TRPV1 modulator compounds

文档序号：1661274 发布日期：2019-12-27 浏览：18次中文

阅读说明：本技术 Trpv1调节剂化合物 (TRPV1 modulator compounds ) 是由 I·德韦萨·吉内 A·杰纳扎尼 T·皮拉里 A·费尔南德兹·卡瓦哈尔 A·V·费勒·蒙蒂埃尔于 2018-05-10 设计创作，主要内容包括：本发明涉及式(I)的TRPV1调节剂化合物或其药学、兽医学或美容上可接受的盐,或其立体异构体或其混合物,其中m为选自1至3的整数；R1、R2、R6和R6’独立地选自H、(C1-C8)烷基、不饱和(C2-C8)烃和(C3-C6)环烷基,这些基团可选地具有取代基；R3为氢或卤素；R4选自H、(C1-C8)烷基、不饱和(C2-C8)烃、(C3-C6)环烷基、(C6-C12)芳基和(C5-C12)杂芳基,这些基团可选地具有取代基；且R5选自(C3-C28)烷基、不饱和(C3-C28)烃、(C6-C12)芳基和(C5-C12)杂芳基,这些基团可选地具有取代基。本发明还涉及所述化合物的制备方法；含有所述化合物的药学、兽医学或美容组合物；以及其药学、兽医学和美容应用。<Image he="275" wi="700" file="DDA0002260930330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to TRPV1 modulator compounds of formula (I) or a pharmaceutically, veterinarily or cosmetically acceptable salt thereof, or a stereoisomer thereof or a mixture thereof, wherein m is an integer selected from 1 to 3; r 1 、R 2 、R 6 And R 6’ Independently selected from H, (C) 1 ‑C 8 ) Alkyl, unsaturated (C) 2 ‑C 8 ) Hydrocarbons and (C) 3 ‑C 6 ) Cycloalkyl, these groups optionally having a substituent; r 3 Is hydrogen or halogen; r 4 Selected from H, (C) 1 ‑C 8 ) Alkyl, unsaturated (C) 2 ‑C 8 ) Hydrocarbon, (C) 3 ‑C 6 ) Cycloalkyl group, (C) 6 ‑C 12 ) Aryl and (C) 5 ‑C 12 ) Heteroaryl, these groups optionally having a substituent; and R is 5 Is selected from (C) 3 ‑C 28 ) Alkyl, unsaturated (C) 3 ‑C 28 ) Hydrocarbon, (C) 6 ‑C 12 ) Aryl and (C) 5 ‑C 12 ) Heteroaryl, these groups optionally having substituents. The invention also relates to a preparation method of the compound; pharmaceutical, veterinary or cosmetic compositions containing said compounds; and pharmaceutical, veterinary and cosmetic applications thereof.)

1. A compound of formula (I) or a pharmaceutically, veterinarily or cosmetically acceptable salt thereof, or any stereoisomer or mixture thereof of said compound of formula (I) or any pharmaceutically, veterinarily or cosmetically acceptable salt thereof,

wherein the content of the first and second substances,

m is an integer selected from 1 to 3;

R¹、R²、R⁶and R^6’Independently selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbons and (C)₃-C₆) A cycloalkyl group;

wherein (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbons and (C)₃-C₆) The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -COOH, -OH, -NH₂、-COOR₆、-NO₂、-CF₃、-OCF₃、-CN、-OR₆、-CONH₂、-CONHR₆、-CONR₆R₇、-NHR₆、-NR₆R₇、-NHCOR₆、-NHSO₂R₆and-SO₂NHR₆；

R³Is hydrogen or halogen;

R⁴selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

wherein (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -COOH, -OH, -NH₂、-COOR₆、-NO₂、-CF₃、-OCF₃、-CN、-OR₆、-CONH₂、-CONHR₆、-CONR₆R₇、-NHR₆、-NR₆R₇、-NHCOR₆、-NHSO₂R₆and-SO₂NHR₆；

R⁵Is (C)₃-C₂₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

wherein (C)₁-C₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) Heteroaryl is optionally substitutedSubstituted with one or more substituents selected from the group consisting of: halogen, -COOH, -OH, -NH₂、-COOR₆、-NO₂、-CF₃、-OCF₃、-CN、-OR₆、-CONH₂、-CONHR₆、-CONR₆R₇、-NHR₆、-NR₆R₇、-NHCOR₆、-NHSO₂R₆and-SO₂NHR₆；

With the proviso that the compound of formula (I) is not:

but-2-enoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

4-methyl-pentanoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester;

3, 3-dimethylbutyric acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

3-methylbut-2-enoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

4-methyl-pentanoic acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester;

3-methylbut-2-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester;

hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzyl-carbamoyl) methyl ester;

butyric acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester;

butyric acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

hexane-2, 4-dienoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

2-ethylbutanoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester;

but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester;

but-3-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester;

but-3-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester;

undecyl-10-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester;

2-methylpentanoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; and

pentanoic acid 2- (3, 4-dimethoxy-phenethylcarbamoyl) propan-2-yl ester.

2. A compound of formula (I) as claimed in claim 1 wherein m is an integer selected from 1 to 2.

3. A compound of formula (I) as claimed in claim 1 or 2 wherein R¹Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon.

4. A compound of formula (I) as claimed in any one of claims 1 to 3 wherein R²Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon.

5. A compound of formula (I) as claimed in any one of claims 1 to 4 wherein R³Is H.

6. A compound of formula (I) as claimed in any one of claims 1 to 5 wherein R³Is halogen.

7. A compound of formula (I) as claimed in any one of claims 1 to 6 wherein R⁴Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon.

8. A compound of formula (I) as claimed in any one of claims 1 to 7 wherein R⁵Selected from the group consisting of: optionally substituted (C)₃-C₂₈) Alkyl group, and optionally substituted unsaturated (C)₃-C₂₈) A hydrocarbon.

9. A compound of formula (I) as claimed in any one of claims 1 to 8 wherein R⁶And R^6’Independently selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon.

