EA041240B1 - A1 ION CHANNEL INHIBITORS WITH TRANSITOR RECEPTOR POTENTIAL - Google Patents

Description

Cross-reference to related applications

This application claims advantage and priority over U.S. Provisional Application No. 62/624276, filed January 31, 2018, the contents of which are incorporated herein by reference in their entirety.

Technical field

This invention relates to pharmaceutical compounds, compositions and methods for the treatment of pain, respiratory diseases, and inhibition of the ion channel A1 with transient receptor potential A1 (TRPA1).

State of the art

Channel A1 with transient receptor potential (herein TRPA1) is a non-selective cation channel associated with pain in humans. TRPA1 is found in sensory neurons and functions as a detector that helps link the detection of harmful chemicals, tissue damage, and inflammation to pain. TRPA1 activation is believed to cause pain by inducing firing of nociceptive neurons and driving central sensitization in the spinal cord. TRPA1 stimulation can also increase the firing of sensory neurons, resulting in the release of pro-inflammatory neuropeptides such as NK-A, substance P, and CGRP (which cause vasodilation and help recruit immune cells). Various endogenous reactive compounds produced by inflammation activate TRPA1 (including 4-hydroxynonenal released by liposome peroxidation; cyclopentane prostaglandins produced by COX enzymes; hydrogen peroxide produced by oxidative stress). TRPA1 activation also increases TRPA1 sensitivity to cold. In addition, a gain-of-function mutation in TRPA1 causes hereditary episodic pain syndrome; patients suffering from this disease experience episodic pain, which can be caused by a cold. Thus, TRPA1 is thought to play a role in pain associated with nerve injury, cold allodynia, and inflammatory pain.

Compounds that inhibit the TRPA1 ion channel may be useful, for example, in the treatment of conditions improved, cured or prevented by inhibition of the TRPA1 ion channel. For example, pharmaceutical compositions that inhibit TRPA1 can be used to treat pain. It has been demonstrated that inhibition of TRPA1 (eg, through genetic ablation and chemical antagonism) leads to a decrease in the activity of pain behavior in mice and rats. Knockout mice lacking functional TRPA1 have reduced nociceptive responses to TRPA1 activators (including AITC, formalin, acrolein, 4-hydroxynonenal) and, in addition, significantly reduce thermal and mechanical hypersensitivity in response to the inflammatory mediator bradykinin (e.g., Kwan, K. Y. et al Neuron 2006, 50, 277-289; Bautista, D. M. et al Cell 2006, 124, 12691282). In animal models of pain, downregulation of TRPA1 by gene-specific antisense prevented and reversed cold hyperalgesia induced by inflammation and nerve injury (see, e.g., Obata, K. et al., Journal of Clinical Investigation 2005, 115, 2393-2401; Jordt, S. E. et al., Nature 2004, 427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200, 112-123). TRPA1 inhibitor compounds are effective in a variety of rodent pain models. TRPA1 inhibitors have been shown to reduce mechanical hypersensitivity and cold allodynia after complete Freund's adjuvant-induced inflammation (without altering normal cold sensation in control animals) and also improve function in a rat model of monoiodoacetate osteoarthritis. Materazzi, S et al., European Journal of Physiology 2012, 463(4):561-9; Wei H et al., Anesthesiology 2012, 117(1):137-48; Koivisto, A et al., Pharmacol Res. 2012, 65(1):149-58. TRPA1 inhibitor compounds have been shown to reduce the activity of pain behavior in rodents treated with AITC (mustard oil), formalin, cinnamaldehyde, acrolein, and other TRPA1 activators. TRPA1 inhibitor compounds have also shown efficacy in rodent models for postoperative pain, see, for example, Wei et al., Anesthesiology 2012, 117 (1): 137-48; peripheral neuropathy induced by chemotherapy, see, for example, Trevisan, et al.., Cancer Res. 2013 May 15;73(10):3120-31 Online March 11, 2013; and painful diabetic neuropathy, see, for example, Koivisto et al., Pharmacol Res (2011).

Brief summary of the invention

In one embodiment, the present invention relates to compounds selected from the group consisting of

- 1 041240

or its pharmaceutically acceptable salts. According to is one aspect of said compound

or a pharmaceutically acceptable salt thereof. In a more specific aspect, said compound is

In yet another aspect, said compound, or a pharmaceutically acceptable salt thereof, is greater than 95% pure.

In yet another aspect, said compound is greater than 95% pure. In yet another aspect, said compound is

or a pharmaceutically acceptable salt thereof. In another aspect, said compound is

In another embodiment, the present invention relates to a pharmaceutical composition containing the above compound or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention relates to the use of the above compound or a pharmaceutically acceptable salt thereof for the treatment of pain.

In another embodiment, the present invention relates to the use of the above compound or a pharmaceutically acceptable salt thereof for the treatment of chronic pain.

In another embodiment, the present invention relates to the use of the above compound of the compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain.

In another embodiment, the present invention relates to the use of the above compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of chronic pain.

Detailed Description of the Invention

This invention provides compounds of formula I

or their pharmaceutically acceptable salt, where

X is N or CH;

R ¹ is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C1-C6 alkyl-O-Co-C6-alkyl, -Co-C6-alkyl-O-C1-C6- alkyl, -C1-C6-alkyl-C(O)-Co-C6-alkyl, -Co-C6-alkyl-C(O)-C1-C6-alkyl, -C1-C6-alkyl-C(O)N(R ⁷ )2, -C ₁ -C ₆ -alkyl-CN, -C ₁ -C ₆ -haloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, each of which is substituted with (R ⁶ )1-7;

R ² represents H or C ₁ -C ₆ -alkyl;

R ³ represents H or C ₁ -C ₆ -alkyl;

R ⁴ is heteroaryl optionally substituted with (R ⁵ ) _1-3 ;

R ⁵ is independently H, C3-C10 heterocyclyl, C1-C3 alkyl, C1-C3 alkoxy, -C1-C6 alkyl-OC0-C6 alkyl, -C0-C6 alkyl-OC1-C6 alkyl, - N(C1-C3-alkyl)2, C1-C6-haloalkyl, -C1-C3-alkylN(R ⁷ )2, heterocyclylalkyl, halogen or cyano, each of which is optionally substituted with (R ⁶ ) _1-3 ;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, hydroxy, aryl , heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, 6 arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano or halogen or two R together with the atoms to which they are attached may form an optionally substituted 3-7 membered ring;

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ⁹ is H, CH ₂ D, CHD2 or CD ₃ .

In another aspect, this invention provides compounds of formula II

or their pharmaceutically acceptable salt, where

X is N or CH;

R ² is H or C ₁ -C6 alkyl;

R ³ is H or C ₁ -C6 alkyl;

R ⁴ is heteroaryl optionally substituted with (R ⁵ ) _1-3 ;

R ⁵ is independently H, C3-C1o-heterocyclyl, C1-C3-alkyl, C1-C3-alkoxy, -C1-C6-alkyl-O-C0-C6-alkyl, -Co-C6-alkyl-O-C1-C6 -alkyl, -N(C1-C3-alkyl)2, C1-C6-haloalkyl, -C1-C3-alkylN(R ⁷ )2, heterocyclylalkyl, halogen or cyano, each of which is optionally substituted with (R ⁶ ) _1-3 ;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C1C ₆ haloalkyl, hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano or halogen or two R ⁶ together with the atoms to which they are attached may form an optionally substituted 3-7 membered ring;

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ⁸ is H or C ₁ -C ₆ alkyl; And

R ⁹ is H, CD ₃ or C ₁ -C ₆ alkyl.

In another aspect, this invention provides compounds of formula III

- 3 041240 or their pharmaceutically acceptable salt, where

X is N or CH;

R ² represents H or C ₁ -C ₆ -alkyl;

R ⁵ is H, C3-C10-heterocyclyl, C1-C3-alkyl, C1-C3-alkoxy, -C1-C6-alkyl-O-C0-C6-alkyl, -C0-C6-alkyl-O-C1-C6- alkyl, -N(C1-C3-alkyl)2, C1-C6-haloalkyl, -C1-C3-alkyl-N(R ⁷ )2, heterocyclylalkyl, halogen or cyano, each of which is optionally substituted with (R ⁶ ) _{1- 3} ;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, hydroxy, aryl , heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, 6 arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano or halogen or two R together with the atoms to which they are attached may form an optionally substituted 3-7 membered ring; And

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

R ⁹ is H, CD ₃ or C ₁ -C ₆ alkyl.

This invention also relates to compositions containing a compound of formula (I) and a pharmaceutically acceptable excipient, diluent or carrier.

The compounds and compositions described herein can be used to treat a variety of disorders in a subject. For example, this document describes methods of treatment, such as a method of treating a TRPA1-mediated disorder in a subject, which method comprises administering an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof. Methods for treating pain in a subject that include administering an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, are also described herein. Exemplary types of pain include neuropathic pain, such as painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, low back pain, trigeminal neuralgia, postherpetic neuralgia, sciatica, and complex regional pain syndrome; inflammatory pain such as rheumatoid arthritis, osteoarthritis, temporomandibular disorder; PDN or CIPN; visceral pain, such as from pancreatitis, inflammatory bowel disease, colitis, Crohn's disease, endometriosis, pelvic pain, and angina pectoris; pain selected from the group of cancer pain, burn pain, oral pain, fracture and trauma pain, incision pain, bone pain, sickle cell anemia pain, fibromyalgia, and musculoskeletal pain; or pain from hyperalgesia or allodynia.

This invention provides compounds of formula I (I) or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

R ¹ is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C1-C6 alkyl-O-Co-C6 alkyl, -C0-C6 alkyl-O-C1-C6- alkyl, -C1-C6-alkyl-C(O)-C0-C6-alkyl, -C0-C6-alkyl-C(O)-C1-C6-alkyl, -C1-C6-alkyl-C(O)N(R ⁷ )2, -C ₁ -C ₆ -alkyl-CN, -C ₁ -C ₆ -haloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, each of which is substituted with (R ⁶ ) _1-7 ;

R ² represents H or C ₁ -C ₆ -alkyl;

R ³ represents H or C ₁ -C ₆ -alkyl;

R ⁴ is heteroaryl optionally substituted with (R5) _1-3 ;

R ⁵ is independently H, C ₃ -C ₁₀ heterocyclyl, C ₁ -C ₃ alkyl, C ₁ -C _{3 alkoxy, -C 1 -C 6} alkyl-O-Co-C ₆ alkyl, -Co-C ₆ -alkyl-OC ₁ -C ₆ -alkyl, -N(C ₁ -C ₃ -alkyl) ₂ , C ₁ -C ₆ -haloalkyl, -C ₁ -C ₃ -alkylN(R ⁷ )2, heterocyclylalkyl, halo or cyano, each of which is optionally substituted with (R ⁶ )1-3;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, hydroxy, aryl , heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano, or halo, or two ^R6s , together with the atoms to which they are attached, may form an optionally substituted 3-7 membered ring;

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

R ⁹ is H, CH ₂ D, CHD2 or CD ₃ .

In some embodiments, R ¹ is hydroxypropyl, hydroxyethyl, ketopentyl, hydroxymethyl, pyridinylmethyl, oxazolylmethyl, methylisoxazolylmethyl, oxetanylmethyl, oxadiazolylmethyl, methyloxadiazolylmethyl, methoxyethyl, hydroxymethoxypropyl, methoxyketopropyl, ketomethylbutyl, ketopropyl, ketobutyl, acetamido, cyanomethyl, methylacetamido, trifluoroethyl, or trifluoroethyl butynyl.

- 4 041240

In some embodiments, R ¹ is

In some embodiments, R ¹ is heteroarylalkyl optionally substituted with (R ⁷ ) _1-4 .

In some embodiments, R ¹ is 1,2,4 oxadiazolylmethyl, optionally substituted with (R ⁷ ) ₁ . ₂ .

In some embodiments, R ¹ is

In some embodiments, R ² is methyl. In some embodiments, R ² is H.

In some embodiments, R ³ is H.

In some embodiments, R ⁴ is a 6-membered monocyclic heteroaryl optionally substituted with (R ⁵ ) ₁ _ ₃ .

In some embodiments, R ⁴ is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is substituted with (R ⁵ )^.

In some embodiments, R ⁴ is

In some embodiments, R ⁵ is independently H, pyrrolidinyl, trifluoromethyl, trifluoroethyl, halo, methyl, isopropyl, cyano, propyl, ethyl, azabicyclohexyl, difluoroazabicyclohexyl, methoxy, methoxyethyl, dialkylamino, or ethoxy, each of which is optionally substituted with (R6)1 -3.

