阅读说明：本技术 肽酰胺类化合物及其制备方法和在医药上的用途 (Peptide amide compound, preparation method and medical application thereof ) 是由 张晨 黄安邦 叶飞 黄龙彬 黄正刚 王健民 魏用刚 严庞科 郑伟 于 2018-07-19 设计创作，主要内容包括：通式(I)所示的肽酰胺类化合物及其制备方法和在医药上的用途,化合物用于制造治疗或预防哺乳动物的κ阿片样物质受体相关的疾病或病况。<Image he="448" wi="700" file="DDA0002269113960000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The peptide amide compound shown in the general formula (I), the preparation method and the medical application thereof, and the compound is used for manufacturing the kappa opioid receptor related diseases or conditions for treating or preventing mammals.)

A compound of formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof:

wherein the content of the first and second substances,

R¹is selected from

m₁、m₂Each independently selected from 1, 2, 3 or 4;

m₃、m₄each independently selected from 0, 1, 2, 3 or 4; provided that m is₃And m₄Cannot be 0 at the same time;

n₁、n₂each independently selected from 0, 1, 2, 3 or 4;

z is selected from CR^z1R^z2Or NR^z3；

R^z1、R^z2Each independently selected from H, F, Cl, Br, I, OH, CF₃Nitro group, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (═ O) -C_1-6Alkyl, - (CH)₂)_q-C(＝O)O-C_1-6Alkyl, - (CH)₂)_q-NR^1eR^1f、-(CH₂)_q-COOH、-(CH₂)_q-CONH₂、C_3-8Carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF₃O, carboxyl, nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Carbocyclyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O or S, and when said heteroatoms are selected from S, optionally further S, S ═ O or S (═ O)₂；

R^1e、R^1fEach independently selected from H, C_1-6Alkyl, -C (═ O) O-C_1-6Alkyl, -C (═ O) O- (CH)₂)_q-C_3-8Carbocyclyl or-C (═ O) O- (CH₂)_q-3 to 8 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF₃Cyano, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Substituted by substituents of carbocyclic groups or 3-to 8-membered heterocyclic groups containing 1 to 3 membersA heteroatom selected from N, O or S;

or, R^z1And R^z2Form a 3-to 10-membered nitrogen-containing heterocyclic ring with the carbon atom to which it is attached, said ring being optionally further selected from F, Cl, Br, I, OH, CF₃Cyano, nitro, ═ O, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Carbocyclyl or 3-to 8-membered heterocyclyl;

R^1a、R^1beach independently selected from F, CF₃、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or 3 to 8 membered heterocyclyl, said alkyl, alkenyl, alkynyl or heterocyclyl being optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF₃Nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Carbocyclyl or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from any of N, O or S;

R^z3independently selected from H, -C (═ O) -C_1-6Alkyl, -C (═ O) O-C_1-6Alkyl, -C (═ O) -C_3-8Carbocyclyl, -C (═ O) O-C_3-8Carbocyclyl, -C (═ O) O- (3 to 8 membered heterocyclyl), -S (═ O)_p-C_1-6Alkyl, -S (═ O)_p-C_3-8Carbocyclyl, -S (═ O)_p- (3-to 8-membered heterocyclic group), -C (═ O) NR^1gR^1h、-S(＝O)_p-NR¹ⁱR^1jOr 3 to 8 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF₃Nitro, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Carbocyclyl or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from any of N, O or S;

R^1g、R^1h、R¹ⁱ、R^1jeach independently selected from H or C_1-6An alkyl group;

or, R^1g、R^1hForm a 3 to 10 membered heterocyclic ring with the nitrogen atom to which it is attached, said ring being optionally further selected from F, Cl, Br, I, OH, CF₃Cyano, nitro, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl or-S (═ O)_p-C_1-6Alkyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

q is selected from 0, 1, 2, 3 or 4;

p is selected from 0, 1 or 2;

a is selected from 0, 1, 2 or 3;

R⁴independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or- (CH)₂)_q-C_3-8Carbocyclyl, said alkyl, alkenyl, alkynyl or carbocyclyl optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CN, CF₃、NO₂、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Carbocyclyl or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

R²、R³、R⁷、R⁸each independently selected from H, C_1-6Alkyl, -C (═ O) O-C_1-4Alkyl, -C (═ O) O- (CH)₂)_q-C_3-8Carbocyclyl, -C (═ O) O- (CH₂)_q-3 to 8 membered heterocyclyl or

b is selected from 0, 1, 2, 3,4 or 5;

c is selected from 0, 1, 2, 3,4 or 5;

R⁵、R⁶each independently selected from F, Cl, Br, I, CF₃Cyano, nitro, C_1-4Alkyl, -OR^5a、-C(O)OR^5b、-SR^5c、-S(O)R^5d、-S(O)₂R^5eor-NR^5fR^5g；

R^5a、R^5b、R^5c、R^5d、R^5e、R^5fAnd R^5gEach independently selected from H or C_1-4An alkyl group;

or, R^5f、R^5gThe nitrogen atom to which it is attached forms a 5-to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from any of N, O or S.