10. A compound of formula (I) according to claim 1, selected from the group consisting of:

butyric acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl butyrate;

2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl valerate;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl valerate;

3-methylbutyric acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

3-methyl-butyric acid 2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

hexanoic acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

hexanoic acid 2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

hexane-2, 4-dienoic acid (2E,4E) -2- ((4-hydroxy-3-methoxybenzyl) amino) -2-oxoethyl ester;

hexane-2, 4-dienoic acid (2E,4E) -2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl heptanoate;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl heptanoate;

2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl octanoate;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl octanoate;

pelargonic acid 2- ((4-hydroxy-3-methoxybenzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl nonanoate;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

decanoic acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

decanoic acid 2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl dodecanoate;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl dodecanoate;

pentadecanoic acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl pentadecanoate;

stearic acid 2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

stearic acid 2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl oleate;

2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl oleate;

12-hydroxyoctadeca-9-enoic acid (R, Z) -2- ((4-hydroxy-3-methoxybenzyl) amino) -2-oxoethyl ester;

12-hydroxyoctadeca-9-enoic acid (R, Z) -2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

12- (2-phenylacetyloxy) octadec-9-enoic acid (Z) -2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

12- (2-phenyl-acetoxy) octadec-9-enoic acid (Z) -2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

docosahexen-13-enoic acid (Z) -2- ((4-hydroxy-3-methoxybenzyl) amino) -2-oxoethyl ester;

docosal-13-enoic acid (Z) -2- ((4-hydroxy-2-iodo-5-methoxybenzyl) amino) -2-oxoethyl ester;

eicosa-5, 8,11, 14-tetraenoic acid (5Z,8Z,11Z,14Z) -2- ((4-hydroxy-3-methoxy-benzyl) amino) -2-oxoethyl ester;

eicosa-5, 8,11, 14-tetraenoic acid (5Z,8Z,11Z,14Z) -2- ((4-hydroxy-2-iodo-5-methoxy-benzyl) amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyldidodec-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((4-hydroxy-3-methoxybenzyl) -amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyl-docosaccharyl-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((4-hydroxy-2-iodo-5-methoxy-benzyl) amino) -2-oxoethyl ester;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((3, 4-dihydroxybenzyl) -amino) -2-oxoethyl ester;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((4, 5-dihydroxy-2-iodo-benzyl) amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyldidodec-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((3, 4-dihydroxybenzyl) amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyl-docosaccharyl-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((4, 5-dihydroxy-2-iodobenzyl) -amino) -2-oxoethyl ester;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((3, 4-dihydroxy-phenethyl) amino) -2-oxoethyl ester;

3, 7-dimethylocta-2, 6-dienoic acid (E) -2- ((4, 5-dihydroxy-2-iodophenethyl) amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyldidodec-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((3, 4-dihydroxyphenethyl) amino) -2-oxoethyl ester;

4,8,13,17, 21-pentamethyl-docosaccharyl-4, 8,12,16, 20-pentaenoic acid (4E,8E,12E,16E) -2- ((4, 5-dihydroxy-2-iodophenethyl) -amino) -2-oxoethyl ester;

2- ((3, 4-dihydroxyphenethyl) -amino) -2-oxoethyl oleate;

2- ((4, 5-dihydroxy-2-iodophenethyl) amino) -2-oxoethyl oleate;

eicosa-5, 8,11, 14-tetraenoic acid (5Z,8Z,11Z,14Z) -2- ((3, 4-dihydroxyphenethyl) amino) -2-oxoethyl ester; and

eicosa-5, 8,11, 14-tetraenoic acid (5Z,8Z,11Z,14Z) -2- ((4, 5-dihydroxy-2-iodophenethyl) -amino) -2-oxoethyl ester.

11. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 10, which process comprises:

a) reacting a compound of formula (II) with a compound of formula (III) in the presence of formaldehyde to produce a compound of formula (I),

wherein R is¹、R²、R³、R⁵、R⁶、R^6’And m is as defined above;

b) (ii) optionally converting the compound of formula (I) thus obtained into another compound of formula (I) in one or more steps; and

c) optionally reacting the compound of formula (I) obtained in any of steps a) or b) with a base or with an acid to obtain the corresponding salt.

12. A pharmaceutical, veterinary or cosmetic composition comprising: an effective amount of a compound of formula (I), or a pharmaceutically, veterinarily or cosmetically acceptable salt thereof, or any stereoisomer of said compound of formula (I) or a pharmaceutically, veterinarily or cosmetically acceptable salt thereof; and one or more pharmaceutically or veterinarily acceptable excipients or carriers,

wherein the content of the first and second substances,

m is an integer selected from 1 to 3;

R¹、R²、R⁶and R^6’Independently selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbons and (C)₃-C₆) A cycloalkyl group;

R³Is hydrogen or halogen;

R⁴selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

R⁵Is (C)₃-C₂₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

wherein (C)₁-C₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -COOH, -OH, -NH₂、-COOR₆、-NO₂、-CF₃、-OCF₃、-CN、-OR₆、-CONH₂、-CONHR₆、-CONR₆R₇、-NHR₆、-NR₆R₇、-NHCOR₆、-NHSO₂R₆and-SO₂NHR₆。

13. A compound of formula (I) or a pharmaceutically, veterinarily or cosmetically acceptable salt thereof, or any stereoisomer or mixture thereof of said compound of formula (I) or any pharmaceutically, veterinarily or cosmetically acceptable salt thereof,

wherein the content of the first and second substances,

m is an integer selected from 1 to 3;

R¹、R²、R⁶and R^6’Independently selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbons and (C)₃-C₆) A cycloalkyl group;

R³Is hydrogen or halogen;

R⁴selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

R⁵Is (C)₃-C₂₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

Or a composition as claimed in claim 11 for use in the treatment and/or prevention of a condition and/or disease mediated by TRPV 1.

14. The compound of formula (I) or the pharmaceutical composition for use according to claim 13, wherein the condition and/or disease is selected from pain, inflammation and cancer.

15. The compound of formula (I) or the pharmaceutical composition for use according to claim 13, wherein the condition and/or disease is selected from sensitive skin, itching (pruritus), rosacea, acne vulgaris, atopic dermatitis, psoriasis and psoriatic arthritis.

Technical Field

The present invention relates to the fields of pharmacy, veterinary medicine and cosmetology. More particularly, the present invention relates to novel compounds which are modulators of vanilloid receptor 1(TRPV 1). The invention also relates to a preparation method thereof; pharmaceutical, veterinary or cosmetic compositions containing them; and pharmaceutical, veterinary and cosmetic uses thereof.

Background

Nociception is the response of the sensory nervous system to certain noxious or potentially noxious stimuli, including mechanical, thermal, and chemical stimuli. The nociceptors transmit this information to the central nervous system, thereby producing a painful sensation. Most nociceptors are cation channels that include Transient Receptor Potential (TRP) channels.

The TRP family includes more than 30 cation channels, most of which pairs include Ca²⁺、Na⁺And Mg²⁺Divalent and monovalent cations within are permeable. The transient receptor potential vanilloid 1(TRPV1) receptor, also known as capsaicin receptor and vanilloid receptor 1(VR1), is a non-selective cation channel belonging to this family of ion channels. TRPV1 functions to detect and regulate body temperature. In addition, it provides a sensation of heat and pain (nociception) from the scald.

