WO2004110415A2 - Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments - Google Patents
Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments Download PDFInfo
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- WO2004110415A2 WO2004110415A2 PCT/EP2004/051048 EP2004051048W WO2004110415A2 WO 2004110415 A2 WO2004110415 A2 WO 2004110415A2 EP 2004051048 W EP2004051048 W EP 2004051048W WO 2004110415 A2 WO2004110415 A2 WO 2004110415A2
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- 0 C=*N(CC1)CCC1O Chemical compound C=*N(CC1)CCC1O 0.000 description 2
- WRSSEASOIDURFX-UHFFFAOYSA-N CC(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O Chemical compound CC(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O WRSSEASOIDURFX-UHFFFAOYSA-N 0.000 description 1
- MRGKULZNEVNSKA-PHCLJHKRSA-N CC/C(/C)=C\C(\C)=C/[C@H](C)C(NCCc1ccccc1)=O Chemical compound CC/C(/C)=C\C(\C)=C/[C@H](C)C(NCCc1ccccc1)=O MRGKULZNEVNSKA-PHCLJHKRSA-N 0.000 description 1
- LOJVHFJRAKJPKF-KFMHZJNZSA-N C[C@@H](CC[C@@H](C)/C=C\C=C)C(CCN)N1CCNCC1 Chemical compound C[C@@H](CC[C@@H](C)/C=C\C=C)C(CCN)N1CCNCC1 LOJVHFJRAKJPKF-KFMHZJNZSA-N 0.000 description 1
- FSITTZOUOWYCJY-UHFFFAOYSA-N C[n]1c(CN(CC2)CCC2N(CC2)CCN2C(CC2)CC(Cc3ccccc3)N2C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=O)ccc1 Chemical compound C[n]1c(CN(CC2)CCC2N(CC2)CCN2C(CC2)CC(Cc3ccccc3)N2C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=O)ccc1 FSITTZOUOWYCJY-UHFFFAOYSA-N 0.000 description 1
- SVJUFTXRSMRTSK-UHFFFAOYSA-N O=C(c1c[s]cc1)N(CC1)CCC1N(CC1)CCN1C(CC1)CC(Cc2ccccc2)N1C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O Chemical compound O=C(c1c[s]cc1)N(CC1)CCC1N(CC1)CCN1C(CC1)CC(Cc2ccccc2)N1C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O SVJUFTXRSMRTSK-UHFFFAOYSA-N 0.000 description 1
- ZLWIIQDESPNSGI-UHFFFAOYSA-N O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1)C(Cc(cc2F)ccc2F)CC1N(CC1)CCN1C(CC1)CCN1[AlH2] Chemical compound O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1)C(Cc(cc2F)ccc2F)CC1N(CC1)CCN1C(CC1)CCN1[AlH2] ZLWIIQDESPNSGI-UHFFFAOYSA-N 0.000 description 1
- CISWSBXOQNBNFP-UHFFFAOYSA-N O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1)C(Cc2ccccc2)CC1N(CC1)CCN1C1CCNCC1 Chemical compound O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CC1)C(Cc2ccccc2)CC1N(CC1)CCN1C1CCNCC1 CISWSBXOQNBNFP-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- 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
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- 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
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and l,4-di-piperidin-4-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK i antagonistic activity, the use of said formulation for the manufacture of a medicament for the prevention and/or treatment of emesis, in particular nausea and vomiting, pain and/or nociception, in particular in opioid-based acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments and the use of an NK 1 -receptor antagonist for the manufacture of a medicament for the prevention and/or treatment of emesis, in particular nausea and vomiting, respiratory depression and tolerance in opioid-based treatments of pain.
- opioid analgesics and l,4-di-piperidin-4-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK i antagonistic activity the use of said formulation for the manufacture of
- Opioid analgesics are the cornerstone of pain treatment, especially in the segment of moderate to severe acute and chronic pain.
- side-effects such as nausea/vomiting, constipation, respiratory depression and tolerance limit their use.
- the lowering of the high incidence of nausea and vomiting with many clinically used opioids is particularly considered as a major unmet medical need.
- Neurokinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Bertrand and Geppetti, Trends Pharmacol. ScL 17:255-259 (1996) ; Lundberg, Can. J. Physiol. Pharmacol. 73:908- 914 (1995) ; Maggi, Gen. Pharmacol 26:911-944 (1995) ; Regoli et al., Pharmacol. Rev. 46 (1994)). They share the common C-terminal sequence Phe-Xaa-Gly- Leu-Met- NH 2 . Neurokinins released from peripheral sensory nerve endings are believed to be involved in neurogenic inflammation.
- neurokinins may play a role in pain transmission/perception and in some autonomic reflexes and behaviors.
- the three major neurokinins are Substance P (SP), Neurokinin ⁇ (NK A ) and Neurokinin B (NK B ) with preferential affinity for three distinct receptor subtypes, termed NK i , NK 2 , and NK 3 , respectively.
- SP Substance P
- NK A Neurokinin ⁇
- NK B Neurokinin B
- NK i Three distinct receptor subtypes
- NK 1 receptors Species differences in structure of NK 1 receptors are responsible for species-related potency differences of NK i antagonists (Maggi, Gen. Pharmacol. 26:911-944 (1995) ; Regoli et ah, Pharmacol. Rev. 46(4):551-599 (1994)).
