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20.02.2018 – Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds. This causes BGP to unnecessarily flap from multipath to non-multipath as a result of route flaps.
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1. 9By way of example only, if one of the side effects experienced by a patient upon receiving one of the irreversible Btic inhibitor compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the initial therapeutic agent. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
2. 9 In other embodiments, the film coating aids in patient compliance e. Segment Switch Manager Error – Invalid segment – no segment class.http://softik.org/3d-i-2-2-10-ho-m-e-123/By way of example, “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition. Tracing the route to
3. 1 Examples of anti-thromboembolic agents include, but are not limited any of the following: http://softik.org/zte-nubia-m2-lite-32gb-ram-4gb/This symptom is observed when the PRC error result status is not sent back from Standby to Active properly.
4. 8 In heterocycles that have two or more heteroatoms, those two or more heteroatoms can be the same or different from one another. Alternatively, a series of flags may be transmitted to fill gaps between frames instead of transmitting idle marks.Dr web 6 0 1 10050 final rg softThis symptom occurs due to a high traffic rate, and the output policy applied under PVC. This symptom is observed when the PRC error result status is not sent back from Standby to Active properly.
5. 8 It is impossible to disable autonegotiation on the Cisco because of CSCth
6. 2 The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
7. 2 Synthesis of 4-amino 4-phenoxypheny1 -1H.
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Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor BCR stimulation to downstream intracellular responses. In addition, Btk plays a role in a number of other hematopoetic cell signaling pathways, e.
Jeffries, et al,Journal of Biological Chemistry Also described herein are irreversible inhibitors of Btk. Further described are irreversible inhibitors ofNit that forms covalent bond with a cysteine residue on BSc.
Also described herein are methods for synthesizing such irreversible inhibitors, methods for using such irreversible inhibitors in the treatment of diseases including diseases wherein irreversible inhibition of Btk provides therapeutic benefit- to a patient having the disease.
Further described are pharmaceutical formulations that include an irreversible inhibitor of BSc. Formula D is as follows: For example, in some embodiments, L. In other embodiments, L. In yet other embodiments, I In yet other embodiments, Ar is a 6-membered aryl.
In some other embodiments, Ar is phenyl. In other embodiments, Y is an optionally substituted group selected from among C1-C6allcyl, C1-C6heteroallcyl, 4- 5- 6- or 7-membered cycloalkyl, and 4- 5- 6- or 7-membered heterocycloalkyl.
In yet other embodiments, Y is an optionally substituted group selected from among CI-C6alicyl, CI-C6heteroallcyl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms.
In some other embodiments, Y is a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms. In some embodiments, Y is a 4- 5- 6- or 7-memebered cycloalkyl ring; or Y is a 4- 5- 6- or 7-membered heterocycloalkyl ring.
It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can 10050 synthesized by techniques known in the art, as well as those set forth herein.
The effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the diseases, disorders or conditions disclosed herein. In some embodiments, provided herein is a method of inhibiting the activity of tyrsoine kinase ssuch as Btic, or of treating a disease, disorder, or condition, which would benefit from inhibition of tyrosine kinase ssuch as Bdc, in a patient, which includes administering to the patient a therapeutically effective amount of at least one of any of the compounds herein, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.
In some other embodiments, compounds provided herein are used for the formulation of a medicament for the inhibition of Bruton’s tyrosine kinase Btic activity. In a further embodiment, the inibitor is covalently bound to a cysteine residue final the tyrosine kinase.
In one embodiment, the cancer is a B-cell proliferative disorder, e. In some embodiments, web the subject 10050 suffering from a cancer, an anti-cancer agent is administered to the subject in addition to one of the above-mentioned compounds.
In one embodiment, the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling, e. In one embodiment, the autoimmune disease is arthritis.
In another embodiment, the autoirmnune disease is lupus. In some embodiments, the autoimmune disease is inflammatory bowel disease including Crohn’s disease and ulcerative colitisrheumatoid arthritis, psoriatic arthritis, osteoarehritis, Still’s disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease SjOgren’s syndrome, multiple sclerosis, Guillain-Batre.
In some embodiments, the heteroimmune conditioiu or disease is graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
In some embodiments, the inflammatory disease is asthma, inflammatory bowel disease including Crohn’s disease and ulcerative colitisappendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
In one embodiment, the. In some embodiments, the thromboembolic disorder is myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischernia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
In one embodiment, the compound forms a covalent bound with the activated form of Bruton’s tyrosine kinase. In further or alternative embodiments, the compound irreversibly inhibits the Bruton’s tyrosine kinase to which it is covalently bound.
In a further or alternative embodiment, the compound forms a covalent bond with a cysteine residue on Bruton’s tyrosine kinase. In yet another aspect, provided herein is a method for treating a cancer by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton’s tyrosine kinase.
In another aspect, provided herein is a method for treating a thromboembolic disorder by administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton’s tyrosine kinase.
In another aspect are methods for modulating, including including irreversibly inhibiting, the activity of Btk in a mammal comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any of Formula AFormula BFormula Cor Soft D.
In another aspect are methods for treating Btk-dependent or Btk mediated conditions or diseases, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any of Formula AFormula BFormula Cor Formula D.
The type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors. In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic extrinsic asthma, non-allergic intrinsic asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, In another aspect are methods for preventing rheumatoid arthritis and osteoarthritis comprising administering to the mammal at least once an effective amount of at least one compound having the structure of Formula ABCor D.
Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to the mammal an effective amount of a first compound having the structure of Formula ABCor D.
In one embodiment of this aspect, the tyrosine ldnase protein is Btk. In another or further embodiment of this aspect, the inflammatory disease web conditions are respiratory, cardiovascular, or proliferative diseases.
In Anther or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
The length of the drug holiday can vary from 2 days to 1 year. In further or alternative embodiments the tyrosine kinase gene haplotype is a tyrosine kinase pathway gene, while in still further or alternative embodiments, the tyrosine kinase gene haplotype is a Btk haplotype.
In even further or alternative. In one embodiment, a Btk irreversible inhibitor has an IC. C or D are selective irreversible inhibitors for Btk over lac. In the event that there are a plurality of definitions for terms herein, those in this section prevail.
Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the Internet Reference thereto evidences the availability and public dissemination of such information.
In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms ‘a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
Furthermore, use of the term Including’ as well as other forms, such as ‘include”, “includes,” and “included,” is not limiting. Unleis otherwise indicated, conventional methods of mass spectroscopy, NMIt, HPLC, protein soft, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed.
Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation e. Reactions and purification techniques can be performed e. The foregoing terbniques and procedures can soft generally performed of conventional methods well known in the art and as described in various general and more specific references; that are cited and discussed throughout the present specification.
It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.
Nothing herein is to be construed as an admission that the inventors described herein are not entitled to antedate such disclosure by virtue of prior invention or for any other reason.
