WO2002081449A1 - Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors - Google Patents
Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors Download PDFInfo
- Publication number
- WO2002081449A1 WO2002081449A1 PCT/EP2002/003871 EP0203871W WO02081449A1 WO 2002081449 A1 WO2002081449 A1 WO 2002081449A1 EP 0203871 W EP0203871 W EP 0203871W WO 02081449 A1 WO02081449 A1 WO 02081449A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally
- substituted
- compound
- formula
- phenyl
- Prior art date
Links
- 0 CC(C(*)N(C(*)C1*)*2C(*)C(*)NC(*)C2*)C1N(C)I Chemical compound CC(C(*)N(C(*)C1*)*2C(*)C(*)NC(*)C2*)C1N(C)I 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to piperidine derivatives, process for their production, their uses and pharmaceutical compositions containing them.
- X is a direct bond; -CH 2 -; -CH 2 -CH 2 -; -CHR 9 -; -C(O)-; -O-; -NH- or NR 9 ;
- R ! is optionally R 10 and/or Rn-substituted phenyl; optionally Rio and/or Rn-substituted heteroaryl; optionally R 10 and/or Rn-substituted heteroaryl N-oxide; or optionally R 10 and/or Rn-substituted naphthyl;
- R 2 has one of the significances given for R 1f " or is optionally R 10 and/or Rn-substituted fluorenyl; optionally R 10 -substituted d-C 6 alkyl; optionally R 10 -substituted C 2 -C 6 al enyl; optionally R 10 -substituted C 3 -C ⁇ cycloalkyl; optionally R 10 -substituted adamantyl; or optionally R 10 -substituted C 4 -C 8 cycloalkenyl;
- R 3 has one of the significances given for Ri; or is optionally R 10 and/or Rn-substituted fluorenyl; R 10 -substituted C ⁇ -C 6 alkyl; optionally R ⁇ 0 -substituted C 2 -C 6 alkenyl; optionally Rio- substituted C 3 -C 6 cycloalkyl; optionally R ⁇ 0 -substituted adamantyl; or optionally Rio- substituted C 4 -C 8 cycloalkenyl; or
- A is -CH 2 -, -NH-, -NR 9 -, -S-, -SO-, SO 2 - or -O-, n is 0, 1 or 2, and the aromatic rings are each, independently optionally R ⁇ 0 -substituted; each of R4, independently, has one of the significances of R 5 ; or is CN; OH; OR 9 ; F; Cl; Br; or I; each of R 5 , independently, is H; Ci-Ce alkyl; C ⁇ -C ⁇ hydroxyalkyl; C 2 -C 6 alkoxyalkyl; C ⁇ -C 6 halogenoalkyl; phenyl; benzyl; or heteroaryl; each of R 6 , independently, has one of the significances given for R ; each of R 7 , independently, has one of the significances given for R 5 ;
- R 8 is H; C ⁇ -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C ⁇ alkynyl; phenyl; benzyl; CN; CH 2 NH 2 ; CH 2 NHR 9 ;
- each R 9 independently, is C ⁇ -C 6 alkyl; C 3 -C ⁇ cycloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; phenyl; benzyl; heteroaryl; or CF 3 ;
- R 10 represents 1 to 4 substituents independently selected from C ⁇ -C 6 alkyl; C ⁇ -C 6 hydroxyalkyl; C 2 -C 6 alkoxyalkyl; C C ⁇ halogenoalkyl; C 3 -C 6 cycloalkyl; C 2 -C 6 alkenyl; C 3 -C 6 cycloalkenyl; C 2 -C 6 alkynyl; phenyl; heteroaryl; heteroaryl N-oxide ; F; Cl; Br; I; OH; OR 9 ;
- NHC(O)NHR 9 NHC(O)NH 2 ; NR 9 C(O)NHR 9 ; NR 9 C(O)NR 9 R 9 ; NHC(O)OR 9 ; NR 9 C(O)OR 9 ;
- Rn represents two adjacent substituents which form an annulated 4-7 membered nonaromatic ring optionally containing up to two heteroatoms selected independently from
- Y is a direct bond; -C(O)-; -C(O)CH 2 -; -S(O)-; -S(O 2 )-; -C(S)-; -CH 2 -; -C(-CH 2 -CH 2 -)-; -CH(R 4 )- or -C(R 5 ) 2 -. in free form or in salt form.
- Any alkyl, alkenyl or alkynyl may be linear or branched.
- Halogeno is F, Cl, Br or I.
- heteroaryl an aromatic ring system comprising mono-, bi- or tricyclic systems which contains up to 4 heteroatoms independently selected from N, O and S, such as for example furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quin
- Preferred annulated 4-7membered non-aromatic ring as represented by Rn is annulated 5 or 6 membered non aromatic ring optionally containing 1 or 2 oxygen and include e.g. -O-CH 2 -O- or -O-CH 2 -CH 2 -O-, attached to 2 adjacent carbon atoms.
- the compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid, acetic acid when R t R 2 , and /or R 3 comprises an optionally substituted amino group or a heterocyclic residue which can form addition salts.
- addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid, acetic acid when R t R 2 , and /or R 3 comprises an optionally substituted amino group or a heterocyclic residue which can form addition salts.
