JP2022501419A - Analgesia composition - Google Patents

Abstract

The analgesic composition comprises aminoquinoline, an opioid, a non-steroidal anti-inflammatory drug (NSAID), a NE / 5-HT reuptake inhibitor, or a combination thereof. Aminoquinoline enhances the biological activity of opioids, NSAIDs and NE / 5-HT reuptake inhibitors.

Description

Government Support The present invention was made with government support (Grant No. R44-AA-0099930) from the National Institutes of Health. The US Government has certain rights in the present invention.

INDUSTRIAL APPLICABILITY The present invention relates to an analgesic composition comprising an aminoquinoline compound together with an opioid, a norepinephrine / serotonin reuptake inhibitor and / or a nonsteroidal anti-inflammatory drug (NSAID).

Background of the Invention Acute pain in the response to injury is an important mechanism for reducing the degree of injury to an individual, but the nervous system undergoes a change in adaptability beyond a point in time after the injury has healed. May also result in well-perceived pain (chronic pain) (Costigan et al., 2009). This chronic pain may be caused by a stimulus that is usually non-noxious (allodynia), or the response to the noxious stimulus may be significantly worsened (hyperalgesia). Chronic pain is estimated to affect at least 100 million adults in the United States and can adversely affect quality of life (Institute of Medicine, 2011). Pharmacological treatment of neuropathic chronic pain (due to nerve injury) or other chronic pain relies heavily on the use of opiates or derivatives thereof (Reuben et al., 2015). These drugs have many adverse effects, including the development of tolerance / hyperalgesia and opiate addiction resulting in dose escalation (Chou et al., 2015). Further side effects of high-dose and habitual administration of opiates include constipation, sleep-respiratory disorders, fractures, hypothalamic-pituitary adrenal dysregulation and overdose, and effects on the cardiovascular and immune systems (Baldini). et al., 2012). Other drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, muscle relaxants and antidepressants, and drugs that target potential-sensitive calcium channels (gabapentin and pregabalin), are used to treat chronic pain. Although used, these treatments provide limited relief (Lunn et al., 2014; Moore et al., 2014; Schreiber et al., 2015; Smith et al., 2012; Soft et al. , 2017; Lozada, et al., 2008). In addition, high-dose habitual administration of NSAIDs, the second most commonly used drug after opioids for the treatment of chronic pain, has side effects such as gastric symptoms (such as bleeding, ulcers and heaviness), renal failure, hypertension or With hypertension of erythrocytes, including heart symptoms, fluid retention, rash or other allergic reactions (Markum and Hanlon 2010). A third category of drugs for treating chronic pain is the more recently introduced blockers of 5-HT and NE reuptake systems (Smith et al., 2012; Soft et al., 2017). 5-HT / NE reuptake inhibitors are also nausea, G. et al. I. Shows a series of side effects, including disability, insomnia and fatigue. More dangerous is the effect of rushing to stop using these drugs if they do not relieve chronic pain. Such "withdrawal" effects include excessive mood swings, agitation, aggression, nightmares, confusion and electric shock-like sensations in the head and other parts of the body (Fava et al., 2018; Carvalho). et al., 2016). In all cases, dose escalation with opiate / opioid, NSAID or 5-HT / NE reuptake inhibitors for therapeutic success for chronic pain results in the appearance of serious side effects of this drug. Careless discontinuation of treatment results in the appearance of more serious side effects.

The majority of people with chronic pain continue to use opiates / opioids prescribed at high doses for extended periods of time if the pain is not controlled by other drug classes. Due to the marked increase in the use of opiates to treat chronic pain and the associated increased concern about overdose, misuse or diversion problems (called the "opioid crisis"), the prescribed opioids are the lowest and shortest effective doses. It is recommended to limit the duration and, importantly, to develop new non-opioid drug therapies based on scientific information on the etiology of chronic pain (Volkow and McLellan 2016). Taneja et al., 2017; Kirkpatrick et al., 2016).

Numerous attempts have been made to create new and better pain medications by focusing on targets known to be involved in chronic pain (Yekkirala, et al., 2017; Worley 2017). Target selection is the primary focus of chronic pain drug development efforts, and most plans use a single target / site (eg, receptor), which has been the pharmaceutical industry's selection approach for many years. (Ramsay et al., 2018). However, targeting a single molecular entity to control a complex physiological system will limit the efficacy of the drug (Bozuki et al., 2013). More recently, perceptions have changed, in part due to the design of effective multi-target drugs for the treatment of schizophrenia, viral infections, asthma, cardiovascular disease, neurodegenerative diseases and cancer. (Ramsay et al., 2018). Such drugs result in partial inhibition of one or more targets within the network rather than complete inhibition of a single target (Zimmerman et al., 2007; Millan, 2014; Talevi, 2015). ..

With respect to pain, attention can be focused on systems that process sensory information from peripheral receptors and systems that transform information within and between sensory neurons. One of the most studied molecular mechanisms leading to chronic neuropathy pain syndrome is the upregulation of peripheral potential sensitive sodium channel (VSNaC) activity (Wood et al., 2004; Lai, et al.,. 2004; Black et al., 2004; Cogshall et al., 2004; Div-Hajj et al., 2007). Tetrodotoxin-sensitive Nav1.7 channels are located along the processes and cell bodies that slowly process nociceptive neurons, and their role in both acute and chronic pain occurs by genetic engineering in animals and naturally in humans. It has been clearly demonstrated by genetic mutation (Black et al., 2004; Wang et al., 2011; Lawrence, 2012). Nav1.7 channels are particularly associated with inflammation-related pain, the up-regulation of which contributes to increased action potential generation and processing in chronic pain syndrome (Eijkelkamp et al., 2012). In addition, the activity of Nav1.7 channels can amplify orbital potentials and promote activation of other sensory neurons VSNaC, including tetrodotoxin-resistant Nav1.8 channels (Dib-Hajj et al., 2007). Choi & Waxman, 2011). Nav1.8 channels have been linked to the development of both inflammatory and neuropathic pain symptoms. Overall, the upregulation of Nav1.7 and Nav1.8 channel activity in peripheral sensory neurons constitutes a common component of the induction and maintenance of chronic pain syndrome (Wang et al., 2011; Steel & Cummins, 2011). Laedermann et al., 2015).

The role of the excitatory amino acid glutamate in the physiology of normal pain perception and the transmission of chronic pain phenomena is also well established (Davies & Rodge, 1987; Dickenson & Sullivan, 1987; Children & Body, 2007). Activation or damage to sensory neurons causes increased release of glutamate from both peripheral and central neurons, and the released glutamate acts on nearby glutamate (NMDA) receptors for peripheral sensitization. Can contribute (Fernandez-Montoya et al., 2017; Jang et al., 2004). The interaction of glutamate with the NMDA receptor in the dorsal root ganglion (DRG) is also involved in the amplification of sensory signals (Ferrari et al., 2014; Rozanski et al., 2013). Therefore, the NMDA receptor is involved in both the pain sensation and the initiation and amplification of its transmission to the CNS. Upregulation of NMDA receptors is seen in both peripheral neurons and spinal cord after sensory nerve injury, and its upregulation is thought to contribute to chronic neuropathic pain (Peterenko et al., 2003). Specifically, the amount of NMDA receptors containing the GluN2B (NR2B) subunit plays the most important role in the development and maintenance of chronic pain syndrome (Karlsson et al., 2002; Iwata et al., 2007; Gaunitz et al. , 2002; Wilson et al., 2005).

Based on this discussion, drug therapies that can simultaneously inhibit Nav1.7 channel activity and Nav1.8 channel activity and, in particular, the activity of the NMDA receptor (specifically, the NMDA receptor containing the GluN2B subunit) are receptor / channel. It can be beneficial both in preventing the development of chronic pain by inhibiting upregulation and in alleviating pain even after the onset of chronic pain syndrome. Such drug treatments do not need to act in the central nervous system, prevent peripheral sensitization leading to central sensitization and the development of chronic pain, and / or initiate chronic pain signals and transmit to the brain. May weaken.

Costigan et al. , 2009 Institute of Medicine, 2011 Reuben et al. , 2015 Chou et al. , 2015 Baldini et al. , 2012 Lunn et al. , 2014 Moore et al. , 2014 Schreiber et al. , 2015 Smith et al. , 2012 Soft et al. , 2017 Lozada, et al. , 2008 Marcum and Hanlon 2010 Faba et al. , 2018 Carvalho et al. , 2016 Volkow and McLellan 2016 Taneja et al. , 2017 Kirkpatrick et al. , 2016 Yekkirala, et al. , 2017 Worley 2017 Ramsay et al. , 2018 Bozic et al. , 2013 Ramsay et al. , 2018 Zimmerman et al. , 2007 Millan, 2014 Talevi, 2015 Wood et al. , 2004 Lai, et al. , 2004 Black et al. , 2004 Coggeshall et al. , 2004 Div-Hajj et al. , 2007 Wang et al. , 2011 Lawrence, 2012 Eijkelkamp et al. , 2012 Div-Hajj et al. , 2007 Choi & Waxman, 2011 Three & Cummins, 2011 Ladermann et al. , 2015 Devices & Rodge, 1987 Dickenson & Sullivan, 1987 Children & Body, 2007 Ferrandez-Montoya et al. , 2017 Jang et al. , 2004 Ferrari et al. , 2014 Rosenski et al. , 2013 Petrenko et al. , 2003 Karlsson et al. , 2002 Iwata et al. , 2007 Gaunitz et al. , 2002 Wilson et al. , 2005

Abstract of the Invention N-substituted-4-ureido-5,7-dichloro-2-carboxy (or carboxyester) quinolines in combination with opioids, NE / 5-HT reuptake inhibitors or NSAIDs are chronic neuropathic disorders in humans. It is effective in the treatment and prevention of sexual pain.

The analgesic composition embodying the present invention comprises an aminoquinoline compound with opioids, NE / 5-HT reuptake inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or combinations thereof. Aminoquinoline compounds enhance the biological activity of opioids, drugs that block the uptake of serotonin (5-HT) and norepinephrine (NE), and NSAIDs. As a result, co-administration of aminoquinoline compounds makes it possible to reduce the dose of opioids, NE or 5HT reuptake blockers, or NSAIDs used for the desired analgesic (anti-hyperalgesia) effect. In addition, aminoquinoline compounds may present onset of chronic pain and / or exacerbation of chronic pain syndrome when administered early in the course of onset of chronic pain.

Equation (I):

によって表されるアミノキノリン化合物において、その置換基は、以下のように定義される：Ｒ^１は、Ｈ、Ｃ_２−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、ハロ、Ｚ^１Ｒ^９、又はＮ（Ｒ^１０）（Ｒ^１１）である。Ｒ^２は、Ｈ、Ｃ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、ハロ、Ｚ^２Ｒ^１２、Ｎ（Ｒ^１３）（Ｒ^１４）、又はＣ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、ハロ、Ｚ^３Ｒ^１５、Ｎ（Ｒ^１６）（Ｒ^１７）からなる群より選択される１つ以上の部分によって置換されるＣ_１−Ｃ_４アルキルであり；各Ｒ^３、Ｒ^４、Ｒ^５、及びＲ^６は、独立してＨ、Ｃ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、ハロ、Ｚ^３Ｒ^１８、又はＮ（Ｒ^１９）（Ｒ^２０）であり；Ｘ^１は、Ｎ又はＣＨであり；各Ｒ^７及びＲ^８は、独立してＨ、Ｃ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_４アルケニル、Ｃ_２−Ｃ_４アルキニル、アリール、又はＣ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、ニトロ、ハロ、Ｚ^４Ｒ^２１、及びＮ（Ｒ^２２）（Ｒ^２３）からなる群より選択される１つ以上の部分によって置換されるＣ_１−Ｃ_６アルキルであるか；又はＲ^７及びＲ^８は、Ｘ^１と共に５〜８員の飽和、不飽和、又は芳香族有機環式部分又は複素環式部分を形成し；各Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０、Ｒ^２１、Ｒ^２２、及びＲ^２３は、独立してＨ、Ｃ_１−Ｃ_４アルキル、又はＣ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、Ｃ_２−Ｃ_４アルキニル、ハロ、ヘテロアリール、Ｚ^５Ｒ^２４、及びＮ（Ｒ^２５）（Ｒ^２６）からなる群より選択される１つ以上の部分によって置換されるＣ_１−Ｃ_４アルキルである。Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、及びＺ^５の各々は、独立してＯ、Ｓ、ＮＨ、Ｃ（＝Ｏ）Ｏ、Ｏ−Ｃ（＝Ｏ）、Ｃ（＝Ｏ）、又はＣ（＝Ｏ）ＮＨである。Ｒ^１がＺ^１Ｒ^９であり、Ｚ^１がＣ（＝Ｏ）Ｏであり、Ｒ^９がＨ又はＣ_１−Ｃ_２アルキルであり、Ｒ^３及びＲ^５の各々がハロであり、Ｘ^１がＮであり、かつＲ^４及びＲ^６の各々がＨであって、次いでＲ^７及びＲ^８の少なくとも１つはフェニル、アルコキシ−置換フェニル、又はＣ_１−Ｃ_６アルキル基である場合に、各Ｒ^２４、Ｒ^２５、及びＲ^２６は、独立してＣ_１−Ｃ_４アルキルである。

In the aminoquinoline compound represented by, the substituents are defined as follows: R ¹ is H, C _2- C ₄ alkyl, C _2- C ₄ alkenyl, halo, Z ¹ R ⁹ or. N (R ¹⁰ ) (R ¹¹ ). R ² is H, C _1- C ₄ alkyl, C _2- C ₄ alkenyl, halo, Z ² R ¹² , N (R ¹³ ) (R ¹⁴ ), or C _1- C ₄ alkyl, C _2- C ₄ alkenyl, ^{halo, Z 3 R 15, N (} R 16) C 1 -C substituted with one or more moieties selected from the group consisting of ^{(R 17)} is ₄ alkyl; each ^{R 3, R} 4, R ⁵ and R ⁶ are independently H, C _1- C ₄ alkyl, C _2- C ₄ alkenyl, halo, Z ³ R ¹⁸ or N (R ¹⁹ ) (R ²⁰ ); X ¹ is. , N or CH; each R ⁷ and R ⁸ are independently H, C _1- C ₆ alkyl, C _2- C ₄ alkenyl, C _2- C ₄ alkynyl, aryl, or C _1- C ₄ alkyl. , C _2- C ₄ alkenyl, nitro, halo, Z ⁴ R ²¹ _{, and C 1-} C ₆ alkyl substituted by one or more moieties selected from the group consisting of N (R ²² ) (R ^23). Are; or R ⁷ and R ⁸ together with X ^{1 form} 5-8 membered saturated, unsaturated, or aromatic organic or heterocyclic moieties; R ⁹ , R ¹⁰ , R ¹¹ , respectively. R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , and R ²³ are independently H, C _1- C ₄ alkyl, Alternatively, it is selected from the group consisting of _{C 1-} C ₄ alkyl, C _2- C ₄ alkenyl, C _2- C ₄ alkynyl, halo, heteroaryl, Z ⁵ R ²⁴ , and N (R ²⁵ ) (R ^26). _C 1 -C ₄ alkyl which is substituted by more than three parts. Each of Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ is independently O, S, NH, C (= O) O, OC (= O), C (= O), or C (= O) NH. R ¹ is Z ¹ R ⁹ , Z ¹ is C (= O) O, R ⁹ is H or C ₁ −C ₂ alkyl, ^{each of R 3} and R ⁵ is halo, and X ¹ there is N, and a respective ^{R 4} and ^{R 6} are H, then at least one of ^{R 7} and ^{R 8} are phenyl, alkoxy - when it is substituted phenyl, or _C 1 -C ₆ alkyl group, each ^{R 24, R 25,} and ^{R 26} is _C 1 -C ₄ alkyl independently.

