1. A 4-amino-5-cyanopyrimidine compound of the formula (1):
or a pharmaceutically acceptable salt thereof,
wherein
R1 is a hydrogen atom, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a phenylcarbonyl group or a lower alkoxycarbonyl group;
R2 is a lower alkylene group;
R3 is
wherein
R4 is a lower alkylene group, and
Z3 is (c3) an amino group, (c4) an amino-lower alkylamino group, (c5) a piperazino group, (c6) an amino-lower alkylpiperazino group, (c8) a 1,4-diazepan-1-yl group, (c10) a piperidino group, (c11) an aminopiperidino group, (c18) a lower alkylpiperazino group having a saturated heterocycle, (c21) a piperidino group having a saturated heterocycle, or (c22) a lower alkylmorpholino group having a saturated heterocycle;
the amino group of the above (c3) and the amino moiety included as a part of the groups in the above (c4), (c6), and (c11) may be optionally substituted with 1 or 2 substituents selected from the group consisting of a lower alkyl group, a hydroxy-lower alkyl group, a phenyl group, and a lower alkoxycarbonyl group;
the amino moiety included as a part of the groups in the above (c11) may be optionally substituted with an aryl-lower alkylcarbonyl group;
the piperazino group of the above (c5) and 1,4-diazepan-1-yl group of the above (c8) may be substituted with any one of the substituents selected from the group consisting of a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a phenyl group, a lower alkylphenyl group, a hydroxyphenyl group, a cyanophenyl group, a halogenophenyl group, a phenyl-lower alkyl group, a lower alkoxyphenyl-lower alkyl group, a halogenophenoxy-lower alkyl group, a pyridyl group, a lower alkylpyridyl group, a halogeno-lower alkylpyridyl group, a cyanopyridyl group, a pyridyl-lower alkyl group, a lower alkoxycarbonyl group and a lower alkylcarbonyl group on 4-position of the ring system; further
the saturated heterocycle moiety included as a part of the groups in the above (c18), (c21) and (c22) may be a monovalent saturated heterocycle group selected from the group consisting of pyrrolidinyl, pyrrolidino, piperidyl, piperidino, piperazinyl, piperazino, 1,4-diazepan-1-yl, tetrahydrofuryl, 1,3-dioxolanyl, tetrahydrothienyl, morpholinyl, morpholino and tetrahydroimidazolyl, optionally having any one of the substituents selected from the group consisting of a lower alkyl group, a phenyl group, a cyanophenyl group, a lower alkylcarbonyl group, a halogeno-lower alkylphenyl group and a phenyl-lower alkyl group on the nitrogen atom of the ring system; and furthermore
the piperazino group of the above (c5), the piperidino group of the above (c10) and the saturated heterocycle moiety included as a part of the groups in the above (c18), a lower alkylpiperazino group having a saturated heterocycle and (c22) a lower alkylmorpholino group having a saturated heterocycle may be substituted with any one of the substituents selected from the group consisting of a hydroxy group, an oxo group, a lower alkyl group, a hydroxy-lower alkyl group, a phenyl group, a phenyl-lower alkyl group, an aminocarbonyl group and a lower alkylamino group on the carbon atom of the ring system.
2. The 4-amino-5-cyanopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R3 is
wherein
R4 is a lower alkylene group, and
Z3 is
(c3) an amino group which may be optionally substituted with 1 or 2 lower alkyl groups,
(c4) an amino-lower alkylamino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group,
(c5) a piperazino group which may be optionally substituted with any one of substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group,
(c6) an amino-lower alkylpiperazino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 lower alkyl groups,
(c8) a 1,4-diazepan-1-yl group which may be optionally substituted with 1 lower alkyl group,
(c10) a 2-hydroxymethylpiperidino group,
(c11) an aminopiperidino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 lower alkyl groups,
(c18) a lower alkylpiperazino group having a saturated heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidino, piperidyl, piperidino, morpholinyl, and morpholino, optionally having a lower alkyl group on the nitrogen atom of the saturated heterocycle ring system,
(c21) a 4-(1-piperidyl)piperidino group or
(c22) a lower alkylmorpholino group having a saturated heterocycle selected from the group consisting of piperidyl, piperidino, piperazinyl and piperazino, optionally having a lower alkyl group on the nitrogen atom of the saturated heterocycle ring system.