- Ri is optionally R ⁇ 0 -substituted phenyl; optionally R ⁇ 0 -substituted heteroaryl; or optionally Rn-substituted phenyl,
- R is optionally R ⁇ 0 -substituted phenyl; optionally R ⁇ 0 -substituted heteroaryl; optionally Rio-substituted heteroaryl N-oxide; or optionally Ri 0 -substituted naphthyl.
- R 3 is optionally R ⁇ 0 -substituted phenyl; optionally R ⁇ 0 -substituted heteroaryl; or optionally Rio-substituted naphthyl.
- R 4 , R 5 , R 6 or R 7 independently, is H; C ⁇ -C 6 alkyl; or benzyl.
- R 8 is H; C ⁇ -C 6 alkyl; or C 2 -C 6 alkenyl.
- R 9 is C ⁇ -C 6 alkyl; C 3 -C 6 cycloalkyl; C 2 -C ⁇ alkenyl; C 2 -C 6 alkynyl; phenyl; benzyl; heteroaryl; or CF 3 .
- Rio represents 1 to 3 substituents independently selected from C ⁇ -C ⁇ alkyl; C ⁇ -C 6 hydroxyalkyl; C 2 -C 6 alkoxyalkyl; C ⁇ -C ⁇ halogenoalkyl; C 3 -C 6 cycloalkyl; C 2 -C 6 alkenyl; C 3 -C ⁇ cycloalkenyl; C 2 -C 6 alkynyl; phenyl; heteroaryl; heteroaryl N-oxide; F; Cl; Br; I; OH; OR 9 ; CONH 2 ; CONHR 9 ; CONR 9 R 9 ; OC(O)R 9 ; OC(O)OR 9 ; OC(O)NHR 9 ; OC(O)NR 9 R 9 ; OSO 2 R 9 ; COOH; COOR 9 ; CF 3 ; CHF 2 ; CH 2 F; CN; NO 2 ; NH 2 ; NHR 9 ; NR 9 R 9 ; NHC(
- Rn represents -O-CH 2 -O- attached on 2 adjacent carbon atoms.
- X is a direct bond or -CH 2 -. 10.
- Y is -C(O)-.
- R ⁇ 0 may represent 1-3 substituents selected from from C h alky!; phenyl; heteroaryl; heteroaryl N-oxide; F; Cl; Br; I; OH; OR 9 ; CONH 2 ; CONHR 9 ; CONR 9 R 9 ; COOH; COOR 9 ; CF 3 ; CHF 2 ; CH 2 F; NH 2 ; NHR 9 ; NR 9 R 9 ; NHC(O)R 9 ; NR 9 C(O)R 9 ; NHC(O)NHR 9 ; NHC(O)NH 2 ; NR 9 C(O)NHR 9 ; NR 9 C(O)NR 9 R 9 ; NHC(O)OR 9 and NR 9 C(O)OR 9 .
- R 9 is preferably C ⁇ -C 6 alkyl; C 3 -C e cycloalkyl; phenyl; benzyl; or heteroaryl; more preferably Ci-C 6 alkyl.
- the present invention also includes a process for the preparation of a compound of formula
- Y is -CO-, -C(O)CH 2 -, -S(O)- or -S(O 2 )-, amidating a compound of formula II
- Ri and R 3 to R 8 are as indicated above and X' is a direct bond, -CH 2 -,
- R 2 -Y'-A' III wherein R 2 is as defined above, Y * is -CO-, -C(O)CH 2 -, -S(O)- or -S(O 2 )- and A' is a leaving group, e.g.
- reaction steps a), b) or c) may be performed in accordance with methods known in the art or as disclosed in the Examples below.
- R 8 comprises a group which should not participate in the reaction, this group may be protected in accordance with methods known in the art.
- Boc is a protecting group which means tert.-butyloxycarbonyl. This protecting group may be replaced in above reaction scheme by any amino protecting group, e.g. as disclosed in "Protective Groups in Organic Synthesis” by T. W. Greene, J.Wiley & Sons NY, 2 nd ed., Chapter 7, 1991 and references therein, e.g. b ⁇ nzyloxycarbonyl or 9-f luorenylmethoxy carbonyl.
- Compounds of formula IV, used as starting material may be prepared as follows:
- R 2 to R 8 and Y are as defined above and Bn is benzyl.
- Boc tert.-Butyloxycarbonyl
- BINAP 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl
- the mixture is diluted with t-butyl methylether (25 ml), washed with 2N NaOH (25 ml) and brine (25 ml) and dried with sodium sulfate.
- the solvent is removed and the residue purified by chromatography (SiO 2 , t-butyl methylether/cyclohexane 1 :4- ⁇ 1 :0). The title compound is isolated as a colorless solid.
- (4'-Methyl-[1 ,4']bipiperidinyl-4-yl)-diphenyl-amine, used as starting material may be prepared as follows: a) A mixture of phenyl-piperidin-4-yl-amine (4.14 g; 15.0 mmol), iodobenzene (3.06 g; 15.0 mmol), Pd(OAc) 2 (0.14 g; 0.63 mmol); BINAP (0.43 g; 0.69 mmol), t-BuOK (17.5 ml of 1M solution in THF) in toluene (20 ml) is heated at 110°C for 5 h.
