m, CH2OH) and 4.50 (1H, s, br urethane).
Step 2 BOCNH (CH2) 7OH- * > TFA • H2N (CH2) 7OH (crude) The BOC-Amino alcohol (280 mg, 1.2 mol) is dissolved in dichloromethane (3 mL).
Trifluoroacetic acid (3 mL) is added and the mixture is stirred for one hour at room temperature. of the room. The solvent is removed in vacuo and the azeotroped TFA with toluene separates a viscous oil (370 mg, 1.9 moles of TFA).
IR (film): 3420, 2925, 1755 and 1678 cm "1 R) a-MePhe (S) TyrNH (CH-) -.Oh- TFA.H.N (CH-) -OH - Example 13 The acid (0.080g, 0.15 moles) (Intermediate XVI), HBTU (0.057 g, 0.15 moles), HOBT (catalytic amount) and the salt TFA (0.051 mg, 0.15 moles) are dissolved in DMF (10 mL) and cooled to -10 ° C. DIPEA (0.109 mL, 0.45 moles) is added and the solution is Stir at - 10 ° C for two hours. Potassium carbonate (0.20g, 0.15 moles) is added in water (1 mL) and the mixture is stirred vigorously at room temperature for two additional hours. When removing the solvents, the residue is deposited in ethyl acetate (50 mL) and 2 M HCl (50 mL). The organic layer is washed with 2 M HCl (50 mL), 10% Na2CO3 (2 x 50 mL) and saline (50 mL) and dried (MgSO). Purification by chromatography of column on silica using 5% methanol: dichloromethane gives a white solid (58 mg, 61%), mp = 70-76 ° C.
IR (film): 3334, 2933, 1699 and 1652 cm "1. 1H NMR (CDC13): d 0.72 (3H, d, J = 6.8 Hz, CH3), 0.88 (3H, d, J = 6.8 Hz - CH3), 1.20 - 1. 80 (13H,, aCH3, - (CH2) 5 -), 2.02 (1H, m, (CH3) 2CH), 2.76 - 3.80 (8H, m, PI1CH2, ArCH.2, NHCH2, CH2-OH), 4.62 (1H, m, aH), 4.83 (1H, s, urethane), 5.19 (1H, d, J = 8.4 Hz, PhCHOCO), 6.40 (1H, d, amide) and 6.70-7.40 (16H, m, Ar, amide, Ar-OH). m e (FAB): 267, 456, 550 and 632. [? fo = + 47.05 (C = 0.88, MeOH). HPLC column: Cw ultra-sphere, 5 μ, 4.6 x 250 mm.
Solvent: 40 - 100% CH3CN: H2O + 0.1% TFA. 1 mL / min for 30 minutes. Rt = . 7 minutes Purity = 99.1% (+ 0.8% S, R, R isomer).
Analysis calculated for C37Hj0N3O6 • 0.3 H2O: C, 69.63; H, 7.99; N, 6.58.
Found: C, 69.53; H, 7.81; N, 6.57.
SYNTHESIS OF THE INTERMEDIARY XVII O O II Ph '* OC (R) ct-MePheOCH-, Ph' "OC { R? A-MePne-OH R XV 1 Intermediary XVI I The methyl ester (1.5 g, 4.06 moles) (Intermediate XV) is deposited in THF (20 mL).
Monohydrate lithium hydroxide (0.34 g, 8.12 mol) in water (5 mL) is added and the resulting mixture is heated at reflux for 24 hours. When the solvents were removed, the residue was divided between 2 M HCl (70 mL) and ethyl acetate (70 mL). The aqueous layer is back extracted with ethyl acetate (70 mL) and the combined organics are dried (MgSO). Purification by column chromatography using 50% ethyl acetate: hexane gives the acid as a white foam (0.82 g, 57%). IR (film): 3032, 2964, 1711, 1497, 1452 and 1078 cm "1. 1H NMR (CDCi3): d 0.81 (3H, d, J = 6.8 Hz, - CH3), 0.99 (3H, d, J = 6.8 Hz, - CH3), 2.08 ( 1H, m, (CH3) 2CH), 3.14 (1H, d, J = 13.6 Hz, PhCHH), 3.37 (1H, d, J = 12.4 Hz, PhCHH), . 36 (1H, d, J = 6.8 Hz, PhCHOCO), 5.44 (1H, s, urethane) and 6.82-7.40 (10H, m, Ar). m / e (Cl): 133, 180, 224 and 356.
