1. A cap for a bearing device, the cap being attached to one axial end portion of an outer race member of the bearing device to block an opening portion of the one end portion, the cap comprising:
a cylindrical part that is fitted to the outer race member;
a lid part configured to connect to block a posterior end portion of the cylindrical part in a fitting direction;
an annular seal part configured to, when being fitted to the outer race member, intervene in a compressed state between the cap for the bearing device and the outer race member; and
a ventilation part, wherein
in the course of fitting the cylindrical part to the outer race member, the ventilation part allows air to pass between inside and outside of a bearing space, and
in the state where the cylindrical part is fitted to the outer race member, the ventilation of the ventilation part is shut down by the annular seal part.
2. The cap for bearing device according to claim 1, wherein the cylindrical part is fitted to an inner diameter surface of the outer race member.
3. The cap for bearing device according to claim 1, wherein the cylindrical part is fitted to an outer diameter surface of the outer race member.
4. The cap for bearing device according to claim 1, wherein
the ventilation part is formed of a through hole formed in the cylindrical part,
the through hole is positioned anterior to the annular seal part in the cylindrical part in the fitting direction, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
5. The cap for bearing device according to claim 1, wherein
the ventilation part is formed of a slit-like notch extending from an anterior end portion of the cylindrical part in the fitting direction to the posterior end of the cylindrical part in the fitting direction,
the notch is positioned anterior to the annular seal part in the cylindrical part in the fitting direction thereof, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
6. The cap for bearing device according to claim 2, wherein
the ventilation part is formed of a through hole formed in the cylindrical part,
a portion of the annular seal part is fixed to an outer peripheral surface of the cylindrical part,
the through hole is formed in the annular seal part in the vicinity of the fixed portion, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part to block the through hole.
7. The cap for bearing device according to claim 2, wherein
the annular seal part is fixed to the outer peripheral surface of the cylindrical part,
the ventilation part is formed of a through hole formed in the cylindrical part at a section to which the annular seal part is fixed so as to communicate with the annular seal part and the cylindrical part, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
8. The cap for bearing device according to claim 2, wherein
an outward flange portion is provided in the cylindrical part at a section connected to the lid part,
the ventilation part is formed of a through hole formed in the cylindrical part or the outward flange portion,
the annular seal part is fixed to a surface of the outward flange portion on the anterior end side of the cylindrical part in the fitting direction, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the end surface of the outer race member on the one end portion side and the outward flange portion.
9. The cap for bearing device according to claim 3, wherein
the ventilation part is formed of a through hole formed in the cylindrical part,
the annular seal part is fixed to an inner surface of the lid part, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the end surface of the outer race member on the one end portion side and the lid part.
10. The cap for bearing device according to claim 3, wherein
the ventilation part is formed of a through hole formed in the lid part,
the annular seal part is fixed to the inner surface of the lid part,
the through hole is positioned at a centrifugal side of the annular seal part, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the end surface of the outer race member and the lid part.
11. The cap for bearing device according to claim 3, wherein
the annular seal part is fixed to the inner surface of the lid part,
the ventilation part is formed of a through hole formed in the lid part at a section to which the annular seal part is fixed so as to communicate with the annular seal part and the lid part, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the end surface of the outer race member and the lid part.
12. The cap for bearing device according to claim 3, wherein
a portion of the annular seal part is fixed to the inner surface of the lid part,
the ventilation part is formed of a through hole formed in the lid part in the vicinity of the fixed portion of the annular seal part, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the end surface of the outer race member and the lid part to block the through hole.
13. The cap for bearing device according to claim 2, wherein
the ventilation part is formed of a through hole formed in the cylindrical part,
the through hole is positioned anterior to the annular seal part in the cylindrical part in the fitting direction, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
14. The cap for bearing device according to claim 3, wherein
the ventilation part is formed of a through hole formed in the cylindrical part,
the through hole is positioned anterior to the annular seal part in the cylindrical part in the fitting direction, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
15. The cap for bearing device according to claim 2, wherein
the ventilation part is formed of a slit-like notch extending from an anterior end portion of the cylindrical part in the fitting direction to the posterior end of the cylindrical part in the fitting direction,
the notch is positioned anterior to the annular seal part in the cylindrical part in the fitting direction thereof, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
16. The cap for bearing device according to claim 3, wherein
the ventilation part is formed of a slit-like notch extending from an anterior end portion of the cylindrical part in the fitting direction to the posterior end of the cylindrical part in the fitting direction,
the notch is positioned anterior to the annular seal part in the cylindrical part in the fitting direction thereof, and
the annular seal part is configured to, in the state where the cylindrical part is fitted to the outer race member, intervene in the compressed state between the outer race member and the cylindrical part.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. 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 prodrugs thereof, wherein:
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 NR3;
X is a covalent bond or a bivalent radical of formula \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
each R3 independently from each other, is hydrogen or alkyl;
each R1 independently from each other, is selected from the group consisting of Ar1, Ar1-alkyl and di(Ar1)-alkyl;
q is an integer equal to 0 or 1;
R2 is selected from the group consisting of alkyl, Ar2, Ar2-alkyl, Het1 or Het1-alkyl;
Y is a covalent bond or a bivalent radical of formula \u2014C(=O)\u2014 or \u2014SO2\u2014;
each Alk represents, independently from each other, selected from the group consisting a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms and; 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 alkyl, phenyl, halo, cyano, hydroxy, formyl and amino radicals;
L is selected from the group consisting of hydrogen, alkyloxy, Ar3-oxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono-and di(Ar3)amino, Ar3, Ar3-carbonyl, Het2 and Het2-carbonyl;
Ar1 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group consisting of halo, alkyl, cyano, aminocarbonyl and alkyloxy;
Ar1 is naphthalenyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group consisting of halo, nitro, amino, mono- and di(alkyl)amino, cyano, alkyl, hydroxy, alkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl and mono-and di(alkyl)aminocarbonyl;
Ar3 is naphthalenyl or phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group consisting of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo1,2-apyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
Het1 is a monocyclic heterocyclic radical selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocyclic radical selected from the group consisting 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 consisting of halo and alkyl;
Het2 is a monocyclic heterocyclic radical selected from the group consisting of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrrazolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 2H-pyrrolyl, pyrrolinyl, imidazolinyl, pyrrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; or a bicyclic heterocyclic radical selected from the group consisting of benzopiperidinyl, quinolinyl, quinoxalinyl, indolyl, isoindolyl, chromenyl, benzimidazolyl, imidazo 1,2-apyridinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic radical optionally substituted with one or more radicals selected from the group consisting of Ar1, Ar1alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo, alkyloxy, alkyloxyalkyl and alkyloxycarbonyl; and
alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; optionally substituted on one or more carbon atoms with one or more radicals selected from the group consisting of phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals.