- Example 42 [1 , -(2,6-Dimethyl-benzyl)-4'-methyl-[1 ,4']bipiperidiny.-4-yl]-diphenyl- amine
- Bipiperidinyl-4-yl-dipherylamine used as starting materials, may be prepared as follows: a) A mixture of diphenyl-piperidin-4-yl-amine (1.06 g; 4.2 mmol), 4-oxo-piperidine-1 - carboxylic acid tert-butyl ester (1.0 g; 5.0 mmol), AcOH (0.62 g; 10.3 mmol) and Na(OAc) 3 BH (1.0 g; 4.7 mmol) in 1 ,2-dichloroethane (15 ml) is stirred for 4h at 65°C.
- R 2 has one of the significances given in Table 2, may be prepared
- Example 51 ⁇ 4-[(4-Bromo-phenyl)-phenyl-amino]-4'-methyl-[1 ,4']bip_peridinyl-1 '-yl ⁇ - (2,6-dimethyl-phenyl)-methanone
- [4-(4-bromo-pherylamino)-4'-methyl-[1 ,4] bipiperidinyl-1 'yl]-2,6-dimethylphenyl)-methanone, used as starting material, may be prepared as follows: a) 8-(1 -Benzyl-4-methyl-piperidin-4-yl)-1 ,4-dioxa-8-aza-spiro[4.5]decane is prepared from 1 ,4-dioxa-8-aza-spiro[4.5]decane and 1-benzyl-piperidin-4-one following a procedure as described in example 1c). MS/ESI 331 (M+H) + .
- Example 52 ⁇ 4-[Benzyl-(4-bromo-phenyl)-amlno]-4'-methyl-[1 ,4']bipiperidinyl-1 '-yl ⁇ - (2,6-dimethyl-phenyl)-methanone
- Example 58 ⁇ 4-[(4-Bromo-phenyl)-phenyl-amino]-[1 ,4']bipiperidinyl-1 '-yl ⁇ -(4,6- dimethyl-pyrimidin-5-yl)-methanone
- [1 ,4']bipiperidinyl-4-yl-(4-bromo-phenyl)-phenyl-amine used as starting materials may be prepared as follows: a) 4-(4-Bromo-phenylamino)-piperidine-1 -carboxylic acid tert-butyl ester is prepared from 4- bromo-phenylamine and 4-oxo-piperidine-1 -carboxylic acid tert-butyl ester as described in example 51 e). MS/ESI 355 (M+H) + .
- R 2 is as defined in Table 4 below, may be prepared.
- R 2 is as given in Table 5 below, may be prepared.
- R 2 has the significances as indicated in Table 6, may be prepared.
- Example 77 ⁇ 4-[(4-Bromo-phenyl)-phenyl-amlno]-4'-methyl-[1 ,4']bipiperidinyl-1 '-yl ⁇ - (4,6-dimethyl-pyrimidin-5-yl)-methanone
- Example 78 ⁇ 4-[4-Bromo-phenyl)-pheny_-amino]-4'-methyl-[1 ,4']bipiperidinyl-1 '-yl ⁇ - (2,4-dimethyl-1-oxy-pyridin-3-yl)-methanone
- Example 80 ⁇ 4-[1,3-Benzodioxol-5-yl-(2-methyl-thiazol-4-ylmethyl)-amino]-4'- methyl-l ⁇ '-blplperidlnyM'-y ⁇ . ⁇ -dimethyl-phenylJ-methanone
- Example 81 ⁇ 4-[(4-Bromo-phenyl)-pyridin-3-yl-amino]-4'-methyl-[1 ,4']bipiperidinyl-1 '- yl ⁇ -(2,4-dimethyl-1-oxy-pyridin-3-yl)-methanone
- Example 83 (2,4-Dlmethyl-1-oxy-pyridln-3-yl)- ⁇ 4 , -methyl-4-[(2-methyl-thJazol-4- ylmethyl)-phenyl-amino]-[1 ,4']bipiperidinyl-1 '-yl ⁇ -methanone
- Human CCR5 is used to generate stable transfectants in CHO K1 cells. Membranes prepared from these CCR5 transfectants are used in a radioligand binding assay using 125-1 MIP-1 ⁇ as a ligand and the compounds of formula I are tested for inhibitory activity. The data are reported as IC 50 , i.e. the concentration of compound required to achieve 50% inhibition of [1-125]MIP-1 ⁇ binding. In this assay, compounds of formula I have an IC 50 ⁇ 1 ⁇ M. Compounds of Examples 16, 53 and 83 have an IC 50 of 2 to 3 nM, respectively. b) CCR5 functional assay - Ca 2* mobilization
- Human CCR5 is used to generate stable transfectants in CHO K1 cells. These CCR5 transfectants are used for assessing Ca 2+ mobilization in response to stimulation by the CCR5 ligands MIP-1 ⁇ , MIP-1 ⁇ , HCC-1(9-74) or RANTES.
- the cells are loaded with a Ca 2+ -sensitive fluorochrome (Fluo3 or Fluo4). Ligand concentrations between 0.01 - 100 nM are used to induce Ca 2+ mobilization which is monitored in a fluorometer with appropriate settings.
- CCR5 transfectants are generated in Jurkat T cells or the mouse pre B cell line L1.2. Migration of CCR5 transfectants is tested in transwell tissue chamber inserts system with the CCR5 agonist MIP-1 ⁇ at concentrations of 1-100 nM. Cells migrated in response to the agonist compared to a buffer control are quantified in a flow cytometer. The compounds to be tested are added to the cells and the agonist compartments. IC 50 values are calculated f rom concentration-response curves obtained with the compounds in the presence of MIP- 1 ⁇ . In this assay, compounds of formula I have an IC 50 ⁇ 1 ⁇ M. d) Experiments performed in murine animal models show that vessel wall remodeling after experimental injury (e.g. induced by allotransplantation) is significantly inhibited in the absence of functional CCR5.
