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MXPA01000268A - N-substituted naphthalene carboxamides as neurokinin-receptor antagonists - Google Patents

N-substituted naphthalene carboxamides as neurokinin-receptor antagonists

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Publication number
MXPA01000268A
MXPA01000268A MXPA/A/2001/000268A MXPA01000268A MXPA01000268A MX PA01000268 A MXPA01000268 A MX PA01000268A MX PA01000268 A MXPA01000268 A MX PA01000268A MX PA01000268 A MXPA01000268 A MX PA01000268A
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Mexico
Prior art keywords
methyl
cyano
piperidine
dcm
solution
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MXPA/A/2001/000268A
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Spanish (es)
Inventor
Peter Robert Bernstein
Robert Frank Dedinas
Keith Russell
Ashokkumar Bhikkappa Shenvi
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Astrazeneca Ab
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Publication of MXPA01000268A publication Critical patent/MXPA01000268A/en

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Abstract

A compound of formula (I) wherein:R is alkyl;R1 is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl;R2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl where the alkyl groups are the same or different, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different. X1 and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo;and R3, R4, R5, and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl are antagonists of at least one tachykinin receptor and are useful in the treatment of depression, anxiety, asthma, pain, inflammation, urinary incontinence and other disease conditions. Processes for their preparation are described, as are compositions containing them and their use.

Description

- - NAFTALENCARBOXAMIDAS N-SUBSTITUTED AS ANTAGONISTS OF THE NEUROCININ RECEPTOR The invention relates to N-substituted naphthalenecarboxamides, to pharmaceutical compositions containing such compounds, as well as the uses and processes of their preparation. The pharmacological actions of endogenous neuropeptide tachykinin antagonist compounds known as neurokinins are useful when such antagonisms. Tachykinins are a family of neuropeptides which share a common C-terminal amino acid sequence. Mammalian tachykinins include the substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), in addition these are at least two N-terminal extensible NKA forms designated as neuropeptide and a neuropeptide K. Tachykinins are distributed Widely in the peripheral and central nervous system. At least three types of receptors are known by the three main tachykinins and are based on their relative selectivities favoring the SP, NKA and NKB agonists, the receptors are classified as NK1 receptors (neurokinin 1), NK2 (neurokinin 2) and NK3 ( neurokinin 3) respectively. As described above SP, NKA and NKB are found No. Ref.: 125692 . -Afe? Sßs ^ asS ^ within the central nervous system. The SP is co-located frequently with NKA. In the peripheral nervous system, NKA and SP are located predominantly at the termination of the primary afferent neuron sensitive to capsaicin. A second major source of tachykinin in the peripheral neuronal cell body of the myenteric and submucous plexuses of the intestinal tract. Other neuronal sources include the neurons that intervene in the salivary glands and a small proportion of intramural neurons in the urinary bladder. The similar immunoreactivity of tachykinin has been demonstrated at several sites including the endocrine cells of the intestine, the parenchymal cell in the body of the carotid, the chromaffin cell of the adrenal glands, the anterior pituitary cells, eosinophils and the vascular endothelial cell. It has been shown that human lymphocytes produce the substance P. An important action of tachykinin is the neuronal stimulation that is thought, bases its actions on the CNS, for example, the excitation of second-order sensory neurons in the spinal cord. The activation of marrow reflexes and the induction of pain, the induction of central neurochemical responses such as the stimulation of dopamine metabolism, autonomic responses and the modulation of water absorption and == £ SSS-SgS3 ^ ^ iSes-fe -? - ugly **. ..
Salt. In peripheral neuronal stimulation by tachykinin leads to the facilitation of transmitter release for example, the contraction of guinea pigs is particularly mediated by neurogenic mechanisms and particularly by direct effects. Tachykinins modulate neuronal activity in sympathetic ganglia. Tachykinin released from collateral and primary afferent neurons act as mediators of excitatory postsynaptic low excitation potentials.
Central administration of SP and NKA induce tachycardia and an increase in blood pressure in rats via activation of sympathetic nerve activity. Tachykinins produce a vasodilatation that depends on the endothelium which is measurable in vivo as a transient hypotension following an intravenous infusion. The effect is mediated via NKi receptors, located in the endothelial cell and passed to involve the release of nitric oxide. The cell-mediated stimulation of tachykinin The endothelium also induces its proliferation, migration and angiogenesis, indicating a possible role in the growth and I repair. In certain blood vessels tachykinin induces vasoconstriction for example, via the NK2 and NK3 receptors in the rabbit pulmonary artery and the hepatic portal vein of üKfe idio a rat respectively. Smooth muscle contraction mediated by tachykinin seems to be predominant due to a direct spas muscle effect in the muscle. The combination of this direct effect with the stimulated release of tachykinins from tachykinin from the nerve endings forms the basis for their excitatory neurotransmitter states in the airways, urinary tract and intestine. In human bronchi, urinary bladder, urethra and colon, the NK2 receptor is the mediator of its stimulation responses. Tachykinins can also induce smooth muscle relaxation via a NKi receptor mediated stimulation of prostanoid production in the epithelial cell airway. SP, NKA and / or NKB have been implicated in the pathology of numerous conditions that include asthma, allergic rhinitis, chronic obstructive pulmonary diseases (COPD), pulmonary hypertension, airway reactivity, cough, cold, hives, inflammation (which includes neurogenic inflammation), pain, various pain states (including neuropathic pain, visceral pain, eye pain), migraine, tension, headache, angiogenesis, rheumatoid arthritis, psychosis that include depression and anxiety, including major ailments of depression, major depressive disorders with anxiety, cognitive disorders, movement disorders, bipolar disorders, illnesses due to the use of substances, suffering from stress, sleep disorders, movement disorders, panic attacks and social phobias, hobbies, hypomanias, behavior aggressive, premenstrual tension and conditions associated with appetite, loss of memory, emesis , (including emesis of resistance to ondansetron), hypertension, edema, Huntingdon syndrome, Alzheimer's syndrome, schizophrenia, neuronal diseases such as epileptic seizures, spinal cord diseases, Parkinson's disease, gastrointestinal hypermobility, "gastric asthma", condition of gastroesophageal reflux, Crohn's disease, gastric emptying syndrome, ulcerative colitis, irritable bowel syndrome, inflammatory bowel syndrome, hypermobility of the bladder, urinary incontinence, cystitis, obesity, bulimia nervosa, cancer, parathyroid hormone deficiency, loss of bones, growth of mammalian hair, sexual dysfunction, tardive dyskinesia, renal diseases, skin disorders and scabies (for example atopic dermatitis and psoriasis). Examples of reviews covering the use of antagonist tachykinins in various conditions of these conditions are: Maggi, CA. , Patacchini, R, Rovero, P and Giachetti, A (1993). Tachykinin receptor antagonists and T-tachykinin receptors Auton. Pharma col 13, 23-93; Read Me S. (1996), NKi tachykinin receptor of the non-peptide antagonist Med. Res. Rev. 16, 297-31 7; Raffa RB, 5 Possible role (s) of neurokinin in the development of CNS and neurodegenerative or other conditions. Neuroscience & Biobehavioral Reviews. 22 (6): 789-813, 1998 Oct; Holzer P, Implications of tachykinins and peptide of genes related to calcitonin in inflammatory conditions of the intestine. I gave management. 59 (4): 269-83, 1998 Jul-Aug; Maggi CA, tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity. Pharmacologi cal Research. 36 (2): 153-69, 1997 Aug; Kudlacz EM, Expert Opinion. Invest. Drugs (1998), 7 (7), 1055-62; and von Sprecher et al, Drugs (1998), 1 (1), 73-91. The N-substituted naphthalenecarboxamide compounds of the present invention are antagonists to at least one of the tachykinin receptors and are of great value in treating the conditions involved in the treatment. condition In particular, the compounds possess a high degree of NK1 and / or NK2 receptor antagonist activity. Additionally, by manipulating the substituents on the naphthalene and piperidino rings of the formula (I) below, the ratio of the activity of The NK1 and NK2 receptors can be modified, giving compounds that are predominantly active at the NK1 or NK2 receptors, or giving compounds with a balanced activity and, as such, are particularly useful when the combined antagonisms of both receivers are desired. In particular, the preferred compounds of the present invention also possess high degrees of NK1 and / or NK2 antagonisms in oral administration. Accordingly, the present invention provides the (i) compounds of formula (1): wherein R is alkyl; R1 is optionally substituted phenyl, 2-oxo-tetrahydro-1 (2H) -pipmidinyl, or 2-oxo-l-p-peridinyl; R 2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl wherein the alkyl groups are the same or different, hydroxy, thioacyl, thiocarbamoyl, N-alkylcarbamoyl, or N , N-dialkylthiocarbamolo wherein the alkyl groups are the same or different. Xi and X2 are independently hydrogen or halo, with the proviso that at least one of Xi or X2 is halo; And R3, R4, R5, and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl, with the proviso that at least one of R3, R4, R5, and R6 is not hydrogen; and pharmaceutically acceptable salts and in vivo hydrolysable precursors thereof. "Alkyl" means a saturated aliphatic hydrocarbon group which may be linear or branched and having from about 1 to about 20 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl that bind to a linear alkyl chain. Preferred alkyl groups are alkyl groups which are those alkyl groups having from 1 to about 6 carbons, for example C6-6 alkyl. "Acyl" means an alkylcarbonyl group for example C? -6 alkanoyl. "Thioacyl" means an alkylthiocarbonyl group - '• • iiiliiiÉMfcW XMHMÍ & * S? ~ * mK - -for example C? _6 alkylthiocarbonyl. R is alkyl for example C? _6 alkyl such as methyl, ethyl or n-propyl. R is preferably methyl in such a way that in one aspect of the present invention it provides the compounds of the formula (I) wherein R is methyl and pharmaceutically acceptable salts thereof. In a further aspect the present invention provides the compounds of formula (1) wherein R is methyl, R1, Xi and X2 are as mentioned above; and R 2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl or N, N-dialkylthiocarbamoyl, and pharmaceutically acceptable salts thereof. In one aspect R1 is optionally substituted phenyl. Suitable substituents for the phenyl ring include: Alkyl such as C? -6 alkyl for example methyl or ethyl; alkylthio such as C? _6 alkylthio for example methylthio or ethylthio; alkylsulfinyl such as C6-6 alkylsulfinyl by way of methylisulfinyl, ethylsulfinyl or propylsulfinyl; alkylsulfonyl such as C6-6 alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; hydroxy; alkoxy such as C6-6 alkoxy for example methoxy or ethoxy; Not me; halo for example fluoro, chloro bromo or iodo; carboxy; alkoxycarbonyl such as C6-alkoxycarbonyl for example methoxycarbonyl; nitro; alkylamino such as C? _6 alkylamino for example methylamino or ethylamino; di-alkylamino (wherein the alkyl groups may be the same or different) such as di-C? -6 alkylamino for example dimethylamino; trifluoromethyl; carbamoyl; alkylcarbamoyl such as C? -6 alkylcarbamoyl for example methylcarbamoyl; di-alkylcarbamoyl (wherein the alkyl groups may be the same or different) such as di-C? -6-alkylcarbamoyl for example dimethylcarbamoyl; trifluoromethylthio; trifluoromethylsulfinyl; tfluoromethylsulfonyl; alkanesulfonamido such as C6-alkanesulfonamido for example methanesulfonamido; alkanol such as C? _6 alkanoyl for example acetyl; Succinamide; N-alkoxy, N-alkylamino such as N-C? -6 alkoxy, N-C? -6 alkylamino for example N-methoxy, N-methylamino; alkanoylamino such as C6-6 alkanoylamino for example acetamido or propionamido; ureido; alkylureide such as C? _6 alkylureide for example methylureide (MeNHCONH-) di-alkylreido such as C? -6 di-alkylureido for example dimethylureido; alkylsulfonyloxy such as C6-6 alkylsulfonyloxy for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N, N-dialkylamino such as N-oxo-N, N-di-C? _6 alkylamino for example N-oxo-N, N-dimethylamino; alkoxycarbonylamino such as C6-alkoxycarbonylamino for example methoxycarbonylamino; alkoxycarbonylcarbonylamino such as C6-6 alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; alkylcarbamoylalkoxy such as C? -6 alkylcarbamoyl C? -6 alkoxy for example methylcarbamoyl-methoxy; dialkylcarbamoyl C? _6 alkoxy such as di-C? -6 alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; and C? -6 alkyl for example methyl substituted by any of the above-mentioned substituents for example methylsulfinylmethyl. In one aspect R1 is a substituted phenyl group in the ortho position and in a preferred aspect the ortho substituent is C6-6 alkylthio for example methylthio; C? _6 alkylsulfinyl for example methylisulfinyl, ethylsulfinyl or propylsulfinyl; C6-alkylsulfonyl, for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C? -6 alkanesulfonamido for example methanesulfonamido; C? -6 alkanoyl for example acetyl or propionyl; C6-alkoxycarbonyl for example methoxycarbonyl; Succinamide; carbamoyl; C? -6 alkylcarbamoyl for example methylcarbamoyl; di-C? -6 alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; C? -6 alkoxy, C? -6 alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C? _6 alkanoylamino for example acetylamino; ureido, C? -6 alkylureido for example methylureido; di-C? alkyl alkylide, for example dimethylureide; - - Not me; C? -6 alkylamino for example methylamino or ethylamino; di-C? -6 alkylamino for example dimethylamino; C6-alkylsulfonyloxy, for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N, N-di-C? -6 alkylamino for example N-oxo-N, N-5 dimethylamino; C? -6 alkoxycarbonylamino for example methoxycarbonylamino; C_6 alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; C? -6 alkylcarbamoylalkoxy for example methylcarbamoylmethoxy; di-C? -6 alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; or methylsulfinylmethyl. In addition to the ortho substituent, the phenyl group may have additional substituents. In a further aspect the ortho substituent is C 6 alkylthio for example methylthio; C? -6 alkylsulfinyl by example methylisulfinyl, ethylsulfinyl or propylsulfinyl; C6-alkylsulfonyl, for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C? -6 alkanesulfonamido for example methanesulfonamido; C? -6 alkanoyl for example acetyl or propionyl; C-6 Alkoxycarbonyl for example methoxycarbonyl; Succinamide; carbamoyl; C? -6 alkylcarbamoyl for example methylcarbamoyl; di-C? _6 carbamoyl for example dimethylcarbamoyl; C? _6 alkoxy, C? -alkylcarbamoyl for example N-methoxy, N-methoxycarbamoyl; C6-alkanoylamino for example acetylamino; aa ^^ fe ^ aafe ^ tiiija? g Éfe ^ j ^ i, - '> ^^ -ureido, C? -6 alkylureido for example methylureido; di-C? -6 alkylureide for example dimethylureide; Not me; C? -6 alkylamino for example methylamino or ethylamino; or di-C? _6 alkylamino for example dimethylamino. In addition to the ortho substituent, the phenyl group may have additional substituents. Suitable additional substituents, which are optional, for the substituted phenyl ring ortho incl C? _6 alkyl for example methyl or ethyl; C? -6 alkylthio for example methylthio or ethylthio; C? -6 alkylsulfinyl for example methylisulfinyl, ethylsulfinyl or propylsulfinyl; C? _d alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; C? -6 alkoxy for example methoxy, ethoxy or propoxy; halo for example bromine, fluorine, chlorine or iodine; carboxy, C6-alkoxycarbonyl for example methoxycarbonyl; C? -6 alkanoyl for example acetyl or propionyl; nitro; Not me; C? _6 alkylamino for example methylamino or ethylamino; di C 1-6 alkylamino wherein the alkyl groups may be the same or different, for example dimethylamino; trifluoromethyl; CF3S (0) x where x is from 0 to 2, for example trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; C6-alkanoylamino for example acetylamino or propionylamino; C? -6 alkylsulfonamido for example methylsulfonamido; ureido; C? -6 alkylureido by tf¡S *? ¡»iSi? a > ÍM? 6áL * < * eá¡ * Av. - - example methylureido (MeNHCONH-), di-C? _6 alkylureido for example dimethylureido (Me2NCONH-); carbamoyl; C? _6 alkylcarbamoyl for example methylcarbamoyl; di-C? -6 alkylcarbamoyl wherein the alkyl groups may be the same or different, for example dimethylcarbamoyl; and C 1-6 alkyl for example methyl substituted by any of the above-mentioned substituents. Another suitable additional substituent for the ortho substituted ring is hydroxy. In one aspect, additional suitable substituents for an already substituted phenyl group in the ortho position are C? -6 alkyl, C? -6 alkylsulfinyl, C? _6 alkylsulfonyl, C? -6 alkoxy, amino, halo, carboxy, C? 6-alkoxycarbonyl, nitro, N-C? -6 alkylammo, N, N-di-C? -6 alkylamino (wherein the alkyl groups may be the same or different), trifluoromethyl, C? -6 alkylthio, carbamoyl, NC? -6 alkylcarbamoyl and N, N-di-C? -6 alkylcarbamoyl (wherein the alkyl groups may be the same or different), C? _6 alkanoyl, C? _6 alkane sulfonamido, trifluoromethylthio, trifluoromethylsulfinyl, hydroxy, ureido, C-6 alkylureide and d? -C? _6 alkylureide. Preferably these additional substituents are in the 4-position of the phenyl group. Preferred values for the ortho substituent are methylisulfinyl, ethylsulfinyl, propylsulfinyl, methylisulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, methanesulfonamido, acetyl, methoxycarbonyl, succinamido, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, N-methoxy, N-methylcarbamoyl, acetylamino, ureido, methylureido, dimethylureido, amino, methylamino or dimethylamino. In particular, the ortho substituent is methylisulfinyl, methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino. Of these, methylisulfinyl is particularly preferred. Favorably the ortho substituted phenyl ring was not further substituted or replaced by up to three optional substituents. In particular the ortho substituted phenyl ring is not further substituted or substituted at the 4-position, which is the position for the piperidino ring bond, to form a 2,4-disubstituted phenyl group, preferably a MeSO-2, a phenyl group 4 replaced. Preferred substituents are for the substituted phenyl ring ortho are methyl, methoxy, acetyl, acetylamino, methoxycarbonyl, methanesulphonylamino, methylisulfinyl, methylsulfonyl, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfinyl, bromine, fluoro, chloro, hydroxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylureido and dimethyluride. In particular ^ fZV **? ^ **** ^ K 'these preferred substituents may be in the 4-position of the phenyl ring. A preferred class of compounds is that wherein R1 is of the formula (la): (the) wherein Ra is hydrogen, C? -6 alkyl, C? _6 alkylsulfinyl, C? -6 alkylsulfonyl, C? _6 alkoxy, amino, halo, carboxy, C? -6 alkanoyloxy, nitro, NC? -6 alkylamino, C? -6 alkylamino, trifluoromethyl, C? -6 alkylthio, carbamoyl, C? _6 alkylcarbamoyl and di-C? -6 alkylcarbamoyl; and R2 is hydrogen. More preferably, Ra is hydrogen, C6-alkoxy for example methoxy or ethoxy, halo for example bromine, chlorine or fluoro, C6-6 alkylsulfinyl for example methylisulfinyl or carboxy. In one aspect Ra is hydrogen or C? _6 alkoxy. In another aspect Ra is hydrogen, C6-alkoxy or halo.
- - More particularly Ra is hydrogen, methoxy or fluoro. In a particularly preferred aspect Ra is hydrogen. In another particularly preferred aspect Ra is methoxy. The compounds of the invention have a number of chiral centers. It is preferred that the methylisulfinyl ortho substituents is present, has the stereochemistry shown in the formula (Ib): This is the S stereochemistry according to the Cahn-Prelong-Ingold Sequence Rule. The preferred values for R1 are therefore 2 (S) -methylsulfinylphenyl and 4-methoxy-2 (S) -methylsulfinylphenyl. In another aspect R1 is 2-oxotetrahydro-l (2H) -pyrimidmyl. In a further aspect R1 is 2-oxo-l-piperidinyl. . ¿¿¿^ ^ -. ^^ - & jY ^ i? * .y ~ - - - R2 is hydrogen; acyl such as C-6 alkanoyl, for example acetyl or propionyl; alkyl such as C-6 alkyl for example methyl or ethyl; carbamoyl; N-alkylcarbamoyl such as C? -6 alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; N, N-dialkylcarbamoyl such as di-C? -6 alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; thioacyl such as C-.6 alkylthiocarbonyl for example methylthiocarbonyl; thiocarbamoyl (NH2CS-); N-alkylthiocarbamoyl such as C? -6 alkylthiocarbamoyl for example methylcarbamoyl (MeNHCS-); N-N-dialkylthiocarbamoyl such as di-C6-6 alkylthiocarbamoyl for example dimethylthiocarbamoyl (Me2NCS-); alkoxy such as C6-alkoxy for example methoxy or ethoxy; alkanoyloxy such as C6-alkanoyloxy for example acetyloxy or propionoxy; alkoxycarbonyl such as C6-alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; or alkanoylamino such as C? _6 alkanoylamino for example acetylamino. In one aspect R2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl or N, N-dialkylthiocarbamoyl. In a preferred aspect R2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. When R1 is optionally substituted phenyl, preferably R2 is - hydrogen or hydroxy, more preferably hydrogen. When R1 is 2-oxo-tetrahydro-1- (2H) -pyrimidinyl or 2-oxo-1-piperidyl, preferably R2 is hydrogen, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. In another aspect, when R1 is 2-oxo-tetrahydro-l- (2H) -pyrimidinyl or 2-oxo-l-p-peridinyl, R2 is hydrogen or N-C? -6 alkylcarbamoyl for example methylcarbamoyl. PH-X ?, X2 is mono or di phenyl substituted by halo. Preferably halo is chloro or fluoro and in particular pH-X ?, X2 is 4-chloro, 4-fluoro or 3,4-dichloro or 3,4-dichloro. Of these, more 3,4-dichloro is preferred. R3, R4, R5 and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl or alkylsulfonyl (for example C6-6 alkylsulfonyl) with the proviso that at least one of R3-R6 is not hydrogen. Preferably R3 is hydrogen. Preferably R 4 is cyano, nitro or methylsulfonyl. Preferably R5 is hydrogen or cyano. Preferably R6 is hydrogen, cyano or nitro. More preferably R3 and R6 are hydrogen, R4 is cyano or nitro, and R5 is hydrogen or cyano. More preferably R3, R5 and R6 are hydrogen and R4 is cyano or nitro, in particular cyano to form the 3- cyano-naphth-1-yl group. The compounds of the present invention possess a - number of chiral centers to -CH (pH-X ?, X2) -, and possibly in the optional substituents (for example the MeSO- substituent) in the phenyl groups present. The present invention encompasses all isomers, diastereoisomers, atropisomers and mixtures thereof which antagonize tachykinin.
The preferred configuration in -CH (pH-X ?, X2). HE show in the formula (le) below: (you) A preferred class of the compounds is of the formula (II | wherein Ra is hydrogen, C? -6 alkoxy, halo, C? -6 alkylsulfinyl or carboxy; R3 is hydrogen; R4 is cyano or nitro; R5 is hydrogen or cyano; and R6 is hydrogen. In particular Ra is hydrogen, methoxy or fluoro; R3, R5 and R6 are all hydrogen and R4 is cyano or nitro, preferably cyano. In particular, the compounds of the present invention include those of the examples mentioned below. Pharmaceutically acceptable salts of the compounds of formula (I) include those made with organic and inorganic acids that provide a physiologically acceptable anion, such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluene sulfonic acid , acetic, citric, lactic, tartaric, malonic, fumaric, maleic, malic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicylic and quinic acid.
- - In vivo hydrolysable precursors include hydrolysable esters in vivo, amides and carbamates that hydrolyze in the animal body (for example human) to produce the main compounds. Such precursors, for example esters, amides and carbamates can be identified for example, by intravenous administration to an animal, the compound under test and by the subsequent examination of the body fluids of the animal test. Suitable in vivo hydrolysable precursors include carboxy (Rx OOC-) and hydroxy (Ry COO-) esters. To use a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable precursor thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, is formulated in accordance with standard pharmaceutical practices such as a pharmaceutical composition. Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a hydrolysable precursor in vivo and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the invention can be administered in a standard manner by the condition of the condition to be treated, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention can be formulated by knowledge in the art in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely powders. divided or aerosols or sprays by inhalation, and for parenteral use (including intravenous, intramuscular or infusion) aqueous or oily solutions or sterile suspensions or emulsions. In addition to the compounds of the present invention, the pharmaceutical composition of the invention may also contain, or be co-administered (simultaneously or subsequently) with one or more pharmacological agents of value in the treatment of one or more conditions of the conditions referred to herein. . The pharmaceutical compositions of this invention will normally be administered to humans, so that, for example, a daily dose of 0.01 to 25 mg / Kg by weight (and preferably 0.1 to 5 mg / Kg body weight) is accepted. This daily dose can be given in divided doses as necessary, the precise amount of the compound accepted and the manner of administration depends on the weight, age and sex of the patient in question and in particular on the condition of the condition in question. according to the principles known in the art. Typically the dosage unit forms will contain about 1 mg to 500 mg of the compound of this invention. For example, a tablet or capsule by oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of formula (I) or a pharmaceutically acceptable salt or a hydrolysable precursor thereof in vivo. In another example, by administration by inhalation, a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof can be administered in a daily dose in a range of 5 to 100 mg, in one dose simple or divided from 2 to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w / w (and typically 5% w / w) of a compound of the formula (I) can be used. or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. Therefore, in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or a hydrolysable precursor - in vivo thereof for use in a method of the therapeutic treatment of the human or animal body. Yet, in a further aspect the present invention provides a method for treating a condition of suffering wherein the antagonism of at least one of the tachykinin receptors is beneficial which comprises administering to a patient in need thereof, in an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or a hydrolysable precursor in live of it. The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof in the preparation of a medicament for use in a condition of the condition wherein the antagonism of at least one tachykinin receptor is beneficial. In particular, the present invention provides a method of treating a condition of the condition wherein the antagonism of the NK1 and / or NK2 receptors is beneficial. In particular, the present invention provides a method for treating asthma which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. .
In particular, the present invention provides a method for treating chronic pulmonary obstruction disorders which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or a precursor. hydrolysable in vivo thereof. In particular, the present invention provides a method of treating pain which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In particular, the present invention provides a method for treating depression which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. . In particular, the present invention provides a method for treating urinary incontinence which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor of the same. In another aspect, the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof which comprises the processes: a) reacting a compound of the formula (I) with a compound of the formula (IV): Wherein R, R1 - R6, Xx and X2 are as defined hereinbefore; and L and L1 are groups such that the Reductive amination of the compounds of formula (III) and (IV) forming an N-C bond; or 3C "* t« sfeÍ% g,; agaM; «e> b) react a compound of the formula (V) with a compound of the formula (VIj: Wherein R1 - R6, R2, Xx and X2 are as defined above; and L2 is a leaving group; wherein any other functional group is protected, if necessary, and: i) removes any protective group; 11) optionally forming a pharmaceutically acceptable salt or a hydrolysable precursor m alive. The protecting groups can generally be chosen from any of the groups described in the literature or known to those skilled in the art as appropriate for the protection of the group in question, and can be introduced and eliminated by methods & amp? Tt k ^ $ i¡ £ NB [??! - -conventional; see for example: Theodora W. Greene et al., Wiley (1991), Protective Groups in Organic Chemistry; J F W McOmie, Plenum Press (1973) and Kocienski, Philip J, George Thieme Verlag (1994), Protective groups. The removal methods are chosen for the effect of removal of the protective group with minimal disorder of groups to another part of the molecule. It will also be appreciated that certain of the various substituents in the compounds of the formula (I) can be introduced by the standard aromatic substitution reactions or generated by the modifications of the conventional functional groups either before or immediately following the described processes above mentioned. Reagents and reaction conditions for such procedures are well known in the art. The pharmaceutically acceptable salts can be prepared from the corresponding acids in conventional manner. The pharmaceutically unacceptable salts can be useful as intermediates and such are another aspect of the present invention. In vivo hydrolysable precursors can be prepared from the corresponding functional derivatives in conventional manner at any convenient stage of the synthesis. 6S ¿t * & * ¿> It is well known in the art how to prepare optically active forms (for example for the resolution of racemic forms or by the synthesis of the optical active actuation materials) and how to determine them. the tachykinin antagonist properties by standard tests known in the art and those described hereinafter. The compounds of formula (III) and (IV) are reacted under reductive amination conditions. Typically in the compounds of the formula (III) L is hydrogen. Typically in the compounds of formula (IV) L1 is an oxo group that forms an aldehyde radical (ie, L1 and the carbon atom to which it is attached is OHC-). The reaction is typically carried out at a non-extreme temperature, for example 0-100 ° C, in a suitable temperature environment in a substantially inert solvent for example methanol or dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride. Alternatively, in the compounds of the formula (IV), L1 is a leaving group such as halo for example chlorine or bromine or is a sulfonate for example methanesulfonate or p-toluenesulfonate. Such compounds are reacted with compounds of the formula (III) wherein L is hydrogen in the presence of a base.
The compounds of the formula (III) are known or can be prepared in a conventional manner. The compounds of the formula (IV) can be prepared in a conventional manner. For example when L1 is oxo, the compounds of formula (IV) can be prepared by oxidation (VII) of a compound of the formula (VII): wherein X1, X2, R and R3-R6 are as described here above. Suitable oxidation conditions include Swern conditions for example oxidation with oxalyl chloride in the presence of dimethyl sulfoxide. The compounds of the formula (IV) wherein L 1 is a leaving group which can be prepared in a conventional manner from a compound of the formula (VII).
- The compounds of the formula (VII) can be prepared, for example by reacting a compound the formula (VI) with a compound of the formula (VIII): wherein R, X and X2 are as defined above under conventional acylation conditions. The compounds of formula (V) and (VI) can be reacted under conventional acylation conditions wherein the compound of formula (VI) is an acid or an activated acid derivative. Typical derivatives of activated acids are well known in the literature. These can be formed in situ from the acid or these can be prepared, isolated and subsequently reacted. Typically L2 is chlorine, forming the acid chloride. Typically the acylation reaction is carried out in the presence of a non-nucleophilic base, for example diisopropylethylamine, in a substantially inert solvent at a non-extreme temperature. The compounds of the formula (V) are known or can be prepared in a conventional manner. The compounds of the formulas (IV) and (VII) are not only useful intermediates but also have adequate tachykinin antagonist activity, in particular the NK1 receptor. Therefore, in another aspect the present invention provides a compound of the formula (IV) or (VII) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. Particularly more, the present invention provides a compound of the formula (IX): (IX) wherein X1, X2 and R3 R are as defined here above; R8 is -CHO; -CH2OR10 wherein R10 is hydrogen or an ester thereof or C6-6 alkyl; and R9 is hydrogen or a group R - as defined above. Or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. Suitably R9 is C? -6 alkyl for example methyl. In one aspect R8 is aldehyde (-CHO) or is a derivative thereof. A suitable derivative is an acetal, for example in the formula (Rb0) CH (0RC) - wherein Rb and Rc are independently selected from C? _6 alkyl or together form a C2-methylene chain to form a dioxo ring. More suitably Rb and Rc have the same value and are both methyl or ethyl. In a further aspect R8 is -CH2OR10 wherein R10 is hydrogen or C6-6alkyl. Preferably R10 is hydrogen, methyl or ethyl and in particular R10 is hydrogen. Still, in a further aspect R10 may represent a group forming an ester for example by forming a group of the formula -CH2OCORd wherein Rd is C? -6 alkyl for example methyl, aryl for example phenyl or aryl C-6 alkyl for example benzyl Accept them from <; -CHO and hydroxymethyl esters (HOCH2-) can be prepared as standard. The preferred values of X1, X2, R and R3-R6 are as described above by compounds of the formula (1). According to the compounds of the formula (IX), preferably -PhX? X2 - is 3,4-dichlorophenyl and R is methyl.