Equation (II):

のアミノキノリン化合物において、Ｘ^１、Ｒ^１、Ｒ^７及びＲ^８は、上記式（Ｉ）において定義される通りであり、そして各Ｘ^２及びＸ^３は、独立してハロ、ニトロなどの電子求引基であるが、ただし、Ｒ^１がＺ^１Ｒ^９であり、Ｚ^１がＣ（＝Ｏ）Ｏ又はＣ（＝Ｏ）であり、Ｒ^９がＨ又はＣ_１−Ｃ_４アルキルであり、そしてＸ^１がＮである場合に、Ｒ^７及びＲ^８の少なくとも１つは、フェニル又はアルコキシで置換された基ではないという条件の上である。

In the aminoquinoline compounds of, X ¹ , R ¹ , R ⁷ and R ⁸ are as defined in formula (I) above, and each X ² and X ³ are independently electrons such as halo, nitro and the like. Although it is an attracting group, however, R ¹ is Z ¹ R ⁹ , Z ¹ is C (= O) O or C (= O), and R ⁹ is H or C ₁ −C ₄ alkyl. And if X ¹ is N ^{, then at least one of R 7} and R ⁸ is not a phenyl or alkoxy substituted group.

Equation (III):

のアミノキノリン化合物において、Ｘ^２及びＸ^３は、各々独立してハロであり、そしてＸ^１、Ｒ^１、Ｒ^７、Ｒ^８及びＲ^９の各々は、上述の式（Ｉ）及び（ＩＩ）において定義される通りであるが、ただし、Ｒ^９がＨ又はＣ_１−Ｃ_２アルキルであり、そしてＸ^１がＮである場合、Ｒ^７及びＲ^８の少なくとも１つは、フェニル又はアルコキシで置換されたフェニル基ではないという条件の上である。

In the aminoquinoline compounds of, X ² and X ³ are each independently halo, and each of X ¹ , R ¹ , R ⁷ , R ⁸ and R ⁹ has the above formulas (I) and (II). As defined in, however, where R ⁹ is H or C _1- C ₂ alkyl and X ¹ is N, then ^{at least one of R 7} and R ⁸ is replaced with phenyl or alkoxy. On the condition that it is not a phenyl group.

Equation (IV):

のアミノキノリン化合物において、Ｘ^２、Ｘ^３、Ｒ^１、Ｒ^７、及びＲ^８の各々は、上記式（Ｉ）及び（ＩＩ）において定義される通りである。

In the aminoquinoline compounds of, each of X ² , X ³ , R ¹ , R ⁷ , and R ⁸ is as defined in the above formulas (I) and (II).

Equation (V):

のアミノキノリン化合物において、Ｘ^２、Ｘ^３、Ｒ^７、Ｒ^８及びＲ^９の各々は、上記式（Ｉ）及び（ＩＩ）において定義される通りである。

In the aminoquinoline compounds of, each of X ² , X ³ , R ⁷ , R ⁸ and R ⁹ is as defined in the above formulas (I) and (II).

Equation (VI):

のアミノキノリン化合物において、Ｒ^７は、アルキル、シクロアルキル、アミノアルキル又はフェニルであり；Ｒ^８は、Ｈ、アルキル、シクロアルキル、アミノアルキル、又はフェニルであり；Ｅ^１は、−Ｃ（＝Ｏ）ＯＲ^９、−Ｃ（＝Ｏ）Ｒ^９、−Ｃ（＝Ｏ）Ｎ（Ｒ^９）_２、及び−［Ｃ（Ｒ^９）_２］_ｎ−ＯＲ^９であり、「ｎ」は、１、２、３、又は４であり；各Ｒ^９は、独立してＨ、Ｃ_１−Ｃ_４アルキル、又はＣ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、Ｃ_２−Ｃ_４アルキニル、ハロ、ヘテロアリール、Ｚ^５Ｒ^２４、及びＮ（Ｒ^２５）（Ｒ^２６）からなる群より選択される１つ以上の部分によって置換されるＣ_１−Ｃ_４アルキルであり；Ｚ^５は、Ｏ、Ｓ、Ｃ（＝Ｏ）Ｏ又はＯ−Ｃ（＝Ｏ）であり；各Ｒ^２４、Ｒ^２５、及びＲ^２６は、独立してＣ_１−Ｃ_４アルキル、アルキルであり；各Ｘ^２及びＸ^３は、独立して電子求引基（好ましくはハロゲン又はニトロ）であり；アルキル、シクロアルキル、アミノアルキル、及びフェニル基は、置換されていなくても、アルキル（１〜３炭素）基又はアルキルオキシ基（例えば、１〜３炭素のアルキル又はアルコキシ基）によって１回以上置換されていてもよく；そして酸性又は塩基性の官能基が存在する場合、化合物は、遊離の酸性形態であっても、遊離の塩基性形態であっても、又は薬理学的に許容される付加塩であってもよい。Ｅ^１がＣ（＝Ｏ）ＯＲ^９である場合、Ｒ^７及びＲ^８の少なくとも１つは、フェニルではない。

In the aminoquinoline compounds of, R ⁷ is alkyl, cycloalkyl, aminoalkyl or phenyl; R ⁸ is H, alkyl, cycloalkyl, aminoalkyl, or phenyl; E ¹ is -C (= O). ) OR ⁹ , -C (= O) R ⁹ , -C (= O) N (R ⁹ ) ₂ , and-[C (R ⁹ ) ₂ ] _n- ^{OR 9} , where "n" is 1, 2, 3, or 4; each R ⁹ is independently H, C _1- C ₄ alkyl, or C _1- C ₄ alkyl, C _2- C ₄ alkenyl, C _2- C ₄ alkynyl, halo, ^heteroaryl, Z ^{5 R 24,} and ^N (R 25) a _C 1 -C ₄ alkyl which is substituted by one or more moieties selected from the group consisting of ^{(R 26); Z 5} is, O, S , C (= O) O or O-C (= O); each ^{R 24, R 25,} and ^{R 26,} _C 1 -C ₄ alkyl independently is alkyl; each ^{X 2} and ^{X 3} Are independently electron-withdrawing groups (preferably halogens or nitros); alkyl, cycloalkyl, aminoalkyl, and phenyl groups are alkyl (1 to 3 carbon) groups or alkyloxys, even if not substituted. It may be substituted more than once with a group (eg, an alkyl or alkoxy group of 1-3 carbons); and if acidic or basic functional groups are present, the compound may be in free acidic form. It may be in a free basic form or it may be a pharmacologically acceptable addition salt. When E ¹ is C (= O) OR ⁹ , at least one of ^{R 7} and R ^{8 is not phenyl.}

Particularly preferred for use in the analgesic compositions of the present application are compounds of formula (VI) as free acidic forms, free basic forms, or pharmacologically acceptable addition salts, wherein:
R ⁷ is alkyl (preferably 3-6 carbon alkyl (alky)), or phenyl;
R ⁸ is alkyl (preferably 3-6 carbon alkyl), or phenyl;
E ¹ is -C (= O) R ⁹ or E ¹ is -C (= O) OR ⁹ ;
Each R ⁹ is an H or C _1- C ₄ alkyl; and each X ² and X ³ are independently electron attractants (preferably halogens or nitros).

Administration of the analgesic composition may be oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal or transbuccal route.

Non-limiting examples of compounds of general formula (VI) include derivatives of 2-carboxy-quinolines, such as (N, N-dibutyl) -4-ureido-5,7-dichloro-2-carboxy-quinoline (BCUKA). ), (N, N-diphenyl) -4-ureido-5,7-dichloro-2-carboxy-quinoline (DCUKA), and the like.

The di-substituted-4-ureido-5,7-dichloro-2-carboxy-quinoline compound of formula (VI) has affinity for some or all of the following: Nav1.7, Nav1.8, and NMDA receptors. .. These compounds have beneficial activity in the treatment of degenerative joint pain (eg, osteoarthritis) and chronic pain syndrome resulting from inflammatory and organic damage to peripheral nerves, with organic or febrile allodynia / hyperalgesia. Effectively alleviates.

The compound of formula (VI) is a 5,7-dichloroquinolone-2-carboxylate intermediate (eg, Michael addition of 3,5-dichloroaniline to dimethylacetylenedicarboxylate followed by a thermal ring of the resulting arylmaleate. (Can be obtained by compounding), prepared by amidation with chlorosulfonyl isocyanate to produce (4-amino) -5,7-dichloro-2-carboxy-quinoline ethyl ester (key intermediate). Obtained, which can be imparted with functionality through reaction with the relevant electrophile. For the preparation of monosubstituted urea, a reactive urea intermediate is prepared through a reaction with the primary amine carbonyldiimidazole. The reaction of the resulting imidazole urea with the amino-5,7-dichloro-2-carboxy-quinoline ethyl ester in the presence of sodium hydroxide causes the target monosubstituted urea to be at the 4-position of the quinoline at the same time as the ester hydrolysis. Occurs. Removal of protecting groups, such as tert-butoxycarbonyl (BOC) -protecting groups, is accomplished by trifluoroacetic acid (TFA), such as when used in the synthesis of reactive urea intermediates, to the desired TFA salt. Can occur.

For the preparation of disubstituted urea derivatives, (4-amino) -5,7-dichloro-2-carboxy-quinoline methyl or ethyl ester is acetylated with disubstituted carbamoyl chloride at the 4-amino position ( N, N-disubstituted) -4-ureido-5,7-dichloro-2-carboxy-quinoline ester is formed. Optionally, (N, N-disubstituted) -4-ureido-5,7-dichloro-2-carboxy-quinoline-ester is hydrolyzed to (N, N-2-substituted) -4-ureid. It may be -5,7-dichloro-2-carboxy-quinoline.

DCUKA and DCUK-OEt show affinity for Nav1.7 and Nav1.8, respectively, and DCUKA also shows affinity for the NMDA receptor. DCUK-OEt can also act as a prodrug of DCUKA by ester hydrolysis with carboxylesterase 1 that occurs after in vivo administration.

Illustrate that DCUK-OEt can act as a prodrug for DCUKA. When DCUK-OEt was orally administered to rats in a suspension of a spray-dried dispersion, the data show that blood levels of DCUKA depended on the dose of DCUK-OEt administered. The peak level of DCUKA is about 3 μM after administration of a dose of DCUK-OEt of 50 mg / kg and about 11 μM after administration of a dose of DCUK-OEt of 100 mg / kg. The treatment of cisplatin-induced neuropathic pain with DCUKA (50 mg / kg) is illustrated. In rats treated with the cancer chemotherapeutic agent cisplatin, cisplatin treatment lowers the organic pain threshold, and DCUKA treatment reverses this effect and raises the organic pain threshold to control levels. This data shows the ratio of the organic pain threshold after cisplatin treatment or cisplatin and DCUKA treatment to the organic pain threshold before cisplatin treatment. A comparison of the effects of equimolar doses of DCUKA, BCUKA and gabapentin on reversing cisplatin-induced neuropathic pain, measured by changes in the organic pain threshold, is illustrated. The reversal of neuropathic pain induced by treatment with Complete Freund's adjuvant (CFA) with DCUKA (50 mg / kg) is illustrated. CFA treatment of rat limbs induces inflammation and lowers the organic pain threshold. DCUKA treatment reverses the decline in the organic pain threshold in CFA-treated rats and returns the threshold to baseline levels. This data shows the ratio of the organic pain threshold after CFA or CFA and DCUKA treatment to the organic pain threshold before CFA treatment. A comparison of the effects of DCUKA (50 mg / kg) and BCUKA (50 mg / kg) on reversing neuropathic pain induced by treatment of rats with CFA is shown. This data shows the ratio of the organic pain threshold to the baseline (pre-CFA) organic pain threshold after CFA or CFA and DCUKA or BCUKA treatment. The results of a meta-analysis of experiments to determine the dose-dependent effect of reversing CFA-induced neuropathic pain in DCUKA are shown. The treatment of pain caused by diabetic neuropathy with DCUKA (50 mg / kg) is illustrated. Rats are treated with streptozotocin (STZ) to induce diabetes. Diabetes lowers the organic pain threshold compared to baseline (before STZ treatment). The DCUKA treatment reverses the organic pain threshold relative to baseline. This data shows the ratio of the organic pain threshold to the STZ pre-organic pain threshold after STZ treatment or STZ and DCUKA treatment. The results of a meta-analysis of experiments to determine the dose-dependent effect of DCUKA on reversing STZ-induced neuropathic pain are shown. The treatment of osteoarthritis pain with DCUKA is illustrated. Rats were treated with monoiodoacetic acid (MIA), which initiates an inflammatory response. Cartilage damage and degradation result in chronic neuropathic pain, which is reflected as a lower organic pain threshold compared to baseline measured in animals not receiving MIA or drugs. DCUKA reversed the organic pain threshold in a dose-dependent manner. This data shows the ratio of the organic pain threshold to the organic pain threshold in animals not receiving MIA or drug after MIA or MIA and DCUKA treatment. It is illustrated that administration of DCUKA enhances the ability of morphine to reverse CFA-induced neuropathic pain. It is illustrated that administration of DCUK-OEt increases the ability of morphine to reverse CFA-induced neuropathic pain. The results of an isobologram analysis demonstrating that DCUK-OEt significantly reduces the maximum effective dose required for morphine to reverse pain are shown. It is shown that DCUKA enhances the ability of oxycodone to reverse CFA-induced neuropathic pain. It is shown that DCUKA enhances the ability of methadone to reverse CFA-induced neuropathic pain. It is shown that DCUKA enhances the ability of tramadol to reverse MIA-induced osteoarthritis (neuropathy) pain. It is shown that DCUKA enhances the ability of aspirin to reverse STZ-induced neuropathic pain (diabetic neuropathy). It is shown that DCUKA enhances the ability of diclofenac to reverse CFA-induced neuropathic pain. It is illustrated that administration of DCUKA after CFA injection prevents the development of CFA-induced neuropathic pain as measured by changes in the organic pain threshold. It is illustrated that administration of DCUKA in conjunction with the cancer chemotherapeutic agent cisplatin prevents the development of CFA-induced neuropathic pain as measured by changes in the organic pain threshold.

Detailed Description of Preferred Embodiments The analgesic compositions described herein are well suited for the treatment of chronic (neuropathy) pain syndromes.

The methods described herein target subjects in need of pain relief (eg, human patients or animals) with opioids, NE / 5-HT reuptake inhibitors, and / or non-steroidal anti-inflammatory drugs (NSAIDs). Also comprises treating with an aminoquinoline-containing composition comprising.

Suitable opioids for use in the analgesic compositions of the present application include opiates (ie, naturally occurring plant alkaloids such as morphine, codeine, papaverin, tebain); semi-synthetic opioids such as oxycodon, diamorphine, dihydrocodeine; Synthetic opioids such as phenylpyridine derivatives such as 6-amino-5 (2,3,5-trichlorophenyl) -pyridine-2-carboxylic acid methylamide; phenylpiperidin derivatives such as fentanyl, sulfentanyl, al. Fentanyl and the like; morphinan derivatives such as levorphanol, butorphanol and the like; diphenylheptane derivatives such as mesadon, propoxyphen and the like; benzomorphan derivatives such as pentazocin and phenazocin and the like.

Suitable multi-target drugs for use in analgesic compositions include drugs that act on opiate receptors and / or monoamine reuptake transporters, such as tramadol.