- experimental injury e.g. induced by allotransplantation
- the compounds of formula I are, therefore, useful in the prevention and/or treatment of diseases or disorders mediated by interactions between chemokine receptors, e.g. CCR5, and their ligands, e.g. in transplantation, such as acute or chronic rejection of organ, tissue or cell alto- or xenografts or delayed graft function, autoimmune diseases, e.g.
- rheumatoid arthritis systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g.
- inflammatory bowel disease Crohn's disease or ulcerative colitis
- intrinsic asthma inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock and others, cancer, e.g.
- solid tumors or lymphatic cancer such as T cell lymphomas or T cell leukemias, metastasizing or angiogenesis, infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS.
- toxic shock e.g. superantigen induced
- septic shock e.g. septic shock
- adult respiratory distress syndrome e.g. AIDS.
- viral infections e.g. AIDS.
- transplantation is meant allo- or xeno grafts of e.g. cells, tissues or solid organs, for example pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pabcreas, trachea or oesophagus.
- Chronic rejection is also named graft vessel diseases.
- the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.01 to10 mg/kg per body weight.
- An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
- Suitable unit dosage forms for oral administration comprise from ca. 1 to 500 mg active ingredient.
- the compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
- Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
- the compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
- Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
- the present invention further provides:
- a method for preventing or treating disorders or diseases mediated by interactions between chemokine receptors and their ligands, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
- a method for preventing or treating acute or chronic transplant rejection or inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
- a compound of formula I or a pharmaceutically acceptable salt thereof for use as a pharmaceutical e.g. in any of the methods as indicated under 1.1 or 1.2 above.
- a pharmaceutical composition e.g. for use in any of the methods as in 1.1 or 1.2 above comprising a compound of formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier therefor.
- the compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. in immunosuppressive or immunomodulating regimens or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, a chemotherapeutic agent or an anti-infective agent, e.g. an anti-viral agent such as e.g. an anti-retroviral agent or an antibiotic.
- the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a macrocyclic lactone having immunosuppressive properties, e.g. rapamycin, 40-O-(2- hydroxyethyl)-rapamycin, CCI779 or ABT578; an ascomycin having immunosuppressive properties, e.g.
- a calcineurin inhibitor e.g. cyclosporin A or FK 506
- a macrocyclic lactone having immunosuppressive properties e.g. rapamycin, 40-O-(2- hydroxyethyl)-rapamycin, CCI779 or ABT578
- an ascomycin having immunosuppressive properties e.g.
- ABT-281 , ASM981 , etc. corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15- deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; an accelerating lymphocyte homing agent, e.g. FTY720; monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD11a/CD18, CD25, CD27, CD28, CD40.
- an accelerating lymphocyte homing agent e.g. FTY720
- monoclonal antibodies to leukocyte receptors e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD11a/CD18, CD25, CD27, CD28, CD40.
- LFA-1 antagonists ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or antichemokine antibodies or antichemokine receptor antibodies or low molecular weight chemokine receptor antagonists, e.g. anti MCP-1 antibodies.
- the co-administered immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
- the present invention provides in a yet further aspect:
- a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of formula I and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory, anti-infective or chemotherapeutic drug, e.g. as indicated above.
- a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a CCR5 antagonist, e.g. a compound of formula I as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory, anti-infective or chemotherapeutic drug.
- the kit may comprise instructions for its administration.
- co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
- pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- non-fixed combination means that the active ingredients, e.g. a compound of formula I and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
- cocktail therapy e.g. the administration of 3 or more active ingredients.
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL02363011A PL363011A1 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
IL15742802A IL157428A0 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl derivatives and their use as chemokine receptor inhibitors |
NZ528712A NZ528712A (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
US10/472,653 US20040142920A1 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