- - A preferred class of compounds is that of the formula (X): (X) wherein R is -CHO or an acetal thereof such as (CH30) 2CH-; or an ester thereof eg acetoxymethyl, or R8 methoxymethyl or ethoxymethyl; R4 is cyano or nitro; and R5 is hydrogen or cyano. In particular R5 is hydrogen and R4 is cyano or nitro, more preferably cyano, and R8 is -CHO or -CH2OH. These compounds antagonize the NK1 receptor in particular and are therefore particularly beneficial in the treatment of conditions of conditions mediated through such receptors, for example depression, anxiety, emesis, pain and other conditions of the disease identified in the literature. The compounds of formula (IX) and (X) can be formulated and administered as described herein ^^^^ toSB * 3fa5iWfc- > J - - above in relation to the compounds of the formula (I). The following biological test methods, data and examples serve to illustrate and further describe the invention. The utility of a compound of the invention or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof (referred to above, collectively referred to as a "compound") can be demonstrated by known tests and clinical studies.
Assay Linking the SP Receptor (Test A) The ability of a compound of the invention to antagonize the SP binding to the NK1 receptor can be demonstrated with an assay using the human NK1 receptor expressed in mouse erythroleukemia (MEL) cells. The human NK1 receptor is isolated and characterized as described in: B. Hopkins, et al. "Isolation and Pharmacological Characterization of NK1 Lung Receptor from Human Lung", Biochem, Biophys, Res. Comm., 1991, 180, 1110-1117, and the NKI receptor is expressed in mouse erythroleukemia (MEL) cells using A similar procedure described in Test B below In general, the compounds of the invention having NK1 antagonist activity were tested and demonstrated statistically significant binding activity in Test A with a Kx measurement of 1 microM or typically much less.
Test that binds the Neurocillin A Receptor (NKA) (Test The ability of a compound of the invention to antagonize NKA binding to the NK2 receptor can be demonstrated with an assay using the human NK2 receptor expressed in mouse erythroleukemia cells (MEL), as described in: Aharony, D. , et al. "Isolation and Pharmacological characterization of a hamster neurokinin A cDNA receptor" Molecular Pharmacology, 1994, 45, 9-19. The selectivity of a compound for binding the NK1 and NK2 receptors can be shown by determining these links to other receptors using standard assays, for example, using a tritiated NKB derivative in a tissue for selective preparation by NK3 receptors. In general, the compounds of the invention have an NK2 antagonist activity were tested and statistically demonstrated significant binding activity in Test A and in Test B with a Kx measurement of 1 microM or typically much lower.
? .J j.jaly.-; .---; - - Test that links the Neurocyanin B Receptor (NKB) (Test The ability of a compound of the invention to antagonize the binding of a selective NKB receptor linked to the NK3 receptor can be demonstrated with an assay using the human NK3 receptor, cloned from a human brain expressed in mouse erythroleukemia cells (MEL). ). The human NK3 receptor is expressed in MEL cells with a procedure similar to that described by the NK2 receptor of human in: Aharony, D., et al. "Isolation and Pharmacological Characterization of a Neurocynin A cDNA Receptor from a Hamster" Molecular Pharmacology, 1994, _45, 9-19. The selectivity of a compound to bind to the NK1 and NK2 receptors can be shown by the Determination of these bonds to other receptors using standard assays, for example, using a tritiated derivative of NKB in cloned cells expressing human NK3 receptors. In general, the compounds of the invention having NK2 antagonist activity that were tested, and demonstrated statistically significant binding activity in Test A and Test B with a Kx measurement of 1 microM or typically much lower.
Rabbit Pulmonary Artery: functional in vivo test of NKl & X? ^ aAA - - 'Test D) The ability of a compound of the invention to antagonize the action of the agonist Ac: - [Arg0, Sar3, Met (02) 1l1x] - Substance P (6-11), ASMSP, in a pulmonary lesion can be demonstrated as described in Bialecki et al. Kca channel antagonist reduces NO donor mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268: L152-L159, nineteen ninety five. Segments of damaged tissue from excised lung arteries of white New Zealand rabbits are suspended between stirrups of. stainless steel for isometric relaxation analysis under standard conditions in a physiological saline solution (PSS) containing indomethacin (5 microM, to block cyclooxygenase) and propranolol (1 microM, to block ß adrenergic receptors). The initial tension placed kn each tissue is 2 grams, which is maintained at tr ¿birds of the equilibrium period of 1.0 hour. Fee tissues washed with PSS at 15 minute intervals. After 30 and 45 minutes of washing, the following treatments were added: Thiorfano (1 micro M, to block EC3 .24.11), ((3R) -3- [(lS) -l- (3,4- d? chlorophenyl) -3- (4- [(R 3 S) -2-methylsulfinyl-phenyl] -pipepdmo) propyl] -2-ethyl-2,3-d? h? droisoindole-1- - - one) ( 0.03 micro M; to block described in: "Aharony D., et Characterization of ZD7944: A Novel, Potent and orally-Active Non-Peptide Neurokinin-A (NK-2) Antagonist Receptor Eur. Respir J. 12 (Suppl. 12): 20S, 1998"), and the given concentration of the compound was tested. After equilibration, phenylephrine (3 microM) was added to produce a steady state tissue contraction and a dose relaxation curve for ASMSP was constructed. The curves are completed with each tissue failure to relax, in addition to two consecutive doses. Papaverine (1 milliM) was then added to obtain a maximum relaxation reference. For antagonists that behave in a non-competitive manner, the percent inhibition of relaxation is determined at a given concentration of the antagonist. The percent inhibition is determined when a tested compound produces a statistically significant reduction in the maximum relaxation magnitude and is calculated as a reference percentage of the papaverine response. For antagonists that behave competitively, the powers are determined by calculating the negative value of the logarithm of the apparent dissociation of the constant (PkB) for each concentration tested. Statistical significance is determined when the -sS? ai value of P is < 0.05 using the study t test for damaged comparisons. In general, the compounds of the invention having NK1 antagonist activity were tested and demonstrated statistically significant negative logarithm values of the apparent dissociation of the constant in Test D with a pKB measurement of 6 or typically much higher.
In Vitro Functional Assay of NK2 (Test E) The ability of a compound of the invention to antagonize the action of the antagonist [β-ala8] NKA (4-10), BANK, in a lung tissue can be demonstrated as described in Bialecki et al. The Kca antagonist channel reduces the mediated relaxation of the NO donor of tracheal and vascular smooth muscles. Am. J. Physiol. 268: L152-L159, 1995. "The left and right pulmonary arteries are excised from the malignancy of New Zealand white rabbits.The pulmonary arteries are cut into ring segments and the intimal surface is gently scraped off the endothelium. of damaged pulmonary artery tissue are suspended in stainless steel stirrups for isometric tension analysis developed under standard conditions in a physiological salt solution (PSS) containing mdometacin, (5 microM; to inhibit cyclooxygenases). The initial tension placed on each fabric is 2 grams, which is maintained through 45 minutes of the equilibrium period. The tissues were washed with PPS at 15 minute intervals. After 15 minutes of equilibrating the period, 3 x 10 ~ 2 M KCl was applied for 60 minutes to test the viability of the tissue. The tissues are then washed extensively for 30 minutes. The concentration of the compound was tested, then added for 30 minutes before constructing the cumulative concentration response curve with BANK. The curve was considered complete when each tissue fails to contract additionally for 2 consecutive increases of BANK concentrations. BaCl2 (3 x 10"2 M) was then added to produce a maximum reference shrinkage.The percent inhibition is determined when a tested compound produces a statistically significant reduction in the magnitude of the maximum shrinkage and is calculated as a percent response Reference for BaCl 2. For antagonists that are competitive, the powers are determined by calculating the negative value of the logarithm of the apparent dissociation of the constant (pKB) for each concentration tested.Statistical significance is determined when the value of P is <0.05 - - using the study t tests for damaged comparisons In general, the compounds of the invention having NK2 antagonist activity were tested and demonstrated statistically significant negative logarithm values of the apparent dissociation of the constant in Test E with a measurement of pKB of 6 or typically much higher.
In vivo functional assay of NK1 and NK2 (Test F) The activity of a compound as well as an antagonist of NK1 and / or NK2 receptors can also be demonstrated in vivo in an animal laboratory as described in: Buckner et al. "Differential Blocking by NK1 and NK2 Antagonist Receptors of Bronchoconstriction Tachykinin Induced by Directly Acting Agonists and Indirectly Accepted Capsaicin, Serotonin and 2-Methyl-Serotonin in Anesthetized Guinea-pigs" J. Pharm. Exp. Ther., 1993, Vol 267 (3), pp 1168-1175. The test was carried out as follows. The compounds are tested in guinea pigs pretreated with intravenous indomethacin (10 mg / Kg, 20 min), propranolol (0.5 mg / Kg, 15 min.), And thiorphan (10 mg / kg, 10 min.). Antagonists or vehicles are administered via - intravenously and orally, 30 and 120'r'Binutes prior to the increase in agonist concentrations, respectively. The agonists used in this study are ASMSP (Ac- [Arg6, Sar9, Met (02) 1X] -SP (6-11)) and BANK (ß-ala-8 NKA4-10). It was administered intravenously., ASMSP was selected for NKl receptors, and BANK was selected for NK2 receptors. The maximum response is defined as the zero conductance (GL, 1 / Rp). The ED50 values are calculated (the dose of the agonist results in a reduction of GL to 50% of petrolatum), and converted to the negative logarithm (-logEDso). The ED50 values obtained from the present (P) and absence (A) of agonist, are used to calculate a dose ratio (P / A), an expression of potency. The data are expressed as a mean ± SEM and the statistical differences are determined using ANOVA / Tukey-Kramer and t-tests of the study, a p < 0.05 is considered statistically significant. The compounds of the present invention show marked activity in external tests and are considered useful for the treatment of those conditions in which the NK1 and / or NK2 receptors are involved, for example, in the treatment of asthma and related conditions. The results of tests of representative compounds of the present invention by the above methods are shown in Table 1 Table 1 Clinical Studies Due to the range of effects attributable to the actions of SP, NKA and NKB, compounds that are able to block their actions may also be useful as tools to evaluate the biological actions of other neurotransmitters in the tachykinin family. As a result, other aspects of the invention are provided by the use of a compound of formula I or a salt or precursor thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in the development of the new therapeutic reagents to treat conditions in which the SP or NKA use it in the development of new therapeutic agents for the treatment of the conditions in which SP or NKA are involved or for testing their - -diagnosis EXAMPLES The invention will now be illustrated by the following unlimited examples, in which they apply, unless otherwise stated: (i) the temperature is given in degrees Celsius (° C); unless they are established, operations that are carried out at room temperature, which is, a temperature in the range of 18-25 ° C; (ii) the organic solutions are dried through anhydrous magnesium sulfate; the evaporation of the solvent is carried out using a rotary evaporator under reduced pressure (600-4000 pascals, 4.5-30 mM Hg) with a bath at a temperature of up to 60 ° C; (iii) chromatography, means flash chromatography on silica gel; The thin layer of chromatography (TLC) is carried out on silica gel plates; (iv) in general, the course of the reactions are followed by TLC and the reaction time is given only by the illustration; (v) the melting points are incorrect (dec) and indicate the decomposition; Yl the end products tiifftén satisfactory proton nuclear magnetic resonance spectrum (NMR); (VÜ; when given, the NMR data are in the form of delta values for protons with a higher diagnosis, they are given in parts per million (PPM) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using deuterated chloroform (CDC13) as solvent; conventional abbreviations are used for signal shaping; for the AB spectrum the observed deviation is directly reported; the coupling constants (J) are given in Hz; RA designates an aromatic proton when such an assignment is made; , V111 the ratio of the solvent is given in volume: in terms of volume (v / v); and ix the chemical ionization of the spectral mass (MS) is operated using an automatic system with atmospheric pressure (APCl). Where indicated, the following alternative ionization methods are used; a) desorption by chemical ionization (Cl) using methane reactive gas and a direct exposure probe; or b) impact of electron (El). We report the masses corresponding to the - - major isotopic component of the lower mass of the compounds with multiple masses with little equivalent abundance (isotope partition).
Terms and abbreviations: the compositions of the solvent mixture are given as percentages of volume or volume ratio. In cases where the NMR spectrum is complex, only diagnostic signals, atmospheres, atmospheric pressure, Boc are reported; t-butoxycarbonyl, Cbz; benzyloxy-arbonyl, DCM; methylene chloride, DMF; N; N-dimethyl formamide, DMSO; dimethyl sulfoxide, Et20; diethyl ether, EtOAC; ethyl acetate, FAB; bombardment of fast atoms, h; hour (s), HPLC: liquid high pressure chromatography, min; minutes, NMR; nuclear magnetic resonance, psi; pounds per square inch, TFA; trifluoroacetic acid, THF; tetrahydrofuran. Examples of the compounds of the formula (I) are prepared either by reductive amination [process a); reacting compounds of formula (III) and (IV)] or acylation [process b); by reacting compounds of formula (V) and (VI). Standard reductive amination refers to typical procedures wherein a solution of an amine (1-1.2 equivalents), an aldehyde (1.2-1 equivalents) and an acetic acid (2 equivalents) are acidified in methanol for 5 to 60 minutes before adding NaBH3CN (1.7 equivalents). After 1 to 16 hours the reaction was optionally concentrated, DCM was dissolved, and washed with saturated sodium bicarbonate and then purified by chromatography.
Standard acylation refers to the typical procedure in which an acid chloride (1- 1.2 equivalents) is added to a stirred solution of an amine (1-1.2 equivalents) and triethylamine (2 equivalents) in DMC. After 1 to 16 hours the reaction was optionally concentrated, dissolved in DMC, and washed with saturated sodium bicarbonate and then purified by chromatography.
It was noted that a final compound was converted to citrate salt, the free base was combined with citric acid (1.0 equivalent) in methanol, concentrated under reduced pressure and dried under vacuum (25-70 ° C). When it was indicated that a compound was isolated by filtration of Et20, the citrate salt of the compound was stirred in Et2 for 12 to 18 h, removed by filtration, washed with Et20, and dried under vacuum at 25-70 ° C. C. In a few cases the free base was dissolved in DCM or acetonitrile, combined with citric acid in methanol, and the resulting mixture was concentrated and, optionally, washed with Et20. &M S ii á * Mx > It was noted that a final compound was converted to the hydrochloride salt, a solution of HCl in Et20 was added with stirring to the solution of the purified free base in DMC or methanol. The resulting precipitate was collected by filtration and dried under vacuum.
Example 1 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -10 1-piperinyl] butyl] -N-methyl-3-cyano-l- naftamide A stirred solution containing 3-cyano-l-naphthoic acid (0.1 g, 0.5 mmol), N, N-diisopropylethylamine (0.16 g, 1.26 mmol), and dry DCM (2.5 mL) was treated with a solution of tetramethylfluoroformamide hexafluorophosphate (TFFH) (0.16 g, 0.60 mmol) in dry DCM (1.0 mL). After 10 minutes, a solution containing N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] - was added. N-methylamino (0.22 g, 0.5 mmol) and dry DCM (0.6), and the The solution was stirred for 60 hours, then diluted with DCM and 1M aqueous acetic acid. After mixing, the layer was allowed to separate, the organic layers were removed, and the aqueous layers were extracted with additional DCM (2x). The organic extracts were combined, washed (NaHCO3 saturated), dried with (Na2SO4), filtered, and the DMC was evaporated in vacuo. The residue was purified by chromatography (0-10% CH3OH in DCM) to give the title compound (0.25 g) as a white foam residue. MS: m / z 5 632 (M + H). The product was converted to citrate salt and isolated by Et20 filtration to give N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfonylphenyl] citrate hydrate ] -l-piperidinyl] butyl] -N-methyl-3-cyano-1-naphthamide (1: 1: 0.75) (290 mg) as a white solid MS: m / z 632 (M + H). Analysis for C35H35C12N302S C6H807 • 0.75 H20: calculated: C, 58.74; H, 5.35; N, 5.01. Found C, 58.74; H, 5.24; N, 5.02. The title compound can also be converted in a manner similar to citrate hydrate (1.0: 1.0: 1.0). Alternatively, the title compound above was prepared by reacting the amine with 3-cyano-naphthoyl chloride. The required chloride acid was prepared as follows: a stirred mixture containing 3-cyano-l-naphthoic acid (0.18 g, 0.93 mmol) and dry DCM (7.5 mL) was treated with Oxalyl chloride (0.14 g, 1.15 mmol) and dry DMF (10 μL) at room temperature. After 4 hours, the solvent was evaporated in vacuo. The off-white solid residue was dissolved in dry DCM and used without further purification. Chloride was reacted using standard acylation conditions of 3-cyano-l-naphthoyl with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N- methyl «feLna. The product was converted to citrate salt and isolated by filtering Et20 to give citrate salt (740 mg) as a white solid. MS: m / z 632 (M + H). Analysis for C 34 H 35 Cl 2 N 3 O 4 S-C 6 H 8 7 7-0.5 H 2 O-0.40 C 4 H 10 O 4 (Et 20): calc'd: C, 59.26; H, 5.60; N, 4.87. Found: C, 59.14; H, 5.52; N, 4.78. In a similar manner, the title compound can also be converted to citrate hydrate (1.0: 1.0: 0.5).
The requirement of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methylamine was prepared as follows. (a) [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-N-Boc-amine. (S) -N- [2- (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-N-Boc-amine (Miller, SC, WO 9505377) (51.7 g, 149.3 mmol), 4- [ (S) -2-methylsulfinylphenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ, Jr.; Veale, CA., WO 9516682) (36.7g, 164.3 mmol), and glacial acetic acid (9.9 g, 165.0 mmol) was dissolved in methanol (1000 mL), and the solution was stirred for 15 minutes. Sodium cyanoborohydride (10.4 g, 165.5 mmol) was added in portions as a solid for 30 minutes. The mixture was stirred for 20 hours, then treated with saturated sodium bicarbonate (500 mL). The methanol was removed in vacuo, and the residue was washed with DCM (4 x 400 mL). The organic layer was washed with brine (300 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (0-6% methanol in DCM) to give a white foam (77.2 g, 93%). MS: 553 (M + H). XH-NMR (CDCl3) d 1.40 (s, 9H, t-C4H9); 1.61-2.04 (m, 9H, CH); 2.14-2.23 (m, 2H, CH); 2.62-2.79 (m, 6H, NCH3, SOCH3); 2.91-3.00 (m, 3H, CH); 3.27-3.54 (m, 2H, CH); 7.00-7.09 (m, 1H, aromatic); 7.21-7.53 (m, 5H, aromatic); 7.95-8.04 (m, 1H, aromatic). (b) [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methylamine. N- [(S) -2- (3, 4-dichlorophenyl) -4 [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methylamine-N-Boc-amine (77.0 g, 139.0 mmol) was dissolved in DCM (1200 mL ). To the stirred solution was added trifluoroacetic acid (160.0 g, 1.40 mol) dropwise over 15 minutes. The mixture was stirred for 4 hours, then trifluoroacetic acid (80.0 g, 0.70 mol) was added and the mixture was stirred an additional 1.5 hours. The mixture was washed with aqueous sodium carbonate (225g, 1500 mL of water), water (2 x 500 mL), then dried with (MgSO4). Filtration and concentration left the crude product as a yellow gum. Purification - by chromatography (0-20% methanol / DCM) provided a slightly yellow foam (61.8 g, 98%). MS: 453 (M + H). 1 H-NMR (CDCl 3) d 1.64-2.09 (m, 7H, CH); 2.27-2.35 (m, 2H, CH); 2.46 (S, 3H, NCH3); 2.68 (s, 3H, SOCH3); 2.74-3.05 (m, 7H, CH); 3.39-3.78 (bs, 1H, NH); 7.07-7.10 (m, 1H, aromatic); 7.23-7.50 (m, 5H, aromatic); 7.95-7.99 (m, 1H, aromatic).
The requirement of 3-cyano-l-naphthoic acid (Dewar, JS and Grisdale, PJ; J. Amer. Chem. Soc, 84, 3541-3546 (1992) was prepared as follows, (c) 3-cyano acid -l-naphthoic acid Using the procedure of the Rule, HG and Thompson, SB; J. Chem Soc. 1764-1767 (1937), 1, 8-naphthalic anhydride was brominated and converted to 3-bromo-l- acid. Naphthoic acid was esterified to methyl 3-bromo-l-naphthoate according to the following procedures. 3-Bromo-naphthoic acid (103.0 g, 410 mmol) was dissolved in DCM (1250 mL) and the solution was cooled to 0 ° C. Oxalyl chloride (67.5 g, 532 mmol) was added in one portion followed by a catalytic amount of DMF (1.5 mL), and the resulting solution was allowed to warm to room temperature and stir for 4 hours. The mixture was evaporated in vacuo, and the g'¿ £ ».i _. • residue was concentrated a second time with toluene. The resulting chloride acid was dissolved in methanol (1250 ml) and stirred at the temperature for 18 hours, the mixture was evaporated in vacuo, and the residue was purified by chromatography (eluent: DCM: hexane 1: 3) to give methyl 3-bromo-1-naphthoate as a white solid (106.9 g, 98%). XH-NMR (CDCl3) d 4.01 (s, 3H, C02CH3); 7.50-7.69 (M, 2H, aromatic); 7.78-7.87 (d, 1H, aromatic); 8.18 (s, 1H, aromatic); 8.25 (s, 1H, aromatic); 8.80-8.94 (d, 1H, aromatic). Using the procedure of Dewar, JS and Grisdale, PJ; J. Amer. Chem. Soc., 84, 3541-3546 (1962), methyl-3-bromo-l-naphthoate was converted to methyl 3-cyano-l-naphthoate and then saponified (liOH) of the title compound.
Example 1 A The title compound of example 1 can also be prepared in the following manner: a) Anhydrous dimethyl sulfoxide (1.69) in dichloromethane (5 ml) was added to oxalyl chloride (1.37 g) in dichloromethane (12 ml) a - 60 ° C to -50 ° C. N- [(S) -2- (3, 4- dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide (2.31 g) in dichloromethane (14 ml) was added to this solution with agitation. After 30 minutes triethylamine (2.19 g) was added and the reaction was stirred at low temperature for one hour - - additional, before allowing to warm up to room temperature. The reaction was quenched with HCl, and the organic phase was washed with HCl, saturated NaHCO 3 and brine. The organic phase was then added dropwise to a slurry of 4- [(S) -2-methylsulfinylphenyl] piperidine (1.33 g) in dichloromethane at room temperature added. After 15 minutes complex borane-piperidine (0.25 g) was added. The reaction was stirred overnight, quenched with water and the dichloromethane phase was washed with brine and concentrated under reduced pressure to give a colored foam This was treated with an equivalent of fumaric acid in hot ethanol. The solution was stirred at 70 ° C and allowed to slowly cool to room temperature to form crystals hydrogen fumarate title product (recrystallized from ethanol / water).
Example 2 N- [(S) -2- (3,4-dichlorophenyl) -4- [4-. { 4-methoxy- (S) -2-methylsulfinylphenyl} -l-piperidinyl] butyl] -N-methyl-3-cyano-1-naphtamide In the same manner as in example 1A, anhydrous dimethylsulfoxide in dichloromethane was added to oxalyl chloride in dichloromethane at a temperature of -60 ° C to -50 ° C. N- [(S) -2- (3, -dichlorophenyl) -4-oxo-butyl] -N- was added ^^^^ ¿£ »^ & * ££ -¿a - methyl-3-cyano-l-naphthamide in dichloromethane to" this solution with stirring. After 30 minutes, triethylamine was added and the reaction was stirred at low temperature for 3.5 hours before being allowed to warm to room temperature. The reaction was quenched with HCl, and the organic phase was washed with HCl, saturated with NaHCO 3 and brine. The organic phase was then added to a solution of 4- [4-methoxy- (S) -2-methylsulfinylphenyl] piperidine in methanol at 20 ° C. After 15 minutes complex borane-piperidine was added over 45 minutes. The reaction was stirred for 20 hours, quenched with HCl and the dichloromethane phase was washed with HCl, NaHC03 and brine and concentrated under reduced pressure to give a yellow foam. This was treated with an equivalent of fumaric acid in hot ethanol. The solution was stirred at 70 ° C for 1 hour, it was heated to reflux and water was added dropwise. After an additional hour at reflux, the mixture was allowed to cool slowly to room temperature to form crystals of hydrogen fumarate of the title product (recrystallized from water / ethanol). In another procedure the title compound was prepared by reductive amination in methanol with acetic acid and sodium cyanoborohydride and converted to citrate salt as follows. l? y To a solution of N- [(S) -2- (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-cyano-l-naphtide (0.154 g) and 4- (4-methoxy-2- (S) -methylsulfinylphenyl) piperidine (0.097 g) in 7 mL of MeOH was added 35 mL of acetic acid. The mixture was stirred for 30 minutes and 0.045 g of sodium cyanoborohydride (as a solution in 2 mL of MeOH) was added. The reaction mixture was stirred at room temperature under N2 atmosphere overnight (18 hours). At the end of this period the reaction was quenched with 10 mL of saturated NaHCO3, evaporated, dissolved in 10 mL of H20, and extracted with CH2C12. The organic layers were combined, dried with Na 2 SO, filtered and concentrated under reduced pressure to give a foam which was purified by silica chromatography (19: 1, CH 2 C 12: MeOH weight / 0.5% NH 3 (aqueous)). The purified product was dissolved in 3 mL of CH2C12 and treated with 50 mL of Et20 containing 3 mL of saturated HCl (g) Et20. After stirring for 10 minutes the precipitate was filtered under a fixed stream of N2 to give 0.210 g of white powder; mp 165-170 ° C; XH NMR (DMSO-d6) d 1.60-2.40 (m, 5), 2.55-2.65 (m, 3), 2.71 (s, 3), 2.80-3.30 (m, 5), 3.36 (s, 3), 3.45 -3.70 (m, 3), 3.82 (s, 3), 6.85-7.09 (m, 10), 8.10 (m, l), 8.63 (m, 1), 10.64 (m, 1); MS: m / z 662 (M + H). The 4- (4-methoxy-2- (S) -methylsulfinylphenyl) -piperidine requirement was prepared as follows. ? * - afass »fcs - (a) 2-bromo-5-methoxyphenol (2). To a solution of 3-methoxyphenol (129.03 g) and benzoyl peroxide (1.00 g) in 500 mL 1,1,1-trichloroethane (TCE) was added slowly to a solution of bromide (167.90 g in 150 mL in 1.1 , 1-TCE) for 1 hour. During the addition reaction the flask was irradiated with a GE ultraviolet lamp (275 Wats, 120 volts) which caused a gentle reflux. The HBr released was trapped in a glass containing sfafa < ^ fea8fe ^ £ fe? iáíi¿á - - a solution of 126.02 g of NaHC03 and 800 L of H20. When the bromide addition is complete the reaction mixture is purged with N2 for 20 minutes. The reaction mixture was extracted with saturated NaHCO 3 until the pH of the aqueous extract was neutral. The organic layer was dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to give a reddish oil. The crude product was purified by vacuum distillation (150 ° C, 150 millitor) to give 161.78 g of a viscous liquid; XH NMR (CDC13) d 3.77 (s, 3), 5.57 (s, l), 6.42 (m, l), 6.60 (d, l), 7.30 (d, l). (b) 2-bromo-5-methoxy- (N, N-dimethylthiocarbamoyloxy) phenol (3). To a stirred solution of 2-bromo-5-methoxyphenol (161.78 g) and 1,4-diazabicyclo- [2.2.2] octane (180.03 g) in 1 L DMF was slowly added 200 g of dimethylthiocarbamoyl chloride in four separate portions of 50 g for 30 minutes. When the addition was complete, the mixture was stirred overnight (18 hr) under N2 atmospheres. At the end of this period the mixture was poured into 4 L of H20 distilled with rapid stirring. The precipitated product was collected by filtration and washed with H20. The crude product was air dried for 4 hours and crystallized from methanol to give white crystals (139.19 g); XH NMR (300 MHz, CDCl 3) d 3.38 (s, 3), 3.47 (s, 3), 3.79 (s, 3), 6.71 (m, 2), 7.45 fci, 1); MS: m / z 290 (M + H). (c) -bromo-3- (N, N-dimethylcarbamoylthio) methoxybenzene (4) A solution of 2-bromo-5-methoxy- (N, N-dimethylthiocarbamoyloxy) phenol (139.19 g) and N, N-diethylaniline (350 mL) was degassed (4 cycles) and then heated under reflux under N2 for 3.5 hours . The brown solution concentrated (short-route distillation) in approximately 100 mL and the residue was poured into 500 mL of ice cold 6N HCl with rapid stirring. The mixture was cooled to room temperature, 100 mL of Et20 was added, and a heavy precipitate formed which was collected by filtration. East precipitate (crude product) cinnamon color was briefly dried in air and reserved. The filtrate was extracted with Et20. The Et20 extracts were combined, dried with MgSO4, filtered, and concentrated under reduced pressure to give a brown solid (additional crude product). The crude product was purified by crystallizing methanol to give off white crystals (82.04 g). 1 H NMR (300 MHz, CDC13) d 3.05 (br s, 3), 3.12 (br s, 3), 3.79 (s, 3), 6.82 (dd, 1), 7.19 (d, l), 7.55 (d, 1); MS: 290 (M + H). - - (d) 4-bromo-3- (methylthio) -methoxybenzene (5) To a solution of KOH (120.01 g) in 500 mL of methanol was added 82.04 g of 4-bromo-3- (N, N-5 dimethylcarabmoylthio) methoxybenzene. The mixture was heated under reflux to an N2 atmosphere for 2 hours, then cooled to 0 ° C and neutralized with 400 mL of 6N HCl. The mixture was cooled to 0 ° C and extracted with DCM. The organic extract was combined, dried over Na 2 SO, filtered and concentrated reduced pressure to give a clear brown liquid. This liquid was dissolved in 600 mL of anhydrous DMF and treated with 80.90 g of anhydrous K2C03. The resulting mixture was stirred for 20 minutes and then 68.40 g of methyl iodide was added slowly over 15 minutes. The resulting mixture was stirred at room temperature under an N2 atmosphere overnight (18 hours). At the end of this period the reaction mixture was introduced into 2.8 L of distilled H20 and extracted with Et20. The organic layer was combined, dried over MgSO4, filtered and concentrated under reduced pressure give a light yellow liquid (65.03 g). XH NMR (CDCl 3) d 2.45 (s, 3), 3.80 (s, 3), 6.55 (dd, 1), 6.66 (d, 1), 7.39 (d, l). 4-hydroxy-4- (4-methoxy-2-methylthiophenyl) -N-Cbz-piperidino (7) Cerium (III) chloride üßptahydrate (181.38 g) was heated under high vacuum at 100 ° C for 2 days thereafter at 140 ° C for two days. This material was transferred to a dry flask equipped with a mechanical stirrer, suspended in 700 mL of anhydrous THF, and stirred while cooling to -78 ° C. A solution of 4-bromo-2- (methylthio) methoxybenzene in 500 mL of anhydrous THF was cooled to -78 ° C and treated dropwise with n-butyllithium (11.5 mL of a 2.5 M solution in hexane) for 1 hour. hours The temperature of the reaction flask was maintained below -70 ° C during the addition. This mixture was stirred at -78 ° C for 1.5 hours and transferred via a wide-center isolated cannula into a flask containing the stirred suspension of CeCl3 at -78 ° C. The peach color suspension The resulting mixture was stirred for 1.5 hours at -78 ° C and then a solution of l-benzyloxycarbonyl-4-piperidone (65.10 g in 200 mL of anhydrous THF) was added via a cannula for 30 minutes. When the addition was complete, the reaction mixture was warmed to room temperature and stirred throughout the night (18 hours). At the end of this period the reaction mixture was quenched with 500 mL of saturated NH4C1 and stirred for 30 minutes. The organic layer was decanted, concentrated under reduced pressure, and reserved. The grayish remnant of the suspension was stirred with 1 L of DCM and filtered through Celita The Celite filter paste was washed with DCM. All organic extracts were combined, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to give a viscous oil which was purified by silica chromatography (1: 1, EtOAc: hexane) to give 85.00 g of an oil.