SYNTHESIS OF EXAMPLE 14 Carbamic Acid. f 1-methyl-2-oxo-2 - [(1-phenylethyl) aminol-1 - (phenylmethyl) ethyl] -. (R) or (S) -2-methyl-1-phenylpropyl ester. R - (R * S *) 1 - (R) a-MePheNH S Ph XVII Example 14 DCCI (29 mg, 0.14 mol) is added to a stirred solution of the acid (46 mg, 0.13 mol) (Intermediate XVII) and HOBT H2O (25 mg, 0.16 mol) in ethyl acetate (2 mL) at room temperature and stir for two hours. The mixture is filtered and the solid is washed with ethyl acetate (3mL). The filtrate is added to (S) -α-methylbenzylamine (23 mg, 0.19 mol) in ethyl acetate (1 inL) and the mixture is stirred for 26 hours. The solution is washed with 5% citric acid (2 x 10 mL), saturated NaHCO3 (2 x 10 mL) and saline (10 mL), dried (MgSO) and filtered. The solution is cooled to -10 ° C for two hours and filtered. Evaporation gives a white solid (41 mg, 70%) p 151-161 ° C. IR (film): 3326, 3031, 2930, 1721, 1694, 1645, 1485 and 1078 cm "1. 1H NMR (CDC13): at 0.81 (3H, d, J = 6.8 Hz, -CH3), 0.98 (3H, d, J = 6.6 Hz, -CH3), 1.32 (3H, d, J = 6.8 Hz, -CH3 ), 2.02 - 2.11 (1H, m, (CH3) 2CH), 3.14 (1H, d, J = 13.9 Hz, PhCHH), 3.28 (1H, d, J = 13.4 Hz, PhCHH), 4.93-5.00 (1H, m, CH3CHNHCO), 5.26 (1H, b, urethane), 5.38 (1H, d, J = 7.6 Hz, PhCHOCO), 6.39 (1H, d, J = 7.1 amide), 6.99-7.01 (2H, m, Ar) and 7.14-7.36 (13H, m, Ar). m / e (Cl): 133, 283, 327 and 459. [a] 20D = + 10.3 ° (C = 0.53, acetone). Analysis calculated for C2 H3 N2O3 • 0.25 H2O: C, 75.21; H, 7.51; N, 6.05. It was found: C, 75.42; H, 7.60; N, 6.31.
SYNTHESIS FOR EXAMPLE 15 fl-Methyl-1- (1-methyl-1-phenyl-ethylcarbamoyl) -2-phenyl-ethyl-carbamic acid 2-methyl-1-phenyl-propyl ester Ph XVI I Example The acid (50 mg, 0.14 mol) (Intermediate XVII), HBTU (53 mg, 0.14 mol) and DIPEA (24.5 μL, 0.14 mol) are dissolved in DMF (3 mL) and stirred for 5 minutes. Cummylamine (20 mg, 0.15 mol) and DIPEA (23.5 μL, 0.14 mol) are mixed and the solution is stirred overnight. The solvent is removed, the residue is dissolved in ethyl acetate (50 mL) and washed with 1 M HCl (3 x 30 mL), saturated with NaHCO 3 (3 x 30 mL), water (30 mL) and saline (30 mL) and dried (MgSO4). The evaporation and purification of the waste by column chromatography 25% ethyl acetate: heptane is used to give a white foam (57 mg, 86%), p = 115-123 ° C.