TRPV1 is present in painful sensory nerves as well as other tissues such as brain, kidney, bronchial epithelial cells and epidermal keratinocytes. It plays an important role in pain transduction pathways and has a well-defined pro-inflammatory role in a variety of diseases and injury conditions.

There are two inhibition mechanisms of the TRPV1 receptor: i) desensitization of the receptor by a TRPV1 agonist, and ii) inhibition of the receptor by a TRPV1 antagonist. Thus, both agonists and antagonists are useful against conditions mediated by inhibition of the TRPV1 receptor.

With respect to TRPV1 agonists, it is believed that when TRPV1 is continuously activated via prolonged exposure to the agonist, excess calcium enters the nerve fibers, triggering a process that results in long-term, reversible impairment of nociceptor function, thus providing pain relief. Capsaicin or capsaicin analog Resiniferatoxin (RTX) is known as a TRPV1 agonist. Capsaicin acts as an anti-inflammatory, antipruritic, antipsoriatic and anti-pruritic agent, and has been reported to cause apoptosis and/or inhibit the proliferation of malignant cancer cells. However, the use of capsaicin as a therapeutic agent is difficult because of its irritant effect and burning sensation which causes the patient to stop treatment prematurely. In addition, capsaicin accumulation in the skin is known to cause Cancer in long-term treatments (Cancer Res.2011,71(8), 2809-2814).

On the other hand, TRPV1 antagonists, such as AMG9810([ (E) -3- (4-t-butylphenyl) -N- (2, 3-dihydro-benzo [ b ] [1,4] dioxin-6-yl) acrylamide ]), block TRPV1 activity, thus alleviating pain. TRPV1 antagonists have been disclosed to be effective in patients with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Furthermore, recent data indicate that TRPV1 antagonists may also be useful in the treatment of conditions other than pain, such as urinary acute incontinence, chronic cough, and irritable bowel syndrome. However, like capsaicin, TRPV1 antagonist AMG9810 has been reported to promote mouse skin tumorigenesis (Carcinogenesis 2011,32(5), pages 779-785).

Furthermore, TRPV1 inhibitory compounds have been shown to be good candidates for the treatment and prevention of skin aging processes including heat-induced skin aging, UV-induced photoaging and intrinsic skin aging, as well as other skin conditions such as sensitive skin, itch (pruritus) and rosacea (rosacea).

Although much work has been done in recent years in the study of TRPV1 modulators, only a few drugs have reached advanced levels of clinical development. Accordingly, there remains a need to develop compounds that exhibit increased activity in conditions and/or diseases mediated by TRPV1 and that overcome the problems of the prior art compounds.

Disclosure of Invention

The present inventors have discovered novel compounds as TRPV1 modulators that have a 3, 4-dioxy substituted phenyl moiety attached to a substituted (acetoxy) acetamidoalkyl moiety. As demonstrated in the examples, compounds of the invention include both TRPV1 agonists and TRPV1 antagonists. In addition, in an in vivo model of inflammation, the compounds of the invention do not exhibit any toxicity and exhibit a significant antinociceptive effect. Accordingly, the compounds may be useful for the treatment and/or prevention of conditions and/or diseases mediated by inhibition of TRPV 1.

The compounds of the invention have the advantage that, after having performed their effect, they can be metabolized as a result of ester bonds which are susceptible to hydrolysis by esterases and are therefore subsequently eliminated. Thus, the compounds do not accumulate in the body and are particularly suitable for the treatment or prevention of chronic diseases which require periodic administration of the active compound. Thus, the compounds of the present invention not only exhibit enhanced activity but also avoid the side effects found in the prior art compounds developed to date, such as irritation by capsaicin or carcinogenic activity due to its accumulation in the skin.

Thus a first aspect of the present invention relates to a compound of formula (I) or a pharmaceutically, veterinary or cosmetically acceptable salt thereof, or any stereoisomer of the compound of formula (I) or any pharmaceutically, veterinary or cosmetically acceptable salt thereof, or a mixture thereof,

wherein the content of the first and second substances,

m is an integer selected from 1 to 3;

R¹、R²、R⁶and R^6’Independently selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbons and (C)₃-C₆) A cycloalkyl group;

R³Is hydrogen or halogen;

R⁴selected from the group consisting of: H. (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

R⁵Is (C)₃-C₂₈) Alkyl, unsaturated (C)₃-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group;

wherein (C)₁-C₈) Alkyl, unsaturated (C)₂-C₂₈) Hydrocarbon, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -COOH, -OH, -NH₂、-COOR₆、-NO₂、-CF₃、-OCF₃、-CN、-OR₆、-CONH₂、-CONHR₆、-CONR₆R₇、-NHR₆、-NR₆R₇、-NHCOR₆、-NHSO₂R₆and-SO₂NHR₆；

With the proviso that the compound of formula (I) is not:

but-2-enoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; 4-methyl-pentanoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; 4-methyl-pentanoic acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester; hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; butyric acid (3, 4-dimethoxy-benzylcarbamoyl) -methyl ester; butyric acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; hexane-2, 4-dienoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; 2-ethylbutanoic acid (3, 4-dimethoxy-phenethylcarbamoyl) methyl ester; but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; undecyl-10-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 2-methylpentanoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; and 2- (3, 4-dimethoxy-phenethylcarbamoyl) propan-2-yl valerate.

Another aspect of the present invention relates to a process for the preparation of a compound of formula (I) above, comprising:

a) reacting a compound of formula (II) with a compound of formula (III) in the presence of formaldehyde to produce a compound of formula (I),

wherein R is¹、R²、R³、R⁵、R⁶、R^6’And m is as defined above;

b) optionally converting the compound of formula (I) thus obtained into another compound of formula (I) in one or more steps; and

c) optionally reacting the compound of formula (I) obtained in any of steps a) or b) with a base or with an acid to obtain the corresponding salt.

The compounds of the present invention may be formulated into different types of compositions. Thus, another aspect of the present invention relates to a pharmaceutical, veterinary or cosmetic composition comprising an effective amount of a compound of formula (I) as described above; and one or more pharmaceutically, veterinarily or cosmetically acceptable excipients or carriers, said compound of formula (I) comprising: but-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) -methyl ester; hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzylcarbamoyl) methyl ester; butyric acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; butyric acid (3, 4-dimethoxy-phenethylcarbamoyl) -methyl ester; hexane-2, 4-dienoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 2-ethylbutanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; undecyl-10-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester; 2-methylpentanoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; and 2- (3, 4-dimethoxyphenethylcarbamoyl) -propan-2-yl valerate.

