US008O26254B2

(12) United States Patent (10) Patent No.: US 8,026,254 B2 Chen (45) Date of Patent: Sep. 27, 2011

(54) THERAPEUTICAGENTS USEFUL FOR g: 338 St.Sh et al.i TREATING PAIN 6,576,650 B1 6, 2003 Yaksh 6,586,430 B1 7/2003 Armour et al. (75) Inventor: Zhengming Chen, Belle Mead, NJ (US) 6,608,052 B2 8/2003 Breitfelder et al. 6,703.525 B2 3/2004 Kapadia et al. (73) Assignee: Purdue Pharma, L.P., Stamford, CT 6,790,854 B2 9/2004 Tsushima et al. (US) 7,202,259 B2 * 4/2007 Chen ...... 514/326 7,557,219 B2 7/2009 Brown et al. (*) Notice: Subject to any disclaimer, the term of this 2009,024.0056 A1 9, 2009 Brown et al. patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. CA 94.9560 6, 1974 EP 1097924 5, 2001 (21) Appl. No.: 12/615,510 EP 1219294 T 2002 EP 1277737 1, 2003 1-1. EP 1325912 T 2003 (22) Filed: Nov. 10, 2009 WO WO 97.24325 7/1997 WO WO99/45O11 9, 1999 (65) Prior Publication Data WO WOOOf 39 125 T 2000 WO WOO1/39775 6, 2001 US 201O/OO69.437 A1 Mar. 18, 2010 WO WOO1,70689 A1 9, 2001 WO WOO2,381.85 5, 2002 Related U.S. Application Data (62) Division of application No. 1 1/729,660, filed on Mar. OTHER PUBLICATIONS 28, 2007, now Pat. No. 7,687,518, which is a division Ankier, “New hot plate tests to quantify antinociceptive and narcotic of application No. 10/714,066, filed on Nov. 13, 2003, antagonist activities”, Eur, J. Pharmacol. 27.1-4 (1974). now Pat. No. 7,202,259. Bernton et al., “Release of multiple hormones by a direct action of interleukin-1 on pituitary cells'. Science 238:519-521 (1987). (60) Provisional application No. 60/427,381, filed on Nov. Bristow et al., “L-745,870, a subtype selective dopamine D, receptor 18, 2002, provisional application No. 60/460,278, antagonist, does not exhibit a neuroleptic-like profile in rodent behav filed on Apr. 3, 2003, provisional application No. ioral tests”. J. Pharmacol. Exp. Ther. 283: 1256-1263 (1997). 60/488,488, filed on Jul. 17, 2003. Chen et al., “Molecular cloning and functional expression of a u-opioid receptor from rat brain' Mol. Pharmacol. 44:8-12 (1993). (51) Int. C. Cheng and Prusoff, “Relationship between the inhibition constant A6 IK3I/445 (2006.01) (K) and the concentration of inhibitor which causes 50 per cent (52) U.S. Cl...... 514/315; 514/317; 514/326 inhibition (Iso) of an enzymatic reaction'. Biochem. Pharmacol. (58) Field of Classification Search ...... 514/315, 22:3099-3108 (1973). 514/317, 326 Childers, "Opiate-inhibited adenylate cyclase in rat brain membranes See application file for complete search history. depleted of G-stimulated adenylate cyclase'. J. Neurochem. 50:543 553 (1988). D'Amour and Smith, “A method for determining loss of pain sensa (56) References Cited tion”. J. Pharmacol. Exp. Ther. 72:74-79 (1941). Duggan and North, “Electrophysiology of opioids'. Pharmacol. Rev. U.S. PATENT DOCUMENTS 35:219-281 (1983). 3,536,809 A 10/1970 AppleZweig Evans et al., "Cloning of a delta opioid receptor by functional expres 3,598,122 A 8, 1971 Zaffaroni sion”, Science 258(5090): 1952-1955 (1992). 3,598,123 A 8, 1971 Zaffaroni 3,845,770 A 11/1974 Theeuwes et al. (Continued) 3,916,899 A 11/1975 Theeuwes et al. 4,008,719 A 2f1977 Theeuwes et al. 5,059,595 A 10, 1991 Grazie 5,073,543 A 12/1991 Marshall et al. Primary Examiner — Rebecca Anderson 5, 120,548 A 6, 1992 McClelland et al. (74) Attorney, Agent, or Firm — Dechert LLP 5,354,556 A 10/1994 Sparks et al. 5,591,767 A 1/1997 Mohr et al. 5,606,037 A 2f1997 Attardo et al. (57) ABSTRACT 5,639,476 A 6, 1997 OShlack et al. 5,674,533 A 10, 1997 Santus et al. 4-Tetrazolyl-4-phenylpiperidine Compounds, compositions 5,698,155 A 12/1997 Grosswald et al. comprising an effective amount of a 4-Tetrazolyl-4-phenylpi 5,733,566 A 3, 1998 Lewis peridine Compound, methods for treating or preventing pain 5,736,523 A 4, 1998 Attardo et al. 5,849,737 A 12/1998 Chaplanet al. or diarrhea in an animal comprising administering to an ani 5,849,761 A 12, 1998 Yaksh mal in need thereof an effective amount of a 4-Tetrazolyl-4- 5,994,372 A 11, 1999 Yaksh phenylpiperidine Compound and methods for stimulating 6,136,839 A 10/2000 Isakson et al. opioid-receptor function in a cell comprising contacting a cell 6,166,039 A 12, 2000 Yaksh capable of expressing an opioid receptor with an effective 6,166,085 A 12/2000 Chaplanet al. 6,221,888 B1 4/2001 Durette et al. amount of a 4-Tetrazolyl-4-phenylpiperidine Compound are 6,358,945 B1 3, 2002 Breitfelder et al. disclosed. 6,362.203 B1 3/2002 Mogi et al. 6,423,519 B1 7/2002 Bergnes et al. 6,486,142 B2 11/2002 Leblanc et al. 18 Claims, No Drawings US 8,026,254 B2 Page 2

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Pizey, “Thionyl Chloride.” Ch. 4 in Synthetic Reagents, John Wiley & Sons, New York, vol. 1, pp. 321-357 (1974). * cited by examiner US 8,026,254 B2 1. 2 THERAPEUTICAGENTS USEFUL FOR There remains a clear need for new drugs that are useful for TREATING PAN treating or preventing pain or diarrhea and that reduce or avoid one or more side effects associated with traditional CROSS REFERENCE TO RELATED therapy for treating pain or diarrhea. APPLICATIONS Citation of any reference in Section 2 of this application is not an admission that Such reference is prior art to the present This application is a divisional of application Ser. No. application. 11/729,660, filed Mar. 28, 2007, now U.S. Pat. No. 7,687,518 B2, which is a divisional of application Ser. No. 10/714,066, 3. SUMMARY OF THE INVENTION filed Nov. 13, 2003, now U.S. Pat. No. 7,202,259 B2, which 10 claims the benefit under 35 U.S.C. S 119(e) of U.S. provi The present invention encompasses compounds having the sional application Ser. No. 60/427,381, filed Nov. 18, 2002, formula (Ia): U.S. provisional application Ser. No. 60/460,278, filed Apr. 3, 2003, and U.S. provisional application Ser. No. 60/488,488 filed Jul. 17, 2003, the contents of all of which are incorpo 15 (Ia) rated herein by reference. G / NN 1. FIELD OF THE INVENTION \ The present invention relates to 4-Tetrazolyl-4-phenylpip \ N eridine Compounds, compositions comprising an effective Air N amount of a 4-Tetrazolyl-4-phenylpiperidine Compound and iii. N methods for preventing or treating pain or diarrhea in an H(R), animal comprising administering to an animal in need of such Ar R1 (Rs), N4 treatment or prevention an effective amount of a 4-Tetrazolyl 25 4-phenylpiperidine Compound. and pharmaceutically acceptable salts thereof, wherein: 2. BACKGROUND OF THE INVENTION Ar is —C-Cs cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or -(5- to 7-membered) heteroaryl, each being Pain is the most common symptom for which patients seek 30 unsubstituted or substituted with one or more R groups: medical advice and treatment. Pain can be acute or chronic. Ar is phenyl, naphthyl, anthryl, phenanthryl or -(5- to While acute pain is usually self-limited, chronic pain can 7-membered) heteroaryl, each being unsubstituted or substi persist for 3 months or longer and lead to significant changes tuted with one or more R groups; in a patient's personality, lifestyle, functional ability or over G is —H, -L-(CH2)COR. -L-(CH2),Rs —(C-C alky all quality of life (K. M. Foley, Pain, in Cecil Textbook of 35 lene)COR, or —(C-C alkylene)Rs: Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed. L= C(O)— —SO or - SO : 1996). R= H, C(O)NH2, C(O)NHOH,-COR-CHO, Pain has been traditionally managed by administering a —CN. —(C-C alkyl), —C(O)NH(C-C alkyl). —C(O)N non-opioid analgesic, such as acetylsalicylic acid, choline (C-C alkyl). magnesium trisalicylate, acetaminophen, ibuprofen, fenopro 40 fen, diflusinal and naproxen; or an opioid analgesic, Such as morphine, hydromorphone, methadone, levorphanol, fenta O O nyl, oxycodone and oxymorphone. Id. | / \ | (CH2). U.S. Pat. No. 6,576,650 B1, U.S. Pat. No. 6,166,039, and -C-N N-R, -C-NS s U.S. Pat. No. 5,849,761, to Yaksh and U.S. Pat. No. 6,573, 45 N / (CH2) 282, to Yakshet al. describe 1.4 substituted piperidine deriva O O tives allegedly useful as peripherally active antihyperalgesic opiates. U.S. Pat. No. 6,362,203 B1 to Mogi et al. describes 4 hydroxy-4-phenylpiperidine derivatives that are alleged to 50 exhibit peripheral analgesic action. RandR are each independently-halogen, —C-C alkyl, Canadian Patent Publication No. 949560 of Carron et al. —O(C-C alkyl), NH(C-C alkyl) or—N(C-C alkyl); describes piperidine derivatives bearing substituents at the 1 R. H. —C-Co alkyl, -CHO(C-C alkyl), —CHN and 4 positions that are alleged to be useful as analgesics. (C-C alkyl), or —CH-NHCC-C alkyl); International Publication No. WO O2/38185A2 of Dunn et 55 R= NH, -NHSOR –C(O)NH –C(O)NHOH, al. describes 1,4-substituted piperidine compounds that are - SONH –C(O)NH(C-C alkyl), C(O)N(C- allegedly useful as an antihyperalgesic opiate. C alkyl). —SONHCC-C alkyl). —SON(C-C alkyl). The Abstract of International Publication No. WO —H. —OH, -CN. —C-Cs cycloalkyl, phenyl, naphthyl, 01/70689 A1 also discloses piperidine derivatives carrying anthryl, phenanthryl, or -(5- to 7-membered) heteroaryl, each Substituents at the 1 and 4 positions that are allegedly useful 60 being unsubstituted or substituted with one or more R. as opioid 8 receptoragonists. groups: Traditional opioid analgesics exert their pharmacological activity once they have passed through the blood-brain bar m an integer ranging from 0 to 4. rier. But this blood-brain barrier passage can lead to undesir in an integer ranging from 1 to 4, able central nervous system-mediated side effects, such as 65 p=0 or 1: respiratory depression, increased drug tolerance, increased qan integer ranging from 0 to 3; and drug dependence, constipation and unwanted euphoria. ran integer ranging from 1 to 6.