IR (film): 3285, 2975, 1716, 1668 and 1496 cm'1. 1H NMR (CDC13): d 0.82 (3H, d, J = 6.4 Hz, CH3CHCHQ 1.00 (3H, d, J = 6.4 Hz, CH3CHCH3), 1.41 (3H, s, aCH3), 1.52 (6H, s, CH3 x 2), 2.08 (1H, m, CH3CHCH3), 3.12 (1H, d, J = 14 Hz, PhCHh), 3.34 (1H, d, J = 14 Hz, PhCHH), 5.16 (1H, s, urethane), 5.40 (1H, d, J = 7.6 Hz, PhCHOCO), 6.39 (1H, s, amide) and 7.04-7.35 (15H, m, Ar). m / e (APCI): 473.5 MH +. HPLC 60-100% B for 20 minutes. A = H2O, B = CH3CN + 0. 1% TFA. Rt = 16.51 minutes (98%).
Analysis calculated for C30H36N2O3: C, 76.24; H, 7.68; N, 5.93.
Found: C, 76.03; H, 7.64; N, 6.01 SYNTHESIS OF EXAMPLE 16 fl - (2-Hydroxy-1-phenyl-ethylcarbamoyl) -1-methyl-2-phenyl-ethyl-carbamic acid 2-methyl-1-phenyl-propyl ester Ph 'R "0C (R) a-MePhe0H Ph RO XVII Example 16 DIPEA (36 mg, 0.20 mole) is added to a solution of the acid (50 mg, 0.14 mole) (Intermediate XVII), HfiTU (53 mg, 0.14 moles) and (R) -2-phenylglycinol (19 mg, 0. 14 moles), in DMF (3 mL). The reaction of the mixture is stirred overnight at room temperature and allowed to evaporate to dry. The residue is partitioned between ethyl acetate and 0.1 M HCl .. Further purification by column chromatography on silica using 40% ethyl acetate: hexane gives a white amorphous solid (60 mg, 90%), mp = 124 - 130 ° C. IR (film): 3395, 2963, 1706, 1659, 1495 and 1079 cm'1. 1H NMR (CDC13): d 0.81 (3H, d, J = 8 Hz), 1.48 (3H, s), 2.04 (1H, m), 3.09 and 3.30 (2H, ABq, J = 15Hz), 3.70 (2H, m), 4.95 (1H, m), 5.24 (1H, s), 5.38 (1H, d, J = 7 Hz), 6.93 (1H, d, J = 7 Hz), 7.04 (2H, m), 7.12 ( 2H, m) and 7.20-7.30 (1H, m). Analysis calculated for C 29 H 3 N 2 O 4: C, 73.39; H, 7.22; N, 5.90. Found: C, 73.11; H, 7.23; N, 5.72.
SYNTHESIS OF EXAMPLE 17 [1-Methyl-2-phenyl-1 - (1-phenyl-ethylcarbamoyl) -ethyl] -carbamic acid 1- (4-flouro-phenyl) -2-methyl-propyl ester BOCRaMePhe-OH? BOC (R) a - MePheNH S Ph Step 1 Add DCCI (0.81 g, 3.9 moles) to a stirred solution of BOC (R) - to -MePheOH (1.0 g, 3.58 moles) and HOBT »H2O (0.69 g, 4.48 moles) in ethyl acetate (100 mL) at room temperature for 2 hours. The reaction mixture is filtered and a solution of (s) -α-methylbenzylamine (0.65 g, 5.37 mol) in ethyl acetate (25 mL) is added dropwise over 30 minutes. The mixture is stirred for 16 hours, extracted with a solution of 10% citric acid (2 x 25 mL), saturated NaHCO3 (25 mL) and once with saline (25 mL) and dried (MgSO4). Further purification by column chromatography on silica using 25% ethyl acetate: hexane gives a solid (1.23 g, 90%), mp = 154 ° C. IR (film): 3329, 2975, 1684, 1646 and 1519 cm '1. 1H NMR (CDC13): d 1.41 (3H, s, CH3), 1.44 (9H, s, C (CH3) 3), 1.48 (3H , d, J = 6.8 Hz, CH3CH), 3.07 (1H, d, J = 13.6 Hz, PhCHH), 3.42 (1H, d, J = 13.6 Hz, PhCHH), 4.73 (1H, b, NHCO2 -), 5.09-5.13 (1H, m, PhCH (CH3) NH), 6.60 (1H, b, CONH), 7.09 - 7.11 (2H, m, Ar) and 7.23-7.33 (8H, m, Ar). m / e (Cl): 383, 327, 283, 178 and 134. [a] 20D = +28.2 (C = 1.15, acetone). Analysis calculated for C23H30N2O3 • 0.1 H2O: C, 71.14; H, 7.84; N, 7.22. Found: C, 71.04; H, 7.78; N, 7.14.