Suitable NSAIDs for use in analgesic compositions include aspirin, acetic acid derivatives (eg, indomethacin, slindac, etdrac, tolmethin, ketorolac, nabmeton, diclofenac, etc.), propionic acid derivatives (eg, ibuprofen, naproxen, phenoprofen). , Ketoprofen, flurubiprofen, oxaprodin, etc.), enolic acid derivatives (eg, pyroxycam, meroxycam, tenoxicam, etc.), phenamic acid derivatives (eg, mefenamic acid, meclofenamic acid, flufenamic acid, etc.), and the above pharmaceutically acceptable The salt to be made is mentioned.

Examples of NSAID salts suitable for use in the compositions of the present application are pharmaceutically acceptable salts of the acetic acid derivative, such as indomethacin salts (eg, indomethacin sodium, indomethacinmeglumin, etc.), tolmethine salts (eg, tolmethin). Quetrolac salts (eg, ketrolactromethamine, etc.), diclofenac salts (eg, diclofenac sodium, diclofenac diethylamine, diclofenac eporamine, etc.), and pharmaceutically acceptable salts of the propionic acid derivatives described above, eg, Ibuprofen salts (eg, ibuprofen lysine, ibuprofen methylglucamine, etc.), naproxen salts (eg, naproxen piperazin naproxen sodium, etc.), phenoprofen salts (eg, phenoprofen calcium, etc.).

The aminoquinoline compounds of formulas (I), (II), (III), (IV), (V) and (VI) can be prepared by any conventional method known to those of skill in the art. For example, US Pat. No. 6,962,930 to Tabakoff et al. And US Pat. No. 7,923,458 to Tabakoff et al. (Incorporated by reference in their entirety) are specific quinoline compounds similar to those of the present invention. The preparation of the analog is described, which is readily applicable to the preparation of the desired aminoquinoline compound. Scheme 1 provides a general scheme for preparing an aminoquinoline compound of formula (I) and a structurally related compound or analog compound from the 4-amino-substituted quinoline compound (A), wherein the R substituent. Is the same as in equation (I). The amino group of the compound (A) reacts with the activated acylated compound (B) containing a leaving group (LG) which is reactive with the aromatic amino group to obtain the compound of the formula (I). Form. Substituted quinoline compounds having an amino group at the 4-position of the quinoline ring structure, for example, compound (A) having various substitution patterns in the quinoline ring system, and their preparation are well known to those skilled in the art of chemistry. For example, Protective Groups in Organic Synthesis, 3rd Edition, Green and Wuts, John Wiley & Sons, Inc. The protecting group described in (1999) (incorporated herein by reference) is used in the preparation of compound (A), compound (B) and / or coupling of compound (A) to compound (B). In, it may be necessary or desired to be used to facilitate the preparation and / or isolation of the compounds of formula (I).

Scheme 1.

As used herein, the term "aminoquinoline compound" is used herein as the formulas (I), (II), (III), (IV), (V) and (VI). Refers to the compound shown in. Aminoquinoline compounds are useful for chronic pain and various other symptoms.

The term "alkyl", as used herein, is linear, branched or cyclic ("cycloalkyl") and has not been substituted or substituted (ie, its). Refers to a _{saturated hydrocarbon group (represented by the formula C n} H _{2n + 1} ) in which one or more hydrogens are replaced by another atom or branch.

"Aryl" refers to either a 6-carbonbenzene ring or a condensed 6-carbon ring of another aromatic derivative (eg, Howley's Condensed Chemical Dictionary (13th Edition), RJ Lewis, ed., J. Wiley & Sons, Inc., New York (1997)). Aryl groups include, but are not limited to, phenyl and naphthyl.

A "heteroaryl" ring is an atom that contains at least one carbon atom in the ring and is one or more, typically 1-4, non-carbon atoms that form the ring, i.e., a heteroatom. It is an aromatic ring containing (typically O, N or S). Heteroaryls include, but are not limited to: morpholinyl, piperazinyl, piperidinyl, pyridyl, pyrrolidinyl, pyrimidinyl, triazinyl, flanyl, quinolinyl, isoquinolinyl, thienyl, imidazolinyl, thiazolyl, indrill, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl. , Benzothiazolyl, benzoxazolyl, isooxazolyl, triazolyl, tetrazolyl, indazolyl, indolinyl, indrill-4,7-dione, 1,2-dialkyl-indrill, 1,2-dimethyl-indrill, and 1,2-dialkyl-indrill. -4,7-Zeon can be mentioned.

"Alkoxy" means −OR, where R is the alkyl defined above, such as methoxy, ethoxy, propoxy, 2-propoxy and the like.

"Alkenyl" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched chain monovalent hydrocarbon radical of 3 to 6 carbon atoms containing at least one double bond (eg,). , Ethenyl, Propenil, etc.).

"Alkynyl" means a linear monovalent hydrocarbon radical with 2 to 6 carbon atoms or a branched chain divalent hydrocarbon radical with 3 to 6 carbon atoms containing at least one triple bond (eg,). Ethynyl, propynyl, etc.).

"Halide" and "halo" refer to halogen atoms containing fluorine, chlorine, bromine and iodine.

Classification of substituents is known, for example, C _1-6 alkyl, which here includes each of its individual substituent members, eg, C ₁ alkyl, C ₂ alkyl, C ₃ alkyl and C ₄ alkyl. Say that.

"Replaced" means that one or more hydrogen atoms on the indicated atom are replaced with those selected from the indicated group, provided that the normal valence of this indicated atom. And this substitution is conditional on yielding a stable compound.

An "unsubstituted" atom has all the hydrogen atoms supported by its valence. If the substituent is, for example, a "keto", the two hydrogens on this atom will be replaced. Substituents and / or combinations of variables are allowed only if such combinations yield stable compounds; "stable compounds" or "stable structures" are useful from the reaction mixture. It means a compound that is strong enough to withstand isolation to a degree of purity and formulation into an effective therapeutic agent.

"Pharmaceutically acceptable", when used in reference to a salt or carrier, is a generally acceptable substance as suitable for administration to or contact with the human body or parts thereof. Say. A pharmaceutically acceptable salt is a substance in which the parent compound (eg, the aminoquinoline compound of formula (I)) or any other therapeutic agent or excipient has been modified by producing the acid or salt thereof. be. Examples of pharmaceutically acceptable salts are, but are not limited to, mineral or organic acid salts of basic residues (eg, amines), or alkaline or organic salts of acidic residues (eg, carboxylic acids). However, it can be mentioned. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts are derived from inorganic acids (eg, hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, etc.); and prepared from organic acids. Salts to be (eg, acetate, propionate, succinate, glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, pamoate, maleate , Hydroxymalate, phenylacetate, glutamate, benzoate, salicylate, sulfanylate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, (Succinate, ISEthionate, etc.), and the like. Pharmaceutically acceptable salts are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions or other problems or complications, commensurate with the profit / loss ratio. These forms of the compound.

The pharmaceutically acceptable salt form of the aminoquinoline compounds provided herein is synthesized by conventional chemical methods from the parent compound containing a basic or acidic moiety. In general, such salts are produced, for example, by reacting the free acid or free base forms of these compounds with the theoretical amount of the appropriate base or acid in water or in an organic solvent or in a mixture thereof. Prepared. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is described in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa. , 1985, p. It is found in 1418, the disclosure of which is incorporated herein by reference.

A "prodrug" is any covalent carrier that releases the active parent drug of an aminoquinoline compound in vivo when such a prodrug is administered to a mammalian subject. The prodrug of the aminoquinoline compound of the present invention modifies the functional groups present in the compound (this modification is cleaved either by conventional operation including enzymatic conversion or in vivo to become the parent compound). Prepared by. As a prodrug, a hydroxy group, an amine group or a sulfhydryl group binds to any group and cleaves when administered to a mammalian subject to form a free hydroxyl group, amino group or sulfhydryl group, respectively. Compounds are mentioned. Examples or prodrugs include, but are not limited to, acetate derivatives, formate derivatives and benzoate derivatives of alcohol and amine functional groups in the aminoquinoline compounds of the invention. Compounds that effectively function as prodrugs for the aminoquinoline compounds of the invention can be identified using conventional techniques known in the art. For examples of such prodrug derivatives, see, for example, (a) Design of Prodrug edited by H. et al. Bundgaard, (Elsevier, 1985) and Methods in Enzymemogy, Vol. 42, p. 309-396, edited by K.K. Wider et al. (Academic Press, 1985); (b) A Textbook of Drug Design and Development, edited by Krogsgard-Larsen and H. et al. Bundgaard, Chapter 5 "Design and Application of Prodrug," by H. et al. Bundgaard p. 113-191 (1991); (c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); (d) H. et al. Bundgaard et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and (e) N. et al. Kakeya et al., Chem. Pharm. Bull. , 32: 692 (1984), each of which is incorporated herein by reference.

In addition, the invention also includes solvates of aminoquinoline compounds, metabolites, and pharmaceutically acceptable salts.

The term "solvate" refers to an aggregate of a molecule and one or more solvent molecules. A "metabolite" is a pharmacologically active product of a particular compound or salt thereof, which is produced in the body via in vivo metabolism. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of aminoquinoline compounds, including compounds produced by a process comprising contacting the compound of the invention with a mammal for a sufficient period of time to produce a metabolite thereof.

Pharmaceutical compositions and therapeutic regimens.
In one aspect, the invention presents a pharmaceutically effective amount of an aminoquinoline compound with an opioid or NSAID as a pharmaceutically acceptable carrier (eg, diluent, complexing agent, additive, excipient, adjuvant, etc.). The pharmaceutical composition contained therein is provided. The aminoquinoline composition may exist, for example, in salt form, microcrystal form, nanocrystal form, nanoparticle form, microparticle form, and / or amorphous form. The carrier may be an organic or inorganic carrier suitable for external, intestinal or parenteral administration. The aminoquinoline compositions of the present invention are, for example, pills, pellets, capsules, liposomes, suppositories, intranasal sprays, solutions, emulsions, suspensions using conventional non-toxic, pharmaceutically acceptable carriers. Agents, aerosols, targeted chemical delivery systems, and any other form well known in the pharmaceutical pharmaceutical field suitable for such use may be formulated. Non-limiting examples of carriers that can be used include water, glucose, lactose, acacia rubber, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and preparations. Other carriers suitable for producing the formulation in solid, semi-solid, liquid or in aerosol form include. In addition, auxiliaries, stabilizers, thickeners and colorants and fragrances may be used.

The pharmaceutical composition comprises at least one aminoquinoline compound described herein as an opioid, NE- or 5HT uptake inhibitor and / or NSAID and pharmaceutically acceptable carrier, vehicle, or physiologically acceptable. Contains in combination with diluents such as aqueous buffers of pH (eg, pH 7-8.5), polymer-based nanoparticle vehicles, liposomes and the like. The pharmaceutical composition may be delivered in any suitable dosage form, eg, a liquid, gel, solid, cream, or paste dosage form. In one embodiment, the composition may be applied to obtain a sustained release of the aminoquinoline compound.

In some embodiments, the pharmaceutical composition is oral, rectal, intranasal, topical, transdermal, intravaginal, parenteral (intramuscular, intraperitoneal). Suitable forms for administration (including subcutaneous and intravenous), spinal cord (epidural, intrathecal), and central (ventricular). The composition may be conveniently provided within separate dosing units, where appropriate. The pharmaceutical composition of the present invention may be prepared by any method well known in the pharmaceutical art. Some preferred modes of administration include intravenous (iv), topical, subcutaneous, oral and spinal cord. For systemic administration, the aminoquinoline compound will generally be administered to the subject in dosages ranging from about 1 milligram (mg / kg) to about 200 mg / kg of aminoquinoline compound per kilogram of body weight. Let's go. Typically, the dosage administered should be sufficient to provide the subject with a concentration of about 100 nanomolar (nM) to about 100 micromolar (mM) of the aminoquinoline compound.

Suitable pharmaceutical compositions for oral administration include capsules, cashiers, or tablets each containing a predetermined amount of one or more aminoquinoline compounds as powder or granules. In another embodiment, the oral composition is a solution, suspension, or emulsion. Alternatively, the aminoquinoline compound containing the analgesic composition may be hypoused as a bolus agent, a licking agent or a paste. Tablets and capsules for oral administration may include conventional excipients such as binders, fillers, lubricants, disintegrants, colorants, flavor additives, preservatives, or wetting agents. Tablets may be coated according to methods well known in the art, if desired. Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Alternatively, the composition may be provided as a dry formulation for pre-use composition in water or another suitable vehicle. Such liquid preparations may include conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (which may include cooking oil), preservatives and the like. Typically, additives, excipients, etc. are in the composition for oral administration in a concentration range well known in the field of pharmaceutical formulations that is suitable for its intended use or function in the composition. ,included.

Preservation in which a pharmaceutical composition for parenteral, spinal, or central administration (eg, by bolus injection or continuous infusion) is added in an ampoule, prefilled syringe, small volume infusion or multidose container, preferably. It may be provided in unit dose form, including the fee. Compositions for parenteral administration may be suspensions, solutions, or emulsions and may include excipients such as suspending agents, stabilizing agents, and dispersants. Typically, additives, excipients, etc. are in the composition for parenteral administration, a concentration range well known in the field of pharmaceutical formulations suitable for its intended use or function in the composition. And included. The aminoquinoline compound is included in the composition within a therapeutically useful and effective concentration range determined by conventional methods well known in the medical and pharmaceutical fields.

The pharmaceutical composition for topical administration to the epidermis (mucosal surface or skin surface) can be formulated as an ointment, cream, lotion, gel, or transdermal patch. Such transdermal patches may contain, for example, penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole. The ointment and cream may contain, for example, an aqueous or oily base to which suitable thickeners, gelling agents, colorants and the like have been added. Lotions and creams include aqueous or oily bases and typically also include one or more of emulsifiers, stabilizers, dispersants, suspending agents, thickeners, colorants and the like. The gel preferably comprises an aqueous carrier base and contains a gelling agent such as a crosslinked polyacrylic acid polymer, a derivatized polysaccharide (eg carboxymethyl cellulose) and the like. Typically, additives, excipients, etc. are in the composition for topical administration, in a concentration range well known in the field of pharmaceutical formulations, suitable for its intended use or function in the composition. , Will be included.

A pharmaceutical composition suitable for transbuccal or sublingual administration is a lozenge containing a pain-relieving agent in a flavor-adding base (eg, sucrose, acacia, or tragacanth); an aminoquinoline compound as an inactive base (eg,). , Gelatin and glycerin or sucrose and acacia); and mouthwash containing the active ingredient in a suitable liquid carrier. Pharmaceutical composition for topical administration The dosage form may include a penetration enhancer, if desired. Typically, additives, excipients, etc. are in the composition for topical oral administration, a concentration range well known in the field of pharmaceutical formulations suitable for its intended use or function in the composition. And included. Analgesics are included in the composition within a therapeutically useful and effective concentration range determined by conventional methods well known in the medical and pharmaceutical fields.

For rectal administration, analgesics are provided in solid or semi-solid (eg, cream or paste) carriers or vehicles. For example, such a rectal composition may be provided as a unit dose suppository. Suitable carriers or vehicles include cocoa butter and other materials commonly used in the art. Typically, additives, excipients, etc. are in the composition for rectal administration, in a concentration range well known in the pharmaceutical pharmaceutical field, suitable for its intended use or function in the composition. , Will be included.

The analgesic compositions of the invention suitable for intravaginal administration are provided as pessaries, tampons, creams, gels, pastes, foams or sprays containing the aminoquinolines of the invention in combination with carriers known in the art. Alternatively, compositions suitable for intravaginal administration may be delivered in liquid or solid dosage form. Typically, additives, excipients, etc. are in the composition for intravaginal administration, a concentration range well known in the field of pharmaceutical formulations suitable for its intended use or function in the composition. And will be included.