XH NMR (CDC13) d 1.99 (m, 2), 2.12 (m, 2), 2.52 (s, 3), 3.39 (m, 2), 3.81 (s, 3), 4.10 (m, 3), 5.15 (s, 2), 6.71 (dd, 1), 6.95 (d, 1), 7.24 (d, 1), 7.37 (m, 5); MS: 387 (M + H). 4- (4-methoxy-2-methylethyl) -N-Cbz-piperidine To a pasty mixture of 4-hydroxy-4- (4-methoxy-2- (methylthio) -phenyl) -N-Cbz-piperidine (50.09 g) in ice triethylsilane was stirred rapidly in triethylsilane (29.12 g) was slowly added acid trifluoroacetic (29.60 g). When the addition was complete the reaction mixture was warmed to room temperature and stirred overnight (18 hours). At the end of this period the mixture was poured into 300 mL of saturated NaHCO 3 and extracted with DCM. The extracts were combined, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to give an oil. The product was purified by silica chromatography (40: 1 to 20: 1 gradient, DCM: EtOAc) to give 42.50 g of an oil. XH NMR (CDCl 3) d 1.57 (m, 2), 1.83 (d, 2), 2.46 (s, 3), 2.91 (m, 2), 3.06 (tt, 1), 3.80 (s, 3), 4.33 ( m, 2), 5.14 (s, 2), 6.68 (dd, 1), 6.76 (d, 1), 7.04 (d, 1), 7.36 (m, 5); MS: m / z 394 (m + Na). (g) 4- (4-methoxy-2- (S) -methylsulfinylphenyl) -N-Cbz-piperidine (9) To a 500 mL flask was added 11.56 g of diethyl-D-tartrate, 140 mL of anhydrous DCM 7.96 g of titanium isoproproxide (IV), 0.50 g of H20. The yellow-brown solution was stirred for 30 minutes and then treated with 10.78 g of 4- (4-methoxy-2-methylthiophenyl) -N-Cbz-piperidine dissolved in 40 mL of DCM. The reaction mixture was then immersed in a water / glycol bath pre-cooled to -30 ° C. After stirring for 30 minutes (a bath at -36 ° C), 5.6 mL of a 6M solution of tert-butylhydroperoxide in nonane was slowly added to the reaction mixture for 6 days under an atmosphere of N2 (bath at room temperature). -38 ° C temperature). At the end of this period the reaction was quenched with 50 mL of H20 and stirred vigorously for 1 hour while it was warmed to room temperature. The mixture was then treated with 100 mL of 2.5 M NaOH and stirred for an additional 20 minutes, filtered through Celite and the layers were separated.
The filtered paste was washed with DCM twice and each portion was used to extract the aqueous layer. The organics were combined, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. This gave a light yellow oil which was purified by silica chromatography (4: 1, EtOAc: DCM). XH NMR (CDC13) d 1.62 (m, 2), 1.79 (m, 2), 2.86 (m, 3), 2.87 (s, 3), 4.34 (m, 2), 5.16 (s, 2), 7.00 ( dd, 1), 7.18 (d, 1), 7.36 (m, 5), 7.52 (d, 1); MS: m / z 410 (m + Na). (h) 4- (4-methoxy-2- (S) -methylsulfinylphenyl) piperidine (10).
To a solution of KOH (1.50 g) in 20 mL of 1: 1 EtOH: H20 was added 1.23 g of 4- (4-methoxy-2- (S) -methylsulfinylphenyl) -N-Cbz-piperidine. The resulting mixture was heated under reflux to an N2 atmosphere for 18 hours, evaporated, dissolved in 10 mL of H20, and extracted with CHCl3. The organic extracts were combined, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica chromatography (19: 1, DCM: MeOH with 0.5% aqueous solution of NH 4 OH) to give 0.38 g of white solid. 2H NMR (CDC13) d 1.69 (m, 2), 1.82 (m, 2), 2.38 (m, 1), 2.70 (s, 3), 2.75 (m, 2), 3.22 (m, 2), 3.88 ( s, 3), 7.01 (dd, 1), 7.28 (d, 1), 7.51 (d, 1); MS: 254 (M + H). safc & amp; & amp;! $ > '* ^' f '* ^^, The intermediate N- [2 - "(S) - (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphtamide was prepared as follow. (i) 3-cyano-l-naphthoyl chloride 3-cyano-l-naphthoic acid (Example 1) (15.9 g, 80. 6 mmol) was suspended in DCM (450 mL). To the stirred suspension was added oxalyl chloride at room temperature (12.8 g, 100 mmol) in one portion followed by a catalytic amount (5 drops) of DMF. The mixture was stirred for 5 hours to give a clear solution. The mixture was concentrated in vacuo, and the residue was concentrated twice with toluene to give the crude acid chloride as a light yellow solid (17.4 g, quantitative). XH-NMR (300 MHz, d6 acetone) d 7.86-7.91 (t, 1H, aromatic); 7.98-8.04 (t, 1H, aromatic); 8.28-8.32 (d, 1H, aromatic): 8.66-8.72 (d, 1H, aromatic); 8.80 (s, 1H, aromatic); 8.93 (s, 1H, aromatic). (j) N- [(S) -2- (3,4-dichlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-1-naphthamide. (S) -2- (3,4-dichlorophenyl) -4-hydroxybutylamine (Miller, SC; WO 9410146) (20.8 g, 83.8 mmol) was dissolved in DCM (700 mL). To the stirred solution was added 10% sodium bicarbonate (300 mL), and the mixture was cooled to 0 ° C.
A solution of 3-cyano-l-naphthoyl chloride (17.4 g, 80.6 mmol), was dissolved in DCM (300 mL) was added dropwise over 30 minutes. The mixture was then allowed to warm to room temperature and stirred for 20 hours. Layers 5 were separated, and the aqueous phase was washed with DCM (300 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo to give a white foam. Purification by chromatography (silica gel, 0-25% acetonitrile in DCM) provided the desired product as a white foam (27.0 g, 78%). XH-NMR (DMSO-d6) d 1.46-1.60 (m, 1H, CH); 1.77-1.91 (m, 3H, CH); 4.38-4.41 (t, 1H, CH); 4.54- 4.57 (t, 2H, CH); 6.43 (broad, 1H, OH); 6.84-7.26 (m, 2H, aromatic); 7.44-7.54 (m, 3H, aromatic); 7.57-7.80 (m, 7H, aromatic); 8.04-8.33 (m, 2H, aromatic); 8.61 (s, 1H, aromatic).
In an alternative N- [(S) -2- (3, 4-dichlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-l-naphthamide can be prepared as follows: To a stirred slurry of 3- cyano-l-naphthoic acid (4.53 g) in acetonitrile (36 mL) at room temperature, 1-hydroxybenzotriazole (0.31 g) and subsequently (S) -2- (3,4-dichlorophenyl) -4-hydroxybutylamine ( 8.33 g) in acetonitrile. The mixture was stirred for 15 minutes before 1- (3-dimethylaminopropyl) -3- hydrochloride. * e & $ xßm & - > Ethylcarboiimide (5.26 g) in a ratio of (1: 1 of "-I-acetonitrile: water was added dropwise over 1 hour.) The mixture was stirred at room temperature for 18 hours, and HCl (68 mL). ) and methyl t-butyl ether (68 mL) was added consecutively The organic phase was treated with NaOH, stirred at 45 ° C for 3 hours, cooled, washed and concentrated under reduced pressure to give a foam. This foam was redissolved in acetonitrile, heated to 80 ° C, water was added and then cooled to give the desired product 10 as a white solid. (K) N- [(S) -2- (3,4-dichlorophenyl) ) -4-oxobutyl] -N-methyl-3-cyano-1-naphtamide.
A solution of oxalyl chloride (15.9 g, 125.4 mmol) was dissolved in DCM (350 mL), cooled to -78 ° C. DMSO (196.6 g, 251 mmol) was added dropwise for 10 minutes while maintaining the temperature of the reaction mixture below -70 ° C. The mixture was stirred for 30 minutes at -78 ° C. A solution of N- [(S) -2- (3,4-dichlorophenyl) -4-20 hydroxybutyl] -N-methyl-3-c-ano-l-naphthamide (26.8 g, 62.77 mmol) was dissolved in DCM (350 mL) and added by dripping for 30 minutes while, the temperature of the mixture was kept below -70 ° C. The mixture was allowed to stir for one hour at -78 ° C, then was heated to -50 ° C and stirred < fcaa ^ a »» fe¡ i »ito¿Maa? o ^, -n" j »» »,. > », - - for another 30 minutes. The mixture was cooled to -78 ° C and a solution of triethylamine (25.4 g, 251 mmol) was dissolved in DCM (70 mL) was added dropwise for 10 minutes. The mixture was then allowed to gradually warm to room temperature and was stirred for 20 hours. The mixture was then washed with 0.5N hydrochloric acid (2x 250 mL), water (250 mL), and saturated sodium bicarbonate (250 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0-20% Et20 in DCM) to provide the desired product as a light yellow foam (26.0 g, 97%). MS: 425 (M + H). XH-NMR (DMSO-d6) d 2.63 (bs, 3H, NCH3); 2.99-3.93 (m, 5H, CH); 6.91- 7.15 (m, 1H, aromatic); 7.33-7.81 (m, 6H, aromatic); 8.62 (s, 1H, aromatic); . 5 and 9.73 (simple, 1H total, CHO). Example 3 Citrate of N- [2- (4-chlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-3-nitro-l-naphtamide Using standard reductive amination conditions 4- [(S) -2-methersulfinylphenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ, Jr.; Veale, CA. WO 9516682) was reacted with N- [ 2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-nitro-l-naphth-t-amide and converted to the citrate salt. MS m / z 618 (M + H); Analysis by C34H36CIN304S • 1.08 C6H807 -1.0 H20: calculated: C, 57.63; H, 5.57; N, 4.98; found: C, 57.67; H, 5.47; N, 4.78.
The required aldehyde was prepared as follows: (a) 2- [[3-cyano-3- (4-chlorophenyl)] propyloxy] -2H-tetrahydropyran.
To a mixture frozen at (0 ° C) of 60% sodium hydride (3.73g, 93.3 mmol) in THF (80 mL) was added dropwise a solution of 4-chlorobenzylcyanide (13.0 g, 85.8 mmol) in THF (20 mL) and the solution was stirred at room temperature for 3 hours. The solution was cooled (in an ice bath) and 2- (2-bromoethoxy) -2H-tetrahydropranol (15g, 71.7 mmol) was added dropwise and the solution was stirred at room temperature overnight. Saturated ammonia chloride was added and the mixture was extracted with EtOAc. The combined organic extracts were dried (HgS04), filtered, and concentrated in vacuo. Purification was carried out by means of chromatography (30%, 50%, 60% and 80% DCM in hexane) to give the title compound (19.7g, 98% product) as a yellow oil. 1 H-NMR (CDC13): d 1.53-1.64 (m, 4H, CH) 1.71-1.82 (m, 2H, CH); 2.09-2.16 (m, 2H, CH) 3.52-3.57 (, 2H, CH) 3.80-3.93 (m, 2H, CH) 4.05-4.10 (t, 1H, CH) 4.55-4.60 (m, 1H, CH) 7.28-7.41 (m, 4H, ArH ). MS m / z 284 (M + H). (b) 2- [[4-amino-3- (4-chlorophenyl)] butyloxy] -2H-tetrahydropyran. To a mixture of Raney nickel (8.0 g) in ethanol (20 mL) was added a solution of 2- [[3-cyano-3- (4-chlorophenyl)] propyloxy] -2H-tetrahydropyran (25g, 89.4mmol) in Ethanol (160 mL). The nitrogen was bubbled through the mixture for 5 minutes and ammonia hydroxide (30%, 120 mL) was added. The mixture was placed in a Parr apparatus under hydrogen (50 psi) for 5 days and filtered through Celite. The filtrate was concentrated, DCM and water were added and the layers were separated. The organic layer was dried with (MgSO), filtered, and concentrated in vacuo. Purification was performed by chromatography (1-5% methanol in DCM) to give the title compound (13.0 g, 51%) as a light yellow oil. XH-NMR (CDC13): d 1.51 (m, 4H, CH) 1.65 (m, 1H, CH) 1.74-1.82 (m, 2H, CH) 1.95-2.01 (m, 1H, CH) 2.76-2.97 (m, 3H, CH) 3.16-3.18 (m, 1H, CH) 3.41-3.44 (m, 1H, CH) 3.57-3.80 (m, 2H, CH) 4.41-4.49 (dd.1HCH) 7.11-7.16 (m, 2H , ArH) 7.28-7.30 (m, 2H, ArH). MS 284 (M + H). (c) 4-amino-3- (4-chlorophenyl) -1-butanol.
To a solution of 2- [[4-amino-3- (4-chlorophenyl)] butyloxy] -2H-tetrahydropyran (13.0 g, 45.7 mmol) in methanol (90 mL) was added 6N HCl (11 mL) and the solution it was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous solution was extracted with Et20, the pH was adjusted to 14 with 5N sodium hydroxide and the mixture was extracted with EtOAc. The combined EtOAc extracts were washed with a saturated sodium chloride solution, dried (MgSO 4), filtered and concentrated in vacuo to give the title compound (9.0 g, 99%). ^ -NMR (CDC13): d 1.80-1.96 (m, 2H, CH) 2.53 (s, 3H, OH, NH) 2.71-2.75 (m, 1H, CH) 2.83-3.00 (m, 2H, CH) 3.49- 3.57 (m, 1H, CH) 3.63-3.70 (m, 1H, CH) 7.10-7.15 (dd.2H, ArH) 7.27-7.30 (dd, 2H, ArH). MS m / z 200 (M + H). (d) 3- (4-chlorophenyl) -4- (ethoxycarbonylamino) -1-butanol.
Ethyl chloroformate (4.7 mL, 49.5 mmol) was added dropwise to a stirred solution with stirring (-40 ° C) of 3- (4-chlorophenyl) -4-amino-1-butanol (9.0 g, 45 mmol) and triethylamine (7.2 mL, 5.18 mmol) in DMC (125 mL). The solution was stirred at room temperature for 30 minutes and poured into 1N HCl (60 mL). The organic layer was washed with IN HCl (70 mL), saturated sodium bicarbonate (70 mL) and saturated sodium chloride; dried with (MgSO4), filtered and the solvent removed to give the title compound (11.4 g, 93%) as a yellow oil. XH-NMR (CDC13): d 1.18-1.23 (t, 3H CH) 1.75-1.84 (m, 1H, CH) 1.90-1.99 (m, 1H, CH) 2.94-2.99 (m, 1H, CH) 3.21-3.30 (m, 1H, CH) 3.47-3.65 (m, 3H, CH) 4.04-4.11 (q, 2H, CH) 4.58 (s, 1H, OH or NH) 7.12- 7.15 (d, 2H, ArH) 7.26-7.37 (m, 2H, ArH); MS m / z 272 (M + H). (e) 3- (4-chlorophenyl) -4-N-methylamino-1-butanol.
This material has been reported (H. Kubota, A. Kafefuda, H. Nagaoka, O. Yamamoto, K. Ikeda, M. Takeuchi, T. Shibanuma, Y. Isomura, Chem. Pharm. Bull., 46 (2), 242-254 (1998)); however, the preparation was not exemplified and is therefore presented here. To a mixture cooled by stirring (0 ° C) of lithium aluminum hydride (.36 g, 93 mmol) and THF (55 mL) was added dropwise to a solution of 3- (4-chlorophenyl) -4- (ethoxycarbonylamino) -1-butanol (11.4 g, 42 mmol) in THF (110 mL). The mixture was heated under reflux for 1 hour, cooled (in an ice bath) and saturated sodium sulfate (14 mL) was added. The mixture was stirred at room temperature for 30 minutes and sodium sulfate (14g) was added. The mixture was stirred at room temperature - - for 30 minutes, it was filtered through celite, washed with THF, and the filtrate was concentrated in vacuo. Chromatography (1-10% methanol in DCM) gave the title compound (5.85g, 65%) as a yellow oil. XH-NMR (CDC13): d 1.86- 1.94 (m, 2H, CH) 2.44 (s, 3H, CH) 2.69-2.86 (m, 5H, CH, OH and NH) 3.51-3.58 (m, 1H, CH) 3.66-3.77 (m, 1H, CH) 7.09-7.12 (d, 2H, CH) 7.25-7.29 (d, 2H, CH). MS m / z 214 (M + H). (f) N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-nitro-l-naphthalenecarboxamide.
To a stirred mixture of 3-nitro-l-naphthoic acid (Kice, JL, Lotey H; J. Org. Chem., 54, 3596 (1989) (0.76 g, 3.5 mmol) in dry DCM (12 mL) was added. Oxalyl chloride (0.38 mL, 4.38 mmol) and DMF (30 μL) The solution was stirred at room temperature for 3 hours and concentrated to provide the acid chloride (0.824 g quantitative) as an off-white solid which was used without further purification To a stirred-cooled mixture (0 ° C) of 3- (4-chloro-phenyl) -4-methylamino-l-butanol (0.745 g, 3.5 mmol), DCM (30 mL) and NaOH IN (4.37) mL) was added dropwise a solution of 3-nitro-l-naphthoyl chloride (0.824 g, 3.5 mmol) in DCM (12 mL) .The mixture was stirred at 0 ° C for 2.5 h, water was added, the layers separated and the aqueous layer was & -, -Wa aüfcgg - The combined organic extracts were dried (MgSO), filtered and concentrated in vacuo. Chromatography (0%, 50%, 100% EtOAc in Et20) gave the title compound (1.25 g, 87%) as a light yellow solid. MS m / z 413 (M + H). (g) N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-nitro-1-naphthamide To a stirred solution by stirring (-78 ° C) oxalyl chloride (0.4 mL, 4.55 mmol) in DCM (10 mL) was added a solution of DMSO (0.64 mL, 9.10 mmol) in DCM (5 mL). The solution was stirred at -78 ° C for 5 minutes and a solution of N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-nitro-1-naphthalenecarboxamide (1.25 g, 3.03 mmol) in DCM (6 mL) and DMSO (3.4 mL) drop was added. The solution was stirred at -78 ° C for 15 minutes and triethylamine was added. (2.54 mL, 18.2 mmol). The solution was then stirred at -78 ° C for 30 minutes and at room temperature for 2 hours. DCM (75 mL) and 1 N HCl (75 mL) were added, the layers were separated, and the organic layer was dried (MgSO 4), filtered, and concentrated in vacuo. Chromatography (silica gel; DCM in Et20, 1: 1) to provide the desired compound (1.15 g, 92%) as a light yellow solid. MS m / z 411 (M + H).
Example 4 N- [2- (4-chlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-l-5-naphtamide Citrate Using conditions of Standard reductive amination 4- [(S) -2-methylsulfinylphenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ, Jr;; Veale, CA., WO 9516682) was reacted with N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-10 3-cyano-l-naphthalenecarboxamide and converted to citrate salt. 1 H-NMR (CDCl 3) (evidence of amide rotational isomer) d 8.19 (s), 7.92 (m), 7.67-7.32 (br m), 6.98-6.58 (br m), 4.49-3.98 (br m) 3.49- 1.25 (br m), 0.87 (t J = 7.5); MS m / z 598.3 (M + H). 15 The requisite aldehyde was prepared as follows: (a) N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-1-naphthamide. Oxalyl chloride (195 μL, 2.23 mmol) was added to a solution of 3-cyano-l-naphthoic acid (Example 1, subpart (c)) (400 mg, 2.03 mmol) in DCM (10 mL). The solution was stirred for three hours, during this time three portions (each 30 μL) of 10% DMF in DCM were added. The solution it was concentrated as a white powder under reduced pressure, dried under vacuum, and dissolved in DCM (15 mL). After cooling to 0 ° C, N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methylamine (example 3) (434 mg, 2.03 mmol, dissolved in 5 mL of DCM) and NaOH was added (1.0 m, 2.54 mL). After warming to room temperature, stirring was continued overnight. The mixture was extracted with 30 mL portions of 0.5 M HCl and saturated sodium bicarbonate, dried (MgSO4), filtered, and concentrated under reduced pressure to give a slightly yellow foam (692 mg, 1.76 mmol, 87% ). XH-NMR (CDC13) (evidence of amide rotational isomer) d 8.09 (s), 7.85 (m), 7.72-7.50 (br m), 7.43-4.35 (br m), 6.92 (d, J = 6.3), 6.85 (d, J = 7.8), 6.69 (m), 6.65 (m), 4.57 (br m), 3.99 (br m), 3.70 (m), 3.50-3.10 (br m) 2.67 (s), 2.03 ( m), 1.89 (m), 1.58 (m); MS m / z 393.0 (M + H). (b) N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide. A solution of DMSO (356 μL, 5.01 mmol) in DCM (5 mL) was added dropwise over 5 minutes to a stirred solution of oxalyl chloride (219 μL, 2.51 mmol) in DCM (5 mL) at -70 ° C. . After stirring for 15 minutes, N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-l-naphtamide (788 mg, 2.01 mmol) was added dropwise as a solution in DCM (5 mL). Stirring was continued for 45 minutes at -70 ° C, warmed to -45 ° C, and stirred for 30 minutes. The solution was cooled to -70 ° C and triethylamine (1.41 mL, 10.03 mmol) (dissolved in 5 mL of DCM) was added dropwise. After stirring for 15 minutes, the mixture was allowed to warm to room temperature, diluted with DCM, and extracted with 0.5 m HCl (30 mL), saturated sodium bicarbonate (30 L), dried with (MgSO4), and concentrated as a clear oil which was purified by chromatography (50% EtOAc in hexanes) to give the product as a clear oil (543 mg, 1.39 mmol, 70%). XH-NMR (CDC13) (evidence of amide rotational isomer) d 9.71 (s), 9.60 (s9, 8.18 (m), 7.86 (t, J = 7.8), 7.68-7.29 (m), 7.51 (m), 6.87, (t, J = 7.2) 6.67 (d, J = 8.4), 6.57 (m), 4.56 (br m), 3.98 (br m), 3.71, (br m), 3.42 (m), 2.97, (m), 2.67 (m); MS m / z 391.0 (M + H).
Example 5 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-methylsulfinyl-6-fluorophenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano- citrate l-naphthamide, using standard reductive amination conditions »And ^ ME! T: j? ^ Md *, S.
- - N- [(S) -2- (3,4-dichlorophenyl) -N-methyl-3-cyano-l-n-phthamide was reacted with 4- (2-methylsulfinyl-6-fluorophenyl) -piperidino and converted to citrate salt. Ms m / z 650 (M + H); Analysis for C35H34C12N302SF- 1.05 C6H807-1.1 H20; calculated; C, 56.87; H; 5.15; N, 4.81; found; C, 59.88; H, 5.16; N, 4.71.
The requisite 4- (2-methylsulfinyl-6-fluorophenyl) -piperidine was prepared as follows: (a) 4- (2,6-difluorophenyl) -pyridine To a stirred mixture of 4-bromo-pyridine hydrochloride (1.12 g, 5.76 mmol), tetrakis (triphenylphosphine) palladium (0.2 g, 0.173 mmol), benzene (12.5 mL) and sodium carbonate (2.14 g, 20.2 mmol) in Water (10 mL) was added 2,6-difluorobenzene boronic acid (1.0 g, 6.33 mmol) in ethanol (3 mL). The mixture was heated under reflux overnight, extracted with EtOAc, dried (MgSO), filtered, concentrated and purified by chromatography to give the product as a white solid (0.19 g, 16%). XH-NMR (CDC13) d 8.71 (d, 2H), 7.40 (m, 3H), 7.05 (t, 2H). MS m / z 192 (M + H). (b) 4 - (-2-thiomethyl-6-fluorophenyl) -pyridine.
- - A mixture of 4- (2,6-dichlorophenyl) -pyridine (0.45 g, 2.35 mmol), methyl mercaptan sodium salt (0.21 g, 3.00 mmol) in DMF (10 mL) was heated at 100 ° C throughout the night. The mixture was diluted with EtOAc and saturated NaCl, the organic layer was dried, filtered, concentrated, and purified by chromatography to give the product as a yellow solid (0.44 g, 85%). * H-NMR (CDC13) d 8.71 (d, 2H), 7.32 (m, 3H), 7.07 (d, 1H), 6.97 t, 1H), 2.39 (s, 3H). MS m / z 220 (M + H). (c) 4- (2-thiomethyl-6-fluoro-phenyl) -piperidine.
A mixture of 4- (2-thiomethyl-6-fluorophenyl) -piperidine (0.54 g, 2.46 mmol), HCl (0.5 mL) and Pt02 (0.54 g) in ethanol (20 mL) was stirred under hydrogen (50 psi) during 22 hours The mixture was filtered through Celite, washed with ethanol, concentrated and diluted with EtOAc and saturated with NaHCO3. The organic layer was dried, filtered, concentrated and purified by chromatography to give the product as a pink solid (0.14 g, 25%). X H-NMR (CDCl 3) d 7.16 (m, 1 H), 7.97 (d, 1 H), 6.80 (m, 1 H), 3.17 (m, 2 H), 2.70 (t, 2 H), 2.46 (s, 3 H), 2.08 (q, 2H), 1.70 (m, 4H). MS m / z 226 (M + H). (d) 4- (2-methylsulfinyl-6-fluoro-phenyl) piperidine. d ^^^ Aj ^ fflg ^ ggj ^^ gs ^^^^^^^^ j ^ - A solution of 4- (2-thiomethyl-6-fluoro-phenyl) -piperidine (0.14 g, 0.62 mmol), Et20 (5 mL), and IN HCl in Et20 (0.7 mL, 0.68 mmol) was stirred 5 minutes at room temperature. room temperature and evaporated. For the residue in dioxane (3.7 mL) and ethanol (1.8 mL), sodium periodate (0.14 g, 0.654 mmol) in water (1 L) was added at 0 ° C. The reaction mixture was stirred at room temperature for 9 days. The solvent was evaporated and the residue was dissolved in methanol (5 mL). KOH (0.035 g, 0.62 mmol) in methanol (2 mL) was added and the solution was filtered. The filtrate was concentrated and redissolved in DCM. The The solution was filtered again and the filtrate was concentrated to give the product as a slightly yellow oil (0.15 g, quantitative). XH-NMR (CDC13) d 7.81 (d, 1H), 7.44 (m, 1H), 7.16 (m, 1H), 3.22 (m, 2H), 2.70 (m, 5H), 2.18 (m, 2H), 1.84 (s, 2H), 1.74 (d, 1H), 1.56 (d, 1H). MS m / z 242 (M + H).
Example 6 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-methylsulfinyl-5-bromophenyl] -l-piperidinyl] -buty] -N-methyl-3-cyano- citrate l-naphtamide Using standard reductive amination conditions N- [2- (S) - (3,4-dichlorophenyl) -4 -oxo-butyl] -N-methyl-3-cyano-l- Naphthamide was reacted with 4- (2-methylsulfinyl-5-bromo-phenyl) -piperidine and converted to citrate salt. MS m / z 712 (M + H). The requisite 4- (2-methylsulfinyl-5-bromophenyl) -piperidine was prepared as follows: (a) N-phenolomethoxycarbonyl-4- (2-methylthio-5-bromophenyl) -piperidine. A solution containing N-phenyl-methoxy-carbonyl-4- (2-met? Lt? Ofenyl) -piperidine (Jacobs, R; Shenvi, A; EP 10 630887) (100 mg) in glacial acetic acid (0.50 mL) it was frozen in an ice bath of dry ice / acetone. To the frozen mixture was added a solution of bromine (68 mg) in glacial acetic acid (1.00 mL) for 5 minutes. The reaction was warmed to room temperature for 1 hour, heated to 40 ° C for 30 minutes, cooled to 0 ° C, then poured into crushed ice (25 mL).
The mixture was extracted with EtOAc (30 mL), washed with water (15 mL), saturated NaHCO 3 (3 xl 5 mL) and brine (15 mL), dried (MgSO 4), filtered and concentrated under reduced pressure to give the product as an oil (60 mg). 1 H NMR (CDC13) d 1.51 (m, 2 H), 1.75 (m, 2 H), 2.82 (br s, 2 H), 3.04 (m, 1 H), 4.26 (br s, 2 H), 5.08 (s, 2 H), 6.99 (dd, J = 9.0, 3.0, 1H), 7.18 (d, J = 2.1, 1H), 7.23 (dd, J = 9.0, 3.0, 1H), 7.29 (m, 5H); MS m / z 442, 444 (M + Na). (b) N-Phenylmethoxy-carbonyl-4- (2-methylsulfinyl-5-bromophenyl) -piperidine.
To a solution containing N-phenyl-methoxycarbonyl-4- (2-methylthio-5-bromo-phenyl) -piperidine (0.202 g) in methanol (0.67 ml), DCM (0.33 ml), and glacial acetic acid (1.0 mL) was added 30% H202 (48 μL) by dropwise and stirred at the room temperature for 18 hours. It was then cooled and poured into cold water as ice (50 mL). The mixture was extracted with EtOAc (3 x 75 mL), washed with saturated NaHCO 3 (2 x 20 mL), dried (MgSO 4), filtered, concentrated, and purified by chromatography (1: 1 hexane: EtOAc, then EtOAc) to give the product (250 mg) as a white solid. XH NMR (CDC13) d 1.66 (br m, 2H), 1.87 (m, 2H), 2.70 (s, 3H), 2.90 (br m, 3H), 4.36 (br s, 2H), 5.17 (s, 2H) , 7.39 (m, 6H), 7.61 (dd, J = 8.7, 2.1, 1H), 7.87 (d, J = 8.4, 1H); MS m / z 458, 460 (M + Na). 20 (c) 4- (2-Methylsulfinyl-5-bromophenyl) -piperidine trifluoroacetate A solution containing N-phenyl-methoxy-carbonyl-4- (2-methylsulfinyl-5-bromo-phenyl) -piperidine (125 mg ) in ^ j ^ ^ U ^ it? K ^ Ui ^^^^ andMi ^^ Jí ^^^ Ti ^ - ,. ^ .- ~ -Y? - ^.-j-JA? .. 1 - -acid trifluoroacetic acid (7.0 mL) was heated at 80 ° C for 45 minutes. The reaction was cooled in an ice bath, diluted with DCM (25 mL), and concentrated. The residue was redissolved and concentrated with three portions of DCM (20 mL) to give the product as a tan oil (140 mg). XH NMR (CDC13) d 1.91 (br m, 1H), 2.21 (m, 3H), 2.83 (s, 3H), 3.18 (br m, 3H), 3.52 (br s, 2H), 7.53 (s, 1H) , 7.69 (d, J = 7.5, 1H), 7.87 (d, J = 8.4, 1H), 8.53 (br s, 1H), 8.83 (br s, 1H); MS m / z 302.304 (M + H).
Example 7 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [(R, S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl citrate. -3-cyano-1-naphtamide Using standard reductive amination conditions (except that the acetic acid-sodium acetate buffer was replaced by acetic acid) N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl- 3-Cyano-l-naphthamide (255 mg, 0.60 mmol) was reacted with 4- [(RS) -2-methylsulfinyl-phenyl] piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ Jr; Véale, CA; WO 9516682) (201 mg, 0.595 mmol), was converted to citrate salt, and isolated by filtration of Et20 to give the title compound (290.7 mg) as a white powder. MS m / z 632 (M + H); Analysis for C35H35C12N302S • C6H807 • H20: calculated: C, 58.43; H, 5.38; N, 4.98; found: C, 58.20; H, 5.28; N, 4.95.