The compound according to claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof,

m₁、m₂、m₃、m₄each independently selected from 1 or 2;

n₁、n₂each independently selected from 0, 1 or 2;

z is selected from CR^z1R^z2Or NR^z3；

R^z1、R^z2Each independently selected from H, C_1-4Alkyl, - (CH)₂)_q-C(＝O)O-C_1-4Alkyl, - (CH)₂)_q-NR^1eR^1f、-(CH₂)_q-COOH、-(CH₂)_q-CONH₂、C_3-6Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF₃O, carboxyl, nitro, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Carbocyclyl or 3-to 6-membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S, and when said heteroatoms are selected from S, optionally furtherFor S, S ═ O or S (═ O)₂；

R^1e、R^1fEach independently selected from H, C_1-4Alkyl, -C (═ O) O-C_1-4Alkyl or-C (═ O) O- (CH)₂)_q-C_3-6Carbocyclyl, said alkyl or carbocyclyl optionally further substituted with 0-3 substituents selected from F, Cl, Br, I, OH, CF₃Nitro, cyano, methyl, ethyl, methoxy, ethoxy, phenyl;

or, R^z1And R^z2Is capable of forming a 4 to 6 membered nitrogen containing heterocyclic ring to which it is attached, said ring being optionally further substituted with a substituent of ═ O;

R^1a、R^1bindependently selected from F, CF₃Methyl, ethyl, propyl or isopropyl;

R^z3each independently selected from H, -C (═ O) -C_1-4Alkyl, -C (═ O) -C_3-6Carbocyclyl, -C (═ O) O-C_1-4Alkyl, -S (═ O)_p-C_1-4Alkyl, -S (═ O)_p-C_3-6Carbocyclyl, -C (═ O) NR^1gR^1h、-S(＝O)_p-NR¹ⁱR^1jOr 3 to 6 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-3 substituents selected from F, Cl, Br, I, OH, CF₃Nitro, cyano, amino, methyl, ethyl, methoxy, ethoxy, cyclopropyl or phenyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

R^1g、R^1h、R¹ⁱ、R^1jeach independently selected from H or C_1-4An alkyl group;

or, R^1g、R^1hForm a 4-to 6-membered heterocyclic ring with the nitrogen atom to which it is attached, said ring being optionally further selected from F, Cl, Br, I, OH, CF₃Cyano, nitro, methyl, ethyl, methoxy, ethoxy or-S (═ O)_p-C_1-4Alkyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

p is selected from 2;

q is selected from 0 or 1;

a is selected from 3;

R⁴selected from propyl or isopropyl;

R²、R³、R⁷、R⁸each independently selected from H, C_1-4Alkyl, -C (═ O) O-C_1-4Alkyl or-C (═ O) O-benzyl;

b is selected from 0;

c is selected from 0.

A compound according to claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from compounds of formula (II):

R¹is selected from

m₁、m₂、m₃、m₄Each independently selected from 1 or 2;

n₁、n₂each is independently selected from 0 or 2;

R^1a、R^1bis independently selected from F;

z is selected from CR^z1R^z2Or NR^z3；

R^z1、R^z2Each independently selected from H, carboxyl,

Or, R^z1And R^z2Capable of forming a lactam with the carbon atom to which it is attached

R^z3Each independently selected from H, -C (═ O) -C_1-4Alkyl, -C (═ O) -C_3-6Carbocyclyl, -C (═ O) O-C_1-4Alkyl, -S (═ O)_p-C_1-4Alkyl, -S (═ O)_p-C_3-6Carbocyclyl, -C (═ O) NR^1gR^1h、-S(＝O)_p-NR¹ⁱR^1jOr 3 to 6 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0-3 substituents selected from F, Cl, Br, I, OH, CF₃Nitro, cyano, amino, methyl, ethyl, methoxy, ethoxy, cyclopropyl or phenyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

R^1g、R^1h、R¹ⁱ、R^1jeach independently selected from H or C_1-4An alkyl group;

or, R^1g、R^1hForm a 4-to 6-membered heterocyclic ring with the nitrogen atom to which it is attached, said ring optionally further selected from F, CF₃Methyl, methoxy or-S (═ O)_p-C_1-4Alkyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, O or S;

p is selected from 2;

R²、R³、R⁷、R⁸each independently selected from H, methyl or-C (═ O) O-tert-butyl.

A compound according to claim 3, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from compounds of formula (II):

R^z3each independently selected from H,

A compound according to claim 4, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof,

R¹is selected from

The compound according to claim 5, selected from one of the following structures, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof:

a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetate salt.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, and one or more pharmaceutically acceptable carriers and/or excipients.

Use of a compound of any one of claims 1 to 7, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition of claim 8, in the manufacture of a medicament for the treatment or prevention of a kappa opioid receptor-associated disease or condition in a mammal.

The use of claim 9, wherein the kappa opioid receptor-associated disease or condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.

The use of claim 9, wherein the pain is selected from the group consisting of: neuropathic pain, somatic pain, visceral pain, and skin pain.

The use of claim 9, wherein the pain is selected from the group consisting of: arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post-medical treatment pain, ocular pain, otitis pain, breakthrough cancer pain and pain associated with GI disorders.

A method of treating or preventing a kappa opioid receptor-associated disease or condition in a mammal, comprising administering a compound of any one of claims 1-7, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition of claim 8.

The method of claim 13, wherein the kappa opioid receptor-associated disease or condition is selected from the group consisting of: pain, inflammation, pruritus, edema, hyponatremia, hypokalemia, ileus, cough and glaucoma.

The method of claim 14, wherein the pain is selected from the group consisting of: neuropathic pain, somatic pain, visceral pain, and skin pain.

The method of claim 14, wherein the pain is selected from the group consisting of: arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, dyspepsia, post-surgical pain, post-medical treatment pain, ocular pain, otitis pain, breakthrough cancer pain and pain associated with GI disorders.