Also included in the invention are analgesic compositions suitable for intranasal administration. Such intranasal compositions include, in addition to analgesics, delivery vehicles and liquid sprays, dispersible powders or drops, suitable devices for delivery. The drop can be formulated with an aqueous or non-aqueous base that also contains one or more of a dispersant, a solubilizer, or a suspending agent. Liquid sprays are conveniently delivered from pressure packs, syringes, nebulizers, or other convenient means of delivering aerosols containing aminoquinoline. Pressurized packs include suitable high pressure gases such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases known in the art. Aerosol dosages are of aminoquinoline. It can be controlled by a valve provided to deliver the measured amount, or the pharmaceutical composition for administration by inhalation or infusion is suitable such as a dry powder composition (eg, a painkiller and lactose or starch). Can be provided in the form of a powder mixture with a powder base, such as a powder composition, in which the powder is contained, for example, in a capsule, cartridge, gelatin pack, or blister pack (with the assistance of an inhalant or blowing agent). Can be provided in unit dosage form within (administered from). Typically, additives, excipients, etc. are intended in the composition, in the composition for intranasal administration. It will be included in a concentration range well known in the field of pharmaceutical formulations that is suitable for the application or function.

Methods to relieve chronic pain (eg, neuropathic pain) include opioids and / or NSAIDs and / or 5-HT / in effective amounts of aminoquinoline compounds in patients suffering from one of the above symptoms. Includes administration with a NE uptake inhibitor. Preferably, the analgesic composition is administered parenterally or enterally. Dosing of an effective amount of the aminoquinoline compound may vary depending on the age and symptoms of each individual patient being treated. Suitable dosages of aminoquinoline compounds typically range from about 1 mg / kg to about 200 mg / kg, and aminoquinoline compounds are opioids, NSAIDs and / or 5-HT / NE uptake inhibitors (of these). Can be administered with (in all doses) from one tenth of the recommended dose of a particular compound. Such a dosage form can be administered at least once a day, at least once a week, at least once a month, and the like.

As used herein, the terms "alleviate," "inhibit," "block," "prevent," "alleviating," "relieving," and "antagonists." When referring to a composition, the compound is an onset, severity, of a symptom, event or activity as compared to a symptom, event or activity normally present without the application of a composition containing the compound. Size, volume or related symptoms of at least about 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30 %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 100% reduction. The terms "increase," "increase," "increase," "upward control," "improve," "activate," and "agonist" are not applicable when referring to a compound. Compared to the symptoms, events or activities normally present in, this compound reduces the onset, severity, magnitude, volume or related symptoms of the symptoms, events or activities by at least about 7.5%, 10%. 1,12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60% , 65%, 70%, 75%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000% increase.

The following examples are included to demonstrate certain aspects of the invention. The techniques disclosed in the present examples (representing techniques known to function well in the practice of the present invention) can be considered to constitute preferred embodiments for their practice. , Those skilled in the art should understand. However, one of ordinary skill in the art can make many changes in the particular embodiments disclosed in view of the present disclosure and still obtain similar or similar results without departing from the spirit and scope of the invention. Should be understood. This embodiment is provided for purposes of illustration only and is not intended to be limiting.

Method of augmentation / synergistic confirmation.

The definition of enhancement / synergy in drug effect is relatively simple, but the approach to show synergy is not always fixed. An overview of the methodology by Focquier and Gued (2015) focuses on analytical approaches for measuring the efficacy of drug combinations and provides a brief description of the methods currently used. This method is categorized as an "effect-based strategy" consisting of four approaches: (1) subthreshold combinations; (2) highest single agent approach; (3) chemotactic response and (4) Bliss independence. Model; as well as a "dose-effect based strategy" first described by Loewe (1926) and now called isobologram analysis (Tallalida 2001). Within this "effect-based strategy", all four approaches have been utilized to test for enhanced / synergistic effects using the described drug combinations. All four approaches presented consistent results.

Use of DCUKA to Increase the Efficacy of Opioids / NSAIDs / 5-HT and NE Reuptake Inhibitors The following data indicate that the dose of DCUKA is equivalent to the threshold dose for alleviating chronic pain, but that of chronic inflammatory pain. Administered with low-dose opioids, NSAIDs or norepinephrines and / or compounds that reduce pain by inhibiting synaptic uptake of serotonin (eg, tramadol) in a rat model (Freund adjuvant model) or a rat model of osteoarthritis (MIA). If so, it is shown to increase the efficacy of opioids, NSAIDs and / or serotonin / norepinephrine reuptake inhibitors in alleviating chronic pain. For opioids other than morphine, the "Morphine Equivalent Dose Scale" or "Morphine Milligram Equivalent (MME)" standard is used to ascertain a particular daily dose of morphine and the amount of another analgesic that is effective. obtain. Administration of DCUKA, or DCUK-OEt (acting as a prodrug for DCUKA) with morphine, increases the potency of morphine 4-5 fold. Using MME to calculate the dose of another analgesic given on a daily dose basis (the dose of the analgesic in question and the number of times this dose is administered per day), DCUKA or DCUK for pain treatment The addition of -OEt allows for a reduction in analgesic dose in the same manner as a reduction in morphine dose when morphine is given with DCUKA / DCUK-OEt.

Calculation of the dose of analgesic given when DCUKA or DCUK-OEt is used to enhance the analgesic effect.

The dose of another analgesic when given with DCUKA can be calculated by the following formula:
Opioid Pain Pain Dose = Daily dose of morphine used in similar situations ÷ MME ÷ DCUKA or DCUK-OEt to calculate the dose of oxycodone as a multiple based on the increase in opioid efficacy as a result of the addition. The following information is used: (1) The MME for the opioid of interest (in this case, oxycodone) is 1.5 (Von Korff et al., Clin. J. Pain 24 (6): 521-527 (2008). )); (2) Daily dose of morphine required to treat the level of pain reported by the patient. The use of a rating scale is important in this regard (Schneider et al., 2003). For moderate to severe pain, a single dose of morphine (oral) can vary between 10 and 30 mg, and such doses are taken 6 times daily (ie, 60-180 mg / day). ); (3) Multiples of opioid dose that can be reduced by adding DCUKA to the dosing regimen for pain.

The dose of DCUKA for humans can vary between 150-450 mg given 2-3 times daily. When DCUKA is administered in this way, the dose of opioid used can be reduced by a factor of 4-5 (this multiple is determined based on the data in FIGS. 11 and 12). Pain care specialists must closely monitor the patient to prepare the dosage needed to ease the patient. This can be achieved by increasing the dose of opioid or DCUKA within the recommended range.

Example of actual dose calculation

Oxycodone / day starting dose = (60 mg [morphine day starting dose]) ÷ (1.5 [MME]) ÷ (5 = opioid reduction factor) = 8 mg / day methadone / day starting dose = (60) ÷ (4) ) ÷ (5) = 3 mg / day.
Methadone given to control pain is usually dosed upwards over a 6-week period. The dose reduction given with DCUKA can be dose determined as well.

Similar calculations can be made for other opioids approved for use in humans for the treatment of chronic pain syndrome. It should be apparent to those skilled in the art that there are significant differences between individuals in the amount of perceived pain, and that perceived pain can also vary depending on the cause of the pain and the degree of damage. be. This example is an example in which a method of reducing the dose of opioids in combination with the administration of DCUKA can be considered while maintaining the level of painlessness / antihyperalgesia. If further control of pain is needed, the daily dose of DCUKA and / or opioids may be gradually increased (the increase includes 25-50% of the daily dose of DCUKA or opioids).

For use with DCUKA of NSAIDs, the same principles apply, except that the multiples at which the dose of NSAIDs can be reduced when given with DCUKA are in the range of about 5 to about 6.

Daily dose of diclofenac = (60 mg [daily dose of morphine]) ÷ (0.10) ÷ (6) = 100 mg
For humans inoculated with diclofenac sodium, the recommendation is not to exceed 225 mg / day.

Therefore, based on the finding that DCUKA and its prodrug (DCUK-OEt) can increase the efficacy of opioids and NSAIDs, downward revision of daily doses of opioids and NSAIDs results in reduced side effects while maintaining pain relief. ..

In the absence of published MEE values for NE / 5-HT reuptake inhibitors, we present the effects of tramadol given in conjunction with DCUKA for the treatment of osteoarthritis (FIG. 9). You can use the data you have. Tramadol has been shown to weaken opioids but have a substantial effect as a NE / 5-HT reuptake inhibitor (Barber, 2011). Other NE / 5-HT reuptake inhibitors include duloxetine, venlafaxine, milnacipran and the like. This data shows that the dose of NE / 5-HT reuptake inhibitor can be halved when given to humans with a 2-3 dose / day of 150-450 mg DCUKA.

Example 1. Preparation of compound of formula (VI) Derivatives of kynurenic acid containing a tertiary ureid group, including 5,7-dichloro-4- (3,3-diphenylureido) quinoline-2-carboxylic acid (DCUKA, 7a). , Reactive carbamoyl chloride intermediate (6ab) may be synthesized as previously described (Snell et al., 2000). However, improvements can be achieved in this synthesis due to the simultaneous ester hydrolysis during the final acylation reaction. One compound embodiment, 5,7-dichloro-4- (3,3-dibutylureido) quinoline-2-carboxylic acid (BCUKA, 7b), is synthesized in Scheme 2 as described and illustrated in Synthetic Steps I-. In IV, synthesized via this method (reagents and conditions (I): MeOH, reflux, 16h. (II): Ph ₂ O, 250 ° C., 2h. (III): (a) ClSO ₂ NCO, MeCN, Reflux, 2h. (B) HCl, MeOH, RT, 30min. (IV): NaH, DMF, 0 ° C. to RT, 16h).

Scheme 2.

Synthesis stage I.
3,5-Dichloroaniline (1,5.00 g, 30.9 mmol) and dimethylacetylenedylene carboxylate (2, 3.80 ml, 30.9 mmol) were combined under nitrogen in anhydrous MeOH (60 ml) and Reflux over 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The resulting yellow solid was recrystallized from MeOH (twice) to give a mixture of cis and transisomers of the target dimethylanilinomalate (3) as pale yellow crystals (5.23 g, 17.2 mmol). ). ^{The absorption peak values (ppm) found in the 1} HNMR spectrum carried out in deuterated DMSO are 3.57 & 3.67 (3H, s), 3.72 & 3.80 (3H, s), 5.35 & 5.58. It was (1H, s), 6.98 & 7.12 (2H, _application ), 7.23 & 7.31 (1H, _application ), 9.52 & 9.64 (1H, br, s).

Synthetic stage II.
Dimethylanilinomalate (3,3.50 g, 11.5 mmol) was added little by little to diphenyl ether (70 ml) at 250 ° C. The temperature of the resulting solution was maintained at 250 ° C. for 2 hours, then cooled to room temperature and diluted with hexane (100 ml). The resulting precipitate was removed by filtration, washed with hexane (50 ml) and suspended in reflux ethanol before filtering out soluble impurities. The collected solid was dried under vacuum to give the desired quinolone carboxylate (4) as an off-white solid (3.10 g, 11.4 mmol). ^{The absorption peak values (ppm) found in the 1} HNMR spectrum carried out in deuterated DMSO were 3.96 (3H, s), 6.59 (1H, s), 7.42 (1H, s), It was 7.97 (1H, s) and 12.05 (1H, br). This process can be adapted to move against high temperatures in the presence of diphenyl ether using a continuous flow device (Cao, 2017).

Synthetic step III.
Chlorosulfonyl isocyanate (1.20 ml, 13.8 mmol) was added to the slurry in anhydrous MeCN (35 ml) of quinoline carboxylate (4, 2.50 g, 9.19 mmol) at room temperature. The mixture was refluxed for 1.5 hours, at which point heating was stopped and a solution of 1.0 M in anhydrous MeOH (20 ml) of HCl was added. The reaction mixture was cooled to room temperature after 1 hour with stirring until a precipitate formed. The precipitate was filtered out, washed with MeCN and air dried. The filter cake was suspended in water (50 ml) and a saturated sodium carbonate solution (about 5 ml) was added to the suspension up to pH 10 to increase the viscosity of the suspending agent. The resulting solid was collected by filtration, washed with cold water and dried under vacuum (40 ° C.) to give the target aminoquinoline (5) as an off-white solid (1.82 g, 6.71 mmol). .. ^{The absorption peak values (ppm) found in the 1} HNMR spectrum carried out in deuterated DMSO were p4.05 (3H, s), 6.04 (2H, s), 7.33 (1H, s), and. It was 7.47 (1H, d, J = 1.9Hz) and 8.10 (1H, d, J = 1.9Hz).

Synthetic stage IV.
Acylation of aminoquinoline (5) and simultaneous ester hydrolysis to yield 5,7-dichloro-4- (3,3-dibutylureido) quinoline-2-carboxylic acid (BCUKA, 7b) was carried out as follows. N, N-dibutylcarbamoyl chloride (6b, 96 mg, 0.50 mmol) and aminoquinoline (5,113 mg, 0.42 mmol) were dissolved in anhydrous DMF (2 ml) and cooled to 0 ° C. Sodium hydride dispersion in mineral oil (60%, 35 mg, 0.83 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours. The reaction _{was quenched by addition to saturated NH 4} Cl solution (1 ml) and then adjusted to pH 3 with 1.0 M HCl aqueous solution. Extraction with EtOAc (2x10 ml) followed by washing and drying with saturated brine (5 ml) (Na ₂ SO ₄ ) gave the crude product as a pale yellow oil. 5,7-Dichloro-4- (3,3-dibutylureido) quinoline-2-carboxylic acid (DBCUKA, 7b), pale yellow solid, by compound purification via silica gel chromatography (9: 1 DCM: MeOH). Obtained as (82 mg, 0.20 mmol). The ^{absorption peak values (ppm) found in the 1} HNMR spectrum carried out in _{CDCl 3} were 1.00 (6H, t, J = 7.4Hz), 1.36-1.45 (4H, m), 1. .64-1.72 (4H, m), 3.39-3.45 (4H, m), 5.17 (1H, s), 7.69 (1H, s), 8.30 (1H, s) ), 9.16 (1H, s).

Carbamoyl chloride is limited in its market availability and is also characterized by a particularly high reactivity (especially to hydrolysis) and subsequent low stability. This is especially apparent in the case of mono-n-substituted carbamoyl chlorides. Therefore, it was beneficial to utilize an alternative reduced reactivity carbamoyl cation equivalent to prepare a mono-n-substituted analog of kynurenic acid. Carbamoylimidazole (eg, 9a-d) has been shown to be a suitable reactive species for the synthesis of various functional groups including urea, thiourea, carbamate, thiocarbamate and amides (eg, 9a-d). Grzyb et al., 2005). Derivatives of kynurenic acid, including secondary ureido groups, were prepared using this approach in the synthetic steps V-VII described and illustrated in Scheme 3 (reagents and conditions: (V): CDI, DCM, 0 ° C.). ~ RT, 16h. (VI): 5,NaH, DMF, 0 ° C. ~ RT, 16h. (VII) TFA, DCM, RT, 16h.).

Scheme 3.