BOC (R) a-MePheNH s Ph > TFA »(R) a-MePheNH S Ph Step 2 The protected BOC amine (500 mg, 1.31 moles) is dissolved in dichloromethane: TFA (5 mL, 1: 1 mixture) and stirred at room temperature for one hour. The solvents are removed in vacuo and diethyl ether is added to the resulting syrup to precipitate a white solid (493 mg, 95%). IR (film): 3269, 3066, 2561, 1668, 1202 and 1135 cm '1. 1 H NMR (DMSO-d6): d 1.38 (3H, d, J = 6.8 Hz, CH3CH), 1.50 (3H, s, CÜ ), 3.04 (1H, d, J = 14.0 Hz, PhCHH), 3.22 (1H, d, J = 14.4 Hz, PhCHH), 4.89-4.93 (1H, m, CH3CH), 7.17-7.34 (10H, m, Ar ), 8.04 (3H, b, + NH3) and 8.67 (1H, d, J = 7.6 Hz, CONHCH).
Step 3 A 2.0 M solution of magnesium chloride isopropyl (6.0 mL, 12.0 moles) in ether is added dropwise for 5 minutes to a stirred solution of p-fluorobenzaldehyde (1.Olg, 8.15 moles) in ether (20 mL). , cool in a bath of ice water and stir for 20 minutes. The mixture is stirred at room temperature for 40 minutes and turned off with a 10% citric acid solution (25 mL). The layers are separated and the aqueous solution is back extracted with ether (2 x 25 mL). The combined ether extracts are washed with saline (25 mL) and dried (MgSO4). Evaporation and further purification by column chromatography on silica using 30% diethyl ether: hexane yield alcohol (0.97 g, 71%). IR (film): 3379, 2962, 2874, 1605, 1510, 1224 and 1157 cm '1. 1H NMR (CDC13): d 0.78 (3H, d, J = 7.2 Hz, CfcCHCH), 0.99 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.85 (1H, b, CH-OH), 1.86 - 1.96 (1H, m, CH3CHCH3), 4.35 (1H, d, J = 6.8 Hz, Ar CHOH), 7.00 - 7.05 (2H, m, Ar) and 7.25 - 7.30 (2H, m, Ar). m / e (CI): 151, 125, 109 and 97. Analysis calculated for C 10 H 3FO: C, 70.40; H, 7.79; N, 1 1.29. It was found: C, 71.17; H, 7.70; N, 10.99.
Pyridine (0.44 mL, 5.44 moles) in dichloromethane anhydride (10 mL) is added dropwise for 50 minutes to a solution of the alcohol (0.823 g, 4.95 moles) and p-nitrophenylchloroformate (1.10 g, 5.44 moles and dichloromethane anhydride (10 mL). The solution is allowed to warm to room temperature and stirred for 20 hours.The solvent is removed in vacuo and the residue is taken up in diethyl ether (50 mL), washed with a solution of 10% citric acid (2 x 25 mL) and saline (25 mL) and dried (MgSO 4). Evaporation and further purification by column chromatography on silica using 10% ether: hexane gives the carbonate (1.35 g, 82%). IR (film): 2968, 1765, 1526, 1347, 1255, 1217 and 1160 cm "1. 1 H NMR (CDC13): d 0.83 (3H, d, J = 6.8 Hz, CHsCHCH,), 1.10 ( 3H, d, J = 6.8 Hz, CH3CHCH3) 2.19 - 2.25 (1H, m, CH3CHCH3), 5.34 (1H, d, J = 8.0 Hz, ArCHO -), 7.06 -7.10 (2H, m, Ar), 7.31 - 7.36 (4H, m, Ar) and 8.25 (2H, d, J = 8.4 Hz, Ar). calculated for d7Hi6N FNO3: C, 61.26; H, 4.84; N, 4.20; F, 5.70. Found: C, 61.30; H, 4.90; N, 4.1 1; F, 5.68.