In some embodiments, R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

- 5 041240

In some embodiments, R ⁵ is C1-C3 alkyl or C1-C6 haloalkyl. In some embodiments, R ⁵ is CF3.

In some embodiments, R ⁴ is

is CF3.

In some embodiments, R ⁷ is H, methyl, ethyl, or CF ₃ .

In some embodiments, R ⁹ is H. In some embodiments, R ⁹ is CD ₃ .

In some embodiments, R ¹ is

R ² is H or methyl; R ⁴ is

R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

- 6 041240

R ³ is H or methyl;

R ⁷ is H, methyl, ethyl or CF3; and R ⁹ is H or CD3.

In some embodiments, X is N.

In some embodiments, X is CH.

In some embodiments, R ¹ is -CH2-heteroaryl optionally substituted with (R ⁶ )i-2; and R ⁴ is 6-membered heteroaryl optionally substituted with (R5) 1-3.

In some implementations

R ¹ is -CH ₂ -heteroaryl optionally substituted with one R ⁶ ;

R ² is methyl;

R ³ is H;

R ⁴ is

R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

R ³ is H or methyl;

R ⁷ is H, methyl, ethyl or CF3; And

R ⁹ is H or CD ₃ .

In some embodiments, the compound is a compound of formula (Ia)

In some embodiments, the compound is a compound of formula (Ib)

In some embodiments, the compound is a compound of formula (Ic)

- 7 041240

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compound is selected from the group consisting of

In another aspect, this invention provides a compound of formula II

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

R ² represents H or C ₁ -C ₆ -alkyl;

R ³ represents H or C ₁ -C ₆ -alkyl;

R ⁴ is heteroaryl optionally substituted with (R ⁵ ) _1-3 ;

R ⁵ is independently H, C3-C10 heterocyclyl, C1-C3 alkyl, C1-C3 alkoxy, -C1-C6 alkyl-O-C0-C6 alkyl, -C0-C6 alkyl-O-C1-C6 -alkyl, -N(C1-C3-alkyl)2, C1-C6-haloalkyl, -C1-C3-alkylN(R ⁷ )2, heterocyclylalkyl, halo or cyano, each of which is optionally substituted with (R ⁶ )1-3 ;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, hydroxy, aryl , heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano, or halo, or two ^R6s , together with the atoms to which they are attached, may form an optionally substituted 3-7 membered ring;

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl;

R ⁸ is H or C ₁ -C ₆ alkyl;

R ⁹ is H, CD ₃ or C ₁ -C ₆ alkyl.

In some embodiments, R ⁹ is methyl.

In some embodiments, R ² is methyl.

In some embodiments, R ² is H.

In some embodiments of R ³ H.

In some embodiments, R ⁴ is a 6-membered monocyclic heteroaryl,

- 8 041240 optionally substituted (R ⁵ ) _1-3 .

In some embodiments, R ⁴ is or pyridazinyl, each of which is substituted with (R ⁵ ) _1-2 .

In some embodiments, R ⁴ is pyridinyl, pyrimidinyl, pyrazinyl

In some embodiments, R ⁵ is independently H, pyrrolidinyl, trifluoromethyl, trifluoroethyl, halo, methyl, isopropyl, cyano, propyl, ethyl, azabicyclohexyl, difluoroazabicyclohexyl, methoxy, methoxyethyl, dialkylamino, or ethoxy, each of which is optionally substituted (R ⁶ ) 1-3.

In some embodiments, R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

In some embodiments, R ⁵ is C ₁ -C ₃ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, R ⁵ is CF ₃ .

In some embodiments, R ⁴ is a CF ₃ battle.

and R ⁵ is co In some embodiments, R ⁷ is H, methyl, ethyl, or CF ₃ .

In some embodiments, R ⁸ is methyl.

In some embodiments, R ² is H or methyl; R ⁴ is

R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

- 9 041240

R ³ is H or methyl;

R ⁷ is H, methyl, ethyl or CF ₃ ; R ⁸ is H or Ci-C6-alkyl; and R ⁹ is methyl.

In some embodiments, X is N.

In some embodiments, X is CH.

In some implementations

R ² is methyl;

R ³ is H;

R ⁴ is

R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

R ³ is H or methyl;

R ⁷ is H, methyl, ethyl or CF3;

R ⁸ is C ₁ -C ₆ alkyl; And

R ⁹ is methyl.

In some embodiments, the compound is a compound of formula (IIa)

In some implementations, the compound is selected from the group consisting of

In another aspect, this invention provides compounds of formula III

- 10 041240

or their pharmaceutically acceptable salt, where:

X is N or CH;

R ² represents H or C ₁ -C ₆ -alkyl;

R ⁵ is independently H, C3-C10 heterocyclyl, C1-C3 alkyl, C1-C3 alkoxy, -C1-C6 alkyl-O-C0-C6 alkyl, -C0-C6 alkyl-O-C1-C6 -alkyl, -N(C1-C3-alkyl)2, C1-C6-haloalkyl, -C1-C3-alkylN(R ⁷ )2, heterocyclylalkyl, halo or cyano, each of which is optionally substituted with (R ⁶ ) _1-3 ;

R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, hydroxy, aryl , heteroaryl, heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heteroarylalkyl, haloalkyl, keto, cyano, or halo, or two ^R6s , together with the atoms to which they are attached, may form an optionally substituted 3-7 membered ring;

R ⁷ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

R ⁹ is H, CD ₃ or C ₁ -C ₆ alkyl.

In some embodiments, R ⁹ is methyl.

In some embodiments, R ² is methyl.

In some embodiments, R ² is H.

In some embodiments, R ⁵ is independently H, pyrrolidinyl, trifluoromethyl, trifluoroethyl, halo, methyl, isopropyl, cyano, propyl, ethyl, azabicyclohexyl, difluoroazabicyclohexyl, methoxy, methoxyethyl, dialkylamino, or ethoxy, each of which is optionally substituted (R ⁶ ) 1-3.

In some embodiments, R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

In some embodiments, R ⁵ is C ₁ -C ₃ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, R ⁵ is -CF ₃ .

In some embodiments, R ⁷ is H, methyl, ethyl, or -CF ₃ .

In some embodiments, R ² is H or methyl;

R ⁵ is independently H, -CF ₃ , cyanomethyl, bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,

R ⁹ is methyl.

In some embodiments, X is N.

In some embodiments, X is CH.

In some embodiments, the compound is a compound of formula (IIIa)

- 11 041240

In some embodiments, the compound is selected from the group consisting of

In yet another aspect, this invention provides a pharmaceutical composition comprising at least one compound of this invention, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.

In yet another aspect, this invention provides a compound of this invention for use as a medicine.

In yet another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a TRPA1-mediated disorder in a subject.

In some embodiments, the TRPA1-mediated disorder is selected from the group consisting of: pain, inflammatory disease, dermatological disorder, and respiratory disease.

In yet another aspect, this invention provides a compound of formula

wherein the compound is greater than 95% pure, or a pharmaceutically acceptable salt thereof. In yet another aspect, this invention provides a compound of formula

where the compound has a purity of more than 95%.

In yet another aspect, this invention provides a pharmaceutical composition containing a compound of formula

or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient, diluent or carrier.

In yet another aspect, this invention provides a pharmaceutical composition containing a compound of formula

- 12 041240 in admixture with a pharmaceutically acceptable excipient, diluent or carrier.

In some embodiments, the pharmaceutical composition is for oral administration.

In yet another aspect, the present invention provides a method of treating pain in a subject, comprising administering an effective amount of a compound of formula

or a pharmaceutically acceptable salt thereof.

In some implementations, the connection is

In certain embodiments, illustrative compounds of formulas (I), (II) or (III) include the compounds described in table. 1 and in the examples.

- 13 041240

Table 1

This description is not limited in its application to the details of the methods and compositions described herein. In addition, the phraseology and terminology used in this document is for the purposes of description and should not be construed as limiting.

Chemical definitions

At various places in the present description, the substituents of the compounds of the invention are described in groups or in ranges. In particular, the invention is intended to include every single sub-combination of members of such groups and ranges. For example, the term C ₁ . ₆ αlkyl is specifically designed to individually describe methyl, ethyl, propyl, butyl, and pentyl.

- 14 041240

For compounds of the invention in which the variable occurs more than once, each variable may be a different moiety selected from the Markush group defining the variable. For example, when a structure is described having two R groups that are both present in the same compound; the two R groups may represent different groups selected from the Markush group defined for R.

In addition, it should be understood that certain features of the invention, which are described in the context of separate embodiments for clarity, may also be provided in combination in one embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

When a compound of this invention is shown in the form of a chemical name and in the form of a formula, in case of any discrepancy, the formula shall prevail.

An asterisk may be used in subformulas to indicate a bond that is linked to the main molecule as defined.

As used herein, alkyl by itself or as part of another substituent means, unless otherwise noted, straight or branched chain and may have multiple carbon atoms, optionally designated (i.e., C ₁ -C ₆ - means one to six carbon atoms). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, npropyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, homologues and isomers, for example, n -pentyl, n-hexyl and the like.

As used herein, the term alkenyl may be a straight or branched hydrocarbon chain containing at least one double bond and having two to six carbon atoms (ie C ₂ -C6 alkenyl). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1, 4-dienyl and the like.

As used herein, the term alkoxy may be a straight or branched alkoxy group (eg C ₁ -C6 alkyl-O-) having one to six carbon atoms (ie C ₁ -C ₆ alkoxy). Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, t-butyloxy, pentyloxy or hexyloxy and the like.

As used herein, the term alkynyl may be a straight or branched hydrocarbon chain containing at least one triple bond having two to six carbon atoms (ie C ₂ -C6 alkynyl). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

As used herein, the term amide or amido refers to a chemical moiety with the formula -C(O)NR ^a - or -NR ^a C(O)-, where R ^a is H or C ₁ -C ₆ alkyl.

As used herein, the term amino or amine refers to the -NH2 radical group.

As used herein, aryl refers to a polyunsaturated aromatic hydrocarbon moiety that can be one or more rings (e.g., 1 to 2 rings) that are fused together or covalently bonded, having six to twelve carbon atoms (i.e., C ₆ -C ₁₂ -aryl). Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl, and the like.

As used herein, the term arylalkyl refers to an (aryl)alkyl radical where the aryl and alkyl moieties are as defined in the specification.

As used herein, the term aryloxy refers to -O-(aryl), where the aryl moiety is as defined herein.

As used herein, the term arylalkoxy refers to -O-(arylalkyl), where the arylalkyl moiety is as defined herein.

As used herein, the term cyano refers to the -CN radical.

As used herein, the term cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen and may be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms (ie C ₃ -C ₁₀ cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.

As used herein, halo or halogen, independently or as part of another substituent, means, unless otherwise indicated, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The term halide, by itself or as part of another substituent, refers to a fluoride atom, a chloride atom, a bromide atom, or an iodide atom.

As used herein, haloalkyl and haloalkoxy may include alkyl and alkoxy structures that are substituted with one or more halogen groups, or combinations thereof. For example, the terms fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which halogen is fluorine (eg, -C ₁ -C ₆ -alkyl-CF ₃ , OC ₁ -C ₆ -alkyl-CHF ₂ ). Non-limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluoromethyl, and fluoroisopropyl.

As used herein, the term heteroaryl refers to a 5-14 membered aromatic radical (e.g., C ₂ -C ₁₃ heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur, and which may be monocyclic or bicyclic. ring system. The polycyclic heteroaryl group may or may not be fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). The term heteroaryl is intended to include all possible isomeric forms. Examples of heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, oxadiazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl , triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.

As used herein, the term heterocyclyl can be a stable 3-18 membered non-aromatic mono-, di-, or tricyclic ring radical that contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, azabicyclohexyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxomorpholinyl and the like.

As used herein, heteroarylalkyl refers to a (heteroaryl)alkyl radical wherein the heteroaryl and alkyl moieties are as defined herein.

As used herein, the term heteroaryloxy refers to -O-(heteroaryl), where the heteroaryl moiety is as defined in the specification.

As used herein, the term heterocycloalkyl refers to a (heterocyclyl)alkyl moiety and can be a stable 3-18 membered non-aromatic ring moiety that contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl groups include, but are not limited to, groups such as dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like multiple alkyl moieties as defined herein.

As used herein, the term hydroxy or hydroxyl refers to -OH.