Example 8 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- (R) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano- citrate l-naph amide Using standard reductive amination conditions (except that the acetic acid-sodium acetate buffer was replaced by acetic acid) N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] - N-methy1-3-cyano-l-naphtamide (468 mg, 1.1 mmol) was reacted with 4 - [(R) -2-methylsulfinylphenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ Jr; Véale, CA; WO 9516682) (232 mg, 1.04 mmol), was converted to citrate salt, and isolated by Et20 filtration to give the title compound (651.2 mg) as a white powder. MS m / z 632 (M + H); Analysis for C35H35C12N302S • C6H807- H20: calculated: C, 58.43; H, 5.38; N, 4.98; found: C, 58.10; H, 5.20; N, 4.82.
Example 9 - - N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-6- citrate cyano-l-naphtamide.
Using chloride standard acylation conditions 6-cyano-l-naphthoyl (prepared from 6-cyanonaphthoic acid using oxalyl chloride) was reacted with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S ) -2-methylsulfinylphenyl] -1- piperidinyl] butyl] -N-metalamine (Example 1, subpart (b)) and the product was converted to citrate salt. Analysis for C35H35Cl2N302S 1.0 -C6H8070.9-H2O: calculated: C, 58.56; H, 5.37; N, 5.00; found: C, 58.64; H, 5.23; N, 4.81.
The 6-cyano-naphthoic intermediate acid was prepared as described below and provides advantages over a previously published method (Dewar, MJS and Grisdale, PJ; J: Amer Chem. Soc., 84, 3541 (1962)). a) Methyl 6-hydroxl-naphthoate To a solution of 6-hydroxy-naphthoic acid (2.5 g, 13.3 mmol) in DCM (44 mL) was added oxalyl chloride (1.45 mL, 16.6 mmol) and 2 drops of DMF. The solution was stirred at room temperature for 4.5 hours and concentrated. Methanol (20 mL) was added to the reaction mixture and the solution it was heated under reflux for 15 minutes. The solution was cooled to room temperature and concentrated in vacuo. Chromatography (silica gel, 1% and 2% methanol in DCM) gave the title compound as a yellow solid (2.22 g, 83%). XH NMR (CDC13) d 4.00 (s, 3H, CH3), 5.54 (s, 1H, OH) 7.20-7.26 (m, 2H, ArH) 7.41-7.46 (t, 1H, ArH) 7.83-7.86 (dd, 1H , ArH) 8.01-8.04 (dd, 1H, ArH) 8.80-8.85 (d, 1H, ArH). MS m / z 203 (M + H). (b) Methyl 6-trifluoromethylsulfonyloxy-1-naphthoate. To a stirred solution (0 ° C) of methyl 6-hydroxy-1-naphthoate (2.15 g, 10.6 mmol) in DCM (50 mL) was added triethylamine (1.48 mL, 10.6 mmol) and trifluoromethanesulfonic anhydride (1.79 mL). , 10.6 mmol). The solution was poured into saturated sodium bicarbonate, the separated layers and the aqueous layer were extracted with EtOAc. The combined organic layers were dried with (MgSO4), filtered and concentrated in vacuo to give the title compound as a yellow oil (4.23 g). H-NMR (CDC13) (contains triethylamine) d 4.00 (s, 3H, CH3), 7.48-7.52 (dd, 1H, ArH) 7.60-7.65 (t, 1H, ArH) 7.80-7.81 (d, 1H, ArH) 8.04-8.07 (d, 1H, ArH) 8.28-8.32 (d, 1H, ArH) 9.60-9.09 (d, 1H, ArH). MS m / z 335 (M + H). (c) methyl 6-cyano-l-naphthoate '! ^ < tiá 3? A mt & amp;, - To a solution of methyl 6-trifluoromethylsulfonyloxy-1-naphthoate (3.5 g, 105 mmol) in DMF (14 mL) was added zinc cyanide (0.86 g, 7.33 mmol) and tetrakis ( triphenylphosphine) palladium (0.48 g, 0.415 mmol). The solution was heated at 80 ° C for 45 minutes and poured into a solution of saturated sodium bicarbonate. The mixture was extracted with EtOAc, the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (silica gel; EtOAc in hexane, 1: 9) to give the title of the compound (1.00 g, 45% in 2 steps) as a white solid. XH-NMR (CDC13) d 4.03 (s, 3H, CH), 7.65-7.67 (t, 1H, ArH) 7.73-7.76 (dd 1H, ArH) 8.07-8.10 (d, 1H, ArH) 8.28 (d, 1H , ArH) 8.35-8.38 (d, 1H, ArH) 9.10 (d, 1H, ArH). MS m / z 212 (M + H). (d) 6-cyano-naphthoic acid To a stirred solution of methyl 6-cyano-l-naphthoate (1.0 g, 4.73 mmol) in THF (55 mL) and water (22 mL) was added IN NaOH (10 mL, 9.93 mmol) and enough methanol to clarify the solution. The solution was stirred at room temperature overnight and concentrated in vacuo. The aqueous residue was acidified to a pH of 1 with IN HCl and extracted with EtOAc. The combined organic layers were dried (MgSO), - were filtered and concentrated in vacuo to provide the desired compound (0.67 g, 82%) as a white solid. XH-NMR (DMSO d6) d 7.57-7.80 (t, 1H, ArH) 7.91-7.95 (dd, 1H, ArH) 8.25-8.36 (m, 2H, ArH) 8.71 (d, 1H, ArH) 9.02-9.0p8 (d, 1H, ArH) 13.4 (s, 1H, acid). MS m / z 196 (M-1).
Example 10 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-4-cyano- citrate l-naphthamide To a mixture containing 4-cyano-l-naphthoic acid (0.090 g, 0.45 mmol), DCM (3 mL), oxalyl chloride (0.063 g, 0. 50 mmol) and DMF (about 5 μL) was stirred for 3 hours and concentrated to give 4-cyano-l-naphthoyl chloride as a whitish solid that was used directly.
Using standard acylation conditions 4-cyano-1-naphthaoyl chloride (0.090 g) was reacted with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2 -methylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methylamino to give the free base (0.215 g) which was converted to citrate salt. MS m / z 631 (M + H). The requisite 4-cyano-l-naphthoic acid was prepared as follows, (a) methyl 4-bromo-l-naphthoate. A solution of 4-bromo-l-naphthoic acid (Fischer, A; et al, J. Chem. Soc, 1426 (1958)) oxalyl chloride (2.56 g), and DMF (5 μL) in DCM (100 mL) ) was stirred for 3 hours, concentrated, then redissolved in DCM (5 mL). Methanol was added and stirring was continued overnight. Concentration and purification was followed by chromatography (DCM) the product was given as a white solid (4.85 g). XH-NMR (DMSO d6) d 8.83-8.77 (m, 1H), 8.31-8.25 (m, 1H), 8.01 (s, 1H), 7.82-7.75 (m, 2H), 3.96 (s, 3H); MS m / z 265 (M + H). (b) 4-cyano-l-naphthoic acid A solution of methyl 4-bromo-l-naphthoate (0.509 g) copper cyanide (I), (0.174 g) 1 drop of pyridine, and DMF (5 mL) was heated under reflux at 180 ° C for 5 hours. The hot solution was poured into 10 mL of concentrated aqueous NH 4 OH and extracted with DCM. The organic phase was washed successively with IN HCl (20 mL) and brine (40 mL), dried over Na 2 SO 4, filtered and concentrated to give methyl 4-cyano-l-naphthoate a colorless oil (0.213 g). MS m / z 196 (M-1). XH-NMR (DMSO d6) d 8.74-8.69 (m, 1H), 8.29-8.15 (m, 3H), 7.92-7.83 (m, 2H), 3.99 (s, 3H). The methyl ester was saponified by stirring a solution of methyl ester, LiOH-H20 (1 equivalent), THF (3 mL), water (1 mL) and methanol (1 mL) overnight at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et20. The aqueous layer was acidified to pH 2 by the addition of IN HCl and extracted with Et20. The organic layer was washed with water (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated to give 4-cyano-l-naphthoic acid as an oil.
Example 11 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3 citrate, 6-dicyano-1-naphtamide.
Using the standard acylation conditions N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (S) -2-methyl-sulfinylphenyl] -l-piperidinyl] butyl] -N-methylamino 3,6-dicyano-l-naphthoyl chloride (prepared from 3,6-dicyano-l-naphthoic acid using oxalyl chloride) was reacted and the product converted to citrate salt. MS m / z 657.2 (M + H). The requisite carboxylic acid was prepared as follows. (a) 3-cyano-6-methoxy-1-naphthoic acid A solution of ethyl 3-bromo-6-methoxy-1-naphthoate (Wrobel, et al: J. Med. Chem., 34, 2504 (1991) (206 mg, 0.66 mmol), Zn (CN) 2, and tetrakis (triphenylphosphine) palladium (36 mg, 0.031 mmol) in DMF (12 mL) was stirred at 80 ° C for 1 hour. The mixture was diluted with DCM, washed with water, dried with MgSO 4, filtered and concentrated as a yellow precipitate, and purified by chromatography (5% EtOAc in hexanes) to give methyl 3-cyano-6- methoxy-l-naphthoate as a white powder (150 mg, 0.588 mmol, 88%). The ester was saponified by stirring in 2% water in THF with 1.5 equivalents of LiOH at 80 ° C for 3 hours to give the title compound. 1H-NMR 10 (DMSO d6) d 8.99 (d, J = 9.6, 1H), 8.33 (s, 1H), 7.45 (dd, J = 9.3, 2.7, 1H), 7.26 (s, 1H), 7.22 (d , J = 2.4, 1H). (b) 3-cyano-6-hydroxy-1-naphthoic acid A mixture of ethyl 3-cyano-6-methoxy-1-naphthoate (715 15 mmol, 2.80 mmol) and pyridine hydrochloride (4.0 g) was heated to 200 ° C for 3 hours. After cooling the solid was dissolved in IN HCl and extracted into DCM, dried with MgSO4, filtered and concentrated to give a tan precipitate (559 mg, 2.62 mmol, 94%). * H-NMR (DMSO d6) d 10.38 (s, 20 1H), 8.73 (d, J = 9.3, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.38 (m, 2H). (c) ethyl 3-cyano-6-hydroxy-l-naphthoate. To a solution 3-cyano-6-hydroxy-naphthoic acid Facts & fa * i? , > • * & * * .. (363 mg, 1.70 mmol), oxalyl chloride (1.0 mL) in DCM (15 mL) was added 3 drops of DMF for 2 hours. The solvent was removed under reduced pressure, methanol (20 mL) was added, followed by triethylamine (0.5 mL). After stirring for 2 hours the solvent was removed under reduced pressure the residue was redissolved in CDM, washed with IN HC1, then saturated sodium bicarbonate, dried (MgSO4) and concentrated to give a yellow precipitate (346 mg 1.52 mmol, 89%). XH-NMR (CDC13) d 8.92 (d, J = 9.3, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.37 (dd, J = 9.3, 2.1, 1H), 7.26 (s, 2H) ), 4.02 (s, 3H). (d) ethyl 3-cyano-6-trifluoromethylsulfonyloxy-1-naphthoate.
To a cooled (0 ° C) solution of ethyl 3-cyano-6-hydroxy-1-naphthoate (346 mg, 1.52 mmol) and triethylamine (254 μL) in DCM was added trifluoromethanesulfonic anhydride (307 μL). The mixture was allowed to warm to room temperature with mixing, and after 2 hours it was quenched by the addition of methanol (2 mL), concentrated, and purified by chromatography (20% EtOAc in hexanes) to give the product as a white precipitate (438 mg, 1.22 mmol, 80%). XH NMR (CDC13) d 9.20 (d, J = 9.6, 1H), 8.41 (s, 1H), 7.88 (d, J = 2.7, 1H), 7.66 (dd, J = 9.6, 2.7, 1H), 4.06 ( s, -3H). (e) ethyl 3,6-dicyano-l-naphthoate. A solution of ethyl 3-cyano-6-trifluoromethylsulfonyloxy-1-naphthoate (438 mg, 1.22 mmol), Zn (CN) 2 (86 mg, 0.732 mmol) and tetrakis (triphenylphosphine) palladium (59 mg, 0.051 mmol) in DMF (8 mL) was stirred at 80 ° C for 1 hour. The mixture was diluted with Et20, washed with water, dried with MgSO4, filtered and concentrated. Following chromatographic purification (DCM) the product was recovered as a white powder (267 mg, 1.13 mmol, 93%). ^ -NMR (CDC13) d 9.18 (d, J = 9.0, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.91 (dd, J = 9.0, 1.5, 1H ), 4.06 (s, 3H). The ester was saponified by stirring with 1.2 equivalents of LiOH in 3% water in THF at 80 ° C for 2 hours. The mixture was concentrated under reduced pressure and diluted with the DCM resulting in the precipitation of the desired product which was isolated as a powder by filtration.
Example 12 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl- citrate hydrate 3, 4-dicyano-1-naphtamide.
To a stirred solution of 3,4-dicyano-l-naphthoic acid (121 mg, 0.542 mmol) in dried DCM (5 mL) was added oxalyl chloride (80.0 mg, 0.63 mmol) and DMF (10 μL).
After 3 hours at room temperature the DCM was removed in vacuo to give 3,4-dicyano-l-naphthoyl chloride. Using standard acylation conditions the 3,4-dicyano-l-naphthoyl chloride was reacted with N - [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2- methylsulfinylphenyl] -1-piperidinyl] butyl] -N-methylamine (271 mg, 0.597 mmol), was converted to citrate salt and isolated by filtration of Et20 to give the title compound (291.7 mg) as a white powder. Ms m / z 657 (M + H); Analysis for C36H34C12N402S • C6H807 -H20: calculated: C, 58.13; H, 5.11; N, 6.46; found: C, 58.20; H, 5.03; N, 6.36. The required 3,4-dicano-l-naphthoic acid was prepared as follows. 3, 4-dicyano-l-naphthoic acid. A mixture containing methyl 3,4-dibromo-l-naphthoate (126 mL, 0.366 mmol), copper (I) cyanide (618 mg, 6.89 mmol), pyridine (0.1 mL), and dry N-methylpyrrolidone (2.0 mL) was heated at about 150 ° C for 1 hour, at room temperature, diluted with water, NH 4 OH and EtOAc. The mixture was briefly stirred and filtered. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The «? ia »g» .Jriaa > »^ -» - - combined organic extracts were washed (diluted aqueous NH 4 OH and saturated NaHCO 3), dried (Na 2 SO 4), filtered and the EtOAc was removed in vacuo. The products were separated by chromatography (5-15% EtOAc in hexane and hexane: DCM (2: 1)) to give methyl 3,4-dicyano-l-naphthoate (22 mg, 25%) [XH NMR (CDC13 ) d 9.01 (m, 1H), 8.41 (m, 1H), 8.36 (s, 1H), 7.9 (m, 2H), 4.08 (s, 3H), Ms (El) m / z 236 (M)], Methyl 3-bromo-4-cyano-1-naphthoate (21.9 mg, 20.6%) [XH NMR (CDC13) d 8.86 (, 1H), 8.31 (s, 1H), 8.28 (m, 1H), 7.75 (m , 2H), 4.05 (s, 3H), MS (El) m / z 289 (M). ], and methyl 4-bromo-3-cyano-l-naphthoate (28.3 mg, 26.6%) [XH NMR (CDC13) d 9.02 (m, 1H), 8. 43 (m, 1H), 8.28 (s, 1H), 7.8 (m, 2H), 4.04 (s, 3H); MS (El) m / z 289 (M)]. The esters were saponified separately by stirring with 1.1-1.2 equivalents of LiOH in THF: water: methanol (20: 10: 1) at room temperature. The solutions were concentrated in vacuo, further diluted with water, acidified with IN HCl, extracted with EtOAc, dried with Na 2 SO 4, filtered and the EtOAc removed in vacuo to give the individual carboxylic acids. Prior to use, the 3,4-dicyanoyl-1-naphthoic acid was further purified by chromatography (10-20% methanol in DCM to give the title compound (15.3 mg, 87%) as an off-white solid. El) m / z 222 (M).
The required 3,4-dibromo-l-naphthoate was prepared as follows. (a) methyl 3,4-dibromo-l-naphthoate. To a mixture of anhydrous cupric bromide (7.95 g, . 6 mmol) and dry acetonitrile (30 mL) was added to a solution of methyl 3-amino-1-naphthoate (Adcock, W; Dewar, MJS; J. Am. Chem. Soc, 89, 386 (1967) (2.35 g. 11.68 mmol) in dry acetonitrile (10 mL) The dark mixture was stirred at room temperature for 2 hours, cooled (in an ice bath), and tert-butyl nitrite (1.83 g, 17.76 mmol) was added. was added dropwise for approximately 10 minutes.The dark green-black mixture was allowed to warm to room temperature and was stirred overnight The mixture was treated with water (100 mL) and 3N HCl (100 mL), concentrated in vacuo, and extracted with DCM. The DCM extracts were washed (saturated with NH4C1), dried with (Na2SO4), filtered, DCM was removed in vacuo, and the residue was purified by chromatography (4: 1 hexane DCM) to give the desired compound (3.72 g, 93%) as an off-white solid.1H NMR (CDC13) d 8.89 (m, 1H), 8.41 (m, 1H), 8.34 (s, 1H), 7.66 (m , 2H), 4.01 (s, 3H), MS (El) m / z 344 (M).
Example 13 - - N- [-2- (3,4-difluorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3-nitro citrate -l- naftamide. Using standard reductive amination conditions 5 4- [(S) -2-methylsulfinylphenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ, Jr.; Veale, CA., WO 9516682) was made react with N- [2- (3, 4-difluorophenyl) -4-oxobutyl] -N-meth? l-3-nitro-l-naphthyl thiamide and it was converted to the citrate salt. MS m / z 620 (M + H). Analysis for C3 H35F2N3? 4S • 1.0 10 C6H807 - 1.0 H20: calculated: C, 57.89; H, 5.47; N, 5.06. Found C, 57.78; H, 5.32; N, 4.96. The required aldehyde was prepared as follows. (a) 2- [[3-cyano-3- (3, -difluorophenyl)] propyloxy] -2H-15-tetrahydropyran. To a stirred mixture (0 ° C) of 60% sodium hydride (4.12 g, 103 mmol) in THF (95 mL) was added dropwise a solution of 3,4-difluorobenzyl cyanide. (15.0 g, 98 mmol) in THF (25 mL) and the solution was stirred to the room temperature for 3 hours. The solution cooled (in an ice bath) and 2- (2-bromoethoxy) -2H-tetrahydropyran (20.5 g, 98 mmol) was added dropwise and the solution was stirred at room temperature overnight. The saturated ammonium chloride was added and the mixture was extracted with EtOAc.
The combined organic extracts were dried with MgSO 4, filtered and concentrated in vacuo. Chromatography (20%, 90% and 95% DCM in hexane) gave the title compound (16.05 g, 58%) as a yellow oil. XH-NMR (CDC13) d 1.55-1.63 (m, 4H, CH2), 1.75-1.80 (m, 2H, CH2), 2.10-2.19 (m, 2H, CH2) 3.52-3.58 (m, 2H, CH2) 3.82 -4.06 (m, 2H, CH2) 4.08-4.11 (t, 1H, CH) 4.56-4.60 (m, 1H, CH) 7.08-7.27 (m, 3H, ArH). (b) 2- [[4-amino-3- (3,4-difluorophenyl)] butyloxy] -2H-tetrahydropyran. To a mixture of Raney nickel (5.6 g) in ethanol (20 mL) was added to 2- [[3-cyano-3- (3,4-difluorophenyl)] propyloxy] -2H-tetrahydropranin (8.34 g, 89.4 mmol) in ethanol (144 mL). Ammonium hydroxide (30% 120 mL) was added and the mixture was placed in a Parr apparatus under hydrogen (50 psi) for 4 days. The hydrogenation reaction was combined with a similar reaction (7.70 g, 27.4 mmol of nitrile initiator) and filtered through Celite. The filtrate was concentrated, DCM and water were added and the layers separated. The organic layer was washed twice with water, dried with (Na2SO4), filtered, and concentrated in vacuo to give 15.40 g (95%) of the title compound as a yellow oil. MS m / z 286 (M + H). ft * 't - "**? • $" *! &"**" (c) 4-amino-3- (3,4-difluorophenyl) -1-butanol To a solution cooled by stirring (5 °) C) of 2- [[4-amino-3- (3,4-difluorophenyl)] butyloxy] -2H-tetrahydropyran (14.18 g, 49.7 mmol) in ethanol (100 mL) was added dropwise 6N HCl (11 mL) The solution was stirred at room temperature overnight The reaction mixture was poured into water and DCM, the layers were separated The aqueous phase was basified with 5N NaOH and extracted with DCM The combined extracts of DCM dried with (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (8.45 g, 85%). XH-NMR (300 CDC13) d 1.80-1.94 (m, 2H, CH) 2.28 (br s, 3H, NH2 / OH) 2.69-2.76 (m, 1H, CH) 2.81-2.88 (dd 1H, CH) 2.94-2.99 (dd, 1H, CH) 3.49-3.57 (m, 1H, CH) 3.64 -3.71 (m, 1H, CH) 6.88-7.18 (m, 3H, ArH) MS m / z 202 (M + H). d) 3- (3,4-difluorophenyl) -4- (ethoxycarbonylamino) -1-butanol Ethyl chloroformate (3.9 mL, 40.8 mmol) was added to a solution cooled by stirring (-40 ° C) of 4-amino -3- (3,4-difluorophenyl) -1-butanol (7.45 g, 37 mmol) and triethylamine (5.94 mL, 42.6 mmol) in DCM (180 mL). The solution was stirred at room temperature for 30 minutes and at room temperature overnight. The material was washed twice with IN HCl, twice with saturated sodium bicarbonate; dried with Na 2 SO 4, filtered and the solvent removed to give the title compound (8.85 g, 88%) as a yellow oil. XH-NMR (CDC13) d 1.18-1.23 (t, 3H, CH) 1.72-1.98 (m, 3H) 2.96-3.00 (m, 1H, CH) 3.24-3.29 (m, 1H, CH) 3.45-4.04 (m , 3H, CH), 4.06-4.14 (m, 2H, CH) 4.66 (br s, 1H, OH or NH) 6.91-7.37 (m, 3H, ArH). MS m / z 274 (M + H). (e) 3- (3,4-difluorophenyl) -N-methyl-4-amino-1-butanol. To a stirred mixture (-10 ° C) of lithium aluminum hydride (2.46 g, 65 mmol) and dry THF (50 mL) was added dropwise a solution of 3- (3,4-difluorophenyl) -4 - (Ethoxy-carbonylamino) -1-butanol (8.85 g, 32.4 mmol) in THF (40 mL). The solution was heated under reflux for 1.25 h, cooled in (ice bath) and a solution of saturated sodium sulfate (150 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, filtered through celite, washed with THF and the solvent removed in vacuo. The residue was dissolved in DCM, washed with water, dried with Na 2 SO 4, filtered and the solvent removed in vacuo. The purification was carried out by means of chromatography (2-5% and 10% methanol in DCM) to í¡ > kA??, and »< .- 40® - t- afíB-Aft. - -provide the title compound (5.20 g, 75%) as a brown-gray oil. H-NMR (CDC13) d 1.85-1.96 (, 2H, CH) 2.45 (s, 3H, CH3) 2.74-2.85 (m, 3H, CH) 3.37 (br s, 2H, NH, OH) 3.50-3.58 (m , 1H, CH), 3.66-3.73 (m, 1H, CH) 6.87-7.35 (m, 3H, ArH). MS m / z 216 (M + H). (f) N- [2- (3, -difluorophenyl) -4-hydroxybutyl] -N-methyl-3-nitro-1-naphtamide. To a stirred mixture (0 ° C) of 3- (3,4-difluorophenyl) -N-methyl-4-aminho-1-butanol (0.781 g, 3.63 mmol) in DCM (30 mL) and NaOH IN ( 4.53 mL) was added dropwise a solution of 3-nitro-l-naphthoyl chloride (example 3) (0.855 g, 3.63 mmol) in DCM (12 mL). The mixture was stirred at 0 ° C for 2.5 hours, water was added and the mixture was extracted with DCM. The combined organic layers were dried with MgSO, filtered and concentrated in vacuo. Purification was performed by chromatography (0%, 50%, 100% EtOAc in Et20) to give the title compound (1.25 g, 83%) as a light yellow solid. MS m / z 415 (M + H). (g) N- [2- (3, 4-difluorophenyl) -4-oxobutyl] -N-methyl-3-nitro-1-naphtamide. To a solution cooled by stirring (-78 ° C) oxalyl chloride (0.39 mL, 4.52 mmol) in DCM (10 mL) was í Sa? Sfee.! - - added DMSO (0.64 mL, 9.05 mmol) in DCM (5 mL). The solution was stirred at -78 ° C for 5 minutes and a solution of N- [2- (3,4-difluorophenyl) -4-hydroxybutyl] -N-methyl-3-nitro-l-naphtamide (1.25 g, 3.02 mmol) in DCM (6 mL) and DMSO (3.4 mL) was added dropwise. The solution was stirred at -78 ° C for 15 minutes and triethylamine (2.52 mL, 18.1 mmol) was added. Stirring was continued at -78 ° C for 30 minutes and then at room temperature for 2 hours. DCM (75 mL) and IN HCl (75 mL) were added, the layers separated, and the layer Organic was dried with MgSO 4, filtered and concentrated in vacuo. Purification was carried out by chromatography (silica gel: 50% Et20 in DCM (volume / volume) to afford the desired compound (1.15 g, 93%) as a slightly yellow solid MS m / z 413 (M + H). EXAMPLE 14 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl- citrate hydrate 3-nitro-l-naphthamide (1: 1: 0.75) To a stirred solution of 3-nitro-l-naphthoic acid (Kice, JL; Lotey H,; J. Org. Chem., 54, 3596 (1989 )) (0.36 g, 1.66 mmol) in DCM (2 mL) was added oxalyl chloride (0.26 g, 2.06 mmol) per drip via syringe. DMF (5 μL) was added and the solution was stirred overnight > s ^ 5t8 jÉ8 & a ^? ^^ faSá .tsSüJ - - ambient temperature. The DCM was removed in vacuo, toluene (2 mL) was added and also removed in vacuo. The residue was added under high vacuum for 2 hours and was used without further purification. Using standard acylation conditions, 3-nitro-l-naphthoyl chloride was reacted with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] - 1-piper? Dinyl] butyl] -N-methylamine and converted to the citrate salt. MS: 652 (M + H); Analysis for C34H35C12N3? 4SC6H807 0.75 • H20: calculated: C, 56.87; H, 5.13; N, 4.97; found: C, 56.01; H, 5.17; N, 4.80. The title compound was also converted to citrate hydrate etherate (1.0: 1.0: 0.5: 0.15).
Example 15 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-6-nitro citrate -l-naphthamide A solution of 6-nitro-l-naphthoic acid (0.2 g, 0.922 mmol) (Dewar, MJS and Grisdale, PJ; J. Amer Chem. Soc., 84, 3541 (1962)) in thionyl chloride (2 mL) was heated under reflux for 3 hours. The solution was concentrated in vacuo, then the residual solvent was coevaporated twice with toluene to give the acid chloride (0.217 g, quantitative) as an off white solid which was used without purification. - - additional. Using standard acylation conditions, 6-nitro-l-naphthoyl chloride was reacted with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] - 1-piperidinyl] butyl] -N-methylamino, converted to citrate salt, and isolated by filtration d 'and Et20 MS m / z 652 (M + H); 4And analysis for C34H35C? 2N3? 4SC6H8? 7o -H20: calculated: C, 55.68; H, 5.26; N, 4.87; found: C, 55.78; H, 5.20; N, 4.75.
Example 16 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -1-piperidinylpiperidinyl] butyl] -N-methyl-3-methylsulfonyl-1 -naftamide Using standard acylation conditions 0.450 g of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -1-piperidinylpiperidinyl] butyl] -N-methylamino (Example 1, sub part (b)) was reacted with 0.234 g of 3-methylsulfinyl-1-naphthoyl chloride and the resulting product was converted to the hydrochloride salt. The requisite acid chloride was prepared from the corresponding acid using oxalyl chloride; under these conditions the sulfoxide was oxidized to sulfone. 1U NMR (DMSO-d6) 1.9 (m, 2H), 2.75 (s, 3H), 3.2 (m, 3H), 3.4 (s, 3H), 7.0-8.0 (m, 11H), 8.3 (m, 1H) 8.6 (s, 1H); MS m / z 685 (M + H); mp 175-180 ° C.
- - The requisite 3-methylsulfinyl-l-naphthoic acid is prepared as follows, (a) methyl 3-N, N-dimethylthiocarbamoyloxy? -l-naphthoate.
A solution of 3-hydroxy-l-naphthoate in DMF (100 mL) was treated with 1,4-diazabicyclo [2,2,2] octane (2.24 g) and N, N-dimethylthiocarbomoyl chloride (2.48 g) . After stirring for 16 hours at room temperature the mixture was poured into cold water (200 mL), stirred for 4 hours, and filtered to collect the solid which was washed with water and dried to give the material of the product. Title. 1H NMR (CDC13) d 3.4 (s, 3H), 3.5 (s, 3H), 3.96 (s, 3H), 7.6 (m, 2H), ^ r *? *,. - - 7.7 (d, J = 5, 1H), 7.8 (m, 1H), 8.0 (d, J = 5, 1H), 9.0 (d, J = 915, 1H), MS m / z 258 (M- OCH3). (b) methyl 3- (N, N-dimethylcarbamoylthio) -1-naphthoate. A solution of methyl 3-N, N-dimethylthiocarbamoyloxy) -1-naphthoate in N, N-dimethylaniline (30 mL) was heated under reflux for 20 hours, cooled and poured into concentrated hydrochloric acid containing ice. The solid precipitate was collected by filtration, washed with water, and dried to obtain the titled material. H NMR (CDC13) d 3.0 (s, 3H), 3.2 (s, 3H), 4.0 (s, 3H), 7.6 (m, 1H), 7.7 (m, 1H), 7.8 (d, J = 10, 1H ), 8.2 (s, 1H), 8.3 (d, J = 2, 1H), 9.0 (d, J = 2, 1H), 9.0 (d, J = 10, 1H); MS m / z 258 (M-OMe). c) 3-thio-l-naphthoic acid A solution of 0.91 g of methyl 3-N, N-dimethylcarbamoylthio-1-naphthoate in methanol was treated with 1.3 potassium hydroxide and the reaction mixture was heated under reflux for 1 hour. The mixture was concentrated, dissolved in water and extracted with Et20. The aqueous layer was acidified with hydrochloric acid and the resulting precipitate was filtered and dried to give 0.56 g of the titled product. - - (d) methyl 3-thiomethyl-l-naphthoate. A solution of 3-thio-l-naphthoic acid erT DMF was treated with 1.36 of potassium carbonate followed by 0.62 mL of methyl iodide and heated at 80 ° C for 4 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried, concentrated and purified by chromatography. Elution with 9: 1 hexane: EtOAc gave 0.545 g of the titled product. XH NMR (CDC13) d 2.6 (s, 3H), 4.0 (s, 3H), 7.5 (m, 2H), 7.8 (m, 2H), 7.8 (m, 2H), 8.1 (s, 1H), 8.8 ( m, 1H); MS m / z 233. (e) methyl 3-methylsulfinyl-1-naphthoate. A solution of methyl 3-thiomethyl-l-naphthoate in THF was treated with sodium periodate dissolved in 10 mL of water. After stirring for 1 hour the mixture was concentrated, diluted with water, and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give the titled product. H NMR (CDC13) d 2.9 (s, 3H), 4.0 (s, 3H), 7.7 (m, 2H), 8.0 (d, J = 15, 1H), 8.4 (s, 1H), 9.0 (d, J = 15, 1H); MS m / z 249 (M + H). (f) 3-methylsulfinyl-1-naphthoic acid. Methyl 3-methylsulfinyl-1-naphthoate was converted into the desired material by heating a solution of the material in methanol (10 mL) and sodium hydroxide IN (2 mL) under reflux for 1 hour. The reaction mixture was acidified with 5% HCl, extracted with ethyl acetate and the organic layer was dried with magnesium sulfate and concentrated under reduced pressure: ΔTI NMR (CDC13) d 3.15 (s, 3H), 7.6 ( m, 2H), 8.05 (m, 1H), 8.6 (s, 1H), 9.1 (m, 1H); MS m / z 235 (M + H) Example 17: N- [2- (3, 4 -dichlorophenyl) -4- [4- [(S) -2- (methylsulfinyl) -phenyl] -l-piperidinyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano-l-naph-amide. the standard reductive amination conditions N- [2- (3, 4-difluorophenyl) -4-oxobutyl] -N-methyl-3-c-ano-1-naphthalamide (0.255 g, 0.65 mmol) was reacted with 4- [(S) -2-methylsulfmyl-phenyl] -piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht, CJ. Jr.; Veale, CA., Wo 9516682) (0.155 g, 0.65 mmol) and he became citrate salt (white solid 0.25 g, 64%). MS m / z 600 (M + H); Analysis for C35H35F2N302S- 1.0 C6H807-1.5 H20: calculated: C, 60.13; H, 5.66; N, 5.13; found: C, 60.16; H, 5.60; N, 5.05. The required N- [2- (3,4-difluorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-1-naphthamide was prepared as follows, (a) N- [2- (3,4-difluorophenyl) ) -4-hydroxybutyl] -N-methyl-3-cyano-1-naphthalenecarboxamidamide.