PheNH S 'Ph DMAP (31 mg, 0.25 mol) is added to a solution of amine salt (75 mg, 0.189 mol) and carbonate (76 mg, 0.227 mol) in DMF (5 mL) and stirred at room temperature for one day . S added additional carbonate (41 mg, 0.123 mol) and stirred continuously for three days. The reaction mixture is diluted with ethyl acetate (50 mL) and washed with a solution of 10% potassium carbonate (6 x 25 mL) and saline (25 mL). Dry (MgSO4) and chromatograph on silica using 25% EtOAc: hexane followed by HPLC prepared using 70% to 90% CH3: H2O gives the product (1.5 mg, 2%), mp 142-165 ° C. IR (film): 3330, 2922, 1671, 1439, 1203 and 1135 cm '1. 1H NMR (CDC13): d 0.76 - 0.79 (3H, m, CHs), 0.93 - 0.98 (3H, m, CH), 1.26 - 1.49 (6H, m, 2 x CHs), 1.99 - 2.05 (1H, m, CHsCHCHs), 3.08 - 3.33 (2H, m, PhCHH), 4.98 - 5.06 (1H, m, PhCHNHCO), 5.21 and 5.34 (1H , 2s, OCONH), 5.35 (1H, d, J = 7.6 Hz, PhCHO -), 6.29 - 6.35 (1H, m, CONH), 6.93 - 7.04 (4H, m, Ar) and 7.12 - 7.34 (10H, m , Ar). m / e (Cl): 477, 283 and 151. HPLC: 99.7%.

Claims (14)

1. A compound of the formula or a pharmaceutically acceptable salt wherein: •, A and "indicate all stereoisomers in these carbon atoms; Ar1 is phenyl unsubstituted or substituted by from 1 to 3 substitutes chosen from: alkyl, halogen, nitro, trifluoromethyl, cyano, hydroxy and alkoxy, Ar 1 may also be pyridine, R 1 is hydrogen or a straight or branched or cycloalkyl of from 1 to 7 atoms; Ar1 and R1 form a chain of 5 to 8 atoms when they are attached to a bond; n is an integer from 0 to 2; A is OCONH, CONH, CO2, NHCONH, CH2NH and COCH2; Ar2 is phenyl as defined in Ar1 above; pyridine, thiophene, naphthyl, nature, benzofuran, benzothiofene or imidazole; X is - OCONH - CONH -, - CO2 -, - NHCONH -, - CH2NH -, - CONCH3 -, - CH2O -, - CH = CH -; R2 is hydrogen, methyl. phenyl, benzyl, CH2C6H1 1 or R3 is hydrogen or methyl; Y is - (CH2) m -, - (CH2) mO -, where m is an integer of from 1 to 5, - CONH -, - CH2NH, - COCH2 - or - CH = CH -; And R4 is hydrogen, straight or branched alkyl of from 1 to 8 atoms unsubstituted or substituted by a substitute chosen from: hydrogen, OR5, NHCOCH3, NR5R6, SO2CH3, SO2NH2, NHCONH2, CONR5R6, COR5 wherein R and R are each independently hydrogen or alkyl and R - (CH2) V "V (CH2) qR7, - (CH,) M- (CK f - (CH -NO- CH- O CH) 0 (CH.}. .. R (CH -O (CHJ R wherein p is an integer from 0 to 5, q is an integer from 0 to 4 and R7 is hydrogen, hydroxy, alkoxy, CONR5R6 or NHCONR5R6 wherein R5 and R6 are as described above.