- the human NK i receptor closely resembles the NK i receptor of guinea-pigs and gerbils but differs markedly from the NK i receptor of rodents.
- the development of neurokinin antagonists has led to date to a series of peptide compounds of which might be anticipated that they are metabolically too labile to be employed as pharmaceutically active substances (Longmore J. et al, DN&P 8(l):5-23 (1995)).
- NK i -antagonists have been studied for a wide variety of indications including emesis, (stress-related) anxiety states, inflammatory responses, smooth muscle contraction and pain perception.
- NK 1 - antagonists are in development for indications such as emesis, anxiety and depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, visceral pain, neurogenic inflammation, asthma, micturition disorders, pancreatitis and nociception.
- a particular class of compounds with predominantly NK i -activity reduces to a large extent a number of unwanted side-effects associated with opioid analgesics, thereby increasing the total tolerability of said opioids in pain treatment, in particular in opioid-based acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments. More specifically, it was found in opioid-based treatments of pain that emesis was inhibited, respiratory depression was reduced, the tolerance for opioids was prevented and constipation was not worsened.
- Formulations containing NK i -antagonists and opioid analgesics for the prevention and/or treatment of pain and/or nociception are disclosed in WO 96/20009 (Merck, July 4, 1996), US 5,880,132 (Merck, March 9, 1999) and WO 97/25988 (EIi Lilly, July 24, 1997). There is no mentioning of the reduction of side-effects apart from emesis.
- the compounds of the present invention differ from the compounds of the prior art in the substitution of the piperazinyl moiety, being a substituted piperidinyl moiety as well as in their improved ability as potent, orally and centrally active neurokinin antagonists with therapeutic value in combinations with opioid analgesics for reduction of certain opioid-induced side-effects and increasing the tolerability of said opioids.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutical Iy acceptable carrier and, as active ingredients, a therapeutically effective amount of an opioid analgesic and a compound according to Formula (I)
- n is an integer, equal to 0, 1 or 2 ;
- m is an integer, equal to 1 or 2, provided that if m is 2, then n is 1 ;
- p is an integer equal to 1 or 2 ;
- Q is O or NR 3 ;
- X is a covalent bond or a bivalent radical of formula -Q-, -S- or -NR 3 - ; eachR 3 independently from each other, is hydrogen or alkyl ; each R 1 independently from each other, is selected from the group of Ar 1 ,
- R 2 is alkyl, Ar 2 , Ar 2 -alkyl, Het 1 or Het'-alkyl ;
- Ar 1 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of halo, alkyl, cyano, aminocarbonyl and alkyloxy ;
- Ar 2 is naphthalenyl or phenyl, each optionally substituted with 1 , 2 or 3 substituents, each independently from each other, selected from the group of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono- and di(alkyl)aminocarbonyl ;
- Ar 3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2- ⁇ ]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
- Het 1 is a monocyclic heterocyclic radical selected from the group of pyrrolyl, pyrazolyl, imidazolyl, fliranyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl ; or a bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl ; each monocyclic and bicyclic heterocyclic radical may optionally be substituted on any atom by a radical selected from the group of halo and alkyl ; Het 2 is a monocyclic heterocyclic radical selected from the group of
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredients, an opioid analgesic and a therapeutically effective amount of a compound according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof, wherein : n is 1 ; m is 1 ;
- X is a covalent bond ; each R 1 is ⁇ r 1 or ⁇ r 1 -alkyl ; q is 0 or 1 ;
- R 2 is Ar 2 ;
- each ⁇ lk represents, independently from each other, a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms ; or a cyclic saturated or unsaturated hydrocarbon radical having from 3 to 6 carbon atoms ; each radical optionally substituted on one or more carbon atoms with one or more phenyl, halo, cyano, hydroxy, formyl and amino radicals ;
- L is selected from the group of hydrogen, alkyloxy, At ⁇ -oxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono-and di(Ar 3 )amino, Ar 3 and Het 2 ;
- ⁇ r 1 is phenyl, optionally substituted with 1 , 2 or 3 alkyl radicals ;
- Ar 2 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals ;
- Ar 3 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo[l,2- ⁇ ]pyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano ;
- Het 2 is a monocyclic heterocyclic radical selected from the group of pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl ; or a bicyclic heterocyclic radical selected from the group of benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, chromenyl and benzimidazolyl ; each monocyclic and bicyclic radical optionally substituted with one or more radicals selected from the group of Ar 1 , Ar 'alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo and alkyloxycarbonyl ; and al
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutical ⁇ acceptable carrier and, as active ingredients, an opioid analgesic and a therapeutically effective amount of a compound according to Formula (I), the pharmaceutical ⁇ acceptable acid or base addition salts thereof, the stereochemical ⁇ isomeric forms thereof, the TV-oxide form thereof and a prodrug thereof, wherein R 1 is ⁇ r'methyl and attached to the 2-position or R 1 is Ar 1 and attached to the 3-position, as exemplified in either of the following formulas for compounds according to Formula (I) wherein m and n are equal to 1 and Ar is an unsubstituted phenyl.
- ⁇ r'methyl is an unsubstituted benzyl radical.
