# US 6,294,556 B1 · Arylglycinamide derivatives, methods of producing these substances and pharmaceutical compositions containing such compounds

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- Number: US 6,294,556 B1
- Document ID: US6294556B1
- Status: Granted
- Kind: B1
- Application number: 09/511,629
- Filed: 2000-02-18
- Granted: 2001-09-25
- Earliest claimed: 1995-04-14
- Assignees: Boehringer Ingelheim GmbH
- Inventors: Gerd Schnorrenberg; Horst Dollinger; Franz Esser; Hans Briem; Birgit Jung; Georg Speck
- Web page: https://patentgrep.com/patent/US6294556B1

## CPC

- C07D 295/145: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/58: attached in position 4
- C07D 211/62: attached in position 4
- C07D 211/64: having an aryl radical as the second substituent in position 4
- C07D 211/66: having a hetero atom as the second substituent in position 4
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 471/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to new arylglycinamide derivatives of general formula I and the pharmaceutically acceptable salts thereof, wherein R1 and R2 together with the N to which they are bound form a ring of the formula wherein p is 2 or 3 and X denotes oxygen, N(CH2)nR6 or CR7R8, and R3, R4, R5, R6, R7, R8, Ar and n have the meanings given in the specification, and the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin)-antagonists.

## Claims

### Claim 1

An arylglycinamide derivative of formula I:
or the pharmaceutically acceptable salts thereof, wherein
Ar is unsubstituted or mono- to penta-substituted phenyl, or unsubstituted or mono- or di-substituted naphthyl, in which the substituents of the phenyl and naphthyl are independently selected from the group consisting of halogen, hydroxy, (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 and NR9R10, wherein R9 and R10 are independently selected from the group consisting of hydrogen, methyl and acetyl; or
Ar is phenyl substituted by —O—CH2—O or —O—(CH2)2—O—;
R1 and R2 together with the N to which they are bound form a ring of the formula
wherein
p is 2 or 3,
X is CR7R8, wherein R7 and R8 have one of the following meanings:
(a) R7 and R8 are each hydrogen when R3 is unsubstituted or substituted phenyl;
(b) R7 is phenyl,
phenyl substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, (C1-4)alkyl, O—(C1-4)alkyl, CF3 and OCF3,
piperidinyl,
1-methylpiperidinyl,
when R8 is hydrogen, —CONH2, —NHC(O)CH3, —N(CH3)C(O)CH3, CN, —C(O)NH(C1-3)alkyl, or —C(O)N((C1-3)alkyl)2; or
(c) R7 and R8 together form the group
R3 is hydrogen, (C1-4)alkyl, unsubstituted phenyl or mono- to tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of halogen, (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 and NR9R10, wherein R9 and R10 are independently selected from the group consisting of hydrogen, methyl and acetyl;
R4 is phenyl (C1-4)alkyl or naphthyl (C1-4)alkyl, wherein phenyl is optionally substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, (C1-4)alkyl, O—(C1-4)alkyl, CF3, OCF3 and NR9R10, wherein R9 and R10 are independently selected from the group consisting of hydrogen, methyl and acetyl; and
R5 is hydrogen, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, —CH2C(O)NH2, hydroxy or phenyl (C1-4)alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is unsubstituted or substituted phenyl and R7 and R8 are each hydrogen.

### Claim 3 (depends on 2)

The compound of claim 2, wherein said compound is selected from the group consisting of
or the HCl salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R7 and R8 together form the group

### Claim 5 (depends on 4)

The compound of claim 4, wherein said compound is selected from the group consisting of
or the HCl salt thereof.

### Claim 6 (depends on 5)

The compound of claim 5, which is

### Claim 7 (depends on 1)

The compound of claim 1, wherein R7 is other than hydrogen and R8 is hydrogen.

### Claim 8 (depends on 7)

The compound of claim 7, wherein said compound is selected from the group consisting of
or the HCl salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8, wherein said compound is selected from the group consisting of

### Claim 10 (depends on 1)

The compound of claim 1, wherein R8 is selected from the group consisting of —NHC(O)CH3 and —N(CH3)C(O)CH3.