3. The 4-amino-5-cyanopyrimidine compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein
R1 is a hydrogen atom or a lower alkylcarbonyl group;
R2 is a methylene group;
R3 is
wherein
R4 is a lower alkylene group, and
Z3 is
(c3) an amino group which may be optionally substituted with 1 or 2 lower alkyl groups,
(c4) an amino-lower alkylamino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group,
(c5) a piperazino group which may be optionally substituted with any one of substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group,
(c6) an amino-lower alkylpiperazino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 lower alkyl groups,
(c8) a 1,4-diazepan-1-yl group which may be optionally substituted with 1 lower alkyl group,
(c10) a 2-hydroxymethylpiperidino group,
(c11) an aminopiperidino group wherein the amino moiety included as a part of the groups may be optionally substituted with 1 or 2 lower alkyl groups,
(c18) a pyrrolidino-lower alkylpiperazino group, piperidyl-lower alkylpiperazino, optionally having a lower alkyl group on the nitrogen atom of the piperidine ring system, or a morpholino-lower alkylpiperazino group,
(c21) a 4-(1-piperidyl)piperidino group or
(c22) a piperidino-lower alkylmorpholino or piperazino-lower alkylmorpholino, optionally having a lower alkyl group on the nitrogen atom of the morpholino ring system.
4. A 4-amino-5-cyanopyrimidine compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following 1)-3):
1) 3-{6-4-(4-acetylaminophenyl)-6-amino-5-cyanopyrimidin-2-ylsulfanylmethylpyridin-2-yl}-N-(piperidin-1-ylethyl)propionamide,
2) 3-{6-4-(4-acetylaminophenyl)-6-amino-5-cyanopyrimidin-2-ylsulfanylmethylpyridin-2-yl}-N-methyl-N-(1-methylpiperidin-4-yl)propionamide, and
3) 3-{6-4-(4-acetylaminophenyl)-6-amino-5-cyanopyrimidin-2-ylsulfanylmethylpyridin-2-yl}-N-(4-methylpiperazin-1-yl) propionamide.
5. A medicine for the treatment of ocular hypertension or glaucoma comprising a 4-amino-5-cyanopyrimidine compound as set forth in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
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 suturing method comprising:
introducing a body of a suturing device into a minimally invasive aperture in a patient, the body of the device extending along a device axis toward a first clamp;
advancing a needle loader through the minimally invasive aperture with the needle loader supporting a needle in a delivery position providing a delivery profile;
moving the needle relative to the needle loader into a large profile needle loading position aligned with the first clamp;
grasping the needle with the first clamp while the needle is supported by the needle loader in the needle loading position within the patient; and
releasing the needle from the needle loader while the needle is supported with the first clamp.
2. The suturing method of claim 1, wherein moving the needle into the needle loading position comprises rotating the needle from the needle delivery position to the needle loading position.
3. The suturing method of claim 1, wherein rotating the needle comprises rotating a needle holder portion of the needle loader supporting the needle in a pre-determined alignment relative the needle holder portion.
4. The suturing method of claim 2, wherein a plane of curvature of the needle is substantially aligned with the device axis when supported with the needle loader in the delivery position, and wherein the plane of curvature of the needle is transverse to the device axis when supported with the needle loader in the needle loading position.
5. The suturing method of claim 4, wherein moving the needle to the needle loading position comprises rotating the needle supported in the needle loader until the plane of curvature of the needle is substantially perpendicular to the device axis.
6. The suturing method of claim 1, wherein moving the needle comprises manually moving a proximal portion of the device.
7. The suturing method of claim 6, wherein moving the needle from a proximal portion of the device comprises manipulating a proximal handle of the device.
8. The suturing method of claim 3, wherein rotating the needle comprises applying a force to a portion of the needle thereby rotating the needle holding portion of the needle loader and the needle supported therein.
9. The suturing method of claim 8, wherein applying a force to a portion of the needle comprises pushing the needle against a tissue.