As mentioned above, the compounds of the present invention are useful for the treatment and/or prevention of conditions or diseases mediated by the inhibition of TRPV 1. Accordingly, another aspect of the present invention relates to compounds of formula (I) as defined above for use in the treatment and/or prevention of a condition or disease mediated by the inhibition of TRPV1, the compounds of formula (I) comprising: but-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) -methyl ester; hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzylcarbamoyl) methyl ester; butyric acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; butyric acid (3, 4-dimethoxy-phenethylcarbamoyl) -methyl ester; hexane-2, 4-dienoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 2-ethylbutanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; undecyl-10-enoic acid (3, 4-dimethoxy-benzylcarbamoyl) methyl ester; 2-methylpentanoic acid (3, 4-dimethoxybenzylcarbamoyl) methyl ester; and 2- (3, 4-dimethoxyphenethylcarbamoyl) -propan-2-yl valerate.

Drawings

Figure 1 shows the effect of a compound of the invention (example 37) administered intravenously in a CFA-induced paw inflammation model compared to vehicle (V) in left hind paw (a) and right hind paw (B). The graph shows paw withdrawal delay (tt) over time (t) in response to thermal stimulation (n-6 mice/group). Data are given as mean ± SEM n ═ 6. Two-way ANOVA method and Bonferroni post hoc assays. P < 0.05; p < 0.01, P < 0.001, P < 0.0001.

Figure 2 shows the effect of the compound of the invention (example 37) by intraplantar administration in a CFA-induced paw inflammation model, compared to vehicle (V), in left hind paw (a) and right hind paw (B). The graph shows paw withdrawal delay (tt) over time (t) in response to thermal stimulation (n-6 mice/group). Data are given as mean ± SEM n ═ 6. Two-way ANOVA method and Bonferroni post hoc assays. P < 0.05; p < 0.01, P < 0.001, P < 0.0001.

Figure 3 shows the effect of the compound of the invention (example 37) (black bar) compared to the control (white bar) in an in vivo model of itching consisting of measuring histamine-induced licking behaviour. The graph shows the time taken to lick the injected paw relative to the time after histamine injection (t (min)). P < 0.001.

Figure 4 shows the effect of the compound of the invention (example 37) (black bar) compared to the control (white bar) in an in vivo non-histaminergic model of pruritus consisting of measuring chloroquine-induced pruritus lick behavior. The graph shows the time taken to lick the injected paw relative to the time after chloroquine injection (t (min)). P < 0.05, p < 0.001.

Detailed Description

Unless otherwise indicated, all terms as used herein in the present application shall be understood as having the ordinary meaning as known in the art. Other more specific definitions for certain terms as used in this application are set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set forth definition provides a broader definition.

"protecting group" (PG) refers to a group of atoms which, when attached to a reactive group in a molecule, shields, reduces or prevents reactivity.

The expression "substituted with one or more substituents" means that a group may be substituted with one or more, preferably 1,2, 3 or 4 substituents, provided that the group has sufficient positions for easy substitution.

For the purposes of the present invention, the room temperature is from 20 ℃ to 25 ℃.

Term "(C)_p-C_n) Alkyl "refers to a saturated branched or straight hydrocarbon chain containing p to n carbon atoms and containing only single bonds. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, 1-methylpropyl, 2-methylpropyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, and the like.

The term "unsaturated (C)_p-C_n) Hydrocarbon "refers to an unsaturated branched or straight hydrocarbon chain containing p to n carbon atoms and one or more double bonds and/or one or more triple bonds. Thus, the term "unsaturated (C)_p-C_n) Hydrocarbon "encompasses (C)_p-C_n) Alkenyl and (C)_p-C_n) Alkynyl, wherein the term "(C)_p-C_n) Alkenyl "refers to radicals containing p to n carbon atomsAnd an unsaturated branched or straight hydrocarbon chain having at least one or more double bonds; and the term "(C)_p-C_n) Alkynyl "refers to an unsaturated branched or straight hydrocarbon chain containing p to n carbon atoms and at least one or more triple bonds. Unsaturated (C)_p-C_n) Non-limiting examples of hydrocarbyl groups include ethenyl, propenyl, allyl, oleyl, ethynyl, propyn-1-yl, propyn-2-yl, but-1-en-3-ynyl, hex-1, 3-dien-5-ynyl, and the like.

The term "halogen" means fluoro, chloro, bromo or iodo.

Term "(C)₃-C₆) Cycloalkyl "refers to a known saturated, unsaturated, or aromatic ring system comprising one or more rings and 3 to 6 ring members selected from C, CH, O, N, NH, and S. (C)₃-C₆) Non-limiting examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, aziridinyl, oxiranyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furanyl, homopiperidinyl, imidazopyridinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrimidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like. For ring systems containing a CH member and an NH member, the ring may be attached to the rest of the molecule via a C or N atom.

Term "(C)₆-C₁₂) Aryl "refers to a known aromatic ring system comprising one or more rings and 6 to 12 ring members, wherein all ring members comprise carbon atoms. (C)₆-C₁₂) Examples of aryl groups include phenyl and naphthalene.

Term "(C)₅-C₁₂) Heteroaryl "refers to a known aromatic ring system comprising one or more rings and 5 to 12 ring members, wherein one or more ring members, preferably 1,2, 3 or 4 ring members, are selected from the group consisting of chemically possible NH,n, O and S. The remaining ring members of the heteroaryl ring are independently selected from C, CH, O, N, NH, and S. (C)₅-C₁₂) Non-limiting examples of heteroaryl rings include furan-2-yl, furan-3-yl, thiophen-2-yl, indol-2-yl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, triazolyl, and the like. For ring systems containing a CH member and an NH member, the ring may be attached to the rest of the molecule via a C or N atom.

A group (C) as defined in the present invention_p-C_n) Alkyl, unsaturated (C)_p-C_n) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) Heteroaryl groups have no substituent or may have a substituent as described herein, provided that the substituent is located at any available position.

The term "known ring system" as used herein refers to a ring system: which are chemically feasible, are known in the art, and are therefore intended to exclude those ring systems which are not chemically possible.

In embodiments of the invention referring to compounds of formula (I) wherein certain groups are not indicated (e.g. by indicating some substitution of the group or by indicating that the group has no substituent), it is understood that possible substitution of the group is as defined in formula (I). The same applies when referring to a specific group "optionally having substituents".

The invention also includes tautomeric forms of the compounds of formula (I). The term "tautomer" means such isomers: their structure differs at the location of the atom, typically a hydrogen atom, and one or more multiple bonds, and they are capable of easily and reversibly changing from one to another. Tautomers are used indiscriminately in this application. Thus, as an example, a hydroxyphenyl group is considered equivalent to its tautomeric form: cyclohexa-2, 4-dienone. For the purposes of the present invention, all tautomers are considered to be equivalent.