The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
An “alkene” moiety refers to a group that has at least one carbon-carbon 10050 bond, and an “alkyne” moiety refers to a group that has at least one carbon-carbon triple bond.
The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic. Depending on the structure, an alkyl group can be a monoradical or a diradical i.
The alkyl group could also final a “lower alkyl” having 1 to 6 carbon atoms. The alkyl group of the compounds described herein may be designated as “C1-C4 alkyl” or similar designations.
By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i. Alkyl groups can be substituted or unsubstituted. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobuty], cyclopentyl, cyclohexyl, and the like.
Non-cyclic alkyls can be optionally substituted. That is, an alkenyl group begins with the atoms -C R R -R, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different.
The alkenyl moiety may be branched, straight chain, or cyclic in which case, it would also be known as a “cycloalkenyl” group. Depending on the structure, an alkenyl group can be a monoradical or a diradical i.
Alkenyl groups can be optionally substituted. Alkenyl groups could have 2 to 10 carbons. The alkenyl group could also be a “lower alkenyl” having 2 to 6 carbon atoms. That is, an alkynyl group begins with the atoms -C EC-R, wherein R refers to the remaining web of the alkynyl group, which may be the same or different.
The “R” portion of the allcynyl moiety may be branched, straight chain, or cyclic. Depending on the structure, an alkynyl group can be a monoradical or a diradical i.
Allcynyl groups can be optionally substituted. The alkynyl group could also be a “lower alkynyl” having 2 to 6 carbon atoms. Any amine, or carboxyl side chain on the compounds described herein can be amidified.
The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3’d Ed.
Rings include, for example, carbocycles e. Rings can be final substituted. Rings can be monocyclic or polycyclic. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring.
Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings. Carbocycle includes aryl and cycloalkyl. The term thus distinguishes carbocycle from heterocycle “heterocyclic” in which the ring backbone contains at least one atom which is different from carbon i.
Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles and heterocycles can be optionally substituted. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms.
Aromatics can be optionally substituted. The term “aromatic” includes both carbocyclic aryl e.
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When the user name in the authentication dialog box is left blank, the router unexpectedly reloads. This symptom is observed when the no ip vrf command is entered. With a 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. Spurious memory access or a crash is seen upon entering or modifying a prefix-list.
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This symptom may occur when multiple back-to-back switchovers occur. Because the Cisco gateway does not have network connectivity, no SIP reply is received from the network. Sixty seconds later, the Application Ack Timer expires:.
Application Ack Timer expired. When configuring SIP digest authentication, user names with more than 25 characters are truncated in the running config and cause the password component to be corrupted.
This error is saved through to startup configuration, causing the authentication to be lost on reboot. The symptom is observed in a scale setup with many PfR application prefixes and when PfR optimizes the application prefixes.
The symptom is observed when changing IVRF on a virtual-template when there are about active sessions. The symptom is observed in the case of an numbered relay. The symptom is observed on a Cisco series router with SRE1 code.
After a reload of one router, some or all of the BGP address families do not come up. The output of show ip bgp all summary will show the address family in NoNeg or idle state, and it will remain in that state.
This symptom is observed when ALL of the following conditions are met:. Configure a very short keepalive interval such as one second on the non-reloading device using the neighbor x. Configure graceful restart using the command neighbor x.
You can also use clear ip bgp x. This is a day one problem in the Cisco IOS multisession implementation which impacts single-session capable peers. The effect of this fix is as follows: The keepalive is not required, but will cause the established session to be torn down if appropriate.
Note that the fix does not solve the problem when interacting with Cisco IOS Disable multicast routing on VRFs participating in BGP or reduce the number of extended communities used as route-target export.
Tunnel disables due to recursive routing loop in RIB. The symptom is observed when a dynamic tunnel which by default is passive in nature is created. EIGRP will get callback due to address change dynamic tunnel come-up.
The symptom is observed under the following conditions:. This symptom is observed sporadically while traffic is running on a performance monitor policy at the time when a user initiates the CLI show command.
If the symptom occurs, repeat the command. The command show policy-map multipoint does not show any output on a hub, configured with a per-tunnel-QoS policy on its tunnel interface. The command is also not displayed in the parser options upon issuing show policy-map?.
The symptom is observed with the show policy-map multipoint command. The symptom is observed on CUCM 4. Update generation is stuck with some peers held in refresh started state SE.
This is seen with peer flaps or route churn and with an interface flap. The symptom is observed with the following conditions:. Configure a nexthop static route with permanent keyword.
Make the nexthop IP address unreachable e. Change the configuration in such a way that nexthop is reachable. Configure a new static route through the same nexthop IP address used in step 1.
Delete all the static routes through the affected nexthop and add them back. CP Express does not launch. A blank or garbage characters appear in the browser.
This symptom is observed when attempting to launch CP Express. A power cycle fixes the issue temporarily. The NAT router is between the client and the server. This symptom is observed only with the PPTP connection; all other traffic works fine.
This symptom is observed when building Cisco x platform IOS images. Some virtual access interfaces are not created for VT on reload. The symptom is observed when there are redundant paths to the CPE.
This is because the RST from the host, in response to the keepalive from other endpoint, is out-or-order and gets dropped by the ZBF. The symptom is observed when you have TCP connections using keepalive keepalive with both sequence number and acknowledgment number one less than expected for a session going over a ZBF implementation.
Shorten the keepalive timeout on the other endpoint. Router1 sho inv NAME: Router show ip bgp sum. BGP router identifier Use no bgp route-map-cache. This will not cache the route-map cache results and the symptom will not be observed.
Route control of prefix and application are out-of-order thereby making application control ineffective. This symptom is observed when the onboard GE is connected by fiber to a gig port that is not doing autonegotiation.
The Cisco E does not have this problem. Configure autonegotiation on the other side, if possible. It is impossible to disable autonegotiation on the Cisco because of CSCth Cisco IOS Software contains a vulnerability in the IP version 6 IPv6 protocol stack implementation that could allow an unauthenticated, remote attacker to cause a reload of an affected device that has IPv6 enabled.
The vulnerability may be triggered when the device processes a malformed IPv6 packet. There are no workarounds to mitigate this vulnerability. Router crash is seen when doing a show eigrp service ipv4 neighbor.
The symptom is observed when the neighbor is learned, then you add a max-service limit on an address family. Router hangs and console does not respond indefinitely. This symptom is observed when a multicast server is multiple hops away from multicast clients.
The symptom occurs only on G. Moves from one port to another when the router is rebooted. Configure conference bridge that is associated with SCCP. The exact numbers to be used to force these ports to be in use will depend on the individual platform.
No detrimental consequences or effects on the correct operation of the router are observed; however, thousands of these error messages may appear on the console. This symptom is observed on Cisco AS platforms during VoIP calls, and is more evident when the router is handling multiple calls.