10. The suturing method of claim 8, wherein applying a force to a portion of the needle comprises pushing the needle with a tool.
11. The suturing method of claim 8, wherein applying a force to a portion of the needle comprises pushing the first clamp against the needle.
12. The suturing method of claim 1, wherein releasing the needle from the needle loader comprises axially moving the needle loader away from the needle when supported with the first clamp.
13. The suturing method of claim 1, wherein the needle loader releasably couples to the body of the device with a coupling member, and wherein releasing the needle from the needle loader comprises de-coupling the coupling member.
14. The suturing method of claim 13, wherein releasing the needle loader from the body of the device comprises applying a force on the needle loader with a tool thereby de-coupling the coupling member.
15. The suturing method of claim 1, wherein grasping the needle with the first clamp comprises grasping a base portion of a needle with the first clamp, the needle having a needle axis extending from the base portion to a tissue penetrating portion having a sharp end, said method further comprising:
after releasing the needle from the needle loader, inserting the sharp end of the needle through a tissue of the patient while the first clamp holds the needle and after release of the needle from the needle loader;
grasping the tissue penetrating portion of the needle with a second clamp of the suturing device;
releasing the base portion of the needle from the first clamp; and
pulling the base end of the needle through the tissue while the second clamp holds the needle by moving the second clamp relative to the tissue.
16. The suturing method of claim 15, wherein inserting the needle comprises moving the body of the device while the first clamp holds the needle at a substantially fixed location relative to the body of the device.
17. The suturing method of claim 15, wherein pulling the base end of the needle comprises pulling the needle by moving the body of the device while the second clamp holds the needle at a substantially fixed location relative to the body of the device.
18. The suturing method of claim 15, wherein inserting the sharp end of the needle through the tissue and pulling the base end of the needle through the tissue each comprise moving the body of the suturing device by a physician manually holding a proximal portion of the suturing device.
19. The suturing method of claim 15, wherein releasing the needle from the needle holder is effected by manually actuating a mechanism on the proximal portion of the body of the device.
20. The suturing method of claim 15, wherein the grasping and releasing steps are effected by manually actuating a handle of the suturing device with a hand of a surgeon.
21. The suturing method of claim 15, wherein grasping and releasing of the clamps are effected by moving a handle between a first configuration relative to the body and a second configuration relative to the body, movement of the handle from the first configuration to the second configuration and back to the first configuration defining a handle actuation cycle, and wherein the needle alternates at least once between being supported by the first clamp and being supported by the second clamp with each handle actuation cycle.
22. The suturing method of claim 1, wherein the needle loader is coupled with the body of the suturing device such that introducing the body of the suturing device concurrently advances the needle loader to the surgical site.
23. The suturing method of claim 1, wherein advancing the needle loader comprises advancing the needle loader through the body of the suturing device, wherein the needle loader is slidably positionable within the body of the device.
24. The suturing method of claim 1, said method further comprising:
selecting a needle from a plurality of standard surgical needles;
coupling the needle with the needle loader so that the needle is releasably supported with the needle loader; and
coupling the needle loader supporting the needle to the distal portion of the device body to facilitate introduction of the needle to the surgical site and loading of the needle for suturing.
25. The suturing method of claim 1, said method further comprising:
selecting a needle from a plurality of standard surgical needles, each of the plurality of needles releasably supported with a needle loader;
coupling the needle loader supporting the selected needle with the body of the device to facilitate introduction of the needle to the surgical site and loading of the needle for suturing.
26. An endoscopic suturing device for use with a suturing needle to suture a target tissue of a patient accessible via a minimally invasive surgical aperture, the device comprising:
a body having a proximal portion and a distal portion with a device axis extending therebetween;
a first clamp disposed near the distal portion and operatively coupled to the body such that, when actuated from the proximal portion of the device, the first clamp grasps the needle when the needle is in a needle loading position;
a needle loader coupleable to the body and releasably supporting the needle with the needle movable within the patient between a needle delivery position and a needle loading position,
wherein, in the needle delivery position, the needle has a delivery profile to facilitate introduction of the needle through the minimally invasive aperture, and
wherein, in the needle loading position, the needle has a larger profile and is aligned with the first clamp to facilitate grasping with the first clamp within the patient for suturing of the target tissue with the needle.