2. A pharmaceutical composition according to claim 1, wherein
n is 1;
m is 1;
p is 1;
Q is O;
X is a covalent bond;
each R1 is Ar1 or Ar1-alkyl;
q is 0 or 1;
R1 is Ar2;
Y is a covalent bond or a bivalent radical of formula \u2014C(=O)\u2014 or \u2014SO2\u2014;
each Alk represents, independently from each other, selected from the group consisting a covalent bond; a bivalent straight or branched, saturated or unsaturated hydrocarbon radical having from 1 to 6 carbon atoms and; 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 consisting of hydrogen, alkyloxy, Ar3-oxy, alkyloxycarbonyl, mono- and di(alkyl)amino, mono-and di(Ar3)amino, Ar3 and Het2;
Ar1 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals;
Ar2 is phenyl, optionally substituted with 1, 2 or 3 alkyl radicals;
Ar3 is phenyl, optionally substituted with 1, 2 or 3 substituents each independently from each other selected from the group consisting of alkyloxy, alkyl, halo, hydroxy, pyridinyl, morpholinyl, pyrrolidinyl, imidazo 1,2-apyridinyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, amino and cyano;
Het2 is a monocyclic heterocyclic radical selected from the group consisting 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 consisting of benzopiperidinyl, quinolinyl,. quinoxalinyl, indolyl, chromenyl and benzimidazolyl; each monocyclic and bicyclic radical optionally substituted with one or more radicals selected from the group consisting of Ar1, Ar1alkyl, halo, hydroxy, alkyl, piperidinyl, pyrrolyl, thienyl, oxo and alkyloxycarbonyl; and
alkyl is a straight hydrocarbon radical having 1 to 6 carbon atoms, optionally substituted with one or more halo radicals.
3. A pharmaceutical composition according to claim 1, wherein R1 is Ar1 methyl and attached to the 2-position or R1 is Ar1 and attached to the 3-position.
4. A pharmaceutical composition according to claim 1, wherein the R2\u2014X\u2014C(=Q)-moiety is 3,5-di-(trifluoromethyl) phenylcarbonyl.
5. A pharmaceutical composition according to claim 1 wherein, the compound according to Formula (I) is selected from the group of consisting:
{4-4-(1-Benzoyl-piperidin-4-yl)-piperazin-1-yl-2-benzyl-piperidin-1-yl}-(3,5-bis-trifluoromethyl-phenyl)-methanone and
(2-Benzyl-4-{4-1-(4-methyl-1,2,3thiadiazole-5-carbonyl)-piperidin-4-yl-piperazin-1-yl} -piperidin-1-yl)-(3 ,5-bis-trifluoromethyl-phenyl)-methanone.
6. A pharmaceutical composition according to claim 1 wherein, the compound according to Formula (I) is a compound 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.
7. A pharmaceutical composition according to claim 1, wherein it is formulated for simultaneous, separate or sequential use.
8. A pharmaceutical composition according to claim 1, wherein the opioid analgesic is one or more compounds selected from the group consisting of alfentanil, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, remifentanil and sufentanil; or a pharmaceutical acceptable salt or derivative thereof.
9. A pharmaceutical composition according to claim 8, wherein the opioid analgesic is one or more compounds selected from the group consisting of oxycodone, codeine, morphine, fentanyl, buprenorphine, hydrocodone, hydromorphone and pharmaceutical acceptable salts and derivatives thereof.
10. A pharmaceutical composition according to claim 9, wherein the opioid analgesic is one or more compound selected from the group of morphine sulphate and fentanyl citrate.
11. A pharmaceutical composition according to claim 1, wherein it is in a form suitable to be orally administered.
12. The use of a pharmaceutical composition according to claim 1, for the prevention andor treatment of pain andor nociception.
13. The use of a pharmaceutical composition according to claim 1, for the opioid-based prevention andor treatment of acute and chronic pain, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments.
14. The use of a pharmaceutical composition according to claim 1, for the prevention andor treatment of emesis in opioid-based treatments of pain.
15. The use of a pharmaceutical composition according to claim 14 for for the prevention andor treatment of nausea and vomiting in opioid-based treatments of pain.
16. The use of an NK1-receptor antagonist, in particular an NK1-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 prevention andor treatment of respiratory depression in opioid-based treatments of pain.
17. The use of an NK1-receptor antagonist, in particular an NK1-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 andor overcoming the tolerance observed with opioids in opioid-based treatments of pain.