There is no limitation on the type of salt of the compound of the present invention that may be used, provided that when it is used for therapeutic purposes, the salt is pharmaceutically, cosmetically or veterinarily acceptable. The term "pharmaceutically, cosmetically or veterinarily acceptable salts" covers salts which are commonly used to form alkali metal salts and to form addition salts of the free acids or free bases.

The preparation of pharmaceutically, cosmetically or veterinarily acceptable salts of the compounds of formula (I) may be carried out by methods known in the art. For example, they can be prepared by conventional chemical methods from parent compounds containing basic or acidic moieties. In general, such salts are prepared, for example, by reacting the free acid or free base form of the compound with a stoichiometric amount of a suitable pharmaceutically, cosmetically or veterinarily acceptable base or acid in water or an organic solvent, or in a mixture thereof. The compounds of formula (I) and their salts differ in some physical properties, but are equivalent for the purposes of the present invention.

The compounds of the invention may be in crystalline form or as free solvated compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the invention. Solvation methods are generally known in the art. In general, for the purposes of the present invention, solvated forms with pharmaceutically, cosmetically or veterinarily acceptable solvents (e.g., water and ethanol, etc.) are equivalent to unsolvated forms.

Some of the compounds of the present invention may have chiral centers that may give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of an individual compound that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers). The present invention relates to each of said stereoisomers and mixtures thereof.

Diastereomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be performed on any chiral synthetic intermediate or compound of the invention. Optically pure isomers can also be obtained separately using enantiospecific synthesis.

In all embodiments of the invention referring to compounds of formula (I), even if it is not specifically mentioned, it always embraces pharmaceutically, cosmetically or veterinarily acceptable salts of the compounds of formula (I), as well as stereoisomers or mixtures of stereoisomers of any compound of formula (I) or any pharmaceutically acceptable salt thereof.

In a first aspect of the invention, the compounds of the invention are not the compounds listed in table 1:

TABLE 1

As can be seen in the above table, all cited compounds except the last compound are commercial products unrelated to the relevant bibliographic reference. Compounds having CAS RN 182553-24-8 are disclosed in references J.org.chem.1997,62, 2080-. Said documents disclose only the chemical synthesis of compounds and thus do not belong to the chemical field of the present invention, i.e. none of said documents describes the ability of said compounds to modulate TRPV1 nor its use in the treatment and/or prevention of related conditions and/or diseases.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein m is an integer selected from 1 to 2. In a more specific embodiment, m is 1. In another more specific embodiment, m is 2.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is¹Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group, and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon. More specifically, R¹Is H or (C) optionally having a substituent₁-C₈) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₆) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₃) An alkyl group. Even more particularly, R¹Is H or methyl.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is²Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group, and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon. More specifically, R²Is H or (C) optionally having a substituent₁-C₈) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₆) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) (C) wherein alkyl group may be substituted₁-C₃) An alkyl group. Even more particularly, R²Is H or methyl, even more particularly R²Is H.

In another embodiment, optionally withOne or more combinations of features of various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is³Is a halogen, more particularly iodine.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is⁴Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group, and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon. More specifically, R⁴Is H or (C) optionally having a substituent₁-C₈) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₆) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₃) An alkyl group. Even more particularly, R⁴Is H.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is⁶And R^6’Selected from the group consisting of: H. optionally substituted (C)₁-C₈) Alkyl group, and optionally substituted unsaturated (C)₂-C₈) A hydrocarbon. More specifically, R⁶And R^6’Independently H or optionally substituted (C)₁-C₈) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₆) An alkyl group. Even more specifically, (C) optionally having a substituent₁-C₈) Alkyl is optionally substituted (C)₁-C₃) An alkyl group. Even more particularly, R⁶And R^6’Is H.

In another embodiment, optionally with each of the above or belowOne or more combinations of features of one embodiment, the invention relates to a compound of formula (I) as described previously, wherein R is⁵Selected from the group consisting of: optionally substituted (C)₃-C₂₈) Alkyl group and optionally substituted unsaturated (C)₃-C₂₈) A hydrocarbon. More specifically, R⁵Is optionally substituted (C)₆-C₂₈) Alkyl or unsaturated (C) optionally having substituent₆-C₂₈) A hydrocarbon. Even more particularly, R⁵Is optionally substituted (C)₉-C₂₆) Alkyl or unsaturated (C) optionally having substituent₉-C₂₆) A hydrocarbon.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as described previously, wherein R is⁵Selected from the group consisting of: propyl, butyl, 2-methylpropyl, pentyl, penta-1, 3-dienyl, hexyl, heptyl, octyl, 2, 6-dimethylhepta-1, 5-dienyl, nonyl, undecyl, tetradecyl, heptadecyl-8-enyl, 11-hydroxyheptadecyl-8-enyl, heneicosyl-12-enyl, nonadecyl-4, 7,10, 13-tetraenyl, 3,7,12,16, 20-pentamethylheneicosyl-3, 7,11,15, 19-pentaenyl, icosyl-5, 8,11, 14-tetraen-2-yl and heptadecyl-8-enyl. More specifically, R⁵Are 2, 6-dimethylhepta-1, 5-dienyl, undecyl and 3,7,12,16, 20-pentamethylheneicosyl-3, 7,11,15, 19-pentaalkenyl.

in another embodimentWherein R is as defined above, optionally in combination with one or more features of the various embodiments described above or below, the present invention relates to a compound of formula (I) wherein R is as defined previously⁶Selected from the group consisting of:

in another embodiment of the invention, the compound of formula (I) is selected from the group consisting of:

also forming part of the invention is a process for the preparation of a compound of formula (I) as defined above by coupling a compound of formula (II) with a compound of formula (III) in the presence of formaldehyde to produce a compound of formula (I), as shown in the following scheme:

wherein R is⁴Is H, and R¹、R²、R³、R⁵、R⁶、R^6’And m is as defined above. This conversion (Passerini multicomponent reaction) is carried out in the presence of a suitable solvent, for example dichloromethane, at a suitable temperature, preferably under reflux.

At R¹And/or R²In the case of hydrogen, the above transformations may also be carried out using precursors of compounds of formula (II), in which the hydroxyl group is conveniently protected with a protecting group. After reaction with a compound of formula (III) in the presence of formaldehyde, the protecting group is removed and the compound of formula (I) can be converted to another compound of formula (I) if desired. Introduction and/or removal of protecting Groups is carried out by standard methods well known in the art as described, for example, in t.w.green and p.g.m.wuts, Protective Groups in Organic Chemistry (Wiley, 3rd edition 1999, chapter 2, pages 17-200). Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl, and tribenzyl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers. For example, the hydroxamic acid protecting group is tetrabutyldimethylsilyl and the deprotection is carried out in a suitable solvent (e.g. tetrahydrofuran) in the presence of tetra-n-butylammonium fluoride (TBAF) in an acidic medium (e.g. with acetic acid).