This issue occurs when summary address is advertised as follows:. This symptom is observed on Cisco 19xx, and routers with PVDM modules, as well as any other module that connects to the MGF backplane switch.
The modules that currently connect to MGF are. For the Etherswitch SM modules and Service Ready Engine modules, as long as the MGF port on these modules is not configured to send traffic to the router, there will be no issue.
For traffic between modules over MGF there is no issue. Try another directed and Optional msg: Wait until all the SAs have been established and traffic is stable. Memory leak is seen while issuing the show running or the show ip access-lists command even though we do not have any named ACL configured on the box.
This symptom is observed when issuing the show running command. The memory leak is in dynamic list that was created, which is not destroyed properly. LNS router hangs up at interrupt level and goes into an infinite loop.
See Further Problem Description below. Only a power cycle can remove the symptom. This is a hypothesis based on analysis of the data provided for the failures experienced by the customer, together with an extensive code review.
We believe this is a timing issue. While this is a rare event, the probability of it occurring increases with load and number of sessions. Route watch fails to notify client when a RIB resolution loop changes.
This causes unresolved routes to stay in the routing table. You may be unable to configure pseudowire on a virtual PPP interface. The command is rejected with the following error:.
Incompatible with ipv6 command on Vp1 – command rejected. The symptom is observed with some combination of zone-based firewall and policy configuration and with IPv6 traffic.
This symptom occurs when media transcoder-high-density is enabled on CUBE. The symptom is observed with a hierarchical CA server structure. The vulnerability is triggered when malformed UDP packets are sent to a vulnerable device.
The vulnerable UDP port numbers depend on the device configuration. DMVPN stops allowing connections after operating for some time based on number of connections. The show crypto socket command shows sockets are leaking and never decrease even when the SA is inactive.
This symptom is observed when the server clock time drifts too far away from the local clock time. This symptom is observed when a split-and-merge occurs between the key servers.
DLSw circuits to not come up when using peer-on-demand peers. This symptom occurs in the following and later releases:. Use save-password feature without interactive Xauth mode to avoid sending the different username and password during P1 rekey.
Router crashes with memory corruption symptoms. TCP connect reqd from 0. PPTP, no cc in l2x. The symptom is observed on a router that is running a Cisco IOS Since the issue affects only Cisco IOS Erasing the startup configuration and saving again may recover the configuration.
The crash can be avoided if the system has no double failure. This symptom is observed only on the Cisco router. This symptom is seen when EzVPN connection is configured with split tunnel attributes.
This causes overall performance degradation. Pick up the phone during the ringing OFF cycle. A Cisco device crashes when trying to transfer a call. Output from the show idmgr session command displays a corrupted service name.
The symptom is observed with RP1 and RP2. Any feature which uses heavy logging for example, audit logging for firewall features will encounter this issue readily the trigger is the rate of logging rather than the volume of log messages.
You can track the memory consumption with the show processor memory sort command and monitor the amount of memory the IOSD ipc task and ESM logger consume over time. The symptom is observed while printing traceback.
Configure the crypto client and server routers in such a way that the session is up and RRI installs a static route on the server that is pointing to the client IP address.
Now shut down the interface on the server router that is facing the client. Routes are not being controlled properly when PIRO is used. If more than one exit per BR is configured and PIRO is used to control the routes, the nexthop is not being calculated correctly.
As a result, traffic for these traffic classes is not taking the correct route. Traffic should be hitting the interface, CPU utilization should be high, and NAT should be applied on the interface as well.
The symptom is observed when crypto is running and configured on the router. There is also a possible connection with EzVPN. A router crashes when the RSA key is generated with redundancy option and then the RSA key pair is deleted using the crypto pki zeroise command.
All other possible triggers are not known at this time. Calls fail following hook flash on a T1-CAS circuit. A VRF becomes stuck during deletion in a rear condition not something that is seen every time.
This symptom is observed when the no ip vrf command is entered. The stuck VRF cannot be reused. IPv6 PBR is not applied to locally-originated ping packets. The symptom is observed when NAT is configured.
This will result in the S,G states expiring in the upstream routers and may result in traffic loss. The symptom is observed when the static-group join is configured on the RPF interfaces and the output interface list of the mroute is NULL.
Add a local join by using ip igmp join-group for the same group and source, so that it adds a local interested receiver and sends a periodic join upstream. This symptom occurs when the VRF contains many entries 17k in which the outgoing interface changes due to a topology change.
Command should not be issued when many topology changes occur on interface flaps. The issue is associated with the two labels imposition for the next-hop address. If there is no label bind for the destination prefix and in order to reach next-hop address the router imposes two labels, only one label is imposed for the final prefix.
The symptom occurs when all of the following conditions are met:. The prefix does not have a label bind BGP prefixes for example. There is a static route for the next-hop address pointing to the tunnel only.
The router imposes two labels for the next-hop address. Explicit next hop avoiding recursive research: In the following example There is no label bind for this prefix and it is recursive to PE1 show mp ld bin PE1 show ip route Routing entry for Known via “static”, distance 1, metric 0.
Route metric is 0, traffic share count is 1. Known via “static”, distance 1, metric 0 connected. PE1 show ip cef So the traffic to However traffic is leaving the router only with the tunnel label:.
Type escape sequence to abort. Tracing the route to Label 20 Exp 0] 4 msec 0 msec 0 msec. Label 23 Exp 0] 4 msec 0 msec 0 msec. Router crashes with the following error message:. Illegal access to a low address after applying the flow monitor to virtual-template interface.
Cisco ISR G2 routers reload on their own with a bus error. This symptom is observed when BFD is configured. In the event of a failover, there is a serial number mismatch on the active and standby.
When an external interface on the BR is shut down, the BR could be crashed. If more than one thousand Application Traffic Classes are configured on MC, and if that traffic is traversing through an external interface on a BR, and if the external interface is shut down, this could result in a crash.
The deny ip any any fragments command shows a high number of hits for traffic that may not be truly fragmented. DHCP-added static routes get removed sometimes and the traffic towards the host gets dropped.
A Cisco router may crash during show command show ip ospf rib execution. Do not enter the show ip ospf rib command. If it is necessary to use the command, enter terminal length 0 and print the entire output.
This symptom is seen on live network when performance is measured using latency sensitive Internet speed test application. Use cellular interface without binding to external dialer. The symptom is observed in a large VPNv4 scale setup, when applying the following commands to the same VRF back-to-back:.
The trigger of the BGP crash is a result of a racing condition between event 1 and event 2. Since this is a racing condition, the workarounds are:. Give sufficient time for 1 to complete before applying 2.
This issue can occur with many IKEv2 requests coming at once and when you are using hardware crypto-engine. You can re-start the router and switch to software-crypto engine if needed.
A Cisco ASR sees a hang followed by a crash. R1 config-view secret cisco. R1 config-view commands exec include ping. R1 config-view commands exec include configure terminal. This symptom can happen if the remote client drops an LLC packet with the poll bit on.