2. A compound according to Claim 1 wherein: • is S or R, - ** is R and "is S; Ar1 is phenyl unsubstituted or substituted with from 1 to 2 substituted substitutes of: alkyl, halogen, cyano and alkoxy; R1 is a straight, branched or cyclic alkyl of from 1 to 6 atoms, or Ar1 and R1 form a chain of 7 atoms, n is an integer from 0 to 1, A is OCONH, CONH, NHCONH or CH2NH; A2 is phenyl as defined in Ar1 above, pyridine, thiophene, naphthyl or benzofuran, X is OCONH, CONH, NHCONH, CH2NH, CONCH3 or COCH2, R2 is hydrogen, phenyl, benzyl or R3 is hydrogen or methyl; Y is (CH2) m, CONH, CH2NH, or COCH2; R 4 is hydrogen, straight or branched alkyl of from 3 to 7 atoms with a substitute chosen from: OR 5, NHCOCH 3, SO 2 CH 3, SO 2 NH 3, NHCONH 2, CONR 5 R 6, COR 5, wherein R 5 and R 6 are each independently hydrogen or alkyl and wherein p is an integer from 0 to 2, q is an integer from 0 to 3 and R7 is hydroxy, alkoxy, CONR5R6 or NHCONR5R6.
3. A compound according to Claim 1 wherein • is S or R, A is R and "is S; Ar1 is phenyl unsubstituted or substituted by halogen, cyano or alkyl; R1 is a branched or cyclic of from 3 to 6 atoms, or Ar1 and R1 form a chain of 7 atoms, n is 0, A is OCONH, or NHCONH, A2 is phenyl unsubstituted or substituted by halogen, cyano or alkyl or Ar2 is thiophene, naphthyl or benzofuran, X is CONH, CH2NH or COCH2; R is hydrogen, phenyl or R3 is hydrogen or methyl; And it's CH2 or CONH; R4 is hydrogen, alkyl which is a straight chain of from 4 to 6 atoms with a substitute chosen from: bidroxy, NHCOCH3, NHCONH2.
4. A compound according to claim 1 and chosen from: Carbamic acid, [2 - [(9-amino-9-oxononyl) amino] -1-methyl-2-oxo-1 -) phenylmethyl) ethyl] -, 2-methyl - 1 - phenylpropyl ester, [R - (R *, S *)] -; Carbamic acid, [2 - [(9-amino-9-oxononyl) amino] -1-methyl-2-oxo-1- (phenylmethyl) ethyl] -, 1- (4-chloro-phenyl) -2-methylpropyl ester; [1- (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid cyclopentyl-phenyl-methyl ester; [1 - (8-Carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 6,7,8,9-tetrahydro-5H-benzocycloethene-5-yl-ester; and [1 - (8-carbamoyl-octylcarbamoyl) -1-methyl-2-femyl-ethyl] -carbamic acid 2,2-dimethyl-1-2,3,4-tetrahydro-naphthalen-1-yl-ester;
5. A compound according to Claim 1 and chosen from: Carbamic acid, [1-methyl-2-oxo-2 - [(1-phenylethyl) -amino] -1 (phenylmethyl) ethyl] -, (R) or (S) - 2-methyl-1-phenylpropyl ester, [R - (R *, S *)] -; [1-methyl-1 - (1-methyl-1-phenyl-ethylcarbamoyl) -2-phenyl-ethyl] - carbamic acid 2 - . 2-methyl-1-phenyl-propyl ester; and [1 - (2-hydroxy-1-phenyl-ethylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester;
6. A compound according to Claim 1 and chosen from: Carbamic acid, [2 - [(8-hydroxyoctyl) amino] -1- (1H-indol-3-ylmethyl) -1-methyl-2-oxoethyl] -, 2 - methyl-1-phenylpropyl ester; [2 - (2-fluoro-phenyl) -1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester; [2 - (2,3-difluoro-phenyl) -1-methyl-1- (7-ureido-heptylcarbamoyl) -ethyl] -carbamic acid 2-methyl-1-phenyl-propyl ester; and [1 - (8-carbamoyl-octylcarbamoyl) -1-methyl-2-phenyl-ethyl] -carbamic acid 6.6 - dimethyl-6,7,8,9-tetrabidro-5H-benzocycloethene-5-yl ester;
7. A compound according to Claim 1 and chosen from:. { 1 - [1 - (6-hydroxy-hexylcarbamoyl) -2- (4-hydroxy-phenyl) -ethylcarbamoyl] - 1-methyl-2-phenyl-ethyl} - carbamic acid-2-methyl-1-phenyl-propyl ester; . { 1 - [1 - (7-hydroxy-heptylcarbamoyl) -2- (4-hydroxy-phenyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} - carbamic acid 2-methyl-1-phenyl-propyl ester; Y . { 1 - [2 - (4-hydroxy-phenyl) -1- (6-ureido-hexylcarbamoyl) -ethylcarbamoyl] -1-methyl-2-phenyl-ethyl} Carbamic acid 2-methyl-1-phenyl-propyl ester.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
9. A method for treating disorders of the central nervous system in a mammal comprising the administration of the composition according to claim 1 to said mammal.