DE60234167T DE60234167D1 (en) | 2001-04-09 | 2002-04-08 | BIPIPERIDIN DERIVATIVES AND THEIR USE AS INHIBITORS OF CHEMOKIN RECEPTORS |
SK1242-2003A SK12422003A3 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptor inhibitors |
BR0208741-3A BR0208741A (en) | 2001-04-09 | 2002-04-08 | Piperidine Derivatives |
AT02730122T ATE446950T1 (en) | 2001-04-09 | 2002-04-08 | BIPIPERIDINE DERIVATIVES AND THEIR USE AS CHEMOKINE RECEPTOR INHIBITORS |
CA2439241A CA2439241C (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
EP02730122A EP1379504B1 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
KR1020037013161A KR100616039B1 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-Derivatives and Their Use as Chemokine Receptors Inhibitors |
AU2002302511A AU2002302511B2 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
HU0303724A HUP0303724A3 (en) | 2001-04-09 | 2002-04-08 | Chemokine receptors inhibitor bipiperidinyl-derivatives and pharmaceutical compositions containing them and process for preparation of the compounds |
JP2002579437A JP4366079B2 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl derivatives and their use as chemokine receptor inhibitors |
MXPA03009220A MXPA03009220A (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors. |
NO20034324A NO20034324D0 (en) | 2001-04-09 | 2003-09-26 | Bipiperidinyl derivatives and their use as chemokine receptor inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0108876.4 | 2001-04-09 | ||
GBGB0108876.4A GB0108876D0 (en) | 2001-04-09 | 2001-04-09 | Organic Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002081449A1 true WO2002081449A1 (en) | 2002-10-17 |
Family
ID=9912541
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/003871 WO2002081449A1 (en) | 2001-04-09 | 2002-04-08 | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors |
Country Status (27)
Country | Link |
---|---|
US (1) | US20040142920A1 (en) |
EP (1) | EP1379504B1 (en) |
JP (1) | JP4366079B2 (en) |
KR (1) | KR100616039B1 (en) |
CN (1) | CN100469767C (en) |
AR (1) | AR035815A1 (en) |
AT (1) | ATE446950T1 (en) |
AU (1) | AU2002302511B2 (en) |
BR (1) | BR0208741A (en) |
CA (1) | CA2439241C (en) |
CZ (1) | CZ20032723A3 (en) |
DE (1) | DE60234167D1 (en) |
EC (1) | ECSP034765A (en) |
ES (1) | ES2335393T3 (en) |
GB (1) | GB0108876D0 (en) |
HU (1) | HUP0303724A3 (en) |
IL (1) | IL157428A0 (en) |
MX (1) | MXPA03009220A (en) |
NO (1) | NO20034324D0 (en) |
NZ (1) | NZ528712A (en) |
PE (1) | PE20021004A1 (en) |
PL (1) | PL363011A1 (en) |
PT (1) | PT1379504E (en) |
RU (1) | RU2296751C2 (en) |
SK (1) | SK12422003A3 (en) |
WO (1) | WO2002081449A1 (en) |
ZA (1) | ZA200306432B (en) |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003020716A1 (en) * | 2001-08-29 | 2003-03-13 | Schering Corporation | Piperidine derivatives useful as ccr5 antagonists |
WO2004029041A1 (en) * | 2002-09-24 | 2004-04-08 | Astrazeneca Ab | Novel piperidine derivatives for use in the treatment of chemokine mediated disease states |
WO2004030668A1 (en) * | 2002-10-04 | 2004-04-15 | Ucb, S.A. | 4-aminopiperidine derivatives, processes for their preparation and their use as medicaments |
WO2004031172A1 (en) * | 2002-10-07 | 2004-04-15 | Novartis Ag | Piperidine derivatives as ccr5 inhibitors |
WO2004055011A1 (en) * | 2002-12-13 | 2004-07-01 | Smithkline Beecham Corporation | Heterocyclic compounds as ccr5 antagonists |
WO2004092136A1 (en) * | 2003-04-18 | 2004-10-28 | Ono Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic compound and use thereof |
FR2854158A1 (en) * | 2003-04-25 | 2004-10-29 | Sanofi Synthelabo | New 2-phenylcarbonylamino-4-phenyl-thiazole derivatives, useful for treating e.g. immunoinflammatory diseases and angiogenesis, are inhibitors of chemokine receptors |
WO2004113323A1 (en) * | 2003-06-13 | 2004-12-29 | Schering Aktiengesellschaft | Quinolyl amide derivatives as ccr-5 antagonists |
WO2005042517A3 (en) * | 2003-11-03 | 2005-07-28 | Schering Corp | Bipiperidinyl derivatives useful as inhibitors of chemokine receptors |
WO2006077499A1 (en) * | 2005-01-20 | 2006-07-27 | Pfizer Limited | Chemical compounds |
US7186718B2 (en) | 2001-08-22 | 2007-03-06 | Astrazeneca Ab | Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity |
US7230022B2 (en) | 2004-02-19 | 2007-06-12 | Bristol-Myers Squibb Company | Substituted fused bicyclic amines as modulators of chemokine receptor activity |
US7238691B2 (en) | 2001-09-18 | 2007-07-03 | Astrazeneca Ab | Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity |
US7288563B2 (en) | 2004-02-19 | 2007-10-30 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7307090B2 (en) | 2001-07-02 | 2007-12-11 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
US7381738B2 (en) | 2004-02-19 | 2008-06-03 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7479496B2 (en) | 2004-02-19 | 2009-01-20 | Bristol-Myers Squibb Company | Substituted spiro azabicyclics as modulators of chemokine receptor activity |
US7482363B2 (en) | 2002-03-19 | 2009-01-27 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
US7495013B2 (en) | 2003-04-01 | 2009-02-24 | Astrazeneca Ab | Chemical compounds |
US7517989B2 (en) | 2002-03-19 | 2009-04-14 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
US8314127B2 (en) | 2005-07-21 | 2012-11-20 | Astrazeneca Ab | Piperidine derivatives |