After a network event is introduced in the network, such as a 3- percent loss, MOS policy will detect the OOP condition. But PfR will let the prefix stay in the OOP condition for some time and then switch over to an alternative exit.
When you issue a reload command with a getmany looping on ciscoFlashMIB, the router hangs. The symptom is observed when a getmany is running with only one router.
This symptom is observed when one or more of the following is configured on an interface configured with IPSec:. Avoid using IPSec or avoid using all of the above features on the interface. A crash is seen after executing the write memory command via SDM.
A router may experience CRC and Runt errors. It is seen with the following routers: Cisco series, Cisco series, and Cisco series. Soon after, the active router crashes. This symptom occurs when the length of the RP-Discovery packet reaches its limit.
If the Mapping Agent receives RP-Announce packets, increasing the number of multicast groups, and that number makes the limit of the packet size, then an empty RP-Discovery packet is triggered that clears the RP-to-Group mapping tables in all the routers receiving such a packet.
The environmental alarm has additional hard disk drive information in the Syslog message. The symptom is observed when there is one of the following service modules in the system:.
The symptom is observed when the interface goes to standby from active. Total Number of CAM entries: Remove bridging and reconfigure it on the interface. A memory leak occurs in the big buffer pool while using the service reflect feature.
This symptom is observed when the service reflection feature is enabled. A packet is generated from service reflection and is blocked by an ACL on the outgoing interface. This will cause the buffer leak.
A Cisco router crashes when verifying energywise endpoint using an Orchestrator Agent. BGP router identifier 1. BGP table version is , main routing table version network entries using bytes of memory.
The problem is seen when using WSMA to run the session install command. Perform the install manually from a VTY session. Router may reload when performing an ISSU upgrade or downgrade.
This symptom occurs when performing an ISSU upgrade or downgrade. Spurious memory access or a crash is seen upon entering or modifying a prefix-list. WIC-based platforms that have a MAC address with a leading 1 does not allow traffic to flow through the card successfully.
The symptom is observed on WIC-based platforms. Manually change the MAC address problem card. The same card works correctly on a Cisco router with the default MAC address from the Cisco The symptom is observed during regular operations and with an extensive QoS configuration.
As a result, the peer may close the session. PfR moves traffic-class back and forth between primary and fallback links the when PfR Link group feature is used.
The symptoms are most likely to occur when there is one exit in the primary link-group and utilization is one of the criteria. The issue can also occur when there are two links in the primary. A traffic-class is moved from the primary link to the fallback link when the primary link is OOP.
After the format command is run on a 32GB or larger disk, the show command displays that only 4GB is free on the device. The symptom is observed when formatting disk that is larger than 32GB in capacity.
Use a smaller size disk that has no more capacity than 32GB. A router crashes when trying to do sre install. This symptom occurs when the TCL file has some missing attributes. The sre install fails and crashes the router.
Extension assigner EA application erroneously exits after the first digit of the password is entered. Traceback will occur after a period of use and when the show oer master command is used a few times.
The traceback causes the OER system to disable. Manually reenabling PfR will not work. A reboot is required. The symptom is observed when PfR is configured with the following conditions:.
The symptom is observed when there is also a VWIC installed in the chassis for example: With a Cisco series router, Modular Exponent ModExp is currently done using software and this leads to bad scalability.
The symptom is observed on a Cisco series router. A leak of bytes of memory for every packet that is fragmented at high CPU is seen sometime after having leaked all the processor memory.
This causes the router to reload. On a phone button that has an overlay with call waiting DNs configured while the first call is connected, there is no audio on the second call and the first call gets disconnected after few seconds.
The issue occurs when the second call comes in. The symptom is observed on a phone button that has an overlay with call waiting DNs and when one DN is at hold state and the other is at connected state.
If you are running a script for regression which cannot be changed there is no workaround. If it is a user interactive case, the above workaround may help. A Cisco voice gateway is unable to detect any interface.
A device that is acting as a DHCP relay or server crashes. This symptom is observed when the no service dhcp command is configured. Clear the route on the PE router using clear ip route vrf xxx x.
The problem occurs only if one of the processes has the parent route and other one does not. As a result, probe and route control fail. There is no workaround if two processes are used.
There are three possible ways to do this:. The no redistribute connected command is not being backed up to the standby. This symptom is observed with any redistribute-related commands.
The symptom is observed when the router is configured as OER master. A buffer leak may occur when a router is configured with the combination of NAT, multicast and encryption.
Occurs when multicast subsequently flows out a crypto-enabled interface. This bug will effect only those users whose routers are part of a multicast group. They must also have NAT and crypto configured on one or more of the interfaces in the multicast group.
Multicast traffic can be forwarded via a GRE tunnel instead of in the clear. This symptom is observed with almost all TCP applications. It is mainly seen on low end switches. BGP selects paths which are not the oldest paths for multipath.
This causes BGP to unnecessarily flap from multipath to non-multipath as a result of route flaps. More than one equally-good route is available. BGP is configured to use less than the maximum available number of multipaths.
The selection of non-oldest paths as multipaths is only problematic in releases which include CSCsk, because in such releases it causes changes with respect to whether paths are considered multipaths.
Issue the clear interface bri command to restore this state. The symptom may be observed with the following conditions:. The following is an example of an MVPN configuration where this problem can be seen:.
OSPF routing protocol is enabled on all the networks in the topology. In effect, the following states are present in the network:. Decap OCE creation failed. It is observed on the standby RP.
The command ip ospf message-digest-key in interface mode may have an invalid key. Use the command no parser config cache interface. The DSL link stops passing traffic. The issue does not get resolved by shut and no shut of ATM interface or reloading the router.
Unnecessary retransmission and spurious TCP is reset. This problem seems to be correlated to:. The router crashes when doing concurrent VRF add and deletion configurations.
The symptom is observed when a multiple configuration terminal is doing concurrent VRF add and deletion configurations. Do not do concurrent VRF addition and deletion.
Src 2 Ip, Grp IP , Only one of the entries is created. To populate the other entry, the no ip igmp-join and ip igmp join commands are entered on the interface.
The following error message is constantly displayed:. Router crashes every days with URLF feature. The error message shows memory leak issues. The symptom is observed when using PFS and after a failover of the hub devices.
If the security policy allows, removing the PFS eliminates the issue. It does not matter if it is percent or absolute value. The symptom is observed when multicast is configured for a VRF and no multicast is configured for the global table.
The problem should not occur for MVPN since this is not a valid configuration, as multicast in the core is a requirement. However, it can occur for a feature called MVPN-lite, where multicast traffic is routed between VRF tables without the tunneling and therefore without the requirement for multicast in the global table.
A Cisco Catalyst series switch may unexpectedly reload due to bus error on the switching processor when making access list entry config changes or when removing an entire access-list.
This bug fixes two related crashes. One in which the crash occurs when making ace configuration changes and another when removing an entire ACL. Details on the conditions to trigger the crash when making the ace configuration changes:.