- - To a stirred mixture (0 ° C) of 3- (3,4-difluorophenyl) -N-methyl-4-amino-1-butanol (example 13 subpart (e)) (0.48 g, 2.23 mmol) 14 mL DCM and 10% aqueous NaOH (2.80 mL) were added via cannula to a solution of 3-cyano-l-naphthoyl chloride in 10 mL of DCM and the mixture was stirred overnight while it was heated to room temperature. ambient. The reaction was poured into a mixture of water and DCM, the organic phase was collected, washed twice and dried with Na2SO4. The product was purified by chromatography (30% ether in hexane and 50% ether in hexane) to give the title compound as a white solid (0.65 g, 74%). MS m / z 395 (M + H); * H NMR (CDC13) d 1.93-2.06 (m, 1H), 2.61 (s, 3H), 3.17-3.74 (m, 6H), 7.17-7.90 (m, 8H), 8.21 (s, 1H) (b) N- [2- (3, -d? fluorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide. To a stirred solution (-78 ° C) of oxalyl chloride (0.22 mL, 2.47 mmol) and DCM (8.0 mL) was added via cannula a solution of DMSO (0.35 mL, 4.93 mmol) and DCM (5 mL) , and the mixture was stirred for 5 minutes. A solution of N- [2- (3, 4-difluorophenyl) -4-hydroxybutyl] -N-methyl-3-c-ano-l-naphthalenecarboxamide (0.65 g, 1.65 mmol), DCM (8.0-L) and DMSO (1.9 mL) was added lentspf »through a cannula followed after 15 minutes by triethylamine (1.38 mL, 9.87 mmol). After an additional 15 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight. Purification was performed by chromatography (1: 1 hexane in ether) to provide the desired compound as a white solid (0.516 g, 80%). MS m / z 393 (M + H); XH NMR (CDC13) d 2.68 (s, 3H), 2.95 (t, 2H), 3.24-3.31 (d, 1H), 3.60-3.83 (m, 2H), 7.22-7.91 (m, 8H), 8.22 (s) , 1H), 9.80 (s, 1H).
Example 18 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [-2- (methylsulfonyl) -phenyl] -l-piperidinyl] butyl] -N-methyl-3- citrate cyano-1-naph amide. Using standard reductive amination conditions 4- (2-methylsulfonylphenyl) piperidine (Shenvi, AB; Jacobs, RT; Miller, SC; Ohnmacht CA: Véale, CA. WO 9516682) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-c-ano-l-naphthalamide. The product was converted to citrate salt. MS m / z 648 (M + H); Analysis for C 35 H 35 C 12 N 3 N 303 S-C 6 H 807: calculated: C, 58.57; H, 5.15; N, 5.00. found: c, 58.92; H, 5.31; N, 5.01. Example 19 - - N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-oxoethylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano- citrate The Naphtamide A solution of 4- (2-oxoethylphenyl) -piperidine-N-5-boc-amine was stirred in a solution of DCM (3 mL) and trifluoroacetic acid (1 mL) for 1 hour, concentrated under pressure reduced, the residual solvent was coevaporated twice with methanol, and dried under high vacuum to provide the N-deprotected 4- (2-acetylphenyl) piperidine. Using standard reductive amination conditions 4- (2-acetylphenyl) piperidine was reacted with N- [2- (S) - (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l- Naphthamide and converted to citrate salt. MS m / z 612 (M + H). 4- (2-oxethylphenyl) -piperidine-N-Boc-amine was prepared as follows. (a) 4- (2-Oxoethylphenyl) -1,2,5,6-tetrahydropyridino-N-Boc-amine. Based on the procedure of Laborde, E; Kiely, JS; Lesheski, LE; Schroeder, MC; J. Het. Chem .; 28, 191, (1991), a solution of 4- (tributylstannyl) -1, 2, 5, 6-tetrahydropyridine-N-Boc-amine (2.0 g, 4.04 mmol), 2'-bromoacetophenone (653 μL, 4.85 mmol), and tetrakis (triphenylphosphine) palladium (480 mg) was stirred at 100 ° C in toluene (35 mL). After 3 hours a second portion of tetrakis (triphenylphosphine) palladium (450 mg). After a total of 7 hours the reaction mixture was allowed to cool and stirring was continued overnight. The reaction mixture was concentrated and partially purified by chromatography (10-30% EtOAc in hexanes) (774 mg, 2.57 mmol, 64%). To remove traces containing tin impurities, the material was further purified by HPLC prepared (C18, 10-100% CH3CN in water with 0.1% TFA). MS m / z 324 (M + Na). ? NMR (CDC13) d 7.56 (d, J = 7.5, 1H), 7.45 (t, J = 7.5 1H), 7.35 (t, J = 7.5, 1H), 7.22 (t, J = 7.5, 1H), 5.54 ( br s, 1H), 4.02 (d, J = 2.7, 2H), 3.66 (t, J = 5.7, 2H), 2.48 (s, 3H), 2.40 (br s, 2H), 1.50 (s, 9H). (b) 4- (2-Oxoethylphenyl) -piperidine-N-Boc-amine. A mixture of 4- (2-acetylphenyl) -1,2,5,6-tetrahydropyridine-N-Boc-amine (4754 mg, 1.57 mmol) and 10% Pd / c (150 mg) was stirred in methanol (30 mL ) under hydrogen (1 atm) for 16 hours, filtered through celite, washed with DCM, and concentrated to give the product as a yellow oil (397 mg, 1.31 mmol, 83%). MS m / z 204 (M-Boc).
Example 20 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methoxycarbonyl-enyl] -l-piperidinyl] butyl] -N-methyl-3- citrate ga »J3tA« as ».. * afe & *. , - cyanonaphtamide O N - [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methoxycarbonylphenyl] -1- piperidinyl] butyl] -N-methylamine hydrochloride (0.155 g) was dissolved in DCM (10 mL), triethylamine (0.061 g) was added followed by 3-cyano-l-naphthoyl chloruror (0.069 g). The mixture was stirred overnight, diluted with saturated sodium bicarbonate and extracted with EtOAc. The organic phase was dried and evaporated. The residue was purified by chromatography with DCM: methanol (30: 1) as the eluent to give the free base (0.170 g) which was converted to citrate salt. MS: m / z 658 (M + H). XH NMR (DMSO d6) d 8.80-6.70 (m, 13H), 3.84 (s, 3H, OCH3), 2.55 (m, 3H, N-CH3) The requisite amine was prepared as follows. [a) 4- (2-methoxycarbonylphenyl) pyridine hydrochloride. methyl 2-bromobenzoate (1400 g) and tetrakis (triphenylphosphine) palladium (0) (0.225 g) were combined in dry 1,2-dimethoxyethane (50 mL) under hydrogen. The mixture was stirred for 20 minutes with pyridine-4-boronic acid (0.800 g) (prepared according to the method described by Lamothe, M; Pauwels, PJ; Belliard, K; Schambel, P; and halazy, S; J. Med. Chem., 40, 3542 (1997) was added followed immediately by a solution of sodium carbonate (1610 g) in water (15 mL) .The mixture was heated under reflux for 15 hours, then extracted with EtOAc The organic extracts were dried, evaporated and the residue was purified by chromatography with DCM: methanol (20: 1) as the eluent to give the free base of pyridine.The free base was dissolved in DCM and treated with a Excess of ethereal hydrogen chloride to give the title compound (0.900 g) as a white solid MS: m / z 214 (M + H) 1U NMR (CDCL3) d 8.63 (D, 2H), 7.93 (M, 1H), 7.55 (m, 3H), 7.30 (m, 2H), 3.67 (s, 3H). (b) 4- (2-methoxycarbonylphenyl) piperidine hydrochloride. 4- (2-methoxycarbonylphenyl) piperidine hydrochloride (0.595 g) was dissolved in acetic acid (30 mL), platinum dioxide (0.240 g) was added and the mixture was stirred under hydrogen (50 psi) for 3 hours. The solution was filtered, - - acidified with 4M CH1 and evaporated to give the piperidine hydrochloride (0.243 g) as a white solid. MS m / z 220 (M + H). (c) N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methoxycarbonylphenyl] -l-piperidinyl] butyl] -N-methyl-N-Boc-amine. N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-N-Boc-amine (0.261 g) (Miller, SC, WO 9505377) was added to a solution of 4- (2-methoxycarbonylphenyl) hydrochloride of piperidine (0.600 g) and triethylamine (0.282 g) in methanol (30 mL). The mixture was stirred for 5 minutes, then a solution of methanol (3 mL) of sodium cyanoborohydride was added. (0.250 g). The reaction was stirred overnight at room temperature. The methanol was evaporated and the residue was partitioned between EtOAc (20 mL) and aqueous sodium bicarbonate (10 mL). The organic phase was dried and evaporated. The residue was purified by chromatography, with EtOAc as eluent, to give the desired compound (0.600 g). MS: m / z 549 (M + H). 0 XH NMR (CDCL3) d 7.81-7.05 (m, 7H), 3.88 (s, 3H), 3.60-1.85 (m, 19H), 1.41 (s, 9H). (d) N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methoxycarbonylphenyl] -l-piperidinyl] butyl] -N-methylamine hydrochloride - N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-carboxymethylphenyl] -l-piperidinyl] butyl] -N-methyl-N-Boc-amma (0.085 g) is dissolved in EtOAc (5 mL), cooled to 0 ° C and hydrogen chloride was bubbled through the solution for 5 minutes. The solution was stirred for an additional 5 minutes, then evaporated and used directly in the next reaction.
Example 21 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-methylsulfonylaminophenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-1- citrate Naphtamide 4- (2-methylsulfonylaminophenyl) piperidine hydrochloride (0.076 g) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3 -cyano-l-naphthalenecarboxamide (0.123 g) using the method described in Example 20, subpart c. The product was converted to citrate salt to give the title compound (0.122 g) as a white solid. MS m / z 663 * (M + H). lH NMR (DMSO-d6) d 9.14 (m, 1H), 8.62 (m, 1H), 8.05 (m, 1H), 7.95-6.90 (m, 10H), 3.17 (s, 3H, S, CH3), 2.97 (s, 3H, N-CH3). The amine requirement was prepared as follows. - < aes «t. ^ J. - - (a) 4- (2-aminophenyl) piperidine. Following the Ullmann coupling of 2-nitrobromobenzene and 4-bromopyridine (Shimizu, N; Kitamura, T .; Watanabe, K; Yamaguchi, T .; Shigyo, H .; Ohta, T; Tetrahedron Lett. 34, 3421 (1993), the title compound was prepared by hydrogenation of 4- (2-nitrophenyl) pyridine using the general method described in Example 20 subpart (b) MS m / z 177 (M + H). (b) 4- (2-aminophenyl) -N-Boc-piperidine. A solution of 4- (2-aminophenyl) piperidine (4.04 g) in water (200 mL) was adjusted to pH 9 by the addition of potassium carbonate and cooled in a cold water bath. A solution of di-tert-butyl dicarbonate (5.20 g) in 1,4-dioxane (80 mL) was added dropwise. The mixture was stirred to > . Ssff- fcJ ^ MRfl & amp; ^ j - -allow the gradual warming to room temperature for 3 hours.Additionally potassium carbonate was added as necessary to maintain pH 9. The reaction was extracted with Et20.The organic extracts were dried and evaporated.The residue was purified by chromatography, with 3: 1 hexanes: EtOAc as eluent, to give the title compound (3.26 g) MS m / z 177 (M-Boc), 299 (M + Na) X H NMR (DMSO-d 6) d 6.87 (m, 2 H), 6.65 (d, 1 H), 6.52 (m, 1 H), 4.91 (s, 2 H, NH 2), 4.04 (m, 2 H) ), 2.76 (m, 3H), 1.70 (m, 2H), 1.42 (s, 9H), 1.34 (m, 2H). (c) 4- (2-methylsulfonylaminophenyl) -N-boc-piperidine. Methanesulfonyl chloride (0.035 g) was added to a solution of 4- (2-aminophenyl) -N-Boc-piperidine (0.070 g) and pyridine (0.027 g) in DCM (3 mL) and stirred overnight. The reaction was diluted with dilute sodium bicarbonate and extracted with EtOAc. The extracts were dried and evaporated to give the title compound (0.093 g) as a colorless oil. MS m / z 255 (m-Boc), 377 (M + Na). (d) 4- (2-methylsulfonylaminophenyl) piperidine hydrochloride.
A solution of 4- (2-methylsulfonamidophenyl) -N-boc-pipepdine (0.093 g) was dissolved in EtOAc (5 mL) and cooled in a cold water bath. The hydrogen chloride was bubbled through the solution for 5 minutes and continued to stir for an additional 5 minutes, then evaporated to give the desired compound (0.076 g) as a white solid. MS m / z 255 (M + H). X H NMR (DMSO-d 6) d 7.30 (m, 4 H), 3.29 (m, 5 H), 2.99 (s, 3 H, S-CH 3), 1.82 (m, 4 H).
Example 22 N- [2- (S) - (3,4-dichlorophenyl) -4- (4- [2-acetamidophenyl] -l-piperidinyl) butyl] -N-methyl-3-cyano-l-naphthamide citrate 4- (2-Acetamidophenyl) -piperidine hydrochloride (0.070 g) was reacted with N- [2- (S) - (3,4-d? Chlorophenyl) -4-oxobutyl] -N-meth? -3-c? Ano-l-naphthalamide (0.130 g) using the method described in Example 20 subpart c. The product was concentrated to citrate salt to give the title compound (0.102 g) as a white solid. MS m / z 627 (M + H). XH NMR (DMSO-de) d 8.0 (m, 1H), 8.6 (m, 1H), 8.1 (m, 1H), 7.90-6.80 (m, 10H), 2.60 (s, 3H, N-CH3), 2.04 (s, 3H, CO-CH3). The requisite amine was prepared as follows. (a) 4- (2-acetam-dofen? l) -N-Boc-piperidine, - - Acetyl chloride (0.060 g) was added to a solution of 4- (2-aminophenyl) -N-Boc-piperidine ( 0.070 g) (example 21 subpart (b)) and triethylamine (0.090 g 9 in DCM (2 mL), was stirred overnight The reaction was diluted with Et20 and extracted sequentially with aqueous sodium bicarbonate and IN HCl. The organic extract was dried and evaporated to give the title compound (0.070 g) as a colorless oil MS m / z 341 (M + Na) H NMR (CDC13) d 7.26 (m, 4H), 7.69 (br, 1H), 4.15 (m, 2H), 2.67 (m, 3H), 2.23 (s, 3H), 1.75 (m, 4H), 1.48 (s, 9H). (b) 4- (2-acetamidophenyl) piperidine hydrochloride. 4- (2-acetamidophenyl) -N-Boc-piperidine (0.70 g) was deprotected using the method described in example 21 subpart (d) to give the desired compound (0.057 g). MS m / z 627 (m + H); XH NMR (DMSO-d6) d 9.47 (s, 1H), 8.80 (br, 2H), 7.22 (m, 4H), 3.35 (m, 2H), 2.95 (m, 3H), 2.07 (s, 3H), 1.82 (m, 4H).
Example 23 N- [2- (S) - (3,4-dichlorophenyl) -4- (4- [2- (1-pyrrolidine-2, 5-dione) phenyl] -l-piperidinyl) -butyl citrate] -N-Methyl-3-cyano-1-naphthamide 4- [2- (1-pyrrolidino-2, 5-dione) phenyl] piperidine hydrochloride (0.073 g) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide (0.116 g) using the method described in Example 20 subpart c. The product was converted to citrate salt to give the title compound (0.081 g) as a white solid. MS m / z 667 (M + H); XH NMR (DMSO-d6) d 9.51 (br, 1H), 8.63 (br, 1H), 8.09 (m, 1H), 7.9-7.0 (m, 10H), 2.61 (m, 3H, N-CH3).
The requirement 4- [2- (1-pyrrolidino-2, 5-dione) phenyl] piperidine was prepared as follows. (a) 4- (2- (l-pyrrolidone-2, 5-dione) pheny1-N-Boc-piperidine, succinic anhydride (0.032 g) and 4- (2-aminophenyl) -N-Boc-piperidine (0.070) g) (example 21, subpart (b)) were combined in m-xylene containing a catalytic amount of triethylamine and heated under reflux overnight The reaction was diluted with aqueous sodium bicarbonate and extracted with EtOAc. Organic extracts were dried and evaporated to give the title compound (0.080 g) as a white solid.Ms m / z 259 (M-Boc). (b) 4- (2- (1-pyrrolidine-2, 5-dione) phenyl) piperidine. 4- (2- (1-pyrrolidine-2, 5-dione) phenyl) -N-Boc-pipepdine (0.80 g) was deprotected using the method described in Example 21 subpart (d) to give the desired compound (0.061 g) as a white solid. MS m / z 259 (M + H); XH NMR (DMSO-d6) d 7.50 (m, 1H), 7.37 (m, 2H), 7.14 (m, 1H), 3.32 (m, 2H), 2.83 (m, 6H), 1.85 (m, 3H), 1.68 (m, 2H).
Example 24 N- [2- (S) - (3,4-dichlorophenyl) -4- (4- [2-. {3-methylureido) citrate } phenyl] -l-piperidinyl) butyl] -N-methyl-3-cyano-l-naphtamide hydrochloride of 4- [2-. { 3-methylureido} phenyl] piperidine (0.052 g) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide (0.100 g) using the method described in example 20 subpart c. The product was converted to citrate salt to give the title compound (0.125 g) as a white solid. MS m / z 642 (M + H); XH NMR (DMSO-d6) d 8.63 (br, 1H), 8.08 (m, 1H), 7.95-6.90 (m, 11H), 6.19 (br, 1H), 2.65 (m, 3H). The requisite amine was prepared as follows. (a) 4- [2- (3-methylureido) phenyl] -N-Boc-piperidine. Triphosgene (0.062 g) was added to a solution of 4- (2-ammophene?) -N-Boc-pipepdine (0.055 g) (example 21 subpart (b)) in DCM (5 mL). Triethylamine (0.025 g) was added rapidly with vigorous stirring. After 15 minutes it - - added methylamine 2M in THF (2 mL) and the mixture was stirred for 1 hour. The reaction was diluted with IN HCl and extracted with DCM. The organic extracts were dried and evaporated to give the title compound (0.076 g) as a colorless oil. MS m / z 234 (M-Boc); : H NMR (CDC13) d 7.28 (m, 5H), 6.00 (s, 1H), 4.44 (m, 1H), 4.23 (br, 2H), 3.75 (m, 1H), 3.00 (m, 1H), 2.81 (d, 3H), 1.85 (m, 1H), 1.69 (m, 3H), 1.48 (s, 9H). 0 (b) 4- [2- (3-methylureido) phenyl] piperidine hydrochloride. 4- [3-methylureidophenyl] -N-Boc-piperidine (0.074 g) was deprotected using the method described in Example 21 5 subpart (d) to give the desired compound (0.052 g) as a waxed solid. MS m / z 234 (M + H).
EXAMPLE 25 N- [2- (S) - (3,4-dichlorophenyl) -4- (4- [2-. {3-dimethylureido} phenyl] -l-piperidinyl) butyl] citrate -methyl-3-cyano-l-naphtamide. The compound was prepared according to the method described in Example 24 by substituting dimethylamine for methylamine in subpart (a). MS m / z 656 (M + H). 1ti NMR yes.r- - - (DMSO-de) d 8.63 (br 1H), 8.08 (m, 1H), 7.95-6.90 (m, 11H), 2.91 (s, 6H), 2.91 (s, 6H), 2.60 ( s, 3H).
Example 26 N- [2- (S) - (3,4-dichlorophenyl) -4- (4- [2-dimethylaminophenyl] -l-piperidinyl) butyl] -N-methyl-3-cyano-l-naphthamide citrate . 4- (2-dimethylaminophenyl) piperidine dihydrochloride (0.063 g) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide (0.100 g) using the method described in example 20 subpart c. The product was converted to citrate salt to give the title compound (0.105 g) as a white solid. MS m / z 613 (M + H). XH NMR (DMSO-de) d 8.63 (s, 1H), 8.06 (, 1H), 7.95-7.0 (m, 11H), 2.59 (s, 6H), 2.55 (m, 3H). The amine requirement was prepared as follows. (a) 4- (2-dimethylaminophenyl) -N-Boc-piperidine. Formaldehyde (37% weight in water, 0.50 mL) was added to a solution of 4- (2-aminophenyl) -N-Boc-piperidine (0.065 g) (example 21 subpart (b) and acetic acid (10 μL) in methanol (2 mL). The mixture was stirred for 5 minutes. A solution of iodine cyanoborohydride (0.100 g) in methanol (2 mL) was added and the mixture was stirred overnight. The i¡? * > leibárí ??? a3 # ma && amp; amp; - reaction was concentrated, the residue was mixed with aqueous sodium bicarbonate and extracted with Et20. The organic extracts were dried and concentrated to give the title compound (0.071 g) as a waxed solid. MS m / z 305 (M + H). (b) 4- (2-dimethylaminophenyl) piperidine dihydrochloride. 4- (2-dimethylaminophenyl) -N-Boc-piperidine (0.070 g) was deprotected using the method described in (example 21 subpart (d)) to give the title compound (0.063 g) as a waxed solid. MS m / z 205 (M + H).
Example 27 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-trifluoromethylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano-1- citrate naftamide. Using standard reductive amination conditions N- [2- (S) - (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-cyano-1-naphthamide was reacted with 4- [2- trifluoromethylsulfinyl-phenyl] piperidine and converted to citrate salt. 1 H NMR (DMSO-d 6) d 8.62 (d, 1 H), 8.08 (br m, 1 H), 7.92 (m, 1 H), 7.65-6.41 (m, 10 H), 4.54 (m, 1 H), 4.11-1.60 ( 18H); MS m / Z 686 (M + H). The 4- [2- trifluoromethylsulfinylphenyl] piperidine requirement was prepared as follows. (a) N-Phenylmethoxycarbonyl-4- [2-thiophenyl] piperidine.
Based on Young's procedure, RN; Gauthier, JY; Coombs, W; Tetrahedron Lett., 25, 1753, (1984) a solution of N-phenylmethoxycarbonyl-4- (2-methylsulfinylphenyl) -piperidine (2.80 mmol) in trifluoroacetic anhydride (50 mL) was heated under reflux at 40 ° C for 1 hour. The mixture was concentrated and the residue was stirred with a mixture in a 1: 1 ratio of methanol: triethylamine (50 mL) for 15 minutes. The mixture was concentrated again and purified by chromatography (15% EtOAc in hexane) to give the product as a white precipitate (76%). 1 NMR (DMSO-de) d 7.39 (m, 4H), 7.20 (d, 1H), 7.19 (d, 1H), 7.10 (m, 3H), 5.29 (s, 1H), 5.09 (s, 2H), 4.10 (br d, 2H); 2.89 (m, 3H), 1.77 (br d, 2H), 1.57 (m, 2H); MS m / z 326 (M-H). (b) N-Phenylmethoxycarbonyl-4- (2-trifluoromethylthiophenyl) pipepdine. Based on the Koshechko procedure, VG; Kiprianova, LA; Fileleeva, Ll; Tetrahedron Lett, 33 6677 (1992) a flask equipped with 3 necks with a drip funnel and a dry ice condenser under hydrogen, was charged with DMF (9.5 mL) and triethylamine (0.5 mL). The solution was stirred at room temperature and purged with a stream of nitrogen for 20 minutes. The trifluoromethyl iodide (0.6 mL) was condensed into the distillation funnel and N-phenylmethoxycarbonyl-4- (2-thiophenyl) piperidine (780 g) was added to the stirred solution of DMF followed by the addition of methyl viologen dichloride hydrate ( 43 mg). Stirring was continued for 5 minutes, then trifluoromethyl iodide was added rapidly to the dark blue solution and the mixture was stirred for 1 hour. The mixture was then poured into ice water and stirred until all bubbling ceased (20 minutes). The mixture was extracted into Et20, washed with brine, dried with MgSO4, concentrated and purified by chromatography (25% EtOAc in hexane) to give the product (650 mg, 70%) as a colorless oil. XH NMR (DMSO-d6) d 7.95 (d, 1H), 7.55 (m, 3H), 7.36 (m, 5H), 5.10 (s, 2H), 4.16 (br d, 2H), 3.46 (m, 1H) 2.93 (br s, 2H); 1.53 (m, 4H); MS m / z 396 (M + H). (c) N-Phenylmethoxycarbonyl-4- (2-trifluoromethylsulfinylphenyl) piperidine. To a solution of N-phenylmethoxycarbonyl-4- (2-trifluoromethylthiophenyl) piperidine (650 mg) in DCM (20 mL) at 0 ° C was added 3-chloroperoxybenzoic acid (0.57 g) in small portions. The ice bath was removed and continued stirring overnight. The white slurry was diluted with saturated NaHCO 3 (10 mL) and water, extracted into DCM, washed with brine, dried with MgSO 4, concentrated and purified by chromatography (25% EtOAc in hexane) to give the product as a white solid (500 mg, 74%). 1 H NMR (DMSO-de) d 8.12 (d, 1H), 7.62 (m, 3H), 7.37 (m, 5H), 5.10 (s, 2H), 4.14 (m, 2H), 3.12 (m, 3H), 1.79 (m, 4H); MS m / z 412 (M + H). (d) 4- (2-trifluoromethylsulfinylphenyl) piperidine. A solution of N-phenylmethoxycarbonyl-4- [2-trifluoromethylsulfinylphenyl] piperidine (230 mg) was dissolved in trifluoroacetic acid (5 mL) and the mixture was heated under reflux at 80 ° C for 10 minutes. The mixture was concentrated, neutralized by the addition of 2N NaOH (5 mL), extracted into chloroform, dried with MgSO 4, concentrated and purified by chromatography (15% methanol in DCM with 1% NH 40 H). give the product (100 mg, 65%). 1 H NMR (DMSO-de) d 8.10 (d, 1H), 7.83 (m, 1H), 7.61 (m, 2H), 2.91 (m, 2H), 2.57 (m, 3H), 1.74 (m, 2H), 1.54 (m, 2H); MS m / z 278 (M + H).
Example 28 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-trifluoromethylthiophenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-1-naphthamide citrate.
Using standard reducing amination conditions N- [2- (S) - (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-cyano-1-naphthamide was reacted with 4- (2-trifluoromethylthiophenyl) -piperidine except NaOAc (2.0 equivalents), was added in place of acetic acid. The product was converted to citrate salt. XH NMR (DMSO-d6) d 8.62 (d, 1H), 8.08 (m, 1H), 7.75 (m, 5H), 7.53-6.44 (br m, 6H), 4.49 (m, 1H), 3.45-0.85 ( 18H); MS m / z 670 (M + H).
The 4- (2-trifluoromethylthiophenyl) piperidine 15 requirement was prepared as follows. 4- (2-trifluoromethylthiophenyl) piperidine. A solution of n-phenylmethoxycarbonyl-4- [2-trifluoromethylthiophenyl] piperidine in trifluoroacetic acid was deprotected Cbz by heating under reflux (at 80 ° C) for 10 minutes. The mixture was concentrated to provide the product as an oil. XH NMR (DMSO-d6) d 7.69 (d, 1H), 7.59 (m, 1H), 7.50 (d, 1H), 7.32 (m, 1H), 3.32 (m, 2H), 3.00 (br d, 2H) , 2.57 (m, 3H), 1.56 (m, 4H); MS m / z 262 (M + H).
EXAMPLE 29 N- [2- (S) - (3,4-Dichlorophenyl) -4- [4- [2-ethylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-l-naphthalamide Citrate . Using the standard reducing amination conditions N- [2- (S) - (3, 4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-cyano-1-naphthamide was reacted with 4- [2 -ethyl-sulfinylphenyl] piperidine and converted to citrate salt. XH NMR (DMSO-d6) d 8.62 (d, 1H), 8.08 (m, 1H), 7.73 (m, 5H), 7.53-6.43 (m, 6H), 4.54 (m, 1H), 3.34-1.78 (21H) ), 1.08 (t, 3H); MS m / z 646 (M + H). The 4- [2-ethylsulfinylphenyl] piperidine requirement was prepared as follows. (a) N-Phenylmethoxycarbonyl-4- (2-ethylthiophenyl) piperidine. Iodoethane (0.24 ml) was added to a mixture of N-phenylmethoxycarbonyl-4- (2-thiophenyl) piperidine (example 27) (1.0 g) and K2CO3 (0.42 g) in DMF (10 ml), after 2 hours the solution Dilute with water and extract into EtOAc The organic layer was washed with brine (3x), dried with MgSO 4, concentrated and purified by chromatography (10% EtOAc / hexane as eluent to give the product as an oil ( 1.04 g, 95%). XH NMR (DMSO-d6) d 7.37 (m, 5H), 7.19 - - (m, 4H), 5.09 (s, 2H), 4.13 (br d, 2H), 3.16 (m, 1H), 3.02 (m, 4H), 1.70 (br d, 2H), 1.54 (m, 2H), 1.24 (t, 3H), MS m / z 356 (M + H). (b) N-Phenylmethoxycarbonyl-4- (2-ethylsulfinylphenyl) piperidine. To a solution of N-phenylmethoxycarbonyl-4- (2-ethylthiophenyl) piperidine (1.04 g) in a mixture with a 1: 1 ratio of THF: methanol (30 mL) was added periodate.
Sodium (1.88 g) and the mixture was allowed to stir overnight. The white slurry was diluted with NaHCO 3 and water. The mixture was extracted into DCM, washed with brine, dried with MgSO 4, concentrated and purified by chromatography (25% EtOAc in hexane) as eluent to give the product (1.0 g, 92%). XH NMR (DMSO-d6) d 7.55 (m, 1H), 7.48 (m, 3H), 7.35 (m, 5H), 5.15 (s, 2H), 4.11 (br d, 2H), 2.93 (m, 4H) , 2.66 (m, 1H), 1.64 (m, 4H), 1.11 (t, 3H); MS m / z 372 (M + H). (c) 4- [2-ethylsulfinylphenyl] piperidine. N-Phenylmethoxycarbonyl-4- [2-ethylsulfinylphenyl] piperidine was deprotected according to the method described for the deprotection of 4- [2-trifluoromethylsulfinylphenyl] - piperidine (example 27, step (d)). XH NMR (DMSO-d6) d 7.74 (d, 1H), 7.46 (m, 3H), 3.0 (m, 2H), 2.92 (m, 2H), 2.75 (m, 1H), 2.60 (m, 2H), 1.66 (m, 2H), 1.56 (m, 2H), 1.10 (t, 3H); MS m / z 238 (M + H).