- the pharmaceutical composition comprises a compound selected from the group of : o ⁇ 4-[4-(1 -benzoyl-piperidin-4-yl)-piperazin- 1 -yl] -2-benzyl-piperidin- 1 -yl ⁇ -(3,5-bis- trifluoromethyl-phenyl)-methanone ; and o (2-benzyl-4- ⁇ 4-[l -(4-methyl-[l ,2,3]thiadiazole-5-carbonyl)-piperidin-4-yl]-piperazin- 1 -yl ⁇ -piperidin- 1 -yl)-(3 ,5-bis-trifluoromethyl-phenyl)-methanone.
- the pharmaceutical composition comprises a compound according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof, with compound number 5, 110, 97, 45, 22, 151 , 80, 62, 104, 8, 78, 12, 39, 113, 16, 56, 143, 36, 77, 106, 102, 6, 3, 142, 51, 9, 13, 32, 139, 4, 108, 89, 116, 2, 42, 140, 85, 37, 65, 133, 79, 64, 7, 141, 132, 134, 119, 90, 11, 26, 10 and 144 as cited in the Experimental section.
- Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and a prodrug thereof, with compound number 5, 110, 97, 45, 22, 151 , 80, 62, 104, 8, 78, 12, 39, 113, 16, 56,
- alkyl is defined as a monovalent straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl ; alkyl further defines a monovalent cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, for example cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- alkyl also comprises an alkyl radical that is optionally substituted on one or more carbon atoms with one or more phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals, for example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl and polyhaloalkyl, in particular difluoromethyl and trifluoromethyl.
- halo is generic to fluoro, chloro, bromo and iodo.
- the pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salts forms that the compounds according to the invention are able to form.
- Said salts can be obtained by treating the base form of the compounds according to the invention with appropriate acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid ; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.
- inorganic acids for example hydrohalic acid
- the compounds according to the invention containing acidic protons may also be converted into their therapeutically active non-toxic metal or amine addition salts forms by treatment with appropriate organic and inorganic bases.
- Appropriate base salts forms comprise, for example, the ammonium salts, the alkaline and earth alkaline metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, and salts with amino acids, for example arginine and lysine.
- salt forms can be converted into the free forms by treatment with an appropriate base or acid.
- addition salt as used in the framework of this application also comprises the solvates that the compounds according to the invention as well as the salts thereof, are able to form. Such solvates are, for example, hydrates and alcoholates.
- N-oxide forms of the compounds according to the invention are meant to comprise those compounds according to the invention wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more tertiary nitrogens (e.g. of the piperazinyl orpiperidinyl radical) are N-oxidized.
- Such N-oxides can easily be obtained by a skilled person without any inventive skills and they are obvious alternatives for the compounds according to the invention since these compounds are metabolites, which are formed by oxidation in the human body upon uptake .
- oxidation is normally the first step involved in drug metabolism ( Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70- 75).
- the metabolite form of a compound can also be administered to a human instead of the compound per se, with much the same effects.
- the compounds according to the invention possess at least 2 oxydizable nitrogens (tertiary amines moieties). It is therefore highly likely that N-oxides are to form in the human metabolism.
- the compounds according to Formula (I) may be converted to the corresponding N-oxide forms following art -known procedures for converting a trivalent nitrogen into its N-oxide form.
- Said N-oxidation reaction may generally be carried out by reacting the starting material according to Formula (I) with an appropriate organic or inorganic peroxide.
- Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
- appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
- Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
- stereochemically isomeric forms as used hereinbefore defines all the possible isomeric forms that the compounds according to Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S -configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans- configuration. Compounds encompassing double bonds can have an E or Z- stereochemistry at said double bond. Stereochemically isomeric forms of the compounds according to Formula (I) are obviously intended to be embraced within the scope of this invention.
- the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number is arbitrarily always in the " ⁇ " position of the mean plane determined by the ring system.
- the position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in compounds according to Formula (I)) relative to the position of the highest priority substituent on the reference atom is denominated " ⁇ ", if it is on the same side of the mean plane determined by the ring system, or " ⁇ ", if it is on the other side of the mean plane determined by the ring system.
- Compounds according to the invention and some of the intermediate compounds have at least two stereogenic centers in their structure, namely at the 2- or 3 -position of the piperidinyl-moiety (R and S) and at the 4-position, where the attached radical may be either in the cis or trans position with respect to the radical at the 2- or 3 -position on the piperidinyl-moiety.
- the invention also comprises pharmaceutical compositions according to the invention comprising derivative compounds (usually called "pro-drugs") of the pharmacologically-active compounds according to the invention, which are degraded in vivo to yield the compounds according to the invention.
- Pro-drugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded.
- Pro -drugs axe particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al. , “Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.
- Pro-drugs forms of the pharmacologically-active compounds according to the invention will generally be compounds according to the invention, having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the formula -COOR", where R x is a C i ⁇ alkyl, phenyl, benzyl or one of the following groups
- X Amidated groups include groups of the formula - C0NR y R z , wherein R y is H, C i ⁇ alkyl, phenyl or benzyl and R z is -OH, H, C i ⁇ alkyl, phenyl or benzyl.
- Compounds according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This base will hydrolyze with first order kinetics in aqueous solution.
- the compounds according to Formula (I) as prepared in the processes described below may be synthesized in the form of racemic mixtures ofenantiomers that can be separated from one another following art-known resolution procedures.