10. A method for treating gastrointestinal disorders in a mammal comprising administering the composition according to claim 1 to said mammal.
11. A method for treating respiratory disorders in a mammal comprising administering the composition according to claim 1 to said mammal.
12. A method for treating inflammatory disorders in a mammal comprising administering the composition according to claim 1 to said mammal.
13. A method for treating disorders of circulatory insufficiency in a mammal comprising the administration of the composition according to claim 1 to said mammal.
14. A method for antagonizing the effects of NKB on NK3 receptors in a mammal comprising the administration of a compound according to claim 1 to said mammal.
MXPA/A/1997/005841A 1995-03-20 1997-07-31 No peptides as antagonists of the taquiquin MXPA97005841A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/406,607 US5554641A (en) 1995-03-20 1995-03-20 Nonpeptides as tachykinin antagonists
US08406607 1995-03-20
PCT/US1996/003373 WO1996029304A1 (en) 1995-03-20 1996-03-12 Nonpeptides as tachykinin antagonists

Publications (2)

Publication Number Publication Date
MX9705841A MX9705841A (en) 1997-11-29
MXPA97005841A true MXPA97005841A (en) 1998-07-03

Family

ID=

Similar Documents

Publication Publication Date Title
EP0817770B1 (en) Nonpeptides as tachykinin antagonists
US5610145A (en) Tachykinin antagonists
CA2087652A1 (en) Biaryl substituted 4-amino-butyric acid amides
US5739164A (en) Pharmaceutical compounds for the treatment of CNS diseases
HUT73428A (en) Thiazolidine derivatives, preparation thereof and drugs containing same
IE51918B1 (en) Bicyclic compounds their production and use
HRP20020264A2 (en) 2&#39;-substituted 1,1&#39;-biphenyl-2-carbonamides, method for the production thereof, use thereof as a medicament and pharmaceutical preparations containing said compounds
JPS6112911B2 (en)
MXPA05005977A (en) Arylene-carboxylic acid (2-amino-phenyl)-amide derivatives as pharmaceutical agents.
EP0024965B1 (en) Fluorinated methyl beta-alanine derivatives, their preparation and pharmaceutical compositions containing them
US5356925A (en) N-(mercaptoalkyl)ureas and carbamates
IE67290B1 (en) Novel cholecystokinin antagonists their preparation and therapeutic use
US5643904A (en) Substituted hexahdryoazepinones and tetrahydrobenzazepinones
AU704261B2 (en) Novel tricyclic amides, processes for their preparation and the pharmaceutical compositions which contain them
CA1329617C (en) Resolved amino pyrrolidine neuroprotective agents
MXPA97005841A (en) No peptides as antagonists of the taquiquin
IL118869A (en) ANTIMICROBIAL MIXTURES COMPRISING α-AMINO ACIDS AND CYCLOPENTANE-β-AMINO ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP0605667A1 (en) Diamine derivatives having selective affinity for sigma receptors
JP4064237B2 (en) Prodrugs of excitatory amino acids
FR2700540A1 (en) alpha-methyl- (R) -tryptophyl-arylcycloalkylalkylamides ligands to gastrin receptors, their preparation and their use in therapy.
EP0826663B1 (en) Alkynylamino acid derivatives and their use as pharmaceutical compounds
KR900006685B1 (en) Transglutaminase Inhibitor
MXPA00005677A (en) Hemiasterlin analogs
CA2233077A1 (en) Pharmaceutical compounds