A general example of synthesis stage V.
N-Butylamine (8a, 100 μl, 74 mg, 1.01 mmol) in DCM (1 ml) is added to a solution of CDI (0.197 g, 1.21 mmol) in DCM (5 ml) at 0 ° C., followed by the reaction mixture. Was warmed to RT and mixed overnight. The solution is diluted with DCM (10 ml), washed with water (2x10 ml) and brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness to make the target carbamoylimidazole (9a) colorless. Obtained as oil (115 mg, 0.69 mmol). The ^{absorption peak values (ppm) found in the 1} HNMR spectrum carried out in _{CDCl 3} were 0.97 (3H, t, J = 7.4Hz), 1.42 (2H, qt, J = 7.6). 7.3Hz), 1.63 (2H, tt, J = 7.3, 7.0Hz), 3.44 (2H, dt, J = 7.0, 6.7Hz), 6.75 (1H, br) ), 7.07 (1H, s), 7.42 (1H, s), 8.17 (1H, s).

N- (3- (Dimethylamino) propyl) -1H-imidazole-1-carboxamide (9b) was prepared from 3-dimethylaminopropylamine (8b) as described in Synthetic Step V. The ^{absorption peak values (ppm) found in the 1} HNMR spectrum carried out in _{CDCl 3} were 1.77 (2H, tt, J = 5.7, 5.5Hz), 2.32 (6H, s), 2. .56 (2H, t, J = 5.5Hz), 3.54 (2H, dt, J = 5.9, 5.5Hz), 7.07 (1H, s), 7.27 (1H, s) , 8.04 (1H, s), 9.34 (1H, br).

tert-Butyl (3- (1H-imidazol-1-carboxamide) propyl) carbamate (9c) was prepared from tert-butyl (3-aminopropyl) carbamate (8c) as described in step V of synthesis. The ^{absorption peak values (ppm) found in the 1} HNMR spectrum carried out in _{CDCl 3} were 1.49 (9H, s), 1.73 (2H, tt, J = 5.8, 5.7Hz), 3. .30 (2H, dt, J = 6.4,5.7Hz), 3.48 (2H, dt, J = 6.0,5.8Hz), 4.91 (1H, br), 7.11 ( It was 1H, s), 7.52 (1H, s), 7.92 (1H, br), and 8.25 (1H, s).

Synthesis of tert-butyl (3- (1H-imidazol-1-carboxamide) propyl) (methyl) carbamate (9d) from N- (3-aminopropyl) -N-methylcarbamic acid tert-butyl ester (8d). Prepared as described in V. The ^{absorption peak values (ppm) found in the 1} HNMR spectrum carried out in _{CDCl 3} were 1.49 (9H, s), 1.74-1.80 (2H, br), 2.87 (3H, s). ), 3.35-3.43 (4H, m), 7.09 (1H, s), 7.53 (1H, s), 8.11 (1H, br), 8.25 (1H, s) Met.

A general example of synthetic stage VI.
The use of carbamoylimidazoles (9a-d) in a manner similar to carbamoyl chloride in Synthetic Step IV may allow one step involving acylation of aminoquinoline (5) and simultaneous ester hydrolysis. This approach is used for the synthesis of 4- (3-butylureido) -5,7-dichloroquinoline-2-carboxylic acid (10a) as follows; N-butyl-1H-imidazole-1 -Carboxamide (9a, 125 mg, 0.95 mmol) and aminoquinoline (5, 215 mg, 0.79 mmol) were dissolved in anhydrous DMF (4 ml) and cooled to 0 ° C. Sodium hydroxide dispersion (60%, 63 mg, 1.58 mmol) in mineral oil was added and the mixture was warmed to room temperature and stirred for 16 hours. The reaction was _{quenched via the addition of saturated NH 4} Cl solution (3 ml) and then adjusted to pH 3 with 1.0 M aqueous HCl solution. After extraction with EtOAc (2x20 ml), washed with saturated brine (10 ml) and dried (Na ₂ SO ₄ ) to give the crude product as a pale orange residue. 4- (3-Butylureido) -5,7-dichloroquinoline-2-carboxylic acid (10a) was added by compound purification via reverse phase (C18) silica gel chromatography (1: 1 H _{2 O: MeCN).} Obtained as a beige solid (142 mg, 0.39 mmol). ^{Absorption peak values (ppm) found in 1} HNMR spectrum performed in deuterated DMSO were 0.92 (3H, t, J = 7.3Hz), 1.31-1.38 (2H, m). ), 1.44-1.52 (2H, m), 3.16 (2H, dt, J = 6.6, 6.0Hz), 7.47 (1H, br), 7.87 (1H, d). , J = 2.2Hz), 8.11 (1H, d, J = 2.2Hz), 8.68 (1H, s), 9.12 (1H, br).

5,7-Dichloro-4- (3- (3- (dimethylamino) propyl) ureido) quinoline-2-carboxylic acid (10b), N- (3- (dimethylamino) propyl) -1H-imidazole-1 -Prepared from carboxamide (9b) as described in Synthetic Step VI. Due to the zwitterionic nature of the target compound, acidification to pH 1/2 was performed by TFA followed by reverse phase (C18) chromatography to give the product in TFA salt form. D ₂ O absorption peak value found in the ¹ HNMR spectrum was carried out in (ppm) are, 1.87-2.00 (2H, m), 2.87 (6H, s), 3.12-3. It was 20 (2H, m), 3.21-3-31 (2H, m), 7.13 (1H, s), 7.48 (1H, s), 8.06 (1H, s). D ₂ O ¹⁹ FNMR absorption peak value found in the spectrum was carried out in (ppm) was -75.6.

4- (3- (3-((tert-butoxycarbonyl) amino) propyl) ureido) -5,7-dichloroquinoline-2-carboxylic acid (10c), tert-butyl (3- (1H-imidazole-1) -Carboxamide) Propyl) Carbamate (9c) was prepared as described in Synthetic Step VI. ^{Absorption peak values (ppm) found in 1} HNMR spectrum carried out in deuterated DMSO were 1.39 (9H, s), 1.60 (2H, tt, J = 6.8, 6.6Hz). , 2.95-3.02 (2H, m), 3.12-3.18 (2H, m), 6.83 (1H, br), 7.45 (1H, br), 7.85 (1H) , S), 8.10 (1H, s), 8.65 (1H, s), 9.15 (1H, br).

4- (3- (3-((tert-butoxycarbonyl) (methyl) amino) propyl) ureido) -5,7-dichloroquinoline-2-carboxylic acid (10e), tert-butyl (3- (1H-) It was prepared from imidazole-1-carboxamide) propyl) methylcarbamate (9d) as described in Synthetic Step VI. ^{The absorption peak values (ppm) found in 1} HNMR spectrum performed in deuterated DMSO were 1.39 (9H, s), 1.63-1.71 (2H, m), 2.79 (3H). , S), 3.08-3.16 (2H, m), 3.19-3.26 (2H, m), 7.27 (1H, br), 7.68 (1H, d, J = 1) It was 0.8 Hz), 8.29 (1H, d, J = 1.8 Hz), 8.40 (1H, br), and 8.97 (1H, br).

General example of synthetic stage VII.
TFA (173 μL, 2.25 mmol) was added to a solution of Boc-protected amine (10c, 103 mg, 0.23 mmol) in DCM (4 ml). After stirring for 16 hours at room temperature, the solvent was removed under reduced pressure and the residue was purified by reverse phase chromatography purified directly by _{(C18,1:: 1 H 2 O} MeCN), 4- (3- (3- Amino The TFA salt form of propyl) ureido) -5,7-dichloroquinoline-2-carboxylic acid (10d) was obtained as a white solid (64 mg, 0.14 mmol). D ₂ O (1.0% TFA) the absorption peak value found in the ¹ HNMR spectrum was performed in (ppm) is, 1.61 (2H, tt, J = 6.9,7.1Hz), 2. 72 (2H, t, J = 7.1Hz), 3.04 (2H, t, J = 6.9Hz), 7.62 (1H, s), 7.89 (1H, s), 8.71 ( It was 1H, s).

5,7-Dichloro-4- (3- (3- (methylamino) propyl) ureido) quinoline-2-carboxylic acid (10f), 4- (3- (3-((tert-butoxycarbonyl)) (methyl) ) Amino) propyl) ureido) -5,7-dichloroquinoline-2-carboxylic acid (10e) prepared as described in Synthetic Step VI. D ₂ O (1.0% TFA) the absorption peak value found in the ¹ HNMR spectrum was performed in (ppm) is, 1.81 (2H, tt, J = 6.8,7.7Hz), 2. 55 (3H, s), 2.94 (2H, t, J = 7.8Hz), 3.22 (2H, t, J = 6.8Hz), 7.78 (1H, d, J = 1.9Hz) ), 8.01 (1H, d, J = 1.9Hz), 8.77 (1H, s). D ₂ O ¹⁹ FNMR absorption peak value found in the spectrum was carried out in (ppm) was -73.4. The compound structure is shown in Scheme 4.

Scheme 4.

Synthesis of 3- (2-butylyl-5,7-dichloroquinoline-4-yl) -1,1-diphenylurea

A. 5,7-Dichloro-4- (3,3-diphenylureido) -N-methoxy-N-methylquinoline-2-carboxamide (11)
Carbonyldiimidazole (72 mg, 0.44 mmol) and diisoproylethylamine (115 uL, 0.66 mmol) were added to 5,7-dichloro-4- (3,3-diphenylureido) quinoline-2-carboxylic acid (3,3-diphenylureido). DCUKA; 100 mg, 0.22 mmol) was added to a solution in dry N, N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, after which N, O-dimethylhydroxylamine hydrochloride (86 mg, 0.88 mmol) was added. The resulting pale yellow solution was stirred at room temperature for an additional 16 hours, at which point the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and saturated sodium hydrogen carbonate solution (2x15 mL) and It was washed with 0.1 MHCl (2x15 mL) and then with water (15 mL) and brine (10 mL). The organic phase was dried (MgSO _4), and evaporated to dryness. The target compound was purified by chromatography on silica (1: 1 hexane: EtOAc) to give it as a white solid (81 mg, 0.16 mmol, 73%). Rf 0.33 (1: 1 hexane: EtOAc); p. 207-210 ° C; 1H NMR (400MHz, CDCl ₃ ) 3.40 (3H, s), 3.75 (3H, br), 7.28 (1H, s), 7.34-7.37 (2H,) m), 7.41-7.49 (8H, m), 8.03 (1H, d, J = 2.0Hz), 8.87 (1H, s), 9.39 (1H, s).

B. 3- (2-Butylyl-5,7-dichloroquinoline-4-yl) -1,1-diphenylurea (12)
A solution of n-propylmagnesium chloride (1.0 M, 1.12 mL, 1.12 mmol) in 2-methyltetrahydrofuran was added to 5,7-dichloro-4- (3,3-diphenylureido) -N-methoxy-N-. Methylquinoline-2-carboxamide (11, 70 mg, 0.14 mmol) was added dropwise to a solution in dry tetrahydrofuran (10 mL) at −10 ° C. under nitrogen. After the addition, the reaction mixture was stirred at −10 ° C. for 30 minutes, then warmed to room temperature and further stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL) and the product ketone 12 was extracted with ethyl acetate (3x15 mL). The organic extract was washed with brine (10 mL), dried (silyl ₄ ) and evaporated to dryness. The residue was purified via chromatography on silica (4: 1 hexane: EtOAc) to give the target compound as a pale yellow solid (32 mg, 0.07 mmol, 47%). Rf0.45 (4: 1 hexane: EtOAc); p. 161-164 ° C; 1H NMR (400MHz, CDCl ₃ ) 1.03 (3H, t, J = 7.4Hz), 1.80 (2H, qt, J = 7.3, 7.4Hz), 3.24 (2H, t, J = 7.3Hz), 7.28 (1H, s), 7.34-7.38 (2H, m), 7.42-7.49 (8H, m), 8.09 (1H, d, J = 2.1Hz), 9.15 (1H, s), 9.31 (1H, s).

Synthesis of 5,7-dichloro-4- (3,3-diphenylureido) -N-ethylquinoline-2-carboxamide (13)

Carbonyldiimidazole (143 mg, 0.88 mmol) and diisopropylethylamine (230 uL, 1.32 mmol) with 5,7-dichloro-4- (3,3-diphenylureido) quinoline-2-carboxylic acid (DCUKA; 200 mg (0.44 mmol) was added to a solution in dry N, N-dimethylformamide (25 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, after which ethylamine (2.0 M, 0.66 mL, 1.32 mmol) was added in THF. The resulting pale yellow solution was stirred at room temperature for an additional 16 hours, at which point the reaction was complete. The solvent is removed under reduced pressure, the residue is dissolved in ethyl acetate (50 mL) and with saturated sodium hydrogen carbonate solution (2x30 mL) and 0.1 M HCl (2x30 mL), then with water (25 mL) and brine (25 mL). Washed. The organic phase was dried (MgSO _4), and evaporated to dryness. Target ethylamide 13 was passed through silica gel chromatography (1: 1 hexane: EtOAc) to give an off-white solid (148 mg, 0.31 mmol, 71%). Rf0.43 (1: 1 hexane: EtOAc); M. p. 202-205 ° C; 1H NMR (400MHz, CDCl ₃ ) 1.31 (3H, t, J = 7.2Hz), 3.56 (2H, q, J = 7.2Hz), 7.28 (1H, s) ), 7.32-7.37 (2H, m), 7.41-7.49 (8H, m), 7.99 (1H, s), 8.01 (1H, br), 9.28 ( 1H, s), 9.32 (1H, s).

Synthesis of 5,7-dichloro-4- (3,3-diphenylureido) -N-isopropylquinoline-2-carboxamide (14)

カルボニルジイミダゾール（１４６ｍｇ、０．８８ｍｍｏｌ）及びジイソプロピルエチルアミン（ｄｉｉｓｏｐｒｏｙｌｅｔｈｙｌａｍｉｎｅ）（２３０ｕＬ、１．３２ｍｍｏｌ）を、５，７−ジクロロ−４−（３，３−ジフェニルウレイド）キノリン−２−カルボン酸（ＤＣＵＫＡ；２００ｍｇ、０．４４ｍｍｏｌ）の乾燥Ｎ，Ｎ−ジメチルホルムアミド中溶液（２５ｍＬ）に加えた。反応混合物を、室温で、窒素下で２時間にわたって撹拌し、その後、イソプロピルアミン（１１０μＬ、１．３２ｍｍｏｌ）を加えた。得られた淡黄色溶液を、室温でさらに１６時間撹拌し、この時点で溶媒を減圧下で除去して、残渣を酢酸エチル（５０ｍＬ）中に溶解し、飽和炭酸水素ナトリウム溶液（２ｘ３０ｍＬ）及び０．１Ｍ ＨＣｌ（２ｘ３０ｍＬ）で、その後水（２５ｍＬ）及びブライン（２５ｍＬ）で洗浄した。有機相を、乾燥させ（ＭｇＳＯ_４）、乾燥するまで蒸発させた。標的イソプロピルアミド１４を、シリカゲルクロマトグラフィー（１：１ ヘキサン：ＥｔＯＡｃ）を介して、白色固体を得た（１８２ｍｇ、０．３７ｍｍｏｌ、８４％）。Ｒｆ０．５２（１：１ ヘキサン：ＥｔＯＡｃ）；Ｍ．ｐ．１９７−１９９℃；１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ−ｄ６）１．２３（６Ｈ、ｄ、Ｊ＝６．８Ｈｚ）、４．１５（１Ｈ、ｍ）、７．３４−７．３９（２Ｈ、ｍ）、７．４６−７．５５（８Ｈ、ｍ）、７．７６（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）、８．１１（１Ｈ、ｄ、Ｊ＝１．９Ｈｚ）、８．５５（１Ｈ、ｄ、Ｊ＝８．２Ｈｚ）、９．００（１Ｈ、ｓ）、９．２１（１Ｈ、ｓ）。

Carbonyldiimidazole (146 mg, 0.88 mmol) and diisopropylethylamine (230 uL, 1.32 mmol) with 5,7-dichloro-4- (3,3-diphenylureido) quinoline-2-carboxylic acid (DCUKA; 200 mg (0.44 mmol) was added to a solution in dry N, N-dimethylformamide (25 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours, after which isopropylamine (110 μL, 1.32 mmol) was added. The resulting pale yellow solution was stirred at room temperature for an additional 16 hours, at which point the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL), saturated sodium hydrogen carbonate solution (2x30 mL) and 0. .. Washed with 1M HCl (2x30 mL) and then with water (25 mL) and brine (25 mL). The organic phase was dried (ו ₄ ) and evaporated to dryness. Target isopropylamide 14 was passed through silica gel chromatography (1: 1 hexane: EtOAc) to give a white solid (182 mg, 0.37 mmol, 84%). Rf0.52 (1: 1 hexane: EtOAc); M. p. 197-199 ° C; 1H NMR (400MHz, DMSO-d6) 1.23 (6H, d, J = 6.8Hz), 4.15 (1H, m), 7.34-7.39 (2H, m) , 7.46-7.55 (8H, m), 7.76 (1H, d, J = 1.9Hz), 8.11 (1H, d, J = 1.9Hz), 8.55 (1H, d, J = 8.2 Hz), 9.00 (1H, s), 9.21 (1H, s).