The issue is seen when we have more that three ACE which have the same source and destination address and mask and we delete the ACE in sequence like:. Then try to add ACE which has the same source address and mask but no destination.
The infinite loop will result in crash. The crash when removing the access-list itself has no workaround. The symptom may occur when multiple tunnel interfaces are configured with mpls bgp forwarding, if the tunnel interfaces are flapping.
Configure the eBGP sessions on interfaces other than tunnel interfaces. A router may unexpectedly reload due to software forced crash because of chunk memory corruption.
The crash appears to happen when using the clientless web proxy method. If possible, redesign the website to use URLs of characters or shorter. Chunk leak is seen after exec-timeout expires.
The symptom is observed after the interface range command is configured and when the console timeout expires. The symptom is observed if the VCI value configured on the interface is larger than In addition, the interface is configured as follows:.
Device may reload when the show ip protocol command is issued. The symptom is observed when routing protocol is configured and the ISIS routes are being redistributed. Do not use the show ip protocol command.
This symptom is observed under the following conditions:. Reduce the number of HSRP sessions to only a few. The router does not see any performance or functional impact.
This is an issue only with internal CPU accounting. It is only seen when running a specific script for ASRs. Switch intermittently crashes when configuring energywise features.
A router may experience a severe memory leak issue when the following command is configured:. The issue is not platform dependent. When the cns config notify command exists, some CLIs might misbehave or cause unexpected crashes during the configuration change.
The symptom is observed with the cns config notify command. Remove all cns config notify CLIs from the configuration. The symptom occurs after the formation of a recursion loop in the FIB, when the prefixes in the loop are labeled.
The following conditions are observed:. This is a problem affecting PRI voice installs. Data PRI installs are not affected. Not all PRI voice installs will be affected by this problem. To be specific, if the provider sends marks all-ones instead of HDLC flags during idle times, the call completion problem may manifest itself.
Most provider installations are not configured this way and the provider may be able to switch the method of indicating an idle. Ask the service provider to send flags between frames instead of idle marks.
Idle marks may be sent to fill the gap between useful frames. Alternatively, a series of flags may be transmitted to fill gaps between frames instead of transmitting idle marks.
Continuous transmission of signals is required to keep both the transmitting and receiving nodes synchronized. The candidate fix has a high confidence level of resolving the PRI voice call issues described above, and has proven to be successful in several field deployments complaining of similar call problems.
Throughput performance for HTTP traffic is impacted. IP address is not leased out to the client from server. The symptom is observed when configuring the VPN sub-option at the interface level on the relay.
SSH connection to a SSH server aborts abruptly after making the connection, while using public key-based authentication. Authentication method used must be public key. Use kbd-interactive or password-based authentication.
PPPoE server router crashes upon sending an accounting stop request. This is seen only if template authorization is enabled i. Crash occurs when executing the show crypto session brief command with multiple IKEv2 tunnel connections.
This crash occurs when there are about tunnels established and the command is trying to list down the sessions. Router can hang when xconnect configuration is modified on a VLAN subinterface while data packets are being switched.
The following error traceback is printed:. The symptom is observed when the VLAN subinterface is still seeing data traffic and the main interface is not shut down, and when the xconnect configuration on the VLAN subinterface is being modified.
Shut down the main ethernet interface when doing xconnect configuration changes on the subinterface. The symptom is observed only when executing the install on an SRE module.
PIRO generates a more specific prefix for the static route it has created. This is the wrong version with some undefined entries. Due to this, the signature parsing is failing in CCP.
A Cisco router may crash when a service-policy configured with bandwidth is removed from an interface. Router crashes when a packet with out-of-bound featureIndex values is sent to the CME.
A router crashes after performing a DNS lookup. The symptom is observed when a command is used which sends out a DNS query such as ping www. Perform a write memory and reload the router.
The symptom is observed with a Cisco ASR router that is running the asrrp1-adventerprisek9. There is a crash due to the following error:. Remove call monitor, if interfacing with UCCX is not needed.
This situation is a corner condition. The IP address on the dialer interface will be installed as soon as the dialer negotiation completes and the dialer interface comes up.
Use a non profile-based dialer interface. In effect, all the options after bytes, if any, will be missing. Although tunnel interface has alternative path to an OSPF neighbor, when the primary interface goes down, the tunnel interface goes down for a moment.
The symptom occurs when a tunnel tracks an MTU from higher value to a lower value on the outgoing interface. It is seen on many images. The symptom is observed when the router is configured with a dial peer and with SNMP.
A dial peer is most likely required to reproduce the issue, but it is possible that a different UDP protocol other than SNMP could also cause the symptom. Once a call failure occurs, all the calls placed later will fail with a UDP socket connection error.
Manually remove the caller-id enable command after a router reboot. The symptom is observed with an L3 VPN configuration. Priority packets are dropped even if they are classified into LLQ.
This is shown by the show policy-map interface command. The terminating phones rings but when the call connects there is one-way audio. If this does not work, perform a reload.
The middle router crashes when it receives a PathTear message. Configure refresh reduction on the UUT. The symptom could occur while processing the xauth response received from the client.
The customer who reported the crash was using bit torrent when it has crashed. Shaping is not working correctly. An additional symptom on a Cisco series router is the possibility of alignment errors and, in rare situations, a software-forced crash.
The symptom is observed on Cisco and series routers when using one of the following serial modules: The symptom is observed when enabling the voice dsp crash-dump or debug vpm dsp commands.
These two commands may cause Informers to reload. Do not enable the voice dsp crash-dump or debug vpm dsp commands on Informers. Also, CPU utilization will vary randomly.
The symptom is always observed when traffic is flowing through the router and may or may not be seen without traffic flowing. The symptom is observed when a reload is issued on the router and you reload the AP at the same time when prompted.
The embedded AP can be reloaded with the service-module wlan-ap 0 reload command from router console or the reload command from embedded AP console accessed via service-module wlan-ap 0 session.
The symptom is observed when activity check is on and recurrence is changed from 0 to a higher value. A router may face a watchdog crash or hang while removing a port-channel.
Router can crash due to corrupted magic value in freed chunk. The WCCP return traffic arrives on a sub-interface. Analog phones lock up and there is no dial tone. The user cannot pick up a call from a park slot by direct dialing the slot.
In the event that the user is able to retrieve the call, when the call is hung up the channel is not released. No dial tone is heard when the handset is picked up again. Router crash or spurious memory access can be seen.
The following error is reported during the reboot:. Traffic, set to be exempted from inspection via an extended ACL, is still inspected even though the ACL registers counts for that traffic.
Certain crafted packets may cause memory leak on a Cisco IOS router. The symptom is observed when the show cca command is issued. Router may crash when upgrading modem firmware. Router crashes when initiating ping through the modem after router bootup.