- the racemic compounds according to Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated there from by alkali.
- ⁇ n alternative manner of separating the enantiomeric forms of the compounds according to Formula (T) involves liquid chromatography using a chiral stationary phase.
- Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
- said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
- opioid means opium-like or morphine-like in terms of pharmacological action.
- the broad group of opium alkaloids, synthetic derivatives related to the opium alkaloids, and the many naturally occuring and synthetic peptides with morphine-like pharmacological effects is called opioids.
- opioids In addition to having pharmacological effects similar to those ofmorphine, a compound must be antagonized by an opioid antagonist such as naloxone to be classified as an opioid.
- opioid receptors The neuronally located proteins to which opioid agents bind to initiate a biological response. Opioids can act peripherally and centrally.
- Suitable opioids or opioid analgesics for use in the present invention include one or more compounds selected from the group of alfentanil, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine, dihydrocodcine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, remifentanil and sufentanil; and pharmaceutical acceptable salts and derivatives thereof.
- preferred opioid analgesics of use in the present invention are one or more compounds selected from the group of oxycodone, codeine, morphine, fentanyl, buprenorphine, hydrocodone, hydromorphone and pharmaceutical acceptable salts and derivatives thereof.
- Suitable pharmaceutically acceptable salts of the opioid analgesics of use in the present invention include those salts described above in relation to the salts of the NK i -antagonist.
- Preferred salts of opioid analgesics of use in the present invention include alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, codeine phosphate, codeine sulphate, diacetylmorphine hydrochloride, dihydrocodeine bitartrate, fentanyl citrate, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, meperidine hydrochloride, methadone hydrochloride, morphine sulphate, morphine hydochloride, morphine tartrate, nalbuphine hydrochloride, oxymorphone hydrochloride, pentazocine hydrochloride, propoxyphene hydrochloride and propoxyphene napsylate (2-naphthalene sulphonic acid (1 :1) monohydrate).
- Particular preferred opioid analgesics of use in the present invention are morphine, fentanyl and pharmaceutical acceptable salts and derivatives thereof.
- More particular preferred opioid analgesics of use in the present invention are morphine sulphate and fentanyl citrate.
- the compounds according to the invention are potent inhibitors ofneurokinin - mediated effects, in particular those mediated via the NK] receptor, and may therefore be described as neurokinin antagonists, especially as substance P antagonists, as indicated in vitro by the antagonism of substance P-induced relaxation of pig coronary arteries which is described hereinafter.
- the binding affinity of the present compounds for the human, guinea-pig and gerbil neurokinin receptors may be determined in vitro in a receptor binding test using 3 H-substance-P as radioligand.
- the subject compounds also show substance-P antagonistic activity in vivo as may be evidenced by, for instance, the antagonism of substance P-induced plasma extravasation in guinea-pigs, or the antagonism of drug-induced emesis in ferrets (Watson et al, Br. J. Pharmacol. 115:84- 94 (1995)).
- NK receptor antagonists potentiating the analgesic activity of opioids require lower doses, resulting in a reduced risk of opioid side-effects, in particular emesis, respiratory depression and tolerance. But additionally it's seen that at similar doses (not lower opioid doses) there are also benefits of adding NKl to opioid.
- Respiratory depression is the most serious side effect of opioid analgesics and is the primal cause of death from overdose.
- Opioids decrease the sensitivity of chemoreceptors in the brainstem to carbon dioxide, a normal stimulus of ventilatory reflexes. The result is a blunting of the ventilatory response to increases in the carbon dioxide tension (Pco 2 ) m blood and cerebrospinal fluid.
- Pco 2 carbon dioxide tension
- most opioids produce a similar degree of respiratory depression, as shown by an elevation in the blood Pco 2 - This effect is at least additive to that produced by other drugs that depress CNS functions, including general anesthetics and sedative-hypnotics.
- the mild respiratory depression produced by therapeutic doses of opioids is normally of little consequence.
- opioid analgesics must be used cautiously in patients with traumatic head injuries, with emphysema and who are morbidly obese. At three to five times its usual analgesic dose, morphine can cause respiratory arrest in the nontolerant patient. In contrast, much higher doses will have minimal respiratory effects in morphine-tolerant individuals.
- Tolerance refers to a reduced drug effect with repeated use and/or a need for higher doses to produce the same effect. Because tolerance does not occur to the same extent for all effects, drug abusers who take increasing amounts of drugs risk exposure to those effects to which tolerance does not develop. Tolerance develops to many of the effects of opioids. With repeated drug administration, larger doses are necessary to produce the same pharmacological response. The rate of tolerance development varies with the affected tissue of organ. Tolerance develops rapidly to the antiemetic effects of opioids; more gradually to their analgesic, endocrine and respiratory depressant effects ; and virtually not at all to their constipating and miotic effects.
- the compounds according to the invention have shown to reduce unwanted side- effects induced by opioids. Such reduction can be tested by in vivo testing using several species (e.g. ferrets, gerbils, rats, guinea pigs) and several pain models, covering pain models aiming at different states of acute and chronic pain, as well as animal models aiming to profile opioid side effects (such as opioid-induced emesis, GI transit and respiratory depression).
- opioid side effects such as opioid-induced emesis, GI transit and respiratory depression.