US 8,026,254 B2 5 6 R and R are each independently halogen, —C-C alkyl, “—C-C alkyl means a straight or branched non-cyclic —O(C-C alkyl). —NH(C-C alkyl), or—N(C-C alkyl); hydrocarbon chain having from 1 to 6 carbon atoms. Repre R. H. —C-Co alkyl, —CH2O(C-C alkyl), —CHN sentative straight chain —C-C alkyls include methyl, (C-C alkyl), or —CH2NH(C-C alkyl); -ethyl, -n-propyl, -n-butyl, -n-penty1 and -n-hexyl. Represen R= NH, -NHSOR –C(O)NH, -C(O)NHOH, tative branched chain —C-C alkyls include -isopropyl. —SONH = C(O)NH(C-C alkyl), C(O)N(C- -Sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, C alkyl). —SONHCC-C alkyl). —SON(C-C alkyl). 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethyl —H. —OH, -CN. —C-Cs cycloalkyl, phenyl, naphthyl, propyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, anthryl, phenanthryl, or -(5- to 7-membered) heteroaryl, each 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, being unsubstituted or substituted with one or more R. 10 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dim groups: ethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3.3- m an integer ranging from 0 to 4. dimethylbutyl. in an integer ranging from 1 to 4. "—(C-Co.)alkyl means a straight chain or branched non p=0 or 1; cyclic hydrocarbon having from 1 to 10 carbon atoms. Rep qan integer ranging from 0 to 3; and 15 resentative straight chain —(C-C) alkyls include methyl, ran integer ranging from 1 to 6. -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n- A compound of formula (Ia), (Ib), (Ic), (Id) or a pharma octyl, -n-nonyl, and -n-decyl. Representative branched ceutically acceptable salt thereof (each being a "4-Tetrazolyl —(C-Co) alkyls include isopropyl, sec-butyl, isobutyl, 4-phenylpiperidine Compound') is useful for treating or pre -tert-butyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbu venting pain or diarrhea in an animal. tyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, The invention also relates to compositions comprising an 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methyl effective amount of a 4-Tetrazolyl-4-phenylpiperidine Com pentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimeth pound and a pharmaceutically acceptable carrier or excipient. ylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethyl The present compositions are useful for treating or preventing butyl, 2,3-dimethylbutyl, 3.3-dimethylbutyl, 1-methylhexyl, pain or diarrhea in an animal. 25 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl The invention also relates to kits comprising a container hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimeth containing an effective amount of a 4-Tetrazolyl-4-phenylpi ylhexyl, 1,3-dimethylhexyl, 3.3-dimethylhexyl, 1,2-dimeth peridine Compound and instructions for using it to treat or ylheptyl, 1,3-dimethylheptyl, and 3.3-dimethylheptyl. prevent pain or diarrhea. “—C-C alkylene' means a straight chain or branched, The invention further relates to methods for preventing 30 non-cyclic, divalent hydrocarbon having from 1 to 5 carbon pain or diarrhea in an animal, comprising administering to an atoms. Representative straight chain —C-C alkylene animal in need thereof an effective amount of a 4-Tetrazolyl groups are —CH2—, -(CH2). , —(CH2). , —(CH) 4-phenylpiperidine Compound. and —(CH)—. Representative branched —C-Cs alkylene The invention further relates to methods for treating pain or groups include —CH(CH)—, —C(CH)— —CH(CH) diarrhea in an animal, comprising administering to an animal 35 CH , —CHCH(CH) , —CHC(CH) , in need thereof an effective amount of a 4-Tetrazolyl-4-phe —C(CH)2CH2—, —CH(CH)CH(CH)— —CHC nylpiperidine Compound. (CH3)2CH2—, —(CH2)C(CH) , —(CH)(CH2)C- The invention still further relates to methods for stimulat and -CH(CH)CHCH(CH)–. ing opioid-receptor function in a cell, comprising contacting “—C-Cs cycloalkyl means a saturated cyclic hydrocar a cell capable of expressing an opioid receptor with an effec 40 bonhaving from 3 to 8 carbonatoms. Representative—C-Cs tive amount of a 4-Tetrazolyl-4-phenylpiperidine Compound. cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cy The invention still further relates to methods for preparing clohexyl, -cycloheptyl and -cyclooctyl. a pharmaceutical composition, comprising the step of admix "-(5- to 7-membered)heteroaryl' means an aromatic het ing a 4-Tetrazolyl-4-phenylpiperidine Compound and a phar erocycle ring of 5 to 7 members, wherein at least one carbon maceutically acceptable carrier or excipient. 45 atom of the ring is replaced with a heteroatom independently The present invention may be understood more fully by selected from nitrogen, oxygen, and Sulfur. The -(5- to reference to the following detailed description and illustrative 7-membered)heteroaryl's ring contains at least one carbon examples, which are intended to exemplify non-limiting atom. Representative -(5- to 7-membered)heteroaryls include embodiments of the invention. pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, 50 thiazolyl, isoxazolyl pyrazolyl, isothiazolyl pyridazinyl, 4. DETAILED DESCRIPTION OF THE pyrimidinyl, pyrazinyl, thiadiazolyl, and triazinyl. INVENTION “-Halogen' means —F. —Cl. —Br, or —I. The term “animal, includes, but is not limited to, a cow, 4.1 Definitions ape, monkey, chimpanzee, baboon, horse, sheep, pig, 55 chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig As used herein, the terms used above having following and human. meaning: The phrase “pharmaceutically acceptable salt, as used '—C-C alkyl means a straight or branched non cyclic herein, is a salt formed from an acid and the basic nitrogen hydrocarbon chain having from 1 to 3 carbon atoms. Repre group of a 4-Tetrazolyl-4-phenylpiperidine Compound. Illus sentative straight chain and branched chain —C-C alkyls 60 trative salts include, but are not limited, to sulfate, citrate, include -methyl, -ethyl, -n-propyl and isopropyl. acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, '—C-C alkyl means a straight or branched non-cyclic phosphate, acid phosphate, isonicotinate, lactate, Salicylate, hydrocarbon chain having from 1 to 4 carbon atoms. Repre acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, sentative straight chain —C-C alkyls include methyl, ascorbate. Succinate, maleate, gentisinate, fumarate, glucon -ethyl, -n-propyl, and -n-butyl. Representative branched 65 ate, glucaronate, saccharate, formate, benzoate, glutamate, chain —C-C alkyls include -isopropyl, -sec-butyl, -isobu methanesulfonate, ethanesulfonate, benzenesulfonate, tyl, and -tert-butyl. p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2- US 8,026,254 B2 7 8 hydroxy-3-naphthoate)) salts. The term “pharmaceutically In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine acceptable salt also refers to a salt of a 4-Tetrazolyl-4-phe Compounds of formula (Ia) are those wherein G is —H. nylpiperidine Compound having an acidic functional group, In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Such as a carboxylic acid functional group, and a pharmaceu dine Compounds of formula (Ia) are those wherein G is -L- tically acceptable inorganic or organic base. Illustrative bases (CH2)COR. include, but are not limited to, hydroxides of alkali metals In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Such as Sodium, potassium and lithium; hydroxides of alka dine Compounds of formula (Ia) are those wherein G is -L- line earth metal Such as calcium and magnesium; hydroxides (CH),CO.R and L= C(O)—. of other metals, such as aluminum and Zinc, ammonia; and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi organic amines, such as unsubstituted or hydroxy Substituted 10 dine Compounds of formula (Ia) are those wherein G is -L- mono-, di-, or trialkylamines; dicyclohexylamine; tributy (CH),CO.R and L= SO or - SO . lamine:pyridine; N-methyl-N-ethylamine; diethylamine; tri In another embodiment, the 4-Tetrazolyl-4-phenylpiperi ethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl dine Compounds of formula (Ia) are those wherein G is -L- amines). Such as mono-bis- or tris-(2-hydroxyethyl)amine, (CH2)COR and R=H. 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methy 15 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi lamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, dine Compounds of formula (Ia) are those wherein G is -L- such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2- (CH2)COR and R —C-C alkyl. hydroxyethyl)amine; N-methyl-D-glucamine; and amino In another embodiment, the 4-Tetrazolyl-4-phenylpiperi acids such as arginine, lysine, and the like. dine Compounds of formula (Ia) are those wherein G is -L- The terms “treatment of and “treating pain or diarrhea (CH2)COR and R —CHO(C-C alkyl). include the lessening of the severity of or cessation of pain or In another embodiment, the 4-Tetrazolyl-4-phenylpiperi diarrhea. In one embodiment, “treating or “treatment of dine Compounds of formula (Ia) are those wherein G is -L- includes inhibiting, for example decreasing, the overall fre (CH),CO.R and R= -CHNHC-C alkyl) or —CHN quency of episodes of pain or diarrhea. 25 (C-C alkyl). The terms “prevention of and “preventing pain or diar In another embodiment, the 4-Tetrazolyl-4-phenylpiperi rhea include the avoidance of the onset of pain or diarrhea. dine Compounds of formula (Ia) are those wherein G= (C- The phrase “opioid receptor” means a 6-opioid receptor, a Cs alkylene)COOR. K-opioid receptor, a u-opioid receptor or an ORL-1 receptor. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi The phrase “effective amount” when used in connection 30 dine Compounds of formula (Ia) are those wherein with a 4-Tetrazolyl-4-phenylpiperidine Compound means an G= CH-COOR. amount of the 4-Tetrazolyl-4-phenylpiperidine Compound In another embodiment, the 4-Tetrazolyl-4-phenylpiperi that is useful for treating or preventing pain or diarrhea in an dine Compounds of formula (Ia) are those wherein G= animal or stimulating opioid-receptor function in a cell. (CH) COOR. The phrase “effective amount” when used in connection 35 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi with another therapeutic agent means an amount for provid ing the therapeutic effect of that therapeutic agent. dine Compounds of formula (Ia) are those wherein G= When a first group is “substituted with one or more second (CH) COOR. groups, each of one or more of the first group's hydrogen In another embodiment, the 4-Tetrazolyl-4-phenylpiperi atoms is replaced with a second group. 40 dine Compounds of formula (Ia) are those wherein G= In one embodiment, a first group is substituted with up to (CH) COOR. three second groups. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, a first group is substituted with one dine Compounds of formula (Ia) are those wherein G= or two second group. (CH) COOR. In another embodiment, a first group is substituted with 45 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi only one second group. dine Compounds of formula (Ia) are those wherein G is -L- (CH),Rs and Rs NHSO.R. 4.2 The 4-Tetrazolyl-4-phenylpiperidine Compounds In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G is -L- As stated above, the present invention encompasses 4-Tet 50 (CH),Rs and Rs= C(O)NH2, C(O)NHOH, -C(O)NH razolyl-4-phenylpiperidine Compounds having the formula (C-C alkyl), or—C(O)N(C-C alkyl). (Ia): In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G is -L- (CH),Rs and Rs SONH, -SONHC-C alkyl), or (Ia) 55 —SON(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G is -L- (CH),Rs and Rs = NHSOH. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 60 dine Compounds of formula (Ia) are those wherein G is -L- (CH),Rs and L. C(O)—. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (R3) dine Compounds of formula (Ia) are those wherein G is -L- (CH2)Rs and L SO - or —SO—. and pharmaceutically acceptable salts thereof, 65 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi wherein Art, Ar., R-R, G, m, p and q are as defined dine Compounds of formula (Ia) are those wherein G= (C- above. Cs alkylene)Rs. US 8,026,254 B2 9 10 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein dine Compounds of formula (Ia) are those wherein p=1, R is G= CH Rs. —CH, and the carbon atom to which R is attached is in the In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (R) configuration. dine Compounds of formula (Ia) are those wherein G= 5 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (CH) Rs. dine Compounds of formula (Ia) are those wherein p=1, R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —C-C alkyl, and the carbon atom to which R is attached is dine Compounds of formula (Ia) are those wherein G= in the (S) configuration. (CH) Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 10 dine Compounds of formula (Ia) are those wherein p=1, and dine Compounds of formula (Ia) are those wherein G= R is —CH, and the carbonatom to which R is attached is in (CH) Rs. the (S) configuration. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G= 15 dine Compounds of formula (Ia) are those wherein q=0. (CH2)5 Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein m=0. dine Compounds of formula (Ia) are those wherein G= (C- In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Calkylene)Rs and R= C(O)NH2, C(O)NHOH, -C(O) dine Compounds of formula (Ia) are those wherein m=1. NH(C-C alkyl), or—C(O)N(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein m=0, and dine Compounds of formula (Ia) are those wherein p=0. G= CH-Rs and Rs= C(O)NH2, C(O)NHOH, In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —C(O)NH(C-C alkyl), or—C(O)N(C-C alkyl). dine Compounds of formula (Ia) are those wherein m=1 and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 25 p=0. dine Compounds of formula (Ia) are those wherein In another embodiment, the 4-Tetrazolyl-4-phenylpiperi G= CHC(O)N(CH). dine Compounds of formula (Ia) are those wherein m=0, and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi q=0. dine Compounds of formula (Ia) are those wherein G= In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 30 dine Compounds of formula (Ia) are those wherein m=1 and (CH) Rs and R= C(O)NH2, C(O)NHOH, -C(O) q=0. NH(C-C alkyl), or —C(O)N(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein m=0, p=0 dine Compounds of formula (Ia) are those wherein G= and q=0. (CH) Rs and R= C(O)NH2, C(O)NHOH, -C(O) 35 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi NH(C-C alkyl), or —C(O)N(C-C alkyl). dine Compounds of formula (Ia) are those wherein m=1, p=0 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi and q=0. dine Compounds of formula (Ia) are those wherein G= In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (CH), R and R = C(O)NH, C(O)NHOH, -C(O) dine Compounds of formula (Ia) are those wherein R is—Br. NH(C-C alkyl), or—C(O)N(C-C alkyl). 40 —Cl, —I, or —F. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G= dine Compounds of formula (Ia) are those wherein R is (CH) Rs and R= C(O)NH2, C(O)NHOH, -C(O) —O(C-C alkyl). NH(C-C alkyl), or—C(O)N(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 45 dine Compounds of formula (Ia) are those wherein R is dine Compounds of formula (Ia) are those wherein p=0. —C-C alkyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein p=1. dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —NH(C-C alkyl) or - N(C-C alkyl). dine Compounds of formula (Ia) are those wherein p=1 and 50 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi the carbonatom to which R is attached is in the (R)-configu dine Compounds of formula (Ia) are those wherein R is—Br. —Cl, —I, or —F. ration. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein R is dine Compounds of formula (Ia) are those wherein p=1 and 55 —O(C-C alkyl). the carbon atom to which R is attached is in the (S)-configu In another embodiment, the 4-Tetrazolyl-4-phenylpiperi ration. dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —C-C alkyl. dine Compounds of formula (Ia) are those wherein p=1 and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi R is —C-C alkyl. 60 dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —NH(C-C alkyl), or N(C-C alkyl). dine Compounds of formula (Ia) are those wherein p=1 and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi R is —CH. dine Compounds of formula (Ia) are those wherein R is H. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein p=1, R is 65 dine Compounds of formula (Ia) are those wherein R is —C-C alkyl, and the carbonatom to which R is attached is - C(O)NH, C(O)NHOH, -C(O)NH(C-C alkyl), or in the (R) configuration. —C(O)N(C-C alkyl). US 8,026,254 B2 11 12 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein R is dine Compounds of formula (Ia) are those wherein Ar is —C(O)N(CH). cyclohexyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein R is dine Compounds of formula (Ia) are those wherein Ar is —C(O)N(CHCH). cyclohexyl and Ar is phenyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein R is dine Compounds of formula (Ia) are those wherein G-H, and C(O)NHCH. p=0. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 10 dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi -C(O)NH(CHCH). dine Compounds of formula (Ia) are those wherein G-H, and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi q=0. dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —COOR. 15 dine Compounds of formula (Ia) are those wherein G-H, and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi m=0. dine Compounds of formula (Ia) are those wherein R is In another embodiment, the 4-Tetrazolyl-4-phenylpiperi CHO. dine Compounds of formula (Ia) are those wherein G-H, and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi m=1. dine Compounds of formula (Ia) are those wherein R is CN. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G-H, and dine Compounds of formula (Ia) are those wherein R is Ar and Arare phenyl. —(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 25 dine Compounds of formula (Ia) are those wherein G=H, p=0. dine Compounds of formula (Ia) are those wherein R is and q=0. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G=H, p=0. O and m=0. | / \ O 30 -C-N N-R (CH2)r, In another embodiment, the 4-Tetrazolyl-4-phenylpiperi V / -C-NS dine Compounds of formula (Ia) are those wherein G-H. p-0. (CH2) and m=1. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 35 dine Compounds of formula (Ia) are those wherein G=H, p=0. O O and Ari and Ara are phenyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G=H, p=0. q=0, and m=0. 40 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein G=H, p=0. q=0, and m=1. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein Ar is 45 dine Compounds of formula (Ia) are those wherein G=H, p=0. —C-Cs cycloalkyl. q-0, and Ari and Ara are phenyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein Ar is dine Compounds of formula (Ia) are those wherein G=H, p=0. phenyl, naphthyl, anthryl, or phenanthryl. q-0, m=0, and Ari and Arare phenyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 50 dine Compounds of formula (Ia) are those wherein Aris-(5- In another embodiment, the 4-Tetrazolyl-4-phenylpiperi to 7-membered) heteroaryl. dine Compounds of formula (Ia) are those wherein G=H, p=0. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi q-0, m=1, and Ari and Arare phenyl. dine Compounds of formula (Ia) are those wherein Ar is Illustrative 4-Tetrazolyl-4-phenylpiperidine Compounds Substituted with one or more R groups. 55 of formula (Ia) have the following structure: In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein Ara is phenyl, naphthyl, anthryl, or phenanthryl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein Aris-(5- 60 to 7-membered) heteroaryl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ia) are those wherein Ar is ( ) N Substituted with one or more. R groups. R In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 65 dine Compounds of formula (Ia) are those wherein Ari and Ara are phenyl. are pharmaceutically acceptable salts thereof, US 8,026,254 B2 13 14 wherein G and R. are as follows:

Compound No.: G:

ACH

ACJ ACK ACL ACM ACN ACO ACP ACQ ACR ACS ACT ACU ACV ACW ACX US 8,026,254 B2 15 16 -continued

Compound No.: G: ACY ACZ.

D

- CN s

AEE A.

N

C

&

US 8,026,254 B2 27 28 -continued

Compound No.: G: AIP -- O \ / AIQ -- O \ / AIR —CH2SON(CH) -- O \ / AIS

AIT

AIU AIV - C(O)NH2. AIW —COCH AIX - CHO AIY - CN

AIZ AJA AJB

AJC

AD

AJE

AF

The present invention further encompasses compounds and pharmaceutically acceptable salts thereof, wherein Art, having the formula (Ib) Ar, R-R. G. m. p and q are as defined above. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 55 Compounds of formula (Ib) are those wherein G is H. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine (Ib) Compounds of formula (Ib) are those wherein G=-L(CH2)C (O)OR. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 60 Compounds of formula (Ib) are those wherein G=-L(CH2)C (O)OR and L= C(O)—. Ar y -N In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=-L(CH2)C Ar R (R3) (O)OR and L= SO or —SO—. 65 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=-L(CH2)C (O)OR and R=H. US 8,026,254 B2 29 30 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=-L(CH),C Compounds of formula (Ib) are those wherein p=0. (O)OR and R —C-Co alkyl. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Ib) are those wherein p=1. Compounds of formula (Ib) are those wherein G=-L(CH),C In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (O)OR and R= -CHO(C-C alkyl). dine Compounds of formula (Ib) are those wherein p=1 and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine the carbonatom to which R is attached is in the (R)-configu Compounds of formula (Ib) are those wherein G=-L(CH),C ration. (O)OR and R —CH-NH(C-C alkyl) or —CHN(C-C, In another embodiment, the 4-Tetrazolyl-4-phenylpiperi alkyl). 10 dine Compounds of formula (Ib) are those wherein p=1 and In another embodiment, the 4-Tetrazolyl-4-phenylpiperi the carbon atom to which R is attached is in the (S)-configu dine Compounds of formula (Ib) are those wherein G= (C- ration. Cs alkylene)Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 15 dine Compounds of formula (Ib) are those wherein p=1 and dine Compounds of formula (Ib) are those wherein R is —C-C alkyl. G= CH Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ib) are those wherein p=1 and dine Compounds of formula (Ib) are those wherein G= R is —CH. (CH) Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ib) are those wherein p=1, R is dine Compounds of formula (Ib) are those wherein G= —C-C alkyl, and the carbon atom to which R is attached is (CH) Rs. in the (R) configuration. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In another embodiment, the 4-Tetrazolyl-4-phenylpiperi dine Compounds of formula (Ib) are those wherein G= 25 dine Compounds of formula (Ib) are those wherein p=1, R is (CH) Rs. —CH, and the carbon atom to which R is attached is in the In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (R) configuration. dine Compounds of formula (Ib) are those wherein G= In another embodiment, the 4-Tetrazolyl-4-phenylpiperi (CH2)5 Rs. dine Compounds of formula (Ib) are those wherein p=1, R is In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 30 —C-C alkyl, and the carbon atom to which R is attached is Compounds of formula (Ib) are those wherein G= (C-Cs in the (S) configuration. alkylene)COOR. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Ib) are those wherein p=1, R is Compounds of formula (Ib) are those wherein G= CH —CH, and the carbon atom to which R is attached is in the COOR. 35 (S) configuration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G= Compounds of formula (Ib) are those wherein q=0. —(CH) COOR. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein m=0. Compounds of formula (Ib) are those wherein G= 40 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) COOR. Compounds of formula (Ib) are those wherein m=1. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G= Compounds of formula (Ib) are those wherein m=0, and p=0. —(CH) COOR. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 45 Compounds of formula (Ib) are those wherein m=1 and p=0. Compounds of formula (Ib) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) COOR. Compounds of formula (Ib) are those wherein m=0, and q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G is Compounds of formula (Ib) are those wherein m=1 and q=0. -L-(CH),Rs and Rs NHSOR. 50 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein m=0, p=0 and Compounds of formula (Ib) are those wherein G is -L-(CH2) q=0. Rs and R= C(O)NH2, C(O)NHOH, -C(O)NH(C-C, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine alkyl), or —C(O)N(C-C alkyl). Compounds of formula (Ib) are those wherein m=1, p=0 and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 55 q=0. Compounds of formula (Ib) are those wherein G is In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),Rs and Rs= SONH, -SONHCC-C alkyl), or Compounds of formula (Ib) are those wherein R is —Br. —SON(C-C alkyl). —Cl, —I, or —F. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G is -L-(CH2) 60 Compounds of formula (Ib) are those wherein R is —O(C- R and R = NHSOH. Calkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G is Compounds of formula (Ib) are those wherein R is —C-C, -L-(CH2)Rs and L. C(O)—. alkyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 65 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G is -L-(CH2) Compounds of formula (Ib) are those wherein R is NH Rs and L= SO or —SO . (C-C alkyl) or —N(C-C alkyl). US 8,026,254 B2 31 32 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein R is —Br. Compounds of formula (Ib) are those wherein Ar is -(5- to —Cl, —I, or —F. 7-membered) heteroaryl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of (Ib) are those wherein R is —O(C-C alkyl). 5 Compounds of formula (Ib) are those wherein Ar is substi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine tuted with one or more R groups. Compounds of formula (Ib) are those wherein R is —C-C, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine alkyl. Compounds of formula (Ib) are those wherein Art and Arare In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine phenyl. Compounds of formula (Ib) are those wherein R is NH 10 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein A is cyclo (C-C alkyl) or —N(C-C alkyl). hexyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein R is H. Compounds of formula (Ib) are those wherein Ar is cyclo In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine hexyl and Ar is phenyl. Compounds of formula (Ib) are those wherein R is C(O) 15 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine NH = C(O)NHOH, -C(O)NH(C-C alkyl), or - C(O)N Compounds of formula (Ib) are those wherein G-H, and p=0. (C-C alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G-H, and q=0. Compounds of formula (Ib) are those wherein R is C(O) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine N(CH). Compounds of formula (Ib) are those wherein G-H, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine m=0. Compounds of formula (Ib) are those wherein R is C(O) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine N(CHCH). Compounds of formula (Ib) are those wherein G-H, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine m=1. Compounds of formula (Ib) are those wherein R is —C(O) 25 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine NHCH, Compounds of formula (Ib) are those wherein G=H, and Art In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine and Arare phenyl. Compounds of formula (Ib) are those wherein R is C(O) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine NH(CHCH). Compounds of formula (Ib) are those wherein G=H, p=0, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine q=0. 30 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein R is Compounds of formula (Ib) are those wherein G=H, p=0, and —COOR. m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein R is —CHO. Compounds of formula (Ib) are those wherein G=H, p=0, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 35 m=1. Compounds of formula (Ib) are those wherein R is —CN. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=H, p=0, and Compounds of formula (Ib) are those wherein R is —(C-C, Ar and Arare phenyl. alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 40 Compounds of formula (Ib) are those wherein G=H, p=0. Compounds of formula (Ib) are those wherein R is q=0, and m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine O Compounds of formula (Ib) are those wherein G=H, p=0. | / \ O q=0, and m=1. -C-N N-R (CH2)r, 45 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine V / -C-NS Compounds of formula (Ib) are those wherein G=H, p=0. (CH2) q-0, and Ari and Ara are phenyl. O O In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=H, p=0. 50 q 0, m=0, and Art and Ar, are phenyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein G=H, p=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine q-0, m=1, and Ari and Arare phenyl. Compounds of formula (Ib) are those wherein Aris—C-Cs Illustrative 4-Tetrazolyl-4-phenylpiperidine Compounds cycloalkyl. 55 of formula (Ib) have the following structure: In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein Ar is phenyl, naphthyl, anthryl, or phenanthryl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein Ar is -(5- to 60 7-membered) heteroaryl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ib) are those wherein Ar is substi tuted with one or more R groups. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 65 Compounds of formula (Ib) are those wherein Ar is phenyl, naphthyl, anthryl, or phenanthryl. and pharmaceutically acceptable salts thereof, US 8,026,254 B2 33 34 wherein G and R are as follows:

US 8,026,254 B2 49 50 The present invention further encompasses compounds In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine having the formula (Ic): Compounds of formula (Ic) are those wherein G= —(CH) COOR. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine (Ic) 5 Compounds of formula (Ic) are those wherein G= —(CH) COOR. -N In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine N f Compounds of formula (Ic) are those wherein G= \ N —(CH) COOR. 10 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Arg ( iii. N N Compounds of formula (Ic) are those wherein G= H(R), —(CH) COOR. H. R. (R3) 2 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 15 Compounds of formula (Ic) are those wherein G= -L-(CH),Rs and Rs NHSOR. and pharmaceutically acceptable salts thereof, wherein Ars, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine R-R, G, m, p and q are as defined above. Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),Rs and R= C(O)NH –C(O)NHOH, -C(O) Compounds of formula (Ic) are those wherein G is H. NH(C-C alkyl), or—C(O)N(C-C alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein G= Compounds of formula (Ic) are those wherein G= -L-(CH),C(O)OR. -L-(CH),Rs and Rs.--SONH, —SONHCC-C alkyl), or In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —SON(C-C alkyl). Compounds of formula (Ic) are those wherein G= 25 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),C(O)OR and L= C(O)—. Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),Rs and Rs NHSOH. Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),C(O)OR and L= SO or - SO . Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 30 -L-(CH2)Rs and L. C(O)—. Compounds of formula (Ic) are those wherein G= (C-Cs In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine alkylene)Rs. Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH2)Rs and L SO - or —SO—. Compounds of formula (Ic) are those wherein G= CH In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Rs. 35 Compounds of formula (Ic) are those wherein G=(C-C, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine alkylene)Rs. Compounds of formula (Ic) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) Rs. Compounds of formula (Ic) are those wherein p=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 40 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Ic) are those wherein G= dine Compounds of formula (Ic) are those wherein p=1. —(CH) Rs. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Ic) are those wherein p=1 and Compounds of formula (Ic) are those wherein G= the carbonatom to which R is attached is in the (R)-configu —(CH) Rs. 45 ration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Ic) are those wherein G= dine Compounds of formula (Ic) are those wherein p=1 and —(CH2)5 Rs. the carbon atom to which R is attached is in the (S)-configu In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine ration. Compounds of formula (Ic) are those wherein G= 50 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi -L-(CH),C(O)OR and R=H. dine Compounds of formula (Ic) are those wherein p=1 and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine R is —C-C alkyl. Compounds of formula (Ic) are those wherein G= In another embodiment, the 4-Tetrazolyl-4-phenylpiperi -L-(CH),C(O)OR and R. CHC alkyl. dine Compounds of formula (Ic) are those wherein p=1 and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 55 R is —CH. Compounds of formula (Ic) are those wherein G= In another embodiment, the 4-Tetrazolyl-4-phenylpiperi -L-(CH),C(O)OR and R= -CHO(C-C alkyl). dine Compounds of formula (Ic) are those wherein p=1, R is In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —C-C alkyl, and the carbon atom to which R is attached is Compounds of formula (Ic) are those wherein G= in the (R) configuration. -L-(CH),C(O)OR and R —CH-NH(C-C alkyl) or 60 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi —CHN(C-C alkyl). dine Compounds of formula (Ic) are those wherein p=1, R is In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —CH, and the carbon atom to which R is attached is in the Compounds of formula (Ic) are those wherein G= (C-C, (R) configuration. alkylene)COOR. In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 65 dine Compounds of formula (Ic) are those wherein p=1, R is Compounds of formula (Ic) are those wherein G= CH —C-C alkyl, and the carbon atom to which R is attached is COOR. in the (S) configuration. US 8,026,254 B2 51 52 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Ic) are those wherein p=1, R is Compounds of formula (Ic) are those wherein R is —CH, and the carbon atom to which R is attached is in the - COOR. (S) configuration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —CHO. Compounds of formula (Ic) are those wherein q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —CN. Compounds of formula (Ic) are those wherein m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —(C-C, 10 alkyl). Compounds of formula (Ic) are those wherein m=1. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is Compounds of formula (Ic) are those wherein m=0, and p=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein m=1 and p=0. O In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 15 | / V O -C-N N-R (CH2), Compounds of formula (Ic) are those wherein m=0, and q=0. V / -C-NC In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine (CH2) Compounds of formula (Ic) are those wherein m=1 and q=0. O O In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein m=0, p=0 and q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein m=1, p=0 and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine q=0. 25 Compounds of formula (Ic) are those wherein Ars is phenyl, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine naphthyl, anthryl, or phenanthryl. Compounds of formula (Ic) are those wherein R is —Br. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —Cl, —I, or —F. Compounds of formula (Ic) are those wherein Ars is -(5- to In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 7-membered) heteroaryl. Compounds of formula (Ic) are those wherein R is —O(C- 30 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine C. alkyl). Compounds of formula (Ic) are those wherein Ars is substi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine tuted with one or more R groups. Compounds of formula (Ic) are those wherein R is —C-C, In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine alkyl. Compounds of formula (Ic) are those wherein G-H, and p=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 35 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is NH Compounds of formula (Ic) are those wherein G-H, and q=0. (C-C alkyl) or —N(C-C alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein G-H, and m=0. Compounds of formula (Ic) are those wherein R is —Br. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —Cl, —I, or —F. 40 Compounds of formula (Ic) are those wherein G-H, and m=1. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —O(C- Compounds of formula (Ic) are those wherein G-H, and Ars C. alkyl). is phenyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —C-C, 45 Compounds of formula (Ic) are those wherein G=H, p=0, and alkyl. q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is NH Compounds of formula (Ic) are those wherein G=H, p=0, and (C-C alkyl) or —N(C-C alkyl). m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 50 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is H. Compounds of formula (Ic) are those wherein G=H, p=0, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine m=1. Compounds of formula (Ic) are those wherein R is C(O) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine NH, C(O)NHOH, -C(O)NH(C-C alkyl), or - C(O)N Compounds of formula (Ic) are those wherein G=H, p=0, and (C-C alkyl). 55 Ars is phenyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is C(O) Compounds of formula (Ic) are those wherein G=H, p=0. N(CH). q=0, and m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is C(O) 60 Compounds of formula (Ic) are those wherein G=H, p=0. N(CHCH). q=0, and m=1. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is —C(O) Compounds of formula (Ic) are those wherein G=H, p=0. NHCH, q-0, and Ars is phenyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 65 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Ic) are those wherein R is C(O) Compounds of formula (Ic) are those wherein G=H, p=0. NHCHCH q-0, m=0, and Ars is phenyl.

US 8,026,254 B2 62 -continued In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G= Com pound —(CH) COOR. No.: G: R: In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G= CJD -(CH)NHSOH —(CH) COOR. -C-N ) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G= —(CH) COOR. CJE -(CH)NHSOH O 10 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine s -C-N Compounds of formula (Id) are those wherein G is e -L-(CH),Rs and Rs NHSOR. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine CJF —(CH2)NHSOH O 15 Compounds of formula (Id) are those wherein G is -L-(CH),Rs and R= C(O)NH –C(O)NHOH, -C(O) NH(C-C alkyl), or—C(O)N(C-C alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G is The present invention further encompasses compounds -L-(CH),Rs and Rs= SONH, -SONHC-C alkyl), or having the formula (Id) —SON(C-C alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G is (Id) -L-(CH),Rs and Rs NHSOH. 25 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G is -L-(CH2)Rs and L. C(O)— In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G is 30 -L-(CH2)Rs and L SO - or —SO—. (R3) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G= (C-C, and pharmaceutically acceptable salts thereof, wherein Ars, alkylene)Rs. R-R G. m. p. and q are as defined above. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 35 Compounds of formula (Id) are those wherein G= CH Compounds of formula (Id) are those wherein G is H. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Rs. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),C(O)OR. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 40 —(CH) Rs. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),C(O)OR and L= C(O)—. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) Rs. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH),C(O)OR and L= SO or —SO—. 45 Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) Rs. Compounds of formula (Id) are those wherein G=-L-(CH)— In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine C(O)OR and R=H. Compounds of formula (Id) are those wherein G= In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —(CH) Rs. Compounds of formula (Id) are those wherein G= 50 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine -L-(CH2)C(O)OR and Ra C-Co alkyl. Compounds of formula (Id) are those wherein p=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Id) are those wherein G=-L-(CH)— dine Compounds of formula (Id) are those wherein p=1. C(O)CR and R= -CHO(C-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 55 dine Compounds of formula (Id) are those wherein p=1 and Compounds of formula (Id) are those wherein G= the carbon atom to which R is attached is in the (R)-configu -L-(CH),C(O)OR and R —CH-NH(C-C alkyl) or ration. —CH2NCC-C alkyl). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Id) are those wherein p=1 and Compounds of formula (Id) are those wherein G= (C-Cs 60 the carbon atom to which R is attached is in the (S)-configu alkylene)COOR. ration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Id) are those wherein G= CH dine Compounds of formula (Id) are those wherein p=1 and COOR. R is —C-C alkyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 65 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Id) are those wherein G= dine Compounds of formula (Id) are those wherein p=1 and —(CH) COOR. R is —CH. US 8,026,254 B2 63 64 In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Id) are those wherein p=1, R is Compounds of formula (Id) are those wherein R is —C(O) —C-C alkyl, and the carbonatom to which R is attached is N(CH). in the (R) configuration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds of formula (Id) are those wherein R is —C(O) dine Compounds of formula (Id) are those wherein p=1, R is NHCH —CH, and the carbon atom to which R is attached is in the In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine (R) configuration. Compounds of formula (Id) are those wherein R is —C(O) In another embodiment, the 4-Tetrazolyl-4-phenylpiperi NHCHCH. dine Compounds of formula (Id) are those wherein p=1, R is 10 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine —C-C alkyl, and the carbonatom to which R is attached is Compounds of formula (Id) are those wherein R is —C(O) in the (S) configuration. N(CHCH). In another embodiment, the 4-Tetrazolyl-4-phenylpiperi In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine dine Compounds of formula (Id) are those wherein p=1, R is 15 Compounds of formula (Id) are those wherein R is —CH, and the carbon atom to which R is attached is in the - COOR. (S) configuration. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —CHO. Compounds of formula (Id) are those wherein q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —CN. Compounds of formula (Id) are those wherein m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —(C-C, Compounds of formula (Id) are those wherein m=1. alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein m=0, and p=0. 25 Compounds of formula (Id) are those wherein R is In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein m=1 and p=0. O In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine | / \ O Compounds of formula (Id) are those wherein m=0, and q=0. -C-N N-R | -(CH2). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 30 V / -C-NC Compounds of formula (Id) are those wherein m=1 and q=0. (CH2) In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine O O Compounds of formula (Id) are those wherein m=0, p=0 and q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 35 Compounds of formula (Id) are those wherein m=1, p=0 and q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein Ars is phenyl, Compounds of formula (Id) are those wherein R is —Br. naphthyl, anthryl, or phenanthryl. —Cl, —I, or —F. 40 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein Ars is -(5- to Compounds of formula (Id) are those wherein R is —O(C- 7-membered) heteroaryl. C. alkyl). In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein Ars is substi Compounds of formula (Id) are those wherein R is —C-C, 45 tuted with one or more R groups. alkyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein G-H, and p=0. Compounds of formula (Id) are those wherein R is NH In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine (C-C alkyl) or —N(C-C alkyl). Compounds of formula (Id) are those wherein G-H, and q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine 50 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —Br. Compounds of formula (Id) are those wherein G-H, and —Cl, —I, or —F. m=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —O(C- Compounds of formula (Id) are those wherein G-H, and C. alkyl). 55 m=1. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is —C-C, Compounds of formula (Id) are those wherein G=H, and Ar alkyl. is phenyl. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is NH 60 Compounds of formula (Id) are those wherein G=H, p=0, and (C-C alkyl) or —N(C-C alkyl). q=0. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of formula (Id) are those wherein R is H. Compounds of formula (Id) are those wherein G=H, p=0, and In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine m=0. Compounds of formula (Id) are those wherein R is C(O) 65 In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine NH = C(O)NHOH, -C(O)NH(C-C alkyl), or - C(O)N Compounds of formula (Id) are those wherein G=H, p=0, and (C-C alkyl). m=1.

US 8,026,254 B2

-continued Scheme 1 Com pound 1. Br SOCl. No.: G: R: HOC-W-(CH), --- 5 1 1 Br ZNH DIT -(CH2)NHSOCH / \ CI-C(O)-W-(CH), He Na2CO3 -C-N O 2

10 \NS O Br 4 DIU -(CH2)NHSOH —H DIV -(CH2)NHSOH - C(O)NH2. 71 s Na2CO3/DMF DIW -(CH2)NHSOH —CO2CH W m DIX –(CH)NHSOH - CHO DIY -(CH2)NHSOH - CN 3 DIZ -(CH2)NHSOH —CH 15 CN MeSnN DJA —(CH2)NHSOH - C(O)NHCH N --- DJB -(CH)NHSOH —C(O)N(CH), ZN-C(O)-W-(CH2)^ | N Xylenes r DJC -(CH2)NHSOH / \ (R3) e ( R2)a -C-N N-CH

DJD -(CH2)NHSOH -C-N y 25

DJE -(CH2)NHSOH s

le 30

-C-N O

35

4.3 Methods for Making the 4-Tetrazolyl 4 Phenylpiperidine Compounds

The 4-Tetrazolyl-4-phenylpiperidine Compounds of the 40 present invention can be made using conventional organic syntheses and by the following illustrative methods: Scheme 1 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —C(O)NZ, where each Z is a —(C-C alkyl) group or both Zgroups and the 45 nitrogenatom to which they are attached are taken together to form N-(4-R) N'-1-piperazinyl, aziridyl, azetidyl, pyr rolidyl, piperidyl, homopiperidyl, pyrrolyl or morpholinyl. Bromoacids 1 are converted to bromoacid chlorides 2 using thionylchloride (J. S. Pizey, Synthetic Reactions 2: 65 50 m, p, q, R and R are as defined above and —W– is (1974)). Bromoacid chlorides 2 are reacted with ZNH, —C(Ar)(Ar)—or —C(H)(Ar)—. optionally in the presence of base such as Na2CO, to provide reactive intermediates 3, which are treated with 4-cyano-4- Scheme 2 depicts methods for making 4-Tetrazolyl-4-phe phenylpiperidines 4 (Scheme 10) to provide cyanophenyl nylpiperidine Compounds where R is —COR. Bromoacid compounds 5. Cyanophenyl compounds 5 are treated with chlorides 2 (Scheme 1) are reacted with ROH, optionally in MeSnN or MeSiN and tin oxide (S.J. Wittenberg et al., J 55 the presence of a base Such as pyridine, 4-dimethylaminopy Org. Chem. 58:4134-4141 (1993)) to provide 4-Tetrazolyl-4- ridine, triethylamine or Hinig's base, to provide bromoesters phenylpiperide Compounds 6, wherein R is —C(O)NZ and 9. Bromoesters 9 are reacted with 4-cyano-4-phenylpip G is —H. Compounds 6 are reacted with G-X, wherein G is eridines 4 (Scheme 10) to provide cyanophenyl compounds all G, defined above, except hydrogen, and X is a leaving group Such as halogen, trifluoromethane Sulfonate, methane 60 10, which are treated with MeSnN or MeSiN and tin oxide sulfonate or toluenesulfonate, to provide a mixture of 4-Tet (S.J. Wittenberg et al., J. Org. Chem. 58:4139-4141 (1993)) razolyl-4-phenylpiperidine Compounds 7 and 8. Compounds to provide 4-Tetrazolyl-4-phenylpiperidine Compounds 11, 7 and 8 are separable using conventional means. Such as silica where R is ROC(O)— and G is —H, Compounds 11 are gel chromatography, high-performance liquid chromatogra reacted with GX, wherein G and X are as defined above, to phy or recrystallization. Compounds of the formula G-X can 65 provide a mixture of 4-Tetrazolyl-4-phenylpiperidine Com be obtained commercially or made using conventional pounds 12 and 13. Compounds 12 and 13 are separable using organic synthesis methods. conventional means described above. US 8,026,254 B2 75 76

