# US 2014/0194423 A1 · Combination products

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- Number: US 2014/0194423 A1
- Document ID: US20140194423A1
- Status: Published application
- Kind: A1
- Application number: 14/195,947
- Filed: 2014-03-04
- Published: 2014-07-10
- Earliest claimed: 2008-06-30
- Inventors: Baltazar Gomez-Mancilla; Fabrizio Gasparini
- Web page: https://patentgrep.com/patent/US20140194423A1

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/12: Ketones
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/428: condensed with carbocyclic rings
- 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 31/4427: containing further heterocyclic ring systems
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/465: Nicotine; Derivatives thereof
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/16: Anti-Parkinson drugs
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

The invention concerns the combinations of an mGluR modulator, e.g. an mGluR5 modulator and at least one of L-dopa, a dopamine modulator, e.g. a dopamine agonist, a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor.

## Claims

### Claim 1

The use of an mGluR modulator in combination with at least one of
i) L-dopa, or
ii) a dopa decarboxylase inhibitor, or
iii) a catechol-O-methyl transferase inhibitor
iv) a dopamine agonist
or in any case a pharmaceutically acceptable salt thereof;
for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.

### Claim 2 (depends on 1)

Use according to claim 1, wherein the modulator is an mGluR5 modulator.

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

Use according to claim 1 or claim 2, wherein the modulator is an mGluR antagonist.

### Claim 4 (depends on 2, 3)

Use according to claim 2 or claim 3, wherein the modulator is an mGluR5 antagonist.

### Claim 5

Use according to any preceding claim, wherein the modulator is a compound of the formula (I)
wherein
R1 represents optionally substituted alkyl or optionally substituted benzyl; and
R2 represents hydrogen (H), optionally substituted alkyl or optionally substituted benzyl; or
R1 and R2 form together with the nitrogen atom to which they are attached an optionally substituted heterocycle with less than 14 ring atoms;
R3 represents halogen, alkyl, alkoxy, alkylamino or dialkylamino;
R4 represents hydroxy (OH), halogen, alkyl or alkoxy;
Q represents CH, CR4 or N;
V represents CH, CR4 or N;
W represents CH, CR4 or N;
X represents CH or N;
Y represents CH, CR3 or N;
Z represents CH2, NH or O; and
provided that Q, V and W are not N at the same time;
in free base or acid addition salt form.

### Claim 6 (depends on 1, 2, 3, 4)

Use according to any of claims 1 to 4, wherein the modulator is a compound of the formula (II), wherein a compound of the formula (II) is a compound of formula (I) in which at least one of Q, V and W is N, in free base or acid addition salt form.

### Claim 7 (depends on 1, 2, 3, 4)

Use according to any of claims 1 to 4, wherein the modulator is a compound of the formula (IV) or the formula (V):
wherein
m is 0 or 1,
n is 0 or 1 and
A is hydroxy
X is hydrogen and
Y is hydrogen, or
A forms a single bond with X or with Y;
R0 is hydrogen, (C1-4alkyl, (C1-4alkoxy, trifluoromethyl, halogen, cyano, nitro, —COOR1 wherein R1 is (C1-4)alkyl or —COR2 wherein R2 is hydrogen or (C1-4alkyl, and
R is —COR3, —COOR3, —CONR4R5 or —SO2R6, wherein R3 is (C1-4alkyl, (C3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl; R4 and R5, independently, are hydrogen or (C1-4alkyl; and R6 is (C1-4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl,
R′ is hydrogen or (C1-4)alkyl and
R″ is hydrogen or (C1-4)alkyl, or
R′ and R″ together form a group —CH2—(CH2)m—
wherein m is 0, 1 or 2, in which case one of n and m is different from 0,
with the proviso that R0 is different from hydrogen, trifluoromethyl and methoxy when n is 0,
A is hydroxy, X and Y are both hydrogen, R is COOEt and R′ and R″ together form a group —(CH2)2—,
OR
wherein
R1 represents hydrogen or alkyl;
R2 represents an unsubstituted or substituted heterocycle or
R2 represents an unsubstituted or substituted aryl;
R3 represents alkyl or halogen;
X represents a single bond or an alkandiyl-group, optionally interrupted by one or more oxygen atoms or carbonyl groups or carbonyloxy groups;
in free base or acid addition salt form.