As used herein, the term nitro refers to -NO2.

As used herein, the term keto refers to -C=O.

Many of the terms above can be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of each other.

As used herein, the term substituted is intended to include all permitted substituents on organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight, carbocyclic and heterocyclic, aromatic and non-aromatic substituents on organic compounds (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may itself be further substituted) as well as halogen, carbonyl (for example, aldehyde, ketone, ester, carboxyl or formyl), thiocarbonyl (for example, thioether, thiocarboxylate or thioformate), amino, -N(R ^b )(R ^c ), where each R ^b and R ^{c is} independently H or C1-C6 alkyl, cyano, nitro, -SO2N(R ^b )(R ^c ), -SOR ^d and S(O)2R ^d , where R ^b , R ^c and R ^d are each independently is H or C ₁ -C ₆ -alkyl. Illustrative substituents include, for example, those described herein above. Allowable substituents may be one or more and the same or different for the respective organic compounds. For the purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any of the allowable substituents of the organic compounds described herein that satisfy the valency of the heteroatoms. This invention is in no way intended to limit the allowable substituents of organic compounds.

It is understood that substitution or substituted includes the implicit condition that such substitution corresponds to the allowable valency of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as rearrangement, cyclization, elimination etc.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms are methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more complete list of abbreviations used by organics in the art is given in the first issue of each volume of the Journal of Organic Chemistry; this list is usually presented in a table entitled Standard List of Abbreviations. The abbreviations contained in this list and all abbreviations used by those skilled in the art are incorporated herein by reference.

Contemplated equivalents to the compounds described above include compounds that otherwise match them and that have the same general properties (e.g., the ability to inhibit TRPA1 activity) where one or more simple substituent variants are prepared that do not adversely affect the efficacy of the compound. . In general, the compounds of this invention can be prepared by the methods illustrated in the general reaction schemes, such as those described below, or by modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. These reactions can also use variants that are known per se, but not mentioned in this document.

For the purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, on the inside cover. Also for the purposes of this invention, the term hydrocarbon is intended to include all valid compounds having at least one hydrogen and one carbon atom. In a broad aspect, acceptable hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds, which may or may not be substituted.

Definitions

As used herein, the singular refers to one or more (eg, at least one) grammatical subject matter.

About and approximately usually mean an acceptable degree of error for the quantity being measured, taking into account the nature or accuracy of the measurements. Exemplary degrees of error are within 20%, typically within 10%, and more typically within 5% of a given value or range of values.

As used herein, an amount of a compound or combination effective to treat a disorder (e.g., a disorder as described herein), a therapeutically effective amount, an effective amount, or an effective treatment refers to an amount of a compound or combination that is effective when administered to a subject, either single or multiple times. dose, in curing a subject or in treating, alleviating, alleviating, or improving the symptoms of a subject with a disorder (eg, a disorder as described herein) that exceeds the expected effect in the absence of such treatment.

As noted above, some embodiments of these compounds may contain a basic functional group such as amino or alkylamino and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term pharmaceutically acceptable salts in this respect refers to the relatively non-toxic inorganic and organic acid salts of the compounds disclosed herein. These salts can be obtained in situ during the final isolation and purification of the compounds of this invention, or by separately reacting the purified compound of this invention in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphylate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate and the like (see, for example, Berge et al. (1977) Pharmaceutical Salts, J. Pharm. Sci. 66: 1-19).

In other instances, the compounds disclosed herein may contain one or more acidic functionalities and thus are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term pharmaceutically acceptable salts in these instances refers to the relatively non-toxic inorganic and organic base addition salts of the compounds disclosed herein. These salts may also be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable organic primary , secondary or tertiary amine. Exemplary alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Typical organic amines useful for basic salt formation include

- 17 041240 ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The term treat or treatment, as used herein, refers to the use or administration of a compound, alone or in combination with, an additional agent to a subject, e.g., a subject who has a disorder (e.g., a disorder as described herein), a symptom of the disorder, or a predisposition to a disorder, for the purpose of treating, healing, alleviating, alleviating, modifying, correcting, alleviating, ameliorating, or influencing the disorder.

As used herein, the term subject is intended to refer to humans and non-human animals. Typical human subjects include a human subject having a disorder, such as the disorder described herein. The term non-human animals of this invention includes all vertebrates, e.g. non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or farm animals, e.g. sheep, dogs, cats, cows , pigs, etc.

The terms antagonist and inhibitor are used interchangeably to refer to an agent that reduces or suppresses biological activity, for example, to suppress the activity of an ion channel such as TRPA1. TRPA1 inhibitors include inhibitors having any combination of the structural and/or functional properties disclosed herein.

An effective amount of, for example, a TRPA1 antagonist, with respect to the inhibition or treatment methods in question, refers to the amount of the antagonist in a formulation that, when used as part of a desired dosing regimen, results in the desired clinical or functional outcome. Without wishing to be bound by theory, an effective amount of a TRPA1 antagonist for use in the methods of this invention includes an amount of a TRPA1 antagonist effective to attenuate one or more in vitro or in vivo functions of the TRPA1 channel. Exemplary functions include, but are not limited to, membrane polarization (eg, an antagonist may prevent cell depolarization), ion influx, cell ion concentration, external current, and internal current. Compounds that antagonize TRPA1 function include compounds that antagonize TRPA1 functional activity in vitro or in vivo. When a particular functional activity is only readily detectable in an in vitro assay, the ability of a compound to inhibit TRPA1 function in that in vitro assay serves as a reasonable indication of the compound's activity. In some embodiments, the effective amount is an amount sufficient to inhibit TRPA1 mediated current and/or an amount sufficient to inhibit TRPA1 mediated ion flux.

As used herein, the term hydrate refers to a compound formed by combining water with a parent compound.

The term prevention, when used in relation to a condition such as local recurrence (e.g. pain), a disease such as cancer, a syndrome complex such as heart failure, or any other disease, is well known in the art and includes the administration of a composition that reduces frequency or delay the onset of symptoms of a medical condition in a subject relative to a subject who is not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancers in a population of patients receiving prophylactic treatment compared to an untreated control population and/or delaying the onset of detectable cancers in a treated population compared to an untreated control population, e.g., statistically and /or a clinically significant amount. Prevention of infection includes, for example, reducing the number of diagnoses of infection in a treated population compared to an untreated control population and/or delaying the onset of symptoms of an infection in a treated population compared to an untreated control population. Pain prevention includes, for example, reducing the amount or, alternatively, slowing the pain experienced by subjects in a treated population compared to an untreated control population.

As used herein, the term solvate refers to a compound formed by solvation (eg, a compound formed by combining solvent molecules with solute molecules or ions).

The terms TRPA1, TRPA1 protein and TRPA1 channel are used interchangeably throughout the application. These terms refer to an ion channel (for example, a polypeptide) containing the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5 in WO 2007/073505, or an equivalent polypeptide, or a functional bioactive fragment thereof . In some embodiments, the term refers to a polypeptide comprising, consisting of, or consisting essentially of the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5. TRPA1 includes polypeptides that retain the function of TRPA1 and contain (i) all or part of the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5; (ii) the amino acid sequence shown in SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5 1 to 2, 3, 5, 7, 10, 15, 20, 30, 50, 75 or more conservative amino acid substitutions; (iii) an amino acid sequence that is at least 70%, 75%

- 18 041240

80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5; and (iv) their functional fragments. The polypeptides of this invention also include homologs, such as orthologues and paralogs of SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5.

In some embodiments, said methods comprise treating an inflammatory disease in a subject, the method comprising administering an effective amount of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.

In some embodiments, said methods comprise the treatment of neuropathy in a subject which comprises administering an effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the neuropathy is caused by diabetes, chemical damage, chemotherapy, and/or trauma.

In some embodiments, said methods comprise the treatment of a dermatological disorder in a subject, said methods comprising administering an effective amount of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof. Typical dermatological disorders include atopic dermatitis, acute pruritus, psoriasis, urticaria, eczema, dyshidrotic eczema, mouth ulcers, and diaper rash.

In some embodiments, said methods comprise treating a respiratory condition in a subject, said methods comprising administering an effective amount of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof. Typical respiratory conditions include obstructive diseases such as chronic obstructive pulmonary disease. Additional typical respiratory conditions include asthma and cough.

In another aspect of the present invention, there is provided a pharmaceutical formulation suitable for patient or veterinary use, comprising an effective amount of a compound of formula (I), (II) or (III) (or a salt or solvate, hydrate, oxidative metabolite or prodrug of a compound or its salts) and one or more pharmaceutically acceptable excipients. This invention also provides for the use of compounds of formula (I), (II) or (III) in the manufacture of a medicament or pharmaceutical preparation for the treatment or reduction of the symptoms of any of the diseases or conditions specified in the description. Compounds of formula (I), (II) or (III) for use in the treatment of a particular disease or condition may be formulated for administration by a route appropriate for the particular disease or condition.

Compounds of formula (I), (II) or (III) may be administered alone or in combination with another therapeutic agent. For example, compounds of formula (I), (II) or (III) may be administered together with one or more of an anti-inflammatory agent, an anti-acne agent, an anti-wrinkle agent, an anti-scar agent, an anti-scar agent, an anti-psoriasis agent, an antiproliferative agent, an antifungal agent. agent, an antiviral agent, an antiseptic, an anti-migraine agent, a keratolytic agent, or a hair growth inhibitor.

Compounds of formula (I), (II) or (III) can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiac, intradermally, parenterally , transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, sublingual, or by inhalation.

In some embodiments, the compounds of formula (I), (II) or (III) can be applied topically.

In some embodiments, the implementation of the compounds of formula (I), (II) or (III) can be administered orally.

In some embodiments, the implementation of the compounds of formula (I), (II) or (III) can be administered parenterally.

Compounds of formula (I), (II) or (III) include molecules having aqueous solubility suitable for oral or parenteral (eg intravenous) administration resulting in or resulting in the treatment of the disorder described herein, eg the treatment of pain. In some embodiments, said compound is formulated into a composition suitable for oral administration. The efficacy in inhibiting the TRPA1 ion channel of the compounds of formula (I), (II) or (III) described herein was measured using the method of example 1. In table. 2 discloses the in vitro inhibition efficacy of TRPA1 activity by exemplary compounds (measured by the method of Example 1).

Preferred compounds of formula (I), (II) or (III) include compounds that inhibit the TRPA1 ion channel with an IC ₅₀ value obtained by the method of Example 1 of less than about 1 μM.

Compounds of formula (I) can inhibit the TRPA1 ion channel. In some embodiments, said compound of formula (I), (II), or (III) may be administered as part of an oral or parenteral (eg, intravenous) pharmaceutical composition for the treatment of the disorder described herein (eg, pain) in a therapeutically effective manner.

Some of the compounds disclosed herein may exist in certain geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (1)-isomers, racemic mixtures thereof, and other mixtures thereof falling within within the scope of the invention. For example, if a single chiral center is present in the molecule, the invention includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically or diastereomerically pure compounds. The composition may contain, for example, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95% or more than 99% of one enantiomer or diastereomer. Additional asymmetric carbon atoms may be present on a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

The enantiomeric excess or % enantiomeric excess of the composition can be calculated using the equation shown below.

In the example below, the composition contains 90% of one enantiomer, eg the S-enantiomer, and 10% of the other enantiomer, ie the R-enantiomer.

ee = (90-10)/100 = 80%

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

The diastereomeric excess or % diastereomeric excess of the composition can be calculated using the equation shown below. In the example below, the composition contains 90% of one diastereomer and 10% of the other enantiomer.

ee = (90-10)/100 = 80%.

Thus, a composition containing 90% of one diastereomer and 10% of the other diastereomer is said to have an excess of 80% diastereomer.

In addition, compounds of formula (I) (II) or (III) may contain one or more isotopes of the atoms present in formula (I), (II) or (III). For example, compounds of formula (I), (II) or (III) may include: those in which H (or hydrogen) is replaced by any isotopic form of hydrogen, including 1H, ^2H or D (deuterium), and ^3H (tritium) ; those in which C is substituted by any isotopic form of carbon, including ¹² C, ¹³ C and ¹⁴ C; those in which O is substituted by any isotopic form of oxygen, including ¹⁶ O, ¹⁷ O, and ¹⁸ O; those in which N is replaced by any isotopic form of nitrogen, including ¹³ N, ¹⁴ N, and ¹⁵ N; those in which P is replaced by any isotopic form of phosphorus, including ³¹ P and ³² P; those in which S is replaced by any isotopic form of sulfur, including ³² S and ³⁵ S; those in which F is substituted by any isotopic form of fluorine, including ¹⁹ F and 18 F; etc. In one embodiment, the compounds represented by formulas (I), (II) or (III) contain isomers of the atoms therein in their natural amount.