-continued Scheme 2

CI-C(O)-W-(CH), -Br -esROH 2 5 RO-C(O)-W-(CH3)1 Br - 4 - ROCO-W-(CH), I-1 9

N CN MeSnN 10 ROC(O)-W-(CH2)^ | Y Xylenes 13 s (R3) la (R2) m, p, q, R and R are as defined above and —W– is 10 —C(Ar)(Ar)—or —C(H)(Ar)—. 15 Scheme 3 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —C(O)NH(C-C, alkyl). Compounds 11 (Scheme 2) are protected with a base N G1-X stable protecting group such as a mesitylenesulfonamide; ROC(O)-W-(CH2)^ He cyclohexylcarbamate; 1,1-dimethyl-2.2.2-trichloroethylcar bamate; N-(1-ethoxy)ethyl group; or a similar protecting group (See T. W. Greene et al., Protective Groups in Organic 11 Synthesis 615-631 (1999)) to provide protected compounds 14. Compounds 14 are hydrolyzed using hydroxide base, optionally in the presence of methanol, to provide after work 25 up acids 15, which are amidated using (C-C)NH2 to provide protected compounds 16. Compounds 16 are deprotected ROC(O)-W-(CH)1 N using a strong acid (Greene at 615-631) to provide 4-Tetra Zolyl-4-phenylpiperidine Compounds 17 where R is C(O) NH(C-C alkyl) and G is —H. Compounds 17 are reacted with G-X, wherein G and X areas defined above, to provide 30 a mixture of 4-Tetrazolyl-4-phenylpiperidine Compounds 18 12 and 19. Compounds 18 and 19 are separable using conven tional means described above.

protecting -OH 11 group (P) ROC(O)-W-(CH3)1 --

HOC(O)-W-(CH)1 N

16 US 8,026,254 B2 77 78 -continued

17

18

19

30 m, p, q, R and R are as defined above and —W– is -continued —C(Ar)(Ar)—or —C(H)(Ar)—. Scheme 4 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —C(O)NHOH. Acids 35 15 (Scheme 3) are treated with NH-OH to provide protected compounds 20, which are deprotected using strong acid (Greene at 615-631) to provide 4-Tetrazolyl-4-phenylpiperi dine Compounds 21 where R is—C(O)NHOH and G is —H. Compounds 21 are reacted with G-X, wherein G and X are 40 22 as defined above, to provide a mixture of 4-Tetrazolyl-4- phenylpiperidine Compounds 22 and 23. Compounds 22 and 23 are separable using conventional means described above.

45

N NHOH HONH-C(O)-W-(CH)1 15

50

23 -P HONH-C(O)-W-(CH), He

55 m, p, q, R and R are as defined above and —W– is —C(Ar)(Ar)—or —C(H)(Ar)—. 2O Scheme 5 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —H. Bromides 24 are

treated with 4-cyano-4-phenylpiperidines 4 to provide 60 cyanophenyl intermediates 25, which are reacted with MeSnN, or MeSiN and tin oxide (S.J. Wittenberg et al., J. G Org. Chem. 58:4139-4141 (1993)) to provide 4-tetrazolyl-4- He phenylpiperidine Compounds 26 where R and -G are —H. Compounds 26 are reacted with G-X, wherein G and X are 65 as defined above, to provide a mixture of 4-Tetrazolyl-4- 21 phenylpiperidine Compounds 27 and 28. Compounds 27 and 28 are separable using conventional means described above. US 8,026,254 B2 79 80 -continued Scheme 5 H-W-(CH3)1"Br - 24

N CN MeSnN H-W-(CH)1 | N s (R3) le (R2)R 10 25

N1 v X 15 N G1 H-W-(CH3)1 He

25 N H-W-(CH)1

30 OHC-W-(CH3)1

N m, p, q, R and R are as defined above and —W– is H-W-(CH)1 —C(Ar)(Ar)—or —C(H)(Ar)—. Scheme 7 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —(C-C alkyl). Com pounds 27 (Scheme 5) are treated with a strong base such as NaNH and quenched with (C-C alkyl)-X, where X is defined above, to provide protected Compounds 32. Com m, p, q, R and R are as defined above and —W– is 45 pounds 32 are deprotected (Greene at 615-631) to provide —C(Ar)(Ar)—or —C(H)(Ar)—. 4-Tetrazolyl-4-phenylpiperidine Compounds 33 where R is Scheme 6 depicts methods for making 4-Tetrazolyl-4-phe —(C-C alkyl) and G is H. Compounds 33 are reacted with nylpiperidine Compounds where R is —CHO. 4-Tetrazolyl G-X, wherein G and X are as defined above, to provide a mixture of 4-Tetrazolyl-4-phenylpiperidine Compounds 34 4-phenylpiperidine Compounds 27 (Scheme 5) are treated 50 with a strong base such as NaNH2 and quenched with dim and 35, which are separable using conventional means ethylformamide (see U.T. Mueller-Westerhoffet al., Synlett described above. 975 (1994)) to provide after work up protected aldehydes 28. Protected aldehydes 28 are deprotected (Greene at 615-631) to provide 4-Tetrazolyl-4-phenylpiperidine Compounds 29 55 NaNH2 where R— is —CHO and -G is —H. Compounds 29 are 27 He

reacted with G-X, wherein G and X areas defined above, to provide a mixture of 4-Tetrazolyl-4-phenylpiperidine Com pounds 30 and 31, which are separable using conventional means described above. 60

(C1-C4 alkyl)-W-(CH2) 11 N

NaNH2 65 27 DMF 32 US 8,026,254 B2 81 82 -continued -continued

(C1-C4 alkyl)-W-(CH2) 11 N

33 10 38

15

34 39

m, p, q, and R2 and R are as defined above and —W - is —C(Ar)(Ar)—or —C(H)(Ar)—. (C-C alkyl)-W-(CH2), 11 Scheme 9 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds wherein R is —CN. 4-Tetrazolyl 25 4-phenylpiperidine Compounds 37 (Scheme 8) are treated with PhP and CC1 (W. J. Rogers, Synthesis 41 (1997)) to provide 4-Tetrazolyl-4-phenylpiperidine Compounds 40 35 wherein R is CN and G is —H. Compounds 40 are reacted with G-X, wherein G and X areas defined above, to provide 30 a mixture of 4-Tetrazolyl-4-phenylpiperidine Compounds 41 m, p, q, R and R are as defined above and —W– is and 42, which are separable using conventional means —C(Ar)(Ar)—or —C(H)(Ar)—. described above. Scheme 8 depicts methods for making 4-Tetrazolyl-4-phe nylpiperidine Compounds where R is —C(O)NH. Pro tected esters 14 (Scheme 3) are treated with NH (See M. B. 35 Scheme 9 Smith et al., March's Advanced Organic Chemistry. Reac Ph3P 37 --> tions, Mechanisms, and Structure 510-511 (2001)) to provide CCl4 protected amides 36, which are deprotected (Greene at 615 631) to provide 4-Tetrazolyl-4-phenylpiperidine Compounds 37 where R is —C(O)NH2 and -G is —H, Compounds 37 are 40 reacted with G-X, wherein G and X areas defined above, to G1-X provide a mixture of 4-Tetrazolyl-4-phenylpiperidine Com NC-W-(CH)1 pounds 38 and 39, which are separable using conventional means defined above. 45

NH 14 3

50

N NC-W-(CH)1 --

55

60 NC-W-(CH)1 N

65 37 US 8,026,254 B2 83 84 m, p, q, and R2 and R are as defined above and —W - is certain 4-Tetrazolyl-4-phenylpiperidine Compounds of For —C(Ar)(Ar)—or —C(H)(Ar)—. mula I (a) and Formula I (b) (e.g. structures AAT and BAT), Scheme 10 depicts methods for making 4-cyano-4-phe and certain 4-Tetrazolyl-4-phenylpiperidine Compounds of nylpiperidines 4. (R)-Substituted aminodiols 43 are Formula I (c) and Formula I (d) (e.g. structures CAT and N-alkylated using benzyl chloride 44 in NaHCO/HO to 5 provide N-benzyl diols 45, which are chlorinated using DAT), are tautomers of each other. Each structure depicted SOCl to provide dichlorides 46. Dichlorides 46 are con herein is intended to encompass all tautomers thereof, each of densed with deprotonated (NaNH in toluene) benzyl cya which is understood to be included in the present invention, nides 47 to provide benzyl compounds 48, which are deben whether specifically disclosed or not, and whether or not the Zylated using H and Pd/C (95% EtoH) to provide 4-cyano tautomer depicted herein represents a tautomer in excess 10 relative to any other tautomerthereof. Accordingly, the inven 4-phenylpiperides 4. tion also encompasses 4-Tetrazolyl-4-phenylpiperidine Compounds and their uses as described herein in the form of Scheme 1() their individual tautomers. In addition, one or more hydrogen, carbon or other atoms OH 15 of a 4-Tetrazolyl-4-phenylpiperidine Compound can be replaced by an isotope of the hydrogen, carbon or other A 1. NaHCO3 NH (R3) - - - - - atoms. Such compounds, which are encompassed by the N 2. benzyl chloride (44) present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding OH assayS. 43 4.4 Therapeutic Uses of the OH 4-Tetrazolyl-4-phenylpiperidine Compounds