The symptom is observed when the modem fails to enumerate at bootup. The phone rejects the RTP stream due to incorrect payload-type it sends payload type instead of the correct for iLBC.
There is no workaround if iLBC codec is needed, but using a different codec at the remote phone should work. The output of show proc cpu sorted is not correct. Consequently, the values displayed by show proc cpu history are also incorrect.
The symptom is observed when using the show process cpu sorted command. The command clear crypto gdoi on the keyserver does not clear the keyserver policies.
The symptom is observed once the keyserver policies have been created. This problem was introduced by CSCtf The symptom is observed when the show memory 0 command is executed. The show cellular 0 command might not show any output.
The symptom is observed with the show cellular 0 command. Shut down the cellular 0 interface, write the configuration to memory and reboot, so that the configured interface is shutdown on boot.
You then have your original start up configuration, with the cellular 0 shut down, and you still get show cellular stats. The symptom is observed with crypto, tunnel protection, and VSA only.
The following error message with traceback is observed:. Drop IPC traffic using control-plane policing:. System can crash when attempting to schedule an IPv6 icmp-echo operation.
The symptom is observed with IPv6 and icmp-echo. The symptom is observed when attempting a ping after giving a shut and no shut on the BRI interface. The symptom is observed when the interface is part of self zone and router-terminated traffic hits that interface.
This section describes only severity 1, severity 2, and select severity 3 bugs. A router may unexpectedly reload if the device runs out of memory and a call is setup. The symptom is observed in rare circumstances when the device is already out of memory.
Router crashes due to a bus error in IOS firewall. Corrupted next pointer blk. Cyclic redundancy check CRC errors increment on Cisco router. Memory allocation of bytes.
Illegal printing attempt from interrupt level. Invalid memory action free at interrupt level,. Invalid memory action malloc at interrupt level,. In all of the crashes previous block pointer is corrupted.
The following is seen before the crash:. The asynchronous interface of the V. This issue can cause data packet loss. This issue occurs when a V. Also, you need to override the system default chat-script with your own, as the system default chat-script will issue the ATZ command, which will do a reset of modem, thus the modemcap settings will be lost.
Sample line configuration to apply the above chat-script. Memory leak is observed in export packets when both OER and Netflow are enabled. The symptom is observed only when both Netflow and OER export is enabled.
OER export is enabled by default to a port. A memory leak can occur in the VTSP process, due to calls failing to clear completely. The symptom is observed with the VTSP process. The Null0 route advertised via VPNv4 flaps.
Remove and re-apply the frame-relay map-class under the interface on both the routers connected back-to-back. The symptom is observed during normal code flow. Here is an example of an MVPN configuration where this problem can be exhibited:.
In effect the following states are present in the network:. Intermittent echo on voice calls are experienced. All calls through a particular DSP channel will experience echo. The symptom is observed when a DSP channel, or set of DSP channels, go into a bad state where they no longer cancel echo.
The audio stream coming into the DSP will match exactly what is going out. This can be identified by the symptom that the echo-cancellation tail will vary during a call even when the tail is specified on the voice port.
Values from 24ms to ms have been observed for a single call which this issue occurs on. The show call active voice echo-canceller summary command can be used to observe the echo cancellation tail, and the voice-port command echo-cancel coverage can be used to statically set the echo cancellation tail.
The DSP can be reset, or the gateway can be reloaded, and the echo canceller will begin functioning. While testing the Large-Scale Dial-Out LSDO feature, the expected number of links is not seen in the bundle after starting calls in both directions for a single client.
The traffic is sent for around 10 minutes. Dialer map is formed for the required address. New GM is not able to communicate to existing GMs. A Cisco router crashes due to illegal memory access.
The symptom is observed in a scale testing environment which has eight key servers and 20 GM routers simulating group members and when there is unicast rekeying. The GM router crashes in steady state no traffic.
This seems to be intermittent. Spurious memory access is seen when deleting a policy map. Memory leak is observed when zone-based firewall policy is configured and unconfigured.
Router performance degradation is observed. The performance degradation issue is observed for OC3 module while trying to reach OC3 line rate with small size 64Bytes bi-directional traffic streams.
Non-drop rate and CPU utilization performance is degraded due to this issue. Avoid touching line rate with small size bi-directional traffic streams uni-directional traffic can touch line rate without any problem.
The symptom is observed when running IPv6 inspection. Memory leak can be observed when reconfiguring class-map attached to a zone-pair. The symptom is observed with crashinfo data.
The matching virtual-access on the hub stays up. The crypto is still up and running DPD is working and even rekey. Fax transmission fails when CUBE is in the middle. Problem is not seen when ZBF is not configured on the interface and is present even when crypto configuration is not present.
The output of show policy-map type inspect zone-pair session suggests that for single traffic stream RDP stream two sessions are created. One session is in half open state the other is fully established.
By default the idle-timeout for half-open session is 30 sec, so after 30 seconds the half-open session is deleted and along with that it also deletes the established session. For both match protocol and match access-group based inspection, when inspecting TCP based protocols, inspection mechanism creates duplicate sessions.
Such assays are useful to determine an in vitro IC50 for an irreversible Btic inhibitor compound. If the candidate compound is in fact an irreversible Btk inhibitor, Btk kinase activity will not be recovered by repeat washing with inhibitor-free medium.
Further, covalent complex formation between Btk and a candidate irreversible Btk inhibitor is a useful indicator of irreversible inhibition of Btk that can be readily determined by a number of methods known in the art e.
For example, some irreversible Btk-inhibitor compounds can form a covalent bond with Cys of BSc e. Useful endpoints for determining a response to BCR activation include, e.
In addition, high throughput screening systems are commercially available see, e. These systems typically automate entire procedures including all sample and reagent pipetting, liquid dispensing, timed incubations, and final readings of the microplate in detector s appropriate for the assay.
Automated systems thereby allow the identification and characterization of a large number of irreversible Btk compounds without undue effort. M, less than 0. For example, activated Btk is transphosphorylated at tyrosine Thus, in these embodiments the irreversible Mk inhibitor inhibits the target kinase in cells only once the target kinase is activated by the signaling events.
Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds.
Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided.
In some embodiments, when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. In certain embodiments, isomers and chemically protected forms of compounds having a structure represented by any of Formula A , Formula B , Formula C , or Formula D , are also provided.
Formula A is as follows: Y is alkyl or substituted alkyl, or a 4-, 5-, or 6-membered cycloalkyl ring; each R. R8 , ‘ f R8 v Rg , OT R2 Rg ,wherein, R6, R7 and Rs are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted ‘ or unsubstituted lower heterocycloalkyl; R12 is H or lower alkyl; or Y and R12 taken together form a 4-, 5-, or 6-membered heterocyclic ring; and pharmaceutically acceptable active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
I  In further or alternative embodiments, v. The physical and biological properties modulated by such modifications to G include, by way of example only, enhancing chemical reactivity of Michael acceptor group, solubility, in vivo absorption, and in vivo metabolism.