EXAMPLE 30 N- [2- (S) - (3,4-Dichlorophenyl) -4- [4- [2- (1-methyl) ethylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3 Citrate - cyano-1-naphtamide.
N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2- (1-methyl) ethylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano-1 -naftamide was prepared using the procedure described by N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-ethylsulfenyl] -l-piperidinyl] butyl] -N-methyl-3- cyano-l-naphthamide (example 29) except 2-iodopropane was used in place of iodoethane. XH NMR (DMSO-de) d 8.64 (d, 1H), 8.08 (m, 1H), 7.69 (m, 2H), 2.92 (m, 2H), 2.75 (m, 1H), 2.60 (m, 2H), 1.66 (m, 5H), 7.45-6.43 (m, 6H), 4.54 (m, 1H), 3.67-1.71 (19H), 1.9 (d, 3H), 0.94 (d, 3H); MS m / z 660 (M + H).
Example 31 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2- (N-methyl-N-methoxyaminocarbonyl) phenyl] -l-piperidinyl] butyl] citrate methyl-3-cyano-1-na tamide. Using standard reductive amination conditions 4- (2-N-methyl-N-methoxycarboxamidophenyl) piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl- 3-cyano-1-naphthamide and converted to citrate salt. Ms m / z (M + H). The requisite 4- (2-N-methyl-N-methoxycarboxamidophenyl) piperidine was prepared as follows. (a) 2- (N-methyl-N-methoxycarboxamido) phenylpiperidine trifluoroacetate A mixture of 4- (2-carboxyphenyl) -1-N-Boc-piperidine (prepared by amine protection and mediated LiOH saponification of the methyl ester of the material obtained from example 20, subpart (b)) (176 mg), oxalyl chloride (76 μL), potassium carbonate (10 mg) and DMF (10 μL) was stirred in DCM (5 mL) for 2 hours. The mixture was concentrated to give the acid chloride which was used without purification. To a solution of the acid chloride (10 mL) was added N, 0 -dimethylhydroxylamine hydrochloride (62 mg), and triethylamine (176 μL). The mixture was stirred for 2 hours, diluted with DCM (50 mL), washed with IN HCl and saturated sodium bicarbonate, dried with MgSO 4, filtered, and concentrated to provide 2- (N-methyl-N- methoxycarboxamido) phenyl-1-N-Boc-piperidine- as a clear oil (205 mg). Material N was deprotected by stirring for 1 hour in a 5: 1 mixture of DCM: trifluoroacetic acid to give the product as a trifluoroacetate salt. Example 32 Citrate of N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2- (N-methyl-N-methylaminocarbonyl) phenyl] -l-piperidinyl] -butyl] - N-methyl-3-cyano-1-naphtamide. 10 Using standard reductive amination conditions 4- (2-N-methylaminocarbonylphenyl) -piperidine (prepared according to the procedure described in Example 31, except for N, O-dimethylhydroxylamine hydrochloride was replaced with methyl amine (2M solution in THF)) was reacted with N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide and was converted to citrate salt. MS m / z 627 (M + H).
Example 33 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2- (N, N-dimethylaminocarbonyl) phenyl] -l-piperidinyl] butyl] -N-methyl citrate -3- cyano-1-naphtamide. Using standard reductive amination conditions 4- (2-N, N-dimethylaminocarbonylphenyl) piperidine (prepared according to the procedure described in Example 31, except i¡á? ím? ¡¡¡¡¡¡¡¡¡¡Mk for N, O-dimethylhydroxylamine hydrochloride was replaced with dimethyl amine (2M solution in THF)) was reacted with N- [2- (S) - (3, 4 -dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide and converted to citrate salt. MS m / z 641 (M + H).
Example 34 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-trifluoromethylphenyl] -l-piperidinyl] butyl] -N-methyl-3-nitronaphtamide citrate. N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-trifluoromethyl-phenyl] -1- piperidinyl] butyl] -N-methylamine hydrochloride (0.155 g) was dissolved in DCM (10 ml). mL). Triethylamine (0.061 g) was added followed by 3-nitro-1-naphthoyl chloride (0.069 g) (3-nitro-l-naphthoic acid preparation (Kice, JL, Lotey H, J. Org. Chem., 54, 3596 (1989)) and oxalyl chloride). The mixture was stirred overnight, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried and evaporated. The residue was purified by chromatography, with DCM. methanol (30: 1) as eluent to give the free base (0.170 g) which was converted to citrate salt. MS: m / z 658 (M + H). XH NMR (DMSO- de) d 9.05 (m, 1H), 8.40-6.00 (m, 12H), 3.60-0.90 (m, 16H), 2.55 (m, 3H, N-CH3). The amine requirement was prepared as follows. (a) 4- (2-trifluoromethylphenyl) pyridine hydrochloride. 4-Bromopyridine hydrochloride (1.94 g) and tetrakis (triphenylphosphine) palladium (o) (0.36 g) were combined in dry 1, 2-dimethoxyethane (50 mL) under nitrogen. The mixture was stirred for 20 minutes then 2-trifluoromethylphenylboronic acid (1.94 g) was added followed immediately by a solution of sodium carbonate (2.48 g in water (15 mL) .The mixture was heated under reflux for 5 hours, then the mixture was heated under reflux for 5 hours. extracted with EtOAc The organic extracts were dried and evaporated The residue was purified by chromatography with DCM: methanol (20: 1) as eluent to give the pyridine free base.The free base was dissolved in DCM and - -se treated with an excess of ether hydrogen chloride to give the title compound (1.96 g) as a white solid MS: m / z 224 (M + H) aH NMR (CDC13) d 8.88 (d, 2H), 7.90 (m, 3H), 7.76 (m, 2H), 7.38 (, 1H). (b) 4- (2-trifluoromethylphenyl) piperidine hydrochloride. 4- (2-trifluoromethylphenyl) piperidine hydrochloride (0.250 g) was dissolved in acetic acid (15 mL), platinum dioxide (0.100 g) was added and the mixture was stirred under hydrothrene (50 psi) for 4 hours. The solution was filtered, acidified with 4N HCl and evaporated to give the piperidine hydrochloride (0.243 g) as a white solid. MS: m / z (M + H). XH NMR (DMSO d6) d 7.71 (m, 2H), 7.57 (d, J = 9, 1H), 7.44 (m, 1H), 3.38 (m, 2H), 3.10 (m, 3H), 2.11 (m, 2H), 1.82 (m, 2H). (c) N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-trifluoromethylphenyl] -l-piperidinyl] butyl] -N-methyl-N-Boc-amine. N- [(S) -2- (3, -dichlorophenyl) -4-oxobutyl] -N-methyl-N-Boc-amine (0.261 g) (Miller, SC; WO 9505377) was added to a solution of 4- (2-trifluoromethylphenyl) piperidine hydrochloride (0.180 g) and triethylamine (0.076 g) in methanol (15 mL). The mixture was stirred for 5 minutes, then a solution of . < G- > The solution was stirred overnight at room temperature, methanol was evaporated and the residue was partitioned between EtOAc (20 mL) and sodium bicarbonate. aqueous sodium (10 mL) The organic phase was dried and evaporated The residue was purified by chromatography with DCM: methanol (40: 1) as eluent to give the title compound (0.328 g) MS: m / z 559 (M + H). (d) N- [(S) -2- (3, -dichlorophenyl) -4- [4- [2- 10 trifluoromethylphenyl] -1-piperidinyl] butyl] -N-methylamine hydrochloride. N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-tpfluoromethylphenyl] -1-p-peridyl] butyl] -N-methyl-N-Boc-amine hydrochloride (0.328) g) was dissolved in EtOAc (20 mL) was cooled to 0 ° C and hydrogen chloride was bubbled through solution 15 for 10 minutes. The solution was evaporated to give the desired compound (0.311 g) as a white solid. MS m / z 559 (M + H). Example 35 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [2-methylsulfonyl) -4-methoxyphenyl] -l-piperidinyl] -butyl] -N-methyl- hydrochloride 3-cyano-1-naphtamide. Using standard reductive amination conditions N- [2- (S) - (3, 4-d? Chlorophenyl) -4-oxo-butyl] -N-methyl-3-cyano-l-naphthamide (0.130 g) was reacted with 4- (2- ix .-? .- i.-r. Y & n.-r-Y:. JA. »» Tíßa = _í, - -naftamide (0.130 g) was reacted with 4- (2-methylsulfonyl-4-methoxyphenyl) piperidine (0.082 g) and the product (0.074 g) was converted to hydrochloride salt. MS m / z 678 (M + H). 1ti NMR (DMSO d6) d 10.57 (m, 1H), 8.62 (m, 1H), 8.10 (m, 1H), 7.95-7.00 (m, 10H), 3.83 (s, 3H), 3.32 (s, 3H) , 3.64-1.65 (, 19H). The requirement 4- (2-methylsulfonyl-4-methoxyphenyl) piperidine was prepared as follows (a) 4- (4-methoxy-2-methylsulfonylphenyl) -N-Cbz-piperidma. To a stirred solution of sodium periodate (0.267 g) dissolved in 20 mL 1: 1 THF: H20 was added 4- (4-methox? -2-methylthiophen I) -N-Cbz-piperidine (0.45 g) [Example 2 (f)] followed by 100 μL of an Os0 solution 4% w / w. The mixture was stirred at room temperature for 18 hours, poured into 20 mL of saturated NaHCO 3 and extracted with DCM (3 x 30 mL). The organic extracts were combined, dried over Na2SO4, and evaporated to give 0.319 g of 4- (4-methoxy-2- (methylsulfonyl) phenyl) -N-Cbz-piperidine as an oil then by chromatography (4: 1 DCM : EtOAc). XH NMR (CDC13) d 7.56 (d, 1H), 7.47-7.30 (m, 5H), 7.12 (dd, 1H), 5.17 (s, 2H), 4.45-4.20 (m, 2H), 3.85 (s, 3H) ), 3.61 (tt, 1H), 3.11 (s, 3H), 3.01-2.78 (m, 2H), 1.85-1.5 (m, 4H). (b) 4- (4-methoxy-2-methylsulfonylphenyl) piperidine To a solution of KOH (1.50 g) in 20 mL of 1: 1 EtOH: H20 was added 1.23 g of 4- (4-methoxy-2-methylsulfonylphenyl) ) -N-Cbz-piperidine. The resulting mixture was heated under reflux to an N2 atmosphere for 18 hours, evaporated, and dissolved in 10 mL of H20, and extracted with CHC13. The organic extracts were combined, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (20: 1 DCM in methanol containing 0.5% aqueous NH40H). MS m / Z 270 (M + H).
Example 36 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -l-piperidinyl] -butyl] hydrate citrate N-methyl-3-cyano-l-naphthamide (1: 1: 1.5).
A stirred solution containing 3-cyano-1-naphthoic acid (0.1 g, 0.5 mmol) [Example 1], N, N, diisopropylethylamine (0.16 g, 1.27 mmol) and dry DCM (2.5 mL) was treated with a solution of hexafluorophosphate tetramethylfluoroformamidinio (TFFH) (0.16 g, 0.61 mmol) and dry DCM (1.0 mL). After 10 minutes, a solution containing N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo- - (1 (2H) -pyrimidinyl] -l-piperidinyl] butyl] -N-methylamine (Miller, SC, WO 9505377) (0.21 g, 0.51 mmol) was added dry DCM (1.0 mL), and the solution was stirred for 60 hours DCM and 1M aqueous acetic acid were further added. after mixing, the layers were allowed to separate, the organic layer was removed, and the aqueous HOAc layer was extracted with additional DCM (2x). The organic extracts were combined, washed (saturated NaHC03), dried over Na2SO4, filtered and the DCM was evaporated in vacuo. The residue was purified by Chromatography (0-10% methanol in DCM) was converted to citrate salt and isolated by filtering Et20 to give the title compound (210 mg) as a white solid. MS: m / z 592 (M + H). Analysis for C32H35C12N502 «CeHßC l.S H20: calculated: C, 56.23; H, 5.71; N, 8.63. found: C, 56.31; H, 5.34; N, 8.34.
Example 37 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-oxo-l-pieridinyl] -l-piperidinyl] butyl] -N-methyl-3- citrate hydrate cyano-l-na tamida 20 (1: 1: 0.75).
Using standard acylation conditions 3-cyano-l-naphthoyl chloride (prepared from 3-cyano-naphthoic acid and oxalyl chloride) was reacted with N- . ^ ... Ül ^^ i '^ ^ .., ^^, - 1 - [(S) -2- (3, 4-dichlorophenyl) -4- [4- (2-oxo-l-piperidinyl) -1- piperidinyl] butyl] -N-methylamine (Miller, SC, WO 9410146).
A portion of the product was converted to citrate salt and isolated by Et2O filtration to give the title compound as a white solid. MS: m / z 591 (M + H). Analysis for C33H36C12N02 • C6H807- 0.75 H20; calculated: C, 58.76; H, 5.75; N, 7.03 found: C, 58.80; H, 5.63; N, 6.88.
Example 38 N- [2 (S) - (3,4-dichlorophenyl) -4- [4- (tetrahydro-2-oxo-1 (2H) -pyrimidinyl) -l-piperidinyl] -butyl] citrate methyl-4-cyano-l-naphthalenecarboxamide. Using standard acylation conditions, 4-cyano-l-naphthoyl chloride (prepared from 4-cyano-l-naphthoic acid and oxalyl chloride) was reacted with (S) -2- (3,4-dichlorophenyl) -N -methyl-4- [(tetrahydro-2-oxo-l (2H) -pyrimidinyl) piperidinyl] butanamine (Miller, SC, WO 9505377). The product was converted to citrate salt. MS: m / z 592 (M + H). The requirement 4-cyano-l-naphthoic acid was prepared as follows, (a) Methyl 4-bromo-l-naphthoate. A solution of 4-bromo-l-naphthoic acid (Fischer, S & J ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ - ^^^^^^ ,,. et al, J. Chem. Soc., 1426 (1958)) oxalyl chloride (2.56 g), and DMF (5 μL) in DCM (100 mL) was stirred for 3 hours, concentrated, then redissolved in DCM ( 5 L). Methanol was added and stirring was continued overnight. Concentration and purification was continued by chromatography (DCM), the product was obtained as a white solid (4.85 g). X H NMR (DMSO-d 6): d 8.83-8.77 (m, 1 H), 8.31-8.25 (m, 1 H), 8.01 (s, 1 H), 7.82-7.75 (m, 2 H), 3.96 (s, 3 H); MS m / z 265 (M + H). (b) 4-cyano-l-naphthoic acid. A solution of methyl 4-bromo-l-naphthoate (0.509 g) copper cyanide (I) (0.174 g), 1 drop of pyridine, and DMF (5 mL) was heated under reflux at 180 ° C for 5 hours. The hot solution was poured into 10 mL of concentrated aqueous NH 4 OH and extracted with DCM. The organic phase was washed successively with IN HCl (20 mL) and brine (40 mL), dried over Na 2 SO 4, filtered and concentrated to give methyl 4-cyano-l-naphthoate a colorless oil (0.213 g). MS m / z 196 (M-1). X H NMR (DMSO-d 6): d 874-8.69 (m, 1 H), 8.29-8.15 (m, 3 H), 7.92-7.83 (m, 2 H), 3.99 (s, 3 H). The methyl ester was saponified by stirring a solution of methyl ester, LiOH-H20 (1 equivalent), THF (3 mL), water (1 mL) and methanol (1 mL) over the entire Éj ^^ l ^ i ^^ g togi ^^^^ J; = 5ßfe, -2i - -night at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et20. The aqueous layer was washed with water (30 mL) and brine (40 mL), dried with sodium sulfate, filtered and concentrated to give 4-cyano-l-naphthoic acid as an oil.
Example 39 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -l-piperidinyl] -butyl citrate] -N -methyl-6-cyano-1-naphthamide To a stirred solution of 6-cyano-l-naphthoic acid (0.2 g, 1.01 mmol) in dry DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.26 mmol) and 2 drops of DMF The solution was stirred at room temperature for 3 hours and concentrated to provide the acid chloride: 6-cyano-l-naphthoyl chloride (0.219 g), as an off-white solid which was used without purification Additional using standard acylation conditions (s) -2- (3, 4-dichlorophenyl) -N-methyl-4- [(tetrahydro-2-oxo-l (2H) -pyrimidinyl) piperidinyl] butamine (Miller, SC; WO 95053779 was reacted with 6-cyano-l-naphthoyl chloride and converted to citrate salt MS m / z 592 (M + H) Analysis for C32H35Cl2N5O2-1.0 C6H8O7-1.0 H20: calculated: C, 56.86; H, 5.65; N, 8.72, found: C, 56.81; H, 5.51; N, 8.54. ^ lyJfS '' - - EXAMPLE 40 N- [2- (4-Chlorophenyl) -4- [4- [tetrahydro-2-oxo-l (2H) -pyrimidinyl] -l-piperidinyl] butyl] -N-methyl-3-nitro- citrate l- 5 naphthamide. Using standard reductive amination conditions 4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) was reacted with N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-nitro-l-naphthamide 10 [example 3] and converted to the citrate salt. MS m / z 578 (M + H). Analysis for C3? H36Cl2N5? 4 • 1.0 C6H80 • 0.8 H20: calculated: C, 56.64; H, 5.86; N, 8.92. found: C, 56.60; H, 5.74; N, 8.69.
Example 41 N- [2- (3, 4-difluorophenyl) -4- [4- [tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -l-piperidinyl] butyl] -N-methyl-3 citrate -nitro-l-naftamide. 20 Using standard reductive amination conditions 4- (tetrahydro-2-oxo-l (2H) -pipmidinyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) was reacted with N- [2- (3,4-d? Fluorophenyl) ) -4-oxobutyl] -N-methyl-3-nitro-l-naphthamide [example 13] and converted to citrate salt. MS - - m / z 580 (M + H). Analysis for C31H35F2N504 • 1.07 C6H8O7-1.06 H20: calculated: C, 55.88; H, 5.72; N, 8.71. found: C, 55.94; H, 5.54; N, 8.51.
Example 42 Citrate of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -l-piperidinyl] -butyl] - N-methyl-3-nitro-1-naphtamide. Using standard reductive amination conditions, 10 N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-nitro-1-naphthalenecarboxamide (0.250 g) was treated with 4- ( tetrahydro-2-oxo-1 (2H) -pyrimidinyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) (0.102 g). The free base (0.102 g) was converted to citrate salt. MS m / z 612 (M + H). Example 43 Citrate of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo-1 (2H) -pyrimidinyl] -l-piperidinyl] -butyl] - N-methyl-6-nitro-1-naphtamide. 20 Using standard reductive amination conditions N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [tetrahydro-2-oxo-l (2H) -pyrimidinyl] -l-piperidinyl] butyl] -N-methylamine (Miller, SC; Wo 9505377) was reacted with 6-nitro-l-naphthoyl chloride (Dewar, MJS and Grisdale, PJ; J. Amer Chem. Soc., - - 84, 3541 (1962)) and converted to citrate salt. MS m / z 612 (M + H). Analysis for C31H35C12N504- 1.05 C6H8O7-0.7 H20: calculated: C, 54.18; H, 5.46; N, 8.47; found: C, 54.31; H, 5.53; N, 8.18. Example 44 Citrate of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2-oxo-1-pireridinyl) -4- (N-methylaminocarbonyl)] -1- piperidinyl] butyl] -N-methyl-3-cyano-l-naphtamide (1: 1: 0.5). 10 Using standard reductive amination conditions N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide was reacted with 4- (2-oxo-1-piperidinyl) -4 - (N-methylaminocarbonyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891). The product was converted to citrate salt. MS m / z 648 (M + H). Analysis for C 35 H 39 Cl 2 N 5 3 3-CeH 8 7 7-0.5-H2O: calculated: C, 57.95; H, 5.69; N, 8. 24; found: C, 57.95; H, 5.63; N, 8.29. The title compound was also converted to citrate monohydrate (1.0: 1.0: 1.0). The intermediate N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphtamide was prepared according to Example 2. Example 45 Hydrate of Citrate of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (2- - - pireridinyl) -4- (N-N-dimethylaminocarbonyl)] -1- piperidinyl] butyl] -N-methyl-3-cyano-l-naphtamide. (1: 1: 0.7) Using standard reductive amination conditions 4- (2-oxo-l-piperidinyl) -4- (N, N-5 dimethylaminocarbonyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) was reacted with N - [2- (S) - (3, 4-dichlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide (example 2). The product was converted to citrate salt. MS m / Z (M + H); Analysis for C36H4? Cl2N5? 3- C6H807 • 0.7 - H20: calculated: 10 C, 58.16; H, 5.85; N, 8.07; found: C, 58.18; H, 5.74; N, 7.97.
EXAMPLE 46 N- (4- [4- (Tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4-15 (methylaminocarbonyl) -l-piperidinyl] -2- (4-chlorophenyl) -butyl) citrate N-methyl-3-cyano-l-naphtamide. Using standard reductive amination conditions N- (4- [4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; Wo 9512577) was reacted with N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-1-naphthamide and converted to citrate salt, 1 H NMR (CDC13) (evidence of amide rotational isomer) d 8.20 (m ), 7.92 (m), 7.69-7.57 (br m), 7.47-7.20 (br m), 6.93 (d, J = 8.4), 6.67 (d, J = 7.8), 6.51 (m) 4.62 (m) 3.49 -3.21 (br m) 2. 58 (s) 2.39-2.17 (br m) 1.95-1.79 (m); MS m / z 615.0 (M + H). The requisite aldehyde was prepared as follows. (a) N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-5-naphthamide. Oxalyl chloride (195 μL, 2.23 mmol) was added to a solution of 3-cyano-l-naphthoic acid (400 mg, 2.03 mmol) in DCM (10 mL). The solution was stirred for three hours, during this time three portions were added (30 μL each one) of 10% DMF in DCM. The solution was concentrated to a white powder under reduced pressure, dried under vacuum, and dissolved in DCM (15 mL). After cooling to 0 ° C, N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methylamine (434 mg, 2.03 mmol, dissolved in 5 mL of DCM) and NaOH (1.0 M, 2.54 mL). After warming to room temperature, stirring was continued overnight. The mixture was extracted with 30 mL portions of 5M HCl and saturated sodium bicarbonate, dried with MgSO 4, filtered and concentrated under reduced pressure to give a slightly yellow foam. (692 mg, 1.76 mmol, 87%). XH NMR (CDC13) (evidence of amide rotational isomers) d 8.09 (s), 7.85 (m), 7.72-7.50 (br m), 7.43-4.35 (br m), 6.92 (d, J = 6. 3) , 6.85 (d, J = 7.8), 6.69 (m) 6.65 (m), 4.57 (br m), 3.99 (br m) 3.70 (m), 3.50-3.10 (br m), 2.67 (s), 2.03 ( m), 1.89 (m), 1.58 (m); MS - -m / z 393.0 (M + H). (b) N- [2- (4-chlorophenyl) -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide. A solution of DMSO (356 μL), 5.01 mmol) in DCM (5 mL) was added dropwise over 5 minutes to a solution of oxalyl chloride (219 μL), 2.51 mmol) in DCM (5 mL) at -70 ° C. C. After stirring for 15 minutes N- [2- (4-chlorophenyl) -4-hydroxybutyl] -N-methyl-3-cyano-l-naphthamide (788 mg, 2.0 mmol) was added dropwise a solution in DCM (5 ml). mL). Stirring was continued for 45 minutes at -70 ° C, warmed to -45 ° C and stirred for 30 minutes. The solution was cooled to -70 ° C and triethylamine (1.41 mL, 10.03 mmol) was added dropwise (dissolved in 5 mL of DCM). After stirring for 15 minutes, the mixture was allowed to warm to room temperature, diluted with DCM, and extracted with 0.5 M HCl (30 mL) saturated sodium bicarbonate (30 mL), dried with MgSO4, and concentrated to a clear oil which was purified by means of chromatography 850% EtOAc in hexane) to give the product as a clear oil (543 mg, 1.39 mmol, 70%). XH NMR (CDC1) (evidence of amide rotational isomers) d 9.71 (s), 9.60 (s), 8.18 (m), 7.86 (t, J = 7.8), 7.68-7.29 (m), 7.51 (m) 6.87 (t, J = 7.2), 6.67 (d, J = 8.4), 6.57 (m), 4.56 (br m), 3.98, (br m), 3.71, (br m), 3.42 (m), 2.97, ( m), 2.67 (m); MS m / z 391.0 (M + H) Example 47 Hydrate citrate of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methyl-aminocarbonyl)] -l-piperidinyl] butyl] -N-methyl-3-cyano-l-naph amide. (1: 1: 2) Using standard reductive amination conditions (except that the buffer acetic acid-sodium acetate was replaced by acetic acid) N- [(S) -2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methyl-3 -cyano-l-naphthamide (145 mg, 0.34 mmol) was reacted with 4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; wo 9512577) (79.1 mg, 0.329 mmol), was converted to citrate salt, and isolated by filtration of Et20 to give the title compound (162.5 mg) as a white powder. MS m / z (M + H); analysis for C34H38C12N603 • C6H807 • 2.0 • H20: calculated: C, 54.73; H, 5.74; N, 9.57; found: C, 54.92; H, 5.41; N, 9.29.
Example 48 N- [2- (4-chlorophenyl) -4- [4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl)] - l -piperidinyl] butyl] citrate -methyl-3-nitro-l-naphtamide.
Using standard reductive amination conditions 4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; WO 9512577) was reacted with N- [2- (4-chlorophenyl) ) -4-oxobutyl] -N-methyl-3-nitro-l-naphtamide and converted to citrate salt. MS m / z 635 (M + H); analysis for C33H39C1N605 '1.0C6H8O7- 1.3 • H20: calculated: C, 56.06; H, 5.88; N; 9.88; found: C, 55.04; H, 5.74; N, 9.74.
Example 49 N- [2- (3,4-difluorophenyl) -4- [4- (tetrahydro-2-oxo-1 (2H) -pyrimidinyl) -4- (methylaminocarbonyl)] -1-piperidinyl] butyl citrate -N-methyl-3-nitro-l-naphtamide. Using standard reductive amination conditions 4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; WO 9512577) was reacted with N- [2- (3, 4 -difluorophenyl) -4-oxobutyl] -N-methyl-3-nitro-1-naphtamide and converted to citrate salt. MS m / z 637 (M + H); Analysis for C33H38F2Ne05 1.1-C6H807 1.2-H20: calculated: C, 54.69; H, 5.70; N; 9.66; found: C, 54.62; H, 5.52; N, 9.46.
Example 50 N- [(S) -2- (3,4-dichlorophenyl) -4-. { 4- (2-oxo-l-piperidinyl) -4-N, N-dimethylaminocarbonyl)} -l-piperidinyl] butyl] -N-methyl-3-nitro-1-naphthamid. Using standard reductive amination conditions N- [(S) -2- (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-n-tro-1-naphthamide (0.10 g) was reacted with 4- (2-oxo-l-piperidinyl) -4- (dimethylaminocarbonyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) (0.060 g). The free base (0.093 g) was converted to citrate salt. MS m / z 682 (M + H).
Example 51 N- [(S) -2- (3, -dichlorophenyl) -4- [4- (tetrahydro-2-oxo-l- (2H) -pyrimidinyl) -4- (methylaminocarbonyl)] -l-piperidinyl] butyl] -N-methyl-3-nitro-l-naphtamide. Using standard reductive amination conditions N- [(S) -2- (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-nitro-l-naphthamide (0.150 g) was treated with 4- (tetrahydro-2-oxo-l (2H) -pyrimidinyl) -4- (methylaminocarbonyl) -1-piperidine (Miller, SC, Wo 9512577) (0.089 g). The free base (0.123 g) was converted to citrate salt. MS m / z 669 (M + H).
Example 52 N- [(S) -2- (3,4-dichlorophenyl) -4- citrate. { 4- (2-oxo-l-piperidinyl) -4- (N-methylaminocarbonyl)} -l-piperidinyl] butyl] - í & X - 3 £? AS? S £? ~ ££ ££.
N-N-methyl-3-nitro-l-naphtha ida. Using standard reductive amination conditions N- [(S) -2- (3,4-dichlorophenyl) -4-oxo-butyl] -N-methyl-3-nitro-l-naphthamide (0.300 g) was treated with 4- (2-oxo-l-piperidyl) -4- (methylaminocarbonyl) piperidine (Miller, SC; Jacobs, RT; Shenvi, AB, EP 739891) (0.1773 g). The free base (0.296 g) was converted to citrate salt. MS m / z 668 (M + H).
Example 53 N- [(S) -2- (3,4-Dichlorophenyl) -4-oxobutyl] -N-methyl-3-nitro-1-naphtamide. By the method of Example 3f, 3-nitro-l-naphthoyl chloride was reacted with (S) -2- (3, -dichlorophenyl) -4-hydroxybutyl-N-methylamino to give N- [(S) -2 - (3,4-dichlorophenyl) -4-hydroxybutyl] -N-methyl-3-nitro-l-naphthamide.
This was reacted by the method of example 3 g to give the compound: x H NMR (300 MHz, CDC13) d 9.65 (s 9, 9.44 (s), 9.07-9.02 (m), 8.38-6.04 (m), 4.44 -1.18 (m); MS APCl, m / z = 445 (M +).
Example 54: N- [2 (S) - (3,4-dichlorophenyl) -4- [4- [4-carbamoyl- (R, S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] citrate methyl-3-cyano-1-naphtamide.