N (R3) SOCl 25 In accordance with the invention, the 4-Tetrazolyl-4-phe nylpiperidine Compounds are administered to an animal, in one embodiment a mammal, in another embodiment a C OH human, for the treatment or prevention of pain. The 4-Tetra 45 Zolyl-4-phenylpiperidine Compounds can be used to treat or Na(+) 30 prevent acute or chronic pain. For example, the 4-Tetrazolyl (-) 4-phenylpiperidine Compounds can be used for, but are not CH-CN limited to, treating or preventing cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic C pain, post operative pain, headache pain, muscle pain, and 35 pain associated with intensive care. (R2) The 4-Tetrazolyl-4-phenylpiperidine Compounds can also N (R3) 47 be used for inhibiting, preventing, or treating pain associated He with inflammation or with an inflammatory disease in an animal. The pain to be inhibited, treated or prevented may be C 40 associated with inflammation associated with an inflamma 46 tory disease, which can arise where there is an inflammation CN of the body tissue, and which can be a local inflammatory H response and/or a systemic inflammation. For example, the --- 4-Tetrazolyl-4-phenylpiperidine Compounds can be used to PoC 45 inhibit, treat, or prevent pain associated with inflammatory Rs), NeX diseases including, but not limited to: organ transplant rejec (R2) tion; reoxygenation injury resulting from organ transplanta 48 tion (see Grupp et al. J. Mol. Cell. Cardiol. 31:297 303 CN (1999)) including, but not limited to, transplantation of the 50 heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoar --(R) thritis and bone diseases associated with increased bone (R3) 21 resorption; inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease: 55 inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; Certain 4-Tetrazolyl-4-phenylpiperidine Compounds can inflammatory diseases of the eye, including corneal dystro have asymmetric centers and therefore existin differentenan phy, trachoma, onchocerciasis, uveitis, sympathetic oph tiomeric and diastereomeric forms. A 4-Tetrazolyl-4-phe thalmitis and endophthalmitis; chronic inflammatory dis nylpiperidine Compound can be in the form of an optical 60 eases of the gum, including gingivitis and periodontitis; isomer or a diastereomer. Accordingly, the invention encom tuberculosis; leprosy, inflammatory diseases of the kidney, passes 4-Tetrazolyl-4-phenylpiperidine Compounds and including uremic complications, glomerulonephritis and their uses as described herein in the form of their individual nephrosis; inflammatory diseases of the skin, including scle optical isomers, diasteriomers, and mixtures thereof, includ rodermatitis, psoriasis and eczema, inflammatory diseases of ing a racemic mixture. 65 the central nervous system, including chronic demyelinating In addition, certain 4-Tetrazolyl-4-phenylpiperidine Com diseases of the nervous system, multiple sclerosis, AIDS pounds can exist as tautomers. For example, where G-H. related neurodegeneration and Alzheimer S disease, infec US 8,026,254 B2 85 86 tious meningitis, encephalomyelitis, Parkinson's disease, the present methods encompass treating or preventing pain, Huntington's disease, amyotrophic lateral Sclerosis, and viral while reducing or eliminating one or more of the aforemen or autoimmune encephalitis; autoimmune diseases, including tioned side effects. Type I and Type II diabetes mellitus; diabetic complications, Without wishing to be bound by theory, it is believed that including, but not limited to, diabetic cataract, glaucoma, the 4-Tetrazolyl-4-phenylpiperidine Compounds are agonists retinopathy, nephropathy (such as microaluminuria and pro for and, accordingly, are capable of stimulating an opioid gressive diabetic nephropathy), polyneuropathy, mononeuro receptor. pathies, autonomic neuropathy, gangrene of the feet, athero The invention also relates to methods for stimulating Sclerotic coronary arterial disease, peripheral arterial disease, opioid-receptor function in a cell comprising contacting a cell nonketotic hyperglycemic hyperosmolar coma, foot ulcers, 10 capable of expressing an opioid receptor with an effective joint problems, and a skin or mucous membrane complication amount of a 4-Tetrazolyl-4-phenylpiperidine Compound. (such as an infection, a shin spot, a candidal infection or The method is also useful for stimulating opioid receptor necrobiosis lipoidica diabeticorum); immune-complex vas function in a cell in vivo, in an animal, in one embodiment a culitis, systemic lupus erythematosus (SLE); inflammatory 15 human, by contacting a cell capable of expressing an opioid diseases of the heart, such as cardiomyopathy, ischemic heart receptor, in an animal, with an effective amount of a 4-Tetra disease hypercholesterolemia, and atherosclerosis; as well as Zolyl-4-phenylpiperidine Compound. In one embodiment, various other diseases that can have significant inflammatory the method is useful for treating or preventing pain or diarrhea components, including preeclampsia, chronic liver failure, in an animal. Brain tissue, spinal chord tissue, immune cells, brain and spinal cord trauma, and cancer. The 4-Tetrazolyl cells of the gastrointestinal tract, and primary afferent nerve 4-phenylpiperidine Compounds can also be used for inhibit cells are examples of tissues and/or cells that are capable of ing, treating, or preventing pain associated with inflammatory expressing an opioid receptor. This method can be used in disease that can, for example, be a systemic inflammation of vitro, for example, as an assay to select cells that express an the body, exemplified by gram-positive or gram negative opioid receptor. shock, hemorrhagic or anaphylactic shock, or shock induced 25 by cancer chemotherapy in response to pro-inflammatory 4.4.1 Therapeutic/Prophylactic Administration and cytokines, e.g., shock associated with pro-inflammatory Compositions of the Invention cytokines. Such shock can be induced, e.g., by a chemothera peutic agent that is adminstered as a treatment for cancer. Due to their activity, the 4-Tetrazolyl-4-phenylpiperidine In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 30 Compounds are advantageously useful in Veterinary and dine Compounds are administered to an animal, in one human medicine. As described above, the 4-Tetrazolyl-4- embodiment a mammal, in another embodiment a human, for phenylpiperidine Compounds are useful for treating or pre the treatment or prevention of diarrhea. The 4-Tetrazolyl-4- venting pain or diarrhea in an animal in need thereof. phenylpiperidine Compounds can be used to treat or prevent When administered to an animal, the 4-Tetrazolyl-4-phe acute or chronic diarrhea. For example, the 4-Tetrazolyl-4- 35 nylpiperidine Compounds can be administered as a compo phenylpiperidine Compounds can be used for, but are not nent of a pharmaceutical composition that comprises a phar limited to, treating or preventing acute diarrhea caused by a maceutically acceptable carrier or excipient. The present virus, such as but not limited to Norwalk-virus, Norwalk-like compositions, which comprise a 4-Tetrazolyl-4-phenylpip virus, Rotavirus, and Cytomegaloviurs: protozoa, Such as but eridine Compound, are in one embodiment administered not limited to Girardia lamlia, Crpytosporidium and Entam 40 orally. The compositions of the invention can also be admin oeba histolytica; and bacteria, including but not limited to istered by any other convenient route, for example, by infu Stapylococcus aureus, Bacillus cereus, Clostridium perfirin sion or bolus injection, by absorption through epithelial or gens, enterotoxigenic E. coli, Vibrio cholera, enterohemmor mucocutaneous linings (e.g., oral mucosa, rectal, and intesti rhagic E. coli O157:H5, Vibrio parahaemolyticus, nal mucosa, etc.) and can be administered together with Clostridium difficile, Campylobacter jejuni, Salmonella, 45 another therapeutic agent. Administration can be systemic or enteroinvasive E. coli, Aeromonas, Plesiomonas, Yersinia local. Various delivery systems are known, e.g., encapsula enterocolitica, Chlamydia, Nisseria gonorrhoeae, and List tion in liposomes, microparticles, microcapsules, capsules, eria monocytogenes. For example, the 4-Tetrazolyl-4-phe etc., and can be used to administer the 4-Tetrazolyl-4 phe nylpiperidine Compounds can be used for treating or prevent nylpiperidine Compounds. ing chronic diarrhea classified as that including, but not 50 Methods of administration include but are not limited to limited to, osmotic diarrhea, secretory diarrhea, or resulting intradermal, intramuscular, intraperitoneal, intravenous, Sub from an inflammatory condition, a malabsorption syndrome, cutaneous, intranasal, epidural, oral, Sublingual, intracere a motility disorder, and a chronic infection. bral, intravaginal, transdermal, rectal, by inhalation, or topi Applicants believe that unlike traditional opioid agonists cal, particularly to the ears, nose, eyes, or skin. The mode of and nonsteroidal anti-inflammatory agents, the 4-Tetrazolyl 55 administration is left to the discretion of the practitioner. In 4-phenylpiperidine Compounds do not significantly cross the most instances, administration will result in the release of the blood-brain barrier. Accordingly, Applicants believe that the 4-Tetrazolyl-4-phenylpiperidine Compounds into the blood administration of an effective amount of a 4-Tetrazolyl-4- Stream. phenylpiperidine Compound to an animal results in fewer In specific embodiments, it may be desirable to administer side effects, including respiratory depression, unwanted 60 the 4-Tetrazolyl-4-phenylpiperidine Compounds locally. euphoria, sedation, constipation, increased drug tolerance, This may be achieved, for example, and not by way of limi and increased drug dependence, that can result from the tation, by local infusion during Surgery, topical application, administration of traditional opioid agonists or nonsteroidal e.g., in conjunction with a wound dressing after Surgery, by anti-inflammatory agents. In one embodiment, the adminis injection, by means of a catheter, by means of a Suppository, tration of an effective amount of a 4-Tetrazolyl-4-phenylpip 65 or by means of an implant, said implant being of a porous, non eridine Compound to an animal results in none of the afore porous, or gelatinous material, including membranes, such as mentioned side effects. Therefore, in certain embodiments, sialastic membranes, or fibers. US 8,026,254 B2 87 88 Pulmonary administration can also be employed, e.g., by diluted with saline or water, about 25 to about 30% propylene use of an inhaler or nebulizer, and formulation with an aero glycol (PG) diluted with saline or water, and about 2 to about Solizing agent, or via perfusion in a fluorocarbon or synthetic 30% hydroxypropyl B-cyclodextrin diluted with water. pulmonary Surfactant. In certain embodiments, the 4-Tetra Suitable pharmaceutically acceptable carriers or excipients Zolyl-4-phenylpiperidine Compounds can be formulated as a 5 for Subcutaneous and intramuscular administration of the Suppository, with traditional binders and excipients such as 4-Tetrazolyl-4-phenylpiperidine Compounds include, but are triglycerides. not limited to, water, normal (about 0.9%) saline, about 25 to In another embodiment, the 4-Tetrazolyl-4-sphenylpiperi about 30% PEG diluted with saline or water, and about 25 to dine Compounds can be delivered in a vesicle, in particular a about 30% PG diluted with Saline or water. liposome (see Langer, Science 249:1527-1533 (1990) and 10 Suitable pharmaceutically acceptable carriers or excipients Treat et al., Liposomes in the Therapy of Infectious Disease for oral administration of the 4-Tetrazolyl-4-phenylpiperi and Cancer 317-327 and 353–365 (1989). dine Compounds include, but are not limited to, water, normal In yet another embodiment, the 4-Tetrazolyl-4-phenylpip (about 0.9%) saline, about 25 to about 30% polyethylene eridine Compounds can be delivered in a controlled-release glycol PEG diluted with saline or water, about 2 to about 30% system (see, e.g., Goodson, in Medical Applications of Con- 15 hydroxypropyl B-cyclodextrin diluted with water, about 25 to trolled Release, supra, vol. 2, pp. 115-138 (1984)). Other about 30% PG diluted with saline or water, and about 1 to controlled release systems discussed in the review by Langer, about 5% methylcellulose diluted with water. Science 249:1527-1533 (1990) may be used. In one embodi Suitable pharmaceutically acceptable carriers or excipients ment, a pump may be used (Langer, Science 249:1527-1533 for intracerebroventricular and intrathecal administration of (1990); Sefton, CRC Crit. Ref Biomed. Eng., 14:201 (1987): 20 the 4-Tetrazolyl-4-phenylpiperidine Compounds include, but Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. are not limited to, normal (about 0.9%) saline. Engl.J. Med. 321:574 (1989)). In another embodiment, poly The present compositions can take the form of Solutions, meric materials can be used (see Medical Applications of Suspensions, emulsion, tablets, pills, pellets, capsules, cap Controlled Release (Langer and Wise eds., 1974); Controlled Sules containing liquids, powders, Sustained release formula Drug Bioavailability, Drug Product Design and Performance 25 tions, Suppositories, aerosols, sprays, Suspensions, or any (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macro other form suitable for use. In one embodiment, the compo mol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., sition is in the form of a capsule (see e.g., U.S. Pat. No. Science 228:190 (1985): During et al., Ann. Neurol. 25:351 5,698,155). Other examples of suitable pharmaceutical (1989); and Howard et al., J. Neurosurg, 71:105 (1989)). In excipients are described in Remington's Pharmaceutical Sci yet another embodiment, a controlled release system can be 30 ences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), placed in proximity of a target of a 4-Tetrazolyl-4-phenylpi incorporated herein by reference. peridine Compound thus requiring only a fraction of the In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine systemic dose. Compounds are formulated in accordance with routine pro The present compositions can optionally comprise a Suit cedures as a composition adapted for oral administration to an able amount of a pharmaceutically acceptable excipient so as 35 animal, particularly a human being. Compositions for oral to provide the form for proper administration to the animal. delivery may be in the form of tablets, lozenges, aqueous or Such pharmaceutical excipients can be liquids, such as oily Suspensions, granules, powders, emulsions, capsules, water and oils, including those of petroleum, animal, Veg syrups, or elixirs, for example. Orally administered compo etable, or synthetic origin, Such as peanut oil, soybean oil, sitions can contain preserving agents, coloring agents, and mineral oil, sesame oil and the like. The pharmaceutical 40 one or more agents, for example, Sweetening agents such as excipients can be saline, gum acacia, gelatin, starch paste, fructose, aspartame or saccharin and flavoring agents such as talc, keratin, colloidal silica, urea, and the like. In addition, peppermint, oil of wintergreen, or cherry, to provide a phar auxiliary, stabilizing, thickening, lubricating, and coloring maceutically palatable preparation. Moreover, where in tablet agents may be used. When administered to an animal, the or pill form, the compositions can be coated to delay disinte pharmaceutically acceptable excipients can be sterile. Water 45 gration and absorption in the gastrointestinal tract thereby is a particularly useful excipient when the 4-Tetrazolyl-4- providing a Sustained action over an extended period of time. phenylpiperidine Compound is administered intravenously. Selectively permeable membranes Surrounding an osmoti Saline solutions and aqueous dextrose and glycerol solutions cally active driving compound are also suitable for orally can also be employed as liquid excipients, particularly for administered compositions. In these later platforms, fluid injectable solutions. Suitable pharmaceutical excipients also 50 from the environment surrounding the capsule is imbibed by include starch, glucose, lactose, Sucrose, gelatin, malt, rice, the driving compound, which Swells to displace the agent or flour, chalk, silica gel, Sodium Stearate, glycerol monostear agent composition through an aperture. These delivery plat ate, talc, Sodium chloride, dried skim milk, glycerol, propy forms can provide an essentially Zero order delivery profile as lene, glycol, water, ethanol, and the like. The present compo opposed to the spiked profiles of immediate-release formula sitions, if desired, can also contain minor amounts of wetting 55 tions. A time delay material Such as glycerol monostearate or or emulsifying agents, or pH buffering agents. glycerol Stearate may also be used. Oral compositions can Suitable pharmaceutically acceptable carriers or excipients include standard excipients such as mannitol, lactose, starch, for intravenous administration of the 4-Tetrazolyl-4-phe magnesium Stearate, sodium saccharin, cellulose and magne nylpiperidine Compounds include, but are not limited to, sium carbonate. In one embodiment, such excipients are of normal (about 0.9%) saline, about 25 to about 30% polyeth- 60 pharmaceutical grade. ylene glycol (“PEG') diluted with saline or water, and about In another embodiment, the 4-Tetrazolyl-4-phenylpiperi 2 to about 30% hydroxypropyl B-cyclodextrin diluted with dine Compounds can be formulated for intravenous adminis Water. tration. In one embodiment, compositions for intravenous Suitable pharmaceutically acceptable carriers or excipients administration comprise the compound dissolved in sterile for intraperitoneal administration of the 4-Tetrazolyl-4-phe- 65 isotonic aqueous buffer. Where necessary, the compositions nylpiperidine Compounds include, but are not limited to, may also include a solubilizing agent. Compositions for intra normal (about 0.9%) saline, about 25 to about 30% PEG venous administration can optionally include a local anes US 8,026,254 B2 89 90 thetic Such as lignocaine to lessen pain at the site of the der or condition causing the pain and can be determined by injection. Generally, the ingredients are Supplied either sepa standard clinical techniques. In addition, in vitro or in vivo rately or mixed together in unit dosage form, for example, as assays can optionally be employed to help identify optimal a dry lyophilized powder or water-free concentrate in a her effective dosage amounts. The precise dose to be employed metically sealed container Such as an ampoule or Sachette 5 can also depend on the intended route of administration, and indicating the quantity of active agent. Where the 4-Tetra the degree or severity of the pain or diarrhea and should be Zolyl-4-phenylpiperidine Compounds are to be administered decided according to the judgment of the practitioner and by infusion, they can be dispensed, for example, from an each patient’s circumstances in view of published clinical infusion bottle containing sterile pharmaceutical grade water studies. Suitable effective dosage amounts, however, range or saline. Where the 4-Tetrazolyl-4-phenylpiperidine Com 10 from about 10 micrograms to about 2500 milligrams about pounds are administered by injection, an ampoule of sterile every 4 h, although typically about 100 mg or less. In one water for injection or saline can be provided so that the embodiment, the effective dosage amount ranges from about ingredients may be mixed prior to administration. 0.01 milligrams to about 100 milligrams of a 4-Tetrazolyl-4- The 4-Tetrazolyl-4-phenylpiperidine Compounds can be phenylpiperidine Compound about every 4 h, in another administered by controlled-release means or by delivery 15 embodiment about 0.020 milligrams to about 50 milligrams devices that are well known to those of ordinary skill in the about every 4 h, and in another embodiment about 0.025 art. Examples include, but are not limited to, those described milligrams to about 20 milligrams about every 4 h. The dos in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598, age amounts described herein refer to total amounts admin 123; 4,008,719:5,674,533:5,059,595; 5,591,767; 5,120,548; istered; that is, if more than one 4-Tetrazolyl-4-phenylpiperi 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of dine Compound is administered, the effective dosage which is incorporated herein by reference. Such dosage forms amounts correspond to the total amount administered. can be used to provide slow or controlled release of one or Where a cell capable of expressing an opioid receptor is more active ingredients using, for example, hydropropylm contacted with a 4-Tetrazolyl-4-phenylpiperidine Compound ethyl cellulose, other polymer matrices, gels, permeable in vitro, the effective amount will typically range from about membranes, osmotic systems, multilayer coatings, micropar 25 0.01 mg to about 100 mg/L, in one embodiment from about ticles, liposomes, microspheres, or a combination thereof to 0.1 mg to about 50 mg/L, and in another embodiment from provide the desired release profile in varying proportions. about 1 mg to about 20 mg/L, of a solution or Suspension of a Suitable controlled release formulations known to those of pharmaceutically acceptable carrier or excipient. ordinary skill in the art, including those described herein, can Where a cell capable of expressing an opioid receptor is be readily selected for use with the 4-Tetrazolyl-4-phenylpi 30 contacted with a 4-Tetrazolyl-4-phenylpiperidine Compound peridine Compounds. The invention thus encompasses single in vivo, the effective amount will typically range from about unit dosage forms suitable for oral administration such as, but 0.01 mg to about 100 mg/kg of body weight per day, in one not limited to, tablets, capsules, gelcaps, and caplets that are embodiment from about 0.1 mg to about 50 mg/kg body adapted for controlled release. weight per day, and in another embodiment from about 1 mg Controlled release pharmaceutical compositions can have 35 to about 20 mg/kg of body weight per day. a common goal of improving drug therapy over that achieved The 4-Tetrazolyl-4-phenylpiperidine Compounds can be by their non controlled counterparts. In one embodiment a assayed in vitro or in vivo for its their ability to treator prevent controlled-release composition comprises a minimal amount pain or diarrhea prior to use in humans. Animal model sys of a 4-Tetrazolyl-4-phenylpiperidine Compound to cure or tems can be used to demonstrate the 4-Tetrazolyl-4-phenylpi control the condition in a minimum amount of time. Advan 40 peridine Compounds safety or efficacy. tages of controlled release compositions include extended The present methods for treating or preventing pain or activity of the drug, reduced dosage frequency, and increased diarrhea in an animal can further comprise administering to patient compliance. In addition, controlled release composi the animal an effective amount of another therapeutic agent. tions can favorably affect the time of onset of action or other The present methods for stimulating opioid-receptor func characteristics, such as blood levels of the 4-Tetrazolyl-4- 45 tion in a cell can further comprise contacting the cell with an phenylpiperidine Compound, and can thus reduce the occur effective amount of another therapeutic agent. rence of side (e.g., adverse) effects. Examples of other therapeutic agents include, but are not In one embodiment, controlled release compositions can limited to, an opioid agonist, a non-opioid analgesic, a non initially release an amount of a 4-Tetrazolyl-4-phenylpiperi steroid antiinflammatory agent, an antimigraine agent, a Cox dine Compound that promptly treats or prevents pain or diar 50 II inhibitor, an antiemetic, a B-adrenergic blocker, an anticon rhea, and gradually and continually release other amounts of Vulsant, an antidepressant, a Ca2+-channel blocker, an the 4-Tetrazolyl-4-phenylpiperidine Compound to maintain anticancer agent, an anti-anxiety agent, an agent for treating this level of therapeutic or prophylactic effect over an or preventing an addictive disorder and mixtures thereof. extended period of time. To maintain this constant level of the Effective amounts of the other therapeutic agents are well 4-Tetrazolyl-4-phenylpiperidine Compound in the body, the 55 knownto those skilled in theart. However, it is well within the 4-Tetrazolyl-4-phenylpiperidine Compound can be released skilled artisan's purview to determine the other therapeutic from the dosage form at a rate that will replace the amount of agent's optimal effective-amount range. In one embodiment 4-Tetrazolyl-4-phenylpiperidine Compound being metabo of the invention, where another therapeutic agent is adminis lized and excreted from the body. Controlled release of an tered to an animal, the effective amount of the 4-Tetrazolyl active ingredient can be stimulated by various conditions 60 4-phenylpiperidine Compound is less than its effective including, but not limited to, changes in pH, changes in tem amount would be where the other therapeutic agent is not perature, concentration or availability of enzymes, concen administered. In this case, without being bound by theory, it is tration or availability of water, or other physiological condi believed that the 4-Tetrazolyl-4-phenylpiperidine Compound tions or compounds. and the other therapeutic agent act synergistically to treat or The amount of the 4-Tetrazolyl-4-phenylpiperidine Com 65 prevent pain or diarrhea. pounds that is effective in the treatment or prevention of pain Examples of useful opioid agonists include, but are not or diarrhea can depend on the nature or severity of the disor limited to, alfentanil, allylprodine, alphaprodine, anileridine, US 8,026,254 B2 91 92 benzylmorphine, bezitramide, buprenorphine, butorphanol, The other therapeutic agent can also be an antiemetic clonitaZene, codeine, desomorphine, dextromoramide, dezo agent. Useful antiemetic agents include, but are not limited to, cine, diampromide, diamorphone, dihydrocodeine, dihydro metoclopromide, domperidone, prochlorperazine, promet morphine, dimenoxadol, dimepheptanol, dimethylthiam hazine, chlorpromazine, trimethobenzamide, ondansetron, butene, dioxaphetyl butyrate, dipipanone, eptazocine, granisetron, hydroxy Zine, acetylleucine monoethanolamine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto alizapride, aZasetron, benzquinamide, bietanautine, bro nitaZene fentanyl, heroin, hydrocodone, hydromorphone, mopride, buclizine, clebopride, cyclizine, dimenhydrinate, hydroxypethidine, isomethadone, ketobemidone, levorpha diphenidol, dolasetron, meclizine, methallatal, metopi nol, levophenacylmorphan, lofentanil, meperidine, meptazi mazine, nabilone, oxyperndyl, pipamazine, Scopolamine, nol, metazocine, methadone, metopon, morphine, myro 10 Sulpiride, tetrahydrocannabinol, thiethylperazine, thioprop phine, nalbuphine, narceline, nicomorphine, norlevorphanol, erazine, tropisetron, and mixtures thereof. normethadone, nalorphine, normorphine, norpipanone, Examples of useful f-adrenergic blockers include, but are opium, oxycodone, oxymorphone, papaveretum, pentaZo not limited to, acebutolol, alprenolol, amoSulabol, arotinolol. cine, phenadoxone, phenomorphan, phenazocine, phenope atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopin 15 dolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupra ridine, piminodine, piritramide, proheptazine, promedol, pro nolol, butidrine hydrochloride, butofilolol, carazolol, car peridine, propiram, propoxyphene, Sufentanil, tilidine, teolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, tramadol, pharmaceutically acceptable salts thereof, and mix epanolol, esmolol, indenolol, labetalol, levobunolol, mepin tures thereof. dolol, metipranolol, metoprolol, moprolol, nadolol, nadox In certain embodiments, the opioid agonist is selected from olol, nebivalol, nifenalol, nipradillol, Oxprenolol, penbutolol, codeine, hydromorphone, hydrocodone, oxycodone, dihy pindolol, practolol, pronethalol, propranolol, Sotalol, Sulfi drocodeine, dihydromorphine, morphine, tramadol, oxymor malol, talinolol, tertatolol, tilisolol, timolol, toliprolol, and phone, pharmaceutically acceptable salts thereof, and mix Xibenolol. tures thereof. Examples of useful anticonvulsants include, but are not Examples of useful non opioid analgesics include non Ste 25 limited to, acetylpheneturide, albutoin, aloxidone, aminoglu roidal anti-inflammatory agents, such as aspirin, ibuprofen, tethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenopro beclamide, buramate, calcium bromide, carbamazepine, cin fen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, romide, clomethiazole, clonazepam, decimemide, diethadi oxaprozin, pramoprofen, muroprofen, trioxaprofen, Supro one, dimethadione, doxenitroin, eterobarb, ethadione, etho fen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, 30 Suximide, ethotoin, felbamate, fluoresone, gabapentin, indomethacin, Sulindac, tolmetin, Zomepirac, tiopinac, 5-hydroxytryptophan, lamotrigine, magnesium bromide, Zidometacin, acemetacin, fentiazac, clidanac, oXpinac, mefe magnesium sulfate, mephenyloin, mephobarbital, methar namic acid, meclofenamic acid, flufenamic acid, niflumic bital, methetoin, methSuximide, 5-methyl-5-(3-phenan acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, thryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobar Sudoxicam, isoxicam, and pharmaceutically acceptable salts 35 bital, nimetazepam, nitrazepam, oXcarbazepine, thereof, and mixtures thereof. Examples of other suitable non paramethadione, phenacemide, phenetharbital, pheneturide, opioid analgesics include the following, nonlimiting, chemi phenobarbital, phensuximide, phenylmethylbarbituric acid, cal classes of analgesic, antipyretic, nonsteroidal antiinflam phenyloin, phethenylate sodium, potassium bromide, pre matory drugs: salicylic acid derivatives, including aspirin, gabaline, primidone, progabide, Sodium bromide, Solanum, Sodium salicylate, choline magnesium trisalicylate, Salsalate, 40 strontium bromide, Suclofenide, Sulthiame, tetrantoin, tiaga diflunisal, salicylsalicylic acid, SulfaSalazine, and olsalazin; bine, topiramate, trimethadione, Valproic acid, valpromide, para aminophennol derivatives including acetaminophen and vigabatrin, and Zonisamide. phenacetin; indole and indene acetic acids, including Examples of useful antidepressants include, but are not indomethacin, Sulindac, and etodolac; heteroaryl acetic acids, limited to, binedaline, caroXaZone, citalopram, (S)-citalo including tolmetin, diclofenac, and ketorolac, anthranilic 45 pram, dimethazan, fencamine, indalpine, indeloxazine acids (fenamates), including mefenamic acid, and meclofe hydrocholoride, nefopam, nomifensine, oxitriptan, oxyper namic acid; enolic acids, including oxicams (piroxicam, tine, paroxetine, Sertraline, thiaZesim, traZodone, benmoxine, tenoxicam), and pyrazolidinediones (phenylbutaZone, iproclozide, iproniazid, isocarboxazid, nialamide, octa oxyphenthartaZone); and alkanones, including nabumetone. moxin, phenelZine, cotinine, rolicyprine, rolipram, mapro For a more detailed description of the NSAIDs, see Paul A. 50 tiline, metralindole, mianserin, mirtazepine, adinazolam, Insel, Analgesic Antipyretic and Antiinflammatory Agents amitriptyline, amitriptylinoxide, amoxapine, butriptyline, and Drugs Employed in the Treatment of Gout, in clomipramine, demexiptiline, desipramine, dibenzepin, Goodman & Gilman's The Pharmacological Basis of Thera dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imi peutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon pramine N-oxide, iprindole, lofepramine, melitracen, metap eds., 9th ed 1996) and Glen R. Hanson, Analgesic, Antipyretic 55 ramine, nortriptyline, noxiptilin, opipramol, pizotyline, and Anti Inflammatory Drugs in Remington: The Science and propizepine, protriptyline, quinupramine, tianeptine, trimi Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed. pramine, adrafinil, benactyzine, bupropion, butacetin, dioxa 19th ed. 1995) which are hereby incorporated by reference in drol, dulloxetine, etoperidone, febarbamate, femoxetine, fen their entireties. Suitable Cox-II inhibitors and 5-lipoxygenase pentadiol, fluoxetine, fluvoxamine, hematoporphyrin, inhibitors, as well as combinations thereof, are described in 60 hypericin, levophacetoperane, medifoxamine, milnacipran, U.S. Pat. No. 6,136,839. Cox II inhibitors include, but are not minaprine, moclobemide, nefazodone, oxafloZane, pibera limited to, rofecoxib and celecoxib. line, prolintane, pyriSuccideanol, ritanserin, roXindole, Examples of useful antimigraine agents include, but are not rubidium chloride, Sulpiride, tandospirone, thoZalinone, limited to, alpiropride, dihydroergotamine, dolasetron, ergo tofenacin, toloxatone, tranylcypromine, L-tryptophan, Ven cornine, ergocorninine, ergocryptine, ergot, ergotamine, 65 lafaxine, Viloxazine, and Zimeldine. flumedroXone acetate, fonazine, lisuride, lomerizine, methy Examples of useful Ca2+-channel blockers include, but are Sergide oxetorone, pizotyline, and mixtures thereof. not limited to, bepridil, clentiazem, diltiazem, fendiline, gal US 8,026,254 B2 93 94 lopamil, mibefradil, prenylamine, semotiadil, terodiline, Zelesin; aldesleukin; ALL-TK antagonists; altretamine; Verapamil, amlodipine, aranidipine, barnidipine, benidipine, ambamustine; amidox; amifostine; aminolevulinic acid; cilnidipine, efonidipine, elgodipine, felodipine, isradipine, amrubicin; amsacrine; anagrelide; anastroZole; androgra lacidipine, lercanidipine, manidipine, nicardipine, nife pholide, angiogenesis inhibitors; antagonist D; antagonist G: dipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, antarelix; anti dorsalizing morphogenetic protein-1, antian cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, drogen, prostatic carcinoma; antiestrogen; antineoplaston; etafenone, fantofarone, and perhexyline. antisense oligonucleotides; aphidicolin glycinate; apoptosis Examples of useful anticancer agents include, but are not gene modulators; apoptosis regulators; apurinic acid, ara limited to, acivicin, aclarubicin, acodazole hydrochloride, CDP-DL-PTBA; arginine deaminase; asulacrine; atames acronine, adoZelesin, aldesleukin, altretamine, ambomycin, 10 tane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3: ametantrone acetate, aminoglutethimide, amsacrine, anastro aZasetron; azatoxin; azatyrosine; baccatin III derivatives; bal Zole, anthramycin, asparaginase, asperlin, azacitidine, anol; batimastat; BCR/ABL antagonists; benzochlorins; ben aZetepa, azotomycin, batimastat, benzodepa, bicalutamide, Zoylstaurosporine; beta lactam derivatives; beta alethine; bisantrene hydrochloride, bisnafide dimesylate, bizelesin, betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta bleomycin Sulfate, brequinar sodium, bropirimine, buSulfan, 15 mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene cactinomycin, calusterone, caracemide, carbetimer, carbopl A: bizelesin; breflate; bropirimine; budotitane; buthionine atin, carmustine, carubicin hydrochloride, carzelesin, cedef Sulfoximine; calcipotriol; calphostin C; camptothecin deriva ingol, chlorambucil, cirolemycin, cisplatin, cladribine, cri tives; canarypox IL-2; capecitabine; carboxamide-amino Snatol mesylate, cyclophosphamide, cytarabine, dacarbazine, triazole; carboxyamidotriazole; CaRest M3; CARN 700; car dactinomycin, daunorubicin hydrochloride, decitabine, dex tilage derived inhibitor; carZelesin; casein kinase inhibitors ormaplatin, deZaguanine, deZaguanine meSylate, diaziquone, (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; docetaxel, doxorubicin, doxorubicin hydrochloride, drolox chloroquinoxaline Sulfonamide; cicaprost; cis porphyrin, ifene, droloxifene citrate, dromoStanolone propionate, dua cladribine; clomifene analogues; clotrimazole; collismycin Zomycin, edatrexate, eflornithine hydrochloride, elsamitru A. collismycin B; combretastatin A4, combretastatin ana cin, enloplatin, enpromate, epipropidine, epirubicin 25 logue; conagenin, crambescidin 816; crisinatol; cryptophycin hydrochloride, erbulozole, esorubicin hydrochloride, estra 8, cryptophycin A derivatives; curacin A; cyclopentan mustine, estramustine phosphate Sodium, etanidazole, etopo thraquinones; cycloplatam, cypemycin; cytarabine ocfosfate; side, etoposide phosphate, etoprine, fadrozole hydrochloride, cytolytic factor, cytostatin; dacliximab, decitabine; dehy fazarabine, fenretinide, floxuridine, fludarabine phosphate, drodidemnin B; deslorelin; dexamethasone; dexifosfamide: fluorouracil, fluorocitabine, fosquidone, fostriecin Sodium, 30 dexraZoxane; dexVerapamil; diaziquone; didemnin B; didox; gemcitabine, gemcitabine hydrochloride, hydroxyurea, ida diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol; rubicin hydrochloride, ifosfamide, ilmofosine, interleukin II 9-dioxamycin; diphenyl spiromustine; docetaxel; docosanol: (including recombinant interleukin II or rIL2), interferon dolasetron: doxifluridine; droloxifene; dronabinol; duocar alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa mycin SA; ebselen; ecomustine, edelfosine; edrecolomab; n3, interferon beta-I a, interferon gamma-Ib, iproplatin, 35 eflornithine; elemene; emitefur; epirubicinepristeride; estra irinotecan hydrochloride, lanreotide acetate, letrozole, leu mustine analogue; estrogen agonists; estrogen antagonists; prolide acetate, liarozole hydrochloride, lometrexol sodium, etanidazole; etoposide phosphate; exemestane; fadrozole; lomustine, losoxantrone hydrochloride, masoprocol, may fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; tansine, mechlorethamine hydrochloride, megestrol acetate, flezelastine; fluasterone; fludarabine; fluorodaunorunicin melengestrol acetate, melphalan, menogaril, mercaptopu 40 hydrochloride; forfenimex; formestane; fostriecin: fotemus rine, methotrexate, methotrexate sodium, metoprine, meture tine; gadolinium texaphyrin; gallium nitrate; galocitabine; depa, mitindomide, mitocarcin, mitocromin, mitogillin, ganirelix; gelatinase inhibitors; gemcitabine; glutathione mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone inhibitors; hepsulfam; heregulin; hexamethylene bisaceta hydrochloride, mycophenolic acid, nocodazole, nogalamy mide; hypericin; ibandronic acid; idarubicin; idoxifene; idra cin, Ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomy 45 mantone; ilmofosine; illomastat; imidazoacridones; imiqui cin, pentamustine, peplomycin Sulfate, perfosfamide, pipo mod; immunostimulant peptides; insulin-like growth factor-1 broman, piposulfan, piroXantrone hydrochloride, receptor inhibitor; interferon agonists; interferons; interleu plicamycin, plomestane, porfimer Sodium, porfiromycin, kins; iobenguane; iododoxorubicin: 4-ipomeanol; iroplact; prednimustine, procarbazine hydrochloride, puromycin, irsogladine, isobengaZole; isohomohalicondrin B; itasetron; puromycin hydrochloride, pyrazofurin, riboprine, rogletim 50 jasplakinolide; kahalalide F. lamellarin-N triacetate; lan ide, Safingol, Safingol hydrochloride, Semustine, simtraZene, reotide; leinamycin; lenograstim; lentinan Sulfate; leptolsta sparfosate Sodium, sparsomycin, spirogermanium hydro tin; letrozole; leukemia inhibiting factor, leukocyte alpha chloride, Spiromustine, spiroplatin, streptonigrin, StreptoZo interferon; leuprolide+estrogen-progesterone; leuprorelin; cin, Sulofenur, talisomycin, tecogalan Sodium, tegafur, telox levamisole; liarozole; linear polyamine analogue; lipophilic antrone hydrochloride, temoporfin, teniposide, teroxirone, 55 disaccharide peptide; lipophilic platinum compounds; lisso testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, clinamide 7: lobaplatin; lombricine; lometrexol; lonidamine: tirapazamine, toremifene citrate, trestolone acetate, tricirib losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium ine phosphate, trimetrexate, trimetrexate glucuronate, trip texaphyrin; lysofylline; lytic peptides; maitansine; mannosta torelin, tubuloZole hydrochloride, uracil mustard, uredepa, tin A; marimastat; masoprocol; maspin; matrilysin inhibitors; vapreotide, verteporfin, vinblastine sulfate, Vincristine sul 60 matrix metalloproteinase inhibitors; menogaril; merbarone; fate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Vingly meterelin; methioninase; metoclopramide; MIF inhibitor; cinate sulfate, Vinleurosine sulfate, vinorelbine tartrate, Vin mifepristone; miltefosine; mirimostim; mismatched double rosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin, Stranded RNA, mitoguaZone; mitolactol, mitomycin ana Zinostatin, Zorubicin hydrochloride. logues; mitonafide; mitotoxin fibroblast growth factor Examples of other anti cancer drugs include, but are not 65 saporin, mitoxantrone; mofarotene; molgramoStim; mono limited to, 20-epi-1.25 dihydroxyvitamin D3; 5-ethynylu clonal antibody, human chorionic gonadotrophin; monophos racil; abiraterone; aclarubicin; acylfulvene; adecypenol; ado phoryl lipid A+myobacterium cell wall sk; mopidamol; mul US 8,026,254 B2 95 96 tiple drug resistance gene inhibitor, multiple tumor lorazepam, oxazepam, and prazepam, non-benzodiazepine Suppressor-1 based therapy; mustard anticancer agent; agents, such as buspirone; and tranquilizers, such as barbitu my caperoxide B; mycobacterial cell wall extract; myriapor ates. one; N-acetyldinaline; N-substituted benzamides; nafarelin; Examples of useful anti-diarrheal agents include, but are nagrestip; naloxone-pentazocine; napavin; naphterpin, nar not limited to, loperamide, diphenoxylate with atropine, tograstim; nedaplatin: nemorubicin; neridronic acid; neutral clonidine, octreotide, and cholestyramine. endopeptidase; nilutamide; nisamycin; nitric oxide modula A 4-Tetrazolyl-4-phenylpiperidine Compound and the tors; nitroxide antioxidant; nitrullyn, O6-benzylguanine; oct other therapeutic agent can act additively or, in one embodi reotide; okicenone, oligonucleotides; onapristone; ment, Synergistically. In one embodiment, a 4-Tetrazolyl-4- ondansetron; ondansetron; oracin; oral cytokine inducer, 10 phenylpiperidine Compound is administered concurrently ormaplatin: osaterone; oxaliplatin, oxaunomycin; paclitaxel; with another therapeutic agent; for example, a composition paclitaxel analogues; paclitaxel derivatives; palauamine; comprising an effective amount of a 4-Tetrazolyl-4-phenylpi palmitoylrhizoxin; pamidronic acid; panaxytriol: peridine Compound, an effective amount of another thera panomifene; parabactin; paZelliptine; pegaspargase; peutic agent can be administered. Alternatively, a composi 15 tion comprising an effective amount of a 4-Tetrazolyl-4- peldesine; pentosan polysulfate sodium; pentostatin: pentro phenylpiperidine Compound and a different composition Zole; perflubron; perfosfamide; perillyl alcohol; phenazino comprising an effective amount of another therapeutic agent mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo can be concurrently administered. In another embodiment, an carpine hydrochloride; pirarubicin; piritrexim; placetin A; effective amount of a 4-Tetrazolyl-4-phenylpiperidine Com placetin B; plasminogen activator inhibitor, platinum com pound is administered prior or Subsequent to administration plex; platinum compounds; platinum-triamine complex; por of an effective amount of another therapeutic agent. In this fimer Sodium; porfiromycin; prednisone; propyl bis-acri embodiment, the 4-Tetrazolyl-4-phenylpiperidine Com done; prostaglandin J2, proteasome inhibitors; protein pound is administered while the other therapeutic agent exerts A-based immune modulator, protein kinase C inhibitor, pro its therapeutic effect, or the other therapeutic agent is admin tein kinase C inhibitors, microalgal; protein tyrosine phos 25 istered while the 4-Tetrazolyl-4-phenylpiperidine Compound phatase inhibitors; purine nucleoside phosphorylase inhibi exerts its preventive or therapeutic effect for treating or pre tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin venting pain or diarrhea. polyoxyethylene conjugate, raf antagonists; raltitrexed: A composition of the invention is prepared by a method ramosetron; ras farnesyl protein transferase inhibitors; ras comprising admixing a 4-Tetrazolyl-4-phenylpiperidine inhibitors: ras-GAP inhibitor; retelliptine demethylated; rhe 30 Compound or a pharmaceutically acceptable salt thereof and nium Re 186 etidronate; rhizoxin: ribozymes: RII retinamide: a pharmaceutically acceptable carrier or excipient. Admixing rogletimide; rohitukine; romurtide; roquinimex: rubiginone can be accomplished using methods known for admixing a B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A: compound (or salt) and a pharmaceutically acceptable carrier Sargramostim; Sdi 1 mimetics; Semustine; senescence or excipient. In one embodiment the composition is prepared derived inhibitor 1; sense oligonucleotides; signal transduc 35 such that the 4-Tetrazolyl-4-phenylpiperidine Compound is tion inhibitors; signal transduction modulators; single chain present in the composition in an effective amount. antigen binding protein; sizofuran; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin 4.4.2 Kits binding protein; Sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem 40 The invention encompasses kits that can simplify the cell inhibitor; stem cell division inhibitors; stipiamide: administration of a 4-Tetrazolyl-4-phenylpiperidine Com stromelysin inhibitors; sulfinosine; Superactive vasoactive pound to an animal. intestinal peptide antagonist; Suradista; Suramin; Swainso A typical kit of the invention comprises a unit dosage form nine; synthetic glycosaminoglycans; tallimustine; tamoxifen of a 4-Tetrazolyl-4-phenylpiperidine Compound. In one methiodide; tauromustine; tazarotene; tecogalan Sodium; 45 embodiment, the unit dosage form is a container, in one tegafur, tellurapyrylium; telomerase inhibitors; temoporfin; embodiment a sterile container, containing an effective temozolomide; teniposide; tetrachlorodecaoxide; tetraZom amount of a 4-Tetrazolyl-4-phenylpiperidine Compound and ine; thaliblastine; thiocoraline; thrombopoietin; thrombopoi a pharmaceutically acceptable carrier or excipient. The kit etin mimetic; thymalfasin; thymopoietin receptor agonist; can further comprise a label or printed instructions instructing thymotrinan; thyroid stimulating hormone; tin ethyl etiopur 50 the use of the 4-Tetrazolyl-4-phenylpiperidine Compound to purin; tirapazamine; titanocene bichloride; top sentin; treat or prevent pain or diarrhea. The kit can also further toremifene; totipotent stem cell factor; translation inhibitors: comprise a unit dosage form of another therapeutic agent, for tretinoin; triacetyluridine; triciribine; trimetrexate; triptore example, a container containing an effective amount of the lin; tropisetron; turosteride; tyrosine kinase inhibitors; tyr other therapeutic agent. In one embodiment, the kit comprises phostins; UBC inhibitors; ubenimex; urogenital sinus derived 55 a container containing an effective amount of a 4-Tetrazolyl growth inhibitory factor; urokinase receptorantagonists; vap 4-phenylpiperidine Compound and an effective amount of reotide; variolin B; vector system, erythrocyte gene therapy: another therapeutic agent. Examples of other therapeutic velaresol; veramine; verdins; verteporfin; vinorelbine; vinx agents include, but are not limited to, those listed above. altine; vitaxin; Vorozole; Zanoterone; Zeniplatin: Zilascorb: Kits of the invention can further comprise a device that is and Zinostatin stimalamer. 60 useful for administering the unit dosage forms. Examples of Therapeutic agents useful for treating or preventing an Such devices include, but are not limited to, Syringes, drip addictive disorder include, but are not limited to, methadone, bags, patches, enema bags, and inhalers. desipramine, amantadine, fluoxetine, buprenorphine, an opi The following examples are set forth to assist in under ate agonist, 3-phenoxypyridine, or a serotonin antagonist. standing the invention and should not, of course, be construed Examples of useful anti-anxiety agents include, but are not 65 as specifically limiting the invention described and claimed limited to, benzodiazepines, such as alprazolam, chlordiaz herein. Such variations of the invention, including the substi epoxide, clonazepam, cloraZepate, diazepam, halazepam, tution of all equivalents now known or later developed, which US 8,026,254 B2 97 98 would be within the purview of those skilled in the art, and -continued changes in formulation or minor changes in experimental N design, are to be considered to fall within the scope of the N N invention incorporated herein. s / NH N 5. EXAMPLES Examples 1-7 relate to the synthesis of illustrative 4-Tet razolyl-4-phenylpiperidine Compounds of the present inven tion. 10 ()" 5.1 Example 1