27. The suturing device of claim 26, further comprising:
a second clamp disposed near the distal portion and operatively coupled to the body such that, when actuated from the proximal portion of the device, the second clamp grasps the needle when aligned with the second clamp;
a linkage effecting movement of each of the first and second clamps between a retracted position and a grasping position by axial and rotation movement of each of the first and second clamps, wherein each clamp is rotated laterally away from the needle and retracted proximally away from the needle in the retracted position to increase clearance between the retracted clamp and the tissue andor needle.
28. The suturing device of claim 26, wherein a plane of curvature of the needle is substantially aligned with the device axis when supported with the needle loader in the needle delivery position, and wherein the plane of curvature of the needle is transverse to the device axis when supported with the needle loader in the needle loading position.
29. The suturing device of claim 28, wherein the plane of curvature of the needle is substantially perpendicular to the device axis when supported with the needle loader in the needle loading position.
30. The suturing device of claim 26, wherein the needle loader comprises:
an elongate member positionable near the distal portion of the body of the device;
a needle holding member rotatable between at least the needle delivery position and the needle loading positions.
31. The suturing device of claim 30, wherein a proximal portion of the elongate member is releasably coupleable with the distal portion of the body of the device.
32. The suturing device of claim 30, wherein the rotatable needle holding member has a 90 degree range of rotational motion.
33. The suturing device of claim 30, wherein the needle holding member is pivotally coupled near a distal portion of the elongate member.
34. The suturing device of claim 30, wherein rotation of the needle holding member in one direction terminates in the needle delivery position, and wherein rotation of the needle holding member in the opposite direction terminates in the needle loading position.
35. The suturing device of claim 30, wherein the rotatable needle holding member comprises a needle receiving slot in one side for supporting the needle in a pre-determined alignment relative the needle holding member.
36. The suturing device of claim 35, wherein the needle receiving slot is dimensioned so as to secure the needle with an interference fit.
37. The suturing device of claim 35, wherein the needle receiving slot is dimensioned so as to secure the needle with a resilient snap fit.
38. The suturing device of claim 30, wherein the elongate member comprises a needle receiving notch in a side of the elongate member for supporting a portion of the needle when supported with the needle holding member in the delivery position.
39. The suturing device of claim 38, wherein the needle receiving notch of the elongate member faces in the opposite direction as the needle receiving slit of the needle holding member when positioned in the needle delivery position so as to further secure the needle in the delivery position and inhibit loss of the needle during delivery.
40. The suturing device of claim 30, wherein the distal portion of the device body comprises a distal aperture for receiving the proximal portion of the elongate body for coupling to the body of the device.
41. The suturing device of claim 40, wherein the proximal portion of the elongate member comprises a coupling member for coupling with the device.
42. The suturing device of claim 41, wherein the coupling member comprises a bulbous or spherical feature that interfaces with a receiving feature of the device body.
43. The suturing device of claim 42, wherein the receiving feature of the device body comprises a side hole for receiving the bulbous or spherical feature so as to securely couple the elongate body in a pre-determined alignment when the needle loader when coupled to the body of the device.
44. The suturing device of claim 41, wherein the coupling member is releasably coupleable with the distal portion of the body of the device.
45. The suturing device of claim 41, wherein the coupling member is coupleable with a rod extending along the body of the device such that axial movement of the rod effects axial movement of the needle loader relative the first clamp.
46. The suturing device of claim 30, wherein the needle holding member rotates between the delivery position and the needle loading position when a force is applied to a portion of the needle when supported within the needle holding member.
47. The suturing device of claim 27, wherein at least one of the first or second clamp is positioned such that axial movement of the first or second clamp when moving from the retracted position to the grasping position pushes a portion of the needle so as to rotate the needle holder from the delivery position to the needle loading position.
48. The suturing device of claim 47, further comprising a chamfered projection disposed on at least one of the first or second clamps such that the chamfered projection nudges the needle supported by the needle holder into the needle loading position when the clamp is moved axially along the device axis.