### Claim 8

Use according to any preceding claim, wherein the disorder is Parkinson's associated levodopa (L-dopa) induced dyskinesia.

### Claim 9

Use according to any preceding claim, wherein the disorder is Parkinson's Disease non-L-dopa induced dyskinesia.

### Claim 10

Use according to any preceding claim, wherein the Dopa decarboxylase inhibitors are, carbidopa or benserazide.

### Claim 11

Use according to any preceding claim, wherein the Catechol-O-methyl transferase inhibitors are tolcapone or entacapone.

### Claim 12

Use according to any preceding claim, wherein the Dopamine agonists are bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine or lisuride.

### Claim 13

A method for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluR modulator.

### Claim 14 (depends on 2, 3, 4, 5, 6, 7, 13)

A method according to claim 13, wherein the mGluR modulator is as defined in any of claims 2 to 7.

### Claim 15 (depends on 13, 14)

A method according to claim 13 or claim 14, wherein the mGluR modulator is an mGluR5 modulator.

### Claim 16 (depends on 14)

A method according to claim 14, wherein the mGluR modulator is an mGluR5 antagonist.

### Claim 17 (depends on 8, 9, 13, 14, 15, 16)

A method according to any of claims 13 to 16, wherein the disorder is as defined in claim 8 or claim 9.

### Claim 18

A combination comprising an mGluR modulator or a pharmaceutically acceptable salt thereof, and at least one of
v) L-dopa, or
vi) a dopa decarboxylase inhibitor, or
vii) a catechol-O-methyl transferase inhibitor
viii) a dopamine agonist
or in any case a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 2, 3, 4, 5, 6, 7, 15)

The combination of claim 15, wherein the mGluR modulator is as defined in any one of claims 2 to 7.

### Claim 20 (depends on 10, 11, 12, 15, 16)

The combination of claim 15 or 16, wherein the dopa decarboxylase inhibitor, the catechol-O-methyl transferase inhibitor and the dopamine agonist are as defined in claims 10, 11 and 12.

### Claim 21

A pharmaceutical composition comprising an mGluR modulator and at least one of
ix) L-dopa, or
x) a dopa decarboxylase inhibitor, or
xi) a catechol-O-methyl transferase inhibitor
xii) a dopamine agonist
for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.

### Claim 22 (depends on 2, 3, 4, 5, 6, 7, 15)

A composition according to claim 15, wherein the mGluR modulator is as defined in any of claims 2 to 7.

### Claim 23 (depends on 15, 16)

A composition according to claim 15 or claim 16, wherein the mGluR modulator is an mGluR5 modulator.

### Claim 24 (depends on 16, 17)

A composition according to claim 16 or claim 17, wherein the mGluR modulator is an mGluR5 antagonist.

### Claim 25 (depends on 8, 9, 16, 17, 18)

A composition according to any of claims 16 to 18, wherein the disorder is as defined in claim 8 or claim 9.

### Claim 26 (depends on 16, 17, 18)

A composition according to any of claims 16 to 18, which is for the treatment, prevention or delay of progression of Parkinson's Disease.

### Claim 27

A kit comprising
(a) an amount of an mGluR modulator or a pharmaceutically acceptable salt thereof in a first unit dosage form;
(b) an amount of at least one active ingredient selected from L-dopa, or a dopa decarboxylase inhibitor, or a catechol-O-methyl transferase inhibitor, or a dopamine agonist or, in each case, where appropriate, a pharmaceutically acceptable salt thereof; and
(c) a container for containing said first, second etc. unit forms; and
(d) instructions for using the modulator in the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.

### Claim 28 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 27)

A kit according to claim 27, wherein the mGluR modulator is as defined in any of claims 2 to 7 and wherein the disorder is as defined in claim 8 or claim 9.