In some embodiments, the compounds described herein (for example, the compound of formula (I), (II) or (III)), enriched in deuterium. Deuterium (D or ² H) is a stable non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen occurs naturally as a mixture of the isotopes 1H (hydrogen or protium), D ( ² H or deuterium), and T ( ³ H or tritium). The natural frequency of occurrence of deuterium is 0.015%. It will be recognized by one skilled in the art that in all chemical compounds with an H atom, the H atom is actually a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been increased to a level greater than its natural a frequency of 0.015% should be considered unnatural and, as a result, new compared to their unfortified counterparts.

The effect of deuterium modification on the metabolic properties of a compound is not predictable, even when deuterium atoms are included in known metabolic sites. It is only by actually preparing and testing the deuterated compound that it can be determined whether the metabolic rate will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many compounds have multiple sites where metabolism is possible. The site(s) where deuterium replacement is required and the degree of deuteration required to see an effect on metabolism, if any, will differ for each compound. Unless otherwise indicated, when a position is specifically designated as H or hydrogen, the position is understood to have hydrogen with its isotopic composition in natural frequency of occurrence. Also, unless otherwise noted, when an item is specifically designated as D or deuterium, the item means the presence of deuterium with an abundance that is at least 3000 times the natural abundance of deuterium, which is 0.015% (i.e. the term D or deuterium means at least 45% deuterium inclusion).

As used herein, the term isotopic enrichment factor means the ratio between the isotopic abundance of D at a given position in a compound of this invention and the natural abundance of that isotope.

Increasing the amount of deuterium present in a compound (eg, a compound of formula (I)) is referred to as deuterium enrichment, and such compounds are referred to as deuterium enriched compounds. Unless otherwise stated, percentage enrichment refers to the percentage of deuterium present in the compound.

In other embodiments, said compound of this invention has an isotopic enrichment factor for each deuterium present at the location indicated in the pot.

- 20 041240 in the deuterium site of the compound, at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 ( 75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6633.3 (99, 5% inclusion of deuterium). It is understood that the isotopic enrichment factor of each deuterium present in the region designated as the deuteration region is independent of the other deuterium regions. For example, if two deuteration sites are present on a compound, one site may be deuterated at 52.5% while the other may be deuterated at 75%. The resulting compound will be considered a compound in which the isotopic enrichment factor is at least 3500 (52.5%).

In some embodiments, the compounds of formula (I), (II), or (III) include an amount of deuterium enrichment that is greater than the amount of deuterium enrichment present in naturally occurring compounds. All percentages given for the amount of deuterium present are mole percent.

In the laboratory, it can be difficult to achieve 100% deuteration at any point in the laboratory amount of a compound (eg, a milligram or more). When 100% deuteration is specified, or a deuterium atom is specifically specified in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium enrichment can be achieved by exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.

Certain compounds disclosed herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of this invention. Some of the compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this invention and are intended to be within the scope of this invention.

Pharmaceutical compositions

Pharmaceutical compositions containing compounds described herein, such as compounds of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, can be used to treat or alleviate the disorder described herein, for example, a disorder, sensitive to inhibition. TRPA1 ion channel in subjects (eg, humans and animals).

The amount and concentration of the compounds of formula (I), (II) or (III) in the pharmaceutical compositions, as well as the amount of the pharmaceutical composition administered to the subject, may be selected based on clinically relevant factors such as the medical characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in pharmaceutical compositions, the efficacy and potency of compounds, and the route of administration of pharmaceutical compositions. For further information on routes of administration and dosing regimens, the reader may refer to Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry ( Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Although the compound disclosed herein may be administered alone, it is preferred to administer the compound as a pharmaceutical composition in which the compound is combined with one or more pharmaceutically acceptable diluents, excipients, or carriers. The compounds disclosed herein may be formulated for administration by any convenient route for human or veterinary use. In some embodiments, said compound included in a pharmaceutical formulation may itself be active or may be a prodrug, eg capable of being converted to the active compound under physiological conditions.

As used herein, the phrase "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers and/or dosage forms that, upon careful medical examination, are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions. response or other problems or complications and have an acceptable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances used in pharmaceuticals

- 21 041240 tic compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA - butylated hydroxyanisole), butylated hydroxytoluene (BHT butylated hydroxytoluene), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Solid dosage forms (eg, capsules, tablets, pills, dragees, powders, granules, and the like) may contain one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: (1) excipients or prologues such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) retarding dissolution agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) dyes.

Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide. or mixtures thereof.

Powders and aerosols may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The dispensers may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to form a unit dosage form will vary depending on the host being treated, the particular route of administration. The amount of active ingredient that can be combined with the carrier material to form a unit dosage form will usually be that amount of the compound that produces a therapeutic effect. Typically, from 100%, this amount will comprise from 1 to 99% of the active ingredient, preferably from 5 to 70%, most preferably from 10 to 30%.

Tablets and other solid dosage forms of the pharmaceutical compositions disclosed herein, such as dragees, capsules, pills, and granules, may optionally be packed or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. . They can also be formulated to provide a slow or controlled release of the active ingredient therein, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition in which they release the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally with a delay. Examples of potting compositions that can be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, if desired, with one or more of the excipients described above.

Dosage forms for topical or transdermal administration of a compound of this invention include powders, spray formulations, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants.

The formulations disclosed herein can be delivered via the device. Typical devices include, but are not limited to, a catheter, wire, stent, or other intraluminal device. Additional exemplary delivery devices also include a patch, bandage, mouth guard, or dental appliance. Transdermal patches have the additional advantage of providing controlled delivery of the compound disclosed herein to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound through the skin. The rate of such a flux can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic preparations, eye ointments, drops, solutions and the like are also considered to be within the scope of this invention.

In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of drug absorption is then dependent on its rate of dissolution, which in turn may be dependent on crystal size and crystalline form. Alternatively, delayed absorption of a parenteral dosage form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are obtained by forming microencapsular matrices of the compounds in question in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectables are also prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissues.

When the compounds disclosed herein are administered as medicaments to humans and animals, they may be administered per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in association with a pharmaceutically acceptable carrier.

These preparations can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraparentally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoid, intraspinal, intrasternal or by inhalation.

One specific embodiment is an antitussive composition for oral administration comprising an agent that inhibits both TRPA1-mediated current with an IC ₅₀ of 1 μmol or less and an orally acceptable pharmaceutical carrier in the form of an aqueous liquid or oral soluble solid. selected from the group consisting of syrup, elixir, suspension, spray, lozenge, chewable lozenge, powder and chewable tablet. Such antitussive compositions may include one or more additional agents for the treatment of cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H3 inhibitors, β-adrenergic receptor agonists, xanthine derivatives, a-adrenergic agonists receptors, mast cell stabilizers, expectorants and NK1, NK2 and NK3 tachykinin receptor antagonists.

Another embodiment is a metered aerosol dispenser containing an aerosol pharmaceutical composition for pulmonary or nasal delivery containing an agent that inhibits TRPA1-mediated current with an IC ₅₀ of 1 micromole or less. For example, it may be a metered dose inhaler, a dry powder inhaler, or an aerosol dispenser.

Doses

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and route of administration, without toxicity to the patient.

The selected dosage level will depend on a variety of factors, including the activity of the particular compound disclosed herein, or its ester, salt or amide, pathway

- 23 041240 administration, time of administration, rate of excretion of a particular compound, duration of treatment, other drugs, compounds and / or materials used in combination with a specific compound used, age, sex, weight, condition, general health and previous medical history of the patient , which is being treated, and similar factors are well known in the field of medicine.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may start doses of the compounds of this invention used in a pharmaceutical composition at levels below those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of this invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Typically, intravenous, intracerebroventricular, intrathecal, and subcutaneous doses of the compounds of this invention to a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. For example, the dose may be 1-50, 1-25, or 5-10 mg/kg.

If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.

Methods of treatment

The compounds described herein may be used to treat or prevent the disorder described herein.

For example, compounds with TRPA1 inhibitory activity are provided herein to prevent, treat, or alleviate symptoms of a disease or condition associated with TRPA1. Compounds of formula (I), (II) or (III) or pharmaceutical compositions containing one or more compounds of formula (I), (II) or (III) may be administered to treat the disorders, conditions or diseases described herein, such as those that are treatable by TRPA1 inhibition. For example, pharmaceutical compositions containing compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, are useful as a perioperative analgesic, for example in the treatment of mild to moderate acute postoperative pain and in the treatment of moderate to severe acute pain as an adjunct to opioid analgesics. Pharmaceutical compositions containing a therapeutically effective dose of compounds of formula (I), (II) or (III) can be administered to a patient for the treatment of pain in a clinically safe and effective manner, including one or more separate administrations of pharmaceutical compositions containing compounds of formula (I), ( II) or (III). Additional illustrative methods include the treatment of peripheral diabetic neuropathy (PDN) and chemotherapy-induced peripheral neuropathy (CIPN). For example, a pharmaceutical composition containing a therapeutically effective dose of compounds of formula (I) (II) or (III), or their pharmaceutically acceptable salts, can be administered (for example, intravenously) to a subject in need of it several times a day (for example, twice a day ( BID)) during a course of treatment of one or more days to treat pain in a subject. Pharmaceutical compositions containing compounds of formulas (I), (II) or (III) may also be used to treat or alleviate respiratory conditions such as obstructive diseases, e.g. chronic obstructive pulmonary disease (COPD), asthma (e.g. caused by the common cold, exercise-induced asthma, allergy-induced asthma, and occupational asthma) and cough.

Those skilled in the treatment of diseases associated with mediating the TRPA1 receptor will be able to determine a therapeutically effective amount of a compound of formula (I), (II) or (III) from the test results below. In general, a suitable daily dose of a compound of this invention will be that amount of the compound which is the lowest dose capable of producing a therapeutic effect. Such an effective dose usually depends on various factors. Typically, oral, sublingual, rectal, intravenous, topical, transdermal, inhalation, and intracerebroventricular doses of the compounds of this invention to a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. For example, the dose may be 1-50, 1-25, or 5-10 mg/kg. For example, a therapeutically effective dose is contemplated to be about 0.001 to about 50 mg/kg per kg of body weight, more preferably about 0.01 to about 10 mg/kg per kg of body weight of the patient being treated. It may be appropriate to administer a therapeutically effective dose in the form of two or more sub-doses at regular intervals throughout the day. These sub-doses may be formulated as unit dosage forms, for example, each containing from about 0.1 mg to about 1000 mg, more specifically from about 1 to about 500 mg of the active ingredient per dosage unit.

The exact dose and frequency of administration depends on the particular compound of formula (I), (II) or (III) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and also other drugs that the patient may be taking, as is well known to those skilled in the art. In addition, said therapeutically effective amount may be reduced or increased depending on the response of the treating patient and/or depending on the judgment of the physician prescribing the compounds of this invention. Thus, the effective daily amount ranges mentioned above are indicative only. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition.

Exemplary disorders suitable for treatment with a compound or composition described herein are provided below.

Pain

Compounds of formula (I), (II) or (III) which are useful in TRPA1 modulation may be used in pharmaceutical analgesics suitable for the treatment and/or prevention of pain in mammals, especially humans. Endogenous TRPA1 activators are produced in many pathological conditions, including tissue damage, inflammation, and metabolic stress. The compounds and pharmaceutical compositions of this invention can be administered to treat pain resulting from TRPA1 activation, including neuropathic pain. Suitable neuropathic pain conditions include, but are not limited to, painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, low back pain, trigeminal neuralgia, postherpetic neuralgia, sciatica, and complex regional pain syndrome.

The compositions and methods provided herein may also be used in connection with treatment in the treatment of inflammation and inflammatory pain. Such disorders include rheumatoid arthritis, osteoarthritis, temporomandibular disorder. In some embodiments, the compositions and methods provided herein can be used to treat headache, such as migraine.

The disclosed compounds may also be useful in the treatment of visceral pain and inflammation. Related diseases include pancreatitis, inflammatory bowel disease, colitis, Crohn's disease, endometriosis, pelvic pain, and angina pectoris.