Wherein R is⁴Compounds of formula (I) which are H may be converted to compounds in which R is⁴A compound of formula (I) selected from the group consisting of: (C)₁-C₈) Alkyl, unsaturated (C)₂-C₈) Hydrocarbon, (C)₃-C₆) Cycloalkyl group, (C)₆-C₁₂) Aryl and (C)₅-C₁₂) A heteroaryl group. Which can be prepared by reacting a compound of the formula R with a base such as potassium carbonate, sodium hydride, butyllithium or lithium diisopropylamide in the presence of a suitable solvent such as acetonitrile, tetrahydrofuran or dimethylformamide⁴Alkylation of compound (I) with an alkylating agent of X, wherein X is a leaving group, for example a halogen atom. Conditions such as solvent and temperature will depend on the base used.

Alternatively, the compounds of formula (I) may be prepared by coupling an amine of formula (VI) with a compound of formula (VII), as shown in the following scheme:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R^6’And m is as defined above, and R is H. This conversion can optionally be carried out in the presence of an activating agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 20(edc. hcl) and hydroxybenzotriazole (HOBt), preferably in the presence of a base such as N-methylmorpholine (NMM), in a suitable solvent such as dichloromethane, chloroform or dimethylformamide at a temperature from room temperature to the boiling temperature of the solvent, preferably at room temperature.

The compound of formula (II) may be prepared from a compound of formula (IV) which may be prepared from a compound of formula (V), as shown in the scheme below

In the above scheme, R¹、R²、R³、R⁶、R⁶And m is as defined above. Alternatively, in the above transformation, R¹And/or R²May be a group R to be subsequently converted into¹And/or R²A protecting group of (1). Such groups may be introduced and removed under conditions well known in the art as indicated above.

The conversion of a compound of formula (V) to a compound of formula (IV) may be carried out in the presence of an ester of formic acid (e.g. methyl formate or ethyl formate), optionally in a suitable solvent (e.g. methanol) and optionally in a base (e.g. K)₂CO₃) In the presence of oxygen at a suitable temperature, preferably at 35 ℃. Alternatively, the compound of formula (V) may be converted to the compound of formula (IV) by using a large excess of acetic anhydride and formic acid at 0 ℃. The reaction can be carried out with or without a solvent. If a solvent is used, THF may be a good choice.

The compound of formula (IV) can be in POCl₃And a base such as triethylamine in a suitable solvent such as dichloromethane at a suitable temperature, preferably 0 c, to form the compound of formula (II).

Wherein R is³The compound of formula (I) which is iodine may be prepared from compounds wherein R is³The compound of formula (IV) which is H is prepared in the presence of iodine and silver trifluoroacetate in a suitable solvent such as chloroform. The resulting compounds may be converted into compounds of formula (I) as defined previously.

The compounds of formulae (III), (V), (VI) and (VII) are commercially available or can be obtained by conventional synthetic methods. For example, wherein R⁴The compounds of formula (VI) other than H may be prepared from the compounds of formula (V) by alkylation.

The compounds of formula (I) may also be converted in one or more steps to another compound of formula (I). One skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are disclosed in the examples, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified according to the present invention using conventional chemical methods well known to those skilled in the art.

The invention also relates to a pharmaceutical, veterinary or cosmetic composition comprising an effective amount of a compound of the invention, and a pharmaceutically, veterinary or cosmetically acceptable excipient or carrier.

The compositions of the present invention may be immediate or sustained release systems.

The term "sustained release" is used herein to refer to a compound that provides a gradual release of the compound over a period of time, and preferably, but not necessarily, provides a relatively constant release level over a period of time for a system for delivering the compound.

Examples of sustained release or carrier systems include, but are not limited to, liposomes, mixed liposomes, oleosomes, niosomes, exosomes, nanoparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed micelles of phospholipid surfactants, millimeter spheres, microspheres and nanospheres, fat spheres, millimeter capsules, microcapsules and nanocapsules, and microemulsion and nanoemulsion forms that can be added to achieve greater penetration of the active ingredient and/or to improve its pharmacokinetic and pharmacodynamic properties. Preferred sustained release or carrier systems are liposomes, mixed micellar phospholipids and microemulsions, most preferably water-in-oil microemulsions with internal reverse micellar structures.

The expression "effective amount" as used herein refers to the amount of product which, after its application, provides the desired cosmetic or therapeutic effect. An effective amount (also recited herein as a therapeutically effective amount) that provides a therapeutic effect is an amount of the compound that, when administered, is sufficient to prevent the progression, or alleviate to some extent, one or more of the symptoms of the disease in question. The particular dose of a compound administered according to the present invention may vary according to the particular conditions surrounding the case, including the compound administered, the route and frequency of administration, the age, the condition of the patient, the nature or severity of the condition, the disorder or condition to be treated or prevented, and similar considerations.

Generally, the amount of the compound of the invention in the composition is preferably from 0.00000001% to 20% by weight, relative to the total weight of the composition; more preferably from 0.000001 to 20 wt%, even more preferably from 0.0001 to 10 wt%, and still more preferably from 0.0001 to 5 wt%.

The expression "pharmaceutically or veterinarily acceptable excipient or carrier" means an excipient or carrier suitable for the preparation of a composition for pharmaceutical or medical use in humans and animals. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical or veterinary composition. It must also be suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications consistent with a reasonable risk/benefit relationship.

The expression "cosmetically acceptable excipient or carrier" means an excipient or carrier suitable for the preparation of a composition for cosmetic use. Each component must be cosmetically acceptable in the sense of being compatible with the other ingredients of the cosmetic composition. It must also be suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications consistent with a reasonable risk/benefit relationship.

In a specific embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound of formula (I) as defined previously, and one or more pharmaceutically or veterinarily acceptable excipients or carriers.

In another specific embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a cosmetic composition comprising a therapeutically effective amount of a compound of formula (I) as defined previously, and one or more pharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions may be formulated for buccal, oral, topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches, micro-patches, and the like. Systemic administration is for example oral or parenteral. For the purposes of the present invention, the term "parenteral" includes nasal, atrial, ocular, rectal, urethral, vaginal, subcutaneous, intradermal, intravascular, intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intracerobrospinal, intra-articular, intrahepatic, intrathoracic, intratracheal, intrathecal, and intraperitoneal, as well as any other similar injection or infusion technique.