Synthesis of Compound AAA To a solution of (C) (0.5 mmol) in 10 ml toluene were 15 added 2 equivalents of MeSiN and 0.1 eq of dibutyl tinox ide. The mixture was stirred at reflux under an argon atmo sphere for 24 hours. LC/MS indicated a complete reaction. Scheme 11 The solvent was evaporated in vacuo. The crude materials was dissolved in CHCl and loaded onto the column which was loaded with 5 g of silica gel. Flash chromatography was ( ) Br H-N CN carried out eluting with 5% EtN, 25% ethyl acetate and 70% DIEA Hexane, then 10% EtN, 40% EtOAc, 50% Hexane. Finally -- DMF eluting with 2% NH/HO, 15% methanol, and 83% CHC1. H 80° C. This gave the compound (AAA) as a solid. Compound 25 (AAA):Yield 30%; Purity (HPLC) >97%; MS: m/z 424.2; H NMR (MeOD): & 2.3-2.5 (m, 4H), 2.8-3.1 (m, 6H), 3.4-3.5 ( ) (B) (m. 2H), 3.9 (t, 1H), 7.1-7.3 (m. 15H). (A) 5.2 Example 2 30 ( ) N CN Synthesis of Compound ACY ( )." Scheme 13 (C) ( ) Br H-N CN 40 DIEA -- To a solution of (A)(3.0 mmol) and (B)(3.0 mmol) in 10 ml DMF DMF were added 1.2 equivalents of DIEA. The mixture was CN 80° C. stirred at 80°C. overnight. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water (20 mlx2). ( ) (B) The aqueous layer was extracted once with ethyl acetate (25 45 ml). The combined organic phases were dried (Na2SO4) and (D) the solvent was removed on a rotoevaporator. The residue was purified by column chromatography (5% NEt/25% EtOAc/ 70% hexane) to give the desired product (C) as a colorless CN solid. Compound (C):Yield: 85%, purity (HPLC) >97%; MS: m/z381.3; H NMR (CDC1): 82.05-2.15 (m, 4H), 2.25-2.35 (m. 2H), 2.4-2.5 (m, 4H), 2.95-3.05 (m, 2H), 4.0 (t, 1H), 7.1-7.4 (m. 11H), 7.4-7.5 (m, 2H), 7.5-7.55 (m, 2H).