### Claim 11 (depends on 10)

The compound of claim 10, wherein said compound is selected from the group consisting of
or the HCl salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R8 is selected from the group consisting of CN, —C(O)NH2, —C(O)NH(C1-3)alkyl and —C(O)N((C1-3)alkyl)2.

### Claim 13 (depends on 12)

The compound of claim 12, wherein said compound is selected from the group consisting of
or the HCl salt thereof.

### Claim 14 (depends on 13)

The compound of claim 13, selected from the group consisting of

### Claim 15 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R3 is unsubstituted phenyl.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R3 is mono- or tri-substituted phenyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R4 is phenyl(C1-3)alkyl, wherein said phenyl is optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halogen, methyl, methoxy, CF3 and OCF3; and R5 is selected from the group consisting of hydrogen, (C1-3)alkyl, CH2COOH, —CH2C(O)NH2 and phenethyl.

### Claim 19 (depends on 18)

The compound of claim 18, wherein R4 is
R5 is hydrogen or methyl.

### Claim 20 (depends on 1)

A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, which is in the form of a solution, suspension or emulsion.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein said carrier is a polylactide, polyglycolide or polyhydroxybutyric acid.

### Claim 23 (depends on 20)

The pharmaceutical composition of claim 20, which is an orally administrable pharmaceutical composition.

### Claim 24 (depends on 1)

A method for the treatment of a neurokinin-mediated disease in an animal subject comprising administering to said animal subject in need of such treatment an effective amount of the compound of claim 1.

### Claim 25 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is selected from the group consisting of collagenosis, dysfunction of the urinary tract, hemorrhoids, nausea, vomiting, and pain.

### Claim 26 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is an inflammatory disease of the respiratory tract, an allergic disease of the respiratory tract, an eye disease, a skin disease, a disease of the gastrointestinal tract, a disease of the joints, or a disease of the central nervous system.

### Claim 27 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is an inflammatory or allergic disease of the respiratory tract selected from the group consisting of asthma, chronic bronchitis, emphysema, rhinitis and coughs.

### Claim 28 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is an eye disease selected from the group consisting of conjunctivitis and iritis.

### Claim 29 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is a skin disease selected from the group consisting of eczema, urticaria, psoriasis, sunburn, insect bites, insect stings, neurodermititis, itching and postherpetic pain.

### Claim 30 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is a disease of the gastrointestinal tract selected from the group consisting of gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel and Hirschsprung's disease.

### Claim 31 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is a disease of the joints selected from the group consisting of rheumatoid arthiritis, reactive arthritis and Reiter syndrome.

### Claim 32 (depends on 24)

The method of claim 24, wherein said neurokinin-mediated disease is a disease of the central nervous system selected from the group consisting of dementia, Alzheimer's disease, schizophrenia, psychosis, depression, headaches and epilepsy.

### Claim 33 (depends on 32)

The method of claim 32, wherein said disease is a migraine headache or a tension headache.

### Claim 34 (depends on 24)

The method of claim 24, wherein the method for said administering is orally administering.

### Claim 35 (depends on 1, 22)

A process for preparing a compound of claim 1, comprising the steps of:
(a) reacting a compound of formula
or an acid halide or alkylester thereof with an amine of formula
wherein R1-R5 and Ar are defined as in claim 22; and
(b) isolating the product of step (a) as a free compound or as a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 1, 22)

A process for preparing a compound of claim 1, comprising the steps of:
(a) reacting a compound of formula
or an acid halide or alkylester thereof with an amine of formula
wherein R1-R4 and Ar are defined as in claim 22 and R5 is hydrogen;
(b) N-alkylating, at R5, the product of step (a); and
(c) isolating the product of step (b) as a free compound or as a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 1, 22)

A process for preparing a compound of claim 1, comprising the steps of:
(a) reacting a compound of formula
with an amine of formula
wherein R1-R5 and Ar are defined as in claim 22 and Hal is halogen; and
(b) isolating the product of step (a) as a free compound or as a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 1, 22)

A process for preparing a compound of claim 1, comprising the steps of:
(a) reacting a compound of formula
with an amine of formula
wherein R1-R4 and Ar are defined as in claim 22, R5 is hydrogen and Hal is halogen;
(b) N-alkylating, at R5, the product of step (a); and
(c) isolating the product of step (b) as a free compound or as a pharmaceutically acceptable salt thereof.