Example 2. Use of DCUK-OEt as an in vivo prodrug for DCUKA This example shows that after oral administration of DCUK-OEt to rats, ester hydrolysis results in the rapid formation of DCUKA in vivo. This study was performed according to NIH Guide for the Care and Use of Laboratory Animals. A spray-dried dispersant of DCUK-OEt was prepared by Catalent Pharma using the polymer HPMCAS-MG (HPMCAS-MG SDD). This SDD contained 15 mg of DCUK-OEt and 85 mg of polymer per 100 mg of SDD. A preparation of 0.5% hydroxypropylmethylcellulose (HPMC) was prepared by heating 100 ml of water to 60-75 ° C. Another aliquot of 100 ml of water was cooled to 5 ° C. 500 mg of HPMC was added to 50 ml of hot water with stirring, followed by 50 ml of cold water. Stirring was continued until a clear liquid was formed. To make a suspension of SDD, 15 ml of an aliquot of 0.5% HPMC was added to a vial containing 1 g of SDD. The mixture was ground until a uniform slurry containing 10 mg / ml DCUK-OEt was formed. Four rats per group were fed 50 mg / kg or 100 mg / kg DCUK-OEt in this suspension by oral tube feeding. Blood samples were collected from the carotid artery at 0 minutes before dosing, 30 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes after dosing, and in vitro DCUK-OEt hydrolysis to DCUKA by enzymes present in rat blood. Placed in NaF-containing tubes to minimize degradation.

Levels of DCUK-OEt and DCUKA in whole blood samples were measured by evaluation by LC-MS / MS method. Internal standards DCUKA-d10 and DCUKA-OEt-d10 were synthetically prepared (Wempe laboratory, UC Denver School of Pharmacy, Med. Chem. Core Facility). Stock 10.0 mM DMSO solutions of DCUKA, DCUKA-OEt, DCUKA-d10 and DCUKA-OEt-d10 were prepared for standard curves and internal standards, and standard materials and samples were prepared at 4: 1 (methanol: acetonitrile, 1). Diluted to 1): The used water (10 mM NH4OAc, 0.1% formic acid) solution was flowed directly into the mass spectrometer.

Applied Biosystems with Shimadzu HPLC (Shimadzu Scientific Instruments, Inc .; Columbia, MD) and Leap Autosampler (LEAP Technologies; Carrboro, NC). For liquid chromatography, Agilent Technologies with column guards, Zorbax extended-C18 250x4.6 mm, 5 columns were used at 40 ° C. at a flow rate of 0.6 mL / min. The mobile phase consisted of A: 10 mM (NH4OAc), 0.1% formic acid in H2O, and B: 50:50 ACN: MeOH. The chromatographic method used was as follows: 95% A for 2.0 minutes; tilt to 95% B for 7.0 and 9.0 minutes, and finally back to 95% A. Maintained at 18.0 and 2.0 minutes (20.0 minutes for all runtimes). The compounds were monitored via an electrospray ionization ion mode (ESI +) using the following conditions: i) ion spray voltage of 5500 V; ii) temperature, 450 ^o C; iii) curtain gas (CUR; set to 10). And collision-activated decomposition (CAD; set to 12) gas is nitrogen; iv) ion degassing 1 (GS1) and 2 (GS2); v) inlet potential set to 10V; vi) quadruple 1 (Q1) And quadruple 3 (Q3) set to unit derivation; vii) residence time set to 200 msec; and viii) declustering potential (DP), collision energy (CE), and collision cell exit potential (CXP). The voltage (V). Samples (10 μL) were analyzed by LC / MS-MS using the following fragmentation for quantification: DCUKA, 452 → 168 m / z, t _R = 5.3 min; DCUKA-OEt: 480 → 168 m. / Z, t _R = 5.6 minutes; internal standard DCUKA-d10: 462 → 178m / z; and internal standard DCUKA-OEt-d10: 490 → 178m / z.

FIG. 1 illustrates that DCUK-OEt can contribute as a prodrug for DCUKA after in vivo administration. Data are plotted as mean ± SD values from 3-4 rats per group (not including data from one outlier after 60 minutes of 100 mg / kg dose). DCUK-OEt of 50 mg / kg or 100 mg / kg, which is a spray-dried dispersion prepared using the polymer HPMCAS-MG, was administered to 4 rats per group by tube feeding as an HPMC suspension. Blood was obtained from the carotid artery at the indicated time and DCUKA levels were determined by LC-MS / MS analysis. The results show the blood level of DCUKA obtained after administration of DCUK-OEt. DCUK-OEt was detectable only after the 100 mg / kg dose. The highest levels of DCUK-OEt were 0.49 μM and 0.24 μM 60 minutes after DCUK-OEt administration and 0.08 μM 90 minutes after DCUK-OEt administration. The level of DCUK-OEt was below the detection level in the 4th rat in the group. In contrast, as shown in FIG. 1, DCUKA levels reached approximately 3 μM after 50 mg / kg of DCUK-OEt and 100 mg / kg of CUK-OEt.

Example 3. Treatment of neuropathy pain with DCUKA, BCUKA and DCUK-OEt This example demonstrates the ability of DCUKA, BCUKA and DCUK-OEt to reverse neuropathy pain (cisplatin (cancer chemotherapeutic), complete Freund's adjuvant). (CFA) (measured as organic or febrile pain induced by diabetes (streptzotocin-induced pain) or monoiodoacetate (MIA) (osteoarthritis pain)).

All studies were performed according to the NIH Guide for the Care and Use of Laboratory Animals.

Drug. For in vivo studies of cisplatin, CFA and STZ-induced pain, DCUKA or BCUKA or DCUK-OEt, or gabapentin was prepared in 50% gelatin / 50% canola oil emulsion (using this emulsion as a vehicle). Gelatin was prepared by adding 0.8 g of gelatin Knox (Kraft FoodsNorth America, Tarrytown NY) and 0.06 g of tartrate acid (McCormick and Co., Inc., Hunt Valley, MD) to 30 ml of purified water. The solution was heated at 98 ° C. for 20 minutes and then cooled to 50 ° C. 6 ml of 95% alcohol and water were added to make 50 ml of gelatin. Various amounts of DCUKA or BCUKA or DCUK-OEt, or gabapentin were added to 5 ml of canola oil (Safeway Inc., Pleasanton, CA), stirred and sonicated for 5 minutes (VWR BIOSONIK IV, 70%). Then, the drug suspending agent was added to 5 ml of gelatin, stirred and sonicated. The emulsion was diluted with vehicle as desired and warmed to 37 ° C for oral administration to animals. Immediately prior to oral tube feeding, the emulsion was stirred using a vortex mixer.

For in vivo studies of MIA-induced pain, DCUKA was combined with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS 1000). DCUK-OEt (2.5 g) was weighed and placed in a clean glass beaker and TPGS 1000 (47.5. ml) was added slowly. The mixture was mixed over 2-3 minutes to make a creamy white aqueous suspension. The suspension was encapsulated in Torpac capsules (Torpac, Fairfield, NJ) and delivered orally to rats using a Torpac capsule syringe (Wempe et al., 2012).

Neuropathic pain was caused using four different agents. Cisplatin (Sigma-Aldrich, St. Louis, MO) was dissolved in a 0.9% aqueous saline solution. Streptozotocin (Sigma-Aldrich) was dissolved in 20 mM sodium citrate buffer, pH = 4.5. A complete Freund's adjuvant (CFA) was obtained from Sigma-Aldrich. Sodium monoiodoacetate was obtained from Sigma-Aldrich and dissolved in physiological saline.

Measurement of organic hyperalgesia. These studies were performed on male Sprague-Dawley rats (Taconic, Germantown PA or Harlan, Indianapolis IN) approximately 8 weeks old. Rats were placed in an AAALAC-quality certified facility with controlled lighting, temperature and humidity. Pain was tested using an electronic von Frey anesthesia monitor (IITC Life Science, Woodland Hills, CA). Rats were placed in a hanging chamber with a metal mesh floor and acclimatized for approximately 20 minutes. Organic stimuli were applied to the central surface of the sole of the hind foot. Two different methods were used. In the first, a series of von Frey filaments with different intensity ranges (g) were used to increase the intensity of the filament applied to the foot, and the application of the force generated to each filament was displayed by an electrical sensor. Each filament was applied 5 times until a withdrawal reaction (“flinch” after application of the filament) occurred on the foot. The test was discontinued if the filament caused foot withdrawal in 4 of the 5 tests or if maximum irritation (10% of body weight) was reached. The foot withdrawal threshold was calculated in g using the average of the four values. In the second method, a semi-flexible filament was placed against the central surface of the sole of the foot and the pressure was increased until foot detachment was observed. The pressure (force of g) (foot withdrawal threshold) at foot withdrawal was recorded by an electric transducer. Five measurements were made per test and the average value was calculated. In both methods, a sensation of 3 minutes was left between measurements to avoid sensitization.

Acute effects of DCUKA, BCUKA, DCUK-OEt and gabapentin on reversing neuropathic pain (organic hyperalgesia) caused by cisplatin, complete Freund's adjuvant (CFA), streptozotocin (STZ) or monoiodoacetate (MIA). Acute effect of DCUKA on cisplatin-induced pain: Two methods were used for cisplatin administration. 1) Cisplatin was dissolved in 0.9% physiological saline (1 mg / ml) and injected intravenously into the tail vein at a volume of 1.5 or 2.5 ml / kg of body weight. After intravenous injection of cisplatin, the same amount of saline was injected (Joseph and Levine, 2009). The cisplatin dose was 1.5 or 2.5 mg / kg in each experiment. 2) Cisplatin was dissolved in 0.9% physiological saline and injected intraperitoneally on the 1st, 4th, 8th and 12th days. The cisplatin doses were 2 mg / kg, 1 mg / kg, 2 mg / kg and 2 mg / kg, respectively, and the total dose was 7 mg / kg. A fresh solution of cisplatin was prepared daily prior to injection and 0.9% saline (2 ml) was injected subcutaneously after cisplatin injection (to avoid nephrotoxicity). In all experiments, rats were tested for baseline pain sensitivity (organic pain threshold) prior to any cisplatin treatment. The experimental design using intravenous injection was as follows: (1) Starting 1 hour after cisplatin injection, rats were orally (canola oil / gelatin) orally (by intragastric tube feeding), 3 It was given twice daily (every 12 hours) daily over a day (these rats are controls for the study of prevention of cisplatin-induced pain; see below). On day 4, rats were again tested for organic pain threshold. On day 5, rats were given 50 mg / kg DCUKA or vehicle and the organic pain threshold was tested 1 hour later. 2) Four days after cisplatin treatment, rats were given various doses of DCUKA (12.5, 25, 50, or 75 mg / kg) or vehicle by intragastric tube feeding to set an organic pain threshold of 1. Tested after hours. 3) Six days after cisplatin treatment, the organic pain threshold was measured and rats were given 50 mg / kg DCUKA or vehicle orally. The organic pain threshold was tested after 1 hour. 4) Six days after cisplatin treatment, rats were given various doses of DCUKA (25, 50 or 75 mg / kg) or vehicles, and 1 hour later, the organic pain threshold was measured. The experimental design for an experiment in which cisplatin was administered intraperitoneally was as follows: 14 days after cisplatin treatment (1st, 4th, 8th, 12th), the organic pain threshold was tested. Rats were then given 50 mg / kg DCUKA or vehicle orally and the organic pain threshold was measured after 1 hour. The data were reported as the ratio of the organic pain threshold measured after DCUKA treatment to the baseline cisplatin pre-organic pain threshold (measured on the same foot).

Data analysis for cisplatin experiments: Acute effects and meta-analysis of DCUKA:
Depending on the experimental design, it consists of either a one-way ANOVA with repeated measurements or a two-way ANOVA with repeated measurements (Proc Mixed, SAS v9.3, Cary, NC). Treatment and time were the main fixed independent effects tested. In one experimental process, the time and interaction between the two was evaluated. The animal identification number was used as a repeated measurement for one animal, as multiple measurements were taken before and after treatment and including the right and left feet. All models were tested for equal variance between treatment groups (Barlett's test for variance uniformity) and normality (Kolmogorov-Smirnov goodness-of-fit test). If the data did not meet these assumptions, we therefore adjusted in a mixed model. Some analyzes used Fisher's LSD post-test to compare the statistical significance between different treatment doses (p-value <0.05), and all analyzes were treatment group and baseline values. Fisher's LSD post-test was used to compare the statistical significance between and.

Experiments were included in the meta-analysis if the following requirements were met: 1. Organic pain was measured using the von Frey test. Cisplatin treatment successfully elicited pain (25% reduction in organic pain threshold) and 3. Organic pain was measured within 90 minutes after DCUKA administration. A mixed model using the DCUKA dose as a fixed independent variable with 5 different class levels, study identification as both random and repeat measurements, and rat identification as a randomized effect, overall for neuropathic pain. Used to determine efficacy (Proc Mixed, SAS v9.3, Cory, NC). The Fisher's LSD post-test was used for comparison of DCUKA doses.

Comparison of the effects of DCUKA, BCUKA and gabapentin on cisplatin-induced pain. Cisplatin intraperitoneally on day 1 (2 mg / kg), day 4 (1 mg / kg), day 8 (2 mg / kg) and day 12 (2 mg / kg) (total dose 7 mg / kg) It was administered. Cisplatin was prepared daily and 2 ml of 0.9% saline was subcutaneously administered after each cisplatin injection. On day 14, the organic pain threshold was measured and equimolar doses to vehicle (canola oil / gelatin), DCUKA (50 mg / kg), BCUKA (50 mg / kg) or gabapentin (30 mg / kg, DCUKA and BCUKA). ) Was given to the rat. After 1 and 2 hours, the organic pain threshold was tested again. Data are reported as the ratio of the organic pain threshold measured after DCUKA, BCUKA or gabapentin treatment to the baseline organic pain threshold (measured on the same foot). The statistical analysis was a two-way ANOVA for repeated measurements (Proc Mixed, SAS v9.3). Treatment and time were the main fixed independent effects and interactions were also tested. Animal identification numbers were used for repeated measurements. The Fisher's LSD post-test was used to compare the significance (p <0.05) between different times within the treatment group.