Additional exemplary pain indications for which the compounds disclosed herein may be useful include temporomandibular disorder, cancer pain (resulting from underlying disease or treatment), burn pain, oral pain, oral pain. mouth due to cancer treatment, pain caused by crushing and trauma, incisional pain, bone pain, sickle cell anemia, fibromyalgia, and musculoskeletal pain. TRPA1 has been shown to play a role in cancer-related pain (see, for example, Trevisan et al., Cancer Res March 11, 2013); postoperative pain (see, for example, Wei et al., Anasthesiology, V 117, No. 1 (2012); pathological pain (see, for example, Chen et al., Pain (2011).); and pain associated with chemical damage (see, for example, Macpherson et al, The Journal of Neuroscience, October 17, 2007 27(42):1141211415).

Hyperalgesia (eg, mechanical hyperalgesia, cold hyperalgesia) or hypersensitivity to pain (eg, acute, chronic). Multiple chemical sensitivity is a chemical exposure disorder with multi-organ symptoms including respiratory symptoms and headache.

Allodynia (eg, cutaneous allodynia, eg, cephalic, extracephalic) is pain caused by a stimulus that does not normally cause pain, such as temperature or physical stimuli, and is distinct from hyperalgesia, which usually refers to an extreme, exaggerated response to a stimulus that usually painful.

Migraine

Compounds of formulas (I), (II) or (III) which are useful in modulating TRPA1 may be used in the formulation of pharmaceutical preparations suitable for the treatment and/or prevention of migraine in mammals, especially humans. Exposure to TRPA1 activators has been shown to induce migraine in susceptible populations. Such activators include, but are not limited to, umbellulone, nitroglycerin, cigarette smoke, and formaldehyde. Accordingly, the TRPA1 antagonists of the present invention represent a significant potential therapeutic agent for the treatment of both chronic and acute migraine.

Inflammatory diseases and disorders

The compositions and methods provided herein may also be used in connection with the treatment of inflammatory diseases. These diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and immune system disorders. TRPA1 has been shown to play a role in pain and inflammation of the pancreas (see, for example, Schwartz et al., Gastroenterology. April 2011; 140 (4): 1283-1291.). Peripheral neuropathy, such as diabetic neuropathy, is a specific condition that includes both a neuronal and an inflammatory component. Not being

- 25 041240 associated with a mechanistic theory, the TRPA1 antagonists of this invention may be useful in the treatment of peripheral neuropathies, including, but not limited to, diabetic neuropathy. In addition to their use in the treatment of peripheral neuropathies (eg, to reduce inflammation), inhibitors may also be useful in reducing pain associated with peripheral neuropathy. TRPA1 has been shown to play a role in neuropathy and neuropathic pain (see, for example, Wei et al., Anesthesiology 2009; 111: 147-54; and Koivisto et al., Pharmacological Research, 2011).

Neurogenic inflammation often occurs when neuronal hyperexcitability results in the release of peptides that cause inflammation. These peptides include substance P and CGRP.

Blocking TRPA1 reduces neuronal activity and thus can block neurogenic inflammation. For example, neurogenic inflammation in the airways can lead to asthma and allergic rhinitis symptoms, and neurogenic inflammation in the dura can also mediate migraine pain.

Pancreas

Pancreatitis is an inflammation of the pancreas. The pancreas is a large gland located behind the stomach and close to the duodenum. Generally, digestive enzymes do not become active until they reach the small intestine, where they begin to digest food. But if these enzymes become active inside the pancreas, they begin to digest the pancreas itself. TRPA1 has been shown to play a role in pancreatic pain and inflammation (see, for example, Schwartz et al., Gastroenterology. April 2011; 140(4): 1283-1291).

Acute pancreatitis is usually, though not exclusively, caused by gallstones or alcohol abuse. Acute pancreatitis usually starts with pain in the upper abdomen that can last for several days. The pain can be severe and may become constant. The pain may be isolated from the abdomen or may radiate to the back and other areas. Sometimes and in some patients the pain is sudden and intense. In other cases, or for other patients, the pain begins as a mild pain that gets worse after eating. Someone with acute pancreatitis often looks and feels very sick. Other symptoms may include bloating and tenderness, nausea, vomiting, fever, and a fast pulse. Severe cases of acute pancreatitis can cause dehydration and low blood pressure, and can even lead to organ failure, internal bleeding, or death.

During acute attacks of pancreatitis, blood levels of amylase and lipase often rise at least 3-fold. Changes may also occur in the levels of glucose, calcium, magnesium, sodium, potassium, and bicarbonate in the blood.

Current treatment depends on the severity of the attack. Treatment is generally designed to support vital body functions, control pain, and prevent complications. Although acute pancreatitis usually resolves in a few days, treatment for pain during an attack is often required. The compounds disclosed herein can be used to relieve pain associated with acute pancreatitis.

Chronic pancreatitis may develop if damage to the pancreas continues. Chronic pancreatitis occurs when digestive enzymes attack and destroy the pancreas and nearby tissues, causing scarring and pain. Chronic pancreatitis can be caused by alcoholism or blocked, damaged, or narrowed pancreatic ducts. In addition, hereditary factors seem to influence the disease, and in some cases there is no definite cause (so-called idiopathic pancreatitis).

Most people with chronic pancreatitis have abdominal pain. The pain may increase with eating or drinking, radiate to the back, or become constant and disabling. Other symptoms include nausea, vomiting, weight loss, and fatty stools.

Pain relief is the first step in treating chronic pancreatitis. After the pain is overcome, a diet high in carbohydrates and fats is drawn up. Pancreatic enzymes may be used to help compensate for decreased production of enzymes from a damaged pancreas. Sometimes insulin or other medicines are needed to control blood glucose levels.

Although pain is usually managed with drug therapy, surgery may be necessary to relieve the pain.

Surgery may be needed to drain an enlarged pancreatic duct or even to remove part of a severely damaged pancreas.

Pain is often present in chronic pancreatitis. For example, pain is present in approximately 75% of patients with alcoholic chronic pancreatitis, 50% of patients with late onset idiopathic chronic pancreatitis, and 100% of patients with early onset idiopathic chronic pancreatitis (DiMagno, 1999, Gastroenterology 116(5): 1252-1257) .

A minority of patients with pain have easily identifiable lesions that are relatively easy to treat surgically or endoscopically. In other patients, pain is thought to result from a number of causes, including increased intrapancreatic pressure, ischemia, and fibrosis. However, without being bound by theory, these phenomena are unlikely to be the main cause of pain.

Rather, pain may result from neuronal sensitization caused by injury to the perineum and subsequent exposure of the nerves to mediators and inflammatory products.

Given the importance of effective pain management in patients with chronic pancreatitis, additional treatments for pain symptoms are important and useful. The compounds disclosed herein can be used to treat pain associated with chronic pancreatitis; they may be used alone or as part of an overall therapeutic plan for patients with chronic pancreatitis. For example, the compounds may be administered with pancreatic enzymes and/or insulin as part of a therapeutic regimen for the treatment of patients with chronic pancreatitis.

Cancer treatments are not only painful, but can even be toxic to healthy tissue. Some chemotherapy agents can cause painful neuropathy. Accordingly, the compounds disclosed herein may represent a significant potential therapeutic agent for the treatment of pain and/or inflammation associated with cancer treatment that causes neuropathy.

The main function of prostaglandins is to protect the gastric mucosa. Included in this function is the modulation of intracellular calcium levels in human gastric cells, which plays a critical role in cell proliferation. Therefore, inhibition of prostaglandins by non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit calcium influx into gastric cells (Kokoska et al. (1998) Surgery (St Louis) 124 (2): 429-437). NSAIDs that are most effective at reducing inflammation also cause the most damage to the gastrointestinal tract (Canadian Family Physician, January 5, 1998, p. 101. Thus, the ability to independently modulate calcium channels in certain cell types may help mitigate this side effect of anti-inflammatory therapy. Additionally or alternatively, the administration of the TRPA1 inhibitory compounds described herein can be used in combination with NSAIDs, thereby contributing to pain relief using a reduced dosage of NSAIDs.

TRPA1 may mediate ongoing nociception in chronic pancreatitis; and may be involved in the transformation of acute to chronic inflammation and hyperalgesia in pancreatitis. TRPA1 can also mediate irritation and burning, for example, in the mucosa of the nose and mouth and the respiratory tract.

neuropathy

Because TRPA1 hyperactivity can lead to toxic calcium overload, TRPA1 antagonists are also useful in the prevention of neuropathy associated with diabetes, chemical damage, chemotherapy, drugs such as statins, HIV/AIDS, Fabry disease, vitamin deficiency, hereditary polyneuropathy such as Charcot-Marie-Tooth and injuries. Peripheral neurodegenerative diseases such as amyotrophic lateral sclerosis can also be treated with a TRPA1 antagonist.

Lung disease and cough

The compositions and methods provided herein may also be used in connection with the treatment of lung diseases, including, but not limited to, asthma (including exercise-induced asthma, atopic asthma, allergic asthma), chronic obstructive pulmonary disease (COPD, emphysema ), cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, bronchiolitis obliterans (popcorn worker lung), diseases caused by chemical exposure, including exposure to diacetyl, formaldehyde and other irritants. These conditions also include tuberculosis, restrictive lung diseases including asbestosis, radiation fibrosis, hypersensitivity pneumonitis, respiratory distress syndrome in infants, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, sarcoidosis, eosinophilic pneumonia, lymphangioleiomyomyomatosis, pulmonary Langerhans cell histocytosis, pulmonary alveolar proteninosis, respiratory tract infections, including upper respiratory tract infections (eg, colds, sinusitis, tonsillitis, pharyngitis, and laryngitis) and lower respiratory tract infections (eg, pneumonia); respiratory tract tumors, malignant (eg, small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell undifferentiated cancer, carcinoid, mesothelioma, metastatic lung cancer, metastatic germ cell cancer, metastatic renal cell carcinoma) or benign (eg, pulmonary hamartoma , congenital malformations such as pulmonary sequestration and congenital cystic adenomatoid malformation (CCAM - congenital cystic adenomatoid malformation)); diseases of the pleural cavity (for example, empyema and mesothelioma); and pulmonary vascular diseases such as pulmonary embolism such as thromboembolism and air embolism (iatrogenic), pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation and damage to the capillaries in the lungs leading to leakage of blood into the alveoli. Other conditions that can be treated include disorders that affect the mechanics of breathing (eg, obstructive sleep apnea, central sleep apnea, Guillain-Barré syndrome, and myasthenia gravis).

- 27 041240

The compounds of this invention may also be useful in the treatment, reduction, or prevention of cough (with or without sputum production), asthma-associated cough, influenza-associated cough, cough with blood (hemoptysis), cough of unknown etiology, and cough due to chemical exposure.

Dermatological disorders

A number of pruritic agents activate TRPA1 directly or through activation of receptors that bind to TRPA1 during signal transduction. The compositions and methods provided herein may also be used in connection with the treatment of pruritus. Indications include, but are not limited to, conditions caused by exposure to exogenous chemicals such as contact dermatitis, poison ivy, pruritus due to cancer including lymphomas, pruritus due to drugs such as chloroquine, pruritus due to active drug metabolites, or itching caused by dry skin.

Additional illustrative diagnoses include atopic dermatitis, psoriasis, urticaria, eczema, dyshidrotic eczema, mouth ulcers, diaper rash.

Itching

Itching or acute itching, although it has an important protective function, for example, warning against harmful substances in the environment, can also be a debilitating condition, which, for example, accompanies numerous skin diseases, systemic diseases and diseases of the nervous system. Some forms of pruritus are mediated by histamine signaling as they are susceptible to treatment with, for example, antihistamines. However, most pathophysiological pruritic conditions are unresponsive to antihistamine treatment. Compounds and pharmaceutical compositions according to this invention can be entered for the treatment of pruritus.

Atopic dermatitis (AD) is a chronic itching and inflammatory skin disease. Patients with severe AD may develop asthma and allergic rhinitis, also known as atopic march. Skin rash and itching may be associated with atopic disease. Chronic itching, such as in AD and psoriasis; includes pathophysiological features such as severe scratching, extensive epidermal hyperplasia such as eczema, renal insufficiency, cirrhosis of the liver, nervous system disorders, and certain types of cancer.

Allergic contact dermatitis is a common skin condition associated with inflammation and persistent itching.

The methods disclosed herein can inhibit skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine scratch-resistant behavior. The methods disclosed herein can inhibit an allergic response to, for example, exogenous stimulants, eg, haptens, oxazolone, urushiol (eg, from poison ivy).