- the present invention therefore also relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention and/or treatment of pain and/or nociception.
- the present invention relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the opioid-based prevention and/or treatment of acute and chronic pain, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments.
- a pharmaceutical composition according to the invention for the manufacture of a medicament for the opioid-based prevention and/or treatment of acute and chronic pain, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments.
- the present invention further relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention and/or treatment ofemesis in opioid-based treatments of pain.
- the present invention further relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention and/or treatment of emesis in opioid-based treatments of pain, wherein the emesis is nausea and vomiting.
- the present invention also relates to the use of an NK i -receptor antagonist, in particular an NK i -receptor antagonist according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, for the manufacture of a medicament for the prevention and/or treatment of respiratory depression in opioid- based treatments of pain.
- an NK i -receptor antagonist in particular an NK i -receptor antagonist according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, for the manufacture of a medicament for the prevention and/or treatment of respiratory depression in opioid- based treatments of pain.
- the present invention also relates to the use of an NK i -receptor antagonist, in particular an NK i -receptor antagonist according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, for the manufacture of a medicament for reducing and/or overcoming the tolerance observed with opioids, e.g. when daily administered in chronic neuropathic pain.
- an NK i -receptor antagonist in particular an NK i -receptor antagonist according to Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, for the manufacture of a medicament for reducing and/or overcoming the tolerance observed with opioids, e.g. when daily administered in chronic neuropathic pain.
- compositions of this invention an effective amount of the active ingredient, optionally in addition salt form, is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- the pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
- compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- Other compositions may be compositions in a form suitable for sublingual, intranasal or pulmonary application or suitable as eye droplets.
- Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- NK i -receptor antagonists are especially advantageous.
- the NK i -receptor antagonist and the opioid analgesic may be formulated in a single pharmaceutical product or composition or alternatively in individual pharmaceutical products or compositions for simultaneous, separate or sequential use in accordance with the present invention.
- the pharmaceutical product or composition may also be a product comprising the NK i -receptor antagonist and the opioid analgesic as separate unit dosages.
- the NK, -receptor antagonist and the opioid analgesic are presented in a ratio which is consistent with the manifestation of the desired effect.
- the ratio by weight of the NK i -antagonist to the opioid analgesic will suitably be approximately 1 to 1.
- this ratio will be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.
- ⁇ suitable dosage level for the NK i -receptor antagonist is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg day.
- the compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day.
- the opioid analgesic may be administered at a dosage level up to conventional dosage levels for such analgesics, but preferably at a reduced level in accordance with the present invention. Suitable dosage levels will depend upon the analgesic effect of the chosen opioid analgesic, but typically suitable levels will be about 0.001 to 25 mg/kg per day, preferably 0.005 to 10 mg/kg per day, and especially 0.005 to 5 mg/kg day.
- the compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day.
- an NK i -receptor antagonist and an opioid analgesic required for use in the prevention and/or treatment of pain and nociception will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the human in need of such a treatment, and will ultimately be at the discretion of the attendant physician.
- the compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
- the compounds of Formula (I) are conveniently prepared by reductively N-alkylating an intermediate of Formula (II) wherein R 1 , R 2 , X, Q, m, n and p are defined as in Formula (I), with a N-substituted piperidinon of Formula (I ⁇ ) wherein R 1 , AIk, Y, L and q are defined as in Formula (I).
- Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol or toluene or a mixture thereof, and in the presence of an appropriate reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
- a borohydride e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
- a complex-forming agent such as, for example, titanium(IV)- isopropylate as described in J. Org. Chem, 1990, 55, 2552-2554.
- Using said complex- forming agent may also result in an improved cis/ trans ratio in favor of the trans isomer.
- hydrogen it may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
- a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
- a dehydrating agent such as, for example, aluminium ferNbutoxide.
- an appropriate catalyst- poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction.
- reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
- a compound according to the invention is pharmacological active and can be converted into a compound according to the invention in which the ⁇ lk-Y-Alk-L-moiety is hydrogen by reductive hydrogenation using e.g. hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
- the resulting compound according to the invention can then be converted into other compounds according to the invention by art-known transformations, e.g. acylation and alkylation.
- the compounds of Formula (P) can be prepared by reacting a final compound of Formula (V) wherein R 1 , R 2 , X, Q, m, n, p and q are defined as in Formula (I) with an acyl compound of Formula (V) wherein AIk and L are defined as in Formula (I) and W 1 is an appropriate leaving group such as, for example, a halo, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy.
- the reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g.
- dichloromethane an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction.
- the reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.
- the compounds of Formula (I a ) can also be prepared by reacting a final compound of Formula (I 1 ) wherein R 1 , R 2 , X, Q, m, n, p and q are defined as in Formula (I) with a carboxylic acid of Formula (VI) wherein AIk and L are defined as in Formula (I)(base-catalyzed nucleophilic addition reaction).
- the reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g.
- methyl isobutylketone and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction.
- the reaction may conveniently be carried at a temperature ranging between room temperature and reflux temperature.
- the compounds of Formula (I b ) can be prepared by reacting a final compound of Formula (V) wherein R 1 , R 2 , X, Q, m, n, p and q are defined as in Formula (I) with a keto -compound of Formula (VTI) wherein W 2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy.
- the reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g.
- dichloromethane an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction.