Acute effect of DCUKA on complete Freund's adjuvant (CFA) -induced neuropathic pain. After measuring the baseline foot withdrawal threshold, CFA (0.1 ml) was subcutaneously administered under light to the central surface of the sole of the left hind foot (5% for induction and 2 for maintenance). %). Rats were caged for 48 hours. Paper beds were used to avoid pressure neuropathy caused by hard beds. At 48 or 60 hours after CFA injection, rats were given a vehicle (canola oil / gelatin) orally by intragastric tube feeding or various doses of DCUKA to set the organic pain threshold. Determined after 1 hour. Data are expressed as the ratio of organic pain threshold to baseline organic pain threshold measured after DCUKA treatment.

Data analysis of CFA experiments. Meta-analysis of acute effects of 50 mg / kg DCUKA and DCUKA dose response. Each experiment was analyzed by one-way ANOVA (Proc Glm or Proc Mixed, SAS v9.3, Cary, NC). The treatment group was the fixed independent effect tested. All models were tested for equal variance between treatment groups (Barlett's test for variance uniformity) and normality (Kolmogorov-Smirnov goodness-of-fit test). If the data did not meet these assumptions, a mixed model was used. All analyzes used the Fisher's LSD post-test to compare the statistical significance between different treatment groups (p-value <0.05).

Comparison of the effects of DCUKA and BCUKA on CFA-induced neuropathic pain. The baseline organic pain threshold was determined and the animals were treated with CFA as described above. Forty-eight hours after aCFA treatment, rats were fed vehicle (canola oil / gelatin) (n = 17), 50 mg / kg DCUKA (n = 17) or 50 mg / kg BCUKA (n = 6). The organic pain threshold is tested after 1 hour and the data are reported as the ratio of the baseline pain threshold measured on the same foot to the pain threshold after vehicle, DCUKA or BCUKA treatment. One-way ANOVA followed by Fisher's LSD post-test was used to determine statistical significance (p <0.05).

Acute effects of DCUKA on streptozotocin (STZ) -induced neuropathic pain (a model of diabetic neuropathic pain). After measuring the baseline limb detachment threshold, baseline body weight and blood glucose concentration were determined (blood glucose was measured in tail blood using ASCENSIA CONTOUR Blood Glucose Monitoring System, Bayer, Pittsburg, PA). Rats were fasted overnight and injected intraperitoneally with vehicle (20 mM sodium citrate, pH 4.5, Sigma-Aldrich) or STZ in a 50 mg / kg vehicle. STZ solution was prepared daily and used within 10 minutes. Rats were fed a diet 30 minutes after STZ treatment. Three days after STZ treatment, blood glucose levels were measured again and rats with blood glucose levels above 350 mg / dl were considered "diabetes". When blood glucose levels were below 350 mg / dl Rats were given a second dose of STZ (45 mg / kg) using the same procedure. Fourteen days after the first STZ treatment, rats were orally fed vehicle (canola oil / gelatin) or various doses of DCUKA and organic pain thresholds were tested at various testing times after these treatments. Data are expressed as the ratio of organic pain threshold to baseline organic pain threshold (measured on the same foot) after DCUKA treatment.

Individual experimental analysis. If the ratio of organic pain threshold to baseline was outside the corresponding treatment group mean ± 2 standard deviations, the data points were considered as outliers and excluded from the dataset. Nuclear tests were analyzed by one-way ANOVA (Proc Glm or Proc Mixed, SAS v9.3, Cary, NC). The treatment group was the fixed independent effect tested. All models were tested for equal variance between treatment groups (Barlett's test for variance uniformity) and normality (Kolmogorov-Smirnov goodness-of-fit test). If the data did not meet these assumptions, a mixed model was used. All analyzes used the Fisher's LSD post-test to compare the statistical significance between different treatment groups (p-value <0.05).

Acute effect of DCUKA on monoiodoacetate (MIA) -induced neuropathic pain (model of osteoarthritis neuropathic pain). Rats were anesthetized with isoflurane, shaved on the right knee and injected with vehicle or MIA to induce disease. Animals were weighed weekly until pain measurements were taken on day 20. Baseline paw withdrawal measurements were performed on animals not treated with MIA. On day 21, the fauna were orally dosed with vehicle or DCUKA (1 or 2 capsules, po .; dose approximately 50 mg / kg or 100 mg / kg). The organic pain threshold was tested 90 minutes after drug administration. At the end of the test, blood was drawn from the tail vein to determine DCUKA levels by LC-MS / MS analysis. Data are expressed as the ratio of the organic pain threshold after DCUKA treatment to the organic pain threshold determined in animals without drug or MIA treatment.

Data analysis of MIA experiments. Experiments were analyzed by one-way ANOVA (Sigma Plot 12) and using the Holm-Sidak post-test for all pair comparisons. A P-value <0.05 was considered statistically significant. Since administration of 1 capsule of DCUKA had no statistically significant effect on the organic pain threshold (Fig. 8), the blood level of Kindolor after this treatment was evaluated. It was determined that after administration of one capsule, a blood level of Kindolor <500 ng / ml (<1.1 mM) was obtained, and this blood level is not effective in the treatment of MIA-induced neuropathic pain. I regarded it as.

FIG. 2 shows that DCUKA (50 mg / kg) treatment reverses the neuropathic pain caused by treatment of rats with the cancer chemotherapeutic agent cisplatin. The result of combining 6 experiments is shown. Processing average ± 1 SEM was plotted. Compared to the control (0 mg / kg DCUKA) ^* P value is <0.0001. In all experiments, rats were tested for baseline organic pain thresholds prior to cisplatin treatment. After the cisplatin treatment described above, the rats were given DCUKA and after 1 hour the organic pain threshold was redetermined. The results show the ratio of the organic pain threshold to the baseline (before cisplatin treatment) organic pain threshold measured 1 hour after administration of the vehicle or DCUKA.

FIG. 3 shows cisplatin, which is a chemotherapeutic agent. The effects of DCUKA (50 mg / kg), BCUKA (50 mg / kg) and gabapentin (neuron tin, 30 mg / kg) on neuropathic pain induced by are compared graphically. Mean organic pain threshold ± 1 standard error was plotted for each treatment group and time. ^* P <0.05 compared to the corresponding pretreatment group. Rats were tested for baseline organic pain thresholds prior to cisplatin treatment and treated with cisplatin as described above. After cisplatin treatment, the organic pain threshold was measured and rats were given oral doses of vehicle, DCUKA, BCUKA, or gabapentin. The organic pain threshold was measured again 1 and 2 hours after these treatments. The data are ratios of organic pain thresholds measured before and after 1 and 2 hours of administration of DCUKA, BCUKA or gabapentin. Cisplatin treatment alone (“pre-treatment”) significantly reduced the organic pain threshold compared to baseline, and DCUKA and BCUKA significantly reversed the reduction in the organic pain threshold. Gabapentin did not significantly reverse the cisplatin-induced reduction in the organic pain threshold at equimolar doses of DCUKA and BCUKA.

FIG. 4 illustrates that DCUKA treats neuropathic pain (causing an inflammatory response) induced by treatment with a complete Freund's adjuvant (CFA) in rats. The data combined 3 experiments. In each experiment, the baseline organic pain threshold (force to cause foot detachment, g) was first measured using an electrical von Frey anesthesia monitoring device. Rats were then injected with 0.1 ml of complete Freund's adjuvant (CFA) on the central surface of the sole of the hind left foot. After 48-60 hours, when CFA-induced pain developed, oral administration of vehicle (gelatin / canola oil emulsion) or 50 mg / kg DCUKA was given. After 1 hour, the organic pain threshold was measured again. The results show the ratio of the organic pain threshold to the baseline organic pain threshold measured after vehicle or DCUKA treatment. Post-Fisher's LSDt test for pair comparison showed a significant ( ^* ) difference between 50 mg / kg DCUKA and 0 mg / kg DCUKA (p-value <0.0001). CFA treatment reduced the organic pain threshold by approximately 60%, DCUKA treatment reversed this effect, and the organic pain threshold was not significantly different from the baseline level in the CFA treated foot. Was increased.

FIG. 5 illustrates a comparison of the effects of DCUKA (50 mg / kg) and BCUKA (50 mg / kg) on treating neuropathic pain induced by CFA treatment. The organic pain threshold for each animal is expressed as a ratio to the baseline injected into the paw only. Mean organic pain threshold ± 1 standard error is plotted for each treatment group. Compared to the vehicle, ^* P <0.05. Baseline organic pain thresholds were measured and rats were treated with CFA as described above. After 48 hours, the rats were given vehicle (canola oil / gelatin), DCUKA or BCUKA, and after 1 hour, the organic pain threshold was measured. CFA treatment lowers the organic pain threshold by about 40% of baseline, and treatment with DCUKA (n = 17) or BCUKA (n = 6) lowers the organic pain threshold to a level that is not significantly different from baseline. Invert to.

The dose-dependent effect of DCUKA on neuropathic pain caused by CFA was determined using a meta-analytic approach. The results are shown in FIG. The organic pain threshold for each animal is expressed as a ratio to the baseline injected into the paw only. Mean organic pain threshold ± 1 standard error was plotted for each treatment group. This is based on the processed averages from the 5 studies included in the meta-analysis. ^* P <0.05 compared to the vehicle (0 mg / kg) treatment group. In all experiments with CFA, the baseline organic pain threshold was measured by an electrical von Frey anesthesia monitoring device. CFA was injected into the central surface of the sole of the left hind paw, and 48 hours after injection, rats were given an oral vehicle (gelatin / canola oil) or DCUKA. The organic pain threshold was given again 60 minutes after administration of the vehicle or DCUKA. For the experiments included in the meta-analysis, the requirements are: 1) CFA treatment caused a reduction of at least 25% at the organic pain threshold; 2) the pain threshold was set 60 minutes after DCUKA or vehicle administration. It was measured. Five experiments testing different doses of DCUKA met these requirements. The organic pain threshold is expressed as mean ± SEM as a ratio to the baseline organic pain threshold. These are significant overall effects of DCUKA (F (5,125) = 7.71, P <0.0001). CFA treatment reduced the organic pain threshold by approximately 60%, and this effect was significantly reversed by DCUKA at doses of 30 mg / kg and above. That is, the pain threshold returned to baseline levels.

FIG. 7 shows that DCUKA reverses the neuropathic pain associated with diabetes. Diabetes is induced in rats by injection of streptozotocin (STZ), as described above. Post-Fiser's LSDt test for pair comparison showed a significant ( ^* ) difference between 50 mg / kg DCUKA and 0 mg / kg DCUKA (difference = 0.60, p-value <0.0001). The combined data from the three experiments are shown. In each experiment, the baseline organic pain threshold was tested using an electrical von Frey anesthesia monitoring device. 14 days after STZ treatment, vehicle (gelatin / canola oil) or 40 or 50 mg / kg DCUKA (these doses did not have a significant difference in efficacy) was administered orally and 90 minutes later, organically. Pain was assessed. The results show the ratio of the organic pain threshold to the baseline organic pain threshold after vehicle / DCUKA treatment. STZ lowered the organic pain threshold by approximately 40%, and this effect was reversed to baseline levels by DCUKA treatment.

The dose dependence of the effect of DCUKA on STZ-induced neuropathic pain was determined by a meta-analytic approach. The requirements for the experiments included in the meta-analysis are as follows: 1) STZ treatment induced neuropathic pain, which is measured as a decrease in the organic pain threshold of at least 25%; 2) pain. Measured 90 minutes after vehicle or DCUKA treatment. Four experiments that met these criteria were included in the meta-analysis.

FIG. 8 shows the dose dependence of the effect of DCUKA on treating STZ-induced neuropathic pain. Data are reported as the ratio of organic pain threshold to baseline pain threshold (measured on the same foot) after vehicle or DCUKA treatment. Compared to the vehicle treatment group, ^* P <0.05. The effect of DCUKA on the organic pain threshold was generally significant (F (7, 115 = 8.48, p <0.0001). STZ treatment reduced the pain threshold by approximately 40%. DCUKA at doses of 30 mg / kg and above reversed the effect of STZ, increasing the pain threshold and returning it to baseline levels.

FIG. 9 shows the dose dependence of DCUKA for treating MIA-induced neuropathic pain. Data were reported as the mean ± SEM ratio of the baseline pain threshold measured in animals not treated with MIA or drug to the organic pain threshold after vehicle (0 capsules) or DCUKA treatment (1 or 2 capsules). Compared to the vehicle group, ^* P <0.05 (analysis of variance and post-hoc comparison). The effect of DCUKA on the organic pain threshold was generally significant (F (2,26) = 4.07, p = 0.029). MIA treatment resulted in a reduction of approximately 60% in the pain threshold, and a DCUKA dose of approximately 100 mg / kg (2 capsules) significantly reversed the effect of MIA.

Example 4 DCUKA and DCUK-OEt increase the effect of morphine on CFA-induced neuropathic pain.
The following data demonstrate that low doses of DCUKA with morphine have a synergistic effect on the reduction of inflammatory drug-induced organic allodynia and febrile hyperalgesic pain.

CFA treatment and measurement of the organic pain threshold are described in Example 3. In this experiment, the organic pain threshold was tested at baseline. Forty-eight hours after CFA treatment, vehicle, DCUKA or morphine, or a combination of DCUKA and morphine was injected 30 minutes before the measurement of the organic pain threshold.

Heat hypersensitivity test (radiant heat foot withdrawal test). Rats were placed on a glass surface in a clear plastic chamber and acclimatized 15 minutes before testing. Thermal sensitivity was measured by using foot withdrawal latency to radiant thermal stimuli. A radiant heat source (ie, infrared) was activated with a timer to focus on the central surface of the sole of the left hind foot. A motion detector that stopped both the ramp and the timer when the foot was released determined the foot detachment latency. This latency was measured before and after administration of the drug or vehicle. A maximum cutoff of 33 seconds was used to prevent tissue damage. In this experiment, rats were injected with DCUK-OEt and immediately after injection with increased dose ratio morphine and tested 30 minutes later.

FIG. 10A demonstrates that the combination of DCUKA and morphine doses, each of which has no pain-causing effect, results in a complete reversal of inflammation-induced chronic pain. These data show that the combination of DCUKA and morphine has a greater effect than the additive effect of each drug alone, as determined by each of the "effect-based strategy" approaches discussed by Focquier & Guedj (2015). Consistent with the conclusion. This figure illustrates a "sub-threshold combination" approach in which a combination of ineffective doses of a drug provides a sufficient effect. FIGS. 10B and 10C provide evidence that the combination of DCUK-OEt and morphine provides an effect that exceeds the additive effect as compared to the effect of either drug alone. In this case, febrile hyperalgesia caused by CFA treatment was tested. _{The ED 50} anti-hyperalgesic response to morphine was significantly reduced by administration of DCUK-OEt at a dose ratio of> 30: 1 to morphine. For example, a dose of 0.2 mg / kg of morphine results in an antihyperalgesic response of approximately 20%. When combined with 6.4 mg of DCUK-OEt, the response is increased to 40%. DCUK-OEt had a DCUK-OEt / morphine dose ratio of 18: 1 (HP <0. 7) and 32: 1 ( ^* P <0.05) lowered the ED50.

Example 5 DCUKA enhances the effectiveness of oxycodone and methadone in treating FA-induced neuropathic pain.
The following data demonstrate that low doses of DCUKA enhance the effect of low doses of oxycodone or methadone on reducing organic allodynia caused by inflammatory agents. Data are presented as the mean ± SEM ratio of the organic pain threshold after drug or vehicle (VEH) treatment to the organic pain threshold before treatment with Freund's adjuvant (FA) in the treated foot. P <0.05 (n = 8 / group, analysis of variance and post-hoc comparison) compared to vehicle-treated group.