US8410144B2 (en) | 2009-03-31 | 2013-04-02 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
WO2015091415A1 (en) | 2013-12-19 | 2015-06-25 | Bayer Pharma Aktiengesellschaft | Substituted bipiperidinyl derivatives as adrenoreceptor alpha 2c antagonists |
EP2861302A4 (en) * | 2012-05-14 | 2016-08-24 | Prostagene Llc | Using modulators of ccr5 for treating cancer |
US9624199B2 (en) | 2013-12-19 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Substituted bipiperidinyl derivatives |
US9624198B2 (en) | 2013-12-19 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyltetrahydroquinolines |
US9944621B2 (en) | 2013-12-19 | 2018-04-17 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyl tetrahydroquinolines |
US10952415B2 (en) | 2011-03-09 | 2021-03-23 | Richard G. Pestell | Prostate cancer cell lines, gene signatures and uses thereof |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7498346B2 (en) * | 2003-12-11 | 2009-03-03 | Genzyme Corporation | Chemokine receptor binding compounds |
US20080108586A1 (en) * | 2006-09-06 | 2008-05-08 | Incyte Corporation | Combination therapy for human immunodeficiency virus infection |
JP2010512340A (en) * | 2006-12-06 | 2010-04-22 | ジェンザイム・コーポレーション | Chemokine receptor binding compound |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011128A1 (en) * | 1996-09-10 | 1998-03-19 | Dr. Karl Thomae Gmbh | Modified aminoacids, pharmaceuticals containing these compounds and method for their production |
WO1998011082A1 (en) * | 1996-09-12 | 1998-03-19 | Roche Diagnostics Gmbh | New amino alcohol derivatives, process for the production thereof and medicaments and reagents containing these compounds |
DE19643331A1 (en) * | 1996-10-21 | 1998-04-23 | Thomae Gmbh Dr K | 1- (4-Piperidinyl) -piperidinylenes, medicaments containing these compounds, their use and process for their preparation |
WO2000066559A1 (en) * | 1999-05-04 | 2000-11-09 | Schering Corporation | Piperidine derivatives useful as ccr5 antagonists |
WO2000076972A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
WO2001098268A2 (en) * | 2000-06-21 | 2001-12-27 | Bristol-Myers Squibb Pharma Company | Piperidine amides as modulators of chemokine receptor activity |
WO2002022592A2 (en) * | 2000-09-14 | 2002-03-21 | Schering Corporation | Substituted urea neuropeptide y y5 receptor antagonists |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW531537B (en) * | 1995-12-27 | 2003-05-11 | Janssen Pharmaceutica Nv | 1-(1,2-disubstituted piperidinyl)-4-substituted piperidine derivatives |
US5952349A (en) * | 1996-07-10 | 1999-09-14 | Schering Corporation | Muscarinic antagonists for treating memory loss |
US6391865B1 (en) * | 1999-05-04 | 2002-05-21 | Schering Corporation | Piperazine derivatives useful as CCR5 antagonists |
AR036366A1 (en) * | 2001-08-29 | 2004-09-01 | Schering Corp | USEFUL PIPERIDINE DERIVATIVES AS CCR5 ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS, THE USE OF SUCH DERIVATIVES FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND A KIT |
GB0223223D0 (en) * | 2002-10-07 | 2002-11-13 | Novartis Ag | Organic compounds |
-
2001
- 2001-04-09 GB GBGB0108876.4A patent/GB0108876D0/en not_active Ceased
-
2002
- 2002-04-05 AR ARP020101270A patent/AR035815A1/en not_active Application Discontinuation
- 2002-04-08 CA CA2439241A patent/CA2439241C/en not_active Expired - Fee Related
- 2002-04-08 PL PL02363011A patent/PL363011A1/en not_active Application Discontinuation
- 2002-04-08 AT AT02730122T patent/ATE446950T1/en not_active IP Right Cessation
- 2002-04-08 NZ NZ528712A patent/NZ528712A/en unknown
- 2002-04-08 JP JP2002579437A patent/JP4366079B2/en not_active Expired - Fee Related
- 2002-04-08 SK SK1242-2003A patent/SK12422003A3/en not_active Application Discontinuation
- 2002-04-08 CZ CZ20032723A patent/CZ20032723A3/en unknown
- 2002-04-08 RU RU2003130642/04A patent/RU2296751C2/en not_active IP Right Cessation
- 2002-04-08 KR KR1020037013161A patent/KR100616039B1/en not_active IP Right Cessation
- 2002-04-08 MX MXPA03009220A patent/MXPA03009220A/en active IP Right Grant
- 2002-04-08 PT PT02730122T patent/PT1379504E/en unknown
- 2002-04-08 PE PE2002000282A patent/PE20021004A1/en not_active Application Discontinuation
- 2002-04-08 BR BR0208741-3A patent/BR0208741A/en not_active IP Right Cessation
- 2002-04-08 CN CNB028079507A patent/CN100469767C/en not_active Expired - Fee Related
- 2002-04-08 AU AU2002302511A patent/AU2002302511B2/en not_active Ceased
- 2002-04-08 WO PCT/EP2002/003871 patent/WO2002081449A1/en not_active Application Discontinuation
- 2002-04-08 HU HU0303724A patent/HUP0303724A3/en unknown
- 2002-04-08 EP EP02730122A patent/EP1379504B1/en not_active Expired - Lifetime
- 2002-04-08 ES ES02730122T patent/ES2335393T3/en not_active Expired - Lifetime
- 2002-04-08 DE DE60234167T patent/DE60234167D1/en not_active Expired - Lifetime
- 2002-04-08 US US10/472,653 patent/US20040142920A1/en not_active Abandoned
- 2002-04-08 IL IL15742802A patent/IL157428A0/en unknown
-
2003
- 2003-08-19 ZA ZA200306432A patent/ZA200306432B/en unknown
- 2003-09-11 EC EC2003004765A patent/ECSP034765A/en unknown
- 2003-09-26 NO NO20034324A patent/NO20034324D0/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998011128A1 (en) * | 1996-09-10 | 1998-03-19 | Dr. Karl Thomae Gmbh | Modified aminoacids, pharmaceuticals containing these compounds and method for their production |