- the reaction may conveniently be carried at a temperature ranging between room temperature and reflux temperature.
- the compounds of Formula (I c ) can be prepared by reductive amination/ alkylation of a final compound of Formula (V) wherein R 1 , R 2 , X, Q, m, n, p and q are defined as in Formula (I) with a compound of Formula (VIII) wherein ⁇ lk and L are defined as in Formula (J) and W ⁇ is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy.
- a halogen e.g. chloro or bromo
- a sulfonyloxy leaving group e.g. methanesulfonyloxy or benzenesulfonyloxy.
- the reaction can be performed in a reaction-inert solvent such as, for example, a chlorinated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction.
- a reaction may conveniently be carried at a temperature ranging between room temperature and reflux temperature.
- intermediates of formula (II) may be prepared by reductively N-alkylating an intermediate of formula (IX) with an intermediate of formula (X) in which W 4 is a benzyl radical, after which the compound according to Formula (X) is subsequently reduced to yield an intermediate compound according to Formula (II).
- Said reductive N-alkylation may be performed in a reaction- inert solvent such as, for example, dichloromethane, cthanol, toluene or a mixture thereof, and in the presence of an appropriate reducing agent such as, for example, a borohydride, e.g.
- borohydride sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
- a borohydride is used as a reducing agent, it may be convenient to use a complex-forming agent such as, for example, titanium(FV)isopropylate as described in J. Org. Chem, 1990, 55, 2552-2554. Using said complex-forming agent may also result in an improved cis/ trans ratio in favor of the trans isomer.
- a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal.
- RT room temperature
- DIPE diisopropylether
- MIK methyl isobutyl keton
- BIN ⁇ P means [l,l'-binaphthalene]-2,2'-diylbis[diphenylphosphine]
- NMP means l-methyl-2- pyrrolidinonc
- Pd 2 (dba) 3 means tris(dibenzylideneacetone)dipalladium
- DMF means N,N-dimethylforrnamide.
- melting points were obtained with a B ⁇ chi melting point apparatus B-545.
- the heating medium is a metal block.
- the melting of the sample is visually observed by a magnifying lens and a big light contrast.
- Melting points are measured with a temperature gradient of either 3 or 10 degrees Celsius/minute. Melting points are given in Table 6.
- the HPLC gradient was supplied by a Waters Alliance HT 2790 system with a columnheater set at 40 0 C. Flow from the column was split to a Waters 996 photodiode array (PD ⁇ ) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS Cl 8 column (3.5 mm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min.
- Three mobile phases (mobile phase A 95% 25mM ammoniumacetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50% B and 50% C in 6.5 min., to 100 % B in 1 min, 100% B for 1 min. and reequilibrate with 100 % A for 1.5 min. An injection volume of 10 mL was used.
- Mass spectra were acquired by scanning from 100 to 1000 in 1 s using a dwell time of 0.1 s.
- the capillary needle voltage was 3kV and the source temperature was maintained at 140 0 C .
- Nitrogen was used a the nebulizer gas.
- Cone voltage was 10 V for positive ionzation mode and 20 V for negative ionization mode.
- Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system. Data is given in Table 7.
- Example Cl Binding experiment for h-NKu h-NK? and h-NK 3 receptors
- the compounds according to the invention were investigated for interaction with various neurotransmitter receptors, ion channels and transporter binding sites using the radioligand binding technique.
- Membranes from tissue homogenates or from cells, expressing the receptor or transporter of interests, were incubated with a radioactively labelled substance ([ 3 H]- or [ 125 I] ligand) to label a particular receptor.
- a radioactively labelled substance [ 3 H]- or [ 125 I] ligand
- labelled membranes were harvested and rinsed with excessive cold buffer to remove non-bound radioactivity by rapid filtration under suction. Membrane bound radioactivity was counted in a scintillation counter and results were expressed in counts per minute (cpm).
- the compounds were dissolved in DMSO and tested at 10 concentrations ranging from 10 " '° to lO -5 M.
- ⁇ ll selected compounds show (sub)nanomolar affinity for the h-NKj receptor most of them with more than 100-fold selectivity towards the h-NK 2 and h-NK 3 receptors.
- a Krebs buffer 140 mM NaCl, 1 mM MgCl 2 XoH 2 O, 5 mM KCl, 10 mM glucose, 5 mM HEPES; 1.25 mM CaCl 2 ; pH 7.4
- the cells were preincubated with a concentration range of antagonists for 20 min at RT and Ca ⁇ - signals after addition of the agonists were measured in a Fluorescence Image Plate Reader (FLIPR from Molecular Devices, Crawley, England). The peak of the Ca ⁇ - transient was considered as the relevant signal and the mean values of corresponding wells were analysed as described below.
- the sigmoidal dose response curves were analysed by computerised curve -fitting, using the GraphPad Program.
- the EC 50 -value of a compound is the effective dose showing 50 % of maximal effect.
- For mean curves the response to the agonist with the highest potency was normalised to 100 %.
- For antagonist responses the ICso-value was calculated using non-linear regression.
- the antiemetic effects have been determined using the loperamide-induced retching model (i.e. retching induced by an opioid) in ferrets. To exclude species differences in antiemetic activity, both compounds have also been tested for antiemetic activity against apomorphine in dogs.