Models of disease and injury

Compounds that antagonize TRPA1 function may be useful in the prevention and treatment of any of the above injuries, diseases, disorders or conditions. In addition to in vitro activity assays for these compounds, their efficacy can be readily tested in one or more animal models. Numerous animal models exist for the study of pain. Different models use different agents or procedures to model pain caused by injury, disease, or other conditions (Blackburn-Munro (2004) Trends in Pharmacological Sciences 25: 299-305 (see, for example, Tables 1, 3, or 4)). The behavioral characteristics of the infected animals can then be observed. Compounds or procedures that can reduce pain in animals can be readily tested by observing the behavioral characteristics of infected animals in the presence or absence of the test compound(s) or procedure.

Illustrative behavioral tests used to study chronic pain include tests of spontaneous pain, allodynia, and hyperalgesia. Posture, gait, and nociphagenic signs (eg, paw licking, excessive grooming, excessive exploratory behavior, guarding of an injured body part, and self-injury) can be observed to evaluate spontaneous pain. To measure induced pain, behavioral responses can be examined after exposure to heat (eg, a thermal injury model).

Exemplary animal pain models include, but are not limited to, those described in the Trevisan model and described in Covisto's reference, including streptozotocin-induced painful diabetic neuropathy, bortezomib-induced peripheral neuropathy, and oxaliplatin-induced peripheral neuropathy; Chung model, nerve injury model, carageenan-induced hyperalgesia model, Freund's complete adjuvant-induced hyperalgesia model, thermal injury model, formalin model, and Bennett model.

In Trevisan, a model of chemotherapy-induced peripheral neuropathy involves the induction of the CIPN phenotype in mice by treatment with bortezomib or oxaliplatin (Trevisan et al., Cancer research 73, 3120-3131, 2013). Treating an animal with a TRPA1 inhibitor can be assessed using any of a variety of nociceptive tests such as the von Frey hair test, hot plate test, simulated cold, chemical hyperalgesia, or rotarod test.

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The model of peripheral diabetic neuropathy (PDN) at Koivisto's source includes the induction of diabetes mellitus (DM) in rats with streptozotocin and the evaluation of the axon reflex induced by intraplantar administration of a TRPA1 agonist. (Pharmacological Research 2011) Treatment with a compound that inhibits TRPA1 can be assessed by reducing DM-induced axon skin reflex attenuation.

Chung's model of neuropathic pain (without inflammation) involves ligation of one or more spinal nerves (Chung et al. (2004) Methods Mol Med 99: 35-45; Kim and Chung (1992) Pain 50: 355-363). Ligation of spinal nerves results in various behavioral changes in animals, including thermal hyperalgesia, cold allodynia, and ongoing pain. Compounds that antagonize TRPA1 can be administered to ligated animals to evaluate if they reduce these ligation-induced behavioral changes compared to those seen in the absence of the compound.

Carrageenan-induced hyperalgesia and complete hyperalgesia induced by Freund's adjuvant (CFA-complete Freund's adjuvant) are models of inflammatory pain (Walker et al. (2003) Journal of Pharmacol Exp Ther 304: 56-62; McGaraughty et al. (2003) Br J Pharmacol 140: 1381-1388 Honore et al (2005) J Pharmacol Exp Ther). Compounds that antagonize TRPA1 can be administered to animals exposed to carrageenan or CFA to evaluate whether they reduce cold hypersensitivity, mechanical or thermal sensitivity compared to that observed in the absence of the compound. In addition, the ability of compounds that antagonize TRPA1 function to reduce cold and/or mechanical hypersensitivity can also be assessed in these models. Generally, the carrageenan-induced hyperalgesia model is believed to mimic acute inflammatory pain, and the CFA model is believed to mimic chronic pain and chronic inflammatory pain.

Exemplary models of inflammatory pain include the intraplantar bradykinin rat model. Briefly, the basic thermal sensitivity of animals is assessed on the Hargreave apparatus. TRPA1 blockers are then administered systemically. Subsequently, bradykinin is injected into the paw, and hyperalgesia develops. The heat output delay is then measured at several time points over the next few hours (Chuang et al., 2001; Vale et al., 2004).

Inflammation is often an important factor in pain. Thus, it is useful to identify compounds that act as anti-inflammatory agents. Many compounds that reduce nerve activity also prevent neurogenic inflammation. To measure inflammation directly, rat paw volume can be assessed using a plethysmometer. After a baseline measurement, carrageenan can be injected into the paw and volume monitored for several hours in vehicle or drug treated animals. Drugs that reduce paw swelling are considered anti-inflammatory.

Migraine is associated with significant pain and an inability to perform normal tasks. There are several models of migraine, including the neurogenic inflammation model in rats (see Buzzi et al. (1990) Br J Pharmacol; 99: 202-206) and the Burstein model (see Strassman et al., (1996) Nature 384: 560- 564).

The Bennett model uses prolonged paw ischemia to reflect chronic pain (Xanthos et al. (2004) J Pain 5: S1). This provides an animal model of chronic pain, including postoperative pain, complex regional pain syndrome, and reflex sympathetic dystrophy. Prolonged ischemia causes behavioral changes in animals, including hyperalgesia to mechanical stimuli, sensitivity to cold, pain sensations (eg, paw shaking, licking, and/or craving), and hyperpathy. Compounds that antagonize TRPA1 can be administered to infected animals to evaluate if they reduce any or all of these behaviors compared to those observed in the absence of the compound. Similar experiments can be carried out on a model of thermal injury or UV burn, which can be used to simulate postoperative pain.

Additional models of neuropathic pain include models of central pain based on spinal cord injury. Chronic pain occurs due to damage to the spinal cord, for example, due to weight being dropped on the area of the spinal cord being surgically affected (eg, weight loss model). In addition, spinal cord injury can be caused by crushing or squeezing the spinal cord, delivery of a neurotoxin, use of photochemicals, or hemisection of the spinal cord.

Additional models of neuropathic pain include models of peripheral nerve injury. Illustrative models include, but are not limited to, the neuroma model, the Bennett model, the Seltzer model, the Chung model (ligation at L5 or L5/L6), the sciatic nerve cryoneurolysis model, the lower caudal trunk resection model, and the sciatica inflammatory neuritis model.

Identifier (Id).

Exemplary disease-specific neuropathic pain models are also available. Diabetes and herpes zoster are two diseases often accompanied by neuropathic pain. Even after episodes of acute herpes zoster, some patients continue to suffer from postherpetic neuralgia and experience persistent pain for many years. Neuropathic pain caused by herpes zoster and/or postherpetic neuralgia can be studied in the postherpetic neuralgia (PHN) model. Diabetic neuropathy can be studied in diabetic mouse models as well as chemically induced diabetic neuropathy models.

As stated above, cancer pain can have any of several causes, and there are numerous animal models for studying cancer pain associated, for example, with chemotherapeutic agents or tumor infiltration. Exemplary toxin-associated pain models include the vincristine-induced peripheral neuropathy model, the taxol-induced peripheral neuropathy model, and the cisplatin-induced peripheral neuropathy model. An example of a model of cancer pain caused by tumor infiltration is the CIP cancer invasion pain model.

Primary and metastatic bone cancer is associated with severe pain. Several models of bone cancer pain exist, including the femur bone cancer (FBC) mouse pain model, the calcaneus bone cancer (CBC) mouse model, and the tibia tibia (TBC) model of tibial bone cancer (TBC). bone cancer).

Identifier.

An additional pain model is the formalin model. Like the carrageenan and CFA models, the formalin model involves administering the stimulus intradermally or parenterally to the animal. Formalin injection, a 37-40% formaldehyde solution, is the most commonly used intradermal paw injection (formalin test). Injection of a 0.5-15% formalin solution (usually about 3.5%) into the dorsal or plantar surface of the fore or hind paw causes a biphasic painful reaction of increasing and decreasing intensity within about 60 minutes after injection. Typical responses include raising the paw, licking it, biting it, or shaking it. These responses are considered nociceptive. The initial response phase (also known as the early phase), which lasts 3 to 5 minutes, is likely due to direct chemical stimulation of the nociceptors. This is followed by 10-15 minutes, during which the animals have minor manifestations of behavior indicative of nociception. The second phase of this response (also known as the late phase) begins approximately 15–20 min after formalin injection and lasts 20–40 min, initially with an increase in both the amount and frequency of nociceptive behavior, peaking, then falling. The intensity of these nociceptive behaviors depends on the concentration of formalin used. The second stage includes a period of sensitization, during which inflammation occurs. The two phases of formalin injection sensitivity make the formalin model a suitable model for studying nociceptive and acute inflammatory pain. It may also model, in some respects, neuropathic pain.

In addition to any of the aforementioned chronic pain models, compounds that antagonize TRPA1 function can be tested in one or more acute pain models. Valenzano et al. (2005) Neuropharmacology 48: 658-672. Whether compounds are being tested in models of chronic pain, acute pain, or both, these studies are usually (though not exclusively) conducted in, for example, mice, rats, or guinea pigs. In addition, the compounds can be tested in various cell lines that provide an in vitro pain assay.

Many people who need pain treatment suffer from visceral pain. Animal models of visceral pain include the rat model of uterine inflammatory pain (Wesselmann et al., (1997) Pain 73: 309-317), injection of mustard oil into the gastrointestinal tract to mimic irritable bowel syndrome (Kimball et al., (2005) Am J Physiol Gastrointest Liver Physiol, 288 (6): G1266-73), injection of mustard oil into the bladder to mimic an overactive bladder or bladder cystitis (Riazimand (2004), BJU 94: 158-163). The effectiveness of a compound for TRPA1 can be assessed by reducing writhing, gastrointestinal inflammation, or bladder excitability.

To test the effectiveness of TRPA1 antagonists for treating cough, experiments can be easily performed using a cough model on a guinea pig cough model (Tanaka and Maruyama (2003) Journal Pharmacol Sci 93: 465-470; McLeod et al. (2001) Br J Pharmacol 132: 1175 -1178). In short, guinea pigs serve as a useful animal model for coughing because, unlike other rodents such as mice and rats, guinea pigs actually cough. In addition, guinea pig cough appears to mimic human cough in terms of posture, behavior, and appearance of the coughing animal.

To induce coughing, conscious guinea pigs are exposed to a triggering agent such as citric acid or capsaicin. The response of the animal is measured by counting the number of coughs. The effectiveness of a cough suppressant, such as a compound that inhibits TRPA1, can be measured by administering an agent and evaluating the ability of the agent to reduce the amount of cough induced by exposure to citric acid, capsaicin, or another similar pathogen.

- 30 041240 cough. Thus, TRPA1 inhibitors for use in the treatment of cough can be easily evaluated and identified.

Additional cough models may also include an unconscious guinea pig model (Rouget et al. (2004) Br J Pharmacol 141: 1077-1083). Any of the above models can be adapted for use with other coughing animals. Examples of additional animals capable of coughing include cats and dogs.

The compounds of the invention can be tested in several models of asthma. One example is the mouse ovalbumin model of asthma (Caceres Al et al., Proc Natl Acad Sci US A. 2009 Jun 2;106(22):9099-104; Epub 2009 May 19). In this model, ovalbumin is injected into the intraperitoneal cavity several times over a period of 2 weeks. Around the third week, animals are challenged with intranasal ovalbumin and airway hyperresponsiveness, inflammation, and inflammatory cytokine production can be measured. Compounds are dosed at the stage of introduction into the models. TRPA1 knockout mice can be changed to the above models as reported by Caceres et al.

An example of a large animal model of asthma is the consciousness allergy sheep model as described in Abraham, WM et al. can be used to assess the effect of compounds on the antigen-induced response of asthma in the late stage (Abraham WM., Am J Respir Crit Care Med. 2000 Aug; 162 (2 Pt 1): 603-11). Briefly, baseline airway sensitivity is measured with a plethysmograph in conscious sheep prior to administration of a molten extract of Ascaris suum for asthma induction. After obtaining the baseline indications, the animals are given a nebulized dose of Ascaris suum. Antigen sensitivity is defined as a decrease in pulmonary flow resistance from baseline. Once animals demonstrate antigen sensitivity, test compounds can be administered and additional pulmonary flow resistance readings obtained to assess changes in airway sensitivity. Models on horses and beagle dogs are sometimes also used.