55 Scheme 12 (E)

To a solution of (D)(3.0 mmol) and (B)(3.0 mmol) in 10 ml N DMF were added 1.2 equivalents of DIEA. The mixture was MeSiN 60 He stirred at 80°C. overnight. The reaction mixture was cooled, toluene, reflux diluted with ethyl acetate, and washed with water (20 mlx2). dibutyltinoxide The aqueous layer was extracted once with ethyl acetate (25 ml). The combined organic phases were dried (NaSO) and the solvent was removed on rotoevaporator. The residue was ( )." 65 purified by column chromatography (5% NEts/25% EtOAc/ (C) 70% hexane) to give the desired product (E) as a colorless solid. Compound (E):Yield: 80%; purity (HPLC) >97%; MS: US 8,026,254 B2 99 100 m/z 406.2; H NMR (CDC1): 82.0-2.1 (m, 4H), 2.5-2.7 (m, -continued 6H), 2.9-3.0 (m, 2H), 7.3-7.5 (m. 15H). O An-Nullsf 1n Scheme 14 FN y/ -- NC N MeSiN -e- 10 ADI Xylene, reflux N N11S SN ( ) CN O Ph Ph N N- n-1 (E) 15 N y/ O N1SN NC / NH BDI N

To a solution of compound (ACY) (0.45 mmol) in dry DMF was added triethylamine (0.54 mmol), followed by the ( ) CN alkylating agent Br (CH2)C(O)O(CHCH) (0.54 mmol). 25 The resulting mixture was stirred at 80° C. overnight. After ACY completion of the reaction, the cooled mixture was parti tioned between ether and brine, and the organic phase was To a solution of (E) (4.0 mmol) in 15 ml p-xylene were separated, dried (MgSO), and the solvent was removed at the added 1.1 equivalents of MeSnN. The mixture was stirred at rotary evaporator to yield a colorless to pale yellow gum. reflux under an argon atmosphere for 36 hours. The reaction 30 Trituration with ether/hexanes or ether?ethylacetate (1:1, 10 mixture was cooled and poured into 150 ml 1M NaOH. mL) precipitated compound (ADI) as a white solid from the Diethyl ether (150 ml) was added and this solution was mother liquor: yield: 24%; purity (HPLC) >97%; MS: m/z. allowed to stir at room temperature for 1 hour. The layers 549.3 (M+1); H NMR (DMSO d6): 8 2.2-2.6 (m, 6H), 2.7- were separated and the aqueous layer extracted with diethyl 2.9 (m, 4H), 3.05 (t,3H), 3.2-3.4 (m, 4H), 3.95 (q, 2H), 4.9 (t, ether (150 mlx1). The aqueous layer was acidified to pH 6.3 35 with acetic acid/ammonium acetate. The solid was filtered, 2H), 7.1-8.1 (m, 17H). washed with water (100 ml), and triturated with cold metha The mother liquor comprises compound (ADI) and com nol to give the product as a white solid. Flash chromatography pound (BDI), which are separated using conventional sepa eluting with ethyl acetate, then ethyl acetate:methanol (70: ration methods. 30), gave compound (ACY) as a white solid. Compound 40 (ACY) (5.0 g, 11.14 mmol) was suspended in boiling metha nol (200 mL) with stirring. Sulfamic acid (1.08 g 11.14 5.4 Example 4 mmol) in hot water (5 mL) was added to form a clear solution. This was allowed to cool slowly for several hours, then fil tered to provide the sulfamate salt of compound (ACY) (4.46 Synthesis of Compound ADQ and BDQ g, 73%) as white needles. Compound (ACY) (sulfamate salt): 45 purity >97% (HPLC); MS: m/z 449.2: "H NMR (DMSO-d6): 8 2.25-2.4 (m, 2H), 2.4-2.5 (m, 2H), 2.55-2.65 (m, 2H), 2.7-2.85 (m, 4H), 3.1-3.25 (m, 2H), 3.3-3.4 (bs, 2H), 7.2-7.3 Scheme 16 (m,3H), 7.3-7.4 (m, 4H), 7.4-7.5 (m, 8H). N 50 N1 SN 5.3 Example 3 \ / y/- NH He1) DMF, NEts Synthesis of Compound ADI and BDI 55 NC

ACY Scheme 15 N N N% YN NHSOCH 1 S. / N- 2-13 N N 1) DMF, NEt 60 FN NH O Ph Ph N y/ N ~~ y/ -- NC NC 65 ACY ADQ US 8,026,254 B2 101 102 -continued To a solution of (ACY) (0.78 mmol) in dry DMF (5 mL) 1 N was added triethylamine (0.94 mmol), followed by 2-bro N1 NN moacetamide (0.27 mmol). The resulting mixture was heated \ { at 80° C. overnight. After completion of the reaction, the 5 cooled mixture was partitioned between ether and brine, and y/ N1 NHsoch, the organic phase was separated, dried (MgSO4), and the solvent removed at the rotary evaporator to yield a paleyellow NC gum. Flash chromatography (SiO, ether:methanol:ammo nium hydroxide (1000:4:1)) gave compound (ACZ) as a BDQ 10 white solid. (48% yield). Compound (ACZ): purity >97% (HPLC); MS: m/z 506.2 (M+1); H NMR (DMSO d6): 81.8 To a solution of compound (ACY) (0.45 mmol) in dry (m. 2H), 2.2 (m, 4H), 2.6-2.8 (m, 6H), 5.35 (s. 2H), 7.0–7.5 DMF was added triethylamine (0.54 mmol), followed by the (m. 16H), 7.7 (m, 1H). alkylating agent (Br (CH)NHSOCH) (0.54 mmol). The Further chromotography provides compound (BCZ). resulting mixture was stirred at 80° C. overnight. After 15 completion of the reaction, the cooled mixture was parti 5.6 Example 6 tioned between ether and brine, and the organic phase was separated, dried (MgSO), and the solvent was removed at the Synthesis of Compound AFD rotary evaporator to yield a colorless to pale yellow gum. Trituration with ether/hexanes or ether?ethylacetate (1:1, 10 mL) precipitated compound (ADQ) as a white solid from the mother liquor: yield: 59%; purity (HPLC) >97%; MS: m/z. 570.2 (M+1): 'H NMR (CDOD): 8 2.1-2.3 (m, 6H), 2.6-2.7 Br (m. 2H), 2.75 (s.3H)2.85 (d. 4H), 3.25-3.35 (m. 1H), 3.6 (t, 25 O 2H), 4.65 (t, 2H), 7.15-7.2 (m, 1H), 7.25-7.35 (m, 6H), 7.38 7.45 (m, 8H). HO SOCl. The mother liquor comprises compound comprises com He pound (ADQ) and compound (BDQ), which are separated using conventional separation methods. 30

5.5 Example 5 (F) -- CH Synthesis of Compounds ACZ and BCZ Br H3 C N. O 35 O YH HC1'N, Br M C HC Scheme 17 N N1/S SN 40 Na2CO3 O \ / NH 1) DMF, NEt Ph Ph N Her (G) (H) 2) B1 NeoNH, 45 NC 4-Bromo-2,2-diphenylbutyric acid (compound (F), 23 g, 72 mmol) was suspended in 150 mL of chloroform, and 20 ACY mL of thionyl chloride (270 mmol) was added dropwise. N After addition of the thionyl chloride, 0.2 mL of dimethylfor mamide was added, and the resulting solution heated at reflux 50 for about 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-bromo-2,2-diphenylbu tyric acid chloride (compound (G) as a pale yellow oil that was used int the following step without further purifiction. NC To 100 mL of saturated aqueous NaCO was added 50 mL of a 2M solution of dimethylamine in tetrahydrofuran. The ACZ N resulting solution was cooled to 0°C. and a solution of com N1/S NN pound (G), prepared as described above, dissolved in 100 mL f of toluene was added dropwise. The resulting mixture was N 60 allowed to stir for about 12 hours. The organic and aqueous Ph Ph N N1NH, layers of the reaction mixture were separated and the aqueous y/ O layer was extracted with 30 mL of toluene and then extracted NC 3 times with 100 mL of chloroform and the organics were combined. The combined organic extracts were washed with BCZ 65 water (30 mL), dried (KCO), and the solvent was removed under reduced pressure to provide a residue that was crystal lized from methyl isobutyl ketone to provide 12 g (53% yield) US 8,026,254 B2 103 104 of dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammo -continued nium bromide (compound (H)). N1/ NSN \ NH/ N

O Br NN 10 ( ) / AFD

15 To a solution of compound (I) (0.5 mmol) in 10 ml toluene (H) were added 2 equivalents of MeSiN and 0.1 eq of dibutyl tinoxide. The mixture was stirred at reflux under an argon atmosphere for 24 hours. LC/MS indicated the reaction was CN complete. The solvent was evaporated under reduced pres H-N Na2CO3 sure. The crude product was dissolved in CHCl and loaded Hess DMF onto the column containing 5 g of silica gel. Flash chroma 80° C. tography was carried out eluting with 5% EtN, 25% ethyl acetate and 70% hexane, then 10% EtN, 40% EtOAc, 50% hexane, and finally eluting with 2% NH/HO, 15% methanol (B) 25 and 83% CHC1. Compound (AFD) was obtained as a solid (yield: 35%); purity >97% (HPLC); MS: m/z 495.2; H NMR (DMSO d6): 8 2.2 (bs, 3H), 2.3-2.4 (m, 2H), 2.5 (m, 3H), 2.6-2.7 (m, 2H), 2.7–2.8 (m, 2H), 2.9 (bs, 3H), 3.3-3.4 (bs, 3H), 7.2-7.3 (m, 3H), 7.3-7.4 (m, 4H), 7.4-7.5 (m, 8H). N 30 5.7 Example 7

Synthesis of Compounds AFE and BFE 35 ()Y1N (I) Scheme 21 NN To a solution of compound (H) (3.0 mmol) and (B) (3.0 40 M NH mmol) in 10 ml DMF were added 3 equivalents of Na2CO. N N e The mixture was stirred at 80° C. for 3 hours. The reaction N mixture was cooled, diluted with ethyl acetate, and washed with water (20 mlx2). The aqueous layer was extracted once with ethyl acetate (25 ml). The combined organics were dried 45 1) DMF, NEt (NaSO) and the solvent was removed on a rotoevaporator. N O The residue was purified by column chromatography (5% -> NEts/25% EtOAc/70% hexane) to give product compound (I) Ph NMe2 NH2 as colorless crystals: (yield: 81%); purity (HPLC): >97%; MS: m/z 452.2; H NMR (CDC1): 8 2.0-2.1 (m, 4H), 2.2 (m, 50 2H), 2.3-2.4 (m, 5H), 2.4-2.5 (m, 2H), 2.9 (m, 2H), 3.0 (bs, Ph O 3H), 7.2-7.3 (m, 3H), 7.3-7.5 (m, 12H). AFD