Using standard reductive alkylation conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.115 g) was reacted with 4- ( 4- carbamoyl-2- (R, S) -methylsulfinylphenyl) piperidine (0.071 g) and converted to citrate salt. MS m / z 675 (M +); 1 H NMR (DMSO d6) d 8.70-8.58 (m, 1H), 8.25-6.40 (m, 13H), 3.60-1.50 (m, 26H); Analysis for C36H36Cl2N4? 3S • 1.0 citric acid- 1.0 H2O-0.25 Et20: calculated, C, 57.11; H, 5.41; N, 6.20; found: C, 57.06; H, 5.18; N, 6.28. The requisite 4- (4-carbamoyl-2- (R, S) -methylsulfinylphenyl) piperidine was prepared as follows: (a) 4- [2-methylsulfini-1-4-bromophenyl] piperidine. To a stirred solution of 4- (2-sulfinylphenyl) piperidine (Jacobs, R; Shenvi, A; EP 630887) (0.496 g) dissolved in 5 mL of acetic acid was added to a solution of bromine (0.175 g in 15 mL of acetic acid). The mixture was heated at 75 ° C for 80 minutes. The cooled mixture was quenched with 3 mL of H20, the solvent was evaporated and the residue was dissolved in H20. The aqueous mixture was basified to pH 14 by the addition of KOH and extracted with CHC13. (3 x 15 mL). The organic extracts were combined, dried over Na 2 SO 4, evaporated and purified by chromatography (19: 1 DCM: methanol containing 0.5% NH 4 OH $? uáatis & * -j &frf aqueous) to give the product (0.421 g) as a slightly yellow solid. MS m / z 302 (M + H). XH NMR (CDC1) d 7.86 (d, 1H), 7.61 (dd, 1H), 7.52 (d, 1H), 3.25-3.35 (m, 2H), 3.08-2.60 (m, 7H), 2.04-1.61 (m , 4H). b) 4- [2-methylsulfinyl-4-bromophenyl] -N-Cbz-piperidine. To a stirred solution of 4- [2-methylsulfinyl-4-bromophenyl] piperidine (2.70 g) dissolved in 140 mL of THF was added 2.60 mL of triethylamine followed by 1.74 g of benzyl chloroformate. After 18 hours the THF was evaporatedThe residue was dissolved in 100 mL of DCM, extracted with 0.5 M HCl (3 x 40 mL) and saturated with NaHCO 3 (2 x 50 mL). The organic extract was dried over Na 2 SO 4 and evaporated to give an oil which was purified by chromatography (4: 1 EtOAc: DCM) to give 3.39 g of product. 1 H NMR (CDCl 3) d 7.87 (d, 1 H), 7.61 (dd, 1 H), 7.49-7.32 (m, 6 H), 5.17 (s, 2 H), 4.30-4.21 (m, 2 H), 2.99-2.75 (m , 3H), 2.70 (s, 3H), 1.95-1.55 (m, 4H). c) 4- [2-methylsulfinyl-l-4-methoxycarbonylphenyl] -N-Cbz-piperidine. To a mixture of DMSO (75 mL) and MeOH (75 mL) was added 1,3-b? S (diphenyl-phosphino) propane (0.536 g), palladium acetate (0.331 g), 4- [2-methylsulfinyl- 4-bromo-phenyl] -N-Cbz-piperidine (2840 g), and 2.00 L of triethylamine. The mixture purged with carbon monoxide for 20 minutes and then heated to 70 ° C under carbon monoxide (1 atmosphere) for 18 hours. The mixture was poured into 250 mL of H20 and extracted with 1: 1 EtOAc; Et20 (2 x 75 mL). The organic layer was extracted with H20 (5 x 75 mL), dried over Na 2 SO, and evaporated. The residue was purified by chromatography (4: 1 EtOAc: DCM) to give 2.39 g of product. MS m / z 416 (M + H). XH NMR (CDC13) d 8.17-8.07 (m, 2H), 7.96 (d, 1H), 7.42-7.28 (m, 5H), 5.18 (s, 2H), 4.50-4.32 (m, 2H), 3.95 (s) , 3H), 2.99-2.80 (m, 3H), 2.73 (s, 3H), 1.95-1.55 (m, 4H). d) l-Benzyloxycarbonyl-4- (4-carboxy-2- (R, S) -sulfinylphenyl) piperidine To a solution of 4- [2-methylsulfinyl-4-methoxycarbonylphenyl] -N-Cbz-piperidine (0.120 g) was dissolved in 10 mL 1: 1 THF: H20 was added 0.038 g of LiOH. After heating 1 mixture at 60 ° C for 18 hours, 2 mL of 1M HCl was added and the mixture was extracted with DCM (3 x 10 mL). The organic extracts were combined, dried over Na 2 SO 4, evaporated and purified by chromatography (10: 1 DCM: methanol containing 1.5% aqueous NH 4 OH) to give a solid (0.107 g). MS m / z 402 (M + H). XH NMR (CDCl 3) d 8.05-7.72 (m, 3H), 7.48-7.15 (m, 5H), 6.61 (br, 1H), 5.11 (s, 2H), 4.50-4.05 (m, 2H), 2.95- 2.50 (m, 3H), 3.60 (s, 3H), 1.93-1.38 - - (m, 4H) e) 4 (4-carbamoyl-2- (R, S) -sulfinylphenyl) piperidine. To a solution of l-benzyloxycarbon? L-4- (4-carbox? -2- (R, S) -sulf? N? Lphenyl) piperidine (1.28 g) was dissolved in 45 mL of DCM was added 1.45 mL of N , N-diisopropylethylamine. The mixture was stirred for 10 minutes and then 1017 g of tetramethylfluoroformamidiniohexafluorophosphate was added and stirring was continued for 1 hour. At the same point NH3 was bubbled through the solution for 30 minutes. Then 20 mL of saturated NaHCO 3 was added and the resultant was extracted with DCM (3 x 10 mL). The extracts were combined, dried over Na 2 SO 4 and evaporated. The material was recrystallized from EtOAc; MeOH (3: 1). H NMR (CDCl 3) d 8.09 (d, 1H), 7.85-7.78 (d, 2H), 7.42-7.30 (m, 5H), 6.16 (br s, 1H), 5.72 (br s, 1H), 5.17 (s, 2H), 4.50 -4.2 (m, 2H), 2.99-2.78 (, 3H), 2.73 (s, 3H), 1.95-1.60 (m, 4H): MS m / z 423 (M + Na). The N- deprotection of 1-benzyloxycarbonyl-4- (4-carboxamide-2- (R, S) -sulfinylphenyl) piperidine was carried out using trifluoroacetic acid under standard conditions. 1H NMR (CDC13) TFA-d4) d 8.17 (d, 1H), 8.04 (dd, 1H), 7.98 (d, 1H), 3.79-3.61 (m, 2H), 3.45-3.20 (m, 3H), 2.97 (s, 3H), 2.42-1.95 (m, 4H); S m / z 267 (M + H).
Example 55 N- [2-S) - (3,4-dichlorophenyl) -4- [4- [2- (R, S) -methylsulfinyl-4-methoxycarbonylphenyl] -l-piperidinyl] butyl] citrate methyl-3-cyano-l-naphtamide. Using standard reductive alkylation conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.250 g) was reacted with 4- [ 2- (R, S) -methylsulfinyl-4-methoxycarbonylphenyl] piperidine (0.164 g) and converted to citrate salt. MS m / z 690 (M +); 1 H NMR (DMSO d6) d 8.70-8.58 (m, 1H), 8.20-7.40 (m, 11H), 3.89 (s, 3H), 3.55-2.30 (m, 19H), 2.20-1.50 (m, 7H). The requisite 4- (2- (R, S) -sulfinyl-4-methoxycarbonylphenyl) piperidine was prepared as follows. N-tert-butylcarbamate-4- [2- (R, S) -methylsulfinyl-4-methoxycarbonylphenyl] -piperidine was prepared from 4- (2- (R, S) -sulfinyl-4-bromophenyl) piperidine in an analogous manner described for N-benzyloxycarbonyl-4- [2- (R, S) -methylsulphinyl-4-methoxycarbonylphenyl] piperidine (example 54). N-protection was achieved using di (tert-butyl) dicarbonate in dioxane solvent using aqueous NaOH as a base. The carbonylation of N-tert-butylcarbamate-4- (2- (R, S) -sulfinyl-4-bromophenyl) piperidine was carried out using a procedure similar to that described in Example 54 to give N-tert-butylcarbamate-4- ( 2- (R, S) - sulfinyl- 4-methoxycarbonylphenyl) piperidine. 1H NMR (CDC16) d 8.15-8.05 (m, 2H), 7.99-7.95 (m, 1H), 4.40-4.15 (m, 2H), 3.95 (s, 3H), 2.95-2.65 (m, 3H), 2.73 (s, 3H), 1.95-1.45 (m, 4H), 1.50 (s, 9H). The N-deprotection of N-tert-butylcarbamate-4- (2- (R, S) -sulfinyl-4-methoxycarbonylphenyl) piperidine was performed using trifluoroacetic acid under standard conditions to give 4- (2- (R, S ) -sulfinyl-4-methoxycarbonylphenyl) piperidine. 1H NMR (CDCle) d 8.15-8.03 (m, 3H), 3.94 (s, 3H), 3.30-3.15 (m, 2H), 2.90-2.65 (m, 4H), 2.72 (s, 3H), 1.95-1.50 (m, 4H), Ms m / z 282 (M + H).
Example 56 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [4-hydroxy- (R, S) -2- (methylsulfinyl) phenyl] -l-piperidinyl] butyl citrate ] -N-methyl-3-cyano-1-naphtamide. Using standard reductive alkylation conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.429 g) was reacted with 4- ( 4- hydroxy-2- (R, S) -methylsulfinyl) phenyl) piperidine (0.239 g) and converted to citrate salt. MS m / z 648 (M +); XH NMR (DMSO d6) d 9.93-9.78 (m, 1H), 8.70-8.58 (m, 1H), 8.20-8.00 (m, 1H), a7.85-6.40 (m, 10H), 3.55-2.30 (m , 19H), 2.20-1.50 (m, 7H); Analysis for C35H35Cl2N3? 3S • 1.0 citric acid-1.5 H2O-0.25 Et20: calculated, C, 56.92; H, 5.52; N, 4.74; found: C, 57. 03; H, 5.26; N, 4.90. The piperidine was prepared as follows (a) 4- [4-methoxy-2-methylthiophenyl] piperidine. l-benzyloxycarbonyl-4- [4-methoxy-2-methylthiophenyl] piperidine (example 2) was N-deprotected using trifluoroacetic acid under standard conditions to give 4- [4-methoxy-2-methylthiophenyl] piperidine; 1ti NMR (CDC13) d 7.15 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 3.80 (s, 3H), 3.18 (dm, 2H), 3.01 (tt, 1H), 2.78 ( td, 2H), 2.45 (s, 3H), 1.82 (dm, 2H), 1.66 (s, 1H), 1.58 (qd, 2H); MS m / z 238 (M + H). b) 4- [4-hydroxy-2-methylthiophenyl] piperidine. A mixture of pyridinium hydrobromide (20.76 g) and 4- [4-methoxy-2-methylthiophenyl] piperidine (6.16 g) was heated at 225 ° C for 18 hours. The reaction mixture was cooled, dissolved in 200 mL of H20, adjusted to a pH of 7 with INK KOH, and extracted with hexane (4 x 50 mL). The aqueous layer was concentrated under reduced pressure to give an oil which was dissolved in 200 mL of EtOH and stirred for 0.5 hour. The precipitate was filtered, washed with EtOH (2x 40 mL). The filtrate and all washings were combined and concentrated under reduced pressure. The crude product was purified by chromatography (9: 1 DCM: MeOH) to give 6.06 g of 4- [4-hydroxy-2-methylthiophenyl] piperidine as the hydrobromide salt. 1H NMR (DMSO d6) d 9.44 (s, 1H), 8.49 (m, 2H), 6.97 (d, 1H), 6.66 (d, 1H), 6.58 (dd, 1H), 3.43-3.30 (dm, 2H) , 3.13-2.95 (m, 3H), 2.42 (s, 3H), 1.91-1.61 (m, 4H); MS m / z 225 (M + H). c) 4- [4-hydroxy-2- (R, S) -methylsulfinylphenyl] piperidine. To a rapidly stirred slurry of hydrobromide 4- [4-hydroxy-2-methylthiophenyl] piperidine (2.57 g) and triethylamine (4.00 mL) in 200 mL of THF were slowly added 2.50 mL of benzyl chloroformate for 10 minutes. The mixture was stirred for 18 hours, quenched with 20 mL of saturated NaHCO 3 and THF, concentrated under reduced pressure. The residue was stirred with 50 mL of NaHCO 3 and extracted with DCM (3 x 50 mL): the extracts were combined, dried in NaSO 4 and concentrated under reduced pressure to give an oil which was dissolved in 160 mL 1: 1 THF: H20. To this was added 0.26 g of LiOH and the mixture was stirred for 18 hours. THF was evaporated under reduced pressure, the aqueous residue was acidified with 15 mL of IN HCl, and this was extracted with DCM (4 x 40 mL). The extracts were combined, dried with Na2SO4, and concentrated under reduced pressure to give an oil which was purified by chromatography (2: 3 EtOAc: hexane) to give 1.71 g of 1 H NMR solid product (CDC13) d 7.45-7.25 (m, 5H), 6.99 (d, 1H), 6.70 (d, 1H), 6.59 (dd, 1H), 5.16 (s, 2H), 5.03 (s, 1H), 4.41 -4.25 (m, 2H), 3. 04 (tt, 1H), 3.00-2.83 (m, 2H), 2.44 (s, 3H), 1.90-1.45 (m, 4H); MS m / z 358 (M + H). l-benzyloxycarbonyl-4- [4-hydroxy-2-methylthiophenyl] piperidine was oxidized with NaI04 in 1: 1 THF: H20 using standard conditions to give l-benzyloxycarbonyl-4- [4-hydroxy-2- (R, S) -methylsulfimlfenyl] piperidine; 1H NMR (CDC13) d 8.50 (s, 1H), 7.79 (d, 1H), 7.42-7.30 (m, 5H), 7.12 (d, 1H), 6.95 (dd, 1H), 5.16 (s, 2H), 4.42- 4.20 (m, 2H), 2. 95-2.65 (m, 3H), 2.74 (s, 3H), 1.90-1.50 (m, 4H); MS m / z 374 (M + H). l-benzyloxycarbonyl-4- [4-hydroxy-2- (R, S) -methylsulfinylphenyl] piperidine was N-deprotected using trifluoroacetic acid under standard conditions to give 4- [4-hydroxy-2- (R, S)] -methylsulfinylphenyl] piperidine and used without purification. MS m / z 240 (M + H).
Example 57 N- [2 (S) - (3,4-dichlorophenyl) -4- [4- [4-chloro- (R, S) -2-methylsulfinylphenyl] -l-? Iperidinyl] butyl] citrate -methyl-3-cyano-l-naphtamide. Using standard reductive alkylation conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.302 g) was reacted with 4- ( 4-chloro-2- (R, S) -methylsulfinyl) phenyl) piperidine (0.181 g) and converted to citrate salt. MS m / z 666 (M +); XH NMR (DMSO d6) d 8.70-8.58 (m, 1H), 8.20-8.00 (m, 1H), 7.85-6.40 (m, 11H), 3.50-1.50 (m, 26H); analysis for C35H34Cl3N3? 3S-1.0 citric acid-1.5 H2O-0.25 Et20: calculated, C, 56.03; H, 5.26; N, 4.67; found: C, 55.98; H, 5.02; N, 4.67. The requisite 4- (4-chloro-2- (R, S) -methylsulfinylphenyl) piperidine was prepared according to the procedures described in Example 2 except that 3-chlorophenol was used in place of 3-methoxyphenol. Oxidation of the thiomethyl adduct was carried out according to the procedures described in example 16, subpart (e). 3-chlorophenol (24.28 g) was reacted with bromine (29.78 g) to give 6.15 g of 2-bromo-5-chlorophenol (minor isomer) and 24.60 g of 4-bromo-3-chlorophenol (major isomer) after purification by column chromatography (10: 1 hexane: EtOAc); minor isomer? H NMR (CDC13) d 7.37 (d, 1H), 7.04 (d, 1H), 6.82 (dd, 1H), 5.55 (s, 1H). Major isomer: H NMR (CDC13) d 7.36 (d, 1H), 6.91 (d, 1H), 6.57 (dd, 1H), 5.75 (s, 1H). Analytical data for the following intermediaries. 2-bromo-5-chloro- (N, N-dimethylthiocarbamoyl) phenol; * H NMR (CDC13) d 7.52 (d, 1H), 7.18 (d, 1H), 7.13 (dd, 1H), 3.47 (s, 3H), 3.39 (s, 3H); MS m / z 296 (M +). 4-chloro-2- (N, N-dimethylthiocarbamoyl) -bromobenzene; XH NMR (CDC1) d 7.68-7.55 (m, 2H), 7.23 (dd, 1H), 3.12 (s, 3H), 3.05 (s, 3H); MS m / z 296 (M +). 4-chloro-2- (thiomethyl) bromobenzene. 1 H NMR (CDC13) d 7.43 (d, 1 H), 7.06 (d, 1 H), 6.97 (dd, 1 H), 2.48 (s, 3 H). 1- benzyloxycarbonyl-1-4-hydroxy-4- (4-chloro-2-methylthiophenyl) piperidine; XH NMR (CDC13) d 7.43-7.30 (m, 5H), 7.18-7.10 (m, 3H), 5.16 (s, 2H), 4.42-4.20 (m, 2H), 3.07 (tt, 5 1H), 3.50- 3.25 (m, 2H), 2.52 (s, 3H), 2.15-1.90 (m, 4H); MS m / z 414 (M + Na). l-benzyloxycarbonyl-4- (4-chloro-2-methylthiophenyl) piperidine;; 1 NMR (CDC13) d 7.43-7.30 (m, 5H), 7.18-7.10 (m, 3H), 5.16 (s, 2H), 4.42-4.20 (m, 2H), 3.07 (tt, 1H), 3.50-3.25 (m, 2H), 2.52 (s, 3H), 2.15-1.90 (m, 4H); MS 10 m / z 398 (M + Na). l-benzyloxycarbonyl-4- (4-chloro-2- (R, S) -methylsulfinylphenyl) -piperidine;; X H NMR (CDCl 3) d 7.98 (d, 1 H), 7.42 (dd, 1 H), 7.41-7.30 (m, 5 H), 7.21 (d, 1 H), 5.16 (s, 2 H), 4.43-4.21 (m, 2 H) ), 2.96-2.78 (m, 3H), 2.71 (s, 3H), 1.92-1.51 (m, 4H), 4- (4-chloro-2- (R, S) -15-methylsulfinylphenyl) piperidine; XH NMR (CDC13) d 7.97 (d, 1H), 7.43 (dd, 1H), 7.28 (d, 1H), 3.30-3.10 (m, 2H), 2.71 (s, 3H), 2.83-2.61 (m, 3H) ), 1.92-1.51 (m, 5H); MS m / z 258 (M + H).
Example 58 20 N- [(S) -2- (3, 4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methyl- citrate Hydrate 3- trifluoromethyl-1-naphtamide. Using standard acylation conditions, 3-trifluoromethyl-1-naphthoyl chloride (0.11 g) was reacted - - with N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methylamine (0.19 g) is converted to citrate salt, and isolated by filtration with diethyl ether to give title compound 5 (0.3 g) as an off-white powder. MS APCl, m / z 675 (M +); 1tt NMR (300 MHz, DMSO d6) d 11.0 (broad), 8.55-8.40 (m), 8.30- 8.10 (m), 7.91-7.63 (m), 7.62-7.45 (), 7.44-7.12 (m), 7.05 - 6.85 (m), 3.20-2.76 (m), 2.75-2.55 (m), 2.20-1.65 (m); calculated for C35H35C12 F3N303S, 1 C6H807, I H20, C 10 56.60, H 5.12, N, 3.16; found: C, 55.42, H 5.02, N 3.12. The requisite 3-trifluoromethyl-1-naphthoyl chloride was prepared as follows. a) 4-bromo-2-naphthoic acid 15 A solution of 4-bromo-2-naphthoic acid methyl ester (Adcock, W; Wells, PR; Aust J. Chem., 18, 1965; 1351-1364) ( 2.23 g) in THF (50 mL) was treated with a solution of LiOH (hydrate) (0.39 g) and H20 (25 mL). Methanol (5 mL) was added and the mixture was stirred at 25 ° C for several days. The The mixture was concentrated in vacuo, treated with additional H20, washed with diethyl ether, acidified with 10% aqueous HCl and extracted with a mixture of EtOAc and DCM (1: 2). The extracts were dried with Na 2 SO 4, filtered and the solvent was removed in vacuo. The whitish solid residue was triturated with ether ^^^^^^ M ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ dried under reduced pressure to give the product (1.6 g, 76%) as a whitish solid. MS El, m / z = 250 (M); 2H NMR (DMSO d6) d 13.44 (bs, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 8.23-8.18 (m, 2H), 7.87-7.83 (t, 1H), 7.76-7.71 ( t, 1H). b) S-ethyl ester of 4-bromo-2-thionaphthoic acid A mixture containing 4-bromo-2-naphthoic acid (1.34 g) and dry DCM (15 mL) was treated with oxalyl chloride (0.83 g) at 25 ° C. A catalytic amount of DMF was added, the mixture was stirred for 4 hours, then the DMC was removed in vacuo. The solid residue was redissolved in dry DCM (15 mL), cooled (in an ice bath), ethanethiol (0.85 mL) was added dropwise. After 10 minutes, TEA (1.6 mL) was added and the mixture allowed to warm to 25 ° C. After stirring for 16 hours, the mixture was diluted with aqueous NaHCO 3 and extracted with DCM. The extracts were dried with Na 2 SO 4, filtered and the solvent removed in vacuo. The dark red-orange residue was purified by chromatography (10% CH2C12 in hexane); lH NMR (300 MHz, CDC13) d 8.48 (s, 1H), 8.28-8.25 d, 1H), 7.99-7.96 (d, 1H), 7.75-7.70 (t, 1H), 7.64-7.59 (t, 1H) , 3.18-3.11 (q, 2H), 1.42-1.37 (t, 3H). c) ethyl ester of 4-bromo-2-dithiophthalic acid A mixture containing s-ethyl ester of 4-bromo-2-thionaphthoic acid (1.49 g), 2,4-bis (4-methoxyphenyl) -1, 3- dithia-2, 4-d? phosphetane-2, 4-disulfide (Lawesson's reagent) (1.43 g), and dry toluene (25 mL) was heated under reflux for 20 hours, allowed to cool then diluted with diethyl ether . The solution was washed with [aqueous NaHC03 and H20], dried with Na2SO, filtered and the solvent removed in vacuo. The dark red residue was purified by chromatography (10% CH2C12 in hexane) to give the product (1.35 g) (85.6%) as a red solid. MS El, m / z = 310/312 (M),? H NMR (300 MHz, CDC13) d 8.47 (s, 1H), 8.44 (s, 1H), 8.24-8.22 (d, 1H), 7.97-7.95 (d, 1H), 7.71-7.67 (t, 1H), 7.61-7.57 (t, 1H), 3.46-3.39 (q, 2H), 1.48-1.43 (t, 3H) .1.42-1.37 (t, 3H) . d) 1-bromo-3-trifluoromethylnaphthalene. Based on the procedure of Kuroboshi, M and Hiyama, T (Chemistry Letters, 827-830 (1992), a solution containing 4-bromo-2-dithiophthalic acid ethyl ester (0.18 g) and DCm (4 mL) was cooled at 0 ° C and treated with HF / pyridine (70:30% weight) (0.6 mL) After several minutes, 1,3-dibromo-5,5-dimethylhydatoin (0.68 g) was added in one portion. The reaction was allowed to warm to 25 ° C, stirred for 1.5 hours, poured into a saturated aqueous NaHCO 3 solution and NaHS 3 and extracted with diethyl ether.The diethyl ether extracts were dried with Na 2 SO 4, filtered, The solvent was removed in vacuo.The residue was purified by chromatography (hexane) to give the product (0.08 g, 50%) as a colorless liquid MS m / z = 274/276 (M); XH NMR (300 MHz, CDC13) d 8.31-8.28 (d, 1H), 8.13 (s, 1H), 7.96-7.93 (s, d, 2H), 7.77-7.72 (t, 1H), 7.68-7.63 (t, 1H), 19F NMR (282 MHz, CDCI3) d -62.91 (s) 10 e) 3-trifluoric acid methyl ester romethyl-1-naphthoic A mixture containing l-bromo-3-trifluoromethylnaphthalene (0.44 g), 1,3-bis- (diphenylphosphino) propane (0.13 g), palladium acetate (0.08 g) g), and TEA (0.45 mL) in DMSO (10 mL) and MeOH (10 mL) was placed under an atmosphere of carbon monoxide. The mixture was heated at 70 ° C for 22 hours, cooled, diluted with MeOH, filtered through celite, and rinsed with MeOH. The combined and washed filtrates were evaporated in vacuo. He The residue was dissolved in EtOAc, washed (with water and brine), dried with Na 2 SO 4, filtered and the solvent removed in vacuo. The residue was purified by chromatography (10% DCM in hexane) to give the product (0.24 g) (58.6%) as a colorless liquid. MS El, m / z = 254 (M); ? H NMR (300 MHz, . »- - -CDC13) d 8.99-8.97 (d, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 8.00-9-7.97 (d1H), 7.78-7.72 (t, 1H) 7.67-7.63 (t, 1H), 4.04 (s, 3H); 19F NMR (282 MHz, CDC13) d -60.42 (s). f) 3-trifluoromethyl-1-naphthoic acid A solution of 3-trifluoromethyl-1-naphthoic acid methyl ester (0.23 g) in THF (5 mL) was treated with a solution of LiOH (hydrate) (0.044 g) and H20 (1.5 mL). Methanol (0.5 mL) was added and the mixture was stirred at 25 ° C for 3.5 hours. The mixture was concentrated in vacuo, treated with additional H20, acidified (1N aqueous HCl) and extracted with DCM. The extracts were dried (NaS04 anhydrous) were filtered and the solvent was removed in vacuo to give the product (0.21 g) (95.8%) as an off-white solid. MS El, m / z = 240 (M); H NMR (300 MHz, CDC13) d 9.14-9.12 (d, 1H), 8.58 (s, 1H), 8.40 (s, 1H), 8.05-8.02 (d 1H), 7.83-7.78 (t, 1H), 7.71 -7.66 (t, 1H); 19 F NMR (376 MHz, CDCl 3) d -61.53 (s). g) 3-trifluoromethyl-1-naphthoyl chloride. A mixture containing 3-trifluoromethyl-1-naphthoic acid (0.10 g) and dry DCM (5 mL) was treated with oxalyl chloride (0.065 g) at 25 ° C. A catalytic amount of DMF was added, the mixture was stirred for 4 hours, then the DCM was removed in vacuo. The solid residue was redissolved in dry DCM - and used without further purification.
Example 59 N- [2 (S) - (3,4-dichlorophenyl) -4- [4- [4- (R, S) -5 (methylsulfinyl) phenyl] -l-piperidinyl] butyl] -N- hydrochloride methyl-3-cyano-l-naphtamide. Using standard reductive amination conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl] -N-methyl-3-cyano-l-naphthamide (0.150 g) was reacted with 4- (4- (R, S) -methyl- 0 sulf? N? Lphenyl) piperidine (0.079 g) and converted to hydrochloride salt. MS m / z 632 (M +). XH NMR (DMSO d6) d 10.49 (m, 1H), 8.63 (m, 1H), 8.10 (m, 1H), 7.90-6.50 (m, 10H), 2.73 (s, 3H), 3.77-1.70 (m, 19H).
Example 60 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [3-fluoro-4-methylsulfinylphenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano -l- naftamide. Using standard reductive amination conditions 0 N- [2- (S) - (3, -d? Chlorophen? L)] -4-oxobutyl-N-met? L-3-cyano-l-naphthamide (0.213 g) is Reacted with 4- (3-fluoro-4-methyl-sulfonylphenyl) piperidine (0.120 g) and converted to hydrochloride salt. (0.276 g). mp 175-180 ° C; H NMR (300 MHz, CDC13) d 10.76 (m, 1H), 8.63 (s, 1H), 8.25 (m, 1H), 7.9-6.9 (m, 9H), 6.5 (br., 1H), 4.5 (br., 1H), 2.82 (two spikes, 3H) 2. 5 (two peak, 3H), 2.4-1.8 (m, S APCi, m / z = 650 (M + The N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [3-fluoro-4-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-methylamine requirement was prepared from bromo-2-fluorophenol using procedures according to those described in example 2a-h for 4- (4-methoxy-2-methylsulfinyl-phenyl) piperidine except for the oxidation (step g) of the intermediate 4- (3-fluoro- 4-methylthiophenyl) -N-Cbz-piperidine; this is carried out as described in example 16e and the splitting of group Cbz (step h) which is carried out as described in example 6c.; XH NMR (300 MHz, CDC13) d 8.8 (t, J = 10Hz, 1H), 7.3 (m, 1H), 6.97 (m, 1H), 3.3 (m, 2H), 1.85 (m, 2H), 1.65 ( m, 2H); MS APCl, m / z = 242 (M +); Example 61 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [4-methylsulfonyloxyphenyl] -1-piperidinyl] butyl] -N-methyl-3-cyano-1-naphtamide. To a solution of N- [(S) -2- (3, -dichlorophenyl) -4- [4- [2-hydroxyphenyl] -1-piperidonyl] butyl] -N-methyl-3-cyano-l- Naphthamide (100 mg) in DCM (2 mL) at 0 ° C was added triethylamine (0.030 mL) and methanesulfonyl chloride (0.016 mL). 1. * The stirred solution was warmed to room temperature for an additional 2 hours, triethylamine (two drops) and methanesulfonyl chloride (1 drop) were added, stirring was continued for 30 minutes and the mixture was concentrated and purified by chromatography (5-10). % MeOH in DCM (110 mg) .1H NMR (300 MHz, DMSO-d6) d 8.64 (d, 1H), 8.10 (m, 1H), 6.40-7.90 (m), 4.10 (bs), 3.50 (d) , 3H), 2.40-3.45 (m), 2.13 (m), 1.60-2.00 (m), MS APCl, m / z = 664 (M +); The N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-hydroxyphenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano-l-naphthamide required It was prepared as follows. 2-benzyloxybromobenzene (242.3 g) was reacted with l-benzyloxycarbonyl-4-piperidone (214.7 g) according to the method described by example 2e to give 4-hydroxy-4- (2-benzyloxyphenyl) -N-Cbz-piperidine (226.75 g) then the extraction and chromatography was performed using 10-30% ethyl acetate in hexanes. XH NMR (300 MHz, CDC13) d 7.40-7.21 (m, 12H), 6.98 (m, 2H), 5.12 (s, 4H), 4.11 (br s, 3H), 3.35 (br s, 2H), 2.03 ( br s, 4H). A sample of this material (235 g) was reacted with triethylsilane (405 mL) and trifluoroacetic acid (195 mL) according to the method described by Example 2f. Following extraction and chromatography (10-25% ethyl acetate in hexane), residual triethylsilane was removed by distillation (50-60 ° C, 800-900 millitorr) to give 4- (2-benzyloxyphenyl) -N-Cbz. -piperidine (179.3 g). A solution of this material (4.01 g) in ethanol (60 L) was stirred for 24 hours with palladium hydroxide in carbon [Pearlman's catalyst] (2.2 g) under hydrogen (50 psi). The catalyst was removed by filtration, the filtrate was concentrated and triturated with acetone to give 4- (2-hydroxyphenyl) -piperidine (0.75 g) as a white powder. X H NMR (300 MHz, DMSO-d 6) d 8.49 (s, 1 H), 7.02 (m, 2 H), 6.82 (d, 1 H), 6.72 (t, 1 H), 3.20 (br d, 2 H), 3.02 (m , 1H), 2.85 (tt, 2H), 1.74 (m, 4H). Using standard reductive amination conditions N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutylN-methyl-3-cyano-l-naphthamide (0.213 g) was reacted with 4- ( 2-hydroxyphenyl) -piperidine to give N - [(S) -2- (3, -d? Chlorophenyl) -4- [4- [2-hydroxyphenyl] -l-pipepdinyl] butyl] -N-met? L- 3-cyano-l-naphtamide.