After the baseline organic pain test, the right hind leg of the rat was injected with a mixture of incomplete Freund's adjuvant (FA) and Mycobacterium butyricum (similar to complete Freund's adjuvant). After 72 hours, the organic pain test was repeated using the complete version of the Von Frey test procedure described in Example 3. Rats were tested with a series of von Frey hairs in the range of 3.16 to 5.18 absolute thresholds. Each hair was applied 3 times to determine to which hardness the rat responded 100%. Data were analyzed by the Psychofit program. On day 4, to determine the response to the individual drug, the group of rats was given a dose of vehicle or DCUKA (1 or 2 capsules, po., As described in Example 3) or a dose of oxycodone (as described in Example 3). A dose of 0.1, 0.25 or 1 mg / kg ip) or methadone (1.5, 2.5 or 3.5 mg / kg ip) is given, and the von Frey test is performed 75-90 minutes after dosing. did. On day 8, the effect of the combination of low dose (1 capsule) DCUKA and low dose oxycodone or methadone was evaluated. Rats were fed DCUKA + vehicle, oxycodone + vehicle, methadone + vehicle, or DCUKA + oxycodone or DCUKA + methadone at doses determined from the early stages of the study. FIG. 11 demonstrates that a combination of DCUKA (1 capsule) and oxycodone (0.1 mg / kg), each of which is not effective for producing antihyperalgesia, results in reduction of inflammation-induced chronic pain. These data show that the combination of DCUKA and oxycodone is greater than the additive effect of each drug alone, as determined by all four of the "effect-based strategy" approaches discussed by Focquier and Guedj (2015). Consistent with the conclusion that it has an effect. This figure illustrates a "sub-threshold combination" approach in which a combination of ineffective doses of a drug provides a sufficient effect. The solid line is for animals treated with Freund's adjuvant and vehicle. Shows the baseline organic pain threshold ratio. Increases above this line indicate a (non-significant) effect of DCUKA or oxycodone alone. The dashed line indicates the expected additive effect of the drug combination. The increased effect of the drug combination above the dashed line (ie, DCUKA + oxycodone 0.1 mg / kg) indicates a "positive combination effect" (Focquier and Guedj, 2015).

FIG. 12 demonstrates that methadone (1.5 or 3.5 mg / kg) enhances the effect of reducing inflammation-induced chronic pain with DCUKA (1 capsule). Data are expressed as the mean ± SEM ratio of the organic pain threshold to the organic pain threshold before treatment with Freund's adjuvant (FA) in the foot treated after drug or vehicle (VEH) treatment. ^* P <0.05 compared to DCUKA / VEH or methadone 1.5 mg / kg alone ^{; **} P <0.05 compared to DCUKA / VEH or methadone 3.5 mg / kg alone. + P <0.05 as compared to VEH (n = 8 / group, analysis of variance and post-hoc comparison).

These data show that the combination of DCUKA and methadone has a greater effect than the additive effect of each drug alone, as determined by each of the "effect-based strategy" approaches discussed by Focquier and Guedj (2015). Consistent with the conclusion of having. For 1.5 mg / kg methadone, this figure illustrates a "sub-threshold combination" approach in which a combination of ineffective doses of the drug provides sufficient effect. The solid black line shows the baseline organic pain threshold ratio in animals treated with the front adjuvant and vehicle. An increase above this line represents a (non-significant) effect of DCUKA or methadone (1.5 mg / kg) alone. The gray line shows the expected additive effect of the combination of DCUKA and 1.5 mg / kg methadone. The increased effect of the combination of DCUKA and methadone 1.5 mg / kg indicates a "positive combination effect" (Focquier and Guedj, 2015). For 3.5 mg / kg methadone, the figure illustrates a "best single agent" approach where the effect of the drug combination is greater than the effect provided by the individual ingredients. The dashed line indicates the expected additive effect of 3.5 mg / kg methadone and DCUKA. The increased effect of the drug combination above this line reflects the "positive combination effect" (Focquier and Guedj, 2015).

Example 6 DCUKA enhances the effectiveness of tramadol for treating MIA-induced neuropathic pain.
The following data demonstrate that in the MIA osteoarthritis model, another model of chronic pain, low-dose DCUKA, along with another low-dose narcotic analgesic (tramadol), synergistically reduce hyperalgesia. do. Tramadol acts on the m-opiate receptor and is also a serotonin and norepinephrine reuptake inhibitor.

As described in Example 3, after administration of MIA, the acute effects of different doses of DCUKA in rats were first tested 21 days after MIA treatment. The results are shown in FIG. Administration of 1 capsule of DCUKA (approximately 50 mg / kg) had no significant effect on MIA-induced pain. The blood level of DCUKA 2 to 2.5 hours after dosing was then measured to be <500 ng / ml (<1.1 μM). This blood level of DCUKA was not thought to be effective in reducing MIA-induced neuropathic pain. Rats were retested for organic pain threshold 29 days after treatment with MIA (pain threshold was reassessed on day 28 and determined that there was no significant difference between the initial test and day 20. did). In rats, as described in Example 3, vehicle, 1 capsule (low dose) DCUKA, p. o. 5, mg / kg (low dose) p. o. Tramadol or 1 capsule of DCUKA + 5 mg / kg tramadol was given 90 minutes prior to the measurement of the organic pain threshold and after the test for evaluation of DCUKA levels by the LC-MS / MS method described in Example 2. Blood was drawn from the carotid artery.

Data analysis. The data are expressed as the ratio of the baseline organic pain thresholds for no MIA and no drug treatment to the organic pain threshold after drug treatment. Two outlier data for the DCUKA + tramadol group are removed from the analysis. Animals with a blood level of DCUKA <500 ng / ml (a level already known to be ineffective for reversal of MIA-induced neuropathic pain) are considered to be given a "low dose" of DCUKA. .. Data from these animals were used for analysis of differences between groups by one-way ANOVA and Holm-Sidak test for all pair comparisons.

FIG. 13 shows the dose of DCUKA (1 capsule, where the blood level of DCUKA is <500 ng / ml) and which has no significant effect on the organic pain threshold as compared to the vehicle. It is demonstrated that tramadol (5 mg / kg), when combined, results in a significant reversal of the reduction in pain threshold caused by MIA treatment. The data are obtained by averaging the organic pain threshold after treatment with low dose DCUKA, low dose (5 mg / kg) tramadol, or a combination of low dose DCUKA and low dose tramadol vs. organic pain threshold before MIA treatment. Expressed as ± SEM. Compared to all other groups, ^* P <0.05 (ANOVA and post-hoc comparison).

These data show that the combination of DCUKA and tramadol has a greater effect than the additive effect of each drug alone, as determined by each of the "effect-based strategy" approaches discussed by Focquier and Guedj (2015). Consistent with the conclusion of having. The figure illustrates a "best single agent" approach where the effect of the drug combination is greater than the effect provided by the individual ingredients. The solid line shows the baseline organic pain threshold ratio in animals treated with MIA and vehicle. The (non-significant) effect of tramadol is indicated by an increase above baseline, and this increase is indicated by a dashed line. The effect of the drug combination above the dashed line reflects the "positive combination effect" (Focquier and Guedj, 2015).

Example 7 DCUKA enhances the effect of aspirin on treating STZ-induced neuropathic pain.
The following data demonstrate that in chronic pain, another model, the STZ diabetic neuropathic model, DCUKA can synergize with another analgesic (aspirin) to reduce allodynia.

As described in Example 3, after administration of streptozotocin (STZ), the rats were subjected to a von Frey apparatus. Was tested for allodynia. 60 minutes before the test, rats were divided into 4 groups. Group 1 was given a vehicle; Group 2 was given DCUKA; Group 3 was given aspirin; and Group 4 was given a combination of DCUKA and aspirin.

FIG. 14 shows that when combined with doses of DCUKA (12.5 mg / kg) or aspirin (25 mg / kg), each of which has no significant effect on allodynia, the hyperresponsiveness is completely reversed, ie. Demonstrate returning the pain threshold to baseline levels. These data show that the combination of DCUKA and aspirin has a greater effect than the additive effect of each drug alone, as determined by each of the "effect-based strategy" approaches discussed by Focquier and Guedj (2015). Consistent with the conclusion of having. This figure illustrates a "sub-threshold combination" approach in which a combination of ineffective doses of a drug provides a sufficient effect.

Example 8 DCUKA enhances the effect of treating FA-induced neuropathic pain.
The following data indicate that low dose DCUKA (1 capsule, as described in Example 1) enhances the effect of low dose diclofenac on alleviating organic allodynia caused by inflammatory agents. Demonstrate. Data are expressed as the mean ± SEM ratio of the organic pain threshold to the organic pain threshold before treatment with Freund's adjuvant (FA) in the treated foot after drug or vehicle (VEH) treatment. ^* P <0.05 compared to DCUKA or diclofenac 1.5 mg / kg alone ^{; **} P <0.05 compared to DCUKA or diclofenac 10 mg / kg alone (analysis of variance and post-hoc comparison).

Rats were treated with Freund's adjuvant and tested for organic pain as described in Examples 2 and 5. A group of rats was given different doses of diclofenac on day 4 to determine the appropriate dose for the experiment to test the combined effect of DCUKA and diclofenac. Different groups of rats were tested on day 4 for administration of 1 capsule of DCUKA or a low dose of diclofenac alone and in combination. FIG. 15 shows that DCUKA enhances the effect of diclofenac on reducing inflammation-induced chronic pain. These data show that the combination of DCUKA and diclofenac has a greater effect than the additive effect of each drug alone, as determined by each of the "effect-based strategy" approaches discussed by Focquier and Guedj (2015). Consistent with the conclusion of having. For 1.5 mg / kg diclofenac, this figure illustrates a "sub-threshold combination" approach in which a combination of ineffective doses of the drug provides a sufficient effect. The solid black line shows the baseline organic pain threshold ratio in animals treated with the front adjuvant and vehicle. An increase above this line represents a (non-significant) effect of DCUKA or diclofenac (1.5 mg / kg) alone. The gray line shows the expected additive effect of the combination of DCUKA and 1.5 mg / kg diclofenac. The increased effect of the combination of DCUKA and diclofenac 1.5 mg / kg above the gray line indicates a "positive combination effect". For 10 mg / kg diclofenac, the figure illustrates a "best single agent" approach where the effect of the drug combination is greater than the effect provided by the individual ingredients. The dashed line shows the expected additive effect of DCUKA and diclofenac 10 mg / kg. The increased effect of the drug combination above this dashed line indicates a "positive combination effect" (Focquier and Guedj, 2015).

Example 9 Prevention of cisplatin and CFA-induced neuropathic pain with DCUKA.
The following data show that treatment of animals with DCUKA after injury but prior to the onset of neuropathic pain can prevent the onset of pain. Rats were treated with cisplatin or CFA and the organic pain threshold was measured as described in Example 3.

Prevention of CFA-induced neuropathic pain with DCUKA. After baseline measurement of the organic pain threshold, rats were treated with CFA as described above. After CFA injection, rats were given vehicle (canola oil / gelatin) (n = 7) or 50 mg / kg DCUKA (n = 7) orally by intragastric tube feeding. Rats were then subjected to three or more treatments with vehicle or DCUKA at 12 hour intervals. After 60 hours of CFA treatment, the organic pain threshold was tested again.

Prevention of cisplatin-induced neuropathic pain with DCUKA. One day after baseline measurement of the organic pain threshold, rats were given cisplatin i. p. I injected it. Cisplatin injections were given again on days 4, 8, and 12. Starting 1 hour after the first cisplatin injection, rats were given 50 mg / kg DCUKA or vehicle via intragastric tube feeding twice daily for 14 days. After the final treatment (day 15), the organic pain threshold was tested again. The pain threshold was then tested weekly for 4 weeks without further treatment.

FIG. 16 shows that DCUKA can prevent the development of neuropathic pain due to CFA.
The data show the ratio of the pre-organic pain threshold to the CFA baseline organic pain threshold 60 hours after CFA treatment. CFA treatment significantly reduced the pain threshold by approximately 70%. However, when the animals were given DCUKA daily prior to the test, the threshold did not decrease (P = 0.16) and remained close to the baseline pain threshold. That is, DCUKA has the ability to prevent the onset of inflammatory pain when given after administration of an inflammatory agent. Student's t-test was used to compare pain thresholds between groups, and paired t-test was used to compare pain thresholds within groups.

FIG. 17 illustrates that repeated DCUKA treatments over the period between cisplatin administration and pain testing prevented the development of pain in a rat cisplatin-induced neuropathic pain model. The data are expressed as the average ± SEM of the organic pain threshold (foot detachment threshold). Injection of cisplatin resulted in a significant reduction in the organic pain threshold over days in rats chronically treated with vehicle. Repeated DCUKA treatment resulted in a significant reduction in the pain threshold compared to baseline before cisplatin administration. This result shows that DCUKA has the ability to prevent the development of chemotherapeutic-induced neuropathic pain, which is obtained after administration of the chemotherapeutic agent.

Two-way repeated measures ANOVA revealed a statistically significant difference (P = 0.023) between the two treatments, DCUKA and vehicle. The individual P-values shown in the graph are for DCUKA vs. vehicle and were calculated by the multiple comparison method. In addition, a significant difference was detected in the pain threshold in the cisplatin and vehicle groups (days 15, 19, 25, 32) as compared with the day 0 before cisplatin administration, but on the 0th day before cisplatin injection. Compared to the values, there was no significant difference in the pain threshold between the cisplatin and DCUKA groups.

Preferred embodiments of the present invention are described above herein, including the best modes for carrying out the present invention, which are known to us. Modifications of these preferred embodiments within the scope of the invention will be apparent to those of skill in the art upon reading the above description. Accordingly, the invention includes all modifications and equivalents of the subject matter defined by the claims herein. Further, any combination of the above elements in all possible variants thereof is included by the present invention unless otherwise indicated in the specification or apparently inconsistent with the context. ..

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Claims (6)

The following formula:

During the ceremony:
R ⁷ is alkyl (preferably 3-6 carbon alkyl), or phenyl;
R ⁸ is alkyl (preferably 3-6 carbon alkyl), or phenyl;
E ¹ is -C (= O) OR ⁹ ;
Each R ⁹ is an H or C _1- C ₄ alkyl;
Each X ² and X ³ are independently electron attracting groups (preferably halogens or nitros).
From the group consisting of oxycodone, methadone, tramadone, and a mixture thereof, which is different from the above aminoquinoline compound and is composed of the aminoquinoline compound of the above in the free acid form, in the free base form, or as a pharmacologically acceptable addition salt. A pharmaceutical composition comprising with the analgesic of choice. The composition according to claim 1, wherein the aminoquinoline compound is 5,7-dichloro-4- (3,3-dibutyl phthalate) quinolone-2-carboxylic acid (BCUKA). The composition according to claim 1, wherein the aminoquinoline compound is 5,7-dichloro-4- (3,3-diphenylureido) quinolone-2-carboxylic acid (DCUKA). The composition according to claim 1, wherein the aminoquinoline compound is 5,7-dichloro-4- (3,3-diphenylureido) quinolone-2-carboxyethyl ester DCUK-OEt). A method for treating chronic pain in a subject comprising the aminoquinoline compound of the formula according to claim 1 and an analgesic selected from the group consisting of oxycodone, methadone, tramadol, and a mixture thereof, which is different from the aminoquinoline compound. Pharmaceutical composition for use in. Analgesia in patients suffering from chronic pain, comprising the aminoquinoline compound of the formula according to claim 1 and an analgesic agent selected from the group consisting of oxycodone, methadone, tramadol, and a mixture thereof, which is different from the aminoquinoline compound. A pharmaceutical composition for use in a method of enhancing the effect of a compound.

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