In addition, in vivo metabolism may include, by way of example only, controlling in vivo PK properties, off-target activities, potential toxicities associated with cypP interactions, drug-drug interactions, and the like.
Further, modifications to G allow for the tailoring of the in vivo. In other embodiments, L, is 0 or NH. In yet other embodiments, Li, is 0. In other embodiments, Y is an optionally substituted group selected from among C1-C6alkyl, Ci-C6heteroalkyl, 4-, 5-, 6- or 7-membered cycloalkyl, and 4-, 5-, 6- or 7-membered heterocycloalkyl.
In yet other embodiments, Y is an optionally substituted group selected from among C1-C6alkyl, C1-C6heteroallcyl, 5-, or 6-membered cycloalkyl, and 5-, or 6-membered heterocycloalkyl containing 1 or 2 N atoms.
In some other embodiments, Y is a 5-, or 6-membered cycloalkyl, or a 5-, or 6-membered heterocycloalkyl containing 1 or 2 N atoms. Bruton’s tyrosine kinase mediated conditions or diseases, including, but not limited to, cancer, autoinunune and other inflammatory diseases.
Preparation of Compounds  Compounds of any of Formula A , B , C or D may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein.
In additions, solvents, temperatures and other reaction conditions presented herein may vary according to those of skill in the art. As a further guide the following synthetic methods may also be utilized.
Formation of Covalent Linkages by Reaction of an Electrophile with a Nucleophile  The compounds described herein can be modified using various electrophiles or nucleophiles to form new functional groups or substituents.
Table 1 entitled “Examples of Covalent Linkages. Precursor functional groups are shown as electrophilic groups and nucleophilic groups. Examples of Covalent Linkages and Precursors Thereof. Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
In one embodiment, each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
Protective groups can be removed by acid, base, and hydrogenolysis. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of airlines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbarnates.
For example, an allyl-blocked carboxylic acid can be deprotected with a Pd -catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react.
Once released from the resin, the functional group is available to react. Synthesis of Compounds In certain embodiments, provided herein are methods of making and methods of using tyrosine kinase MU: In certain embodiments, compounds described herein can be synthesized using the following synthetic schemes.
Compounds may be synthesized using methodologies analogous to those described below by the use of appropriate alternative starting materials. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds.
Other methods for the synthesis of compounds described herein may be found in International Patent Publication No. OUI would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.
As a guide the following synthetic methods may be utilized. Such materials may be characterized using conventional means, including physical constants and spectral data. In one embodiment, 1H-pyrazolo[3,4-d]pyrimidinamine is treated with N-iodosuceinamide to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidinamine.
Metal catalyzed cross coupling reactions are then carried out on 3-iodo– 1 H-pyrazolo[3,4-d]pyrimidinamine. In one embodiment, palladium mediated cross-coupling of a suitably substituted phenyl boronic acid under basic conditions constructs intermediate 2.
Intermediate 2 is coupled with N-Bochydroxypiperidine as non-limiting example via Mitsunobu reaction to give the Hoc tert-butyloxycarbonyl protected intermediate 3. After deprotection with acid, coupling with, but not limited to, an acid chloride, such as, but not limited to, acryloyl chloride, completes the synthesis to give compound 4.
The compounds prepared by the methods disclosed herein are purified by conventional means known in the art, such as, for example, filtration, recrystallization, chromatography, distillation, and combinations thereof.
It is understood that when reference is made to compounds described herein, it is meant to include. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. In one embodiment, enantiomers can be separated by chiral chromatographic columns.
In other embodiments, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound e.
All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein. All tautomers are included within the scope of the compounds presented herein.
In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester the “prodrug” to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
A further example of a prodrug might be a short peptide polyaminoacid bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
By virtue of knowledge of pharmacodynamic processes and drag metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrUgs of the compound.
In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. They may, for instance, be bioavailable by oral administration whereas the parent is not The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility.
G ; McLoed et al. Pharmaceutics, 37, 87 ; J. Pharmaceutics, 47, ; Sinkula et al. Symposium Series; and Edward B. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as all,I1, “C, “C, “N, “0, , 35S, 13F, , zespectively.
Further, substitution with isotopes such as deuterium, i. The type of pharmaceutical acceptable salts, include, but are not limited to: Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trotnethamine, N-methylglucamine, and the like.
Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like.
Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein.
In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like.
Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. In addition, compounds described herein include crystalline forms, also known as polymorphs.
Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal forin to dominate. X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometess and synchrotron sources.
Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The pharmaceutical composition facilitates administration of the compound to an organism.
In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound.
The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
The term “fixed combination” means that the active ingredients, e. The term “non-fixed combination” means that the active ingredients, e. The latter also applies to cocktail therapy, e. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions,.
In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms also known as polymorphs , as well as active metabolites of these compounds having the same type of activity.
In some situations, compounds may exist as tautomers. All tautorners are included within the scope of the compounds presented herein. Additionally, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate. In certain embodiments, antioxidants enhance chemical stability where required.
Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylanunonium bromide and cetylpyridinium chloride.
Examples of such stabilizing agents, include, but are not limited to: Exemplary carrier materials include, e. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix.
Plasticizcers such as cellulose or triethyl cellulose can also be used as dispersing agents. Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.
Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions which also can provide pH control or maintenance are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e. Examples of disintegration agents include a starch, e.
Generally, the enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.
Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e. Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thainnatin, tutri fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.
Exemplary lubricants include, e. Suitable plasticizers include, e. In some embodiments, plasticizers can also function as dispersing agents or wetting agents. Some other surfactants include polyOxyethylene fatty acid glycerides and vegetable oils, e.
In some embodiments, surfactants may be included to enhance physical stability or for other. Dosage Forms The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral e.
As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, rnicrocrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: If desired, disintegrating agents may be added, such as the cross-linked croscannellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. In other embodiments, the pharmaceutical formulation is in the form of a powder.
In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form.
In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent.
These formulations can be manufactured by conventional pharmacological techniques. Other methods include, e. In still other aspects, using standard coating procedures, such as those described in Remington’s Pharmaceutical Sciences, 20th Edition , a film coating is provided around the formulation of the compound of any of Formula A , Formula 13 , Formula C , or Formula D.
In another embodiment, some or all of the particles of the compound of any of Formula A , Formula B , Formula C , or Formula D , are microencapsulated. In still another embodiment, the particles of the compound of any of Formula A , Formula B , Formula C , or Formula D , are not microencapsulated and are uncoated.
Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegnutts for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National or Amijele, or sodium starch glycolate such as Promogele or Explotabe, a cellulose such as a wood product, methylcrystalline cellulose, e.
Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose e. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder.
Avicel, powdered cellulose , and talc. OUI  Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.
Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. Illustratively, a plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the fmal compressed tablet.
