# US 5,872,146 A · Mercapto alkyl peptidyl compounds having MMP and TNF inhibitory activity

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- Number: US 5,872,146 A
- Document ID: US5872146A
- Status: Granted
- Kind: A
- Application number: 08/832,929
- Filed: 1997-04-04
- Granted: 1999-02-16
- Earliest claimed: 1996-04-04
- Assignees: Chiroscience Limited
- Inventors: Andrew Douglas Baxter; John Gary Montana; David Alan Owen
- Web page: https://patentgrep.com/patent/US5872146A

## CPC

- C07K 5/0207: {containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Described herein are compounds of formula (I): ##STR1## which have MMP and TNF inhibitory activity.

## Claims

### Claim 1

A compound of general formula (I): ##STR9## wherein: R.sup.1 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, (C.sub.1-6 alkyl)aryl, aryl, and C.sub.1-6 alkyl-AR.sup.9 where A is selected from the group consisting of O, NR.sup.9, and S(O).sub.m where m=0-2, and R.sup.9 is selected from the group consisting of H, C.sub.1-4 alkyl aryl, and (C.sub.1-4 alkyl)aryl; if A=NR.sup.9 the R.sup.9 groups may be the same or different;
R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-6 alkyl;
R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl-R.sup.6, aryl-R.sup.6, cyclo(C.sub.3-6)alkyl-R.sup.6, C.sub.1-6 alkyl-aryl-R.sup.6, and C.sub.1-6 alkyl-cyclo (C.sub.3-6) alkyl-R.sup.6, and R.sup.6 is an amidino or guanidino group;
X is NR.sup.4 R.sup.5 where R.sup.4 is selected from the group consisting of hydrogen, aryl, cyclo(C.sub.3-6)alkyl, and C.sub.1-6 alkyl-cyclo(C.sub.3-6)alkyl; and R.sup.5 is hydrogen or C.sub.1-6 alkyl; or NR.sup.4 R.sup.5 is a ring;
R.sup.7 is hydrogen or R.sup.10 CO where R.sup.10 is selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkylaryl, cyclo(C.sub.3-6)alkyl, C.sub.1-4 alkyl-cyclo(C.sub.3-6)alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkenyl-aryl, and aryl;
R.sup.8 is C.sub.1-4 alkyl-R.sup.11 ;
R.sup.11 is phthalimido;
R.sup.12 is hydrogen or is selected from the group consisting of COR.sup.9, CO.sub.2 R.sup.9 (where R.sup.9 is not H), CONHR.sup.9, and SO.sub.2 R.sup.9 (where R.sup.9 is not H); and
R.sup.13 is selected from the group consisting of OH, OC.sub.1-4 alkyl, aryl, and C.sub.1-4 alkylaryl;
or a salt, solvate, or hydrate thereof.

### Claim 2 (depends on 1)

The compound, according to claim 1, wherein R.sup.1 is C.sub.1-6 alkyl or C.sub.1-6 alkyl-AR.sup.9, and A is O or S(O).sub.0-2.

### Claim 3 (depends on 1)

The compound, according to claim 1, wherein R.sup.2 is H.

### Claim 4 (depends on 1)

The compound, according to claim 1, wherein R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl-R.sup.6, aryl-R.sup.6, and C.sub.1-6 alkylaryl-R.sup.6.

### Claim 5 (depends on 1)

The compound, according to claim 1, wherein R.sup.4 is aryl.

### Claim 6 (depends on 1)

The compound, according to claim 1, wherein R.sup.5 is H.

### Claim 7 (depends on 1)

The compound, according to claim 1, wherein R.sup.8 is C.sub.1-4 alkyl-R.sup.11.

### Claim 8 (depends on 1)

The compound, according to claim 1, wherein R.sup.9 is selected from the group consisting of H, C.sub.1-4 alkyl and C.sub.1-4 alkylaryl.

### Claim 9 (depends on 1)

The compound, according to claim 1, wherein R.sup.10 is C.sub.1-4 alkyl or aryl.

### Claim 10 (depends on 1)

The compound, according to claim 1, wherein R.sup.13 is OH or OC.sub.1-4 alkyl.

### Claim 11 (depends on 1)

The compound, according to claim 1, selected from the group consisting of:
N-(2-mercapto-5-phthalimidopentanoyl)-L-leucyl-L-argininamide;
N-(2-mercapto-5-phthalimidopentanoyl)-L-isoleucyl-L-argininamide;
N-(2-mercapto-5-phthalimidopentanoyl)-L-norvalyl-L-argininamide; and
N-(2-mercapto-5-phthalimidopentanoyl)-L-valyl-L-argininamide.

### Claim 12 (depends on 1)

The compound, according to claim 1, in the form of a single enantiomer or diastereomer.

### Claim 13 (depends on 1)

A pharmaceutical composition for use in therapy, comprising a compound of claim 1, and a pharmaceutically acceptable diluent, or carrier.

### Claim 14 (depends on 1)

A method for treating a condition associated with matrix metalloproteinases or that is mediated by TNF.alpha. or L-selectin sheddase which comprises administering an effective amount of a compound of claim 1.

### Claim 15 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of cancer, inflammation and inflammatory disease, dermatological disorders, fever, cardiovascular effects, haemorrhage, coagulation and acute phase response, cachexia, anorexia, acute infection, HIV infection, shock states, graft versus host reactions, autoimmune disease, reperfusion injury, meningitis, and migraine.

### Claim 16 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of tumour growth, angiogenesis, tumour invasion and spread, metastases, malignant ascites, and malignant pleural effusion.

### Claim 17 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of cerebral ischaemia, ischaemic heart disease, rheumatoid arthritis, osteoarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn's disease, and ulcerative colitis.

### Claim 18 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of corneal ulceration, retinopathy, and surgical wound healing.

### Claim 19 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of psoriasis, atopic dermatitis, chronic ulcers, and epidermolysis bullosa.

### Claim 20 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of periodontitis and gingivitis.

### Claim 21 (depends on 14)

The method, according to claim 14, wherein the condition is selected from rhinitis, allergic conjunctivitis, eczema, and anaphylaxis.

### Claim 22 (depends on 14)

The method, according to claim 14, wherein the condition is selected from the group consisting of restenosis, congestive heart failure, endometriosis, atherosclerosis, and endosclerosis.