# US 6,720,341 B2 · Preventives/remedies for kidney diseases

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- Number: US 6,720,341 B2
- Document ID: US6720341B2
- Status: Granted
- Kind: B2
- Application number: 10/240,174
- Filed: 2002-10-17
- Published: 2003-05-22
- Granted: 2004-04-13
- Earliest claimed: 2000-03-31
- Assignees: Mitsubishi Pharma Corporation
- Inventors: Toshiki Moriyama; Enyu Imai
- Web page: https://patentgrep.com/patent/US6720341B2

## CPC

- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61P 13/12: of the kidneys
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/81: Amides; Imides
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound having a Rho kinase inhibitory activity, such as (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)-cyclohexane, has a renal interstitial fibrosis inhibitory action in renal interstitial fibrosis model mice and various other actions, and therefore, is useful as an agent for the prophylaxis or treatment of renal diseases.

## Claims

### Claim 1

A method for the prophylaxis or treatment of renal disease which accompanies renal fibrosis, which comprises administering a pharmaceutically effective amount of a compound having a Rho kinase inhibitory activity to a patient in need thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I),
wherein
Ra is a group of the formula
in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or a group of the formula
wherein R6 is hydrogen, alkyl or formula: —NR8R9
wherein R8 and R9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, R7 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R6 and R7 in combination show a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
or R and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula
wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, tetrahydrofurftiryl, carbamoylalkyl, phthalimidoalkyl, amidino or a group of the formula
wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, α-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q1 is hydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl,
W is alkylene,
Q2 is hydrogen, halogen, hydroxy or aralkyloxy,
X is alkylene,
Q3 is hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3 -oxo-2,3,4,5-tetrahydropyridazin-6-yl;
and Y is a single bond, alkylene or alkenylene, and
in the formula (c),
a broken line is a single bond or a double bond, and
R5 is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy;
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

### Claim 3 (depends on 1, 2)

The method of claim 1 or 2, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I′),
wherein
Ra′ is a group of the formula
wherein
R′ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
R1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
or R′ and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula
wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl, and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrro[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, or a pharmaceutically acceptable acid addition salt thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane or a pharmaceutically acceptable acid addition salt thereof.

### Claim 6 (depends on 1, 2)

The method of claim 1 or 2, wherein the renal disease accompanying renal fibrosis is interstitial renal fibrosis.