- Table 10 ED 50 S (95% CL; mg/kg) for inhibition and blockade of loperamide-induced retching as a function of time after oral, s.c. and i.v. administration.
- Intravenous route 1 0.88 (0.59-1.3) 0.26 (0.17-0.39)
- Table 11 ED 50 S (95% CL; mg/kg) for blockade of loperamide (0.31 mg/kg, s.c.)- induced retching in ferrets at 1 h after subcutaneous or 2 h after oral administration.
- GR-203040 a 0.064 (0.037-0.11) 0.20 (0.12-0.35) 3.1
- NK i receptor antagonist prevents the increase in tracheal vascular permeability produced by hypertonic saline. J Pharmacol Exp Ther 266:270-273, 1993. d) Kramer et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 28i:i640-i 645, 1998. e) Snider et al. Effect of CP-96,345, a nonpeptide substance P receptor antagonist, on salivation in rats. Proc Natl Acad Sci 88:10042-10044, 1991.
- ED 50 estimated based on a limited number of animals tested per dose group. Compound 77 was also found more potent than Compound 3 1 h after i.v. injection, both for inhibition of retching (ED 50 : 0.15 and 0.39 mg/kg, respectively) and for blockade of retching (ED 50 : 0.26 and 0.88 mg/kg, respectively).
Abstract
Description
Claims
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EP04766038A EP1635811A2 (en) | 2003-06-10 | 2004-06-07 | Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments |
MXPA05013295A MXPA05013295A (en) | 2003-06-10 | 2004-06-07 | Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments. |
AU2004246817A AU2004246817A1 (en) | 2003-06-10 | 2004-06-07 | Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments |
NZ544232A NZ544232A (en) | 2003-06-10 | 2004-06-07 | Substituted 1,4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opoid-based treatments |
US10/560,476 US20060128721A1 (en) | 2003-06-10 | 2004-06-07 | Novel formulations of opioid-based treatments of pain comprising substituted 1,4-di-piperidin-4-yl-piperazine derivatives |
BRPI0411290-3A BRPI0411290A (en) | 2003-06-10 | 2004-06-07 | opioid-based pain treatment formulations containing substituted 1,4-di-piperidin-4-yl-piperazine derivatives |
CA002527856A CA2527856A1 (en) | 2003-06-10 | 2004-06-07 | Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments |
JP2006516137A JP2006527236A (en) | 2003-06-10 | 2004-06-07 | Substituted 1,4-di-piperidin-4-yl-piperazine derivatives in combination with opioid analgesics and their use for the treatment of pain and side effects associated with opioid based treatments |
IL172423A IL172423A0 (en) | 2003-06-10 | 2005-12-07 | Novel formulations for opioid -based treatments of pain comprising substituted 1,4-di-piperidin-4-yl-piperazine derivatives |
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US7842662B2 (en) | 2006-11-10 | 2010-11-30 | Cara Therapeutics, Inc. | Synthetic peptide amide dimers |
CA3120681A1 (en) * | 2012-04-17 | 2013-10-24 | Purdue Pharma L.P. | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
CN108902893B (en) | 2013-02-08 | 2022-02-25 | 通用磨坊公司 | Low sodium food |
CN105209436B (en) * | 2013-03-15 | 2019-02-01 | 南洋理工大学 | 3- piperidines ketone compound and its purposes as neurokinine-1 (NK1) receptor antagonist |
CN108503579B (en) * | 2018-03-28 | 2021-03-26 | 南京医科大学 | Fentanyl analogs and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996020009A1 (en) | 1994-12-23 | 1996-07-04 | Merck Sharp & Dohme Limited | Use of a tachykinin antagonist and an opioid analgesic |
WO1997025988A1 (en) | 1996-01-17 | 1997-07-24 | Eli Lilly And Company | Methods of treating or preventing pain or nociception |
WO2001030348A1 (en) | 1999-10-25 | 2001-05-03 | Janssen Pharmaceutica N.V. | Use of substance p antagonists for influencing the circadian timing system |
WO2002062784A1 (en) | 2001-02-06 | 2002-08-15 | F. Hoffmann-La Roche Ag | Piperidinee derivatives as neurokinin 1 antagonists |
WO2004033428A1 (en) | 2002-10-08 | 2004-04-22 | Janssen Pharmaceutica N.V. | Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2287404A (en) * | 1994-03-15 | 1995-09-20 | Pfizer | Antiinflammatory and analgesic compositions |
NZ321575A (en) * | 1995-10-30 | 1999-05-28 | Janssen Pharmaceutica Nv | 1-(1,2-disubstituted piperidinyl)-4- substituted piperazine derivatives |
-
2004
- 2004-06-07 WO PCT/EP2004/051048 patent/WO2004110415A2/en active Application Filing
- 2004-06-07 US US10/560,476 patent/US20060128721A1/en not_active Abandoned
- 2004-06-07 CN CNA2004800202370A patent/CN1822828A/en active Pending
- 2004-06-07 BR BRPI0411290-3A patent/BRPI0411290A/en not_active IP Right Cessation
- 2004-06-07 MX MXPA05013295A patent/MXPA05013295A/en unknown