WO1998011082A1 (en) * | 1996-09-12 | 1998-03-19 | Roche Diagnostics Gmbh | New amino alcohol derivatives, process for the production thereof and medicaments and reagents containing these compounds |
DE19643331A1 (en) * | 1996-10-21 | 1998-04-23 | Thomae Gmbh Dr K | 1- (4-Piperidinyl) -piperidinylenes, medicaments containing these compounds, their use and process for their preparation |
WO2000066559A1 (en) * | 1999-05-04 | 2000-11-09 | Schering Corporation | Piperidine derivatives useful as ccr5 antagonists |
WO2000076972A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
WO2001098268A2 (en) * | 2000-06-21 | 2001-12-27 | Bristol-Myers Squibb Pharma Company | Piperidine amides as modulators of chemokine receptor activity |
WO2002022592A2 (en) * | 2000-09-14 | 2002-03-21 | Schering Corporation | Substituted urea neuropeptide y y5 receptor antagonists |
Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7307090B2 (en) | 2001-07-02 | 2007-12-11 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
US7186718B2 (en) | 2001-08-22 | 2007-03-06 | Astrazeneca Ab | Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity |
US8034933B2 (en) | 2001-08-29 | 2011-10-11 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
US7442703B2 (en) | 2001-08-29 | 2008-10-28 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
WO2003020716A1 (en) * | 2001-08-29 | 2003-03-13 | Schering Corporation | Piperidine derivatives useful as ccr5 antagonists |
US7384948B2 (en) | 2001-08-29 | 2008-06-10 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
US7238691B2 (en) | 2001-09-18 | 2007-07-03 | Astrazeneca Ab | Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity |
US7517989B2 (en) | 2002-03-19 | 2009-04-14 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
US7482363B2 (en) | 2002-03-19 | 2009-01-27 | Astrazeneca Ab | Piperidine derivatives useful as modulators of chemokine receptor activity |
WO2004029041A1 (en) * | 2002-09-24 | 2004-04-08 | Astrazeneca Ab | Novel piperidine derivatives for use in the treatment of chemokine mediated disease states |
EP1693061A1 (en) * | 2002-10-04 | 2006-08-23 | Ucb, S.A. | Use of 4-aminoderivatives for the preparation of a medicament for treating neurological diseases |
WO2004030668A1 (en) * | 2002-10-04 | 2004-04-15 | Ucb, S.A. | 4-aminopiperidine derivatives, processes for their preparation and their use as medicaments |
US7399771B2 (en) | 2002-10-07 | 2008-07-15 | Novartis Ag | Piperidine derivatives as CCR5 inhibitors |
WO2004031172A1 (en) * | 2002-10-07 | 2004-04-15 | Novartis Ag | Piperidine derivatives as ccr5 inhibitors |
CN100334083C (en) * | 2002-10-07 | 2007-08-29 | 诺瓦提斯公司 | Piperidine derivatives as CCR5 inhibitors |
WO2004055011A1 (en) * | 2002-12-13 | 2004-07-01 | Smithkline Beecham Corporation | Heterocyclic compounds as ccr5 antagonists |
US7452992B2 (en) | 2002-12-13 | 2008-11-18 | Smithkline Beecham Corporation | Heterocyclic compounds as CCR5 antagonists |
US7495013B2 (en) | 2003-04-01 | 2009-02-24 | Astrazeneca Ab | Chemical compounds |
WO2004092136A1 (en) * | 2003-04-18 | 2004-10-28 | Ono Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic compound and use thereof |
FR2854158A1 (en) * | 2003-04-25 | 2004-10-29 | Sanofi Synthelabo | New 2-phenylcarbonylamino-4-phenyl-thiazole derivatives, useful for treating e.g. immunoinflammatory diseases and angiogenesis, are inhibitors of chemokine receptors |
US7777041B2 (en) | 2003-04-25 | 2010-08-17 | Sanofi-Aventis | 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof |
WO2004096798A2 (en) * | 2003-04-25 | 2004-11-11 | Sanofi-Aventis | Derivatives of 2-acylamino-4-phenylthiazole, preparation method thereof and use of same as chemokine antagonists |
WO2004096798A3 (en) * | 2003-04-25 | 2006-01-26 | Sanofi Aventis | Derivatives of 2-acylamino-4-phenylthiazole, preparation method thereof and use of same as chemokine antagonists |
US7504511B2 (en) | 2003-04-25 | 2009-03-17 | Sanofi-Aventis | 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof |
WO2004113323A1 (en) * | 2003-06-13 | 2004-12-29 | Schering Aktiengesellschaft | Quinolyl amide derivatives as ccr-5 antagonists |
JP2007505951A (en) * | 2003-06-13 | 2007-03-15 | シエーリング アクチエンゲゼルシャフト | Quinolylamide derivatives as CCR-5 antagonists |
WO2005042517A3 (en) * | 2003-11-03 | 2005-07-28 | Schering Corp | Bipiperidinyl derivatives useful as inhibitors of chemokine receptors |
JP2008031180A (en) * | 2003-11-03 | 2008-02-14 | Schering Corp | Bipiperidinyl derivative useful as inhibitors of chemokine receptors |
JP4757802B2 (en) * | 2003-11-03 | 2011-08-24 | シェーリング コーポレイション | Bipiperidinyl derivatives useful as inhibitors of chemokine receptors |
US7652142B2 (en) | 2003-11-03 | 2010-01-26 | Schering Corporation | Bipiperidinyl derivatives useful as inhibitors of chemokine receptors |
JP2007510653A (en) * | 2003-11-03 | 2007-04-26 | シェーリング コーポレイション | Bipiperidinyl derivatives useful as inhibitors of chemokine receptors |
US7381738B2 (en) | 2004-02-19 | 2008-06-03 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7479496B2 (en) | 2004-02-19 | 2009-01-20 | Bristol-Myers Squibb Company | Substituted spiro azabicyclics as modulators of chemokine receptor activity |