The choice of formulation type will depend on the following: the nature of the active compound, the site of administration, the kinetics and duration of release of the compound of the invention, and the condition to be treated.

In a specific embodiment, the composition of the present invention is a topical composition, optionally in combination with one or more features of the various embodiments described above or below.

In another specific embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition of the present invention is a transdermal composition.

In another specific embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition of the invention is an intrabuccal or oral composition.

Buccal and oral formulations include solid and liquid preparations such as lozenges, capsules, pills, solutions, emulsions, syrups, elixirs and the like. The person skilled in the art will know the appropriate excipients to be used in the formulation. Non-limiting examples of excipients include: disintegrants, for example microcrystalline cellulose, corn starch, sodium starch, glycolates and alginic acid; binders, such as starch, pregelatinized starch, polyvinylpyrrolidone (PVP), copovidone, acacia, xanthan gum, tragacanth gum, cellulose derivatives (e.g., Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), Ethylcellulose (EC), and carboxymethylcellulose (CMC)); lubricants, such as magnesium stearate or sodium lauryl sulfate; slip aids such as colloidal silica, starch and talc; sweeteners such as sucrose, glucose, fructose, maltose, lactose, sorbitol, xylitol, mannitol, maltulose, isomaltulose, maltitol, isomalt, lactulose and lactitol; coloring and flavoring agents, and the like.

In general, topical or transdermal formulations include creams, various emulsions (such as non-limiting emulsions of oil and/or silicone in water, water/oil/water or water/silicone/water, and oil/water/oil or silicone/water/silicone emulsions), anhydrous compositions, aqueous dispersions, oils, milk, balms, foams, gels, pomades, powders, lotions, cream gels, hydroalcoholic solutions, water glycol solutions, hydrogels, wipes, soaps, shampoos, conditioners, essences, polysaccharide films, ointments, mousses, ointment powders, sticks, dry pastes, pencils and evaporators, sprays (including "leave-on" formulations and "rinse-off" formulations), where the compound is dispersed or dissolved in a suitable excipient.

Topical or transdermal applications may be incorporated into various types of solid fittings by techniques known to those skilled in the art, such as, but not limited to: a bandage, gauze, T-shirt, sock, stocking, undergarment, waistband, glove, diaper, napkin, dressing, bed cover, wet wipe, adhesive patch, non-adhesive patch, occlusive patch, microelectronic patch or mask; or can be incorporated into various cosmetic array products such as, for example, cosmetic bases (e.g., fluid cosmetic bases and lotions), skin cleansers, milk removers, concealers, eye shadows, lipsticks, lip glosses, powders, and the like.

The topical composition as defined above comprises a pharmaceutical, veterinary or cosmetic excipient or carrier suitable for topical application, including adhesives, emollients, skin penetration enhancers, emulsifiers, surfactants, thickeners, viscosity increasing agents, pH modifiers, antioxidants, preservatives, solvents, dyes, pigments, fragrances or mixtures thereof. The excipient or carrier used has an affinity for use on the skin, is well tolerated, is stable, and is used in an amount suitable to provide the desired consistency and ease of application. Suitable excipients and/or carriers and their amounts can be readily determined by one skilled in the art depending on the type of formulation being prepared.

The compositions of the present invention may also include a liquid carrier, such as water, oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, castor oil), polysorbates, sorbitan esters, ether sulfates, betaines, glycosides, maltosides, fatty alcohols, nonoxynol, poloxamers, polyoxyethylene, polyethylene glycol, dextrose, glycerol, and digitonin, and the like.

Examples of binders include, but are not limited to, povidone, alginates, and traganth, among others. Examples of emollients or skin penetration enhancers include, but are not limited to, lauryl alcohol, oleyl alcohol, eucalyptol, sodium lauryl sulfate, glyceryl monooleate, sorbitan monooleate, isopropyl myristate, glyceryl myristate, propylene glycol, dimethyl isosorbide, palmitoyl isopropionate, oleic acid, and the like, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazepan-2-one), alcohols, urea, ethoxydiglycol, acetone, polyethylene glycol, and the like. If desired, the compositions of the present invention may be applied to the local area to be treated by iontophoresis, sonophoresis, electroporation, microelectronic patches, mechanical pressure, osmotic pressure gradients, occlusive curing, microinjection, or by needle-free injection of pressure (e.g., oxygen injection), or any combination thereof, to achieve enhanced penetration of the compounds of the present invention. The area of administration will be determined by the nature of the condition to be treated or prevented.

Examples of emulsifiers or surfactants include, but are not limited to, polysorbate 80, polysorbate 20, sorbitan groups (spans), lecithin, and potassium hexadecyl hydrogen phosphate, and the like.

Examples of thickening or viscosifying agents include, but are not limited to: synthetic polymers, such as carbomers (crosslinked polymers of acrylic acid); cellulose polymers such as hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose, and block copolymers based on ethylene oxide and propylene oxide (pluronic compound), and the like.

Examples of pH adjusting agents or buffers include, but are not limited to: sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium benzoate, potassium benzoate, sodium citrate, sodium acetate, sodium tartrate, diethanolamine, triethanolamine, sodium hydroxide, citric acid, and the like.

Examples of antioxidants include, but are not limited to: ascorbic acid, sodium ascorbate, sodium bisulfite, sodium sulfite, sodium metabisulfite, curcumin, tetrahydrocurcumin, diacetyltetrahydrocurcumin, resveratrol, quercetin, hesperidin, myricetin, naringin, alpha-lipoic acid, monothioglycerol, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), propyl gallate and the like.

Examples of preservatives include, but are not limited to: methyl paraben, sodium methyl paraben, propyl paraben, sodium propyl paraben, benzalkonium chloride, diazolidinyl urea, benzethonium chloride, chlorocresol, thimerosal, sorbic acid, potassium sorbate, benzyl alcohol and the like.

Examples of solvents include, but are not limited to, ethanol, isopropanol, water, propylene glycol, polyethylene glycol, substituted glycols (e.g., cremophor), or mixtures thereof, and the like.

The compounds of the invention may also be adsorbed onto solid organic polymeric or solid mineral carriers such as, but not limited to, bentonite, silica, starch or maltodextrin, and the like.

As noted above, the compounds of the present invention are TRPV1 modulators. Some compounds of the invention, especially wherein R³Compounds of formula (I) that are H are TRPV1 agonists. Some compounds of the invention, especially wherein R³Compounds of formula (I) that are halogens, particularly iodine, are TRPV1 antagonists.