55 Scheme 20 NN O NA N eN NH2 N MeSiN 60 -- Ph Ph N -- O toluene, reflux dibutyltin oxide

( ) -N 65 O NMe2 (I) AFE US 8,026,254 B2 105 106 -continued -continued N O NN N N N N n1n NH N Nuá. NH2 Ph Ph N Ph Ph N OR i EO CH3 O NMe2 O NMe2 10 BFW BFE To a solution of compound (AFD) (0.40 mmol) in dry DMF To a solution of compound (AFD) (0.40 mmol) in dry DMF was added triethylamine (0.45), followed by the alkylating was added triethylamine (0.45), followed by the alkylating 15 agent agent Br (CH2)C(O)NH2 (0.45 mmol). The resulting agent Br (CH2)C(O)NH2 (0.45 mmol). The resulting mixture mixture was stirred at 80°C. overnight. After completion of was stirred at 80°C. overnight. After completion of the reac the reaction, the cooled mixture was poured into 1M NaOH tion, the cooled mixture was poured into 1MNaOH (150 mL) (150 mL) and extracted with ethyl acetate (2x100 mL). The and extracted with ethyl acetate (2x100 mL). The organic organic extracts were dried (MgSO) and the solvent evapo extracts were dried (MgSO) and the solvent evaporated at the rated at the rotary evaporator to leave a gum. Flash chroma rotary evaporator to leave a gum. Flash chromatography of tography of the residue (SiO, ether:methanol:ammonium the residue (SiO, ether:methanol:ammonium:hydroxide hydroxide (200:10:1)) provided compound (AFV) as a col (200:10:1)) provided compound (AFE) as a colorless gum: orless gum: (yield: 26%); purity >97% (HPLC); MS: m/z (yield 69%); purity >97% (HPLC); MS: m/z.552.3 (M+1): 1H 25 616.3 (M+1); H NMR (DMSO d6): 8 2.1-2.2 (brs, 3H), NMR (DMSO d6): 8 2.2-23 (brs, 3H), 2.35-3.0 (m. 11H), 2.3-2.4 (m, 5H), 2.75 (s.3H)2.9-2.10 (brs, 3H), 3.3-3.4 (m, 3.3-3.4 (m, 4H), 7.15-7.5 (m, 16H), 7.8 (brs, 1H). 6H), 3.5 (m, 3H), 4.65 (m, 2H), 7.15-7.5 (m, 16H). Further chromatography provides compound (BFE). Further chromatography provides compound (BFV). 30 5.9 Example 22 5.8 Example 8 L- and ORL-1-Receptor-Binding Affinity Assays Synthesis of Compounds AFV and BFV The following example will demonstrate that 4-Tetrazolyl 35 4-phenylpiperidine Compounds bind to u- or ORL-1-recep tors and, accordingly, are useful for treating or preventing pain or diarrhea. Scheme 22 N 5.9.1 Materials and Methods A NH 40 N M -2 ORL-1 Receptor Membrane Preparation N All reagents are obtained from Sigma (St. Louis, Mo.) unless noted otherwise. Membranes from recombinant HEK 1) DMF, NEt Her 293 cells expressing the human opioid receptor-like (ORL-1) HCOS N 3 2 45 receptor (Perkin Elmer, Boston, Mass.) are prepared by lys ing cells in ice-cold hypotonic buffer (2.5 mMMgCl, 50 mM Br 1n-NH HEPES, pH 7.4) (10 mL/10 cm dish), followed by homog Ph NMe2 enization with a tissue grinder/teflon pestle. Membranes are collected by centrifugation at 30,000xg for 15 min at 4°C., and pellets are resuspended in hypotonic buffer to a final Ph O concentration of 1-3 mg/mL. Protein concentrations are AFD determined using the BioRad (Hercules, Calif.) protein assay reagent with bovine serum albumen as standard. Aliquots of the ORL-1 receptor membranes are stored at -80° C. 55 L- and ORL-1-Receptor-Binding-Assay Procedures Radioligand dose-displacement binding assays for ORL-1 ANN N and a receptors use 0.1 nM H-nociceptin or 0.2nM H N diprenorphine (NEN, Boston, Mass.), respectively, with 5-20 leN t mg membrane protein/well in a final volume of 500 ml bind 60 ing buffer (10 mM MgCl, 1 mM EDTA, 5% DMSO, 50 mM Ph Ph N o==o -- HEPES, pH 7.4). Reactions are carried out in the absence or CH presence of increasing concentrations of unlabled nociceptin (American Peptide Company, Sunnyvale, Calif.) or naloxone, for ORL-1 and L, respectively. All reactions are conducted in O NMe2 65 96-deep well polypropylene plates for 1-2 hat room tempera AFW ture. Binding reactions are terminated by rapid filtration onto 96-well Unifilter GF/C filter plates (Packard, Meriden, US 8,026,254 B2 107 108 Conn.) presoaked in 0.5% polyethylenimine using a 96-well filter plates (Packard, Meriden, Conn.) using a 96-well tissue tissue harvester (Brandel, Gaithersburg, Md.) followed per harvester (Brandel, Gaithersburg, Md.) followed by three forming by three filtration washes with 500 uL of ice-cold filtration washes with 200 uL of ice-cold binding buffer (10 binding buffer. Filter plates are subsequently dried at 50° C. mM NaH2PO, 10 mM NaHPO, pH 7.4). Filter plates are for 2-3 h. BetaScint scintillation cocktail (Wallac, Turku, 5 subsequently dried at 50° C. for 2-3 h. BetaScint scintillation Finland) is added (50 ul/well), and plates are counted using a cocktail (Wallac, Turku, Finland) is added (50 uL/well) and Packard Top-Count for 1 min/well. The data are analyzed plates are counted using a Packard Top-Count for 1 min/well. using the one-site competition curve fitting functions in Data are analyzed using the sigmoidal dose-response curve GraphPad PRISM v. 3.0 (San Diego, Calif.). fitting functions in GraphPad PRISM, V. 3.0. 10 5.9.2 L-Receptor-Binding Data 5.10.2 u-Receptor Function Data Generally, the lower the Ki value, the more effective the LGTPECs is the concentration of a compound providing 4-Tetrazolyl-4-phenylpiperidine Compounds are at treating 50% of the maximal response for the compound at a LL recep or preventing pain or diarrhea. Typically, the 4-Tetrazolyl-4- tor. 4-Tetrazolyl-4-phenylpiperidine Compounds typically phenylpiperidine Compounds will have a Ki (nM) of about having all GTPEC.so (nM) of about 5000 or less stimulate LL 300 or less for binding to u-opioid receptors. In one embodi opioid receptor function. In one embodiment, the 4-Tetra ment, the 4-Tetrazolyl-4-phenylpiperidine compounds will Zolyl-4-phenylpiperidine Compounds will have a LL GTP have a Ki (nM) of about 100 or less. In another embodiment, ECs (nM) of about 1000 or less. In still another embodiment, the 4-Tetrazolyl-4-phenylpiperidine Compounds of the the 4-Tetrazolyl-4-phenylpiperidine Compounds will have a present invention will have a Ki (nM) of about 10 or less. In L GTP ECs (nM) of about 100 or less. In still another still another embodiment, the 4-Tetrazolyl-4-phenylpiperi embodiment, the 4-Tetrazolyl-4-phenylpiperidine Com dine Compounds will have a Ki (nM) of about 1 or less. In still pounds will have all GTP. ECso (nM) of about 10 or less. In another embodiment, the 4-Tetrazolyl-4-phenylpiperidine still another embodiment, the 4-Tetrazolyl-4-phenylpiperi Compounds will have a Ki (nM) of about 0.1 or less. Com dine Compounds will have a LL GTPEC.so (nM) of about 1 or pound AFD, an illustrative 4-Tetrazolyl-4-phenylpiperidine 25 less. In still another embodiment, the 4-Tetrazolyl-4-phe Compound, has a Ki (nM) of 3.2 for binding to u-opioid nylpiperidine Compounds will have a LL GTP ECs (nM) of receptors. about 0.1 or less. LGTP Emax % is the maximal effect elicited by a com 5.9.3 ORL-1-Receptor-Binding Data pound relative to the effect elicited by D-Ala2, N-methyl Phe-A, Gly-ol5-enkephalin (“DAMGO), a standard Lago 30 nist. Generally, the LL GTP Emax (%) value measures the Generally, the lower the Ki value, the more effective the efficacy of a compound to treat or prevent pain or diarrhea. 4-Tetrazolyl-4-phenylpiperidine Compounds are at treating Typically the 4-Tetrazolyl-4-phenylpiperidine Compounds or preventing pain or diarrhea. Typically, the 4-Tetrazolyl-4- will have a LL GTP Emax (%) of greater than 50%. In one phenylpiperidine Compounds will have a Ki (nM) of about embodiment the 4-Tetrazolyl-4-phenylpiperidine Com 10,000 or less for ORL-1 receptors. In one embodiment, the pounds will have all GTP Emax (%) of greater than 75%. In 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki 35 still another embodiment the 4-Tetrazolyl-4-phenylpiperi (nM) of about 2000 or less. In another embodiment, the dine Compounds will have all GTPEmax (%) of greater than 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki 88%. In still another embodiment the 4-Tetrazolyl-4-phe (nM) of about 1000 or less. In still another embodiment, the nylpiperidine Compounds will have a LL GTP Emax (%) of 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki greater than 100%. (nM) of about 100 or less. In still another embodiment, the 40 4-Tetrazolyl-4-phenylpiperidine Compounds will have a Ki 5.10.3 ORL-1-Receptor Function Data (nM) of about 10 or less. ORL-1 GTP ECso is the concentration of a compound 5.10 Example 23 providing 50% of the maximal response for the compound at 45 an ORL-1 receptor. 4-Tetrazolyl-4-phenylpiperidine Com L- and ORL-1-Opioid Receptor YS Functional pounds having a ORL-1 GTPEC.so (nM) of about 10,000 or Activity less stimulate ORL-1 opioid-receptor function. In one embodiment, the 4-Tetrazolyl-4-phenylpiperidine Com The following example will demonstrate that 4-Tetrazolyl pounds will have a ORL-1 GTP ECs (nM) of about 1000 or 4-phenylpiperidine Compounds stimulate u- or ORL-1-re less. In still another embodiment, the 4-Tetrazolyl-4-phe ceptor function and, accordingly, are useful for treating or 50 nylpiperidine Compounds will have a ORL-1 GTPEC.so (nM) preventing pain or diarrhea. of about 100 or less. In still another embodiment, the 4-Tet razolyl-4-phenylpiperidine Compounds will have a ORL-1 5.10.1 Materials and Methods GTPEC.so (nM) of about 50 or less. In still another embodi ment, the 4-Tetrazolyl-4-phenylpiperidine Compounds will SIGTPYS functional assays are conducted using freshly 55 have a ORL-1 GTP ECs (nM) of about 10 or less. thawed ORL-1 or L-receptor membranes, as appropriate. ORL-1 GTP Emax % is the maximal effect elicited by a Assay reactions are prepared by sequentially adding the fol compound relative to the effect elicited by nociceptin, a stan lowing reagents to binding buffer (100 mM NaCl, 10 mM dard ORL-1 agonist. Generally, the ORL-1 GTP Emax (%) MgCl2, 20 mM HEPES, pH 7.4) on ice (final concentrations value measures the efficacy of a compound to treat or prevent indicated): membrane protein (0.066 mg/mL for ORL-1 pain or diarrhea. Typically the 4-Tetrazolyl-4-phenylpiperi receptor and 0.026 mg/mL for L-receptor), Saponin (10 60 dine Compounds have a ORL-1 GTP Emax (%) of greater mg/ml), GDP (3 mM) and SIGTPYS (0.20 nM; NEN). The than 50%. In one embodiment the 4-Tetrazolyl-4-phenylpip prepared membrane solution (190 uL/well) is transferred to eridine Compounds will have a ORL-1 GTP Emax (%) of 96-shallow well polypropylene plates containing 10 LIL of greater than 75%. In still another embodiment the 4-Tetra 20x concentrated Stock Solutions of the agonist nociceptin Zolyl-4-phenylpiperidine Compounds will have a ORL-1 prepared in dimethyl sulfoxide (“DMSO). Plates are incu 65 GTP Emax (%) of greater than 88%. In still another embodi bated for 30 minatroom temperature with shaking. Reactions ment the 4-Tetrazolyl-4-phenylpiperidine Compounds will are terminated by rapid filtration onto 96-well Unifilter GF/B have a ORL-1 GTP Emax (%) of greater than 100%. US 8,026,254 B2 109 110 The present invention is not to be limited in scope by the 6. A composition comprising a compound or a pharmaceu specific embodiments disclosed in the examples which are tically acceptable salt of a compound of formula (Ib): intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. A number of references have been cited, the entire disclo sures of which are incorporated herein by reference. 10 What is claimed is: (R3) 1. A composition comprising a compound or a pharmaceu tically acceptable salt of a compound of formula (Ia): wherein 15 Ar is —C-Cs cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or -(5- to 7-membered) heteroaryl, each being unsubstituted or substituted with one or more R. groups: CN Ar is phenyl, naphthyl, anthryl, phenanthryl or -(5- to 2O 7-membered) heteroaryl, each being unsubstituted or Substituted with one or more R groups; ( ) N G is —H. -L-(CH2)C(O)CR -L-(CH2)Rs, —(C-Cs alkylene)C(O)OR, or —(C-C alkylene)Rs: O N-CH L is —C(O)— —S(O) - or —S(O)—: CH3 25 R is -H, -C(O)NH2, C(O)NHOH, -C(O)OR, —C(O)H, —CN, —(C-C alkyl). —C(O)NH(C-C, alkyl), or—C(O)N(C-C alkyl); wherein RandR are each independently-halogen, —C-C alkyl, Ar is —C-Cs cycloalkyl, phenyl, naphthyl, anthryl, —O(C-C alkyl). —NH(C-C alkyl) or —N(C-C, phenanthryl or -(5- to 7-membered) heteroaryl, each 30 alkyl). being unsubstituted or substituted with one or more R. R is —H. —C-Co alkyl, —CH2O(C-C alkyl). groups; —CH2N(C-C alkyl), or —CH2NH(C-C alkyl); Ar is phenyl, naphthyl, anthryl, phenanthryl or -(5- to R is NH, -NHS(O).R.—C(O)NH-C(O)NHOH, 7-membered) heteroaryl, each being unsubstituted or —S(O)NH2. —C(O)NH(C-C alkyl). —C(O)N(C- Substituted with one or more R groups; C alkyl). —S(O)NH(C-C alkyl). —S(O)N(C-C, G is —H, -L-(CH2)C(O)OR. -L-(CH2)Rs, —(C-Cs 35 alkyl). —H. —OH, -CN. —C-C cycloalkyl, phenyl, alkylene)C(O)CR, or —(C-C alkylene)Rs: naphthyl, anthryl, phenanthryl, or -(5- to 7-membered) L is —C(O)— —S(O) or —S(O)—, heteroaryl, each being unsubstituted or substituted with R is -H, -C(O)NH2, C(O)NHOH, -C(O)OR, one or more R groups: —C(O)H, —CN, —(C-C alkyl), —C(O)NH(C-C, m is an integer ranging from 0 to 4: alkyl), or—C(O)N(C-C alkyl); 40 n is an integer ranging from 1 to 4: RandR are each independently-halogen, —C-C alkyl, p is 0 or 1; and —O(C-C alkyl), NH(C-C alkyl) or N(C-C, q is an integer ranging from 0 to 3: alkyl). a pharmaceutically acceptable carrier, and atherapeutic agent R is —H. —C-Co alkyl, —CH2O(C-C alkyl). selected from an opioid analgesic, a non-opioid analgesic, an —CHN(C-C alkyl), or —CH-NH(C-C alkyl); 45 anti-emetic agent, and an anti-diarrheal agent. Rs is NH, -NHS(O).R.—C(O)NH2, C(O)NHOH, 7. The composition of claim 6, wherein the therapeutic —S(O)NH2. —C(O)NH(C-C alkyl). —C(O)N(C- agent is an opioid analgesic. C alkyl). —S(O)NH(C-C alkyl). —S(O)N(C-C, 8. The composition of claim 6, wherein the therapeutic alkyl). —H. —OH, -CN. —C-Cs cycloalkyl, phenyl, agent is a non-opioid analgesic. naphthyl, anthryl, phenanthryl, or -(5- to 7-membered) 50 9. The composition of claim 6, wherein the therapeutic heteroaryl, each being unsubstituted or substituted with agent is an anti-emetic agent. one or more R groups: 10. The composition of claim 6, wherein the therapeutic agent is an anti-diarrheal agent. m is an integer ranging from 0 to 4: 11. The composition of claim 1, wherein the compound of n is an integer ranging from 1 to 4: formula (Ia) is selected from p is 0 or 1; and 55 q is an integer ranging from 0 to 3: a pharmaceutically acceptable carrier, and atherapeutic agent selected from an opioid analgesic, a non-opioid analgesic, an anti-emetic agent, and an anti-diarrheal agent. 2. The composition of claim 1, wherein the therapeutic 60 agent is an opioid analgesic. 3. The composition of claim 1, wherein the therapeutic agent is a non-opioid analgesic. ( ) N 4. The composition of claim 1, wherein the therapeutic O N-CH agent is an anti-emetic agent. 65 5. The composition of claim 1, wherein the therapeutic CH3 agent is an anti-diarrheal agent. US 8,026,254 B2 111 -continued -continued N O N22-N -n. s -N OH ( ) N O N-CH 10 CH3 N N12 YH, and -N 15 ( ) N

N O O N-CH 2 N. s N? -Y CH - N O N OH 2N. s N2- -n. ( ) N N NH2 25 O N-CH ( ) N O N-CH

30 N12 N.YNH, and FN and pharmaceutical salts thereof. 13. The composition of claim 12, wherein the compound of 35 formula (Ia) is

O N-CH CH3 40 1N \ { O, N? Ar y -N N H1NaN 45 H(R), N Ar R (R3) 21

or a pharmaceutical salt thereof. O N-CH H 50 14. The composition of claim 12, wherein the compound of formula (Ia) is and pharmaceutical salts thereof. 12. The composition of claim 11, wherein the compound of N formula (Ia) is selected from 55 N? S-re N OH N N O 2N. s C t / N?- -> N NH2 60 O N -CH ( ) N CH3 O N -CH 65 or a pharmaceutical salt thereof. CH 15. The composition of claim 14, wherein the therapeutic agent is an opioid analgesic. US 8,026,254 B2 113 114 16. The composition of claim 14, wherein the therapeutic 18. The composition of claim 14, wherein the therapeutic agent is a non-opioid analgesic. agent is an anti-diarrheal agent. 17. The composition of claim 14, wherein the therapeutic agent is an anti-emetic agent. k . . . .