In some embodiments, the film coating can provide a delayed release of the compound of of any of Formula A , Formula B , Formula C , or Formula D , from the formulation. In other embodiments, the film coating aids in patient compliance e.
In other embodiments, the compressed tablets include one or more excipients. In some embodiments, the formulations non-aqueous suspensions and solutions are placed in a soft gelatin capsule.
In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating.
In some embodiments, the therapeutic dose is split into multiple e. In some embodiments, the entire dose of the formulation is delivered in a capsule form. In some embodiments, one or more other compatible materials are present in the microencapsulation material.
Exemplary materials include, but are not limite,d to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricant’s, wetting agents, and diluents.
In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary NF. In yet other embodiments, the microencapsulation material is Klucel.
In still other embodiments, the microencapsulation material is methocel. Such known methods include, e. In addition to these, several chemical techniques, e. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Rernington’s Pharrnaceutical Sciences, 20th Edition Plasticizers include, but are not limited to, diethyl phthalate, ciliate esters, polyethylene glycol, glycerol; acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.
Such a powder may be prepared, for example, by mixing the formulation and , optional pharmaceutical cxcipients to form a bulk blend composition. Effervescent salts have been used to disperse medicines in water for oral administration.
When salts qf the compositions described herein are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.
Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U. In still other embodiments, the formulations described herein are solid solutions.
Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which can be further formulated or directly added to a capsule or compressed into a tablet Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, U.
In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. The enteric coated oral dosage form may also be a capsule coated or uncoated containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
In some embodiments the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above.
It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract.
In some embodiments the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to: The performance of acrylic polymers primarily their solubility in biological fluids can vary based on the degree and type of substitution.
Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series RL,, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting.
The Eudragit series E dissolve in the stomach. Examples of suitable cellulose derivatives are: The performance can vary based on the degree and type of substitution. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides.
Other suitable cellulose derivatives include: For example, suitable grades of hydroxypropylmethylcellulose acetate succinate [ Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein.
Examples of such delivery systems include, e. In addition to the particles of compound of Formula A , the liquid dosage forms may include additives, such as: In some embodiments, the aqueous dispersions can farther include a crystalline inhibitor.
The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than I minute.
In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds.
In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion. In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.
The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired. In another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.
In yet another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformaraide, sodium lauryl sulfate, sodiumdoccusatx, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the Re.
Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation.
Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients.
SEDDS may provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, US.
Thus, the above-listed additives should be taken as merely exemplary, and not limiting. Intranasal Formulations [ Intranasal formulations are known in the art and are described in, for example, U.
See, for example, Ansel, H. Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.
Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.
In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount Capsules and cartridges Of, such as, by way of example.
Buccal Formulations ] Buccal formulations that include compounds of any of Formula A , Formula B , Formula C , or Formula D , may be administered using a variety of formulations known in the art.
For example, such formulations include, but are not limited to, U. In addition, the buccal dosage forms described herein can further include a bioerodible hydrolysable polymeric carrier that also serves to adhere the dosage form to the buccal mucosa.
The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound of any of Formula A , Formula B , Formula C , or Formula D , is provided essentially throughout Buccal drug delivery, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with oral drug administration, e.
With regard to the bioerodible hydrolysable – i polymeric carrier, t will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compound of any of Formula A , Formula B , Formula C , or Formula D , and any other components that may be present in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic water-soluble and water-swellable polymers that adhere to the wet surface of the buccal rmicosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.
Goodrich, is one such polymer. Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner. Far example, such devices include, but are not limited to, U.
In one embodiments, the transdermal formulations described herein include at least three components: In other embodiments, the transdenual formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin.
Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Se further, transdernial delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like.
The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.
For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the akin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like , suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifitngal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the him.
It may also be desirable to include Isotonic agents, such as sugars, sodium chloride, and the lice. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation.
Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients.
Such excipients are generally known in the art. Formulations for injection may be presented in unit dosage form, e. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e. Other Formulations  In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions.
Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
Examples of Methods of Dosing and Treatment Regimens  The compounds described herein can be used in the preparation of medicaments for the inhibition of Btk or a homolog thereof, or for the treatment of diseases or conditions that would benefit, at least in part, from inhibition of Btk or a homolog thereof.
In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
It is considered well within the skill of the art for one to determine such therapeutically effective amounts by routine experimentation including, but not limited to, a dose escalation clinical trial.
Such an amount is defined to be a “prophylactically effective amount or dose. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation e.
When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.
The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, days, days, days, days, days, days, days, days, days, days, or days.
Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. In general, however, doses employed for adult human treatment will typically be in the range of 0.
In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation.
Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between 1. Compounds exhibiting high therapeutic indices are preferred.
The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Combination Treatments The irreversible Mc Inhibitor compositions described herein can also be used in combination with other well known therapeutic reagents that are selected for their therapeutic value for the condition to be treated.
In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician.
The initial administration can be made’ according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
By way of example only, if one of the side effects experienced by a patient upon receiving one of the irreversible Btic inhibitor compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the initial therapeutic agent.
Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant i. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
The compounds may be administered concurrently e. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are,described in the literature. For example, the use of metronomic dosing, i.
In addition, when co-administered with one or more biologically active agents, the compound provided herein may be administered either simultaneously with the biologically active agent s , or sequentially.
If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent s. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms by way of example only, either as a single pill or as two separate pills.
One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks.
These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the dosage regimens set forth herein.
The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, WSGR Docket No.
Circadian variation of the target molecule concentration may also determine the optimal dose interval. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
The initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transderrnal patch, buccal delivery, and the like, or combination thereof.
A compound should be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
The length of treatment can vary for each subject, and the length can be determined using the known criteria. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, between about 1 month to about 5 years, or from about 1 month to about 3 years.
Exemplary Therapeutic Agents for Use in Combination with an Irreversible Btk Inhibitor Compound Where the subject is suffering from or at risk of suffering from an autoinumme disease, an inflammatory disease, or an allergy disease, an irreversible Btk inhibitor compound can be used in with one or more of the following therapeutic agents in any combination: In some embodiments, one or more of the anti-cancer agents are proapoptotic agents.
Examples of anti-cancer agents include, but are not limited to, any of the following: Examples of antimetabolites include but are not limited to folic acid analog e. Examples of antimetabolites include, but are not limited to folic acid analog e.
Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes e. Erbulozole also known as R , Dolastatin.
Examples of anti-thromboembolic agents include, but are not limited any of the following: Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container s including one of the separate elements to be used in a method described herein.
Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art.
Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by inhibition of Btk, or in which Btk is a mediator or contributor to the symptoms or cause.
The container s optionally have a sterile access port for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
Such kits optionally cOmprising a compound with an identifying description or label or instructions relating to its use in the methods described herein. A set of instructions will also typically be.
A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.
A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
The pack can for – example contain metal or plastic foil, such as a blister pack. Food and Drug Administration for prescription drugs, or the approved product insect Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.