For the purposes of the present invention, a TRPV1 agonist as defined herein can have an EC of ≦ 10 μ M, preferably ≦ 1 μ M, more preferably ≦ 500nM₅₀The TRPV1 is activated in value and an antagonist of TRPV1 as defined herein is capable of an IC of 50. mu.M or less, preferably 30. mu.M or less, more preferably 10. mu.M or less₅₀Values inhibit TRPV1, wherein activation/inhibition of TRPV1 is measured in a fluorescence assay (e.g., an in vitro assay) as described in the examples of the invention.

Thus, the compounds of the present invention block TRPV1 either via direct desensitization of the receptor in the case of TRPV1 agonists or in the case of antagonists, resulting in loss of TRPV1 activity. A further advantage of using a TRPV1 antagonist is that it does not cause burning sensations when administered.

Accordingly, the compounds of the present invention are useful for the treatment and/or prevention of conditions or diseases mediated by the inhibition of TRPV 1.

Accordingly, the present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament or cosmetic composition for the treatment and/or prevention of a condition or disease mediated by the inhibition of TRPV1, comprising: but-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-phenethyl-carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-benzyl carbamoyl) methyl ester; 3-methyl-2-butenoic acid (3, 4-dimethoxybenzyl carbamoyl) -methyl ester; hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzyl carbamoyl) methyl ester; butyric acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; butyric acid (3, 4-dimethoxyphenethylcarbamoyl) -methyl ester; hexane-2, 4-dienoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 2-ethylbutanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; undecyl-10-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 2-Methylpentanoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; and 2- (3, 4-dimethoxyphenethylcarbamoyl) propan-2-yl valerate.

A method for the treatment and/or prevention of a condition or disease mediated by inhibition of TRPV1, which method comprises administering to a subject, including a human being, in need thereof an effective amount of a compound of formula (I) as defined above, comprising: but-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-phenethyl-carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; 3, 3-dimethylbutyric acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 3-methylbut-2-enoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 4-methylpentanoic acid (3, 4-dimethoxy-benzyl carbamoyl) methyl ester; 3-methyl-2-butenoic acid (3, 4-dimethoxybenzyl carbamoyl) -methyl ester; hexane-2, 4-dienoic acid (2E,4E) - (3, 4-dimethoxybenzyl carbamoyl) methyl ester; butyric acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; butyric acid (3, 4-dimethoxyphenethylcarbamoyl) -methyl ester; hexane-2, 4-dienoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; 2-ethylbutanoic acid (3, 4-dimethoxyphenethylcarbamoyl) methyl ester; but-2-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; but-3-enoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; undecyl-10-enoic acid (3, 4-dimethoxybenzyl-carbamoyl) methyl ester; 2-Methylpentanoic acid (3, 4-dimethoxybenzyl carbamoyl) methyl ester; and 2- (3, 4-dimethoxyphenethylcarbamoyl) propan-2-yl valerate.

In one embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the condition or disease mediated by inhibition of TRPV1 is selected from pain, inflammation and cancer.

Anti-tumor activity of TRPV1 is disclosed, for example, in Breast Cancer 201613, 8, pp 243-252 and nat. Rev. drug Discov.2011,10(8), pp 601-20.

Inhibition of TRPV1 is also associated with pain relief and reduced inflammation. For example, in j.pain 2006,7(10), pages 735-46, it is disclosed that potent non-competitive antagonists of TRPV1 exhibit anti-inflammatory and analgesic activity in preclinical models of acute and chronic pain. In the context of the present invention, pain may be associated with: post-herpetic neuralgia, herpes zoster (shingles/herpes zoster), diabetic neuropathy, post-mastectomy pain syndrome, oral neuralgia, trigeminal neuralgia, temporomandibular joint disorders, cluster headaches, osteoarthritis, arthritic pain, rhinopathy, oral mucositis, skin allergies, detrusor hyperreflexia, lumbago/hematuria syndrome, neck pain, back pain, amputation stump pain, reflex sympathetic dystrophy, and pain due to skin tumors.

Inhibition of TRPV1 may also be a palladium target for the treatment of certain skin diseases such as sensitive skin, itching (pruritus), rosacea, acne vulgaris (ace vulgaris), atopic dermatitis, psoriasis and psoriatic arthritis.

Sensitive skin is a skin condition in which the skin is prone to itching and irritation as experienced by subjective sensations when cosmetics and toiletries are used. Inhibition of TRPV1 by TRPV1 antagonists for the treatment of sensitive skin is disclosed in exp.

Itching (pruritus) may be defined as a feeling of discomfort skin associated with a strong desire to scratch. In Journal of Dermatological Science 2012,65, pages 81-85, it is disclosed that TRPV1 expression is found to be increased in nerve fibers within aging skin, suggesting an important role of TRPV1 in the pathophysiology of skin symptoms associated with aging (e.g. pruritus).

Rosacea is a long-term skin condition characterized by redness of the face, small and superficial dilated vessels on the skin of the face, papules, pustules, and swelling. It has been disclosed that in affected skin of patients with various types of rosacea, altered expression patterns of TRPV1 have been identified; this suggests that TRPV1 may be involved in the pathogenesis of rosacea (br.j. pharmacol.2014,171(10), p.2568-2581).

Psoriasis is a long-lasting autoimmune disease characterized by spots of abnormal skin, usually red, itchy and flaky. Acne vulgaris is a long-term skin disease that occurs when the hair follicles are blocked by dead skin cells and oil from the skin, and is characterized by comedones or whiteheads, papules, oily skin and possible scars. Atopic dermatitis is a type of skin inflammation (dermatitis). Which results in itching, redness, swelling and chapped skin. Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. Psoriatic arthritis is typically characterized by swelling of the entire finger and toes.

The role of TRPV1 in the above-mentioned diseases and/or conditions is described, for example, in artritis Res Ther 2014,16(5), 470; j Invest Dermatol.2009,129(2), pages 329-39; and J Invest Dermatol.2011,131(7), pages 1576-9.

Thus, in another embodiment of the present invention, optionally in combination with one or more features of the various embodiments described above or below, the condition or disease mediated by inhibition of TRPV1 is selected from the group consisting of sensitive skin, itch (pruritus), rosacea, acne vulgaris, atopic dermatitis, psoriasis and psoriatic arthritis.

Throughout the specification and claims, the word "comprise", and variations of the word, such as "comprises" and "comprising", are not intended to exclude other technical features, additives, components or steps. Furthermore, the word "comprising" covers the case where "consists of … …". Other objects, advantages and features of the present invention will become apparent to those skilled in the art upon examination of the present specification or may be learned by practice of the invention. The following examples and figures are provided by way of illustration and are not intended to limit the present invention. Reference signs placed in parentheses in the claims referring to the drawings are intended only to improve the intelligibility of the claims and shall not be construed as limiting the scope of the claims. Moreover, the invention encompasses all possible combinations of the specific and preferred embodiments described herein.

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