Example 62 N- [2- (S) - (3,4-dichlorophenyl) -4- [4- [3-methoxy-4- (R, S) -methylsulfinylphenyl] -l-piperidinyl] butyl] -N-hydrochloride -methyl-3-cyano-1-naph amide. Using standard reducing alkylation conditions N- [2- (S) - (3,4-dichlorophenyl) -4-oxobutyl-N-methyl-3-c-ano-1-naphthamide (0.128 g) was reacted with 4- (3-methoxy-4- (R, S) -methylsulfinylphenyl) pl-rridridine (0.080 g) and converted to hydrochloride salt MS m / z 662 (M +). XH NMR (DMSO d6) d 10.30 ( m, 1H), 8.63 (m, 1H), 8.10 (, 1H), 7.90-6.85 (m, 10H), 3.86 (s, 3H), 3.35 (s, 3H), 2.68 (s, 3H), 3.77-1.78 (m, 16H). The requisite 4- (3-methoxy-4- (R, S) - (methylsulfinylphenyl) piperidine was prepared according to the procedures described by Example 2, except 2-methoxyphenol which was used in place of 3-methoxyphenol. The abbreviated protocols and the analytical data are the following: 4-bromo-2-methoxyphenol: 2-methoxyphenol (129.03 g) (used in place of 3-methoxyphenol according to example 2) was reacted with bromine (167.94 g) to give 161.78 g of product after purification by vacuum distillation. XH NMR (CDC13) d 7.10-6.90 (m, 2H), 6.78 (d, 1H), 5.66 (s, 1H), 3.84 (s, 3H). 4-Bromo-2-methoxy- (N, N-dimethylthiocarbamoyl) phenol: 4-bromo-2-methoxyphenol (20.45 g) was reacted with N, N-dimethylthiocarbamoyl chloride (15.75 g) to give 18.28 g of the product after of the recrystallization of MeOH. MS m / z 290 (M +). 1H NMR (CDC13) d 7. 18-7.09 (m, 2H), 6.90 (d, 1H), 3.82 (s, 3H), 3.45 (s, 3H), 3. 35 (s, 3H). 5-bromo-2- (N, N-dimethylthiocarbamoyl) -methoxybenzene: 4-bromo-2-methoxy- (N, N- dimethylthiocarbamoyl) phenol (18.28 g) was rearranged to give 13.81 g of the product after recrystallization from MeOH. MS m / z 290 (M +). : H NMR (CDC13) d 7.09 (dd, 1H), 6.99 (d, 1H), 6.95 (d, 1H), 3.89 (s, 3H), 2.41 (s, 3H). l-Benzyloxycarbonyl-4-hydroxy-4- (3-methoxy-4-methylthiophenyl) piperidine: 5-bromo-2- (thiomethyl) methoxybenzene (5.49 g) was reacted with l-benzyloxycarbonyl-4-piperidine (5.72 g) to give 4.50 g of oil after chromatography (1: 1 EtOAc: hexane). MS m / z 410 (M + Na). * H NMR (CDCI3) d 7.43-7.30 (m, 5H), 7.21-6.92 (m, 3H), 5.16 (s, 2H), 4. 30-4.10 (m, 2H), 3.90 (s, 3H9, 3.31-3.20 (m, 2H), 2.44 (s, 3H), 2.13-1.60 (m, 4H). l-Benzyloxycarbonyl-4- (3-methoxy-4-methylthiophenyl) piperidine: 1-benzyloxycarbonyl-4-hydroxy-4- (3-methoxy-4-methylthiophenyl) piperidine (4.50 g) was reduced to yield 3.22 g of an oil then by chromatography (20: 1 DCM: EtOAc). XH NMR (CDCl 3) d 7.43-7.30 (m, 5H), 7.13 (d, 1H), 6.79 (dd, 1H), 6.67 (d, 1H), 5.16 (s, 2H), 4.35-4.20 (m, 2H) ), 3.88 (s, 3H), 2.96-2.72 (m, 2H), 2.62 (tt, 1H), 2.42 (s, 3H), 1.91-1.50 (m, 4H). l-benzyloxycarbonyl-4- (3-methoxy-4- (R, S) -metilsulfinilfenil) piperidine: To a stirred solution of NaI04 (2.06 g) dissolved in 40 mL 1: 1 THF: H20 was added 1-benzyloxycarbonyl-4- (3-methoxy-4-methylthiophenyl) piperidine (1.23 g). The mixture was stirred at room temperature for 18 hours, poured into 60 mL of H20, and , -,? -. ? J what - i ^ tj i¡¡!? * 'I., -? - I He pulled with DCM (3 x 40 mL). The extracts were combined, dried over Na 2 SO 4 and evaporated to give 0.94 g of an oil, then with chromatography (20: 1 DCM: EtOAc). XH NMR (CDC13) d 7.74 (d, 1H), 7.47-7.30 (m, 5H), 7.02 (dd, 1H), 6.73 (d, 1H), 5.16 (s, 2H), 4.35-4.20 (m, 2H) ), 3.88 (s, 3H), 2.98-2.78 (m, 2H), 2.76 (s, 3H), 2.73 (tt, 1H), 1.95-1.55 (m, 4H). 4- (3-methoxy-4- (R, S) -methylsulfinylphenyl) piperidine (0.94 g) was hydrolyzed to give 0.52 g of a white solid after 1 chromatography (10: 1 DCM: MeOH weight / 0.5% aqueous NH 3) . MS m / z 254 (M + H). XH NMR (CDC13) d 7.73 (d, 1H), 7.05 (dd, 1H), 6.79 (d, 1H), 3.88 (s, 3H), 3.35-3.20 (m, 2H), 2.90-2.60 (m, 3H) ), 2.77 (s, 3H), 1.95-1.61 (m, 4H).
Example 63 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2- [2-oxopyrrolidinylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano- citrate l-naphtamide. Using standard reducing amination conditions described in Example 20c, 4- (2-oxopyrrolidinylphenyl) piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl- 3-Cyano-l-naphthamide, the product was converted to citrate salt and recovered as a white powder. MS: m / z = 653 (M + H). 1H NMR (DMSO d6) (selected resonances) d 8.6 (m, 1H), 8.1 (m, 1H), 7.90-6.80 (m, 11H), 2.50 (s, * 3H, C0-N-CH3). Analysis calculated for C38H38N402C12, 2.8 H20, 1.0 citric acid, C 58.97, H 5.80, N 6.25, found C 58.89, H 5.50, N 6.16. The requisite 4- (2-oxopyrrolidinylphenyl) piperidine was prepared as follows. a) 3- [N- (2- { 1- [tert-butyloxycarbonyl] -4-piperidyl.}. phenyl) carbamoyl] propanoate. 3-Carbomethoxypropionyl chloride (0.120 g) was added to a solution of tert-butyl 4- (2-aminophenyl) piperidinecarboxylate (0.211 g) (example 21) and triethylamine (0.081 g) in DCM (10 mL) and stirred at room temperature throughout the night. The reaction was diluted with aqueous HCl. The organic phase was dried and evaporated to give the title compound (0.310 g) as a yellow oil. MS: m / z = 291 (M-Boc). 1H NMR (CDC13) d 7.53 (m, 1H), 7.19 (m, 3H), 4.25 (br, 1H, NH), 3.72 (s, 3H), 2.82-2.64 (M, 6H), 1.78-1.39 (M , 7H), 1.54 (S, 9H). b) 4- [(2- { l- [tert-butyloxycarbonyl] -4-piperidyl.}. phenyl) amino] butanoate. A solution of borane in tetrahydrofuran (1M, 3mL) was added to methyl 3- [N- (2- {1- [tert-butyloxycarbonyl] -4-piperidyl} phenyl) carbamoyl] propanoate (0.298 g) dissolved in tetrahydrofuran (12 mL) under hydrogen. The mixture was refluxed for 2 hours, cooled to room temperature, aqueous IN HCl (5 L) was added and stirred for an additional 15 minutes. The solution was partially concentrated, diluted with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were dried and evaporated, and the residue was purified by chromatography, (4: 1 hexanes: ethyl acetate) to give the title compound (0.110 g) as a yellowish oil. MS: m / z = 277 (M-Boc). XH NMR (CDC13) d 7.11 (m, 3H), 6.72 (m, 2H), 4.27 (br, 1H, NH), 3.69 (s, 3H, OCH3), 3.20 (m, 2H), 2.83 (m, 2H ), 2.46 (m, 3H), 2.05 (m, 2H), 1.84 (m, 3H), 1.69 (m, 2H), 1.54 (s, 9H). c) 4- acid [(2- {1- [tert-Butyloxycarbonyl] -4-piperidyl} phenyl) amino] butanoic. Aqueous sodium hydroxide IN (0.5 mL) and methanol (0.5 mL) were added to a solution of 4- [(2- {1- [tert-butyloxycarbonyl] - - piperidyl] phenyl) amino] butanoate methyl (0.110 g) in tetrahydrofuran (3 mL) and the mixture was stirred for 3 hours. The reaction was diluted with IN aqueous HCl and extracted with DCM. The organic extracts were dried and evaporated to give the title compound (0.100 g) as a yellow oil. MS: m / z = 363 (M + H). d) 1- (2- (4-piperidyl) phenyl) pyrrolidin-2-one hydrochloride. Diisopropylethylamine (0.065 g)hydrochloride, 1-hydroxybenzotriazole (0.040 g) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (0.096 g) were added to hydrochloride of 4- [(2- {1-l- [tert-butyloxycarbonyl]] -4-piperidyl.}. Phenyl) amino] butanoic (0.100 g) in DCM (6 mL) and the mixture was stirred overnight. The reaction was diluted with aqueous IN HCl and extracted with DCM. The organic extracts were dried and evaporated to give the title compound (0.100 g) as a yellow oil. MS: m / z = 367 (M + Na), 245 (M-Boc). This material was N-deprotected with HCl using conditions described by Example 21 d to give 1- (2- (4-piperidyl) phenyl) pyrrolidin-2-one hydrochloride. MS m / z = 245 (M + H).
Example 64 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2- (N-oxo-N, N-dimethylamino) phenyl] -l-piperidinyl] butyl] citrate N-methyl-3-cyano-l-naphtamide. Using the standard reducing amination conditions described in example 20c, 4- (2- (N-oxo-N, N-dimethylamino) phenylpiperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl) ] -4-oxobutyl-N-methyl-3-cyano-l-naphthamide, the product was converted to citrate salt and recovered as • • • • • • • • white powder. MS: m / z = 629 (M + H). XH NMR (DMSO d6) (selected resonances) d 8.6 (m, 1H), 8.1 (, 1H), 7.90-6.80 (m, 11H), 3.83 (s, 6H, Ar-N (0) CH3), 2.50 ( s, 3H, CO-N-CH3). The requisite 4- (2-oxo-N, N-dimethylamino) phenyl) piperidine was prepared as follows. a) 4- [2- (N-Oxo-N, N-dimethylamino) phenyl] piperidine hydrochloride. 3-Chloroperoxybenzoic acid (0.125 g) was added in DCM (2 mL) of tert-butyl 4- [2-N, N-d? Methylaminophenyl] piperidinecarboxylate (0.220 g) in DCM (10 L) was added and stirred for 1 hour. The reaction mixture was extracted sequentially with aqueous sodium sulfite and aqueous sodium bicarbonate. The organic phase was dried and evaporated to give tert-butyl 4- [2- (N-oxo-N, N-dimethylamino) phenyl] piperidinecarboxylate (0.206 g) as a white solid foam. MS: m / z = 321 (M + H). This material was N-deprotected with HCl according to the conditions described by Example 21 d, to give 4- [2- (N-oxo-N, -dimethylamino) phenyl] -piperidine hydrochloride which was used without purification.
Example 65 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methoxycarbonylaminophenyl] -l-piperidinyl] -butyl] -N-methyl-3-cyano-1- citrate naftamide.
Using the standard reducing amination conditions described in Example 20c, 4- (2-methoxy-carbonylaminophenyl) piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N -methyl-3-cinna-1-naphthamide, the product was converted to citrate salt and recovered as a white powder. MS: m / z = 643 (M + H). XH NMR (DMSO of) selected resonances) d 8.91 (m, 1H), 8.64 (m, 1H), 8.12 (m, 1H), 7.90-6.80 (m, 10H), 6.30 (br, 1H, NH), 3.77 (s, 3H, OCH3), 2.50 (s, 3H, CO-N-CH3).
The requisite 4- (2-methoxycarbonylaminophenyl) piperidine was prepared as follows. Methyl chloroformate (0.065 g) was added to a solution of tert-butyl 4- (2-amino-phenyl) piperidine carboxylate (0.172 g) (example 21) and triethylamine in DCM (4 mL) and was stirred throughout. overnight it was diluted with aqueous HCl IN. The organic phase was dried and evaporated to give tert-butyl 4- (2-methoxycarbonylaminophenyl) piperidinocarboxylate (0.207 g) as an oil. MS: m / z = 235 (M-Boc). ? H NMR (CDC13) d 7.21 (m, 4H), 6.30 (br, 1H NH), 4.24 (m, 2H), 3.72 (s, 3H, OCH3), 2.77 (m, 3H), 1.67 (, 4H), 1.49 (s, 9H). This material was N-deprotected with HCl according to the procedures of Example 21d, to give hydrochloride 4 - (2-methoxy-carbonylaminophenyl) piperidine.
Example 66 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2- (methoxy-1,2-dioxoethylamino) phenyl] -l-piperidinyl] butyl] citrate methyl-3-cyano-l-naphtamide.
Using the standard reducing amination conditions described in Example 20c, 4- (2- (methoxy-1,2-dioxoethylamino) phenyl) piperidine was reacted with N- [2- (S) - (3, -dichlorophenyl)] -4-oxobutyl-N-methyl-3-cyano-l-naphthamide, the product was converted to citrate salt and recovered as a white powder. MS: m / z = 671 (M + H). 1H NMR (DMSO d6) selected resonances) d 8.62 (m, 1H), 8.10 (m, 1H), 7.90-6.80 (m, 11H), 6.45 (br, 1H, NH), 3.84 (s, 3H, 0CH3) 2.50 (s, 3H, CO-N-CH3).
The requisite 4- (2-methoxy-l, 2-dioxoethylamino) phenyl) piperidine was prepared as follows.
In accordance with the procedure described for example 65, tert-butyl 4- (2-aminophenyl) -piperidine carboxylate was reacted with methyl oxalyl chloride (instead of methyl chloroformate) to give 4-methylcarbonylate. - tert-Butyl (2-methoxy-l, 2-dioxoethylamino) phenyl) piperidine. MS: m / Z = 362 (M + H). * H NMR (CDC13) d 7.83 (m, 1H), 6.30 (br, 1H NH), 4.24 (m, 2H), 3.72 (s, 3H, OCH3), 2.77 (m, 3H), 1.67 (m, 4H ), 1.51 (s, 9H). This material was N-deprotected using HCl according to the procedure described by Example 21d to give 4- (2- (methoxy-1,2-dioxoethylamino) phenyl) piperidine.
Example 67 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2- (N, N-dimethylcarbamoylmethoxy) phenyl] -l-piperidinyl] butyl] -N-methyl- citrate 3-cyano-1-naphtamide.
Using the standard reductive amination conditions described in Example 20c, 4- [2- (N, N-dimethylcarbamoylmethoxy) phenyl] piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl)] - 4-oxobutyl-N-methyl-3-cyano-1-naphthamide, the product was converted to citrate salt and recovered as a white powder. MS: m / z = 671 (M + H). MR XH N (DMSO d6) selected resonances) d 8.62 (m, 1H), 8.10 (m, - - 1H), 7.90-6.80 (m, 11H), 4.83 (s, 2H), 4.10 (m, 1H), 2.50 (s, 3H, CO-N-CH3).
The requisite 4- [2- (N, N-dimethylcarbamoylmethoxy) phenyl] piperidine was prepared as follows. a) Benzyl 4- [2- (methoxycarbonylmethoxy) phenyl] piperidinocarbamate. Potassium carbonate (0.300 g) and methyl bromoacetate (0.300 g) were added to a solution of 1-benzyloxycarbonyl-4- (2-hydroxyphenyl) piperidine (0.544 g) in acetone (15 mL) and the mixture was heated under reflux for 48 hours. The reaction was filtered, evaporated and the residue was purified by chromatography, (3: 1 hexane: ethyl acetate) to give benzyl 4- [2- (methoxycarbonylmethoxy) phenyl] piperidinocarbonate (0.825 g) as a yellow oil. MS: m / z = 384 (M + H). XH NMR (CDC13) d 7.62-6.70 (m, 9H, Ar-H), 5.22 (s, 2H, Ph-CH2), 4.70 (s, 2H, 0-CH2-CO), 3.7989 (s, 3H, OCH3 ), 3.25 (m, 1H), 2.93 (m, 3H), 1.89 (M, 2H9, 1.62 (m, 3H). b) 4- [2- (Hydroxycarbonylmethoxy) phenyl] piperidinocarbamate benzyl. 4- [2- Benzyl (methoxycarbonylmethoxy) phenyl] piperidinocarbamate (0.825 g) was dissolved in a mixture of tetrahydrofuran (10 ml), methanol (3 ml) and IN sodium hydroxide (10 ml) and stirred for 90 minutes. The reaction was acidified with IN aqueous HCl and extracted with diethyl ether: the organic phase was dried and evaporated to give the title compound (0.462 g) as a colorless oil. : H NMR (CDC13) d 7.62-6.709 (m, 9H, Ar-H), 5.22 (s, 2H, ph-CH2), 4.70 (s, 2H, 0-CH2-CO), 3.25 (m, 1H) , 2.93 (, 3H), 1.89 (m, 2H), 1.62 (m, 3H). c) 4- [2- (N, N-dimethylcarabmoylmethoxy) phenyl] piperidinocarbamate benzyl. A solution of oxalyl chloride (1.25 ml) and a catalytic amount of DMF was added to benzyl 4- [2- (hydroxycarbonylmethoxy) phenyl] piperidinecarbamate (0.462 g) in DCM (20 ml) at 0 ° C. The mixture was heated to room temperature and stirred for 3 hours. The reaction was concentrated, the residue was redissolved in DCM (20 ml). A 1M solution of dimethylamine in tetrahydrofuran (10 ml) was added and stirred 1 hour. The reaction was extracted sequentially with IN aqueous HCl, aqueous sodium bicarbonate and brine. The organic phase was dried and evaporated to give the title compound (0.433 g) as a colorless oil. MS: m / z = 397 (M + H). 1H NMR (CDC13) d 7.62-6.70 (m, 9H, Ar-H), 5.22 (s, 2H, Ph-CH2), 4.70 (s, 2H, 0-CH2-CO), 3.25 (m, 1H), 3.10 (s, 3H, N-CH3), 3.03 (s, 3 H, N-CH 3), 3.03 (s, 3 H, N-CH 3), 2.94 (m, 3 H), 1.89 (m, 2 H), 1.62 (m, 3 H). d) 4- [2- (N, N-dimethylcarbamoylmethoxy) phenyl] piperidine hydrochloride. A solution of ethanol (20 ml) of benzyl 4- [2- (N, N-dimethylcarbamoylmethoxy) -phenyl] piperidinocarbamate (0.425 g) was N-deprotected by hydrogenation at 1 atm in the presence of 5% palladium in catalyst of carbon (0.200 g) for 3 hours to give the title compound (0.275 g) as a colorless oil. MS m / Z = 263 (M + H). XH NMR (CDC13) d 7.25-6.70 (m, 4H, Ar-H), 4.70 (s, 2H, 0-CH2-CO), 3.25 (m, 1H), 3.10 (s, 3H, N-CH3), 3.03 (s, 3H, N-CH3), 2.94 (m, 3H), 1.89 (m, 2H), 1.62 (m, 3H).
Example 68 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methylsulfinylmethylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-1-naphthamide citrate 30% aqueous hydrogen peroxide was added to a solution of N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methylthiophenylphenyl] -l-piperidinyl] butyl] -N- methyl-3-cyano-l-naphthamide (0.070 g) in acetic acid (2 ml) and the mixture was afr ^ idK stirred for 30 minutes. The acetic acid evaporatedThe residue was redissolved in ethyl acetate and extracted with aqueous sodium bicarbonate. The organic phase was dried and evaporated and the residue was converted to citrate salt under standard conditions to give the title compound (0.078 g) as a white powder. MS: m / z = 646 (M + H). H NMR (CDC13, selected resonances) d 8.21 (m, 1H), 7.90 (m, 1H), 7.95-7.00 (m, 11H), 4.30 (m, 1H, Ar-CH2-S), 3.96 (m, 1H , Ar-CH2-S), 3.22 (s, 3H, S-CH3), 2.51 (s, 3H, N-CH3). a) Tert-Butyl 4- (2-hydroxymethylphenyl) piperidinocarbamate A 1M borane solution in tetrahydrofuran (6 mL) was added to a solution of tert-butyl 4- (2-hydroxycarbonylphenyl) piperidinocarbamate (0.915 g) (prepared from 4- (2-methoxy-carbonylphenyl) piperidine [example 20] by N-protection using di-tert-butyldicarbonate followed by saponification of the methyl ester with lithium hydroxide) in tetrahydrofuran (20 ml) at 0 ° C. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with methanol and IN aqueous HCl then extracted with diethyl ether. The organic phase was separated and extracted sequentially with sodium bicarbonate watery and brine. The organic phase was dried and evaporated to give the title compound (0.906 g) as a colorless oil. MS: m / z = 192 (M-Boc). H NMR (CDC13) d 7.28 (m, 4H, Ar-H), 4.75 (d, 2H, Ar-CH2-0), 3.05 (m, 1H), 2.83 (m, 3H), 1.70 (m, 5H) , 1.49 (s, 9H). b) tert-butyl 4- (2-chloromethylphenyl) piperidinocarbamate. Hexachloroacetic acid (2.61 g) was added to a solution of triphenylphosphine (0.830 g) and tert-butyl 4- (2-hydroxymethylphenyl) piperidinocarbamate (0.838 g) in toluene (25 ml). The reaction was stirred for 1 hour until it was evaporated. The residue was purified by chromatography (6: 1 hexane: ethyl acetate) to give the title compound (0.867) as a colorless oil. MS: m / z = 210 (M + H). 2H NMR (CDC13) d 7.28 (m, 4H, Ar-H), 4.75 (d, 2H, Ar-CH2-Cl), 3.05 (m, 1H), 2.83 (m, 3H), 1.70 (m, 5H) , 1.49 (s, 9H). c) 4- (2-methylthiomethylphenyl) piperidine. Sodium thiomethoxide (0.220 g) tetra-n-butylammonium bromide (0 lOOg) and tert-butyl 4- (2-chloromethylphenyl) piperidincarbamate (0.867 g) were combined in acetone (20 mL) under nitrogen and stirred for 6 hours. hours, then heated under reflux for 90 minutes. The reaction was diluted with aqueous sodium bicarbonate and diethyl ether. The organic phase was dried and evaporated and the residue was purified by chromatography (6: 1 hexane: ethyl acetate) to give tert-butyl 4- (2-methylthiomethylphenyl) piperidinocarbamate (0.471 g) as a yellow oil. MS: m / z = 210 (M + H). 1H NMR (CDC1) d 7.18 (m, 4H, Ar-H), 3.68 (s, 2H, Ar-CH2-Cl), 3.04 (m, 1H), 2.80 (m, 3H), 2.40 (m, 3H) , S-CH3), 1.70 (m, 5H), 1.49 (s, 9H). This material was N-deprotected with HCl according to the conditions described in Example 21d to give 4- (2-methylthiomethylphenyl) piperidine. XH NMR (CDC13) d 7.30 (m, 4H, Ar-H), 3.77 (s, 2H), 3.63 (m, 2H), 3.10 (m, 3H), 2.25 (m, 2H), 2.04 (s, 3H) , S-CH3), 1.95 (m, 2H). d) N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [2-methylthiomethylphenyl] -l-piperidinyl] butyl] -N-methyl-3-cyano-l-naphtamide. Using the reductive amination conditions described in Example 63, 4- (2-methylthiomethylphenyl) piperidine was reacted with N- [2- (S) - (3,4-dichlorophenyl)] -4-oxobutyl-N-methyl- 3-Cyano-l-naphthamide, the product was isolated by extraction and used without purification. Ms: m / z = 630 (M + H).
Example 69 N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] butyl] -N-ethyl-3-cyano-l -naphtamide Using standard acylation conditions, 3-cyano-l-naphthoic acid (0.118 c) was converted to acid chloride and reacted with N- [(S) -2- (3,4-dichlorophenyl) - 4- [4- [(S) -2-methylsulfinylphenyl] -l-piperidinyl] -1- and piperidinyl] butyl] -N-ethylamine '(0.336 g) (prepared according to the methods described by N- [(S) -2- (3,4-dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -1-piperidinyl] butyl] -N-methylamma, except that the ethyl chloroformate was used in place of acetyl chloride for the acylation with amine prior to reduction of the amine). Mp 115-118 ° C (dec); XH NMR (300 MHz, DMS0-d6) d 8.65 (d9), 8.10 (m), 7.95-7.15 (m), 6.50 (m), 3.60 (s), 3.25-2.95 (m), 2.95-2.40 (m) ), 2.40-1.70 (m), 1.35 (m), 0.9 (m); MS APCl, m / z = 646 (M +).
Example 70 The following examples represent the dosage form pharmaceutical that can be used by therapeutic or prophylactic administration of a compound of formula 1 or IX or an acceptable pharmaceutical salt or hydrolysable ester m of the same referred to herein above as well as to Compound X '): - - (And tablet mq / tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (tablet pc mg / tablet 'Compound X' 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Starch glycolate 15.0 sodium Magnesium stearate 5.0 500.0 111 Capsule mg / capsule 'Compound X' 5.9 Lactose 392.9 sodium lauryl sulfate 1.2 400.0 (iv) Capsule 2 mq / capsule 'Compound X' 29.6 lactose 331.4 sodium lauryl sulfate 1.0 362.0 (v) Injection 1 (lmg / mL) mg / mL 'Compound X' (1.0 acid free form) dibasic sodium phosphate 12.0 sodium phosphate monobasic 0.7 sodium chloride 4.5 Sodium hydroxide solution q.s. 1. 0 N (pH adjusted to 7.0-7.5) water for injection q.s. to 1 mL, (i) Injection 2 (10 mg / mL) mg / mL 'Compound X' (10.0 acid free form) monobasic sodium phosphate 0.3 dibasic sodium phosphate 1.1 polyethylene glycol 400 200.0 Sodium hydroxide solution qs 0.1 N (pH adjusted to 7.0-7.5) water for injection qs to 1 L. (vii) Aerosol 'Compound X' i g HFA 227 or HFA 134a with 5% ethanol It will be appreciated that the above pharmaceutical compositions may vary according to well-known pharmaceutical techniques to accommodate the different amounts and types of active ingredients 'Compound X'. The aerosol (vii) * - - can be used in conjunction with a standard aerosol dispenser that measures the dose.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following

Claims (17)

1. A compound of the formula (I) (i) characterized in that: R is alkyl; R1 is optionally substituted phenyl, 2-oxo-tetrahydro-1 (2H) -pyrimidinyl, or 2-oxo-1-piperidinyl; R 2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, laclanylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl wherein the alkyl group is the same or different, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl, or N , N-dialkylthiocarbamoyl wherein the alkyl group is the same or different. , Jt . "M") Xi and X2 is independently hydrogen or halo, provides that at least one of Xi or X2 is halo; and R3, R4, R, 5, and R6 is independently hydrogen, cyano, nitro, trifluoromethoxy, or alkylsulfonyl, provides at least one of R3, R4, R5, and R6 is not hydrogen; Or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
2. A compound according to claim 1 characterized in that R1 is phenyl optionally substituted by C? -6alkyl, C? _6alkylthio; Ci-ßalkylsulfyl; Ci- 6alkylsulfonyl; C? -6alcoxy; hydroxy; Not me; halo; carboxy; Ci-6alcoxycarbonyl; nitro; C? -6alkylamino; di-C? -6alkylamino; trifluoromethyl; carbamoyl; C?-Alkylcarbamoyl; trifluoromethylthio, trifluoromethylsulfonyl; trif luoromet ilsulf onyl; Cx-ealquenosulfonamido; Ci-ßalcanoyl; N-C? _6alkoxy, N-C? -6alkylamino; C? -6alkanoylamino; ureido; C? _ 6alquilureido; di-Ci-βalkylureide; C? -6alkylsulf onyloxy; 2-oxopyrrolidino; N-oxo-N, N-di-C? _6alkylamino; C? -6a lcoxycarboni lamino; C? _6alkoxycarboni lamino; C6-alkylcarbamoylC6-6alkoxy, -diCi-ßalkyl carbamoi-C? -6alkoxy; and C? -6alkyl substituted by any of the substituents.
- 3. A compound according to claim 1 or claim 2 characterized in that R1 is a phenyl group substituted in the ortho position by C? -6alkitio; C? _ 6alkylsulfinyl; C? -6alkylsulfonyl; trifluoromethylthio; 5-trifluoromethylsulfinyl; C? -6alkanesulfonamide; C6-alkanoyl; C? -6alkoxycarbonyl; Succinamide; carbamoyl; Ci- 6 alkylcarbamoyl; di-C? -6-alkylcarbamoyl; C? -6alcoxy; C? _6alcoxi; C? -6 alkylcarbamoyl; C? _6alcanoylamino; ureido; C-alkylquilureide, di-C? -6alkylureide; Not me; C 1-6 alkylamino or 10 di-C? 6alkylamino and optionally is further substituted.
4. a compound according to any one of claims 1 to 3, characterized in that R1 is phenyl substituted in the ortho position by methylisulfinyl, 15-methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino.
5. A compound according to any of claims 1 to 4 characterized in that R1 is: (the) ss.-a 'wherein R is hydrogen, halo, Ci-β-alkylsulfinyl carboxy
6. A compound according to any one of claims 1-5 characterized in that R1 is phenyl and any ortho-methylsulfinyl substituent has the (S) configuration .
7. A compound according to any of claims 1 to 4 characterized in that R1 is 2-10-oxotetrahydro-1 (2H) -pyrimidinyl.
8. A compound according to any of claims 1 to 4, characterized in that R1 is 2-oxo-1-piperidinyl.
9. A compound according to any of claims 1 to 8, characterized in that R1 is hydrogen.
10. A compound according to any of claims 1 to 6 which is: fe &amp-afe ^ characterized in that Ra is hydrogen, Ci-ealkoxy, halo, C? -6alkylsulfinyl or carboxy; R3 is hydrogen; R4 is cyano or nitro; R5 is hydrogen or cyano; and R6 is hydrogen.
11. N- [(S) -2- (3,4-Dichlorophenyl) -4- [4- [(S) -2-methylsulfinylphenyl] -1-piperidinyl] butyl] -N-methyl-3-cyano-l-naphtamide or a pharmaceutically acceptable salt thereof.
12. N- [(S) -2- (3,4-dichlorophenyl) -4- [4-. { 4-methoxy- (S) -2-methylsulfinylphenyl} -l-piperidinyl] butyl] -N-methyl-3-cyano-l-naphtamide or a pharmaceutically acceptable salt thereof.
13. A compound of the formula (IX). •• C tsg aiiK.- *, h ** y »y ^ -á 'sty r- ^ < -. . M? and (IX) characterized in that R9 is hydrogen or a group R as defined in claim 1, X?, X2 and R3-R6 are as defined in claim 1; and R8 is -CHO, -CH2OR10 wherein R10 is hydrogen or an ester thereof or Ci-ealkyl, or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
14. A compound according to any of claims 1-10 and 13 in the form of a base or a pharmaceutically acceptable salt characterized in that R is methyl.
15. A pharmaceutical composition which comprises a compound according to any of claims 1 to 14 and a pharmaceutically acceptable carrier. 15 ^ m ^? I & ^^^ -
16. A method for treating a condition of disease or disease wherein the antagonism of at least one tachykinin receptor is beneficial, which comprises administering to a patient in need of an effective amount. of a compound of any of claims 1 to 14.
17. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or a The in vivo hydrolysable precursor thereof, wherein the process is characterized in that it comprises: a) reacting a compound of formula 15 (III) with a compound of formula (IV) you..-. - ñ * ^ XM M wherein R, Rx-R6, Xi and X2 are as defined in claim 1; and L and L1 are groups such that the reductive amination of the compounds of formula (III) and (IV) form an N-C bond; or b) reacting a compound of the formula (V) with a compound of the formula (VI): (SAW) wherein R1-R6, R2, Xi and X2 are as defined in claim 1; and L2 is a leaving group; wherein any other functional group is protected, if necessary, and: 1) eliminates any protective group; ii) optionally forming a pharmaceutically acceptable salt or a hydrolysable precursor in vivo. 10 fifteen twenty ÉM ^ Sl ^^ j? F? AiSi? Mn? Ml? ^ LSx '^^ Mírjsa ^ - ^^. «T» te tf »^ aS ^^ ¿^^ gt & ^^^^^^ & "?
MXPA/A/2001/000268A 1998-07-10 2001-01-09 N-substituted naphthalene carboxamides as neurokinin-receptor antagonists MXPA01000268A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9814886.9 1998-07-10
GB9821699.7 1998-10-07
GB9821703.7 1999-03-09
GB9909840.2 1999-04-30

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MXPA01000268A true MXPA01000268A (en) 2001-09-07

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