- 2004-06-07 CA CA002527856A patent/CA2527856A1/en not_active Abandoned
- 2004-06-07 KR KR1020057023011A patent/KR20060006098A/en not_active Application Discontinuation
- 2004-06-07 EP EP04766038A patent/EP1635811A2/en not_active Withdrawn
- 2004-06-07 JP JP2006516137A patent/JP2006527236A/en not_active Withdrawn
- 2004-06-07 AU AU2004246817A patent/AU2004246817A1/en not_active Abandoned
- 2004-06-08 CL CL200401421A patent/CL2004001421A1/en unknown
- 2004-06-08 MY MYPI20042196A patent/MY144580A/en unknown
- 2004-06-09 AR ARP040101992A patent/AR044490A1/en not_active Application Discontinuation
- 2004-06-09 TW TW093116490A patent/TW200510382A/en unknown
-
2005
- 2005-12-07 IL IL172423A patent/IL172423A0/en unknown
- 2005-12-09 ZA ZA200510044A patent/ZA200510044B/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996020009A1 (en) | 1994-12-23 | 1996-07-04 | Merck Sharp & Dohme Limited | Use of a tachykinin antagonist and an opioid analgesic |
US5880132A (en) | 1994-12-23 | 1999-03-09 | Merck Sharp & Dohme Limited | Tachykinin antagonist and an opioid analgesic effective at treating pain or nociception |
WO1997025988A1 (en) | 1996-01-17 | 1997-07-24 | Eli Lilly And Company | Methods of treating or preventing pain or nociception |
WO2001030348A1 (en) | 1999-10-25 | 2001-05-03 | Janssen Pharmaceutica N.V. | Use of substance p antagonists for influencing the circadian timing system |
WO2002062784A1 (en) | 2001-02-06 | 2002-08-15 | F. Hoffmann-La Roche Ag | Piperidinee derivatives as neurokinin 1 antagonists |
WO2004033428A1 (en) | 2002-10-08 | 2004-04-22 | Janssen Pharmaceutica N.V. | Substituted 1,4-di-piperidin-4-yl-piperazine derivatives and their use as neurokinin antagonists |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006067310A3 (en) * | 2004-12-17 | 2007-05-10 | Sod Conseils Rech Applic | Use of a dihydroim1dazopyrazine derivative for treating or preventing pain |
WO2006067312A3 (en) * | 2004-12-17 | 2007-05-31 | Sod Conseils Rech Applic | Painkilling association comprising a dihydroimidazopyrazine derivative |
WO2006067312A2 (en) * | 2004-12-17 | 2006-06-29 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Painkilling association comprising a dihydroimidazopyrazine derivative |
US7880002B2 (en) | 2004-12-29 | 2011-02-01 | Millennium Pharmaceuticals, Inc. | Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists |
US8648197B2 (en) | 2004-12-29 | 2014-02-11 | Millennium Pharmaceuticals, Inc. | Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists |
US8399455B2 (en) | 2004-12-29 | 2013-03-19 | Millennium Pharmaceuticals, Inc. | Compounds useful as chemokine receptor antagonists |
US8168788B2 (en) | 2004-12-29 | 2012-05-01 | Millennium Pharmaceuticals, Inc. | Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists |
US7635698B2 (en) | 2004-12-29 | 2009-12-22 | Millennium Pharmaceuticals, Inc. | Compounds useful as chemokine receptor antagonists |
JP2008531659A (en) * | 2005-03-03 | 2008-08-14 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Substituted oxa-diaza-spiro- [5.5] -undecanone derivatives and their use as neurokinin antagonists |
US8604200B2 (en) | 2005-03-08 | 2013-12-10 | Janssen Pharmaceutica N.V. | Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists |
EP2021005A4 (en) * | 2006-05-03 | 2009-11-25 | Cnsbio Pty Ltd | Methods and composition for treatment of inflammatory pain |
JP2009535364A (en) * | 2006-05-03 | 2009-10-01 | シーエヌエスバイオ ピーティーワイ リミテッド | Methods and compositions for the treatment of inflammatory pain |
EP2021005A1 (en) * | 2006-05-03 | 2009-02-11 | Cnsbio Pty Ltd | Methods and composition for treatment of inflammatory pain |
RU2617409C1 (en) * | 2015-12-24 | 2017-04-25 | Федеральное государственное бюджетное учреждение науки Институт элементоорганических соединений им. А.Н. Несмеянова Российской академии наук (ИНЭОС РАН) | Acrylic and methacrylic acid amides with n-alkylpiperazine piperidines and method for their preparation |
Also Published As
Publication number | Publication date |
---|---|
CL2004001421A1 (en) | 2005-05-27 |
IL172423A0 (en) | 2006-04-10 |
AR044490A1 (en) | 2005-09-14 |
KR20060006098A (en) | 2006-01-18 |
JP2006527236A (en) | 2006-11-30 |
MXPA05013295A (en) | 2006-03-09 |
AU2004246817A1 (en) | 2004-12-23 |
CA2527856A1 (en) | 2004-12-23 |
MY144580A (en) | 2011-10-14 |
EP1635811A2 (en) | 2006-03-22 |
CN1822828A (en) | 2006-08-23 |
WO2004110415A3 (en) | 2005-02-10 |
BRPI0411290A (en) | 2006-08-29 |
ZA200510044B (en) | 2007-04-25 |
TW200510382A (en) | 2005-03-16 |
US20060128721A1 (en) | 2006-06-15 |
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