US7288563B2 (en) | 2004-02-19 | 2007-10-30 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7230022B2 (en) | 2004-02-19 | 2007-06-12 | Bristol-Myers Squibb Company | Substituted fused bicyclic amines as modulators of chemokine receptor activity |
WO2006077499A1 (en) * | 2005-01-20 | 2006-07-27 | Pfizer Limited | Chemical compounds |
US8314127B2 (en) | 2005-07-21 | 2012-11-20 | Astrazeneca Ab | Piperidine derivatives |
US8410144B2 (en) | 2009-03-31 | 2013-04-02 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
US10952415B2 (en) | 2011-03-09 | 2021-03-23 | Richard G. Pestell | Prostate cancer cell lines, gene signatures and uses thereof |
US9453836B2 (en) | 2012-05-14 | 2016-09-27 | Richard G. Pestell | Use of modulators of CCR5 in the treatment of cancer and cancer metastasis |
EP2861302A4 (en) * | 2012-05-14 | 2016-08-24 | Prostagene Llc | Using modulators of ccr5 for treating cancer |
US11633397B2 (en) | 2012-05-14 | 2023-04-25 | Richard G. Pestell | Use of modulators of CCR5 in the treatment of cancer and cancer metastasis |
US9624199B2 (en) | 2013-12-19 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Substituted bipiperidinyl derivatives |
US9624198B2 (en) | 2013-12-19 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyltetrahydroquinolines |
US9944621B2 (en) | 2013-12-19 | 2018-04-17 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyl tetrahydroquinolines |
EP3329920A2 (en) | 2013-12-19 | 2018-06-06 | Bayer Pharma Aktiengesellschaft | Adrenoreceptor alpha2c receptor antagonists |
US10323020B2 (en) | 2013-12-19 | 2019-06-18 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyl tetrahydroquinolines |
WO2015091415A1 (en) | 2013-12-19 | 2015-06-25 | Bayer Pharma Aktiengesellschaft | Substituted bipiperidinyl derivatives as adrenoreceptor alpha 2c antagonists |
US10961221B2 (en) | 2013-12-19 | 2021-03-30 | Bayer Pharma Aktiengesellschaft | Substituted piperidinyl tetrahydroquinolines |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1379504B1 (en) | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors | |
AU2002302511A1 (en) | Bipiperidinyl-derivatives and their use as chemokine receptors inhibitors | |
FI104631B (en) | Process for the preparation of new 1-acyl-2-aralkyl-4- (alkyl) -aminopiperidine compounds | |
CA1281719C (en) | N-aryl-n-(4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds | |
US6790854B2 (en) | Diphenylalkylamine derivatives useful as opioid receptor agonists | |
EP0383579A1 (en) | N-Phenyl-N-(4-piperidinyl)amides useful as analgesics | |
IL196059A (en) | Piperidine derivatives and their use as modulators of chemokine receptor activity (especially ccr5) | |
US4806547A (en) | Isoquinoline derivatives, analgesic compounds thereof and method of treating pain | |
NZ289498A (en) | Piperidinylpiperazine derivatives such as various piperidinylpiperazinylacetylphenoxy acetic acid derivatives, pharmaceutical compositions | |
AU2002353691A1 (en) | Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5) | |
US20050148583A1 (en) | Phenoxyalkylamine derivatives useful as opioid delta receptor ligands | |
US20080249111A1 (en) | Piperdine Derivatives as CCR5 Inhibitors | |
SK141998A3 (en) | Piperidines and pyrrolidines | |
US4912109A (en) | N-heterocyclic-N-(4-piperidinyl) amides and pharmaceutical compositions and methods employing such compounds | |
US5100903A (en) | N-aryl-n-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds | |
CA2069423A1 (en) | Azacyclic derivatives | |
US4954506A (en) | N-heterocyclic-N-(4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds | |
JPWO2005030722A1 (en) | N-substituted-N- (4-piperidinyl) amide derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LT LU LV MA MD MK MN MX NO NZ OM PH PL PT RO RU SE SG SI SK TJ TM TN TR TT UA US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1-2003-500986 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002730122 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 157428 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003/06432 Country of ref document: ZA Ref document number: 200306432 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2439241 Country of ref document: CA Ref document number: 2002302511 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10472653 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12422003 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV2003-2723 Country of ref document: CZ Ref document number: 528712 Country of ref document: NZ Ref document number: 1582/CHENP/2003 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002579437 Country of ref document: JP Ref document number: 1020037013161 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/009220 Country of ref document: MX Ref document number: 028079507 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 03090558 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1200301005 Country of ref document: VN |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-2723 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 2002730122 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 528712 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 528712 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 2002302511 Country of ref document: AU |
|
WWR | Wipo information: refused in national office |
Ref document number: PV2003-2723 Country of ref document: CZ |