Additional models may include the Brown Norway rat model and the C57BL/6J mouse asthma model as described in Raemdonck et al. (Raemdonck K et al., Thorax. 2012 Jan;67(1):19-25; Epub 2011 Aug 13). Briefly, Brown Norway rats and C57BL/6J mice can be sensitized and challenged with aerosolized ovalbumin. Once sensitivity is confirmed by decreased lung function as measured by whole body plethysmograph readings, the compounds of this invention may be administered. Visual and auditory signs of respiratory distress may also be present, including wheezing.

Dermatitis

Currently, there are many models of dermatological diseases in mice. For example, Liu et al. describe multiple patterns of contact dermatitis caused by oxazolone and urushiol (Liu B et al., FASEB J. 2013 Sep;27(9):3549-63; Epub 2013 May 30). Briefly, Trpa1 knockout mice receive topical oxazolone or urushiol to induce dermatitis and pruritus reactions. The thickness of the epidermis can also be measured by taking sections of the ears and measuring problem areas in comparison to untreated ears. Compounds for in vivo treatment can be determined by administering the compounds to animals before or after treatment with ozazolone or urushiol. The scratching behavior is recorded by video cameras located above the surveillance cameras. Observers unfamiliar with the treatment groups record the time the animals spend scratching for 30 minutes.

An alternative mouse model of pruritic dry skin involves administration of acetone, ether, and water to mice, as reported by Wilson et al. (Wilson SR et al., J Neurosci. 2013 May 29; 33(22):9283-94) In this model, the area to be treated is shaved and mice receive topical administration of acetone and ether twice a day to the area to be observed, for example, through the cheek or caudal part of the back. In vivo efficacy of therapeutic compounds can be determined by administering the compounds to animals before or after administration of acetone and ether. The scratching behavior is recorded by a camera for 20 minutes and quantified by observers unaware of the treatment group.

In addition, pruritus can be caused by direct injection of an pruritic agent. Examples of these agents can be found in Akayimo and Carstens, 2013. Some examples are chloroquine (Wilson et al., 2011), bile acids, TSLP (Wilson et al., 2013) and IL-31 (Cevikbas et al., 2014). As a rule, scratching attacks in a certain period are recorded by a blind group.

There are numerous models of urinary incontinence in rodents. These include models of incontinence caused by nerve damage, urethral involvement, and inflammation. Urethral impact models include the rat bladder outflow obstruction model. (Pandita, RK, and Andersson KE. Effects of intravesical administration of the K+ channel opener, Z. D6169, in conscious rats with and without bladder outflow obstruction. J Urol 162: 943-948, 1999). Models of inflammation include the injection of mustard oil into the bladder.

To test the efficacy of a TRPA1 inhibitor compound in the treatment of urinary incontinence in rats following bladder outlet obstruction (BOO), different concentrations of the compound (eg, low, medium, and high concentration) can be administered. The efficacy of various doses of a TRPA1 inhibitory compound can be compared with controls administered with excipients alone (dummy control). Efficacy can be further compared with rats administered with a positive control such as atropine. Atropine is expected to reduce overactive bladder after partial bladder occlusion in the BOO model. It should be noted that when testing compounds in the BOO model, the compounds may be administered directly to the bladder or urethra (eg, via a catheter), or the compounds may be administered systemically (eg, orally, intravenously, parenterally, etc.).

Several rat models of pancreatitis pain have recently been described (Lu, 2003, Anesthesiology 98 (3): 734-740; Winston et al., 2003, Journal of Pain 4 (6): 329-337). Lu et al. induced pancreatitis by systemic delivery of dibutyline dichloride in rats. In rats, an increase in the withdrawal syndrome was observed after stimulation of the abdomen with von Frey filament and a decrease in the latent period of withdrawal after thermal stimulation for 7 days. The pain condition induced in these animals was also characterized by elevated levels of substance P in the spinal cord (Lu, et al., 2003). To test the effectiveness of a TRPA1 inhibitor in this model, the TRPA1 inhibitor can be administered after or simultaneously with the delivery of dibutyl dichloride. Control animals can be administered with a vehicle or a known analgesic. Pain score can be measured. The effectiveness of a TRPA1 inhibitor can be assessed by comparing the signs of pain observed in animals treated with a TRPA1 inhibitor and animals that did not receive a TRPA1 inhibitor. In addition, the effectiveness of a TRPA1 inhibitor can be compared with that of known pain medications.

The effectiveness of von Frey filament testing as a measure of nociceptive behavior has also been demonstrated by induction of pancreatitis by systemic administration of L-arginine (Winston et al, 2003). The efficacy of a TRPA1 inhibitor can be similarly tested following systemic L-arginine-induced pancreatitis.

Lu et al. also described direct behavioral assays of pancreatic pain using acute noxious pancreatic stimulation via an indwelling ductal cannula in awake and freely moving rats. These analyzes included observation of cell crossing, brood care, and hindlimb extension in response to intrapancreatic infusion of bradykinin. Intrathecal administration of D-APV (an NMDA receptor antagonist) or morphine alone partially reduced the behavior of visceral pain in this model. Combinations of both reduced pain behavior to baseline. The effectiveness of a TRPA1 inhibitor can be similarly tested in this system.

Any of the above animal models can be used to evaluate the efficacy of a TRPA1 inhibitor in the treatment of pain associated with pancreatitis. Efficacy can be compared to no treatment or placebo control. Additionally or alternatively, the effectiveness can be evaluated in comparison with one or more known pain medications.

Examples

In vitro characterization of exemplary compounds of this invention.

Example 1 TRPA1 ion channel inhibition measurement method.

The compounds of formulas (I), (II) or (III) inhibit the TRPA1 channel, as demonstrated by measuring the in vitro inhibition of human TRPA1, presented in the data tables shown in table. 2 using the procedure described in del Camino et al., The Journal of Neuroscience, 30 (45): 15165-15174 (November 10, 2010), incorporated herein by reference and summarized below. Data for TRPA1 inhibition were obtained by this method for the indicated compounds of formula (I), (II) or (III), and the corresponding data are included in table. 2 below. All currents were recorded in whole cell configuration using EPC-9 and EPC-10 amplifiers and Patchmaster software (HEKA) or similar. The patch pipettes had a resistance of 1.5-3 M and were compensated for up to 75% of the series resistance. The standard pipette solution consisted of 140 mM CsAsp, 10 mM EGTA, 10 mM HEPES, 2.27 mM, 20 MgCl ₂ , 1.91 mM CaCl ₂ and up to 0.3 mM Na ₂ GTP with pH adjusted to 7.2 s with CsOH. Alternatively, a solution containing 145 mM CsCl, 10 mM HEPES, 10 mM EGTA and up to 0.3 mM Na ₂ GTP and 1 mM MgCl ₂ (pH 7.2 adjusted with CsOH) can be used. The standard bath solution contained 150 mM NaCl, 10 mM HEPES, 10 mM glucose, 4.5 mM KCl, 1 mM EGTA, 3 mM MgCl ₂ , adjusted to pH 7.4 with NaOH. In some cases, instead of EGTA was added 2 mm CaCl ₂ and the concentration of MgCl ₂ was reduced to 1 mm.

Data was obtained either by continuous recording at -60 mV or by applying voltage linearly from the holding potential of -40 mV every 4 s. Continuous recordings were collected at 400 Hz with offline digital filtering at 10 Hz for presentation. Voltage drops were applied from -100 mV or -80 mV to +100 mV or +80 mV over 400 ms and data was acquired at 10 kHz and filtered at 2.9 kHz. Internal and external currents were analyzed and linearized at -80 and 80 mV respectively. Correction for the liquid transition potential was not used.

Solutions were changed using a gravitational continuous focal perfusion system. To achieve rapid temperature changes, two temperature controls and perfusion systems were

- 32 041240 applied at the same time. For temperatures greater than or equal to 22°C, a Warner Instruments bipolar temperature controller (TC-344B) and built-in heater (SHM-8) were used. For temperatures below 22°C, a Warner Instruments temperature controller (CL-100) and a thermal cooling module (TCM-1) were used. Temperatures were confirmed using a thermistor (Warner Instruments, TA-29), with measured cell temperatures estimated to be within ±2°C of those reported.

The antagonistic effects of compounds of formula (I), (II) or (III) against human TRPA1 (hTRPAI) in whole cell fragment configuration were evaluated using the in vitro assay described above. The current activation tested was 10 μM AITC and the concentrations tested ranged from 320 pM to 3.2 μM.

The compounds of this invention were also tested for solubility in normal Ringer's solution. Briefly, compound solubility was determined by dissolving a standard range of 10 mM stock DMSO compounds in normal Ringer's solution (pH 7.4 at room temperature). After stirring and incubation for 40 min at room temperature, the solutions were filtered, quenched with acetonitrile and analyzed by liquid chromatography. Solubility limits were determined by comparison with a standard curve. The solubility limit was found to exceed 31.3 μM. Solubility is reported as greater than if there is more than a 2-fold increase between the last 2 dilutions tested.

In table. 2 shows the solubility values and IC ₅₀ values of hTRPA1 achieved for the test compounds.

Table 2 Antagonistic effects of compounds against human TRPA1

No. Connected AND I hTRPAI IC so (nM) Solubility (µM) 100 >10000 >31.3 101 559 >31.3 102 172 >31.3 103 47.6 >31.3 104 7090 >31.3 105 566 >31.3 106 - >31.3 107 - >31.3

In vivo efficacy of exemplary compounds of this invention.

Example 2. Formalin model.

Exemplary compounds of this invention can be tested in the formalin-induced pain test published by Dubuisson et al., Pain 1977 Dec; 4 (2): 161-74 (included in this description by reference in its entirety).

Example 3 General Experimental Procedures

General procedures.

All reactions proceeded in an inert atmosphere, usually nitrogen. All non-aqueous reactions were carried out using solvents. All reactions were stirred either with a magnetic stirrer or mechanical stirring from above. It is assumed that all saturated extraction solutions are aqueous (eg, saturated NH ₄ Cl). Drying organic solutions with a drying agent means that the drying agent has been removed from the organic solution by filtration. Chromatography refers to column chromatography on silica gel. Preparative thin layer chromatography (TLC) was performed on plates. The concentration of the reaction mixtures involves concentration under reduced pressure and the use of a rotary evaporator. Drying of end products involves drying under high vacuum conditions. Sonication involves the use of an ultrasonic bath. All ¹ H-NMR data were obtained at 400 MHz. Mass spectra were obtained in positive ion mode and are presented as protonated MH+ species. LCMS was performed on a SHIMADZU LCMS-2010EV instrument (Chromolith SdeedROP, RP-18e column. 50x4.6 mm. mobile phase: Solvent A: CH3CN/H2O/HCOOH=10/90/0.05. Solvent B: CH3CN/H2O/HCOOH =90/10/0.05 0.8 min@10% W. 2.7 min gradient (10-95% W) then 0.8 min@95% W. Flow rate: 3 ml/min temperature: 40 °C). Preparative HPLC was also carried out on a SHIMADZU LC-8A instrument. (Column: YMC Pack ODS-A (150*30mm, 10 µm)) or LC-6AD (Column: Shim=Pack PREP-ODS-H (250*20mm, 10 µm)) with UV detection, which was controlled by solution LC software

- 33 041240

Chemstation, with H2O (0.1% HCOOH) and MeOH (CH ₃ CN) as mobile phase at the indicated flow rate. Chiral HPLC was performed using a CHIRALPAK IB column (150*4.6 mm, 5 µm) with a mobile phase consisting of hexanes/EtOH (65/35, 0.8 ml/min, run time 25 min) at 30°C using 15 µl injection volume (1 mg/ml in MeOH) and UV detector set to 220/254 nm.

Abbreviations:

Vp Benzyl DCM dichloromethane. DIG Ν,Ν'-diisopropylcarbodiimide DMAP 4-dimethylaminopyridine DMF Ν,Ν-dimethylformamide DMSO Dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EA ethyl acetate Ether diethyl ether h hours Η About Ac HOAT acetic acid 1-hydroxy-7-azabenzotriazole LAH MeOH lithium aluminum hydride methanol.

min minutes n-BuLi n-butyllithium Pd/C palladium on activated carbon, typically 10% palladium RE petroleum ether. CT room temperature Sat. aq. SEM Saturated water 2-(trimethylsilyl)ethoxymethyl TBAI tetrabutylammonium iodide TEA triethylamine TFA trifluoroacetic acid TLC thin layer chromatography THF tetrahydrofuran

Example 4 Synthesis of Compounds 100, 101, 106 and 107

- 34 041240

Get connection 2.

To a solution of 1 (84 g, 297 mmol) in DMSO (300 ml) was added benzyl bromide (60 g, 353 mmol). The mixture was stirred at 50° C. overnight. The mixture was then cooled to room temperature and HCl (300 ml, 2 mol/l) was added and the mixture was stirred at 70°C for 2 h. The reaction mixture was cooled to room temperature, filtered and the precipitate was washed with water and ethanol and dried in vacuo, to give 2 (55 g, 76.8% yield) as a gray solid.

Get connection 3.

To a solution of 2 (40 g, 166 mmol) in HOAc (480 ml) and water (60 ml) was added sodium nitrite (13.8 g, 200 mmol) in water (10 ml) at 50°C dropwise, the mixture was stirred at 50°C for 1 hour, then cooled to room temperature and stirred for another 2 hours. The mixture was filtered, the precipitate was washed with water and ethanol and dried to give 3 (38 g, 94.6% yield) as a yellow solid.

Getting connection 4.

To a solution of 3 (28 g, 115.7 mmol), potassium carbonate (32 g, 232 mmol) in DMF (300 ml) was added SEMCI (19.2 g, 115.7 mmol) at 0°C dropwise, the reaction mixture stirred at room temperature overnight after addition. The mixture was poured into ice water and extracted with EA (100 mlx3), the extracted organic layers were washed with water, brine and dried over anhydrous sodium sulfate, then concentrated, the residue was purified by silica gel flash chromatography (PE/EA=1:1) to give 4 ( 15 g, 34.8% yield as a white solid.

Getting connection 6.

To a solution of 4 (15 g, 40.3 mmol) and potassium carbonate (11.1 g, 80.6 mmol) in DMF (150 mL) was added methyl bromoacetate 5 (12.2 g, 81 mmol) and the mixture was stirred at room temperature. temperature during the night. The reaction mixture was poured into water and the precipitate was collected to give 6 (14 g, 78.2% yield) as a white solid which was used directly in the next step.

Getting connection 7.

Wet Pd/C (0.8 g, 50% in H2O) was added to a solution of 6 (8 g, 18 mmol) in ethanol (50 ml), charged with H ₂ in a balloon, and the mixture was stirred at room temperature under an H ₂ atmosphere for night. The reaction mixture was filtered through a pad of celite and concentrated to give the desired 7 (5.4 g, 85% yield) as a gray solid which was used directly in the next step.

Getting connection 8.

- 35 041240

To a solution of 7 (5 g, 14 mmol) in toluene (40 ml) was added N-hydroxyacetimidamide (2.07 g, 28 mmol) and the mixture was stirred at reflux overnight. The reaction mixture was poured into water and extracted with EA (x4), the extracted organic layers were concentrated and the residue was purified by flash chromatography (EA) on silica gel to give 8 (3 g, 56.7% yield) as a white

th solid.

Preparation of compounds 10 and 10'.

x sn MIGI x=sn, 10

X=N, 10'

To a solution of 8 (1.5 g, 3.97 mmol), 9 (1.0 eq.) (either X=CH or X=N) and potassium carbonate (1.1 g, 8.0 mmol) in DMF ( 30 ml) was added sodium iodide (1.2 g, 8.0 mmol) and stirred at room temperature overnight. The reaction was quenched with water and extracted with EA (x3), the extracted layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by flash chromatography on silica gel (PE/EA=1:1) to give 10:1.5 g, yield 56 .2%; or 10': 1.4 g, 52.4% yield, both as a white solid.

Preparation of compounds 100 and 101.

X=CH, 10 X=CH: 101

X=N, 10' X=H: 100

HCl/EA (2 mol/l, 10 ml). The mixture was stirred at room temperature overnight, then concentrated, and the residue was purified by preparative HPLC to give (Compound 101: 0.6 g, 73.8% yield, >95% purity; or Compound 100: 0.9 g, yield 79.7%, >95% pure, both as a white solid.

Analytical data for compound 101:

1H NMR DMSO-d ₆₄₀₀ MHz, δ 12.28 (s, 1H), 11.25 (s, 1H), 9.66 (s, 2H), 8.35 (s, 1H), 8.12 ( d, J=7.6 Hz, 1H), 8.05-7.98 (m, 2H), 5.79 (d, J=7.2 Hz, 1H), 5.27 (dd, J=24 .0 Hz, 16.8 Hz, 2H), 2.26 (s, 3H), 1.88 (d, J=6.8 Hz, 3H);

LCMS (ESI): m/z 543 (M+H)+;

HPLC: >99.9% (254 nm, MeOH), >99.9% (220 nm, MeOH), >99.9% (254 nm, ACN), 99.1% (220 nm, ACN).

Compound 100 analytical data:

1H NMR DMSO-d6 400 MHz,

12.32 (s, 1H), 11.64 (s, 1H), 9.70 (s, 2H), 9.35 (s, 1H), 9.23 (s, 1H), 8.38 (s , 1H), 5.80 (d, J=6.4 Hz, 1H), 5.27 (dd, J=22.4 Hz, 16.8 Hz, 2H), 2.26 (s, 3H), 1.90 (d, J=6.8 Hz, 3H);

LCMS (ESI): m/z 544 (M+H) ⁺ ;

HPLC: 97.7% (254 nm, MeOH), 98.4% (220 nm, MeOH), 97.7% (254 nm, ACN), 97.9% (220 nm, ACN).

Preparation of Compound 106 and Compound 107.

To a solution (101: 340 mg, 0.63 mmol or 100: 490 mg, 0.9 mmol) and potassium carbonate (1.2 eq.) in DMF (30 ml) was added CD3I (1.2 eq.), then stirred at room temperature overnight. The mixture was poured into ice water and the precipitate was collected to give the desired product (107: 0.21 g, 59.6% yield, >95% purity; or 106: 0.37 g, 73.4% yield, >95% purity) both as a white solid.

- 36 041240

Compound 107 analytical data:

1H NMR DMSO-d ₆₄₀₀ MHz, δ 12.28 (s, 1H), 9.66 (s, 2H), 9.34 (s, 1H), 9.23 (s, 1H), 8.47 ( s, 1H), 5.82 (s, 1H), 5.84-5.79 (m, 1H), 5.32 (t, J=20.0 Hz, 2H), 2.33 (s, 3H ), 1.91 (d, J=7.2 Hz, 3H);

LCMS (ESI): m/z 560 (M+H)+;

HPLC: 96.7% (254 nm, MeOH), 96.9% (220 nm, MeOH), 98.0% (254 nm, ACN), 98.4% (220 nm, ACN).

Compound 106 analytical data:

1H NMR (DMSO-d6 400 MHz) δ 11.66 (s, 1H), 9.70 (s, 2H), 9.35 (s, 1H), 9.23 (s, 1H), 8.38 ( s, 1H), 5.80 (d, J=6.4 Hz, 1H), 5.27 (dd, J=22.4 Hz, 16.8 Hz, 2H), 2.26 (s, 3H) , 1.90 (d, J=6.8 Hz, 3H);

LCMS (ESI): m/z 561 (M+H)+;

HPLC: 99.5% (254 nm, MeOH), 99.7% (220 nm, MeOH), 99.0% (254 nm, ACN), 99.0% (220 nm, ACN).

Example 5 Synthesis of Compounds 102 and 104

Iron filings ( ₅₀₀ mg, 9 mmol) and NH ₄ Cl (480 mg, 8 mmol), and the suspension was heated at 60°C and continued to stir for 2 h. The mixture was cooled to room temperature and filtered on a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a black residue which was purified by preparative HPLC to give 102 (350 mg, 34.7% yield, >95% purity) and 104 (18θ mg, 19.3% yield, >95% purity) both as a white solid.

Compound 102 analytical data:

1H NMR DMSO-d ₆₄₀₀ MHz, δ 11.63 (s, 1H), 11.05 (s, 1H), 9.70 (s, 2H), 9.35 (s, 1H), 8.43 ( s, 1H), 5.85-5.80 (m, 1H), 4.77 (dd, J=25.2 Hz, 17.6 Hz, 2H), 3.76 (s, 3H), 2, 51 (s, 3H), 1.92 (d, J=7.6 Hz, 3H);

LCMS (ESI): m/z 561 (M+H)+;

HPLC: 98.4% (254 nm, MeOH), 98.5% (220 nm, MeOH), 98.4% (254 nm, ACN), 98.6% (220 nm, ACN). Analytical data for compound 104: 1H NMR DMSO-d6 400 MHz, δ 11.64 (s, 1H), 9.71 (s, 2H), 9.36 (s, 1H), 9.23 (s, 1H), 8.40 (s, 1H), 7.50 (s, 1H), 5.88-5.83 (m, 1H) 4.36 (m, 2H), 3.46 (s, 3H), 1, 91 (d, J=7.2 Hz, 3H);

LCMS (ESI): m/z 519 (M+H)+;

HPLC: >99.9% (254 nm, MeOH), >99.9% (220 nm, MeOH), >99.9% (254 nm, ACN), >99.9% (220 nm, ACN).

Example 6 Synthesis of Compounds 103 and 105

103p

EiOH/HjO

Η ₂ Ν

_CF3

105

Using the same procedure as for the synthesis of compounds 102 and 104, but using 11 as starting material, we obtained 103 (310 mg, 30.8% yield, >95% purity) and 105 (60 mg, 6.4 yield %, >95%) both as a white solid.

Compound 103 analytical data:

-

Claims (17)

¹ H NMR DMSO-d ₆₄₀₀ MHz, δ 11.26 (s, 1H), 11.04 (s, 1H), 9.67 (s, 2H), 8.41 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.05-7.98 (m, 2H), 5.835.79 (m, 1H), 4.83 (dd, J= 27.2 Hz, 17, 2 Hz, 2H), 3.47 (s, 3H), 2.12 (s, 3H), 1.90 (d, J=7.2 Hz, 3H); LCMS (ESI): m/z 560 (M+H)+; HPLC: >99.9% (254 nm, MeOH), >99.9% (220 nm, MeOH), >99.9% (254 nm, ACN), >99.9% (220 nm, ACN). Compound 105 analytical data: ¹ H NMR DMSO-d6 400 MHz, δ 11.27 (s, 1H), 9.67 (s, 2H), 8.39 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.05-8.00 (m, 2H), 7.51 (s, 1H), 7.01 (s, 1H), 5.86-5.82 (m, 1H), 4.38 -4.36 (m, 2H), 3.46 (s, 3H), 1.89 (d, J=7.2 Hz, 3H); LCMS (ESI): m/z 518 (M+H)+; HPLC: 95.5% (254 nm, MeOH), 96.4% (220 nm, MeOH), 96.1% (254 nm, ACN), 97.1% (220 nm, ACN). Equivalents The disclosure of each patent, patent application and publication cited herein is hereby incorporated herein by reference in their entirety. Although this invention has been disclosed with reference to specific aspects, it is obvious that other specialists in the art can develop other aspects and variants of this invention without departing from the true essence and scope of the invention. The appended claims are intended to include all such aspects and equivalents. Any patent, publication, or other disclosure material, in whole or in part, that is indicated as incorporated herein by reference is incorporated in this document only to the extent that the incorporated material does not conflict with existing definitions, statements, or other set of disclosure materials filed herein. disclosure. As such, and to the extent necessary, this disclosure, as expressly set forth herein, takes precedence over any conflicting material incorporated herein by reference. While this invention has been specifically demonstrated and described with reference to its preferred embodiments, those skilled in the art will appreciate that various changes in form and detail may be made without departing from the scope of the invention as encompassed by the appended claims. CLAIM 1. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that said compound is or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, which is - 38 041240 4. A compound according to claim 2, characterized in that said compound or a pharmaceutically acceptable salt thereof is more than 95% pure. 5. A compound according to claim 3, characterized in that said compound is more than 95% pure. 6. The compound according to claim 1, characterized in that said compound is or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 6, which is 8. A pharmaceutical composition containing a compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 9. A pharmaceutical composition containing a compound according to claim 5 or 7 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 10. The use of a compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, for the treatment of pain. 11. Use of a compound according to claim 5 or 7 for the treatment of pain. 12. The use of a compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, for the treatment of chronic pain. 13. Use of a compound according to claim 5 or 7 for the treatment of chronic pain. 14. The use of a compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain. 15. The use of a compound according to claim 5 or 7 for the manufacture of a medicament for the treatment of pain. 16. The use of a compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of chronic pain. 17. The use of a compound according to claim 5 or 7 for the manufacture of a medicament for the treatment of chronic pain. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2